bluuebunny/crossref_metadata_2025_split huggingface dataset:
Identification of Genetic Predisposition to Sjögren’s Syndrome by Whole Exome Sequencing
Authors: Guo Qiwei , Li Qiaowei , Lu Huiqin , Shi Yingying , Guo Jintao , Wang Hao , Deng Qiuxiao , Li Yihang , Liu Yuan , Shi Guixiu , Chen Shiju 
Published: March 2024

AbstractA comprehensive understanding of the genetic predisposition associated with the initiation and development of Sjögren’s syndrome (SjS) is imperative. This would not only enrich our knowledge of the pathogenesis underlying this autoimmune disease but also address the long-standing clinical challenges of more timely diagnosis and effective treatment to retain organ function and improve prognosis. In this study, we used whole exome sequencing analysis of 50 patients with SjS to investigate the predisposing variants, genes, and their associated biological functions. Hundreds of predisposing genes were identified, and numerous biological processes and pathways were highlighted; suggesting a heterogeneity of genetic predisposition to SjS. Female patients carrying a greater number of enriched variants tended to have higher levels of serum IgG and corresponding systemic involvement, demonstrating the pivotal role of genetic predisposition in the pathogenesis of SjS. Biological function analysis indicated that a subset of SjS and neuropathies may share a similar genetic predisposition. Our results showed that extracellular matrix-receptor interactions, macrophage-associated biological functions, and motor proteins may play important roles in the pathogenesis of SjS, and macrophage-associated biological functions may be associated with early onset SjS in female patients. Furthermore, the identification of highly enriched variants in the patient cohort provides the possibility of advancing the diagnosis of SjS. In conclusion, our study provides an extensive framework for analysis of the genetic predisposition to SjS which can facilitate further focused and in-depth investigation of the pathogenetic mechanisms of specific genes, biological processes, and pathways; thereby contributing to the pathophysiology, diagnosis, and therapeutics of SjS.
Ischemia promotes hypertrophic nerve trunk formation and enteric neuron cell death in Hirschsprung’s disease
Authors: Xu Deshu , Liang Weiwei , Lan Chaoting , Li Lanying , Zhong Weiyong , Yao Meng , Zuo Xiaoyu , Zeng Jixiao , Zhong Wei , Wu Qiang , Lew Andrew M , Zhou Wenhao , Xia Huimin , Bai Fan , Zhang Yuxia , Zhang Yan 
Published: March 2024

ABSTRACTObjectiveEnteric nervous system dysfunction is linked to digestive and neurological disorders. Hirschsprung’s disease (HSCR) is characterized by the loss of enteric neuron cells (ENCs) in the distal colon. Embryonic enteric neural crest cell (ENCC) migration defects contribute to HSCR development in some infants, but postnatal factors that regulate ENC fate are undetermined. We sought to establish how postnatal changes contribute to HSCR by profiling the colonic microenvironment of HSCR infants.DesignIn this study, we recruited infants with HSCR, infants with anorectal malformations but normal ENC development (CT), and a group of age-matched healthy control subjects. Laboratory findings and clinical manifestations were recorded. Single-cell and spatial transcriptome sequencing were applied to colonic tissues from a sub-cohort of CT and HSCR infants. Patient specimens, a mouse model of neonatal ischemic enterocolitis, andSox10knockdown mouse (Sox10WT/MUT) were used to reveal the factors that lead to ENC loss in HSCR infants.ResultsWe discover that intestinal ischemia promotes CLDN1+hypertrophic nerve trunk formation and ENC death. Mechanistically, ischemia leads to defective nitric oxide (NO) signaling in ENCs, which aggravates mitochondria damage and caspase-mediated apoptosis that can be ameliorated by a NO donor drug.ConclusionWe show that ischemia contributes to postnatal ENC loss in HSCR infants and suggest that NO donor drugs may alleviate ischemia-related ENC death.
Randomized Controlled Comparative Effectiveness Trial of Risk Model-Guided Clinical Decision Support for Suicide Screening
Authors: Walsh Colin G. , Ripperger Michael A. , Novak Laurie , Reale Carrie , Anders Shilo , Spann Ashley , Kolli Jhansi , Robinson Katelyn , Chen Qingxia , Isaacs David , Acosta Lealani Mae Y. , Phibbs Fenna , Fielstein Elliot , Wilimitis Drew , Musacchio Schafer Katherine , Hilton Rachel , Albert Dan , Shelton Jill , Stroh Jessica , Stead William W. , Johnson Kevin B. 
Published: March 2024

AbstractSuicide prevention requires risk identification, appropriate intervention, and follow-up. Traditional risk identification relies on patient self-reporting, support network reporting, or face-to-face screening with validated instruments or history and physical exam. In the last decade, statistical risk models have been studied and more recently deployed to augment clinical judgment. Models have generally been found to be low precision or problematic at scale due to low incidence. Few have been tested in clinical practice, and none have been tested in clinical trials to our knowledge.MethodsWe report the results of a pragmatic randomized controlled trial (RCT) in three outpatient adult Neurology clinic settings. This two-arm trial compared the effectiveness of Interruptive and Non-Interruptive Clinical Decision Support (CDS) to prompt further screening of suicidal ideation for those predicted to be high risk using a real-time, validated statistical risk model of suicide attempt risk, with the decision to screen as the primary end point. Secondary outcomes included rates of suicidal ideation and attempts in both arms. Manual chart review of every trial encounter was used to determine if suicide risk assessment was subsequently documented.ResultsFrom August 16, 2022, through February 16, 2023, our study randomized 596 patient encounters across 561 patients for providers to receive either Interruptive or Non-Interruptive CDS in a 1:1 ratio. Adjusting for provider cluster effects, Interruptive CDS led to significantly higher numbers of decisions to screen (42%=121/289 encounters) compared to Non-Interruptive CDS (4%=12/307) (odds ratio=17.7, p-value <0.001). Secondarily, no documented episodes of suicidal ideation or attempts occurred in either arm. While the proportion of documented assessments among those noting the decision to screen was higher for providers in the Non-Interruptive arm (92%=11/12) than in the Interruptive arm (52%=63/121), the interruptive CDS was associated with more frequent documentation of suicide risk assessment (63/289 encounters compared to 11/307, p-value<0.001).ConclusionsIn this pragmatic RCT of real-time predictive CDS to guide suicide risk assessment, Interruptive CDS led to higher numbers of decisions to screen and documented suicide risk assessments. Well-powered large-scale trials randomizing this type of CDS compared to standard of care are indicated to measure effectiveness in reducing suicidal self-harm.ClinicalTrials.govIdentifier:NCT05312437
Identification of plasma proteomic markers underlying polygenic risk of type 2 diabetes and related comorbidities
Authors: Loesch Douglas P. , Garg Manik , Matelska Dorota , Vitsios Dimitrios , Jiang Xiao , Ritchie Scott C. , Sun Benjamin B. , Runz Heiko , Whelan Christopher D. , Holman Rury R. , Mentz Robert J. , Moura Filipe A. , Wiviott Stephen D. , Sabatine Marc S. , Udler Miriam S. , Gause-Nilsson Ingrid A. , Petrovski Slavé , Oscarsson Jan , Nag Abhishek , Paul Dirk S. , Inouye Michael 
Published: March 2024

AbstractIntroductionType 2 diabetes (T2D) is a heterogeneous disorder for which disease-causing pathways are incompletely understood. Here, we mapped genetic risk for T2D and its comorbidities to proteins, mechanistic pathways and clinical outcomes using proteogenomic data from a population-scale biobank and two randomized controlled trials.MethodsWe tested polygenic scores (PGS) for T2D and its cardiometabolic comorbidities, plus five partitioned T2D PGS (beta cell, lipodystrophy, liver lipid, obesity, and liver lipid), for association with 2,922 circulating proteins in 54,306 multi-ancestry participants (of which 42,452 were unrelated and without prevalent cardiometabolic disease) from the UK Biobank (UKB). Then, we tested the PGS-associated proteins for association with incident cardiometabolic complications in two cardiovascular outcome trials among T2D patients with proteogenomic data: EXSCEL (N=2,823) and DECLARE-TIMI 58 (N=915). We assessed causality using two-sample Mendelian randomization and mediation.ResultsWe identified 839 unique proteins significantly associated with any T2D PGS and 1,005 proteins that were associated with at least one cardiometabolic PGS. Some PGS-associated proteins such as TFF3, EFEMP1, and MMP12 were in turn associated with renal and cardiovascular trial outcomes. PGS association patterns revealed shared pathways, e.g., complement cascade, cholesterol metabolism, IGF signaling. The proteins underlying these pathways, such as LPA, C1S, and IGFBP2, were consistently associated with clinical trial outcomes or identified via causal inference.ConclusionsThis proteogenomic study revealed proteins and mechanistic pathways underlying T2D and related comorbidities, advancing our understanding of T2D pathobiology and identifying putative biomarkers. All our results are available in an online data portal (https://public.cgr.astrazeneca.com/t2d-pgs/v1/).
The link between theANPEPgene and type 2 diabetes mellitus may be mediated by the disruption of glutathione metabolism and redox homeostasis
Authors: Korvyakova Yaroslava , Azarova Iuliia , Klyosova Elena , Postnikova Maria , Makarenko Victor , Bushueva Olga , Solodilova Maria , Polonikov Alexey 
Published: March 2024

AbstractAminopeptidase N (ANPEP), a membrane-associated ectoenzyme, has been identified as a susceptibility gene for type 2 diabetes (T2D) by genome-wide association and transcriptome studies; however, the mechanisms by which this gene contributes to disease pathogenesis remain unclear. The aim of this study was to determine the comprehensive contribution of ANPEP polymorphisms to T2D risk and annotate the underlying mechanisms. A total of 3206 unrelated individuals including 1579 T2D patients and 1627 controls were recruited for the study. Twenty-three common functional single nucleotide polymorphisms (SNP) of ANPEP were genotyped by the MassArray-4 system. Six polymorphisms, rs11073891, rs12898828, rs12148357, rs9920421, rs7111, and rs25653, were found to be associated with type 2 diabetes for the first time (Pperm≤0.05). Common haplotype rs9920421G-rs4932143G-rs7111T was strongly associated with increased risk of T2D (Pperm=5.9×10-12), whereas two rare haplotypes such as rs9920421G-rs4932143C-rs7111T (Pperm=6.5×10-40) and rs12442778A-rs12898828A-rs6496608T-rs11073891C (Pperm=1.0×10-7) possessed strong protection against disease. We identified 38 and 109 diplotypes associated with T2D risk in males and females, respectively (FDR≤0.05). ANPEP polymorphisms showed associations with plasma levels of fasting blood glucose, aspartate aminotransferase, total protein and glutathione (P<0.05), and several haplotypes were strongly associated with the levels of reactive oxygen species and uric acid (P<0.0001). A deep literature analysis has facilitated the formulation of a hypothesis proposing that increased plasma levels of ANPEP as well as liver enzymes such as aspartate aminotransferase, alanine aminotransferase and gamma-glutamyltransferase serve as an adaptive response directed towards the restoration of glutathione deficiency in diabetics by stimulating the production of amino acid precursors for glutathione biosynthesis.HighlightsPolymorphisms, rs11073891, rs12898828, rs12148357, rs9920421, rs7111, and rs25653 ofANPEP, were discovered as novel susceptibility markers for type 2 diabetes mellitus.ne common and two rare haplotypes ofANPEPare strongly associated with increased and decreased risk of type 2 diabetes, respectively.Thirty eight and one hundred and nineANPEPdiplotypes influenced disease risk in males and females, respectively.Polymorphisms ofANPEPwere associated with plasma levels of fasting blood glucose, aspartate aminotransferase, total protein, glutathione, reactive oxygen species and uric acid in diabetics.Increased plasma levels of ANPEP and liver enzymes (AST, ALT, and GGT) in T2D patients may reflect an adaptive response to glutathione deficiency through the formation of more amino acid precursors of glutathione.
Intra-species quantification reveals differences in activity and sleep levels in the yellow fever mosquito,Aedes aegypti
Authors: Ajayi Oluwaseun M. , Susanto Emily E. , Wang Lyn , Kennedy Jasmine , Ledezma Arturo , Harris Angeli’c , Smith Evan S. , Chakraborty Souvik , Wynne Nicole E. , Sylla Massamba , Akorli Jewelna , Otoo Sampson , Rose Noah H. , Vinauger Clément , Benoit Joshua B. 
Published: March 2024

AbstractAedes aegyptiis an important mosquito vector of human disease with a wide distribution across the globe. Climatic conditions and ecological pressure drive differences in the biology of several populations of this mosquito, including blood-feeding behavior and vector competence. However, no study has compared activity and/or sleep among different populations/lineages ofAe. aegypti. Having recently established sleep-like states in three mosquito species with observable differences in timing and amount of sleep among species, we investigated differences in activity and sleep levels among 17Ae. aegyptilines drawn from both its native range in Africa and its invasive range across the global tropics. Activity monitoring indicates that all the lines show consistent diurnal activity, but significant differences in activity level, sleep amount, number of sleep bouts, and bout duration were observed among the lines. Variations in specific activity and sleep parameters were explained by differences in host preference, ancestry, and human population density for the lineages collected in Africa. This study provides evidence that the diurnal sleep and activity profiles forAe. aegyptiare consistent, but there are significant population differences forAe. aegyptisleep and activity levels and interactions with humans may significantly impact mosquito activity and sleep.
PH-SENSITIVE NANODROPLETS FOR CONTROLLED DELIVERY OF BERBERINE CHLORIDE
Authors: Hao Shengjie , Wang Shiyu , Cao Jiaqi , Xue Zhiyuan , Luo Zeyu , Wu Peirun , Chen Guilin 
Published: March 2024

ABSTRACTBackgroundThe development of nanocarriers with precise control over drug release is crucial for targeted therapy. This study focuses on the design and optimization of pH-sensitive gelatin/perfluorohexane (PFH) nanodroplets loaded with berberine chloride, a model drug relevant to traditional Chinese medicine.Subjects and MethodsNanodroplets were prepared using an emulsion technique, with optimization of parameters including homogenization rate, polymer concentration, surfactant, drug, and perfluorocarbon conte nt.ResultsThe optimized formulation resulted in nanodroplets with a mean particle size of 281.7 nm and a drug encapsulation efficiency of 66.8 ± 1.7%. Characterization studies confirmed successful encapsulation and pH-responsive behavior. Ultrasound stimulation significantly enhanced drug release, with 150 kHz frequency proving more effective than 1 MHz. Stability studies demonstrated prolonged stability over one month at 4°C. Following 10 minutes of ultrasound irradiation, the nanodroplets exhibited 89.4% cumulative drug release.ConclusionsIn conclusion, these pH-sensitive nanodroplets show potential for delivering berberine chloride in a controlled manner, connecting traditional Chinese medicine with contemporary drug delivery methods.
Design principles for accurate folding of DNA origami
Authors: Aksel Tural , Navarro Erik J. , Fong Nicholas , Douglas Shawn M. 
Published: March 2024

AbstractWe describe design principles for accurate folding of three-dimensional DNA origami. To evaluate design rules, we reduced the problem of DNA strand routing to the known problem of shortest-path finding in a weighted graph. To score candidate DNA strand routes we used a thermodynamic model that accounts for enthalpic and entropic contributions of initial binding, hybridization, and DNA loop closure. We encoded and analyzed new and previously reported design heuristics. Using design principles emerging from this analysis, we redesigned and fabricated multiple shapes and compared their folding accuracy using electrophoretic mobility analysis and electron microscopy imaging. We demonstrate accurate folding can be achieved by optimizing staple routes using our model, and provide a computational framework for applying our methodology to any design.
Development of covalent probes to captureLegionella pneumophilaeffector enzymes
Authors: Kloet Max S. , Mukhopadhyay Rishov , Mukherjee Rukmini , Misra Mohit , Jeong Minwoo , Talavera Ormeño Cami M. P. , Moutsiopoulou Angeliki , Tjokrodirijo Rayman T. N. , van Veelen Peter A. , Shin Donghyuk , Ðikić Ivan , Sapmaz Aysegul , Kim Robbert Q. , van der Heden van Noort Gerbrand J. 
Published: March 2024

AbstractUpon infection of host cells,Legionella pneumophilareleases a multitude of effector enzymes into the cells cytoplasm that hijack a plethora of cellular activities, including the hosts ubiquitination pathways. Effectors belonging to the SidE-family are involved in non-canonical serine phosphoribosyl ubiquitination of host substrate proteins contributing to the formation of a Legionella-containing vacuole that is crucial in the onset of Legionnaires’ disease. This dynamic process is reversed by effectors called Dups that hydrolyse the phosphodiester in the phosphoribosyl ubiquitinated protein. We installed reactive warheads on chemically prepared ribosylated ubiquitin to generate a set of probes targeting these Legionella enzymes. In vitro tests on recombinant DupA revealed that a vinyl sulfonate warhead was most efficient in covalent complex formation. Mutagenesis and x-ray crystallography approaches were used to identify the site of covalent crosslinking to be an allosteric cysteine residue. The subsequent application of this probe highlights the potential to selectively enrich the Dup enzymes from Legionella-infected cell lysates.
RFW captures species-level full profile of metagenomic functions via integrating genome annotation information
Authors: Mi Kai , Liu Xingyin 
Published: March 2024

AbstractFunctional profiling on whole-metagenome shotgun sequencing (WMS) has made great contribution to the development of our understanding in microbe-host interactions. In this work, we revealed that severe microbial functional information loss of current functional profiling methods existed at both taxon-level and community-level. To correct the distortion brought by information incompleteness, we developed a new framework, RFW (Reference based functional profile inference on WMS), to infer microbial functional abundance on WMS through utilizing information from genome function annotation and WMS taxonomic profile. Furthermore, we built up a new algorithm for absolute abundance change quantification of microbial function between groups under RFW framework. By applying RFW to several datasets related to autism spectrum disorder and colorectal cancer, we revealed that RFW greatly renewed our knowledge in downstream analysis, including differential microbial function identification, association analysis between microbial function and host phenotype, etc. RFW are open-source and freely available athttps://github.com/Xingyinliu-Lab/RFW.
Nascent matrix deposition supports alveolar organoid formation from aggregates in synthetic hydrogels
Authors: Eiken Madeline K. , Childs Charlie J. , Brastrom Lindy K. , Frum Tristan , Plaster Eleanor M. , Shachaf Orren , Pfeiffer Suzanne , Levine Justin E. , Alysandratos Konstantinos-Dionysios , Kotton Darrell N. , Spence Jason R. , Loebel Claudia 
Published: March 2024

HighlightsAlveolar organoids are formed with a two-step, Matrigel-free method in a semi-synthetic hyaluronic acid (HA) hydrogelThe two-step method offers control over alveolar size, density, and growthAlveolar organoids maintain their AT2 identity in HA hydrogelsAlveolar organoids secrete nascent extracellular matrix supporting organoid growth without MatrigelSummaryHuman induced pluripotent stem cell (iPSC) derived alveolar organoids have emerged as a system to model the alveolar epithelium in homeostasis and disease. However, alveolar organoids are typically grown in Matrigel, a mouse-sarcoma derived basement membrane matrix that offers poor control over matrix properties, prompting the development of synthetic hydrogels as a Matrigel alternative. Here, we develop a two-step culture method that involves pre-aggregation of organoids in hydrogel-based microwells followed by embedding in a synthetic hydrogel that supports alveolar organoid growth, while also offering considerable control over organoid and hydrogel properties. We find that the aggregated organoids secrete their own nascent extracellular matrix (ECM) both in the microwells and upon embedding in the synthetic hydrogels. Thus, the synthetic gels described here allow us to de-couple exogenous and nascent ECM in order to interrogate the role of ECM in organoid formation.
Analytical analysis of the generation of a rotating driving magnetic field on the outer surface of a magnetic pinch load with a helical return current post
Authors: Duan Shu-Chao , He Ge-Guang , Zhou Shao-Tong , Kan Ming-Xian , Wang Gang-Hua 
Published: March 2024

A recently emerging approach adopts a directionally time-varying (rotating) magnetic field to drive a pinch load, aiming to mitigate the inherent magneto-Rayleigh-Taylor instability in dynamic Z pinches. A helical return current post (RCP) serves as a functional structural element capable of generating the requisite driving magnetic field for this purpose in the load region. This paper first calculates the current azimuthally induced on the outer surface of a magnetically pinched load within this type of RCP using a zero-dimensional lumped-parameter circuit model. The results show that the induced current deviates significantly from the presumed “perfect” induced current (100% amplitude) as reported in the literature [S. A. Sorokin, ); P. F. Schmit , ); G. A. Shipley , ); and P. C. Campbell , ], with an effective coefficient of current induction considerably less than 1. However, even when the load is fully compressed to the axis, the effective coefficient does not approach zero but rather converges to a finite value that solely depends on the aspect ratio of the RCP. This is quite favorable for the suppression of magneto-Rayleigh-Taylor instability in the Z pinch. As for the pointlike X pinch, the axial magnetic field does not tend to zero but a finite value, though the effective coefficient tends to zero, and this result may be used to suppress the instability in X pinch and improve the time stability and spatiotemporal unity of hot spots. In addition, the anode and cathode plates have the potential to enhance the current induced in the load. This paper then analyzes the axial distribution and time behavior of the induced current adopting an approximate analytical method and numerical integration and finds an approximate invariance that can be well characterized by δt, the product of the normalized skin depth and time. Similar values of δt indicate similar axial distribution characteristics. When δt is lower than, at, or higher than the critical region (∼0.1–0.3), the axial distribution appears dumbbell shaped, nearly flat, and arched, respectively. These distributively induced currents can be exploited to achieve quasispherical, near flat, and dumbbell-shaped implosions, respectively.

Published by the American Physical Society
2024