bluuebunny/crossref_metadata_2025_split huggingface dataset:
p38-mitogen activated kinases mediate a developmental regulatory response to amino acid depletion and associated oxidative stress in mouse blastocyst embryos
Authors: Bora Pablo , Thamodaran Vasanth , Šušor Andrej , Bruce Alexander W. 
Published: October 2019

AbstractMaternal starvation coincident with preimplantation development has profound consequences for placental-foetal development, with various identified pathologies persisting/manifest in adulthood; the ‘Developmental Origin of Health and Disease’ (DOHaD) hypothesis/model. Despite evidence describing DOHaD-related incidence, supporting mechanistic and molecular data relating to preimplantation embryos themselves are comparatively meagre. We recently identified the classically recognised stress-related p38-mitogen activated kinases (p38-MAPK) as regulating formation of the extraembryonic primitive endoderm (PrE) lineage within mouse blastocyst inner cell mass (ICM). Thus, we wanted to assay if PrE differentiation is sensitive to amino acid availability, in a manner regulated by p38-MAPK. Although blastocysts appropriately mature, without developmental/morphological or cell fate defects, irrespective of amino acid supplementation status, we found the extent of p38-MAPK inhibition induced phenotypes was more severe in the absence of amino acid supplementation. Specifically, both PrE and epiblast (EPI) ICM progenitor populations remained unspecified and there were fewer cells and smaller blastocyst cavities. Such phenotypes could be ameliorated, to resemble those observed in groups supplemented with amino acids, by addition of the anti-oxidant NAC (N-acetyl-cysteine), although PrE differentiation deficits remained. Therefore, p38-MAPK performs a hitherto unrecognised homeostatic early developmental regulatory role (in addition to direct specification of PrE), by buffering blastocyst cell number and ICM cell lineage specification (relating to EPI) in response to amino acid availability, partly by counteracting induced oxidative stress; with clear implications for the DOHaD model.
Megabodies expand the nanobody toolkit for protein structure determination by single-particle cryo-EM
Authors: Uchański Tomasz , Masiulis Simonas , Fischer Baptiste , Kalichuk Valentina , Wohlkönig Alexandre , Zögg Thomas , Remaut Han , Vranken Wim , Aricescu A. Radu , Pardon Els , Steyaert Jan 
Published: October 2019

ABSTRACTNanobodies (Nbs) are popular and versatile tools for structural biology because they have a compact single immunoglobulin domain organization. Nbs bind their target proteins with high affinities while reducing their conformational heterogeneity, and they stabilize multi-protein complexes. Here we demonstrate that engineered Nbs can also help overcome two major obstacles that limit the resolution of single-particle cryo-EM reconstructions: particle size and preferential orientation at the water-air interface. We have developed and characterised novel constructs, termed megabodies, by grafting Nbs into selected protein scaffolds to increase their molecular weight while retaining the full antigen binding specificity and affinity. We show that the megabody design principles are applicable to different scaffold proteins and recognition domains of compatible geometries and are amenable for efficient selection from yeast display libraries. Moreover, we used a megabody to solve the 2.5 Å resolution cryo-EM structure of a membrane protein that suffers from severe preferential orientation, the human GABAAβ3 homopentameric receptor bound to its small-molecule agonist histamine.
Increased expression of genetically-regulatedFLT3implicated in Tourette’s Syndrome
Authors: Liao Calwing , Vuokila Veikko , Catoire Hélène , Akçimen Fulya , Ross Jay P. , Bourassa Cynthia V. , Dion Patrick A. , Meijer Inge A. , Rouleau Guy A. 
Published: October 2019

AbstractTourette’s Syndrome (TS) is a neurodevelopmental disorder that is characterized by motor and phonic tics. A recent TS genome-wide association study (GWAS) identified a genome-wide significant locus. However, determining the biological mechanism of GWAS signals remains difficult. Here, we conduct a TS transcriptome-wide association study (TWAS) consisting of 4,819 cases and 9,488 controls and found that increased expression ofFLT3in the dorsolateral prefrontal cortex (DLPFC) is associated with TS. We further showed that there is global dysregulation ofFLT3across several brain regions and probabilistic causal fine-mapping of the TWAS signal prioritizesFLT3with a posterior inclusion probability of 0.849. We validated the gene’s expression in 100 lymphoblastoid cell lines, establishing that TS cells had a 1.72 increased fold change compared to controls. A phenome-wide association study points towardsFLT3having links with immune-related pathways such as monocyte count. We also identify several splicing events inMPHOSPH9, CSGALNACT2andFIP1L1associated with TS, which are also implicated in immune function. This analysis of expression and splicing begins to explore the biology of TS GWAS signals.
A transcription start site map in human pancreatic islets reveals functional regulatory signatures
Authors: Varshney Arushi , Kyono Yasuhiro , Elangovan Venkateswaran Ramamoorthi , Wang Collin , Erdos Michael R. , Narisu Narisu , Albanus Ricardo D’Oliveira , Orchard Peter , Stitzel Michael L. , Collins Francis S. , Kitzman Jacob O. , Parker Stephen C. J. 
Published: October 2019

AbstractIdentifying the tissue-specific molecular signatures of active regulatory elements is critical to understand gene regulatory mechanisms. Here, we identify transcription start sites (TSS) using cap analysis of gene expression (CAGE) across 57 human pancreatic islet samples. We identify 9,954 reproducible CAGE tag clusters (TCs), ~20% of which are islet-specific and occur mostly distal to known gene TSSs. We integrated islet CAGE data with histone modification and chromatin accessibility profiles to identify epigenomic signatures of transcription initiation. Using a massively parallel reporter assay, we validate transcriptional enhancer activity (5% FDR) for 2,279 of 3,378 (~68%) tested islet CAGE elements. TCs within accessible enhancers show higher enrichment to overlap type 2 diabetes genome-wide association study (GWAS) signals than existing islet annotations, which emphasizes the utility of mapping CAGE profiles in disease-relevant tissue. This work provides a high-resolution map of transcriptional initiation in human pancreatic islets with utility for dissecting functional enhancers at GWAS loci.
Striatal iron content is linked to reduced fronto-striatal brain function under working memory load
Authors: Rodrigue Karen M. , Daugherty Ana M. , Foster Chris M. , Kennedy Kristen M. 
Published: October 2019

AbstractNon-heme iron accumulation contributes to age-related decline in brain structure and cognition via a cascade of oxidative stress and inflammation, although its effect on brain function is largely unexplored. Thus, we examine the impact of striatal iron on dynamic range of BOLD modulation to working memory load. N=166 healthy adults (age 20-94) underwent cognitive testing and an imaging session including n-back (0-, 2-, 3-, and 4-back fMRI), R2*-weighted imaging, and pcASL to measure cerebral blood flow. A statistical model was constructed to predict voxelwise BOLD modulation by age, striatal iron content and an age × iron interaction, controlling for cerebral blood flow, sex, and task response time. A significant interaction between age and striatal iron content on BOLD modulation was found selectively in the putamen, caudate, and inferior frontal gyrus. Greater iron was associated with reduced modulation to difficulty, particularly in middle-aged and younger adults with greater iron content. Further, iron-related decreases in modulation were associated with poorer executive function in an age-dependent manner. These results suggest that iron may contribute to differences in functional brain activation prior to older adulthood, highlighting the potential role of iron as an early factor contributing to trajectories of functional brain aging.
Identification of drug modifiers for RYR1 related myopathy using a multi-species discovery pipeline
Authors: Volpatti Jonathan , Endo Yukari , Groom Linda , Brennan Stephanie , Noche Ramil , Zuercher William , Roy Peter , Dirksen Robert T. , Dowling James J. 
Published: October 2019

AbstractRyanodine receptor type I-related myopathies (RYR1-RMs) represent the largest group of non-dystrophic myopathies. RYR1-RMs are associated with severe disabilities and early mortality; despite these facts, there are currently no available treatments. The goal of this study was to identify new therapeutic targets for RYR1-RMs. To accomplish this, we developed a novel discovery pipeline using nematode, zebrafish, and mammalian cell models of the disease. We first performed large-scale drug screens inC. elegansand zebrafish. 74 positive hits were identified inC. elegans, while none were uncovered in the zebrafish. Targeted testing of these hits in zebrafish yielded positive results for two compounds. We examined these compounds using newly createdRyr1knockout C2C12 cells, and found that p38 inhibition impaired caffeine-induced Ca2+release. Lastly, we tested one p38 inhibitor in myotubes fromRyr1Y524S/+(YS) mice, and demonstrated that it blunts the aberrant temperature-dependent increase in resting Ca2+in these cells. In all, we developed a unique platform for RYR1-RM therapy development that is potentially applicable to a broad range of neuromuscular disorders.
The interplay of top-down focal attention and the cortical tracking of speech
Authors: Lesenfants D , Francart T 
Published: October 2019

AbstractMany active neuroimaging paradigms rely on the assumption that the participant sustains attention to a task. However, in practice, there will be momentary distractions, potentially influencing the results. We investigated the effect of focal attention, objectively quantified using a measure of brain signal entropy, on cortical tracking of the speech envelope. The latter is a measure of neural processing of naturalistic speech. We let participants listen to 44 minutes of natural speech, while their electroencephalogram was recorded, and quantified both entropy and cortical envelope tracking. Focal attention affected the later brain responses to speech, between 100 and 300 ms latency. By only taking into account periods with higher attention, the measured cortical speech tracking improved by 47%. This illustrates the impact of the participant’s active engagement in the modeling of the brain-speech response and the importance of accounting for it. Our results suggests a cortico-cortical loop that initiates during the early-stages of the auditory processing, then propagates through the parieto-occipital and frontal areas, and finally impacts the later-latency auditory processes in a top-down fashion. The proposed framework could be transposed to other active electrophysiological paradigms (visual, somatosensory, etc) and help to control the impact of participants’ engagement on the results.
Scale-resolved analysis of brain functional connectivity networks with spectral entropy
Authors: Nicolini Carlo , Forcellini Giulia , Minati Ludovico , Bifone Angelo 
Published: October 2019

Functional connectivity is derived from inter-regional correlations in spontaneous fluctuations of brain activity, and can be represented in terms of complete graphs with continuous (real-valued) edges. The structure of functional connectivity networks is strongly affected by signal processing procedures to remove the effects of motion, physiological noise and other sources of experimental error. However, in the absence of an established ground truth, it is difficult to determine the optimal procedure, and no consensus has been reached on the most effective approach to remove nuisance signals without unduly affecting the network intrinsic structural features. Here, we use a novel information-theoretic approach, based on von Neumann entropy, which provides a measure of information encoded in the networks at different scales. We also define a measure of distance between networks, based on information divergence, and optimal null models appropriate for the description of functional connectivity networks, to test for the presence of nontrivial structural patterns that are not the result of simple local constraints. This formalism enables a scale-resolved analysis of the distance between an empirical functional connectivity network and its maximally random counterpart, thus providing a means to assess the effects of noise and image processing on network structure.We apply this novel approach to address a few open questions in the analysis of brain functional connectivity networks. Specifically, we demonstrate a strongly beneficial effect of network sparsification by removal of the weakest links, and the existence of an optimal threshold that maximizes the ability to extract information on large-scale network structures. Additionally, we investigate the effects of different degrees of motion at different scales, and compare the most popular processing pipelines designed to mitigate its deleterious effect on functional connectivity networks.
Q203 containing fully intermittent oral regimens exhibited high sterilizing activity against Mycobacterium ulcerans in mice
Authors: Chauffour Aurélie , Robert Jérôme , Veziris Nicolas , Aubry Alexandra , Pethe Kevin , Jarlier Vincent 
Published: October 2019

AbstractBuruli ulcer (BU), caused by Mycobacterium ulcerans is currently treated by a daily combination of rifampin and either injectable streptomycin or oral clarithromycin. An intermittent oral regimen would facilitate the treatment supervision. We first evaluated the bactericidal activity of newer antimicrobials against M. ulcerans using a BU animal model. The imidazopyridine amine Q203 exhibited high bactericidal activity whereas tedizolid (oxazolidinone close to linezolid), selamectine and ivermectine (avermectine compound) and the benzothiazinone PBTZ169 were not active. Consequently, Q203 was evaluated for its bactericidal and sterilizing activities in combined intermittent regimens. Q203 given twice a week in combination with one of the other long half-life compounds, rifapentine or bedaquiline, sterilized the mice footpads in 8 weeks, i.e. after a total of only 16 doses, and prevented relapse during a period of 20 weeks after stopping the treatment. These results are very promising for future intermittent oral regimens which would greatly simplify BU treatments in the field.Author summaryThe current treatment of Buruli ulcer (BU), infection caused by Mycobacterium ulcerans is based on a daily antibiotic combination of rifampin associated with streptomycin or clarithromycin. A shorter or intermittent treatment without an injectable drug would clearly simplify the management on the field. We evaluated the bactericidal activity of several new antimicrobials drugs in a mice model of BU and found that the Q203 exhibited the highest bactericidal effect. We subsequently identified new antibiotic combinations containing Q203 with high sterilizing activity when administrated twice a week for 8 weeks.
Championing Health Promotion through Group Patient and Family Education Activities in the Outpatient Department of a Tertiary Care Hospital
Authors: Almahameed Mahmoud Ibrahim , Kakish Shadi F. , Abu-Shaheen Amani 
Published: October 2019

AbstractBackgroundHealth education involves not only providing relevant information but also facilitating health-related behavior change. Patient education during the waiting period plays an essential role in promoting health and improving patient satisfaction rates.ObjectiveTo promote health by educating patients and their companions during their waiting period at the King Fahad Medical City (KFMC) Hospital, Riyadh, with the help of nurses and assess their satisfaction rate.MethodsA cross-sectional study, including patients and their companions in the waiting rooms of the various OPD’s, was conducted. Group teaching sessions were conducted, followed by the assessment of patient and nurse satisfaction rate, and compliance rate using evaluation forms. Pre-implementation surveys were conducted to assess the drawbacks, based on which procedure was modified, and feedback was recorded using an electronic iPad. Data were collected with the help of questionnaires filled at the end of each teaching session and analyzed using descriptive analysis. Results of both the assessment and re-assessment were compared in terms of the number of attendees.ResultsThere was an improvement in number of attendees (4362 vs. 3392), patient satisfaction rate (90% vs. 78%), nurse satisfaction rate (83.09% vs. 33.18%) and compliance rate (100% vs. 65%) post-modifications. Few loopholes in terms of inappropriate environment and time of the lecture were also observed.ConclusionThe health educators can assist people in achieving their health goals by organizing structured health education activities, providing appropriate health education materials, and effective training. However, the satisfaction rates of people and health educators should be assessed by conducting routine feedback surveys.
The origin and diversification of pteropods predate past perturbations in the Earth’s carbon cycle
Authors: Peijnenburg Katja T.C.A. , Janssen Arie W. , Wall-Palmer Deborah , Goetze Erica , Maas Amy , Todd Jonathan A. , Marlétaz Ferdinand 
Published: October 2019

SummaryPteropods are a group of planktonic gastropods that are widely regarded as biological indicators for assessing the impacts of ocean acidification (OA). Their thin aragonitic shells are highly sensitive to acute changes in ocean chemistry. However, to gain insight into their potential to adapt to current climate change, we need to accurately reconstruct their evolutionary history and assess their responses to past changes in Earth’s carbon cycle. Here, we resolve the phylogeny and timing of pteropod evolution with a phylogenomic dataset incorporating 21 new species and new fossil evidence. In agreement with traditional taxonomy, we recovered the first molecular support for a division between sea butterflies (Thecosomata: mucus-web feeders) and sea angels (Gymnosomata: active predators). Molecular dating demonstrated that these two lineages diverged in the early Cretaceous, and that all main pteropod clades, including shelled, partially-shelled and unshelled groups, diverged in the mid to late Cretaceous. Hence, these clades originated prior to and subsequently survived major global change events, including the Paleocene Eocene Thermal Maximum (PETM), which is the closest analogue to modern-day ocean acidification and warming. Our findings indicate that aragonitic calcifiers have been resilient to extreme perturbations in the Earth’s carbon cycle over evolutionary timescales.
Interactions of a bacterial RND transporter with a transmembrane small protein in a lipid environment
Authors: Du Dijun , Neuberger Arthur , Orr Mona Wu , Newman Catherine E. , Hsu Pin-Chia , Samsudin Firdaus , Szewczak-Harris Andrzej , Ramos Leana M. , Debela Mekdes , Khalid Syma , Storz Gisela , Luisi Ben F. 
Published: October 2019

AbstractThe small protein AcrZ inEscherichia coliinteracts with the transmembrane portion of the multidrug efflux pump AcrB and increases the resistance of the bacterium to a subset of the antibiotic substrates of that transporter. It is not clear how the physical association of the two proteins selectively changes activity of the pump for defined substrates. Here, we report cryo-EM structures of AcrB and the AcrBZ complex in lipid environments, and comparisons suggest that conformational changes occur in the drug binding pocket as a result of AcrZ binding. Simulations indicate that cardiolipin preferentially interacts with the AcrBZ complex, due to increased contact surface, and we observe that the drug sensitivity of bacteria lacking AcrZ is exacerbated when combined with cardiolipin deficiency. Taken together, the data suggest that AcrZ and lipid cooperate to allosterically modulate the activity of AcrB. This mode of regulation by a small protein and lipid may occur for other membrane proteins.
Genomic evidence for a hybrid origin of the yeast opportunistic pathogenCandida albicans
Authors: Mixão Verónica , Gabaldón Toni 
Published: October 2019

AbstractOpportunistic yeast pathogens are of increasing medical concern.Candida albicans, the species with the highest incidence, is a natural commensal of humans that can adopt a pathogenic behaviour. This species is highly heterozygous, is an obligate diploid, and cannot undergo meiosis, adopting instead a parasexual cycle. The origin of these traits is unknown and we hypothesize they could result from ancestral hybridization. We tested this idea by analyzing available genomes ofC. albicansisolates and comparing them to those of hybrid and non-hybrid strains of otherCandidaspecies. Our results show compelling evidence thatC. albicansis an evolved hybrid, with levels and patterns of ancestral heterozygosity that cannot be fully explained under the paradigm of vertical evolution. Although the level of inferred divergence between the putative parental lineages (2.8%) is not clearly beyond current species boundaries in Saccharomycotina, we show here that all analyzedC. albicansstrains derive from a single hybrid ancestor, which diverged by extensive loss of heterozygosis. This finding has important implications for our understanding ofC. albicansevolution, including the loss of the sexual cycle, the origin of the association with humans, and the evolution of virulence traits.
Genomic signature of ongoing alkaline adaptation in a Schizothoracine fish (Cyprinidae) inhabiting soda lake on the Tibetan Plateau
Authors: Tong Chao , Li Miao , Tang Yongtao , Zhao Kai 
Published: October 2019

AbstractComparative genomics has elucidate the molecular footprints of adaptations to extreme environments at high altitude including hypoxia, but insight into the genomic basis of saline and alkaline adaptation in highland fish has rarely been provided. The increasing of water salinization is a growing threat to Tibetan endemic fish species. Here we performed one of the first comparative genomics studies and began to characterize genomic signature of alkaline adaptation in a Schizothoracine fish inhabiting soda lake on the Tibetan Plateau. We found that expansions of lineage-specific genes associated with ion transport and transmembrane functions, genome-wide elevated rate of molecular evolution in Schizothoracine fishes relative to other lowland teleost fish species. In addition, we found specific changes in the rate of molecular evolution between G. p. kelukehuensis and other teleost fishes for ion transport-related genes. Furthermore, we identified a set of genes associated with ion transport and energy metabolism underwent positive selection. Using tissue-transcriptomics, we found that most REGs and PSGs in G. p. kelukehuensis were broadly expressed across three tissues and significantly enriched for ion transport functions. Finally, we identified a set of ion transport-related genes with evidences for both selection and co-expressed which contributed to alkaline tolerance in G. p. kelukehuensis. Altogether, our study identified putative genomic signature and potential candidate genes contributed to ongoing alkaline adaptation in Schizothoracine fish.