bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Bioengineered Platform for Enhanced Observability of Patterned Gastrointestinal Organoid Monolayers with Bilateral Access
Authors: Hofer Moritz , Duque-Correa Maria A. , Lutolf Matthias P. 
Published: January 2024

AbstractStudying the physiology and pathology of gastrointestinal (GI) tissues requires tools that can accurately mimic their complex architecture and functionalityin vitro. Organoids have emerged as one such promising tool, though their closed structures with poorly accessible lumen and limited observability makes readouts challenging. In this study, we introduce a bioengineered organoid platform that generates bilaterally accessible 3D tissue models, allowing independent manipulation of both the apical and basal sides of patterned epithelial monolayers. We successfully constructed gastric, small intestinal, caecal, and colonic epithelial models that faithfully reproduce tissue-respective geometries and exhibit high physiological relevance, evidenced by the regionalization of stem cells and transcriptional resemblance to real epithelia. The gained observability allowed single-cell tracking over time and studies into the motility of cells in immersion and air-liquid interface cultures. Additionally, this model recapitulatedTrichuris murisinfection of the caecum epithelium, allowing the first live imaging of syncytial tunnel formation. Overall, this platform offers accessible organoids with improved observability, making it a valuable tool for investigating the dynamics of GI epithelial cells and their interactions with pathogens.
Discovery of SARS-CoV-2 papain-like protease (PLpro) inhibitors with efficacy in a murine infection model
Authors: Garnsey Michelle R. , Robinson Matthew C. , Nguyen Luong T. , Cardin Rhonda , Tillotson Joseph , Mashalidis Ellene , Yu Aijia , Aschenbrenner Lisa , Balesano Amanda , Behzadi Amin , Boras Britton , Chang Jeanne S. , Eng Heather , Ephron Andrew , Foley Tim , Ford Kristen K. , Frick James M. , Gibson Scott , Hao Li , Hurst Brett , Kalgutkar Amit S. , Korczynska Magdalena , Lengyel-Zhand Zsofia , Gao Liping , Meredith Hannah R. , Patel Nandini C. , Polivkova Jana , Rai Devendra , Rose Colin R. , Rothan Hussin , Sakata Sylvie K. , Vargo Thomas R. , Qi Wenying , Wu Huixian , Liu Yiping , Yurgelonis Irina , Zhang Jinzhi , Zhu Yuao , Zhang Lei , Lee Alpha A. 
Published: January 2024

AbstractVaccines and first-generation antiviral therapeutics have provided important protection against coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, there remains a need for additional therapeutic options that provide enhanced efficacy and protection against potential viral resistance. The SARS-CoV-2 papain-like protease (PLpro) is one of two essential cysteine proteases involved in viral replication. While inhibitors of the SARS-CoV-2 main protease (Mpro) have demonstrated clinical efficacy, known PLproinhibitors have to date lacked the inhibitory potency and requisite pharmacokinetics to demonstrate that targeting PLprotranslates toin vivoefficacy in a preclinical setting. Herein, we report the machine learning-driven discovery of potent, selective, and orally available SARS-CoV-2 PLproinhibitors, with lead compound PF-07957472 (4) providing robust efficacy in a mouse-adapted model of COVID-19 infection.
Scorpion α-toxin LqhαIT specifically interacts with a glycan at the pore domain of voltage-gated sodium channels
Authors: Phulera Swastik , Dickson Callum J. , Schwalen Christopher J. , Khoshouei Maryam , Cassell Samantha J. , Sun Yishan , Condos Tara , Whicher Jonathan , Weihofen Wilhelm A. 
Published: January 2024

AbstractVoltage-gated sodium (Nav) channels sense membrane potential and drive cellular electrical activity. Numerous protein toxins have been identified that modulate Nav gating, and structures of Nav channels in complex with these toxins helped elucidate the molecular mechanisms of voltage-dependent channel gating. The deathstalker scorpion α-toxin LqhαIT exerts a strong action potential prolonging effect on Nav channels. Biochemical studies show that LqhαIT features a functionally essential epitope at its C-terminus that is not shared with related scorpion α-toxins. To elucidate the mechanism of action of LqhαIT, we determined a 3.9 Å cryo-electron microscopy (cryo-EM) structure of LqhαIT in complex with the Nav channel fromPeriplaneta americana(NavPas). We found that LqhαIT binds to voltage sensor domain 4 and traps it in a “S4 down” conformation to stabilize the open state. To promote binding, the functionally essential C-terminal epitope of LqhαIT forms an extensive interface with the glycan scaffold linked to Asn330 of NavPas that augments a small protein-protein interface between NavPas and LqhαIT. A combination of molecular dynamics simulations, structural comparisons, and prior mutagenesis experiments demonstrate the functional importance of this toxin-glycan interaction. These findings help establish a structural basis for the specificity achieved by scorpion α-toxins and provide crucial insights for the development and optimization of new Nav channel modulators.
RAPID HEMATOCRIT ESTIMATION USING A FOLD-CREASE INDUCED FAST FLOWING PAPER SENSOR
Authors: Dash Amaan , Mukhopadhyay Manikuntala , Shaw Jyoti , Bhattacharya Maitreyee , DasGupta Sunando 
Published: January 2024

AbstractIncreased evaporative losses and flow obstructions can present substantial impediments to current paper analytical devices (µPADs) for efficient on-site testing of biological fluids. Strategic enhancements in wicking rates of paper may thereby counter these limitations and enable on-demand healthcare monitoring. Therefore, herein we have leveraged the features of paper fold-crease regions, for the very first time, and developed a novel fast-flowing platform using laser printing to accelerate fluid flow through paper. A series of extensive experiments have been conducted to optimize the design and maximize wicking rates of µPADs for smaller liquid volumes, making it well-suited for analysing biofluids. The investigation delves into structural alterations within the creased regions, employing both static and dynamic force application strategies. A first-generation Washburn type model in excellent agreement with the experimental findings is developed, providing a comprehensive insight into the fundamental physics involved. Finally, the folded channels are utilized for a distance-based hematocrit sensor employing grade-1 filter paper at very low-cost, simplified fabrication, lesser sample volume and faster analysis. The findings of this work unveil a plethora of potentialities for employing paper and paper folds to develop affordable medical devices with advanced analytical functionalities, specifically tailored for the resource-constrained settings.Graphical Abstract
Functional validation ofEIF2AK4(GCN2) missense variants associated with pulmonary arterial hypertension
Authors: Emanuelli Giulia , Zhu JiaYi , Morell Nicolas W , Marciniak Stefan J 
Published: January 2024

AbstractPulmonary arterial hypertension (PAH) is a disorder with a large genetic component. Biallelic mutations ofEIF2AK4, which encodes the kinase GCN2, are causal in two ultra-rare subtypes of PAH, pulmonary veno-occlusive disease and pulmonary capillary haemangiomatosis.EIF2AK4variants of unknown significance have also been identified in patients with classical PAH, though their relationship to disease remains unclear. To provide patients with diagnostic information and enable family testing, the functional consequences of such rare variants must be determined, but existing computational methods are imperfect. We applied a suite of bioinformatic and experimental approaches to sixteenEIF2AK4variants that had been identified in patients. By experimentally testing the functional integrity of the integrated stress response (ISR) downstream of GCN2, we determined that existing computational tools have insufficient sensitivity to reliably predict impaired kinase function. We determined experimentally that severalEIF2AK4variants identified in patients with classical PAH had preserved function and are therefore likely to be non-pathogenic. The dysfunctional variants of GCN2 that we identified could be subclassified into three groups: misfolded, kinase-dead, and hypomorphic. Intriguingly, members of the hypomorphic group were amenable to paradoxical activation by a type-1.5 GCN2 kinase inhibitor. This experiment approach may aid in the clinical stratification ofEIF2AK4variants and potentially identify hypomorophic alleles receptive to pharmacological activation.
Highly parameterized polygenic scores tend to overfit to population stratification via random effects
Authors: Aw Alan J. , McRae Jeremy , Rahmani Elior , Song Yun S. 
Published: January 2024

AbstractPolygenic scores (PGSs), increasingly used in clinical settings, frequently include many genetic variants, with performance typically peaking at thousands of variants. Such highly parameterized PGSs often include variants that do not pass a genome-wide significance threshold. We propose a mathematical perspective that renders the effects of many of these nonsignificant variants random rather than causal, with the randomness capturing population structure. We devise methods to assess variant effect randomness and population stratification bias. Applying these methods to 141 traits from the UK Biobank, we find that, for many PGSs, the effects of non-significant variants are considerably random, with the extent of randomness associated with the degree of overfitting to population structure of the discovery cohort. Our findings explain why highly parameterized PGSs simultaneously have superior cohort-specific performance and limited generalizability, suggesting the critical need for variant randomness tests in PGS evaluation. Supporting code and a dashboard are available athttps://github.com/songlab-cal/StratPGS.
Unveiling Endoglin non canonical regulation: spotlight on the new role of the uPAR pathway
Authors: Munsch Gaëlle , Proust Carole , Deiber Clémence , Meguerditchian Caroline , Caro Ilana , Tusseau Maud , Guilhem Alexandre , Mohamed Shirine ,   INVENT consortium, Goyenvalle Aurélie , Debette Stéphanie , Jaspard-Vinassa Béatrice , Dupuis-Girod Sophie , Trégouët David-Alexandre , Soukarieh Omar 
Published: January 2024

AbstractEndoglin, encoded byENG, is a transmembrane glycoprotein crucial for endothelial cell biology. Loss-of-functionENGvariants cause Hereditary Hemorrhagic Telangiectasia (HHT). Despite advances in HHT diagnosis and management, the molecular origin of some cases and the source of clinical heterogeneity remain unclear.We propose a comprehensivein silicoanalysis of all 5’UTRENGsingle nucleotide variants that could lead to Endoglin deficiency by altering upstream Open Reading Frames (upORFs). Experimentally, we confirm that variants creating uAUG-initiated overlapping upORFs associate with reduced Endoglin levelsin vitroand characterize the effect of a uCUG-creating variant identified in two suspected HHT patients.Using plasma proteogenomics resources, we identify eight loci associated with soluble Endoglin levels, includingABOand uPAR-pathway loci and experimentally demonstrate the association between uPAR and Endoglin in endothelial cells.This study provides new insights into Endoglin’s molecular determinants, opening avenues for improved HHT management and other diseases involving Endoglin.Key pointsNew insights on the characterization ofENGnon-coding variants, in particular those altering upstream Open Reading Frames in the 5’UTR.Leverage of large-scale plasma proteogenomics results combined with functional assays revealed new actors in Endoglin regulation.
Transfer learning with randomized controlled trial data for postprandial glucose prediction
Authors: Hotta Shinji , Kytö Mikko , Koivusalo Saila , Heinonen Seppo , Marttinen Pekka 
Published: January 2024

AbstractIn recent years, numerous methods have been introduced to predict glucose levels using machine-learning techniques on patients’ daily behavioral and continuous glucose data. Nevertheless, a definitive consensus remains elusive regarding modeling the combined effects of diet and exercise for optimal glucose prediction. A notable challenge is the propensity for observational patient datasets from uncontrolled environments to overfit due to skewed feature distributions of target behaviors; for instance, diabetic patients seldom engage in high-intensity exercise post-meal. In this study, we introduce a unique Bayesian transfer learning framework using randomized controlled trial (RCT) data, primarily targeting postprandial glucose prediction. Initially, we gathered balanced training data from RCTs on healthy participants by randomizing behavioral conditions. Subsequently, we pretrained the model’s parameter distribution using RCT data from the healthy cohort. This pretrained distribution was then adjusted, transferred, and utilized to determine the model parameters for each patient. Our framework’s efficacy was appraised using data from 68 gestational diabetes mellitus patients in uncontrolled settings. The evaluation underscored the enhanced performance attained through our framework. Furthermore, when modeling the joint impact of diet and exercise, the synergetic model proved more precise than its additive counterpart.
Prevalence of Internet Usage Complaints Among Undergraduate Students
Authors: Nnaemeka Emmanuel Mgbedo , Zavradashvili Nana 
Published: January 2024

AbstractInternet access has aided lots of students in achieving academic purposes. This study aimed to examine the prevalence of internet usage complaints on students health, during mandatory online studies among undergraduate students from the University of Georgia (UG), Tbilisi. This cross-sectional was conducted among undergraduate students from UG using a web designed questionnaire. The survey contained sociodemographic characteristics, internet access, and health complains. The study was reviewed and approved by the Institutional Review Board (IRB). Most of participants were females (70.5%), from School of Health Sciences (207, 32.9%), in first year of study (354, 56.2%), and usually spend time on social media (Facebook, Instagram, Twitter, WhatsApp, etc.) (315, 50%). Students reported different complaints such as internet craving, feeling guilty after internet use, internet dyscontrol, back, and neck pain. There was no significant difference in sociodemographic variables. Our findings suggested that the prolonged use of internet could have some health implications among students.
Characterization and comparison of immunity against MPXV for individuals infected with MPXV or vaccinated with modified vaccinia Ankara vaccines
Authors: Wiedemann Aurélie , Surénaud Mathieu , Hubert Mathieu , Zaragoza José-Luis Lopez , Ribeiro Alexandre , Rodrigues Cécile , Foucat Emile , Diombera Harouna , Krief Corinne , Schwartz Olivier , Lelièvre Jean-Daniel , Lévy Yves 
Published: January 2024

AbstractThe 2022 monkeypox virus (MPXV) outbreak has revitalized questions about immunity against MPXV and vaccinia-based vaccines (VAC-V), but studies are limited. We analyzed immunity against MPXV in individuals infected with MPXV or vaccinated with the licensed modified vaccinia Ankara vaccine (MVA)-BN or an experimental MVA-HIVB vaccine. The frequency of neutralizing antibody (NAb) responders was higher among MPXV-infected individuals than MVA vaccinees. Both MVA vaccines induced similar and strong humoral responses. Similarly, we show a higher frequency and magnitude (5-fold) of T-cell responses, mainly mediated by CD8+T cells, against a peptide pool containing selected sequences from MPXV, Variola, and VAC-V in MPXV-infected individuals than MVA vaccinees. We describe a hierarchy of cross-reactive T-cell responses against five peptide pools that are highly homologous between VAC-V and MPXV 2022, with the highest frequency of responders against MVA-121L and MVA-018L proteins. Both vaccines stimulated a notable frequency of polyfunctional CD4+and CD8+T-cell responses, with a subset of CD4+T cells showing a mixed cytokine profile. Finally, we found that smallpox vaccination in childhood positively affected humoral but not T-cell vaccine responses, whereas these responses were not affected in people living with HIV. These findings contribute to deciphering and monitoring the profile of immunity to MPXV and MVA. In the context of a potential threat of the reemergence of smallpox following bioterrorism, the diversification and availability of potent vaccines is crucial. The comparable immunogenicity of both MVA vaccines emphasizes the potential utility of MVA-HIVB as a valuable new tool for controlling MPXV outbreaks.
Factors Associated with Delayed Hospital Arrival after Stroke Onset: An Observational Study in Thanh Hoa Province, Vietnam
Authors: Truong Hoa Thi , Nguyen Sam Hoanh , Le Cuong Van , Tokuno Shinichi , Kuchiba Aya , Nakahara Shinji 
Published: January 2024

ABSTRACTBackgroundDelayed hospital arrival lowers the proportion of patients with stroke receiving recanalization therapy and results in poor outcomes. This study investigated the factors associated with pre-hospital delays in hospital arrival after stroke onset in the Thanh Hoa Province, Vietnam.MethodsClinical data were collected from stroke patients within 7 days of symptom onset who were prospectively registered in this study. Patients and/or their relatives were interviewed using a structured questionnaire about patient social demographics, address, post-stroke support actions, and stroke awareness. Pre-hospital delay in hospital arrival was dichotomized into ≤ 4.5 hours and > 4.5 hours, and multivariable logistic regression analysis was used to investigate factors associated with the delay.ResultOf the 328 participants analyzed, 181 (55.4%) arrived at the hospital 4.5 hours after the symptom onset. The patients’ and relatives’ awareness of stroke was poor. Pre-hospital delays were longer for patients living > 10 km away from a healthcare facility and those with secondary or lower education levels, with odds ratios of 2.07 and 1.98, respectively. Seeking care at a district or private hospital as the first point of healthcare or non-use of emergency medical services did not show significant associations.DiscussionThe study revealed that most patients with stroke did not arrive at the hospital in time for recanalization therapy. Moreover, the low stroke awareness among patients and their relatives is concerning. Further research is needed to investigate the reasons for pre-hospital delays and develop targeted interventions to improve stroke awareness and reduce these delays.
Extended Reality for Neuraxial Anesthesia and Pain Procedures: A Scoping Review
Authors: Cho James S. , Thaker Devaunsh M. , Jotwani Rohan , Hao David 
Published: January 2024

ABSTRACTBackgroundExtended reality technology, encompassing augmented reality, mixed reality, and virtual reality, has the potential to enhance the teaching and performance of neuraxial procedures. The diverse applications of extended reality include immersive simulations and novel modes of procedural navigation.ObjectivesThis scoping review aims to explore the preclinical, clinical, and educational applications of extended reality for neuraxial procedures while suggesting directions for future research.Evidence reviewA systematic search was conducted across PubMed, Embase, Web of Science, Cochrane Central Register of Controlled Trials, and Google Scholar until December 2023. Additional sources were identified via citation searching of relevant articles. The findings are reported using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR).Findings41 studies, including three pending clinical trials were included. The majority of included studies were published after 2015. Extended reality technology was applied in diverse ways for teaching, simulation, and navigation, but only four of the completed studies described clinical use. For the display of visuals, computer screens were most commonly used, followed by head-mounted devices, laser projectors, and semi-transparent mirrors.ConclusionsInterest in utilizing extended reality technology for neuraxial procedures is growing. Preliminary work shows promise for this technology in both education and clinical practice, but achieving accurate image registration without disrupting existing workflows remains an ongoing barrier to clinical testing. Additional research is needed to assess the cost-effectiveness and reliability of this technology.
Reliable prediction of childhood obesity using only routinely collected EHRs is possible
Authors: Gupta Mehak , Phan Thao-Ly T. , Eckrich Daniel , Bunnell H. Timothy , Beheshti Rahmatollah 
Published: January 2024

AbstractObjectiveIdentifying children at high risk of developing obesity can offer a critical time to change the course of the disease before it establishes. Numerous studies have tried to achieve this; but practical limitations remain, including (i) relying on data not present in routinely available pediatric data (like prenatal data), (ii) focusing on a single age prediction (hence, not tested across ages), and (iii) not achieving good results or adequately validating those.MethodsA customized sequential deep learning model was built to predict the risk of childhood obesity, focusing especially on capturing the temporal patterns. The model was trained only on routinely collected EHRs, containing a list of features identified by a group of clinical experts, and sourced from 36,191 diverse children aged 0 to 10. The model was evaluated using extensive discrimination, calibration, and utility analysis; and was validated temporally, geographically, and across various subgroups.ResultsOur results are mostly better (and never worse) than all previous studies, including those that focus on single-age predictions or link EHRs to external data. Specifically, the model consistently achieved an area under the curve (AUROC) of above 0.8 (with most cases around 0.9) for predicting obesity within the next 3 years for children 2 to 7. The validation results show the robustness of the model. Furthermore, the most influential predictors of the model match important risk factors of obesity.ConclusionsOur model is able to predict the risk of obesity for young children using only routinely collected EHR data, greatly facilitating its integration with the periodicity schedule. The model can serve as an objective screening tool to inform prevention efforts, especially by helping with very delicate interactions between providers and families in primary care settings.
SKSR1 identified as key virulence factor inCryptosporidiumby genetic crossing
Authors: He Wei , Sun Lianbei , Hou Tianyi , Yang Zuwei , Yang Fuxian , Zhang Shengchen , Wang Tianpeng , Li Na , Guo Yaqiong , Sibley L. David , Feng Yaoyu , Xiao Lihua 
Published: January 2024

AbstractCryptosporidium parvumis a major cause of severe diarrhea. Although isolates of this zoonotic parasite exhibit significant differences in infectivity and virulence, the genetic determinants for these traits are not clear. In this study, we used classical genetics to cross twoC. parvumisolates of different virulence and used bulked segregant analysis of whole-genome sequence data from the progeny to identify quantitative trait loci (QTL) associated withCryptosporidiuminfectivity and virulence. Of the 26 genes in three QTL, two had loss-of-function mutations in the low-virulence isolates. Deletion of theSKSR1gene or expression of the frame-shift mutant sequence reduced the pathogenicity of infectionin vivo. SKSR1 is a polymorphic secretory protein expressed in small granules and secreted into the parasite-host interface. These results demonstrate that SKSR1 is an important virulence factor inCryptosporidium,and suggest that this extended family may contribute to pathogenesis.