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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 67,118 bioRxiv papers from 295,271 authors.

Most downloaded bioRxiv papers, since beginning of last month

65,744 results found. For more information, click each entry to expand.

621: Histone methyltransferase DOT1L controls state-specific identity during B cell differentiation
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Posted to bioRxiv 31 Oct 2019

Histone methyltransferase DOT1L controls state-specific identity during B cell differentiation
242 downloads immunology

Muhammad Assad Aslam, Mir Farshid Alemdehy, Eliza Mari Kwesi-Maliepaard, Marieta Caganova, Iris N Pardieck, Teun van den Brand, Fitriari Izzatunnisa Muhaimin, Tibor van Welsem, Iris de Rink, Ji-Ying Song, Elzo de Wit, Ramon Arens, Klaus Rajewsky, Heinz Jacobs, Fred van Leeuwen

Development of naïve peripheral B cells into terminally differentiated plasma cells is a highly controlled process guided by epigenetic mechanisms. Here we identified a central role for the histone H3K79 methyltransferase DOT1L in controlling B cell development. Upon deletion of Dot1L early in the B-cell lineage, naïve and activated B cells prematurely acquired plasma cell features and failed to establish germinal centers (GC) and normal humoral immune responses in vivo . Transcriptome analyses revealed that DOT1L promotes expression of oncogenic, pro-proliferative and pro-GC transcription factors. Simultaneously, DOT1L indirectly promotes repression of anti-proliferative targets of the Polycomb Repressor Complex 2. Our findings show that DOT1L fine tunes the transcriptional and epigenetic landscape in B cells. In doing so it establishes a critical epigenetic barrier warranting B cell naivety and prohibiting their premature differentiation towards plasma cells.

622: scGAIN: Single Cell RNA-seq Data Imputation using Generative Adversarial Networks
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Posted to bioRxiv 12 Nov 2019

scGAIN: Single Cell RNA-seq Data Imputation using Generative Adversarial Networks
242 downloads bioinformatics

Mohamed Khaled Gunady, Jayaram Kancherla, Héctor Corrada Bravo, Soheil Feizi

Single cell RNA sequencing (scRNA-seq) provides a rich view into the heterogeneity underlying a cell population. However single-cell data are usually noisy and very sparse due to the presence of dropout genes. In this work we propose an approach to impute missing gene expressions in single cell data using generative adversarial networks (GANs). By learning an approximate distribution of the data, our approach, scGAIN, can impute dropouts in simulated and real single cell data. The work in this paper discusses how to adopt GAIN training model into the domain of imputing single cell data. Experiments show that scGAIN gives competitive results compared to the state-of-the-art approaches while showing superiority in various aspects in simulation and real data. Imputation by scGAIN successfully recovers the underlying clustering of different subpopulations, provides sharp estimates around true mean expressions and increase the correspondence with matched bulk RNAseq experiments.

623: PheGWAS: A new dimension to visualize GWAS across multiple phenotypes
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Posted to bioRxiv 08 Jul 2019

PheGWAS: A new dimension to visualize GWAS across multiple phenotypes
242 downloads bioinformatics

Gittu George, Sushrima Gan, Yu Huang, Philip Appleby, A.S. Nar, Radha Venkatesan, Viswanathan Mohan, Colin N.A. Palmer, Alex S.F Doney

Motivation PheGWAS was developed to enhance exploration of phenome-wide pleiotropy at the genome-wide level through the efficient generation of a dynamic visualization combining Manhattan plots from GWAS with PheWAS to create a three-dimensional “landscape”. Pleiotropy in sub-surface GWAS significance strata can be explored in a sectional view plotted within user defined levels. Further complexity reduction is achieved by confining to a single chromosomal section. Comprehensive genomic and phenomic coordinates can be displayed. Results PheGWAS is demonstrated using summary data from Global Lipids Genetics Consortium (GLGC) GWAS across multiple lipid traits. For single and multiple traits PheGWAS highlighted all eight-eight and sixty-nine loci respectively. Further, the genes and SNPs reported in GLGC were identified using additional functions implemented within PheGWAS. Not only is PheGWAS capable of identifying independent signals but also provide insights to local genetic correlation (verified using HESS) and in identifying the potential regions that share causal variants across phenotypes (verified using colocalization tests). Availability and Implementation The PheGWAS software and code are freely available at (<https://github.com/georgeg0/PheGWAS>). Contact a.doney{at}dundee.ac.uk, g.z.george{at}dundee.ac.uk

624: Viral manipulation of functionally distinct neurons from mice to humans
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Posted to bioRxiv 18 Oct 2019

Viral manipulation of functionally distinct neurons from mice to humans
241 downloads neuroscience

Douglas C Vormstein-Schneider, Jessica D Lin, Kenneth A Pelkey, Ramesh Chittajallu, Baolin Guo, Mario Arias Garcia, Sofia Sakopoulos, Olivia Stevenson, Gates Schneider, Qiangge Zhang, Jitendra Sharma, Tom P Franken, Jared Smith, Ian Vogel, Vanessa Sanchez, Leena A Ibrahim, Timothy Burbridge, Emilia Favuzzi, Giuseppe A Saldi, Qing Xu, Lihua Guo, Xiaoqing Yuan, Kareem A. Zaghloul, Ehsan Sabri, Ethan M Goldberg, Orrin Devinsky, Renata Batista-Brito, John Reynolds, Guoping Feng, Zhanyan Fu, Chris J McBain, Gord J Fishell, Jordane Dimidschstein

Recent success in identifying gene regulatory elements in the context of recombinant adeno-associated virus vectors have enabled cell type-restricted gene expression. However, within the cerebral cortex these tools are presently limited to broad classes of neurons. To overcome this limitation, we developed a strategy that led to the identification of multiple novel enhancers to target functionally distinct neuronal subtypes. By investigating the regulatory landscape of the disease gene Scn1a, we identified enhancers that target the breadth of its expression, including two selective for parvalbumin and vasoactive intestinal peptide cortical interneurons. Demonstrating the functional utility of these elements, we found that the PV-specific enhancer allowed for the selective targeting and manipulation of fast-spiking cortical interneurons across species, from mice to humans.

625: Structural robustness affects the engineerability of aminoacyl-tRNA synthetases for genetic code expansion
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Posted to bioRxiv 02 Nov 2019

Structural robustness affects the engineerability of aminoacyl-tRNA synthetases for genetic code expansion
241 downloads synthetic biology

Katherine T Grasso, Megan J. R. Yeo, Christen M. Hillenbrand, Elise D. Ficaretta, James S. Italia, Rachel L. Huang, Abhishek Chatterjee

The ability to engineer the substrate specificity of natural aminoacyl-tRNA synthetase/tRNA pairs facilitates the site-specific incorporation of noncanonical amino acids (ncAAs) into proteins. The Methanocaldococcus jannaschii derived tyrosyl-tRNA synthetase (MjTyrRS)/tRNA pair has been engineered to incorporate numerous ncAAs into protein expressed in bacteria. However, it cannot be used in eukaryotic cells due to cross-reactivity with its host counterparts. The E. coli derived tyrosyl-tRNA synthetase (EcTyrRS)/tRNA pair offers a suitable alternative to this end, but a much smaller subset of ncAAs has been genetically encoded using this pair. Here we report that this discrepancy, at least partly, stems from the lower structural robustness of EcTyrRS relative to MjTyrRS. We show that engineered TyrRS mutants in general exhibit significantly lower thermostability relative to their wild-type counterparts. Derived from a thermophilic archaeon, MjTyrRS is a remarkably sturdy protein and tolerates extensive active site engineering without a catastrophic loss of stability at physiological temperature. In contrast, EcTyrRS exhibits significantly lower thermostability, rendering some of its engineered mutants insufficiently stable at physiological temperature. Our observations identify the structural robustness of an aaRS as an important factor that significantly influences how extensively it can be engineered. To overcome this limitation, we have further developed chimeras between EcTyrRS and its homolog from a thermophilic bacteria, which offer an optimal balance between thermostability and activity. We show that the chimeric bacterial TyrRSs show enhanced tolerance for destabilizing active site mutations, providing a potentially more engineerable platform for genetic code expansion.

626: Spatially-mapped single-cell chromatin accessibility
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Posted to bioRxiv 22 Oct 2019

Spatially-mapped single-cell chromatin accessibility
241 downloads genetics

Casey A Thornton, Ryan M Mulqueen, Kristof A Torkenczy, Eve G Lowenstein, Andrew J Fields, Frank J Steemers, Kevin M. Wright, Andrew C Adey

High-throughput single-cell genomic assays resolve the heterogeneity of cell states in complex tissues; however, the spatial orientation within the network of interconnected cells is lost. As cell localization is a necessary dimension in understanding complex tissues and disease states, we present a novel method for highly-scalable spatially-resolved single-cell profiling of chromatin states. We use high density multiregional sampling to perform single-cell combinatorial indexing on Microbiopsies Assigned to Positions for the Assay for Transposase Accessible Chromatin (sciMAP-ATAC) to produce single-cell data of equivalent quality to non-spatial single-cell ATAC-seq. We apply sciMAP-ATAC in the adult mouse cortex to discriminate cortical layering of glutamatergic neurons and establish the spatial ordering of single cells within intact tissue. We then leverage this spatially-oriented cell dataset by combining it with non-spatially resolved whole brain sci-ATAC-seq data and assess layer-specific marker gene chromatin accessibility and transcription factor motif enrichment. Using sciMAP-ATAC seq, we identify sets of regulatory elements that spatially vary in the cortex, which includes canonical layer-specific markers and previously unannotated putative regulatory elements.

627: Community-Led Research Discovers Links Between Elusive Symptoms And Clinical Tests
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Posted to bioRxiv 19 May 2017

Community-Led Research Discovers Links Between Elusive Symptoms And Clinical Tests
241 downloads clinical trials

Irene S. Gabashvili

Human breath and body odors have been used for diagnosis of serious and life-threatening conditions since the dawn of medical practice. More recently, it has been recognized that malodors without accompanying physical symptoms could be a sign of psychologically but not physically debilitating disorders such as Trimethylaminuria (TMAU). Self-reported intermittent odors without apparent cause, are, however, still treated with suspicion by medical professionals. Most cases of socially-disabling idiopathic malodor remain undiagnosed and there are no guidelines for diagnostic tests nor treatment options that extend beyond TMAU. Internationally-recruited volunteers with undiagnosed body odor and halitosis enrolled to participate in our study, registered as NCT02692495 at clinicaltrials.gov. Each volunteer underwent several blood and urine tests conducted by Biolab Medical Unit, a medical referral laboratory in London, specializing in nutritional and environmental medicine. Intestinal permeability measurements were strikingly different for subjects that named the nose/mouth as the malodor source(s) versus other, often unidentified, body regions. Furthermore, metabolite levels in blood and urine allowed matching of participants by dietary sensitivities and the type of odor reported, emphasizing the potential of harnessing patients' olfactory observations. In discussing the anecdotal “People are Allergic to Me” condition (PATM), we show how it fits into the picture. Clinical trial registration ID #NCT02692495.

628: Preparation for upcoming attentional states in the hippocampus and medial prefrontal cortex
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Posted to bioRxiv 31 Oct 2019

Preparation for upcoming attentional states in the hippocampus and medial prefrontal cortex
241 downloads neuroscience

Eren Gunseli, Mariam Aly

Goal-directed attention is usually studied by providing individuals with explicit instructions on what they should attend to. But in daily life, we often use past experiences to guide our attentional states. Given the importance of memory for predicting upcoming events, we hypothesized that memory-guided attention is supported by neural preparation for anticipated attentional states. We examined preparatory coding in the human hippocampus and mPFC, two regions that are important for memory-guided behaviors, in two tasks - one where attention was guided by memory and another in which attention was explicitly instructed. Hippocampus and mPFC exhibited higher activity for memory-guided vs. explicitly instructed attention. Furthermore, representations in both regions contained information about upcoming attentional states. In the hippocampus, this preparation was stronger for memory-guided attention, and occurred alongside stronger coupling with visual cortex during attentional guidance. These results highlight the mechanisms by which memories are used to prepare for upcoming attentional goals.

629: The latitudinal gradient in hand-wing-index: global patterns and predictors of wing morphology in birds
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Posted to bioRxiv 24 Oct 2019

The latitudinal gradient in hand-wing-index: global patterns and predictors of wing morphology in birds
240 downloads evolutionary biology

Catherine Sheard, Montague H. C. Neate-Clegg, Nico Alioravainen, Samuel E.I. Jones, Claire Vincent, Hannah E. A. MacGregor, Tom P. Bregman, Santiago Claramunt, Joseph Tobias

An organism's ability to disperse influences many fundamental processes in ecology. However, standardised estimates of dispersal ability are rarely available, and thus the patterns and drivers of broad-scale variation in dispersal ability remain unclear. Here we present a global dataset of avian hand-wing index (HWI), an estimate of wingtip pointedness widely adopted as a proxy for flight efficiency and dispersal in birds. We show that HWI is correlated with geography and ecology across 10,391 (>99 %) bird species, increasing at higher latitudes and in migratory and/or non-territorial species. After controlling for these effects, the strongest predictor of HWI is temperature variability (i.e. seasonality), with secondary effects of diet and habitat type. Our analyses (1) reveal a prominent latitudinal gradient in HWI shaped by ecological and environmental factors, and (2) provide a global index of avian dispersal ability for wider use in community ecology, macroecology, and macroevolution.

630: Single-cell transcriptomics reveals expansion of cytotoxic CD4 T-cells in supercentenarians
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Posted to bioRxiv 20 May 2019

Single-cell transcriptomics reveals expansion of cytotoxic CD4 T-cells in supercentenarians
240 downloads immunology

Kosuke Hashimoto, Tsukasa Kouno, Tomokatsu Ikawa, Norihito Hayatsu, Yurina Miyajima, Haruka Yabukami, Tommy Terooatea, Takashi Sasaki, Takahiro Suzuki, Matthew Valentine, Giovanni Pascarella, Yasushi Okazaki, Harukazu Suzuki, Jay W Shin, Aki Minoda, Ichiro Taniuchi, Hideyuki Okano, Yasumichi Arai, Nobuyoshi Hirose, Piero Carninci

Supercentenarians, people who have reached 110 years of age, are a great model of healthy aging. Their characteristics of delayed onset of age-related diseases and compression of morbidity imply that their immune system remains functional. Here we performed single-cell transcriptome analysis of 61,202 peripheral blood mononuclear cells (PBMCs), derived from seven supercentenarians and five younger controls. We identified a marked increase of cytotoxic CD4 T-cells (CD4 CTLs) coupled with a substantial reduction of B-cells as a novel signature of supercentenarians. Furthermore, single-cell T-cell receptor sequencing of two supercentenarians revealed that CD4 CTLs had accumulated through massive clonal expansion, with the most frequent clonotypes accounting for 15% to 35% of the entire CD4 T-cell population. The CD4 CTLs exhibited substantial heterogeneity in their degree of cytotoxicity as well as a nearly identical transcriptome to that of CD8 CTLs. This indicates that CD4 CTLs utilize the transcriptional program of the CD8 lineage while retaining CD4 expression. Our study reveals that supercentenarians have unique characteristics in their circulating lymphocytes, which may represent an essential adaptation to achieve exceptional longevity by sustaining immune responses to infections and diseases.

631: Nested oscillatory dynamics in cortical organoids model early human brain network development
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Posted to bioRxiv 29 Jun 2018

Nested oscillatory dynamics in cortical organoids model early human brain network development
240 downloads neuroscience

Cleber A. Trujillo, Richard D Gao, Priscilla D. Negraes, Isaac A. Chaim, Alain Domissy, Matthieu Vandenberghe, Anna Devor, Gene W Yeo, Bradley Voytek, Alysson R Muotri

Structural and transcriptional changes during early brain maturation follow fixed developmental programs defined by genetics. However, whether this is true for functional network activity remains unknown, primarily due to experimental inaccessibility of the initial stages of the living human brain. Here, we analyzed cortical organoids that spontaneously developed periodic and regular oscillatory network events that are dependent on glutamatergic and GABAergic signaling. These nested oscillations exhibit cross-frequency coupling, proposed to coordinate neuronal computation and communication. As evidence of potential network maturation, oscillatory activity subsequently transitioned to more spatiotemporally irregular patterns, capturing features observed in preterm human electroencephalography (EEG). These results show that the development of structured network activity in the human neocortex may follow stable genetic programming, even in the absence of external or subcortical inputs. Our model provides novel opportunities for investigating and manipulating the role of network activity in the developing human cortex.

632: Psychoactive plant- and mushroom-associated alkaloids from two behavior modifying cicada pathogens
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Posted to bioRxiv 24 Jul 2018

Psychoactive plant- and mushroom-associated alkaloids from two behavior modifying cicada pathogens
239 downloads ecology

Greg Boyce, Emile Gluck-Thaler, Jason C. Slot, Jason E Stajich, William J. Davis, Tim Y. James, John R. Cooley, Daniel G. Panaccione, Jørgen Eilenberg, Henrik H. De Fine Licht, Angie M. Macias, Matthew C. Berger, Kristen L. Wickert, Cameron M. Stauder, Ellie J. Spahr, Matthew D. Maust, Amy M. Metheny, Chris Simon, Gene Kritsky, Kathie T. Hodge, Richard A. Humber, Terry Gullion, Dylan P. G. Short, Teiya Kijimoto, Dan Mozgai, Nidia Arguedas, Matt T. Kasson

Entomopathogenic fungi routinely kill their hosts before releasing infectious spores, but select species keep insects alive while sporulating, which enhances dispersal. Transcriptomics and metabolomics studies of entomopathogens with post-mortem dissemination from their parasitized hosts have unraveled infection processes and host responses, yet mechanisms underlying active spore transmission by Entomophthoralean fungi in living insects remain elusive. Here we report the discovery, through metabolomics, of the plant-associated amphetamine, cathinone, in four Massospora cicadina-infected periodical cicada populations, and the mushroom-associated tryptamine, psilocybin, in annual cicadas infected with Massospora platypediae or Massospora levispora, which appear to represent a single fungal species. The absence of some fungal enzymes necessary for cathinone and psilocybin biosynthesis along with the inability to detect intermediate metabolites or gene orthologs are consistent with possibly novel biosynthesis pathways in Massospora. The neurogenic activities of these compounds suggest the extended phenotype of Massospora that modifies cicada behavior to maximize dissemination is chemically-induced.

633: von Willebrand Factor D and EGF Domains is an evolutionarily conserved and required feature of blastemas capable of multi-tissue appendage regeneration
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Posted to bioRxiv 14 Nov 2019

von Willebrand Factor D and EGF Domains is an evolutionarily conserved and required feature of blastemas capable of multi-tissue appendage regeneration
239 downloads developmental biology

Nicholas D. Leigh, S. Sessa, A.C. Dragalzew, Duygu Payzin-Dogru, J.F. Sousa, A.N. Aggouras, K. Johnson, G.S. Dunlap, B.J. Haas, M. Levin, Igor Schneider, Jessica L Whited

Regenerative ability varies tremendously across species. A common feature of regeneration of appendages such as limbs, fins, antlers, and tails is the formation of a blastema--a transient structure that houses a pool of progenitor cells that regenerate the missing tissue. We have identified the expression of von Willebrand Factor D and EGF Domains ( vwde ) as a common feature of blastemas capable of regenerating limbs and fins in a variety of highly regenerative species. Further, vwde expression is tightly linked to the ability to regenerate appendages. Functional experiments demonstrate a requirement for vwde in regeneration and indicate that Vwde is a potent mitogen in the blastema. These data identify a key role for vwde in regenerating blastemas and underscore the power of an evolutionarily-informed approach for identifying conserved genetic components of regeneration.

634: FtsW exhibits distinct processive movements driven by either septal cell wall synthesis or FtsZ treadmilling in E. coli
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Posted to bioRxiv 21 Nov 2019

FtsW exhibits distinct processive movements driven by either septal cell wall synthesis or FtsZ treadmilling in E. coli
239 downloads biophysics

Xinxing Yang, Ryan McQuillen, Zhixin Lyv, Polly Phillips-Mason, Ana De La Cruz, Joshua W McCausland, Hai Liang, Kristen E DeMeester, Catherine L Grimes, Piet de Boer, Jie Xiao

During bacterial cell division, synthesis of new septal peptidoglycan (sPG) is crucial for successful cytokinesis and cell pole morphogenesis. FtsW, a SEDS (Shape, Elongation, Division and Sporulation) family protein and an indispensable component of the cell division machinery in all walled bacterial species, was recently identified in vitro as a new monofunctional peptidoglycan glycosyltransferases (PGTase). FtsW and its cognate monofunctional transpeptidase (TPase) class b penicillin binding protein (PBP3 or FtsI in E. coli) may constitute the essential, bifunctional sPG synthase specific for new sPG synthesis. Despite its importance, the septal PGTase activity of FtsW has not been documented in vivo. How its activity is spatiotemporally regulated in vivo has also remained unknown. Here we investigated the septal PGTase activity and dynamics of FtsW in E. coli cells using a combination of single-molecule imaging and genetic manipulations. We showed that FtsW exhibited robust activity to incorporate an N-acetylmuramic acid analog at septa in the absence of other known PGTases, confirming FtsW as the essential septum-specific PGTase in vivo. Furthermore, we identified two populations of processively moving FtsW molecules at septa. A fast-moving population is driven by the treadmilling dynamics of FtsZ and independent of sPG synthesis. A slow-moving population is driven by active sPG synthesis and independent of FtsZ treadmilling dynamics. We further identified that FtsN, a potential sPG synthesis activator, plays an important role in promoting the slow-moving, sPG synthesis-dependent population. Our results support a two-track model, in which inactive sPG synthase molecules follow the fast treadmilling 'Z-track' to be distributed along the septum; FtsN promotes their release from the 'Z-track' to become active in sPG synthesis on the slow 'sPG-track'. This model integrates spatial information into the regulation of sPG synthesis activity and could serve as a mechanism for the spatiotemporal coordination of bacterial cell wall constriction.

635: Fine-tuning Polygenic Risk Scores with GWAS Summary Statistics
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Posted to bioRxiv 18 Oct 2019

Fine-tuning Polygenic Risk Scores with GWAS Summary Statistics
239 downloads genetics

Zijie Zhao, Yanyao Yi, Yuchang Wu, Xiaoyuan Zhong, Yupei Lin, Timothy J Hohman, Jason Fletcher, Qiongshi Lu

Polygenic risk scores (PRSs) have wide applications in human genetics research. Notably, most PRS models include tuning parameters which improve predictive performance when properly selected. However, existing model-tuning methods require individual-level genetic data as the training dataset or as a validation dataset independent from both training and testing samples. These data rarely exist in practice, creating a significant gap between PRS methodology and applications. Here, we introduce PUMAS (Parameter-tuning Using Marginal Association Statistics), a novel method to fine-tune PRS models using summary statistics from genome-wide association studies (GWASs). Through extensive simulations, external validations, and analysis of 65 traits, we demonstrate that PUMAS can perform a variety of model-tuning procedures (e.g. cross-validation) using GWAS summary statistics and can effectively benchmark and optimize PRS models under diverse genetic architecture. On average, PUMAS improves the predictive R2 by 205.6% and 62.5% compared to PRSs with arbitrary p-value cutoffs of 0.01 and 1, respectively. Applied to 211 neuroimaging traits and Alzheimer’s disease, we show that fine-tuned PRSs will significantly improve statistical power in downstream association analysis. We believe our method resolves a fundamental problem without a current solution and will greatly benefit genetic prediction applications.

636: Deep Learning-Based Point-Scanning Super-Resolution Imaging
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Posted to bioRxiv 21 Aug 2019

Deep Learning-Based Point-Scanning Super-Resolution Imaging
238 downloads bioinformatics

Linjing Fang, Fred Monroe, Sammy Weiser Novak, Lyndsey Kirk, Cara R. Schiavon, Seungyoon B. Yu, Tong Zhang, Melissa Wu, Kyle Kastner, Yoshiyuki Kubota, Zhao Zhang, Gulcin Pekkurnaz, John Mendenhall, Kristen Harris, Jeremy Howard, Uri Manor

Point scanning imaging systems (e.g. scanning electron or laser scanning confocal microscopes) are perhaps the most widely used tools for high resolution cellular and tissue imaging. Like all other imaging modalities, the resolution, speed, sample preservation, and signal-to-noise ratio (SNR) of point scanning systems are difficult to optimize simultaneously. In particular, point scanning systems are uniquely constrained by an inverse relationship between imaging speed and pixel resolution. Here we show these limitations can be mitigated via the use of deep learning-based super-sampling of undersampled images acquired on a point-scanning system, which we termed point-scanning super-resolution (PSSR) imaging. Oversampled, high SNR ground truth images acquired on scanning electron or Airyscan laser scanning confocal microscopes were ‘crappified’ to generate semi-synthetic training data for PSSR models that were then used to restore real-world undersampled images. Remarkably, our EM PSSR model could restore undersampled images acquired with different optics, detectors, samples, or sample preparation methods in other labs. PSSR enabled previously unattainable 2 nm resolution images with our serial block face scanning electron microscope system. For fluorescence, we show that undersampled confocal images combined with a multiframe PSSR model trained on Airyscan timelapses facilitates Airyscan-equivalent spatial resolution and SNR with ∼100x lower laser dose and 16x higher frame rates than corresponding high-resolution acquisitions. In conclusion, PSSR facilitates point-scanning image acquisition with otherwise unattainable resolution, speed, and sensitivity. ![Figure][1]</img> [1]: pending:yes

637: Decoding and encoding models reveal the role of the depth of processing in the brain representation of meaning
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Posted to bioRxiv 04 Nov 2019

Decoding and encoding models reveal the role of the depth of processing in the brain representation of meaning
238 downloads neuroscience

David Soto, Usman Ayub Sheikh, Ning Mei, Roberto Santana

How the brain representation of conceptual knowledge vary as a function of processing goals remains unclear. We hypothesized that the brain representation of semantic categories is shaped by the depth of processing. Participants were presented with visual words during functional MRI. During shallow processing, participants had to read the items. During deep processing, they had to mentally simulate the features associated with the words. Multivariate classification, informational connectivity and encoding models were used to reveal how the depth of processing determines the brain representation of word meaning. Decoding accuracy in putative substrates of the semantic network was enhanced when the depth processing was high, and the brain representations were more generalizable in semantic space relative to shallow processing contexts. This pattern was observed even in association areas in inferior frontal and parietal cortex. Deep information processing during mental simulation also increased the informational connectivity within key substrates of the semantic network. To further examine the properties of the words encoded in brain activity, we compared computer vision models - associated with the image referents of the words - and word embeddings. Computer vision models explained more variance of the brain responses across multiple areas of the semantic network. These results indicate that the brain representation of word meaning is highly malleable by the depth of processing imposed by the task, relies on access to visual representations and is highly distributed, including prefrontal areas previously implicated in semantic control.

638: Somatic Truth Data from Cell Lineage
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Posted to bioRxiv 31 Oct 2019

Somatic Truth Data from Cell Lineage
237 downloads bioinformatics

Megan Shand, Jose Soto, Lee Lichtenstein, David Benjamin, Yossi Farjoun, Yehuda Brody, Yosef E Maruvka, Paul C Blainey, Eric Banks

Existing somatic benchmark datasets for human sequencing data use germline variants, synthetic methods, or expensive validations, none of which are satisfactory for providing a large collection of true somatic variation across a whole genome. Here we propose a dataset of short somatic mutations, that are validated using a known cell lineage. The dataset contains 56,974 (2,687 unique) Single Nucleotide Variations (SNV), 6,370 (316 unique) small Insertions and Deletions (Indels), and 144 (8 unique) Copy Number Variants (CNV) across 98 in silico mixed truth sets with a high confidence region covering 2.7 gigabases per mixture. The data is publicly available for use as a benchmarking dataset for somatic short mutation discovery pipelines.

639: Modeling phylogenetic biome shifts on a planet with a past
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Posted to bioRxiv 07 Nov 2019

Modeling phylogenetic biome shifts on a planet with a past
237 downloads evolutionary biology

Michael Landis, Erika J. Edwards, Michael J. Donoghue

The spatial distribution of biomes has changed considerably over deep time, so the geographical opportunity for an evolutionary lineage to shift into a new biome depends on how the availability and connectivity of biomes has varied temporally. To better understand how lineages shift between biomes in space and time, we developed a phylogenetic biome shift model in which each lineage shifts between biomes and disperses between regions at rates that depend on the lineage's biome affinity and location relative to the spatiotemporal distribution of biomes at any given time. To study the behavior of the biome shift model in an empirical setting, we developed a literature-based representation of paleobiome structure for three mesic forest biomes, six regions, and eight time strata, ranging from the Late Cretaceous (100 Ma) through the present. We then fitted the model to a time-calibrated phylogeny of 119 Viburnum species to compare how the results responded to various realistic or unrealistic assumptions about paleobiome structure. Ancestral biome estimates that account for paleobiome dynamics reconstructed a warm temperate (or tropical) origin of Viburnum, which is consistent with previous fossil-based estimates of ancestral biomes. In Viburnum, imposing unrealistic paleobiome distributions led to ancestral biome estimates that eliminated support for tropical origins, and instead inflated support for cold temperate ancestry during the warmer Paleocene and Eocene. The biome shift model we describe is applicable to the study of evolutionary systems beyond Viburnum, and the core mechanisms of our model are extensible to the design of richer phylogenetic models of historical biogeography and/or lineage diversification. We conclude that biome shift models that account for dynamic geographical opportunities are important for inferring ancestral biomes that are compatible with our understanding of Earth history.

640: Selective K-ATP channel-dependent loss of pacemaking in vulnerable nigrostriatal dopamine neurons by α-synuclein aggregates
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Posted to bioRxiv 15 Nov 2019

Selective K-ATP channel-dependent loss of pacemaking in vulnerable nigrostriatal dopamine neurons by α-synuclein aggregates
236 downloads neuroscience

Poonam Thakur, Kelvin C Luk, Jochen Roeper

Parkinson disease (PD), one of the most common neurodegenerative disorder, is believed to be driven by toxic α-synuclein aggregates eventually resulting in selective loss of vulnerable neuron populations, prominent among them, nigrostriatal dopamine (DA) neurons in the lateral substantia nigra (l-SN). How α-synuclein aggregates initiate a pathophysiological cascade selectively in vulnerable neurons is still unclear. Here, we show that the exposure to low nanomolar concentrations of α-synuclein aggregates (i.e. fibrils) but not its monomeric forms acutely and selectively disrupted the electrical pacemaker function of the DA subpopulation most vulnerable in PD. This implies that only dorsolateral striatum projecting l-SN DA neurons were electrically silenced by α-synuclein aggregates, while the activity of neither neighboring DA neurons in medial SN projecting to dorsomedial striatum nor mesolimbic DA neurons in the ventral tegmental area (VTA) were affected. Moreover, we demonstrate functional K-ATP channels comprised of Kir6.2 subunit in DA neurons to be necessary to mediate this acute pacemaker disruption by α-synuclein aggregates. Our study thus identifies a molecularly defined target that quickly translates the presence of α-synuclein aggregates into an immediate impairment of essential neuronal function. This constitutes a novel candidate process how a protein-aggregation-driven sequence in PD is initiated that might eventually lead to selective neurodegeneration.

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