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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 Read source abstracts and check manuscript versions; preprints are not peer reviewed.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 649 records · Page 36Linked to original sources

bioRxiv2018

Characteristic impairments of goal-directed and habitual control in bulimia nervosa

The relationship between clinical eating disorder symptom severity and balance of model-based (MB) and model-free (MF) control is unclear, and these traits predictive capacity is untested in this population. In 25 healthy controls (HCs), 25 subjects with binge eating disorder (BED), and 25 subjects with bulimia nervosa (BN), we show an inverse relationship between symptom severity and MB (though not MF) control. However, trial-by-trial behavioural data discriminated BN from other groups (area under receiver operating characteristic curve of 0.78; 95% CI=0.64-0.92) based primarily on impaired MF control. Our data--including analyses of reaction time and theory-driven computational modeling--support the hypothesis that among pathological binge eating groups, BN may be characterized by impaired value function learning. Our results suggest that trial-by-trial analysis of behavioural data may provide unique insights into the BN phenotype, which may thus be computationally distinct from the related disorder of BED and the HC state.

neuroscience↗

bioRxiv2018

WDR5 regulates epithelial-to-mesenchymal transition in breast cancer cells via TGFB

Even if the mortality rate in breast cancer (BC) has recently decreased, development of metastases and drug resistance are still challenges to successful systemic treatment. The epithelial-to-mesenchymal transition (EMT), as well as epigenetic dynamic modifications, plays a pivotal role in invasion, metastasis, and drug resistance. Here, we report that WDR5, the core subunit of histone H3 K4 methyltransferase complexes, is crucial in coordinating EMT and regulating epigenetic changes that drive metastasis. We show that silencing of WDR5 in BC up-regulates an epithelial signature in triple negative and luminal B like patients by transcriptional repression of mesenchymal genes and reduction of the metastatic properties of these cells. Moreover, we demonstrate that this regulation is mediated by inhibition of the TGF{beta} signaling both at the transcriptional and post-translational level, suggesting an active role of WDR5 in guiding tumor plasticity upon oncogenic insults, regardless of the pathological BC subtypes.\n\nWe therefore suggest that WDR5 inhibition could be a successful pharmacologic approach to inhibit EMT and sensitize breast cancer cells to chemotherapy.

cancer biology↗

bioRxiv2018

Maternal group 2 innate lymphoid cells control fetal growth and protect from endotoxin-induced abortion in mice

Group 2 innate lymphoid cells (ILC2s) adapt to tissue physiology and contribute to immunity, inflammatory pathology and metabolism. We show that mouse uterine ILC2s have a heightened type-2 gene signature and expand during pregnancy. Indeed, maternal ILC2s promote fetal growth and protect against fetal mortality upon systemic endotoxin challenge. Absence of ILC2s leads to utero-placental abnormalities, including poor vascular remodelling, increased Il1b and decreased Il4, Il5, and Il13 gene expression, and reduced alternative activation of dendritic cells (DCs) and macrophages. Placentas exhibit signs of adaptation to stress, including larger maternal blood spaces and increased expression of nutrient transporter genes. Endotoxin induces the expansion of IL-1{beta}-producing uterine DCs and, in response, more uterine ILC2s produce IL-4, IL-5 and IL-13. In a protective feedback mechanism, these cytokines suppress IL-1{beta}-producing DCs, in line with a protective role of uILC2s against endotoxin-induced abortion. Uterine ILC2s emerge as pivotal for both normal and complicated pregnancies.

immunology↗

bioRxiv2018

Regulation of the Unfolded Protein Response by BiP AMPylation protects photoreceptors from light-dependent degeneration

In response to environmental, developmental, and pathological stressors, cells engage homeostatic pathways to maintain their function. Among these pathways, the Unfolded Protein Response protects cells from the accumulation of misfolded proteins in the ER. Depending on ER stress levels, the ER-resident Fic protein catalyzes AMPylation or de-AMPylation of BiP, the major ER chaperone and regulator of the Unfolded Protein Response. This work elucidates the importance of the reversible AMPylation of BiP in maintaining the Drosophila visual system in response to stress. After 72 hours of constant light, photoreceptors of fic-null and AMPylation-resistant BiPT366A mutants, but not wild-type flies, display loss of synaptic function, disintegration of rhabdomeres, and excessive activation of ER stress reporters. Strikingly, this phenotype is reversible: photoreceptors regain their structure and function within 72 hours once returned to a standard light:dark cycle. These findings show that Fic-mediated AMPylation of BiP is required for neurons to adapt to transient stress demands.

cell biology↗

bioRxiv2018

Pins & Needles: Towards Limb Disownership in Augmented Reality

The seemingly stable construct of our bodily self depends on the continued, successful integration of multisensory feedback about our body, rather than its purely physical composition. Accordingly, pathological disruption of such neural processing is linked to striking alterations of the bodily self, ranging from limb misidentification to disownership, and even the desire to amputate a healthy limb. While previous embodiment research has relied on experimental setups using supernumerary limbs in variants of the Rubber Hand Illusion, we here used Augmented Reality to directly manipulate the feeling of ownership for ones own, biological limb. Using a Head-Mounted Display, participants received visual feedback about their own arm, from an embodied first-person perspective. In a series of three studies, in independent cohorts, we altered embodiment by providing visuotactile feedback that could be synchronous (control condition) or asynchronous (400ms delay, Real Hand Illusion). During the illusion, participants reported a significant decrease in ownership of their own limb, along with a lowered sense of agency. Supporting the right-parietal body network, we found an increased illusion strength for the left upper limb as well as a modulation of the feeling of ownership during anodal transcranial direct current stimulation. Extending previous research, these findings demonstrate that a controlled, visuotactile conflict about ones own limb can be used to directly and systematically modulate ownership - without a proxy. This not only corroborates the malleability of body representation but questions its permanence. These findings warrant further exploration of combined VR and neuromodulation therapies for disorders of the bodily self.

neuroscience↗

bioRxiv2018

Diffusion-weighted magnetic resonance spectroscopy enables cell-specific monitoring of astrocyte reactivity in vivo

The diffusion of brain intracellular metabolites, as measured using diffusion-weighted magnetic resonance spectroscopy in vivo, is thought to specifically depend on the cellular structure constraining them. However, it has never been established that variations of metabolite diffusion, e.g. as observed in some diseases, could indeed be linked to alterations of cellular morphology. Here we demonstrate, in a mouse model of reactive astrocytes, that advanced diffusion-weighted magnetic resonance spectroscopy acquisition and modeling techniques enable non-invasive detection of reactive astrocyte hypertrophy (increased soma radius, increased fiber radius and length), as inferred from variations of myo-inositol diffusion, and as confirmed by confocal microscopy ex vivo. This establishes that specific alterations of intracellular metabolite diffusion can be measured and related to cell-specific morphological alterations. Furthermore, as reactive astrocytes are a hallmark of many brain pathologies, this work opens exciting perspectives for neuroscience and clinical research.

bioinformatics↗

bioRxiv2018

Neuropathological correlates and genetic architecture of microglial activation in elderly human brain

Microglia, the resident immune cells of the brain, have important roles in brain health. However, little is known about the regulation and consequences of microglial activation in the aging human brain. We assessed the effect of microglial activation in the aging human brain by calculating the proportion of activated microglia (PAM), based on morphologically defined stages of activation in four regions sampled postmortem from up to 225 elderly individuals. We found that cortical and not subcortical PAM measures were strongly associated with {beta}-amyloid, tau-related neuropathology, and rates of cognitive decline. Effect sizes for PAM measures are substantial, comparable to that of APOE {varepsilon}4, the strongest genetic risk factor for Alzheimers disease. Mediation modeling suggests that PAM accelerates accumulation of tau pathology leading to cognitive decline, supporting an upstream role for microglial activation in Alzheimers disease. Genome-wide analyses identified a common variant (rs2997325) influencing cortical PAM that also affected in vivo microglial activation measured by positron emission tomography using [11C]-PBR28 in an independent cohort. Finally, we identify overlaps of PAMs genetic architecture with those of Alzheimers disease, educational attainment, and several other traits.

genomics↗

bioRxiv2018

Imprint of parity and age at first birth on the genomic landscape of subsequent breast cancer

BackgroundAlthough parity and age at first birth are among the most known extrinsic factors that modulates breast cancer risk, their impact on the biology of subsequent breast cancer has never been explored in depth. In this study, we investigate the imprint of parity and age at first birth on the pattern of somatic mutations, somatic copy number alterations (SCNAs), transcriptomic profiles, and tumor infiltrating lymphocytes (TILs) levels of subsequent breast cancer.\n\nMethodsA total of 313 patients with primary breast cancer with available whole genome and RNA sequencing data were included in this study. We used a multivariate analysis adjusted for age at diagnosis, pathological stage, molecular subtypes and histological subtypes. We compared nulliparous vs. parous, late parous vs. early parous, and nulliparous vs. pregnancy associated breast cancer (PABC) patients. Late and early parous patients were grouped by using the median age at first birth as a cut-off value. PABC was defined as patients diagnosed up to 10 years postpartum.\n\nResultsGenomic alterations of breast cancer are associated with age at first birth but not parity status alone. Independently of clinicopathological features, early parous patients developed tumors characterized by a higher number of Indels (Padj = 0.002), a lower frequency of CDH1 mutations (1.2% vs. 12.7% Padj = 0.013), a higher frequency of TP53 mutations (50% vs. 22.5%; Padj = 0.010) and MYC amplification (28% vs. 7% Padj = 0.008), and a lower prevalence of mutational signature 2. PABC were associated with increased TILs infiltration (Padj = 0.0495).\n\nConclusionsThese findings highlight an unprecedented link between reproductive history and the genomic landscape of subsequent breast cancer. With the rapid development of precision oncology, this work advocates that reproductive history should not be underestimated in future clinical studies of breast cancer.

cancer biology↗

bioRxiv2018

Effects of vitamin D on inflammatory and oxidative stress responses of human bronchial epithelial cells exposed to particulate matter.

BackgroundParticulate matter (PM) pollutant exposure, which induces oxidative stress and inflammation, and vitamin D insufficiency, which compromises immune regulation, are detrimental in asthma.\n\nObjectivesMechanistic cell culture experiments were undertaken to ascertain whether vitamin D abrogates PM-induced inflammatory responses of human bronchial epithelial cells (HBECs) through enhancement of antioxidant pathways.\n\nMethodsTranscriptome analysis, PCR and ELISA were undertaken to delineate markers of inflammation and oxidative stress; with comparison of expression in primary HBECs from healthy and asthmatic donors cultured with reference urban PM in the presence/absence of vitamin D.\n\nResultsTranscriptome analysis identified over 500 genes significantly perturbed by PM-stimulation, including multiple pro-inflammatory cytokines. Vitamin D altered expression of a subset of these PM-induced genes, including suppressing IL6. Addition of vitamin D suppressed PM-stimulated IL-6 production, although to significantly greater extent in healthy versus asthmatic donor cultures. Vitamin D also differentially affected PM-stimulated GM-CSF, with suppression in healthy HBECs and enhancement in asthmatic cultures. Vitamin D increased HBEC expression of the antioxidant pathway gene G6PD, increased the ratio of reduced to oxidised glutathione, and in PM-stimulated cultures decreased the formation of 8-isoprostane. Pre-treatment with vitamin D decreased CXCL8 and further decreased IL-6 production in PM-stimulated cultures, an effect abrogated by inhibition of G6PD with DHEA, supporting a role for this pathway in the anti-inflammatory actions of vitamin D.\n\nConclusionsIn a study using HBECs from 18 donors, vitamin D enhanced HBEC antioxidant responses and modulated the immune response to PM, suggesting that vitamin D may protect the airways from pathological pollution-induced inflammation.

immunology↗

bioRxiv2018

Endo-lysosomal sorting and degradation of Tau mediates glucocorticoid-driven hippocampalmalfunction

Emerging studies implicate Tau as an essential mediator of neuronal atrophy and cognitive impairment in Alzheimers disease (AD), yet the factors that precipitate Tau dysfunction in AD are poorly understood. Chronic environmental stress and elevated glucocorticoids (GC), the major stress hormones, are associated with increased risk of AD, and have been shown to trigger intracellular Tau accumulation and downstream Tau-dependent neuronal dysfunction. However, the mechanisms through which stress and GC disrupt Tau clearance and degradation in neurons remain unclear. Here, we demonstrate that Tau undergoes degradation via endolysosomal sorting in a pathway requiring the small GTPase Rab35 and the endosomal sorting complex required for transport (ESCRT) machinery. Furthermore, we find that GC impair Tau degradation by decreasing Rab35 levels, and that AAV-mediated expression of Rab35 in the hippocampus rescues GC-induced Tau accumulation and related neurostructural deficits. These studies indicate that the Rab35/ESCRT pathway is essential for Tau clearance and part of the mechanism through which GC precipitate brain pathology.

neuroscience↗

bioRxiv2018

Ensemble Feature Selection and Meta-Analysis of Cancer miRNA Biomarkers

The role of microRNAs (miRNAs) in cellular processes captured the attention of many researchers, since their dysregulation is shown to affect the cancer disease landscape by sustaining proliferative signaling, evading program cell death, and inhibiting growth suppressors. Thus, miRNAs have been considered important diagnostic and prognostic biomarkers for several types of tumors. Machine learning algorithms have proven to be able to exploit the information contained in thousands of miRNAs to accurately predict and classify cancer types. Nevertheless, extracting the most relevant miRNA expressions is fundamental to allow human experts to validate and make sense of the results obtained by automatic algorithms. We propose a novel feature selection approach, able to identify the most important miRNAs for tumor classification, based on consensus on feature relevance from high-accuracy classifiers of different typologies. The proposed methodology is tested on a real-world dataset featuring 8,129 patients, 29 different types of tumors, and 1,046 miRNAs per patient, taken from The Cancer Genome Atlas (TCGA) database. A new miRNA signature is suggested, containing the 100 most important oncogenic miRNAs identified by the presented approach. Such a signature is proved to be sufficient to identify all 29 types of cancer considered in the study, with results nearly identical to those obtained using all 1,046 features in the original dataset. Subsequently, a meta-analysis of the medical literature is performed to find references to the most important biomarkers extracted by the methodology. Besides known oncomarkers, 15 new miRNAs previously not ranked as important biomarkers for diagnosis and prognosis in cancer pathologies are uncovered. Such miRNAs, considered relevant by the machine learning algorithms, but still relatively unexplored by specialized literature, could provide further insights in the biology of cancer.

bioinformatics↗

bioRxiv2018

A novel co-segregating DCTN1 splice site variant in a family with Bipolar Disorder may hold the key to understanding the etiology

A novel co-segregating splice site variant in the Dynactin-1 (DCTN1) gene was discovered by Next Generation Sequencing (NGS) in a family with a history of bipolar disorder (BD) and major depressive diagnosis (MDD). Psychiatric illness in this family follows an autosomal dominant pattern. DCTN1 codes for the largest dynactin subunit, namely p150Glued, which plays an essential role in retrograde axonal transport and in neuronal autophagy. A GT[->]TT transversion in the DCTN1 gene, uncovered in the present work, is predicted to disrupt the invariant canonical splice donor site IVS22+1G>T and result in intron retention and a premature termination codon (PTC). Thus, this splice site variant is predicted to trigger RNA nonsense-mediated decay (NMD) and/or result in a C-terminal truncated p150Glued protein (ct-p150Glued), thereby negatively impacting retrograde axonal transport and neuronal autophagy. BD prophylactic medications, and most antipsychotics and antidepressants, are known to enhance neuronal autophagy. This variant is analogous to the dominant-negative GLUED Gl1 mutation in Drosophila which is responsible for a neurodegenerative phenotype. The newly identified variant may reflect an autosomal dominant cause of psychiatric pathology in this affected family. Factors that affect alternative splicing of the DCTN1 gene, leading to NMD and/or ct-p150Glued, may be of fundamental importance in contributing to our understanding of the etiology of BD as well as MDD.

genetics↗

bioRxiv2018

HmtVar: a brand-new resource for human mitochondrial variations and pathogenicity data

Human mitochondrial data are currently of great interest for both clinicians and researchers, due to the involvement of mitochondria in a number of physiological and pathological processes. Thanks to new sequencing technologies and modern databases, the huge amount of information about mitochondrial genome variability can be exploited to gain interesting insights into the relationship between DNA variants, phenotypes and diseases. For this reason, we have developed the new HmtVar resource, a variant-focused database which allows to explore a dataset of over 30000 human mitochondrial variants together with their pathogenicity prediction. Mitochondrial variation data, initially gathered from the HmtDB platform, are further integrated with in-house pathogenicity assessments based on well-established variants pathogenicity evaluation criteria, as well as with a set of additional annotations from third-party resources. This approach led to a comprehensive collection of information of crucial importance for human mitochondrial variation studies and investigation of common and rare diseases in which the mitochondrion is involved to some extent.\n\nHmtVar is accessible at https://www.hmtvar.uniba.it and its data can be retrieved using either a web interface through the Query page or a state-of-the-art API for programmatic access.

bioinformatics↗

bioRxiv2018

Robust detection of tandem repeat expansions from long DNA reads

Tandemly repeated sequences are highly mutable and variable features of genomes. Tandem repeat expansions are responsible for a growing list of human diseases, even though it is hard to determine tandem repeat sequences with current DNA sequencing technology. Recent long-read technologies are promising, because the DNA reads are often longer than the repetitive regions, but are hampered by high error rates. Here, we report robust detection of human repeat expansions from careful alignments of long (PacBio and nanopore) reads to a reference genome. Our method (tandem-genotypes) is robust to systematic sequencing errors, inexact repeats with fuzzy boundaries, and low sequencing coverage. By comparing to healthy controls, we can prioritize pathological expansions within the top 10 out of 700000 tandem repeats in the genome. This may help to elucidate the many genetic diseases whose causes remain unknown.

genetics↗

bioRxiv2018

Deletion of class II ARF causes essential tremors through Nav1.6 traffic impairment

ADP-ribosylation factors (ARFs) are a family of small monomeric GTPases consisting of three classes. In the present study, we generated class II ARF-deficient mice (ARF4+/-/ARF5-/-) and found that they exhibited severe movement-associated tremors. Treatment of the mice with propranolol and gabapentin, which alleviate symptoms in patients with essential tremors, similarly reduced the amplitude of the pathologic tremors. In vivo electrophysiological recordings of the ARF4+/-/ARF5-/- mice revealed that they exhibited reduced excitability of their cerebellar Purkinje cells. Immunohistochemical studies revealed that ARF4+/-/ARF5-/- mice exhibit a severe, selective reduction of Nav1.6 proteins that are important for maintaining repetitive action potential firing in the axon initial segments (AISs) of the Purkinje cells. This decrease in Nav1.6 protein expression and the consequent tremors were alleviated by Purkinje cell-specific expression of ARF5. These results indicate that class II ARF mediates the selective trafficking of Nav1.6 to the AISs in cerebellar Purkinje cells, and suggest that the essential tremors can be ascribed to the reduced intrinsic excitability of Purkinje cells, caused by the selective decrease of Nav1.6 proteins in the AISs.

neuroscience↗

bioRxiv2018

Exacerbation of blood brain barrier dysfunction and brain injury after aneurysmal subarachnoid hemorrhage in endothelial specific S1PR1 knock out mice.

Blood brain barrier (BBB) dysfunction upon ischemia and hypoxia has been implicated in the exacerbation of neuronal injury in stroke. Despite the therapeutic potential of the cerebrovascular endothelium, the limited understanding of the endothelial signaling pathways governing BBB function restricts progress towards developing novel therapeutic approaches specifically targeting the endothelium. Sphingosine-1-phosphate (S1P) is a potent modulator of endothelial function via its receptors (S1PR). Recent human and mouse studies indicate that vasoprotective endothelial S1P signaling via S1PR1 may be impaired in cardiovascular and inflammatory diseases. Herein, we investigated the expression of S1PR1 in the mouse and human cerebrovascular endothelium and the role of endothelial-specific S1PR1 signaling in brain injury in a mouse model of aneurysmal subarachnoid hemorrhage (SAH), the most devastating type of stroke. We found that S1PR1 is the most abundant S1PR transcript in the mouse brain and in mouse and human brain endothelial cells (20-100 mRNA copies per cell). S1PR1 transcripts were significantly enriched (~6 fold) in mouse cortical microvessels compared to total brain. Using the S1PR1-eGFP knock in mouse, we found that S1PR1-eGFP is abundantly expressed in the cerebrovascular endothelium in the mouse brain. A similar pattern of expression was observed in human brain samples. Endothelial specific deletion of S1PR1 in adult mice (S1pr1 flox/floxxCdh5-CreERT2, referred to as S1pr1iECKO), resulted in exacerbation of brain edema, neuronal injury and worsened neurological outcomes upon SAH compared to S1pr1 flox/flox littermates. No differences in the subarachnoid blood, hemostasis or cerebral blood flow changes during and after SAH were found between groups. Mechanistically, S1pr1iECKO exhibited aggravated BBB dysfunction and increased phosphorylation of myosin light chain (MLC) in isolated cortical microvessels, a downstream effector of the Rho-ROCK pathway implicated in endothelial inflammation and barrier dysfunction. Taken together, our data indicate that S1PR1 is an endogenous protective signaling pathway in the endothelium, critical to maintain BBB function and to mitigate neuronal injury in pathological conditions. Thus, the therapeutic and diagnostic potential of the endothelial sphingosine-1-phosphate pathway in stroke deserves further study.

neuroscience↗

bioRxiv2018

Grey matter biomarker identification in Schizophrenia: detecting regional alterations and their underlying substrates

State-of-the-art approaches in Schizophrenia research investigate neuroanatomical biomarkers using structural Magnetic Resonance Imaging. However, current models are 1) voxel-wise, 2) difficult to interpret in biologically meaningful ways, and 3) difficult to replicate across studies. Here, we propose a machine learning framework that enables the identification of sparse, region-wise grey matter neuroanatomical biomarkers and their underlying biological substrates by integrating well-established statistical and machine learning approaches. We address the computational issues associated with application of machine learning on structural MRI data in Schizophrenia, as discussed in recent reviews, while promoting transparent science using widely available data and software. In this work, a cohort of patients with Schizophrenia and healthy controls was used. It was found that the cortical thickness in left pars orbitalis seems to be the most reliable measure for distinguishing patients with Schizophrenia from healthy controls.\n\nHighlightsO_LIWe present a sparse machine learning framework to identify biologically meaningful neuroanatomical biomarkers for Schizophrenia\nC_LIO_LIOur framework addresses methodological pitfalls associated with application of machine learning on structural MRI data in Schizophrenia raised by several recent reviews\nC_LIO_LIOur pipeline is easy to replicate using widely available software packages\nC_LIO_LIThe presented framework is geared towards identification of specific changes in brain regions that relate directly to the pathology rather than classification per se\nC_LI

neuroscience↗

bioRxiv2018

Predicting local tissue mechanics using immunohistochemistry

Local tissue stiffness provides an important signal to which cells respond in vivo. However, assessing tissue mechanics is currently challenging and requires sophisticated technology. We here developed a model quantitatively predicting nervous tissue stiffness heterogeneities at cellular resolution based on cell density, myelin and GFAP fluorescence intensities. These histological parameters were identified by a correlation analysis of atomic force microscopy-based elasticity maps of spinal cord sections and immunohistochemical stainings. Our model provides a simple tool to estimate local stiffness distributions in nervous tissue, and it can easily be expanded to other tissue types, thus paving the way for studies of the role of mechanical signals in development and pathology.

biophysics↗