bluuebunny/crossref_metadata_2025_split huggingface dataset:
Probing compression versus stretch activated recruitment of cortical actin and apical junction proteins using mechanical stimulations of suspended doublets
Authors: Gao Xumei , Acharya Bipul R. , Otto Engl Wilfried Claude , De Mets Richard , Thiery Jean Paul , Yap Alpha S. , Viasnoff Virgile 
Published: April 2018

ABSTRACTWe report an experimental approach to study the mechanosensitivity of cellcell contact upon mechanical stimulation in suspended cell-doublets. The doublet is placed astride an hourglass aperture, and a hydrodynamic force is selectively exerted on only one of the cells. The geometry of the device concentrates the mechanical shear over the junction area. Together with mechanical shear, the system also allows confocal quantitative live imaging of the recruitment of junction proteins (e.g. E-cadherin, ZO-1, Occludin and actin). We observed the time sequence over which proteins were recruited to the stretched region of the contact. The compressed side of the contact showed no response. We demonstrated how this mechanism polarizes the stress-induced recruitment of junctional components within one single junction. Finally, we demonstrated that stabilizing the actin cortex dynamics abolishes the mechanosensitive response of the junction. Our experimental design provides an original approach to study the role of mechanical force at a cell-cell contact with unprecedented control over stress application and quantitative optical analysis.
TFEA.ChIP: A tool kit for transcription factor binding site enrichment analysis capitalizing on ChIP-seq datasets
Authors: Puente-Santamaria Laura , del Peso Luis 
Published: April 2018

AbstractThe identification of transcription factors (TFs) responsible for the co-regulation of specific sets of genes is a common problem in transcriptomics. Herein we describe TFEA.ChIP, a tool to estimate and visualize TF enrichment in gene lists representing transcriptional profiles. To generate the gene sets representing TF targets, we gathered ChIP-Seq experiments from the ENCODE Consortium and GEO datasets and used the correlation between Dnase Hypersensitive Sites across cell lines to generate a database linking TFs with the genes they interact with in each ChIP-Seq experiment. In its current state, TFEA.ChIP covers 327 different transcription factors from 1075 ChIP-Seq experiments, with over 150 cell types being represented. TFEA.ChIP accepts gene sets as well as sorted lists differentially expressed genes to compute enrichment scores for each of the datasets in its internal database using an Fisher’s exact association test or a Gene Set Enrichment Analysis. We validated TFEA.ChIP using a wide variety of gene sets representing signatures of genetic and chemical perturbations as input and found that the relevant TF was correctly identified in 103 of a total of 144 analyzed datasets with a median area under the curve (AUC) of 0.86. In depth analysis of an RNAseq dataset, illustrates that the use of ChIP-Seq data instead of PWM-based provides key biological context to interpret the results of the analysis. To facilitate its integration into transcriptome analysis pipelines and allow easy expansion and customization of the TF-gene database, we implemented TFEA.ChIP as an R package that can be downloaded from Bioconductor: https://www.bioconductor.org/packages/devel/bioc/html/TFEA.ChIP.html and github: https://github.com/LauraPS1/TFEA-drafts In addition, make it available to a wide range of researches, we have also developed a web application that runs the package from the server side and enables easy exploratory analysis through interactive graphs: https://www.iib.uam.es/TFEA.ChIP/
The rodent lateral orbitofrontal cortex represents expected Pavlovian outcome value but not identity
Authors: Panayi Marios C. , Killcross Simon 
Published: April 2018

AbstractThe orbitofrontal cortex (OFC) is critical for updating reward-directed behaviours flexibly when task contingencies are reversed, or when outcomes are devalued. We systematically examined the generality of these findings using lesions of the rodent lateral OFC (LO) in instrumental action-outcome, and Pavlovian cue-outcome, learning using specific satiety and taste aversion methods of outcome devaluation. LO lesions disrupted outcome devaluation in Pavlovian but not instrumental procedures. Furthermore, this effect was only observed when using taste-aversion devaluation. Using a specific Pavlovian-to-Instrumental transfer procedure, we established that LO is not necessary for the representation of specific outcome properties, but rather in using these properties to access the current motivational value of outcomes. The role of LO in outcome devaluation and reversal learning was also dissociable between anterior and posterior subregions. These novel dissociable task- and subregion-specific effects suggest a way to reconcile contradictory findings between rodent and non-human primate OFC research.
TGF-β induced CXCL13 in CD8+ T cells is associated with tertiary lymphoid structures in cancer
Authors: Workel HH , Lubbers JM , Arnold R , Prins T , van der Vlies P , de Lange K , Bosse T , van Gool I , Eggink FA , Wouters MCA , Komdeur FL , Creutzberg CL , Kol A , Plat A , Glaire M , Church DN , Nijman HW , de Bruyn M 
Published: April 2018

AbstractCoordinated immune responses against human tumors are frequently characterized by tertiary lymphoid structures (TLS) which predict improved prognosis. The development of TLS is dependent on the chemokine CXCL13, reported to be secreted by dendritic cells and follicular helper T cells only. We report the unexpected finding that CXCL13 is also secreted by activated CD8+ T cells following stimulation by transforming growth factor beta (TGF-β). Using single cell RNA sequencing we found that expression ofCXCL13in CD8+ T cells was restricted to the intraepithelial CD103+ population. Accordingly, CD8+ T cells activated in the presence of TGF-β simultaneously upregulated CD103 and secreted CXCL13.CXCL13expression was strongly correlated with neo-antigen burden and cytolytic gene signatures in bulk tumors. In line with this, TLS were abundant in neo-antigen-high, CD103+ T cell-enriched tumors. TGF-β thus appears to play a role in coordinating immune responses against human tumors through CD8-dependent CXCL13-associated formation of TLS.
Determining protein structures using genetics
Authors: Schmiedel Jörn M. , Lehner Ben 
Published: April 2018

SummaryDetermining the three dimensional structures of macromolecules is a major goal of biological research because of the close relationship between structure and function. Structure determination usually relies on physical techniques including x-ray crystallography, NMR spectroscopy and cryo-electron microscopy. Here we present a method that allows the high-resolution three-dimensional structure of a biological macromolecule to be determined only from measurements of the activity of mutant variants of the molecule. This genetic approach to structure determination relies on the quantification of genetic interactions (epistasis) between mutations and the discrimination of direct from indirect interactions. This provides a new experimental strategy for structure determination, with the potential to reveal functional and in vivo structural conformations at low cost and high throughput.
Genetic studies of accelerometer-based sleep measures in 85,670 individuals yield new insights into human sleep behaviour
Authors: Jones Samuel E. , Hees Vincent T. van , Mazzotti Diego R. , Marques-Vidal Pedro , Sabia Séverine , der Spek Ashley van , Dashti Hassan S. , Engmann Jorgen , Kocevska Desana , Tyrrell Jessica , Beaumont Robin N. , Hillsdon Melvyn , Ruth Katherine S. , Tuke Marcus A. , Yaghootkar Hanieh , Sharp Seth , Jie Yingjie , Harrison Jamie W. , Freathy Rachel M. , Murray Anna , Luik Annemarie I. , Amin Najaf , Lane Jacqueline M. , Saxena Richa , Rutter Martin K. , Tiemeier Henning , Kutalik Zoltan , Kumari Meena , Frayling Timothy M. , Weedon Michael N. , Gehrman Philip , Wood Andrew R. 
Published: April 2018

ABSTRACTSleep is an essential human function but its regulation is poorly understood. Identifying genetic variants associated with quality, quantity and timing of sleep will provide biological insights into the regulation of sleep and potential links with disease. Using accelerometer data from 85,670 individuals in the UK Biobank, we performed a genome-wide association study of 8 accelerometer-derived sleep traits, 5 of which are not accessible through self-report alone. We identified 47 genetic associations across the sleep traits (P<5×10-8) and replicated our findings in 5,819 individuals from 3 independent studies. These included 26 novel associations for sleep quality and 10 for nocturnal sleep duration. The majority of newly identified variants were associated with a single sleep trait, except for variants previously associated with restless legs syndrome that were associated with multiple sleep traits. Of the new associated and replicated sleep duration loci, we were able to fine-map a missense variant (p.Tyr727Cys) in PDE11A, a dual-specificity 3’,5’-cyclic nucleotide phosphodiesterase expressed in the hippocampus, as the likely causal variant. As a group, sleep quality loci were enriched for serotonin processing genes and all sleep traits were enriched for cerebellar-expressed genes. These findings provide new biological insights into sleep characteristics.
Dynamic causal modelling of fluctuating connectivity in resting-state EEG
Authors: Van de Steen Frederik , Almgren Hannes , Razi Adeel , Friston Karl , Marinazzo Daniele 
Published: April 2018

ABSTRACTFunctional and effective connectivity are known to change systematically over time. These changes might be explained by several factors, including intrinsic fluctuations in activity-dependent neuronal coupling and contextual factors, like experimental condition and time. Furthermore, contextual effects may be subject-specific or conserved over subjects. To characterize fluctuations in effective connectivity, we used dynamic causal modelling (DCM) of cross spectral responses over 1 min of electroencephalogram (EEG) recordings during rest, divided into 1-sec windows. We focused on two intrinsic networks: the default mode and the saliency network. DCM was applied to estimate connectivity in each time-window for both networks. Fluctuations in DCM connectivity parameters were assessed using hierarchical parametric empirical Bayes (PEB). Within-subject, between-window effects were modelled with a second-level linear model with temporal basis functions as regressors. This procedure was conducted for every subject separately. Bayesian model reduction was then used to assess which (combination of) temporal basis functions best explain dynamic connectivity over windows. A third (between-subject) level model was used to infer which dynamic connectivity parameters are conserved over subjects. Our results indicate that connectivity fluctuations in the saliency network comprised both subject-specific components and a common component. For the default mode network, connectivity trajectories only showed a common component. For both networks, connections to higher order regions appear to monotonically increase during the one minute period. These results not only establish the predictive validity of dynamic connectivity estimates – in virtue of detecting systematic changes over subjects – they also suggest a network-specific dissociation in the relative contribution of fluctuations in connectivity that depend upon experimental context. We envisage these procedures could be useful for characterizing brain state transitions that may be explained by their cognitive or neuropathological underpinnings.
Frequencies of circulating Th1-biased T follicular helper cells in acute HIV-1 infection correlate with the development of HIV-specific antibody responses and lower set point viral load
Authors: Baiyegunhi Omolara , Ndlovu Bongiwe , Ogunshola Funsho , Ismail Nasreen , Walker Bruce D. , Ndung’u Thumbi , Ndhlovu Zaza M. 
Published: April 2018

AbstractDespite decades of focused research, the field has yet to develop a prophylactic vaccine. In the RV144 vaccine trial, non-neutralizing antibody responses were identified as a correlate for prevention of HIV acquisition. However, factors that predict the development of such antibodies are not fully elucidated. We sought to define the contribution of circulating T follicular helper (cTfh) cell subsets to the development of non-neutralizing antibodies in HIV-1 clade C infection. Study participants were recruited from an acute HIV-1 clade C infection cohort. Plasma anti-gp41, -gp120, -p24 and -p17 antibodies were screened using a customized multivariate Luminex assay. Phenotypic and functional characterization of cTfh were performed using HLA class II tetramers and intracellular cytokine staining. In this study, we found that acute HIV-1 clade C infection skewed differentiation of functional cTfh subsets towards increased Tfh1 (p=0.02) and Tfh2 (p<0.0001) subsets, with a concomitant decrease in overall Tfh1-17 (that shares both Tfh1 and Tfh17 properties) (p=0.01) and Tfh17 subsets (p<0.0001) compared to HIV negative subjects. Interestingly, the frequencies of Tfh1 during acute infection (5.0-8.0 weeks post-infection) correlated negatively with set point viral load (p=0.03, r=-60) and were predictive of p24-specific plasma IgG titers at one year of infection (p=0.003, r=0.85). Taken together, our results suggest that circulating the Tfh1 subset plays an important role in the development of anti-HIV antibody responses and contributes to HIV suppression during acute HIV-1 infection. These results have implications for vaccine studies aimed at inducing long lasting anti-HIV antibody responses.ImportanceThe HIV epidemic in southern Africa accounts for almost half of the global HIV burden with HIV-1 clade C being the predominant strain. It is therefore important to define immune correlates of clade C HIV control that might have implications for vaccine design in this region. T follicular helper (Tfh) cells are critical for the development of HIV-specific antibody responses and could play a role in viral control. Here we showed that the early induction of circulating Tfh1 cells during acute infection correlated positively with the magnitude of p24-specific IgG and was associated with lower set point viral load. This study highlights a key Tfh cell subset that could limit HIV replication by enhancing antibody generation. This study underscores the importance of circulating Tfh cells in promoting non-neutralizing antibodies during HIV-1 infection.
Early detection of active Human Cytomegalovirus infection after living-donor liver transplantation
Authors: Rizk Mohamed Anies , Agha Salah Abd Elfatah , Zaki Maysaa El Sayed , El-Mashad Noha Badr El-Deen , El-Saadany Mohamed Mahmoud Fahmy 
Published: April 2018

AbstractHuman cytomegalovirus (HCMV) is a member of the beta herpes virinae. It is one of the most important virus in transplantation. It has direct and indirect impact on liver transplant recipient outcome. We aimed to diagnose early active HCMV infection in living donor liver transplant (LDLT) recipients. Also, to correlate the associated clinical and laboratory findings with HCMV infection. Here, we investigate 76 LDLT recipients for early detection of active HCMV infection in a period of 1-6 months after liver transplantation upon their suggested clinical data. These samples were collected in the period from 4/2013 to 12/ 2015 at Gastroenterology center, Mansoura University. They were 68 males and 8 females. HCMV infection diagnosed by ELISA (Ig M, Ig G) and real time PCR. Seventy-four patients were IgG seropositive recipient. Three patients (3.9%) were positive IgM. Ten samples from 76 patients (13.2%) were positive by real-time polymerase chain reaction (PCR). In this study, we concluded that, LDLT recipients are at high risk of HCMV infection (13.2%) and the most suitable method for HCMV detection was PCR.
Implicit but not explicit exposure to threat conditioned stimulus prevents spontaneous recovery of threat potentiated startle responses in humans
Authors: Oyarzún JP , Càmara E , Kouider S , Fuentemilla L , de Diego-Balaguer R 
Published: April 2018

ABSTRACTIt has long been posited that threat learning operates and forms under an affective and a cognitive learning system that are supported by different brain circuits. A primary drawback in exposure-based therapies is the high rate of relapse when higher order inhibitory structures failed to inhibit the emotional responses driven by the defensive circuit. It has been shown that implicit exposure of fearful stimuli leads to a long-lasting reduction of avoidance behavior in patients with phobia through the facilitation of fear processing areas in the absence of subjective fear. Despite the potential benefits of this approach in the treatment of phobias and PTSD, implicit exposure to fearful stimuli is still under-investigated. Here, we used unconscious presentation of threat-conditioned stimuli in healthy humans, using a continuous flash suppression technique. We found that implicit exposure of a conditioned stimulus reduced, on the following day, defensive responses to the conditioned stimulus measured by threat-potentiated startle responses but not by the electrodermal activity. Our results suggest that implicit exposure using CFS might facilitate the modulation of the affective component of fearful memories, representing an important therapeutic target to further advance exposure-based psychotherapies.
Self-organised segregation of bacterial chromosomal origins
Authors: Hofmann Andreas , Mäkelä Jarno , Sherratt David , Heermann Dieter , M. Murray Seán 
Published: April 2018

AbstractIn spite of much effort, many aspects of chromosome organisation and segregation in bacteria remain unclear. Even for Escherichia coli, the most widely studied bacterial model organism, we still do not know the underlying mechanisms. Like many other bacteria, the chromosomal origin of replication in E. coli is dynamically positioned throughout the cell cycle. Initially maintained at mid-cell, where replication occurs, origins are subsequently partitioned to opposite quarter positions. The Structural Maintenance of Chromosomes (SMC) complex, MukBEF, which is required for correct chromosome compaction and organisation, has been implicated in this behaviour but the mode of action is unknown. Here, we build on a recent self-organising model for the positioning of E. coli MukBEF, to propose an explanation for the positioning and partitioning of origins. We propose that a specific association of MukBEF with the origin region, results in a non-trivial feedback between the self-organising MukBEF gradient and the origins, leading to accurate positioning and partitioning as an emergent property. We compare the model to quantitative experimental data of origin dynamics and their colocalisation with MukBEF clusters and find excellent agreement. Overall, the model suggests that MukBEF and origins act together as a self-organising system for chromosome segregation and introduces protein self-organisation as an important consideration for future studies of chromosome dynamics.
Benchmarking Statistical Multiple Sequence Alignment
Authors: Nute Michael , Saleh Ehsan , Warnow Tandy 
Published: April 2018

AbstractThe estimation of multiple sequence alignments of protein sequences is a basic step in many bioinformatics pipelines, including protein structure prediction, protein family identification, and phylogeny estimation. Statistical co-estimation of alignments and trees under stochastic models of sequence evolution has long been considered the most rigorous technique for estimating alignments and trees, but little is known about the accuracy of such methods on biological benchmarks. We report the results of an extensive study evaluating the most popular protein alignment methods as well as the statistical co-estimation method BAli-Phy on 1192 protein data sets from established benchmarks as well as on 120 simulated data sets. Our study (which used more than 230 CPU years for the BAli-Phy analyses alone) shows that BAli-Phy is dramatically more accurate than the other alignment methods on the simulated data sets, but is among the least accurate on the biological benchmarks. There are several potential causes for this discordance, including model misspecification, errors in the reference alignments, and conflicts between structural alignment and evolutionary alignments; future research is needed to understand the most likely explanation for our observations. multiple sequence alignment, BAli-Phy, protein sequences, structural alignment, homology
TheDrosophilaTNF Eiger activates caspase-dependent necrosis when apoptosis is blocked
Authors: Li Mingli , Fan Yun 
Published: April 2018

AbstractEiger (Egr), the homolog of the mammalian tumor-necrosis factor (TNF), is the ligand of the c-Jun N-terminal kinase (JNK) stress response signaling pathway inDrosophila. Although expression of Egr frequently leads to apoptosis, it has also been implicated in activation of non-apoptotic cell death. However, it is not yet clear how Egr can induce both apoptosis and non-apoptotic cell death, and if so, how such processes are coordinated. Here, we show that expression of Egr in the developingDrosophilaeye induces apoptosis and non-apoptotic developmental defects, both of which are JNK-dependent. Intriguingly, when apoptotic effector caspases DrICE and Dcp-1 are defective or inhibited, expression of Egr induces necrosis characterized by loss of cell membrane integrity, translucent cytoplasm and aggregation of cellular organelles. Surprisingly, the induction of necrosis depends on the catalytic activity of the initiator caspase Dronc and the input from JNK signaling independently of their roles in apoptosis. Therefore, similar to the mammalian caspase-8, caspases inDrosophilaalso have dual roles in promoting TNF-mediated apoptosis and inhibiting necrosis.
The Amyloid Precursor-like Protein APL-1 Regulates Axon Regeneration
Authors: Zeng Lewie , El Bejjani Rachid , Hammarlund Marc 
Published: April 2018

AbstractMembers of the Amyloid Precursor Protein (APP) family have important functions during neuronal development. However, their physiological functions in the mature nervous system are not fully understood. Here we use theC. elegansGABAergic motor neurons to study the post-developmental function of the APP-like protein APL-1 in vivo. We find thatapl-1has minimum roles in the maintenance of gross neuron morphology and function. However, we show thatapl-1is an inhibitor of axon regeneration, acting on mature neurons to limit regrowth in response to injury. The small GTPase Rab6/RAB-6.2 also inhibits regeneration, and does so in part by maintaining protein levels of APL-1. To inhibit regeneration, APL-1 functions via the E2 domain of its ectodomain; the cytoplasmic tail, transmembrane anchoring, and the E1 domain are not required for this function. Our data defines a novel role for APL-1 in modulating the neuronal response to injury.
Possibilities for improvement of humoral innate immunity in turkeys and hens in conditions of thermal stress by the immunomodulator Immunobeta
Authors: Bozakova N. , Sotirov L. , Denev S. , Koynarski Ts. 
Published: April 2018

SummaryThe experiments for evaluation of the effect of Immunobeta were performed with turkeys and organically reared layer hens. Turkeys received Immunobeta at a dose of 4 g/kg feed during the beginning of lay (cold period), thermoneutral period and hot summer period. In hens, two dietary levels of Immunobeta were tested: 2 g/kg and 4 g/kg. Blood serum and egg lysozyme levels, alternative pathway of complement activation (APCA) and beta-lysins concentrations were determined. It was found out that Immunobeta had a beneficial effect on serum lysozyme, APCA activity and beta-lysins in turkeys and hens. The lysozyme concentration in egg white was statistically significantly higher in eggs produced by birds treated with both doses of the immunomodulator.