bluuebunny/crossref_metadata_2025_split huggingface dataset:
PLCG2as a Risk Factor for Alzheimer’s Disease
Authors: Tsai Andy P. , Dong Chuanpeng , Preuss Christoph , Moutinho Miguel , Lin Peter Bor-Chian , Hajicek Nicole , Sondek John , Bissel Stephanie J. , Oblak Adrian L. , Carter Gregory W. , Liu Yunlong , Landreth Gary E. , Lamb Bruce T. , Nho Kwangsik 
Published: May 2020

AbstractAlzheimer’s disease (AD) is characterized by robust microgliosis and phenotypic changes that accompany disease pathogenesis. Indeed, genetic variants in microglial genes are linked to risk for AD. Phospholipase Cγ2 (PLCG2) participates in the transduction of signals emanating from immune cell-surface receptors that regulate the inflammatory response and is selectively expressed by microglia in the brain. A rare variant inPLCG2(P522R) was previously found to be protective against AD, indicating thatPLCG2may play a role in AD pathophysiology. Here, we report that a rare missense variant inPLCG2confers increased AD risk (p=0.047; OR=1.164 [95% CI=1.002-1.351]). Additionally, we observed thatPLCG2expression levels are increased in several brain regions of AD patients, correlating with brain amyloid deposition. This provides further evidence thatPLCG2may play an important role in AD pathophysiology. Together, our findings indicate thatPLCG2is a potential new therapeutic target for AD.
Discordant evolution of organellar genomes in peas (PisumL.)
Authors: Bogdanova Vera S. , Shatskaya Natalia V. , Mglinets Anatoliy V. , Kosterin Oleg E. , Vasiliev Gennadiy V. 
Published: May 2020

AbstractPlastids and mitochondria have their own small genomes which do not undergo meiotic recombination and may have evolutionary fate different from each other and nuclear genome, thus highlighting interesting phenomena in plant evolution. We for the first time sequenced mitochondrial genomes of pea (PisumL.), in 38 accessions mostly representing diverse wild germplasm from all over pea geographical range. Six structural types of pea mitochondrial genome were revealed. From the same accessions, plastid genomes were sequenced. Bayesian phylogenetic trees based on the plastid and mitochondrial genomes were compared. The topologies of these trees were highly discordant implying not less than six events of hybridisation of diverged wild peas in the past, with plastids and mitochondria differently inherited by the descendants. Such discordant inheritance of organelles is supposed to have been driven by plastid-nuclear incompatibility, known to be widespread in pea wide crosses and apparently shaping the organellar phylogenies. The topology of a phylogenetic tree based on the nucleotide sequence of a nuclear geneHis5coding for a histone H1 subtype corresponds to the current taxonomy and resembles that based on the plastid genome. Wild peas (Pisum sativumsubsp.elatiuss.l.) inhabiting Southern Europe were shown to be of hybrid origin resulting from crosses of peas similar to those presently inhabiting south-east and north-east Mediterranean in broad sense.
Feeding dihydroquercetin and vitamin E to broiler chickens reared at standard and high ambient temperatures
Authors: Pirgozliev V. , Westbrook C. , Woods S. , Mansbridge S.C. , Rose S.P. , Whiting I.M. , Yovchev D. , Atanasov A.G. , Kljak K. , Staykova G.P. , Ivanova S. , Karagecili M.R. , Karadas F. , Stringhini J.H. 
Published: May 2020

AbstractThe use of natural antioxidants, in particular polyphenols such as dihydroquercetin (DHQ), in animal nutrition have recently increased in popularity. This may partly be due to the risk of increased incidences of heat stress associated with raising livestock in warmer ambient temperatures, facilitated by global warming, reducing antioxidant capacity. The current research demonstrates the effect of dietary DHQ, vitamin E and standard or high ambient temperatures on growth performance, energy and nutrient metabolism, gastrointestinal tract development (GIT), jejunal villus morphometry and antioxidant status in broiler chickens. Each of the four experimental diets were fed to 16 pens of five birds, which were allocated to four rooms (four pens in each room). The temperature in two rooms was maintained at a constant 35 °C (high temperature; HT), and the temperature in the other two rooms was gradually reduced from 27 °C at 7d of age to 22 °C at 20d of age (standard temperature; ST). Rearing birds at HT reduced: feed intake, weight gain, weight of small intestine, total GIT, liver, spleen, heart, villus height, villus surface area and lowered blood glutationperoxidase (GSH-Px). Dietary DHQ increased blood GSH-Px and total antioxidant status, increased heart weight and reduced caecal size. When fed separately, DHQ and vitamin E improved hepatic vitamin E concentration. Feeding vitamin E increased spleen and liver weights. When fed together, DHQ and vitamin E reduced villus height, villus height to crypt depth ratio and villus surface area. Temperature and antioxidants did not affect energy and nutrient metabolism. There were no effects of dietary antioxidants on growth performance of broiler chickens and there were no mortalities. At present it is unclear if feeding antioxidants (in particular DHQ) at different levels, using different dietary formulations, and rearing birds under a range of environmental conditions may be effective at enhancing production performance and bird health in hot ambient climates.
Neural Network Predicts Need for Red Blood Cell Transfusion for Patients with Acute Gastrointestinal Bleeding Admitted to the Intensive Care Unit
Authors: Shung Dennis , Castro Egbert , Huang Jessie , Tay J. Kenneth , Simonov Michael , Laine Loren , Krishnaswamy Smita 
Published: May 2020

Structured SummaryBackgroundAcute gastrointestinal bleeding is the most common gastrointestinal cause for hospitalization. For high risk patients requiring intensive care unit stay, predicting transfusion needs during the first 24 hours using dynamic risk assessment may improve resuscitation.AimsProvide dynamic risk prediction for red blood cell transfusion in admitted patients with severe acute gastrointestinal bleeding.MethodsA patient cohort admitted for acute gastrointestinal bleeding (N = 2,524) was identified from the Medical Information Mart for Intensive Care III (MIMIC-III) critical care database, separated into training (N = 2,032) and validation (N = 492) sets. 74 demographic, clinical, and laboratory test features were consolidated into 4-hour time intervals over the first 24 hours from admission. The outcome measure was the transfusion of red blood cells during each 4-hour time interval. A long short-term memory (LSTM) model, a type of Recurrent Neural Network (RNN), was compared to the Glasgow-Blatchford Score (GBS).ResultsThe LSTM model performed better than GBS overall (AUROC 0.81 vs 0.63;P<0.001)and at each 4-hour interval (P<0.01). At high sensitivity and high specificity cutoffs, the LSTM model outperformed GBS (P<0.001). The LSTM model performed better in patients directly admitted from the ED to ICU (0.82 vs 0.63;P<0.001), upper GIB (0.84 vs 0.68;P<0.001), lower GIB (0.77 vs 0.58;P<0.001), and unspecified GIB (0.85 vs 0.64;P<0.001).ConclusionsA LSTM model can be used to predict the need for transfusion of packed red blood cells over the first 24 hours from admission to help personalize the care of high-risk patients with acute gastrointestinal bleeding.Data AccessAll clinical data from MIMIC-III was approved under the oversight of the Institutional Review Boards of Beth Israel Deaconess Medical Center (Boston, MA) and the Massachusetts Institute of Technology (Cambridge, MA). Requirement for individual patient consent was waived because the project did not impact clinical care and all protected health information was deidentified. The data was available on PhysioNet were derived from protected health information that has been de-identified and not subject to HIPAA Privacy Rule restrictions. All use of the data was performed with credentialed access under the oversight of the data use agreement through PhysioNet and the Massachusetts Institute of Technology.
High-Resolution Metabolic Mapping of the Cerebellum Using a Zoomed Magnetic Resonance Spectroscopic Imaging
Authors: Emir Uzay E. , Sood Jaiyta , Chiew Mark , Thomas Albert , Lane Sean P. 
Published: May 2020

AbstractPurposeThe human cerebellum plays an important role in functional activity cerebrum which is ranging from motor to cognitive activities since due to its relaying role between spinal cord and cerebrum. The cerebellum poses many challenges to magnetic resonance spectroscopic imaging (MRSI) due to the caudal location, the susceptibility to physiological artifacts and partial volume artifact due to its complex anatomical structure. Thus, in present study, we propose a high-resolution MRSI acquisition scheme for the cerebellum.MethodsA zoomed or reduced-field of view (rFOV) metabolite-cycled full-intensity magnetic resonance spectroscopic imaging (MRSI) at 3T with a nominal resolution of 62.5 μL was developed. Single-slice rFOV MRSI data were acquired from the cerebellum of 5 healthy subjects with a nominal resolution of 2.5□×□2.5□mm2 in 9□minutes 36. Spectra were quantified with LCModel. A spatially unbiased atlas template of the cerebellum was used for analyzing metabolite distributions in the cerebellum.ResultsThe high quality of the achieved spectra enabled to generate a high-resolution metabolic map of total N-acetylaspartate, total creatine, total choline, glutamate+glutamine and myo-inositol with Cramér-Rao lower bounds below 50%. A spatially unbiased atlas template of the cerebellum-based region of interest (ROIs) analysis resulted in spatially dependent metabolite distributions in 9 ROIs. The group-averaging across subjects in the Montreal Neurological Institute-152 template space allowed to generate a very high-resolution metabolite maps in the cerebellum.ConclusionThese findings indicate that very high-resolution metabolite probing of cerebellum is feasible using rFOV or zoomed MRSI at 3T.
Split-ends is modulating lipid droplet content in adultDrosophilaglial cells and is protective against paraquat toxicity
Authors: Girard Victor , Goubard Valérie , Querenet Matthieu , Seugnet Laurent , Pays Laurent , Nataf Serge , Dufourd Eloïse , Cluet David , Mollereau Bertrand , Davoust Nathalie 
Published: May 2020

ABSTRACTGlial cells are early sensors of neuronal injury and are able to store lipids in lipid droplets under oxidative stress conditions. Here, we investigated the glial functions of Spen in the context of Parkinson’s disease (PD). Using a data mining approach, we first found that the human ortholog ofspen,SPEN/SHARPbelongs to the set of astrocyte-expressed genes which mRNA levels are significantly different in thesubstantia nigraof PD patients as compared to controls. Interestingly, the retrieved list of differentially expressed genes was enriched in genes involved in lipid metabolism. In aDrosophilamodel of PD, we observed thatspenmutant flies were more sensitive to paraquat intoxication. Moreover, the glia-restricted knockdown ofspenled to the expansion and the accumulation of lipid droplets as well as the inhibition of Notch pathway. Taken together our results show that Spen regulates lipid metabolism and storage in glial cells and by these means contribute to glia-mediated functions in the context of neurodegeneration.
Developing a Fully-glycosylated Full-length SARS-CoV-2 Spike Protein Model in a Viral Membrane
Authors: Woo Hyeonuk , Park Sang-Jun , Choi Yeol Kyo , Park Taeyong , Tanveer Maham , Cao Yiwei , Kern Nathan R. , Lee Jumin , Yeom Min Sun , Croll Tristan I. , Seok Chaok , Im Wonpil 
Published: May 2020

ABSTRACTThis technical study describes all-atom modeling and simulation of a fully-glycosylated full-length SARS-CoV-2 spike (S) protein in a viral membrane. First, starting from PDB:6VSB and 6VXX, full-length S protein structures were modeled using template-based modeling, de-novo protein structure prediction, and loop modeling techniques in GALAXY modeling suite. Then, using the recently-determined most occupied glycoforms, 22 N-glycans and 1 O-glycan of each monomer were modeled using Glycan Reader & Modeler in CHARMM-GUI. These fully-glycosylated full-length S protein model structures were assessed and further refined against the low-resolution data in their respective experimental maps using ISOLDE. We then used CHARMM-GUI Membrane Builder to place the S proteins in a viral membrane and performed all-atom molecular dynamics simulations. All structures are available in CHARMM-GUI COVID-19 Archive (http://www.charmm-gui.org/docs/archive/covid19), so researchers can use these models to carry out innovative and novel modeling and simulation research for the prevention and treatment of COVID-19.
Adenosine triphosphate Binding Cassette subfamily C member 1 (ABCC1) overexpression reduces APP processing and increases alpha- versus beta-secretase activity,in vitro
Authors: Jepsen Wayne M. , De Both Matthew , Siniard Ashley L. , Ramsey Keri , Piras Ignazio S. , Naymik Marcus , Henderson Adrienne , Huentelman Matthew J. 
Published: May 2020

AbstractThe organic anion transporter Adenosine triphosphate Binding Cassette subfamily C member 1 (ABCC1), also known asMRP1, has been demonstrated in murine models of Alzheimer’s disease (AD) to export amyloid beta (Abeta) from the endothelial cells of the blood-brain barrier to the periphery, and that pharmaceutical activation of ABCC1 can reduce amyloid plaque deposition in the brain. Here, we show that ABCC1 is not only capable of exporting Abeta from the cytoplasm of human cells, but also that it’s overexpression significantly reduces Abeta production and increases the ratio of alpha- versus beta-secretase mediated cleavage of the Amyloid Precursor Protein (APP), likely via indirect modulation of alpha-, beta-, and gamma-secretase activity.
SugarQuant: a streamlined pipeline for multiplexed quantitative site-specific N-glycoproteomics
Authors: Fang Pan , Ji Yanlong , Silbern Ivan , Doebele Carmen , Ninov Momchil , Lenz Christof , Oellerich Thomas , Pan Kuan-Ting , Urlaub Henning 
Published: May 2020

AbstractSite-specific regulation of protein N-glycosylation is essential in human cells. However, accurate quantification of glycosylation sites and their individual glycan moieties in a cell-wide manner is still technically challenging. Here, we introduce SugarQuant, an integrated mass spectrometry-based pipeline comprising fast protein aggregation capture (PAC)-based sample preparation, optimized multi-notch MS3 LC-MS acquisition (Glyco-SPS-MS3) and a data-processing tool (GlycoBinder) that allows for confident, global identification and quantification of intact glycopeptides in complex biological samples. PAC greatly reduces the overall samplehandling time without compromising sensitivity. Glyco-SPS-MS3 combines high-resolution MS2 and MS3 scans, resulting in enhanced reporter signals of isobaric mass tags, improved detection of N-glycopeptide fragments, and significantly lowered interference in multiplexed quantification. GlycoBinder enables streamlined processing of Glyco-SPS-MS3 data, followed by a two-step database search which increases the identification rates of intact glycopeptides by up to 22% when compared with one-step database search strategies. SugarQuant was applied to identify and quantify more than 5,000 unique glycoforms in Burkitt’s lymphoma cells, and determined complex site-specific glycosylation changes that occurred upon inhibition of fucosylation at high confidence.
Exploring the Sequence Fitness Landscape of a Bridge Between Protein Folds
Authors: Tian Pengfei , Best Robert B. 
Published: May 2020

AbstractMost foldable protein sequences adopt only a single native fold. Recent protein design studies have, however, created protein sequences which fold into different structures apon changes of environment, or single point mutation, the best characterized example being the switch between the folds of the GA and GB binding domains of streptococcal protein G. To obtain further insight into the design of sequences which can switch folds, we have used a computational model for the fitness landscape of a single fold, built from the observed sequence variation of protein homologues. We have recently shown that such coevolutionary models can be used to design novel foldable sequences. By appropriately combining two of these models to describe the joint fitness landscape of GA and GB, we are able to describe the propensity of a given sequence for each of the two folds. We have successfully tested the combined model against the known series of designed GA/GB hybrids. Using Monte Carlo simulations on this landscape, we are able to identify pathways of mutations connecting the two folds. In the absence of a requirement for domain stability, the most frequent paths go via sequences in which neither domain is stably folded, reminiscent of the propensity for certain intrinsically disordered proteins to fold into different structures according to context. Even if the folded state is required to be stable, we find that there is nonetheless still a wide range of sequences which are close to the transition region and therefore likely fold switches, consistent with recent estimates that fold switching may be more widespread than had been thought.Author SummaryWhile most proteins self-assemble (or “fold”) to a unique three-dimensional structure, a few have been identified that can fold into two distinct structures. These so-called “metamorphic” proteins that can switch folds have attracted a lot of recent interest, and it has been suggested that they may be much more widespread than currently appreciated. We have developed a computational model that captures the propensity of a given protein sequence to fold into either one of two specific structures (GA and GB), in order to investigate which sequences are able to fold to both GA and GB (“switch sequences”), versus just one of them. Our model predicts that there is a large number of switch sequences that could fold into both structures, but also that the most likely such sequences are those for which the folded structures have low stability, in agreement with available experimental data. This also suggests that intrinsically disordered proteins which can fold into different structures on binding may provide an evolutionary path in sequence space between protein folds.
Spatial organization of transcribed eukaryotic genes
Authors: Leidescher Susanne , Ribisel Johannes , Ullrich Simon , Feodorova Yana , Hildebrand Erica , Bultmann Sebastian , Link Stephanie , Thanisch Katharina , Mulholland Christopher , Dekker Job , Leonhardt Heinrich , Mirny Leonid , Solovei Irina 
Published: May 2020

SUMMARYDespite the well-established role of nuclear organization in gene expression regulation, little is known about the reverse: how transcription shapes the spatial organization of the genome. Owing to small sizes of most previously studied genes and the limited resolution of microscopy, the structure and spatial arrangement of a single transcribed gene are still poorly understood. Here, we make use of several long highly expressed genes and demonstrate that they form transcription loops with polymerases moving along the loops and carrying nascent RNAs. Transcription loops can span across microns resembling lampbrush loops and polytene puffs. Extension and shape of transcription loops suggest their intrinsic stiffness, which we attribute to decoration with multiple voluminous nascent RNPs. Our data contradict the model of transcription factories and indicate that although microscopically resolvable transcription loops are specific for long highly expressed genes, the mechanisms underlying their formation can represent a general aspect of eukaryotic transcription.
Selective inhibition of human translation by a drug-like compound that traps terminated protein nascent chains on the ribosome
Authors: Li Wenfei , Chang Stacey Tsai-Lan , Ward Fred. R , Cate Jamie H. D. 
Published: May 2020

AbstractMethods to directly inhibit gene expression using small molecules hold promise for the development of new therapeutics targeting proteins that have evaded previous attempts at drug discovery. Among these, small molecules including the drug-like compound PF-06446846 (PF846) selectively inhibit the synthesis of specific proteins, by stalling translation elongation1–4. These molecules also inhibit translation termination4by an unknown mechanism. Using cryo-electron microscopy (cryo-EM) and biochemical approaches, we show that PF846 arrests translation at the stop codon by slowing hydrolysis of the protein nascent chain (NC) from peptidyl-site (P-site) tRNA by eukaryotic release factor 1 (eRF1). After NC hydrolysis from the P-site tRNA, PF846 traps the NC in the ribosome exit tunnel in a compact α-helical conformation that induces 28S rRNA nucleotide rearrangements propagating back to the ribosome peptidyl transferase center (PTC). Mutational analyses and human cell-based experiments elucidate the pivotal amino acids of the NC required for PF846-dependent termination arrest, all of which face the PF846 side of the ribosome exit tunnel. The structural and functional data support a model in which PF846 inhibits translation termination by inducing allosteric conformational rearrangements in the NC and PTC that suppress peptidyl-tRNA hydrolysis promoted by eRF1, and trap the NC in the ribosome exit tunnel. This unprecedented mechanism of action reveals new principles of translation termination and lays the foundation for new therapeutic strategies.
Reverse Pneumatic Artificial Muscles for Application in Low-Cost Artificial Respirators
Authors: Mirvakili Seyed M , Sim Douglas , Langer Robert 
Published: May 2020

AbstractOne of the main challenges associated with mechanical ventilators is their limited availability in pandemics and other emergencies. Therefore, there is a great demand for mechanical ventilators to address this issue. In this work, we propose a low-cost, portable, yet high-performance design for a volume-controlled mechanical ventilator. We are employing pneumatic artificial muscles, such as air cylinders, in the reverse mode of operation to achieve mechanical ventilation. The current design of the device can operate in two modes: controlled mode and assisted mode. Unlike most ICU ventilators, our device does not need a high-pressure air pipeline to operate. With the current design, mechanical ventilation for respiration rate ranging from 10 b/min to 30 b/min with a tidal volume range of 150 mL to 1000 mL and I:E ratio of 1:1 to 1:5 can be performed. We achieved a total cost of less $400 USD to make one device. We estimate the device to cost less than $250 USD when produced in larger volumes.
Travelling spindles create necessary conditions for spike-timing-dependent plasticity in humans
Authors: Dickey Charles W. , Sargsyan Anna , Madsen Joseph R. , Eskandar Emad N. , Cash Sydney S. , Halgren Eric 
Published: May 2020

AbstractSleep spindles facilitate memory consolidation in the cortex during mammalian non-rapid eye movement (NREM) sleep. In rodents, phase-locked firing during spindles may facilitate spike-timing-dependent plasticity (STDP) by grouping pre- and post-synaptic cell firing within ∼25ms. Currently, microphysiological evidence in humans for conditions conducive for STDP during spindles is absent. We analyzed local field potentials and supragranular unit spiking during spindles from 10×10 arrays of microelectrodes at 400µm pitch in humans. We found strong tonic and phase-locked increases in firing and co-firing within 25ms during spindles. Co-firing, spindle co-occurrence, and spindle coherence were greatest between sites within ∼2mm, and high co-firing of units on different electrodes was largely restricted to moments of high spindle coherence between those electrodes. Spindles propagated at ∼0.23m/s in distinct patterns, with correlated cell co-firing sequences. These results suggest that spindles may organize spatiotemporal patterns of neuronal co-firing which promote memory consolidation during NREM sleep.