bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genome-wide misexpression associated with hybrid sterility inMimulus(monkeyflower)
Authors: Kerwin Rachel E. , Sweigart Andrea L. 
Published: August 2019

ABSTRACTDivergence in gene expression regulation is common between closely related species and may give rise to incompatibilities in their hybrid progeny. In this study, we investigated the relationship between regulatory evolution within species and reproductive isolation between species. We focused on a well-studied case of hybrid sterility betweenMimulus guttatusandM. nasutus, two closely related yellow monkeyflower species, that is caused by two epistatic loci,hybrid male sterility 1(hms1) andhybrid male sterility 2(hms2). We quantified and compared global transcript abundance across male and female reproductive tissues (i.e.stamens and carpels) ofM. guttatusandM. nasutus, as well as sterile and fertile progeny from an advancedM. nasutus-M. guttatusintrogression line that carries thehms1-hms2incompatibility. We observed substantial variation in transcript abundance betweenM. guttatusandM. nasutus, including distinct but overlapping patterns of tissue-biased expression, providing evidence for regulatory divergence between these species. Furthermore, we found pervasive genome-wide misexpression exclusively associated with hybrid sterility – only observed in the affected tissues (i.e.stamens) of sterile introgression hybrids. Examining patterns of allele-specific expression in sterile and fertile hybrids, we found evidence ofcis-andtrans-regulatory divergence, as well ascis-transcompensatory evolution (likely to be driven by stabilizing selection). However, regulatory divergence does not appear to cause misexpression in sterile hybrids, which instead likely manifests as a downstream consequence of sterility itself.
TRIM21 and PHLDA3 Negatively Regulate the Cross-Talk between the PI3K/AKT Pathway and PPP Metabolism
Authors: Cheng Jie , Huang Yan , Zhang Xiaohui , Yu Yue , Zhang Wanru , Wu Shumin , Jiao Jing , Wang Mei , Tran Linh , Zhang Liuzhen , Wang Mengyao , Yan Wenyu , Wu Yilin , Chi Fangtao , Jiang Peng , Zhang Xinxiang , Wu Hong 
Published: August 2019

SUMMARYPI3K/AKT signaling is known to regulate cancer metabolism but whether metabolic pathway feedbacks and regulates the PI3K/AKT pathway is unclear. Here, we demonstrate the important reciprocal cross-talks between the PI3K/AKT signal and PPP branching metabolic pathways. PI3K/AKT activation stabilizes G6PD, the rate-limiting enzyme of PPP, by inhibiting a newly identified E3 ligase TIRM21, and promotes PPP. PPP metabolites, in turn, reinforce AKT activation and further promote cancer metabolic reprogramming by blocking the expression of an AKT inhibitor PHLDA3. Knockout TRIM21 or PHLDA3 promotes the cross-talks and cell proliferation. Importantly, PTEN null human cancer cells and in vivo murine models are sensitive to anti-PPP treatments, suggesting the importance of PPP in maintaining AKT activation even in the presence of a constitutively activated PI3K pathway. Our study suggests that blockade of these reciprocal cross-talks may have a therapeutic benefit for cancers with PTEN loss or PI3K/AKT activation.
Analysis of promoter-associated chromatin interactions reveals biologically relevant candidate target genes at endometrial cancer risk loci
Authors: O’Mara Tracy A. ,   Endometrial Cancer Association Consortium, Spurdle Amanda B. , Glubb Dylan M. 
Published: August 2019

AbstractThe identification of target genes at genome-wide association study (GWAS) loci is a major obstacle for GWAS follow-up. To identify candidate target genes at the 16 known endometrial cancer GWAS risk loci, we performed HiChIP chromatin looping analysis of endometrial cell lines. To enrich for enhancer-promoter interactions, a mechanism through which GWAS variation may target genes, we captured loops associated with H3K27Ac histone, characteristic of promoters and enhancers. Analysis of HiChIP loops contacting promoters revealed enrichment for endometrial cancer GWAS heritability and intersection with endometrial cancer risk variation identified 103 HiChIP target genes at 13 risk loci. Expression of four HiChIP target genes (SNX11,SRP14,HOXB2andBCL11A) was associated with risk variation, providing further evidence for their regulation. Network analysis functionally prioritized a set of proteins that interact with those encoded by HiChIP target genes, and this set was enriched for pan-cancer and endometrial cancer drivers. Lastly, HiChIP target genes and prioritized interacting proteins were over-represented in pathways related to endometrial cancer development. In summary, we have generated the first global chromatin looping data from endometrial cells, enabling analysis of all known endometrial cancer risk loci and identifying biologically relevant candidate target genes.
Diet-responsive Transcriptional Regulation of Insulin in a Single Neuron Controls Systemic Metabolism
Authors: Handley Ava , Wu Qiuli , Sherry Tessa , Pocock Roger 
Published: August 2019

SUMMARYTo maintain metabolic homeostasis, the nervous system must adapt and respond to an ever-changing environment. Transcription factors are key drivers of this adaptation, eliciting gene expression changes that can alter neuronal activity. Here we show inCaenorhabditis elegansthat the terminal selector transcription factor ETS-5 not only establishes the identity of the BAG sensory neurons, but is re-purposed to shape the functional output of the BAG neurons post-mitotically. We find that ETS-5 directly regulates the expression of INS-1, an insulin-like peptide, in the BAG sensory neurons. INS-1 expression in the BAG neurons, and not in other INS-1-expressing neurons, decreases intestinal lipid levels and promotes foraging behaviour. Usingin vivoanalysis, we show that elevated intestinal lipid stores, driven by a high glucose diet, downregulates ETS-5-driven expression of INS-1. Together, our data reveal an inter-tissue regulatory loop by which a single neuron can control systemic metabolism, and that the activity of this neuron is modulated by the metabolic state of the organism.
About a tetraploid ivy in Sicily: from autochthonous Hedera to horticultural-invasive-hybrid package?
Authors: Fridlender Alain , Pech N. 
Published: August 2019

AbstractIn Sicily, H. helix is the unique known native species whereas H. helix susbsp. poetarum is putatively naturalized in some forests and H. canariensis cultivated in various urban’s garden. Trichome morphology and genome size of some ivies from various west Mediterranean forests were compared to Sicilian ones. Ivies from southern Italy, continental France, Corsica and Mallorca belong to typical European diploid stellate trichomes Hedera helix. Hexaploid ivies from southern Spain have been identified as native H. iberica. Contrariwise, Sicilian ivies studied are related to western European H. hibernica (tetraploids with stellate trichomes). Is H. helix the most widespread and indigenous ivy in Sicily? Therefore, it would be the first time that tetraploid would be reported in Sicily where it could possibly correspond to an unnoticed autochthonous taxon. However, our results let us think it rather represents an invasive which impact on this island rich in endemic species could be considerable.
Priors for Genotyping Polyploids
Authors: Gerard David , Ferrão Luís Felipe Ventorim 
Published: August 2019

AbstractMotivationEmpirical Bayes techniques to genotype polyploid organisms usually either (i) assume technical artifacts are knowna priorior (ii) estimate technical artifacts simultaneously with the prior genotype distribution. Case (i) is unappealing as it places the onus on the researcher to estimate these artifacts, or to ensure that there are no systematic biases in the data. However, as we demonstrate with a few empirical examples, case (ii) makes choosing the class of prior genotype distributions extremely important. Choosing a class that is either too flexible or too restrictive results in poor genotyping performance.ResultsWe propose two classes of prior genotype distributions that are of intermediate levels of flexibility: the class of proportional normal distributions and the class of unimodal distributions. We provide a complete characterization of and optimization details for the class of unimodal distributions. We demonstrate, using both simulated and real data, that using these classes results in superior genotyping performance.Availability and ImplementationGenotyping methods that use these priors are implemented in the updog R package available on the Comprehensive R Archive Network:https://cran.r-project.org/package=updog. All code needed to reproduce the results of this paper is available on GitHub:https://github.com/dcgerard/reproduce_prior_sims.Contactdgerard@american.edu
Analysis of Independent Differences (AID) detects complex thermal proteome profiles independent of shape and identifies candidate panobinostat targets
Authors: Panov Alexandra , Gygi Steven P. 
Published: August 2019

AbstractIdentifying global cellular targets of small molecules is a challenge for drug discovery. Thermal proteome profiling (TPP) is a recent technique that uses quantitative proteomics to identify all small molecule protein targets in a single experiment. One current TPP analysis method relies on two major assumptions: sigmoidal melting curve behavior and that intra-condition dependencies preclude an independent and identically distributed model. Herein, we use a previously published panobinostat TPP dataset to show that these assumptions do not hold true and present a novel, shape-independent method, named Analysis of Independent Differences (AID). For each temperature, AID models the differences between conditions of fractions of non-denatured protein as an independent Normal distribution, resulting in a Multivariate Normal observation for each protein. The log of a Multivariate Normal p-value ranks the proteins from most to least likely shifted, and individual Normal p-values within each protein allow for qualitative inspection. Applying AID to the panobinostat dataset revealed known targets in the top 3% of most shifted proteins, as well as candidate targets involved in myeloid leukocyte activation. AID detects complex melting profiles and can be extended to any number of temperature channels, ligand-protein or protein-protein interactions, or general curve data for deeper biological insight.
Intra-genus metabolic diversity facilitates co-occurrence of multiple Ferrovum species at an acid mine drainage site
Authors: Grettenberger Christen L. , Havig Jeff R. , Hamilton Trinity L. 
Published: August 2019

ABSTRACTBackgroundFerrovum spp. are abundant in acid mine drainage sites globally where they play an important role in biogeochemical cycling. All known taxa in this genus are Fe(II) oxidizers. Thus, co-occurring members of the genus could be competitors within the same environment. However, we found multiple, co-occurring Ferrovum spp. in Cabin Branch, an acid mine drainage site in the Daniel Boone National Forest, KY.ResultsHere we describe the distribution of Ferrovum spp. within the Cabin Branch communities and metagenome assembled genomes (MAGs) of two new Ferrovum spp.. In contrast to previous studies, we recovered multiple 16S rRNA gene sequence variants suggesting the commonly used 97% cutoff may not be appropriate to differentiate Ferrovum spp. We also retrieved two nearly-complete Ferrovum spp. genomes from metagenomic data. The genomes of these taxa differ in several key ways relating to nutrient cycling, motility, and chemotaxis.ConclusionsPreviously reported Ferrovum genomes are also diverse with respect to these categories suggesting that the genus Ferrovum contains substantial metabolic diversity. This diversity likely explains how the members of this genus successfully co-occur in Cabin Branch and why Ferrovum spp. are abundant across geochemical gradients.
Pumilio Proteins Exert Distinct Biological Functions and Multiple Modes of Post-Transcriptional Regulation in Embryonic Stem Cell Pluripotency and Early Embryogenesis
Authors: Uyhazi Katherine E. , Yang Yiying , Liu Na , Qi Hongying , Huang Xiao A. , Mak Winifred , Weatherbee Scott D. , Song Xiaoling , Lin Haifan 
Published: August 2019

ABSTRACTGene regulation in embryonic stem cells (ESCs) has been extensively studied at the epigenetic-transcriptional levels, but not at the post-transcriptional levels. Pumilio (Pum) proteins are among the few known translational regulators required for stem cell maintenance in invertebrates and plants. Here we report the essential function of two murine Pum proteins, Pum1 and Pum2, in ESCs and early embryogenesis. Pum1/2 double mutants are developmentally delayed at the morula stage and lethal by embryonic day 8.5 (e8.5). Correspondingly, Pum1/2 double mutant ESCs display severely reduced self-renewal and differentiation, revealing the combined function of Pum1 and Pum2 in ESC pluripotency. Remarkably, Pum1-deficient ESCs show increased expression of pluripotency genes but not differentiation genes, indicating that Pum1 mainly promote differentiation; whereas Pum2-deficient ESCs show decreased expression of pluripotency genes and accelerated differentiation, indicating that Pum2 promotes self-renewal. Thus, Pum1 and Pum2 each uniquely contributes to one of the two complementary aspects of pluripotency. Furthermore, we show that Pum1 and Pum2 achieve ESC functions by forming a negative auto- and inter-regulatory feedback loop that directly regulates at least 1,486 mRNAs. Pum1 and Pum2 regulate target mRNAs not only by repressing translation as expected but also by promoting translation and enhancing or reducing mRNA stability of different target mRNAs. Together, these findings reveal the distinct roles of individual mammalian Pum proteins in ESCs and their collectively essential functions in ESC pluripotency and embryogenesis. Moreover, they demonstrate three novel modes of regulation of Pum proteins towards target mRNAs.SIGNIFICANCE STATEMENTThis report demonstrates the essential functions of mammalian Pumilio (Pum) proteins for embryonic stem cells (ESCs) pluripotency and embryogenesis. Moreover, it reveals the contrasting but complementary function of individual Pum proteins in regulating distinct aspects of ESC pluripotency, despite their largely overlapping expression and extremely high homology. Furthermore, it unravels a complex regulatory network in which Pum1 and Pum2 form a negative auto- and inter-regulatory feedback loop that regulates 1,486 mRNAs not only by translational repression as expected but also by promoting translation and enhancing or reducing stability of different target mRNAs, which reveals novel modes of post-transcriptional regulation mediated by Pum.
Why MontaneAnolisLizards are Moving Downhill While Puerto Rico Warms
Authors: Battey C. J. , Otero Luisa M. , Gorman George C. , Hertz Paul E. , Lister Bradford C. , García Andrés , Burrowes Patricia A. , Huey Raymond B. 
Published: August 2019

1AbstractBecause Puerto Rico has warmed in recent decades, ectotherms there should have shifted their elevational ranges uphill. However, by comparing historical versus recent distributional records ofAnolislizards, we found that three “montane-forest” species have instead moved downhill in recent decades, almost to sea level. This downward shift appears related to the massive regeneration of Puerto Rican forests – especially in lowland areas – which started in the mid-20th century when the island’s economy began shifting from agriculture to manufacturing. The magnitude of local cooling caused by regenerated forests swamps recent climate warming, seemingly enabling cool-adapted “montane” lizards to track forests as they spread downhill from mountain refugia into abandoned plantations. Thus, contemporary distributional patterns are likely converging to those prior to the arrival of European settlers, who cleared most lowland forests for agriculture, thereby restricting forests and associated fauna to high-elevation remnants. In contrast with the montane species, three lowland species expanded their ranges to higher elevations in recent decades; but whether this movement reflects warming, land-use shifts, or hurricane-induced destruction of upland forests is unclear.
LIS1 determines cleavage plane positioning by regulating actomyosin-mediated cell membrane contractility
Authors: Moon Hyang Mi , Hippenmeyer Simon , Luo Liqun , Wynshaw-Boris Anthony 
Published: August 2019

ABSTRACTHeterozygous loss of human PAFAH1B1 (coding for LIS1) results in the disruption of neurogenesis and neuronal migration via dysregulation of microtubule (MT) stability and dynein motor function/localization that alters mitotic spindle orientation, chromosomal segregation, and nuclear migration. Recently, human induced pluripotent stem cell (iPSC) models revealed an important role for LIS1 in controlling the length of terminal cell divisions of outer radial glial (oRG) progenitors, suggesting cellular functions of LIS1 in regulating neural progenitor cell (NPC) daughter cell separation. Here we examined the late mitotic stages NPCs in vivo and mouse embryonic fibroblasts (MEFs) in vitro from Lis1-deficient mutants. Lis1-deficient neocortical NPCs and MEFs similarly exhibited cleavage plane displacement with mislocalization of furrow-associated markers, associated with actomyosin dysfunction and cell membrane hyper-contractility. Thus, it suggests LIS1 acts as a key molecular link connecting MTs/dynein and actomyosin, ensuring that cell membrane contractility is tightly controlled to execute proper daughter cell separation.
Speed and diffusion of kinesin-2 are competing limiting factors in flagellar length control model
Authors: M R , H NL , M WF , Q H 
Published: August 2019

AbstractFlagellar length control in Chlamydomonas is a tractable model system for studying the general question of organelle size regulation. We have previously proposed that diffusive return of the kinesin motor that powers intraflagellar transport can play a key role in length regulation. Here we explore how the motor speed and diffusion coefficient for the return of kinesin-2 affect flagellar growth kinetics. We find that the system can exist in two distinct regimes, one dominated by motor speed and one by diffusion coefficient. Depending on length, a flagellum can switch between these regimes. Our results indicate that mutations can affect length in distinct ways. We discuss our theory’s implication for flagellar growth influenced by beating and provide possible explanations for the experimental observation that a beating flagellum is usually longer than its immotile mutant. These results demonstrate how our simple model can suggest explanations for mutant phenotypes.Statement of SignificanceThe eukaryotic flagellum is an ideal case study in organelle size control because of its simple linear shape and well-understood building mechanism. In our previous work, we proved that flagellar length in the green algae Chlamydomonas can be controlled by the diffusive gradient of the kinesin-2 motors that deliver building blocks to the tip. In this study, we expand on the analytical formulation of the diffusion model to show how physical parameters affect final length and regeneration time, enhancing the model’s potential to explain length mutants and motivate future research with precise predictions.
Lipopolysaccharide Simulations are Sensitive to Phosphate Charge and Ion Parameterization
Authors: Rice Amy , Rooney Mary T. , Greenwood Alexander I. , Cotten Myriam L. , Wereszczynski Jeff 
Published: August 2019

AbstractThe high proportion of lipopolysaccharide (LPS) molecules in the outer membrane of Gram-negative bacteria make it a highly effective barrier to small molecules, antibiotic drugs, and other antimicrobial agents. Given this vital role in protecting bacteria from potentially hostile environments, simulations of LPS bilayers and outer membrane systems represent a critical tool for understanding the mechanisms of bacterial resistance and the development of new antibiotic compounds that circumvent these defenses. The basis of these simulations are parameterizations of LPS, which have been developed for all major molecular dynamics force fields. However, these parameterizations differ in both the protonation state of LPS as well as how LPS membranes behave in the presence of various ion species. To address these discrepancies and understand the effects of phosphate charge on bilayer properties, simulations were performed for multiple distinct LPS chemotypes with different ion parameterizations in both protonated or deprotonated lipid A states. These simulations show that bilayer properties, such as the area per lipid and inter-lipid hydrogen bonding, are highly influenced by the choice of phosphate group charges, cation type, and ion parameterization, with protonated LPS and monovalent cations with modified nonbonded parameters providing the best match to experiments. Additionally, alchemical free energy simulations were performed to determine theoretical pKa values for LPS, and subsequently validated by 31P solid-state NMR experiments. Results from these complementary computational and experimental studies demonstrate that the protonated state dominates at physiological pH, contrary to the deprotonated form modeled by many LPS force fields. In all, these results highlight the sensitivity of LPS simulations to phosphate charge and ion parameters, while offering recommendations for how existing models should be updated for consistency between force fields as well as to best match experiments.
Discovery of genes encoding a Streptolysin S-like toxin biosynthetic cluster in a select highly pathogenic methicillin resistantStaphylococcus aureusJKD6159 strain
Authors: Kane Trevor , Carothers Katelyn E. , Bao Yunjuan , Yeo Won-Sik , Bae Taeok , Park Claudia , Fields Francisco R. , Vu Henry M. , Hammers Daniel E. , Ross Jessica N. , Ploplis Victoria A. , Castellino Francis J. , Lee Shaun W. 
Published: August 2019

AbstractBackgroundStaphylococcus aureus(S. aureus) is a major human pathogen owing to its arsenal of virulence factors, as well as its acquisition of multi-antibiotic resistance. Here we report the identification of a Streptolysin S (SLS) like biosynthetic gene cluster in a highly virulent community-acquired methicillin resistantS. aureus(MRSA) isolate, JKD6159. Examination of the SLS-like gene cluster in JKD6159 shows significant homology and gene organization to the SLS-associated biosynthetic gene (sag) cluster responsible for the production of the major hemolysin SLS in Group AStreptococcus.ResultsWe took a comprehensive approach to elucidating the putative role of the sag gene cluster in JKD6159 by constructing a mutant in which one of the biosynthesis genes (sagB homologue) was deleted in the parent JKD6159 strain. Assays to evaluate bacterial gene regulation, biofilm formation, antimicrobial activity, as well as complete host cell response profile and comparativein vivoinfections in Balb/Cj mice were conducted.ConclusionsAlthough no significant phenotypic changes were observed in our assays, we postulate that the SLS-like toxin produced by this strain ofS. aureusmay be a highly specialized virulence factor utilized in specific environments for selective advantage; studies to better understand the role of this newly discovered virulence factor inS. aureuswarrant further investigation.