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Berlin Brandenburg

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  • 1
    Language: English
    In: The Journal of clinical investigation, 01 March 2018, Vol.128(3), pp.1043-1056
    Description: Congenital long QT syndrome (LQTS) is an inherited channelopathy associated with life-threatening arrhythmias. LQTS type 2 (LQT2) is caused by mutations in KCNH2, which encodes the potassium channel hERG. We hypothesized that modifier genes are partly responsible for the variable phenotype severity observed in some LQT2 families. Here, we identified contributors to variable expressivity in an LQT2 family by using induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) and whole exome sequencing in a synergistic manner. We found that iPSC-CMs recapitulated the clinical genotype-phenotype discordance in vitro. Importantly, iPSC-CMs derived from the severely affected LQT2 patients displayed prolonged action potentials compared with cells from mildly affected first-degree relatives. The iPSC-CMs derived from all patients with hERG R752W mutation displayed lower IKr amplitude. Interestingly, iPSC-CMs from severely affected mutation-positive individuals exhibited greater L-type Ca2+ current. Whole exome sequencing identified variants of KCNK17 and the GTP-binding protein REM2, providing biologically plausible explanations for this variable expressivity. Genome editing to correct a REM2 variant reversed the enhanced L-type Ca2+ current and prolonged action potential observed in iPSC-CMs from severely affected individuals. Thus, our findings showcase the power of combining complementary physiological and genomic analyses to identify genetic modifiers and potential therapeutic targets of a monogenic disorder. Furthermore, we propose that this strategy can be deployed to unravel myriad confounding pathologies displaying variable expressivity.
    Keywords: Arrhythmias ; Cardiology ; Genetics ; Ion Channels ; Ips Cells ; Mutation ; Long Qt Syndrome -- Genetics ; Monomeric Gtp-Binding Proteins -- Genetics ; Potassium Channels, Tandem Pore Domain -- Genetics
    ISSN: 00219738
    E-ISSN: 1558-8238
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  • 2
    In: PLoS ONE, 2013, Vol.8(12)
    Description: Thermal layering in reservoirs upstream from hydroelectric dams can create temperature gradients in fishways used by upstream migrating adults. In the Snake River, Washington, federally-protected adult salmonids ( Oncorhynchus spp.) often encounter relatively cool water in dam tailraces and lower ladder sections and warmer water in the upstream portions of ladders. Using radiotelemetry, we examined relationships between fish passage behavior and the temperature difference between the top and bottom of ladders (∆T) at four dams over four years. Some spring Chinook salmon ( O. tshawytscha ) experienced ∆T ≥ 0.5 °C. Many summer and fall Chinook salmon and summer steelhead ( O. mykiss ) experienced ∆T ≥ 1.0 °C, and some individuals encountered ΔT 〉 4.0°C. As ΔT increased, migrants were consistently more likely to move down fish ladders and exit into dam tailraces, resulting in upstream passage delays that ranged from hours to days. Fish body temperatures equilibrated to ladder temperatures and often exceeded 20°C, indicating potential negative physiological and fitness effects. Collectively, the results suggest that gradients in fishway water temperatures present a migration obstacle to many anadromous migrants. Unfavorable temperature gradients may be common at reservoir-fed fish passage facilities, especially those with seasonal thermal layering or stratification. Understanding and managing thermal heterogeneity at such sites may be important for ensuring efficient upstream passage and minimizing stress for migratory, temperature-sensitive species.
    Keywords: Research Article
    E-ISSN: 1932-6203
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  • 3
    Language: English
    In: Journal of experimental zoology. Part B, Molecular and developmental evolution, September 2018, Vol.330(6-7), pp.330-340
    Description: Caudal-fin lepidotrichia is composed of numerous segments, which are linked to each other by intersegmental joints. During fish growth, lepidotrichia elongate by the addition of new segments at their distal margin, whereas the length of each segment remains constant after it is formed. In the present paper, we examined whether the water temperature affects the segmentation pattern of the juvenile and adult caudal fin. For this purpose, zebrafish (Danio rerio) embryos and larvae were exposed to three different temperature conditions (24°C, 28°C, and 32°C) from the pharyngula stage (1 day postfertilization [dpf]) to metamorphosis, whereas the control temperature (28°C) was applied to all the groups before and after this period. Results demonstrated that water temperature had a significant effect on the length of the segments of each lepidotrichium, at both the juvenile and adult stages. Moreover, at higher temperatures, there was a significant proximal shift of the position of the first bifurcation of the second lepidotrichium of the dorsal lobe. At all the experimental conditions, the length of proximal segment was not constant during fish growth, but it followed a discontinuous saltatory growth. Histological analysis of the proximal lepidotrichia segments revealed that the observed apparent growth of segments is the result of fusions between segments. Fusion occurs not by mineralization of the intersegmental joints, but by bone deposition around the joints.
    Keywords: Joints ; Lepidotrichia ; Phenotypic Plasticity ; Segments ; Teleosts ; Temperature ; Animal Fins -- Embryology ; Zebrafish -- Embryology
    ISSN: 15525007
    E-ISSN: 1552-5015
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  • 4
    Language: English
    In: eLife, 29 September 2015, Vol.4
    Description: Perforin-2 (MPEG1) is an effector of the innate immune system that limits the proliferation and spread of medically relevant Gram-negative, -positive, and acid fast bacteria. We show here that a cullin-RING E3 ubiquitin ligase (CRL) complex containing cullin-1 and βTrCP monoubiquitylates Perforin-2 in response to pathogen associated molecular patterns such as LPS. Ubiquitylation triggers a rapid redistribution of Perforin-2 and is essential for its bactericidal activity. Enteric pathogens such as Yersinia pseudotuberculosis and enteropathogenic Escherichia coli disarm host cells by injecting cell cycle inhibiting factors (Cifs) into mammalian cells to deamidate the ubiquitin-like protein NEDD8. Because CRL activity is dependent upon NEDD8, Cif blocks ubiquitin dependent trafficking of Perforin-2 and thus, its bactericidal activity. Collectively, these studies further underscore the biological significance of Perforin-2 and elucidate critical molecular events that culminate in Perforin-2-dependent killing of both intracellular and extracellular, cell-adherent bacteria.
    Keywords: Cif ; E. Coli ; Epec ; Mpeg1 ; Nedd8 ; Perforin-2 ; Yersinia Pseudotuberculosis ; Human ; Immunology ; Infectious Disease ; Microbiology ; Mouse ; Host-Pathogen Interactions ; Microbial Viability ; Cell Cycle -- Drug Effects ; Enteropathogenic Escherichia Coli -- Immunology ; Pore Forming Cytotoxic Proteins -- Toxicity ; Virulence Factors -- Metabolism ; Yersinia Pseudotuberculosis -- Immunology
    E-ISSN: 2050-084X
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  • 5
    Language: English
    In: Proceedings of the National Academy of Sciences of the United States of America, 7 April 2009, Vol.106(14), pp.5681-5686
    Description: Although somatic cell nuclear transfer (SCNT) cloning is more efficient in cattle than in any other species tested so far, there is a high rate of pregnancy failure that has been linked to structural and functional abnormalities of the placenta. We tested the hypothesis that these changes may originate from disturbed embryo-maternal interactions in the peri-implantation period. Therefore, we evaluated the response of the endometrium to SCNT embryos (produced from 7 different fetal fibroblast cell lines) as compared with embryos derived from in vitro fertilization (IVF). SCNT embryos and IVF embryos were cultured under identical conditions to the blastocyst stage (day 7) and were transferred to corresponding recipients, which were slaughtered at day 18 of pregnancy. The mRNA profiles of endometrium samples were obtained using a custom cDNA microarray enriched for transcripts differentially expressed in the endometrium and/or oviduct epithelium during the estrous cycle and/or early pregnancy. Overall, the variation in mRNA profiles was greater in the SCNT group than in the IVF group. Furthermore, 58 transcripts were differentially abundant in endometria from SCNT and IVF pregnancies. Prominent examples are orphan nuclear receptor COUP-TFII and connexin 43, both known to play important roles in uterine receptivity and conceptus placentation. These findings suggest that placental failure in bovine clone pregnancies may originate from abnormal embryomaternal communication that develops during the peri-implantation period. Endometrium transcriptome profiles may serve as a tool to evaluate SCNT embryos for their ability to establish pregnancy and develop a functional placenta.
    Keywords: Biological sciences -- Biology -- Developmental biology ; Biological sciences -- Biology -- Developmental biology ; Biological sciences -- Biology -- Developmental biology ; Biological sciences -- Biology -- Anatomy ; Biological sciences -- Biology -- Zoology ; Physical sciences -- Chemistry -- Chemical compounds ; Biological sciences -- Biology -- Cytology ; Biological sciences -- Biology -- Genetics ; Biological sciences -- Biology -- Cytology ; Biological sciences -- Biology -- Developmental biology ; Biological sciences -- Biology -- Developmental biology ; Biological sciences -- Biology -- Developmental biology ; Biological sciences -- Biology -- Developmental biology ; Biological sciences -- Biology -- Anatomy ; Biological sciences -- Biology -- Zoology ; Physical sciences -- Chemistry -- Chemical compounds ; Biological sciences -- Biology -- Cytology ; Biological sciences -- Biology -- Genetics ; Biological sciences -- Biology -- Cytology ; Biological sciences -- Biology -- Developmental biology
    ISSN: 00278424
    E-ISSN: 10916490
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  • 6
    Language: English
    In: Vaccine, 2011, Vol.29(14), pp.2619-2625
    Description: The ER-resident chaperone gp96, when released by cell lysis, induces an immunogenic chemokine signature and causes innate immune activation of DC and NK cells. Here we show that intraperitoneal immunization with a genetically engineered, secreted form of gp96, gp96-Ig chaperoning SIV antigens, induces high levels of antigen specific CD8 CTL in the rectal and vaginal mucosa of Rhesus macaques. The frequency of SIV Gag- and SIV Tat-tetramer positive CD8 CTL in the intestinal mucosa reached 30–50% after the third immunization. Tetramer positive CD8 CTL expressed appropriate functional (granzyme B) and migration markers (CD103). The polyepitope specificity of the mucosal CD8 and CD4 response is evident from a strong, multifunctional cytokine response upon stimulation with peptides covering the gag, tat and env proteins. Induction of powerful mucosal effector CD8 CTL responses by cell-based gp96 -Ig immunization may provide a pathway to the development of safe and effective SIV/HIV vaccines.
    Keywords: Gp96-Chaperone ; Mucosa ; Non-Human Primate ; Rectum ; Vagina ; Medicine ; Biology ; Veterinary Medicine ; Pharmacy, Therapeutics, & Pharmacology
    ISSN: 0264-410X
    E-ISSN: 1873-2518
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  • 7
    Language: English
    In: Current Alzheimer Research, 2015, Vol.12(9), p.814-828
    Description: A potential strategy to alleviate the aggregation of intrinsically disordered proteins (IDPs) is to maintain the native functional state of the protein by small molecule binding. However, the targeting of the native state of IDPs by small molecules has been challenging due to their heterogeneous conformational ensembles. To tackle this challenge, we applied a high-throughput chemical microarray surface plasmon resonance imaging screen to detect the binding between small molecules and monomeric full-length Tau, a protein linked with the onset of a range of Tauopathies. The screen identified a novel set of drug-like fragment and lead-like compounds that bound to Tau. We verified that the majority of these hit compounds reduced the aggregation of different Tau constructs in vitro and in N2a cells. These results demonstrate that Tau is a viable receptor of drug-like small molecules. The drug discovery approach that we present can be applied to other IDPs linked to other misfolding diseases such as Alzheimer's and Parkinson's diseases.
    Keywords: Alzheimer'S Disease Drug Discovery High Throughput Screening Inhibitor Protein Aggregation Tau Taupathies Therapeutic.
    ISSN: 1567-2050
    E-ISSN: 1875-5828
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  • 8
    Language: English
    In: The Journal of biological chemistry, 10 January 2014, Vol.289(2), pp.956-67
    Description: Understanding the formation and propagation of aggregates of the Alzheimer disease-associated Tau protein in vivo is vital for the development of therapeutics for this devastating disorder. Using our recently developed live-cell aggregation sensor in neuron-like cells, we demonstrate that different variants of exogenous monomeric Tau, namely full-length Tau (hTau40) and the Tau-derived construct K18 comprising the repeat domain, initially accumulate in endosomal compartments, where they form fibrillar seeds that subsequently induce the aggregation of endogenous Tau. Using superresolution imaging, we confirm that fibrils consisting of endogenous and exogenous Tau are released from cells and demonstrate their potential to spread Tau pathology. Our data indicate a greater pathological risk and potential toxicity than hitherto suspected for extracellular soluble Tau.
    Keywords: Alzheimer Disease ; Amyloid ; Endocytosis ; Fluorescence Lifetime Imaging Microscopy ; Propagation ; Protein Aggregation ; Superresolution Microscopy ; Tau ; Endocytosis ; Neurofibrillary Tangles -- Metabolism ; Neurons -- Metabolism ; Tau Proteins -- Metabolism
    ISSN: 00219258
    E-ISSN: 1083-351X
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  • 9
    Language: English
    In: Thrombosis and haemostasis, April 2016, Vol.115(4), pp.781-8
    Description: Platelet-monocyte interactions are strongly implicated in thrombo-inflammatory injury by actively contributing to intravascular inflammation, leukocyte recruitment to inflamed sites, and the amplification of the procoagulant response. Instant blood-mediated inflammatory reaction (IBMIR) represents thrombo-inflammatory injury elicited upon pancreatic islet transplantation (islet-Tx), thereby dramatically affecting transplant survival and function. Developmental endothelial locus-1 (Del-1) is a functionally versatile endothelial cell-derived homeostatic factor with anti-inflammatory properties, but its potential role in IBMIR has not been previously addressed. Here, we establish Del-1 as a novel inhibitor of IBMIR using a whole blood-islet model and a syngeneic murine transplantation model. Indeed, Del-1 pre-treatment of blood before addition of islets diminished coagulation activation and islet damage as assessed by C-peptide release. Consistently, intraportal islet-Tx in transgenic mice with endothelial cell-specific overexpression of Del-1 resulted in a marked decrease of monocytes and platelet-monocyte aggregates in the transplanted tissues, relative to those in wild-type recipients. Mechanistically, Del-1 decreased platelet-monocyte aggregate formation, by specifically blocking the interaction between monocyte Mac-1-integrin and platelet GPIb. Our findings reveal a hitherto unknown role of Del-1 in the regulation of platelet-monocyte interplay and the subsequent heterotypic aggregate formation in the context of IBMIR. Therefore, Del-1 may represent a novel approach to prevent or mitigate the adverse reactions mediated through thrombo-inflammatory pathways in islet-Tx and perhaps other inflammatory disorders involving platelet-leukocyte aggregate formation.
    Keywords: Developmental Endothelial Locus 1 (Del-1) ; Gpib ; Instant Blood-Mediated Inflammatory Reaction (Ibmir) ; Mac-1 Integrin ; Coagulation ; Islet Transplantation ; Platelet-Monocyte Aggregates ; Islets of Langerhans Transplantation ; Blood Platelets -- Physiology ; Carrier Proteins -- Metabolism ; Inflammation -- Genetics ; Islets of Langerhans -- Metabolism ; Monocytes -- Physiology ; Thrombosis -- Genetics
    ISSN: 03406245
    E-ISSN: 2567-689X
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  • 10
    Language: English
    In: Sci Rep, 2017, Vol.7(1), pp.2397-2397
    Description: The human growth hormone (hGH) minigene used for transgene stabilization in mice has been recently identified to be locally expressed in the tissues where transgenes are active and associated with phenotypic alterations. Here we extend these findings by analyzing the effect of the hGH minigene in TgC6hp55 transgenic mice which express the human TNFR1 under the control of the mesenchymal cell-specific CollagenVI promoter. These mice displayed a fully penetrant phenotype characterized by growth enhancement accompanied by perturbations in metabolic, skeletal, histological and other physiological parameters. Notably, this phenotype was independent of TNF-TNFR1 signaling since the genetic ablation of either Tnf or Tradd did not rescue the phenotype. Further analyses showed that the hGH minigene was expressed in several tissues, also leading to increased hGH protein levels in the serum. Pharmacological blockade of GH signaling prevented the development of the phenotype. Our results indicate that the unplanned expression of the hGH minigene in CollagenVI expressing mesenchymal cells can lead through local and/or systemic mechanisms to enhanced somatic growth followed by a plethora of primary and/or secondary effects such as hyperphagia, hypermetabolism, disturbed glucose homeostasis, altered hematological parameters, increased bone formation and lipid accumulation in metabolically critical tissues.
    Keywords: Article;
    ISSN: 2045-2322
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