bluuebunny/crossref_metadata_2025_split huggingface dataset:
Matrix Vesicles from Osteoblasts Promote Atherosclerotic Calcification
Authors: Wang Xiaoli , Ren Jie , Zhang Zhen , Fang Fei , Wang Erxiang , Li Jianwei , He Weihong , Shen Yang , Liu Xiaoheng 
Published: April 2024

AbstractBackgroundsVascular calcification often occurs with osteoporosis, a contradictory association known as “the calcification paradox”. Osteoblast-derived matrix vesicles (Ost-MVs) have been implicated in bone mineralization, and also have a potential role in ectopic vascular calcification. Herein, we aim to investigate the contributions that Ost-MVs make to the bone–vascular calcification paradox and the underlying mechanisms.Methods and ResultsHyperlipidemia-induced atherosclerotic calcification in mice was accompanied with bone mineral loss, as evidenced by reduced deposition of Ost-MVs in the bone matrix and increased release of Ost-MVs into the circulation. Intravenous injection of fluorescent DiІ-labeled Ost-MVs revealed a marked fluorescence accumulation in the aorta of atherogenic mice, whereas no fluorescence signals were observed in normal controls. Using proteomics to analyze proteins in non-matrix bound Ost-MVs and mineralized SMC-derived MVs (SMC-MVs), we found Lamp1 was specifically expressed in SMC-MVs, and Nid2 was exclusively expressed in Ost-MVs. We further demonstrated that both Lamp1 and Nid2 were co-localized with Collagen І within calcific plaques, indicating the involvement of both Ost-MVs and SMC-MVs in atherosclerotic calcification. Mechanistically, LPS-induced vascular injury facilitated the transendothelial transport of Ost-MVs. The recruitment of circulating Ost-MVs was regulated by remodeled Collagen І during calcification progression. Furthermore, the phenotypic transition of SMCs determined the endocytosis of Ost-MVs. Finally, we demonstrated that either recruited Ost-MVs or resident SMC-MVs accelerated atherosclerotic calcification, depending on the Ras-Raf-ERK signaling.ConclusionAtherosclerotic calcification-induced Ost-MVs are released into circulation, facilitating the transport from bone to plaque lesions and exacerbating artery calcification progression. The mechanisms of Ost-MVs recruitment include vascular injury allowing transendothelial transport of Ost-MVs, collagen І remodeling promoting Ost-MVs aggregation, and SMC phenotypic switch to facilitate Ost-MVs uptake. Our results further revealed that both recruited Ost-MVs and calcifying SMC-MVs aggravate calcification through the Ras-Raf-ERK pathway.
Lipid-dependent conformational dynamics of bacterial ATP-binding cassette transporter Sav1866
Authors: Badiee Shadi A , Hettige Jeevapani , Moradi Mahmoud 
Published: April 2024

AbstractSav1866, a bacterial ATP-binding cassette (ABC) exporter, plays a crucial role in cellular processes by facilitating the efflux of a diverse range of substrates, including drugs, chemotherapeutic agents, peptides, and lipids. This efflux activity significantly impacts the effectiveness of various therapies against bacterial infections. In our recent investigation, we focused on understanding the conformational dynamics of Sav1866 within different lipid environments. Specifically, we explored its behavior in environments composed of DMPC and POPE lipids, which exhibit crucial distinctions not only in their headgroup polarity but also in the length and saturation of their hydrophobic tails. Our extensive set of equilibrium microsecond-level all-atom molecular dynamics (MD) simulations revealed significant distinctions in transporter behavior influenced by these lipid compositions. We observed a rapid transition to an occluded-inward-facing (IF-occ) conformation in POPE environments, contrasting with a channel-like behavior in DMPC environments, deviating from the expected alternating access mechanism (AAM). These findings underscore the significant impact of lipid compositions on ABC transporter function, offering new perspectives on membrane transport mechanisms.
RiboDiffusion: Tertiary Structure-based RNA Inverse Folding with Generative Diffusion Models
Authors: Huang Han , Lin Ziqian , He Dongchen , Hong Liang , Li Yu 
Published: April 2024

AbstractRNA design shows growing applications in synthetic biology and therapeutics, driven by the crucial role of RNA in various biological processes. A fundamental challenge is to find functional RNA sequences that satisfy given structural constraints, known as the inverse folding problem. Computational approaches have emerged to address this problem based on secondary structures. However, designing RNA sequences directly from 3D structures is still challenging, due to the scarcity of data, the non-unique structure-sequence mapping, and the flexibility of RNA conformation. In this study, we propose RiboDiffusion, a generative diffusion model for RNA inverse folding that can learn the conditional distribution of RNA sequences given 3D backbone structures. Our model consists of a graph neural network-based structure module and a Transformer-based sequence module, which iteratively transforms random sequences into desired sequences. By tuning the sampling weight, our model allows for a trade-off between sequence recovery and diversity to explore more candidates. We split test sets based on RNA clustering with different cut-offs for sequence or structure similarity. Our model outperforms baselines in sequence recovery, with an average relative improvement of 11% for sequence similarity splits and 16% for structure similarity splits. Moreover, RiboDiffusion performs consistently well across various RNA length categories and RNA types. We also apply in-silico folding to validate whether the generated sequences can fold into the given 3D RNA backbones. Our method could be a powerful tool for RNA design that explores the vast sequence space and finds novel solutions to 3D structural constraints.
Spatial mapping reveals unique cellular interactions and enhanced tertiary lymphoid structures in responders to anti-PD-1 therapy in mucosal head and neck cancers
Authors: Ferguson A.L. , Beddow T. , Patrick E. , Willie E. , Elliott M.S. , Low T.H. , Wykes J. , Hui M.H. , Palme C.E. , Boyer M. , Clark J.R. , Lee J.H. , Palendira U. , Gupta R. 
Published: April 2024

AbstractSurvival in recurrent/metastatic head and neck mucosal squamous cell carcinoma (HNmSCC) remains poor. Anti-programmed death (PD)-1 therapies have demonstrated improved survival with lower toxicity when compared to standard chemotherapy. However, response to anti-PD-1 therapy remains modest, at 13-17%.We evaluated the tumor microenvironment (TME) using Imaging Mass Cytometry (IMC) on 27 tumor specimens from 24 advanced HNmSCC patients prior to receiving anti-PD-1 based treatment. We show significantly increased central memory T cells and B cells in responders (n=8) when compared to non-responders (n=16). Spatial mapping identified interactions between phenotypically distinct malignant squamous cells with CD8+ T cells, CD4+ Tregs and endothelial cells in responders, and avoidance of these cells in non-responders. Importantly, regional analysis shows responders have more abundant tertiary lymphoid structures (TLS), with TLS proportion >20% also associated with longer progression free survival. Together these findings define the immune landscape associated with response to anti-PD-1 treatment in HNmSCCs.
Manuscript Title: Facility-based HIV self-testing as an additional testing option in health facilities: A systematic review and meta-analysis
Authors: McGee Kathleen , Jamil Muhammad S. , Siegfried Nandi , Radebe Busisiwe Msimanga , Barr-DiChiara Magdalena , Baggaley Rachel , Johnson Cheryl 
Published: April 2024

AbstractFacility-based HIV self-testing (FB-HIVST) has been used across settings to improve testing accessibility and achieve global testing and treatment targets by 2030. The effectiveness of FB-HIVST remains uncertain; thus, we conducted a review to assess the risk and benefits of FB-HIVST to inform global guidance. We searched across nine electronic databases covering the period up to February 01, 2022, and included publications that directly compared FB-HIVST to standard HIV testing services (SOC) or no intervention. Meta-analysis was conducted on comparable outcomes using random-effects model for relative risks (RR) and 95% confidence intervals. Other outcomes were summarized descriptively. Risk of bias was assessed using Cochrane’s Risk of Bias tool. Certainty of evidence was assessed using Grading of Recommendations, Assessment, Development and Evaluations (GRADE). After screening 2,203 articles, 11 studies were found eligible, including 4 randomized controlled trials (RCT), 2 cohort studies, 3 economic evaluations, and 2 qualitative studies. Meta-analyses of four RCTs demonstrated that FB-HIVST may increase testing uptake (RR=2.47; 95% CI= 0.96, 6.33) and may lead to greater HIV diagnosis (RR=3.77; 95% CI=0.81, 17.44). Overall GRADE certainty was low. Trials found FB-HIVST as acceptable and feasible to many users, with minimal risk of social harm. A single RCT reported on linkage to care and observed that, among total enrolled, FB-HIVST compared to SOC may increase linkage to care threefold (RR= 3.26; 95% CI: 0.68, 15.62; low-certainty evidence). FB-HIVST was found to be cost-effective in a high-burden outpatient department, but determined to be quite variable. FB-HIVST is safe and may be an effective method to increase testing coverage and the diagnoses, particularly in high-burden HIV settings or sites with limited staff and resources. Findings from this review informed WHO’S guideline development process and its recommendation that FB-HIVST be offered as an additional testing option at facilities.PROSPERO Number: CRD42022302619
Baseline functional connectivity predicts who will benefit from neuromodulation: evidence from primary progressive aphasia
Authors: Wang Zeyi , Gallegos Jessica , Tippett Donna , Onyike Chiadi U , Desmond John E , Hillis Argye E , Frangakis Constantine E , Caffo Brian , Tsapkini Kyrana 
Published: April 2024

AbstractBackgroundIdentifying the characteristics of individuals who demonstrate response to an intervention allows us to predict who is most likely to benefit from certain interventions. Prediction is challenging in rare and heterogeneous diseases, such as primary progressive aphasia (PPA), that have varying clinical manifestations. We aimed to determine the characteristics of those who will benefit most from transcranial direct current stimulation (tDCS) of the left inferior frontal gyrus (IFG) using a novel heterogeneity and group identification analysis.MethodsWe compared the predictive ability of demographic and clinical patient characteristics (e.g., PPA variant and disease progression, baseline language performance) vs. functional connectivity alone (from resting-state fMRI) in the same cohort.ResultsFunctional connectivity alone had the highest predictive value for outcomes, explaining 62% and 75% of tDCS effect of variance in generalization (semantic fluency) and in the trained outcome of the clinical trial (written naming), contrasted with <15% predicted by clinical characteristics, including baseline language performance. Patients with higher baseline functional connectivity between the left IFG (opercularis and triangularis), and between the middle temporal pole and posterior superior temporal gyrus, were most likely to benefit from tDCS.ConclusionsWe show the importance of a baseline 7-minute functional connectivity scan in predicting tDCS outcomes, and point towards a precision medicine approach in neuromodulation studies. The study has important implications for clinical trials and practice, providing a statistical method that addresses heterogeneity in patient populations and allowing accurate prediction and enrollment of those who will most likely benefit from specific interventions.
Moving from GWAS signals to rare functional variation in inflammatory bowel disease through application of GenePy2 as a potential DNA biomarker
Authors: Cheng Guo , Ashton James J , Collins Andrew , Beattie R Mark , Ennis Sarah 
Published: April 2024

AbstractObjectivesWe adopt a weighted variant burden score GenePy2.0 for the UK Biobank phase 2 cohort of inflammatory bowel disease (IBD), to explore potential genomic biomarkers underpinning IBD’s known associations.DesignNucleating from IBD GWAS signals, we identified 794 GWAS loci, including target genes/LD-blocks (LDBs) based on linkage-disequilibrium (LD) and functional mapping. We calculated GenePy2.0–a burden score of target regions integrating variants with CADDPhred>15 weighted by deleteriousness and zygosity. Collating with other burden-based test, GenePy-based Mann-Whitney-U tests on cases/controls with varying extreme scores were used. Significance-levels and effect sizes were used for tuning the optimal GenePy thresholds for discriminating patients from controls. Individual’s binarized GenePy status (above or below threshold) of candidate regions, was subject to itemset association test via the sparse Apriori algorithm.ResultsA tailored IBD cohort was curated (nCrohn’s_Disease(CD)=891, nUlcerative_Colitis(UC)=1409, nControls=60118). Analysing 885 unified target regions (794 GWAS loci and 104 monogenic genes with 13 overlaps), the GenePy approach detected statistical significance (permutationp<5.65×10-5) in 35 regions of CD and 25 of UC targets exerting risk and protective effects on the disease. Large effect sizes were observed,e.g. CYLD-AS1 (Mann-Whitney-□=0.89[CI:0.78-0.96]) in CD/controls with the top 1% highest scores of the gene. Itemset association learning further highlighted an intriguing signal whereby GenePy status ofIL23RandNOD2were mutually exclusive in CD but always co-occurring in controls.ConclusionGenePy score per IBD patient detected ‘deleterious’ variation of large effect underpinning known IBD associations and proved itself a promising tool for genomic biomarker discovery.What is already known on this topicInflammatory bowel disease (IBD) is a genetically heterogeneous disease with both common polygenic, and rare monogenic, presentations. Previous studies have identified known genetic variants associated with disease.What this study addsA genomic biomarker tool, tailored for large cohort, GenePy2.0 is developed. It’s rank-based test is more powerful than mutation-burden based test in validating known associations and finding new associations of IBD. We identified large risk and protective effects of ‘pathogenic genes/loci’ in IBD, including expanding previous associations to wider genomic regions.How this study might affect research, practice or policyGenePy2.0 facilitates analysis of diseases with genetic heterogeneity and facilitates personalised genomic analysis on patients. The revealed genetic landscape of IBD captures both risk and protective effects of rare ‘pathogenic’ variants, alongside more common variation. This, could provide a fresh angle for future targeted therapies in specific groups of patients.
Comparison of the Sensitivity and Specificity of Commercial Anti-Dengue Virus IgG Tests to Identify Persons Eligible for Dengue Vaccination
Authors: Medina Freddy A. , Vila Frances , Adams Laura E. , Cardona Jaime , Carrion Jessica , Lamirande Elaine , Acosta Luz N. , De León-Rodríguez Carlos M. , Beltran Manuela , Grau Demian , Rivera-Amill Vanessa , Balmaseda Angel , Harris Eva , Madewell Zachary J. , Waterman Stephen H. , Paz-Bailey Gabriela , Whitehead Stephen , Muñoz-Jordán Jorge L. 
Published: April 2024

AbstractThe Advisory Committee on Immunization Practices (ACIP) recommended that dengue pre-vaccination screening tests for Dengvaxia administration have at least 98% specificity and 75% sensitivity. This study evaluates the performance of commercial anti-DENV IgG tests to identify tests that could be used for pre-vaccination screening. First, for 7 tests, we evaluated sensitivity and specificity in early convalescent dengue virus (DENV) infection, using 44 samples collected 7-30 days after symptom onset and confirmed by RT-PCR. Next, for the 5 best performing tests and two additional tests (with and without an external test reader) that became available later, we evaluated performance to detect past dengue infection among a panel of 44 specimens collected in 2018-2019 from healthy 9-16-year-old children from Puerto Rico. Finally, a full-scale evaluation was done with the 4 best performing tests using 400 specimens from the same population. We used virus focus reduction neutralization test and an in-house DENV IgG ELISA as reference standards.Of seven tests, five showed ≥75% sensitivity detecting anti-DENV IgG in early convalescent specimens with low cross-reactivity to Zika virus. For the detection of previous DENV infections the tests with the highest performance were the Euroimmun NS1 IgG ELISA (sensitivity 84.5%, specificity 97.1%) and CTK Dengue IgG rapid test R0065C with the test reader (sensitivity 76.2% specificity 98.1%). There are IgG tests available that can be used to accurately classify individuals with previous DENV infection as eligible for dengue vaccination to support safe vaccine implementation.
A Biomarker-Centric Framework for the Prediction of Future Chronic Pain
Authors: Fillingim Matt , Tanguay-Sabourin Christophe , Parisien Marc , Zare Azin , Guglietti Gianluca V. , Norman Jax , Petre Bogdan , Bortsov Andrey , Ware Mark , Perez Jordi , Roy Mathieu , Diatchenko Luda , Vachon-Presseau Etienne 
Published: April 2024

AbstractChronic pain is a multifactorial condition presenting significant diagnostic and prognostic challenges. Biomarkers for the classification and the prediction of chronic pain are therefore critically needed. In this multi-dataset study of over 523,000 participants, we applied machine learning to multi-dimensional biological data from the UK Biobank to identify biomarkers for 35 medical conditions associated with pain (e.g., clinical diagnosis of rheumatoid arthritis, fibromyalgia, stroke, gout, etc.) or self-reported chronic pain (e.g., back pain, knee pain, etc). Biomarkers derived from blood immunoassays, brain and bone imaging, and genetics were effective in predicting medical conditions associated with chronic pain (area under the curve (AUC) 0.62-0.87) but not self-reported pain (AUC 0.50-0.62). Among the biomarkers identified was a composite blood-based signature that predicted the onset of various medical conditions approximately nine years in advance (AUC 0.59-0.72). Notably, all biomarkers worked in synergy with psychosocial factors, accurately predicting both medical conditions (AUC 0.69– 0.91) and self-report pain (AUC 0.71–0.92). Over a period of 15 years, individuals scoring high on both biomarkers and psychosocial risk factors had twice the cumulative incidence of diagnoses for pain-associated medical conditions (Hazard Ratio (HR): 2.26) compared to individuals scoring high on biomarkers but low on psychosocial risk factors (HR: 1.06). In summary, we identified various biomarkers for chronic pain conditions and showed that their predictive efficacy heavily depended on psychological and social influences. These findings underscore the necessity of adopting a holistic approach in the development of biomarkers to enhance their clinical utility.
Role of Thromboinflammation Interaction in the Serious-Critical COVID-19 Pneumonia: A Single-center Retrospective Study
Authors: Li Jiatao , Liu Shimeng 
Published: April 2024

AbstractAimTo describe the potential role of thromboinflammation in thromboembolism and the progress of coronavirus disease 2019 (COVID-19).MethodsThe retrospective study included sequentially hospitalized patients with the diagnosis of COVID-19 pneumonia during the first pandemic (December 1, 2022, to January 31, 2023) at a medical center in Beijing, China. Risks of critical medical support requirements, thrombosis events, and death were valued in the multivariate logistic regression models, where age (≥ 80 vs. < 80 years old), nadir platelets level (≤100 vs. > 100 10^9/L), C-reactive protein (CRP) level at admission (≥ 80 vs. < 80 mg/L), D-dimer level at admission (≥ 1.0 vs. < 1.0 mg/L) were dichotomized.ResultsA total of 88 patients were included (median age 77 years, 72% male). During hospitalization, 35 (40%) patients required critical medical support, 22 (29%) had disseminated intravascular coagulation (DIC), 11 (13%) had radiologically supported thrombosis events, and 26 (30%) died. Increased age (odds ratio [OR]: 5.22,95% confidence interval [CI]: 1.27-21.53;p=0.02), elevated CRP levels (OR: 9.26, 95% CI: 2.24-38.37;p<0.01), decreased nadir platelet level (OR: 13.47, 95% CI: 1.91-94.84;p<0.01), elevated D-dimer level (OR: 5.21, 95 CI%: 0.96-28.21;p=0.06) were associated with the requirements of critical care. Increased age (OR: 10.87, 95% CI: 3.05-38.80;p<0.01), elevated CRP levels (OR: 6.14, 95% CI:1.68-22.47;p<0.01), decreased nadir platelet levels (OR: 5.96, 95% CI: 1.34-26.47;p=0.02) and D-dimers (≥1.0 vs. <1.0 mg/L, OR: 2.26, 95% CI: 0.68-7.44;p=0.18) were associated with death. Increased age (OR: 2.40,95% CI: 0.60-9.67;p=0.22), decreased nadir platelet levels (OR: 1.31, 95% CI: 0.22-7.96;p=0.77), inflmmation status, including D-dimers (≥1.0 vs. <1.0 mg/L, OR:4.62, 95% CI: 0.89-24.04;p=0.07) and CRP (≥80 vs. <80 mg/mL, OR:5.44, 95% CI: 1.05-28.27;p=0.04) were significantly associated with the risks of thromboembolism.ConclusionsThe retrospective study indicated thromboinflammation promoted thromboembolism and was associated with the outcomes of COVID-19 pneumonia.
Patient preferences for features associated with leadless versus conventional transvenous cardiac pacemakers
Authors: Reed Shelby D. , Yang Jui-Chen , Wallace Matthew J. , Sutphin Jessie , Johnson F. Reed , Ozdemir Semra , Delgado Stephanie , Goates Scott , Harbert Nicole , Lo Monica , Rajagopalan Bharath , Ip James E. , Al-Khatib Sana M. 
Published: April 2024

AbstractBackgroundRegulatory approval of the first dual-chamber leadless pacemaker (PM) system provides patients an alternative to conventional transvenous pacemakers.ObjectiveTo quantify patients’ preferences for pacemaker features.MethodsPatients with a de-novo PM indication were recruited from 7 US sites to complete a discrete-choice experiment (DCE) survey. Patients chose between pairs of experimentally designed, hypothetical PMs that varied according to PM type (removable leadless, non-removable leadless, conventional transvenous); battery life (5, 8, 12, 15 years); time since regulatory approval (2, 10 years); discomfort for 6 months (none, discomfort); complication risk and infection risk (1%, 5%, 10%/20% for each). Patients with a de-novo pacemaker indication were recruited to complete a web-based survey from seven US sites between May 11, 2022 to May 24, 2023.ResultsChoice data from 117 patients indicated that complication risks and infection risks were the most influential. On average, patients preferred removable leadless pacemakers over both non-removable leadless pacemakers (p=0.001) and conventional transvenous pacemakers (p=0.031). However, latent-class analysis revealed two distinct preference classes. One class preferred leadless pacemakers (50.5%) and the other class preferred conventional transvenous pacemakers (49.5%). The conventional PM class prioritized pacemakers with ten rather than two years since regulatory approval (p<0.001) whereas the leadless PM class was insensitive to years since regulatory approval (p=0.83). All else equal, patients would accept maximum risks of complications or infections ranging about 5% to 18% to receive their preferred pacemaker type.ConclusionLatent-class analysis revealed strong patient preferences for the type of PM, with a nearly equal split between recent leadless PM technology and conventional transvenous PMs.These findings can inform shared decision making between healthcare providers and patients.