bluuebunny/crossref_metadata_2025_split huggingface dataset:
Silencing XIST on the future active X: Searching human and bovine preimplantation embryos for the repressor
Authors: Aksit Melis A , Yu Bo , Roelen Bernard AJ , Migeon Barbara R. 
Published: October 2021

ABSTRACTX inactivation is the means of equalizing the dosage of X chromosomal genes in male and female eutherian mammals, so that only one X is active in each cell. The XIST locus (in cis) on each additional X chromosome initiates the transcriptional silencing of that chromosome, making it an inactive X. How the active X in both males and females is protected from inactivation by its own XIST locus is not well understood in any mammal. Previous studies of autosomal duplications suggest that gene(s) on the short arm of human chromosome 19 repress XIST function on the active X. Here, we examine the time of transcription of some candidate genes in preimplantation embryos using single-cell RNA sequencing data from human embryos and qRT-PCR from bovine embryos. The candidate genes assayed are those transcribed from 19p13.3-13.2, which are widely expressed and can remodel chromatin. Our results confirm that XIST is expressed at low levels from the future active X in embryos of both sexes; they also show that the XIST locus is repressed in both sexes when pluripotency factors are being upregulated, during the 4-8 cell and morula stages in human and bovine embryos – well before the early blastocyst (E5) when XIST on the inactive X in females begins to be upregulated. Our data suggest a role for DNMT1, UHRF1, SAFB and SAFB2 in XIST repression; they also exclude XACT and other 19p candidate genes and provide the transcriptional timing for some genes not previously assayed in human or bovine preimplantation embryos.
Choose carefully, act quickly: Efficient decision making with selective inhibition in attractor neural networks
Authors: Liu Belle , Lo Chung-Chuan , Wu Kuo-An 
Published: October 2021

AbstractThe ability to decide swiftly and accurately in an urgent scenario is crucial for an organism’s survival. The neural mechanisms underlying the perceptual decision and trade-off between speed and accuracy have been extensively studied in the past few decades. Among several theoretical models, the attractor neural network model has successfully captured both behavioral and neuronal data observed in many decision experiments. However, a recent experimental study revealed additional details that were not considered in the original attractor model. In particular, the study shows that the inhibitory neurons in the posterior parietal cortex of mice are as selective to decision making results as the excitatory neurons, whereas the previous attractor model assumes the inhibitory neurons to be unselective. In this study, we investigate the attractor model with selective inhibition (selective model), which can be considered as a general case of the previous attractor model (unselective model). Our model reproduces several behavioral and neurophysiological observations. To analyze the dynamics of the selective model, we reduce it and show that selectivity adds a time-varying component to the energy landscape. This time dependence of the energy landscape allows the selective model to integrate information carefully in initial stages, then quickly converge to an attractor once the choice is clear. This results in the selective model having a more efficient speed-accuracy trade-off that is unreachable by unselective models.
Engineered endosymbionts capable of directing mammalian cell gene expression
Authors: Madsen Cody S. , Makela Ashley V. , Greeson Emily M. , Hardy Jonathan W. , Contag Christopher H. 
Published: October 2021

SummaryModular methods for directing mammalian gene expression would enable advances in tissue regeneration, enhance cell-based therapeutics and improve modulation of immune responses. To address this challenge, engineered endosymbionts (EES) that escape endosomal destruction, reside in the cytoplasm of mammalian cells, and secrete proteins that are transported to the nucleus to control host cell gene expression were developed. Microscopy confirmed that EES escape phagosomes, replicate within the cytoplasm, and can secrete reporter proteins into the cytoplasm that were then transported to the nucleus. Synthetic operons encoding the mammalian transcription factors,Stat-1andKlf6orKlf4andGata-3were recombined into the EES genome. Using controlled induction, these EES were shown to direct gene expression in J774A.1 macrophage/monocyte cells and modulate the host cell fates. Expressing mammalian transcription factors from engineered intracellular bacteria as endosymbionts comprises a new tool for directing host cell gene expression for therapeutic and research purposes.Graphical abstract
Immunodominant and neutralizing linear B cell epitopes spanning the spike and membrane proteins of Porcine Epidemic Diarrhea Virus
Authors: Polyiam Kanokporn , Ruengjitchatchawalya Marasri , Mekvichitsaeng Phenjun , Kaeoket Kampon , Hoonsuwan Tawatchai , Joiphaeng Pichai , Roshorm Yaowaluck Maprang 
Published: October 2021

AbstractPorcine Epidemic Diarrhea Virus (PEDV) is the causative agent of PED, an enteric disease that causes high mortality rates in piglets. PEDV is an alphacoronavirus that has high genetic diversity. Insights into neutralizing B cell epitopes of all genetically diverse PEDV strains are of importance, particularly for designing a vaccine that can provide broad protection against PEDV. In this work, we aimed to explore the landscape of linear B cell epitopes on the spike (S) and membrane (M) proteins of global PEDV strains. All amino acid sequences of the PEDV S and M proteins were retrieved from the NCBI database and grouped. Immunoinformatics-based methods were next developed and used to identify putative linear B cell epitopes from 14 and 5 consensus sequences generated from distinct groups of the S and M proteins, respectively. ELISA testing predicted peptides with PEDV-positive sera revealed 9 novel immunodominant epitopes on the S protein. Importantly, 7 of these novel immunodominant epitopes and other subdominant epitopes were demonstrated to be neutralizing epitopes by neutralization-inhibition assay. Additionally, our study shows the first time that M protein is also the target of neutralizing antibodies as 7 neutralizing epitopes in the M protein were identified. Conservancy analysis revealed that epitopes in the S1 subunit are more variable than those in the S2 subunit and M protein. In this study, we offer the immunoinformatics approach for linear B cell epitope identification and a more complete profile of linear B cell epitopes across the PEDV S and M proteins, which may contribute to the development of a greater PEDV vaccine as well as peptide-based immunoassays.
A gender-bias-mitigated, data-driven precision medicine system to assist in the selection of biological treatments of grade 3 and 4 knee osteoarthritis: development and preliminary validation of precisionKNEE
Authors: Heidari Nima , Parkin James , Olgiati Stefano , Meloni Davide , Fish Brady , Noorani Ali , Slevin Mark , Azamfirei Leonard 
Published: October 2021

IntroductionOsteoarthritis is a leading cause of global disability and is set to worsen with the concurrent rise in rates of obesity and an ageing population [1]. Current clinical solutions are sub-optimal with regards to their invasiveness and outcomes. Orthopaedic biologics is an emerging field that offers alternative and parallel treatment options to address this problem. Determining which patients will benefit most from these novel treatments is key in developing clinical pathways.MethodsOur dataset included 329 patients treated with microfragmented fat injection (MFAT) over a 2 year period. Clinico-demographic data was recorded as well as 1-year Oxford Knee Score (OKS). The data was modelled to predict OKS 1-year response using Random Forest Regressors. Gender-bias was mitigated and outliers were hidden from the training model. The model was validated on raw test data and on a subset of patients with Kellgren-Lawrence grade 3 and 4 radiological evidence of arthritis, age greater than 64, preoperative OKS less than or equal to 27 and idiopathic aetiology of arthritis.ResultsThe mean age and mean body mass index (BMI) of patients in our dataset was 66.4 years, 26.9 respectively. 53.5% of patients had Kellgren-Lawrence grade 4 arthritis.The final models RMSE was 6.72, MAE was 5.38 and r-squared was 0.23 on raw test data. An RMSE of 9.77 and MAE of 7.81 was achieved when validating the model on our subset of patients. Wilcoxon signed rank tests found no evidence of predicted results being statistically significantly different to ground truth values (p ¿ 0.05).Preoperative OKS and Kellgren-Lawrence arthritis grade was the most important feature in our model.DiscussionOur model is performant and able to predict 1 year OKS response outcome within our set of patients. We have found key features of prediction and would recommend these are researched further to improve model performance.Our dataset does not compare outcomes with other standard treatments. We also don’t compare outcomes with other biologic treatments.Ultimately, this research can be used as a tool to benefit both patients and clinicians in a combined decision-making process.
Neutralizing antibodies against SARS-CoV-2 variants of concern elicited by the Comirnaty® COVID-19 vaccine in nursing home residents
Authors: Sánchez-Sendra Beatriz , Albert Eliseo , Zulaica Joao , Torres Ignacio , Giménez Estela , Botija Pilar , Beltrán María José , Rodado Celia , Geller Ron , Navarro David 
Published: October 2021

ABSTRACTImmunosenescence may impact the functionality and breadth of vaccine-elicited humoral immune responses. The ability of sera to neutralize the SARS-CoV-2 spike protein (S) from Beta, Gamma, Delta, and Epsilon variants of concern (VOCs) relative to the ancestral Wuhan-Hu-1 strain was compared in Comirnaty® COVID-19-vaccinated elderly nursing home residents (n=30) or younger individuals (n=18) and non-vaccinated individuals who recovered from severe COVID-19 (n=19). In all groups, some participants lacked NtAb against one or more VOCs, mainly the Beta variant (15-20%). Serum NtAb titers were lowest against the Beta variant followed by Gamma, Epsilon, and Delta variants. Fold change reduction in NtAb titers relative to the ancestral strain was greatest for the Beta variant (6.7-18.8) followed by Gamma (3.6-6.2), Epsilon (2.9-5.8), and Delta (3.5-4.3) variants, regardless of the study group considered. In summary, older age, frailty, and concurrence of co-morbidities had no impact on the serum NtAb activity profile against SARS-CoV-2 VOCs.
A clinical trial to evaluate the dayzz smartphone app on employee sleep, health, and productivity at a large US employer
Authors: Robbins Rebecca , Weaver Matthew D. , Quan Stuart F. , Sullivan Jason P. , Cohen-Zion Mairav , Glasner Laura , Qadri Salim , Czeisler Charles A. , Barger Laura 
Published: October 2021

AbstractSleep deficiency is a hidden cost of our 24-7 society, with 70% of adults in the US admitting that they routinely obtain insufficient sleep. Further, it is estimated that 50-70 million adults in the US have a sleep disorder. Undiagnosed and untreated sleep disorders are associated with diminished health for the individual and increased costs for the employer. Research has shown that adverse impacts on employees and employers can be mitigated through sleep health education and sleep disorder screening and treatment programs. Smartphone applications (app) are increasingly commonplace and represent promising, scalable modalities for such programs. The dayzz app is a personalized sleep training program that incorporates assessment of sleep disorders and offers a personalized comprehensive sleep improvement solution. Using a sample of day workers affiliated with a large institution of higher education, we will conduct a single-site, parallel-group, randomized, waitlist control trial. Participants will be randomly assigned to either use the dayzz app throughout the study or receive the dayzz app at the end of the study. We will collect data on feasibility and acceptability of the dayzz app; employee sleep, including sleep behavioral changes, sleep duration, regularity, and quality; employee presenteeism, absenteeism, and performance; employee mood; adverse and safety outcomes; and healthcare utilization on a monthly basis throughout the study, as well as collect more granular daily data from the employee during pre-specified intervals. Our results will illuminate whether a personalized smartphone app is a viable approach for improving employee sleep, health, and productivity.
ToKSA - Tokenized Key Sentence Annotation - a Novel Method for Rapid Approximation of Ground Truth for Natural Language Processing
Authors: Fairfield Cameron J , Cambridge William A , Cullen Lydia , Drake Thomas M , Knight Stephen R , Masson Neil , Mills Nicholas L , Pius Riinu , Shaw Catherine A , Wu Honghan , Wigmore Stephen J , Spiliopoulou Athina , Harrison Ewen M 
Published: October 2021

ABSTRACTObjectiveIdentifying phenotypes and pathology from free text is an essential task for clinical work and research. Natural language processing (NLP) is a key tool for processing free text at scale. Developing and validating NLP models requires labelled data. Labels are generated through time-consuming and repetitive manual annotation and are hard to obtain for sensitive clinical data. The objective of this paper is to describe a novel approach for annotating radiology reports.Materials and MethodsWe implemented tokenized key sentence-specific annotation (ToKSA) for annotating clinical data. We demonstrate ToKSA using 180,050 abdominal ultrasound reports with labels generated for symptom status, gallstone status and cholecystectomy status. Firstly, individual sentences are grouped together into a term-frequency matrix. Annotation of key (i.e. the most frequently occurring) sentences is then used to generate labels for multiple reports simultaneously. We compared ToKSA-derived labels to those generated by annotating full reports. We used ToKSA-derived labels to train a document classifier using convolutional neural networks. We compared performance of the classifier to a separate classifier trained on labels based on the full reports.ResultsBy annotating only 2,000 frequent sentences, we were able to generate labels for symptom status for 70,000 reports (accuracy 98.4%), gallstone status for 85,177 reports (accuracy 99.2%) and cholecystectomy status for 85,177 reports (accuracy 100%). The accuracy of the document classifier trained on ToKSA labels was similar (0.1-1.1% more accurate) to the document classifier trained on full report labels.ConclusionToKSA offers an accurate and efficient method for annotating free text clinical data.
Functional analysis of a common BAG3 allele associated with protection from heart failure
Authors: Perez-Bermejo Juan A , Judge Luke M , Jensen Christina L , Wu Kenneth , Truong Annie , Ho Jaclyn J , Carter Matthew , Runyon Wendy V , Kaake Robyn M , Pulido Ernst , Watry Hannah L , Mandegar Mohammad A , Swaney Danielle L , So Po-Lin , Krogan Nevan J , Conklin Bruce R 
Published: October 2021

AbstractMultiple genetic association studies have correlated a common allelic block linked to the BAG3 gene with a decreased incidence of heart failure, but the molecular mechanism for such protection remains elusive. One of the variants in this allele block is coding, changing cysteine to arginine at position 151 of BAG3 (rs2234962-BAG3C151R). Here, we use induced pluripotent stem cells (iPSC) to test if the BAG3C151Rvariant alters protein and cellular function in human cardiac myocytes. Quantitative protein interaction network analysis identified specific changes in BAG3C151Rprotein interaction partners in cardiomyocytes but not in iPSCs or an immortalized cell line. Knockdown of BAG3 interacting factors in cardiomyocytes followed by myofibrillar analysis revealed that BAG3C151Rassociates more strongly with proteins involved in the maintenance of myofibrillar integrity. Finally, we demonstrate that cardiomyocytes expressing the BAG3C151Rvariant have improved response to proteotoxic stress in an allele dose-dependent manner. This study suggests that the BAG3C151Rvariant increases cardiomyocyte protection from stress by enhancing the recruitment of factors critical to the maintenance of myofibril integrity, hinting that this variant could be responsible for the cardioprotective effect of the haplotype block. By revealing specific changes in preferential binding partners of the BAG3C151Rprotein variant, we also identify potential targets for the development of novel cardioprotective therapies.
A genetic screen identifies a protective type III interferon response toCryptosporidiumthat requires TLR3 dependent recognition
Authors: Gibson Alexis R. , Sateriale Adam , Dumaine Jennifer E. , Engiles Julie B. , Gullicksrud Jodi A. , O’Dea Keenan , Doench John G. , Beiting Daniel P. , Hunter Christopher A. , Striepen Boris 
Published: October 2021

AbstractCryptosporidiumis a leading cause of severe diarrhea and diarrheal-related death in children worldwide. As an obligate intracellular parasite,Cryptosporidiumrelies on intestinal epithelial cells to provide a niche for its growth and survival, but little is known about the contributions that the infected cell makes to this relationship. Here we conducted a genome wide CRISPR/Cas9 knockout screen to discover host genes required forCryptosporidium parvuminfection and/or host cell survival. Gene enrichment analysis indicated that the host interferon response, glycosaminoglycan (GAG) and glycosylphosphatidylinositol (GPI) anchor biosynthesis are important determinants of susceptibility toC. parvuminfection. Several of these pathways are linked to parasite attachment and invasion and C-type lectins on the surface of the parasite. Evaluation of transcript and protein induction of innate interferons revealed a pronounced type III interferon response toCryptosporidiumin human cells as well as in mice. Treatment of mice with IFNλ reduced infection burden and protected immunocompromised mice from severe outcomes including death, with effects that required STAT1 signaling in the enterocyte. Initiation of this type III interferon response was dependent on sustained intracellular growth and mediated by the pattern recognition receptor TLR3. We conclude that host cell intrinsic recognition ofCryptosporidiumresults in IFNλ production critical to early protection against this infection.Author SummaryCryptosporidiuminfection is an important contributor to global childhood mortality. There are currently no vaccines available, and the only drug has limited efficacy in immunocompromised individuals and malnourished children who need it most. To discover which host proteins are essential forCryptosporidiuminfection, we conducted a genome wide knockout screen in human host cells. Our results confirm the importance of glycosaminoglycans on the surface of epithelial cells for attachment and invasion of the parasite. We also found that host GPI anchor biosynthesis and interferon signaling pathways were enriched by our screen. Examining the role of interferon signaling further we found a type III interferon response, IFNλ, was generated in response to infection and shown to be initiated in the infected cell. Utilizing mouse models of infection, we found that the type III interferon response was important early during infection with its induction likely preceding IFNγ, a key cytokine for the control of this infection. We also determined that TLR3 was the pattern recognition receptor responsible for IFNλ production duringCryptosporidiuminfection. Our work shows that IFNλ acts directly on the enterocyte and its use in treating immunocompromised mice produced striking reductions in infection.
Major transcriptomic, epigenetic and metabolic changes underly the pluripotency continuum in rabbit preimplantation embryos
Authors: Bouchereau Wilhelm , Jouneau Luc , Archilla Catherine , Aksoy Irène , Moulin Anais , Daniel Nathalie , Peynot Nathalie , Calderari Sophie , Joly Thierry , Godet Murielle , Jaszczyszyn Yan , Pratlong Marine , Severac Dany , Savatier Pierre , Duranthon Véronique , Afanassieff Marielle , Beaujean Nathalie 
Published: October 2021

AbstractDespite the growing interest in the rabbit model for developmental and stem cell biology, the characterization of embryos at the molecular level is still poorly documented. We conducted a transcriptome analysis of rabbit pre-implantation embryos from E2.7 (morula stage) to E6.6 (early primitive streak stage) using bulk and single-cell RNA-sequencing. In parallel, we studied oxidative phosphorylation and glycolysis and analysed active and repressive epigenetic modifications during blastocyst formation and expansion. We generated a transcriptomic, epigenetic, and metabolic map of the pluripotency continuum in rabbit preimplantation embryos and identified novel markers of naive pluripotency that might be instrumental for deriving naive pluripotent stem cell lines. Although the rabbit is evolutionarily closer to mice than to primates, we found that the transcriptome of rabbit epiblast cells shares common features with that of humans and non-human primates.Summary StatementRabbit preimplantation embryos share characteristics with human and monkey embryos with respect to timing of early lineage segregation and expression of marker genes for naive and primed pluripotency.
The potential of CYP2D6 phenotyping to improve opioid dosing strategies
Authors: Cassidy Ridley , Main Ewan 
Published: October 2021

AbstractBackgroundPrescription opioids account for more than 40% of opioid induced mortalities. With the trend towards increased opioid prescribing set to continue rising, opioid-based adverse drug reactions, (ADRs) and their associated human and financial cost present a major global public health concern. The review examined the relationship between CYP2D6 phenotypes and opioid metabolising. The aim was to establish whether screening for CYP2D6 phenotypes would improve existing opioid dosing strategies and reduce ADRs.MethodA systematic review was conducted using the online Web of Science database. Selected key words and Boolean operator combinations were used to search the relevant literature. Identified studies were screened against pre-defined inclusion/exclusion criteria. Eligible studies were subject to full review and quality assessment. A narrative analysis was performed to synthesise data from the studies included in the final review.ResultsThe review yielded five studies that met the eligibility criteria and were subject to full review. Four of the five studies reported significant effects of CYP2D6 phenotypes on opioid metabolising or opioid based ADRs. Three studies focused exclusively on pharmacokinetics, two studies focused exclusively on ADRs, and one study considered pharmacokinetics and ADRs. All pharmacokinetic studies reported a significant association between CYP2D6 phenotypes and opioid metabolising. Only one of the studies reported a significant association between CYP2D6 phenotypes and ADRs.ConclusionThe majority of evidence considered in the review supports the role of CYP2D6 in the metabolising of opioids and opioid based ADRs. Consequently, CYP2D6 screening should be considered as a potential mechanism for improving existing opioid dosing strategies and reducing ADRs. There is a need for further higher quality primary data studies focusing specifically on CYP2D6 phenotyping in the context of dosage strategies and exploring impact in longitudinal designs. Future studies should also seek to develop cost effective CYP2D6 screening methods to help support the clinical significance of CYP2D6 phenotyping.