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  • 1. Aahlin, Kristofer
    et al.
    Arvidsson, Per I.
    Huerta, Fernando
    Yngve, Ulrika.
    Preparation of 1-(4-(5-amino-6-(oxazolo[4,5-c]pyridin-2-yl)pyrazin-2-yl)benzoyl)piperazine derivatives as glycogen synthase kinase 3 inhibitors.2011Patent (Other (popular science, discussion, etc.))
    Abstract [en]

    Title compds. I [R1 = H or Me], and their pharmaceutically acceptable salts, are prepd. and disclosed as glycogen synthase kinase 3 (GSK3) inhibitors. Thus, e.g., II was prepd. by cyclization of 3-amino-N-(4-hydroxypyridin-3-yl)pyrazine-2-carboxamide (prepn. given) to get intermediate 3-(oxazolo[4,5-c]pyridin-2-yl)pyrazin-2-amine, which underwent bromination followed by Suzuki reaction with (4-methylpiperazin-1-yl)(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanone. Compds. of the invention were tested for their selective inhibitory activity of GSK3β, e.g., II exhibited Ki value of 2.3 nM. The invention compds. are useful for the treatment of cognitive disorders, diabetes, cancer, etc. [on SciFinder(R)]

  • 2.
    Aare, Sudhakar Reddy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Intensive Care Unit Muscle Wasting: Skeletal Muscle Phenotype and Underlying Molecular Mechanisms2012Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Acute quadriplegic myopathy (AQM), or critical illness myopathy, is a common debilitating acquired disorder in critically ill intensive care unit (ICU) patients characterized by generalized muscle wasting and weakness of limb and trunk muscles. A preferential loss of the thick filament protein myosin is considered pathognomonic of this disorder, but the myosin loss is observed relatively late during the disease progression. In attempt to explore the potential role of factors considered triggering AQM in sedated mechanically ventilated (MV) ICU patients, we have studied the early effects, prior to the myosin loss, of neuromuscular blockade (NMB), corticosteroids (CS) and sepsis separate or in combination in a porcine experimental ICU model. Specific interest has been focused on skeletal muscle gene/protein expression and regulation of muscle contraction at the muscle fiber level. This project aims at improving our understanding of the molecular mechanisms underlying muscle specific differences in response to the ICU intervention and the role played by the different triggering factors.

    The sparing of masticatory muscle fiber function was coupled to an up-regulation of heat shock protein genes and down-regulation of myostatin are suggested to be key factors in the relative sparing of masticatory muscles. Up-regulation of chemokine activity genes and down-regulation of heat shock protein genes play a significant role in the limb muscle dysfunction associated with sepsis. The effects of corticosteroids in the development of limb muscle weakness reveals up-regulation of kinase activity and transcriptional regulation genes and the down-regulation of heat shock protein, sarcomeric, cytoskeletal and oxidative stress responsive genes. In contrast to limb and craniofacial muscles, the respiratory diaphragm muscle responded differently to the different triggering factors. MV itself appears to play a major role for the diaphragm muscle dysfunction. By targeting these genes, future experiments can give an insight into the development of innovative treatments expected at protecting muscle mass and function in critically ill ICU patients.

    List of papers
    1. Mechanisms underlying the sparing of masticatory versus limb muscle function in an experimental critical illness model
    Open this publication in new window or tab >>Mechanisms underlying the sparing of masticatory versus limb muscle function in an experimental critical illness model
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    2011 (English)In: Physiological Genomics, ISSN 1094-8341, E-ISSN 1531-2267, Vol. 43, no 24, p. 1334-1350Article in journal (Refereed) Published
    Abstract [en]

    Acute quadriplegic myopathy (AQM) is a common debilitating acquired disorder in critically ill intensive care unit (ICU) patients which is characterized by tetraplegia/generalized weakness of limb and trunk muscles. Masticatory muscles, on the other hand, are typically spared or less affected, yet the mechanisms underlying this striking muscle-specific difference remain unknown. This study aims to evaluate physiological parameters and the gene expression profiles of masticatory and limb muscles exposed to factors suggested to trigger AQM, such as mechanical ventilation, immobilization, neuromuscular blocking agents (NMBA), corticosteroids (CS) and sepsis for five days by using a unique porcine model mimicking the ICU conditions. Single muscle fiber cross-sectional area and force-generating capacity, i.e., maximum force normalized to fiber cross-sectional area (specific force), revealed maintained masseter single muscle fiber cross-sectional area and specific-force after five days exposure to all triggering factors. This is in sharp contrast to observations in limb and trunk muscles, showing a dramatic decline in specific force in response to five days exposure to the triggering factors. Significant differences in gene expression were observed between craniofacial and limb muscles, indicating a highly complex and muscle specific response involving transcription and growth factors, heat shock proteins, matrix metalloproteinase inhibitor, oxidative stress responsive elements and sarcomeric proteins underlying the relative sparing of cranial versus spinal nerve innervated muscles during exposure to the ICU intervention.

    National Category
    Neurology
    Identifiers
    urn:nbn:se:uu:diva-164317 (URN)10.1152/physiolgenomics.00116.2011 (DOI)000298403600002 ()22010006 (PubMedID)
    Available from: 2011-12-19 Created: 2011-12-19 Last updated: 2017-12-08Bibliographically approved
    2. The role of sepsis in the development of limb muscle weakness in a porcine intensive care unit model
    Open this publication in new window or tab >>The role of sepsis in the development of limb muscle weakness in a porcine intensive care unit model
    Show others...
    2012 (English)In: Physiological Genomics, ISSN 1094-8341, E-ISSN 1531-2267, Vol. 44, no 18, p. 865-877Article in journal (Refereed) Published
    Abstract [en]

    Severe muscle wasting and loss of muscle function in critically ill mechanically ventilated intensive care unit (ICU) patients have significant negative consequences on their recovery and rehabilitation that persist long after their hospital discharge; moreover the underlying mechanisms are unclear. Mechanical ventilation (MV) and immobilization-induced modifications play an important role in these consequences, including endotoxin induced sepsis. The present study aims to investigate how sepsis aggravates ventilator and immobilization-related limb muscle dysfunction. Hence, biceps femoris muscle gene expression was investigated in pigs exposed to ICU intervention, i.e., immobilization, sedation, and MV, alone or in combination with sepsis for five days. In previous studies, we have shown that ICU intervention alone or in combination with sepsis did not affect muscle fiber size on day 5, but a significant decrease was observed in single fiber maximal force normalized to cross-sectional area (specific force) when sepsis was added to the ICU intervention. According to microarray data, the addition of sepsis to the ICU intervention induced a deregulation of more than 500 genes, such as an increased expression of genes involved in chemokine activity, kinase activity and transcriptional regulation. Genes involved in the regulation of the oxidative stress response, cytoskeletal/sarcomeric and heat shock proteins were on the other hand down-regulated when sepsis was added to the ICU intervention. Thus, sepsis has a significant negative effect on muscle function in critically ill ICU patients and chemokine activity and heat shock protein genes are forwarded to play an instrumental role in this specific muscle wasting condition.

    Keyword
    Sepsis, porcine, muscle wasting, intensive care
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-180380 (URN)10.1152/physiolgenomics.00031.2012 (DOI)000309109100001 ()
    Available from: 2012-09-05 Created: 2012-09-05 Last updated: 2017-12-07Bibliographically approved
    3. Effects of corticosteroids in the development of limb muscle weakness in a porcine intensive care unit model
    Open this publication in new window or tab >>Effects of corticosteroids in the development of limb muscle weakness in a porcine intensive care unit model
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    2013 (English)In: Physiological Genomics, ISSN 1094-8341, E-ISSN 1531-2267, Vol. 45, no 8, p. 312-320Article in journal (Refereed) Published
    Abstract [en]

    Severe muscle wasting is a debilitating condition in critically ill intensive care unit (ICU) patients, characterized by general muscle weakness and dysfunction, resulting in a prolonged mobilization, delayed weaning from the ventilator and a decreased quality of life post-ICU. The mechanisms underlying limbmuscle weakness in ICU patients are complex and involve the impact of primary disease, but also factors common to critically ill ICU patients such as sepsis, mechanical ventilation (MV), immobilization and systemic administration of corticosteroids (CS).  These factors may have additive negative effects on skeletal muscle structure and function, but their respective role alone remain unknown. The primary aim of this study was to examine how CS administration potentiates ventilator and immobilization-related limb muscle dysfunction at the gene level. Comparing biceps femoris gene expression in pigs exposed to MV and CS for five days with only MV pigs for the same duration of time showed a distinct deregulation of 186 genes using microarray. Surprisingly, the decreased force-generation capacity at the single muscle fiber reported in response to the addition of CS administration in mechanically ventilated and immobilized pigs was not associated with an additional up-regulation of proteolytic pathways. On the other hand, an altered expression of genes regulating kinase activity, cell cycle, transcription, channel regulation, oxidative stress response , cytoskeletal, sarcomeric and heat shock protein as well as protein synthesis at the translational level appear to play an additive deleterious role for the  limb muscle weakness in immobilized ICU patients.

     

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-180375 (URN)10.1152/physiolgenomics.00123.2012 (DOI)000317662000002 ()23429211 (PubMedID)
    Available from: 2012-09-05 Created: 2012-09-05 Last updated: 2017-12-07Bibliographically approved
    4. Diaphragm muscle weakness in an experimental porcine intensive care unit model
    Open this publication in new window or tab >>Diaphragm muscle weakness in an experimental porcine intensive care unit model
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    2011 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 6, no 6, article id e20558Article in journal (Refereed) Published
    Abstract [en]

    In critically ill patients, mechanisms underlying diaphragm muscle remodeling and resultant dysfunction contributing to weaning failure remain unclear. Ventilator-induced modifications as well as sepsis and administration of pharmacological agents such as corticosteroids and neuromuscular blocking agents may be involved. Thus, the objective of the present study was to examine how sepsis, systemic corticosteroid treatment (CS) and neuromuscular blocking agent administration (NMBA) aggravate ventilator-related diaphragm cell and molecular dysfunction in the intensive care unit. Piglets were exposed to different combinations of mechanical ventilation and sedation, endotoxin-induced sepsis, CS and NMBA for five days and compared with sham-operated control animals. On day 5, diaphragm muscle fibre structure (myosin heavy chain isoform proportion, cross-sectional area and contractile protein content) did not differ from controls in any of the mechanically ventilated animals. However, a decrease in single fibre maximal force normalized to cross-sectional area (specific force) was observed in all experimental piglets. Therefore, exposure to mechanical ventilation and sedation for five days has a key negative impact on diaphragm contractile function despite a preservation of muscle structure. Post-translational modifications of contractile proteins are forwarded as one probable underlying mechanism. Unexpectedly, sepsis, CS or NMBA have no significant additive effects, suggesting that mechanical ventilation and sedation are the triggering factors leading to diaphragm weakness in the intensive care unit.

    National Category
    Physiology
    Research subject
    Clinical Neurophysiology
    Identifiers
    urn:nbn:se:uu:diva-155622 (URN)10.1371/journal.pone.0020558 (DOI)000291730000014 ()21698290 (PubMedID)
    Available from: 2011-06-27 Created: 2011-06-27 Last updated: 2018-01-12Bibliographically approved
  • 3.
    Abbasi, Mina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Translational aspects of unbound brain to plasma concentration ratios2012Independent thesis Advanced level (professional degree), 20 credits / 30 HE creditsStudent thesis
    Abstract [en]

    Introduction:  The unbound brain-to-plasma concentration ratio (Kp,uu,brain) is one of the most important indicators for brain penetration in the area of CNS drug discovery and development. Kp,uu,brain can be calculated by combining the total brain-to-plasma concentration ratio (Kp,brain),  the brain free fraction (fu,brain) and  the plasma free fraction (fu,p).

    Aim:  This study has three purposes, to calculate Kp,uu,brain from publications in humans,  to collect data regarding species differences in Kp,uu,brain and to see whether Kp,uu,brain in humans differs in different  brain regions or not.

    Materials and Methods:  The values of Kp, brain were derived from positron emission tomography (PET), MRS (Magnetic Resonance Spectroscopy), and brain surgery for tumor removal. fu,brain and fu,p were collected from brain homogenate, equilibrium dialysis and ultrafiltration studies.

    Results:  Data on Kp,brain was sparse in the literature. Kp,uu,brain was calculated for sixteen different drugs in humans. According to the calculation, nine of these sixteen compounds were found to be actively influxed into the brain, six were actively effluxed from the BBB and one had a passive diffusion. Depending on the compound, Kp,uu,brain was higher or smaller in humans compared to mice and rats.  Kp,uu,brain for five compounds were calculated for different brain regions. Four compounds had a higher Kp,uu,brain value in almost all other regions than the cerebellum and one had a higher Kp,uu,brain in cerebellum than in the other regions.

    Conclusions:  No definite conclusion on Kp,uu,brain in humans, species differences in Kp,uu,brain  or Kp,uu,brain  in different human brain regions could be reached in this study. In view of the importance of Kp,uu,brain  in CNS drug discovery and development, more studies on Kp,uu,brain in humans and in the other species are required.

  • 4.
    Abberud, Madelene
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Time to first antibiotic administration in The Alfred Emergency and Trauma Centre for suspected febrile neutropenia: a retrospective chart review2012Independent thesis Advanced level (professional degree), 20 credits / 30 HE creditsStudent thesis
    Abstract [en]

    Introduction: Febrile neutropenia (FN) is a frequent complication of chemotherapy use in cancer patients. There is evidence to suggest that the time to antibiotic administration is associated with increase survival and effective clinical outcome. The Australian consensus guidelines for the management of FN in adult cancer patients recommends treatment within 30 minutes to patients with features of systemic compromise. A study performed at The Alfred Hospital in 2010 revealed a median time of 145 minutes to first antibiotic administration. A new guideline was therefore developed and education was implemented. This study was conducted to evaluate the intervention. Aim: To determine time to first antibiotic prescribing and administration for patients with suspected FN presenting to the Alfred Emergency and Trauma centre. Materials and Methods: The electronic medical record of 112 episodes of suspected FN presenting between March and August 2012 were reviewed.  Data were retrospective collected according to a FN data spreadsheet. An observational study were also performed at  The Alfred Emergency and Trauma centre during October and November 2012 to determine time to first antimicrobial prescribing, because this data could not be collected from the electronic medical record. Results: The median time from presentation to antibiotic prescribing was 68 minutes. The median time from presentation to antibiotic administration was 121 minutes. Conclusions: The implementation of the new guidelines has reduced the time with 16.6%, but the target first antibiotic administration within 30 minutes has not been reached.

  • 5.
    Abdeldaim, Guma M. K.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Bacteriology.
    Strålin, Kristoffer
    Department of Infectious Diseases, Örebro University Hospital.
    Kirsebom, Leif A.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Microbiology.
    Olcén, Per
    Department of Clinical Microbiology, Örebro University Hospital.
    Blomberg, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Virology.
    Herrmann, Björn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Bacteriology.
    Detection of Haemophilus influenzae in respiratory secretions from pneumonia patients by quantitative real-time polymerase chain reaction2009In: Diagnostic microbiology and infectious disease, ISSN 0732-8893, E-ISSN 1879-0070, Vol. 64, no 4, p. 366-373Article in journal (Refereed)
    Abstract [en]

    A quantitative real-time polymerase chain reaction (PCR) based on the omp P6 gene was developed to detect Haemophilus influenzae. Its specificity was determined by analysis of 29 strains of 11 different Haemophilus spp. and was compared with PCR assays having other target genes: rnpB, 16S rRNA, and bexA. The method was evaluated on nasopharyngeal aspirates from 166 adult patients with community-acquired pneumonia. When 104 DNA copies/mL was used as cutoff limit for the method, P6 PCR had a sensitivity of 97.5% and a specificity of 96.0% compared with the culture. Of 20 culture-negative but P6 PCR-positive cases, 18 were confirmed by fucK PCR as H. influenzae. Five (5.9%) of 84 nasopharyngeal aspirates from adult controls tested PCR positive. We conclude that the P6 real-time PCR is both sensitive and specific for identification of H. influenzae in respiratory secretions. Quantification facilitates discrimination between disease-causing H. influenzae strains and commensal colonization.

  • 6.
    Abdeldaim, Guma
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Microbiology and Infectious Medicine, Clinical Bacteriology. Benghazi Univ, Fac Med, Dept Med Microbiol & Parasitol, Benghazi, Libya..
    Svensson, Erik
    Statens Serum Inst, Int Reference Lab Mycobacteriol, Copenhagen, Denmark..
    Blomberg, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Microbiology and Infectious Medicine, Clinical Virology.
    Herrmann, Björn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Microbiology and Infectious Medicine, Clinical Bacteriology.
    Duplex detection of the Mycobacterium tuberculosis complex and medically important non-tuberculosis mycobacteria by real-time PCR based on the rnpB gene2016In: Acta Pathologica, Microbiologica et Immunologica Scandinavica (APMIS), ISSN 0903-4641, E-ISSN 1600-0463, Vol. 124, no 11, p. 991-995Article in journal (Refereed)
    Abstract [en]

    A duplex real-time PCR based on the rnpB gene was developed for Mycobacterium spp. The assay was specific for the Mycobacterium tuberculosis complex (MTB) and also detected all 19 tested species of non-tuberculous mycobacteria (NTM). The assay was evaluated on 404 clinical samples: 290 respiratory samples and 114 from tissue and other nonrespiratory body sites. M. tuberculosis was detected by culture in 40 samples and in 30 samples by the assay. The MTB assay showed a sensitivity similar to Roche Cobas Amplicor MTB-PCR (Roche Molecular Systems, Pleasanton, CA, USA). There were only nine samples with non-tuberculous mycobacteria detected by culture. Six of them were detected by the PCR assay.

  • 7.
    Abdel-Rehim, Mohamed
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy.
    Influence of ammonia as carrier gas on separation and detection performance in capillary gas chromatography 1994Doctoral thesis, comprehensive summary (Other academic)
  • 8.
    Abdi, Hafsa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Finns det någon koppling mellan Alzheimers sjukdom och Diabetes Mellitus?2014Independent thesis Basic level (professional degree), 10 credits / 15 HE creditsStudent thesis
    Abstract [sv]

    Alzheimers sjukdom är en neurodegenerativ sjukdom vars orsak är okänd, kännetecknas av en gradvis försämring av kognitiva funktioner. Alzheimers sjukdom och Diabetes Mellitus har flera gemensamma patofysiologiska samband, bland annat insulinresistens. Försämrad insulinsignalering kan leda till kognitiv funktionsförsämring, som i sin tur kan leda till Alzheimers sjukdom. Båda insulin och amyloid-β metaboliseras av insulinnedbrytande enzym (IDE), defekt i IDE kan delvis orsaka amyloid-β ansamlingar. Syftet med detta arbete är att undersöka om försämrad insulinsignalering kan leda till kognitiv försämring och påskynda utvecklingen av Alzheimers sjukdom.

    Jag har gjort en systematisk litteraturöversikt för att undersöka detta. Det är större risk att drabbas av Alzheimers sjukdom om man har Diabetes Mellitus. Man såg ett samband mellan försämrad insulinsignalering och försämrad kognitiv funktion. Förhöjda glukosnivåer var förenade med kognitiv försämring, medan nedsatt glukosnivå inte hade någon betydelse vid kognitiv försämring. Dessutom påskyndar en hög glukosnivå omvandlingen från MCI (mild kognitivs vikt) till Alzheimers sjukdom. Trots detta resultat krävs det mer forskning inom området eftersom olika metoder användes på de olika studierna vilket kan ge ett falskt samband.

  • 9.
    Abdulhameed, Ingi
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Bedömning av njurfunktionen hos cancerpatinter vid dosering av karboplatin2014Independent thesis Advanced level (degree of Master (One Year)), 20 credits / 30 HE creditsStudent thesis
    Abstract [sv]

    Introduktion: Vid behandling av ett flertal cancertyper används läkemedlet karboplatin som doseras efter njurfunktionen. Karboplatin utsöndras huvudsakligen via njurarna och elimineringen bestäms framför allt av den glomerulära filtrationshastigheten (GFR). Därför krävs det en noggrann bedömning av njurfunktionen för en korrekt behandling. GFR kan både mätas till exempel med iohexolclearance eller skattas med hjälp av matematiska formler. Det råder en osäkerhet om vilka GFR-metoder som är lämpligast för att skatta njurfunktionen hos cancerpatienter som behandlas med karboplatin.

    Syfte: Att undersöka vilken eller vilka av följande sex GFR skattnings metoder, Cockcroft -Gault med okompenserat kreatinin (CGold), Cockcroft–Gault (CG) med kompenserat kreatinin, cystatin C-GFR, Modification of Diet in Renal Disease Study (MDRD4), Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) samt Lund-Malmö formeln (LM-reviderad), som bäst korrelerar till ”gold standard” metoden iohexolclearance, för att bättre kunna dosera karboplatin till cancerpatienter.

    Material och metoder: Femtioåtta cancerpatienter från Radiumhemmet som under 2013 genomfört iohexolclearance innan behandlingsstart med karboplatin inkluderades. GFR hos dessa patienter beräknades med ovanstående formler. Överensstämmelse mellan iohexolclearance och övriga GFR metoder bestämdes med bland annat linjär regression, bias och precision.

    Resultat: CGold och Cystatin C tenderar att underskatta GFR medan MDRD4, CKD-Epi och CG tenderar att överskatta GFR. LM-reviderad överensstämmer med iohexolclearance.

    Konklusion: Lund-Malmö formeln (LM-reviderad) är den metod som bäst korrelerar till ”gold standard” metoden iohexolclearance.

  • 10.
    Abdulkarim, Farhad
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Molecular Biology.
    Hughes, Diarmaid
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Molecular Biology.
    Homologous recombination between the tuf genes of Salmonella typhimurium1996In: Journal of Molecular Biology, ISSN 0022-2836, E-ISSN 1089-8638, Vol. 260, no 4, p. 506-522Article in journal (Refereed)
    Abstract [en]

    The genes coding for the translation factor EF-Tu, tufA and tufB are separated by over 700 kb on the circular chromosome of Salmonella typhimurium. The coding regions of these genes have 99% identity at the nucleotide level in spite of the presumed ancient origin of the gene duplication. Sequence comparisons between S. typhimurium and Escherichiacoli suggest that within each species the two tuf genes are evolving inconcert. Here we show that each of the S. typhimurium tuf genes cantransfer genetic information to the other. In our genetic system thetransfers are seen as non-reciprocal, i.e. as gene conversion events.However, the mechanism of recombination could be reciprocal, with sisterchromosome segregation and selection leading to the isolation of aparticular class of recombinant. The amount of sequence informationtransferred in individual recombination events varies, but can be close tothe entire length of the gene. The recombination is RecABCD-dependent,and is opposed by MutSHLU mismatch repair. In the wild-type, this typeof recombination occurs at a rate that is two or three orders of magnitudegreater than the nucleotide substitution rate. The rate of recombinationdiffers by six orders of magnitude between a recA and a mutS strain.Mismatch repair reduces the rate of this recombination 1000-fold. The rateof recombination also differs by one order of magnitude depending onwhich tuf gene is donating the sequence selected for. We discuss threeclasses of model that could, in principle, account for the sequencetransfers: (1) tuf mRNA mediated recombination; (2) non-allelic reciprocalrecombination involving sister chromosomes; (3) non-allelic geneconversion involving sister chromosomes, initiated by a double-strandbreak close to one tuf gene. Although the mechanism remains to bedetermined, the effect on the bacterial cells is tuf gene sequencehomogenisation. This recombination phenomenon can account for theconcerted evolution of the tuf genes.

  • 11.
    Abdulkarim, Farhad
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Molecular Biology.
    Liljas, Lars
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Molecular Biology.
    Hughes, Diarmaid
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Molecular Biology.
    Mutations to kirromycin resistance occur in the interface of domains I and III of EF-Tu.GTP1994In: FEBS Letters, ISSN 0014-5793, E-ISSN 1873-3468, Vol. 352, p. 118-122Article in journal (Refereed)
    Abstract [en]

    The antibiotic kirromycin inhibits protein synthesis by binding to EF-Tu and preventing its release from the ribosome after GTP hydrolysis.We have isolated and sequenced a collection of kirromycin resistant tuf mutations and identified thirteen single amino acid substitutions at sevendifferent sites in EF-Tu. These have been mapped onto the 3D structures of EF-Tu’GTP and EF-Tu.GDP. In the active GTP form of EF-Tu themutations cluster on each side of the interface between domains I and III. We propose that this domain interface is the binding site for kirromycin.

  • 12.
    Abdulkarim, Farhad
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Molecular Biology.
    Tuohy, TMF
    Buckingham, RH
    Hughes, Diarmaid
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Molecular Biology.
    Missense substitutions lethal to essential functions of EF-Tu1991In: Biochimie, ISSN 0300-9084, E-ISSN 1638-6183, Vol. 73, no 12, p. 1457-1464Article in journal (Refereed)
    Abstract [en]

    We have used a simple selection and screening method to isolate function defective mutants of EF-Tu. From 28 mutants tested, 12 different missense substitutions, individually lethal to some essential function of EF-Tu, were identified by sequencing. In addition we found a new non-lethal missense mutation. The frequency of isolation of unique mutations suggests that this method can be used to easily isolate many more. The lethal mutations occur in all three structural domains of EF-Tu, but most are in domain II. We aim to use these mutants to define functional domains on EF-Tu.

  • 13.
    Abdulla Karim, Dana
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Ersättning av två aminosyror i 9S-dioxygenas-allenoxidsyntas av Colletotrichum graminicola samt förkortning av dioxygenasdomänen för 3D-strukturanalys2015Independent thesis Advanced level (degree of Master (One Year)), 20 credits / 30 HE creditsStudent thesis
    Abstract [sv]

    Oxylipiner är oxiderade metaboliter av fleromättade fettsyror. Hos svampar är dessa inblandade i kommunikation, reproduktion, reglering av mykotoxinproduktion och modulering av växtförsvarssystemet vid infektion. Colletotrichum graminicola tillhör de mest kända och viktigaste svampar som orsakar skador på grödor. Genen EFQ_27323 från C. graminicola kodar för 9S-dioxygenas-allenoxidsyntas (9S-DOX-AOS) och vid inkubation med linolsyra bildar hydroperoxyoctadekadiensyra (9-HPODE).

     

    Syftet med projektet är dels att ändra kiraliteten av 9S-DOX-AOS i genen EFQ_27323 genom att ersätta aminosyrorna Ile590 och Leu601 mot Gly590 och Phe601, respektive, och dels att förkorta DOX-domänen av enzymet för vidare 3D-strukturanalyser.

     

    Site directed mutagenesis används för mutationer av gener genom PCR-tekniken. Mutanten både transformeras och uttrycks i E.coli (BL21) med hjälp av expressionsvektorn pET101D-TOPO. De uttryckta enzymerna inkuberas med linolsyra (18:2n-6) och aktiviteten och dess kiralitet analyseras med hjälp av LC-MS/MS.

     

    Ersättningen av Ile590 med Gly590 ändrade kiraliteten av 9S-HPODE till 9R-HPODE med 20 % medan dubbelmutanten, d.v.s. Gly590 och Phe601 ändrade kiraliteten med 58 %. Enzymet förlorar sin 9-HPODE aktivitet när en förkortning av DOX-domän utan CYP-domän genomförs.

     

    Specifika aminosyrasubstitutioner i aktivt centrum påverkar regio- och stereoselektiviteten. Aminosyrorna i genen EFQ_27323, Gly590 och Phe601 istället för Ile590 med Leu601 ändrar kiraliteten från 9S-DOX-AOS till 9R-DOX-AOS

  • 14.
    Abdulla, Salim
    et al.
    Ifakara Hlth Inst, Dar Es Salaam, Tanzania..
    Ashley, Elizabeth A.
    Univ Oxford, Nuffield Dept Clin Med, Ctr Trop Med & Global Hlth, Oxford, England.;Mahidol Univ, Mahidol Oxford Trop Med Res Unit MORU, Fac Trop Med, Bangkok 10700, Thailand..
    Bassat, Quique
    Univ Barcelona, Ctr Invest Saude Manhica Manhica Mozamb & ISGloba, Barcelona Ctr Int Hlth Res CRESIB, Hosp Clin, Barcelona, Spain..
    Bethell, Delia
    AFRIMS, Dept Immunol & Med, Bangkok, Thailand..
    Bjorkman, Anders
    Karolinska Inst, Dept Microbiol Tumour & Cell Biol, Malaria Res, Stockholm, Sweden..
    Borrmann, Steffen
    Kenya Govt Med Res Ctr, Wellcome Trust Res Programme, Kilifi, Kenya.;Univ Magdeburg, Sch Med, D-39106 Magdeburg, Germany..
    D'Alessandro, Umberto
    Inst Trop Med, Unit Malariol, B-2000 Antwerp, Belgium.;MRC Unit, Fajara, Gambia..
    Dahal, Prabin
    Univ Oxford, Nuffield Dept Clin Med, Ctr Trop Med & Global Hlth, Oxford, England.;WorldWide Antimalarial Resistance Network WWARN, Oxford, England..
    Day, Nicholas P.
    Univ Oxford, Nuffield Dept Clin Med, Ctr Trop Med & Global Hlth, Oxford, England.;Mahidol Univ, Mahidol Oxford Trop Med Res Unit MORU, Fac Trop Med, Bangkok 10700, Thailand..
    Diakite, Mahamadou
    Univ Bamako, Malaria Res & Training Ctr, Bamako, Mali..
    Djimde, Abdoulaye A.
    Dondorp, Arjen M.
    Univ Oxford, Nuffield Dept Clin Med, Ctr Trop Med & Global Hlth, Oxford, England.;Mahidol Univ, Mahidol Oxford Trop Med Res Unit MORU, Fac Trop Med, Bangkok 10700, Thailand..
    Duong, Socheat
    Ctr Parasitol Entomol & Malaria Control, Phnom Penh, Cambodia..
    Edstein, Michael D.
    Fairhurst, Rick M.
    NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD USA..
    Faiz, M. Abul
    Malaria Res Grp MRG & Dev Care Fdn, Dhaka, Bangladesh..
    Falade, Catherine
    Univ Ibadan, Coll Med, Ibadan, Nigeria..
    Flegg, Jennifer A.
    Monash Univ, Sch Math Sci, Clayton, Vic 3800, Australia..
    Fogg, Carole
    Univ Portsmouth, Portsmouth, Hants, England..
    Gonzalez, Raquel
    Ctr Invest Saude Manhica Manhica Mozamb, Barcelona, Spain.;CRESIB, Barcelona, Spain..
    Greenwood, Brian
    London Sch Hyg & Trop Med, Fac Infect & Trop Dis, London WC1, England..
    Guerin, Philippe J.
    Univ Oxford, Nuffield Dept Clin Med, Ctr Trop Med & Global Hlth, Oxford, England.;WorldWide Antimalarial Resistance Network WWARN, Oxford, England..
    Guthmann, Jean-Paul
    Epicentre, Paris, France..
    Hamed, Kamal
    Novartis Pharmaceut, E Hanover, NJ USA..
    Hien, Tran Tinh
    Htut, Ye
    Dept Med Res, Lower Myanmar, Yangon, Myanmar..
    Juma, Elizabeth
    Kenya Govt Med Res Ctr, Nairobi, Kenya..
    Lim, Pharath
    NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD USA.;US & Natl Ctr Parasitol Entomol & Malaria Control, Phnom Penh, Cambodia..
    Mårtensson, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centrum för klinisk forskning i Sörmland (CKFD). Karolinska Inst, Dept Microbiol Cell & Tumour Biol, Dept Publ Hlth Sci, Malaria Res, Stockholm, Sweden..
    Mayxay, Mayfong
    Univ Oxford, Nuffield Dept Clin Med, Ctr Trop Med & Global Hlth, Oxford, England.;Mahosot Hosp, Lao Oxford Mahosot Hosp, Wellcome Trust Res Unit LOMWRU, Viangchan, Laos.;Univ Hlth Sci, Fac Postgrad Studies, Viangchan, Laos..
    Mokuolu, Olugbenga A.
    Univ Ilorin, Dept Paediat & Child Hlth, Ilorin, Nigeria..
    Moreira, Clarissa
    Univ Oxford, Nuffield Dept Clin Med, Ctr Trop Med & Global Hlth, Oxford, England.;WorldWide Antimalarial Resistance Network WWARN, Oxford, England..
    Newton, Paul
    Univ Oxford, Nuffield Dept Clin Med, Ctr Trop Med & Global Hlth, Oxford, England.;Mahosot Hosp, Lao Oxford Mahosot Hosp, Wellcome Trust Res Unit LOMWRU, Viangchan, Laos..
    Noedl, Harald
    Med Univ Vienna, Inst Specif Prophylaxis & Trop Med, Vienna, Austria..
    Nosten, Francois
    Univ Oxford, Nuffield Dept Clin Med, Ctr Trop Med & Global Hlth, Oxford, England.;Mahidol Univ, Shoklo Malaria Res Unit, Mahidol Oxford Trop Med Res Unit, Fac Trop Med, Bangkok 10700, Thailand..
    Ogutu, Bernhards R.
    Kenya Govt Med Res Ctr, US Army Med Res Unit, Kisumu, Kenya..
    Onyamboko, Marie A.
    Univ Oxford, Nuffield Dept Clin Med, Ctr Trop Med & Global Hlth, Oxford, England.;Kinshasa Sch Publ Hlth, Kinshasa, DEM REP CONGO..
    Owusu-Agyei, Seth
    Kintampo Hlth Res Ctr, Kintampo, Ghana..
    Phyo, Aung Pyae
    Mahidol Univ, Shoklo Malaria Res Unit, Mahidol Oxford Trop Med Res Unit, Fac Trop Med, Bangkok 10700, Thailand..
    Premji, Zul
    Muhimbili Univ Hlth & Allied Sci, Dar Es Salaam, Tanzania..
    Price, Ric N.
    Univ Oxford, Nuffield Dept Clin Med, Ctr Trop Med & Global Hlth, Oxford, England.;WorldWide Antimalarial Resistance Network WWARN, Oxford, England.;Menzies Sch Hlth Res, Global & Trop Hlth Div, Darwin, NT, Australia.;Charles Darwin Univ, Darwin, NT 0909, Australia..
    Pukrittayakamee, Sasithon
    Mahidol Univ, Fac Trop Med, Bangkok 10700, Thailand..
    Ramharter, Michael
    Med Univ Vienna, Div Infect Dis & Trop Med, Dept Med 1, Vienna, Austria.;Univ Tubingen, Inst Tropenmed, Tubingen, Germany.;Ctr Rech Med Lambarene, Lambarene, Gabon..
    Sagara, Issaka
    Univ Bamako, Fac Med Pharm & Odontostomatol, Dept Epidemiol Parasit Dis, Malaria Res & Training Ctr, Bamako, Mali..
    Se, Youry
    AFRIMS, Phnom Penh, Cambodia..
    Suon, Seila
    Natl Ctr Parasitol Entomol & Malaria Control, Phnom Penh, Cambodia..
    Stepniewska, Kasia
    Univ Oxford, Nuffield Dept Clin Med, Ctr Trop Med & Global Hlth, Oxford, England.;WorldWide Antimalarial Resistance Network WWARN, Oxford, England..
    Ward, Stephen A.
    Univ Liverpool, Liverpool Sch Trop Med, Dept Parasitol, Liverpool L3 5QA, Merseyside, England..
    White, Nicholas J.
    Univ Oxford, Nuffield Dept Clin Med, Ctr Trop Med & Global Hlth, Oxford, England.;Mahidol Univ, Mahidol Oxford Trop Med Res Unit MORU, Fac Trop Med, Bangkok 10700, Thailand..
    Winstanley, Peter A.
    Univ Warwick, Warwick Med Sch, Coventry CV4 7AL, W Midlands, England..
    Baseline data of parasite clearance in patients with falciparum malaria treated with an artemisinin derivative: an individual patient data meta-analysis2015In: Malaria Journal, ISSN 1475-2875, E-ISSN 1475-2875, Vol. 14, article id 359Article in journal (Refereed)
    Abstract [en]

    Background: Artemisinin resistance in Plasmodium falciparum manifests as slow parasite clearance but this measure is also influenced by host immunity, initial parasite biomass and partner drug efficacy. This study collated data from clinical trials of artemisinin derivatives in falciparum malaria with frequent parasite counts to provide reference parasite clearance estimates stratified by location, treatment and time, to examine host factors affecting parasite clearance, and to assess the relationships between parasite clearance and risk of recrudescence during follow-up. Methods: Data from 24 studies, conducted from 1996 to 2013, with frequent parasite counts were pooled. Parasite clearance half-life (PC1/2) was estimated using the WWARN Parasite Clearance Estimator. Random effects regression models accounting for study and site heterogeneity were used to explore factors affecting PC1/2 and risk of recrudescence within areas with reported delayed parasite clearance (western Cambodia, western Thailand after 2000, southern Vietnam, southern Myanmar) and in all other areas where parasite populations are artemisinin sensitive. Results: PC1/2 was estimated in 6975 patients, 3288 of whom also had treatment outcomes evaluate d during 28-63 days follow-up, with 93 (2.8 %) PCR-confirmed recrudescences. In areas with artemisinin-sensitive parasites, the median PC1/2 following three-day artesunate treatment (4 mg/kg/day) ranged from 1.8 to 3.0 h and the proportion of patients with PC1/2 > 5 h from 0 to 10 %. Artesunate doses of 4 mg/kg/day decreased PC1/2 by 8.1 % (95 % CI 3.2-12.6) compared to 2 mg/kg/day, except in populations with delayed parasite clearance. PC1/2 was longer in children and in patients with fever or anaemia at enrolment. Long PC1/2 (HR = 2.91, 95 % CI 1.95-4.34 for twofold increase, p < 0.001) and high initial parasitaemia (HR = 2.23, 95 % CI 1.44-3.45 for tenfold increase, p < 0.001) were associated independently with an increased risk of recrudescence. In western Cambodia, the region with the highest prevalence of artemisinin resistance, there was no evidence for increasing PC1/2 since 2007. Conclusions: Several factors affect PC1/2. As substantial heterogeneity in parasite clearance exists between locations, early detection of artemisinin resistance requires reference PC1/2 data. Studies with frequent parasite count measurements to characterize PC1/2 should be encouraged. In western Cambodia, where PC1/2 values are longest, there is no evidence for recent emergence of higher levels of artemisinin resistance.

  • 15.
    Abdulrasul, Ali
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Neurosteroids and Alzheimer’s disease: Mechanistic studies of neuroprotection and neurogenesis2015Independent thesis Advanced level (professional degree), 20 credits / 30 HE creditsStudent thesis
    Abstract [en]

    Alzheimer’s disease (AD) and its consequent memory and cognitive impairments continue to be unhaltable and incurable to this day. Yet, recent studies demonstrating neuroprotective effects of some neurosteroids have shown a potential of these steroids to modulate AD progression in vitro and in vivo. In the present study, the effects of neurosteroids were studied on hydrogen peroxide (H2O2), as well as staurosporine-induced toxicity in SH-SY5Y neuroblastoma cells. Moreover, underlying mechanisms were investigated. Cell viability was measured with MTT-assay. The results demonstrated that the neurosteroids investigated reduced hydrogen peroxide-induced toxicity. One of the neurosteroid even reduced staurosporine-induced toxicity. Moreover, the present study also showed neurogenic properties for one of the neurosteroid studied.  In conclusion, this report demonstrates that neurosteroids act neuroprotective against hydrogen peroxide-induced toxicity and that one of the neurosteroids studied even acts neuroprotective against staurosporine-induced toxicity and possesses neurogenic effects. 

  • 16. Abdurahman, Samir
    et al.
    Vegvari, Akos
    Youssefi, Masoud
    Levi, Michael
    Höglund, Stefan
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry.
    Andersson, Elin
    Horal, Peter
    Svennerholm, Bo
    Balzarini, Jan
    Vahlne, Anders
    Activity of the small modified amino acid alpha-hydroxy glycineamide on in vitro and in vivo human immunodeficiency virus type 1 capsid assembly and infectivity2008In: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 52, no 10, p. 3737-3744Article in journal (Refereed)
    Abstract [en]

    Upon maturation of the human immunodeficiency virus type 1 (HIV-1) virion, proteolytic cleavage of the Gag precursor protein by the viral protease is followed by morphological changes of the capsid protein p24, which will ultimately transform the virus core from an immature spherical to a mature conical structure. Virion infectivity is critically dependent on the optimal semistability of the capsid cone structure. We have reported earlier that glycineamide (G-NH2), when added to the culture medium of infected cells, inhibits HIV-1 replication and that HIV-1 particles with aberrant core structures were formed. Here we show that it is not G-NH2 itself but a metabolite thereof, alpha-hydroxy-glycineamide (alpha-HGA), that is responsible for the antiviral activity. We show that alpha-HGA inhibits the replication of clinical HIV-1 isolates with acquired resistance to reverse transcriptase and protease inhibitors but has no effect on the replication of any of 10 different RNA and DNA viruses. alpha-HGA affected the ability of the HIV-1 capsid protein to assemble into tubular or core structures in vitro and in vivo, probably by binding to the hinge region between the N- and C-terminal domains of the HIV-1 capsid protein as indicated by matrix-assisted laser desorption ionization-mass spectrometry results. As an antiviral compound, alpha-HGA has an unusually simple structure, a pronounced antiviral specificity, and a novel mechanism of antiviral action. As such, it might prove to be a lead compound for a new class of anti-HIV substances.

  • 17. Abela, D
    et al.
    Ritchie, H
    Ababneh, D
    Gavin, C
    Nilsson, Mats F
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Niazi, M Khalid Khan
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Centre for Image Analysis.
    Carlsson, K
    Webster, WS
    The effect of drugs with ion channel-blocking activity on the early embryonic rat heart2010In: Birth defects research. Part B. Developmental and reproductice toxicology, ISSN 1542-9733, E-ISSN 1542-9741, Vol. 89, no 5, p. 429-440Article in journal (Refereed)
    Abstract [en]

    This study investigated the effects of a range of pharmaceutical drugs with ion channel-blocking activity on the heart of gestation day 13 rat embryos in vitro. The general hypothesis was that the blockade of the IKr/hERG channel, that is highly important for the normal functioning of the embryonic rat heart, would cause bradycardia and arrhythmia. Concomitant blockade of other channels was expected to modify the effects of hERG blockade. Fourteen drugs with varying degrees of specificity and affinity toward potassium, sodium, and calcium channels were tested over a range of concentrations. The rat embryos were maintained for 2 hr in culture, 1 hr to acclimatize, and 1 hr to test the effect of the drug. All the drugs caused a concentration-dependent bradycardia except nifedipine, which primarily caused a negative inotropic effect eventually stopping the heart. A number of drugs induced arrhythmias and these appeared to be related to either sodium channel blockade, which resulted in a double atrial beat for each ventricular beat, or IKr/hERG blockade, which caused irregular atrial and ventricular beats. However, it is difficult to make a precise prediction of the effect of a drug on the embryonic heart just by looking at the polypharmacological action on ion channels. The results indicate that the use of the tested drugs during pregnancy could potentially damage the embryo by causing periods of hypoxia. In general, the effects on the embryonic heart were only seen at concentrations greater than those likely to occur with normal therapeutic dosing.

  • 18.
    Abelson, Anna-Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Genetic Risk Factors for Systemic Lupus Erythematosus: From Candidate Genes to Functional Variants2008Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The aim of this thesis has been to identify genetic variants that increase the susceptibility for Systemic Lupus Erythematosus (SLE), an autoimmune disease caused by a complex interplay between various genetic and environmental factors.

    Five different candidate genes were selected through different strategies, and were analysed for association with SLE in an attempt to distinguish some of the underlying mechanisms of this disease. Two of these genes, PD-L1 and PD-L2, appeared not to contain any major risk factors for SLE in the analysed European and Latin American populations. In two other genes, CD24 and STAT4, there appeared to be population-specific effects. The A57V amino acid substitution in the CD24 gene, previously implicated with multiple sclerosis, was associated in a Spanish cohort, with a weak trend in German samples, and no association in Swedish. The previously reported and highly convincing association of the STAT4 transcription factor gene was confirmed in all our cohorts. Interestingly, the results indicate the presence of at least two independent risk variants: the first, represented by a previously reported SNP, was the strongest in individuals of Northern European ancestry, and the second was more pronounced in individuals from Southern Europe and Latin America. We also report the identification of a novel susceptibility gene. The BANK1 gene, encoding a scaffold protein involved in B-cell activation, contains functional variants affecting important domains, which are associated in all investigated cohorts from Europe and Latin America.

    These results confirm the existence of replicable associations between genetic variants and SLE, which are common and present in many populations. The results also illustrate a certain degree of heterogeneity, where some risk factors could have variable effect in different populations.

    List of papers
    1. No evidence of association between genetic variants of the PDCD1 ligands and SLE
    Open this publication in new window or tab >>No evidence of association between genetic variants of the PDCD1 ligands and SLE
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    2007 (English)In: Genes and Immunity, ISSN 1466-4879, E-ISSN 1476-5470, Vol. 8, no 1, p. 69-74Article in journal (Refereed) Published
    Abstract [en]

    PDCD1, an immunoreceptor involved in peripheral tolerance has previously been shown to be genetically associated with systemic lupus erythematosus (SLE). PDCD1 has two ligands whose genes are located in close proximity on chromosome 9p24. Our attention was drawn to these ligands after finding suggestive linkage to a marker (gata62f03, Z=2.27) located close to their genes in a genome scan of Icelandic families multiplex for SLE. Here, we analyse Swedish trios (N=149) for 23 single nucleotide polymorphisms (SNPs) within the genes of the PDCD1 ligands. Initially, indication of association to eight SNPs was observed, and these SNPs were therefore also analysed in Mexican trios (N=90), as well as independent sets of patients and controls from Sweden (152 patients, 448 controls) and Argentina (288 patients, 288 controls). We do not find support for genetic association to SLE. This is the first genetic study of SLE and the PDCD1 ligands and the lack of association in several cohorts implies that these genes are not major risk factors for SLE.

    Keyword
    systemic lupus erythematosus, genetic association, linkage disequilibrium, autoimmunity, PD-L1, PD-L2
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-97760 (URN)10.1038/sj.gene.6364360 (DOI)000243783500009 ()17136123 (PubMedID)
    Available from: 2008-11-14 Created: 2008-11-14 Last updated: 2017-12-14Bibliographically approved
    2. Association of a CD24 Gene Polymorphism with Susceptibility to Systemic Lupus Erythematosus
    Open this publication in new window or tab >>Association of a CD24 Gene Polymorphism with Susceptibility to Systemic Lupus Erythematosus
    Show others...
    2007 (English)In: Arthritis and Rheumatism, ISSN 0004-3591, E-ISSN 1529-0131, Vol. 56, no 9, p. 3080-3086Article in journal (Refereed) Published
    Abstract [en]

    Objective. To determine the potential role of the CD24 A57V gene polymorphism in systemic lupus erythematosus (SLE).

    Methods. We studied 3 cohorts of Caucasian patients and controls. The Spanish cohort included 696 SLE patients and 539 controls, the German cohort included 257 SLE patients and 317 controls, and the Swedish cohort included 310 SLE patients and 247 controls. The CD24 A57V polymorphism was genotyped by polymerase chain reaction, using a predeveloped TaqMan allele discrimination assay. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated.

    Results. In the Spanish cohort there was a statistically significant difference in the distribution of the CD24 V allele between SLE patients and controls (OR 3.6 [95% CI 2.13-6.16], P < 0.0001). In addition, frequency of the CD24 V/V genotype was increased in SLE patients compared with controls (OR 3.7 [95% CI 2.16-6.34], P < 0.00001). We sought to replicate this association with SLE in a German population and a Swedish population. A similar trend was found in the German group. The CD24 V/V genotype and the CD24 V allele were more frequent in SLE patients than in controls, although this difference was not statistically significant. No differences were observed in the Swedish group. A meta-analysis of the Spanish and German cohorts demonstrated that the CD24 V allele has a risk effect in SLE patients (pooled OR 1.25 [95% Cl 1.08-1.46], P = 0.003). In addition, homozygosity for the CD24 V risk allele significantly increased the effect (pooled OR 2.1,9 [95% Cl 1.50-3.22], P = 0.00007).

    Conclusion. These findings suggest that the CD24 A57V polymorphism plays a role in susceptibility to SLE in a Spanish population.

    Keyword
    Antigens; CD24/*genetics, Cohort Studies, Female, Genetic Predisposition to Disease, Humans, Lupus Erythematosus; Systemic/*genetics, Male, Polymorphism; Genetic
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-97761 (URN)10.1002/art.22871 (DOI)000249832600030 ()17763438 (PubMedID)
    Available from: 2008-11-14 Created: 2008-11-14 Last updated: 2017-12-14Bibliographically approved
    3. Functional Variants in the B-Cell Gene BANK1 are Associated with Systemic Lupus Erythematosus
    Open this publication in new window or tab >>Functional Variants in the B-Cell Gene BANK1 are Associated with Systemic Lupus Erythematosus
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    2008 (English)In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 40, no 2, p. 211-216Article in journal (Refereed) Published
    Abstract [en]

    Systemic lupus erythematosus (SLE) is a prototypical autoimmune disease characterized by production of autoantibodies and complex genetic inheritance(1-3). In a genome-wide scan using 85,042 SNPs, we identified an association between SLE and a nonsynonymous substitution (rs10516487, R61H) in the B-cell scaffold protein with ankyrin repeats gene, BANK1. We replicated the association in four independent case-control sets (combined P = 3.7 x 10(-10); OR = 1.38). We analyzed BANK1 cDNA and found two isoforms, one full-length and the other alternatively spliced and lacking exon 2 (Delta 2), encoding a protein without a putative IP3R-binding domain. The transcripts were differentially expressed depending on a branch point-site SNP, rs17266594, in strong linkage disequilibrium (LD) with rs10516487. A third associated variant was found in the ankyrin domain (rs3733197, A383T). Our findings implicate BANK1 as a susceptibility gene for SLE, with variants affecting regulatory sites and key functional domains. The disease-associated variants could contribute to sustained B cell-receptor signaling and B-cell hyperactivity characteristic of this disease.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-97762 (URN)10.1038/ng.79 (DOI)000252732900020 ()
    Available from: 2008-11-14 Created: 2008-11-14 Last updated: 2017-12-14Bibliographically approved
    4. STAT4 Associates with SLE through two independent effects that correlate with gene expression and act additively with IRF5 to increase risk
    Open this publication in new window or tab >>STAT4 Associates with SLE through two independent effects that correlate with gene expression and act additively with IRF5 to increase risk
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    2009 (English)In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 68, no 11, p. 1746-1753Article in journal (Refereed) Published
    Abstract [en]

    OBJECTIVES: To confirm and define the genetic association of STAT4 and systemic lupus erythematosus, investigate the possibility of correlations with differential splicing and/or expression levels, and genetic interaction with IRF5. METHODS: 30 tag SNPs were genotyped in an independent set of Spanish cases and controls. SNPs surviving correction for multiple tests were genotyped in 5 new sets of cases and controls for replication. STAT4 cDNA was analyzed by 5'-RACE PCR and sequencing. Expression levels were measured by quantitative PCR. RESULTS: In the fine-mapping, four SNPs were significant after correction for multiple testing, with rs3821236 and rs3024866 as the strongest signals, followed by the previously associated rs7574865, and by rs1467199. Association was replicated in all cohorts. After conditional regression analyses, two major independent signals represented by SNPs rs3821236 and rs7574865, remained significant across the sets. These SNPs belong to separate haplotype blocks. High levels of STAT4 expression correlated with SNPs rs3821236, rs3024866 (both in the same haplotype block) and rs7574865 but not with other SNPs. We also detected transcription of alternative tissue-specific exons 1, indicating presence of tissue-specific promoters of potential importance in the expression of STAT4. No interaction with associated SNPs of IRF5 was observed using regression analysis. CONCLUSIONS: These data confirm STAT4 as a susceptibility gene for SLE and suggest the presence of at least two functional variants affecting levels of STAT4. Our results also indicate that both genes STAT4 and IRF5 act additively to increase risk for SLE.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-102290 (URN)10.1136/ard.2008.097642 (DOI)000270700900016 ()19019891 (PubMedID)
    Available from: 2009-05-06 Created: 2009-05-06 Last updated: 2017-12-13Bibliographically approved
  • 19.
    Abiri, Pojan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Användandet av webbsajten Sil Online – Svenska informationstjänster för läkemedel: En enkät- och intervjustudie2015Independent thesis Advanced level (degree of Master (Two Years)), 20 credits / 30 HE creditsStudent thesis
    Abstract [sv]

    Introduktion: Sil, Svenska informationstjänster för läkemedel, tillhandahåller kvalitetssäkrad läkemedelsinformation till aktörer inom hälso- och sjukvård. Sil Online (www.silonline.se) möjliggör åtkomsten till informationen i Sil databasen.

    Syfte: Att utvärdera vilka som är användare av Sil Online, i vilket ändamål användningen sker samt vilken information som söks på Sil Online för att skapa underlag för framtidsutveckling av webbsajten.

    Material och metoder: En deskriptiv tvärsnittsstudie bestående av en kvantitativ webbenkätundersökning (tidsperiod: 2015-03-05 till 2015-04-02) och en kvalitativ intervjuerundersökning bland frivilliga respondenter på webbenkäten.

    Resultat: Den största användargruppen bland respondenterna av webbenkäten var farmacevter (67 %), följt av systemutvecklare (16 %) varav majoriteten (43 %) jobbade inom hälso- och sjukvård eller förvaltning och administration inom landsting och kommuner (24 %). Aktuell läkemedelsinformation söktes av majoriteten av användarna (78 %) och mer än hälften (77 %) tyckte att det var lätt att hitta på webbsajten. Intervjurespondenterna saknade information om syftet med Sil Online men tyckte att det var en informativ sajt med unik information om licensläkemedel och listor med landstingens rekommenderade läkemedel. Tydligare instruktioner skulle förbättra användarvänlighet och marknadsföring skulle vidga användarkretsen.

    Konklusion: Sil Online upplevs vara en användarvänlig och informativ webbsajt. Studien visar att det finns potential för utveckling inom presentation och marknadsföring av webbsajten.

  • 20.
    Abood, Ekhlas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Identifying Medication History Errors at Iraqi Hospital Admissions Using The Swedish-LIMM model2016Independent thesis Advanced level (degree of Master (One Year)), 40 credits / 60 HE creditsStudent thesis
    Abstract [en]

    Abstract

    Background and Objective: An accurate medication history list is an integral part of the patient assessment at hospital admission. The objective of the study was to describe the frequency, type, and predictors of unintentional medication errors and to evaluate the quality of the clinical pharmacy services focusing on the acceptance of the recommendations made by the clinical pharmacist.

    Setting and methods: A descriptive study was conducted at two internal medicine wards at Baghdad Teaching Hospital in Iraq using Lund Integrated Medicines Management (LIMM)-based medication reconciliation. The study pharmacist conducted medication interviews for patients shortly after hospital admission to obtain the most accurate pre-admission medication history list. This list was compared with the medication list in the patient’s medical chart. Intended addition, withdrawal of a drug, or changes to the dose/ dosage form in the patient’s medical list was considered as medication discrepancies. However, medication discrepancies were considered as medication errors based on no identified clinical reason.

    Results: A total of 114 patients were included in this study. Over two-thirds of the study patients (73.7%) experienced 215 medication errors identified by a clinical pharmacist conducting medication reconciliation. Most errors were omission (87.9%). Cardiovascular agents followed by NSAID were commonly in error (53%) and (10.2%) respectively. In a logistic regression model, age (odds ratio (OR), 1.055: 95% confidence interval (CI) 1.010 - 1.102), female gender (OR, 3.468: 95% CI 1.232- 9.761) and number of medications at admission (OR, 0.810: 95% CI 0.681-0.963) were predictors for medication history errors at admission.

    Conclusions: Medication errors at the time of hospital admission are common and undetected.  A structured approach like the LIMM-based medication reconciliation at Iraqi hospital is needed to detect these errors.

  • 21.
    Aboye, Teshome L.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Strömstedt, Adam A.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Gunasekera, Sunithi
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Bruhn, Jan G.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    El-Seedi, Hesham
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Rosengren, K. Johan
    Göransson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    A Cactus-Derived Toxin-Like Cystine Knot Peptide with Selective Antimicrobial Activity2015In: ChemBioChem (Print), ISSN 1439-4227, E-ISSN 1439-7633, Vol. 16, no 7, p. 1068-1077Article in journal (Refereed)
    Abstract [en]

    Naturally occurring cystine knot peptides show a wide range of biological activity, and as they have inherent stability they represent potential scaffolds for peptide-based drug design and biomolecular engineering. Here we report the discovery, sequencing, chemical synthesis, three-dimensional solution structure determination and bioactivity of the first cystine knot peptide from Cactaceae (cactus) family: Ep-AMP1 from Echinopsis pachanoi. The structure of Ep-AMP1 (35 amino acids) conforms to that of the inhibitor cystine knot (or knottin) family but represents a novel diverse sequence; its activity was more than 500 times higher against bacterial than against eukaryotic cells. Rapid bactericidal action and liposome leakage implicate membrane permeabilisation as the mechanism of action. Sequence homology places Ec-AMP1 in the plant C6-type of antimicrobial peptides, but the three dimensional structure is highly similar to that of a spider neurotoxin.

  • 22.
    Aboye, Teshome Leta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Engineering of the Ultra-stable Cystine Knot Framework of Microproteins: Design, Chemical Synthesis and Structural Studies2011Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Ultra-stable cystine knotted microproteins, in which two disulfides and their connecting backbones form a circle that is penetrated by the third disulfide bonds, have attracted high interest due to their resistance to degradation in vitro and potential for the development of peptide drugs. This thesis gives new insights into engineering of that framework of microproteins, including approaches to their chemical synthesis, backbone engineering, structural and biological evaluations.

    Synthetic and oxidative folding approaches for bracelet cyclotides, a family of cyclic cystine knotted microproteins, was developed using a model peptide, cycloviolacin O2. Following assembly of the peptide chain, protected peptide was generated by mild cleavage that was subsequently thioesterified and cyclized in solution. The cyclic peptide was oxidatively folded under optimized conditions containing co-solvent and non-ionic detergent affording native cycloviolacin O2 as a major product. To gain further insights into the heterogeneity, efficiency and kinetics of cyclotides’ oxidative folding, the intermediates that accumulate in oxidative refolding pathways of all cyclotide subfamilies: Möbius, bracelet and the hybrid cyclotides were quantitatively determined under four different folding conditions. The results were used for defining major folding pathways, which indicated that Möbius cyclotides might accumulate heterogeneous folding intermediates with one-, two- and three-disulfides, whereas bracelet tend to accumulate a homogenous intermediate with three-disulfides, depending on the buffer systems used.

    Furthermore, to probe the internal factors contributing to inefficiency of oxidative folding, as well as undesired bioactivities of bracelet cyclotides (e.g., cytotoxic activity), polymer-hybridized cyclotides were designed by replacing non-conserved residues with small isosteric polymers. The designed hybrid analogs in which hybridization involved replacement of loop 3 with isosteric polymers showed improved synthetic and oxidative folding properties. The cytoxicity of a model hybrid designed with replacement of loop 3 and 5 exhibited no cytotoxic activity at concentration of 128-fold relative to that of native peptide. Furthermore, 1D and 2D 1H NMR analysis of this hybrid showed that it had well structured fold.

    List of papers
    1. Discovery, synthesis, and structural determination of a toxine-like disulfide-rich peptide from the cactus Trichoserus pachanoi
    Open this publication in new window or tab >>Discovery, synthesis, and structural determination of a toxine-like disulfide-rich peptide from the cactus Trichoserus pachanoi
    Show others...
    (English)Manuscript (preprint) (Other academic)
    Identifiers
    urn:nbn:se:uu:diva-145716 (URN)
    Available from: 2011-02-10 Created: 2011-02-10 Last updated: 2011-05-04
    2. Ultra-stable peptide scaffolds for protein engineering-synthesis and folding of the circular cystine knotted cyclotide cycloviolacin O2
    Open this publication in new window or tab >>Ultra-stable peptide scaffolds for protein engineering-synthesis and folding of the circular cystine knotted cyclotide cycloviolacin O2
    2008 (English)In: ChemBioChem (Print), ISSN 1439-4227, E-ISSN 1439-7633, Vol. 9, no 1, p. 103-113Article in journal (Refereed) Published
    Abstract [en]

    The cyclic cystine knot motif, as defined by the cyclotide peptide family, is an attractive scaffold for protein engineering. To date, however, the utilisation of this scaffold has been limited by the inability to synthesise members of the most diverse and biologically active subfamily, the bracelet cyclotides. This study describes the synthesis and first direct oxidative folding of a bracelet cyclotide-cycloviolacin O2-and thus provides an efficient method for exploring the most potent cyclic cystine knot peptides. The linear chain of cycloviolacin O2 was assembled by solid-phase Fmoc peptide synthesis and cyclised by thioester-mediated native chemical ligation, and the inherent difficulties of folding bracelet cyclotides were successfully overcome in a single-step reaction. The folding pathway was characterised and was found to include predominating fully oxidised intermediates that slowly converted to the native peptide structure.

    Keyword
    cyclotides, native chemical ligation, peptides, protein folding, synthesis, thioesters
    National Category
    Pharmaceutical Sciences
    Identifiers
    urn:nbn:se:uu:diva-98767 (URN)10.1002/cbic.200700357 (DOI)000252292200017 ()18058973 (PubMedID)
    Available from: 2009-03-03 Created: 2009-03-03 Last updated: 2018-01-13Bibliographically approved
    3. An Efficient Approach for the Total Synthesis of Cyclotides by Microwave Assisted Fmoc-SPPS
    Open this publication in new window or tab >>An Efficient Approach for the Total Synthesis of Cyclotides by Microwave Assisted Fmoc-SPPS
    2010 (English)In: International Journal of Peptide Research and Therapeutics, ISSN 1573-3149, Vol. 16, no 3, p. 167-176Article in journal (Refereed) Published
    Abstract [en]

    Cyclotides are mini-proteins of approximately 30 amino acid residues that have a unique structure consisting of a head-to-tail cyclized backbone and a knotted arrangement of three disulfide bonds. This unique cyclotide structure provides exceptional stability to chemical, enzymatic and thermal treatments and has been implicated as an ideal drug scaffold for the development into agricultural and biotechnological agents. In the current work, we present the first method for microwave assisted Fmoc-SPPS of cyclotides. This protocol adopts a strategy that combines optimized microwave assisted chemical reactions for Fmoc-SPPS of the peptide backbone, the cleavage of the protected peptide and the introduction of a thioester at the C-terminal carboxylic acid to obtain the head-to-tail cyclized cyclotide backbone by native chemical ligation. To exemplify the utility of this protocol in the synthesis of a wide array of different cyclotide sequences we synthesized representative members from the three cyclotide subfamilies-the Mobius kalata B1, the bracelet cycloviolacin O2 and the trypsin inhibitory MCoTI-II. In addition, a "one pot" reaction promoting both cyclization and oxidative folding of crude peptide thioester was adapted for kalata B1 and MCoTI-II.

    Keyword
    Cyclotides, Microwave chemistry, Fmoc-SPPS, Circular proteins, Cystine knot, Native chemical ligation
    National Category
    Pharmaceutical Sciences
    Identifiers
    urn:nbn:se:uu:diva-134899 (URN)10.1007/s10989-010-9221-0 (DOI)000281682600007 ()
    Available from: 2010-12-02 Created: 2010-12-02 Last updated: 2018-01-12Bibliographically approved
    4. Interlocking disulfides in circular proteins: toward efficient oxidative folding of cyclotides.
    Open this publication in new window or tab >>Interlocking disulfides in circular proteins: toward efficient oxidative folding of cyclotides.
    Show others...
    2011 (English)In: Antioxidants and Redox Signaling, ISSN 1523-0864, E-ISSN 1557-7716, Vol. 14, no 1, p. 77-86Article in journal (Refereed) Published
    Abstract [en]

    Cyclotides are ultrastable plant proteins characterized by the presence of a cyclic amide backbone and three disulfide bonds that form a cystine knot. Because of their extreme stability, there has been significant interest in developing these molecules as a drug design scaffold. For this potential to be realized, efficient methods for the synthesis and oxidative folding of cyclotides need to be developed, yet we currently have only a basic understanding of the folding mechanism and the factors influencing this process. In this study, we determine the major factors influencing oxidative folding of the different subfamilies of cyclotides. The folding of all the cyclotides examined was heavily influenced by the concentration of redox reagents, with the folding rate and final yield of the native isomer greatly enhanced by high concentrations of oxidized glutathione. Addition of hydrophobic solvents to the buffer also enhanced the folding rates and appeared to alter the folding pathway. Significant deamidation and isoaspartate formation were seen when oxidation conditions were conducive to slow folding. The identification of factors that influence the folding and degradation pathways of cyclotides will facilitate the development of folding screens and optimized conditions for producing cyclotides and grafted analogs as stable peptide-based therapeutics.

    National Category
    Pharmaceutical Sciences
    Identifiers
    urn:nbn:se:uu:diva-139359 (URN)10.1089/ars.2010.3112 (DOI)000284572100009 ()20486762 (PubMedID)
    Available from: 2010-12-23 Created: 2010-12-23 Last updated: 2018-01-12Bibliographically approved
    5. Design, synthesis, structural and biological evaluation of backbone-engineered cyclotides
    Open this publication in new window or tab >>Design, synthesis, structural and biological evaluation of backbone-engineered cyclotides
    (English)Manuscript (preprint) (Other academic)
    Identifiers
    urn:nbn:se:uu:diva-145719 (URN)
    Available from: 2011-02-10 Created: 2011-02-10 Last updated: 2011-05-04
  • 23.
    Aboye, Teshome Leta
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Clark, Richard J.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Burman, Robert
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Roig, Marta Bajona
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Craik, David J.
    University of Queensland, Institute for Molecular Bioscience.
    Göransson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Interlocking disulfides in circular proteins: toward efficient oxidative folding of cyclotides.2011In: Antioxidants and Redox Signaling, ISSN 1523-0864, E-ISSN 1557-7716, Vol. 14, no 1, p. 77-86Article in journal (Refereed)
    Abstract [en]

    Cyclotides are ultrastable plant proteins characterized by the presence of a cyclic amide backbone and three disulfide bonds that form a cystine knot. Because of their extreme stability, there has been significant interest in developing these molecules as a drug design scaffold. For this potential to be realized, efficient methods for the synthesis and oxidative folding of cyclotides need to be developed, yet we currently have only a basic understanding of the folding mechanism and the factors influencing this process. In this study, we determine the major factors influencing oxidative folding of the different subfamilies of cyclotides. The folding of all the cyclotides examined was heavily influenced by the concentration of redox reagents, with the folding rate and final yield of the native isomer greatly enhanced by high concentrations of oxidized glutathione. Addition of hydrophobic solvents to the buffer also enhanced the folding rates and appeared to alter the folding pathway. Significant deamidation and isoaspartate formation were seen when oxidation conditions were conducive to slow folding. The identification of factors that influence the folding and degradation pathways of cyclotides will facilitate the development of folding screens and optimized conditions for producing cyclotides and grafted analogs as stable peptide-based therapeutics.

  • 24.
    Abrahamsson, Bertil
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy.
    Biopharmaceutical aspects of extended release tablets based on the hydrophilic matrix principle 1997Doctoral thesis, comprehensive summary (Other academic)
  • 25.
    Abrantes, João A.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Nielsen, Elisabet I.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Uppsala Univ, Dept Pharmaceut Biosci, Uppsala, Sweden..
    Korth-Bradley, J.
    Pfizer Inc, Collegeville, PA USA..
    Harnisch, L.
    Pfizer Ltd, Global Clin Pharmacol, Sandwich, Kent, England..
    Jönsson, Siv
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Elucidation of Factor VIII Activity Pharmacokinetics: A Pooled Population Analysis in Patients With Hemophilia A Treated With Moroctocog Alfa2017In: Clinical Pharmacology and Therapeutics, ISSN 0009-9236, E-ISSN 1532-6535, Vol. 102, no 6, p. 977-988Article in journal (Refereed)
    Abstract [en]

    This study investigated the disposition of coagulation factor VIII activity in 754 patients with moderate to severe hemophilia A following the administration of moroctocog alfa, a B-domain deleted recombinant factor VIII. Data analyzed included patients aged 1 day to 73 years enrolled in 13 studies conducted over a period of 20 years in 25 countries. A two-compartment population pharmacokinetic model with a baseline model described the pooled data well. Body size, age, inhibitors, race, and analytical assay were identified as significant predictors of factor VIII disposition. In addition, simulations of prophylactic dosing schedules in several pediatric cohorts showed large variability and suggest that younger patients would require higher weight-adjusted doses than adolescents to achieve target factor VIII trough activity when receiving every other day or twice weekly dosing.

  • 26.
    Abu Hamdeh, Sami
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Shevchenko, Ganna
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Mi, Jia
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Musunuri, Sravani
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Bergquist, Jonas
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Marklund, Niklas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Proteomic differences between focal and diffuse traumatic brain injury in human brain tissueIn: Article in journal (Other academic)
    Abstract [en]

    The early molecular response to severe traumatic brain injury (TBI) was evaluated using biopsies of structurally normal-appearing cortex, obtained at location for intracranial pressure (ICP) monitoring, from 16 severe TBI patients. Mass spectrometry (MS; label free and stable isotope dimethyl labeling) quantitation proteomics showed a strikingly different molecular pattern in TBI in comparison to cortical biopsies from 11 normal pressure hydrocephalus patients. Diffuse TBI showed increased expression of peptides related to neurodegeneration (Tau and Fascin, p<0.05), reduced expression related to antioxidant defense (Glutathione S-transferase Mu 3, Peroxiredoxin-6, Thioredoxin-dependent peroxide reductase; p<0.05) and increased expression of potential biomarkers (e.g. Neurogranin, Fatty acid-binding protein, heart p<0.05) compared to focal TBI. Proteomics of human brain biopsies displayed considerable molecular heterogeneity among the different TBI subtypes with consequences for the pathophysiology and development of targeted treatments for TBI.

  • 27.
    Abu Hamdeh, Sami
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Waara, Erik Rollman
    Möller, Christer
    Söderberg, Linda
    Basun, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics. BioArctic Neuroscience AB, Stockholm, Sweden.
    Alafuzoff, Irina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Hillered, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Lannfelt, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics. BioArctic Neuroscience AB, Stockholm, Sweden.
    Ingelsson, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Marklund, Niklas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Rapid amyloid-β oligomer and protofibril accumulation in traumatic brain injury2017In: Brain Pathology, ISSN 1015-6305, E-ISSN 1750-3639Article in journal (Refereed)
    Abstract [en]

    Deposition of amyloid-β (Aβ) is central to Alzheimer's disease (AD) pathogenesis and associated with progressive neurodegeneration in traumatic brain injury (TBI). We analyzed predisposing factors for Aβ deposition including monomeric Aβ40, Aβ42 and Aβ oligomers/protofibrils, Aβ species with pronounced neurotoxic properties, following human TBI. Highly selective ELISAs were used to analyze N-terminally intact and truncated Aβ40 and Aβ42, as well as Aβ oligomers/protofibrils, in human brain tissue, surgically resected from severe TBI patients (n = 12; mean age 49.5 ± 19 years) due to life-threatening brain swelling/hemorrhage within one week post-injury. The TBI tissues were compared to post-mortem AD brains (n = 5), to post-mortem tissue of neurologically intact (NI) subjects (n = 4) and to cortical biopsies obtained at surgery for idiopathic normal pressure hydrocephalus patients (iNPH; n = 4). The levels of Aβ40 and Aβ42 were not elevated by TBI. The levels of Aβ oligomers/protofibrils in TBI were similar to those in the significantly older AD patients and increased compared to NI and iNPH controls (P < 0.05). Moreover, TBI patients carrying the AD risk genotype Apolipoprotein E epsilon3/4 (APOE ε3/4; n = 4) had increased levels of Aβ oligomers/protofibrils (P < 0.05) and of both N-terminally intact and truncated Aβ42 (P < 0.05) compared to APOE ε3/4-negative TBI patients (n = 8). Neuropathological analysis showed insoluble Aβ aggregates (commonly referred to as Aβ plaques) in three TBI patients, all of whom were APOE ε3/4 carriers. We conclude that soluble intermediary Aβ aggregates form rapidly after TBI, especially among APOE ε3/4 carriers. Further research is needed to determine whether these aggregates aggravate the clinical short- and long-term outcome in TBI.

  • 28. Abu-Bakar, A'edah
    et al.
    Arthur, Dionne M.
    Wikman, Anna S.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Rahnasto, Minna
    Juvonen, Risto O.
    Vepsalainen, Jouko
    Raunio, Hannu
    Ng, Jack C.
    Lang, Matti A.
    Metabolism of bilirubin by human cytochrome P450 2A62012In: Toxicology and Applied Pharmacology, ISSN 0041-008X, E-ISSN 1096-0333, Vol. 261, no 1, p. 50-58Article in journal (Refereed)
    Abstract [en]

    The mouse cytochrome P450 (CYP) 2A5 has recently been shown to function as hepatic "Bilirubin Oxidase" (Abu-Bakar, A., et al., 2011. Toxicol. Appl. Pharmacol. 257, 14-22). To date, no information is available on human CYP isoforms involvement in bilirubin metabolism. In this paper we provide novel evidence for human CYP2A6 metabolising the tetrapyrrole bilirubin. Incubation of bilirubin with recombinant yeast microsomes expressing the CYP2A6 showed that bilirubin inhibited CYP2A6-dependent coumarin 7-hydroxylase activity to almost 100% with an estimated K-i of 2.231 mu M. Metabolite screening by a high-performance liquid chromatography/electrospray ionisation mass spectrometry indicated that CYP2A6 oxidised bilirubin to biliverdin and to three other smaller products with m/z values of 301,315 and 333. Molecular docking analyses indicated that bilirubin and its positively charged intermediate interacted with key amino acid residues at the enzyme's active site. They were stabilised at the site in a conformation favouring biliverdin formation. By contrast, the end product, biliverdin was less fitting to the active site with the critical central methylene bridge distanced from the CYP2A6 haem iron facilitating its release. Furthermore, bilirubin treatment of HepG2 cells increased the CYP2A6 protein and activity levels with no effect on the corresponding mRNA. Co-treatment with cycloheximide (CHX), a protein synthesis inhibitor, resulted in increased half-life of the CYP2A6 compared to cells treated only with CHX. Collectively, the observations indicate that the CYP2A6 may function as human "Bilirubin Oxidase" where bilirubin is potentially a substrate and a regulator of the enzyme.

  • 29. Abu-Bakar, A'edah
    et al.
    Lämsä, Virpi
    Arpiainen, Satu
    Moore, Michael R.
    Lang, Matti A.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Pharmaceutical Biochemistry.
    Hakkola, Jukka
    Regulation of CYP2A5 gene by the transcription factor nuclear factor (erythroid-derived 2)-like 22007In: Drug Metabolism And Disposition, ISSN 0090-9556, E-ISSN 1521-009X, Vol. 35, no 5, p. 787-794Article in journal (Refereed)
    Abstract [en]

    We have previously shown that cadmium, a metal that alters cellular redox status, induces CYP2A5 expression in nuclear factor (erythroid-derived 2)-like 2 wild-type (Nrf2(-/-)) mice but not in the knockout (Nrf2(-/-)) mice. In the present studies, the potential role of Nrf2 in cadmium-mediated regulation of Cyp2a5 gene was investigated in mouse primary hepatocytes. Cadmium chloride (CdCl2) caused a time-dependent induction of the CYP2A5 at mRNA, protein, and activity levels, with a substantial increase observed within 3 h of exposure. Immunoblotting showed cadmium-dependent nuclear accumulation of Nrf2 within 1 h of exposure. Cotransfection of mouse primary hepatocytes with Cyp2a5 promoter-luciferase reporter plasmids and Nrf2 expression plasmid resulted in a 3-fold activation of Cyp2a5 promoter-mediated transcription relative to the control. Deletion analysis of the promoter localized the Nrf2 responsive region to an area from -2656 to -2339 base pair. Computer-based sequence analysis identified two putative stress response elements (StRE) within the region at positions -2514 to -2505 and -2386 to -2377. Chromatin immunoprecipitation and electrophoretic mobility shift assays showed that interaction of the more proximal StRE with Nrf2 was stimulated by CdCl2. Finally, site-directed mutagenesis of the proximal StRE in Cyp2a5 promoter-luciferase reporter plasmids abolished Nrf2 mediated induction. Collectively, the results indicate that Nrf2 activates Cyp2a5 transcription by directly binding to the StRE in the 5'-flanking region of the gene. This acknowledges Cyp2a5 as the first phase I xenobiotic-metabolizing gene identified under the control of the StRE-Nrf2 pathway with a potential role in adaptive response to cellular stress.

  • 30. Abuzooda, Thana
    et al.
    Amini, Ahmad
    Swedish Drug Agency,751 03 Uppsala, Sweden.
    Abdel-Rehim, Mohamed
    Graphite-based microextraction by packed sorbent for online extraction of β-blockers from human plasma samples2015In: Journal of chromatography. B, ISSN 1570-0232, E-ISSN 1873-376X, Vol. 992, p. 86-90Article in journal (Refereed)
    Abstract [en]

    In the present work a new graphitic material (Carbon-XCOS) was used as a sorbent for microextraction by packed sorbent (MEPS). The β-blockers metoprolol and acebutolol in plasma samples were extracted and detected online using Carbon-MEPS syringe and liquid chromatography and tandem mass spectrometry (LC-MS/MS). Factors affecting the MEPS performance such as conditioning, washing and elution solutions were investigated. The validation of the bioanalytical method was performed using human plasma. The standard curve ranged from 10 to 2000nM and the lower limit of quantification (LLOQ) was set to 10nM. The method validation showed good accuracy and precision for the quality control (QC) samples at three concentration levels (30, 800 and 1600nM). The accuracy values of the QC samples were in the range of 86-108% (n=18). The precision values of intra- and inter-day for QC samples ranged from 4.4% to 14.4% (RSD) for the both studied analytes. The coefficient of determination (R(2)) values were ≥0.999 (n=3).

  • 31. Achen, M G
    et al.
    Jeltsch, M
    Kukk, E
    Mäkinen, T
    Vitali, A
    Wilks, A F
    Alitalo, K
    Stacker, S A
    Vascular endothelial growth factor D (VEGF-D) is a ligand for the tyrosine kinases VEGF receptor 2 (Flk1) and VEGF receptor 3 (Flt4).1998In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 95, no 2Article in journal (Refereed)
    Abstract [en]

    We have identified a member of the VEGF family by computer-based homology searching and have designated it VEGF-D. VEGF-D is most closely related to VEGF-C by virtue of the presence of N- and C-terminal extensions that are not found in other VEGF family members. In adult human tissues, VEGF-D mRNA is most abundant in heart, lung, skeletal muscle, colon, and small intestine. Analyses of VEGF-D receptor specificity revealed that VEGF-D is a ligand for both VEGF receptors (VEGFRs) VEGFR-2 (Flk1) and VEGFR-3 (Flt4) and can activate these receptors. However. VEGF-D does not bind to VEGFR-1. Expression of a truncated derivative of VEGF-D demonstrated that the receptor-binding capacities reside in the portion of the molecule that is most closely related in primary structure to other VEGF family members and that corresponds to the mature form of VEGF-C. In addition, VEGF-D is a mitogen for endothelial cells. The structural and functional similarities between VEGF-D and VEGF-C define a subfamily of the VEGFs.

  • 32. Achen, M G
    et al.
    Roufail, S
    Domagala, T
    Catimel, B
    Nice, E C
    Geleick, D M
    Murphy, R
    Scott, A M
    Caesar, C
    Makinen, T
    Alitalo, K
    Stacker, S A
    Monoclonal antibodies to vascular endothelial growth factor-D block its interactions with both VEGF receptor-2 and VEGF receptor-3.2000In: European Journal of Biochemistry, ISSN 0014-2956, E-ISSN 1432-1033, Vol. 267, no 9Article in journal (Refereed)
    Abstract [en]

    Vascular endothelial growth factor-D (VEGF-D), the most recently discovered mammalian member of the VEGF family, is an angiogenic protein that activates VEGF receptor-2 (VEGFR-2/Flk1/KDR) and VEGFR-3 (Flt4). These receptor tyrosine kinases, localized on vascular and lymphatic endothelial cells, signal for angiogenesis and lymphangiogenesis. VEGF-D consists of a central receptor-binding VEGF homology domain (VHD) and N-terminal and C-terminal propeptides that are cleaved from the VHD to generate a mature, bioactive form consisting of dimers of the VHD. Here we report characterization of mAbs raised to the VHD of human VEGF-D in order to generate VEGF-D antagonists. The mAbs bind the fully processed VHD with high affinity and also bind unprocessed VEGF-D. We demonstrate, using bioassays for the binding and cross-linking of VEGFR-2 and VEGFR-3 and biosensor analysis with immobilized receptors, that one of the mAbs, designated VD1, is able to compete potently with mature VEGF-D for binding to both VEGFR-2 and VEGFR-3 for binding to mature VEGF-D. This indicates that the binding epitopes on VEGF-D for these two receptors may be in close proximity. Furthermore, VD1 blocks the mitogenic response of human microvascular endothelial cells to VEGF-D. The anti-(VEGF-D) mAbs raised to the bioactive region of this growth factor will be powerful tools for analysis of the biological functions of VEGF-D.

  • 33. Ackermann, Paul
    et al.
    Spetea, Mariana
    Nylander, Ingrid
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Ploj, Karolina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Ahmed, Mahmood
    Kreicbergs, Andris
    An opioid system in connective tissue: A study of Achilles tendon in the rat2001In: Journal of Histochemistry and Cytochemistry, ISSN 0022-1554, E-ISSN 1551-5044, Vol. 49, no 11, p. 1387-1395Article in journal (Refereed)
    Abstract [en]

    The occurrence of endogenous opioids and their receptors in rat achilles tendon was analyzed by immunohistochemistry (IHC), radioimmunoassay (RIA), and in vitro binding assays. The investigation focused on four enkephalins, dynorphin B, and nociceptin/orphanin FQ. Nerve fibers immunoreactive to all enkephalins (Met-enkephalin, Leu-enkephalin, Met-enkephalin-Arg-Gly-Lys, Met-enkephalin-Arg-Phe) were consistently found in the loose connective tissue and the paratenon, whereas dynorphin B and nociceptin/orphanin FQ could not be detected. The majority of enkephalin-positive nerve fibers exhibited varicosities predominantly seen in blood vessel walls. Measurable levels of Met-enkephalin-Arg-Phe and nociceptin/orphanin FQ were found in tendon tissue using RIA, whereas dynorphin B could not be detected. In addition to the endogenous opioids identified, delta -opioid receptors on nerve fibers were also detected by IHC. Binding assays to characterize the opioid binding sites showed that they were specific and saturable for [H-3]-naloxone (K-d 7.01 +/- 0.98 nM; B-max 23.52 +/- 2.23 fmol/mg protein). Our study demonstrates the occurrence of an opioid system in rat achilles tendon, which may be assumed to be present also in other connective tissues of the locomotor apparatus. This system may prove to be a useful target for pharmacological therapy in painful and inflammatory conditions by new drugs acting selectively in the periphery.

  • 34.
    Adams, Hieab H. H.
    et al.
    Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands.;Erasmus MC, Dept Radiol & Nucl Med, Rotterdam, Netherlands..
    Hibar, Derrek P.
    Univ Southern Calif, Keck Sch Med, USC Mark & Mary Stevens Neuroimaging & Informat I, Imaging Genet Ctr, Los Angeles, CA USA..
    Chouraki, Vincent
    Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA.;Univ Lille, RID AGE Risk Factors & Mol Determinants Aging Rel, CHU Lille, Inserm,Inst Pasteur Lille, Lille, France.;Framingham Heart Dis Epidemiol Study, Framingham, MA USA..
    Stein, Jason L.
    Univ Southern Calif, Keck Sch Med, USC Mark & Mary Stevens Neuroimaging & Informat I, Imaging Genet Ctr, Los Angeles, CA USA.;Univ N Carolina, Dept Genet, Chapel Hill, NC USA.;Univ N Carolina, UNC Neurosci Ctr, Chapel Hill, NC USA..
    Nyquist, Paul A.
    Johns Hopkins Univ, Dept Neurol, Dept Anesthesia Crit Care Med, Dept Neurosurg, Baltimore, MD 21218 USA..
    Renteria, Miguel E.
    QIMR Berghofer Med Res Inst, Brisbane, Qld, Australia..
    Trompet, Stella
    Leiden Univ, Med Ctr, Dept Cardiol, Leiden, Netherlands..
    Arias-Vasquez, Alejandro
    Radboud Univ Nijmegen, Med Ctr, Dept Human Genet, Nijmegen, Netherlands.;Radboud Univ Nijmegen, Med Ctr, Dept Psychiat, Nijmegen, Netherlands.;Radboud Univ Nijmegen, Med Ctr, Dept Cognit Neurosci, Nijmegen, Netherlands.;Radboud Univ Nijmegen, Donders Inst Brain Cognit & Behav, Nijmegen, Netherlands..
    Seshadri, Sudha
    Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA.;Framingham Heart Dis Epidemiol Study, Framingham, MA USA..
    Desrivieres, Sylvane
    Kings Coll London, Inst Psychiat Psychol & Neurosci, MRC SGDP Ctr, London, England..
    Beecham, Ashley H.
    Univ Miami, Miller Sch Med, Dept Human Genet, Dr John T Macdonald Fdn, Miami, FL 33136 USA.;Univ Miami, Miller Sch Med, John P Hussman Inst Human Gen, Miami, FL 33136 USA..
    Jahanshad, Neda
    Univ Southern Calif, Keck Sch Med, USC Mark & Mary Stevens Neuroimaging & Informat I, Imaging Genet Ctr, Los Angeles, CA USA..
    Wittfeld, Katharine
    German Ctr Neurodegenerat Dis DZNE Rostock Greifs, Greifswald, Germany.;Univ Med Greifswald, Dept Psychiat, Greifswald, Germany..
    Van der Lee, Sven J.
    Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands..
    Abramovic, Lucija
    UMC Utrecht, Dept Psychiat, Brain Ctr Rudolf Magnus, Utrecht, Netherlands..
    Alhusaini, Saud
    McGill Univ, Montreal Neurol Inst, Dept Neurol & Neurosurg, Montreal, PQ, Canada.;Royal Coll Surgeons Ireland, Dublin 2, Ireland..
    Amin, Najaf
    Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands..
    Andersson, Micael
    Umea Univ, Dept Integrat Med Biol, Umea, Sweden.;Umea Univ, Umea Ctr Funct Brain Imaging, Umea, Sweden..
    Arfanakis, Konstantinos
    IIT, Dept Biomed Engn, Chicago, IL 60616 USA.;Rush Univ, Med Ctr, Rush Alzheimers Dis Ctr, Chicago, IL 60612 USA.;Rush Univ, Med Ctr, Dept Diagnost Radiol & Nucl Med, Chicago, IL 60612 USA..
    Aribisala, Benjamin S.
    Univ Edinburgh, Brain Res Imaging Ctr, Edinburgh, Midlothian, Scotland.;Lagos State Univ, Dept Comp Sci, Lagos, Nigeria.;Univ Edinburgh, Dept Neuroimaging Sci, Scottish Imaging Network, Edinburgh, Midlothian, Scotland..
    Armstrong, Nicola J.
    Univ New South Wales, Sch Psychiat, Ctr Hlth Brain Ageing, Sydney, NSW, Australia.;Murdoch Univ, Math & Stat, Perth, WA, Australia..
    Athanasiu, Lavinia
    Univ Oslo, Inst Clin Med, NORMENT KG Jebsen Ctr, Oslo, Norway.;Oslo Univ Hosp, Div Mental Hlth & Addict, NORMENT KG Jebsen Ctr, Oslo, Norway..
    Axelsson, Tomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Beiser, Alexa
    Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA.;Framingham Heart Dis Epidemiol Study, Framingham, MA USA.;Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA..
    Bernard, Manon
    Univ Toronto, Hosp Sick Children, Toronto, ON, Canada..
    Bis, Joshua C.
    Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA USA..
    Blanken, Laura M. E.
    Erasmus MC, Generat R Study Grp, Rotterdam, Netherlands.;Erasmus MC Sophia Childrens Hosp, Dept Child & Adolescent Psychiat Psychol, Rotterdam, Netherlands..
    Blanton, Susan H.
    Univ Miami, Miller Sch Med, Dept Human Genet, Dr John T Macdonald Fdn, Miami, FL 33136 USA.;Univ Miami, Miller Sch Med, John P Hussman Inst Human Gen, Miami, FL 33136 USA..
    Bohlken, Marc M.
    UMC Utrecht, Dept Psychiat, Brain Ctr Rudolf Magnus, Utrecht, Netherlands..
    Boks, Marco P.
    UMC Utrecht, Dept Psychiat, Brain Ctr Rudolf Magnus, Utrecht, Netherlands..
    Bralten, Janita
    Radboud Univ Nijmegen, Med Ctr, Dept Human Genet, Nijmegen, Netherlands.;Radboud Univ Nijmegen, Donders Inst Brain Cognit & Behav, Nijmegen, Netherlands..
    Brickman, Adam M.
    Columbia Univ, Med Ctr, Taub Inst Res Alzheimers Dis & Aging Brain, New York, NY USA.;Columbia Univ, GH Sergievsky Ctr, Med Ctr, New York, NY USA.;Columbia Univ, Dept Neurol, Med Ctr, New York, NY USA..
    Carmichael, Owen
    Pennington Biomed Res Ctr, 6400 Perkins Rd, Baton Rouge, LA 70808 USA..
    Chakravarty, M. Mallar
    Douglas Mental Hlth Univ Inst, Cerebral Imaging Ctr, Montreal, PQ, Canada.;McGill Univ, Dept Psychiat & Biomed Engn, Montreal, PQ, Canada..
    Chauhan, Ganesh
    Univ Bordeaux, INSERM Unit U1219, Bordeaux, France..
    Chen, Qiang
    Lieber Inst Brain Dev, Baltimore, MD USA..
    Ching, Christopher R. K.
    Univ Southern Calif, Keck Sch Med, USC Mark & Mary Stevens Neuroimaging & Informat I, Imaging Genet Ctr, Los Angeles, CA USA.;Univ Calif Los Angeles, Sch Med, Interdept Neurosci Grad Program, Los Angeles, CA USA..
    Cuellar-Partida, Gabriel
    QIMR Berghofer Med Res Inst, Brisbane, Qld, Australia..
    Den Braber, Anouk
    Vrije Univ Amsterdam, Biol Psychol, Neurosci Campus Amsterdam, Amsterdam, Netherlands.;Vrije Univ Amsterdam, Med Ctr, Amsterdam, Netherlands..
    Doan, Nhat Trung
    Univ Oslo, Inst Clin Med, NORMENT KG Jebsen Ctr, Oslo, Norway..
    Ehrlich, Stefan
    Tech Univ Dresden, Fac Med, Div Psychol & Social Med & Dev Neurosci, Dresden, Germany.;Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA.;Massachusetts Gen Hosp, Martinos Ctr Biomed Imaging, Charlestown, MA USA..
    Filippi, Irina
    Univ Paris Sud, Univ Paris Descartes, NSERM Unit Neuroimaging & Psychiat 1000, Paris, France.;Hosp Cochin, AP HP, Maison Solenn Adolescent Psychopathol & Med Dept, Paris, France..
    Ge, Tian
    Massachusetts Gen Hosp, Martinos Ctr Biomed Imaging, Charlestown, MA USA.;Massachusetts Gen Hosp, Ctr Human Genet Res, Psychiat & Neurodev Genet Unit, Boston, MA 02114 USA.;Harvard Med Sch, Boston, MA USA.;Broad Inst MIT & Harvard, Stanley Ctr Psychiat Res, Boston, MA USA..
    Giddaluru, Sudheer
    Univ Bergen, Dept Clin Sci, NORMENT KG Jebsen Ctr Psychosis Res, N-5020 Bergen, Norway.;Haukeland Hosp, Ctr Med Genet & Mol Med, Dr Einar Martens Res Grp Biol Psychiat, Bergen, Norway..
    Goldman, Aaron L.
    Lieber Inst Brain Dev, Baltimore, MD USA..
    Gottesman, Rebecca F.
    Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD 21205 USA..
    Greven, Corina U.
    Radboud Univ Nijmegen, Med Ctr, Dept Cognit Neurosci, Nijmegen, Netherlands.;Karakter Child & Adolescent Psychiat Univ Ctr, Nijmegen, Netherlands.;Kings Coll London, Med Res Council Social, Genet & Dev Psychiat Ctr, Inst Psychol Psychiat & Neurosci, London, England..
    Grimm, Oliver
    Heidelberg Univ, Med Fac Mannheim, Cent Inst Mental Hlth, Mannheim, Germany..
    Griswold, Michael E.
    Univ Mississippi, Med Ctr, Ctr Biostat & Bioinformat, Jackson, MS 39216 USA..
    Guadalupe, Tulio
    Max Planck Inst Psycholinguist, Language & Genet Dept, Nijmegen, Netherlands.;Int Max Planck Res Sch Language Sci, Nijmegen, Netherlands..
    Hass, Johanna
    Tech Univ Dresden, Fac Med, Dept Child & Adolescent Psychiat, Dresden, Germany..
    Haukvik, Unn K.
    Univ Oslo, Inst Clin Med, NORMENT KG Jebsen Ctr, Oslo, Norway.;Diakonhjemmet Hosp, Dept Res & Dev, Oslo, Norway..
    Hilal, Saima
    Natl Univ Singapore, Dept Pharmacol, Singapore, Singapore.;Natl Univ Hlth Syst, Mem Aging & Cognit Ctr, Singapore, Singapore..
    Hofer, Edith
    Med Univ Graz, Clin Div Neurogeriatr, Dept Neurol, Graz, Austria.;Med Univ Graz, Inst Med Informat Stat & Documentat, Graz, Austria..
    Hoehn, David
    Max Planck Inst Psychiat, Dept Translat Res Psychiat, Munich, Germany..
    Holmes, Avram J.
    Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA.;Yale Univ, Dept Psychol, New Haven, CT USA..
    Hoogman, Martine
    Radboud Univ Nijmegen, Med Ctr, Dept Human Genet, Nijmegen, Netherlands.;Radboud Univ Nijmegen, Donders Inst Brain Cognit & Behav, Nijmegen, Netherlands..
    Janowitz, Deborah
    Univ Med Greifswald, Dept Psychiat, Greifswald, Germany..
    Jia, Tianye
    Kings Coll London, Inst Psychiat Psychol & Neurosci, MRC SGDP Ctr, London, England..
    Kasperaviciute, Dalia
    UCL, Inst Neurol, London, England.;Epilepsy Soc, Gerrards Cross, Bucks, England.;Imperial Coll London, Dept Med, London, England..
    Kim, Sungeun
    Indiana Univ, Sch Med, Ctr Computat Biol & Bioinformat, Indianapolis, IN USA.;Indiana Univ, Sch Med, Indiana Alzheimer Dis Ctr, Indianapolis, IN USA..
    Klein, Marieke
    Radboud Univ Nijmegen, Med Ctr, Dept Human Genet, Nijmegen, Netherlands.;Radboud Univ Nijmegen, Donders Inst Brain Cognit & Behav, Nijmegen, Netherlands..
    Kraemer, Bernd
    Heidelberg Univ, Dept Gen Psychiat, Sect Expt Psychopathol & Neuroimaging, Heidelberg, Germany..
    Lee, Phil H.
    Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA.;Massachusetts Gen Hosp, Ctr Human Genet Res, Psychiat & Neurodev Genet Unit, Boston, MA 02114 USA.;Harvard Med Sch, Boston, MA USA.;Broad Inst MIT & Harvard, Stanley Ctr Psychiat Res, Boston, MA USA.;Harvard Med Sch, Massachusetts Gen Hosp, Lurie Ctr Autism, Lexington, MA USA..
    Liao, Jiemin
    Singapore Natl Eye Ctr, Singapore Eye Res Inst, Singapore, Singapore..
    Liewald, David C. M.
    Univ Edinburgh, Ctr Cognit Ageing & Cognit Epidemiol Psychol, Edinburgh, Midlothian, Scotland..
    Lopez, Lorna M.
    Univ Edinburgh, Ctr Cognit Ageing & Cognit Epidemiol Psychol, Edinburgh, Midlothian, Scotland..
    Luciano, Michelle
    Univ Edinburgh, Ctr Cognit Ageing & Cognit Epidemiol Psychol, Edinburgh, Midlothian, Scotland..
    Macare, Christine
    Kings Coll London, Inst Psychiat Psychol & Neurosci, MRC SGDP Ctr, London, England..
    Marquand, Andre
    Radboud Univ Nijmegen, Donders Inst Brain Cognit & Behav, Nijmegen, Netherlands.;Radboud Univ Nijmegen, Donders Ctr Cognit Neuroimaging, Nijmegen, Netherlands..
    Matarin, Mar
    UCL, Inst Neurol, London, England.;Epilepsy Soc, Gerrards Cross, Bucks, England.;UCL Inst Neurol, Reta Lila Weston Inst, London, England.;UCL Inst Neurol, Dept Mol Neurosci, London, England..
    Mather, Karen A.
    Univ New South Wales, Sch Psychiat, Ctr Hlth Brain Ageing, Sydney, NSW, Australia..
    Mattheisen, Manuel
    Aarhus Univ, Dept Biomed, Aarhus, Denmark.;iPSYCH, Lundbeck Fdn Initiat Integrat Psychiat Res, Aarhus, Denmark.;iPSYCH, Lundbeck Fdn Initiat Integrat Psychiat Res, Copenhagen, Denmark.;Aarhus Univ, iSEQ, Ctr Integrated Sequencing, Aarhus, Denmark..
    Mazoyer, Bernard
    UMR5296 Univ Bordeaux, CNRS, CEA, Bordeaux, France..
    Mckay, David R.
    Yale Univ, Dept Psychiat, New Haven, CT 06520 USA.;Olin Neuropsychiat Res Ctr, Hartford, CT USA..
    McWhirter, Rebekah
    Univ Tasmania, Menzies Inst Med Res, Hobart, Tas, Australia..
    Milaneschi, Yuri
    VU Univ Med Ctr GGZ Geest, EMGO Inst Hlth & Care Res, Dept Psychiat, Amsterdam, Netherlands.;VU Univ Med Ctr GGZ Geest, Neurosci Campus Amsterdam, Amsterdam, Netherlands..
    Mirza-Schreiber, Nazanin
    Max Planck Inst Psychiat, Dept Translat Res Psychiat, Munich, Germany..
    Muetzel, Ryan L.
    Erasmus MC, Generat R Study Grp, Rotterdam, Netherlands.;Erasmus MC Sophia Childrens Hosp, Dept Child & Adolescent Psychiat Psychol, Rotterdam, Netherlands..
    Maniega, Susana Munoz
    Univ Edinburgh, Brain Res Imaging Ctr, Edinburgh, Midlothian, Scotland.;Univ Edinburgh, Dept Neuroimaging Sci, Scottish Imaging Network, Edinburgh, Midlothian, Scotland.;Univ Edinburgh, Ctr Cognit Ageing & Cognit Epidemiol Psychol, Edinburgh, Midlothian, Scotland..
    Nho, Kwangsik
    Indiana Univ, Sch Med, Ctr Neuroimaging Radiol & Imaging Sci, Indianapolis, IN USA.;Indiana Univ, Sch Med, Ctr Computat Biol & Bioinformat, Indianapolis, IN USA.;Indiana Univ, Sch Med, Indiana Alzheimer Dis Ctr, Indianapolis, IN USA..
    Nugent, Allison C.
    NIMH, Exp Therapeut & Pathophysiol Branch, Intramural Res Program, NIH, Bethesda, MD 20892 USA..
    Loohuis, Loes M. Olde
    Univ Calif Los Angeles, Ctr Neurobehav Genet, Los Angeles, CA USA..
    Oosterlaan, Jaap
    Vrije Univ Amsterdam, Dept Clin Neuropsychol, Amsterdam, Netherlands..
    Papmeyer, Martina
    Univ Edinburgh, Royal Edinburgh Hosp, Div Psychiat, Edinburgh, Midlothian, Scotland.;Univ Bern, Univ Hosp Psychiat, Translat Res Ctr, Div Syst Neurosci Psychopathol, CH-3012 Bern, Switzerland..
    Pappa, Irene
    Erasmus MC, Generat R Study Grp, Rotterdam, Netherlands.;Erasmus Univ, Sch Pedag & Educ Sci, Rotterdam, Netherlands..
    Pirpamer, Lukas
    Med Univ Graz, Clin Div Neurogeriatr, Dept Neurol, Graz, Austria..
    Pudas, Sara
    Umea Univ, Dept Integrat Med Biol, Umea, Sweden.;Umea Univ, Umea Ctr Funct Brain Imaging, Umea, Sweden..
    Puetz, Benno
    Max Planck Inst Psychiat, Dept Translat Res Psychiat, Munich, Germany..
    Rajan, Kumar B.
    Rush Univ, Med Ctr, Rush Inst Healthy Aging, Chicago, IL 60612 USA..
    Ramasamy, Adaikalavan
    UCL Inst Neurol, Reta Lila Weston Inst, London, England.;UCL Inst Neurol, Dept Mol Neurosci, London, England.;Kings Coll London, Dept Med & Mol Genet, London, England.;Univ Oxford, Jenner Inst Labs, Oxford, England..
    Richards, Jennifer S.
    Radboud Univ Nijmegen, Med Ctr, Dept Cognit Neurosci, Nijmegen, Netherlands.;Radboud Univ Nijmegen, Donders Inst Brain Cognit & Behav, Nijmegen, Netherlands.;Karakter Child & Adolescent Psychiat Univ Ctr, Nijmegen, Netherlands..
    Risacher, Shannon L.
    Indiana Univ, Sch Med, Ctr Neuroimaging Radiol & Imaging Sci, Indianapolis, IN USA.;Indiana Univ, Sch Med, Indiana Alzheimer Dis Ctr, Indianapolis, IN USA..
    Roiz-Santianez, Roberto
    Univ Cantabria IDIVAL, Sch Med, Dept Med & Psychiat, Univ Hosp Marques de Valdecilla, Santander, Spain.;CIBERSAM Ctr Invest Biomed Red Salud Med, Santander, Spain..
    Rommelse, Nanda
    Radboud Univ Nijmegen, Med Ctr, Dept Psychiat, Nijmegen, Netherlands.;Radboud Univ Nijmegen, Donders Inst Brain Cognit & Behav, Nijmegen, Netherlands.;Karakter Child & Adolescent Psychiat Univ Ctr, Nijmegen, Netherlands..
    Rose, Emma J.
    Trinity Coll Dublin, Psychosis Res Grp, Dept Psychiat, Dublin, Ireland.;Trinity Coll Dublin, Trinity Translat Med Inst, Dublin, Ireland..
    Royle, Natalie A.
    Univ Edinburgh, Brain Res Imaging Ctr, Edinburgh, Midlothian, Scotland.;Univ Edinburgh, Dept Neuroimaging Sci, Scottish Imaging Network, Edinburgh, Midlothian, Scotland.;Univ Edinburgh, Ctr Cognit Ageing & Cognit Epidemiol Psychol, Edinburgh, Midlothian, Scotland.;Univ Edinburgh, Ctr Clin Brain Sci, Edinburgh, Midlothian, Scotland..
    Rundek, Tatjana
    Univ Miami, Miller Sch Med, Dept Neurol, Miami, FL 33136 USA.;Univ Miami, Miller Sch Med, Dept Epidemiol & Publ Hlth Sci, Miami, FL 33136 USA..
    Saemann, Philipp G.
    Max Planck Inst Psychiat, Dept Translat Res Psychiat, Munich, Germany..
    Satizabal, Claudia L.
    Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA.;Framingham Heart Dis Epidemiol Study, Framingham, MA USA..
    Schmaal, Lianne
    Orygen, Melbourne, Vic, Australia.;Univ Melbourne, Ctr Youth Mental Hlth, Melbourne, Vic, Australia.;Vrije Univ Amsterdam, Med Ctr, Dept Psychiat, Neurosci Campus Amsterdam, Amsterdam, Netherlands..
    Schork, Andrew J.
    Univ Calif San Diego, Dept Neurosci, Multimodal Imaging Lab, San Diego, CA 92103 USA.;Univ Calif San Diego, Dept Cognit Sci, San Diego, CA 92103 USA..
    Shen, Li
    Indiana Univ, Sch Med, Ctr Neuroimaging Radiol & Imaging Sci, Indianapolis, IN USA.;Indiana Univ, Sch Med, Ctr Computat Biol & Bioinformat, Indianapolis, IN USA.;Indiana Univ, Sch Med, Indiana Alzheimer Dis Ctr, Indianapolis, IN USA..
    Shin, Jean
    Univ Toronto, Hosp Sick Children, Toronto, ON, Canada..
    Shumskaya, Elena
    Radboud Univ Nijmegen, Med Ctr, Dept Human Genet, Nijmegen, Netherlands.;Radboud Univ Nijmegen, Donders Inst Brain Cognit & Behav, Nijmegen, Netherlands.;Radboud Univ Nijmegen, Donders Ctr Cognit Neuroimaging, Nijmegen, Netherlands..
    Smith, Albert V.
    Iceland Heart Assoc, Kopavogur, Iceland.;Univ Iceland, Fac Med, Reykjavik, Iceland..
    Sprooten, Emma
    Yale Univ, Dept Psychiat, New Haven, CT 06520 USA.;Olin Neuropsychiat Res Ctr, Hartford, CT USA.;Univ Edinburgh, Royal Edinburgh Hosp, Div Psychiat, Edinburgh, Midlothian, Scotland.;Icahn Sch Med Mt Sinai, Dept Psychiat, New York, NY 10029 USA..
    Strike, Lachlan T.
    QIMR Berghofer Med Res Inst, Brisbane, Qld, Australia.;Univ Queensland, Queensland Brain Inst, Brisbane, Qld, Australia..
    Teumer, Alexander
    Univ Med Greifswald, Inst Community Med, Greifswald, Germany..
    Thomson, Russell
    Tordesillas-Gutierrez, Diana
    CIBERSAM Ctr Invest Biomed Red Salud Med, Santander, Spain.;Valdecilla Biomed Res Inst IDIVAL, Neuroimaging Unit, Technol Facil, Santander, Cantabria, Spain..
    Toro, Roberto
    Inst Pasteur, Paris, France..
    Trabzuni, Daniah
    UCL Inst Neurol, Reta Lila Weston Inst, London, England.;UCL Inst Neurol, Dept Mol Neurosci, London, England.;King Faisal Specialist Hosp & Res Ctr, Dept Genet, Riyadh, Saudi Arabia..
    Vaidya, Dhananjay
    Johns Hopkins Univ, Sch Med, Dept Med, GeneSTAR Res Ctr, Baltimore, MD 21205 USA..
    Van der Grond, Jeroen
    Leiden Univ, Med Ctr, Dept Radiol, Leiden, Netherlands..
    Van der Meer, Dennis
    Univ Groningen, Univ Med Ctr Groningen, Dept Psychiat, Groningen, Netherlands..
    Van Donkelaar, Marjolein M. J.
    Radboud Univ Nijmegen, Med Ctr, Dept Human Genet, Nijmegen, Netherlands.;Radboud Univ Nijmegen, Donders Inst Brain Cognit & Behav, Nijmegen, Netherlands..
    Van Eijk, Kristel R.
    UMC Utrecht, Human Neurogenet Unit, Brain Ctr Rudolf Magnus, Utrecht, Netherlands..
    Van Erp, Theo G. M.
    Univ Calif Irvine, Dept Psychiat & Human Behav, Irvine, CA 92717 USA..
    Van Rooij, Daan
    Radboud Univ Nijmegen, Med Ctr, Dept Cognit Neurosci, Nijmegen, Netherlands.;Radboud Univ Nijmegen, Donders Inst Brain Cognit & Behav, Nijmegen, Netherlands.;Univ Groningen, Univ Med Ctr Groningen, Dept Psychiat, Groningen, Netherlands..
    Walton, Esther
    Tech Univ Dresden, Fac Med, Dept Child & Adolescent Psychiat, Dresden, Germany..
    Westlye, Lars T.
    Oslo Univ Hosp, Div Mental Hlth & Addict, NORMENT KG Jebsen Ctr, Oslo, Norway.;Univ Oslo, Dept Psychol, NORMENT KG Jebsen Ctr, Oslo, Norway..
    Whelan, Christopher D.
    Univ Southern Calif, Keck Sch Med, USC Mark & Mary Stevens Neuroimaging & Informat I, Imaging Genet Ctr, Los Angeles, CA USA.;Royal Coll Surgeons Ireland, Dublin 2, Ireland..
    Windham, Beverly G.
    Univ Mississippi, Med Ctr, Dept Med, Jackson, MS 39216 USA..
    Winkler, Anderson M.
    Yale Univ, Dept Psychiat, New Haven, CT 06520 USA.;Univ Oxford, FMRIB Ctr, Oxford, England..
    Woldehawariat, Girma
    NIMH, Exp Therapeut & Pathophysiol Branch, Intramural Res Program, NIH, Bethesda, MD 20892 USA..
    Wolf, Christiane
    Univ Wurzburg, Dept Psychiat Psychosomat & Psychotherapy, Wurzburg, Germany..
    Wolfers, Thomas
    Radboud Univ Nijmegen, Med Ctr, Dept Human Genet, Nijmegen, Netherlands.;Radboud Univ Nijmegen, Donders Inst Brain Cognit & Behav, Nijmegen, Netherlands..
    Xu, Bing
    Kings Coll London, Inst Psychiat Psychol & Neurosci, MRC SGDP Ctr, London, England..
    Yanek, Lisa R.
    Johns Hopkins Univ, Sch Med, Dept Med, GeneSTAR Res Ctr, Baltimore, MD 21205 USA..
    Yang, Jingyun
    Rush Univ, Med Ctr, Rush Alzheimers Dis Ctr, Chicago, IL 60612 USA.;Rush Univ, Med Ctr, Dept Neurol Sci, Chicago, IL 60612 USA..
    Zijdenbos, Alex
    Biospect Inc, Montreal, PQ, Canada..
    Zwiers, Marcel P.
    Radboud Univ Nijmegen, Donders Inst Brain Cognit & Behav, Nijmegen, Netherlands.;Radboud Univ Nijmegen, Donders Ctr Cognit Neuroimaging, Nijmegen, Netherlands..
    Agartz, Ingrid
    Univ Oslo, Inst Clin Med, NORMENT KG Jebsen Ctr, Oslo, Norway.;Diakonhjemmet Hosp, Dept Res & Dev, Oslo, Norway.;Karolinska Inst, Ctr Psychiat Res, Dept Clin Neurosci, Stockholm, Sweden..
    Aggarwal, Neelum T.
    Rush Univ, Med Ctr, Rush Alzheimers Dis Ctr, Chicago, IL 60612 USA.;Rush Univ, Med Ctr, Rush Inst Healthy Aging, Chicago, IL 60612 USA.;Rush Univ, Med Ctr, Dept Neurol Sci, Chicago, IL 60612 USA..
    Almasy, Laura
    Univ Texas Rio Grande Valley, Sch Med, South Texas Diabet & Obes Inst, Edinburg, TX USA.;Univ Texas Rio Grande Valley, Sch Med, South Texas Diabet & Obes Inst, Edinburg, TX USA.;Univ Texas Rio Grande Valley, Sch Med, South Texas Diabet & Obes Inst, San Antonio, TX USA.;Univ Penn, Dept Genet, Perelman Sch Med, Philadelphia, PA 19104 USA.;Childrens Hosp Philadelphia, Dept Biomed & Hlth Informat, Philadelphia, PA 19104 USA..
    Ames, David
    Royal Melbourne Hosp, Natl Ageing Res Inst, Melbourne, Vic, Australia.;Univ Melbourne, Acad Unit Psychiat Old Age, Melbourne, Vic, Australia..
    Amouyel, Philippe
    Univ Lille, RID AGE Risk Factors & Mol Determinants Aging Rel, CHU Lille, Inserm,Inst Pasteur Lille, Lille, France..
    Andreassen, Ole A.
    Univ Oslo, Inst Clin Med, NORMENT KG Jebsen Ctr, Oslo, Norway.;Oslo Univ Hosp, Div Mental Hlth & Addict, NORMENT KG Jebsen Ctr, Oslo, Norway..
    Arepalli, Sampath
    NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA..
    Assareh, Amelia A.
    Univ New South Wales, Sch Psychiat, Ctr Hlth Brain Ageing, Sydney, NSW, Australia..
    Barral, Sandra
    Columbia Univ, Med Ctr, Taub Inst Res Alzheimers Dis & Aging Brain, New York, NY USA..
    Bastin, Mark E.
    Univ Edinburgh, Brain Res Imaging Ctr, Edinburgh, Midlothian, Scotland.;Univ Edinburgh, Dept Neuroimaging Sci, Scottish Imaging Network, Edinburgh, Midlothian, Scotland.;Univ Edinburgh, Ctr Cognit Ageing & Cognit Epidemiol Psychol, Edinburgh, Midlothian, Scotland.;Univ Edinburgh, Ctr Clin Brain Sci, Edinburgh, Midlothian, Scotland..
    Becker, Diane M.
    Johns Hopkins Univ, Sch Med, Dept Med, GeneSTAR Res Ctr, Baltimore, MD 21205 USA..
    Becker, James T.
    Univ Pittsburgh, Dept Psychiat, Pittsburgh, PA USA.;Univ Pittsburgh, Dept Neurol, Pittsburgh, PA 15260 USA.;Univ Pittsburgh, Dept Psychol, Pittsburgh, PA 15260 USA..
    Bennett, David A.
    Rush Univ, Med Ctr, Rush Alzheimers Dis Ctr, Chicago, IL 60612 USA.;Rush Univ, Med Ctr, Dept Neurol Sci, Chicago, IL 60612 USA..
    Blangero, John
    Univ Texas Rio Grande Valley, Sch Med, South Texas Diabet & Obes Inst, Edinburg, TX USA.;Univ Texas Rio Grande Valley, Sch Med, South Texas Diabet & Obes Inst, Edinburg, TX USA.;Univ Texas Rio Grande Valley, Sch Med, South Texas Diabet & Obes Inst, San Antonio, TX USA..
    van Bokhoven, Hans
    Radboud Univ Nijmegen, Med Ctr, Dept Human Genet, Nijmegen, Netherlands.;Radboud Univ Nijmegen, Donders Inst Brain Cognit & Behav, Nijmegen, Netherlands..
    Boomsma, Dorret I.
    Vrije Univ Amsterdam, Biol Psychol, Neurosci Campus Amsterdam, Amsterdam, Netherlands.;Vrije Univ Amsterdam, Med Ctr, Amsterdam, Netherlands..
    Brodaty, Henry
    Univ New South Wales, Sch Psychiat, Ctr Hlth Brain Ageing, Sydney, NSW, Australia.;UNSW, Dementia Collaborat Res Ctr Assessment & Better, Sydney, NSW, Australia..
    Brouwer, Rachel M.
    UMC Utrecht, Dept Psychiat, Brain Ctr Rudolf Magnus, Utrecht, Netherlands..
    Brunner, Han G.
    Radboud Univ Nijmegen, Med Ctr, Dept Human Genet, Nijmegen, Netherlands.;Radboud Univ Nijmegen, Donders Inst Brain Cognit & Behav, Nijmegen, Netherlands.;Maastricht Univ, Med Ctr, Dept Clin Genet, Maastricht, Netherlands..
    Buckner, Randy L.
    Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA.;Harvard Univ, Dept Psychol, Ctr Brain Sci, 33 Kirkland St, Cambridge, MA 02138 USA..
    Buitelaar, Jan K.
    Radboud Univ Nijmegen, Med Ctr, Dept Cognit Neurosci, Nijmegen, Netherlands.;Radboud Univ Nijmegen, Donders Inst Brain Cognit & Behav, Nijmegen, Netherlands.;Karakter Child & Adolescent Psychiat Univ Ctr, Nijmegen, Netherlands..
    Bulayeva, Kazima B.
    Dagestan State Univ, Dept Evolut & Genet, Makhachkala, Dagestan, Russia..
    Cahn, Wiepke
    UMC Utrecht, Dept Psychiat, Brain Ctr Rudolf Magnus, Utrecht, Netherlands..
    Calhoun, Vince D.
    Mind Res Network, Albuquerque, NM USA.;LBERI, Albuquerque, NM USA.;Univ New Mexico, Dept ECE, Albuquerque, NM 87131 USA..
    Cannon, Dara M.
    NIMH, Exp Therapeut & Pathophysiol Branch, Intramural Res Program, NIH, Bethesda, MD 20892 USA.;Natl Univ Ireland Galway, Ctr Neuroimaging & Cognit Genom NICOG, NCBES Galway Neurosci Ctr, Coll Med Nursing & Hlth Sci,Clin Neuroimaging Lab, Galway, Ireland..
    Cavalleri, Gianpiero L.
    Royal Coll Surgeons Ireland, Dublin 2, Ireland..
    Chen, Christopher
    Natl Univ Singapore, Dept Pharmacol, Singapore, Singapore.;Natl Univ Hlth Syst, Mem Aging & Cognit Ctr, Singapore, Singapore..
    Cheng, Ching -Yu
    Singapore Natl Eye Ctr, Singapore Eye Res Inst, Singapore, Singapore.;Duke NUS Grad Med Sch, Acad Med Res Inst, Singapore, Singapore.;Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Ophthalmol, Singapore, Singapore..
    Cichon, Sven
    Univ Basel, Dept Biomed, Div Med Genet, Basel, Switzerland.;Univ Bonn, Inst Human Genet, Bonn, Germany.;Res Ctr Julich, Inst Neurosci & Med INM1, Julich, Germany..
    Cookson, Mark R.
    NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA..
    Corvin, Aiden
    Trinity Coll Dublin, Psychosis Res Grp, Dept Psychiat, Dublin, Ireland.;Trinity Coll Dublin, Trinity Translat Med Inst, Dublin, Ireland..
    Crespo-Facorro, Benedicto
    Univ Cantabria IDIVAL, Sch Med, Dept Med & Psychiat, Univ Hosp Marques de Valdecilla, Santander, Spain.;CIBERSAM Ctr Invest Biomed Red Salud Med, Santander, Spain..
    Curran, Joanne E.
    Univ Texas Rio Grande Valley, Sch Med, South Texas Diabet & Obes Inst, Edinburg, TX USA.;Univ Texas Rio Grande Valley, Sch Med, South Texas Diabet & Obes Inst, Edinburg, TX USA.;Univ Texas Rio Grande Valley, Sch Med, South Texas Diabet & Obes Inst, San Antonio, TX USA..
    Czisch, Michael
    Max Planck Inst Psychiat, Dept Translat Res Psychiat, Munich, Germany..
    Dale, Anders M.
    Univ Calif San Diego, Ctr Multimodal Imaging & Genet, San Diego, CA 92103 USA.;Univ Calif San Diego, Dept Neurosci, San Diego, CA 92103 USA.;Univ Calif San Diego, Dept Radiol, San Diego, CA 92103 USA.;Univ Calif San Diego, Dept Psychiat, San Diego, CA 92103 USA.;Univ Calif San Diego, Dept Cognit Sci, San Diego, CA 92103 USA..
    Davies, Gareth E.
    Avera Inst Human Genet, Sioux Falls, SD USA.;Brigham & Womens Hosp, Dept Neurol, Program Translat NeuroPsychiat Gen, 75 Francis St, Boston, MA 02115 USA.;Brigham & Womens Hosp, Dept Psychiat, 75 Francis St, Boston, MA 02115 USA.;Harvard Med Sch, Boston, MA USA.;Broad Inst, Program Med & Populat Genet, Cambridge, MA USA..
    De Geus, Eco J. C.
    Vrije Univ Amsterdam, Biol Psychol, Neurosci Campus Amsterdam, Amsterdam, Netherlands.;Vrije Univ Amsterdam, Med Ctr, Amsterdam, Netherlands..
    De Jager, Philip L.
    Harvard Med Sch, Boston, MA USA.;Broad Inst, Program Med & Populat Genet, Cambridge, MA USA.;Broad Inst, Cambridge, MA USA..
    de Zubicaray, Greig I.
    Queensland Univ Technol, Fac Hlth, Brisbane, Qld, Australia.;Queensland Univ Technol, Inst Hlth & Biomed Innovat, Brisbane, Qld, Australia..
    Delanty, Norman
    Royal Coll Surgeons Ireland, Dublin 2, Ireland.;Beaumont Hosp, Div Neurol, Dublin 9, Ireland..
    Depondt, Chantal
    Univ Libre Bruxelles, Hop Erasme, Dept Neurol, Brussels, Belgium..
    DeStefano, Anita L.
    Framingham Heart Dis Epidemiol Study, Framingham, MA USA.;Haukeland Hosp, Ctr Med Genet & Mol Med, Dr Einar Martens Res Grp Biol Psychiat, Bergen, Norway..
    Dillman, Allissa
    NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA..
    Djurovic, Srdjan
    Univ Bergen, Dept Clin Sci, NORMENT KG Jebsen Ctr Psychosis Res, N-5020 Bergen, Norway.;Oslo Univ Hosp, Dept Med Genet, Oslo, Norway..
    Donohoe, Gary
    Natl Univ Ireland Galway, Cognit Genet & Cognit Therapy Grp, Neuroimaging Cognit & Genom Ctr NICOG, Galway, Ireland.;Natl Univ Ireland Galway, NCBES Galway Neurosci Ctr, Sch Psychol, Galway, Ireland.;Natl Univ Ireland Galway, Discipline Biochem, Galway, Ireland.;Trinity Coll Dublin, Dept Psychiat, Neuropsychiat Genet Res Grp, Dublin 8, Ireland.;Trinity Coll Dublin, Inst Psychiat, Dublin 8, Ireland..
    Drevets, Wayne C.
    NIMH, Exp Therapeut & Pathophysiol Branch, Intramural Res Program, NIH, Bethesda, MD 20892 USA.;Janssen Res & Dev LLC, Titusville, NJ USA..
    Duggirala, Ravi
    Univ Texas Rio Grande Valley, Sch Med, South Texas Diabet & Obes Inst, Edinburg, TX USA.;Univ Texas Rio Grande Valley, Sch Med, South Texas Diabet & Obes Inst, Edinburg, TX USA.;Univ Texas Rio Grande Valley, Sch Med, South Texas Diabet & Obes Inst, San Antonio, TX USA..
    Dyer, Thomas D.
    Univ Texas Rio Grande Valley, Sch Med, South Texas Diabet & Obes Inst, Edinburg, TX USA.;Univ Texas Rio Grande Valley, Sch Med, South Texas Diabet & Obes Inst, Edinburg, TX USA.;Univ Texas Rio Grande Valley, Sch Med, South Texas Diabet & Obes Inst, San Antonio, TX USA..
    Erk, Susanne
    Charite, CCM, Dept Psychiat & Psychotherapy, Berlin, Germany..
    Espeseth, Thomas
    Oslo Univ Hosp, Div Mental Hlth & Addict, NORMENT KG Jebsen Ctr, Oslo, Norway.;Univ Oslo, Dept Psychol, NORMENT KG Jebsen Ctr, Oslo, Norway..
    Evans, Denis A.
    Rush Univ, Med Ctr, Rush Inst Healthy Aging, Chicago, IL 60612 USA..
    Fedko, Iryna
    Vrije Univ Amsterdam, Biol Psychol, Neurosci Campus Amsterdam, Amsterdam, Netherlands.;Vrije Univ Amsterdam, Med Ctr, Amsterdam, Netherlands..
    Fernandez, Guillen
    Radboud Univ Nijmegen, Med Ctr, Dept Cognit Neurosci, Nijmegen, Netherlands.;Radboud Univ Nijmegen, Donders Inst Brain Cognit & Behav, Nijmegen, Netherlands..
    Ferrucci, Luigi
    NIA, Intramural Res Program, Baltimore, MD 21224 USA..
    Fisher, Simon E.
    Radboud Univ Nijmegen, Donders Inst Brain Cognit & Behav, Nijmegen, Netherlands.;Max Planck Inst Psycholinguist, Language & Genet Dept, Nijmegen, Netherlands..
    Fleischman, Debra A.
    Rush Univ, Med Ctr, Rush Alzheimers Dis Ctr, Chicago, IL 60612 USA.;Rush Univ, Med Ctr, Dept Neurol Sci, Chicago, IL 60612 USA.;Rush Univ, Med Ctr, Dept Behav Sci, Chicago, IL 60612 USA..
    Ford, Ian
    Univ Glasgow, Robertson Ctr Biostat, Glasgow, Lanark, Scotland..
    Foroud, Tatiana M.
    Indiana Univ, Sch Med, Ctr Computat Biol & Bioinformat, Indianapolis, IN USA.;Indiana Univ, Sch Med, Med & Mol Genet, Indianapolis, IN USA..
    Fox, Peter T.
    Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA..
    Francks, Clyde
    Radboud Univ Nijmegen, Donders Inst Brain Cognit & Behav, Nijmegen, Netherlands.;Max Planck Inst Psycholinguist, Language & Genet Dept, Nijmegen, Netherlands..
    Fukunaga, Masaki
    Natl Inst Physiol Sci, Div Cerebral Integrat, Aichi, Japan..
    Gibbs, J. Raphael
    UCL Inst Neurol, Reta Lila Weston Inst, London, England.;UCL Inst Neurol, Dept Mol Neurosci, London, England.;NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA..
    Glahn, David C.
    Yale Univ, Dept Psychiat, New Haven, CT 06520 USA.;Olin Neuropsychiat Res Ctr, Hartford, CT USA..
    Gollub, Randy L.
    Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA.;Massachusetts Gen Hosp, Martinos Ctr Biomed Imaging, Charlestown, MA USA.;Harvard Med Sch, Boston, MA USA..
    Goring, Harald H. H.
    Univ Texas Rio Grande Valley, Sch Med, South Texas Diabet & Obes Inst, Edinburg, TX USA.;Univ Texas Rio Grande Valley, Sch Med, South Texas Diabet & Obes Inst, Edinburg, TX USA.;Univ Texas Rio Grande Valley, Sch Med, South Texas Diabet & Obes Inst, San Antonio, TX USA..
    Grabe, Hans J.
    Univ Med Greifswald, Dept Psychiat, Greifswald, Germany..
    Green, Robert C.
    Harvard Med Sch, Boston, MA USA.;Brigham & Womens Hosp, Dept Med, Div Genet, 75 Francis St, Boston, MA 02115 USA..
    Gruber, Oliver
    Heidelberg Univ, Dept Gen Psychiat, Sect Expt Psychopathol & Neuroimaging, Heidelberg, Germany..
    Gudnason, Vilmundur
    Iceland Heart Assoc, Kopavogur, Iceland.;Univ Iceland, Fac Med, Reykjavik, Iceland..
    Guelfi, Sebastian
    UCL Inst Neurol, Reta Lila Weston Inst, London, England.;UCL Inst Neurol, Dept Mol Neurosci, London, England..
    Hansell, Narelle K.
    QIMR Berghofer Med Res Inst, Brisbane, Qld, Australia.;Univ Queensland, Queensland Brain Inst, Brisbane, Qld, Australia..
    Hardy, John
    UCL Inst Neurol, Reta Lila Weston Inst, London, England.;UCL Inst Neurol, Dept Mol Neurosci, London, England..
    Hartman, Catharina A.
    Univ Groningen, Univ Med Ctr Groningen, Dept Psychiat, Groningen, Netherlands..
    Hashimoto, Ryota
    Osaka Univ, Grad Sch Med, Dept Psychiat, Osaka, Japan.;Osaka Univ, United Grad Sch Child Dev, Mol Res Ctr Childrens Mental Dev, Osaka, Japan..
    Hegenscheid, Katrin
    Univ Med Greifswald, Inst Diagnost Radiol & Neuroradiol, Greifswald, Germany..
    Heinz, Andreas
    Charite, CCM, Dept Psychiat & Psychotherapy, Berlin, Germany..
    Le Hellard, Stephanie
    Univ Bergen, Dept Clin Sci, NORMENT KG Jebsen Ctr Psychosis Res, N-5020 Bergen, Norway.;Haukeland Hosp, Ctr Med Genet & Mol Med, Dr Einar Martens Res Grp Biol Psychiat, Bergen, Norway..
    Hernandez, Dena G.
    UCL Inst Neurol, Reta Lila Weston Inst, London, England.;UCL Inst Neurol, Dept Mol Neurosci, London, England.;NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA.;German Ctr Neurodegenerat Dis DZNE, Tubingen, Germany..
    Heslenfeld, Dirk J.
    Vrije Univ Amsterdam, Dept Psychol, Amsterdam, Netherlands..
    Ho, Beng-Choon
    Univ Iowa, Dept Psychiat, Iowa City, IA 52242 USA..
    Hoekstra, Pieter J.
    Univ Groningen, Univ Med Ctr Groningen, Dept Psychiat, Groningen, Netherlands..
    Hoffmann, Wolfgang
    German Ctr Neurodegenerat Dis DZNE Rostock Greifs, Greifswald, Germany.;Univ Med Greifswald, Inst Community Med, Greifswald, Germany..
    Hofman, Albert
    Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands..
    Holsboer, Florian
    Max Planck Inst Psychiat, Dept Translat Res Psychiat, Munich, Germany.;HMNC Brain Hlth, Munich, Germany..
    Homuth, Georg
    Univ Med Greifswald, Interfac Inst Genet & Funct Gen, Greifswald, Germany..
    Hosten, Norbert
    Univ Med Greifswald, Inst Diagnost Radiol & Neuroradiol, Greifswald, Germany..
    Hottenga, Jouke-Jan
    Vrije Univ Amsterdam, Biol Psychol, Neurosci Campus Amsterdam, Amsterdam, Netherlands.;Vrije Univ Amsterdam, Med Ctr, Amsterdam, Netherlands..
    Pol, Hilleke E. Hulshoff
    UMC Utrecht, Dept Psychiat, Brain Ctr Rudolf Magnus, Utrecht, Netherlands..
    Ikeda, Masashi
    Fujita Hlth Univ, Sch Med, Dept Psychiat, Toyoake, Aichi, Japan..
    Ikram, M. Kamran
    Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands.;Natl Univ Singapore, Dept Pharmacol, Singapore, Singapore.;Natl Univ Hlth Syst, Mem Aging & Cognit Ctr, Singapore, Singapore.;Singapore Natl Eye Ctr, Singapore Eye Res Inst, Singapore, Singapore.;Duke NUS Grad Med Sch, Acad Med Res Inst, Singapore, Singapore..
    Jack, Clifford R., Jr.
    Mayo Clin, Dept Radiol, Rochester, MN USA..
    Jenldnson, Mark
    Univ Oxford, FMRIB Ctr, Oxford, England..
    Johnson, Robert
    Univ Maryland, Sch Med, NICHD Brain & Tissue Bank Dev Disorders, Baltimore, MD 21201 USA..
    Jonsson, Erik G.
    Univ Oslo, Inst Clin Med, NORMENT KG Jebsen Ctr, Oslo, Norway.;Univ Oxford, FMRIB Ctr, Oxford, England..
    Jukema, J. Wouter
    Leiden Univ, Med Ctr, Dept Cardiol, Leiden, Netherlands..
    Kahn, Rene S.
    UMC Utrecht, Dept Psychiat, Brain Ctr Rudolf Magnus, Utrecht, Netherlands..
    Kanai, Ryota
    Univ Sussex, Sch Psychol, Brighton, E Sussex, England.;UCL, Inst Cognit Neurosci, London, England.;Araya Brain Imaging, Dept Neuroinformat, Tokyo, Japan..
    Kloszewska, Iwona
    Med Univ Lodz, Lodz, Poland..
    Knopman, David S.
    Mayo Clin, Dept Neurol, Rochester, MN USA..
    Kochunov, Peter
    Univ Maryland, Sch Med, Maryland Psychiat Res Ctr, Dept Psychiat, Baltimore, MD 21201 USA..
    Kwok, John B.
    Neurosci Res Australia, Sydney, NSW, Australia.;UNSW, Sch Med Sci, Sydney, NSW, Australia..
    Lawrie, Stephen M.
    Univ Edinburgh, Royal Edinburgh Hosp, Div Psychiat, Edinburgh, Midlothian, Scotland..
    Lemaitre, Herve
    Univ Paris Sud, Univ Paris Descartes, NSERM Unit Neuroimaging & Psychiat 1000, Paris, France.;Hosp Cochin, AP HP, Maison Solenn Adolescent Psychopathol & Med Dept, Paris, France..
    Liu, Xinmin
    NIMH, Exp Therapeut & Pathophysiol Branch, Intramural Res Program, NIH, Bethesda, MD 20892 USA.;Columbia Univ, Med Ctr, New York, NY USA..
    Longo, Dan L.
    NIA, Genet Lab, NIH, Baltimore, MD 21224 USA..
    Longstreth, W. T., Jr.
    Univ Washington, Dept Neurol, Seattle, WA 98195 USA.;Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA..
    Lopez, Oscar L.
    Univ Pittsburgh, Dept Neurol, Pittsburgh, PA 15260 USA.;Univ Pittsburgh, Dept Psychiat, Pittsburgh, PA USA..
    Lovestone, Simon
    Univ Oxford, Dept Psychiat, Oxford, England.;Kings Coll London, NIHR Dementia Biomed Res Unit, London, England..
    Martinez, Oliver
    Univ Calif Davis, Dept Neurol, Imaging Dementia & Aging IDeA Lab, Sacramento, CA 95817 USA.;Univ Calif Davis, Ctr Neurosci, Sacramento, CA 95817 USA..
    Martinot, Jean-Luc
    Univ Paris Sud, Univ Paris Descartes, NSERM Unit Neuroimaging & Psychiat 1000, Paris, France.;Hosp Cochin, AP HP, Maison Solenn Adolescent Psychopathol & Med Dept, Paris, France..
    Mattay, Venkata S.
    Lieber Inst Brain Dev, Baltimore, MD USA.;Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD 21205 USA.;Johns Hopkins Univ, Sch Med, Dept Radiol, Baltimore, MD 21205 USA..
    McDonald, Colm
    Natl Univ Ireland Galway, Ctr Neuroimaging & Cognit Genom NICOG, NCBES Galway Neurosci Ctr, Coll Med Nursing & Hlth Sci,Clin Neuroimaging Lab, Galway, Ireland..
    McIntosh, Andrew M.
    Univ Edinburgh, Ctr Cognit Ageing & Cognit Epidemiol Psychol, Edinburgh, Midlothian, Scotland.;Univ Edinburgh, Royal Edinburgh Hosp, Div Psychiat, Edinburgh, Midlothian, Scotland..
    McMahon, Katie L.
    Univ Queensland, Ctr Adv Imaging, Brisbane, Qld, Australia..
    McMahon, Francis J.
    NIMH, Exp Therapeut & Pathophysiol Branch, Intramural Res Program, NIH, Bethesda, MD 20892 USA..
    Mecocci, Patrizia
    Univ Perugia, Dept Med, Sect Gerontol & Geriatr, Perugia, Italy..
    Melle, Ingrid
    Univ Oslo, Inst Clin Med, NORMENT KG Jebsen Ctr, Oslo, Norway.;Oslo Univ Hosp, Div Mental Hlth & Addict, NORMENT KG Jebsen Ctr, Oslo, Norway..
    Meyer-Lindenberg, Andreas
    Heidelberg Univ, Med Fac Mannheim, Cent Inst Mental Hlth, Mannheim, Germany..
    Mohnke, Sebastian
    Charite, CCM, Dept Psychiat & Psychotherapy, Berlin, Germany..
    Montgomery, Grant W.
    QIMR Berghofer Med Res Inst, Brisbane, Qld, Australia..
    Morris, Derek W.
    Natl Univ Ireland Galway, Cognit Genet & Cognit Therapy Grp, Neuroimaging Cognit & Genom Ctr NICOG, Galway, Ireland.;Natl Univ Ireland Galway, NCBES Galway Neurosci Ctr, Sch Psychol, Galway, Ireland.;Natl Univ Ireland Galway, Discipline Biochem, Galway, Ireland.;Trinity Coll Dublin, Dept Psychiat, Neuropsychiat Genet Res Grp, Dublin 8, Ireland.;Trinity Coll Dublin, Inst Psychiat, Dublin 8, Ireland..
    Mosley, Thomas H.
    Univ Mississippi, Med Ctr, Dept Med, Jackson, MS 39216 USA..
    Muhleisen, Thomas W.
    Natl Univ Ireland Galway, Ctr Neuroimaging & Cognit Genom NICOG, NCBES Galway Neurosci Ctr, Coll Med Nursing & Hlth Sci,Clin Neuroimaging Lab, Galway, Ireland.;Res Ctr Julich, Inst Neurosci & Med INM1, Julich, Germany..
    Mueller-Myhsok, Bertram
    Max Planck Inst Psychiat, Dept Translat Res Psychiat, Munich, Germany.;Munich Cluster Syst Neurol SyNergy, Munich, Germany.;Univ Liverpool, Inst Translat Med, Liverpool, Merseyside, England..
    Nalls, Michael A.
    NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA..
    Nauck, Matthias
    Univ Med Greifswald, Inst Clin Chem & Lab Med, Greifswald, Germany.;German Ctr Cardiovasc Res DZHK eV, Partner Site Greifswald, Berlin, Germany..
    Nichols, Thomas E.
    Univ Oxford, FMRIB Ctr, Oxford, England.;Univ Warwick, Dept Stat, Coventry, W Midlands, England.;Univ Warwick, Warwick Mfg Grp, Coventry, W Midlands, England..
    Niessen, Wiro J.
    Erasmus MC, Dept Radiol & Nucl Med, Rotterdam, Netherlands.;Erasmus MC, Dept Med Informat, Rotterdam, Netherlands.;Delft Univ Technol, Fac Sci Appl, Delft, Netherlands..
    Noethen, Markus M.
    Univ Bonn, Inst Human Genet, Bonn, Germany.;Univ Bonn, Life & Brain Ctr, Dept Genom, Bonn, Germany..
    Nyberg, Lars
    Umea Univ, Dept Integrat Med Biol, Umea, Sweden.;Umea Univ, Umea Ctr Funct Brain Imaging, Umea, Sweden..
    Ohi, Kazutaka
    Osaka Univ, Grad Sch Med, Dept Psychiat, Osaka, Japan..
    Olvera, Rene L.
    Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA..
    Ophoff, Roel A.
    UMC Utrecht, Dept Psychiat, Brain Ctr Rudolf Magnus, Utrecht, Netherlands.;Univ Calif Los Angeles, Ctr Neurobehav Genet, Los Angeles, CA USA..
    Pandolfo, Massimo
    Univ Libre Bruxelles, Hop Erasme, Dept Neurol, Brussels, Belgium..
    Paus, Tomas
    Univ Toronto, Rotman Res Inst, Toronto, ON, Canada.;Univ Toronto, Dept Psychol, Toronto, ON M5S 1A1, Canada.;Univ Toronto, Dept Psychiat, Toronto, ON M5S 1A1, Canada.;Child Mind Inst, New York, NY USA..
    Pausova, Zdenka
    Univ Toronto, Hosp Sick Children, Toronto, ON, Canada.;Univ Toronto, Dept Phys, Toronto, ON, Canada.;Univ Toronto, Dept Nutr Sci, Toronto, ON, Canada..
    Penninx, Brenda W. J. H.
    Vrije Univ Amsterdam, Med Ctr, Dept Psychiat, Neurosci Campus Amsterdam, Amsterdam, Netherlands..
    Pike, G. Bruce
    Univ Calgary, Dept Radiol, Calgary, AB, Canada.;Univ Calgary, Dept Clin Neurosci, Calgary, AB, Canada..
    Potkin, Steven G.
    Univ Calif Irvine, Dept Psychiat & Human Behav, Irvine, CA 92717 USA..
    Psaty, Bruce M.
    Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA.;Univ Washington, Dept Med, Seattle, WA USA.;Univ Washington, Dept Hlth Serv, Seattle, WA 98195 USA.;Grp Hlth Res Inst, Grp Hlth, Seattle, WA USA..
    Reppermund, Simone
    Univ New South Wales, Sch Psychiat, Ctr Hlth Brain Ageing, Sydney, NSW, Australia.;UNSW Med, Sch Psychiat, Dept Dev Disabil Neuropsychiat, Kensington, NSW, Australia..
    Rietschel, Marcella
    Heidelberg Univ, Med Fac Mannheim, Cent Inst Mental Hlth, Mannheim, Germany..
    Roffman, Joshua L.
    Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA..
    Romanczuk-Seiferth, Nina
    Charite, CCM, Dept Psychiat & Psychotherapy, Berlin, Germany..
    Rotter, Jerome I.
    Univ Calif Los Angeles, Med Ctr, Ilnst Translat Genom & Populat Sci, Los Angeles Biomed Res Inst & Pediat Harbor, Torrance, CA 90509 USA..
    Ryten, Mina
    UCL Inst Neurol, Reta Lila Weston Inst, London, England.;UCL Inst Neurol, Dept Mol Neurosci, London, England.;Kings Coll London, Dept Med & Mol Genet, London, England..
    Sacco, Ralph L.
    Univ Miami, Miller Sch Med, John P Hussman Inst Human Gen, Miami, FL 33136 USA.;Univ Miami, Miller Sch Med, Dept Neurol, Miami, FL 33136 USA.;Univ Miami, Miller Sch Med, Dept Epidemiol & Publ Hlth Sci, Miami, FL 33136 USA.;Univ Miami, Miller Sch Med, Evelyn F McKnight Brain Inst, Miami, FL 33136 USA..
    Sachdev, Perminder S.
    Univ New South Wales, Sch Psychiat, Ctr Hlth Brain Ageing, Sydney, NSW, Australia.;Prince Wales Hosp, Neuropsychiat Inst, Sydney, NSW, Australia..
    Saykin, Andrew J.
    Indiana Univ, Sch Med, Ctr Neuroimaging Radiol & Imaging Sci, Indianapolis, IN USA.;Indiana Univ, Sch Med, Indiana Alzheimer Dis Ctr, Indianapolis, IN USA.;Indiana Univ, Sch Med, Med & Mol Genet, Indianapolis, IN USA..
    Schmidt, Reinhold
    Med Univ Graz, Clin Div Neurogeriatr, Dept Neurol, Graz, Austria..
    Schofield, Peter R.
    Neurosci Res Australia, Sydney, NSW, Australia.;UNSW, Sch Med Sci, Sydney, NSW, Australia..
    Sigurdsson, Sigurdur
    Iceland Heart Assoc, Kopavogur, Iceland..
    Simmons, Andy
    Kings Coll London, Inst Psychiat, Dept Neuroimaging, London, England.;Kings Coll London, Biomed Res Ctr Mental Hlth, London, England.;Kings Coll London, Biomed Res Unit Dementia, London, England..
    Singleton, Andrew
    NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA..
    Sisodiya, Sanjay M.
    UCL, Inst Neurol, London, England.;Epilepsy Soc, Gerrards Cross, Bucks, England..
    Smith, Colin
    Univ Edinburgh, Acad Dept Neuropathol, Ctr Clin Brain Sci, MRC Edinburgh Brain Bank, Edinburgh, Midlothian, Scotland..
    Smoller, Jordan W.
    Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA.;Massachusetts Gen Hosp, Ctr Human Genet Res, Psychiat & Neurodev Genet Unit, Boston, MA 02114 USA.;Harvard Med Sch, Boston, MA USA.;Broad Inst MIT & Harvard, Stanley Ctr Psychiat Res, Boston, MA USA..
    Soininen, Hindu.
    Univ Eastern Finland, Inst Clin Med Neurol, Kuopio, Finland.;Kuopio Univ Hosp, Neuroctr Neurol, Kuopio, Finland..
    Srikanth, Velandai
    Peninsula Hlth & Monash Univ, Dept Med, Melbourne, Vic, Australia..
    Steen, Vidar M.
    Univ Bergen, Dept Clin Sci, NORMENT KG Jebsen Ctr Psychosis Res, N-5020 Bergen, Norway.;Haukeland Hosp, Ctr Med Genet & Mol Med, Dr Einar Martens Res Grp Biol Psychiat, Bergen, Norway..
    Stott, David J.
    Univ Glasgow, Fac Med, Inst Cardiovasc & Med Sci, Glasgow, Lanark, Scotland..
    Sussmann, Jessika E.
    Univ Edinburgh, Royal Edinburgh Hosp, Div Psychiat, Edinburgh, Midlothian, Scotland..
    Thalamuthu, Anbupalam
    Univ New South Wales, Sch Psychiat, Ctr Hlth Brain Ageing, Sydney, NSW, Australia..
    Tiemeier, Henning
    Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands.;Erasmus MC Sophia Childrens Hosp, Dept Child & Adolescent Psychiat Psychol, Rotterdam, Netherlands..
    Toga, Arthur W.
    Univ Southern Calif, Keck Sch Med, Inst Neuroimaging & Informat, Lab Neuro Imaging, Los Angeles, CA USA..
    Traynor, Bryan J.
    NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA..
    Troncoso, Juan
    Johns Hopkins Univ, Brain Resource Ctr, Baltimore, MD USA..
    Turner, Jessica A.
    Georgia State Univ, Atlanta, GA 30303 USA..
    Tzourio, Christophe
    Univ Bordeaux, Institute Neurodegenerat Disorders, CEA, CNRS,UMR 5293, Bordeaux, France..
    Uitterlinden, Andre G.
    Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands.;Erasmus MC, Dept Internal Med, Rotterdam, Netherlands..
    Hernandez, Maria C. Valdes
    Univ Edinburgh, Brain Res Imaging Ctr, Edinburgh, Midlothian, Scotland.;Univ Edinburgh, Dept Neuroimaging Sci, Scottish Imaging Network, Edinburgh, Midlothian, Scotland.;Univ Edinburgh, Ctr Cognit Ageing & Cognit Epidemiol Psychol, Edinburgh, Midlothian, Scotland.;Univ Edinburgh, Ctr Clin Brain Sci, Edinburgh, Midlothian, Scotland..
    Van der Brug, Marcel
    Genentech Inc, San Francisco, CA 94080 USA..
    Van der Lugt, Aad
    Erasmus MC, Dept Radiol & Nucl Med, Rotterdam, Netherlands..
    Van der Wee, Nic J. A.
    Leiden Univ, Med Ctr, Dept Psychiat, Leiden, Netherlands.;Leiden Univ, Med Ctr, Leiden Inst Brain & Cognit, Leiden, Netherlands..
    Van Duijn, Cornelia M.
    Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands..
    Van Haren, Neeltje E. M.
    UMC Utrecht, Dept Psychiat, Brain Ctr Rudolf Magnus, Utrecht, Netherlands..
    Van't Ent, Dennis
    Vrije Univ Amsterdam, Biol Psychol, Neurosci Campus Amsterdam, Amsterdam, Netherlands.;Vrije Univ Amsterdam, Med Ctr, Amsterdam, Netherlands..
    Van Tol, Marie Jose
    Univ Groningen, Univ Med Ctr Groningen, Neuroimaging Ctr, Groningen, Netherlands..
    Vardarajan, Badri N.
    Columbia Univ, Med Ctr, Taub Inst Res Alzheimers Dis & Aging Brain, New York, NY USA..
    Veltman, Dick J.
    Vrije Univ Amsterdam, Med Ctr, Dept Psychiat, Neurosci Campus Amsterdam, Amsterdam, Netherlands..
    Vernooij, Meike W.
    Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands.;Erasmus MC, Dept Radiol & Nucl Med, Rotterdam, Netherlands..
    Voelzke, Henry
    Univ Med Greifswald, Inst Community Med, Greifswald, Germany..
    Walter, Henrik
    Charite, CCM, Dept Psychiat & Psychotherapy, Berlin, Germany..
    Wardlaw, Joanna M.
    Univ Edinburgh, Brain Res Imaging Ctr, Edinburgh, Midlothian, Scotland.;Univ Edinburgh, Dept Neuroimaging Sci, Scottish Imaging Network, Edinburgh, Midlothian, Scotland.;Univ Edinburgh, Ctr Cognit Ageing & Cognit Epidemiol Psychol, Edinburgh, Midlothian, Scotland.;Univ Edinburgh, Ctr Clin Brain Sci, Edinburgh, Midlothian, Scotland..
    Wassink, Thomas H.
    Univ Iowa, Dept Psychiat, Carver Coll Med, Iowa City, IA 52242 USA..
    Weale, Michael E.
    Kings Coll London, Dept Med & Mol Genet, London, England..
    Weinberger, Daniel R.
    Lieber Inst Brain Dev, Baltimore, MD USA.;Johns Hopkins Univ, Sch Med, Dept Psychiat, Baltimore, MD 21205 USA.;Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD 21205 USA.;Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD 21205 USA.;Johns Hopkins Univ, Sch Med, Inst Med Genet, Baltimore, MD USA..
    Weiner, Michael W.
    Univ Calif San Francisco, San Francisco VA Med Ctr, Ctr Imaging Neurodegenerat Dis, San Francisco, CA 94143 USA..
    Wen, Wei
    Univ New South Wales, Sch Psychiat, Ctr Hlth Brain Ageing, Sydney, NSW, Australia..
    Westman, Eric
    Karolinska Inst, Dept Neurobiol Care Sci & Soc, Stockholm, Sweden..
    White, Tonya
    Erasmus MC, Dept Radiol & Nucl Med, Rotterdam, Netherlands.;Erasmus MC Sophia Childrens Hosp, Dept Child & Adolescent Psychiat Psychol, Rotterdam, Netherlands..
    Wong, Tien Y.
    Singapore Natl Eye Ctr, Singapore Eye Res Inst, Singapore, Singapore.;Dagestan State Univ, Dept Evolut & Genet, Makhachkala, Dagestan, Russia.;Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Ophthalmol, Singapore, Singapore..
    Wright, Clinton B.
    Univ Miami, Miller Sch Med, Dept Neurol, Miami, FL 33136 USA.;Univ Miami, Miller Sch Med, Dept Epidemiol & Publ Hlth Sci, Miami, FL 33136 USA.;Univ Miami, Miller Sch Med, Evelyn F McKnight Brain Inst, Miami, FL 33136 USA..
    Zielke, H. Ronald
    Univ Maryland, Sch Med, NICHD Brain & Tissue Bank Dev Disorders, Baltimore, MD 21201 USA..
    Zonderman, Alan B.
    NIA, Lab Epidemiol & Populat Sci, NIH, Bethesda, MD 20892 USA..
    Deary, Ian J.
    Univ Edinburgh, Ctr Cognit Ageing & Cognit Epidemiol Psychol, Edinburgh, Midlothian, Scotland..
    DeCarli, Charles
    Univ Calif Davis, Dept Neurol, Imaging Dementia & Aging IDeA Lab, Sacramento, CA 95817 USA.;Univ Calif Davis, Ctr Neurosci, Sacramento, CA 95817 USA..
    Schmidt, Helena
    Med Univ Graz, Inst Mol Biol & Biochem, Graz, Austria..
    Martin, Nicholas G.
    QIMR Berghofer Med Res Inst, Brisbane, Qld, Australia..
    De Craen, Anton J. M.
    Leiden Univ, Med Ctr, Dept Gerontol & Geriatr, Leiden, Netherlands..
    Wright, Margaret J.
    Univ Queensland, Queensland Brain Inst, Brisbane, Qld, Australia.;Univ Queensland, Ctr Adv Imaging, Brisbane, Qld, Australia..
    Launer, Lenore J.
    NIA, Intramural Res Program, NIH, Bethesda, MD 20892 USA..
    Schumann, Gunter
    Kings Coll London, Inst Psychiat Psychol & Neurosci, MRC SGDP Ctr, London, England..
    Fornage, Myriam
    Univ Texas Hlth Sci Ctr Houston, Inst Mol Med & Human Genet Ctr, Houston, TX 77030 USA..
    Franke, Barbara
    Radboud Univ Nijmegen, Med Ctr, Dept Human Genet, Nijmegen, Netherlands.;Radboud Univ Nijmegen, Med Ctr, Dept Psychiat, Nijmegen, Netherlands.;Radboud Univ Nijmegen, Donders Inst Brain Cognit & Behav, Nijmegen, Netherlands..
    Debette, Stephanie
    Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA.;Lieber Inst Brain Dev, Baltimore, MD USA.;Bordeaux Univ Hosp, Dept Neurol, Bordeaux, France..
    Medland, Sarah E.
    QIMR Berghofer Med Res Inst, Brisbane, Qld, Australia..
    Ikram, M. Arfan
    Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands.;Erasmus MC, Dept Radiol & Nucl Med, Rotterdam, Netherlands.;Erasmus MC, Dept Neurol, Rotterdam, Netherlands..
    Thompson, Paul M.
    Univ Southern Calif, Keck Sch Med, USC Mark & Mary Stevens Neuroimaging & Informat I, Imaging Genet Ctr, Los Angeles, CA USA.;Univ Western Sydney, Sch Comp Engn & Math, Parramatta, NSW, Australia..
    Novel genetic loci underlying human intracranial volume identified through genome-wide association2016In: Nature Neuroscience, ISSN 1097-6256, E-ISSN 1546-1726, Vol. 19, no 12, p. 1569-1582Article in journal (Refereed)
    Abstract [en]

    Intracranial volume reflects the maximally attained brain size during development, and remains stable with loss of tissue in late life. It is highly heritable, but the underlying genes remain largely undetermined. In a genome-wide association study of 32,438 adults, we discovered five previously unknown loci for intracranial volume and confirmed two known signals. Four of the loci were also associated with adult human stature, but these remained associated with intracranial volume after adjusting for height. We found a high genetic correlation with child head circumference (rho(genetic) = 0.748), which indicates a similar genetic background and allowed us to identify four additional loci through meta-analysis (N-combined = 37,345). Variants for intracranial volume were also related to childhood and adult cognitive function, and Parkinson's disease, and were enriched near genes involved in growth pathways, including PI3K-AKT signaling. These findings identify the biological underpinnings of intracranial volume and their link to physiological and pathological traits.

  • 35.
    Adamson, L.
    et al.
    Karolinska Inst, Dept Pathol & Oncol, Stockholm, Sweden..
    Andersson, B.
    Gothenburg Univ, Immunol, Gothenburg, Sweden..
    Kiessling, R.
    Karolinska Inst, Dept Pathol & Oncol, Stockholm, Sweden..
    Nasman-Glaser, B.
    Karolinska Inst, Dept Pathol & Oncol, Stockholm, Sweden..
    Karlsson-Parra, Alex
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    GMP-production of an allogenic DC-based cancer vaccine (INTUVAX) for treatment of patients with metastatic kidney-or primary liver cancer. Comparison of two production platforms for DC-generation2016In: European Journal of Immunology, ISSN 0014-2980, E-ISSN 1521-4141, Vol. 46, p. 946-947Article in journal (Other academic)
  • 36.
    Adane, M.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Gebre-Mariam, T
    Alderborn, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Frenning, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    The use of extragranular disintegrants in multiple-unit tablet formulations: effect on compressibility, compactibility and disintegration2007In: Journal of drug delivery science and technology, ISSN 1773-2247, Vol. 17, no 4, p. 279-284Article in journal (Refereed)
    Abstract [en]

    Multiple-unit tablets formed from mixtures of microcrystalline cellulose pellets and disintegrants (Ac-Di-Sol, Primojel or Kollidon CL) by compaction were investigated with the aim of controlling tablet tensile strength and disintegration time. The effects of pellet porosity, compaction pressure, and type and amount of disintegrant were studied. Primojel made the pellets less prone to deformation during compression, while the other two disintegrants had very minor effects on the compression behavior. Ac-Di-Sol and Primojel generally increased the tablet tensile strength, whereas the effect of Kollidon CL was dependent on the initial pellet porosity. Kollidon CL was found to significantly reduce the disintegration time, but the other two disintegrants had variable efficacy, and for the low-porosity pellets significantly increased the disintegration time. These results are interpreted as resulting from the interplay between the mechanical characteristics of the pellets and the mechanisms of action of the disintegrants.

  • 37.
    Adem, Abdu
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy.
    Characterization of muscarinic and nicotinic receptors in neural and non-neural tissue: changes in Alzheimer's disease 1987Doctoral thesis, comprehensive summary (Other academic)
  • 38.
    Adjan, V. V.
    et al.
    Department of Anatomy and Neurobiology, University of Kentucky, Lexington, USA.
    Hauser, K. F.
    Department of Anatomy and Neurobiology, University of Kentucky, Lexington, USA and Spinal Cord and Brain Injury Research Center, University of Kentucky, Lexington, USA.
    Bakalkin, Georgy
    Experimental Alcohol and Drug Addiction Research Section, Department of Clinical Neuroscience, Karolinska Institute, Stockholm, Sweden.
    Yakovleva, T.
    Experimental Alcohol and Drug Addiction Research Section, Department of Clinical Neuroscience, Karolinska Institute, Stockholm, Sweden.
    Gharibyan, A.
    Experimental Alcohol and Drug Addiction Research Section, Department of Clinical Neuroscience, Karolinska Institute, Stockholm, Sweden.
    Scheff, S. W.
    Department of Anatomy and Neurobiology, 800 Rose Street, MS209, University of Kentucky, Lexington, KY 40536-0298, USA; Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY 40536-0298, USA and Spinal Cord and Brain Injury Research Center, University of Kentucky, Lexington, KY 40536-0298, USA.
    Knapp, P. E.
    Department of Anatomy and Neurobiology, 800 Rose Street, MS209, University of Kentucky, Lexington, KY 40536-0298, USA and Spinal Cord and Brain Injury Research Center, University of Kentucky, Lexington, KY 40536-0298, USA.
    Caspase-3 activity is reduced after spinal cord injury in mice lacking dynorphin: differential effects on glia and neurons2007In: Neuroscience, ISSN 0306-4522, E-ISSN 1873-7544, Vol. 148, no 3, p. 724-36Article in journal (Refereed)
    Abstract [en]

    Dynorphins are endogenous opioid peptide products of the prodynorphin gene. An extensive literature suggests that dynorphins have deleterious effects on CNS injury outcome. We thus examined whether a deficiency of dynorphin would protect against tissue damage after spinal cord injury (SCI), and if individual cell types would be specifically affected. Wild-type and prodynorphin(-/-) mice received a moderate contusion injury at 10th thoracic vertebrae (T10). Caspase-3 activity at the injury site was significantly decreased in tissue homogenates from prodynorphin(-/-) mice after 4 h. We examined frozen sections at 4 h post-injury by immunostaining for active caspase-3. At 3-4 mm rostral or caudal to the injury, >90% of all neurons, astrocytes and oligodendrocytes expressed active caspase-3 in both wild-type and knockout mice. At 6-7 mm, there were fewer caspase-3(+) oligodendrocytes and astrocytes than at 3-4 mm. Importantly, caspase-3 activation was significantly lower in prodynorphin(-/-) oligodendrocytes and astrocytes, as compared with wild-type mice. In contrast, while caspase-3 expression in neurons also declined with further distance from the injury, there was no effect of genotype. Radioimmunoassay showed that dynorphin A(1-17) was regionally increased in wild-type injured versus sham-injured tissues, although levels of the prodynorphin processing product Arg(6)-Leu-enkephalin were unchanged. Our results indicate that dynorphin peptides affect the extent of post-injury caspase-3 activation, and that glia are especially sensitive to these effects. By promoting caspase-3 activation, dynorphin peptides likely increase the probability of glial apoptosis after SCI. While normally beneficial, our findings suggest that prodynorphin or its peptide products become maladaptive following SCI and contribute to secondary injury.

  • 39.
    Adler, Camille
    et al.
    Univ Appl Sci & Arts Northwestern Switzerland, Inst Pharmaceut Technol, Grundenstr 40, CH-4132 Muttenz, Switzerland.;Univ Basel, Inst Pharmaceut Technol, Klingelbergstr 50, CH-4056 Basel, Switzerland..
    Schoenenberger, Monica
    Swiss Nanosci Inst, Nanotech Serv Lab, Klingelbergstr 82, CH-4056 Basel, Switzerland..
    Teleki, Alexandra
    DSM Nutr Prod Ltd, R&D Ctr Formulat & Applicat, POB 2676, CH-4002 Basel, Switzerland..
    Kuentz, Martin
    Univ Appl Sci & Arts Northwestern Switzerland, Inst Pharmaceut Technol, Grundenstr 40, CH-4132 Muttenz, Switzerland..
    Molecularly designed lipid microdomains for solid dispersions using a polymer/inorganic carrier matrix produced by hot-melt extrusion2016In: International Journal of Pharmaceutics, ISSN 0378-5173, E-ISSN 1873-3476, Vol. 499, no 1-2, p. 90-100Article in journal (Refereed)
    Abstract [en]

    Amorphous solid dispersions have for many years been a focus in oral formulations, especially in combination with a hot-melt extrusion process. The present work targets a novel approach with a system based on a fatty acid, a polymer and an inorganic carrier. It was intended to adsorb the acidic lipid by specific molecular interactions onto the solid carrier to design disorder in the alkyl chains of the lipid. Such designed lipid microdomains (DLM) were created as a new microstructure to accommodate a compound in a solid dispersion. Vibrational spectroscopy, X-ray powder diffraction, atomic force microscopy as well as electron microscopic imaging were employed to study a system of stearic acid, hydroxypropylcellulose and aluminum magnesium silicate. beta-carotene was used as a poorly water-soluble model substance that is difficult to formulate with conventional solid dispersion formulations. The results indicated that the targeted molecular excipient interactions indeed led to DLMs for specific compositions. The different methods provided complementary aspects and important insights into the created microstructure. The novel delivery system appeared to be especially promising for the formulation of oral compounds that exhibit both high crystal energy and lipophilicity. (C) 2015 Elsevier B.V. All rights reserved.

  • 40.
    Adler, Camille
    et al.
    Univ Appl Sci & Arts Northwestern Switzerland, Inst Pharmaceut Technol, CH-4132 Muttenz, Switzerland.;Univ Basel, Inst Pharmaceut Technol, CH-4056 Basel, Switzerland..
    Schoenenberger, Monica
    Swiss Nanosci Inst, Nanotech Serv Lab, CH-4056 Basel, Switzerland..
    Teleki, Alexandra
    DSM Nutr Prod Ltd, Res Ctr Formulat & Applicat, CH-4002 Basel, Switzerland..
    Leuenberger, Bruno
    DSM Nutr Prod Ltd, Res Ctr Formulat & Applicat, CH-4002 Basel, Switzerland..
    Kuentz, Martin
    Univ Appl Sci & Arts Northwestern Switzerland, Inst Pharmaceut Technol, CH-4132 Muttenz, Switzerland..
    Flow-through cross-polarized imaging as a new tool to overcome the analytical sensitivity challenges of a low-dose crystalline compound in a lipid matrix2015In: Journal of Pharmaceutical and Biomedical Analysis, ISSN 0731-7085, E-ISSN 1873-264X, Vol. 115, p. 20-30Article in journal (Refereed)
    Abstract [en]

    Assessing the physical state of a low-dose active compound in a solid lipid or polymer matrix is analytically challenging, especially if the matrix exhibits some crystallinity. The aim of this study was first to compare the ability of current methods to detect the presence of a crystalline model compound in lipid matrices. Subsequently, a new technique was introduced and evaluated because of sensitivity issues that were encountered with current methods. The new technique is a flow-through version of cross-polarized imaging in transmission mode. The tested lipid-based solid dispersions (SDs) consisted of beta-carotene (BC) as a model compound, and of Gelucire 50/13 or Geleol mono- and diglycerides as lipid matrices. The solid dispersions were analyzed by (hyper) differential scanning calorimetry (DSC), X-ray powder diffraction (XRPD), and microscopic techniques including atomic force microscopy (AFM). DSC and XRPD could analyze crystalline BC at concentrations as low as 3% (w/w) in the formulations. However, with microscopic techniques crystalline particles were detected at significantly lower concentrations of even 0.5% (w/w) BC. A flow-through cross-polarized imaging technique was introduced that combines the advantage of analyzing a larger sample size with high sensitivity of microscopy. Crystals were detected easily in samples containing even less than 0.2% (w/w) BC. Moreover, the new tool enabled approximation of the kinetic BC solubility in the crystalline lipid matrices. As a conclusion, the flow-through cross-polarized imaging technique has the potential to become an indispensable tool for characterizing low-dose crystalline compounds in a lipid or polymer matrix of solid dispersions. (C) 2015 Elsevier B.V. All rights reserved.

  • 41. Adler, Camille
    et al.
    Teleki, Alexandra
    Kuentz, Martin
    Multifractal and mechanical analysis of amorphous solid dispersions.2017In: International Journal of Pharmaceutics, ISSN 0378-5173, E-ISSN 1873-3476, article id S0378-5173(17)30191-6Article in journal (Refereed)
    Abstract [en]

    The formulation of lipophilic and hydrophobic compounds is a challenge for the pharmaceutical industry and it requires the development of complex formulations. Our first aim was to investigate hot-melt extrudate microstructures by means of multifractal analysis using scanning electron microscopy imaging. Since the microstructure can affect solid dosage form performance such as mechanical properties, a second objective was to study the influence of the type of adsorbent and of the presence of an amorphous compound on extrudate hardness. β-Carotene (BC) was chosen as poorly water-soluble model compound. Formulations containing a polymer, a lipid and two different silica based inorganic carriers were produced by hot-melt extrusion. Based on scanning electron microscopy/energy dispersive X-ray spectroscopy, the obtained images were analyzed using multifractal formalism. The breaking force of the strands was assessed by a three point bending test. Multifractal analysis and three point bending results showed that the nature of interparticle interactions in the inorganic carrier as well as the presence of amorphous BC had an influence on the microstructure and thus on the mechanical performance. The use of multifractal analysis and the study of the mechanical properties were complementary to better characterize and understand complex formulations obtained by hot-melt extrusion.

  • 42. Adler, Camille
    et al.
    Teleki, Alexandra
    Kuentz, Martin
    Multifractal Characterization of Pharmaceutical Hot-Melt Extrudates.2017In: Pharmaceutical research, ISSN 0724-8741, E-ISSN 1573-904X, Vol. 34, no 2, p. 321-332Article in journal (Refereed)
    Abstract [en]

    PURPOSE: Multifractal geometry has become a powerful tool to describe complex structures in many fields. Our first aim was to combine imaging and multifractal analysis to better understand the microstructure of pharmaceutical extrudates. A second objective was to study erosion/dispersion behavior of the formulations because it would condition release of any drug.

    METHODS: Different formulations containing a lipid, a polymer and different silica based inorganic carriers were produced by hot-melt extrusion at various screw speeds. Multifractal analysis was based on scanning electron microscopy/energy dispersive X-Ray spectroscopy images. This microstructural analysis was complemented with dynamic optical imaging of formulation erosion/dispersion behavior.

    RESULTS: Multifractal analysis indicated that inorganic carrier type and concentration as well as the screw speed affected the microstructure of the extrudates. The aqueous erosion/dispersion study showed that only the type and concentration of inorganic carrier were important.

    CONCLUSIONS: The use of microstructural and dispersion analysis appeared to be complementary to better characterize and understand complex formulations obtained by hot-melt extrusion.

  • 43.
    Adolfsson, Åsa
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmacy.
    Mechanical strength of pharmaceutical compacts: Importance of material characteristics, particle characteristics and compaction pressure on interparticulate bonding structure1998Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Factors considered important for the interparticulate bonding structure and mechanical strength of pharmaceutical compacts were studied in this thesis.

    Fractures appear to propagate mainly around rather than through grains during strength testing. Large deviations from theoretical strength values in addition to an effect of particle size were thus obtained when compaction was performed to zero porosity or obtained by extrapolation to zero porosity. When high compaction loads were used, the excess energy was to a large extent used for elastic recovery and/or alteration of the solid-state structure.

    Filtering out of weak distance forces (intermolecular forces) by compaction in a liquid with a sufficiently high dielectric constant appears to provide reliable information on interparticulate bonding mechanisms. The best correlation between physiochemical properties of the liquids and the gradual decrease in tensile strength of the compacts was achieved using the dielectric constant. The weak distance forces appeared to be screened out when the liquid compaction medium had a dielectric constant of 18. The remaining tensile strength was then believed to be the result of interparticulate bonding by solid bridges for most materials. However, for most pharmaceutical materials, weak distance forces seem to dominate. Of all the materials tested, solid bridges seemed to be the most important bonding mechanism for sodium and potassium chloride. Increasing the particle size and compaction pressure of materials with the capacity to form solid bridges seemed to facilitate the bond formation process. Addition of a dry binder or milling the particles counteracted the formation of solid bridges, probably by reducing the concentration of stress at certain points in the compact, a prerequisite for the establishment of solid bridges.

    Both the tablet surface area and the interparticulate distance may affect the proportion of external surface area participating in interparticulate bonding. For materials prone to develop solid bridges, the actual surface area involved in bond formation is more important than the space between the particles, i.e. compensation of the tensile strength of a tablet for the surface area and the mean interparticulate distance will probably not reflect the nature of the dominating bond type. However, for the other materials, ranking of the materials according to tensile strength adjusted for surface area and mean interparticulate distance gave a reflection of dominating interparticulate bonding type.

  • 44. Adomas, Aleksandra
    et al.
    Eklund, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Johansson, Martin
    Asiegbu, Frederick O.
    Identification and analysis of differentially expressed cDNAs during nonself-competitive interaction between Phlebiopsis gigantea and Heterobasidion parviporum2006In: FEMS Microbiology Ecology, ISSN 0168-6496, E-ISSN 1574-6941, Vol. 57, no 1, p. 26-39Article in journal (Refereed)
    Abstract [en]

    The molecular factors regulating interspecific interaction between the saprotrophic biocontrol fungus Phlebiopsis gigantea and the conifer pathogen Heterobasidion parviporum were investigated. We constructed cDNA libraries and used expressed sequence tag analysis for the identification and characterization of genes expressed during the self and nonself-hyphal interaction. cDNA clones from either the pathogen or biocontrol agent were arrayed on nylon membrane filters and differentially screened with cDNA probes made from mycelia forming the barrage zone during nonself-interactions, mycelia growing outside the barrage zones or monocultures. BlastX analysis of the differentially expressed clones led to the identification of genes with diverse functions, including those with potential as virulence factors, such as hydrophobins. Because of the high sequence conservation (r2 = 0.81) between P. gigantea and H. parviporum, a selected number of genes from either fungus were used to monitor the expression profile under varying interaction conditions by virtual northern blot. The results are discussed with respect to the potential role of the induced genes during the nonself-competitive interaction for space and nutrients between P. gigantea and H. parviporum.

  • 45.
    Adori, Csaba
    et al.
    Karolinska Inst, Dept Neurosci, Retzius Lab, Retzius Vag 8, S-17177 Stockholm, Sweden.
    Barde, Swapnali
    Karolinska Inst, Dept Neurosci, Retzius Lab, Retzius Vag 8, S-17177 Stockholm, Sweden.
    Vas, Szilvia
    Semmelweis Univ, Dept Pharmacodynam, Nagyvarad Ter 4, H-1089 Budapest, Hungary; Hungarian Acad Sci, Neuropsychopharmacol & Neurochem Res Grp, Nagyvarad Ter 4, H-1089 Budapest, Hungary.
    Ebner, Karl
    Leopold Franzens Univ Innsbruck, CMBI, Inst Pharm, Dept Pharmacol & Toxicol, Innrain 80-82-3, A-6020 Innsbruck, Austria.
    Su, Jie
    Karolinska Inst, Dept Physiol & Pharmacol, Nanna Svartz Vag 2, S-17177 Stockholm, Sweden.
    Svensson, Camilla
    Karolinska Inst, Dept Physiol & Pharmacol, Nanna Svartz Vag 2, S-17177 Stockholm, Sweden.
    Mathé, Aleksander A
    Karolinska Inst, Sect Psychiat, Dept Clin Neurosci, Tomtebodavagen 18A, S-17177 Stockholm, Sweden.
    Singewald, Nicolas
    Leopold Franzens Univ Innsbruck, CMBI, Inst Pharm, Dept Pharmacol & Toxicol, Innrain 80-82-3, A-6020 Innsbruck, Austria.
    Reinscheid, Rainer R
    Univ Calif Irvine, Dept Pharmaceut Sci, Irvine, CA 92697 USA.
    Uhlén, Mathias
    Karolinska Inst, Dept Neurosci, Sci Life Lab, S-17165 Stockholm, Sweden; Royal Inst Technol, Albanova Univ Ctr, Sci Life Lab, S-17165 Stockholm, Sweden.
    Kultima, Kim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Bagdy, György
    Semmelweis Univ, Dept Pharmacodynam, Nagyvarad Ter 4, H-1089 Budapest, Hungary; Hungarian Acad Sci, Neuropsychopharmacol & Neurochem Res Grp, Nagyvarad Ter 4, H-1089 Budapest, Hungary.
    Hökfelt, Tomas
    Karolinska Inst, Dept Neurosci, Retzius Lab, Retzius Vag 8, S-17177 Stockholm, Sweden.
    Exploring the role of neuropeptide S in the regulation of arousal: a functional anatomical study.2016In: Brain Structure and Function, ISSN 1863-2653, E-ISSN 1863-2661, Vol. 221, no 7, p. 3521-3546Article in journal (Refereed)
    Abstract [en]

    Neuropeptide S (NPS) is a regulatory peptide expressed by limited number of neurons in the brainstem. The simultaneous anxiolytic and arousal-promoting effect of NPS suggests an involvement in mood control and vigilance, making the NPS-NPS receptor system an interesting potential drug target. Here we examined, in detail, the distribution of NPS-immunoreactive (IR) fiber arborizations in brain regions of rat known to be involved in the regulation of sleep and arousal. Such nerve terminals were frequently apposed to GABAergic/galaninergic neurons in the ventro-lateral preoptic area (VLPO) and to tyrosine hydroxylase-IR neurons in all hypothalamic/thalamic dopamine cell groups. Then we applied the single platform-on-water (mainly REM) sleep deprivation method to study the functional role of NPS in the regulation of arousal. Of the three pontine NPS cell clusters, the NPS transcript levels were increased only in the peri-coerulear group in sleep-deprived animals, but not in stress controls. The density of NPS-IR fibers was significantly decreased in the median preoptic nucleus-VLPO region after the sleep deprivation, while radioimmunoassay and mass spectrometry measurements showed a parallel increase of NPS in the anterior hypothalamus. The expression of the NPS receptor was, however, not altered in the VLPO-region. The present results suggest a selective activation of one of the three NPS-expressing neuron clusters as well as release of NPS in distinct forebrain regions after sleep deprivation. Taken together, our results emphasize a role of the peri-coerulear cluster in the modulation of arousal, and the importance of preoptic area for the action of NPS on arousal and sleep.

  • 46. Adoue, Veronique
    et al.
    Schiavi, Alicia
    Light, Nicholas
    Carlsson Almlöf, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Lundmark, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Ge, Bing
    Kwan, Tony
    Caron, Maxime
    Rönnblom, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Wang, Chuan
    Chen, Shu-Huang
    Goodall, Alison H
    Cambien, Francois
    Deloukas, Panos
    Ouwehand, Willem H
    Syvänen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Pastinen, Tomi
    Allelic expression mapping across cellular lineages to establish impact of non-coding SNPs2014In: Molecular Systems Biology, ISSN 1744-4292, E-ISSN 1744-4292, Vol. 10, no 10, p. 754-Article in journal (Refereed)
    Abstract [en]

    Most complex disease-associated genetic variants are located in non-coding regions and are therefore thought to be regulatory in nature. Association mapping of differential allelic expression (AE) is a powerful method to identify SNPs with direct cis-regulatory impact (cis-rSNPs). We used AE mapping to identify cis-rSNPs regulating gene expression in 55 and 63 HapMap lymphoblastoid cell lines from a Caucasian and an African population, respectively, 70 fibroblast cell lines, and 188 purified monocyte samples and found 40-60% of these cis-rSNPs to be shared across cell types. We uncover a new class of cis-rSNPs, which disrupt footprint-derived de novo motifs that are predominantly bound by repressive factors and are implicated in disease susceptibility through overlaps with GWAS SNPs. Finally, we provide the proof-of-principle for a new approach for genome-wide functional validation of transcription factor-SNP interactions. By perturbing NFκB action in lymphoblasts, we identified 489 cis-regulated transcripts with altered AE after NFκB perturbation. Altogether, we perform a comprehensive analysis of cis-variation in four cell populations and provide new tools for the identification of functional variants associated to complex diseases.

  • 47. af Klinteberg, Britt
    et al.
    Alm, Per-Olof
    Oreland, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Serotonin, personality and smoking2000Conference paper (Refereed)
  • 48.
    Afrakhte, Mozhgan
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
    Growth control mechanisms in normal and neoplastic mammalian cells1998Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The main theme of the studies presented in this thesis is, the growth control mechanisms whose loss in normal cells predispose to or cause cancer. The balance between growth inhibitory and stimulatory mechanisms is crucial for the development and maintenance of a normal animal.

    PDGF, a growth factor for cells of mesenchymal origin, is implicated in normal developmental processes as well as neoplasia. The alternative splicing of exon 6 in PDGF-A gene transcripts gives rise to two different proteins with different compartmentalization properties. The PDGF-A chain homodimers, PDGF-AAL, encoded PDGF A-splice variant remain associated with the cell membrane. Studies of a human fibrosarcoma cell line, U-2197, revealed a high expression level of the cell associated PDGF-AAL which upon release increased autophosphorylation of the endogenous PDGF receptors, suggesting an autocrine loop. PDGF-A gene and PDGFR-α gene found to be co-amplified in the U-2197, indicating an optimised system for growth in these cells, i.e. amplified growth factor receptor as well as a local autocrine supply of the mitogen.

    Members of TGFβ superfamily are potent regulators of the growth and differentiation of a wide range of cell types. Intracellular mediators of TGF-β signalling, SMADs, transduce signals from serine/threonine kinase receptors to the nucleus where they affect transcription of target genes. A new class of SMAD proteins has been identified whose members, the inhibitory SMADS, antagonise TGF-β signals by interfering with agonistic SMADs activity. Smad6 and Smad7 are two closely related TGF-β antagonists identified in mammalian cells. Overexpression of Smad7 inhibited the cellular response to TGF-β whereas expression of an anti-sense Smad7 construct showed an enhancing effect on this response. The inhibitory SMADs may act in a negative feedback loop, as their expression is induced by the same ligands whose action they antagonise.

    Density dependent growth inhibition is a growth control mechanism often lost in transformed and malignant cells. Cells in dense culture are refractory to the mitogen stimulation although, the mitogenic signals were shown to be processed to some extent. The expression of immediate-early genes in dense culture stimulated with mitogen was induced. The activity of cyclin dependent kinases (CDKs), the pivotal kinases in G1/S transition, showed to be density dependent and decreased by increasing cell density. pRb, a tumour suppressor and growth regulatory protein, remained unphosphorylated in mitogen treated dense culture. The cessation of CDKs kinase activity in dense cultures was shown to be accompanied with increasing expression of inhibitory proteins of these kinases, CKIs. The impaired expression of a positive regulator of CDKs, Cdc25A phosphatase, was another feature of dense cultures.

  • 49.
    Aftab, Obaid
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Fryknäs, Mårten
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Hammerling, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Larsson, Rolf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Gustafsson, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Detection of cell aggregation and altered cell viability by automated label-free video microscopy: A promising alternative to endpoint viability assays in high throughput screening2015In: Journal of Biomolecular Screening, ISSN 1087-0571, E-ISSN 1552-454X, Vol. 20, no 3, p. 372-381Article in journal (Refereed)
    Abstract [en]

    Automated phase-contrast video microscopy now makes it feasible to monitor a high-throughput (HT) screening experiment in a 384-well microtiter plate format by collecting one time-lapse video per well. Being a very cost-effective and label-free monitoring method, its potential as an alternative to cell viability assays was evaluated. Three simple morphology feature extraction and comparison algorithms were developed and implemented for analysis of differentially time-evolving morphologies (DTEMs) monitored in phase-contrast microscopy videos. The most promising layout, pixel histogram hierarchy comparison (PHHC), was able to detect several compounds that did not induce any significant change in cell viability, but made the cell population appear as spheroidal cell aggregates. According to recent reports, all these compounds seem to be involved in inhibition of platelet-derived growth factor receptor (PDGFR) signaling. Thus, automated quantification of DTEM (AQDTEM) holds strong promise as an alternative or complement to viability assays in HT in vitro screening of chemical compounds.

  • 50.
    Afzelius, Lovisa
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Computational Modelling of Structures and Ligands of CYP2C92004Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    CYP2C9 is one of our major drug metabolising enzymes and belongs to the cytochrome P450 (CYP) super family. The aim of this thesis was to gain an understanding of the quantitative structure–activity relationships (QSAR) of CYP2C9 substrates and inhibitors. This information will be useful in predicting drug metabolism and the potential for drug–drug interactions. To achieve this, a well characterised data set of structurally diverse, competitive CYP2C9 inhibitors was identified in our laboratory. Several computational methodologies, many based on GRID molecular interaction fields, were applied or developed in order to handle issues such as compound alignment and bioactive conformer selection. First, a traditional 3D QSAR was carried out in GOLPE, generating a predictive model. In this model the selection of a bioactive conformer and alignment was based on docking in a homology model of CYP2C9. Secondly, we introduced the concept of alignment independent descriptors from ALMOND. These descriptors were used to generate quantitatively and qualitatively predictive models. We subsequently derived conformation independent descriptors from molecular interaction fields calculated in FlexGRID. This enabled the derivation of 3D QSAR models without taking into account the selection of an alignment or a bioactive conformer. A subsequent programming effort enabled the conversion of this model back to 3D aligned pharmacophores. Similar alignment independent descriptors were also used in the development of the software MetaSite® that predicts the site of metabolism for CYP2C9 ligands. Finally, as crystal information on this isoform emerged, the performance of molecular dynamics simulations and homology models and the flexibility of the protein were evaluated using statistical analyses.

    These modelling efforts have resulted in detailed knowledge of the structural characteristics in ligand interactions with the cytochrome P450 2C9 isoform.

    List of papers
    1. Competitive CYP2C9 Inhibitors: Enzyme inhibition Studies, Protein Homology Modelling, and Three-Dimensional Quantitative Structure Activity Relationship Analysis
    Open this publication in new window or tab >>Competitive CYP2C9 Inhibitors: Enzyme inhibition Studies, Protein Homology Modelling, and Three-Dimensional Quantitative Structure Activity Relationship Analysis
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    2001 In: Molecular Pharmacology, ISSN 0026-895, Vol. 59, p. 909 - 919Article in journal (Refereed) Published
    Identifiers
    urn:nbn:se:uu:diva-91425 (URN)
    Available from: 2004-02-27 Created: 2004-02-27Bibliographically approved
    2. Discriminant and quantitative PLS analysis of competitive CYP2C9 inhibitors versus non-inhibitors using alignment independent GRIND descriptors.
    Open this publication in new window or tab >>Discriminant and quantitative PLS analysis of competitive CYP2C9 inhibitors versus non-inhibitors using alignment independent GRIND descriptors.
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    2002 In: Journal of Computer-Aided Molecular Design, ISSN 0920-654, Vol. 16, p. 443 - 458Article in journal (Refereed) Published
    Identifiers
    urn:nbn:se:uu:diva-91426 (URN)
    Available from: 2004-02-27 Created: 2004-02-27Bibliographically approved
    3. Predicting Drug Metabolism: A Site of Metabolism Tool Applied to the Cytochrome P450 CYP2C9.
    Open this publication in new window or tab >>Predicting Drug Metabolism: A Site of Metabolism Tool Applied to the Cytochrome P450 CYP2C9.
    2003 In: Journal of Medicinal Chemistry, ISSN 0022-2623, Vol. 46, no 12, p. 2313-2324Article in journal (Refereed) Published
    Identifiers
    urn:nbn:se:uu:diva-91427 (URN)
    Available from: 2004-02-27 Created: 2004-02-27Bibliographically approved
    4. A Conformer and Alignment independent model to predict structurally diverse competitive CYP2C9 inhibitors.
    Open this publication in new window or tab >>A Conformer and Alignment independent model to predict structurally diverse competitive CYP2C9 inhibitors.
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    2004 In: Journal of Medicinal Chemistry, ISSN 0022-2623, Vol. Web Release Date: 13-JanArticle in journal (Refereed) Published
    Identifiers
    urn:nbn:se:uu:diva-91428 (URN)
    Available from: 2004-02-27 Created: 2004-02-27Bibliographically approved
    5. Structural analysis of CYP2C9 and CYP2C5 and critical assessment of molecular modelling techniques.
    Open this publication in new window or tab >>Structural analysis of CYP2C9 and CYP2C5 and critical assessment of molecular modelling techniques.
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    Manuscript (Other academic)
    Identifiers
    urn:nbn:se:uu:diva-91429 (URN)
    Available from: 2004-02-27 Created: 2004-02-27 Last updated: 2010-01-13Bibliographically approved
    6. Virtual receptor site (VRS) derivation for competitive CYP2C9 inhibitors: - a novel approach for structurally diverse compounds.
    Open this publication in new window or tab >>Virtual receptor site (VRS) derivation for competitive CYP2C9 inhibitors: - a novel approach for structurally diverse compounds.
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    Manuscript (Other academic)
    Identifiers
    urn:nbn:se:uu:diva-91430 (URN)
    Available from: 2004-02-27 Created: 2004-02-27 Last updated: 2010-01-13Bibliographically approved
1234567 1 - 50 of 6889
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