bluuebunny/crossref_metadata_2025_split huggingface dataset:
WAPL maintains dynamic cohesin to preserve lineage specific distal gene regulation
Authors: Liu Ning Qing , Maresca Michela , van den Brand Teun , Braccioli Luca , Schijns Marijne M.G.A. , Teunissen Hans , Bruneau Benoit G. , Nora Elphège P. , de Wit Elzo 
Published: August 2019

SUMMARYThe cohesin complex plays essential roles in sister chromatin cohesin, chromosome organization and gene expression. The role of cohesin in gene regulation is incompletely understood. Here, we report that the cohesin release factor WAPL is crucial for maintaining a pool of dynamic cohesin bound to regions that are associated with lineage specific genes in mouse embryonic stem cells. These regulatory regions are enriched for active enhancer marks and transcription factor binding sites, but largely devoid of CTCF binding sites. Stabilization of cohesin, which leads to a loss of dynamic cohesin from these regions, does not affect transcription factor binding or active enhancer marks, but does result in changes in promoter-enhancer interactions and downregulation of genes. Acute cohesin depletion can phenocopy the effect of WAPL depletion, showing that cohesin plays a crucial role in maintaining expression of lineage specific genes. The binding of dynamic cohesin to chromatin is dependent on the pluripotency transcription factor OCT4, but not NANOG. Finally, dynamic cohesin binding sites are also found in differentiated cells, suggesting that they represent a general regulatory principle. We propose that cohesin dynamically binding to regulatory sites creates a favorable spatial environment in which promoters and enhancers can communicate to ensure proper gene expression.HIGHLIGHTSThe cohesin release factor WAPL is crucial for maintaining a pluripotency-specific phenotype.Dynamic cohesin is enriched at lineage specific loci and overlaps with binding sites of pluripotency transcription factors.Expression of lineage specific genes is maintained by dynamic cohesin binding through the formation of promoter-enhancer associated self-interaction domains.CTCF-independent cohesin binding to chromatin is controlled by the pioneer factor OCT4.
DeepBCR: Deep learning framework for cancer-type classification and binding affinity estimation using B cell receptor repertoires
Authors: Hu Xihao , Liu X Shirley 
Published: August 2019

AbstractWe developed a deep learning framework to model the binding specificity of B-cell receptors (BCRs). The DeepBCR framework can predict the cancer type from a repertoire of BCRs and estimate the binding affinity of a single BCR. We designed a peptide encoding network that includes an amino acid encoding layer, k-mer motif layer, and immunoglobulin isotype layer, and used transfer learning to reduce parameters and over-fitting. When we applied the framework to evaluate the three commercial anti-PD1 drugs (Opdivo, Keytruda, and Libtayo), the predicted binding affinities correlate with the real affinities measured in kD values. This validates the prediction and indicates that we can use the framework to select strong antigen-specific binders.
Predicting metabolism during growth by osmotic cell expansion
Authors: Shameer Sanu , Vallarino José G. , Fernie Alisdair R. , Ratcliffe R. George , Sweetlove Lee J 
Published: August 2019

ABSTRACTCell expansion is a significant contributor to organ growth and is driven by the accumulation of osmolytes to increase cell turgor pressure. Metabolic modelling has the potential to provide insights into the processes that underpin osmolyte synthesis and transport, but the main computational approach for predicting metabolic network fluxes, flux balance analysis (FBA), typically uses biomass composition as the main output constraint and ignores potential changes in cell volume. Here we present GrOE-FBA (Growth by Osmotic Expansion-Flux Balance Analysis), a framework that accounts for both the metabolic and ionic contributions to the osmotica that drive cell expansion, as well as the synthesis of protein, cell wall and cell membrane components required for cell enlargement. Using GrOE-FBA, the metabolic fluxes in dividing and expanding cell were analyzed, and the energetic costs for metabolite biosynthesis and accumulation in the two scenarios were found to be surprisingly similar. The expansion phase of tomato fruit growth was also modelled using a multi-phase single optimization GrOE-FBA model and this approach gave accurate predictions of the major metabolite levels throughout fruit development as well as revealing a role for transitory starch accumulation in ensuring optimal fruit development.
Fibroblast growth factor receptor facilitates recurrence of minimal residual disease following trastuzumab emtansine therapy
Authors: Akhand Saeed S. , Purdy Stephen Connor , Liu Zian , Anderson Joshua C. , Willey Christopher D. , Wendt Michael K. 
Published: August 2019

AbstractTrastuzumab-emtansine (T-DM1) is an antibody-drug conjugate (ADC) that efficiently delivers a potent microtubule inhibitor into HER2 overexpressing tumor cells. However, resistance to T-DM1 is emerging as a significant clinical problem. Continuous in vitro treatment of HER2-transformed mammary epithelial cells with T-DM1 did not elicit spontaneously resistant cells. However, induction of epithelial-mesenchymal transition (EMT) via pretreatment with TGF-β1 facilitated acquisition of T-DM1 resistance. Flow cytometric analyses indicated that induction of EMT decreased trastuzumab binding, prior to overt loss of HER2 expression. Kinome analyses of T-DM1 resistant cells indicated increased phosphorylation of ErbB1, ErbB4, and fibroblast blast growth factor receptor 1 (FGFR1). T-DM1 resistant cells failed to respond to the ErbB kinase inhibitors lapatinib and afatinib, but they acquired sensitivity to FIIN4, a covalent FGFR kinase inhibitor. In vivo, T-DM1 treatment led to robust regression of HER2-transformed tumors, but minimal residual disease (MRD) was still detectable via bioluminescent imaging. Upon cessation of the ADC relapse occurred and secondary tumors were resistant to additional rounds of T-DM1, but this recurrent tumor growth could be inhibited by FIIN4. Expression of FGFR1 was upregulated in T-DM1 resistant tumors, and ectopic overexpression of FGFR1 was sufficient to enhance tumor growth, diminish trastuzumab binding, and promote recurrence following T-DM1-induced MRD. Finally, patient-derived xenografts from a HER2+ breast cancer patient who had progressed on trastuzumab failed to respond to T-DM1, but tumor growth was significantly inhibited by FIIN4. Overall, our studies strongly support therapeutic combination of TDM1 and FGFR targeted agents in HER2+ breast cancer.
Quantifying and engineering mucus adhesion of probiotics
Authors: Mays Zachary J. S. , Chappell Todd C. , Nair Nikhil U. 
Published: August 2019

ABSTRACTMucus in the gastrointestinal (GI) tract is the primary point-of-interaction between humans and their gut microbiota. This not only intimates that mucus ensures protection against endogenous and ex-ogenous opportunists but provision for the human microbiota to reside and flourish. With the emergence of living therapeutics, engineered microbes can deliver and produce increasingly complex medicine, and controlling the mucoadhesive properties of different microbial chassis can dictate dose-response in a patient. Here we present a redesigned, in vitro, plate-based assay to measure the mucus adhesion of various probiotics. Cell-mucus interactions were isolated by immobilizing mucus to the plate surface. Binding parameters were derived for each probiotic strain by measuring cell adhesion over a wide range of cell concentrations, providing dose-dependent adhesion metrics. Surface proteins and cell components known to influence mucoadhesion were then heterologously expressed or altered in Lactococcus lactis MG1363 and E. coli Nissle 1917 to control mucus-binding capacity, avidity, and cooperativity.
High-Accuracy Protein Structures by Combining Machine-Learning with Physics-Based Refinement
Authors: Heo Lim , Feig Michael 
Published: August 2019

ABSTRACTProtein structure prediction has long been available as an alternative to experimental structure determination, especially via homology modeling based on templates from related sequences. Recently, models based on distance restraints from co-evoluttionary analysis via machine learning have significantly expanded the ability to predict structures for sequences without templates. One such method, AlphaFold, also performs well on sequences were templates are available but without using such information directly. Here we show that combining machine-learning based models from AlphaFold with state-of-the-art physics-based refinement via molecular dynamics simulations further improves predictions to outperform any other prediction method tested during the latest round of CASP. The resulting models have highly accurate global and local structure, including high accuracy at functionally important interface residues, and they are highly suitable as initial models for crystal structure determination via molecular replacement.
Assessing the motivational effects of ethanol in mice using a discrete-trial current-intensity intracranial self-stimulation procedure
Authors: Barkley-Levenson Amanda M. , Der-Avakian Andre , Palmer Abraham A. 
Published: August 2019

AbstractBackgroundAlcohol (ethanol) produces both rewarding and aversive effects, and sensitivity to these effects is associated with risk for an alcohol use disorder (AUD). Measurement of these motivational effects in animal models is an important but challenging aspect of preclinical research into the neurobiology of AUD. Here, we evaluated whether a discrete-trial current-intensity intracranial self-stimulation (ICSS) procedure can be used to assess both reward-enhancing and aversive responses to ethanol in mice.MethodsC57BL/6J mice were surgically implanted with bipolar stimulating electrodes targeting the medial forebrain bundle and trained on a discrete-trial current-intensity ICSS procedure. Mice were tested for changes in response thresholds after various doses of ethanol (0.5 g/kg-1.75 g/kg), using a Latin square design.ResultsA 1 g/kg dose of ethanol produced a significant reward-enhancement (i.e., lowered response thresholds), whereas a 1.75 g/kg dose produced an aversive effect (elevated response thresholds).ConclusionsThe discrete-trial current-intensity ICSS procedure is an effective assay for measuring both reward-enhancing responses to ethanol as well as aversive responses in the same animal. This should prove to be a useful tool for assessing the effects of experimental manipulations on the motivational effects of ethanol in mice.
Development and evaluation of a rapid on-site water pathogen detection system for water quality monitoring
Authors: Chia Joel Y. , Tay Yu Pei , Poh Daniel , Tay Boon Hunt , Koh Eileen , Teo Joshua , Yap Hoi Ming , Lim Merrill , Soh Li Ting , Lee Yuan Kun , Lee Chi-Lik Ken 
Published: August 2019

ABSTRACTTimely response to outbreak of water-borne diseases caused by bacteria requires efficient monitoring and rapid detection strategies. Herein, we report a rapid DNA-based on-site detection system for specific detection of Pseudomonas aeruginosa. To evaluate the test performance of our method against spiked water samples, parallel tests based on real-time PCR and standard culture methods were concurrently performed. Test sensitivities of between 96.7% and 92.3% were obtained, based on the calculation obtained from qPCR and culture test, respectively, with a corresponding level of specificity of 92.9% and 83.3%. Time-to-result is around 45 min, with a detection limit of 1 CFU/100 mL. Here, a fully-deployable detection method where bacteria of-interest can be detected rapidly with high accuracy was described. This test method can be modified to detect other bacteria of-interest and can also be used in different applications. The test results can be obtained on-site and can therefore be particularly useful in public facilities health surveillance, where regulators can quickly determine if a site is safe or if other emergency response measures are required.IMPORTANCEPseudomonas aeruginosa is a well-established water quality biomarker, known to be associated to humans’ health risks. To ascertain the presence of this pathogen, relevant stakeholders currently rely on standard quantitative ISO methods (APHA 9213E) which require 6 days from sampling to results. This window could potentially lead to waterborne outbreaks if the contaminated water features are not shut down for proper and urgent mitigation. This manuscript describes a method to detect this disease-causing microorganism in its viable forms under 1 hour, with a sensitivity of 1 CFU/100mL. Besides providing valuable information of the quality of water system, this direct monitoring of pathogens can reduce substantial time needed from sampling to reporting. This method can be established as a platform technology for other pathogenic microorganisms. On-going work to develop economic point-of-care prototypes could facilitate quick screening of targeted waterborne pathogens and results in better assessment of public health risk and quick in devising emergency response measures and other management strategies.
Norovirus replication in human intestinal epithelial cells is restricted by the interferon-induced JAK/STAT signalling pathway and RNA Polymerase II mediated transcriptional responses
Authors: Hosmillo Myra , Chaudhry Yasmin , Nayak Komal , Sorgeloos Frederic , Koo Bon-Kyoung , Merenda Alessandra , Lillestol Reidun , Drumright Lydia , Zilbauer Matthias , Goodfellow Ian 
Published: August 2019

AbstractHuman noroviruses (HuNoV) are a leading cause of viral gastroenteritis worldwide and a significant cause of morbidity and mortality in all age groups. The recent finding that HuNoV can be propagated in B cells and mucosa derived intestinal epithelial organoids (IEOs), has transformed our capability to dissect the life cycle of noroviruses. Using RNA-Seq of HuNoV infected intestinal epithelial cells (IECs), we have found that replication of HuNoV in IECs results in interferon-induced transcriptional responses and that HuNoV replication in IECs is sensitive to IFN. This contrasts with previous studies that suggest that the innate immune response may play no role in the restriction of HuNoV replication in immortalised cells. We demonstrate that the inhibition of JAK1/JAK2 enhances HuNoV replication in IECs. Surprisingly, targeted inhibition of cellular RNA polymerase II-mediated transcription was not detrimental to HuNoV replication, but enhanced replication to a greater degree compared to blocking of JAK signalling directly. Furthermore, we demonstrate for the first time that IECs generated from genetically modified intestinal organoids, engineered to be deficient in the interferon response, are more permissive to HuNoV infection. Together our work identifies the IFN-induced transcriptional responses restrict HuNoV replication in IECs and demonstrates that the inhibition of these responses by modifications to the culture conditions can greatly enhance the robustness of the norovirus culture system.ImportanceNoroviruses are a major cause of gastroenteritis worldwide yet the challenges associated with their growth culture has greatly hampered the development of therapeutic approaches and has limited our understanding of cellular pathways that control infection. Here we show that human intestinal epithelial cells, the first point of entry of human noroviruses into the host, limit virus replication by the induction of the innate responses. Furthermore we show that modulating the ability of intestinal epithelial cells to induce transcriptional responses to HuNoV infection can significantly enhance human norovirus replication in culture. Collectively our findings provide new insights into the biological pathways that control norovirus infection but also identify mechanisms to enhance the robustness of norovirus culture.
Metagenomic analysis of soil samples collected from estuarine mangroves of Arabian Sea reveals rich microbiota and high numbers of sulphate reducing bacteria accompanied with methanogen bacteria
Authors: Paingankar Mandar S. , Deobagkar Deepti D. 
Published: August 2019

AbstractThis study reports the analyses of the microbiome of the estuarine soil of mangroves of the Arabian Sea. Mangroves soil samples were collected from 12 locations of Arabian Sea coast of Maharashtra, India. 16S rRNA gene V3–V4 region amplicon sequencing was performed using the Miseq Illumina platform to identify the microbial communities present in the mangroves ecosystem. The metagenomics analysis provided an insight into the abundance, diversity and spatial variations in the mangrove microbial communities in relation to physico-chemical parameters and revealed that Proteobacteria, Flavobacteria and Planctomycetes are abundant in mangroves system. The differences in bacterial abundance, composition and diversity can partly be attributed to the physico-chemical characteristics of the samples, geographical location and anthropogenic activities in the locality. High numbers of sulphate reducing bacteria accompanied with methanogen bacteria were characteristic of Indian mangroves. The results obtained in the current study indicate rich species diversity and add valuable insights about the diversity of microbial communities of the mangroves in Maharashtra along the west coast of India and can provide better information for effective measures for conservation of mangroves. GIS based prediction suggest that the sulphur utilizing communities are under threat from anthropogenic activities and may decline in future if immediate measures are not implemented.
Dynamic coupling of cochlear inner hair cell intrinsic Ca2+action potentials to Ca2+signaling of non-sensory cells
Authors: Ceriani Federico , Johnson Stuart L. , Sedlacek Miloslav , Hendry Aenea , Kachar Bechara , Marcotti Walter , Mammano Fabio 
Published: August 2019

ABSTRACTThe relationship between Ca2+action potential (AP) activity in immature inner hair cells (IHCs) and the spontaneous ATP-dependent intercellular Ca2+signaling in cochlear non-sensory cells (NSCs) of the greater epithelial ridge (GER) is unclear. Here, we determined that IHCs fired asynchronous Ca2+APs also in the absence of Ca2+activity in the GER. Patch clamp recordings from IHCs isolated from the rest of the sensory epithelium confirmed that this firing activity is an intrinsic property of immature IHCs. However, frequency, correlation index and burst duration of IHC APs increased significantly during Ca2+wave propagation in NSCs, and depended on wave extension in the GER. Furthermore, IHC depolarization under whole cell patch clamp conditions triggered Ca2+signals in nearby NSCs with a delay that was proportional to the distance from the stimulated IHC. Thus the immature mammalian cochlea supports bidirectional exchange of Ca2+signals between IHCs and NSCs.IMPACT STATEMENTIn inner hair cells of the developing mammalian cochlea, Ca2+action potentials are both intrinsic and bidirectionally coupled to the ATP-dependent Ca2+signaling of the surrounding non-sensory cells.
The finger 2 tip loop of Activin A is required for the formation of its non-signaling complex with ACVR1 and type II Bone Morphogenetic Protein receptors
Authors: Aykul Senem , Corpina Richard A. , Goebel Erich J. , Cunanan Camille J. , Dimitriou Alexandra , Kim Hyonjong , Zhang Qian , Rafique Ashique , Leidich Raymond , Wang Xin , McClain Joyce , Jimenez Johanna , Nannuru Kalyan C. , Rothman Nyanza J. , Lees-Shepard John B. , Martinez-Hackert Erik , Murphy Andrew J. , Thompson Thomas B. , Economides Aris N. , Idone Vincent 
Published: August 2019

AbstractActivin A functions in BMP signaling in two ways: it either engages ACVR1B to activate Smad2/3 signaling or binds ACVR1 to form a non-signaling complex (NSC). Although the former property has been studied extensively, the roles of the NSC remain unexplored. The genetic disorder fibrodysplasia ossificans progressiva (FOP) provides a unique window into ACVR1/Activin A signaling because in that disease Activin can either signal through FOP-mutant ACVR1 or form NSCs with wild type ACVR1. To explore the role of the NSC, we generated ‘agonist-only’ Activin A muteins that activate ACVR1B but cannot form the NSC with ACVR1. Using one of these muteins we demonstrate that failure to form the NSC in FOP results in more severe disease pathology. These results provide the first evidence for a biological role for the NSC in vivo and pave the way for further exploration of the NSC’s physiological role in corresponding knock-in mice.Impact StatementThe non-signaling complex formed by Activin A and ACVR1 is operant in vivo and is required to temper the degree of heterotopic ossification in the genetic disorder fibrodysplasia ossificans progressiva.
Job insecurity and performance over time: the critical role of job insecurity duration
Authors: Debus Maike E. , Unger Dana , König Cornelius J. 
Published: August 2019

PurposeResearch on the relationship between job insecurity and job performance has thus far yielded inconclusive results. The purpose of this paper is to offer a more dynamic perspective on the effects of job insecurity on job performance.Design/methodology/approachDrawing from cognitive appraisal theory, research on critical life events, and stress reactions as well as more general theorizing around the role of time, this paper proposes that individuals’ job performance reactions to job insecurity will be dynamic over time.FindingsAdopting a person-centered perspective, this paper suggests that there are seven subpopulations that differ in their intra-individual job performance change patterns over time.Research limitations/implicationsThis paper presents potential predictors of subpopulation membership and presents an agenda for future research.Originality/valueWe contribute to the literature by introducing a dynamic perspective to the study of job performance in the context of job insecurity. Delineating a set of open questions that follow from the presented theoretical arguments, the authors also hope to stimulate future research in the context of job insecurity and job performance.
Efficient uncertainty propagation for MAPOD via polynomial chaos-based Kriging
Authors: Du Xiaosong , Leifsson Leifur 
Published: August 2019

Purpose
Model-assisted probability of detection (MAPOD) is an important approach used as part of assessing the reliability of nondestructive testing systems. The purpose of this paper is to apply the polynomial chaos-based Kriging (PCK) metamodeling method to MAPOD for the first time to enable efficient uncertainty propagation, which is currently a major bottleneck when using accurate physics-based models.

Design/methodology/approach
In this paper, the state-of-the-art Kriging, polynomial chaos expansions (PCE) and PCK are applied to “a^ vs a”-based MAPOD of ultrasonic testing (UT) benchmark problems. In particular, Kriging interpolation matches the observations well, while PCE is capable of capturing the global trend accurately. The proposed UP approach for MAPOD using PCK adopts the PCE bases as the trend function of the universal Kriging model, aiming at combining advantages of both metamodels.

Findings
To reach a pre-set accuracy threshold, the PCK method requires 50 per cent fewer training points than the PCE method, and around one order of magnitude fewer than Kriging for the test cases considered. The relative differences on the key MAPOD metrics compared with those from the physics-based models are controlled within 1 per cent.

Originality/value
The contributions of this work are the first application of PCK metamodel for MAPOD analysis, the first comparison between PCK with the current state-of-the-art metamodels for MAPOD and new MAPOD results for the UT benchmark cases.