bluuebunny/crossref_metadata_2025_split huggingface dataset:
Life history effects on neutral diversity levels of autosomes and sex chromosomes
Authors: Amster Guy , Sella Guy 
Published: October 2017

AbstractAll else being equal, the ratio of genetic diversity levels on X and autosomes at selectively neutral sites should mirror the ratio of their numbers in the population and thus equal ¾. Because X chromosomes spend twice as many generations in females as in males, however, the ratio of diversity levels is also affected by sex differences in life history. The effects of life history on diversity levels, notably those of sex-specific age structures and reproductive variances, have been studied for decades, yet existing theory relies on many parameters that are difficult to measure and lacks generality in ways that limit their applicability. We derive general yet simple expressions for these effects and show that life history effects on X-to-autosome (X:A) ratios of diversity levels depend only on sex-ratios of mutation rates, generation times, and reproductive variances. These results reveal that changing the sex-ratio of generation times has opposite effects on X:A ratios of polymorphism and divergence. They also explain how sex-specific life histories modulate the response of X:A polymorphism ratios to changes in population size. More generally, they clarify that sex-specific life history—generation times in particular—should have a marked effect on X:A polymorphism ratios in many taxa and enable the investigation of these effects.Significance StatementUnderstanding the determinants of neutral diversity patterns on autosomes and sex chromosomes provides a bedrock for our interpretation of population genetic data. Sex-specific age-structure and variation in reproductive success have long been thought to affect neutral diversity, but theoretical descriptions of these effects were complicated and/or lacked in generality, stymying attempts to relate diversity patterns of species with their life history. We derive general yet simple expressions for these effects, which clarify how they impact neutral diversity and should enable studies of relative diversity levels on the autosomes and sex chromosomes in many taxa.
In vivocross-linking and transmembrane helix dynamics support a bidirectional non-piston model of signaling withinE. coliEnvZ
Authors: Yusuf Rahmi , Nguyễn Tuyết Linh , Heininger Annika , Lawrence Robert J. , Hall Benjamin A. , Draheim Roger R. 
Published: October 2017

AbstractIn Gram-negative bacteria, porins span the outer membrane and control the influx of several prominent groups of antibiotics. Thus, it should not be surprising that expression of these porins is often altered in clinical isolates exhibiting multidrug resistance (MDR). The major regulator of porin expression inEscherichia coliis EnvZ, a canonical sensor histidine kinase (SHK). It allosterically processes periplasmic interactions with MzrA and cytoplasmic osmosensing into a single unified change in the ratio of its kinase and phosphatase activities. Unfortunately, the role of the EnvZ transmembrane domain (TMD) in bidirectional communication of these signals remains not well understood. Here, we employedin vivosulfhydryl-reactivity to probe the dynamics of the TM2 helices and demonstrate that upon stimulus perception, only the region proximal to the periplasm undergoes conformational rearrangement. Furthermore,in silicocoarse-grained molecular dynamics (CG-MD) simulations with aromatically tuned variants of EnvZ TM2 demonstrate the existence of both tilting and azimuthal rotational components to transmembrane communication while ruling out piston-type repositioning of TM2. Finally, in contrast to a similar analysis of TM1, we identified position-specific mutants possessing a “flipped” phenotype by dual-color fluorescent reporter analysis suggesting that both the periplasmic and cytoplasmic ends of TM2 are critical for maintenance of EnvZ signal output. Taken together, these data strongly support that EnvZ employs a non-piston-type mechanism during transmembrane communication. We conclude by discussing these results within the context of allosteric processing by EnvZ and propose that these results can be used to predict and classify transmembrane communication by various SHKs.ImportanceThe EnvZ sensor histidine kinase serves as the major regulator of porin expression withinEscherichia coli. A long-standing question is how stimulus perception by a bacterial receptor on one side of a biological membrane is transmitted to the opposite side of the membrane. To address this question, we monitored the dynamics of the transmembrane domain of EnvZin vivoand coupled these results within silicosimulations of membrane-embedded EnvZ transmembrane domains. Taken together, these results demonstrate that detection of osmotic stress by the cytoplasmic domain of EnvZ results in non-piston communication across the inner membrane ofE. coli.Thus, in addition to understanding how EnvZ regulates porin balance and antibiotic influx, these results contribute to answering the long-standing question of how transmembrane communication is performed by bacterial receptors. Our work concludes with a framework that correlates receptor domain composition and signal transduction mechanisms that could be employed by other research groups on their particular receptors of interest.
Free energy landscape for the entire transport cycle of triose-phosphate/phosphate translocator
Authors: Takemoto Mizuki , Lee Yongchan , Ishitani Ryuichiro , Nureki Osamu 
Published: October 2017

AbstractSecondary active transporters translocate their substrates using the electrochemical potentials of other chemicals, undergoing large-scale conformational changes. Despite extensive structural studies, the atomic details of the transport mechanism still remain elusive. Here we performed a series of all-atom molecular dynamics simulations of the triose-phosphate/phosphate translocator (TPT), which exports organic phosphates in the chloroplast stroma in strict counter exchange with inorganic phosphate (Pi). Biased sampling methods, including string method and umbrella sampling, successfully reproduced the conformational changes between the inward– and outward-facing states, along with the substrate binding. The free energy landscape of this entire TPT transition pathway demonstrated the alternating access and substrate translocation mechanisms, which revealed Piis relayed by positively charged residues along the transition pathway. Furthermore, the conserved Glu207 functions as a “molecular switch”, linking the local substrate binding and the global conformational transition. Our results provide atomic-detailed insights into the energy coupling mechanism of antiporter.
Complex versus simple models: ion-channel cardiac toxicity prediction
Authors: Mistry Hitesh. B. 
Published: October 2017

AbstractThere is growing interest in applying detailed mathematical models of the heart for ion-channel related cardiac toxicity prediction. However, a debate as to whether such complex models are required exists. Here an assessment in the predictive performance between two established cardiac models, gold-standard and cardiac safety simulator, and a simple linear model Bnet was conducted. Three ion-channel data-sets were extracted from literature. Each compound was designated a cardiac risk category based on information within CredibleMeds. The predictive performance of each model within each data-set was assessed via a leave-one-out cross validation. In two of the data-sets Bnet performed equally as well as the leading cardiac model, cardiac safety simulator, both of these outperformed the gold-standard model. In the 3rd data-set, which contained the most detailed ion-channel pharmacology, Bnet outperformed both cardiac models. These results highlight the importance of benchmarking models but also encourage the development of simple models.
Dynamic Architecture of DNA Repair Complexes and the Synaptonemal Complex at Sites of Meiotic Recombination
Authors: Woglar Alexander , Villeneuve Anne M. 
Published: October 2017

SummaryMeiotic double-strand breaks (DSBs) are generated and repaired in a highly regulated manner to ensure formation of crossovers (COs) while also enabling efficient non-CO repair to restore genome integrity. Here we use Structured-Illumination Microscopy to investigate the dynamic architecture of DSB repair complexes at meiotic recombination sites in relationship to the synaptonemal complex (SC). DSBs resected at both ends are rapidly converted into inter-homolog repair intermediates harboring two populations of BLM helicase and RPA, flanking a single population of MutSγ. These intermediates accumulate until late pachytene, when repair proteins disappear from non-CO sites and CO-designated sites become enveloped by SC-central region proteins, acquire a second MutSγpopulation, and lose RPA. These and other data suggest that the SC protects CO intermediates from being dismantled inappropriately and promotes step-wise CO maturation by generating a transient CO-specific repair compartment, thereby enabling differential timing and outcome of repair at CO and non-CO sites
IMPPAT: A curated database of Indian Medicinal Plants, Phytochemistry And Therapeutics
Authors: Mohanraj Karthikeyan , Karthikeyan Bagavathy Shanmugam , Vivek-Ananth R.P. , Bharath Chand R.P. , Aparna S.R. , Mangalapandi P. , Samal Areejit 
Published: October 2017

AbstractPhytochemical constituents of medicinal plants encompass a diverse space of chemical scaffolds which can be used for rational design of novel drugs. India is rich with a flora of indigenous medicinal plants that have been used for centuries in traditional Indian medicine to treat human maladies. A comprehensive online database on the phytochemistry of Indian medicinal plants will enable the application of systems biology and cheminformatic approaches towards natural product based drug discovery. In this direction, we here present, IMPPAT, a manually curated database ofIndianMedicinalPlants,Phytochemistry,AndTherapeutics. IMPPAT contains 1742 Indian medicinal plants, 9596 phytochemicals and 1124 therapeutic uses which span across 27074 plant-phytochemical associations and 11514 plant-therapeutic associations. Notably, the curation effort led to a non-redundantin silicochemical library of 9596 phytochemicals with standard chemical identifiers and structure information. Using cheminformatic approaches, we have computed the physicochemical properties and drug-likeliness of the phytochemicals in IMPPAT which led to a filtered subset of 960 potential druggable phytochemicals. Moreover, a comparative analysis against FDA approved drugs suggests that majority of the druggable phytochemicals in IMPPAT are good candidates for novel prospective drugs as they have little or no structural similarity with existing drugs. The IMPPAT database is openly accessible at:https://www.imsc.res.in/~asamal/resources/imppat/home.
Effects of demographic stochasticity and life-history strategies on times and probabilities to fixation: an individual-based model
Authors: Abu Awad Diala , Coron Camille 
Published: October 2017

AbstractPrevious works has suggested that the harmonic mean population size can summarize the consequences of demographic fluctuations on the genetic frequencies of populations. We test this hypothesis by studying a model in which the demography and genetic composition of the population are both determined by the behavior of the individuals within the population. We propose an effective population size that allows us to compare our model with the classical Wright-Fisher diffusion both for neutral alleles and those under selection. We find that using our approximation for the effective population size, the Wright-Fisher diffusion provides good results for the times to absorption and probabilities of fixation of a given neutral allele and in cases where selection is not too strong. However, the times and laws to fixation are not always well predicted due to large fluctuations in population size caused by small growth rates or strong competition between individuals, that cannot be captured by the constant population size approximation. The discrepancy between our model and the Wright-Fisher diffusion is accentuated in the presence of demo-genetic feed-back. Our results imply that the Wright-Fisher diffusion is not appropriate when studying probabilities and times to fixation in long-lived species with low reproductive rates.
Estradiol and luteinizing hormone reverse memory loss in phencyclidine model of schizophrenia: Evidence for hippocampal GABA action
Authors: Riordan Alexander J. , Schaler Ari W. , Fried Jackson B. , Paine Tracie A. , Thornton Janice E. 
Published: October 2017

ABSTRACTThe cognitive symptoms of schizophrenia are poorly understood and difficult to treat. Estrogens may mitigate these symptoms via unknown mechanisms. To examine these mechanisms, we tested whether increasing estradiol (E) or decreasing luteinizing hormone (LH) could rescue declarative memory in a phencyclidine (PCP) model of schizophrenia. We then assessed whether changes in cortical or hippocampal GABA may underlie these effects. Female rats were ovariectomized and injected subchronically with PCP. To modulate E and LH, animals received hormone capsules or Antide injections. Short-term episodic memory was assessed using the novel object recognition task. Brain expression of GAD67 was analyzed via western blot, and parvalbumin-containing cells were counted using immunohistochemistry. Some rats received hippocampal infusions of a GABAA agonist, GABAA antagonist, or GAD inhibitor before behavioral testing. We found that PCP reduced hippocampal GAD67 and abolished object recognition. Antide restored hippocampal GAD67 and rescued recognition memory in PCP-treated animals. Estradiol reversed PCP’s amnesic effect but failed to restore hippocampal GAD67. PCP did not cause significant differences in number of parvalbumin-expressing cells or cortical expression of GAD67. Hippocampal infusions of a GABAA agonist restored memory in PCP-treated rats. Blocking hippocampal GAD or GABAA receptors in ovx animals reproduced memory loss similar to PCP and inhibited estradiol’s memory rescue in PCP-treated animals. In summary, decreasing LH or increasing E can reverse memory loss in a PCP model of schizophrenia. Alterations in hippocampal GABA may contribute to both PCP’s effects on declarative memory and the hormones’ ability to reverse them.
An unusual nucleosomal sequence pattern is enriched in mammalian genes
Authors: Wright Gregory M. , Cui Feng 
Published: October 2017

AbstractNucleosomal DNA sequences generally follow a well-known pattern with ∼10-bp periodic WW (where W is A or T) dinucleotides that oscillate in phase with each other and out of phase with SS (where S is G or C) dinucleotides. However, nucleosomes having a DNA sequence pattern inverse to the conventional one have not been systematically analyzed in eukaryotes. Here, we show that anti-WW/SS nucleosomes are widespread and exhibit a species- and context-specific distribution in the genomes. The enrichment of anti-WW/SS nucleosomes in mammalian genomes is positively correlated with RNA Pol II transcriptional levels, but negatively correlated with the presence of the periodic WW or SS sequence patterns. In addition, chromatin remodeling complexes have an impact on the abundance of anti-WW/SS nucleosomes. The data reveal distinct roles ofcis- andtrans-acting factors in the rotational positioning of nucleosomes between non-mammals and mammals. Implications of the anti-WW/SS sequence pattern for RNA Pol II transcription are discussed.
So you think you can PLS-DA?
Authors: Ruiz-Perez Daniel , Guan Haibin , Madhivanan Purnima , Mathee Kalai , Narasimhan Giri 
Published: October 2017

AbstractBackgroundPartial Least-Squares Discriminant Analysis (PLS-DA) is a popular machine learning tool that is gaining increasing attention as a useful feature selector and classifier. In an effort to understand its strengths and weaknesses, we performed a series of experiments with synthetic data and compared its performance to its close relative from which it was initially invented, namely Principal Component Analysis (PCA).ResultsWe demonstrate that even though PCA ignores the information regarding the class labels of the samples, this unsupervised tool can be remarkably effective as a feature selector. In some cases, it outperforms PLS-DA, which is made aware of the class labels in its input. Our experiments range from looking at the signal-to-noise ratio in the feature selection task, to considering many practical distributions and models encountered when analyzing bioinformatics and clinical data. Other methods were also evaluated. Finally, we analyzed an interesting data set from 396 vaginal microbiome samples where the ground truth for the feature selection was available. All the 3D figures shown in this paper as well as the supplementary ones can be viewed interactively at http://biorg.cs.fiu.edu/plsdaConclusionsOur results highlighted the strengths and weaknesses of PLS-DA in comparison with PCA for different underlying data models.
APOLIPOPROTEIN-E (APOE) ε4 AND COGNITIVE DECLINE OVER THE ADULT LIFE COURSE
Authors: Rawle Mark James , Davis Daniel , Bendayan Rebecca , Wong Andrew , Kuh Diana , Richards Marcus 
Published: October 2017

ABSTRACTWe tested the association between APOE-ε4 and processing speed and memory between ages 43 and 69 in a population-based birth cohort. Analyses of processing speed (using a timed letter search task) and episodic memory (a 15-item word learning test) were conducted at ages 43, 53, 60-64 and 69 years using linear and multivariable regression, adjusting for gender and childhood cognition. Linear mixed models, with random intercepts and slopes, were conducted to test the association between APOE and the rate of decline in these cognitive scores from age 43 to 69. Model fit was assessed with the Bayesian Information Criterion. A cross-sectional association between APOE-ε4 and memory scores was detected at age 69 for both heterozygotes and homozygotes (β=−0.68 & β=−1.38 respectively, p=.03) with stronger associations in homozygotes; no associations were observed before this age. Homozygous carriers of APOE-ε4 had a faster rate of decline in memory between ages 43 and 69, when compared to noncarriers, after adjusting for gender and childhood cognition (β=−0.05, p=.04). There were no cross-sectional or longitudinal associations between APOE-ε4 and processing speed. We conclude that APOE-ε4 is associated with a subtly faster rate of memory decline from midlife to early old age; this may be due to effects of APOE-ε4 becoming manifest around the latter stage of life. Continuing follow-up will determine what proportion of this increase will become clinically significant.
Impact of non-LTR retrotransposons in the differentiation and evolution of Anatomically Modern Humans
Authors: Guichard Etienne , Peona Valentina , Malagoli-Tagliazucchi Guidantonio , Abitante Lucia , Jagoda Evelyn , Musella Margherita , Ricci Marco , Rubio-Roldán Alejandro , Sarno Stefania , Luiselli Donata , Pettener Davide , Taccioli Cristian , Pagani Luca , Garcia-Perez Jose Luis , Boattini Alessio 
Published: October 2017

ABSTRACTTransposable Elements are biologically important components of eukaryote genomes. In particular, non-LTR retrotransposons (N-LTRrs) extensively shaped the human genome throughout evolution. In this study, we compared retrotransposon insertions differentially present in the genomes of Anatomically Modern Humans, Neanderthals, Denisovans and Chimpanzees, in order to assess the possible impact of retrotransposition in the differentiation of the human lineage. Briefly, we first identified species-specific N-LTRrs and established their distribution in present day human populations. These analyses shortlisted a group of N-LTRr insertions that were found exclusively in Anatomically Modern Humans. Notably, these insertions targeted genes more frequently than randomly expected and are associated with an increase in the number of transcriptional/splicing variants of those genes they inserted in. The analysis of the functionality of genes targeted by human-specific N-LTRr insertions seems to reflect phenotypic changes that occurred during human evolution. Furthermore, the expression of genes containing the most recent N-LTRr insertions is enriched in the brain, especially in undifferentiated neurons, and these genes associate in networks related to neuron maturation and migration. Additionally, we also identified candidate N-LTRr insertions that have likely produced new functional variants exclusive to modern humans, which show traces of positive selection and are now fixed in all present-day human populations. In sum, our results strongly suggest that N-LTRr impacted our differentiation as a species and have been a constant source of genomic variability all throughout the evolution of the human lineage.
DDK has a primary role in processing stalled replication forks to initiate downstream checkpoint signaling
Authors: Sasi Nanda Kumar , Coquel Flavie , Lin Yea-Lih , MacKeigan Jeffrey P , Pasero Philippe , Weinreich Michael 
Published: October 2017

AbstractCDC7-DBF4 kinase (DDK) is required to initiate DNA replication in eukaryotes by activating the replicative MCM helicase. DDK has also been reported to have diverse and sometimes conflicting roles in the replication checkpoint response in various organisms but the underlying mechanisms are far from settled. Here we show that human DDK promotes limited resection of newly synthesized DNA at stalled replication forks or sites of DNA damage to initiate replication checkpoint signaling. DDK is also required for efficient fork restart and G2/M cell cycle arrest. DDK exhibits genetic interactions with the ssDNA exonuclease EXO1, and we show that EXO1 is also required for nascent strand degradation following exposure to HU, raising the possibility that DDK regulates EXO1 directly. Thus, DDK has a primary and previously undescribed role in the replication checkpoint to promote ssDNA accumulation at stalled forks, which is required to initiate a robust checkpoint response and cell cycle arrest to maintain genome integrity.
Role of the pre-initiation complex in Mediator recruitment and dynamics
Authors: Knoll Elisabeth R. , Zhu Z. Iris , Landsman David , Morse Randall H. 
Published: October 2017

AbstractThe Mediator complex functions in eukaryotic transcription by stimulating the cooperative assembly of a pre-initiation complex (PIC) and recruitment of RNA Polymerase II (Pol II) for gene activation. The core Mediator complex is organized into head, middle, and tail modules, and in budding yeast (Saccharomyces cerevisiae), Mediator recruitment has generally been ascribed to sequence-specific activators engaging the tail module triad of Med2-Med3-Med15 at upstream activating sequences (UASs). We show that med2Δ med3Δ med15Δ yeast are viable and that Mediator lacking Med2-Med3-Med15 is associated with active promoters genome-wide. To test whether Mediator might alternatively be recruited via interactions with the PIC, we examined Mediator association genome-wide after depleting PIC components. We found that depletion of Taf1, Rpb3, and TBP profoundly affected Mediator association at active gene promoters, with TBP being critical for transit of Mediator from UAS to promoter, while Pol II and Taf1 stabilize Mediator association at proximal promoters.