bluuebunny/crossref_metadata_2025_split huggingface dataset:
A study of Mutation in ATP7B gene and its correlation with clinical phenotype and radiological features in Wilson Disease patients
Authors: Chaudhuri Jasodhara , Biswas Samar , Gangopadhyay Goutam , Biswas Tamoghna , Datta Jyotishka , Biswas Atanu , Datta Amlan K , Mukherjee Adreesh , Datta Atanu K , Hazra Avijit 
Published: January 2021

AbstractIntroductionWilson Disease (WD) is an autosomal recessive disease caused by mutations in the ATP7B gene. Clinical manifestations of WD are variable. Identification of prevalent mutations in a given population is necessary to provide mutation-based molecular diagnosis. Previous studies have detected common mutations in this part of the world and our study aimed to correlate genotype with clinical and radiological features.MethodsA descriptive cross-sectional observational study was conducted over a period of two years in a tertiary care hospital and neurology referral unit of Kolkata, India. All WD patients within the study period and meeting the inclusion criteria were included. Demographic data collection, clinical examination and relevant laboratory investigations were done. Magnetic resonance imaging of brain and cognitive assessment by Mini Mental Score Exam (MMSE) were also performed. Blood was collected for genetic analyses. PCR-Sanger sequencing of exons 2,4,6,8,10,14,16,18 of ATP7B gene was done based on previous reports of mutation hotspots of ATP7B gene for WD in Eastern India. Genotype phenotype correlation was attempted using two supervised machine learning methods, viz. logistic regression with an elastic-net penalty and the random forest.ResultsOf 52 WD patients were included in the study, 57.7% were males. The mean age at diagnosis was 13.96 years. Majority (61.8%) of the patients had dystonia on presentation, followed by dysarthria (41.2%), tremor (17.6%) and ataxia (11.8%). The mean MMSE and Frontal Assessment Battery score were 23.74 and 10.63 respectively and both were lower than the normal baseline values.Out of the total cohort of 52 patients,15(28.8%) harbored previously reported common mutations from this part of the country. Of the 15, 12 had the same mutation of c.813C>A(p.cys271Ter).The presence of common mutationswas associated with several distinct clinical phenotypes in the mathematical models but larger sample sizes are needed to corroborate the correlation.ConclusionsWD patients in eastern India have significant genotypic and phenotypic diversity. Further studies with larger samples and screening of remaining exons are warranted.
Quantitative Analysis of Drug Efficacy onC. elegansModels for Neuromuscular Diseases
Authors: Sofela Samuel , Sahloul Sarah , Song Yong-Ak 
Published: January 2021

AbstractCaenorhabditis eleganshas emerged as a powerful model organism for drug screening due to its cellular simplicity, genetic amenability and homology to humans combined with its small size and low cost. Currently, high-throughput drug screening assays are mostly based on image-based phenotyping not exploiting key locomotory parameters of this multicellular model with muscles such as its thrashing force, a critical parameter when screening drugs for muscle-related diseases. In this study, we demonstrated the use of a micropillar-based force assay chip in combination with an imaging assay to evaluate the efficacy of various drugs currently used in treatment of neuromuscular diseases. Using this two-dimensional approach, we showed that the force assay was generally more sensitive in measuring efficacy of drug treatment in Duchenne Muscular Dystrophy and Parkinson’s Disease mutant worms as well as partly in Amyotrophic Lateral Sclerosis model. These results underline the potential of our force assay chip in screening of potential drug candidates for the treatment of neuromuscular diseases when combined with an imaging assay in a two-dimensional analysis approach.
Laterally biased diffusion of males of the water fleaDaphnia magna
Authors: Toyota Kenji , Yasugi Masaki , Tatarazako Norihisa , Iguchi Taisen , Watanabe Eiji 
Published: January 2021

AbstractThe water fleaDaphnia magnais a representative example of zooplankton living in freshwater environments. They primarily propagate via asexual reproduction under normal and healthy environmental conditions. Environmental stimuli that signal a shift to disadvantageous conditions induceD. magnato change their mode of reproduction from asexual to sexual reproduction. During the sexual reproduction phase, they produce special tough eggs (resting eggs), which can survive severe environmental conditions. Despite our increased understanding of their mating behaviours, the sex-specific characteristics of swimming behaviours among daphnid species are poorly understood. In this study, we analysed the swimming patterns and dynamics of female and male adultD. magna. First, we found laterally biased diffusion of males in contrast to the homogeneous, nondirectional diffusion of females. Second, computer modelling analysis using a discrete-time Markov chain simulation, in which the frequencies of turning behaviour were evaluated as probability distributions, explained the greater diffusion of males in the horizontal direction. Under the presumption that high diffusion in the horizontal direction increases the probability of encountering a distant mate, these findings led us to hypothesise that maleD. magnaincrease genotype heterogeneity by effectively selecting the probability distributions of certain motion parameters.Summary statementsWe analysed the swimming behaviours of adult water fleaDaphnia magna, and found apparent sexual differences: laterally biased diffusion of males in contrast to the nondirectional diffusion of females.
MMpred: a distance-assisted multimodal conformation sampling for de novo protein structure prediction
Authors: Zhao Kai-Long , Liu Jun , Zhou Xiao-Gen , Su Jian-Zhong , Zhang Yang , Zhang Gui-Jun 
Published: January 2021

AbstractMotivationThe mathematically optimal solution in computational protein folding simulations does not always correspond to the native structure, due to the imperfection of the energy force fields. There is therefore a need to search for more diverse suboptimal solutions in order to identify the states close to the native. We propose a novel multimodal optimization protocol to improve the conformation sampling efficiency and modeling accuracy of de novo protein structure folding simulations.ResultsA distance-assisted multimodal optimization sampling algorithm, MMpred, is proposed for de novo protein structure prediction. The protocol consists of three stages: The first is a modal exploration stage, in which a structural similarity evaluation model DMscore is designed to control the diversity of conformations, generating a population of diverse structures in different low-energy basins. The second is a modal maintaining stage, where an adaptive clustering algorithm MNDcluster is proposed to divide the populations and merge the modal by adjusting the annealing temperature to locate the promising basins. In the last stage of modal exploitation, a greedy search strategy is used to accelerate the convergence of the modal. Distance constraint information is used to construct the conformation scoring model to guide sampling. MMpred is tested on a large set of 320 non-redundant proteins, where MMpred obtains models with TM-score≥0.5 on 268 cases, which is 20.3% higher than that of Rosetta guided with the same set of distance constraints. The results showed that MMpred can help significantly improve the model accuracy of protein assembly simulations through the sampling of multiple promising energy basins with enhanced structural diversity.AvailabilityThe source code and executable versions are freely available athttps://github.com/iobio-zjut/MMpred.Contactzgj@zjut.edu.cnorzhng@umich.eduorsujz@wmu.edu.cn
Indian genetic heritage in Southeast Asian populations
Authors: Changmai Piya , Jaisamut Kitipong , Kampuansai Jatupol , Kutanan Wibhu , Altınışık N. Ezgi , Flegontova Olga , Inta Angkhana , Yüncü Eren , Boonthai Worrawit , Pamjav Horolma , Reich David , Flegontov Pavel 
Published: January 2021

AbstractThe great ethnolinguistic diversity found today in mainland Southeast Asia (MSEA) reflects multiple migration waves of people in the past. Deeply divergent East Eurasian hunter-gatherers were the first anatomically modern human population known to migrate to the region. Agriculturalists from South China migrated to the region and admixed with the local hunter-gatherers during the Neolithic period. During the Bronze and Iron Ages, the genetic makeup of people in MSEA changed again, indicating an additional influx of populations from South China. Maritime trading between MSEA and India was established at the latest 300 BCE, and the formation of early states in Southeast Asia during the first millennium CE was strongly influenced by Indian culture, and this cultural influence is still prominent today. Several ancient Indian-influenced states were located in present-day Thailand, and various populations in the country are likely to be descendants of people from those states. To systematically explore Indian genetic heritage in MSEA, we generated genome-wide SNP data (the HumanOrigins array) for 119 present-day individuals belonging to 10 ethnic groups from Thailand and co-analyzed them with published data from MSEA using the PCA, ADMIXTURE,f3-statistics, qpAdm, and qpGraph methods. We found South Asian low-level admixture in various MSEA populations which are probably descendants of people from the ancient Indian-influenced states, but failed to find a South Asian genetic component in present-day hunter-gatherer groups and relatively isolated groups from highlands in Northern Thailand. Our results also support close genetic affinity between Kra-Dai-speaking (also known as Tai-Kadai) and Austronesian-speaking populations, which fits a linguistic hypothesis suggesting cladality of the two language families.Author SummaryMainland Southeast Asia is a region with great ethnolinguistic diversity and complex population history. We studied genetic population history of present-day mainland Southeast Asian populations using genome-wide SNP data (the HumanOrigins array). We generated new data for 10 present-day ethnic groups from Thailand, which we further combined with published data from mainland and island Southeast Asians and worldwide populations. We revealed South Asian genetic admixture in various mainland Southeast Asian ethnic groups which are highly influenced by Indian culture, but failed to find it in groups who remained culturally isolated until recently. Our finding suggests that a massive migration of Indian people in the past was responsible for the spread of Indian culture in mainland Southeast Asia. We also found support for a close genetic affinity between Kra-Dai- and Austronesianspeaking populations, which fits a linguistic hypothesis suggesting cladality of the two language families.
Asymmetric Binomial Statistics Explains Organelle Partitioning Variance in Cancer Cell Proliferation
Authors: Peruzzi Giovanna , Miotto Mattia , Maggio Roberta , Ruocco Giancarlo , Gosti Giorgio 
Published: January 2021

ABSTRACTAsymmetric inheritance of organelle and cellular compounds between daughter cells impacts on the phenotypic variability and was found to be a hallmark for differentiation and rejuvenation in stem-like cells as much as a mechanism for enhancing resistance in bacteria populations. Whether the same processes take place in the context of cancer cell lines is still poorly investigated. Here, we present a method that allows the measurement of asymmetric organelle partitioning, and we use it to simultaneously measure the partitioning of three kinds of cellular elements, i.e. cytoplasm, membrane, and mitochondria in a proliferating population of human Jurkat T-cells. For this porpoise, we use multiple live cell markers which permit us both to follow the partitioning process for multiple generations and to investigate the correlations between the partitioning of different cellular constituents. Assuming a minimal model of asymmetric partitioning where cell sub-components are divided according to a biased binomial statistics, we derived exact analytical relationships for the average fluorescence intensity and its fluctuations as a function of the generation, obtaining an excellent agreement with the experimental measurements.We found that although cell cytoplasm is divided symmetrically, mitochondria and membrane lipids are asymmetrically distributed between the two daughter cells and present a stable positive correlation with cytoplasm apportioning, which is incompatible with an independent division mechanism. Therefore, our findings show that asymmetric segregation mechanisms can also arise in cancer cell populations, and that, in this case, membrane lipids and mitochondria do not respectively segregate independently from the cytoplasm. This helps us understand the high phenotypic variability reported in these cancer cell lines. In perspective, this could be particularly relevant in the case of tumor micro-environment diversity, where comprehension of the non-genetic cell heterogeneity could pave the way to novel and more targeted therapies. Moreover, the developed experimental and theoretical apparatus can be easily generalized to different cell kinds and different cell sub-components providing a powerful tool for understanding partitioning-driven heterogeneity.
A zebrafish reporter line reveals immune and neuronal expression of endogenous retrovirus
Authors: Rutherford Holly A. , Clarke Amy , Chambers Emily V. , Petts Jessica J. , Carson Euan G. , Isles Hannah M. , Duque-Jaramillo Alejandra , Renshaw Stephen A , Levraud Jean-Pierre , Hamilton Noémie 
Published: January 2021

AbstractEndogenous retroviruses (ERVs) are fossils left in our genome from retrovirus infections of the past. Their sequences are part of every vertebrate genome and their random integrations are thought to have contributed to evolution. Although ERVs are mainly kept silenced by the host genome, they are found activated in multiple disease states such as auto-inflammatory disorders and neurological diseases. What makes defining their role in health and diseases challenging is the numerous copies in mammalian genomes and the lack of tools to study them. In this study, we identified 8 copies of the zebrafish endogenous retrovirus (zferv). We created and characterised the firstin vivoERV reporter line in any species. Using a combination of live imaging, flow cytometry and single cell RNA sequencing, we mappedzfervexpression to early T cells and neurons. Thus, this new tool identified tissues expressing ERV in zebrafish, highlighting a potential role of ERV during brain development and strengthening the hypothesis that ERV play a role in immunity and neurological diseases. This transgenic line is therefore a suitable tool to study the function of ERV in health and diseases.
Slow oscillation-spindle coupling strength predicts real-life gross-motor learning in adolescents and adults
Authors: Hahn Michael A. , Bothe Kathrin , Heib Dominik P. J. , Schabus Manuel , Helfrich Randolph F. , Hoedlmoser Kerstin 
Published: January 2021

ABSTRACTPreviously, we demonstrated that precise temporal coordination between slow oscillations (SO) and sleep spindles indexes declarative memory network development (Hahn et al., 2020). However, it is unclear whether these findings in the declarative memory domain also apply in the motor memory domain. Here, we compared adolescents and adults learning juggling, a real-life gross-motor task. We found that improved task proficiency after sleep lead to an attenuation of the learning curve, suggesting a dynamic juggling learning process. We employed individualized cross-frequency coupling analyses to reduce inter and intra-group variability of oscillatory features. Advancing our previous findings, we identified a more precise SO-spindle coupling in adults compared to adolescents. Importantly, coupling precision over motor areas predicted overnight changes in task proficiency and learning curve, indicating that SO-spindle coupling is sensitive to the dynamic motor learning process. Our results provide first evidence that regionally specific precisely coupled sleep oscillations support gross-motor learning.
Emergence of XDR high-riskPseudomonas aeruginosaST309 in South America: a global comparative genomic analysis
Authors: Fonseca Érica L. , Morgado Sérgio M. , Caldart Raquel V. , Freitas Fernanda , Vicente Ana Carolina P. 
Published: January 2021

ABSTRACTPseudomonas aeruginosahas been considered one of the major nosocomial pathogens associated with elevated morbidity and mortality worldwide. Outbreaks have been associated with few high-risk pandemicP. aeruginosalineages, presenting a remarkable antimicrobial resistance. However, the biological features involved with the persistence and spread of such lineages among clinical settings remain to be unravel. This study reports the emergence of the ST309P. aeruginosalineage in South America/Brazil, more precisely, in the Amazon region. Global genomic analyses were performed with the Brazilian strain (PA834) and more 41 complete and draft ST309 genomes publicly available, giving insights about ST309 epidemiology and its resistome and mobilome. Antimicrobial susceptibility tests revealed that the Brazilian PA834 strain presented the XDR phenotype, which was mainly due to intrinsic resistance mechanisms. Genomic analyses revealed a heterogeneous distribution of acquired antimicrobial resistance genes among ST309 genomes, which includedblaVIM-2,blaIMP-15andqnrVC1, all of them associated with class 1 integrons. The mobilome mining showed the presence of Integrative and Conjugative Elements, transposons and genomic islands harbouring a huge arsenal of hevy metal resistance genes. Moreover, these elements also carried genes involved with virulence and adaptive traits. Therefore, the presence of such genes in ST309 lineage possibly accounted for the global spread and persistence of this emerging clone, and for its establishment as a pandemic lineage of clinical importance.
An activating mutation inPdgfrbcauses skeletal stem cell defects with osteopenia and overgrowth in mice
Authors: Kwon Hae Ryong , Kim Jang H. , Woods John P. , Olson Lorin E. 
Published: January 2021

AbstractAutosomal dominant PDGFRβgain-of-function mutations in mice and humans cause a spectrum of wasting and overgrowth disorders afflicting the skeleton and other connective tissues, but the cellular origin of these disorders remains unknown. We demonstrate that skeletal stem cells (SSCs) isolated from mice with a gain-of-function D849V point mutation in PDGFRβexhibit SSC colony formation defects that parallel the wasting or overgrowth phenotypes of the mice. Single-cell RNA transcriptomics with the SSC colonies demonstrates alterations in osteoblast and chondrocyte precursors caused by PDGFRβD849V. Mutant SSC colonies undergo poor osteogenesisin vitroand mice with PDGFRβD849Vexhibit osteopenia. Increased expression ofSox9and other chondrogenic markers occurs in SSC colonies from mice with PDGFRβD849V. Increased STAT5 phosphorylation and overexpression ofIgf1andSocs2in PDGFRβD849VSSCs suggests that overgrowth in mice involves PDGFRβD849Vactivating the STAT5-IGF1 axis locally in the skeleton. Our study establishes that PDGFRβD849Vcauses osteopenic skeletal phenotypes that are associated with intrinsic changes in SSCs, promoting chondrogenesis over osteogenesis.
miR-1 coordinately regulates lysosomal v-ATPase and biogenesis to affect muscle contractility upon proteotoxic challenge during ageing
Authors: Schiffer Isabelle , Gerisch Birgit , Kawamura Kazuto , Laboy Raymond , Hewitt Jennifer , Denzel Martin S. , Mori Marcelo A. , Vanapalli Siva , Shen Yidong , Symmons Orsolya , Antebi Adam 
Published: January 2021

AbstractMuscle function relies on the precise architecture of dynamic contractile elements, which must be fine-tuned to maintain motility throughout life. Muscle is also highly plastic, and remodelled in response to stress, growth, neural and metabolic inputs. The evolutionarily conserved muscle-enriched microRNA, miR-1, regulates distinct aspects of muscle biology during development, but whether it plays a role during ageing is unknown. Here we investigated the role ofC. elegansmiR-1 in muscle function in response to proteostatic stress during adulthood.mir-1deletion results in improved mid-life muscle motility, pharyngeal pumping, and organismal longevity under conditions of polyglutamine repeat proteotoxic challenge. We identified multiple vacuolar ATPase subunits as subject to miR-1 control, and the regulatory subunitvha-13/ATP6VIA as a direct target downregulated via its 3’UTR to mediate miR-1 physiology. miR-1 further regulates nuclear localization of lysosomal biogenesis factor HLH-30/TFEB and lysosomal acidification. In summary, our studies reveal that miR-1 coordinately regulates lysosomal v-ATPase and biogenesis to impact muscle function and health during ageing.
Mobile Type VI secretion system loci of the gut Bacteroidales display extensive intra-ecosystem transfer, multi-species sweeps and geographical clustering
Authors: García-Bayona Leonor , Coyne Michael J. , Comstock Laurie E. 
Published: January 2021

AbstractThe human gut microbiota is a dense microbial ecosystem with extensive opportunities for bacterial contact-dependent processes such as conjugation and type VI secretion system (T6SS)-dependent antagonism. In the gut Bacteroidales, two distinct genetic architectures of T6SS loci, GA1 and GA2, are contained on integrative and conjugative elements (ICE). Despite intense interest in the T6SSs of the gut Bacteroidales, there is only a superficial understanding of their evolutionary patterns, and of their dissemination among Bacteroidales species in human gut communities. Here, we combine extensive genomic and metagenomic analyses to better understand their ecological and evolutionary dynamics. We identify new genetic subtypes, document extensive intrapersonal transfer of these ICE to Bacteroidales species within human gut microbiomes, and most importantly, reveal frequent population sweeps of these newly armed strains in multiple species within a person. We further show the distribution of each of the distinct T6SSs in human populations and show there is geographical clustering. We reveal that the GA1 T6SS ICE integrates at a minimal recombination site leading to their integration throughout genomes and their frequent interruption of genes, whereas the GA2 T6SS ICE integrate at one of three different tRNA genes. The exclusion of concurrent GA1 and GA2 T6SSs in individual strains is associated with intact T6SS loci and with an ICE-encoded gene. By performing a comprehensive analysis of mobile genetic elements (MGE) in co-resident Bacteroidales species in numerous human gut communities, we identify 177 MGE that sweep through multiple Bacteroidales species within individual gut microbiomes. We further show that only eight MGE demonstrate multi-species population sweeps in as many human gut microbiomes as the GA1 and GA2 ICE. These data underscore the ubiquity and rapid dissemination of mobile T6SS loci within Bacteroidales communities and across human populations.