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  • 151. Aldskogius, Håkan
    et al.
    Kozlova, Elena
    Dorsal root injury for the study of spinal cord injury repair2012Ingår i: Animal models of spinal cord repair, New York Heidelberg Dordrecht London: Humana Press, 2012, s. 109-129Kapitel i bok, del av antologi (Övrigt vetenskapligt)
    Abstract [en]

    Dorsal root injury provides opportunities for highly reproducible lesions and for detailed anatomical, physiological and behavioral outcome assessment with high precision and validity. Dorsal root injury models are used to several aspects of relevance to spinal cord injury repair: i) mechanisms of regeneration failure in the central nervous system and how to overcome it, ii) axon degeneration, as well as myelin degradation and elimination in the central nervous system - their roles and possible manipulations in spinal cord repair, iii) consequences in the spinal cord of mimicking human plexus injuries by dorsal root avulsion, including its effect on neuron survival, inflammatory processes and vascular dysfunction, and iv) therapeutic strategies which may be translated to the treatment of clinical plexus avulsion injuries. This chapter describes various dorsal root injury models, their relationship to basic and translational aspects of spinal cord injury repair, as well as basic experimental procedures associated with these models in rat and mouse.

  • 152.
    Alemi, Mansour
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Molecular biological techniques as a tool in diagnostic pathology: Applications in B-cell lymphoproliferative disease, medullary thyroid carcinoma and cervical carcinoma2000Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    Identification of malignancy associated with mutations in gene sequences requires detection ofas little as a single base difference. A powerful technique in mutation detection is polymerasechain reaction (PCR) followed by single-strand conformational polymorphism (SSCP) andsequencing.

    The present investigation is focused on improving tests for the following diagnostic questions:(i) clonality in malignancy of lymphoid origin by developing simple laboratory methodsbased on PCR in which the monoclonal B-cell lineage can be distinguished from thepolyclonal, (ii) presence of mutations in RET proto-oncogene involved in sporadic medullarythyroid carcinoma (MTC), and (iii) development of a simple test which can distinguishbetween prototype human papillomavirus 16 (HPV16) and variant HPV16 containing a pointmutation at codon 83 of the E6 gene.

    The rearrangement of the immunoglobulin heavy chain gene can be used as a marker of B-celllineage and clonality. By using PCR with specific primers corresponding to the variable and joining regions, it is possible to detect the rearrangement of a small amount of clonal B-cells ina polyclonal background. This study has shown that the SSCP analysis of PCR fragmentsincreases the sensitivity and the specificity of the test.

    Oncogenic activation of the RET related to somatic missense mutations has been shown insporadic MTC. These mutations are believed to play an important role in the tumorigenesis ofMTC. By combining microdissection of tumor cells followed by PCR-SSCP, fragment sizeanalysis and sequencing, a small proportion of cells with mutation in a subpopulation of cellswithin a tumor can be detected. A variant of HPV 16 has previously been shown to be moreprevalent in invasive cervical carcinoma than in preinvasive lesions. In the present study asimple, rapid PCR-SSCP assay has been developed to identify women who are at increasedrisk of progression to invasive cervical carcinoma.

  • 153.
    Alenius, Malin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Treatment Response in Psychotic Patients in a Naturalistic Setting: Classification, Genes, Drugs, Insight and Social Networks2009Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    Many patients with psychotic symptoms respond poorly to treatment. Various approaches have been made to classify these patients according to treatment response. However, existing classifications have been criticized for various reasons and a new classification system is needed. Further, no satisfactory explanation of the poor treatment response has been apparent. The general aim of this thesis was therefore to develop and validate a new classification method of functional remission in a naturalistic population of patients with psychosis and to utilize this classification to investigate the population from genetic, drug treatment, insight and social network points of view.

    Data for this cross-sectional study of patients (n=123) attending the Psychosis Outpatient Care clinic in the county of Jönköping, Sweden, were obtained from patient interviews, blood samples and information from patient files. The new classification method CANSEPT, which combines the CAN rating scale (CAN), the UKU side effect rating scale (SE) and the patient’s previous treatment history (PT), showed validity in discriminating the patients and was accepted well by the patients. CANSEPT was used to group the patients in the other studies in this thesis.

    The results indicated that the gene polymorphism ABCB1 3435T, was related to worse significant social and clinical needs for patients on olanzapine, while the polymorphism DRD2 Taq1 A1 was related to a greater risk of significant side effects; especially if male, or taking strong dopamine D2-receptor antagonistic drugs. Drug treatment factors were also related to treatment response; longer duration of untreated prodromal and early psychosis was seen for patients with current significant social and clinical needs and non-adherence to treatment was associated with worse significant side effects. Worse treatment outcomes also appeared to be associated with smaller social network groups, worse insight into illness, poorer knowledge of warning signs and worse coping strategies.

    In summary, CANSEPT was shown to be a useful valid, multidimensional tool for classification of treatment response. Gene polymorphisms, duration of untreated illness, non-adherence to treatment, social networks and knowledge should be taken into consideration when investigating inadequate treatment response.

    Delarbeten
    1. Treatmentresponse in psychotic patients classified according to social and clinical needs, drug side effects, and previous treatment; a method to identify functional remission
    Öppna denna publikation i ny flik eller fönster >>Treatmentresponse in psychotic patients classified according to social and clinical needs, drug side effects, and previous treatment; a method to identify functional remission
    Visa övriga...
    2009 (Engelska)Ingår i: Comprehensive Psychiatry, ISSN 0010-440X, E-ISSN 1532-8384, Vol. 50, nr 5, s. 453-462Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    BACKGROUND: Various approaches have been made over the years to classify psychotic patients according to inadequate treatment response, using terms such as treatment resistant or treatment refractory. Existing classifications have been criticized for overestimating positive symptoms; underestimating residual symptoms, negative symptoms, and side effects; or being to open for individual interpretation. The aim of this study was to present and evaluate a new method of classification according to treatment response and, thus, to identify patients in functional remission. METHOD: A naturalistic, cross-sectional study was performed using patient interviews and information from patient files. The new classification method CANSEPT, which combines the Camberwell Assessment of Need rating scale, the Udvalg for Kliniske Undersøgelser side effect rating scale (SE), and the patient's previous treatment history (PT), was used to group the patients according to treatment response. CANSEPT was evaluated by comparison of expected and observed results. RESULTS: In the patient population (n = 123), the patients in functional remission, as defined by CANSEPT, had higher quality of life, fewer hospitalizations, fewer psychotic symptoms, and higher rate of workers than those with the worst treatment outcome. CONCLUSION: In the evaluation, CANSEPT showed validity in discriminating the patients of interest and was well tolerated by the patients. CANSEPT could secure inclusion of correct patients in the clinic or in research.

    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:uu:diva-98078 (URN)10.1016/j.comppsych.2008.11.001 (DOI)000269251100009 ()19683616 (PubMedID)
    Tillgänglig från: 2009-02-11 Skapad: 2009-02-11 Senast uppdaterad: 2017-12-13Bibliografiskt granskad
    2. Gene polymorphism influencing treatment response in psychotic patients in a naturalistic setting
    Öppna denna publikation i ny flik eller fönster >>Gene polymorphism influencing treatment response in psychotic patients in a naturalistic setting
    Visa övriga...
    2008 (Engelska)Ingår i: Journal of Psychiatric Research, ISSN 0022-3956, E-ISSN 1879-1379, Vol. 42, nr 11, s. 884-893Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    RATIONALE: Many patients with psychotic symptoms respond poorly to treatment. Factors possibly affecting treatment response include the presence of polymorphisms in genes coding for various receptor populations, drug-metabolizing enzymes or transport proteins. OBJECTIVES: To investigate whether genetic polymorphisms could be indicators of treatment response to antipsychotic drugs. The genes of interest were the dopamine D2 receptor gene (DRD2), the serotonin 2A and 2C receptor genes (HTR2A and HTR2C), the P-glycoprotein gene (ABCB1 or MDR1) and the drug-metabolizing cytochrome P450 2D6 gene (CYP2D6). MATERIAL AND METHODS: Data for this naturalistic, cross-sectional study of patients requiring antipsychotic drugs and attending the Psychosis Outpatient Care clinic in Jönköping, Sweden were obtained from patient interviews, blood samples and information from patient files. Blood samples were genotyped for DRD2 Taq1 A, Ins/Del and Ser311Cys, HTR2A T102C, HTR2C Cys23Ser, ABCB1 1236C>T, 2677G>T/A, 3435C>T and genetic variants of CYP2D6. The patients (n=116) were grouped according to the CANSEPT method regarding significant social and clinical needs and significant side effects. RESULTS: Patients on olanzapine homozygous for ABCB1 3435T, had more significant social and clinical needs than others. Patients with one or two DRD2 Taq1 A1 alleles had a greater risk of significant side effects, particularly if they were male, Caucasian, had a schizophrenic or delusional disorder or were taking strong dopamine D2-receptor antagonistic drugs. CONCLUSION: If these results are confirmed, patients carrying the DRD2 Taq1 A1 allele would benefit from using drugs without strong dopamine D2 receptor antagonistic properties.

    Nyckelord
    DRD2, 5-HT2, ABCB1, Cytochrome P-450 CYP2D6, Antipsychotic agents, Schizophrenia
    Nationell ämneskategori
    Farmaceutiska vetenskaper Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:uu:diva-98079 (URN)10.1016/j.jpsychires.2007.10.007 (DOI)000258798300002 ()18086475 (PubMedID)
    Tillgänglig från: 2009-02-11 Skapad: 2009-02-11 Senast uppdaterad: 2018-01-13
    3. Current and retrospective antipsychotic drug use in relation to treatment response in a naturalistic setting of psychotic patients
    Öppna denna publikation i ny flik eller fönster >>Current and retrospective antipsychotic drug use in relation to treatment response in a naturalistic setting of psychotic patients
    2009 (Engelska)Artikel i tidskrift (Refereegranskat) Submitted
    Identifikatorer
    urn:nbn:se:uu:diva-98080 (URN)
    Tillgänglig från: 2009-02-11 Skapad: 2009-02-11 Senast uppdaterad: 2011-05-11Bibliografiskt granskad
    4. Knowledge and insight in relation to functional remission in patients with long-term psychotic disorders
    Öppna denna publikation i ny flik eller fönster >>Knowledge and insight in relation to functional remission in patients with long-term psychotic disorders
    2010 (Engelska)Ingår i: Social Psychiatry and Psychiatric Epidemiology, ISSN 0933-7954, E-ISSN 1433-9285, Vol. 45, nr 5, s. 523-529Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    BACKGROUND: Patients with psychotic symptoms often respond poorly to treatment. Outcomes can be affected by biological, physiological and psychological factors according to the vulnerability-stress model. The patient's coping strategies and beliefs have been correlated with outcomes. OBJECTIVES: To investigate the knowledge and insight in relation to treatment response. METHODS: A naturalistic study was performed using patient interviews and information gathered from patient drug charts. Apart from the rating scales used for classification of treatment response (CANSEPT method), the SPKS knowledge of illness and drugs rating scale was utilized. RESULTS: In the group of patients in functional remission (FR; n = 38), 37% had insight into their illness as compared to 10% among those not in functional remission (non-FR; n = 78; P < 0.01). As much as 23% of the non-FR group had no strategy for responding to warning signs versus 8% in the FR group (P < 0.05). CONCLUSIONS: Better treatment outcomes appear to be associated with better insight into illness, higher knowledge of warning signs and better coping strategies.

    Nyckelord
    Health knowledge, Treatment outcome, Schizophrenia, Psychotic disorders, Insight
    Nationell ämneskategori
    Psykiatri
    Identifikatorer
    urn:nbn:se:uu:diva-123011 (URN)10.1007/s00127-009-0096-3 (DOI)000275422700002 ()19626260 (PubMedID)
    Tillgänglig från: 2010-04-22 Skapad: 2010-04-22 Senast uppdaterad: 2017-12-12Bibliografiskt granskad
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  • 154.
    Alenius, Malin
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap, Avdelningen för farmakokinetik och läkemedelsterapi.
    Wadelius, Mia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk farmakogenomik och osteoporos.
    Dahl, Marja-Liisa
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk farmakologi.
    Hartvig, Per
    Lindström, Leif
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap.
    Hammarlund-Udenaes, Margareta
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Gene polymorphism influencing treatment response in psychotic patients in a naturalistic setting2008Ingår i: Journal of Psychiatric Research, ISSN 0022-3956, E-ISSN 1879-1379, Vol. 42, nr 11, s. 884-893Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    RATIONALE: Many patients with psychotic symptoms respond poorly to treatment. Factors possibly affecting treatment response include the presence of polymorphisms in genes coding for various receptor populations, drug-metabolizing enzymes or transport proteins. OBJECTIVES: To investigate whether genetic polymorphisms could be indicators of treatment response to antipsychotic drugs. The genes of interest were the dopamine D2 receptor gene (DRD2), the serotonin 2A and 2C receptor genes (HTR2A and HTR2C), the P-glycoprotein gene (ABCB1 or MDR1) and the drug-metabolizing cytochrome P450 2D6 gene (CYP2D6). MATERIAL AND METHODS: Data for this naturalistic, cross-sectional study of patients requiring antipsychotic drugs and attending the Psychosis Outpatient Care clinic in Jönköping, Sweden were obtained from patient interviews, blood samples and information from patient files. Blood samples were genotyped for DRD2 Taq1 A, Ins/Del and Ser311Cys, HTR2A T102C, HTR2C Cys23Ser, ABCB1 1236C>T, 2677G>T/A, 3435C>T and genetic variants of CYP2D6. The patients (n=116) were grouped according to the CANSEPT method regarding significant social and clinical needs and significant side effects. RESULTS: Patients on olanzapine homozygous for ABCB1 3435T, had more significant social and clinical needs than others. Patients with one or two DRD2 Taq1 A1 alleles had a greater risk of significant side effects, particularly if they were male, Caucasian, had a schizophrenic or delusional disorder or were taking strong dopamine D2-receptor antagonistic drugs. CONCLUSION: If these results are confirmed, patients carrying the DRD2 Taq1 A1 allele would benefit from using drugs without strong dopamine D2 receptor antagonistic properties.

  • 155.
    Alenkvist, Ida
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Epac2 signaling at the β-cell plasma membrane2016Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    Secretion of appropriate amounts of insulin from pancreatic β-cells is crucial for glucose homeostasis. The β-cells release insulin in response to glucose and other nutrients, hormones and neurotransmitters, which trigger intracellular signaling cascades, that result in exocytotic fusion of insulin-containing vesicles with the plasma membrane. Increases of the intracellular concentration of calcium ions ([Ca2+]i) trigger exocytosis, whereas the messenger cyclic adenosine monophosphate (cAMP) amplifies various steps of the secretion process. The protein Epac2 mediates some effects of cAMP, but little is known about its regulation in β-cells. In this study, the spatio-temporal dynamics of Epac2 was investigated in insulin-secreting MIN6-cells and primary β-cells using various cell signaling biosensors and live-cell fluorescence microscopy approaches. Increases in the cAMP concentration triggered translocation of Epac2 from the cytoplasm to the plasma membrane. Oscillations of cAMP induced by glucose and the insulin-releasing hormone GLP-1 were associated with cyclic translocation of Epac2. Analyses of Epac2 mutants showed that the high-affinity cyclic nucleotide-binding domain and Ras-association domains were crucial for the translocation, whereas neither the DEP domain, nor the low-affinity cAMP-binding domain were required for membrane binding. However, the latter domain targeted Epac2 to insulin granules at the plasma membrane, which promoted their priming for exocytosis. Depolarization-induced elevations of [Ca2+]i also stimulated Epac2 translocation, but the effects were complex and in the presence of high cAMP concentrations, [Ca2+]i increases often reduced membrane binding. The stimulatory effect of Ca2+ was mediated by increased Ras activity, while the inhibitory effect reflected reduced concentrations of the membrane phospholipid PtdIns(4,5)P2. Anti-diabetic drugs of the sulfonylurea class, suggested to directly activate Epac2, induced translocation indirectly by depolarizing β-cells to increase [Ca2+]i. Epac2 is an activator of Rap GTPases, and its translocation increased Rap activity at the plasma membrane. It is concluded that the subcellular localization of Epac2 is controlled by a complex interplay between cAMP, Ca2+ and PtdIns(4,5)P2 and that the protein controls insulin release by binding to the exocytosis machinery. These results provide new insights into the regulation of β-cell function and may facilitate the development of new anti-diabetic drugs that amplify insulin secretion.

    Delarbeten
    1. Spatial Control of Epac2 Activity by cAMP and Ca2+-Mediated Activation of Ras in Pancreatic beta Cells
    Öppna denna publikation i ny flik eller fönster >>Spatial Control of Epac2 Activity by cAMP and Ca2+-Mediated Activation of Ras in Pancreatic beta Cells
    2013 (Engelska)Ingår i: Science Signaling, ISSN 1945-0877, E-ISSN 1937-9145, Vol. 6, nr 273, s. ra29-Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    The cAMP (adenosine 3',5'-monophosphate)-activated guanine nucleotide exchange factor (GEF) Epac2 is an important mediator of cAMP-dependent processes in multiple cell types. We used real-time confocal and total internal reflection fluorescence microscopy to examine the spatiotemporal regulation of Epac2, which is a GEF for the guanosine triphosphatase (GTPase) Rap. We demonstrated that increases in the concentration of cAMP triggered the translocation of Epac2 from the cytoplasm to the plasma membrane in insulin-secreting beta cells. Glucose-induced oscillations of the submembrane concentration of cAMP were associated with cyclic translocation of Epac2, and this translocation could be amplified by increases in the cytoplasmic Ca2+ concentration. Analyses of Epac2 mutants identified the high-affinity cAMP-binding and the Ras association domains as crucial for the translocation. Expression of a dominant-negative Ras mutant reduced Epac2 translocation, and Ca2+-dependent oscillations in Ras activity synchronized with Epac2 translocation in single beta cells. The cyclic translocation of Epac2 was accompanied by oscillations of Rap GTPase activity at the plasma membrane, and expression of an inactive Rap1B mutant decreased insulin secretion. Thus, Epac2 localization is dynamically controlled by cAMP as well as by Ca2+-mediated activation of Ras. These results help to explain how oscillating signals can produce pulses of insulin release from pancreatic b cells.

    Nationell ämneskategori
    Naturvetenskap
    Identifikatorer
    urn:nbn:se:uu:diva-201253 (URN)10.1126/scisignal.2003932 (DOI)000318350100002 ()
    Tillgänglig från: 2013-06-10 Skapad: 2013-06-10 Senast uppdaterad: 2017-12-06Bibliografiskt granskad
    2. Two-step membrane recruitment of Epac2 primes secretory granules for exocytosis
    Öppna denna publikation i ny flik eller fönster >>Two-step membrane recruitment of Epac2 primes secretory granules for exocytosis
    (Engelska)Manuskript (preprint) (Övrigt vetenskapligt)
    Nationell ämneskategori
    Cell- och molekylärbiologi
    Identifikatorer
    urn:nbn:se:uu:diva-284568 (URN)
    Tillgänglig från: 2016-04-19 Skapad: 2016-04-18 Senast uppdaterad: 2018-01-10
    3. Localization of Epac2 to the plasma membrane is controlled by an interplay between cAMP, Ca2+ and PtdIns(4,5)P2
    Öppna denna publikation i ny flik eller fönster >>Localization of Epac2 to the plasma membrane is controlled by an interplay between cAMP, Ca2+ and PtdIns(4,5)P2
    (Engelska)Manuskript (preprint) (Övrigt vetenskapligt)
    Nationell ämneskategori
    Cell- och molekylärbiologi
    Identifikatorer
    urn:nbn:se:uu:diva-284580 (URN)
    Tillgänglig från: 2016-04-19 Skapad: 2016-04-18 Senast uppdaterad: 2018-01-10
    4. Sulfonylureas trigger Ca2+-dependent Epac2 recruitment and Rap activation at the plasma membrane in β-cells
    Öppna denna publikation i ny flik eller fönster >>Sulfonylureas trigger Ca2+-dependent Epac2 recruitment and Rap activation at the plasma membrane in β-cells
    (Engelska)Manuskript (preprint) (Övrigt vetenskapligt)
    Nationell ämneskategori
    Cell- och molekylärbiologi
    Identifikatorer
    urn:nbn:se:uu:diva-284582 (URN)
    Tillgänglig från: 2016-04-19 Skapad: 2016-04-18 Senast uppdaterad: 2018-01-10
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  • 156.
    Alenkvist, Ida
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Gandasi, Nikhil R
    Barg, Sebastian
    Tengholm, Anders
    Two-step membrane recruitment of Epac2 primes secretory granules for exocytosisManuskript (preprint) (Övrigt vetenskapligt)
  • 157.
    Alenkvist, Ida
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Idevall-Hagren, Olof
    Tengholm, Anders
    Localization of Epac2 to the plasma membrane is controlled by an interplay between cAMP, Ca2+ and PtdIns(4,5)P2Manuskript (preprint) (Övrigt vetenskapligt)
  • 158.
    Alenkvist, Ida
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Xu, Yunjian
    Tengholm, Anders
    Sulfonylureas trigger Ca2+-dependent Epac2 recruitment and Rap activation at the plasma membrane in β-cellsManuskript (preprint) (Övrigt vetenskapligt)
  • 159.
    Alexander, Michelle
    et al.
    Univ York, York YO10 5DD, N Yorkshire, England.;Univ Aberdeen, Sch Geosci, Dept Archaeol, Aberdeen AB24 3UF, Scotland..
    Ho, Simon Y. W.
    Univ Sydney, Sch Biol Sci, Sydney, NSW 2006, Australia..
    Molak, Martyna
    Polish Acad Sci, Museum & Inst Zool, PL-00679 Warsaw, Poland..
    Barnett, Ross
    Palaeogen & Bioarchaeol Res Network, Res Lab Archaeol, Oxford OX1 3QY, England..
    Carlborg, Örjan
    Swedish University of Agricultural Sciences, Uppsala, Sweden.
    Dorshorst, Ben
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi. Virginia Tech, Dept Anim & Poultry Sci, Blacksburg, VA 24061 USA..
    Honaker, Christa
    Virginia Tech, Dept Anim & Poultry Sci, Blacksburg, VA 24061 USA..
    Besnier, Francois
    Inst Marine Res, Sect Populat Genet, N-5024 Bergen, Norway..
    Wahlberg, Per
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin.
    Dobney, Keith
    Univ Aberdeen, Sch Geosci, Dept Archaeol, Aberdeen AB24 3UF, Scotland..
    Siegel, Paul
    Virginia Tech, Dept Anim & Poultry Sci, Blacksburg, VA 24061 USA..
    Andersson, Leif
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi. Swedish Univ Agr Sci, Dept Anim Breeding & Genet, S-75007 Uppsala, Sweden..
    Larson, Greger
    Palaeogen & Bioarchaeol Res Network, Res Lab Archaeol, Oxford OX1 3QY, England..
    Mitogenomic analysis of a 50-generation chicken pedigree reveals a rapid rate of mitochondrial evolution and evidence for paternal mtDNA inheritance2015Ingår i: Biology Letters, ISSN 1744-9561, E-ISSN 1744-957X, Vol. 11, nr 10, artikel-id 20150561Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Mitochondrial genomes represent a valuable source of data for evolutionary research, but studies of their short-term evolution have typically been limited to invertebrates, humans and laboratory organisms. Here we present a detailed study of 12 mitochondrial genomes that span a total of 385 transmissions in a well-documented 50-generation pedigree in which two lineages of chickens were selected for low and high juvenile body weight. These data allowed us to test the hypothesis of time-dependent evolutionary rates and the assumption of strict maternal mitochondrial transmission, and to investigate the role of mitochondrial mutations in determining phenotype. The identification of a non-synonymous mutation in ND4L and a synonymous mutation in CYTB, both novel mutations in Gallus, allowed us to estimate a molecular rate of 3.13 x 10(-7) mutations/site/year (95% confidence interval 3.75 x 10(-8)-1.12 x 10(-6)). This is substantially higher than avian rate estimates based upon fossil calibrations. Ascertaining which of the two novel mutations was present in an additional 49 individuals also revealed an instance of paternal inheritance of mtDNA. Lastly, an association analysis demonstrated that neither of the point mutations was strongly associated with the phenotypic differences between the two selection lines. Together, these observations reveal the highly dynamic nature of mitochondrial evolution over short time periods.

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  • 160. Alfirevic, A.
    et al.
    Neely, D.
    Armitage, J.
    Chinoy, H.
    Cooper, R. G.
    Laaksonen, R.
    Carr, D. F.
    Bloch, K. M.
    Fahy, J.
    Hanson, A.
    Yue, Q-Y
    Wadelius, Mia
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk farmakogenomik och osteoporos.
    Maitland-van der Zee, A. H.
    Voora, D.
    Psaty, B. M.
    Palmer, C. N. A.
    Pirmohamed, M.
    Phenotype Standardization for Statin-Induced Myotoxicity2014Ingår i: Clinical Pharmacology and Therapeutics, ISSN 0009-9236, E-ISSN 1532-6535, Vol. 96, nr 4, s. 470-476Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    Statins are widely used lipid-lowering drugs that are effective in reducing cardiovascular disease risk. Although they are generally well tolerated, they can cause muscle toxicity, which can lead to severe rhabdomyolysis. Research in this area has been hampered to some extent by the lack of standardized nomenclature and phenotypic definitions. We have used numerical and descriptive classifications and developed an algorithm to define statin-related myotoxicity phenotypes, including myalgia, myopathy, rhabdomyolysis, and necrotizing autoimmune myopathy.

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  • 161. Alfonso, Julieta
    et al.
    Pollevick, Guido
    Castensson, Anja
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Jazin, Elena
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Frasch, Alberto
    Analysis of gene expression in the rat hippocampus using Real Time PCR reveals high inter-individual variation in mRNA expression levels2002Ingår i: Journal of Neuroscience Research, ISSN 0360-4012, E-ISSN 1097-4547, Vol. 67, nr 2, s. 225-34Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    In mammals, gene transcription is a step subjected to tight regulation mechanisms. In fact, changes in mRNA levels in the central nervous system (CNS) can account for numerous phenotypic differences in brain function. We performed a high-resolution analysis of mRNA expression levels for 37 genes selected from a normal rat hippocampus cDNA library. mRNA amounts were quantified using a Real Time PCR SYBR Green assay. We found that, in general, individuals from an inbred rat population (n = 20) have shown 2-3 times differences in the basal level of expression of the genes analyzed. Up to several fold differences among individuals were observed for certain genes. These inter-individual differences were obtained after correction for the different amounts of mRNA in each sample. Power calculations were performed to determine the number of individuals required to detect reliable differences in expression levels between a control and an experimental group. These data indicated that, depending on the variability of the candidate gene selected, it was necessary to analyze from five to 135 individuals in each group to detect differences of 50% in the levels of mRNA expression between two groups investigated. The comparison of mRNA abundance from different genes revealed a wide range of expression levels for the 37 genes, showing a 26,000-fold difference between the highest and lowest expressed gene.

  • 162.
    Alfredsson, Jessica
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Molecular Studies of Mast Cell Migration and Apoptosis: Two Ways of Regulating Mast Cell Numbers at Sites of Inflammation2005Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    Upon activation mast cells release numerous proinflammatory mediators. With this feature, mast cells play an important role in host defense against pathogens, and are involved in tissue remodeling and wound healing. However, in cases of excessive inflammation the effects of mast cells are detrimental. This is observed in allergy, asthma, rheumatoid arthritis, atherosclerosis, certain types of heart failure, and in several other chronic destructive inflammations. Mast cell numbers are typically increased at inflammatory sites. There they act both directly, as effector cells, and in a regulatory manner, secreting agents that recruit and activate other immune cells.

    The studies presented here investigated mechanisms regulating mast cell numbers at sites of inflammation, focusing on cell migration and regulation of survival/apoptosis. We report that SCF-induced mast cell migration requires p38 MAP kinase activity. Moreover, we found that SCF-mediated mast cell survival is regulated through downregulation of the proapoptotic Bcl-2 family member Bim, as well as through phoshorylation of Bim. SCF seems to control Bim protein levels via FOXO transcription factors, and to induce phosphorylation of Bim via the Mek/Erk and the PI3-kinase/Akt signaling pathways. Furthermore, mast cell death triggered by deprivation of SCF and/or IL-3 involves the Bim protein, as demonstrated using bim-/- mast cells. Additional studies revealed that IgE-receptor activation, which occurs in allergy, promotes both prosurvival and proapoptotic signaling events. This includes upregulation of Bim and the prosurvival Bcl-XL and A1, as well as phosphorylation of Akt, FOXO factors, GSK-3β, IκB-α, Bad, and Bim. The simultaneous stimulation of prosurvival and proapoptotic signaling events could be a way to fine-tune the fate of mast cells after IgE-receptor activation and degranulation.

    The new insights about mechanisms involved in mast cell migration and regulation of survival/apoptosis might prove useful for future efforts to design new drugs to be used for mast cell-associated diseases.

    Delarbeten
    1. Stem Cell Factor-Induced Migration of Mast Cells Requires p38 Mitogen-Activated Protein Kinase Activity
    Öppna denna publikation i ny flik eller fönster >>Stem Cell Factor-Induced Migration of Mast Cells Requires p38 Mitogen-Activated Protein Kinase Activity
    2001 Ingår i: Experimental Cell Research, Vol. 267, nr 1, s. 144-151Artikel i tidskrift (Refereegranskat) Published
    Identifikatorer
    urn:nbn:se:uu:diva-92671 (URN)
    Tillgänglig från: 2005-03-11 Skapad: 2005-03-11Bibliografiskt granskad
    2. Stem cell factor promotes mast cell survival via inactivation of FOXO3a mediated transcriptional induction and MEK regulated phosphorylation of the pro-apoptotic protein Bim
    Öppna denna publikation i ny flik eller fönster >>Stem cell factor promotes mast cell survival via inactivation of FOXO3a mediated transcriptional induction and MEK regulated phosphorylation of the pro-apoptotic protein Bim
    Visa övriga...
    Artikel i tidskrift (Refereegranskat) Submitted
    Identifikatorer
    urn:nbn:se:uu:diva-92672 (URN)
    Tillgänglig från: 2005-03-11 Skapad: 2005-03-11Bibliografiskt granskad
    3. Porapoptotic Bcl-2 family member Bim is involved in the control of mast cell survival and is induced together with Bcl-XL upon IgE-receptor activation
    Öppna denna publikation i ny flik eller fönster >>Porapoptotic Bcl-2 family member Bim is involved in the control of mast cell survival and is induced together with Bcl-XL upon IgE-receptor activation
    Visa övriga...
    2005 Ingår i: Cell Death and Differentiation, Vol. 12, nr 2, s. 136-144Artikel i tidskrift (Refereegranskat) Published
    Identifikatorer
    urn:nbn:se:uu:diva-92673 (URN)
    Tillgänglig från: 2005-03-11 Skapad: 2005-03-11Bibliografiskt granskad
    4. IgE-receptor activation of mast cells regulates phosphorylation and expression of forkhead and Bcl-2 family members
    Öppna denna publikation i ny flik eller fönster >>IgE-receptor activation of mast cells regulates phosphorylation and expression of forkhead and Bcl-2 family members
    Manuskript (Övrigt vetenskapligt)
    Identifikatorer
    urn:nbn:se:uu:diva-92674 (URN)
    Tillgänglig från: 2005-03-11 Skapad: 2005-03-11 Senast uppdaterad: 2010-01-13Bibliografiskt granskad
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  • 163.
    Alfredsson Timmins, Jenny
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Functional organisation of the cell nucleus in the fission yeast, Schizosaccharomyces pombe2009Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    In eukaryotes the genome adopts a non-random spatial organisation, which is important for gene regulation. However, very little is known about the driving forces behind nuclear organisation. In the simple model eukaryote fission yeast, Schizosaccharomyces pombe, it has been known for a long time that transcriptionally repressed heterochromatin localise to the nuclear membrane (NM); the centromeres attaches to spindle pole body (SPB), while the telomeres are positioned at the NM on the opposite side of the nucleus compared to the SPB. Studies presented in this thesis aimed at advancing our knowledge of nuclear organisation in Schizosaccharomyces pombe.

    We show that the heterochromatic mating-type region localises to the NM in the vicinity of the SPB. This positioning was completely dependent on Clr4, a histone methyl transferase crucial for the formation of heterochromatin. Additional factors important for localisation were also identified: the chromo domain protein Swi6, and the two boundary elements IR-L and IR-R surrounding this locus. We further identify two other chromo domain proteins; Chp1 and Chp2, as crucial factors for correct subnuclear localisation of this region. From these results we suggest that the boundary elements together with chromodomain proteins in balanced dosage and composition cooperate in organising the mating-type chromatin.

    Gene regulation can affect the subnuclear localisation of genes. Using nitrogen starvation in S. pombe as a model for gene induction we determined the subnuclear localisation of two gene clusters repressed by nitrogen: Chr1 and Tel1. When repressed these loci localise to the NM, and this positioning is dependent on the histone deacetylase Clr3. During induction the gene clusters moved towards the nuclear interior in a transcription dependent manner.

    The knowledge gained from work presented in this thesis, regarding nuclear organisation in the S. pombe model system, can hopefully aid to a better understanding of human nuclear organisation.

    Delarbeten
    1. The Clr4 methyltransferase determines the subnuclear localization of the mating-type region in fission yeast
    Öppna denna publikation i ny flik eller fönster >>The Clr4 methyltransferase determines the subnuclear localization of the mating-type region in fission yeast
    2007 (Engelska)Ingår i: Journal of Cell Science, ISSN 0021-9533, E-ISSN 1477-9137, Vol. 120, nr 11, s. 1935-1943Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    The genome has a non-random spatial distribution in the cell nucleus. In Schizosaccharomyces pombe, it has been shown that the centromeres, telomeres and the mating-type region localize to the nuclear membrane (NM), the former by attaching to the spindle pole body (SPB). In addition, reporter genes inserted into these areas are transcriptionally repressed due to the formation of specialized chromatin structures. Performing live cell analysis we found that in a wild-type strain the mating-type region was positioned in the proximity of the SPB, the location where the pericentromeric heterochromatin is also found. In a strain lacking the histone methyltransferase, Clr4, crucial for the formation of heterochromatin, the mating-type region had a random localization in the nucleus. Moreover, in a strain where the two boundary elements IR-L and IR-R had been deleted the mating-type region was displaced from its position at the proximity of the SPB, but remained in the vicinity of the NM. Moreover, in all investigated strains with silencing deficiencies the distance between the mating-type region and the SPB increased. This result indicates a correlation between transcriptional derepression and displacement of the region. Two different models of how the mating-type chromatin is organized in the nucleus are discussed.

    Nyckelord
    fission yeast, heterochromatin, silencing, subnuclear localization
    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:uu:diva-13023 (URN)10.1242/jcs.03457 (DOI)000246665300013 ()17504808 (PubMedID)
    Tillgänglig från: 2009-08-05 Skapad: 2009-08-05 Senast uppdaterad: 2017-12-11Bibliografiskt granskad
    2. Chromo domain proteins in balanced dosage together with boundary elements cooperate in organising the mating-type chromatin in fission yeast
    Öppna denna publikation i ny flik eller fönster >>Chromo domain proteins in balanced dosage together with boundary elements cooperate in organising the mating-type chromatin in fission yeast
    (Engelska)Manuskript (preprint) (Övrig (populärvetenskap, debatt, mm))
    Abstract [en]

    The chromatin in the cell nucleus has a spatial organisation. For example, in the fission yeast, Schizosaccharomyces pombe, transcriptionally repressed heterochromatin is found at the nuclear membrane (NM). The centromeres and the mating-type region localise in the proximity of the spindle pole body (SPB), while the telomeres are found on the opposite side of the nucleus in the proximity of the nucleolus. In a previous study we used the mating-type region as a model to study the driving force behind nuclear organisation. We proposed two mutually exclusive models to explain what determines the localisation of the mating-type region. The first model suggests that solely the amount of heterochromatin in the region affects the localisation, while the other model stipulates that the boundary elements together with heterochromatin formation anchor the mating-type region in the NM in the vicinity of the SPB. Here, we present data that disproves the first model. We found that in a strain expressing tripled amounts of the chromodomain protein Swi6, a structural component of heterochromatin, the mating-type region was delocalised from the proximity of the SPB. A strain deleted of the histone deacetylase clr3+ also had a delocalised mating-type locus. Interestingly, a strain with a point-mutation in clr3-735 producing an enzymatically inactive protein in normal amounts showed an intermediate phenotype. Most importantly, we identify the chromodomain proteins, Chp1 and Chp2, as crucial factors for correct subnuclear localisation of the mating-type region. We suggest that boundary elements together with chromodomain proteins in balanced dosage and composition cooperate in organising the mating-type chromatin.

    Identifikatorer
    urn:nbn:se:uu:diva-107280 (URN)
    Tillgänglig från: 2009-08-04 Skapad: 2009-08-04 Senast uppdaterad: 2010-01-14Bibliografiskt granskad
    3. Reorganization of chromatin is an early response to nitrogen starvation in Schizosaccharomyces pombe
    Öppna denna publikation i ny flik eller fönster >>Reorganization of chromatin is an early response to nitrogen starvation in Schizosaccharomyces pombe
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    2009 (Engelska)Ingår i: Chromosoma, ISSN 0009-5915, E-ISSN 1432-0886, Vol. 118, nr 1, s. 99-112Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    There are several documented events of changes in subnuclear localization during gene activation. However, there are conflicting data on whether the nuclear periphery is a compartment for gene repression or activation, and whether genes are moved to the pores at the nuclear membrane (NM) or not during gene activation. Nitrogen starvation of fission yeast serves as a good model system for studying gene induction since it causes fast regulation of hundreds of genes. In this study the subnuclear localization of two gene clusters repressed by nitrogen was investigated. During normal growth conditions the gene clusters localized to the nuclear periphery at the opposite side of the nucleus as compared to the spindle pole body (SPB). This constrained localization was dependent on the histone deacetylase Clr3, known to transcriptionally repress genes in these clusters. Already 20 minutes after nitrogen depletion drastic changes in subnuclear localization of the two loci were observed, away from the NM towards the nuclear interior. At least for one of the clusters the movement was clearly transcription dependent. Data presented here illustrates how interconnected events of gene activation and nuclear reorganization are, as well as provides a suggestion of how nuclear organization might be maintained.

    Nationell ämneskategori
    Medicinsk bioteknologi (med inriktning mot cellbiologi (inklusive stamcellsbiologi), molekylärbiologi, mikrobiologi, biokemi eller biofarmaci)
    Identifikatorer
    urn:nbn:se:uu:diva-107289 (URN)10.1007/s00412-008-0180-6 (DOI)000262504300009 ()
    Tillgänglig från: 2009-08-05 Skapad: 2009-08-05 Senast uppdaterad: 2017-12-13Bibliografiskt granskad
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  • 164. Alfstad, K Å
    et al.
    Lossius, M I
    Røste, G K
    Mowinckel, P
    Scheie, D
    Casar Borota, Olivera
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylär och morfologisk patologi. Dept. of Laboratory medicine/Pathology, Umeå University, Umeå Sweden.
    Larsson, P G
    Nakken, K O
    Acute postoperative seizures after epilepsy surgery: a long-term outcome predictor?2011Ingår i: Acta Neurologica Scandinavica, ISSN 0001-6314, E-ISSN 1600-0404, Vol. 123, nr 1, s. 48-53Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    OBJECTIVES: The prognostic value of acute postoperative seizures (APS) after epilepsy surgery is much debated. This study evaluated APS, defined as seizures in the first week post-surgery, as a predictor of long-term seizure outcome, and investigated the utility of other potential outcome predictors.

    MATERIALS AND METHODS: Medical records of 48 patients with temporal and extra-temporal epilepsy surgery were studied. Forty patients had lesional surgery. All had at least 2 year postoperative follow-up.

    RESULTS: At 2 year follow-up, 25 patients (53%) were seizure free. Univariate analysis showed that APS (P = 0.048), using ≥ six AEDs prior to surgery (P = 0.03), pathological postoperative EEG (P = 0.043) and female gender (P = 0.012) were associated with seizure recurrence.

    CONCLUSIONS: Univariate analysis indicate that APS, a high number of AEDs used prior to surgery, and pathological postoperative EEG are possible predictors of seizure recurrence after epilepsy surgery. Only gender retained significance in the multivariate analysis.

  • 165.
    Algady, Walid
    et al.
    Univ Leicester, Dept Genet & Genome Biol, Leicester LE1 7RH, Leics, England.
    Louzada, Sandra
    Wellcome Sanger Inst, Cambridge CB10 1SA, England.
    Carpenter, Danielle
    Univ Leicester, Dept Genet & Genome Biol, Leicester LE1 7RH, Leics, England.
    Brajer, Paulina
    Univ Leicester, Dept Genet & Genome Biol, Leicester LE1 7RH, Leics, England.
    Farnert, Anna
    Karolinska Inst, Dept Med Solna, Div Infect Dis, S-17176 Stockholm, Sweden;Karolinska Univ Hosp, Dept Infect Dis, S-17176 Stockholm, Sweden.
    Rooth, Ingegerd
    Natl Inst Med Res, Nyamisati Malaria Res, Dar Es Salaam, Tanzania.
    Ngasala, Billy
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Internationell mödra- och barnhälsovård (IMCH), Internationell barnhälsa och nutrition. Muhimbili Univ Hlth & Allied Sci, Dept Parasitol & Med Entomol, Dar Es Salaam, Tanzania.
    Yang, Fengtang
    Wellcome Sanger Inst, Cambridge CB10 1SA, England.
    Shaw, Marie-Anne
    Univ Leeds, Leeds Inst Med Res St Jamess, Leeds LS9 7TF, W Yorkshire, England.
    Hollox, Edward J.
    Univ Leicester, Dept Genet & Genome Biol, Leicester LE1 7RH, Leics, England.
    The Malaria-Protective Human Glycophorin Structural Variant DUP4 Shows Somatic Mosaicism and Association with Hemoglobin Levels2018Ingår i: American Journal of Human Genetics, ISSN 0002-9297, E-ISSN 1537-6605, Vol. 103, nr 5, s. 769-776Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Glycophorin A and glycophorin B are red blood cell surface proteins and are both receptors for the parasite Plasmodium falciparum, which is the principal cause of malaria in sub-Saharan Africa. DUP4 is a complex structural genomic variant that carries extra copies of a glycophorin A-glycophorin B fusion gene and has a dramatic effect on malaria risk by reducing the risk of severe malaria by up to 40%. Using fiber-FISH and Illumina sequencing, we validate the structural arrangement of the glycophorin locus in the DUP4 variant and reveal somatic variation in copy number of the glycophorin B-glycophorin A fusion gene. By developing a simple, specific, PCR-based assay for DUP4, we show that the DUP4 variant reaches a frequency of 13% in the population of a malaria-endemic village in southeastern Tanzania. We genotype a substantial proportion of that village and demonstrate an association of DUP4 genotype with hemoglobin levels, a phenotype related to malaria, using a family-based association test. Taken together, we show that DUP4 is a complex structural variant that may be susceptible to somatic variation and show that DUP4 is associated with a malarial-related phenotype in a longitudinally followed population.

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  • 166.
    Alhalaweh, Amjad
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Alzghoul, Ahmad
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Matematisk-datavetenskapliga sektionen, Institutionen för informationsteknologi, Datalogi.
    Bergström, Christel A. S.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Molecular Drivers of Crystallization Kinetics for Drugs in Supersaturated Aqueous Solutions2019Ingår i: Journal of Pharmaceutical Sciences, ISSN 0022-3549, E-ISSN 1520-6017, Vol. 108, nr 1, s. 252-259Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    In this study, we explore molecular properties of importance in solution-mediated crystallization occurring in supersaturated aqueous drug solutions. Furthermore, we contrast the identified molecular properties with those of importance for crystallization occurring in the solid state. A literature data set of 54 structurally diverse compounds, for which crystallization kinetics from supersaturated aqueous solutions and in melt-quenched solids were reported, was used to identify molecular drivers for crystallization kinetics observed in solution and contrast these to those observed for solids. The compounds were divided into fast, moderate, and slow crystallizers, and in silico classification was developed using a molecular K-nearest neighbor model. The topological equivalent of Grav3 (related to molecular size and shape) was identified as the most important molecular descriptor for solution crystallization kinetics; the larger this descriptor, the slower the crystallization. Two electrotopological descriptors (the atom-type E-state index for -Caa groups and the sum of absolute values of pi Fukui(+) indices on C) were found to separate the moderate and slow crystallizers in the solution. The larger these descriptors, the slower the crystallization. With these 3 descriptors, the computational model correctly sorted the crystallization tendencies from solutions with an overall classification accuracy of 77% (test set).

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  • 167.
    Alhalaweh, Amjad
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Alzghoul, Ahmad
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Matematisk-datavetenskapliga sektionen, Institutionen för informationsteknologi, Datalogi.
    Kaialy, Waseem
    Mahlin, Denny
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Bergström, Christel A. S.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Computational predictions of glass-forming ability and crystallization tendency of drug molecules2014Ingår i: Molecular Pharmaceutics, ISSN 1543-8384, E-ISSN 1543-8392, Vol. 11, nr 9, s. 3123-3132Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Amorphization is an attractive formulation technique for drugs suffering from poor aqueous solubility as a result of their high lattice energy. Computational models that can predict the material properties associated with amorphization, such as glass-forming ability (GFA) and crystallization behavior in the dry state, would be a time-saving, cost-effective, and material-sparing approach compared to traditional experimental procedures. This article presents predictive models of these properties developed using support vector machine (SVM) algorithm. The GFA and crystallization tendency were investigated by melt-quenching 131 drug molecules in situ using differential scanning calorimetry. The SVM algorithm was used to develop computational models based on calculated molecular descriptors. The analyses confirmed the previously suggested cutoff molecular weight (MW) of 300 for glass-formers, and also clarified the extent to which MW can be used to predict the GFA of compounds with MW < 300. The topological equivalent of Grav3_3D, which is related to molecular size and shape, was a better descriptor than MW for GFA; it was able to accurately predict 86% of the data set regardless of MW. The potential for crystallization was predicted using molecular descriptors reflecting Hückel pi atomic charges and the number of hydrogen bond acceptors. The models developed could be used in the early drug development stage to indicate whether amorphization would be a suitable formulation strategy for improving the dissolution and/or apparent solubility of poorly soluble compounds.

  • 168.
    Alhalaweh, Amjad
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Alzghoul, Ahmad
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Matematisk-datavetenskapliga sektionen, Institutionen för informationsteknologi, Datalogi.
    Mahlin, Denny
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Bergström, Christel A. S.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Physical stability of drugs after storage above and below the glass transition temperature: Relationship to glass-forming ability2015Ingår i: International Journal of Pharmaceutics, ISSN 0378-5173, E-ISSN 1873-3476, Vol. 495, nr 1, s. 312-317Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Amorphous materials are inherently unstable and tend to crystallize upon storage. In this study, we investigated the extent to which the physical stability and inherent crystallization tendency of drugs are related to their glass-forming ability (GFA), the glass transition temperature (T-g) and thermodynamic factors. Differential scanning calorimetry was used to produce the amorphous state of 52 drugs [ 18 compounds crystallized upon heating (Class II) and 34 remained in the amorphous state (Class III)] and to perform in situ storage for the amorphous material for 12 h at temperatures 20 degrees C above or below the T-g. A computational model based on the support vector machine (SVM) algorithm was developed to predict the structure-property relationships. All drugs maintained their Class when stored at 20 degrees C below the T-g. Fourteen of the Class II compounds crystallized when stored above the T-g whereas all except one of the Class III compounds remained amorphous. These results were only related to the glass-forming ability and no relationship to e. g. thermodynamic factors was found. The experimental data were used for computational modeling and a classification model was developed that correctly predicted the physical stability above the T-g. The use of a large dataset revealed that molecular features related to aromaticity and pi-pi interactions reduce the inherent physical stability of amorphous drugs.

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  • 169.
    Alhalaweh, Amjad
    et al.
    Purdue Univ, Dept Ind & Phys Pharm, Coll Pharm, 575 Stadium Mall Dr, W Lafayette, IN 47907 USA.
    Bergström, Christel A. S.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Taylor, Lynne S.
    Purdue Univ, Dept Ind & Phys Pharm, Coll Pharm, 575 Stadium Mall Dr, W Lafayette, IN 47907 USA.
    Compromised in vitro dissolution and membrane transport of multidrug amorphous formulations.2016Ingår i: Journal of Controlled Release, ISSN 0168-3659, E-ISSN 1873-4995, Vol. 229, s. 172-182Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Herein, the thermodynamic properties of solutions evolving from the non-sink dissolution of amorphous solid dispersions (ASDs) containing two or more drugs have been evaluated, focusing on the maximum achievable supersaturation and tendency of the system to undergo liquid-liquid phase separation (LLPS). Ritonavir (RTV) and atazanavir (ATV) were co-formulated with polyvinylpyrrolidone to produce ASDs with different molar ratios of each drug, and the dissolution profile of each drug was studied under non-sink conditions. The phase behavior of the supersaturated solutions generated by ASD dissolution was compared to that of supersaturated solutions generated by antisolvent addition. Dissolution of an ASD containing RTV, ATV and lopinavir (LPV) was also investigated. A thermodynamic model was used to predict the maximum achievable supersaturation for ASDs containing two and three drugs. In addition, a transport study with Caco-2 cells was conducted to evaluate the impact of co-addition of drugs on membrane transport. It was found that the formulation containing a 1:1 molar ratio of RTV and ATV achieved only 50% of the supersaturation attained by dissolution of the single drug systems. The maximum achievable concentration of ATV decreased linearly as the mole fraction of ATV in the formulation decreased and a similar trend was observed for RTV. For the dispersion containing a 1:1:1 molar ratio of RTV, ATV and LPV, the maximum concentration of each drug was only one third of that achieved for the single drug formulations. The decrease in the achievable supersaturation was well-predicted by the thermodynamic model for both the binary and ternary drug combinations. These observations can be explained by a decrease in the concentration at which the drugs undergo LLPS in the presence of other miscible drugs, thereby reducing the maximum achievable supersaturation of each drug. The reduced free drug concentration was reflected by a decreased flux across Caco-2 cells for the drug combinations compared to drug alone. This study sheds light on the complex dissolution and solution phase behavior of multicomponent amorphous dosage forms, in particular those containing poorly water soluble drugs, which may undergo supersaturation in vivo.

  • 170. Alheim, K
    et al.
    Andersson, C
    Tingsborg, S
    Ziolkowska, M
    Schultzberg, M
    Bartfai, T
    Interleukin 1 expression is inducible by nerve growth factor in PC12 pheochromocytoma cells.1991Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 88, nr 20, s. 9302-6Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Expression of the cytokine interleukin 1 alpha (IL-1 alpha) was demonstrated in the rat PC12 pheochromocytoma cell line by (i) immunohistochemistry using rabbit polyclonal antisera raised against the recombinant murine IL-1 alpha, (ii) an ELISA, and (iii) a specific cell conversion bioassay based on the use of LBRM33-1A5 cells. IL-1 alpha mRNA was demonstrated in the PC12 cells, by PCR amplification. Constitutive expression of IL-1 alpha in PC12 cells was demonstrated in all experiments, although the cellular levels of IL-1 alpha-like immunoreactivity varied. The expression of IL-1 alpha, as studied at the mRNA level, was inducible by mouse nerve growth factor (7S NGF), and the gene product level was inducible in a dose- and time-dependent fashion by 7S NGF. The maximum induction corresponds to a 600% increase in IL-1 alpha-like immunoreactivity above the expression level found in noninduced cells and occurred after a 3-day incubation of the cells with NGF at 0.75 micrograms/ml of culture medium. The significance of the ability of NGF to induce IL-1 expression lies in the fact that IL-1 itself also acts as a growth factor that promotes glial proliferation and, even more importantly, IL-1 itself induces the expression of NGF at peripheral nerve injury [Lindholm, D., Heumann, R., Meyer, M. & Thoenen, H. (1987) Nature (London) 330, 658-659].

  • 171. Al-Henhena, Nawal
    et al.
    Khalifa, Shaden A. M.
    Ying, Rozaida Poh Yuen
    Hassandarvish, Pouya
    Rouhollahi, Elham
    Al-Wajeeh, Nahla Saeed
    Ali, Habibah Mohd
    Abdulla, Mahmood Ameen
    El-Seedi, Hesham R.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Chemopreventive effects of Strobilanthes crispus leaf extract on azoxymethane-induced aberrant crypt foci in rat colon2015Ingår i: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 5, artikel-id 13312Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    In this work, microscopic and histological studies suggest that Strobilanthes crispus ethanol extract reduce azoxymethane (AOM)-induced colonic aberrant crypt foci (ACF) in rats. S. crispus is considered a traditional medicine and used as an antioxidant. Its leaf contains a large amount of phenolic compounds to which its radical scavenging role is attributed and enhance its ability to eradicate oxidative stress reactions. The study was designed to determine the chemopreventive effect of S. crispus ethanol extract in vivo and in vitro by elucidating the effect of the extract on intermediate biomarkers which can be used as effective predictors of colon cancer. S. crispus was analyzed for DPPH free radical scavenging, nitric oxide (NO) and ferric acid reduction. The results indicated that S. crispus oral administration significantly inhibited colorectal carcinogenesis induced by AOM as revealed by the reduction in the number of ACF. S. crispus down-regulated the expression of PCNA, Bcl2 and beta-catenin. Additionally, it exerted a pronounced inhibitory effect on MDA and NO levels and stimulatory effect on CAT and GPx activities. These results demonstrate that S. crispus is a chemopreventive agent for colorectal cancer through the suppression of early and intermediate carcinogenic phases that may be related to its flavonoid content.

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  • 172.
    Al-Henhena, Nawal
    et al.
    Univ Malaya, Fac Med, Dept Biomed Sci, Kuala Lumpur 50603, Malaysia.;Sanaa Univ, Fac Med, Dept Biochem, Sanaa, Yemen..
    Khalifa, Shaden A. M.
    Karolinska Univ Hosp, Dept Expt Hematol, SE-14186 Stockholm, Sweden..
    Ying, Rozaida Poh Yuen
    Univ Malaya, Fac Med, Dept Biomed Sci, Kuala Lumpur 50603, Malaysia..
    Ismail, Salmah
    Univ Malaya, Fac Sci, Inst Biol Sci, Kuala Lumpur 50603, Malaysia..
    Hamadi, Riad
    Sanaa Univ, Fac Med, Dept Biochem, Sanaa, Yemen..
    Shawter, Abdrabu N.
    Univ Malaya, Fac Med, Dept Biomed Sci, Kuala Lumpur 50603, Malaysia..
    Idris, Azila Mohd
    Univ Malaya, Fac Sci, Dept Chem, Kuala Lumpur 50603, Malaysia..
    Azizan, Ainnul
    Univ Malaya, Fac Sci, Dept Chem, Kuala Lumpur 50603, Malaysia..
    Al-Wajeeh, Nahla Saeed
    Univ Malaya, Fac Med, Dept Biomed Sci, Kuala Lumpur 50603, Malaysia..
    Abdulla, Mahmood Ameen
    Univ Malaya, Fac Med, Dept Biomed Sci, Kuala Lumpur 50603, Malaysia..
    El-Seedi, Hesham R.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi. Univ Malaya, Fac Sci, Dept Chem, Kuala Lumpur 50603, Malaysia..
    Evaluation of chemopreventive potential of Strobilanthes crispus against colon cancer formation in vitro and in vivo2015Ingår i: BMC Complementary and Alternative Medicine, ISSN 1472-6882, E-ISSN 1472-6882, Vol. 15, artikel-id 419Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: With cancer being one of the major causes of death around the world, studies are ongoing to find new chemotherapeutic leads. There are common mechanisms for colorectal cancer (CRC) formation. Several are connected with oxidative stress-induced cell apoptosis and others are related to imbalanced homeostasis or intake of drugs/toxins. Plants that have been used for decades in folk and traditional medicine have been accepted as one of the commonest sources of discovered natural agents of cancer chemotherapy and chemoprevention. The aim was to study the antioxidant and chemopreventive effects of Strobilanthes crispus on colorectal cancer formation. Methods: Five groups of rats were injected subcutaneously with AOM, 15 mg/kg body weight, each once weekly for 2 weeks. The cancer group was continued on 10 % Tween-20 feeding for 8 weeks. The standard drug group was continued on 35 mg/kg 5-fluorouracil intraperitoneal injection twice a week for 8 weeks, and the experimental groups were continued on 250 and 500 mg/kg S. crispus extract oral feeding for 8 weeks, respectively. The normal group was injected subcutaneously with normal saline once a week for 2 weeks, followed by oral administration of 10 % Tween-20 for 8 weeks. All the rats were sacrificed after 10 weeks. The colons were evaluated grossly and histopathologically for aberrant crypt foci (ACF). Gene expression was performed for Bax, Bcl2, Defa24, Slc24a3, and APC genes by real-time PCR. S. crispus and its fractions were evaluated for their chemopreventive effects against human colorectal adenocarcinoma cell line HT29 and cytotoxicity for normal human colon epithelial cell line CCD 841, and the active fraction was assessed for its components. Results: We observed significant decrease in total colonic ACF formation, malonaldehyde (MDA) and lactate dehydrogenase (LDH), increase in superoxide dismutase (SOD), up-regulation of APC, Bax and Slc24a3, and down-regulation of Defa24 and Bcl-2 in rats treated with Strobilanthes crispus. Conclusion: Our results support the in vivo protection of S. crispus against CRC formation (azoxymethane-induced aberrant crypt foci) and suggest that the mechanism is highly specific to protect from oxidative insults and the following apoptotic cascade.

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  • 173. Al-Henhena, Nawal
    et al.
    Ying, Rozaida Poh Yuen
    Ismail, Salmah
    Najm, Wala
    Khalifa, Shaden A. M.
    El-Seedi, Hesham
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Abdulla, Mahmood Ameen
    Chemopreventive Efficacy of Andrographis paniculata on Azoxymethane-Induced Aberrant Colon Crypt Foci In Vivo2014Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, nr 11, artikel-id e111118Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Andrographis paniculata is a grass-shaped medicinal herb, traditionally used in Southeast Asia. The aim of this study was to evaluate the chemoprotective effects of A. paniculata on colorectal cancer. A. paniculata ethanol extract was tested on azoxymethane (AOM)-induced aberrant crypt foci (ACF) in vivo and in vitro. A. paniculata treated groups showed a significant reduction in the number of ACF of the treated rats. Microscopically, ACF showed remarkably elongated and stratified cells, and depletion of the submucosal glands of AOM group compared to the treated groups. Histologically, staining showed slightly elevated masses above the surrounding mucosa with oval or slit-like orifices. Immunohistochemically, expression of proliferating cell nuclear antigen (PCNA) and beta-catenin protein were down-regulated in the A. paniculata treated groups compared to the AOM group. When colon tissue was homogenized, malondialdehyde (MDA) and nitric oxide (NO) levels were significantly decreased, whereas superoxide dismutase (SOD) activity was increased in the treated groups compared to the AOM group. A. paniculata ethanol extract showed antioxidant and free radical scavenging activity, as elucidated by the measure of oxidative stress markers. Further, the active fractions were assessed against cell lines of CCD841 and HT29 colon cancer cells.

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  • 174.
    Ali, Ehood
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap. Harvard Medical school / Boston Children's Hospital.
    The Role of the Glycine Receptor’s Alpha 2Subunit in the Behavior of Mice2014Självständigt arbete på avancerad nivå (masterexamen), 20 poäng / 30 hpStudentuppsats (Examensarbete)
  • 175.
    Ali, Ersin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Framtida läkemedel bör rikta sig mot väldigt tidiga stadier av Alzheimers sjukdom2012Självständigt arbete på grundnivå (kandidatexamen), 20 poäng / 30 hpStudentuppsats (Examensarbete)
  • 176.
    Ali Haj, Mahmoud
    et al.
    United Arab Emirates University.
    Kazzam, Elsadig
    United Arab Emirates University.
    Amir, Nahid
    United Arab Emirates University.
    Nyberg, Fred
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Nicholls, Gary M.
    Otago University .
    Adem, Abdu
    United Arab Emirates University.
    Effects of Dehydration and Blockade of Angiotensin II AT1 Receptor on Stress Hormones and Anti-Oxidants in the one-humped camel2013Ingår i: BMC Veterinary Research, ISSN 1746-6148, E-ISSN 1746-6148, Vol. 9, s. 232-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Our objectives were to document and compare plasma levels of Catecholamines, Cortisol,Glutathione and Malondialdehyde in camels after long term dehydration (20 days) in the presenceor absence of angiotensin II AT1 receptor blocker (Losartan) versus levels in non-dehydratedcamels; and to record the effects on glutathione and malondialdehyde activity in liver and kidneyhomogenate in the one-humped camel. Eighteen male camels were used in this study, sixcontrols, six dehydrated and treated with losartan (5mg/kg daily) and six were dehydrated withouttreatment. Our results revealed significant decrease (P<0.05) in plasma epinephrine level in bothtreated and dehydrated camels; while, Plasma norepinephrine showed significant increase in bothdehydrated groups (P< 0.01). Levels of plasma dopamine were also significantly increased (P<0.01) in both dehydrated groups compared to control camels.Plasma levels of cortisol increased significantly across dehydration with or without losartanadministration (P<0.01) compared with time-matched levels in control camels. Losartan had nosignificant modulating effect on the cortisol response to dehydration.Plasma, liver and kidney homogenates revealed significant increase (P<0.05) in glutathione levelsin both dehydrated groups compared to control.Plasma, liver and kidney homogenates for malondialdehyde levels in both treated and dehydratedcamels also showed significant increase (P<0.05 & P<0.01) compared to controls.In conclusion, our study demonstrates that the effect of dehydration with or without losartaninduced oxidative stress in these camels, leading to significant changes in plasma catecholaminesand cortisol levels, together with significant increments in glutathione and malondialdehydeactivities in plasma, liver and kidney homogenate to counter act the damaging effect of the freeradicals in the dehydrated camels.

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  • 177.
    Ali, Muhammad Akhtar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Genomik.
    Understanding Cancer Mutations by Genome Editing2014Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    Mutational analyses of cancer genomes have identified novel candidate cancer genes with hitherto unknown function in cancer. To enable phenotyping of mutations in such genes, we have developed a scalable technology for gene knock-in and knock-out in human somatic cells based on recombination-mediated construct generation and a computational tool to design gene targeting constructs. Using this technology, we have generated somatic cell knock-outs of the putative cancer genes ZBED6 and DIP2C in human colorectal cancer cells. In ZBED6-/- cells complete loss of functional ZBED6 was validated and loss of ZBED6 induced the expression of IGF2. Whole transcriptome and ChIP-seq analyses revealed relative enrichment of ZBED6 binding sites at upregulated genes as compared to downregulated genes. The functional annotation of differentially expressed genes revealed enrichment of genes related to cell cycle and cell proliferation and the transcriptional modulator ZBED6 affected the cell growth and cell cycle of human colorectal cancer cells. In DIP2C-/-cells, transcriptome sequencing revealed 780 differentially expressed genes as compared to their parental cells including the tumour suppressor gene CDKN2A. The DIP2C regulated genes belonged to several cancer related processes such as angiogenesis, cell structure and motility. The DIP2C-/-cells were enlarged and grew slower than their parental cells. To be able to directly compare the phenotypes of mutant KRAS and BRAF in colorectal cancers, we have introduced a KRASG13D allele in RKO BRAFV600E/-/-/ cells. The expression of the mutant KRAS allele was confirmed and anchorage independent growth was restored in KRASG13D cells. The differentially expressed genes both in BRAF and KRAS mutant cells included ERBB, TGFB and histone modification pathways. Together, the isogenic model systems presented here can provide insights to known and novel cancer pathways and can be used for drug discovery.

    Delarbeten
    1. Computational and molecular tools for scalable rAAV mediated genome editing
    Öppna denna publikation i ny flik eller fönster >>Computational and molecular tools for scalable rAAV mediated genome editing
    (Engelska)Manuskript (preprint) (Övrigt vetenskapligt)
    Abstract [en]

    The rapid discovery of potential driver mutations through large scale mutational analyses of human cancers generates a need to characterize their cellular phenotypes. Among the techniques for genome editing, recombinant adeno-associated virus (rAAV) mediated gene targeting is particularly suited to knock-in of single nucleotide substitutions. However, the generation of gene targeting constructs and the targeting process is time consuming and labor-intense. To facilitate rAAV mediated gene targeting, we developed the first software and complementary automation friendly vector tools to generate optimized targeting constructs for editing human protein encoding genes. By computational approaches, rAAV constructs for editing ~72% of bases in protein-coding exons were designed. Similarly, ~81% of genes were predicted to be targetable by rAAV mediated knock-out. A Gateway based cloning system for facile generation of rAAV constructs suitable for robotic automation was developed and used in successful generation of targeting constructs. Together, these tools enable automated rAAV targeting construct design, generation as well as enrichment and expansion of targeted cells with desired integrations.

    Nationell ämneskategori
    Medicinsk genetik
    Identifikatorer
    urn:nbn:se:uu:diva-235563 (URN)
    Tillgänglig från: 2014-11-05 Skapad: 2014-11-05 Senast uppdaterad: 2018-01-11
    2. The transcriptional modulator ZBED6 regulates cell cycle and growth of human colorectal cancer cells
    Öppna denna publikation i ny flik eller fönster >>The transcriptional modulator ZBED6 regulates cell cycle and growth of human colorectal cancer cells
    Visa övriga...
    (Engelska)Manuskript (preprint) (Övrigt vetenskapligt)
    Abstract [en]

    The transcription factor ZBED6 is a repressor of IGF2 whose action impacts development, cell proliferation and growth in placental mammals. In human colorectal cancers, IGF2 overexpression is mutually exclusive with somatic mutations in PI3K signaling components, providing genetic evidence for a role in the PI3K pathway. To understand the role of ZBED6 in tumorigenesis, we engineered and validated somatic cell ZBED6 knock-outs in the human colorectal cancer cell lines RKO and HCT116. Transcriptome analyses revealed enrichment of cell cycle-related processes among differentially expressed genes in both cell lines. Chromatin immunoprecipitation sequencing analyses displayed enrichment of ZBED6 binding at genes upregulated in ZBED6-/- knockout clones. Ten differentially expressed genes were identified as putative direct gene targets and their downregulation by ZBED6 was experimentally validated. Eight of these genes were linked to the Wnt, Hippo, TGF-b, EGFR or PI3K pathways, all involved in colorectal cancer development. Ablation of ZBED6 affected the cell cycle and led to increased growth rate of ZBED6-/- RKO cells. These observations support a role for transcriptional modulation by ZBED6 in cell cycle regulation and growth of colorectal cancers.

    Nationell ämneskategori
    Medicinsk genetik
    Identifikatorer
    urn:nbn:se:uu:diva-235564 (URN)
    Tillgänglig från: 2014-11-05 Skapad: 2014-11-05 Senast uppdaterad: 2018-01-11
    3. DIP2C regulates expression of the tumor suppressor gene CDKN2A
    Öppna denna publikation i ny flik eller fönster >>DIP2C regulates expression of the tumor suppressor gene CDKN2A
    Visa övriga...
    (Engelska)Manuskript (preprint) (Övrigt vetenskapligt)
    Abstract [en]

    The disco-interacting protein 2 homolog C (DIP2C) gene is an uncharacterized candidate

    breast and lung cancer gene. The gene contains a DMAP1 binding domain, pointing to

    potential involvement in DNMT1-dependent methylation. To study the role of DIP2C in

    tumor development, we engineered human DIP2C knockout cell systems by rAAV-mediated

    gene targeting. Homo- and heterozygous RKO DIP2C knockout cells displayed enlarged cells

    and growth retardation. This phenotype was most pronounced in DIP2C-/- knockouts, and

    these cells also displayed a significant decrease in DIP2C mRNA levels. RNA sequencing

    revealed 780 genes affected by the loss of DIP2C, including the cellular senescence marker

    P16INK4a. Functional annotation of the regulated genes shows enrichment of genes involved

    with cell death processes, cell structure and motility. Furthermore, KEGG pathway analysis

    shows association of 19 genes with pathways in cancer. In conclusion, the phenotypic data

    and expression changes induced by loss of DIP2C indicate that the gene function may be

    important for several biological processes implicated in cancer, and that loss of gene function

    may be a trigger of cellular senescence.

    Nationell ämneskategori
    Medicinsk genetik
    Identifikatorer
    urn:nbn:se:uu:diva-235565 (URN)
    Tillgänglig från: 2014-11-05 Skapad: 2014-11-05 Senast uppdaterad: 2018-01-11
    4. Core Ras Pathway Signaling in Human Colorectal Cancers Revealed by Isogenic Modeling of NF1, KRAS and BRAF Mutations
    Öppna denna publikation i ny flik eller fönster >>Core Ras Pathway Signaling in Human Colorectal Cancers Revealed by Isogenic Modeling of NF1, KRAS and BRAF Mutations
    2012 (Engelska)Ingår i: European Journal of Cancer, ISSN 0959-8049, E-ISSN 1879-0852, Vol. 48, nr Suppl.5, s. S118-S118Artikel i tidskrift, Meeting abstract (Refereegranskat) Published
    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:uu:diva-194476 (URN)10.1016/S0959-8049(12)71162-0 (DOI)000313036501006 ()
    Konferens
    22nd Biennial Congress of the European-Association-for-Cancer-Research, JUL 07-10, 2012, Barcelona, SPAIN
    Tillgänglig från: 2013-02-15 Skapad: 2013-02-14 Senast uppdaterad: 2017-12-06Bibliografiskt granskad
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  • 178.
    Ali, Muhammad Akhtar
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Genomik.
    Younis, Shady
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Wallerman, Ola
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Gupta, Rajesh
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Andersson, Leif
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Tobias Sjöblom, Tobias
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    The transcriptional modulator ZBED6 regulates cell cycle and growth of human colorectal cancer cellsManuskript (preprint) (Övrigt vetenskapligt)
    Abstract [en]

    The transcription factor ZBED6 is a repressor of IGF2 whose action impacts development, cell proliferation and growth in placental mammals. In human colorectal cancers, IGF2 overexpression is mutually exclusive with somatic mutations in PI3K signaling components, providing genetic evidence for a role in the PI3K pathway. To understand the role of ZBED6 in tumorigenesis, we engineered and validated somatic cell ZBED6 knock-outs in the human colorectal cancer cell lines RKO and HCT116. Transcriptome analyses revealed enrichment of cell cycle-related processes among differentially expressed genes in both cell lines. Chromatin immunoprecipitation sequencing analyses displayed enrichment of ZBED6 binding at genes upregulated in ZBED6-/- knockout clones. Ten differentially expressed genes were identified as putative direct gene targets and their downregulation by ZBED6 was experimentally validated. Eight of these genes were linked to the Wnt, Hippo, TGF-b, EGFR or PI3K pathways, all involved in colorectal cancer development. Ablation of ZBED6 affected the cell cycle and led to increased growth rate of ZBED6-/- RKO cells. These observations support a role for transcriptional modulation by ZBED6 in cell cycle regulation and growth of colorectal cancers.

  • 179.
    Ali, Zafar
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik. Uppsala universitet, Science for Life Laboratory, SciLifeLab. Human Molecular Genetics Laboratory, National Institute for Biotechnology and Genetic Engineering (NIBGE), PIEAS, Faisalabad, Pakistan.
    Zulfiqar, Shumaila
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Klar, Joakim
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Wikström, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Ullah, Farid
    Human Molecular Genetics Laboratory, National Institute for Biotechnology and Genetic Engineering (NIBGE), PIEAS, Faisalabad, Pakistan.
    Khan, Ayaz
    Human Molecular Genetics Laboratory, National Institute for Biotechnology and Genetic Engineering (NIBGE), PIEAS, Faisalabad, Pakistan.
    Abdullah, Uzma
    Human Molecular Genetics Laboratory, National Institute for Biotechnology and Genetic Engineering (NIBGE), PIEAS, Faisalabad, Pakistan.
    Baig, Shahid
    Human Molecular Genetics Laboratory, National Institute for Biotechnology and Genetic Engineering (NIBGE), PIEAS, Faisalabad, Pakistan.
    Dahl, Niklas
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Homozygous GRID2 missense mutation predicts a shift in the D-serine binding domain of GluD2 in a case with generalized brain atrophy and unusual clinical features2017Ingår i: BMC Medical Genetics, ISSN 1471-2350, E-ISSN 1471-2350, Vol. 18, nr 1, artikel-id 144Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BACKGROUND: Spinocerebellar ataxias comprise a large and heterogeneous group of disorders that may present with isolated ataxia, or ataxia in combination with other neurologic or non-neurologic symptoms. Monoallelic or biallelic GRID2 mutations were recently reported in rare cases with cerebellar syndrome and variable degree of ataxia, ocular symptoms, hypotonia and developmental delay.

    CASE PRESENTATION: We report on a consanguineous family with autosomal recessive childhood onset of slowly progressive cerebellar ataxia and delayed psychomotor development in three siblings. MRI of an adult and affected family member revealed slightly widened cerebral and cerebellar sulci, suggesting generalized brain atrophy, and mild cerebellar atrophy. Using whole exome sequencing we identified a novel homozygous missense variant [c.2128C > T, p.(Arg710Trp)] in GRID2 that segregates with the disease. The missense variant is located in a conserved region encoding the extracellular serine-binding domain of the GluD2 protein and predicts a change in conformation of the protein.

    CONCLUSION: The widespread supratentorial brain abnormalities, absence of oculomotor symptoms, increased peripheral muscle tone and the novel missense mutation add to the clinical and genetic variability in GRID2 associated cerebellar syndrome. The neuroradiological findings in our family indicate a generalized neurodegenerative process to be taken into account in other families segregating complex clinical features and GRID2 mutations.

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  • 180.
    Alim, Abdul
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Allmänmedicin och preventivmedicin. Public Health and Caring Sciences.
    Mechanisms in Tendon Healing: Pain, Biomarkers and the Role of Mast Cells2019Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [sv]

    Senskador och tendinopati är vanliga problem, men de underliggande mekanismerna otillräckligt undersökta. Målet med denna avhandling är att öka kunskapen om mekanismer under läkningen av senor, och hur dessa relaterar till smärta och inflammation.

    Syftet med den första studien var att kvantifiera biomarkörer för läkning av Achillessena, genom analys av prokollagen typ I (PINP) och typ III (PIIINP) hos 65 patienter efter ruptur av Achillessenan. Två veckor efter achillesruptur kvantifierades PINP och PIIINP-nivåerna med mikrodialys följt av ELISA-analys. Ett år efter achillesruptur bedömdes patienternas upplevda besvär med användning av ett validerat formulär, Achilles Tendon Total Rupture Score. Ökad andel PINP och PIIINP av totala mängden protein vid två veckor var signifikant associerat med mindre smärta men ökad fatigue i skadat ben efter ett år.

    I nästa studie utvärderade vi effekten av intermittent pneumatisk kompression (IPC) under två veckor av senans läkning efter achillesruptur. Patienterna fick antingen tilläggsbehandling med IPC eller vanlig behandling i gipsskena utan IPC. Vi kunde visa att behandling med IPC signifikant ökade nivån av PINP i den skadade senan, vilket tyder på förbättrad läkning.

    I den tredje studien undersökte vi mastcellers roll under läkningen av Achillessena efter ruptur i en råttmodell. Tre veckor postoperativt visade vi ett ökat antal mastceller och en högre andel degranulerade av mastceller i den läkande senan jämfört med senan på den andra (den friska) sidan. Vi kunde också påvisa glutamatreceptorn NMDAR1 hos mastceller i den läkande senan.

    I den fjärde studien bedömde vi effekten av glutamatstimulering in-vitro, på mastceller från benmärg hos mus. Degranulering av mastceller kvantifierades genom frisättning av β-hexosaminidas. För att kvantifiera NMDAR på proteinnivå använde vi immunfluorescens, och för att studera uttrycket av NMDAR och associerade gener använde vi RT-qPCR/mikroarray. Vi kunde visa att glutamat inducerar uppreglering av glutamatreceptorer av både jonotropisk och metabotropisk typ i mastceller, både på mRNA- och proteinnivå. NMDAR1 samlokaliserade med glutamat i membranet på mastceller, vilket därmed bekräftar en interaktion mellan glutamat och dess receptor. Glutamat inducerade också uttryck av pro-inflammatoriska proteiner såsom IL-6 och CCL2, samt transkriptionsfaktorer såsom Egr2, Egr3 och FosB. Dessutom upphävde NMDA-kanalblockeraren MK-801 fullständigt effekten av glutamat på mastceller, vilket talar för en funktionell betydelse av interaktionen mellan glutamat och glutamatreceptorer i mastceller.

    Sammantaget visar de fynd som presenteras i denna avhandling möjliga mekanismer för läkning av Achillessena i relation till smärta och funktion och introducerar en ny princip för hur immunceller kan kommunicera med nervceller efter achillesruptur.

    Delarbeten
    1. Procollagen markers in microdialysate can predict patient outcome after Achilles tendon rupture.
    Öppna denna publikation i ny flik eller fönster >>Procollagen markers in microdialysate can predict patient outcome after Achilles tendon rupture.
    2016 (Engelska)Ingår i: BMJ open sport & exercise medicine, ISSN 2055-7647, Vol. 2, nr 1, artikel-id e000114Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    OBJECTIVE: Patients who sustain acute Achilles tendon rupture (ATR) exhibit variable and mostly impaired long-term functional, and patient-reported outcomes. However, there exists a lack of early predictive markers of long-term outcomes to facilitate the development of improved treatment methods. The aim of this study was to assess markers of tendon callus production in patients with ATR in terms of outcome, pain, and fatigue.

    STUDY DESIGN AND SETTING: Prospective cohort study; level of evidence 2. Outpatient orthopaedic/sports medicine department.

    PATIENTS: A total of 65 patients (57 men, 8 women; mean age 41±7 years) with ATR were prospectively assessed.

    ASSESSMENTS: Markers of tendon callus production, procollagen type I N-terminal propeptide (PINP) and procollagen type III N-terminal propeptide (PIIINP), were assessed 2 weeks postoperatively using microdialysis followed by enzymatic quantification. Normalised procollagen levels (n-PINP and n-PIIINP) were calculated as the ratio of procollagen to total protein content. Pain and fatigue were assessed at 1 year using reliable questionnaires Achilles tendon Total Rupture Score (ATRS).

    RESULTS: Patients exhibited fatigue (77.6%) and pain (44.1%) to some extent. Higher levels of n-PINP (R=0.38, p=0.016) and n-PIIINP (R=0.33, p=0.046) were significantly associated with less pain in the limb. Increased concentrations of PINP (R=-0.47, p=0.002) and PIIINP (R=-0.37, p=0.024) were related to more self-reported fatigue in the leg. The results were corroborated by multiple linear regression analyses.

    CONCLUSIONS: Assessment of procollagen markers in early tendon healing can predict long-term patient-reported outcomes after ATR. These novel findings suggest that procollagen markers could be used to facilitate the development of improved treatment methods in patients who sustain ATR.

    TRIAL REGISTRATION NUMBERS: NCT01317160: Results. NCT02318472: Pre-results.

    Ort, förlag, år, upplaga, sidor
    London, UK: , 2016
    Nyckelord
    Achilles, Chronic, Collagen, Injuries, Tendon
    Nationell ämneskategori
    Ortopedi
    Forskningsämne
    Ortopedi
    Identifikatorer
    urn:nbn:se:uu:diva-395018 (URN)10.1136/bmjsem-2016-000114 (DOI)27900179 (PubMedID)
    Tillgänglig från: 2019-10-11 Skapad: 2019-10-11 Senast uppdaterad: 2020-02-19Bibliografiskt granskad
    2. Achilles tendon rupture healing is enhanced by intermittent pneumatic compression upregulating collagen type I synthesis
    Öppna denna publikation i ny flik eller fönster >>Achilles tendon rupture healing is enhanced by intermittent pneumatic compression upregulating collagen type I synthesis
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    2018 (Engelska)Ingår i: Knee Surgery, Sports Traumatology, Arthroscopy, ISSN 0942-2056, E-ISSN 1433-7347, Vol. 26, nr 7, s. 2021-2029Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    PURPOSE AND HYPOTHESIS: Adjuvant intermittent pneumatic compression (IPC) during leg immobilization following Achilles tendon rupture (ATR) has been shown to reduce the risk of deep venous thrombosis. The purpose of this study was to investigate whether IPC can also promote tendon healing.

    METHODS: One hundred and fifty patients with surgical repair of acute ATR were post-operatively leg immobilized and prospectively randomized. Patients were allocated for 2 weeks of either adjuvant IPC treatment (n = 74) or treatment-as-usual (n = 74) in a plaster cast without IPC. The IPC group received 6 h daily bilateral calf IPC applied under an orthosis on the injured side. At 2 weeks post-operatively, tendon healing was assessed using microdialysis followed by enzymatic quantification of tendon callus production, procollagen type I (PINP) and type III (PIIINP) N-terminal propeptide, and total protein content. 14 IPC and 19 cast patients (control group) consented to undergo microdialysis. During weeks 3-6, all subjects were leg-immobilized in an orthosis without IPC. At 3 and 12 months, patient-reported outcome was assessed using reliable questionnaires (ATRS and EQ-5D). At 12 months, functional outcome was measured using the validated heel-rise test.

    RESULTS: At 2 weeks post-rupture, the IPC-treated patients exhibited 69% higher levels of PINP in the ruptured Achilles tendon (AT) compared to the control group (p = 0.001). Interestingly, the IPC-treated contralateral, intact AT also demonstrated 49% higher concentrations of PINP compared to the non-treated intact AT of the plaster cast group (p = 0.002). There were no adverse events observed associated with IPC. At 3 and 12 months, no significant (n.s.) differences between the two treatments were observed using patient-reported and functional outcome measures.

    CONCLUSIONS: Adjuvant IPC during limb immobilization in patients with ATR seems to effectively enhance the early healing response by upregulation of collagen type I synthesis, without any adverse effects. Whether prolonged IPC application during the whole immobilization period can also lead to improved long-term clinical healing response should be further investigated. The healing process during leg immobilization in patients with Achilles tendon rupture can be improved through adjuvant IPC therapy, which additionally prevents deep venous thrombosis.

    LEVEL OF EVIDENCE: Randomized controlled trial, Level I.

    Nyckelord
    Achilles tendon rupture, Intermittent pneumatic compression devices, Microdialysis, Procollagen, Regeneration
    Nationell ämneskategori
    Kirurgi
    Identifikatorer
    urn:nbn:se:uu:diva-395017 (URN)10.1007/s00167-017-4621-8 (DOI)28668970 (PubMedID)
    Tillgänglig från: 2019-10-11 Skapad: 2019-10-11 Senast uppdaterad: 2020-02-19Bibliografiskt granskad
    3. Increased mast cell degranulation and co-localization of mast cells with the NMDA receptor-1 during healing after Achilles tendon rupture
    Öppna denna publikation i ny flik eller fönster >>Increased mast cell degranulation and co-localization of mast cells with the NMDA receptor-1 during healing after Achilles tendon rupture
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    2017 (Engelska)Ingår i: Cell and Tissue Research, ISSN 0302-766X, E-ISSN 1432-0878, Vol. 370, nr 3, s. 451-460Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    The role of inflammation and the mechanism of tendon healing after rupture has historically been a matter of controversy. The purpose of the present study is to investigate the role of mast cells and their relation to the NMDA receptor-1 (a glutamate receptor) during healing after Achilles tendon rupture. Eight female Sprague Dawley rats had their right Achilles tendon transected. Three weeks after rupture, histological quantification of mast cell numbers and their state of degranulation was assessed by histochemistry. Co-localization of mast cell tryptase (a mast cell marker) and NMDA receptor-1 was determined by immunofluorescence. The intact left Achilles tendon was used as control. An increased number of mast cells and a higher proportion of degranulated mast cells were found in the healing Achilles tendon compared to the intact. In addition, increased co-localization of mast cell tryptase and NMDA receptor-1 was seen in the areas of myotendinous junction, mid-tendon proper and bone tendon junction of the healing versus the intact tendon. These findings introduce a possible role for mast cells in the healing phase after Achilles tendon rupture.

    Ort, förlag, år, upplaga, sidor
    Berlin Heidelberg: , 2017
    Nyckelord
    Achilles tendon healing, Mast cells, NMDA, Rats, Tryptase
    Nationell ämneskategori
    Cell- och molekylärbiologi
    Forskningsämne
    Ortopedi; Immunologi
    Identifikatorer
    urn:nbn:se:uu:diva-395522 (URN)10.1007/s00441-017-2684-y (DOI)000416358400010 ()28975451 (PubMedID)
    Tillgänglig från: 2019-10-20 Skapad: 2019-10-20 Senast uppdaterad: 2020-02-06Bibliografiskt granskad
    4. Glutamate Triggers the Expression of Functional Ionotropic and Metabotropic Glutamate Receptors in Mast Cells
    Öppna denna publikation i ny flik eller fönster >>Glutamate Triggers the Expression of Functional Ionotropic and Metabotropic Glutamate Receptors in Mast Cells
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    (Engelska)Manuskript (preprint) (Övrigt vetenskapligt)
    Nyckelord
    Glutamate, glutamate receptors, mast cells, NMDA-receptors, tryptase
    Nationell ämneskategori
    Cell- och molekylärbiologi Immunologi inom det medicinska området
    Forskningsämne
    Immunologi; Neurovetenskap
    Identifikatorer
    urn:nbn:se:uu:diva-394714 (URN)
    Tillgänglig från: 2019-10-09 Skapad: 2019-10-09 Senast uppdaterad: 2019-10-23
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  • 181.
    Alim, Md Abdul
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Allmänmedicin och preventivmedicin. Department of Molecular Medicine and Surgery, Karolinska Institutet.
    Ackermann, Paul W
    Karolinska Inst, Dept Mol Med & Surg, Solna, Sweden.
    Eliasson, Pernilla
    Linkoping Univ, Dept Clin & Expt Med, Linkoping, Sweden.
    Blomgran, Parmis
    Linkoping Univ, Dept Clin & Expt Med, Linkoping, Sweden.
    Kristiansson, Per
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Allmänmedicin och preventivmedicin.
    Pejler, Gunnar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi. Swedish Univ Agr Sci, Dept Anat Physiol & Biochem, Uppsala, Sweden.
    Peterson, Magnus
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Allmänmedicin och preventivmedicin.
    Increased mast cell degranulation and co-localization of mast cells with the NMDA receptor-1 during healing after Achilles tendon rupture2017Ingår i: Cell and Tissue Research, ISSN 0302-766X, E-ISSN 1432-0878, Vol. 370, nr 3, s. 451-460Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The role of inflammation and the mechanism of tendon healing after rupture has historically been a matter of controversy. The purpose of the present study is to investigate the role of mast cells and their relation to the NMDA receptor-1 (a glutamate receptor) during healing after Achilles tendon rupture. Eight female Sprague Dawley rats had their right Achilles tendon transected. Three weeks after rupture, histological quantification of mast cell numbers and their state of degranulation was assessed by histochemistry. Co-localization of mast cell tryptase (a mast cell marker) and NMDA receptor-1 was determined by immunofluorescence. The intact left Achilles tendon was used as control. An increased number of mast cells and a higher proportion of degranulated mast cells were found in the healing Achilles tendon compared to the intact. In addition, increased co-localization of mast cell tryptase and NMDA receptor-1 was seen in the areas of myotendinous junction, mid-tendon proper and bone tendon junction of the healing versus the intact tendon. These findings introduce a possible role for mast cells in the healing phase after Achilles tendon rupture.

    Ladda ner fulltext (pdf)
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  • 182.
    Alim, Md Abdul
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Allmänmedicin och preventivmedicin.
    Grujic, Mirjana
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Ackerman, Paul W.
    Karolinska Institutet, Department of Molecular Medicine and Surgery, Stockholm, Sweden.
    Kristiansson, Per
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Allmänmedicin och preventivmedicin.
    Peterson, Magnus
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Allmänmedicin och preventivmedicin.
    Pejler, Gunnar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi. Swedish University of Agricultural Sciences, Department of Anatomy, Physiology and Biochemistry, Uppsala, Sweden.
    Glutamate Triggers the Expression of Functional Ionotropic and Metabotropic Glutamate Receptors in Mast CellsManuskript (preprint) (Övrigt vetenskapligt)
  • 183.
    Alimohammadi, Mohammad
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Molecular Targets in Autoimmune Polyendocrine Syndrome Type1 and Their Clinical Implications2009Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    Autoimmune diseases occur when the immune system attacks and destroys healthy body tissue. Autoimmunity is known to cause a wide range of disorders, and is suspected to be responsible for many more. Most autoimmune disorders are chronic and cause severe morbidity for the patients, and are also costly for society. A majority of these disorders are today considered as complex diseases with incompletely known etiology. Hence, model systems for studying the pathogenesis of autoimmunity are important to unravel its causes.

    Autoimmune Polyendocrine Syndrome Type 1 (APS-1), (OMIM 240300), is a rare autoimmune disorder. Patients with APS-1 progressively develop multiple organ-specific autoimmune lesions involving both endocrine and non endocrine tissues. Typical autoimmune disease components in APS-1 are hypoparathyroidism, Addison’s disease, vitiligo, alopecia and type 1 diabetes. The gene preventing APS-1 has been identified and designated Autoimmune Regulator (AIRE). It has been shown that mutations of AIRE cause loss of tolerance to self-structures, resulting in organ-specific autoimmunity.

    Although APS-1 is a rare syndrome occurring mainly in genetically isolated populations, the disease components of APS-1 are, in isolated forms, not unusual in the general population and affect many patients. Hence, APS-1 is an attractive model disease for studies of molecular mechanisms underlying organ-specific autoimmunity.

    This thesis concerns investigations in which two novel autoantigens are identified in APS-1 and used in serological diagnosis of the disease. NALP5, is identified as a parathyroid autoantigen - an important finding since autoimmune hypoparathyroidism is one of the cardinal symptoms of APS-1. Additionally, KCNRG is identified as a bronchial autoantigen in APS-1 patients with respiratory symptoms. Finally, studies that compare the immune response in APS-1 patients and the mouse model for APS-1 are presented.

    Delarbeten
    1. Aire deficient mice do not develop the same profile of tissue-specific autoantibodies as APECED patients
    Öppna denna publikation i ny flik eller fönster >>Aire deficient mice do not develop the same profile of tissue-specific autoantibodies as APECED patients
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    2006 (Engelska)Ingår i: Journal of Autoimmunity, ISSN 0896-8411, E-ISSN 1095-9157, Vol. 27, nr 2, s. 96-104Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED, or APS1), is a monogenic autoimmune disease caused by mutations in the autoimmune regulator (AIRE) gene. The three main components of APECED are chronic mucocuteaneous candidiasis, hypoparathyroidism and adrenocortical insufficiency. However, several additional endocrine or other autoimmune disease components, or ectodermal dystrophies form the individually variable clinical picture of APECED. An important feature of APECED is a spectrum of well-characterized circulating autoantibodies, reacting against tissue-specific autoantigens. Aire deficient mice develop some characteristics of APECED phenotype. In order to investigate whether the Aire deficient mice produce autoantibodies similar to human APECED, we studied the reactivity of Aire mouse sera against mouse homologues of 11 human APECED antigens. None of the APECED antigens indicated elevated reactivity in the Aire knock-out mouse sera, implying the absence of APECED associated autoantibodies in Aire deficient mice. These findings were supported by the failure of the autoantigens to activate mouse T-cells. Furthermore, Aire knock-out mice did not express increased levels of anti-nuclear antibodies compared to wt mice. This study indicates that spontaneous induction of tissue-specific autoantibodies similar to APECED does not occur in the rodent model suggesting differences in the immunopathogenic mechanisms between mice and men.

    Nyckelord
    APS1, Autoantigen, Autoimmune regulator, Knock-out mouse
    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:uu:diva-98037 (URN)10.1016/j.jaut.2006.06.001 (DOI)000241661500004 ()16820279 (PubMedID)
    Tillgänglig från: 2009-02-11 Skapad: 2009-02-11 Senast uppdaterad: 2017-12-14Bibliografiskt granskad
    2. Autoimmune Polyendocrine Syndrome Type 1: NALP5 in Autoimmune Polyendocrine Syndrome Type 1
    Öppna denna publikation i ny flik eller fönster >>Autoimmune Polyendocrine Syndrome Type 1: NALP5 in Autoimmune Polyendocrine Syndrome Type 1
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    2006 (Engelska)Ingår i: The New England Journal of Medicine, Vol. 358, nr 10, s. 1018-28Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Background Autoimmune polyendocrine syndrome type 1 (APS-1) is a multiorgan autoimmune disorder caused by mutations in AIRE, the autoimmune regulator gene. Though recent studies concerning AIRE deficiency have begun to elucidate the molecular pathogenesis of organ-specific autoimmunity in patients with APS-1, the autoantigen responsible for hypoparathyroidism, a hallmark of APS-1 and its most common autoimmune endocrinopathy, has not yet been identified.

    Methods We performed immunoscreening of a human parathyroid complementary DNA library, using serum samples from patients with APS-1 and hypoparathyroidism, to identify patients with reactivity to the NACHT leucine-rich-repeat protein 5 (NALP5). Subsequently, serum samples from 87 patients with APS-1 and 293 controls, including patients with other autoimmune disorders, were used to determine the frequency and specificity of autoantibodies against NALP5. In addition, the expression of NALP5 was investigated in various tissues.

    Results NALP5-specific autoantibodies were detected in 49% of the patients with APS-1 and hypoparathyroidism but were absent in all patients with APS-1 but without hypoparathyroidism, in all patients with other autoimmune endocrine disorders, and in all healthy controls. NALP5 was predominantly expressed in the cytoplasm of parathyroid chief cells.

    Conclusions NALP5 appears to be a tissue-specific autoantigen involved in hypoparathyroidism in patients with APS-1. Autoantibodies against NALP5 appear to be highly specific and may be diagnostic for this prominent component of APS-1.

    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:uu:diva-98038 (URN)
    Tillgänglig från: 2009-02-11 Skapad: 2009-02-11 Senast uppdaterad: 2009-09-29Bibliografiskt granskad
    3. NALP5 - a Target for Autoantibodies in AIRE Deficient Mice Reflecting the Autoimmune Status
    Öppna denna publikation i ny flik eller fönster >>NALP5 - a Target for Autoantibodies in AIRE Deficient Mice Reflecting the Autoimmune Status
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    (Engelska)Manuskript (Övrigt vetenskapligt)
    Identifikatorer
    urn:nbn:se:uu:diva-98039 (URN)
    Tillgänglig från: 2009-02-11 Skapad: 2009-02-11 Senast uppdaterad: 2010-05-06Bibliografiskt granskad
    4. Pulmonary Autoimmunity as a Feature of Autoimmune Polyendocrine Syndrome Type 1 and Identification of KCNRG as a Bronchial Autoantigen
    Öppna denna publikation i ny flik eller fönster >>Pulmonary Autoimmunity as a Feature of Autoimmune Polyendocrine Syndrome Type 1 and Identification of KCNRG as a Bronchial Autoantigen
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    2009 (Engelska)Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 106, nr 11, s. 4396-4401Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Patients with autoimmune polyendocrine syndrome type 1 (APS-1) suffer from multiple organ-specific autoimmunity with autoantibodies against target tissue-specific autoantigens. Endocrine and nonendocrine organs such as skin, hair follicles, and liver are targeted by the immune system. Despite sporadic observations of pulmonary symptoms among APS-1 patients, an autoimmune mechanism for pulmonary involvement has not been elucidated. We report here on a subset of APS-1 patients with respiratory symptoms. Eight patients with pulmonary involvement were identified. Severe airway obstruction was found in 4 patients, leading to death in 2. Immunoscreening of a cDNA library using serum samples from a patient with APS-1 and obstructive respiratory symptoms identified a putative potassium channel regulator (KCNRG) as a pulmonary autoantigen. Reactivity to recombinant KCNRG was assessed in 110 APS-1 patients by using immunoprecipitation. Autoantibodies to KCNRG were present in 7 of the 8 patients with respiratory symptoms, but in only 1 of 102 APS-1 patients without respiratory symptoms. Expression of KCNRG messenger RNA and protein was found to be predominantly restricted to the epithelial cells of terminal bronchioles. Autoantibodies to KCNRG, a protein mainly expressed in bronchial epithelium, are strongly associated with pulmonary involvement in APS-1. These findings may facilitate the recognition, diagnosis, characterization, and understanding of the pulmonary manifestations of APS-1.

    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:uu:diva-98040 (URN)10.1073/pnas.0809986106 (DOI)000264278800062 ()19251657 (PubMedID)
    Tillgänglig från: 2009-02-11 Skapad: 2009-02-11 Senast uppdaterad: 2017-12-14Bibliografiskt granskad
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  • 184.
    Alimohammadi, Mohammed
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Dermatologi och venereologi.
    Rostedt Punga, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Klinisk neurofysiologi.
    Neurophysiological Measures of Efficacy and Safety for Botulinum Toxin Injection in Facial and Bulbar Muscles: Special Considerations2017Ingår i: Toxins, ISSN 2072-6651, E-ISSN 2072-6651, Vol. 9, nr 11, artikel-id 352Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    Botulinum toxin (BoNT) injections into facial and bulbar muscles are widely and increasingly used as medical treatments for cervical and facial dystonia, facial hemispasm, correction of facial palsy, hyperhidrosis, as well as cosmetic treatment of glabellar lines associated with grief and anger. Although BoNT treatment is generally considered safe, the diffusion of the toxin to surrounding muscles may result in complications, including difficulties swallowing, in a dose-dependent manner. The sensitivity of clinical examination for detecting adverse events after BoNT treatment is limited. Few reports have highlighted the potential effects on other muscles in the facial area due to the spreading of the toxin. The possibilities of spreading and thus unknown pharmacological BoNT effects in non-targeted muscles emphasise the importance of correct administration of BoNT in terms of dose selection, injection points, and appropriate effect surveillance. In this review article, we will focus on novel objective measures of efficacy and safety regarding BoNT treatment of facial muscles and the reasons why this is important.

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  • 185.
    Alinaghizadeh, Hassan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Arbets- och miljömedicin.
    Radioactive fall-out from the Chernobyl nuclear power plant accident in 1986 and cancer rates in Sweden, a 25-year follow up2019Licentiatavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    Aim: The current research aimed to study the association between exposure to low-dose radiation fallout after the Chernobyl accident in 1986 and the incidence of cancer in Sweden.

    Methods: A nationwide study population, selecting information from nine counties out of 21 in Sweden for the period from 1980 – 2010.

    In the first study, an ecological design was defined for two closed cohorts from 1980 and 1986. A possible exposure response pattern between the exposure to 137Cs on the ground and the cancer incidence after the Chernobyl nuclear power plant accident was investigated in the nine northernmost counties of Sweden (n=2.2 million). The activity of 137Cs at the county, municipality and parish level in 1986 was retrieved from the Swedish Radiation Safety Authority (SSI) and used as a proxy for received dose of ionizing radiation. Information about diagnoses of cancer (ICD-7 code 140-209) from 1958 – 2009 were received from the Swedish Cancer Registry, National Board of Health and Welfare (368,244 cases were reported for the period 1958 to 2009). The incidence rate ratios were calculated by using Poisson Regression for pre-Chernobyl (1980 – 1986) and post-Chernobyl (1986 – 2009) using average deposition of 137Cs at three geographical levels: county (n=9), municipality (n=95), and parish level (n=612). Also, a time trend analysis with age standardized cancer incidence in the study population and in the general Swedish population was drawn from 1980 – 2009.

    In the second study, a closed cohort was defined as all individuals living in the three most contaminated counties in mid-Sweden in 1986. Fallout of 137Cs was retrieved as a digital map from the Geological Survey of Sweden, demographic data from Statistics Sweden, and cancer diagnosis from the Swedish Cancer Registry, National Board of Health and Welfare. Individuals were assigned an annual 137Cs exposure based on their place of residence (1986 through 1990), from which 5-year cumulative 137Cs exposures were calculated, accounting for the physical decay of 137Cs and changing residencies. Hazard ratios for having cancer during the follow-up period, adjusted for age, sex, rural/non-rural residence, and pre-Chernobyl total cancer incidence, were calculated.

    Results: No obvious exposure-response pattern in the age-standardized total cancer incidence rate ratios could be seen in the first study. However, a spurious association between the fallout and cancer incidence was present, where areas with the lowest incidence of cancer before the accident coincidentally had the lowest fallout of cesium-137. Increasing the geographical resolution of exposure from the average values of nine counties to the average values of 612 parishes resulted in two to three times higher degree of variance explanation by regression model. There was a secular trend, with an increase in age standardized incidence of cancer from 1980 – 2009. This trend was stronger in the general Swedish population compared to the nine counties of the present study.

    In the second study, 734,537 people identified were divided into three exposure categories: the first quartile was low exposure (0.0 to 45.4 kBq/m2), the second and third quartiles were intermediate exposure (45.41 to 118.8 kBq/m2), and the fourth quartile was highest exposure (118.81 to 564.71 kBq/m2). Between 1991 and 2010, 82,495 cancer cases were registered in the three counties. Adjusted HRs (95% CI) were 1.03 (1.01 to 1.05) for intermediate exposure, and 1.05 (1.03 to 1.07) for the highest exposure, when comparing to the reference exposure.

    Conclusion: Using the ecological data, there was no exposure response trend; however, after refining the data to the individual level of exposure, there was an overall exposure response pattern. Nonetheless, due to the time dependency, these results were restricted to the age group of 25 – 49 among males. Using register-based data only, for determining the association between low-dose exposure to radiation and the risk of developing cancer, is difficult since we cannot control for other significant factors that are associated with cancer.

    Delarbeten
    1. Cancer incidence in northern Sweden before and after the Chernobyl nuclear power plant accident
    Öppna denna publikation i ny flik eller fönster >>Cancer incidence in northern Sweden before and after the Chernobyl nuclear power plant accident
    2014 (Engelska)Ingår i: Radiation and Environmental Biophysics, ISSN 0301-634X, E-ISSN 1432-2099, Vol. 53, nr 3, s. 495-504Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Sweden received about 5 % of the total release of Cs-137 from the Chernobyl nuclear power plant accident in 1986. The distribution of the fallout mainly affected northern Sweden, where some parts of the population could have received an estimated annual effective dose of 1-2 mSv per year. It is disputed whether an increased incidence of cancer can be detected in epidemiological studies after the Chernobyl nuclear power plant accident outside the former Union of Soviet Socialist Republics. In the present paper, a possible exposure-response pattern between deposition of Cs-137 and cancer incidence after the Chernobyl nuclear power plant accident was investigated in the nine northernmost counties of Sweden (2.2 million inhabitants in 1986). The activity of Cs-137 from the fallout maps at 1986 was used as a proxy for the received dose of ionizing radiation. Diagnoses of cancer (ICD-7 code 140-209) from 1980 to 2009 were received from the Swedish Cancer Registry (273,222 cases). Age-adjusted incidence rate ratios, stratified by gender, were calculated with Poisson regression in two closed cohorts of the population in the nine counties 1980 and 1986, respectively. The follow-up periods were 1980-1985 and 1986-2009, respectively. The average surface-weighted deposition of Cs-137 at three geographical levels; county (n = 9), municipality (n = 95) and parish level (n = 612) was applied for the two cohorts to study the pre- and the post-Chernobyl periods separately. To analyze time trends, the age-standardized total cancer incidence was calculated for the general Swedish population and the population in the nine counties. Joinpoint regression was used to compare the average annual percent change in the general population and the study population within each gender. No obvious exposure-response pattern was seen in the age-adjusted total cancer incidence rate ratios. A spurious association between fallout and cancer incidence was present, where areas with the lowest incidence of cancer before the accident coincidentally had the lowest fallout of Cs-137. Increasing the geographical resolution of exposure from nine county averages to 612 parish averages resulted in a two to three times higher value of variance in the regression model. There was a secular trend with an increase in age-standardized incidence of cancer in both genders from 1980 to 2009, but significant only in females. This trend was stronger and statistically significant for both genders in the general Swedish population compared to the nine counties. In conclusion, using both high quality cancer registry data and high resolution exposure maps of Cs-137 deposition, it was not possible to distinguish an effect of Cs-137 on cancer incidence after the Chernobyl nuclear power plant accident in Sweden.

    Nyckelord
    Cancer, Cesium-137, Chernobyl, Ecological study, Environment, Epidemiology, Ionizing radiation, Nuclear accident, Radiation, Sweden
    Nationell ämneskategori
    Arbetsmedicin och miljömedicin
    Identifikatorer
    urn:nbn:se:uu:diva-231289 (URN)10.1007/s00411-014-0545-6 (DOI)000339898300003 ()24811728 (PubMedID)
    Tillgänglig från: 2014-09-08 Skapad: 2014-09-07 Senast uppdaterad: 2019-03-28Bibliografiskt granskad
    2. Total cancer incidence in relation to 137Cs fallout in the most contaminated counties in Sweden after the Chernobyl nuclear power plant accident: a register-based study
    Öppna denna publikation i ny flik eller fönster >>Total cancer incidence in relation to 137Cs fallout in the most contaminated counties in Sweden after the Chernobyl nuclear power plant accident: a register-based study
    2016 (Engelska)Ingår i: BMJ Open, ISSN 2044-6055, E-ISSN 2044-6055, Vol. 6, nr 12, artikel-id e011924Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    OBJECTIVES: To determine the total cancer incidence in relation to a 5-year exposure to caesium-137 ((137)Cs) from the 1986 Chernobyl nuclear power plant accident.

    METHODS: A closed cohort was defined as all individuals living in the three most contaminated counties in mid-Sweden in 1986. Fallout of (137)Cs was retrieved as a digital map from the Geological Survey of Sweden, demographic data from Statistics Sweden, and cancer diagnosis from the National Board of Health and Welfare. Individuals were assigned an annual (137)Cs exposure based on their place of residence (1986-1990), from which 5-year cumulative (137)Cs exposures were calculated, accounting for the physical decay of (137)Cs and changing residencies. HRs were adjusted for age, sex, rural/non-rural residence and pre-Chernobyl total cancer incidence.

    RESULTS: The 734 537 people identified were categorised by exposure: the first quartile was low exposure (0.0-45.4 kBq/m(2)), the second and third quartiles were intermediate exposure (45.41-118.8 kBq/m(2)), and the fourth quartile was the highest exposure (118.81-564.71 kBq/m(2)). Between 1991 and 2010, 82 495 cancer cases were registered in the 3 counties. Adjusted HRs (95% CI) were 1.03 (1.01 to 1.05) for intermediate exposure and 1.05 (1.03 to 1.07) for the highest exposure compared to the reference exposure.

    CONCLUSIONS: We found a small overall exposure-response pattern of the total cancer incidence related to (137)Cs after adjustment for age, sex, rural residence and pre-Chernobyl cancer incidence.

    Nationell ämneskategori
    Arbetsmedicin och miljömedicin
    Identifikatorer
    urn:nbn:se:uu:diva-311895 (URN)10.1136/bmjopen-2016-011924 (DOI)000391303600003 ()27998898 (PubMedID)
    Tillgänglig från: 2017-01-03 Skapad: 2017-01-03 Senast uppdaterad: 2019-03-28Bibliografiskt granskad
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  • 186.
    Al-kaisy, Muhammad
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Nilsson, Matthias
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Persson, Linda
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Petterson Bergstrand, Madeleine
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Sterby, Mia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Vall, Maria
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Wang, Pin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    En förstudie för framtagning av HIV-proteashämmare: Me-too läkemedel till indinavir2012Självständigt arbete på grundnivå (kandidatexamen), 10 poäng / 15 hpStudentuppsats (Examensarbete)
    Abstract [sv]

    Syftet med denna rapport är att ta fram analoger till indinavir som binder bra till HIV-Iproteaset, wild-type och mutationer. Dessa analoger ska sedan kunna testas experimentelltmed enzymassay och cellbaserad β-galaktosidas aktivitetsassay för att se om de har potentialatt bli nya proteashämmare mot HIV. 80 analoger som tillhandahölls från företagetanlyserades med hjälp av datorsimuleringar för att ta reda på vilka strukturelement som bidrartill bra respektive dålig bindning till HIV-I proteaset och några av de lämpligaste mutationerna.Utifrån resultatet från datoranalysen kunde 48 nya analoger tas fram och även dessaanalyserades med olika beräkningsmoduler. De 30 analogerna med bäst inbindning till wildtypeproteaset och mutationerna valdes ut och rankades. Alla utom en av dessa analoger hadebättre inbindning till proteaset än Indinavir.

  • 187.
    Allander, Lisa
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Fitness and virulence of epidemic and non-epidemic clones of extensively drug-resistant (XDR) carbapenemase-producing Klebsiella pneumoniae2018Självständigt arbete på avancerad nivå (masterexamen), 30 poäng / 45 hpStudentuppsats (Examensarbete)
    Publikationen är tillgänglig i fulltext från 2021-08-31 09:48
  • 188.
    Allen, Marie
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Bjerke, Mia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab. Karolinska Inst, Dept Lab Med, SE-14186 Stockholm, Sweden..
    Edlund, Hanna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för organismbiologi, Evolution och utvecklingsbiologi.
    Nelander, Sven
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Westermark, Bengt
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Origin of the U87MG glioma cell line: Good news and bad news2016Ingår i: Science Translational Medicine, ISSN 1946-6234, E-ISSN 1946-6242, Vol. 8, nr 354, artikel-id 354re3Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Human tumor-derived cell lines are indispensable tools for basic and translational oncology. They have an infinite life span and are easy to handle and scalable, and results can be obtained with high reproducibility. However, a tumor-derived cell line may not be authentic to the tumor of origin. Two major questions emerge: Have the identity of the donor and the actual tumor origin of the cell line been accurately determined? To what extent does the cell line reflect the phenotype of the tumor type of origin? The importance of these questions is greatest in translational research. We have examined these questions using genetic profiling and transcriptome analysis in human glioma cell lines. We find that the DNA profile of the widely used glioma cell line U87MG is different from that of the original cells and that it is likely to be a bona fide human glioblastoma cell line of unknown origin.

  • 189.
    Allkja, Jontana
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    The influence of copper on mast cell during bacterial infections2017Självständigt arbete på avancerad nivå (masterexamen), 30 poäng / 45 hpStudentuppsats (Examensarbete)
    Abstract [en]

    Mast cells are innate immune cells generally known for their harmful effects, particularly their role in asthma and autoimmune diseases. However, they can also recognize pathogens and mount a response to them. Copper is essential for proper cell function and homeostasis. Research has shown that changes in copper levels can affect mast cell morphology and gene expression of many of its immune mediators. It has also been shown that the copper transporter Ctr2 plays an important role in mast cell physiology. In this project, we investigated whether the same effects can be seen when mast cells are stimulated with bacteria, namely Staphylococcus aureus (S. aureus) and Escherichia coli (E. coli). For this purpose, wild type and Ctr2 knockout mast cells were treated with different concentrations of copper for 72 hours and later co-cultured with either S. aureus or E. coli. Wild type cells were also treated with a copper chelator to investigate the effect of copper starvation. Release of IL-6 and CCL2, two common mediators released in response to bacteria, were measured by ELISA, while their gene expression was measured by qPCR. Results showed that either copper starvation or, 10 μM copper cause an increase in IL-6 and CCL2 protein levels, but have no effect on gene expression. The 10 μM copper effect was not observed in the Ctr2 knockout cells. In conclusion, not much is known about the mechanisms involved in the mast cell response to bacteria. However, it appears that copper can affect either different stages of the same pathway, or different pathways in a similar manner.

  • 190.
    Allum, Fiona
    et al.
    McGill Univ, Dept Human Genet, Montreal, PQ H3A 0C7, Canada;McGill Univ, Montreal, PQ H3A 0G1, Canada;Genome Quebec Innovat Ctr, Montreal, PQ H3A 0G1, Canada.
    Hedman, Asa K.
    Karolinska Inst, Cardiovasc Med Unit, Dept Med Solna, S-17176 Stockholm, Sweden.
    Shaol, Xiaojian
    McGill Univ, Dept Human Genet, Montreal, PQ H3A 0C7, Canada;McGill Univ, Montreal, PQ H3A 0G1, Canada;Genome Quebec Innovat Ctr, Montreal, PQ H3A 0G1, Canada.
    Cheung, Warren A.
    McGill Univ, Dept Human Genet, Montreal, PQ H3A 0C7, Canada;McGill Univ, Montreal, PQ H3A 0G1, Canada;Genome Quebec Innovat Ctr, Montreal, PQ H3A 0G1, Canada;Childrens Mercy Hosp & Clin, Kansas City, MO 64108 USA.
    Vijay, Jinchu
    McGill Univ, Dept Human Genet, Montreal, PQ H3A 0C7, Canada;McGill Univ, Montreal, PQ H3A 0G1, Canada;Genome Quebec Innovat Ctr, Montreal, PQ H3A 0G1, Canada.
    Guenard, Frederic
    Univ Laval, Inst Nutr & Funct Foods INAF, Quebec City, PQ G1V 0A6, Canada.
    Kwan, Tony
    McGill Univ, Dept Human Genet, Montreal, PQ H3A 0C7, Canada;McGill Univ, Montreal, PQ H3A 0G1, Canada;Genome Quebec Innovat Ctr, Montreal, PQ H3A 0G1, Canada.
    Simon, Marie-Michelle
    McGill Univ, Dept Human Genet, Montreal, PQ H3A 0C7, Canada;McGill Univ, Montreal, PQ H3A 0G1, Canada;Genome Quebec Innovat Ctr, Montreal, PQ H3A 0G1, Canada.
    Ge, Bing
    McGill Univ, Dept Human Genet, Montreal, PQ H3A 0C7, Canada;McGill Univ, Montreal, PQ H3A 0G1, Canada;Genome Quebec Innovat Ctr, Montreal, PQ H3A 0G1, Canada.
    Moura, Cristiano
    McGill Univ, Dept Epidemiol, Montreal, PQ H3A 1A2, Canada.
    Boulier, Elodie
    McGill Univ, Dept Human Genet, Montreal, PQ H3A 0C7, Canada;McGill Univ, Montreal, PQ H3A 0G1, Canada;Genome Quebec Innovat Ctr, Montreal, PQ H3A 0G1, Canada.
    Rönnblom, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Bernatsky, Sasha
    McGill Univ, Dept Epidemiol, Montreal, PQ H3A 1A2, Canada.
    Lathropl, Mark
    McGill Univ, Dept Human Genet, Montreal, PQ H3A 0C7, Canada;McGill Univ, Montreal, PQ H3A 0G1, Canada;Genome Quebec Innovat Ctr, Montreal, PQ H3A 0G1, Canada.
    McCarthy, Mark, I
    Univ Oxford, Churchill Hosp, Oxford Ctr Diabet Endocrinol & Metab, Old Rd, Oxford OX3 7LJ, England;Univ Oxford, Wellcome Ctr Human Genet, Roosevelt Dr, Oxford OX3 7BN, England;Oxford Univ Hosp NHS Fdn Trust, John Radcliffe Hosp, Oxford NIHR Biomed Res Ctr, Oxford OX3 9DU, England.
    Deloukas, Panos
    Queen Mary Univ London, William Harvey Res Inst, Barts & London Sch Med & Dent, Charterhouse Sq, London EC1M 6BQ, England.
    Tchernof, Andre
    Univ Laval, Quebec Heart & Lung Inst, Quebec City, PQ G1V 0A6, Canada.
    Pastinen, Tomi
    McGill Univ, Dept Human Genet, Montreal, PQ H3A 0C7, Canada;McGill Univ, Montreal, PQ H3A 0G1, Canada;Genome Quebec Innovat Ctr, Montreal, PQ H3A 0G1, Canada;Childrens Mercy Hosp & Clin, Kansas City, MO 64108 USA.
    Vohl, Marie-Claude
    Univ Laval, Inst Nutr & Funct Foods INAF, Quebec City, PQ G1V 0A6, Canada.
    Grundberg, Elin
    McGill Univ, Dept Human Genet, Montreal, PQ H3A 0C7, Canada;McGill Univ, Montreal, PQ H3A 0G1, Canada;Genome Quebec Innovat Ctr, Montreal, PQ H3A 0G1, Canada;Childrens Mercy Hosp & Clin, Kansas City, MO 64108 USA.
    Dissecting features of epigenetic variants underlying cardiometabolic risk using full-resolution epigenome profiling in regulatory elements2019Ingår i: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 10, artikel-id 1209Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Sparse profiling of CpG methylation in blood by microarrays has identified epigenetic links to common diseases. Here we apply methylC-capture sequencing (MCC-Seq) in a clinical population of similar to 200 adipose tissue and matched blood samples (N-total similar to 400), providing high- resolution methylation profiling (>1.3 M CpGs) at regulatory elements. We link methylation to cardiometabolic risk through associations to circulating plasma lipid levels and identify lipid-associated CpGs with unique localization patterns in regulatory elements. We show distinct features of tissue-specific versus tissue-independent lipid-linked regulatory regions by contrasting with parallel assessments in similar to 800 independent adipose tissue and blood samples from the general population. We follow-up on adipose-specific regulatory regions under (1) genetic and (2) epigenetic (environmental) regulation via integrational studies. Overall, the comprehensive sequencing of regulatory element methylomes reveals a rich landscape of functional variants linked genetically as well as epigenetically to plasma lipid traits.

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  • 191.
    Alm, Henrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Proteomic Characterization of Induced Developmental Neurotoxicity2009Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    The developing brain goes through a number of developmental periods during which it displays an increased sensitivity to exogenous disturbances. On such period is the so called “Brain growth spurt” (BGS) which in humans takes place starting from the third trimester of pregnancy and throughout the first few years of life. The corresponding period in rats and mice is the first postnatal weeks. Exposure to relatively modest concentrations of the brominated flame retardant PBDE-99 during the second week of life in mice causes a more or less permanent impairment in the ability of the animals to adjust properly to environmental changes at adulthood. This “late response on early exposure” reflects the long-term consequences of disrupting the developing brain during a sensitive time period.

    The cellular mechanisms underlying the behavioral effects are far from clear. To address the initial damage occurring around the time of exposure, the approach used in this thesis is to use proteomics to analyze the effects of PBDE-99 on protein expression soon (24 hours) after exposure of the neonatal mouse on postnatal day (PND) 10.The thesis comprises the effects on the proteome in three distinct brain parts: cerebral cortex, striatum and the hippocampus. In addition, an in vitro model was developed and used to evaluate the PBDE-99 effects on cultured cerebral cortex cells from embryonic rat brains.

    Gel-based proteomics (2D-DIGE) coupled to MALDI- or ESI-MS has been used throughout for the proteomics experiments, but other techniques aimed at analyzing both proteins and mRNA have also been used to better characterize the effects.

    Even if the protein complements expressed by the different brain parts and separated with 2D-DIGE are seemingly similar, the effects are apparently specific for the different brain regions. In hippocampus, PBDE induces effects on proteins involved in metabolism and energy production, while the effects in striatum point towards effects on neuroplasticity.

    PBDE-99 changes the expression of cytoskeletal proteins in the cerebral cortex 24 hours after exposure. Interestingly, in vitro exposure of cerebral cortex cells to a PBDE-99 concentration in the same order of magnitude as in the in vivo neonatal brain also induces cytoskeletal effects, in the absence of cytotoxicity. This may suggest effects on regulatory aspects of cytoskeletal dynamics such as those involved in neurite sprouting.

    This thesis also addresses the problems involved in presenting proteomics data. Many of the available methods and approaches for presenting transcriptomics data are not suitable for isoform rich protein data. Modifications of existing methods and the development of a new approach (DEPPS) is also presented. Most importantly, the thesis presents the application and usefulness of proteomics as hypothesis generating techniques in neurotoxicology.

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  • 192.
    Alm, Henrik
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap, Avdelningen för toxikologi.
    Kultima, Kim
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap, Avdelningen för toxikologi.
    Scholz, Birger
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap, Avdelningen för toxikologi.
    Nilsson, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap, MMS, medicinsk masspektrometri.
    Andrén, Per E
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap, MMS, medicinsk masspektrometri.
    Fex-Svenningsen, Åsa
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap.
    Dencker, Lennart
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap, Avdelningen för toxikologi.
    Stigson, Michael
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap, Avdelningen för toxikologi.
    Exposure to brominated flame retardant PBDE-99 affects cytoskeletal protein expression in the neonatal mouse cerebral cortex2008Ingår i: Neurotoxicology, ISSN 0161-813X, E-ISSN 1872-9711, Vol. 29, nr 4, s. 628-637Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Polybrominated diphenyl ethers (PBDEs) are environmental contaminants found in human and animal tissues worldwide. Neonatal exposure to the flame retardant 2,2', 4,4',5-pentabromodiphenyl ether (PBDE-99) disrupts normal brain development in mice, and results in disturbed spontaneous behavior in the adult. The mechanisms underlying the late effects of early exposure are not clear. To gain insight into the initial neurodevelopmental damage inflicted by PBDE-99, we investigated the short-term effects of PBDE-99 on protein expression in the developing cerebral cortex of neonatal mice, and the cytotoxic and apoptotic effects of PBDE-99 in primary cultures of fetal rat cortical cells. We used two-dimensional difference gel electrophoresis (2D-DIGE) to analyze protein samples isolated from the cortex of NMRI mice 24h after exposure to a single oral dose of 12 mg/kg PBDE-99 on post-natal day 10. Protein resolution was enhanced by sample pre-fractionation. In the cell model, we determined cell viability using the trypan blue exclusion assay, and apoptosis using immunocytochemical detection of cleaved caspase-3. We determined the identity of 111 differentially expressed proteins, 32 (29%) of which are known to be cytoskeleton-related. Similar to previous findings in the striatum, we found elevated levels of the neuron growth-associated protein Gap43 in the cortex. In cultured cortical cells, a high concentration of PBDE-99 (30 microM) induced cell death without any apparent increase in caspase-3 activity. These results indicate that the permanent neurological damage induced by PBDE-99 during the brain growth spurt involve detrimental effects on cytoskeletal regulation and neuronal maturation in the developing cerebral cortex.

  • 193.
    Alm, Henrik
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap, Avdelningen för toxikologi.
    Scholz, Birger
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap, Avdelningen för toxikologi.
    Fischer, Celia
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för fysiologi och utvecklingsbiologi, Ekotoxikologi.
    Kultima, Kim
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap, Avdelningen för toxikologi.
    Viberg, Henrik
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för fysiologi och utvecklingsbiologi, Ekotoxikologi.
    Eriksson, Per
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för fysiologi och utvecklingsbiologi, Ekotoxikologi.
    Dencker, Lennart
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap, Avdelningen för toxikologi.
    Stigson, Michael
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap, Avdelningen för toxikologi.
    Proteomic evaluation of neonatal exposure to 2,2,4,4,5-pentabromodiphenyl ether2006Ingår i: Journal of Environmental Health Perspectives, ISSN 0091-6765, E-ISSN 1552-9924, Vol. 114, nr 2, s. 254-259Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Exposure to the brominated flame retardant 2,2 ,4,4 ,5-pentabromodiphenyl ether (PBDE-99) during the brain growth spurt disrupts normal brain development in mice and results in disturbed spontaneous behavior in adulthood. The neurodevelopmental toxicity of PBDE-99 has been reported to affect the cholinergic and catecholaminergic systems. In this study we use a proteomics approach to study the early effect of PBDE-99 in two distinct regions of the neonatal mouse brain, the striatum and the hippocampus. A single oral dose of PBDE-99 (12 mg/kg body weight) or vehicle was administered to male NMRI mice on neonatal day 10, and the striatum and the hippocampus were isolated. Using two-dimensional fluorescence difference gel electrophoresis (2D-DIGE), we found 40 and 56 protein spots with significantly (p < 0.01) altered levels in the striatum and the hippocampus, respectively. We used matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-ToF-MS) to determine the protein identity of 11 spots from the striatum and 10 from the hippocampus. We found that the levels of proteins involved in neurodegeneration and neuroplasticity (e.g., Gap-43/neuromodulin, stathmin) were typically altered in the striatum, and proteins involved in metabolism and energy production [e.g., alpha-enolase; gamma-enolase; ATP synthase, H+ transporting, mitochondrial F1 complex, beta subunit (Atp5b); and alpha-synuclein] were typically altered in the hippocampus. Interestingly, many of the identified proteins have been linked to protein kinase C signaling. In conclusion, we identify responses to early exposure to PBDE-99 that could contribute to persistent neurotoxic effects. This study also shows the usefulness of proteomics to identify potential biomarkers of developmental neurotoxicity of organohalogen compounds.

  • 194.
    Alm, Per A
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Logopedi.
    Stamning och skenande tal (løbsk tale): Om orsaker, mekanismer och behandling, med utgångspunkt från hjärnan2008Ingår i: Proceedings fra 1ste nordiske konference om stammen løbsk tale, Nyborg, Danmark, 2008Konferensbidrag (Övrigt vetenskapligt)
  • 195.
    Alm, Per A
    Department of Clinical Neurosciences, Division of Psychiatry, Lund University, Lund, Sweden.
    Stuttering, emotions, and heart rate during anticipatory anxiety:: a critical review2004Ingår i: Journal of fluency disorders, ISSN 0094-730X, E-ISSN 1873-801X, Vol. 29, nr 2, s. 123-133Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Persons who stutter often report their stuttering is influenced by emotional reactions, yet the nature of such relation is still unclear. Psychophysiological studies of stuttering have failed to find any major association between stuttering and the activity of the sympathetic nervous system. A review of published studies of heart rate in relation to stressful speech situations indicate that adults who stutter tend to show a paradoxical reduction of heart rate compared with nonstuttering persons. Reduction of heart rate has also been observed in humans and mammals during anticipation of an unpleasant stimulus, and is proposed to be an indication of anticipatory anxiety resulting in a “freezing response” with parasympathetic inhibition of the heart rate. It is suggested that speech-related anticipatory anxiety in persons who stutter is likely to be a secondary, conditioned reaction based on previous experiences of stuttering.

  • 196.
    Alm, Per A.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Logopedi.
    Stuttering in relation to anxiety, temperament, and personality: Review and analysis with focus on causality2014Ingår i: Journal of fluency disorders, ISSN 0094-730X, E-ISSN 1873-801X, Vol. 40, s. 5-21Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    Anxiety and emotional reactions have a central role in many theories of stuttering, for example that persons who stutter would tend to have an emotionally sensitive temperament. The possible relation between stuttering and certain traits of temperament or personality were reviewed and analyzed, with focus on temporal relations (i.e., what comes first). It was consistently found that preschool children who stutter (as a group) do not show any tendencies toward elevated temperamental traits of shyness or social anxiety compared with children who do not stutter. Significant group differences were, however, repeatedly reported for traits associated with inattention and hyperactivity/impulsivity, which is likely to reflect a subgroup of children who stutter. Available data is not consistent with the proposal that the risk for persistent stuttering is increased by an emotionally reactive temperament in children who stutter. Speech-related social anxiety develops in many cases of stuttering, before adulthood. Reduction of social anxiety in adults who stutter does not in itself appear to result in significant improvement of speech fluency. Studies have not revealed any relation between the severity of the motor symptoms of stuttering and temperamental traits. It is proposed that situational variability of stuttering, related to social complexity, is an effect of interference from social cognition and not directly from the emotions of social anxiety. In summary, the studies in this review provide strong evidence that persons who stutter are not characterized by constitutional traits of anxiety or similar constructs. Educational Objectives: This paper provides a review and analysis of studies of anxiety, temperament, and personality, organized with the objective to clarify cause and effect relations. Readers will be able to (a) understand the importance of effect size and distribution of data for interpretation of group differences; (b) understand the role of temporal relations for interpretation of cause and effect; (c) discuss the results of studies of anxiety, temperament and personality in relation to stuttering; and (d) discuss situational variations of stuttering and the possible role of social cognition. (C) 2014 Elsevier Inc. All rights reserved.

  • 197.
    Almandoz Gil, Leire
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap.
    Characterization of Physiological and Pathological Alpha-Synuclein: Implications for Parkinson’s Disease and Related Disorders2018Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    Aggregated alpha-synuclein is the main component of Lewy bodies and Lewy neurites, intraneuronal inclusions found in the brains of Parkinson’s disease (PD) and dementia with Lewy bodies (DLB) patients (synucleinopathies). Alpha-synuclein is a presynaptic protein, which is most commonly an unfolded monomer in its physiological state. However, under pathological conditions it can start to misfold and enter an aggregation pathway that will lead to the formation of oligomers of increasing size and finally insoluble fibrils. The oligomers have been hypothesized to be the most neurotoxic species, but studies of their properties have been hindered by their heterogeneity and kinetic instability. The overall aim of this thesis was to characterize and compare physiological and pathological forms of alpha-synuclein from different sources: recombinant monomers, oligomers formed in vitro through exposure to oxidative stress related reactive aldehydes, aggregates from a synucleinopathy mouse model and from synucleinopathy patients.

    In paper I we studied the effect of low molar excess of two lipid peroxidation products, 4-oxo-2-nonenal (ONE) and 4-hydroxy-2-nonenal (HNE), on the oligomerization of alpha-synuclein. Through biophysical methods we observed that, although both aldehydes bound to alpha-synuclein directly, ONE produced SDS-stable oligomers more rapidly than HNE. Moreover, ONE induced oligomerization at both acidic and neutral pH, while HNE only formed oligomers at neutral pH.

    In paper II we mapped the surface exposed epitopes of in vitro and in vivo generated alpha-synuclein species by using immunoglobulin Y antibodies raised against short linear peptides covering most of the alpha-synuclein sequence. Monomers were found to react with most antibodies, while the latter part of the N-terminus and mid-region of HNE oligomers and fibrils was found to be occluded in oligomers and fibrils. Through immunohistochemistry we compared alpha-synuclein aggregates in brain tissue from patients with synucleinopathies as well as from a mouse model expressing A30P human alpha-synuclein. Although the exposed epitopes were found to be similar overall, subtle differences were detected in the C-terminus.

    An additional aim of this thesis was to characterize synaptic aggregates of alpha-synuclein. In paper III we obtained synaptosomal preparations of the A30P mouse model and found that a subset of the alpha-synuclein present in the synaptosomes was proteinase K resistant and therefore aggregated. Further biochemical analyses showed that the aggregated alpha-synuclein mainly was of human, i.e. transgenic, origin and that Ser 129 was not phosphorylated, which otherwise is a common post translational modification of alpha-synuclein in Lewy bodies.

    It has been suggested that alpha-synuclein plays a role in neurotransmitter release by binding to the SNARE protein VAMP-2 and thereby chaperoning the SNARE complex assembly. In paper IV we used proximity ligation assay to visualize the co-localization of alpha-synuclein and the SNARE proteins in primary neurons from non-transgenic and A30P transgenic mice.

    In conclusion, in this thesis we have characterized a variety of alpha-synuclein species and shed light on the diversity of alpha-synuclein aggregates. Additionally, we have characterized synaptic species of alpha-synuclein and analyzed the co-localization between alpha-synuclein and SNARE proteins in neurons.

    Delarbeten
    1. Low molar excess of 4-oxo-2-nonenal and 4-hydroxy-2-nonenal promote oligomerization of alpha-synuclein through different pathways
    Öppna denna publikation i ny flik eller fönster >>Low molar excess of 4-oxo-2-nonenal and 4-hydroxy-2-nonenal promote oligomerization of alpha-synuclein through different pathways
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    2017 (Engelska)Ingår i: Free Radical Biology & Medicine, ISSN 0891-5849, E-ISSN 1873-4596, Vol. 110, s. 421-431Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Aggregated alpha-synuclein is the main component of Lewy bodies, intraneuronal inclusions found in brains with Parkinson's disease and dementia with Lewy bodies. A body of evidence implicates oxidative stress in the pathogenesis of these diseases. For example, a large excess (30:1, aldehyde:protein) of the lipid peroxidation end products 4-oxo-2-nonenal (ONE) or 4-hydroxy-2-nonenal (HNE) can induce alpha-synuclein oligomer formation. The objective of the study was to investigate the effect of these reactive aldehydes on alpha-synuclein at a lower molar excess (3:1) at both physiological (7.4) and acidic (5.4) pH. As observed by size-exclusion chromatography, ONE rapidly induced the formation of alpha-synuclein oligomers at both pH values, but the effect was less pronounced under the acidic condition. In contrast, only a small proportion of alpha-synuclein oligomers were formed with low excess HNE-treatment at physiological pH and no oligomers at all under the acidic condition. With prolonged incubation times (up to 96 h), more alpha-synuclein was oligomerized at physiological pH for both ONE and HNE. As determined by Western blot, ONE-oligomers were more SDS-stable and to a higher-degree cross-linked as compared to the HNE-induced oligomers. However, as shown by their greater sensitivity to proteinase K treatment, ONE-oligomers, exhibited a less compact structure than HNE-oligomers. As indicated by mass spectrometry, ONE modified most Lys residues, whereas HNE primarily modified the His50 residue and fewer Lys residues, albeit to a higher degree than ONE. Taken together, our data show that the aldehydes ONE and HNE can modify alpha-synuclein and induce oligomerization, even at low molar excess, but to a higher degree at physiological pH and seemingly through different pathways.

    Nyckelord
    Alpha-synuclein, Oligomers, 4-oxo-2-nonenal, 4-hydroxy-2-nonenal, Oxidative stress
    Nationell ämneskategori
    Medicin och hälsovetenskap Teknik och teknologier Biokemi och molekylärbiologi
    Identifikatorer
    urn:nbn:se:uu:diva-326663 (URN)10.1016/j.freeradbiomed.2017.07.004 (DOI)000406049200038 ()28690195 (PubMedID)
    Forskningsfinansiär
    Vetenskapsrådet, 2011-4519, 2012-2172, 2010-6745Marianne och Marcus Wallenbergs StiftelseHjärnfondenSvenska läkaresällskapetÅke Wibergs Stiftelse
    Anmärkning

    Correction in: Free Radical Biology and Medicine, vol. 117, pages 258-258.

    DOI: 10.1016/j.freeradbiomed.2018.02.007

    Tillgänglig från: 2017-07-19 Skapad: 2017-07-19 Senast uppdaterad: 2019-04-29Bibliografiskt granskad
    2. Mapping of Surface-Exposed Epitopes of In Vitro and In Vivo Aggregated Species of Alpha-Synuclein
    Öppna denna publikation i ny flik eller fönster >>Mapping of Surface-Exposed Epitopes of In Vitro and In Vivo Aggregated Species of Alpha-Synuclein
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    2017 (Engelska)Ingår i: Cellular and molecular neurobiology, ISSN 0272-4340, E-ISSN 1573-6830, Vol. 37, nr 7, s. 1217-1226Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Aggregated alpha-synuclein is the main component of Lewy bodies, intraneuronal deposits observed in Parkinson's disease and dementia with Lewy bodies. The objective of the study was to identify surface-exposed epitopes of alpha-synuclein in vitro and in vivo formed aggregates. Polyclonal immunoglobulin Y antibodies were raised against short linear peptides of the alpha-synuclein molecule. An epitope in the N-terminal region (1-10) and all C-terminal epitopes (90-140) were found to be exposed in an indirect enzyme-linked immunosorbent assay (ELISA) using recombinant monomeric, oligomeric, and fibrillar alpha-synuclein. In a phospholipid ELISA, the N-terminus and mid-region of alpha-synuclein (i.e., 1-90) were associated with phosphatidylserine and thus occluded from antibody binding. The antibodies that reacted most strongly with epitopes in the in vitro aggregates (i.e., 1-10 and epitopes between positions 90-140) also labeled alpha-synuclein inclusions in brains from transgenic (Thy-1)-h[A30P] alpha-synuclein mice and Lewy bodies and Lewy neurites in brains of patients with alpha-synucleinopathies. However, differences in reactivity were observed with the C-terminal antibodies when brain tissue from human and transgenic mice was compared. Taken together, the study shows that although similar epitopes are exposed in both in vitro and in vivo formed alpha-synuclein inclusions, structural heterogeneity can be observed between different molecular species.

    Nyckelord
    Parkinson's disease, Dementia with Lewy bodies, Alpha-synuclein, Epitope mapping
    Nationell ämneskategori
    Geriatrik
    Identifikatorer
    urn:nbn:se:uu:diva-334384 (URN)10.1007/s10571-016-0454-0 (DOI)000409352200007 ()28028735 (PubMedID)
    Forskningsfinansiär
    Vetenskapsrådet, 2011-4519Marianne och Marcus Wallenbergs StiftelseHjärnfondenSvenska läkaresällskapet
    Tillgänglig från: 2017-12-15 Skapad: 2017-12-15 Senast uppdaterad: 2020-02-04Bibliografiskt granskad
    3. Characterization of synaptic aggregates of alpha-synuclein in (Thy-1)-h[A30P] alpha-synuclein mice
    Öppna denna publikation i ny flik eller fönster >>Characterization of synaptic aggregates of alpha-synuclein in (Thy-1)-h[A30P] alpha-synuclein mice
    Visa övriga...
    (Engelska)Manuskript (preprint) (Övrigt vetenskapligt)
    Nationell ämneskategori
    Neurovetenskaper
    Identifikatorer
    urn:nbn:se:uu:diva-342341 (URN)
    Tillgänglig från: 2018-02-20 Skapad: 2018-02-20 Senast uppdaterad: 2018-02-23
    4. In situ proximity ligation assay reveals co-localization of alpha-synuclein and SNARE proteins in murine primary neurons
    Öppna denna publikation i ny flik eller fönster >>In situ proximity ligation assay reveals co-localization of alpha-synuclein and SNARE proteins in murine primary neurons
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    2018 (Engelska)Ingår i: Frontiers in Neurology, ISSN 1664-2295, E-ISSN 1664-2295, Vol. 9, artikel-id 180Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    The aggregation of alpha-synuclein (alpha Syn) is the pathological hallmark of Parkinson's disease, dementia with Lewy bodies and related neurological disorders. However, the physiological function of the protein and how this function relates to its pathological effects remain poorly understood. One of the proposed roles of aSyn is to promote the soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex assembly by binding to VAMP-2. The objective of this study was to visualize the co-localization between aSyn and the SNARE proteins (VAMP-2, SNAP-25, and syntaxin-1) for the first time using in situ proximity ligation assay (PLA). Cortical primary neurons were cultured from either non-transgenic or transgenic mice expressing human aSyn with the A30P mutation under the Thy-1 promoter. With an antibody recognizing both mouse and human aSyn, a PLA signal indicating close proximity between aSyn and the three SNARE proteins was observed both in the soma and throughout the processes. No differences in the extent of PLA signals were seen between non-transgenic and transgenic neurons. With an antibody specific against human aSyn, the PLA signal was mostly located to the soma and was only present in a few cells. Taken together, in situ PLA is a method that can be used to investigate the co-localization of aSyn and the SNARE proteins in primary neuronal cultures

    Ort, förlag, år, upplaga, sidor
    Frontiers Media S.A., 2018
    Nationell ämneskategori
    Neurovetenskaper
    Identifikatorer
    urn:nbn:se:uu:diva-342580 (URN)10.3389/fneur.2018.00180 (DOI)000428063500001 ()29623065 (PubMedID)
    Forskningsfinansiär
    Marianne och Marcus Wallenbergs StiftelseHjärnfondenSvenska läkaresällskapetMagnus Bergvalls Stiftelse
    Tillgänglig från: 2018-02-22 Skapad: 2018-02-22 Senast uppdaterad: 2018-06-28Bibliografiskt granskad
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  • 198.
    Almandoz-Gil, Leire
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Persson, Emma
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Lindström, Veronica
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Ingelsson, Martin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Erlandsson, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Bergström, Joakim
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    In situ proximity ligation assay reveals co-localization of alpha-synuclein and SNARE proteins in murine primary neurons2018Ingår i: Frontiers in Neurology, ISSN 1664-2295, E-ISSN 1664-2295, Vol. 9, artikel-id 180Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The aggregation of alpha-synuclein (alpha Syn) is the pathological hallmark of Parkinson's disease, dementia with Lewy bodies and related neurological disorders. However, the physiological function of the protein and how this function relates to its pathological effects remain poorly understood. One of the proposed roles of aSyn is to promote the soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex assembly by binding to VAMP-2. The objective of this study was to visualize the co-localization between aSyn and the SNARE proteins (VAMP-2, SNAP-25, and syntaxin-1) for the first time using in situ proximity ligation assay (PLA). Cortical primary neurons were cultured from either non-transgenic or transgenic mice expressing human aSyn with the A30P mutation under the Thy-1 promoter. With an antibody recognizing both mouse and human aSyn, a PLA signal indicating close proximity between aSyn and the three SNARE proteins was observed both in the soma and throughout the processes. No differences in the extent of PLA signals were seen between non-transgenic and transgenic neurons. With an antibody specific against human aSyn, the PLA signal was mostly located to the soma and was only present in a few cells. Taken together, in situ PLA is a method that can be used to investigate the co-localization of aSyn and the SNARE proteins in primary neuronal cultures

    Ladda ner fulltext (pdf)
    fulltext
  • 199.
    Almandoz-Gil, Leire
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Persson, Emma
    Rofo, Fadi
    Ekmark-Lewén, Sara
    Ingelsson, Martin
    Bergström, Joakim
    Characterization of synaptic aggregates of alpha-synuclein in (Thy-1)-h[A30P] alpha-synuclein miceManuskript (preprint) (Övrigt vetenskapligt)
  • 200. Almeida, Alexandra D
    et al.
    Boije, Henrik
    Chow, Renee W
    He, Jie
    Tham, Jonathan
    Suzuki, Sachihiro C
    Harris, William A
    Spectrum of Fates: a new approach to the study of the developing zebrafish retina.2014Ingår i: Development, ISSN 0950-1991, E-ISSN 1477-9129, Vol. 141, nr 9, s. 1971-80Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The ability to image cells live and in situ as they proliferate and differentiate has proved to be an invaluable asset to biologists investigating developmental processes. Here, we describe a Spectrum of Fates approach that allows the identification of all the major neuronal subtypes in the zebrafish retina simultaneously. Spectrum of Fates is based on the combinatorial expression of differently coloured fluorescent proteins driven by the promoters of transcription factors that are expressed in overlapping subsets of retinal neurons. Here, we show how a Spectrum of Fates approach can be used to assess various aspects of neural development, such as developmental waves of differentiation, neuropil development, lineage tracing and hierarchies of fates in the developing zebrafish retina.

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