bluuebunny/crossref_metadata_2025_split huggingface dataset:
Haplotype-Based Noninvasive Prenatal Diagnosis for Duchenne Muscular Dystrophy: A pilot study in South China
Authors: Chen Min , Chen Chao , Li Yingting , Yuan Yuan , Lai Zhengfei , Guo Fengyu , Wang Yaoshen , Huang Xiaoyan , Li Shiquan , Wu Renhua , Peng Zhiyu , Sun Jun , Chen Dunjin 
Published: February 2019

AbstractObjectiveTo explore the accuracy and feasibility of noninvasive prenatal diagnosis (NIPD) for Duchenne Muscular Dystrophy (DMD) based on the haplotype approach.MethodsWe recruited singleton pregnancies at-risk of DMD at 12-25 weeks of gestation from 17 families who all had a proband children affected by DMD. We have identified the pathogenic mutations in probands and their mothers by multiplex ligation-dependent probe amplification (MLPA). To construct parental haplotypes, we performed captured sequencing on genomic DNA from parents and probands. The integration analysis of parental haplotypes and targeted sequencing results of maternal plasma DNA were used to infer the fetal haplotype and genotypes inDMDgene. FetalDMDgenotypes were further confirmed by invasive prenatal diagnosis.ResultsWe have successfully performed the haplotype-based NIPD in all recruited families. Ten fetuses were identified as normal, including four female and six male fetuses. Four female fetuses were carriers and the other three male fetuses were affected byDMDwith exons 49-52 deletion, exons 8-37 deletion and c.628G > T mutation, respectively. The results of NIPD were consistent with those of invasive diagnosis.ConclusionHaplotype-based NIPD for DMD by targeted sequencing is promising and has potential for clinical application.
Additional layer of regulation via convergent gene orientation in yeasts
Authors: Gilet Jules , Conte Romain , Torchet Claire , Benard Lionel , Lafontaine Ingrid 
Published: February 2019

AbstractConvergent gene pairs can produce transcripts with complementary sequences. We had shown that mRNA duplexes formin vivoinSaccharomyces cerevisiaevia interactions of their 3′-ends and can lead to post-transcriptional regulatory events. Here we show that mRNA duplex formation is restricted to convergent genes separated by short intergenic distance, independently of their 3′-UTR length. We disclose an enrichment in genes involved in biological processes related to stress among these convergent genes. They are markedly conserved in convergent orientation in budding yeasts, meaning that this mode of post-transcriptional regulation could be shared in these organisms, conferring an additional level for modulating stress response. We thus investigated the mechanistic advantages potentially conferred by 3′-UTR mRNA interactions. Analysis of genome-wide transcriptome data revealed that Pat1 and Lsm1 factors, having 3′-UTR binding preference and participating to the remodeling of messenger ribonucleoprotein particles, bind differently these mRNA duplexes in comparison to canonical mRNAs. Functionally, the translational repression upon stress also appears limited on mRNA duplexes. We thus propose that mRNA duplex formation modulates the regulation of mRNA expression by limiting their access to translational repressors. Our results thus show that post-transcriptional regulation is an additional factor that determine the order of coding genes.
Evolutionary dynamics determines adaptation to inactivation of an essential gene
Authors: Rodrigues João V. , Shakhnovich Eugene I. 
Published: February 2019

AbstractGenetic inactivation of essential genes creates an evolutionary scenario distinct from escape from drug inhibition, but the mechanisms of microbe adaptations in such cases remain unknown. Here we inactivateE.colidihydrofolate reductase (DHFR) by introducing D27G,N,F chromosomal mutations in a key catalytic residue with subsequent adaptation by serial dilutions. The partial reversal G27->C occurred in three evolutionary trajectories. Conversely, in one trajectory for D27G and in all trajectories for D27F,N strains adapted to grow at very low supplement folAmix concentrations but did not escape entirely from supplement auxotrophy. Major global shifts in metabolome and proteome occurred upon DHFR inactivation, which were partially reversed in adapted strains. Loss of function mutations in two genes,thyAanddeoB, ensured adaptation to low folAmix by rerouting the 2-Deoxy-D-ribose-phosphate metabolism from glycolysis towards synthesis of dTMP. Multiple evolutionary pathways of adaptation to low folAmix converge to highly accessible yet suboptimal fitness peak.
Accurate fetal variant calling in the presence of maternal cell contamination
Authors: Nabieva Elena , Sharma Satyarth Mishra , Kapushev Yermek , Garushyants Sofya K. , Fedotova Anna V. , Moskalenko Viktoria N. , Serebrenikova Tatyana , Glazyrina Eugene , Kanivets Ilya V. , Pyankov Denis V. , Neretina Tatyana V. , Logacheva Maria D. , Bazykin Georgii A. , Yarotsky Dmitry 
Published: February 2019

AbstractHigh-throughput sequencing of fetal DNA is a promising and increasingly common method for the discovery of all (or all coding) genetic variants in the fetus, either as part of prenatal screening or diagnosis, or for genetic diagnosis of spontaneous abortions. In many cases, the fetal DNA (from chorionic villi, amniotic fluid, or abortive tissue) can be contaminated with maternal cells, resulting in the mixture of fetal and maternal DNA. This maternal cell contamination (MCC) undermines the assumption, made by traditional variant callers, that each allele in a heterozygous site is covered, on average, by 50% of the reads, and therefore can lead to erroneous genotype calls. We present a panel of methods for reducing the genotyping error in the presence of MCC. All methods start with the output of GATK HaplotypeCaller on the sequencing data for the (contaminated) fetal sample and both of its parents, and additionally rely on information about the MCC fraction (which itself is readily estimated from the high-throughput sequencing data). The first of these methods uses a Bayesian probabilistic model to correct the fetal genotype calls produced by MCC-unaware HaplotypeCaller. The other two methods “learn” the genotype-correction model from examples. We use simulated contaminated fetal data to train and test the models. Using the test sets, we show that all three methods lead to substantially improved accuracy when compared with the original MCC-unaware HaplotypeCaller calls. We then apply the best-performing method to three chorionic villus samples from spontaneously terminated pregnancies.Code and training data availabilityhttps://github.com/bazykinlab/ML-maternal-cell-contamination
Cryptococcus neoformansresist to drastic conditions by switching to viable but non-culturable cell phenotype
Authors: Hommel Benjamin , Sturny-Leclère Aude , Volant Stevenn , Veluppillai Nathanael , Duchateau Magalie , Yu Chen-Hsin , Hourdel Véronique , Varet Hugo , Matondo Mariette , Perfect John R , Casadevall Arturo , Dromer Françoise , Alanio Alexandre 
Published: February 2019

AbstractMetabolically quiescent pathogens can persist in a viable non-replicating state for months or even years. For certain infectious diseases, such as tuberculosis, cryptococcosis, histoplasmosis, latent infection is a corollary of this dormant state, which has the risk for reactivation and clinical disease. During murine cryptococcosis and macrophage uptake, stress and host immunity induce C. neoformans heterogeneity with the generation of a sub-population of yeasts that manifests a phenotype compatible with dormancy (low stress response, latency of growth). In this subpopulation, mitochondrial transcriptional activity is regulated and this phenotype has been considered as a hallmark of quiescence in stem cells. Based on these findings, we worked to reproduce this phenotype in vitro and then standardize the experimental conditions to consistently generate this dormancy inCryptococcus neoformans.We found that incubation of stationary phase yeasts (STAT) in nutriment limited conditions and hypoxia for 8 days (8D-HYPOx) was able to produced cells that mimic the phenotype obtained in vivo. In these conditions, mortality and/or apoptosis occurred in less than 5% of the yeasts compared to 30-40% of apoptotic or dead yeasts upon incubation in normoxia (8D-NORMOx). Yeasts in 8D-HYPOx harbored a lower stress response, delayed growth and less that 1% of culturability on agar plates, suggesting that these yeasts are viable but non culturable cells (VBNC). These VBNC were able to reactivate in the presence of pantothenic acid, a vitamin that is known to be involved in quorum sensing and a precursor of acetyl-CoA. Global metabolism of 8D-HYPOx cells showed some specific requirements and was globally shut down compared to 8D-NORMOx and STAT conditions. Mitochondrial analyses showed that the mitochondrial masse increased with mitochondria mostly depolarized in 8D-HYPOx compared to 8D-NORMox, with increased expression of mitochondrial genes. Proteomic and transcriptomic analyses of 8D-HYPOx revealed that the number of secreted proteins and transcripts detected also decreased compared to 8D-NORMOx and STAT, and the proteome, secretome and transcriptome harbored specific profiles that are engaged as soon as four days of incubation. Importantly, acetyl-CoA and the fatty acid pathway involving mitochondria are required for the generation and viability maintenance of VBNC.All together, these data show that we were able to generate for the first time VBNC phenotype inCryptococcocus neoformans. This VBNC state is associated with a specific metabolism that should be further studied to understand dormancy/quiescence in this yeast.
De novo mutations across 1,465 diverse genomes reveal novel mutational insights and reductions in the Amish founder population
Authors: Kessler Michael D. , Loesch Douglas P. , Perry James A. , Heard-Costa Nancy L. , Cade Brian E. , Wang Heming , Daya Michelle , Ziniti John , Datta Soma , Celedón Juan C , Soto-Quiros Manuel E. , Avila Lydiana , Weiss Scott T. , Barnes Kathleen , Redline Susan S. , Vasan Ramachandran S. , Johnson Andrew D. , Mathias Rasika A. , Hernandez Ryan , Wilson James G. , Nickerson Deborah A. , Abecasis Goncalo , Browning Sharon R. , Zoellner Sebastian , O’Connell Jeffrey R. , Mitchell Braxton D. ,   Trans-Omics for Precision Medicine (TOPMed), TOPMed Population Genetics Working Group, O’Connor Timothy D. 
Published: February 2019

Abstractde novoMutations (DNMs), or mutations that appear in an individual despite not being seen in their parents, are an important source of genetic variation whose impact is relevant to studies of human evolution, genetics, and disease. Utilizing high-coverage whole genome sequencing data as part of the Trans-Omics for Precision Medicine (TOPMed) program, we directly estimate and analyze DNM counts, rates, and spectra from 1,465 trios across an array of diverse human populations. Using the resulting call set of 86,865 single nucleotide DNMs, we find a significant positive correlation between local recombination rate and local DNM rate, which together can explain up to 35.5% of the genome-wide variation in population level rare genetic variation from 41K unrelated TOPMed samples. While genome-wide heterozygosity does correlate weakly with DNM count, we do not find significant differences in DNM rate between individuals of European, African, and Latino ancestry, nor across ancestrally distinct segments within admixed individuals. However, interestingly, we do find significantly fewer DNMs in Amish individuals compared with other Europeans, even after accounting for parental age and sequencing center. Specifically, we find significant reductions in the number of T→C mutations in the Amish, which seems to underpin their overall reduction in DNMs. Finally, we calculate near-zero estimates of narrow sense heritability (h2), which suggest that variation in DNM rate is significantly shaped by non-additive genetic effects and/or the environment, and that a less mutagenic environment may be responsible for the reduced DNM rate in the Amish.SignificanceHere we provide one of the largest and most diverse humande novomutation (DNM) call sets to date, and use it to quantify the genome-wide relationship between local mutation rate and population-level rare genetic variation. While we demonstrate that the human single nucleotide mutation rate is similar across numerous human ancestries and populations, we also discover a reduced mutation rate in the Amish founder population, which shows that mutation rates can shift rapidly. Finally, we find that variation in mutation rates is not heritable, which suggests that the environment may influence mutation rates more significantly than previously realized.
Neural System Identification with Cortical Information Flow
Authors: Ambrogioni L. , Seeliger K. , Güçlü U. , van Gerven M. A. J. 
Published: February 2019

AbstractCortical information flow (CIF) is a new framework for system identification in neuroscience. CIF models represent neural systems as coupled brain regions that each embody neural computations. These brain regions are coupled to observed data specific to that region. Neural computations are estimated via stochastic gradient descent. We show using a large-scale fMRI dataset that, in this manner, we can estimate models that learn meaningful neural computations. Our framework is general in the sense that it can be used in conjunction with any (combination of) neural recording techniques. It is also scalable, providing neuroscientists with a principled approach to make sense of the high-dimensional neural datasets.
Gene pathogenicity prediction of Mendelian diseases via the Random Forest algorithm
Authors: He Sijie , Chen Weiwei , Liu Hankui , Li Shengting , Lei Dongzhu , Dang Xiao , Chen Yulan , Zhang Xiuqing , Zhang Jianguo 
Published: February 2019

AbstractThe study of Mendelian diseases and the identification of their causative genes are of great significance in the field of genetics. The evaluation of the pathogenicity of genes and the total number of Mendelian disease genes are both important questions worth studying. However, very few studies have addressed these issues to date, so we attempt to answer them in this study.We calculated gene pathogenicity prediction (GPP) score by a machine learning approach (random forest algorithm) to evaluate the pathogenicity of genes. When we applied the GPP score to the testing gene set, we obtained accuracy of 80%, recall of 93% and area under the curve (AUC) of 0.87. Our results estimated that a total of 10,399 protein-coding genes were Mendelian disease genes. Furthermore, we found the GPP score was positively correlated with the severity of disease.Our results indicate that GPP score may provide a robust and reliable guideline to predict the pathogenicity of protein-coding genes. To our knowledge, this is the first trial to estimate the total number of Mendelian disease genes.
Comparative study of GenePOC GBS LB Assay and GeneXpert GBS LB Assay for the detection of Group BStreptococcusin prenatal screening samples
Authors: Choera Tsokyi , Jung-Hynes Brittney , Chen Derrick J. 
Published: February 2019

AbstractGroup B Streptococcal (GBS) infections in the United States are a leading cause of meningitis and sepsis in newborns. The CDC, therefore recommends GBS screening for all pregnant women at 35–37 weeks of gestation and administration of intrapartum prophylaxis (in those that tested positive) as an effective means of controlling disease transmission. Several FDA approved molecular diagnostic tests are available for rapid and accurate detection of GBS in antepartum women. In this study, we report a clinical comparison of the Xpert GBS LB assay and a novel FDA-cleared test, GenePOC GBS LB assay. A total of 250 vaginal-rectal swabs from women undergoing prenatal screening were submitted to the University of Wisconsin’s clinical microbiology laboratory for GBS testing. We found 96.8% of samples were concordant between the two tests, while 3.2% were discordant with higher sensitivity observed for the GenePOC GBS LB assay, and higher specificity for the GeneXpert GBS LB assay.
KAP1 is an antiparallel dimer with a natively functional asymmetry
Authors: Fonti Giulia , Marcaida Maria J. , Bryan Louise C. , Traeger Sylvain , Kalantzi Alexandra S. , Helleboid Pierre-Yves J.L. , Demurtas Davide , Tully Mark D. , Grudinin Sergei , Trono Didier , Fierz Beat , Peraro Matteo Dal 
Published: February 2019

AbstractKAP1 (KRAB-domain associated protein 1) plays a fundamental role in regulating gene expression in mammalian cells by recruiting different transcription factors and altering the chromatin state. In doing so, KAP1 acts both as a platform for macromolecular interactions and as an E3 SUMO ligase. This work sheds light on the overall organization of the full-length protein combining solution scattering diffraction data, integrative modeling and single-molecule experiments. We show that KAP1 is an elongated antiparallel dimer with a native asymmetry at the C-terminal domain. This conformation supports our finding that the RING domain contributes to KAP1 auto-SUMOylation. Importantly, this intrinsic asymmetry has key functional implications for the KAP1 network of interactions, as the heterochromatin protein 1 (HP1) occupies only one of the two putative HP1 binding sites on the KAP1 dimer, resulting in an unexpected stoichiometry, even in the context of chromatin fibers.
Mechanics of DNA Replication and Transcription Guide the Asymmetric Distribution of RNAPol2 and Nucleosomes on Replicated Daughter Genomes
Authors: Ziane Rahima , Camasses Alain , Radman-Livaja Marta 
Published: February 2019

AbstractEukaryotic DNA replication occurs in the context of chromatin. Chromatin in its capacity as a transcription regulator, is also thought to have a role in the epigenetic transmission of transcription states from one cell generation to the next. It is still unclear how chromatin structure survives the disruptions of nucleosomal architecture during genomic replication or if chromatin features are indeed instructive of the transcription state of the underlying gene. We have therefore developed a method for measuring chromatin structure dynamics after replication – ChIP -NChAP (Chromatin Immuno-Precipitation - Nascent Chromatin Avidin Pulldown) - which we used to monitor the distribution of RNAPol2 and new and old H3 histones on newly-replicated daughter genomes in S. Cerevisiae. The strand specificity of our sequencing libraries allowed us to uncover the inherently asymmetric distribution of RNAPol2, H3K56ac (a mark of new histones), and H3K4me3 and H3K36me3 (“active transcription marks” used as proxies for old histones) on daughter chromatids. We find a difference in the timing of lagging and leading strand replication on the order of minutes at a majority of yeast genes. Nucleosomes and RNAPol2 preferentially bind to either the leading or the lagging strand gene copy depending on which one replicated first and RNAPol2 then shifts to the sister copy after its synthesis has completed. Our results suggest that active transcription states are inherited simultaneously and independently of their underlying active chromatin states through the recycling of the transcription machinery and old histones, respectively. We find that “active” histone marks do not instruct the cell to reestablish the same active transcription state at its underlying genes. We propose that rather than being a consequence of chromatin state inheritance transcription actually contributes to the reestablishment of chromatin states on both replicated gene copies. Our findings are consistent with a two-step model of chromatin assembly and RNAPol2 binding to nascent DNA that is based on local differences in replication timing between the lagging and leading strand. The model describes how chromatin and transcription states are first restored on one and then the other replicated gene copy, thus ensuring that after division each cell will have “inherited” a gene copy with identical gene expression and chromatin states.
Calcium-dependent protein kinase 5 links calcium-signaling withSARD1-dependent immune memory in systemic acquired resistance
Authors: Guerra Tiziana , Schilling Silke , Sylvester Fabian-Philipp , Conrads Benjamin , Romeis Tina 
Published: February 2019

Summary- Systemic acquired resistance (SAR) prepares infected plants for faster and stronger defense activation upon subsequent attacks. SAR requires an information relay from primary infection to distal tissue and the initiation and maintenance of a self-maintaining phytohormone salicylic acid (SA)-defense loop.- In spatial and temporal resolution we show that calcium-dependent protein kinase CPK5 contributes to immunity and SAR. In local basal resistance CPK5 functions upstream of SA-synthesis, -perception, and -signaling. In systemic tissue, enhanced CPK5 signaling leads to an accumulation of SAR marker genes including transcription factorSystemic Acquired Resistance Deficient 1(SARD1).- Plants of enhanced CPK5-, but not CPK6-, signaling display a ‘super-priming’ phenotype of enhanced resistance toward a secondary bacterial infection. Insard1background, CPK5-mediated basal resistance is still mounted but systemic ‘super-priming’ is lost.- The biochemical analysis determines CPK5 half maximal kinase activity for calcium K50 [Ca2+] to ∼100 nM close to the cytoplasmic resting level. This low activation threshold uniquely qualifies CPK5 to decode subtle changes in calcium prerequisite to immune signal relay and to onset and maintenance of priming at later time points in distal tissue. Our data explain why CPK5 functions as a hub in basal and systemic plant immunity.