bluuebunny/crossref_metadata_2025_split huggingface dataset:
Binding ofLeishmania infantumLPG to the midgut is not sufficient to define vector competence inLutzomyia longipalpissand flies
Authors: Coutinho-Abreu Iliano V. , Oristian James , de Castro Waldionê , Wilson Timothy R. , Meneses Claudio , Soares Rodrigo P. , Borges Valéria M. , Descoteaux Albert , Kamhawi Shaden , Valenzuela Jesus G. 
Published: June 2020

AbstractThe major surface lipophosphoglycan (LPG) ofLeishmaniaparasites is critical to vector competence in restrictive sand fly vectors by mediatingLeishmaniaattachment to the midgut epithelium, considered essential to parasite survival and development. However, the relevance of LPG for sand flies that harbor multiple species ofLeishmaniaremains elusive. We tested binding ofLeishmania infantumwild type (WT), LPG-defective (Δlpg1mutants) and add-back lines (Δlpg1+LPG1) to sand fly midgutsin vitroand their survival inLutzomyia longipalpissand fliesin vivo. Le. infantumWT parasites attached to theLu. longipalpismidgutin vitrowith late-stage parasites binding to midguts in significantly higher numbers compared to early-stage stage promastigotes. Δlpg1mutants did not bind toLu. longipalpismidguts, and this was rescued in the Δlpg1+LPG1lines, indicating that midgut binding is mediated by LPG. WhenLu. longipalpissand flies were infected with eitherLe. infantumWT, Δlpg1, or Δlpg1+LPG1of the BH46 or BA262 strains, the BH46 Δlpg1mutant, but not the BA262 Δlpg1mutant, survived and grew to similar numbers as the WT and Δlpg1+LPG1lines. Exposure of BH46 and BA262 Δlpg1mutants to blood engorged midgut extracts led to the mortality of the BA262 Δlpg1but not the BH46 Δlpg1parasites. These findings suggest thatLe. infantumLPG protects parasites on a strain-specific basis early in infection, likely against toxic components of blood digestion, however, it is not necessary to preventLe. infantumevacuation along with the feces in the permissive vectorLu. longipalpis.IMPORTANCEIt is well established that LPG is sufficient to define the vector competence of restrictive sand fly vectors toLeishmaniaparasites. However, the permissiveness of other sand flies to multipleLeishmaniaspecies suggests that other factors might define vector competence for these vectors. In this study, we investigated the underpinnings ofLeishmania infantumsurvival and development in its natural vectorLutzomyia longipalpis. We found out that LPG-mediated midgut binding persists in late-stage parasites. This observation is paradigm-changing and suggests that only a subset of infective metacyclics lose their ability to attach to the midgut with implications for parasite transmission dynamics. However, our data also demonstrate that LPG is not a determining factor inLeishmania infantumretention in the midgut ofLutzomyia longipalpis, a permissive vector. Rather, LPG appears to be more important in protecting some parasite strains from the toxic environment generated during blood meal digestion in the insect gut. Thus, the relevance of LPG in parasite development in permissive vectors appears to be complex and should be investigated on a strain-specific basis.
Comparative metabolic profile of maize genotypes reveals the tolerance mechanism associated under combined stresses
Authors: Rafique Suphia 
Published: June 2020

AbstractDrought, heat, high temperature, waterlogging, low-N stress, and salinity are the major environmental constraints that limit plant productivity. In tropical regions maize grown during the summer rainy season, and often faces irregular rains patterns, which causes drought, and waterlogging simultaneously along with low-N stress and thus affects crop growth and development. The two maize genotypes CML49 and CML100 were subjected to combination of abiotic stresses concurrently (drought and low-N / waterlogging and low-N). Metabolic profiling of leaf and roots of two genotypes was completed using GC-MS technique. The aim of study to reveal the differential response of metabolites in two maize genotypes under combination of stresses and to understand the tolerance mechanism. The results of un-targeted metabolites analysis show, the accumulated metabolites of tolerant genotype (CML49) in response to combined abiotic stresses were related to defense, antioxidants, signaling and some metabolites indirectly involved in nitrogen restoration of the maize plant. Alternatively, some metabolites of sensitive genotype (CML100) were regulated in response to defense, while other metabolites were involved in membrane disruption and also as the signaling antagonist. Therefore, the present study provides insight into the molecular mechanisms of tolerance under various stresses of maize plants, that governed on the regulation of cell wall remodeling, maintain metabolic homeostasis, defense against the pathogen, proper signaling, and restore growth under stress conditions.
Both HIV and Tat Expression Decrease Prepulse Inhibition with Further Impairment by Methamphetamine
Authors: Walter T. Jordan , Young Jared W. , Milienne-Petiot Morgane , Deben D. S. , Heaton Robert K. , Letendre Scott , Grelotti David J. , Perry William , Grant Igor , Minassian Arpi ,   Translational Methamphetamine AIDS Research Center (TMARC)
Published: June 2020

ABSTRACTHIV infection and methamphetamine (METH) use are highly comorbid and represent a significant public health problem. Both conditions are known to negatively impact a variety of brain functions. One brain function that may be affected by HIV and METH use is sensorimotor gating, an automatic, pre-conscious filtering of sensory information that is thought to contribute to higher order cognitive processes. Sensorimotor gating is often measured using prepulse inhibition (PPI), a paradigm that can be conducted in both humans and animals, thereby enabling cross-species translational studies. While previous studies suggest HIV and METH may individually impair PPI, little research has been conducted on the effects of combined HIV and METH on PPI. The goal of this cross-species study was to determine the effects of METH on PPI in the inducible Tat (iTat) mouse model of HIV and in people with HIV. PPI was measured in the iTat mouse model before, during, and after chronic METH treatment and after Tat induction. Chronic METH treatment decreased PPI in male but not female mice. PPI normalized with cessation of METH. Inducing Tat expression decreased PPI in male but not in female mice. No interactions between chronic METH treatment and Tat expression were observed in mice. In humans, HIV was associated with decreased PPI in both men and women. Furthermore, PPI was lowest in people with HIV who also had a history of METH dependence. Overall, these results suggest HIV and METH may additively impair early information processing in humans, potentially affecting downstream cognitive function.HIGHLIGHTSHIV decreased PPI in men and womenPPI was most decreased in people with HIV and a history of METH dependenceChronic METH treatment decreased PPI in male but not female miceTat expression decreased PPI in male but not female miceChronic METH treatment and Tat expression did not interact to affect PPI in mice
Genome-Wide High Resolution Expression Map and Functions of Key Cell Fate Determinants Reveal the Dynamics of Crown Root Development in Rice
Authors: Garg Tushar , Singh Zeenu , Chennakesavulu Kunchapu , Dwivedi Anuj K. , Varapparambathu Vijina , Singh Raj Suryan , Mushahary Khrang Khrang Khunggur , Yadav Manoj , Sircar Debabrata , Chandran Divya , Prasad Kalika , Jain Mukesh , Yadav Shri Ram 
Published: June 2020

ABSTRACTShoot borne adventitious/crown roots (AR/CR) shape up the root architecture in grasses. Mechanisms underlying initiation and subsequent outgrowth of CR remain largely unknown. Here, we provide genome-wide modulation in the landscape of transcriptional signatures during distinct developmental stages of CR formation in highly derived grass species, rice. Our studies implicate the role of potential epigenetic modifiers, transcription factors and cell division regulators in priming the initiation of CR primordia followed by progressive activation of conserved transcription regulatory modules to ensure their outgrowth. In depth analysis of spatio-temporal expression patterns of key cell fate determinants and functional analyses of riceWUSCHEL RELATED HOMEOBOX10(OsWOX10) andPLETHORA(OsPLT1) genes reveal their unprecedented role in controlling root architecture. We further show thatOsPLT1activates local auxin biosynthesis and forms an integral part ofERF3-OsWOX11-OsRR2regulatory module during CR primordia development. Interestingly,OsPLTgenes, when expressed in the transcriptional domain of root-borne lateral root primordia ofArabidopsis pltmutant, rescued their outgrowth demonstrating the conserved role ofPLTgenes in root primordia outgrowth irrespective of their developmental origin. Together, these findings unveil the molecular framework of cellular reprogramming during trans-differentiation of shoot tissue to root leading to culmination of robust root architecture in grass species which got evolutionary diverged from dicots.
Parabrachial neuron types categorically encode thermoregulation variables during heat defense
Authors: Yang Wen Z. , Du Xiaosa , Zhang Wen , Gao Cuicui , Xie Hengchang , Xiao Yan , Jia Xiaoning , Liu Jiashu , Xu Jianhui , Fu Xin , Tu Hongqing , Fu Xiaoyu , Ni Xinyan , He Miao , Yang Jiajun , Wang Hong , Yang Haitao , Xu Xiao-hong , Shen Wei L. 
Published: June 2020

ABSTRACTHeat defense is crucial for survival and fitness, and its dysregulation may result in deaths due to poor management. Transmission of thermosensory signals into hypothalamic thermoregulation centers represent a key layer of regulation in heat defense. However, the mechanism by which these signals are transmitted into the hypothalamus remains poorly understood. Here, we reveal that glutamatergic prodynorphin and cholecystokinin neuron populations in the lateral parabrachial (LPB) are progressively recruited to defend elevated body temperature. These two nonoverlapping neuron types form circuitries with downstream preoptic hypothalamic neurons to inhibit BAT thermogenesis and activate tail vasodilation, respectively. Both circuitries are selectively activated by warm temperatures and are required for fever limiting. The prodynorphin circuitry is further required for regulation of energy expenditure and weight homeostasis. Thus, these findings establish that the genetic and functional specificity of heat defense neurons occurs as early as in the LPB and uncover categorical neuron types for encoding two heat defense variables, which may provide targets for treating thermoregulation disorders.
Cardiac toxicity predictions: Safety pharmacologists correlate with the CiPA model
Authors: Mistry Hitesh B. , Parikh Jaimit 
Published: June 2020

AbstractThere has been a lot of interest and publicity regarding the use of a complex biophysical model within drug development for predicting the TdeP risk of new compounds. Throughout the development of the complex model numerous groups have shown that a simple linear mechanistic model explains the predictive behaviour of complex mechanistic models. That is the input-output relationship is almost linear even when complex kinetic assays are used. We hypothesized that given this linear relationship that scientist would be able to predict the outcome of the biophysical model. The objective of this pilot study was to assess the feasibility of such an analysis but also assess the initial degree of correlation. A set of 15 compounds with diverse ion-channel blocking against 4 ion-channel currents, IKr, ICaL, INa and INaL, was generated. Safety pharmacologists across numerous companies were approached and asked to categorize the TdeP risk of these compounds using only the % block depicted via a bar chart into one of 3 categories: Risk, No-risk or Unsure. 12 scientists participated in the study, of which 11 correlated strongly with the model (11 person ROC AUC range: 0.86-1, 7 scientists had a value >0.9). The combined prediction of all scientists also correlated strongly with the model. These results highlight that the linear input-output relationship can indeed be predicted by the scientist. A future study exploring the degree of correlation with a wider group of scientists and wider set of compounds would be required to get a more precise estimate of the correlation. We hope this initial exploratory study will encourage the community to pursue this idea.
Human cerebral tissues created via active cellular reaggregation produce functionally interconnected 3D neuronal network to mimic pathological circuit disturbance
Authors: Saberi Aref , Aldenkamp Albert P. , Kurniawan Nicholas A. , Bouten Carlijn V.C. 
Published: June 2020

AbstractVarious characteristics of a developing central nervous system, including sensory input-output1,2, neuronal migration3,4, and regionalization3,5, have been recapitulated through recent advances in the culture of brain organoids. These organoids can model the fundamental processes in brain development and disease. A remaining critical challenge, however, is to achieve complex neuronal networks with functional interconnectivity as in native brain tissue. Generation of current organoid models originates from classic dissociation-reaggregation paradigms6, often relying on mechanically-enforced quick reaggregation of pluripotent stem cells7. Here we describe an alternative method that promotes matrix-supported active (migrative) reaggregation of cells (MARC), reminiscent of in vivo developmental morphing processes, to engineer multi-regional brain tissues in vitro. Measurements of neuronal activity in intact 3D tissues revealed functional interconnectivity, characteristic of cerebral neuronal networks. As a proof of concept, we show that interconnected cerebral tissues produced using this approach can mimic propagation of epileptiform discharges in a custom-built in-vitro platform.
Structural correlates of human muscle nicotinic acetylcholine receptor subunit assembly mediated by δ(+) interface residues
Authors: Epstein Max , Maxwell Susan , Piggot Thomas J. , Beeson David , Bermudez Isabel , Biggin Philip C. 
Published: June 2020

AbstractMuscle nicotinic acetylcholine receptors are a class of heteropentameric ligand-gated cation channels with constituent subunits adopting a fixed stoichiometric arrangement. The specific amino acid residues that govern subunit ordering are however, only partially understood. By integrating all-atom molecular dynamics simulations, bioinformatics, two-electrode voltage clamp electrophysiology and125I-α-bungarotoxin assays of chimeric nAChR subunits, we identify residues across the extracellular, transmembrane and extended M4 helix of the δ subunit that make structural signatures that contribute to intransigent assembly rules. Furthermore, functional differences observed in α2δ2β receptors can be rationalized by changes in dynamical behavior that manifest themselves at the agonist binding site.
UTMOST, A Novel Single And Cross-Tissue TWAS (Transcriptome Wide Association Study), Reveals New ASD (Autism Spectrum Disorder) Associated Genes
Authors: Rodriguez-Fontenla Cristina , Carracedo Angel 
Published: June 2020

ABSTRACTBackgroundASD is a complex neurodevelopmental disorder which may significantly impact on the affected individual’s life. Common variation (SNPs) could explain about 50% of ASD heritability. Despite this fact and the large size of the last GWAS meta-analysis, it is believed that hundreds of risk genes in ASD have yet to be discovered. New tools such as TWAS which integrate tissue-expression and genetic data, are a great approach to identify new ASD susceptibility genes.MethodsThe main goal of this study is to use UTMOST with the public available summary statistics from the largest ASD GWAS meta-analysis as genetic input. In addition, anin silicobiological characterization for the novel associated loci was performed.ResultsOur results have demonstrated the association of 4 genes at the brain level (CIPC, PINX1, NKX2-2andPTPRE) and highlight the association ofNKX2-2, MANBA, ERI1andMITFat the gastrointestinal level. This last finding is quite relevant given the well-established but unexplored relationship between ASD and gastrointestinal symptoms. Cross-tissue analysis has shown the association ofNKX2-2andBLK.ConclusionsUTMOST associated genes together with theirin silicobiological characterization seems to point to different biological mechanisms underlying ASD etiology not only restricted to brain tissue and involving other body tissues such as the gastrointestinal tissue.
Reproducible, portable, and efficient ancient genome reconstruction with nf-core/eager
Authors: Yates James A. Fellows , Lamnidis Thiseas C. , Borry Maxime , Valtueña Aida Andrades , Fagernäs Zandra , Clayton Stephen , Garcia Maxime U. , Neukamm Judith , Peltzer Alexander 
Published: June 2020

AbstractThe broadening utilisation of ancient DNA to address archaeological, palaeontological, and biological questions is resulting in a rising diversity in the size of laboratories and scale of analyses being performed. In the context of this heterogeneous landscape, we present nf-core/eager, an advanced and entirely redesigned and extended version of the EAGER pipeline for the analysis of ancient genomic data. This Nextflow pipeline aims to address three main themes: accessibility and adaptability to different computing configurations, reproducibility to ensure robust analytical standards, and updating the pipeline to the latest routine ancient genomic practises. This new version of EAGER has been developed within the nf-core initiative to ensure high-quality software development and maintenance support; contributing to a long-term lifecycle for the pipeline. nf-core/eager will assist in ensuring that ancient DNA sequencing data can be used by a diverse range of research groups and fields.
Dentate gyrus development requires a cortical hem-derived astrocytic scaffold
Authors: Caramello Alessia , Galichet Christophe , Rizzoti Karine , Lovell-Badge Robin 
Published: June 2020

ABSTRACTDuring embryonic development, radial glial cells give rise to neurons, then to astrocytes following the gliogenic switch. Timely regulation of the switch, operated by several transcription factors, is fundamental for allowing coordinated interactions between neurons and glia. We deleted the gene for one such factor, SOX9, early during mouse brain development and observed a significantly compromised dentate gyrus (DG). We dissected the origin of the defect, targeting embryonicSox9deletion to either the DG neuronal progenitor domain or the adjacent cortical hem (CH). We identified in the latter previously uncharacterized ALDH1L1+ astrocytic progenitors, which form a fimbrial-specific glial scaffold necessary for neuronal progenitor migration towards the developing DG. Our results highlight an early crucial role of SOX9 for DG development through regulation of astroglial potential acquisition in the CH. Moreover, we illustrate how formation of a local network, amidst astrocytic and neuronal progenitors originating from adjacent domains, underlays brain morphogenesis.
Light-dependent translation change of Arabidopsis psbA correlates with RNA structure alterations at the translation initiation region
Authors: Gawroński Piotr , Enroth Christel , Kindgren Peter , Marquardt Sebastian , Karpiński Stanisław , Leister Dario , Jensen Poul Erik , Vinther Jeppe , Scharff Lars B. 
Published: June 2020

SUMMARYmRNA secondary structure influences translation. Proteins that modulate the mRNA secondary structure around the translation initiation region may regulate translation in plastids. To test this hypothesis, we exposed Arabidopsis thaliana to high light, which induces translation of psbA mRNA encoding the D1 subunit of photosystem II. We assayed translation by ribosome profiling and applied two complementary methods to analyze in vivo RNA secondary structure: DMS-MaPseq and SHAPE-seq. We detected increased accessibility of the translation initiation region of psbA after high light treatment, likely contributing to the observed increase in translation by facilitating translation initiation. Furthermore, we identified the footprint of a putative regulatory protein in the 5’ UTR of psbA at a position where occlusion of the nucleotide sequence would cause the structure of the translation initiation region to open up, thereby facilitating ribosome access. Moreover, we show that other plastid genes with weak Shine-Dalgarno sequences (SD) are likely to exhibit psbA-like regulation, while those with strong SDs do not. This supports the idea that changes in mRNA secondary structure might represent a general mechanism for translational regulation of psbA and other plastid genes.SIGNIFICANCERNA structure changes in the translation initiation region, most likely as a result of protein binding, affect the translation of psbA and possibly other plastid genes with weak Shine-Dalgarno sequences.
Multiple linear regression allows weighted burden analysis of rare coding variants in an ethnically heterogeneous population
Authors: Curtis David 
Published: June 2020

AbstractWeighted burden analysis has been used in exome-sequenced case-control studies to identify genes in which there is an excess of rare and/or functional variants associated with phenotype. Implementation in a ridge regression framework allows simultaneous analysis of all variants along with relevant covariates such as population principal components. In order to apply the approach to a quantitative phenotype, a weighted burden score is derived for each subject and included in a linear regression analysis. The weighting scheme is adjusted in order to apply differential weights to rare and very rare variants and a score is derived based on both the frequency and predicted effect of each variant. When applied to an ethnically heterogeneous dataset consisting of 49,790 exome-sequenced UK Biobank subjects and using BMI as the phenotype the method produces a very inflated test statistic. However this is almost completely corrected by including 20 population principal components as covariates. When this is done the top 30 genes include a few which are quite plausibly associated with the phenotype, includingLYPLAL1andNSDHL. This approach offers a way to carry out gene-based analyses of rare variants identified by exome sequencing in heterogeneous datasets without requiring that data from ethnic minority subjects be discarded. This research has been conducted using the UK Biobank Resource.
Bio-informed Protein Sequence Generation for Multi-class Virus Mutation Prediction
Authors: Wang Yuyang , Yadav Prakarsh , Magar Rishikesh , Farimani Amir Barati 
Published: June 2020

AbstractViral pandemics are emerging as a serious global threat to public health, like the recent outbreak of COVID-19. Viruses, especially those belonging to a large family of +ssRNA viruses, have a high possibility of mutating by inserting, deleting, or substituting one or multiple genome segments. It is of great importance for human health worldwide to predict the possible virus mutations, which can effectively avoid the potential second outbreak. In this work, we develop a GAN-based multi-class protein sequence generative model, named ProteinSeqGAN. Given the viral species, the generator is modeled on RNNs to predict the corresponding antigen epitope sequences synthesized by viral genomes. Additionally, a Graphical Protein Autoencoder (GProAE) built upon VAE is proposed to featurize proteins bioinformatically. GProAE, as a multi-class discriminator, also learns to evaluate the goodness of protein sequences and predict the corresponding viral species. Further experiments show that our ProteinSeqGAN model can generate valid antigen protein sequences from both bioinformatics and statistics perspectives, which can be promising predictions of virus mutations.