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Search indexed bioRxiv preprints in genomics, neuroscience, cell biology and bioinformatics. Read source abstracts and check manuscript versions; preprints are not peer reviewed.

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At least 487 records · Page 27Linked to original sources

bioRxiv2017

A potential link between gambling addiction severity and central dopamine levels -- evidence from spontaneous eye blink rates in gamblers and controls

Accumulating evidence points at similarities between substance use disorders and pathological gambling on the behavioral and neural level. In substance addiction, dysregulation of striatal dopamine transmission has been consistently revealed. Due to the neurotoxicity of stimulating substances, it is still debated if this constitutes mainly a consequence of recurrent substance abuse or a vulnerability marker for addiction disorders. For gambling addiction, no clear association with striatal dopamine levels has been unveiled so far. With its presumably negligible dopaminergic toxicity, possible differences in striatal dopamine transmission in gambling addiction might therefore constitute a vulnerability marker. Spontaneous eye blink rate (sEBR) is controversially discussed as a potential proxy measure for striatal dopamine levels. Here we examined sEBR in 21 male problem gamblers and 20 healthy control participants. In addition, participants completed a screening questionnaire for overall psychopathology and self-reported measures of alcohol and nicotine consumption. We found no significant difference in sEBR between gamblers and controls. However, in gamblers, sEBR was negatively associated with addiction severity and positively associated with psychopathology. A final exploratory analysis revealed that healthy controls with low sEBR displayed higher alcohol and nicotine consumption than healthy participants with high sEBR. Although the association between dopamine transmission and sEBR is still debated, our findings reveal that sEBR is sensitive to inter-individual differences in addiction severity in problem gamblers.

neuroscience↗

bioRxiv2017

Comprehensive Cell Type Specific Transcriptomics of the Human Kidney

The human kidney is a complex organ composed of specialized cell types. To better define this cellular complexity, we profiled the individual transcriptomes of 22,469 normal human kidney cells, identifying 27 cell types. We describe three distinct endothelial cell populations, a novel subset of intercalated cells, interstitial macrophage and dendritic cells, and identify numerous novel cell-type-specific markers, many validated using imaging mass cytometry and immunohistochemistry. Receptor-ligand analysis revealed previously unknown intercalated-endothelial and intercalated-distal nephron interactions, suggesting a role in maintenance of vascular integrity and intercalated cell survival. Notably, kidney disease-associated genes were largely expressed in proximal tubules, podocytes, endothelial and myeloid cells, highlighting an underappreciated role for endothelial cells in kidney pathologies. Our analysis also provides a resource of cell type enriched markers, solute carriers, channels and lncRNAs. In summary, this cell-type-specific transcriptome resource provides the foundation for a comprehensive understanding of kidney function and dysfunction at single cell resolution.

cell biology↗

bioRxiv2017

Hepatic NF-kB-inducing Kinase (NIK) Suppresses Liver Regeneration in Chronic Liver Disease

Hepatocyte replication maintains liver homeostasis and integrity. It is impaired in chronic liver disease, promoting disease progression. Herein, we have identified NF-kB-inducing kinase (NIK) as an unrecognized suppressor of hepatocyte replication. Hepatic NIK was aberrantly activated in chronic liver disease. Hepatocyte-specific deletion of NIK or its downstream mediator IKK substantially accelerated hepatocyte proliferation and liver regeneration following partial hepatectomy. Mechanistically, NIK and IKK suppressed the mitogenic JAK2/STAT3 pathway, thereby inhibiting hepatocyte cell cycle progression. Remarkably, inactivation of hepatic NIK largely reversed suppression of the hepatic JAK2/STAT3 pathway, hepatocyte replication, and liver regeneration induced by either chronic liver injury or metabolic stress. Our data suggest that hepatic NIK acts as a rheostat for liver regeneration to restrain liver overgrowth. Pathologic activation of hepatic NIK blocks hepatocyte replication, likely contributing to liver disease progression.

cell biology↗

bioRxiv2017

The PTPRT pseudo-phosphatase domain is a denitrase

Protein tyrosine nitration occurs under both physiological and pathological conditions1. However, enzymes that remove this protein modification have not yet been identified. Here we report that the pseudo-phosphatase domain of protein tyrosine receptor T (PTPRT) is a denitrase that removes nitro-groups from tyrosine residues in paxillin. PTPRT normally functions as a tumor suppressor and is frequently mutated in a variety of human cancers including colorectal cancer2,3. We demonstrate that some of the tumor-derived mutations located in the pseudophosphatase domain impair the denitrase activity. Moreover, PTPRT mutant mice that inactivate the denitrase activity are susceptible to carcinogen-induced colon tumor formation. This study uncovers a novel enzymatic activity that is involved in tumor suppression.

cancer biology↗

bioRxiv2017

Brain, immune system and selenium: a starting point for a new diagnostic marker for Alzheimer’s disease?

The clinical diagnosis of Alzheimers disease (AD) is based primarily on neuropsychological tests, which assess the involutive damage, and imaging techniques that evaluate morphologic changes in the brain. The currently available diagnostic tests do not show complete specificity and do not permit an accurate differentiation between AD and other forms of senile dementia. The correlation of these tests with laboratory investigations based on biochemical parameters could increase the certainty of the diagnosis. In recent years, several biochemical markers for the diagnosis of AD have been proposed, but in most cases they show a limited specificity and their application is invasive, because it generally requires the sampling of cerebrospinal fluid. Therefore, the use of a peripheral biochemical marker could represent a valuable complement for the diagnosis of this disease.\n\nSeveral studies have shown a relationship between the neurodegenerative disorders typical of the ageing process, the weakening of the immune system, alterations in the levels of selenium and of the antioxidant selenoenzymes in brain tissues and blood cells, particularly in neutrophil granulocytes. The levels of peripheral selenoenzymes may reveal a promising clinical parameter for helping in the assessment of the pathological condition in AD.\n\nHighlightsMsrBl is one of the 25 selenoenzymes expressed in the humans\n\nMsrBl is highly expressed in human circulating neutrophils\n\nThe diagnostic markers for Alzheimers disease are still insufficiently validated\n\nThe impairment of some selenoenzymes is associated with Alzheimers disease\n\nNeutrophil MsrBl can be a peripheral marker for the diagnosis of Alzheimers disease

biochemistry↗

bioRxiv2017

Tissue disorder strength measured by quantitative phase imaging as intrinsic cancer marker

Tissue refractive index provides important information about morphology at the nanoscale. Since the malignant transformation involves both intra- and inter-cellular changes in the refractive index map, the tissue disorder measurement can be used to extract important diagnosis information. Quantitative phase imaging (QPI) provides a practical means of extracting this information as it maps the optical path-length difference (OPD) across a tissue sample with sub-wavelength sensitivity. In this work, we employ QPI to compare the tissue disorder strength between benign and malignant breast tissue histology samples. Our results show that disease progression is marked by a significant increase in the disorder strength. Since our imaging system can be added as an upgrading module to an existing microscope, we anticipate that it can be integrated easily in the pathology work flow.

bioengineering↗

bioRxiv2017

Dot2dot: Accurate Whole-Genome Tandem Repeats Discovery

The advent of sequencing technologies and the consequent computational analysis of genomes has confirmed the evidence that DNA sequences contain a relevant amount of repetitions. A particularly important category of repeating sequences is that of tandem repeats (TRs). TRs are short, almost identical sequences that lie adjacent to each other. The abundance of TRs in eukaryotic genomes has suggested that they play a role in many cellular processes and, indeed, are also involved in the onset and progress of several genetic disorders.\n\nBuilding upon the idea that similar sequences can be easily displayed using graphical methods, we formalized the structure that TRs induce in dot plot matrices where a sequence is compared with itself. We further observed that a compact representation of these matrices can be built and searched in linear time in the size of the input sequence. Exploiting this observation, we developed an algorithm fast enough to be suitable for whole-genome discovery of tandem repeats.\n\nWe compared our algorithm with seven state of the art methods using as a gold standard five collections of tandem repeats: pathology-linked, forensic, for population analysis, genealogic-oriented, and variable TRs in regulatory regions. In addition, we run our algorithm on seven reference genomes to test the suitability of our approach for whole-genome analysis. Experiments show that our method: is always more accurate than the other methods, and completes the analysis of the biggest available reference genome in about one day running at a rate of 0.98Gbp/h on a standard workstation.

genomics↗

bioRxiv2018

RNA-binding proteins with mixed charge domains self-assemble and aggregate in Alzheimer’s Disease

U1 small nuclear ribonucleoprotein 70 kDa (U1-70K) and other RNA binding proteins (RBPs) are mislocalized to cytoplasmic neurofibrillary Tau aggregates in Alzheimers disease (AD), yet understanding of the mechanisms that cause their aggregation is limited. Many RBPs that aggregate in neurodegenerative diseases self-assemble into RNA granules through intrinsically disordered low complexity (LC) domains. We report here that a LC domain within U1-70K of mixed charge, containing highly repetitive complementary repeats of basic (R/K) and acidic (D/E) residues, shares many of the same properties of the Q/N-rich LC domains found in the RBPs TDP-43 and FUS. These properties include the ability to self-assemble into oligomers, and to form nuclear granules. To analyze the functional roles of the U1-70K LC domains, we performed co-immunoprecipitation and quantitative mass spectrometry analysis of recombinant U1-70K and deletions lacking the C-terminal LC domain(s). A network-driven approach resolved functional classes of U1-70K interacting proteins that showed dependency on the U1-70K LC domain(s) for their interaction. This included structurally similar RBPs, such as LUC7L3 and RBM25, which require their respective mixed charge domains for reciprocal interactions with U1-70K and for participation in nuclear RNA granules. Strikingly, a significant proportion of RBPs with mixed charge domains have elevated insolubility in AD brain proteome compared to controls. Furthermore, we show that the mixed charge LC domain of U1-70K can interact with Tau from AD brain. These findings highlight mechanisms for mixed charge domains in stabilizing RBP interactions and in potentially mediating co-aggregation with pathological Tau isoforms in AD.

biochemistry↗

bioRxiv2018

GSK3 Controls Migration of the Neural Crest Lineage

Migration of the neural crest lineage is critical to its physiological function. Mechanisms controlling neural crest migration are comparatively unknown, due to difficulties accessing this cell population in vivo. Here, we uncover novel requirements of glycogen synthase kinase 3 (GSK3) in regulating the neural crest. We demonstrate that GSK3 is tyrosine phosphorylated (pY) in neural crest cells and that this activation depends on anaplastic lymphoma kinase (ALK), a protein associated with neuroblastoma. Consistent with this, neuroblastoma cells with pathologically increased ALK activity express high levels of pY-GSK3 and migration of these cells can be inhibited by GSK3 or ALK blockade. In normal neural crest cells, loss of GSK3 leads to increased pFAK and misregulation of Rac1 and lamellipodin, key regulators of cell migration. Genetic reduction of GSK-3 results in failure of migration. All together, this work identifies a role for GSK3 in cell migration during neural crest development and cancer.

developmental biology↗

bioRxiv2018

A testosterone metabolite 19-hydroxyandrostenedione induces neuroendocrine trans-differentiation of prostate cancer cells via an ectopic olfactory receptor

Olfactory receptor OR51E2, also known as a Prostate Specific G-Protein Receptor, is highly expressed in prostate cancer but its function is not well understood. Through in silico and in vitro analyses, we identified 24 agonists and 1 antagonist for this receptor. We detected that agonist 19-hydroxyandrostenedione, a product of the aromatase reaction, is endogenously produced upon receptor activation. We characterized the effects of receptor activation on metabolism using a prostate cancer cell line and demonstrated decreased intracellular anabolic signals and cell viability, induction of cell cycle arrest, and increased expression of neuronal markers. Furthermore, upregulation of neuron-specific enolase by agonist treatment was abolished in OR51E2-KO cells. The results of our study suggest that OR51E2 activation results in neuroendocrine trans-differentiation. These findings reveal a new role for OR51E2 and establish this G-protein coupled receptor as a novel therapeutic target in the treatment of prostate cancer.\n\nSignificanceProstate cancer is the second most common cancer in men. Most deaths from prostate cancer are due to the progression of localized disease into metastatic, castration-resistant prostate cancer characterized by increased number of neuroendocrine-like cells. These neuroendocrine-like cells are non-proliferating, terminally differentiated cells. Olfactory receptor OR51E2, also known as a Prostate Specific G-Protein Receptor, is highly expressed in prostate cancer, and its expression correlates with disease progression. Here, we identify and validate novel endogenous ligands for this receptor. We show that activation of OR51E2 by newly-discovered prostate cancer-relevant agonists facilitates cellular transformation, resulting in neuroendocrine trans-differentiation, a characteristic phenotype of castrate resistant prostate cancer. Our results establish this G-protein coupled receptor as a novel and therapeutic target for castration-resistant prostate cancer.\n\nHighlightsO_LIDiscovery of novel agonists for olfactory receptor OR51E2/PSGR highly relevant to prostate cancer pathology\nC_LIO_LIActivation of OR51E2 receptor by agonist N-acetyl-N-formyl-5-methoxykynurenamine (AFMK) results in release of 19-hydroxyandrostenedione (19-OH AD) from the prostate cancer cells indicating its endogenous production\nC_LIO_LIActivation of OR51E2 receptor by 19-OH AD, AFMK, and propionic acid decreases anabolic and proliferative signals\nC_LIO_LIActivation of OR51E2 receptor by 19-OH AD and AFMK increases markers specific for neuroendocrine trans-differentiation (NEtD)\nC_LIO_LIAblation of the OR51E2 gene in prostate cancer cells treated with agonist 19-OH AD significantly reduces neuron-specific enolase\nC_LI

cancer biology↗

bioRxiv2018

Rapid Identification and Validation of Novel Rheumatoid Arthritis Drug Treatments using an Integrative Bioinformatics Platform

The majority of drugs currently used to treat rheumatoid arthritis (RA) act on a small number of immunomodulatory targets. We applied an integrative biomedical-informatics-based approach and in vivo testing to identify new drug candidates and potential therapeutic targets that could form the basis for future drug development in RA. A computational model of RA was constructed by integrating patient gene expression data, molecular interactions, and clinical drug-disease associations. Drug candidates were scored based on their predicted efficacy across these data types. Ten high-scoring candidates were subsequently screened in a collagen-induced arthritis model of RA. Treatment with exenatide, olopatadine, and TXR-112 significantly improved multiple preclinical endpoints, including animal mobility which was measured using a novel digital platform. These three drug candidates do not act on common RA therapeutic targets; however, links between known candidate pharmacology and pathological processes involved in RA suggest hypothetical mechanisms contributing to the observed efficacy.

bioinformatics↗

bioRxiv2018

A three-dimensional staging system of mouse endometrial gland morphogenesis

Endometrial or uterine glands secrete substances essential for uterine receptivity to the embryo, implantation, conceptus survival, development, and growth. Adenogenesis is the process of gland formation within the stroma of the uterus that occurs after birth. In the mouse, uterine gland formation initiates at postnatal day (P) 5. Subsequently, the developing uterine glands invade into the adjacent stroma. Mouse uterine gland morphology is poorly understood because it is based on two-dimensional (2D) histological observations. To more fully describe uterine gland morphogenesis, we generated three-dimensional (3D) models of postnatal uterine glands from P0 to P21, using light sheet microscopy. At birth (P0), there were no glands. At P8, we found bud- and teardrop-shaped epithelial invaginations. By P11, the forming glands were elongated epithelial tubes. By P21, the elongated tubes had a sinuous morphology. These morphologies are homogeneously distributed along the anterior-posterior axis of the uterus. To facilitate uterine gland analyses, we propose a novel 3D staging system of uterine gland morphology during postnatal development in the mouse. We define 6 stages: Stage 0: Aglandular, Stage 1: Bud, Stage 2: Teardrop, Stage 3: Elongated, Stage 4: Sinuous, and Stage 5: Primary Branches. This staging system provides a standardized key to assess and quantify uterine gland morphology that can be used for studies of uterine gland development and pathology. In addition, our studies suggest that gland formation initiation occurs during P8 and P11. However, between P11 and P21 gland formation initiation stops and all glands elongate and become sinuous.

developmental biology↗

bioRxiv2018

Insights into circovirus host range from the genomic fossil record.

A diverse range of DNA sequences derived from circoviruses (family Circoviridae) have been identified in samples obtained from humans and domestic animals, often in association with pathological conditions. In the majority of cases, however, little is known about the natural biology of the viruses from which these sequences are derived. Endogenous circoviral elements (CVe) are DNA sequences derived from circoviruses that occur in animal genomes and provide a useful source of information about circovirus-host relationships. In this study we screened genome assemblies of 675 animal species and identified numerous circovirus-related sequences, including the first examples of CVe derived from cycloviruses. We confirmed the presence of these CVe in the germline of the elongate twig ant (Pseudomyrmex gracilis), thereby establishing that cycloviruses infect insects. We examined the evolutionary relationships between CVe and contemporary circoviruses, showing that CVe from ants and mites group relatively closely with cycloviruses in phylogenies. Furthermore, the relatively random interspersal of CVe from insect genomes with cyclovirus sequences recovered from vertebrate samples, suggested that contamination might be an important consideration in studies reporting these viruses. Our study demonstrates how endogenous viral sequences can inform metagenomics-based virus discovery. In addition, it raises doubts about the role of cycloviruses as pathogens of humans and other vertebrates.

microbiology↗

bioRxiv2018

The Viral protein Corona Directs Viral Pathogenesis and Amyloid Aggregation

Artificial nanoparticles accumulate a protein corona layer in biological fluids, which significantly influences their bioactivity. As nanosized obligate intracellular parasites, viruses share many biophysical properties with artificial nanoparticles in extracellular environments and here we show that respiratory syncytial virus (RSV) and herpes simplex virus 1 (HSV-1) accumulate a rich and distinctive protein corona in different biological fluids. Moreover, we show that corona pre-coating differentially affects viral infectivity and immune cell activation. Additionally, we demonstrate that viruses bind amyloidogenic peptides in their corona and catalyze amyloid formation via surface-assisted heterogeneous nucleation. Importantly, we show that HSV-1 catalyzes the aggregation of the amyloid beta peptide (A{beta}42), a major constituent of amyloid plaques in Alzheimers disease, in-vitro and in animal models. Our results highlight the viral protein corona as an acquired structural layer that is critical for viral-host interactions and illustrate a mechanistic convergence between viral and amyloid pathologies.

microbiology↗

bioRxiv2018

Zebrafish type I collagen mutants faithfully recapitulate human type I collagenopathies

The type I collagenopathies are a group of heterogeneous connective tissue disorders, that are caused by mutations in the genes encoding type I collagen and include specific forms of Osteogenesis Imperfecta (OI) and the Ehlers-Danlos syndrome (EDS). These disorders present with a broad disease spectrum and large clinical variability of which the underlying genetic basis is still poorly understood. In this study, we systematically analyzed skeletal phenotypes in a large set of zebrafish, with diverse mutations in the genes encoding type I collagen, representing different genetic forms of human OI, and the first zebrafish model of human EDS, which harbors characteristic defects in the soft connective tissues. Furthermore, we provide insight into how zebrafish and human type I collagen are compositionally and functionally related, which is relevant in the interpretation of human type I collagen related disease models. Our studies reveal a high degree of inter-genotype variability in phenotypic expressivity that closely correlates with associated OI severity. Further, we demonstrate the potential for select mutations to give rise to variable phenotypic penetrance, mirroring the clinical variability associated with human disease pathology. Therefore, our work suggests the potential for zebrafish to aid in identifying unknown genetic modifiers and mechanisms underlying the phenotypic variability in OI and related disorders. This will improve diagnostic strategies and enable the discovery of new targetable pathways for pharmacological intervention\n\nSIGNIFICANCE STATEMENTType I collagenopathies are a heterogenous group of connective tissue disorders, caused by genetic defects in type I collagen. Inherent to these disorders is a large clinical variability, of which the underlying molecular basis remains undefined. By systematically analyzing skeletal phenotypes in a large set of type I collagen zebrafish mutants we show that zebrafish models are able to both genocopy and phenocopy different forms of human type I collagenopathies, arguing for a similar pathogenetic basis. This study illustrates the potential of zebrafish as a tool to further dissect the molecular basis of phenotypic variability in human type I collagenopathies to improve diagnostic strategies as well as promote the discovery of new targetable pathways for pharmacological intervention of these disorders.

genetics↗

bioRxiv2018

Association between peripheral neuroinflammation and DATSCAN data of the striatal nuclei in Parkinson Disease

The interplay between peripheral and central inflammation has a significant role in dopaminergic neural death in nigrostriatal pathway, although no direct assessment of inflammation has been performed in relation to dopaminergic neuronal loss in striatal nuclei. In this study, the correlation of neutrophil to lymphocyte ratio (NLR) as a marker of peripheral inflammation to striatal binding ratios (SBR) of DAT-SPECT images in bilateral caudate and putamen nuclei were calculated in 388 drug-naive early PD patients (288 tremor-dominant, 73 PIGD, and 27 intermediate) and 148 controls. NLR was significantly higher in PD patients than age and sex-matched healthy controls. NLR showed a negative correlation to SBR in bilateral putamen in all PD subjects. Among our three subgroups, only TD subgroup showed remarkable results. A positive association between NLR and motor severity was observed in TD subgroup. Besides, NLR could negatively predict the SBR in ipsilateral and contralateral putamen and caudate nuclei in tremulous phenotype. Nonetheless, we found no significant association between NLR and other clinical and imaging findings in PIGD and intermediate subgroups, supporting the presence of distinct underlying pathologic mechanisms between tremor and non-tremor predominant PD at early stages of the disease.

neuroscience↗

bioRxiv2018

Small interfering RNAs based on huntingtin trinucleotide repeats are highly toxic to cancer cells

Trinucleotide repeat (TNR) expansions in the genome cause a number of degenerative diseases. A prominent TNR expansion involves the triplet CAG in the huntingtin (HTT) gene responsible for Huntingtons disease (HD). Pathology is caused by protein and RNA generated from the TNR regions including small siRNA-sized repeat fragments. An inverse correlation between the length of the repeats in HTT and cancer incidence has been reported for HD patients. We now show that siRNAs based on the CAG TNR are toxic to cancer cells by targeting genes that contain long reverse complimentary TNRs in their open reading frames. Of the 60 siRNAs based on the different TNRs, the 6 members in the CAG/CUG family of related TNRs are the most toxic to both human and mouse cancer cells. siCAG/CUG TNR-based siRNAs induce cell death in vitro in all tested cancer cell lines and slow down tumor growth in a preclinical mouse model of ovarian cancer with no signs of toxicity to the mice. We propose to explore TNR-based siRNAs as a novel form of anti-cancer reagents.

cancer biology↗

bioRxiv2018

Simulations of higher-order protein assemblies using a fuzzy framework

Spatiotemporal regulation of the biochemical information is often linked to supramolecular organizations proteins and nucleic acids, which generate membraneless cellular organelles. Owing to difficulties in high-resolution structural studies, the driving forces of assembling these low-complexity polymers have yet to be elucidated. Polymer physics approaches captured the experimentally demonstrated critical role of binding element multivalency and highlighted the importance of linker solvation. Here we present a simulation method based on a fuzzy mathematical framework. This approach is suitable to handle the heterogeneity of interactions pattern generated by redundant binding motifs and the resulted multiplicity of conformational states. Using a hypothetical polymer, fuzzy simulations recapitulate the experimental observations on valency-dependence and are more efficient than the one-to-one binding model. Systematic studies on binding element affinity and linker dynamics demonstrate that these two factors present alternative scenarios to promote polymerization: stronger binding result in more ordered states, whereas increasing dynamics contributes to heterogeneity and a more favorable entropy of the assembly. We propose that the fuzzy framework could be employed to characterize/predict mutations leading to pathological aggregates.

biochemistry↗