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Rxivist combines preprints from bioRxiv with data from Twitter to help you find the papers being discussed in your field. Currently indexing 42,904 bioRxiv papers from 193,370 authors.

Most tweeted bioRxiv papers, last 24 hours

258 results found. For more information, click each entry to expand.

81: Coding of whisker motion across the mouse face
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Posted to bioRxiv 29 Aug 2018

Coding of whisker motion across the mouse face
3 tweets neuroscience

Kyle S Severson, Duo Xu, Hongdian Yang, Daniel O'Connor

Haptic perception synthesizes touch with proprioception, or sense of body position. Humans and mice alike experience rich active touch of the face. Because most facial muscles lack proprioceptor endings, the sensory basis of facial proprioception remains unsolved. Facial proprioception may instead rely on mechanoreceptors that encode both touch and self-motion. In rodents, whisker mechanoreceptors provide a signal that informs the brain about whisker position. Whisking involves coordinated orofacial movements, so mechanoreceptors innervating facial regions other than whiskers could also provide information about whisking. To define all sources of sensory information about whisking available to the brain, we recorded spikes from mechanoreceptors innervating diverse parts of the face. Whisker motion was encoded best by whisker mechanoreceptors, but also by those innervating whisker pad hairy skin and supraorbital vibrissae. Redundant self-motion responses may provide the brain with a stable proprioceptive signal despite mechanical perturbations such as whisker growth and active touch.

82: The macaque anterior cingulate cortex translates counterfactual choice value into actual behavioral change
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Posted to bioRxiv 11 Jun 2018

The macaque anterior cingulate cortex translates counterfactual choice value into actual behavioral change
3 tweets neuroscience

Elsa Fouragnan, Bolton KH Chau, Davide Folloni, Nils Kolling, Lennart Verhagen, Miriam Klein-Flugge, Lev Tankelevitch, Georgios K Papageorgiou, Jean-Francois Aubry, Jerome Sallet, Matthew FS Rushworth

The neural mechanisms mediating sensory-guided decision making have received considerable attention but animals often pursue behaviors for which there is currently no sensory evidence. Such behaviors are guided by internal representations of choice values that have to be maintained even when these choices are unavailable. We investigated how four macaque monkeys maintained representations of the value of counterfactual choices: choices that could not be taken at the current moment but which could be taken in the future. Using functional magnetic resonance imaging, we found two different patterns of activity co-varying with values of counterfactual choices in a circuit spanning hippocampus, anterior lateral prefrontal cortex, and anterior cingulate cortex (ACC). ACC activity also reflected whether the internal value representations would be translated into actual behavioral change. To establish the causal importance of ACC for this translation process, we used a novel technique, Transcranial Focused Ultrasound Stimulation, to reversibly disrupt ACC activity.

83: Linear Input as a Fundamental Motif of Brain Connectivity Organization
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Posted to bioRxiv 14 Feb 2019

Linear Input as a Fundamental Motif of Brain Connectivity Organization
3 tweets neuroscience

Jonathan F O'Rawe, Hoi-Chung Leung

Describing the pattern of region-to-region functional connectivity is an important step towards understanding information transfer and transformation between brain regions. Although fMRI data are limited in spatial resolution, recent advances in technology afford more precise mapping. Here, we extended previous methods, connective field mapping, to 3 dimensions to provide a more concise estimate of the organization and potential information transformation from one region to another. We first replicated previous work with the 3 dimensional model by showing that the topology of functional connectivity between early visual regions maintained along their eccentricity axis or the anterior-posterior dimension. We then examined higher order visual regions (e,g, fusiform face area) and showed that their pattern of connectivity, the convergence and biased sampling, seem to contribute to some of their core receptive field properties. We further demonstrated that linearity of input is a fundamental aspect of functional connectivity of the whole brain, with higher linearity between regions within a network than across networks; that is, high connective linearity was evident between early visual areas, and between prefrontal areas, but less evident between them. By decomposing the whole brain linearity matrix with manifold learning techniques, we found that the principle mode of the linearity maps onto decompositions in both functional connectivity and genetic expression reported in previous studies. The current work provides evidence supporting that linearity of input is likely a fundamental motif of functional connectivity between regions for information processing across the brain, with high linearity preserving the integrity of information from one region to another within a network.

84: Analysis of genetically driven alternative splicing identifies FBXO38 as a novel COPD susceptibility gene
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Posted to bioRxiv 14 Feb 2019

Analysis of genetically driven alternative splicing identifies FBXO38 as a novel COPD susceptibility gene
3 tweets genetics

Aabida Saferali, Jeong H. Yun, Margaret M Parker, Phuwanat Sakornsakolpat, Robert P Chase, Andrew Lamb, Brian D. Hobbs, Marike H Boezen, Xiangpeng Dai, Kim de Jong, Terri H Beaty, Wenyi Wei, Xiaobo Zhou, Edwin K Silverman, Michael H Cho, Peter J Castaldi, Craig P Hersh, COPDGene Investigators, and the International COPD Genetics Consortium Investigators

While many disease-associated single nucleotide polymorphisms (SNPs) are associated with gene expression (expression quantitative trait loci, eQTLs), a large proportion of complex disease genome-wide association study (GWAS) variants are of unknown function. Some of these SNPs may contribute to disease by regulating gene splicing. Here, we investigate whether SNPs that are associated with alternative splicing (splice QTL or sQTL) can identify novel functions for existing GWAS variants or suggest new associated variants in chronic obstructive pulmonary disease (COPD). RNA sequencing was performed on whole blood from 376 subjects from the COPDGene Study. Using linear models, we identified 561,060 unique sQTL SNPs associated with 30,333 splice sites corresponding to 6,419 unique genes. Similarly, 708,928 unique eQTL SNPs involving 15,913 genes were detected at 10% FDR. While there is overlap between sQTLs and eQTLs, 60% of sQTLs are not eQTLs. Co-localization analysis revealed that 7 out of 21 loci associated with COPD (p<1x10-6) in a published GWAS have at least one shared causal variant between the GWAS and sQTL studies. Among the genes identified to have splice sites associated with top GWAS SNPs was FBXO38, in which a novel exon was discovered to be protective against COPD. Importantly, the sQTL in this locus was validated by qPCR in both blood and lung tissue, demonstrating that splice variants relevant to lung tissue can be identified in blood. Other identified genes included CDK11A and SULT1A2. Overall, these data indicate that analysis of alternative splicing can provide novel insights into disease mechanisms. In particular, we demonstrated that SNPs in a known COPD GWAS locus on chromosome 5q32 influence alternative splicing in the gene FBXO38.

85: Voluntary control of illusory contour formation
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Posted to bioRxiv 15 Nov 2017

Voluntary control of illusory contour formation
3 tweets neuroscience

William J Harrison, Reuben Rideaux

The extent to which visual inference is shaped by attentional goals is unclear. Voluntary attention may simply modulate the priority with which information is accessed by higher cognitive functions involved in perceptual decision making. Alternatively, voluntary attention may influence fundamental visual processes, such as those involved in segmenting an incoming retinal signal into a structured scene of coherent objects, thereby determining perceptual organisation. Here we tested whether the segmentation and integration of visual form can be determined by an observer's goals by exploiting a novel variant of the classical Kanizsa figure. We generated predictions about the influence of attention with a machine classifier, and tested these predictions with a psychophysical response classification technique. Despite seeing the same image on each trial, observers' perception of illusory spatial structure depended on their attentional goals. These attention-contingent illusory contours directly conflicted with equally plausible visual form implied by the geometry of the stimulus, revealing that attentional selection can determine the perceived layout of a fragmented scene. Attentional goals, therefore, not only select pre-computed features or regions of space for prioritised processing, but, under certain conditions, also greatly influence perceptual organisation and thus visual appearance.

86: Pain neuroscience education on YouTube: a systematic review
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Posted to bioRxiv 17 Dec 2018

Pain neuroscience education on YouTube: a systematic review
3 tweets scientific communication and education

Lauren C Heathcote, Joshua W Pate, Anna L Park, Hayley B Leake, G Lorimer Moseley, Corey A Kronman, Molly Fischer, Inge Timmers, Laura E Simons

Objectives: The Internet in general, and YouTube in particular, is now one of the most popular sources of health-related information. Pain neuroscience education has become a primary tool for managing persistent pain, based in part on the discovery that information about pain can change pain. Our objective was to examine the availability, characteristics, and content of YouTube videos providing pain neuroscience education. Methods: We conducted a systematic review of videos on YouTube using the search terms Pain Education, What is Pain, and Pain Brain in January 2018. Videos were included if they were in English, were under 10 minutes long, and included information on the neuroscience of pain. Videos were coded for i) descriptive characteristics (e.g., number of views, duration on YouTube), ii) source and style, iii) whether or not they addressed seven pre-determined target concepts of pain neuroscience education (e.g., Pain is not an accurate marker of tissue state), and iv) how engaging they were. Results: We found 106 unique videos that met the inclusion criteria. The videos ranged from having four views to over five million views (Mdn = 1163 views), with the three most highly viewed videos accounting for 75% of the total views. Animated videos were much more highly viewed than non-animated videos. Only a small number of videos had been posted by a clearly-identifiable reputable source such as an academic or medical research institution (10%), although a number of videos were posted by healthcare professionals and professional medical societies. For a small number of videos (7%), the source was unclear. We found 17 videos that addressed at least one target concept of pain neuroscience science education, only nine of which were considered to be engaging. The target concept Pain is a Brain Output was considered to be well addressed by the most videos (N = 11), followed by Pain is a Protector (N = 10). We found only one video that adequately addressed all seven target concepts of pain neuroscience education. Discussion: YouTube contains a variety of videos that practitioners, patients, and families may view to access pain neuroscience education information. A small portion of these videos addressed one or more target concepts of pain neuroscience education in an engaging manner. It is yet to be determined to what extent patients are able to learn information from these videos, to what extent the videos promote behavior change, and thus to what extent the videos may be useful for clinical practice.

87: Efficacy of PCV vaccine is primarily mediated by controlling pneumococcal colonisation density
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Posted to bioRxiv 14 Feb 2019

Efficacy of PCV vaccine is primarily mediated by controlling pneumococcal colonisation density
3 tweets microbiology

Esther L German, Carla Solorzano, Syba Sunny, Felicity Dunne, Jenna F Gritzfeld, Elena Mitsi, Elissavet Nikolaou, Angela D Hyder-Wright, Andrea M Collins, Stephen B Gordon, Daniela Ferreira

Widespread use of Pneumococcal Conjugate Vaccines (PCV) has resulted in a reduction in nasopharyngeal colonisation and invasive pneumococcal disease caused by vaccine-types. In a double-blind, randomised controlled trial using the Experimental Human Pneumococcal Challenge (EHPC) model, PCV-13 (Prevenar-13) conferred 78% protection against colonisation acquisition and a reduction in bacterial intensity (AUC) in experimentally colonised volunteers as measured by classical culture. In this study, we used a multiplex quantitative PCR assay targeting lytA and pneumococcal serotype 6A/B cpsA genes to re-assess the experimental colonisation status of the same trial volunteers. Increase in detection of low-density colonised volunteers by this molecular method led to a decrease of PCV efficacy against colonisation acquisition (29%), as compared to classical culture (83%). For subjects who were colonised following pneumococcal challenge, PCV had a pronounced effect on decreasing colonisation density. These results have implications for vaccine efficacy and surveillance studies as they indicate that the success of PCV vaccination could primarily be mediated by the control of vaccine-type colonisation density which results in decreased transmission and the reported herd effect of PCVs. Studies assessing the impact of PCV should account for density measurements in their design.

88: Abnormalities in Proinsulin Processing in Islets from Individuals with Longstanding T1D
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Posted to bioRxiv 08 Feb 2019

Abnormalities in Proinsulin Processing in Islets from Individuals with Longstanding T1D
3 tweets pathology

Emily K. Sims, Julius Nyalwidhe, Farooq Syed, Henry T. Bahnson, Leena Haataja, Cate Speake, Margaret Morris, Raghavendra G Mirmira, Jerry Nadler, Teresa L. Mastracci, Peter Arvan, Carla J. Greenbaum, Carmella Evans-Molina

Work by our group and others has suggested that elevations in circulating proinsulin relative to C-peptide is associated with development of Type 1 diabetes (T1D). We recently described the persistence of detectable serum proinsulin in a large majority (95.9%) of individuals with longstanding T1D, including individuals with undetectable serum C-peptide. Here we describe analyses performed on human pancreatic sections from the nPOD collection (n=30) and isolated human islets (n=10) to further explore mechanistic etiologies of persistent proinsulin secretion in T1D. Compared to nondiabetic controls, immunostaining among a subset (4/9) of insulin positive T1D donor islets revealed increased numbers of cells with proinsulin-enriched, insulin-poor staining. Laser capture microdissection followed by mass spectrometry revealed reductions in the proinsulin processing enzymes prohormone convertase 1/3 (PC1/3) and carboxypeptidase E (CPE) in T1D donors. Twenty-four hour treatment of human islets with an inflammatory cytokine cocktail reduced mRNA expression of the processing enzymes PC1/3, PC2, and CPE. Taken together, these data provide new mechanistic insight into altered proinsulin processing in long-duration T1D and suggest that reduced β cell prohormone processing is associated with proinflammatory cytokine-induced reductions in proinsulin processing enzyme expression.

89: Architectural traits constrain the evolution of unisexual flowers and sexual segregation within inflorescences: an interspecific approach
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Posted to bioRxiv 26 Jun 2018

Architectural traits constrain the evolution of unisexual flowers and sexual segregation within inflorescences: an interspecific approach
2 tweets evolutionary biology

Ruben Torices, Ana Afonso, Arne A. Anderberg, Jose M. Gomez, Marcos Mendez

Male and female unisexual flowers have repeatedly evolved from the ancestral bisexual flowers in different lineages of flowering plants. This sex specialization in different flowers often occurs within inflorescences. We hypothesize that inflorescence architecture may impose a constraint on resource availability for late flowers, potentially leading to different optima in floral sex allocation and unisexuality. Under this hypothesis we expect that inflorescence traits increasing the difference in resource availability between early and late flowers would be phylogenetically correlated with a higher level of sexual specialization. To test this hypothesis, we performed a comparative analysis of inflorescence traits (inflorescence size, number of flowers and flower density) in the sunflower family, which displays an extraordinary variation in floral sexual specialization at the inflorescence level, i.e. hermaphroditic, gynomonoecious and monoecious species. We found that species with a complete sex separation in unisexual flowers (monoecy) had significantly denser inflorescences. Furthermore, those species arranging their flowers in denser inflorescences also showed greater differences in the size of early and late fruits, a proxy of resource variation between flowers. Our findings support the idea that floral sexual specialization and consequently sexual segregation may be the consequence of different floral sex allocation optima driven by the sequential development of flowers that results in a persistent resource decline from earlier to later flowers.

90: Using DeepLabCut for 3D markerless pose estimation across species and behaviors
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Posted to bioRxiv 24 Nov 2018

Using DeepLabCut for 3D markerless pose estimation across species and behaviors
2 tweets neuroscience

Tanmay Nath, Alexander Mathis, An Chi Chen, Amir Patel, Matthias Bethge, Mackenzie W. Mathis

Noninvasive behavioral tracking of animals during experiments is crucial to many scientific pursuits. Extracting the poses of animals without using markers is often essential for measuring behavioral effects in biomechanics, genetics, ethology & neuroscience. Yet, extracting detailed poses without markers in dynamically changing backgrounds has been challenging. We recently introduced an open source toolbox called DeepLabCut that builds on a state-of-the-art human pose estimation algorithm to allow a user to train a deep neural network using limited training data to precisely track user-defined features that matches human labeling accuracy. Here, with this paper we provide an updated toolbox that is self contained within a Python package that includes new features such as graphical user interfaces and active-learning based network refinement. Lastly, we provide a step-by-step guide for using DeepLabCut.

91: Live Mouse Tracker: real-time behavioral analysis of groups of mice
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Posted to bioRxiv 14 Jun 2018

Live Mouse Tracker: real-time behavioral analysis of groups of mice
2 tweets animal behavior and cognition

Fabrice de Chaumont, Elodie Ey, Nicolas Torquet, Thibault Lagache, Stephane Dallongeville, Albane Imbert, Thierry Legou, Anne-Marie Le Sourd, Philippe Faure, Thomas Bourgeron, Jean-Christophe Olivo-Marin

Preclinical studies of psychiatric disorders require the use of animal models to investigate the impact of environmental factors or genetic mutations on complex traits such as decision-making and social interactions. Here, we present a real-time method for behavior analysis of mice housed in groups that couples computer vision, machine learning and Triggered-RFID identification to track and monitor animals over several days in enriched environments. The system extracts a thorough list of individual and collective behavioral traits and provides a unique phenotypic profile for each animal. On mouse models, we study the impact of mutations of genes Shank2 and Shank3 involved in autism. Characterization and integration of data from behavioral profiles of mutated female mice reveals distinctive activity levels and involvement in complex social configuration.

92: Corticostriatal synaptic weight evolution in a two-alternative forced choice task
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Posted to bioRxiv 13 Feb 2019

Corticostriatal synaptic weight evolution in a two-alternative forced choice task
2 tweets animal behavior and cognition

Catalina Vich, Kyle Dunovan, Timothy V Verstynen, Jonathan Rubin

In natural environments, mammals can efficiently select actions based on noisy sensory signals and quickly adapt to unexpected outcomes to better exploit opportunities that arise in the future. Such feedback-based changes in behavior rely on long term plasticity within cortico-basal-ganglia-thalamic networks, driven by dopaminergic modulation of cortical inputs to the direct and indirect pathway neurons of the striatum. While the firing rates of corticostriatal neurons have been shown to adapt across a range of feedback conditions, it remains difficult to directly assess the corticostriatal synaptic weight changes that contribute to these adaptive firing rates. In this work, we simulate a computational model for the evolution of corticostriatal synaptic weights based on a spike timing-dependent plasticity rule driven by dopamine signaling that is induced by outcomes of actions in the context of a two-alternative forced choice task. Results show that plasticity predominantly impacts direct pathway weights, which evolve to drive action selection toward a more-rewarded action in settings with deterministic reward outcomes. After the model is tuned based on such fixed reward scenarios, its performance agrees with the results of behavioral experiments carried out with probabilistic reward paradigms.

93: Activity-dependent regulation of the proapoptotic BH3-only gene egl-1 in a living neuron pair in C. elegans
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Posted to bioRxiv 13 Feb 2019

Activity-dependent regulation of the proapoptotic BH3-only gene egl-1 in a living neuron pair in C. elegans
2 tweets genetics

Jonathan T. Pierce, Jesse Cohn, Vivek Dwivedi, Nicole Zarate, Robert Horvitz

The BH3-only family of proteins is key for initiating apoptosis in a variety of contexts, and may also contribute to non-apoptotic cellular processes. Historically, the nematode Caenorhabditis elegans has provided a powerful system for studying and identifying conserved regulators of BH3-only proteins. In C. elegans, the BH3-only protein EGL-1 is expressed during development to cell-autonomously trigger most developmental cell deaths. Here we provide evidence that egl-1 is also transcribed after development in the sensory neuron pair URX without inducing apoptosis. We used genetic screening and epistasis analysis to determine that its transcription is regulated in URX by neuronal activity and/or in parallel by orthologs of Protein Kinase G and the Salt-Inducible Kinase family. Because several BH3-only family proteins are also expressed in the adult nervous system of mammals, we suggest that studying egl-1 expression in URX may shed light on mechanisms that regulate conserved family members in higher organisms.

94: Transcriptional signatures of progressive neuropathology in transgenic tau and amyloid mouse models.
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Posted to bioRxiv 13 Feb 2019

Transcriptional signatures of progressive neuropathology in transgenic tau and amyloid mouse models.
2 tweets genomics

Isabel Castanho, Tracey K Murray, Eilis Hannon, Aaron Jeffries, Emma Walker, Emma Laing, Hedley Baulf, Joshua Harvey, Andrew Randall, Karen Moore, Paul O'Neill, Katie Lunnon, David A. Collier, Zeshan Ahmed, Michael J. O'Neill, Jonathan Mill

The onset and progression of Alzheimer's disease (AD) is characterized by increasing intracellular aggregation of hyperphosphorylated tau protein and accumulation of β-amyloid (Aβ) in the neocortex. Despite recent success in identifying genetic risk factors for AD the transcriptional mechanisms involved in disease progression are not fully understood. We used transgenic mice harbouring human tau (rTg4510) and amyloid precursor protein (J20) mutations to investigate transcriptional changes associated with the development of both tau and amyloid pathology. Using highly-parallel RNA sequencing we profiled transcriptional variation in the entorhinal cortex at four time points identifying robust genotype-associated differences in entorhinal cortex gene expression in both models. We quantified neuropathological burden across multiple brain regions in the same individual mice, identifying widespread changes in gene expression paralleling the development of tau pathology in rTg4510 mice. Differentially expressed transcripts included genes associated with familial AD from genetic studies of human patients, and genes annotated to both common and rare variants identified in GWAS and exome-sequencing studies of late-onset sporadic AD. Systems-level analyses identified discrete co-expression networks associated with the progressive accumulation of tau, with these enriched for genes and pathways previously implicated in the neuro-immunological and neurodegenerative processes driving AD pathology. Finally, we report considerable overlap between tau-associated networks and AD-associated co-expression modules identified in the human cortex. Our data provide further support for an immune-response component in the accumulation of tau, and reveal novel molecular pathways associated with the progression of AD neuropathology.

95: Expanding Parkinson's disease genetics: novel risk loci, genomic context, causal insights and heritable risk.
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Posted to bioRxiv 09 Aug 2018

Expanding Parkinson's disease genetics: novel risk loci, genomic context, causal insights and heritable risk.
2 tweets genetics

Mike A Nalls, Cornelis Blauwendraat, Costanza L. Vallerga, Karl Heilbron, Sara Bandres-Ciga, Diana Chang, Manuela Tan, Demis A Kia, Alastair J. Noyce, Angli Xue, Jose Bras, Emily Young, Ranier von Coelln, Javier Simon-Sanchez, Claudia Schulte, Manu Sharma, Lynne Krohn, Lasse Pihlstrom, Ari Siitonen, Hirotaka Iwaki, Hampton Leonard, Faraz Faghri, J. Raphael Gibbs, Dena G. Hernandez, Sonja W Scholz, Juan A Botia, Maria Martinez, Jean-Chrstophe Corvol, Suzanne Lesage, Joseph Jankovic, Lisa M. Shulman, The 23andMe Research Team, System Genomics of Parkinson's Disease (SGPD) Consortium, Margaret Sutherland, Pentti Tienari, Kari Majamaa, Mathias Toft, Alexis Brice, Jian Yang, Ziv Gan-Orr, Thomas M Gasser, Peter M Heutink, Joshua M Shulman, Nicolas A Wood, David A. Hinds, John R Hardy, Huw R Morris, Jacob M Gratten, Peter M. Visscher, Robert R Graham, Andrew B. Singleton, International Parkinson's Disease Genomics Consortium

We performed the largest genome-wide association study of PD to date, involving the analysis of 7.8M SNPs in 37.7K cases, 18.6K UK Biobank proxy-cases, and 1.4M controls. We identified 90 independent genome-wide significant signals across 78 loci, including 38 independent risk signals in 37 novel loci. These variants explained 26-36% of the heritable risk of PD. Tests of causality within a Mendelian randomization framework identified putatively causal genes for 70 risk signals. Tissue expression enrichment analysis suggested that signatures of PD loci were heavily brain-enriched, consistent with specific neuronal cell types being implicated from single cell expression data. We found significant genetic correlations with brain volumes, smoking status, and educational attainment. In sum, these data provide the most comprehensive understanding of the genetic architecture of PD to date by revealing many additional PD risk loci, providing a biological context for these risk factors, and demonstrating that a considerable genetic component of this disease remains unidentified.

96: Unraveling ChR2-driven stochastic Ca2+ dynamics in astrocytes – A call for new interventional paradigms
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Posted to bioRxiv 13 Feb 2019

Unraveling ChR2-driven stochastic Ca2+ dynamics in astrocytes – A call for new interventional paradigms
2 tweets neuroscience

Arash Moshkforoush, Lakshmini Balachandar, Carolina Moncion, Josue Santana, Jorge Riera

Control of astrocytes via modulation of Ca2+ oscillations using techniques like optogenetics can prove to be crucial in therapeutic intervention of a variety of neurological disorders. However, a systematic study quantifying the effect of optogenetic stimulation in astrocytes is yet to be performed. Here, we propose a novel stochastic Ca2+dynamics model that incorporates the light sensitive component – Channelrhodopsin2 (ChR2). Utilizing this model, we studied the effect of various light stimulation paradigms on astrocytes for select variants of ChR2 (wild type, ChETA and ChRET/TC) in both an individual and a network of cells. Our results exhibited a consistent pattern of Ca2+ activity among individual cells in response to optogenetic stimulation, i.e., showing a steady rise in the Ca2+ basal level with increase in pulse width, and distinct regions with maximal spiking probability. Furthermore, we performed a global sensitivity analysis to assess the effect of ChR2 parameters and the model Weiner processes on astrocytic Ca2+ dynamics in the presence and absence of light stimulation, respectively. Results indicated that directing variants towards the first open state of the photo-cycle of ChR2 (O1) enhances spiking activity in astrocytes during optical stimulation. Evaluation of the effect of ChR2 transduction efficiency (heterogeneity) on Ca2+ signaling revealed that the optimal stimulation paradigm of a network does not necessarily coincide with that of an individual cell. Simulation for ChETA-incorporated astrocytes suggest that maximal activity of a single cell reduced the spiking probability of the network of astrocytes at higher degrees of transduction efficiency due to elevation of basal Ca2+ beyond physiological levels. Collectively, the framework presented in this study provides valuable information in the selection of paradigms that elicit optimal astrocytic activity using existing ChR2 constructs, as well as aid in the engineering of future optogenetic constructs.

97: Alternative (backdoor) androgen production and masculinization in the human fetus
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Posted to bioRxiv 09 Jul 2018

Alternative (backdoor) androgen production and masculinization in the human fetus
2 tweets physiology

Peter James O'Shaughnessy, Jean Philippe Antignac, Bruno Le Bizec, Marie-Line Morvan, Konstantin Svecvhnikov, Olle Soder, Iuliia Savchuk, Ana Monteiro, Ugo Soffientini, Zoe Johnston, Michelle Bellingham, Denise Hough, Siladitya Bhattacharya, Natasha Walker, Panagiotis Filis, Paul Fowler

Masculinization of the external genitalia in humans is dependent on formation of 5α-dihydrotestosterone (DHT) through both the canonical androgenic pathway and an alternative (backdoor) pathway. The fetal testes are essential for canonical androgen production but little is known about the synthesis of backdoor androgens despite their known critical role in masculinization. In this study, we have measured plasma and tissue levels of endogenous steroids in second trimester human male fetuses using multi-dimensional and high-resolution mass-spectrometry. Results show that androsterone is the principal backdoor androgen in the fetal circulation and that DHT is undetectable (<1ng/ml). Backdoor pathway intermediates are found primarily in the placenta and fetal liver with significant androsterone levels also in the fetal adrenal. Backdoor intermediates, including androsterone, are mostly undetectable in the fetal testes. This is consistent with transcript levels of enzymes involved in the backdoor pathway (SRD5A1, AKR1C2/4, CYP17A1), as measured by qPCR. These data identify androsterone as the predominant backdoor androgen in the human fetus and show that it is formed primarily in non-gonadal tissue with placental progesterone the likely substrate. Masculinization of the human fetus depends, therefore, on androgen synthesis by both the fetal testes and non-gonadal tissues leading to DHT formation at the genital tubercle. Our findings provide, for the first time, a solid basis to explain why placental insufficiency is associated with disorders of sex development in humans

98: Resting-state cross-frequency coupling networks in human electrophysiological recordings
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Posted to bioRxiv 13 Feb 2019

Resting-state cross-frequency coupling networks in human electrophysiological recordings
2 tweets neuroscience

Felix Siebenhuehner, Sheng H. Wang, Gabriele Arnulfo, Lino Nobili, J. Matias Palva, Satu Palva

Neuronal oscillations underlie temporal coordination of neuronal processing and their synchronization enables neuronal communication across distributed brain areas to serve a variety of sensory, motor, and cognitive functions. The regulation and integration of neuronal processing between oscillating assemblies at distinct frequencies, and thereby the coordination of distinct computational functions, is thought to be achieved via cross-frequency coupling (CFC). Although many studies have observed CFC locally within a brain region during cognitive processing, the large-scale networks of CFC have remained largely uncharted. Critically, also the validity of prior CFC observations and the presence of true neuronal CFC has been recently questioned because non-sinusoidal or non-zero-mean waveforms that are commonplace in electrophysiological data cause filtering artefacts that lead to false positive CFC findings. We used a unique dataset of stereo-electroencephalography (SEEG) and source-reconstructed magnetoencephalography (MEG) data to chart whole-brain CFC networks from human resting-state brain dynamics. Using a novel graph theoretical method to distinguish true inter-areal CFC from potentially false positive CFC, we show that the resting state is characterized by two separable forms of true inter-areal CFC: phase-amplitude coupling (PAC) and n:m-cross-frequency phase synchrony (CFS). PAC and CFS large-scale networks coupled prefrontal, visual and sensorimotor cortices, but with opposing anatomical architectures. Crucially also directionalities between low- and high-frequency oscillations were opposite between CFS and PAC. We also found CFC to decay as a function of distance and to be stronger in the superficial than deep layers of the cortex. In conclusion, these results provide conclusive evidence for the presence of two forms of genuine inter-areal CFC and elucidate the large-scale organization of CFC resting-state networks.

99: Variation across 141,456 human exomes and genomes reveals the spectrum of loss-of-function intolerance across human protein-coding genes
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Posted to bioRxiv 28 Jan 2019

Variation across 141,456 human exomes and genomes reveals the spectrum of loss-of-function intolerance across human protein-coding genes
2 tweets genomics

Konrad Karczewski, Laurent C Francioli, Grace Tiao, Beryl B Cummings, Jessica Alföldi, Qingbo Wang, Ryan L Collins, Kristen M Laricchia, Andrea Ganna, Daniel P. Birnbaum, Laura D Gauthier, Harrison Brand, Matthew Solomonson, Nicholas A Watts, Daniel Rhodes, Moriel Singer-Berk, Eleanor G Seaby, Jack A. Kosmicki, Raymond K Walters, Katherine Tashman, Yossi Farjoun, Eric Banks, Timothy Poterba, Arcturus Wang, Cotton Seed, Nicola Whiffin, Jessica X Chong, Kaitlin E. Samocha, Emma Pierce-Hoffman, Zachary Zappala, Anne H. O'Donnell-Luria, Eric Vallabh Minikel, Ben Weisburd, Monkol Lek, James S Ware, Christopher Vittal, Irina M Armean, Louis Bergelson, Kristian Cibulskis, Kristen M Connolly, Miguel Covarrubias, Stacey Donnelly, Steven Ferriera, Stacey Gabriel, Jeff Gentry, Namrata Gupta, Thibault Jeandet, Diane Kaplan, Christopher Llanwarne, Ruchi Munshi, Sam Novod, Nikelle Petrillo, David Roazen, Valentin Ruano-Rubio, Andrea Saltzman, Molly Schleicher, Jose Soto, Kathleen Tibbetts, Charlotte Tolonen, Gordon Wade, Michael E. Talkowski, The Genome Aggregation Database Consortium, Benjamin M Neale, Mark J. Daly, Daniel G. MacArthur

Genetic variants that inactivate protein-coding genes are a powerful source of information about the phenotypic consequences of gene disruption: genes critical for an organism's function will be depleted for such variants in natural populations, while non-essential genes will tolerate their accumulation. However, predicted loss-of-function (pLoF) variants are enriched for annotation errors, and tend to be found at extremely low frequencies, so their analysis requires careful variant annotation and very large sample sizes. Here, we describe the aggregation of 125,748 exomes and 15,708 genomes from human sequencing studies into the Genome Aggregation Database (gnomAD). We identify 443,769 high-confidence pLoF variants in this cohort after filtering for sequencing and annotation artifacts. Using an improved model of human mutation, we classify human protein-coding genes along a spectrum representing intolerance to inactivation, validate this classification using data from model organisms and engineered human cells, and show that it can be used to improve gene discovery power for both common and rare diseases.

100: The return of the trophic chain: fundamental vs realized interactions in a simple arthropod food web
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Posted to bioRxiv 16 May 2018

The return of the trophic chain: fundamental vs realized interactions in a simple arthropod food web
2 tweets ecology

Inmaculada Torres-Campos, Sara Magalhaes, Jordi Moya-Larano, Marta Montserrat

The mathematical theory describing small assemblages of interacting species (community modules or motifs) has proved to be essential in understanding the emergent properties of ecological communities. These models use differential equations to study pairwise interactions between species. However, as community modules become more complex, it is not certain that all potential interactions will be effectively realized. Here, we use community modules to experimentally explore whether the number of trophic links among species scales with community complexity (i.e., by adding species known to feed on each other from pair-wise trials). To investigate this question, we used a simple mite community present in avocado orchards (Persea americana), composed of two predators (Euseius stipulatus and Neoseiulus californicus), one herbivore as shared prey (Oligonychus perseae), and pollen of Carpobrotus edulis as an alternative food resource. These configurations enabled the potential for (intraguild) predation and (apparent) competition to be expressed. Using a series of controls, we assessed whether the presence of one species affected the survival of another, or its conversion of food into offspring). We found that increasing the number of potential interactions did not result in more complex realized community modules. Instead, all communities were reduced to one or two linear trophic chains. Our results show that trophic links assumed to occur when species are assembled in pairs do not necessarily occur when other components of the community are present. Consequently, food-web structure may be unrealistic in theoretical community modules that are parameterized based on pair-wise interactions observed when alternative prey is absent. This further suggests the need for empirical research to work in concert with theoretical approaches to develop more realistic and predictive food-web models.

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