bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genetic liability to schizophrenia is associated with exposure to traumatic events in childhood
Authors: Sallis Hannah M , Croft Jazz , Havdahl Alexandra , Jones Hannah J , Dunn Erin C , Smith George Davey , Zammit Stanley , Munafò Marcus R 
Published: September 2019

AbstractBackgroundThere is a wealth of literature on the observed association between childhood trauma and psychotic illness. However, the relationship between childhood trauma and psychosis is complex and could be explained, in part, by gene-environment correlation.MethodsThe association between schizophrenia polygenic scores (PGS) and experiencing childhood trauma was investigated using data from the Avon Longitudinal Study of Parents and Children (ALSPAC) and the Norwegian Mother, Father and Child Cohort Study (MoBa). Schizophrenia PGS were derived in each cohort for children, mothers, and fathers where genetic data were available. Measures of trauma exposure were derived based on data collected throughout childhood and adolescence (0-17 years; ALSPAC) and at age 8 years (MoBa).ResultsWithin ALSPAC, we found a positive association between schizophrenia PGS and exposure to trauma across childhood and adolescence; effect sizes were consistent for both child or maternal PGS. We found evidence of an association between the schizophrenia PGS and the majority of trauma subtypes investigated, with the exception of bullying. These results were comparable in MoBa. Within ALSPAC, genetic liability to a range of additional psychiatric traits was also associated with a greater trauma exposure.ConclusionsResults from two international birth cohorts indicate that genetic liability for a range of psychiatric traits is associated with experiencing childhood trauma. GWAS of psychiatric phenotypes may also reflect risk factors for these phenotypes. Our findings also suggest that youth at higher genetic risk might require greater resources/support to ensure they grow-up in a healthy environment.
Complete characterization of the human immune cell transcriptome using accurate full-length cDNA sequencing
Authors: Cole Charles , Byrne Ashley , Adams Matthew , Volden Roger , Vollmers Christopher 
Published: September 2019

ABSTRACTThe human immune system relies on highly complex and diverse transcripts and the proteins they encode. These include transcripts forHumanLeukocyteAntigen (HLA) class I and II receptors which are essential for self/non-self discrimination by the immune system as well as transcripts encoding B cell and T cell receptors (BCR and TCR) which recognize, bind, and help eliminate foreign antigens.HLA genes are highly diverse within the human population with each individual possessing two of thousands of different alleles in each of the 9 major HLA genes. Determining which combination of alleles an individual possesses for each HLA gene (high-resolution HLA-typing) is essential to establish donor-recipient compatibility in organ and bone-marrow transplantations. BCR and TCR genes in turn are generated by recombining a diverse set of gene segments on the DNA level in each maturing B and T cell, respectively. This process generatesadaptiveimmunereceptorrepertoires (AIRR) of composed of unique transcripts expressed by each B and T cells. These repertoires carry a vast amount of health relevant information. Both short-read RNA-seq based HLA-typing1and adaptive immune receptor repertoire sequencing2–5currently rely heavily on our incomplete knowledge of the genetic diversity at HLA6and BCR/TCR loci7,8.Here we used our nanopore sequencing basedRolling CircletoConcatemericConsensus (R2C2) protocol9to generate over 10,000,000 full-length cDNA sequences at a median accuracy of 97.9%. We used this dataset to demonstrate that deep and accurate full-length cDNA sequencing can - in addition to providing isoform-level transcriptome analysis for over 9,000 loci - be used to generate accurate sequences of HLA alleles for HLA allele typing and discovery as well as detailed AIRR data for the analysis of the adaptive immune system without requiring specific knowledge of the diversity at HLA and BCR/TCR loci.
Open source 3D printable replacement parts for the WHO insecticide susceptibility bioassay system
Authors: Tomlinson Sean , Yates Henrietta C. , Oruni Ambrose , Njoroge Harun , Weetman David , Donnelly Martin J. , Van’t Hof Arjen E 
Published: September 2019

BackgroundMalaria vector control and research rely heavily on monitoring mosquito populations for the development of resistance to public health insecticides. One standard method for determining susceptibility in adult mosquito populations is the World Health Organization test (WHO bioassay). The WHO bioassay kit consists of several acrylic pieces that are assembled into a unit. Parts of the kit commonly break, reducing the capacity of insectaries to carry out resistance profiling. Since there is at present only a single supplier for the test kits, replacement parts can be hard to procure in a timely fashion. Here, we present 3D printable versions for all pieces of the WHO bioassay kit.ResultsUsing widely available polylactic acid (PLA) filament as a printing material, we were able to design and print functional replacements for each piece of the WHO bioassay kit. We note no significant difference in mortality results obtained from PLA printed tubes and WHO acrylic tubes. Additionally, we observed no degradation of PLA in response to prolonged exposure times of commonly used cleaning solutions.ConclusionsOur designs can be used to produce replacement parts for the WHO bioassay kit in any facility with a 3D printer, which are becoming increasingly widespread. 3D printing technologies can affordably and rapidly address equipment shortages and be used to develop bespoke equipment in laboratories.
Dynamic clamp constructed phase diagram of the Hodgkin-Huxley action potential model
Authors: Ori Hillel , Hazan Hananel , Marder Eve , Marom Shimon 
Published: September 2019

AbstractExcitability – a threshold governed transient in transmembrane voltage – is a fundamental physiological process that controls the function of the heart, endocrine, muscles and neuronal tissues. The 1950’s Hodgkin and Huxley explicit formulation provides a mathematical framework for understanding excitability, as the consequence of the properties of voltage-gated sodium and potassium channels. The Hodgkin-Huxley model is more sensitive to parametric variations of protein densities and kinetics than biological systems whose excitability is apparently more robust. It is generally assumed that the model’s sensitivity reflects missing functional relations between its parameters or other components present in biological systems. Here we experimentally construct excitable membranes using the dynamic clamp and voltage-gated potassium ionic channels (Kv1.3) expressed inXenopusoocytes. We take advantage of a theoretically derived phase diagram, where the phenomenon of excitability is reduced to two dimensions defined as combinations of the Hodgkin-Huxley model parameters. This biological-computational hybrid enabled us to explore functional relations in the parameter space, experimentally validate the phase diagram of the Hodgkin-Huxley model, and demonstrate activity-dependence and hysteretic dynamics due to the impacts of slow inactivation kinetics. The experimental results presented here provide new in-sights into the gap between technology-guided high-dimensional descriptions, and a lower, physiological dimensionality, within which biological function is embedded.
Representations of complex contexts: A role for hippocampus
Authors: Dimsdale-Zucker Halle R. , Montchal Maria E. , Reagh Zachariah M. , Wang Shao-Fang , Libby Laura A. , Ranganath Charan 
Published: September 2019

AbstractThe hippocampus plays a critical role in supporting episodic memory, in large part by binding together experiences and items with surrounding contextual information. At present, however, little is known about the roles of different hippocampal subfields in supporting this item-context binding. To address this question, we constructed a task in which items were affiliated with differing types of context – cognitive associations that vary at the local, item level and membership in temporally organized lists that linked items together at a global level. Participants made item recognition judgments while undergoing high-resolution fMRI imaging. We performed voxel pattern similarity analyses to answer the question of how human hippocampal subfields represent retrieved information about cognitive states and the time at which a past event took place. As participants recollected previously presented items, activity patterns in the CA23DG subregion carried information about prior cognitive states associated with these items. We found no evidence to suggest reinstatement of information about temporal context at the level of list membership, but exploratory analyses revealed representations of temporal context at a coarse level in conjunction with representations of cognitive contexts. Results are consistent with characterizations of CA23DG as a critical site for binding together items and contexts in the service of memory retrieval.
Alternative splicing regulation by GWAS risk loci for breast cancer
Authors: Machado Juliana , Magno Ramiro , Xavier Joana M , Maia Ana-Teresa 
Published: September 2019

ABSTRACTRecent genome-wide association studies (GWAS) have revealed the association of hundreds of single nucleotide polymorphisms (SNPs) with breast cancer (BC) risk, which mostly locate in non-coding regions, suggesting regulatory roles to the causal variants. Functional characterisation of GWAS loci has been biased towards the effect of regulatory SNPs on transcription factor binding. Here we set out to determine the extent of the contribution of breast cancer risk-associated SNPs to alternative splicing (AS).We screened genome-wide significant (P≤ 5 × 10−8) BC risk SNPs for association with AS, using expression and genotype data from normal breast samples, from the GTEx project. We identified four splicing quantitative trait loci (sQTL). In locus 6p22.1,rs6456883is a significant cis-sQTL for the expression ofZNF311gene isoforms. Three SNPs in locus 8p23.3,rs6682326,rs3008282andrs2906324, were also identified as significant cis-sQTLs/svQTLs for the expression ofRPL23AP53gene isoforms. In-silico functional analysis revealed that these variants can potentially alter enhancer splicing elements within the target genes.Our work shows that BC risk-associated variants at two loci are associated with AS isoforms in normal breast tissue, thus demonstrating that AS plays an important role in breast cancer susceptibility. Furthermore, it supports that all cis-regulatory mechanisms should be considered in the functional characterisation of risk loci.
Fgf-driven Tbx protein activities directly inducemyf5andmyodto initiate zebrafish myogenesis
Authors: Osborn Daniel P.S. , Li Kuoyu , Cutty Stephen J. , Nelson Andrew C. , Wardle Fiona C. , Hinits Yaniv , Hughes Simon M. 
Published: September 2019

AbstractSkeletal muscle derives from dorsal mesoderm that is formed during vertebrate gastrulation. Fibroblast growth factor (Fgf) signalling is known to cooperate with transcription factors of the Tbx family to promote dorsal mesoderm formation, but the role of these proteins in skeletal myogenesis has been unclear. Using the zebrafish, we show that dorsally-derived Fgf signals act through Tbx16 and Tbxta to induce two populations of slow and fast trunk muscle precursors at distinct dorsoventral positions. Tbx16 binds to and directly activates themyf5andmyodgenes that are required for commitment to skeletal myogenesis. Tbx16 activity depends on Fgf signalling from the organiser. In contrast, Tbxta is not required formyf5expression. However, Tbxta binds to a specific site upstream ofmyodnot bound by Tbx16, drivingmyodexpression in the adaxial slow precursors dependent upon Fgf signals, thereby initiating muscle differentiation in the trunk. After gastrulation, when similar muscle cell populations in the post-anal tail are generated from the tailbud, declining Fgf signalling is less effective at initiating adaxial myogenesis, which is instead initiated by Hedgehog signalling from the notochord. Our findings provide insight into the ancestral vertebrate trunk myogenic pattern and how it was co-opted during tail evolution to generate similar muscle by new mechanisms.
A 3D structural affinity model for multi-epitope in silico germinal center simulations
Authors: Robert Philippe A. , Meyer-Hermann Michael 
Published: September 2019

AbstractVaccine development for mutating pathogens is challenged by their fast evolution, the complexity of immunodominance, and the heterogeneous immune history of individuals. Mathematical models are critical for predicting successful vaccine conditions or designing potent antibodies. Existing models are limited by their abstract and poorly structural representations of antigen epitopes. Here, we propose a structural lattice-based model for antibody–antigen affinity. An efficient algorithm is given that predicts the best binding structure of an antibody’s amino acid sequence around an antigen with shortened computational time. This structural representation contains key physiological properties, such as affinity jumps and cross-reactivity, and successfully reflects the topology of antigen epitopes, such as pockets and shielded residues. It is suitable for large simulations of affinity maturation. We perform in silico immunizations via germinal center simulations and show that our model can explain complex phenomena like recognition of the same epitope by unrelated clones. We show that the use of cocktails of similar epitopes promotes the development of cross-reactive antibodies. This model opens a new avenue for optimizing multivalent vaccines with combined antigen cocktails or sequential immunizations, and to reveal reasons for vaccine success or failure on a structural basis.
Physiology-forward identification of bile acid sensitive vomeronasal receptors
Authors: Wong Wen Mai , Cao Jie , Zhang Xingjian , Doyle Wayne I. , Mercado Luis L. , Gautron Laurent , Meeks Julian P. 
Published: September 2019

Abstract/SummaryThe mouse accessory olfactory system (AOS) supports social and reproductive behavior through the sensation of environmental chemosignals. A growing number of excreted steroids have been shown to be potent AOS cues, including bile acids (BAs) found in feces. As is still the case with most AOS ligands, the specific receptors used by vomeronasal sensory neurons (VSNs) to detect BAs remain unknown. To identify VSN BA receptors, we first performed a deep analysis of VSN BA tuning using volumetric GCaMP6f/s Ca2+ imaging. These experiments revealed both broadly and narrowly tuned populations of BA-receptive VSNs with sub-micromolar sensitivities. We then developed a new physiology-forward approach for identifying AOS ligand-receptor interactions, which we call Fluorescence Live Imaging for Cell Capture and RNA-seq, or FLICCR-seq. FLICCR-seq analysis revealed 5 specific V1R-family receptors enriched in BA-sensitive VSNs. These studies introduce a powerful new approach for ligand-receptor matching and reveal biological mechanisms underlying mammalian BA chemosensation.
Diversity of Archaea Domain in Cuatro Cienegas Basin: Archaean Domes
Authors: Medina-Chávez Nahui Olin , Viladomat-Jasso Mariette , Olmedo-Álvarez Gabriela , Eguiarte Luis E , Souza Valeria , De la Torre-Zavala Susana 
Published: September 2019

AbstractHerein we describe the Archaea diversity in a shallow pond in the Cuatro Ciénegas Basin (CCB), Northeast Mexico, with fluctuating hypersaline conditions containing elastic microbial mats that can form small domes where their anoxic inside reminds us of the characteristics of the Archaean Eon, rich in methane and sulfur gases; thus, we named this site the Archaean Domes (AD). These domes only form after heavy rains that are rare in the Chihuahuan desert. CCB is a unique oasis with hundreds of ponds, containing endemic species of animals, plants and highly diverse and unique microbial communities, despite its very biased stoichiometry, due mostly to extreme low phosphorus content (soils, water columns and sediments). This extreme oligotrophy has favored survival of ancestral microorganisms. Whole metagenome sequencing approach was performed for this unusual site in three different seasons to assess the extent of the Archaea biodiversity, with a focus on extremophiles, since members of the Archaea had been underrepresented in different study sites within the oasis. We found a highly diverse Archaea community compassing ∼5% of the metagenomes. The archaeal portion in all three metagenomes maintained its abundance and most of the strains showed to form a resilient core during three seasonal samplings (2016-2017), despite environmental fluctuations. However, relative abundances of all 230 archaeal OTUs (defined using a 97% cutoff) were low enough (<0.1%) to be considered part of the rare biosphere. AD finding and their description within CCB confirms that this particular pond is the most diverse for Archaea that we are aware of and opens new paths for understanding the forces that once drove and keep shaping microbial community assemblage.
Salmonella grows massively and aerobically in fecal matter
Authors: Guerrero Teresa , Zapata Sonia , Trueba Gabriel 
Published: September 2019

SummaryThe use of wastewater for irrigation and animal manure as fertilizer can cause transmission of intestinal pathogens, conditions frequently observed in Low- and Middle-Income Countries (LMICs). Here we tested the ability of Salmonella to grow in the fecal matter; we inoculated freshly isolated Salmonella strains (from chickens) in chicken fecal matter and incubated for 24, 48 and 72 hrs under aerobic and anaerobic conditions. We found that both Salmonella and E. coli multiplied massively in fecal matter outside a host for 72 hrs, being their growth higher in aerobic conditions. Our results have critical implications in waste management, as we demonstrate that aerobic treatments may not be the best to reduce the number of Salmonella in the environment.
Comparing serial X-ray crystallography and microcrystal electron diffraction (MicroED) as methods for routine structure determination from small macromolecular crystals
Authors: Wolff Alexander M , Young Iris D , Sierra Raymond G , Brewster Aaron S , Martynowycz Michael W , Nango Eriko , Sugahara Michihiro , Nakane Takanori , Ito Kazutaka , Aquila Andrew , Bhowmick Asmit , Biel Justin T , Carbajo Sergio , Cohen Aina E , Cortez Saul , Gonzalez Ana , Hino Tomoya , Im Dohyun , Koralek Jake D , Kubo Minoru , Lazarou Tomas S , Nomura Takashi , Owada Shigeki , Samelson Avi , Tanaka Rie , Tanaka Tomoyuki , Thompson Erin M , van den Bedem Henry , Woldeyes Rahel A , Yumoto Fumiaki , Zhao Wei , Tono Kensuke , Boutet Sébastien , Iwata So , Gonen Tamir , Sauter Nicholas K , Fraser James S , Thompson Michael C 
Published: September 2019

AbstractInnovative new crystallographic methods are facilitating structural studies from ever smaller crystals of biological macromolecules. In particular, serial X-ray crystallography and microcrystal electron diffraction (MicroED) have emerged as useful methods for obtaining structural information from crystals on the nanometer to micron scale. Despite the utility of these methods, their implementation can often be difficult, as they present many challenges not encountered in traditional macromolecular crystallography experiments. Here, we describe XFEL serial crystallography experiments and MicroED experiments using batch-grown microcrystals of the enzyme cyclophilin A (CypA). Our results provide a roadmap for researchers hoping to design macromolecular microcrystallography experiments, and they highlight the strengths and weaknesses of the two methods. Specifically, we focus on how the different physical conditions imposed by the sample preparation and delivery methods required for each type of experiment effect the crystal structure of the enzyme.
Effects of predictive and incentive value manipulation on sign- and goal-tracking behavior
Authors: Maria-Rios Cristina E. , Fitzpatrick Christopher J. , Morrow Jonathan D. 
Published: September 2019

AbstractWhen a neutral stimulus is repeatedly paired with an appetitive reward, two different types of conditioned approach responses may develop: a sign-tracking response directed toward the neutral cue, or a goal-tracking response directed toward the location of impending reward delivery. Sign-tracking responses have been postulated to result from attribution of incentive value to conditioned cues, while goal-tracking reflects the assignment of only predictive value to the cue. We therefore hypothesized that sign-tracking would be more sensitive to manipulations of incentive value, while goal-tracking would be more responsive to changes in the predictive value of the cue. We tested sign- and goal-tracking before and after devaluation of a food reward using lithium chloride, and tested whether either response could be learned under negative contingency conditions that precluded any serendipitous reinforcement of the behavior that might support instrumental learning. We also tested the effects on sign- and goal-tracking of blocking the predictive value of a cue using simultaneous presentation of a pre-conditioned cue. We found that sign-tracking was sensitive to outcome devaluation, while goal-tracking was not. We also confirmed that both responses are Pavlovian because they can be learned under negative contingency conditions. Goal-tracking was completely blocked by a pre-conditioned cue, while sign-tracking was only partially reduced. These results indicate that sign- and goal-tracking follow different rules of reinforcement learning and suggest a need to revise current models of associative learning to account for these differences.
Effects of the cannabinoid receptor agonist CP-55,940 on incentive salience attribution
Authors: Gheidi Ali , Cope Lora M. , Fitzpatrick Christopher J. , Froehlich Benjamin N. , Atkinson Rachel , Groves Coltrane K. , Barcelo Clair N. , Morrow Jonathan D. 
Published: September 2019

AbstractPavlovian conditioned approach paradigms are used to characterize the nature of motivational behaviors in response to stimuli as either directed toward the cue (i.e., sign-tracking) or the site of reward delivery (i.e., goal-tracking). Recent evidence has shown that activity of the endocannabinoid system increases dopaminergic activity in the mesocorticolimbic system, and other studies have shown that sign-tracking behaviors are dependent on dopamine. Therefore, we hypothesized that administration of a cannabinoid agonist would increase sign-tracking and decrease goal-tracking behaviors. Forty-seven adult male Sprague Dawley rats were given a low, medium, or high dose of the cannabinoid agonist CP-55,940 (N=12 per group) or saline (N=11) before Pavlovian conditioned approach training. A separate group of rats (N=32) were sacrificed after PCA training for measurement of cannabinoid receptor type 1 (CB1) and fatty acid amide hydrolase (FAAH) using in situ hybridization. Contrary to our initial hypothesis, CP-55,940 dose-dependently decreased sign-tracking and increased goal-tracking behavior. CB1 expression was higher in sign-trackers compared to goal-trackers in the prelimbic cortex, but there were no significant differences in CB1 or FAAH expression in the infralimbic cortex, dCA1, dCA3, dorsal dentate gyrus, or amygdala. These results demonstrate that cannabinoid signaling can specifically influence behavioral biases toward sign- or goal-tracking. Pre-existing differences in CB1 expression patterns, particularly in the prelimbic cortex, could contribute to individual differences in the tendency to attribute incentive salience to reward cues.