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  • 1.
    Abalo, Xesus
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Boije: Zebrafish Neuronal Networks. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Lagman, David
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience. Univ Bergen, Sars Int Ctr Marine Mol Biol, Bergen, Norway.
    Heras, Gabriel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience. Uppsala University, Science for Life Laboratory, SciLifeLab. Karolinska Inst, Dept Physiol & Pharmacol, Stockholm, Sweden.
    del Pozo, Ana
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Boije: Zebrafish Neuronal Networks. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Eggert, Joel
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience. Emory Univ, Dept Med, Atlanta, GA 30322 USA.
    Larhammar, Dan
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Larhammar: Pharmacology.
    Circadian regulation of phosphodiesterase 6 genes in zebrafish differs between cones and rods: Implications for photopic and scotopic vision2020In: Vision Research, ISSN 0042-6989, E-ISSN 1878-5646, Vol. 166, p. 43-51Article in journal (Refereed)
    Abstract [en]

    A correlation is known to exist between visual sensitivity and oscillations in red opsin and rhodopsin gene expression in zebrafish, both regulated by the clock gene. This indicates that an endogenous circadian clock regulates behavioural visual sensitivity, apart from the regulation exerted by the pineal organ. However, the specific mechanisms for cones (photopic vision) and rods (scotopic vision) are poorly understood. In this work, we performed gene expression, cosinor and immunohistochemical analyses to investigate other key genes involved in light perception, encoding the different subunits of phosphodiesterase pde6 and transducin G alpha(T), in constant lighting conditions and compared to normal light-dark conditions. We found that cones display prominent circadian oscillations in mRNA levels for the inhibitory subunit gene pde6ha that could contribute to the regulation of photopic sensitivity by preventing overstimulation in photopic conditions. In rods, the mRNA levels of the inhibitory subunit gene pde6ga oscillate under normal conditions and dampen down in constant light but continue oscillating in constant darkness. There is an increase in total relative expression for pde6gb in constant conditions. These observations, together with previous data, suggest a complex regulation of the scotopic sensitivity involving endogenous and non-endogenous components, possibly present also in other teleost species. The G alpha(T) genes do not display mRNA oscillations and therefore may not be essential for the circadian regulation of photosensitivity. In summary, our results support different regulation for the zebrafish photopic and scotopic sensitivities and suggest circadian regulation of pde6ha as a key factor regulating photopic sensitivity, while the regulatory mechanisms in rods appear to be more complex.

  • 2.
    Cardoso, Joao C. R.
    et al.
    Univ Algarve, Ctr Marine Sci, Comparat Endocrinol & Integrat Biol, Faro, Portugal..
    Bergqvist, Christina
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Larhammar: Pharmacology.
    Larhammar, Dan
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Larhammar: Pharmacology.
    Corticotropin-Releasing Hormone (CRH) Gene Family Duplications in Lampreys Correlate With Two Early Vertebrate Genome Doublings2020In: Frontiers in Neuroscience, ISSN 1662-4548, E-ISSN 1662-453X, Vol. 14, article id 672Article in journal (Refereed)
    Abstract [en]

    The ancestor of gnathostomes (jawed vertebrates) is generally considered to have undergone two rounds of whole genome duplication (WGD). The timing of these WGD events relative to the divergence of the closest relatives of the gnathostomes, the cyclostomes, has remained contentious. Lampreys and hagfishes are extant cyclostomes whose gene families can shed light on the relationship between the WGDs and the cyclostome-gnathostome divergence. Previously, we have characterized in detail the evolution of the gnathostome corticotropin-releasing hormone (CRH) family and found that its five members arose from two ancestral genes that existed before the WGDs. The two WGDs resulted, after secondary losses, in one triplet consisting of CRH1, CRH2, and UCN1, and one pair consisting of UCN2 and UCN3. All five genes exist in representatives for cartilaginous fishes, ray-finned fishes, and lobe-finned fishes. Differential losses have occurred in some lineages. We present here analyses of CRH-family members in lamprey and hagfish by comparing sequences and gene synteny with gnathostomes. We found five CRH-family genes in each of two lamprey species (Petromyzon marinusandLethenteron camtschaticum) and two genes in a hagfish (Eptatretus burgeri). Synteny analyses show that all five lamprey CRH-family genes have similar chromosomal neighbors as the gnathostome genes. The most parsimonious explanation is that the lamprey CRH-family genes are orthologs of the five gnathostome genes and thus arose in the same chromosome duplications. This suggests that lampreys and gnathostomes share the same two WGD events and that these took place before the lamprey-gnathostome divergence.

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  • 3.
    Cui, Hao
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab. Jiangxi Normal Univ, Coll Life Sci, 99 Ziyang Ave, Nanchang 330022, Jiangxi, Peoples R China..
    Xiaowen, Cheng
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Batool, Tahira
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Zhang, Xiao
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Larhammar: Pharmacology.
    Li, Jin-Ping
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Glucuronyl C5-epimerase is crucial for epithelial cell maturation during embryonic lung development2021In: Glycobiology, ISSN 0959-6658, E-ISSN 1460-2423, Vol. 31, no 3, p. 223-230Article in journal (Refereed)
    Abstract [en]

    Glucuronyl C5-epimerase (Hsepi) is a key enzyme in the biosynthesis of heparan sulfate that is a sulfated polysaccharide expressed on the cell surface and in the extracellular matrix of alveolar walls and blood vessels. Targeted interruption of the Hsepi gene, Glce, in mice resulted in neonatal lethality, which is most likely due to lung atelectasis. In this study, we examined the potential mechanisms behind the defect in lung development. Histological analysis of the lungs from embryos revealed no difference in the morphology between wild-type and mutant animals up to E16.5. This suggests that the initial events leading to formation of the lung primordium and branching morphogenesis are not disturbed. However, the distal lung of E17.5-18.5 mutants is still populated by epithelial tubules, lacking the typical saccular structural characteristic of a normal E17.5 lung. Immunostaining revealed strong signals of surfactant protein-C, but a weaker signal of T1 alpha in the mutant lungs in comparison to WT littermates, suggesting differentiation of type I alveolar epithelial cells (AT1) is impaired. One of the parameters contributed to the failure of AT1 maturation is reduced vascularization in the developing lungs.

  • 4.
    Fears, R.
    et al.
    German Natl Acad Sci Leopoldina, European Acad Sci Advisory Council, Halle, Saale, Germany.
    Griffin, G. E.
    St Georges Univ London, Inst Infect & Immun, London, England.
    Larhammar, Dan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Larhammar: Pharmacology.
    ter Meulen, V.
    German Natl Acad Sci Leopoldina, European Acad Sci Advisory Council, Halle, Saale, Germany.
    van der Meer, J. W. M.
    Radboud Univ Nijmegen, Med Ctr, Nijmegen, Netherlands.
    Globalization of Traditional Chinese Medicine: what are the issues for ensuring evidence-based diagnosis and therapy?2020In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 287, no 2, p. 210-213Article in journal (Other academic)
  • 5.
    Garcia-Concejo, Adrian
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Larhammar: Pharmacology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Larhammar, Dan
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Larhammar: Pharmacology.
    Protein kinase C family evolution in jawed vertebrates2021In: Developmental Biology, ISSN 0012-1606, E-ISSN 1095-564X, Vol. 479, p. 77-90Article in journal (Refereed)
    Abstract [en]

    Protein kinase C (PKC) was one of the first kinases identified in human cells. It is now known to constitute a family of kinases that respond to diacylglycerol, phosphatidylserine and for some family members, Ca2+. They have a plethora of different functions, such as cell cycle regulation, immune response and memory formation. In mammals, 12 PKC family members have been described, usually divided into 4 different subfamilies. We present here a comprehensive evolutionary analysis of the PKC genes in jawed vertebrates with special focus on the impact of the two tetraploidizations (1R and 2R) before the radiation of jawed vertebrates and the teleost tetraploidization (3R), as illuminated by synteny and paralogon analysis including many neighboring gene families. We conclude that the vertebrate predecessor had five PKC genes, as tunicates and lancelets still do, and that the PKC family should therefore ideally be organized into five subfamilies. The 1R and 2R events led to a total of 12 genes distributed among these five subfamilies. All 12 genes are still present in some of the major lineages of jawed vertebrates, including mammals, whereas birds and cartilaginous fishes have lost one member. The 3R event added another nine genes in teleosts, bringing the total to 21 genes. The zebrafish, a common experimental model animal, has retained 19. We have found no independent gene duplications. Thus, the genome doublings completely account for the complexity of this gene family in jawed vertebrates and have thereby had a huge impact on their evolution.

  • 6.
    Li, Jin-Ping
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Zhang, Xiao
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Larhammar: Pharmacology.
    Implications of Heparan Sulfate and Heparanase in Amyloid Diseases2020In: Advances in Experimental Medicine and Biology, ISSN 0065-2598, E-ISSN 2214-8019, Vol. 1221, p. 631-645Article in journal (Refereed)
    Abstract [en]

    Amyloidosis refers to a group of diseases characterized by abnormal deposition of denatured endogenous proteins, termed amyloid, in the affected organs. Analysis of biopsy and autopsy tissues from patients revealed the presence of heparan sulfate proteoglycans (HSPGs) along with amyloid proteins in the deposits. For a long time, HSPGs were believed to occur in the deposits as an innocent bystander. Yet, the consistent presence of HSPGs in various deposits, regardless of the amyloid species, led to the hypothesis that these macromolecular glycoconjugates might play functional roles in the pathological process of amyloidosis. In vitro studies have revealed that HSPGs, or more precisely, the heparan sulfate (HS) side chains interact with amyloid peptides, thus promoting amyloid fibrillization. Although information on the mechanisms of HS participation in amyloid deposition is limited, recent studies involving a transgenic mouse model of Alzheimer’s disease point to an active role of HS in amyloid formation. Heparanase cleavage alters the molecular structure of HS, and thus modulates the functional roles of HS in homeostasis, as well as in diseases, including amyloidosis. The heparanase transgenic mice have provided models for unveiling the effects of heparanase, through cleavage of HS, in various amyloidosis conditions.

  • 7.
    Li, Yanying
    et al.
    Chinese Acad Sci, Ningbo Inst Mat Technol & Engn, Cixi Inst Biomed Engn, Zhejiang Engn Res Ctr Biomed Mat,CAS Key Lab Magne, Ningbo 315201, Peoples R China.;Univ Chinese Acad Sci, Beijing 100049, Peoples R China..
    Pan, Yuanbo
    Zhejiang Univ, Affiliated Hosp 2, Sch Med, Dept Neurosurg, Hangzhou 310003, Zhejiang, Peoples R China..
    Wang, Yinjie
    Chinese Acad Sci, Ningbo Inst Mat Technol & Engn, Cixi Inst Biomed Engn, Zhejiang Engn Res Ctr Biomed Mat,CAS Key Lab Magne, Ningbo 315201, Peoples R China..
    Jiang, Zhenqi
    Chinese Acad Sci, Ningbo Inst Mat Technol & Engn, Cixi Inst Biomed Engn, Zhejiang Engn Res Ctr Biomed Mat,CAS Key Lab Magne, Ningbo 315201, Peoples R China..
    Akakuru, Ozioma U.
    Chinese Acad Sci, Ningbo Inst Mat Technol & Engn, Cixi Inst Biomed Engn, Zhejiang Engn Res Ctr Biomed Mat,CAS Key Lab Magne, Ningbo 315201, Peoples R China.;Univ Chinese Acad Sci, Beijing 100049, Peoples R China..
    Li, Mingli
    Chinese Acad Sci, Ningbo Inst Mat Technol & Engn, Cixi Inst Biomed Engn, Zhejiang Engn Res Ctr Biomed Mat,CAS Key Lab Magne, Ningbo 315201, Peoples R China.;Univ Chinese Acad Sci, Beijing 100049, Peoples R China..
    Zhang, Xianyun
    Chinese Acad Sci, Ningbo Inst Mat Technol & Engn, Cixi Inst Biomed Engn, Zhejiang Engn Res Ctr Biomed Mat,CAS Key Lab Magne, Ningbo 315201, Peoples R China..
    Yuan, Bo
    Chinese Acad Sci, Ningbo Inst Mat Technol & Engn, Cixi Inst Biomed Engn, Zhejiang Engn Res Ctr Biomed Mat,CAS Key Lab Magne, Ningbo 315201, Peoples R China..
    Xing, Jie
    Chinese Acad Sci, Ningbo Inst Mat Technol & Engn, Cixi Inst Biomed Engn, Zhejiang Engn Res Ctr Biomed Mat,CAS Key Lab Magne, Ningbo 315201, Peoples R China.;Univ Chinese Acad Sci, Beijing 100049, Peoples R China..
    Luo, Lijia
    Chinese Acad Sci, Ningbo Inst Mat Technol & Engn, Cixi Inst Biomed Engn, Zhejiang Engn Res Ctr Biomed Mat,CAS Key Lab Magne, Ningbo 315201, Peoples R China..
    Larhammar, Dan
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Larhammar: Pharmacology.
    Wu, Aiguo
    Chinese Acad Sci, Ningbo Inst Mat Technol & Engn, Cixi Inst Biomed Engn, Zhejiang Engn Res Ctr Biomed Mat,CAS Key Lab Magne, Ningbo 315201, Peoples R China..
    Li, Juan
    Chinese Acad Sci, Ningbo Inst Mat Technol & Engn, Cixi Inst Biomed Engn, Zhejiang Engn Res Ctr Biomed Mat,CAS Key Lab Magne, Ningbo 315201, Peoples R China..
    A D-peptide ligand of neuropeptide Y receptor Y-1 serves as nanocarrier traversing of the blood brain barrier and targets glioma2022In: Nano Today, ISSN 1748-0132, E-ISSN 1878-044X, Vol. 44, article id 101465Article in journal (Refereed)
    Abstract [en]

    Diseases of the central nervous system (CNS) are challenging for drug treatment because the blood-brain barrier (BBB) restricts entry of drugs into the brain tissue. Therefore, strategies for drug transport across the BBB are an important component in development of CNS drug therapies. Here, a D-amino acid ligand of the neuropeptide Y (NPY) receptor Y1 is described, (D)[Asn(28), Pro(30), Trp(32)]-DNPY (25-36) (termed DAPT), with 2.5 times higher number of hydrogen bonds interacting with the receptor, based on docking into a structural model, than the corresponding peptide with standard L-amino acids (LAPT). Using in vitro BBB models, in vivo healthy mice with intact BBB, and U87-MG orthotopic tumor-bearing mice, we demonstrate that DAPT exhibits significantly higher ability than LAPT to serve as nanocarrier across the BBB and specifically targets gliomas. Using DAPT nanomicelles loaded with IRDye780, it was possible to achieve excellent photothermal therapeutic and photoacoustic cancer imaging. Thus, this study demonstrates the importance of ligand stability and affinity in Y1 receptor-mediated transcytosis and paves the way for versatile brain tumor imaging and therapy using nanomicelles.

  • 8.
    Ma, Haisha
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Lagerström: Sensory circuits.
    Gao, Tianle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Jakobsson, Jon E. T.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Lagerström: Sensory circuits.
    Weman, Hannah M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Lagerström: Sensory circuits.
    Xu, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Larhammar, Dan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Larhammar: Pharmacology.
    Lagerström, Malin C.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Lagerström: Sensory circuits.
    The Neuropeptide Y Y-2 Receptor Is Coexpressed with Nppb in Primary Afferent Neurons and Y-2 Activation Reduces Histaminergic and IL-31-Induced Itch2020In: Journal of Pharmacology and Experimental Therapeutics, ISSN 0022-3565, E-ISSN 1521-0103, Vol. 372, no 1, p. 73-82Article in journal (Refereed)
    Abstract [en]

    Itch stimuli are detected by specialized primary afferents that convey the signal to the spinal cord, but how itch transmission is regulated is still not completely known. Here, we investigated the roles of the neuropeptide Y (NPY)/Y-2 receptor system on scratch behavior. The inhibitory Y-2 receptor is expressed on mouse primary afferents, and intrathecal administration of the Y-2 agonist peptide YY (PYY)(3-36) reduced scratch episode frequency and duration induced by compound 48/80, an effect that could be reversed by intrathecal preadministration of the Y-2 antagonist BIIE0246. Also, scratch episode duration induced by histamine could be reduced by PYY3-36. In contrast, scratch behavior induced by alpha-methyl-5HT, protease-activated receptor-2-activating peptide SLIGRL, chloroquine, topical dust mite extract, or mechanical itch induced by von Frey filaments was unaffected by stimulation of Y2. Primary afferent neurons expressing the Npy2r gene were found to coexpress itch-associated markers such as natriuretic peptide precursor b, oncostatin M receptor, and interleukin (IL) 31 receptor A. Accordingly, intrathecal PYY3-36 reduced the scratch behavior induced by IL-31. Our findings imply that the NPY/Y-2 system reduces histaminergic and IL-31-associated itch through presynaptic inhibition of a subpopulation of itch-associated primary afferents. SIGNIFICANCE STATEMENT The spinal neuropeptide Y system dampens scratching behavior induced by histaminergic compounds and interleukin 31, a cytokine involved in atopic dermatitis, through interactions with the Y-2 receptor. The Y-2 receptor is expressed by primary afferent neurons that are rich in itch-associated neurotransmitters and receptors such as somatostatin, natriuretic peptide precursor b, and interleukin 31 receptors.

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  • 9.
    Ocampo Daza, Daniel
    et al.
    Uppsala Univ, Dept Organismal Biol, Subdept Evolut & Dev, Uppsala, Sweden.;Univ Calif Merced, Dept Mol & Cell Biol, Merced, CA USA..
    Bergqvist, Christina
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Larhammar: Pharmacology.
    Larhammar, Dan
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Larhammar: Pharmacology.
    The Evolution of Oxytocin and Vasotocin Receptor Genes in Jawed Vertebrates: A Clear Case for Gene Duplications Through Ancestral Whole-Genome Duplications2022In: Frontiers in Endocrinology, E-ISSN 1664-2392, Vol. 12, article id 792644Article in journal (Refereed)
    Abstract [en]

    The neuronal and neuroendocrine peptides oxytocin (OT) and vasotocin (VT), including vasopressins, have six cognate receptors encoded by six receptor subtype genes in jawed vertebrates. The peptides elicit a broad range of responses that are specifically mediated by the receptor subtypes including neuronal functions regulating behavior and hormonal actions on reproduction and water/electrolyte balance. Previously, we have demonstrated that these six receptor subtype genes, which we designated VTR1A, VTR1B, OTR, VTR2A, VTR2B and VTR2C, arose from a syntenic ancestral gene pair, one VTR1/OTR ancestor and one VTR2 ancestor, through the early vertebrate whole-genome duplications (WGD) called 1R and 2R. This was supported by both phylogenetic and chromosomal conserved synteny data. More recently, other studies have focused on confounding factors, such as the OTR/VTR orthologs in cyclostomes, to question this scenario for the origin of the OTR/VTR gene family; proposing instead less parsimonious interpretations involving only one WGD followed by complex series of chromosomal or segmental duplications. Here, we have updated the phylogeny of the OTR/VTR gene family, including a larger number of vertebrate species, and revisited seven representative neighboring gene families from our previous conserved synteny analyses, adding chromosomal information from newer high-coverage genome assemblies from species that occupy key phylogenetic positions: the polypteriform fish reedfish (Erpetoichthys calabaricus), the cartilaginous fish thorny skate (Amblyraja radiata) and a more recent high-quality assembly of the Western clawed frog (Xenopus tropicalis) genome. Our analyses once again add strong support for four-fold symmetry, i.e., chromosome quadruplication in the same time window as the WGD events early in vertebrate evolution, prior to the jawed vertebrate radiation. Thus, the evolution of the OTR/VTR gene family can be most parsimoniously explained by two WGD events giving rise to the six ancestral genes, followed by differential gene losses of VTR2 genes in different lineages. We also argue for more coherence and clarity in the nomenclature of OT/VT receptors, based on the most parsimonious scenario.

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  • 10.
    Shebanits, Kateryna
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Larhammar: Pharmacology.
    Günther, Torsten
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Human Evolution. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Johansson, Anna C. V.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Evolution.
    Maqbool, Khurram
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Feuk, Lars
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Jakobsson, Mattias
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Human Evolution.
    Larhammar, Dan
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Larhammar: Pharmacology.
    Copy number determination of the gene for the human pancreatic polypeptide receptor NPY4R using read depth analysis and droplet digital PCR.2019In: BMC Biotechnology, E-ISSN 1472-6750, Vol. 19, article id 31Article in journal (Refereed)
    Abstract [en]

    Background: Copy number variation (CNV) plays an important role in human genetic diversity and has been associated with multiple complex disorders. Here we investigate a CNV on chromosome 10q11.22 that spans NPY4R, the gene for the appetite-regulating pancreatic polypeptide receptor Y4. This genomic region has been challenging to map due to multiple repeated elements and its precise organization has not yet been resolved. Previous studies using microarrays were interpreted to show that the most common copy number was 2 per genome.

    Results: We have investigated 18 individuals from the 1000 Genomes project using the well-established method of read depth analysis and the new droplet digital PCR (ddPCR) method. We find that the most common copy number for NPY4R is 4. The estimated number of copies ranged from three to seven based on read depth analyses with Control-FREEC and CNVnator, and from four to seven based on ddPCR. We suggest that the difference between our results and those published previously can be explained by methodological differences such as reference gene choice, data normalization and method reliability. Three high-quality archaic human genomes (two Neanderthal and one Denisova) display four copies of the NPY4R gene indicating that a duplication occurred prior to the human-Neanderthal/Denisova split.

    Conclusions: We conclude that ddPCR is a sensitive and reliable method for CNV determination, that it can be used for read depth calibration in CNV studies based on already available whole-genome sequencing data, and that further investigation of NPY4R copy number variation and its consequences are necessary due to the role of Y4 receptor in food intake regulation.

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    fulltext
  • 11.
    Xie, Bushan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Nanchang Univ, Dept Gastroenterol, Affiliated Hosp 1, Nanchang, Jiangxi, Peoples R China.
    He, Xingxing
    Nanchang Univ, Dept Gastroenterol, Affiliated Hosp 1, Nanchang, Jiangxi, Peoples R China.
    Guo, Guihai
    Nanchang Univ, Dept Gastroenterol, Affiliated Hosp 1, Nanchang, Jiangxi, Peoples R China.
    Zhang, Xiao
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Larhammar: Pharmacology.
    Li, Jin-Ping
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Liu, Jianping
    Dali Univ, Sch Clin Med, Xue Ren Rd, Dali 671000, Yunnan, Peoples R China.
    Lin, Yingbo
    Karolinska Inst, Dept Oncol Pathol, S-17176 Stockholm, Sweden.
    High-throughput screening identified mitoxantrone to induce death of hepatocellular carcinoma cells with autophagy involvement2020In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 521, no 1, p. 232-237Article in journal (Refereed)
    Abstract [en]

    The use of highly efficient high-throughput screening (HTS) platform has recently gained more attention as a plausible approach to identify de novo therapeutic application potential of conventional anti-tumor drugs for cancer treatments. In this study, we used hepatocellular carcinoma (HCC) cells as models to identify cytotoxic compounds by HTS. To identify cytotoxic compounds for potential HCC treatments, 3271 compounds from three well established small molecule libraries were screened against HCC cell lines. Thirty-two small molecules were identified from the primary screen to induce cell death. Particularly, mitoxantrone (MTX), which is an established antineoplastic drug, significantly and specifically inhibited the growth and proliferation of HCC cells in vitro. Mechanistic studies of LC3-II, p62 and phosphorylation of p70S6K in HepG2 cells revealed that MTX treatment induced mTOR-dependent autophagy activation, which was further confirmed by the autophagic flux assay using lysosomal inhibitor chloroquine (CQ). In the combined treatment of MTX and CQ where autophagy was inhibited by CQ the elevations of cleaved Caspase-3 and PARP were observed, indicating the enhanced apoptosis in HepG2 cells. Taken together, we hypothesize that MTX-induced autophagy plays an pro-survival role in HCC treatment. Combined treatment with autophagy inhibitor may combat the chemo-resistance of HCC to MTX treatment and therefore deserves future clinical investment. 

  • 12.
    Zhang, Xiao
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Larhammar: Pharmacology.
    O'Callaghan, Paul
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Li, Honglian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Tan, Ying-Xia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab. Acad Mil Med Sci, Stem Cell & Regenerat Med Lab, Inst Hlth Serv & Transfus Med, Beijing, Peoples R China..
    Zhang, Ganlin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab. Capital Med Univ, Beijing Hosp Tradit Chinese Med, 23,Back Rd Art Gallery, Beijing 100010, Peoples R China..
    Barash, Uri
    Technion, Canc & Vasc Biol Res Ctr, Rappaport Fac Med, IL-31096 Haifa, Israel..
    Wang, Xiaomin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab. Capital Med Univ, Beijing Hosp Tradit Chinese Med, 23,Back Rd Art Gallery, Beijing 100010, Peoples R China..
    Lannfelt, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Vlodavsky, Israel
    Technion, Canc & Vasc Biol Res Ctr, Rappaport Fac Med, IL-31096 Haifa, Israel..
    Lindahl, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Li, Jin-Ping
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Heparanase overexpression impedes perivascular clearance of amyloid-beta from murine brain: relevance to Alzheimer's disease2021In: Acta neuropathologica communications, E-ISSN 2051-5960, Vol. 9, article id 84Article in journal (Refereed)
    Abstract [en]

    Defective amyloid-beta (A beta) clearance from the brain is a major contributing factor to the pathophysiology of Alzheimer's disease (AD). A beta clearance is mediated by macrophages, enzymatic degradation, perivascular drainage along the vascular basement membrane (VBM) and transcytosis across the blood-brain barrier (BBB). AD pathology is typically associated with cerebral amyloid angiopathy due to perivascular accumulation of A beta. Heparan sulfate (HS) is an important component of the VBM, thought to fulfill multiple roles in AD pathology. We previously showed that macrophage-mediated clearance of intracortically injected A beta was impaired in the brains of transgenic mice overexpressing heparanase (Hpa-tg). This study revealed that perivascular drainage was impeded in the Hpa-tg brain, evidenced by perivascular accumulation of the injected A beta in the thalamus of Hpa-tg mice. Furthermore, endogenous A beta accumulated at the perivasculature of Hpa-tg thalamus, but not in control thalamus. This perivascular clearance defect was confirmed following intracortical injection of dextran that was largely retained in the perivasculature of Hpa-tg brains, compared to control brains. Hpa-tg brains presented with thicker VBMs and swollen perivascular astrocyte endfeet, as well as elevated expression of the BBB-associated water-pump protein aquaporin 4 (AQP4). Elevated levels of both heparanase and AQP4 were also detected in human AD brain. These findings indicate that elevated heparanase levels alter the organization and composition of the BBB, likely through increased fragmentation of BBB-associated HS, resulting in defective perivascular drainage. This defect contributes to perivascular accumulation of A beta in the Hpa-tg brain, highlighting a potential role for heparanase in the pathogenesis of AD.

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