bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cohort Profile: East London Genes & Health (ELGH), a community based population genomics and health study of British-Bangladeshi and British-Pakistani people
Authors: Finer Sarah , Martin Hilary C. , Khan Ahsan , Hunt Karen A , MacLaughlin Beverley , Ahmed Zaheer , Ashcroft Richard , Durham Ceri , MacArthur Daniel G , McCarthy Mark I , Robson John , Trivedi Bhavi , Griffiths Chris , Wright John , Trembath Richard C , van Heel David A 
Published: September 2018

Cohort profile in a nutshellEast London Genes & Health (ELGH) is a large scale, community genomics and health study (to date >34,000 volunteers; target 100,000 volunteers).ELGH was set up in 2015 to gain deeper understanding of health and disease, and underlying genetic influences, in British-Bangladeshi and British-Pakistani people living in east London.ELGH prioritises studies in areas important to, and identified by, the community it represents. Current priorities include cardiometabolic diseases and mental illness, these being of notably high prevalence and severity. However studies in any scientific area are possible, subject to community advisory group and ethical approval.ELGH combines health data science (using linked UK National Health Service (NHS) electronic health record data) with exome sequencing and SNP array genotyping to elucidate the genetic influence on health and disease, including the contribution from high rates of parental relatedness on rare genetic variation and homozygosity (autozygosity), in two understudied ethnic groups. Linkage to longitudinal health record data enables both retrospective and prospective analyses.Through Stage 2 studies, ELGH offers researchers the opportunity to undertake recall-by-genotype and/or recall-by-phenotype studies on volunteers. Sub-cohort, trial-within-cohort, and other study designs are possible.ELGH is a fully collaborative, open access resource, open to academic and life sciences industry scientific research partners.
The folded X-pattern is not necessarily a statistical signature of decision confidence
Authors: Rausch Manuel , Zehetleitner Michael 
Published: September 2018

AbstractRecent studies have traced the neural correlates of confidence in perceptual choices using statistical signatures of confidence. The most widely used statistical signature is the folded X-pattern, which was derived from a standard model of confidence assuming an objective definition of confidence as the posterior probability of making the correct choice given the evidence. The folded X-pattern entails that confidence as the subjective probability of being correct equals the probability 0.75 if the stimulus in neutral about the choice options, increases with discriminability of the stimulus in correct trials, and decreases with discriminability in incorrect trials. Here, we show that the standard model of confidence is a special case in which there is no reliable trial-by-trial evidence about discriminability itself. According to a more general model, if there is enough evidence about discriminability, objective confidence is characterised by different pattern: For both correct and incorrect choices, confidence increases with discriminability. In addition, we demonstrate the consequence if discriminability is varied in discrete steps within the standard model: confidence in choices about neutral stimuli is no longer .75. Overall, identifying neural correlates of confidence by presupposing the folded X-pattern as a statistical signature of confidence is not legitimate.
RTHybrid: a standardized and open-source real-time software model library for experimental neuroscience
Authors: Amaducci Rodrigo , Reyes-Sanchez Manuel , Elices Irene , Rodriguez Francisco B. , Varona Pablo 
Published: September 2018

ABSTRACTClosed-loop technologies provide novel ways of online observation, control and bidirectional interaction with the nervous system, which help to study complex non-linear and partially observable neural dynamics. These protocols are often difficult to implement due to the temporal precision required when interacting with biological components, which in many cases can only be achieved using real-time technology. In this paper we introduce RTHybrid (www.github.com/GNB-UAM/RTHybrid), a free and open-source software that includes a neuron and synapse model library to build hybrid circuits with living neurons in a wide variety of experimental contexts. In an effort to encourage the standardization of real-time software technology in neuroscience research, we compared different open-source real-time operating system patches, RTAI, Xenomai 3 and Preempt-RT, according to their performance and usability. RTHybrid has been developed to run over Linux operating systems supporting both Xenomai 3 and Preempt-RT real-time patches, and thus allowing an easy implementation in any laboratory. We report a set of validation tests and latency benchmarks for the construction of hybrid circuits using this library. With this work we want to promote the dissemination of standardized, user-friendly and open-source software tools developed for open- and closed-loop experimental neuroscience.
The bacterial chromatin protein HupA can remodel DNA and associates with the nucleoid in Clostridium difficile
Authors: Oliveira Paiva Ana M. , Friggen Annemieke H. , Qin Liang , Douwes Roxanne , Dame Remus T. , Smits Wiep Klaas 
Published: September 2018

AbstractThe maintenance and organization of the chromosome plays an important role in the development and survival of bacteria. Bacterial chromatin proteins are architectural proteins that bind DNA, modulate its conformation and by doing so affect a variety of cellular processes. No bacterial chromatin proteins of C. difficile have been characterized to date.Here, we investigate aspects of the C. difficile HupA protein, a homologue of the histone-like HU proteins of Escherichia coli. HupA is a 10 kDa protein that is present as a homodimer in vitro and self-interacts in vivo. HupA co-localizes with the nucleoid of C. difficile. It binds to the DNA without a preference for the DNA G+C content. Upon DNA binding, HupA induces a conformational change in the substrate DNA in vitro and leads to compaction of the chromosome in vivo.The present study is the first to characterize a bacterial chromatin protein in C. difficile and opens the way to study the role of chromosomal organization in DNA metabolism and on other cellular processes in this organism.
Multicenter validation of a machine learning algorithm for 48 hour all-cause mortality prediction
Authors: Mohamadlou Hamid , Panchavati Saarang , Calvert Jacob , Lynn-Palevsky Anna , Barton Christopher , Fletcher Grant , Shieh Lisa , Stark Philip B , Chettipally Uli , Shimabukuro David , Feldman Mitchell , Das Ritankar 
Published: September 2018

AbstractPurposeThis study evaluates a machine-learning-based mortality prediction tool.Materials and MethodsWe conducted a retrospective study with data drawn from three academic health centers. Inpatients of at least 18 years of age and with at least one observation of each vital sign were included. Predictions were made at 12, 24, and 48 hours before death. Models fit to training data from each institution were evaluated on hold-out test data from the same institution and data from the remaining institutions. Predictions were compared to those of qSOFA and MEWS using area under the receiver operating characteristic curve (AUROC).ResultsFor training and testing on data from a single institution, machine learning predictions averaged AUROCs of 0.97, 0.96, and 0.95 across institutional test sets for 12-, 24-, and 48-hour predictions, respectively. When trained and tested on data from different hospitals, the algorithm achieved AUROC up to 0.95, 0.93, and 0.91, for 12-, 24-, and 48-hour predictions, respectively. MEWS and qSOFA had average 48-hour AUROCs of 0.86 and 0.82, respectively.ConclusionThis algorithm may help identify patients in need of increased levels of clinical care.
Dual mechanism of TRKB activation by anandamide through CB1 and TRPV1 receptors
Authors: Craf Diniz , Biojone C , Joca SRL , Rantamäki T , Castrén E , Guimarães FS , Casarotto PC 
Published: September 2018

AbstractBackgroundadministration of anandamide (AEA) or 2-arachidonoylglycerol (2AG) induces CB1 coupling and activation of TRKB receptors, regulating the neuronal migration and maturation in the developing cortex. However, at higher concentrations AEA also engages vanilloid receptor - TRPV1, usually with opposed consequences on behavior.Methods and ResultsUsing primary cell cultures from the cortex of rat embryos (E18) we determined the effects of AEA on phosphorylated TRKB (pTRK). We observed that AEA (at 100 and 200nM) induced a significant increase in pTRK levels. Such effect of AEA at 100nM was blocked by pretreatment with the CB1 antagonist AM251 (200nM) and, at the higher concentration of 200nM by the TRPV1 antagonist capsazepine (200nM), but mildly attenuated by AM251. Interestingly, the effect of AEA or capsaicin (a TRPV1 agonist, also at 200nM) on pTRK was blocked by TRKB.Fc (a soluble form of TRKB able to bind BDNF) or capsazepine, suggesting a mechanism dependent on BDNF release. Using the marble-burying test (MBT) in mice, we observed that the local administration of ACEA (a CB1 agonist) into the prelimbic region of prefrontal cortex (PL-PFC) was sufficient to reduce the burying behavior, while capsaicin or BDNF exerted the opposite effect, increasing the number of buried marbles. In addition, both ACEA and capsaicin effects were blocked by previous administration of k252a (an antagonist of TRK receptors) into PL-PFC. The effect of systemically injected CB1 agonist WIN55,212-2 was blocked by previous administration of k252a. We also observed a partial colocalization of CB1 /TRPV1 /TRKB in the PL-PFC, and the localization of TRPV1 in CaMK2+ cells.Conclusiontaken together, our data indicate that anandamide engages a coordinated activation of TRKB, via CB1 and TRPV1. Thus, acting upon CB1 and TRPV1, AEA could regulate the TRKB-dependent plasticity in both pre- and postsynaptic compartments.
A well-controlled BioID design for endogenous bait proteins
Authors: Vandemoortele Giel , De Sutter Delphine , Moliere Aline , Pauwels Jarne , Gevaert Kris , Eyckerman Sven 
Published: September 2018

ABSTRACTThe CRISPR/Cas9 revolution is profoundly changing the way life sciences technologies are used. Many assays now rely on engineered clonal cell lines to eliminate overexpression of bait proteins. Control cell lines are typically non-engineered cells or engineered clones implying a considerable risk for artefacts because of clonal variation. Genome engineering can also transform BioID, a proximity labelling method that relies on fusing a bait protein to a promiscuous biotin ligase, BirA*, resulting in the tagging of vicinal proteins. We here propose an innovative design to enable BioID for endogenous proteins wherein we introduce a T2A-BirA* module at the C-terminus of endogenous p53 by genome engineering, leading to bi-cistronic expression of both p53 and BirA* under control of the endogenous promoter. By targeting a Cas9-cytidine deaminase base editor to the T2A auto-cleavage site, we can efficiently derive an isogenic population expressing a functional p53-BirA* fusion protein. Using quantitative proteomics we show significant benefits over classical ectopic expression of p53-BirA*, and we provide a first well-controlled view on the proximal proteins of endogenous p53 in colon carcinoma cells. This novel application for base editors expands the CRISPR/Cas9 toolbox and can be a valuable addition for synthetic biology.
Adaptive genomic variation associated with environmental gradients along a latitudinal cline inRana temporaria
Authors: van Rensburg Alexandra Jansen , Cortazar-Chinarro Maria , Laurila Annsi , Van Buskirk Josh 
Published: September 2018

AbstractRana temporariaoccur across a large geographic and environmental gradient in Scandinavia. Several studies involving common garden experiments have established adaptive divergence across the gradient. The main objective of this study was to determine the extent of neutral and adaptive genetic divergence across the latitudinal gradient. Here we sequence genome-wide markers for 15 populations from six regions sampled from southern Sweden to Finland. Using a multivariate approach we find that 68% of the genomic variation is associated with climate or geographically structured climate. Using outlier scans and environmental association analyses we identify a set of potentially adaptive loci and examine their change in allele frequency associated with different climatic variables. Using a gradient forest analysis we identify points along three of the climate variables where allele frequencies change more rapidly than expected if it were a linear association. We identify a large threshold effect associated with BIO5 (mean temperature during the warmest month) which is seen as a rapid change in southern Sweden. By comparing the change in neutral and adaptive allele frequencies across the whole gradient, we identify southern Sweden as a region with the largest divergence between the datasets. This suggests small changes in the climate may result in a mismatch between the adaptive genotypes and the environment in these populations. Overall this study shows that genomic analyses can provide a powerful complement to common garden experiments to improve our understanding of adaptive divergence across heterogeneous landscapes.
Macrophages protect against loss of adipose tissue during cancer cachexia
Authors: Erdem Merve , Möckel Diana , Jumpertz Sandra , John Cathleen , Fragoulis Athanassios , Rudolph Ines , Wulfmeier Johanna , Springer Jochen , Horn Henrike , Koch Marco , Lurje Georg , Lammers Twan , der Kroft Gregory van , Gremse Felix , Cramer Thorsten 
Published: September 2018

AbstractCancer cachexia represents a central obstacle in medical oncology as it is associated with poor therapy response and reduced overall survival. Systemic inflammation is considered to be a key driver of cancer cachexia, however, clinical studies with anti-inflammatory drugs failed to show a robust cachexia-inhibiting effect. To address this contradiction, we investigated the functional importance of innate immune cells for hepatocellular carcinoma (HCC)-associated cachexia. To this end, we used a transgenic HCC mouse model intercrossed with mice harboring a defect in myeloid cell-mediated inflammation. We identified robust cachexia in the HCC mouse model as evidenced by a marked loss of visceral fat and lean mass. Computed tomography-based analyses demonstrated that a subgroup of human HCC patients displays reduced visceral fat mass, complementing the murine data. While the myeloid cell-mediated inflammation defect resulted in reduced expression of pro-inflammatory cytokines in the serum of HCC-bearing mice, this unexpectedly did not translate into diminished, but rather enhanced cachexia-associated fat loss. Defective myeloid cell-mediated inflammation was associated with decreased macrophage abundance in visceral adipose tissue, suggesting a role for local macrophages in the regulation of cancer-induced fat loss. Taken together, myeloid cell-mediated inflammation displays a rather unexpected beneficial function in a murine HCC model. These results demonstrate that immune cells are capable of protecting the host against cancer-induced tissue wasting, adding a further layer of complexity to the pathogenesis of cachexia and providing a potential explanation for the contradictory results of clinical studies with anti-inflammatory drugs.
The nuclear RNAi factor, NRDE2, prevents the accumulation of DNA damage during mitosis in stressful growth conditions
Authors: Asundi Aarati , Venkataramanan Srivats , Cuellar Gina Caldas , Suzuki Atsushi , Floor Stephen N. , Goga Andrei , L’Etoile Noelle 
Published: September 2018

AbstractOrganisms have evolved multiple mechanisms to prevent and repair DNA damage to protect the integrity of the genome, particularly under stressful conditions. Unrepaired DNA damage leads to genomic instability, aneuploidy, and an increased risk for cancer. Before the cell can divide, it must repair damaged DNA and it is thought that this process requires global silencing of most transcription. In C. elegans, NRDE-2, in complex with other nuclear factors and guided by small RNA, directs heterochromatin formation and transcriptional silencing of targeted genes. Additionally, when C. elegans are cultivated at high temperatures, NRDE-2 is required to maintain germ line immortality. However, the role of NRDE-2 in maintaining the physical integrity of the genome is not understood. We show here that loss of NRDE2 in either nematode or human cells induces the accumulation of DNA damage specifically under conditions of stress, such as cultivation at a high temperature in C. elegans or Aurora B Kinase oncogenic overexpression in the MCF10A epithelial breast cell line. In addition, we found that NRDE2 interacts with β-actin in unstressed mammalian cells. This interaction is dramatically reduced upon DNA damage. Monomeric nuclear actin binds to heterochromatin remodeling factors and transcriptional activators while filamentous actin has been implicated in DNA repair processes. Thus, NRDE2 may dissociate from actin when it becomes filamentous as a result of DNA damage. In this way, heterochromatin factors may associate with the actin dependent DNA repair process to allow appropriate mitotic progression and maintain genomic integrity.
Biomarker de-Mendelization: principles, potentials and limitations of a strategy to improve biomarker prediction by reducing the component of variance explained by genotype
Authors: Kjaergaard Alisa D , Bojesen Stig E , Nordestgaard Børge G , Johansen Julia S , Smith George Davey 
Published: September 2018

AbstractIn observational studies, the Mendelian randomization approach can be used to circumvent confounding, bias and reverse causation, and to assess a potential causal association between a biomarker and risk of disease. If, on the other hand, a substantial component of variance of a non-causal biomarker is explained by genotype, then genotype could potentially attenuate the observational association and the strength of the prediction. In order to reduce the component of variance explained by genotype, an approach that can be seen as the inverse of Mendelian randomization - biomarker de-Mendelization - appears plausible.Plasma YKL-40 is a good candidate for demonstrating principles of biomarker de-Mendelization because it is a non-causal biomarker with a substantial component of variance explained by genotype. This approach is an attempt to improve the observational association and the strength of a predictive biomarker; it is explicitly not aimed at detection of causal effects.We studied 21 161 individuals form the Danish general population with measurements of YKL-40 concentration and rs4950928 genotype. Four different methods for biomarker de-Mendelization are explored for alcoholic liver cirrhosis and lung cancer.De-Mendelization methods only improved predictive ability slighly. We observed an interaction between genotype and markers of developing disease with respect to YKL-40 concentration.Even when genotype explains 14% of the variance in a non-causal biomarker, we found no useful empirical improvement in risk prediction by biomarker de-Mendelization. This could reflect the predictive interaction between genotype and disease development being removed which counterbalanced any beneficial properties of the method in this situation.
Whole genome bisulfite sequencing of Down syndrome brain reveals regional DNA hypermethylation and novel disorder insights
Authors: Laufer Benjamin I. , Hwang Hyeyeon , Vogel Ciernia Annie , Mordaunt Charles E. , LaSalle Janine M. 
Published: September 2018

AbstractDown Syndrome (DS) is the most common genetic cause of intellectual disability, in which an extra copy of human chromosome 21 (HSA21) affects regional DNA methylation profiles across the genome. Although DNA methylation has been previously examined at select regulatory regions across the genome in a variety of DS tissues and cells, differentially methylated regions (DMRs) have yet to be examined in an unbiased sequencing-based approach. Here, we present the first analysis of DMRs from whole genome bisulfite sequencing (WGBS) data of human DS and matched control brain, specifically frontal cortex. While no global differences in DNA methylation were observed, we identified 3,152 DS-DMRs across the entire genome, the majority of which were hypermethylated in DS. DS-DMRs were significantly enriched at CpG islands and de-enriched at specific gene body and regulatory regions. Functionally, the hypermethylated DS-DMRs were enriched for one-carbon metabolism, membrane transport, and glutamatergic synaptic signaling, while the hypomethylated DMRs were enriched for proline isomerization, glial immune response, and apoptosis. Furthermore, in a cross-tissue comparison to previous studies of DNA methylation from diverse DS tissues and reference epigenomes, hypermethylated DS-DMRs showed a strong cross-tissue concordance, while a more tissue-specific pattern was observed for the hypomethylated DS-DMRs. Overall, this approach highlights that low-coverage WGBS of clinical samples can identify epigenetic alterations to known biological pathways, which are potentially relevant to therapeutic treatments and include metabolic pathways. These results also provide new insights into the genome-wide effects of genetic alterations on DNA methylation profiles indicative of altered neurodevelopment and brain function.
Imaging of red-shifted photons from bioluminescent tumours using fluorescence by unbound excitation from luminescence
Authors: Sônego Fabiane , Bouccara Sophie , Pons Thomas , Lequeux Nicolas , Danckaert Anne , Tinevez Jean-Yves , Alam Israt S. , Shorte Spencer L. , Tournebize Régis 
Published: September 2018

AbstractEarly detection of tumours is today a major challenge and requires sensitive imaging methodologies coupled with new efficient probes. Bioluminescence imaging has been widely used in the field of oncology and several cancer cell lines have been genetically modified to provide bioluminescence signals. However, photons that are emitted by the majority of commonly used luciferases are usually in the blue part of the visible spectrum, where tissue absorption is still very high, making deep tissue imaging non-optimal and calling for optimised optical imaging methodologies. We have previously shown that red-shifting of bioluminescence signal by Fluorescence Unbound Excitation from Luminescence (FUEL) is a mean to increase bioluminescence signal sensitivity detection in vivo. Here, we applied FUEL to tumour detection in two different subcutaneous tumour models: the auto-luminescent human embryonic kidney (HEK293) cell line and the murine B16-F10 melanoma cell line previously transfected with the plasmid Luc2. Tumour size and bioluminescence were measured over time and tumour vascularization characterized. We then locally injected near infrared emitting Quantum Dots (NIR QDs)in the tumour site and observed a red-shifting of bioluminescence signal by (FUEL) indicating that FUEL could be used to allow deeper tumour detection.