bluuebunny/crossref_metadata_2025_split huggingface dataset:
Multi-hops functional connectivity improves individual prediction of fusiform face activation via a graph neural network
Authors: Wu Dongya , Li Xin , Feng Jun 
Published: September 2020

AbstractBrain connectivity plays an important role in determining the brain region’s function. Previous researchers proposed that the brain region’s function is characterized by that region’s input and output connectivity profiles. Following this proposal, numerous studies have investigated the relationship between connectivity and function. However, based on a preliminary analysis, this proposal is deficient in explaining individual differences in the brain region’s function. To overcome this problem, we proposed that a brain region’s function is characterized by that region’s multi-hops connectivity profile. To test this proposal, we used multi-hops functional connectivity to predict the individual face response of the right fusiform face area (rFFA) via a multi-layers graph neural network and showed that the prediction performance is essentially improved. Results also indicated that the 2-layers graph neural network is the best in characterizing rFFA’s face response and revealed a hierarchical network for the face processing of rFFA.
Whole Exome Sequencing identifies multiple pathogenic variants in a large south Indian family with Primary Open Angle Glaucoma
Authors: Shah Mohd Hussain , Kumaran Manojkumar , Chermakani Prakash , Kader Mohideen Abdul , Ramakrishnan R. , Krishnadas Subbiah. R. , Devarajan Bharanidharan , Sundaresan Periasamy 
Published: September 2020

AbstractPurposeTo identify the pathogenic variants associated with POAG by using Whole Exome Sequencing (WES) data of a large South Indian family.MethodsWe recruited a large five generation of South Indian family (n=84) with positive family history of POAG. All study participants had comprehensive ocular evaluation (of the 84, 19 study subjects were diagnosed as POAG). Sanger sequencing of the candidate genes associated with POAG (MYOC, OPTN and TBK1) showed no genetic variation in the POAG affected family members. Therefore, we performed whole exome sequencing (WES) for 16 samples including (9 POAG and 7 unaffected controls) and the data was analysed using an in-house pipeline for prioritizing the pathogenic variants based on its segregation among the POAG individual.ResultsWe identified one novel and five low-frequency pathogenic variants with consistent co-segregation in all affected individuals. The variant c.G3719A in RPGR-interacting domain of RPGRIP1 that segregated heterozygously with the six POAG cases is distinct from variants causing photoreceptor dystrophies, reported to affect the RPGR protein complex signaling in primary cilia. The cilia in TM cells has been reported to mediate the intraocular pressure (IOP) sensation. Furthermore, we identified a novel c.A1295G variant in Rho guanine nucleotide exchange factors Gene 40 (ARHGEF40) and likely pathogenic variant in the RPGR gene, suggesting that they may alter the RhoA activity essential for IOP regulationConclusionOur study supports that low-frequency pathogenic variants in multiple genes and pathways probably affect the pathogenesis of Primary Open Angle Glaucoma in the large South Indian family.
Deep learning of gene relationships from single cell time-course expression data
Authors: Yuan Ye , Bar-Joseph Ziv 
Published: September 2020

AbstractMotivationTime-course gene expression data has been widely used to infer regulatory and signaling relationships between genes. Most of the widely used methods for such analysis were developed for bulk expression data. Single cell RNA-Seq (scRNA-Seq) data offers several advantages including the large number of expression profiles available and the ability to focus on individual cells rather than averages. However, this data also raises new computational challenges.ResultsUsing a novel encoding for scRNA-Seq expression data we develop deep learning methods for interaction prediction from time-course data. Our methods use a supervised framework which represents the data as a 3D tensor and train convolutional and recurrent neural networks (CNN and RNN) for predicting interactions. We tested our Time-course Deep Learning (TDL) models on five different time series scRNA-Seq datasets. As we show, TDL can accurately identify causal and regulatory gene-gene interactions and can also be used to assign new function to genes. TDL improves on prior methods for the above tasks and can be generally applied to new time series scRNA-Seq data.Availability and ImplementationFreely available athttps://github.com/xiaoyeye/TDL.Contactzivbj@cs.cmu.eduSupplementary informationSupplementary data are available atXXXonline.
Probing Causality of the Brainstem-Hypothalamic Murine Models of Sleep-Wake Regulation
Authors: Bahari Fatemeh , Billard Myles W. , Kimbugwe John , Curay Carlos , Watson Glenn D.R. , Alloway Kevin D. , Gluckman Bruce J. 
Published: September 2020

AbstractSleep-wake regulation is thought to be governed by interactions among several nuclei in midbrain, pons, and hypothalamic regions. Determination of the causal role of these nuclei in state transitions requires simultaneous measurements from the nuclei with sufficient spatial and temporal resolution. We obtained long-term experimental single- and multi-unit measurements simultaneously from multiple nuclei of the putative hypothalamic and brainstem sleep-wake regulatory network in freely behaving rats. Cortical and hippocampal activity, along with head acceleration were also acquired to assess behavioral state. Here, we confirm that the general activity profile of the recorded sleep-wake regulatory nuclei is similar to the patterns presented previously in brief recordings of individual nuclei in head-fixed animals. However, we found that these activity profiles when studied with respect to cortical and behavioral signs of state transitions differ significantly from previous reports. Our findings pose fundamental questions about the neural mechanisms that maintain specific states and the neural interactions that lead to the emergence of sleep-wake states.
Towards understanding Afghanistan pea symbiotic phenotype through the molecular modeling of the interaction between LykX-Sym10 receptor heterodimer and Nod factors
Authors: Solovev Ya.V. , Igolkina A.A. , Kuliaev P.O. , Sulima A.S. , Zhukov V.A. , Porozov Yu.B. , Pidko E.A. , Andronov E.E. 
Published: September 2020

AbstractThe difference in symbiotic specificity between peas of Afghanistan and European phenotypes was interrogated using molecular modeling. Considering segregating amino acid polymorphism, we examined interactions of pea LykX-Sym10 receptor heterodimers with four forms of Nod factor (NF) that varied in natural decorations (acetylation and length of the glucosamine chain). First, we showed the stability of the LykX-Sym10 dimer during molecular dynamics (MD) in solvent and in the presence of a membrane. Then, four NFs were separately docked to one European and two Afghanistan dimers, and the results of these interactions were in line with corresponding pea symbiotic phenotypes. The European variant of the LykX-Sym10 dimer effectively interacts with both acetylated and non-acetylated forms of NF, while the Afghanistan variants successfully interact with the acetylated form only. We additionally demonstrated that the length of the NF glucosamine chain contributes to controlling the effectiveness of the symbiotic interaction. The obtained results support a recent hypothesis that the LykX gene is a suitable candidate for the unidentified Sym2 allele, the determinant of pea specificity towardsRhizobium leguminosarum bv. viciaestrains producing NFs with or without an acetylation decoration. The developed modeling methodology demonstrated its power in multiple searches for genetic determinants, when experimental detection of such determinants has proven extremely difficult.
Epigenetic clock and DNA methylation studies of roe deer in the wild
Authors: Lemaître Jean-François , Rey Benjamin , Gaillard Jean-Michel , Régis Corinne , Gilot Emmanuelle , Pellerin Maryline , Haghani Amin , Zoller Joseph A. , Li Caesar Z. , Horvath Steve 
Published: September 2020

AbstractDNA methylation-based biomarkers of aging (epigenetic clocks) promise to lead to new insights in the evolutionary biology of ageing. Relatively little is known about how the natural environment affects epigenetic aging effects in wild species. In this study, we took advantage of a unique long-term (>40 years) longitudinal monitoring of individual roe deer (Capreolus capreolus) living in two wild populations (Chizé and Trois Fontaines, France) facing different ecological contexts to investigate the relationship between chronological age and levels of DNA methylation (DNAm). We generated novel DNA methylation data from n=90 blood samples using a custom methylation array (HorvathMammalMethylChip40). We present three DNA methylation-based estimators of age (DNAm or epigenetic age), which were trained in males, females, and both sexes combined. We investigated how sex differences influenced the relationship between DNAm age and chronological age through the use of sex-specific epigenetic clocks. Our results highlight that both populations and sex influence the epigenetic age, with the bias toward a stronger male average age acceleration (i.e. differences between epigenetic age and chronological ages) particularly pronounced in the population facing harsh environmental conditions. Further, we identify the main sites of epigenetic alteration that have distinct aging patterns across the two sexes. These findings open the door to promising avenues of research at the crossroad of evolutionary biology and biogerontology.
Single-molecule FRET dynamics of molecular motors in an ABEL Trap
Authors: Dienerowitz Maria , Howard Jamieson A. L. , Quinn Steven D. , Dienerowitz Frank , Leake Mark C. 
Published: September 2020

AbstractSingle-molecule Förster resonance energy transfer (smFRET) of molecular motors provides transformative insights into their dynamics and conformational changes both at high temporal and spatial resolution simultaneously. However, a key challenge of such FRET investigations is to observe a molecule in action for long enough without restricting its natural function. The Anti-Brownian ELectrokinetic Trap (ABEL trap) sets out to combine smFRET with molecular confinement to enable observation times of up to several seconds while removing any requirement of tethered surface attachment of the molecule in question. In addition, the ABEL trap’s inherent ability to selectively capture FRET active molecules accelerates the data acquisition process. In this work we exemplify the capabilities of the ABEL trap in performing extended timescale smFRET measurements on the molecular motor Rep, which is crucial for removing protein blocks ahead of the advancing DNA replication machinery and for restarting stalled DNA replication. We are able to monitor single Rep molecules up to 6 s with sub-millisecond time resolution capturing multiple conformational switching events during the observation time. Here we provide a step-by-step guide for the rational design, construction and implementation of the ABEL trap for smFRET detection of Repin vitro. We include details of how to model the electric potential at the trap site and use Hidden Markov analysis of the smFRET trajectories.
Multiplex-inhibitor bead mass spectrometry reveals differential kinome signatures in newly diagnosed and recurrent glioblastoma
Authors: Jermakowicz Anna , Kurimchak Alison M. , Sarkaria Jann , Komotar Ricardo , Ivan Michael E. , Schürer Stephan , Duncan James S. , Ayad Nagi G. 
Published: September 2020

ABSTRACTGlioblastoma (GBM) is the most common and aggressive adult brain tumor. Despite years of research, clinical trials have not improved the outcome for GBM. Standard of care for newly diagnosed GBM includes surgical resection, followed by radiation and chemotherapy. Tumor recurrence is inevitable and since most patients are not candidates for a second surgical resection, there is an urgent need to identify resistance mechanisms that arise in recurrent GBM. We postulated that examining the differences of activated kinases between newly diagnosed and recurrent GBM may provide insight to resistance mechanisms.To map the kinome landscape of newly diagnosed (nGBM) and recurrent GBM (rGBM) patient derived xenograft tumors, we used Multiplexed Inhibitor Beads and Mass Spectrometry (MIB-MS). We performed pathway analysis of kinases that differed in MIB-binding between nGBM and rGBM to identify kinase-driven signaling pathways. We also analyzed transcriptional profiles to determine the overlap in signaling pathways seen using proteomics or transcriptomics.Using MIB-MS kinome profiling, we found key differences in kinase-driven signaling pathways that may account for the increase in aggressive behavior seen in recurrent GBM. This included a shift in pathways driving cell invasion and proliferation, as well as upregulation of signaling pathways that drive GBM stem-cell like cell differentiation. Analysis of RNA-sequencing showed no statistically significant differences between enriched gene ontologies in nGBM and rGBM, demonstrating the importance of MIB-MS kinome profiling. Collectively, these studies suggest that kinome profiling may inform future clinical trials for kinase inhibitors in GBM.
Para-cellular and transcellular diapedesis are divergent but inter-connected evolutionary events
Authors: Kubick Norwin , Klimovich Pavel , Henckel Patrick , Mickael Michel-Edwar 
Published: September 2020

AbstractInfiltration of the endothelial layer of the blood-brain barrier by leukocytes plays a critical role in health and disease. When passing through the endothelial layer during the diapedesis process lymphocytes can either follow a para-cellular route or a transcellular one. There is a debate whether these two processes constitute one mechanism, or they form two evolutionary distinct migration pathways. We used phylogenetic analysis, HH search, ancestor sequence reconstruction together with functional specificity and positive selection analysis to investigate this intriguing question further. We found that the two systems share several ancient components, such as RhoA protein that plays an important role in controlling actin movement in both mechanisms. However, some of the key components differ between these two transmigration processes. CAV1 genes emerged during Trichoplax adhaerens and it was only reported in trans-cellular process. Para-cellular process core proteins had at least two distinct starting points. First, during drosophila emergence, Tre1 which is homologous to melatonin GPCR receptor diverged. Secondly, PECAM1 emerged from FASL5/3 during elephant shark divergence. Lastly, both systems employ late divergent genes such as ICAM1 and PECAM1. Taken together our results suggest that these two systems constitute different yet interconnected mechanisms of immune cells infiltrations of the brain. Our analysis indicates that this system coevolved with immune cells, evolving to a higher level of complexity in association with the evolution of the adaptive immune system.
Epigenetic clock and methylation studies in the rhesus macaque
Authors: Horvath Steve , Zoller Joseph A. , Haghani Amin , Jasinska Anna J. , Raj Ken , Breeze Charles E. , Ernst Jason , Mattison Julie A. 
Published: September 2020

ABSTRACTMethylation levels at specific CpG positions in the genome have been used to develop accurate estimators of chronological age in humans, mice, and other species. Although epigenetic clocks are generally species-specific, the principles underpinning them appear to be conserved at least across the mammalian class. This is exemplified by the successful development of epigenetic clocks for mice and several other mammalian species. Here, we describe epigenetic clocks for the rhesus macaque (Macaca mulatta), the most widely used nonhuman primate in biological research. Using a custom methylation array (HorvathMammalMethylChip40), we profiled n=281 tissue samples (blood, skin, adipose, kidney, liver, lung, muscle, and cerebral cortex). From these data, we generated five epigenetic clocks for macaques. These clocks differ with regards to applicability to different tissue types (pan-tissue, blood, skin), species (macaque only or both humans and macaques), and measure of age (chronological age versus relative age). Additionally, the age-based human-macaque clock exhibits a high age correlation (R=0.89) with the vervet monkey (Chlorocebus sabaeus), another Old World species. Four CpGs within theKLF14promoter were consistently altered with age in four tissues (adipose, blood, cerebral cortex, skin). It is expected that the macaque clocks will reveal an epigenetic aging rate associated with a host of health conditions and thus lend themselves for identifying and validating anti-aging interventions.
Dorsal raphe nucleus to anterior cingulate cortex 5-HTergic neural circuit modulates consolation and sociability
Authors: Li Lai-Fu , Zhang Li-Zi , He Zhi-Xiong , Zhang Yu-Ting , Ma Huan , Xun Yu-Feng , Yuan Wei , Hou Wen-Juan , Li Yi-Tong , Lv Zi-Jian , Jia Rui , Tai Fa-Dao 
Published: September 2020

ABSTRACTConsolation is a common response to the distress of others in humans and some social animals, but the neural mechanisms underlying this behavior are not well characterized. By using socially monogamous mandarin voles, we found that optogenetic or chemogenetic inhibition of 5-HTergic neurons in the dorsal raphe nucleus (DR) or optogenetic inhibition of 5-HT terminals in the anterior cingulate cortex (ACC) significantly decreased allogrooming time in the consolation test and reduced sociability in the three-chamber test. The release of 5-HT within the ACC and the activity of DR neurons were significantly increased during allogrooming, sniffing and social approaching. Finally, we found that the activation of 5-HT1A receptors in the ACC was sufficient to reverse consolation and sociability deficits induced by the chemogenetic inhibition of 5-HTergic neurons in the DR. Our study provided first direct evidence that DR-ACC 5-HTergic neural circuit is implicated in consolation-like behaviors and sociability.
An in-silico study to determine whether changes to mitochondria organization through engineered mitochondrial dynamics can enhance bioenergetics in cardiomyocytes
Authors: Kumbhari Adarsh , Ghosh Shouryadipta , Kim Peter S. , Rajagopal Vijay 
Published: September 2020

SUMMARYMitochondria are the powerhouse of the cell and owing to their unique energetic demands, heart muscles contain a high density of mitochondria. In conditions such as heart failure and diabetes-induced heart disease, changes in the organization of cardiac mitochondria are common. While recent studies have also shown that cardiac mitochondria split and fuse throughout the cell, a mechanistic understanding of how mitochondrial dynamics may affect energy output is lacking. Using a mathematical model that has been fitted to experimental data, we test if briefly altering fission or fusion rates improves ATP production and supply in cardiomyocytes. Unexpectedly, we found that cardiac bioenergetics, e.g., the ADP/ATP ratio, were robust to changes in fusion and fission rates and consequently mitochondria organization. Our study highlights complex nonlinear feedback loops that are at play in the cross-talk between mitochondrial dynamics and bioenergetics. The study motivate further in-silico and experimental investigations to determine the mechanistic basis for new therapies that target mitochondrial dynamics.
Transcriptome analysis of potato leaves in response to infection with the necrotrophic pathogenAlternaria solani
Authors: Tian Mengjun , Wang Jinhui , Li Zheng , Wang Chen , Zhang Dai , Yang Yiqing , Pan Yang , Zhao Dongmei , Yang Zhihui , Zhu Jiehua 
Published: September 2020

ABSTRACTThe potato early blight was caused byAlternaria solani(Aso). At present, potato early blight resistant varieties are lacking. The experiment of Aso inoculation on a.k.a. Favorita showed that the content of chlorophyll decreased continuously within 2 days after inoculation. In addition, the contents of JA-Ile, SA, ABA and IAA were determined by LC-MS.The results of two defense-related hormones showed that jasmonic acid content decreased significantly, while jasmonic acid content did not change significantly. In order to understand the difference in gene expression of potatoes infected by Aso, the 24 hpi, 36 hpi and 48 hpi transcriptome were determined. The results showed that the gene annotation and cluster analysis of DEGs revealed a variety of defense responses to Aso infection, especially the plant hormone signal transduction pathway. The differential expression of 10 DEGs was confirmed by qPCR analysis. Finally, through weighted gene co-expression network analysis (WGCNA), “samonl” was determined as a key hormone-related network in the process of Aso infection in potatoes. This study provides an important clue for understanding the interaction between potato and Aso and for disease resistance breeding.
Rapid changes in chromatin structure during dedifferentiation of primary hepatocytes in vitro
Authors: Seirup Morten , Sengupta Srikumar , Swanson Scott , McIntosh Brian E. , Colins Mike , Chu Li-Fang , Cheng Zhang , Gorkin David U. , Duffin Bret , Bolin Jennifer M. , Argus Cara , Stewart Ron , Thomson James A. 
Published: September 2020

AbstractPrimary hepatocytes are widely used in the pharmaceutical industry to screen drug candidates for hepatotoxicity, but isolated hepatocytes quickly dedifferentiate and lose their mature metabolic function in culture. Attempts have been made to better recapitulate thein vivoliver environment in culture, but the full spectrum of signals required to maintain hepatocyte functionin vitroremains elusive. Here we studied the dedifferentiation process in detail through RNA-sequencing of hepatocytes cultured over eight days. We identified three distinct phases of dedifferentiation. An early phase, where mature hepatocyte genes are rapidly downregulated in a matter of hours. A middle phase, where fetal genes are activated, leading to hepatocytes with a fetal phenotype. A late phase, where initially rare contaminating non-parenchymal cells over-grow the culture as the hepatocytes gradually die. Using genetically tagged hepatocytes, we demonstrate that the cells reactivating fetal marker alpha-fetoprotein arise from cells previously expressing the mature hepatocyte marker albumin, and not from albumin negative precursor cells, proving that hepatocytes undergo true dedifferentiation. To better understand the signaling events that result in the rapid down-regulation of mature hepatocyte genes, we examined changes in chromatin accessibility of hepatocytes during the first 24h of culture using ATAC-seq. We find that drastic and rapid changes in chromatin accessibility occurs immediately upon start of culture. Using binding motif analysis of the areas of open chromatin sharing similar temporal profiles, we identify several candidate transcription factors potentially involved in the dedifferentiation of primary hepatocytes in culture.