bluuebunny/crossref_metadata_2025_split huggingface dataset:
End-to-end protein-ligand complex structure generation with diffusion-based generative models
Authors: Nakata Shuya , Mori Yoshiharu , Tanaka Shigenori 
Published: December 2022

AbstractThree-dimensional structures of protein-ligand complexes provide valuable insights into their interactions and are crucial for molecular biological studies and drug design. However, their high-dimensional and multimodal nature hinders end-to-end modeling, and earlier approaches depend inherently on existing protein structures. To overcome these limitations and expand the range of complexes that can be accurately modeled, it is necessary to develop efficient end-to-end methods. We introduce an equivariant diffusion-based generative model that learns the joint distribution of ligand and protein conformations conditioned on the molecular graph of a ligand and the sequence representation of a protein extracted from a pre-trained protein language model. Benchmark results show that this protein structure-free model is capable of generating diverse structures of protein-ligand complexes, including those with correct binding poses. Further analyses indicate that the proposed end-to-end approach is particularly effective when the ligand-bound protein structure is not available. The present results demonstrate the effectiveness and generative capability of our end-to-end complex structure modeling framework with diffusion-based generative models. We suppose that this framework will lead to better modeling of protein-ligand complexes, and we expect further improvements and wide applications.
LuxHMM: DNA methylation analysis with genome segmentation via Hidden Markov Model
Authors: Malonzo Maia H. , Lähdesmäki Harri 
Published: December 2022

AbstractDNA methylation plays an important role in studying the epigenetics of various biological processes including many diseases. Although differential methylation of individual cytosines can be informative, given that methylation of neighboring CpGs are typically correlated, analysis of differentially methylated regions is often of more interest.We have developed a probabilistic method and software, LuxHMM, that uses hidden Markov model (HMM) to segment the genome into regions and a Bayesian regression model, which allows handling of multiple covariates, to infer differential methylation of regions. Moreover, our model includes experimental parameters that describe the underlying biochemistry in bisulfite sequencing and model inference is done using either variational inference for efficient genome-scale analysis or Hamiltonian Monte Carlo (HMC).Analyses of real and simulated bisulfite sequencing data demonstrate the competitive performance of LuxHMM compared with other published differential methylation analysis methods.
Genetic Predisposition to High Blood Pressure and Out-of-Office Hypertension: Insights from a Population Sample in Liechtenstein
Authors: Narula Sukrit , Mohammadi-Shemirani Pedrum , Aeschbacher Stefanie , Chong Michael R. , Le Ann , Thériault Sébastien , Grossman Kirsten , Paré Guillaume , Risch Lorenz , Risch Martin , Conen David 
Published: December 2022

AbstractGenetic predisposition is a risk factor for office hypertension. We tested whether genetic background could identify individuals with ambulatory daytime hypertension in a sample of white Europeans from Liechtenstein. We evaluated two measures of predisposition to hypertension: family history and polygenic risk scores (PRS). Our analytic sample contained 1444 participants aged 25 to 41. Of the participants, 12% had office hypertension, while 37% had out-of-office hypertension. The correlation between blood pressure PRS and family history of hypertension was low (R2= 4.96×10−3), but both were strongly associated with ambulatory blood pressure (2.2 mmHg per 1 SD increase [95% CI: 1.6, 2.7] & 2.4 mmHg increase with positive family history [95% CI: 1.3, 3.4], respectively). The PRS provides incremental improvement in predicting ambulatory systolic blood pressure beyond a validated blood pressure prediction score (ΔAIC = - 33), whereas family history does not (ΔAIC = 1). However, the difference in performance between a baseline prediction algorithm for identifying ambulatory systolic daytime hypertension (positive likelihood ratio of 6.87 [95% CI: 5.56, 8.49]; negative likelihood ratio of 0.45 [95% CI: 0.39, 0.51]) and the same model with PRS integrated (positive likelihood ratio of 7.69 [95% CI: 6.18, 9.57]; negative likelihood ratio of 0.43 [95% CI: 0.37, 0.49]) was modest. In conclusion, in a white European sample from Liechtenstein, PRS and family history are distinct constructs that are associated with increased clinical and ambulatory blood pressure. Unlike family history, polygenic risk scores provide incremental information in the identification of individuals with ambulatory hypertension. However, these gains are modest and warrant further development to improve predictive utility at the point-of-care.
A Standardized Metric to Enhance Clinical Trial Design and Outcome Interpretation in Type 1 Diabetes
Authors: Ylescupidez Alyssa , Bahnson Henry T. , O’Rourke Colin , Lord Sandra , Speake Cate , Greenbaum Carla J. 
Published: December 2022

AbstractThe use of a standardized outcome metric enhances clinical trial interpretation and cross-trial comparison. If a disease course is predictable, comparing modeled predictions with outcome data affords the precision and confidence needed to accelerate precision medicine. We demonstrate this approach in type 1 diabetes (T1D) trials aiming to preserve endogenous insulin secretion measured by C-peptide. C-peptide is predictable given an individual’s age and baseline value; quantitative response (QR) adjusts for these variables and represents the difference between the observed and predicted outcome. Validated across 13 trials, the QR metric reduces each trial’s variance and increases statistical power. As smaller studies are especially subject to random sampling variability, using QR as the outcome introduces alternative interpretations of previous clinical trial results. QR can provide model-based estimates that quantify whether individuals or groups did better or worse than expected. QR also provides a purer metric to associate with biomarker measurements. Using data from more than 1,300 participants, we demonstrate the value of QR in advancing disease-modifying therapy in T1D. QR applies to any disease where outcome is predictable by pre-specified baseline covariates, rendering it useful for defining responders to therapy, comparing therapeutic efficacy, and understanding causal pathways in disease.
mTICI 1 vs mTICI 0 before endovascular stroke treatment in middle cerebral artery M1-occlusion – predictor for revascularization success and outcome?
Authors: Jesser Jessica , Weyland Charlotte S. , Potreck Arne , Neuberger Ulf , Breckwoldt Michael O. , Chen Min , Schönenberger Silvia , Bendszus Martin , Möhlenbruch Markus A. 
Published: December 2022

BackgroundEndovascular stroke treatment (EST) has become the treatment of choice for middle cerebral artery (MCA) M1-segment occlusions. Little is known about the implications for revascularization success of occlusions with persisting antegrade perfusion before initiation of treatment (modified Treatment In Cerebral Ischemia (mTICI 1)) compared to a complete occlusion (mTICI 0). Here, we compared the impact of these two states of target vessel occlusion on recanalization success and clinical outcome.MethodsRetrospective, single-center analysis of patients treated for M1-segment MCA occlusion with EST from 01/2015 until 05/2020 in a tertiary stroke center. Primary study endpoint was successful recanalization (mTICI 2c-3) after one thrombectomy attempt (first pass effect). Secondary endpoints were the clinical outcome (as modified Rankin Scale 90 days after stroke onset) and the complication rate. The two study groups were compared in univariate analysis including patient characteristics and procedural details.ResultsIn this study, 422/581 patients (72.6 %) presented with complete M1-occlusion compared to 159/581 (27.4 %) with incomplete M1-occlusion. Neither did the rate of FPE differ between the study groups nor the rate of procedural complications (mTICI 0: 10 (2.4%), mTICI 1: 1 (0.6%), p = 0.304). Patients with incomplete initial occlusion showed a lower mRS at discharge (median (IQR) mTICI0: 4 (3-5) vs. mTICI1: 3 (2 – 6), p = 0.014), but a comparable mRS 90 days after stroke onset (mTICI0: 3 (2-6) vs. mTICI:1 4 (2-6), p = 0.479).ConclusionComplete M1-occlusions (mTICI 0) and incomplete occlusions (mTICI 1) show the same recanalization success and complication rate as well as a comparable clinical outcome. Thus, incomplete M1-occlusions should be treated with the same urgency as initial complete occlusions.
Orally administratedLactobacillus gasseriTM13 andLactobacillus crispatusLG55 Can Restore the Vaginal Health of Patients Recovering from Bacterial Vaginosis
Authors: Qi Fengyuan , Fan Shangrong , Fang Chao , Ge Lan , Lyu Jinli , Huang Zhuoqi , Zhao Shaowei , Zou Yuanqiang , Huang Liting , Liu Xinyang , Liang Yiheng , Zhang Yongke , Zhong Yiyi , Zhang Haifeng , Xiao Liang , Zhang Xiaowei 
Published: December 2022

AbstractBacterial vaginosis (BV) is a common infection of the lower genital tract with a vaginal microbiome dysbiosis caused by decreasing of lactobacilli. Previous studies suggested that supplementation with liveLactobacillusmay benefit the recovery of BV, while the outcomes vary in people from different regions. Herein, we aim to evaluate the effectiveness of oral Chinese-originLactobacilluswith adjuvant metronidazole (MET) on treating Chinese BV patients. In total, 67 Chinese women with BV were enrolled in this parallel controlled trial and randomly assigned to two study groups: a control group treated with MET vaginal suppositories for 7 days and a probiotic group treated with oralLactobacillus gasseriTM13 andLactobacillus crispatusLG55 as an adjuvant to MET for 30 days. By comparing the participants with Nugent scores ≥ 7 and < 7 on days 14, 30, and 90, we found that oral administration of probiotics did not improve BV cure rates (57.14% and 67.74% at day 14, 57.14% and 58.06% at day 30, 32.14% and 48.39% at day 90 for probiotic and control group respectively). However, the probiotics were effective in restoring vaginal health after cure by showing higher proportion of participants with Nugent scores < 4 in the probiotic group compared to the control group (87.50% and 71.43% on day 14, 93.75% and 88.89% on day 30, and 77.78% and 66.67% on day 90). The relative abundance of the probiotic strains was significantly increased in the gut microbiome of the probiotic group compared to the control group at day 14, but no significance was detected after 30 and 90 days. Also, the probiotics were not detected in vaginal microbiome, suggesting thatL. gasseriTM13 andL. crispatusLG55 mainly acted through the gut. A higher abundance ofPrevotella timonensisat baseline was significantly associated with long-term cure failure of BV and greatly contributed to the enrichment of the lipid IVA synthesis pathway, which could aggravate inflammation response. To sum up,L. gasseriTM13 andL. crispatusLG55 can restore the vaginal health of patients recovering from BV, and individualized intervention mode should be developed to improve BV cure rates.
Quantitative multi-organ proteomics of fatal COVID-19 uncovers tissue-specific effects beyond inflammation
Authors: Schweizer Lisa , Schaller Tina , Zwiebel Maximilian , Karayel Özge , Müller-Reif Johannes B. , Zeng Wen-Feng , Dintner Sebastian , Hirschbühl Klaus , Märkl Bruno , Claus Rainer , Mann Matthias 
Published: December 2022

AbstractSARS-CoV-2 directly damages lung tissue via its infection and replication process and indirectly due to systemic effects of the host immune system. There are few systems-wide, untargeted studies of these effects on the different tissues of the human body and nearly all of them base their conclusions on the transcriptome. Here we developed a parallelized mass spectrometry (MS)-based proteomics workflow allowing the rapid, quantitative analysis of hundreds of virus-infected and FFPE preserved tissues. The first layer of response in all tissues was dominated by circulating inflammatory molecules. To discriminated between these systemic and true tissue-specific effects, we developed an analysis pipeline revealing that proteome alterations reflect extensive tissue damage, mostly similar to non-COVID diffuse alveolar damage. The next most affected organs were kidney and liver, while the lymph-vessel system was also strongly affected. Finally, secondary inflammatory effects of the brain correlated with receptor rearrangements and the degradation of neuronal myelin. Our results establish MS-based tissue proteomics as a promising strategy to inform organ-specific therapeutic interventions following COVID-19 infections.
Perception and Readiness Towards Inter-Professional Education Among Different Health Care Disciplines at Khyber Medical University Peshawar
Authors: Ud-din Yaser , Ghani Nasreen , Khatoon Zubaida , Zartasha  , Ali Haidar , Badshah Sadar , Hassan Syed , Ali Mehboob , Iqbal Naveed , Hameed Abdul , Shehzad Qaisar 
Published: December 2022

AbstractInterprofessional learning (IPL) is an approach that teaches students diverse disciplines to communicate with each other about their professional knowledge in order to acquire a more complex one understanding of the current situation. According to WHO definition of IPE “it’s a process between two or more professionals learn about from, and with one another to permit effective association and enhance health outcome. The aim of this study was to measure perception and readiness towards IPE among different health care disciplines. A cross-sectional study was done with two hundred and eighteen post graduate Nursing, public health, physiotherapy, and basic medical sciences students from September,2020 to January,2021 at Khyber Medical University Peshawar Pakistan. Convenient sampling technique was used to collect data. The Readiness for Inter-Professional Learning Scale (RIPLS) and Interdisciplinary Education Perception Scale (IEPS) were used to measure the readiness and perception of students regarding inter-professional leaning. The data were analyzed using software Statistical Package for Social Science (SPSS) (Version 23). The RIPLS was completed by a total of 218 participants (response rate 100%, 61 Nursing students 28%, 51 physiotherapy students 23.4%, 53 public health students 24.3%, and 53 basic medical sciences students 24.3%). As shown in Table 1.1, the majority of respondents were male (51.4%) followed by female (48.6%). Most of the respondents were aged with a mean score of 27.92 ± 3.195. Moreover, majority of respondents have experience less than 5years (75.2%) and (22.8%) has experience above than 5years. Value of perception and readiness in Shapiro-Wilk is .000 which shows that the data variable is not normally distributed. correlation of students towards interprofessional learning by applying Spearman’ rho test. Students’ perception has strong positive correlation with their readiness, p value (.000). Also students’ readiness has strong positive correlation with their perception towards interprofessional learning. This study was to explore the readiness and perception of students towards interprofessional education in different health care students. IPL is beneficial for students to know other professionals to work together for teamwork and collaboration and it also increase communication between different health care professional and patients.
Trans-ethnic Genomic Informed Risk Assessment for Alzheimer’s disease: An International Hundred K+ Cohorts Consortium Study
Authors: Sleiman Patrick M. , Qu Hui-Qi , Connolly John J , Mentch Frank , Pereira Alexandre , Lotufo Paulo A , Tollman Stephen , Choudhury Ananyo , Ramsay Michele , Kato Norihiro , Ozaki Kouichi , Mitsumori Risa , Jeon Jae-Pil , Hong Chang Hyung , Son Sang Joon , Roh Hyun Woong , Lee Dong-gi , Mukadam Naaheed , Foote Isabelle F , Marshall Charles R , Butterworth Adam , Prins Bram P , Glessner Joseph T , Hakonarson Hakon 
Published: December 2022

AbstractBackgroundAlzheimer’s disease (AD) is a complex multifactorial progressive dementia affecting all human populations. As a collaboration model between the International Hundred K+ Cohorts Consortium (IHCC) and the Davos Alzheimer Collaborative (DAC), our aim was to develop a trans-ethnic genomic informed risk assessment (GIRA) algorithm for AD.MethodsThe GIRA model was created to include a polygenic risk score (PRS) calculated from the AD GWAS loci, theAPOEhaplotypes, and non-genetic covariates including age, sex and first 3 principal components of population substructure. The model was first validated using a ancestrally diverse dataset from the eMERGE network, and subsequently validated in a South-Asian population in the UK and 3 East-Asian populations. The distributions of the PRS scores were also explored in populations from 3 African regions. In two validation sites, the PRS was tested for associated with the levels of plasma proteomics markers.ResultsWe created a trans-ethnic GIRA model for the risk prediction of AD and validated the performance of the GIRA model in different populations. The proteomic study in the participant sites identified proteins related to female infertility and autoimmune thyroiditis and associated with the risk scores of AD, highlighting molecular mechanisms underlying the previously observed correlations between these clinical phenotypes.ConclusionsAs the initial effort by the IHCC to leverage existing large scale datasets in a collaborative setting with DAC, we developed a trans-ethnic GIRA for AD with the potential of identifying individuals at high risk of developing AD for future clinical applications. The PRS scores in this model also contribute new research discoveries for the molecular pathogenesis of AD as demonstrated by the proteomic data.
Variations in determining actual orientations of segmented deep brain stimulation leads using the manually refined DiODe algorithm: a retrospective study across different lead designs and medical institutions
Authors: Henry Kaylee R. , Miulli Milina , Nuzov Noa , Nolt Mark J. , Rosenow Joshua , Elahi Behzad , Pilitsis Julie G. , Golestanirad Laleh 
Published: December 2022

AbstractPurposeDirectional deep brain stimulation (DBS) leads have become widely used in the past decade. Understanding the asymmetric stimulation provided by directional leads requires precise knowledge of the exact orientation of the lead in respect to its anatomical target. Recently, the DiODe algorithm was developed to automatically determine the orientation angle of leads from the artifact on postoperative computed tomography (CT) images. However, DiODe results are user-dependent. This study analyzed the significance of lead rotation as well as the user agreement of DiODe calculations across the two most common DBS systems and two independent medical institutions.MethodsData from 104 patients who underwent an anterior-facing unilateral/bilateral directional DBS implantation at either Northwestern Memorial Hospital (NMH) or Albany Medical Center (AMC) were retrospectively analyzed. Actual orientations of the implanted leads were independently calculated by three individual users using the DiODe algorithm in Lead-DBS and patients’ postoperative CT images. Deviation from the intended orientation and user agreement were assessed.ResultsAll leads significantly deviated from the intended 0° orientation (p<0.001), regardless of DBS lead design (p<0.05) or institution (p<0.05). However, a bias of the implantation towards a single direction was seen for the Boston Scientific leads (p=0.014 at NMH, p=0.029 at AMC). A difference of 10° between at least two users occurred in 28% (NMH) and 39% (AMC) of all Boston Scientific and 53% (AMC) and 76% (NMH) of all St. Jude leads.ConclusionOur results show that there is a significant lead rotation from the intended surgical orientation across both DBS systems and both medical institutions, however, a bias towards a single direction was only seen in Boston Scientific leads. Additionally, these results raise questions into the user error that occurs when manually refining the orientation angles calculated with DiODe.
Association of close-range contact patterns with SARS-CoV-2: a household transmission study
Authors: Kleynhans Jackie , Dall’Amico Lorenzo , Gauvin Laetitia , Tizzoni Michele , Maloma Lucia , Walaza Sibongile , Martinson Neil A. , von Gottberg Anne , Wolter Nicole , Makhasi Mvuyo , Cohen Cheryl , Cattuto Ciro , Tempia Stefano ,   the SA-S-HTS Group
Published: December 2022

AbstractBackgroundHouseholds are an important location for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission, especially during periods where travel and work was restricted to essential services. We aimed to assess the association of close-range contact patterns with SARS-CoV-2 transmission.MethodsWe deployed proximity sensors for two weeks to measure face-to-face interactions between household members after SARS-CoV-2 was identified in the household, in South Africa, 2020 - 2021. We calculated duration, frequency and average duration of close range proximity events with SARS-CoV-2 index cases. We assessed the association of contact parameters with SARS-CoV-2 transmission using mixed effects logistic regression accounting for index and household member characteristics.ResultsWe included 340 individuals (88 SARS-CoV-2 index cases and 252 household members). On multivariable analysis, factors associated with SARS-CoV-2 acquisition were index cases with minimum Ctvalue <30 (aOR 10.2 95%CI 1.4-77.4) vs >35, contacts aged 13-17 years (aOR 7.7 95%CI 1.0-58.2) vs <5 years and female contacts (aOR 2.3 95%CI 1.1-4.8). No contact parameters were associated with acquisition (aOR 1.0 95%CI 1.0-1.0) for all three of duration, frequency and average duration.ConclusionWe did not find an association between close-range proximity events and SARS-CoV-2 household transmission. It may be that droplet-mediated transmission during close-proximity contacts play a smaller role than airborne transmission of SARS-CoV-2 in the household, due to high contact rates in households or study limitations.FundingWellcome Trust (Grant number 221003/Z/20/Z) in collaboration with the Foreign, Commonwealth and Development Office, United Kingdom.
Nf1deficiency accelerates mammary development and promotes luminal-basal plasticity
Authors: Tovar Elizabeth A. , Arumugam Menusha , Essenburg Curt J. , Dischinger Patrick S. , Grit Jamie L. , Callaghan Megan E. , Sheridan Rachael T.C. , Turner Lisa , Esquibel Corinne R. , Feenstra Kristin , Madaj Zachary B. , Beddows Ian , Graveel Carrie R. , Steensma Matthew R. 
Published: December 2022

SUMMARYThe tumor suppressorNF1is a critical driver of sporadic breast cancer and NF-related breast cancers. We utilized distinctNf1-deficient immunocompetent rat models to investigateNf1function in mammary development and homeostasis. Here we demonstrate thatNf1deficiency dramatically accelerates mammary morphogenesis, alters TEB cell organization, and proliferation. Notably, we observed a shift in luminal-basal epithelial lineage commitment withinNf1-deficient lines with early tumor onset. In addition, we detected subpopulations of hybrid EMT cells (Ecad+/CK14+) within the invasive edge and stroma ofNf1-deficient tumors.Nf1deficiency restricted luminal progenitor potential and resulted in gene expression changes associated with decreased cell adhesion and increased EMT signatures. Together our findings support a model in whichNf1loss of function results in lineage plasticity throughout mammary morphogenesis and promotes EMT-mediated invasion. This study reveals a previously unknown role for the tumor suppressor neurofibromin in mammary homeostasis and phenotypic plasticity during breast cancer progression.