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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 Read source abstracts and check manuscript versions; preprints are not peer reviewed.

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bioRxiv2017

Interleukin-1β and -6 release from immune cells by DOPA-based melanin as free pigment or complexed to carboxymethylcellulose

We have observed that many polysaccharides can promote the oxidation of 3,4-dihydroxyphenylalanine (DOPA) into melanin-like pigments leading to the formation of water-soluble polysaccharide/melanin complexes. These pigments were characterized by size exclusion chromatography and FT-IR spectroscopy. The effect on the secretion of interleukin (IL)-l{beta} and IL-6 from immune cells by DOPA-based melanin synthesized in the presence or absence of carboxymethylcellulose (CMC) was evaluated. We observed that the melanin/CMC complex had a more potent effect on both IL secretions compared to the melanin prepared from DOPA in the absence of any polysaccharide. The study of the effect of melanins on the IL secretion by immune or other cells will help illuminate the potential contributions of this broad class of pigments to pathological conditions like Parkinsons disease or ochronosis.

biochemistry↗

bioRxiv2017

Impeding transcription of expanded microsatellite repeats by deactivated Cas9

Transcription of expanded microsatellite repeats is associated with multiple human diseases, including myotonic dystrophy, Fuchs endothelial corneal dystrophy, and C9orf72-ALS/FTD. Eliminating or reducing production of RNA and proteins arising from these expanded loci holds therapeutic benefit. Here, we tested the hypothesis that a deactivated form of the Cas9 enzyme impedes transcription across expanded microsatellites. We observed a repeat length-, PAM-, and strand-dependent reduction in the abundance of repeat-containing RNAs upon targeting dCas9 directly to repeat sequences. Aberrant splicing patterns were rescued in DM1 cells, and production of RAN peptides characteristic of DM1, DM2, and C9orf72-ALS/FTD cells was drastically decreased. Systemic delivery of dCas9/gRNA by adeno-associated virus led to reductions in pathological RNA foci, rescue of chloride channel 1 protein expression, and decreased myotonia. These observations suggest that transcription of microsatellite repeat-containing RNAs is more sensitive to perturbation than transcription of other RNAs, indicating potentially viable strategies for therapeutic intervention.

molecular biology↗

bioRxiv2017

Sparse interaction between oligodendrocyte precursor cells (NG2+ cells) and nodes of Ranvier in the central nervous system

Regeneration of propagating action potentials at nodes of Ranvier allows nerve impulses to be conducted over long distances. Proper nodal function is believed to rely on intimate associations among axons, myelinating oligodendrocytes, and perinodal astrocytes. Studies in the optic nerve, corpus callosum, and spinal cord suggest that NG2+ cells are also key constituents of CNS nodes and that these glia may influence conduction efficacy and formation of axon collaterals. However, the prevalence of NG2+ cell processes at CNS nodes of Ranvier has not been rigorously quantified. Here we used a transgenic mouse expressing membrane-targeted EGFP to visualize the fine processes of NG2+ cells and to quantify the spatial relationship between NG2+ cells and nodes of Ranvier in four distinct CNS white matter tracts. NG2+ cell processes came within close spatial proximity to a small percentage of nodes of Ranvier and approximately half of these spatial interactions were estimated to occur by chance. The majority of NG2+ cell process tips were not found in close proximity to nodes and gray matter NG2+ cells in regions of low nodal density were as morphologically complex as their white matter counterparts, indicating that attraction to nodes does not critically influence the elaboration of NG2+ cell processes. Finally, there was no difference in nodal density between small regions devoid of NG2+ cell processes and those containing numerous NG2+ cells processes, demonstrating that the function of CNS nodes of Ranvier does not require ongoing interaction with NG2+ cells.\n\nSignificance StatementEffective propagation of action potentials along neuronal axons is dependent upon periodic regeneration of depolarization at nodes of Ranvier. The position, structural integrity, and function of nodes of Ranvier is believed to be regulated, in part, by intimate physical interactions between nearby glial cells and nodes. Clarifying whether oligodendrocyte precursor cells are obligate members of this nodal support system is critical for defining whether these cells contribute to pathologies in which nodal structure is compromised.

neuroscience↗

bioRxiv2017

Data-driven Modeling of Thrombus Size and Shape in Aortic Dissections: Role of Hemodynamics

Aortic dissection is a pathology that manifests due to micro-structural defects in the aortic wall. Blood enters the damaged wall through an intimal tear, thereby creating a so-called false lumen and exposing the blood to thrombogenic intramural constituents such as collagen. The natural history of this acute vascular injury thus depends, in part, on thrombus formation, maturation, and possible healing within the false lumen. A key question is: Why do some false lumens thrombose completely while other thrombose partially or little at all? An ability to predict the location and extent of thrombus in subjects with dissection could contribute significantly to clinical decision-making, including interventional design. We develop, for the first time, a data-driven particle-continuum model for thrombus formation in a murine model of aortic dissection. In the proposed model, we simulate a final-value problem in lieu of the original initial-value problem with significantly fewer particles that may grow in size upon activation, representing the local concentration of blood-borne species. Numerical results confirm that geometry and local hemodynamics play significant roles in the acute progression of thrombus. Despite geometrical differences between murine and human dissections, mouse models can provide considerable insight and have gained in popularity owing to their reproducibility. Our results for three classes of geometrically different false lumens show that thrombus forms and extends to a greater extent in regions with lower bulk shear rates. Dense thrombi are less likely to form in high-shear zones and in the presence of strong vortices. The present data-driven study suggests that the proposed model is robust and can be employed to assess thrombus formation in human aortic dissections.

bioengineering↗

bioRxiv2017

Nucleolin internalizes Bothrops asper Lys49 phospholipase A2 forming cell surface amyloid-like assemblies

Phospholipases A2 (PLA2s) are a major component of snake venoms. Some of them cause severe muscle necrosis through a still unknown mechanism. Phospholipid hydrolysis is a possible explanation of their toxic action, but catalytic and toxic properties of PLA2s are not directly connected. In addition, viperid venoms contain PLA2-like proteins, which are very toxic even if they lack catalytic activity due to a critical mutation in position 49. Nucleolin, a main component of the nucleolus, is a disordered protein involved in many protein assembly and phase separation phenomena. In some circumstances nucleolin is exposed on the cell surface from where it is involved in the internalization of many ligands.\n\nIn this work we demonstrate that Bothrops asper myotoxin II (Mt-II), a Lys49 PLA2-like toxin, interacts with, and is internalized in cells by nucleolin. The internalization process is functional to the toxicity of the protein, as both an antibody and an aptamer specific for nucleolin protect cells from intoxication. We identified central RRM and the C-terminal R/F-GG domain of nucleolin as the regions involved in the interaction with Mt-II. Finally we observed that Mt-II forms, on the cell surface, amyloid-like assemblies that colocalize with nucleolin and that can be involved in the activation of the internalization process. The presence, in the three dimensional structure of Mt-II and related PLA2 homologues, of four exposed loops enriched in prion-like amino acid sequences reinforces this hypothesis.\n\nPhospholipases A2 | Lys49 myotoxins | nucleolin | amyloid-like | molecular assemblies\n\nSIGNIFICANCEThe main finding of this work, the role of nucleolin as Bothrops asper Mt-II receptor, is a remarkable step forward in understanding the mechanism of action of cytotoxic PLA2s. It may suggest new strategies for anti-venom therapies and explain the anti-tumoral and anti-viral pharmacological action of snake PLA2s, since nucleolin is a receptor for many growth factors and virus.\n\nThe proposed internalization mechanism, via formation of molecular assemblies among Mt-II amyloid-like structures and other proteins, including nucleolin, can be of general validity. Cell surface molecular assemblies couldbepointsofselectionandconcentrationnotonlyofsnake,butalsoofmammaliansecretedPLA2s, proteins involved in different pathologies, and trigger the internalization pathway only when their molarity exceeds a threshold dose.

biochemistry↗

bioRxiv2017

The Early Diagnosis in Lung Cancer by the Detection of Circulating Tumor DNA

BackgroundRemarkable advances for clinical diagnosis and treatment in cancers including lung cancer involve cell-free circulating tumor DNA (ctDNA) detection through next generation sequencing. However, before the sensitivity and specificity of ctDNA detection can be widely recognized, the consistency of mutations in tumor tissue and ctDNA should be evaluated. The urgency of this consistency is extremely obvious in lung cancer to which great attention has been paid to in liquid biopsy field.\n\nMethodsWe have developed an approach named systematic error correction sequencing (Sec-Seq) to improve the evaluation of sequence alterations in circulating cell-free DNA. Averagely 10 ml preoperative blood samples were collected from 30 patients containing pulmonary space occupying pathological changes by traditional clinic diagnosis. cfDNA from plasma, genomic DNA from white blood cells, and genomic DNA from solid tumor of above patients were extracted and constructed as libraries for each sample before subjected to sequencing by a panel contains 50 cancer-associated genes encompassing 29 kb by custom probe hybridization capture with average depth >40000, 7000, or 6300 folds respectively.\n\nResultsDetection limit for mutant allele frequency in our study was 0.1%. The sequencing results were analyzed by bioinformatic expertise based on our previous studies on the baseline mutation profiling of circulating cell-free DNA and the clinicopathological data of these patients. Among all the lung cancer patients, 78% patients were predicted as positive by ctDNA sequencing when the shreshold was defined as at least one of the hotspot mutations detected in the blood (ctDNA) was also detected in tumor tissue. Pneumonia and pulmonary tuberculosis were detected as negative according to the above standard. When evaluating all hotspots in driver genes in the panel, 24% mutations detected in tumor tissue (tDNA) were also detected in patients blood (ctDNA). When evaluating all genetic variations in the panel, including all the driver genes and passenger genes, 28% detected in tumor tissue (tDNA) were also detected in patients blood (ctDNA). Positive detection rates of plasma ctDNA in stage I lung cancer patients is 85%, compared with 17% of tumor biomarkers.\n\nConclusionWe demonstrated the importance of sequencing both circulating cell-free DNA and genomic DNA in tumor tissue for ctDNA detection in lung cancer currently. We also determined and confirmed the consistency of ctDNA and tumor tissue through NGS according to the criteria explored in our studies. Our strategy can initially distinguish the lung cancer from benign lesions of lung. Our work shows that the consistency will be benefited from the optimization in sensitivity and specificity in ctDNA detection.

cancer biology↗

bioRxiv2017

Genetic drivers of repeat expansion disorders localize to 3-D chromatin domain boundaries

More than 25 inherited neurological disorders are caused by the unstable expansion of repetitive DNA sequences termed short tandem repeats (STRs). A fundamental unresolved question is why specific STRs are susceptible to unstable expansion leading to severe pathology, whereas tens of thousands of normal-length repeat tracts across the human genome are relatively stable. Here, we unexpectedly discover that nearly all STRs associated with repeat expansion diseases are located at boundaries demarcating 3-D chromatin domains. We find that boundaries exhibit markedly higher CpG island density compared to loci internal to domains. Importantly, disease-associated STRs are specifically localized to ultra-dense CpG island-rich boundaries, suggesting that these loci might be hotspots for epigenetic instability and topological disruption upon unstable expansion. In Fragile X Syndrome, mutation-length expansion at the Fmr1 gene results in severe disruption of the boundary between TADs. Our data uncover higher-order chromatin architecture as a new dimension in understanding the mechanistic basis of repeat expansion disorders.

genomics↗

bioRxiv2017

Tolerance of chronic HDACi-administration used for treatment of neurological and visceral disease including lung pathogenesis.

Histone deacetylase (HDAC) inhibitors are of significant interest as drugs. However, their use in neurological disorders has raised concern because HDACs are required for brain function. We have previously shown that a triple combination formulation (TCF) of the pan HDACi vorinostat (Vo) improves pharmacokinetic exposure and entry of Vo into the brain. TCF treatment significantly delayed both neurodegeneration and death in the Npc1nmf164 murine model of Niemann Pick Type C (NPC) disease. The TCF induces no metabolic toxicity, but its risk to normal brain functions and potential utility in treating lung disease, a major NPC clinical complication, remain unknown. Here we report that TCF administered for 8-10 months was not detrimental to brain or neuromuscular functions of healthy mice, based on quantitative analyses of major Purkinje neurons in the cerebellum, inflammation in the hippocampus and symptoms of progressive neurocognitive/muscular disease. The TCF was also not injurious to lung tissue but rather improved delivery of Vo to lungs and reduced accumulation of foamy macrophages in Npc1nmf164 mice. Together these data support feasibility of tolerable, chronic administration of an HDACi formulation to treat brain and systemic disease including lung pathology, a frequent cause of death in NPC and possibly other neurological diseases.

neuroscience↗

bioRxiv2018

Neutralizing Gatad2a-Chd4-Mbd3 Axis within the NuRD Complex Facilitates Deterministic Induction of Naive Pluripotency

The Nucleosome Remodeling and Deacytelase (NuRD) complex is a co-repressive complex involved in many pathological and physiological processes in the cell. Previous studies have identified one of its components, Mbd3, as a potent inhibitor for reprogramming of somatic cells to pluripotency. Following OSKM induction, early and partial depletion of Mbd3 protein followed by applying naive ground-state pluripotency conditions, results in a highly efficient and near-deterministic generation of mouse iPS cells. Increasing evidence indicates that the NuRD complex assumes multiple mutually exclusive protein complexes, and it remains unclear whether the deterministic iPSC phenotype is the result of a specific NuRD sub complex. Since complete ablation of Mbd3 blocks somatic cell proliferation, here we aimed to identify alternative ways to block Mbd3-dependent NuRD activity by identifying additional functionally relevant components of the Mbd3/NuRD complex during early stages of reprogramming. We identified Gatad2a (also known as P66), a relatively uncharacterized NuRD-specific subunit, whose complete deletion does not impact somatic cell proliferation, yet specifically disrupts Mbd3/NuRD repressive activity on the pluripotency circuit during both stem cell differentiation and reprogramming to pluripotency. Complete ablation of Gatad2a in somatic cells, but not Gatad2b, results in a deterministic naive iPSC reprogramming where up to 100% of donor somatic cells successfully complete the process within 8 days. Genetic and biochemical analysis established a distinct sub-complex within the NuRD complex (Gatad2a-Chd4-Mbd3) as the functional and biochemical axis blocking reestablishment of murine naive pluripotency. Disassembly of this axis by depletion of Gatad2a, results in resistance to conditions promoting exit of naive pluripotency and delays differentiation. We further highlight context- and posttranslational dependent modifications of the NuRD complex affecting its interactions and assembly in different cell states. Collectively, our work unveils the distinct functionality, composition and interactions of Gatad2a-Chd4-Mbd3/NuRD subcomplex during the resolution and establishment of mouse naive pluripotency.

developmental biology↗

bioRxiv2017

Copy number heterogeneity, large origin tandem repeats, and interspecies recombination in HHV-6A and HHV-6B reference strains

Quantitative PCR is the diagnostic pillar for clinical virology testing, and reference materials are necessary for accurate, comparable quantitation between clinical laboratories. Accurate quantitation of HHV-6 is important for detection of viral reactivation and inherited chromosomally integrated HHV-6 in immunocompromised patients. Reference materials in clinical virology commonly consist of laboratory-adapted viral strains that may be affected by the culture process. We performed next-generation sequencing to make relative copy number measurements at single nucleotide resolution of eight candidate HHV-6A and seven HHV-6B reference strains and DNA materials from the HHV-6 Foundation and Advanced Biotechnologies. 11 of 17 (65%) HHV6 candidate reference materials showed multiple copies of the origin of replication upstream of the U41 gene by next-generation sequencing. These large tandem repeats arose independently in culture-adapted HHV-6A and HHV-6B strains, measuring 1254 bp and 983 bp, respectively. Copy number measured between 4-10X copies relative to the rest of the genome. We also report the first interspecies recombinant HHV-6 strain with a HHV-6A GS backbone and >5.5kb region from HHV-6B Z29 from U41-U43 that covered the origin tandem repeat. Specific HHV-6A reference strains demonstrated duplication of regions at UL1/UL2, U87, and U89, as well as deletion in the U12-U24 region and U94/95 genes. HHV-6 strains derived from cord blood mononuclear cells from different labs on different continents revealed no copy number differences throughout the viral genome. These data indicate large origin tandem duplications are an adaptation of both HHV-6A and HHV-6B in culture and show interspecies recombination is possible within the Betaherpesvirinae.\n\nImportanceAnything in science that needs to be quantitated requires a standard unit of measurement. This includes viruses, for which quantitation increasingly determines definitions of pathology and guidelines for treatment. However, the act of making standard or reference material in virology can alter its very usefulness through genomic duplications, insertions, and rearrangements. We used deep sequencing to examine candidate reference strains for HHV-6, a ubiquitous human virus that can reactivate in the immunocompromised population and is integrated into the human genome in every cell of the body for 1% of people worldwide. We found large tandem repeats in the origin of replication for both HHV-6A and HHV-6B that are selected for in culture. We also found the first interspecies recombinant between HHV-6A and HHV-6B, a phenomenon that is well-known in alphaherpesviruses but to date has not been seen in betaherpesviruses. These data critically inform HHV-6 biology and the standard selection process.

genomics↗

bioRxiv2017

Individual nephron proteomes connect morphology and function in proteinuric kidney disease

In diseases of many parenchymatous organs, heterogenous detoriation of individual functional units determines the clinical prognosis. However, the molecular characterization of these subunits remains a technological challenge that needs to be addressed in order to better understand pathological mechanisms. Sclerotic and proteinuric glomerular kidney disease is a frequent and heterogeneous disease which affects a fraction of nephrons, glomeruli and draining tubules, to variable extents, and for which no treatment exists. Here, we developed and applied an antibody-independent methodology to investigate heterogeneity of individual nephron segment proteomes from mice with proteinuric kidney disease. This \"one-segment-one-proteome-approach\" defines mechanistic connections between upstream (glomerular) and downstream (tubular) nephron segment populations. In single glomeruli from two different mouse models of sclerotic glomerular disease, we identified a coherent protein expression module consisting of extracellular matrix protein deposition (reflecting glomerular sclerosis), glomerular albumin (reflecting proteinuria) and LAMP1, a lysosomal protein. This module was associated with a loss of podocyte marker proteins. In an attempt to target this protein co-expression module, genetic ablation of LAMP1-correlated lysosomal proteases in mice could ameliorate glomerular damage. Furthermore, individual glomeruli from patients with genetic sclerotic and non-sclerotic proteinuric diseases demonstrated increased abundance of lysosomal proteins, in combination with a decreased abundance of the mutated gene products. Therefore, increased glomerular lysosomal load is a conserved key mechanism in proteinuric kidney diseases, and the technology applied here can be implemented to address heterogeneous pathophysiology in a variety of diseases at a sub-biopsy scale

physiology↗

bioRxiv2017

Fibril branching dominates self-assembly of mutant huntingtin exon-1 aggregates in vitro

Huntingtin (HTT) fragments with extended polyglutamine (polyQ) tracts self-assemble into amyloid-like fibrillar aggregates. Elucidating the fibril formation mechanism is critical for understanding Huntingtons disease pathology and for developing novel therapeutic strategies. Here, we performed systematic experimental and theoretical studies to examine the self-assembly of an aggregation-prone N-terminal HTT exon-1 fragment with 49 glutamines (Ex1Q49). Using high resolution imaging techniques such as electron microscopy and atomic force microscopy, we show that Ex1Q49 fragments in cell-free assays spontaneously convert into large, highly complex bundles of amyloid fibrils with multiple ends and fibril branching points. Furthermore, we present experimental evidence that two nucleation mechanisms control spontaneous Ex1Q49 fibrillogenesis: (1) a relatively slow primary fibril-independent nucleation process, which involves the spontaneous formation of aggregation-competent fibrillary structures, and (2) a fast secondary fibril-dependent nucleation process, which involves nucleated branching and promotes the rapid assembly of highly complex fibril bundles with multiple ends. The proposed aggregation mechanism is supported by studies with the small molecule O4, which perturbs early events in the aggregation cascade and delays Ex1Q49 fibril assembly, comprehensive mathematical and computational modelling studies, and seeding experiments with small, preformed fibrillar Ex1Q49 aggregates that promote the assembly of amyloid fibrils. Together, our results suggest that nucleated branching in vitro plays a critical role in the formation of complex fibrillar HTT exon-1 aggregates with multiple ends.

biochemistry↗

bioRxiv2017

A novel dimeric active site and regulation mechanism revealed by the crystal structure of iPLA2β

Calcium-independent phospholipase A2{beta} (iPLA2{beta}) regulates several physiological processes including inflammation, calcium homeostasis and apoptosis. It is linked genetically to neurodegenerative disorders including Parkinsons disease. Despite its known enzymatic activity, the mechanisms underlying pathologic phenotypes remain unknown. Here, we present the first crystal structure of iPLA2{beta} that significantly revises existing mechanistic models. The catalytic domains form a tight dimer. The ankyrin repeat domains wrap around the catalytic domains in an outwardly flared orientation, poised to interact with membrane proteins. The closely integrated active sites are positioned for cooperative activation and internal transacylation. A single calmodulin binds and allosterically inhibits both catalytic domains. These unique structural features identify the molecular interactions that can regulate iPLA2{beta} activity and its cellular localization, which can be targeted to identify novel inhibitors for therapeutic purposes. The structure provides a well-defined framework to investigate the role of neurodegenerative mutations and the function of iPLA2{beta} in the brain.

biochemistry↗

bioRxiv2017

Transplanted Adult Neural Stem Cells Express Sonic Hedgehog In Vivo and Suppress White Matter Neuroinflammation After Experimental Traumatic Brain Injury

Neural stem cells (NSCs) delivered intraventricularly may be therapeutic for diffuse white matter pathology after traumatic brain injury (TBI). To test this concept, NSCs isolated from adult mouse subventricular zone (SVZ) were transplanted into the lateral ventricle of adult mice at two weeks post-TBI followed by analysis at four weeks post-TBI. We examined Sonic hedgehog (Shh) signaling as a candidate mechanism by which transplanted NSCs may regulate neuroregeneration and/or neuroinflammation responses of endogenous cells. Mouse fluorescent reporter lines were generated to enable in vivo genetic labeling of cells actively transcribing Shh or Gli1 after transplantation and/or TBI. Gli1 transcription is an effective readout for canonical Shh signaling. In ShhCreERT2;R26tdTomato mice, Shh was primarily expressed in neurons and was not upregulated in reactive astrocytes or microglia after TBI. Corroborating results in Gli1CreERT2;R26tdTomato host mice demonstrated Shh signaling was not upregulated in the corpus callosum, even after TBI or NSC transplantation. Transplanted NSC expressed Shh in vivo but did not increase Gli1 labeling of host SVZ cells. Importantly, NSC transplantation significantly reduced reactive astrogliosis and microglial/macrophage activation in the corpus callosum after TBI. Therefore, intraventricular NSC transplantation after TBI significantly attenuated neuroinflammation, but did not activate host Shh signaling via Gli1 transcription.

neuroscience↗

bioRxiv2017

Amygdalar atrophy as the genetically mediated hub of limbic degeneration in Alzheimer’s disease

Pharmacological progress, basic science and medical practice can benefit from objective biomarkers that assist in early diagnosis and prognostic stratification of diseases. In the field of Alzheimers disease (AD), the clinical presentation of early stage dementia may not fulfill any diagnostic criteria for years, and quantifying structural brain changes by magnetic resonance imaging (MRI) has shown promise in the discovery of sensitive biomarkers. Although hippocampal atrophy is often used as an in vivo measure of AD, data-driven neuroimaging has revealed complex patterns of regional brain vulnerability that may not perfectly map to anatomical boundaries. In addition to aiding diagnosis, decoding genetic influences on neuroimaging measures of the disease can enlighten molecular mechanisms of the underlying pathology in living patients and guide the therapeutic design.\n\nHere, we aimed to extract a data-driven MRI feature of brain atrophy in AD by decomposing structural neuroimages using independent component analysis (ICA), a method for performing unbiased computational search in high dimensional data spaces. Our study of the AD Neuroimaging Initiative dataset (n=1,100 subjects) revealed a disease-vulnerable feature with a network-like topology, comprising amygdala, hippocampus, fornix and the inter-connecting white-matter tracts of the limbic system. Whole-genome sequencing identified a nonsynonymous variant (rs34173062) in SHARPIN, a gene coding for a synaptic protein, as a significant modifier of this new MRI feature (p=2.1x10-10). The risk variant was brought to replication in the UK Biobank dataset (n=8,428 subjects), where it was associated with reduced cortical thickness in areas co-localizing with those of the discovery sample (left entorhinal cortex p=0.002, right entorhinal cortex p=8.6x10-4; same direction), as well as with the history of AD in both parents (p=2.3x10-6; same direction).\n\nIn conclusion, our study shows that ICA can transform voxel-wise volumetric measures of the brain into a data-driven feature of neurodegeneration in AD. Structure of the limbic system, as the most vulnerable focus of brain atrophy in AD, is affected by genetic variability of SHARPIN. The elevated risk of dementia in carriers of the minor allele supports engagement of SHARPIN in the disease pathways, and its role in neurotransmitter receptor scaffolding and integrin signaling may inform on new molecular mechanisms of AD pathophysiology.\n\nAbbreviationsAlzheimers disease (AD), genome-wide association study (GWAS), independent component analysis (ICA), mild cognitive impairment (MCI), medial temporal circuit (MTC), single-nucleotide polymorphism (SNP), tensor-based morphometry (TBM)

neuroscience↗

bioRxiv2017

Modulation of high frequency by low-frequency Oscillations in the basal ganglia

Modulation of beta band fioscillatory activity (15-30 Hz) by delta band oscillatory activity (1-3 Hz) in the cortico-basal ganglia loop is important for normal basal ganglia functions. However, the neural mechanisms underlying this modulation are poorly understood. To understand the mechanisms underlying such frequency modulations in the basal ganglia, we use large scale subthalamo-pallidal network model stimulated via a delta-frequency input signal. We show that inhibition of external Globus Pallidus (GPe) and excitation of the Subthalamic nucleus (STN) using the delta-band stimulation leads to the same delta-beta interactions in the network model as the experimental results observed in healthy basal ganglia. In addition, we show that pathological beta oscillations in the network model decorrelates the delta-beta link in the network model. In general, using our simulation results, we propose that striato-pallidal inhibition and cortico-subthalamic excitation are the potential sources of the delta-beta link observed in the intact basal ganglia.

neuroscience↗

bioRxiv2017

Safety evaluation of soy leghemoglobin protein preparation derived from Pichia pastoris, intended for use as a flavor catalyst in plant-based meat

The leghemoglobin protein (LegH) from soy (Glycine max) expressed in Pichia pastoris (LegH Prep) imparts a meat-like flavor profile onto plant-based food products. The safety of LegH Prep was evaluated through a series of in vitro and in vivo tests. The genotoxic potential of LegH Prep was assessed using the bacterial reverse mutation assay (Ames test) and the in vitro chromosome aberration test. LegH Prep was non-mutagenic and non-clastogenic in each test, respectively. Systemic and female reproductive toxicity were assessed in two separate 28-day dietary studies in Sprague Dawley rats. There were no mortalities associated with the administration of LegH Prep. There were no clinical observations, body weight, ophthalmological, clinical pathology, or histopathological changes attributable to LegH Prep administration. Female reproductive parameters were comparable between rats treated with LegH Prep and concurrent control rats. These studies establish an NOAEL of 750 mg/kg/day LegH, which is over 100 times greater than the 90th percentile estimated daily intake (EDI). Collectively, this work demonstrates that LegH Prep is safe for its intended use in ground beef analogue products at concentrations up to 0.8% LegH.\n\nAbbreviations

pharmacology and toxicology↗

bioRxiv2017

Predicting cancer outcomes from histology and genomics using convolutional networks

Cancer histology reflects underlying molecular processes and disease progression, and contains rich phenotypic information that is predictive of patient outcomes. In this study, we demonstrate a computational approach for learning patient outcomes from digital pathology images using deep learning to combine the power of adaptive machine learning algorithms with traditional survival models. We illustrate how this approach can integrate information from both histology images and genomic biomarkers to predict time-to-event patient outcomes, and demonstrate performance surpassing the current clinical paradigm for predicting the survival of patients diagnosed with glioma. We also provide techniques to visualize the tissue patterns learned by these deep learning survival models, and establish a framework for addressing intratumoral heterogeneity and training data deficits.

bioinformatics↗