bluuebunny/crossref_metadata_2025_split huggingface dataset:
A memory element imposes epigenetic behavior on intrinsically labile RNAi-induced heterochromatin spread
Authors: Greenstein R.A. , Jones Stephen K. , Spivey Eric C. , Rybarski James R. , Finkelstein Ilya J. , Al-Sady Bassem 
Published: December 2017

ABTRACTThe heterochromatin spreading reaction is a central contributor to the formation of gene-repressive structures, which are re-established with high fidelity following replication. The high fidelity of this process is not obviously encoded in the primary spreading reaction. To resolve origins of stable inheritance of repression, we probed the intrinsic fidelity of spreading events in fission yeast using a system that quantitatively describes the spreading reaction in live single cells. We show that spreading from RNAi-nucleated elements is stochastic, multimodal, and fluctuates dynamically across time. In contrast, a second form of spreading, nucleated by thecis-acting elementREIII, is deterministic, has high memory capacity and acts as the source of locus fidelity.REIIIenables fidelity in part by endowing the locus with resistance to perturbations. Together, our results suggest that epigenetic capacity may not be intrinsically encoded in the spreading reaction, but rather requires collaboration with specialized memory elements.
Osterixfunctions downstream of anti-Müllerian hormone signaling to regulate Müllerian duct regression
Authors: Mullen Rachel D. , Wang Ying , Liu Bin , Moore Emma L. , Behringer Richard R. 
Published: December 2017

AbstractIn mammals, the developing reproductive tract primordium of male and female fetuses consists of the Wolffian duct and the Müllerian duct (MD), two epithelial tube pairs surrounded by mesenchyme. During male development, mesenchyme-epithelia interactions mediate MD regression to prevent its development into a uterus, oviduct and upper vagina. It is well established that transforming growth factor-beta family member anti-Müllerian hormone (AMH) secreted from the fetal testis and its type 1 and 2 receptors expressed in MD mesenchyme regulate MD regression. However, little is known about the molecular network regulating downstream actions of AMH signaling. To identify potential AMH-induced genes and regulatory networks controlling MD regression in a global non-biased manner, we examined transcriptome differences in MD mesenchyme between males (AMH signaling on) and females (AMH signaling off) by RNA-Seq analysis of purified fetal MD mesenchymal cells. This analysis found 82 genes up-regulated in males during MD regression and identifiedOsterix (Osx)/Sp7, a key transcriptional regulator of osteoblast differentiation and bone formation, as a novel downstream effector of AMH signaling during MD regression. Osx/OSX was expressed in a male-specific pattern in MD mesenchyme during MD regression. OSX expression was lost in mutant males without AMH signaling. In addition, transgenic mice ectopically expressing human AMH in females induced a male pattern ofOsxexpression. Together these results indicate that AMH signaling is necessary and sufficient forOsxexpression in the MD mesenchyme. In addition, MD regression was delayed inOsxnull males, identifyingOsxas a new factor that regulates MD regression.SignificanceIn mammals, each embryo forms both male and female reproductive tract organ progenitor tissues. Anti-Müllerian hormone (AMH) secreted by fetal testes acts on mesenchyme cells adjacent to the Müllerian duct (MD) epithelium, the progenitor tissue of the female reproductive tract, to induce MD regression. While AMH and early AMH signaling components are elucidated, downstream gene networks directing this process are largely unknown. A global non-biased approach using whole transcriptome sequencing of fetal MD mesenchymal cells identified 82 factors as potential target genes of AMH includingOsterix (Osx). Our findings providein vivoevidenceOsxis an AMH-induced gene that regulates MD regression. Identification ofOsxmay provide key insights into gene regulatory networks underlying MD regression and male sex differentiation.
Challenges in Using ctDNA to Achieve Early Detection of Cancer
Authors: Haque Imran S , Elemento Olivier 
Published: December 2017

AbstractEarly detection of cancer is a significant unmet clinical need. Improved technical ability to detect circulating tumor-derived DNA (ctDNA) in the cell-free DNA (cfDNA) component of blood plasma via next-generation sequencing and established correlations between ctDNA load and tumor burden in cancer patients have spurred excitement about the possibilities of detecting cancer early by performing ctDNA mutation detection.We reanalyze published data on the expected ctDNA allele fraction in early-stage cancer and the population statistics of cfDNA concentration to show that under conservative technical assumptions, high-sensitivity cancer detection by ctDNA mutation detection will require either more blood volume (150-300mL) than practical for a routine screen or variant filtering that may be impossible given our knowledge of cancer evolution, and will likely remain out of economic reach for routine population screening without multiple-order-of-magnitude decreases in sequencing cost. Instead, new approaches that integrate ctDNA mutations with multiple other blood-based analytes (such as exosomes, circulating tumor cells, ctDNA epigenetics, metabolites) as well as integration of these signals over time for each individual may be needed.
Computational docking reveals evolutionary conservation of a specific interaction between 15d-Prostaglandin-J2 and eIF4A
Authors: Yun So Jeong , Kim Hyunjoon , Lee Seung Gee , Jung Seung-Hyun , Kim Joon Hyun , Ryu Jeong Eun , Singh N. Jiten , Jeon Jouhyun , Han Jin-Kwan , Kim Cheol-Hee , Kim Sanguk , Kim Kwang S. , Jang Sung Key , Kim Woo Jae 
Published: December 2017

ABSTRACT15-deoxy-delta 12,14-prostaglandin J2 (15d-PGJ2) is anti-inflammatory/antineoplastic prostaglandin which functions through covalent binding to cysteine residues of various target proteins. We previously showed that 15d-PGJ2 mediated anti-inflammatory responses are dependent on the translational inhibition through its interaction with eIF4A. Binding of 15d-PGJ2 to eIF4A specifically blocks the interaction between eIF4G and eIF4A leads to the formation of stress granules (SGs), which cluster mRNAs with inhibited translation. Here we show that the binding between 15d-PGJ2 and eIF4A specifically blocks the interaction between the MIF4G domain of eIF4G and eIF4A. To reveal the mechanism of this interaction, we used computational simulation-based docking studies and identified that the carboxyl tail of 15d-PGJ2 could stabilize the binding of 15d-PGJ2 to eIF4A through arginine 295 of eIF4A, which is the first suggestion that the 15d-PGJ2 tail play a physiological role. Interestingly, the putative 15d-PGJ2 binding site on eiF4A is conserved across many species, suggesting a biological role. Our data propose that studying 15d-PGJ2 and its targets will may uncover new therapeutic approaches in anti-inflammatory drug discovery.
Gaze Behaviour During Sensorimotor Adaptation Parcellates the Explicit and Implicit Contributions to Learning
Authors: de Brouwer Anouk J. , Albaghdadi Mohammed , Randall Flanagan J. , Gallivan Jason P. 
Published: December 2017

AbstractSuccessful motor performance relies on our ability to adapt to changes in the environment by learning novel mappings between motor commands and sensory outcomes. Such adaptation is thought to involve two distinct mechanisms: An implicit, error-based component linked to slow learning and an explicit, strategic component linked to fast learning and savings (i.e., faster relearning). Because behaviour, at any given moment, is the resultant combination of these two processes, it has remained a challenge to parcellate their relative contributions to performance. The explicit component to visuomotor rotation (VMR) learning has recently been measured by having participants verbally report their aiming strategy used to counteract the rotation. However, this procedure has been shown to magnify the explicit component. Here we tested whether task-specific eye movements, a natural component of reach planning—but poorly studied in motor learning tasks—can provide a direct read-out of the state of the explicit component during VMR learning. We show, by placing targets on a visible ring and including a delay between target presentation and reach onset, that individual differences in gaze patterns during sensorimotor adaptation are linked to participants’ rates of learning and can predict the expression of savings. Specifically, we find that participants who, during reach planning, naturally fixate an aimpoint, rotated away from the target location, show faster initial adaptation and readaptation 24 hrs. later. Our results demonstrate that gaze behaviour can not only uniquely identify individuals who implement cognitive strategies during learning, but also how their implementation is linked to differences in learning.
Dr.Paso: Drug response prediction and analysis system for oncology research
Authors: Azuaje Francisco , Kaoma Tony , Jeanty Céline , Nazarov Petr V. , Muller Arnaud , Kim Sang-Yoon , Golebiewska Anna , Dittmar Gunnar , Niclou Simone P. 
Published: December 2017

SummaryThe prediction of anticancer drug response is crucial for achieving a more effective and precise treatment of patients. Models based on the analysis of large cell line collections have shown potential for investigating drug efficacy in a clinically-meaningful, cost-effective manner. Using data from thousands of cancer cell lines and drug response experiments, we propose a drug sensitivity prediction system based on a 47-gene expression profile, which was derived from an unbiased transcriptomic network analysis approach. The profile reflects the molecular activity of a diverse range of cancer-relevant processes and pathways. We validated our model using independent datasets and comparisons with published models. A high concordance between predicted and observed drug sensitivities was obtained, including additional validated predictions for four glioblastoma cell lines and four drugs. Our approach can accurately predict anti-cancer drug sensitivity and will enable further pre-clinical research. In the longer-term, it may benefit patient-oriented investigations and interventions.
The essential genome ofEscherichia coliK-12
Authors: Goodall Emily C. A. , Robinson Ashley , Johnston Iain G. , Jabbari Sara , Turner Keith A. , Cunningham Adam. F. , Lund Peter A. , Cole Jeffrey A. , Henderson Ian R. 
Published: December 2017

ABSTRACTTransposon-Directed Insertion-site Sequencing (TraDIS) is a high-throughput method coupling transposon mutagenesis with short-fragment DNA sequencing. It is commonly used to identify essential genes. Single gene deletion libraries are considered the gold standard for identifying essential genes. Currently, the TraDIS method has not been benchmarked against such libraries and therefore it remains unclear whether the two methodologies are comparable. To address this, a high density transposon library was constructed inEscherichia coliK-12. Essential genes predicted from sequencing of this library were compared to existing essential gene databases. To decrease false positive identification of essential gene candidates, statistical data analysis included corrections for both gene length and genome length. Through this analysis new essential genes and genes previously incorrectly designated as essential were identified. We show that manual analysis of TraDIS data reveals novel features that would not have been detected by statistical analysis alone. Examples include short essential regions within genes, orientation-dependent effects and fine resolution identification of genome and protein features. Recognition of these insertion profiles in transposon mutagenesis datasets will assist genome annotation of less well characterized genomes and provides new insights into bacterial physiology and biochemistry.IMPORTANCEIncentives to define lists of genes that are essential for bacterial survival include the identification of potential targets for antibacterial drug development, genes required for rapid growth for exploitation in biotechnology, and discovery of new biochemical pathways. To identify essential genes inE. coli, we constructed a very high density transposon mutant library. Initial automated analysis of the resulting data revealed many discrepancies when compared to the literature. We now report more extensive statistical analysis supported by both literature searches and detailed inspection of high density TraDIS sequencing data for each putative essential gene for the model laboratory organism,Escherichia coli. This paper is important because it provides a better understanding of the essential genes ofE. coli, reveals the limitations of relying on automated analysis alone and a provides new standard for the analysis of TraDIS data.
RANbodies: reporter-nanobody fusions as versatile, small, sensitive immunohistochemical reagents
Authors: Yamagata Masahito , Sanes Joshua R. 
Published: December 2017

ABSTRACTSensitive and specific antibodies are essential for detecting molecules in cells and tissues. However, currently used polyclonal and monoclonal antibodies are often less sensitive than desired, difficult to produce, and available in limited quantities. A promising recent approach to circumvent these limitations is to employ chemically-defined antigen-combining sites called nanobodies, derived from single chain camelid antibodies. Here, we used nanobodies to prepare sensitive unimolecular detection reagents by genetically fusing cDNAs encoding nanobodies to enzymatic or antigenic reporters. We call these fusions between a reporter and a nanobody RANbodies. They can be used to localize epitopes and to amplify signals from fluorescent proteins. They be generated and purified simply and in unlimited amounts, and can be preserved safely and inexpensively in the form of DNA or digital sequence.
Sequence determinants of protein phase behavior from a coarse-grained model
Authors: Dignon Gregory L. , Zheng Wenwei , Kim Young C. , Best Robert B. , Mittal Jeetain 
Published: December 2017

AbstractMembraneless organelles important to intracellular compartmentalization have recently been shown to comprise assemblies of proteins which undergo liquid-liquid phase separation (LLPS). However, many proteins involved in this phase separation are at least partially disordered. The molecular mechanism and the sequence determinants of this process are challenging to determine experimentally owing to the disordered nature of the assemblies, motivating the use of theoretical and simulation methods. This work advances a computational framework for conducting simulations of LLPS with residue-level detail, and allows for the determination of phase diagrams and coexistence densities of proteins in the two phases. The model includes a short-range contact potential as well as a simplified treatment of electrostatic energy. Interaction parameters are optimized against experimentally determined radius of gyration data for multiple unfolded or intrinsically disordered proteins (IDPs). These models are applied to two systems which undergo LLPS: the low complexity domain of the RNA-binding protein FUS and the DEAD-box helicase protein LAF-1. We develop a novel simulation method to determine thermodynamic phase diagrams as a function of the total protein concentration and temperature. We show that the model is capable of capturing qualitative changes in the phase diagram due to phosphomimetic mutations of FUS and to the presence or absence of the large folded domain in LAF-1. We also explore the effects of chain-length, or multivalency, on the phase diagram, and obtain results consistent with Flory-Huggins theory for polymers. Most importantly, the methodology presented here is flexible so that it can be easily extended to other pair potentials, be used with other enhanced sampling methods, and may incorporate additional features for biological systems of interest.Author summaryLiquid liquid phase separation (LLPS) of low-complexity protein sequences has emerged as an important research topic due to its relevance to membraneless organelles and intracellular compartmentalization. However a molecular level understanding of LLPS cannot be easily obtained by experimental methods due to difficulty of determining structural properties of phase separated protein assemblies, and of choosing appropriate mutations. Here we advance a coarse-grained computational framework for accessing the long time scale phase separation process and for obtaining molecular details of LLPS, in conjunction with state of the art enhanced sampling methods. We are able to capture qualitatively the changes of phase diagram due to specific mutations, inclusion of a folded domain, and to variation of chain length. The model is flexible and can be used with different knowledge-based potential energy functions, as we demonstrate. We expect a wide application of the presented framework for advancing our understanding of the formation of liquid-like protein assemblies.
Lhx2 regulates temporal changes in chromatin accessibility and transcription factor binding in retinal progenitor cells
Authors: Zibetti Cristina , Liu Sheng , Wan Jun , Qian Jiang , Blackshaw Seth 
Published: December 2017

AbstractRetinal progenitor cells (RPCs) pass through multiple stages of developmental competence, where they successively acquire and lose the ability to generate individual cell subtypes. To identify the transcriptional regulatory networks that control these transitions, we conducted epigenomic and transcriptomic profiling of early and late-stage RPCs and observed a developmentally dynamic landscape of chromatin accessibility. Open chromatin regions that showed stage-specificity, as well as those shared by early and late-stage RPCs, were selectively targeted by the homeodomain factor Lhx2, which is expressed throughout retinal neurogenesis but also regulates many stage-specific processes in RPCs. Stage-specific Lhx2 binding sites were frequently associated with target sites for transcription factors that are preferentially expressed in either early or late-stage RPCs, and which were predicted to possess pioneer activity.Lhx2loss of function in RPCs led to a loss of chromatin accessibility at both direct Lhx2 target sites and more broadly across the genome, as well as a loss of binding by transcription factors associated with stage-specific Lhx2 target sites. These findings demonstrate a central role for Lhx2 in control of chromatin accessibility in RPCs, and identify transcription factors that may guide stage-specific target site selection by Lhx2.SummaryLhx2 is a central regulator of chromatin accessibility in retinal progenitor cells, and interacts with stage-specific transcription factors to regulate genes that are dynamically expressed during retinal neurogenesis.
Modeling brand resonance score (BRS) – an application in financial services
Authors: Raja Ambedkar Ande , Murugesan Punniyamoorthy , Thamaraiselvan N. 
Published: December 2017

Purpose
The experts in industry and academicians value brand resonance is the prerequisite factor in the firms of financial services. In this regard, the purpose of this paper is to model the brand resonance score (BRS) for modified customer-based brand equity (CBBE) model in mutual fund financial services using structural equation modeling (SEM) and analytic network process (ANP).

Design/methodology/approach
Criteria and sub-criteria relative weights are calculated from the SEM and sub-sub-criteria relative weights are measured through pair-wise comparison matrix for BRS modeling using ANP approach.

Findings
The brand resonance using ANP has been quantified, and BRSs of each brand through brand judgments and brand feelings criteria are calculated using two renowned Indian mutual fund services brands State Bank of India and Hong Kong and Shanghai Banking Corporation.

Research limitations/implications
Interdependency between sub-criteria are not explored. This research study is specific to Indian bank mutual fund services context.

Practical implications
Research findings provide useful guidelines for fund managers/analysts of mutual fund service firms to improve the brand resonance to investors.

Originality/value
The paper explained modeling BRS using ANP technique which helps organizations quantify the brand resonance effectively.
Ertugliflozin plus sitagliptin versus either individual agent over 52 weeks in patients with type 2 diabetes mellitus inadequately controlled with metformin: The VERTIS FACTORIAL randomized trial
Authors: Pratley Richard E. , Eldor Roy , Raji Annaswamy , Golm Gregory , Huyck Susan B. , Qiu Yanping , Sunga Sheila , Johnson Jeremy , Terra Steven G. , Mancuso James P. , Engel Samuel S. , Lauring Brett 
Published: December 2017

AimTo evaluate the efficacy and safety of ertugliflozin and sitagliptin co‐administration vs the individual agents in patients with type 2 diabetes who are inadequately controlled with metformin.MethodsIn this study (Clinicaltrials.gov NCT02099110), patients with glycated haemoglobin (HbA1c) ≥7.5% and ≤11.0% (≥58 and ≤97 mmol/mol) with metformin ≥1500 mg/d (n = 1233) were randomized to ertugliflozin 5 (E5) or 15 (E15) mg/d, sitagliptin 100 mg/d (S100) or to co‐administration of E5/S100 or E15/S100. The primary endpoint was change from baseline in HbA1c at Week 26.ResultsAt Week 26, least squares mean HbA1c reductions from baseline were greater with E5/S100 (−1.5%) and E15/S100 (−1.5%) than with individual agents (−1.0%, −1.1% and −1.1% for E5, E15 and S100, respectively; P < .001 for all comparisons). HbA1c <7.0% (<53 mmol/mol) was achieved by 26.4%, 31.9%, 32.8%, 52.3% and 49.2% of patients in the E5, E15, S100, E5/S100 and E15/S100 groups, respectively. Fasting plasma glucose reductions were significantly greater with E5/S100 and E15/S100 compared with individual agents. Body weight and systolic blood pressure (SBP) significantly decreased with E5/S100 and E15/S100 vs S100 alone. Glycaemic control, body weight and SBP effects of ertugliflozin were maintained to Week 52. Genital mycotic infections were more common among ertugliflozin‐treated patients compared with those treated with S100. Incidences of symptomatic hypoglycaemia and adverse events related to hypovolaemia or urinary tract infection were similar among groups.ConclusionsIn patients with uncontrolled type 2 diabetes while using metformin, co‐administration of ertugliflozin and sitagliptin provided more effective glycaemic control through 52 weeks compared with the individual agents.