bluuebunny/crossref_metadata_2025_split huggingface dataset:
Assessing the interplay between off-target promiscuity, cytotoxicity, and tolerability in rodents to improve the safety profile of novel anti-malarial plasmepsin X inhibitors
Authors: Gerets Helga H J , Delaunois Annie , Cardenas Alvaro , Class Reiner , Fleurance Renaud , de Haro Teresa , Laleu Benoît , Lowe Martin A , Rosseels Marie-Luce , Valentin Jean-Pierre 
Published: July 2024

Abstract
Within drug development, high off-target promiscuity as well as potent cytotoxicity, are associated with a high attrition rate. We investigated the safety profile of novel plasmepsin X (PMX) inhibitors for the treatment of malaria. In our screening cascade, a total of 249 PMX compounds were profiled in a panel of in vitro secondary pharmacology assays containing 44 targets (SafetyScreen44 panel) and in a cytotoxicity assay in HepG2 cells using ATP as an endpoint. Six of the lead compounds were subsequently tested in a 7-d rat toxicology study, and/or in a cardiovascular study in guinea pigs. Overall, compounds with high cytotoxicity in HepG2 cells correlated with high promiscuity (off-target hit rate &gt;20%) in the SafetyScreen44 panel and were associated with poor tolerability in vivo (decedents, morbidity, adverse clinical signs, or severe cardiovascular effects). Some side effects observed in rats or guinea pigs could putatively be linked with hits in the secondary pharmacological profiling, such as the M1 or M2 muscarinic acetylcholine receptor, opioid µ and/or κ receptors or hERG/CaV1.2/Na+ channels, which were common to &gt;50% the compounds tested in vivo. In summary, compounds showing high cytotoxicity and high promiscuity are likely to be poorly tolerated in vivo. However, such associations do not necessarily imply a causal relationship. Identifying the targets that cause these undesirable effects is key for early safety risk assessment. A tiered approach, based on a set of in vitro assays, helps selecting the compounds with highest likelihood of success to proceed to in vivo toxicology studies.
Mediating effects of BMI on the association between DNA methylation regions and 24-h blood pressure in African Americans
Authors: Pan Xiaoqing , Chen Yuru , Yang Yifan , Kidambi Srividya , Liang Mingyu , Liu Pengyuan 
Published: July 2024

Background:
DNA methylation is an important epigenetic mechanism that may influence blood pressure (BP) regulation and hypertension risk. Obesity, a major lifestyle factor associated with hypertension, may interact with DNA methylation to affect BP. However, the indirect effect of DNA methylation on 24-h BP measurements mediated by obesity-related phenotypes such as BMI has not been investigated.

Methods:
Causal mediation analysis was applied to examine the mediating role of BMI in the relation between DNA methylation and 24-h BP phenotypes, including SBP, DBP and mean arterial blood pressure (MAP), in 281 African American participants.

Results:
Analysis of 38 215 DNA methylation regions, derived from 1 549 368 CpG sites across the genome, identified up to 138 methylation regions that were significantly associated with 24-h BP measurements through BMI mediation. Among them, 38 (19.2%) methylation regions were concurrently associated with SBP, DBP and MAP. Genes associated with BMI-mediated methylation regions are potentially involved in various chronic diseases such as coronary artery disease and renal disease, which are often caused or exacerbated by hypertension. Notably, three genes (CDH4, NOTCH1 and COLGALT1) showed both direct associations with 24-h BP measurements and indirect associations through BMI after adjusting for age and sex covariates.

Conclusion:
Our findings suggest that DNA methylation may contribute to the regulation of 24-h BP in African Americans both directly and indirectly through BMI mediation.
Attitudes and Knowledge of Medical Students in South of Israel Toward Medical Cannabis
Authors: Mirzayov Shira , Peleg Roni , Freud Tamar 
Published: July 2024

Background:
Public and medical interest in the use of cannabis has increased in Israel and the world over recent years.

Study Question:
The aim of the study was to assess the attitudes of medical students from the Faculty of Health Sciences of Ben-Gurion University of the Negev on the use of medical cannabis.

Study Design:
This is a cross-sectional study using a self-administered questionnaire completed by medical students from Ben-Gurion University of the Negev, Beer-Sheva, Israel.

Measures and Outcomes:
Attitudes and knowledge toward the use of medical cannabis were evaluated.

Results:
A total of 243 medical students participated in the study. Of these, 111 (46.1%) were from preclinical years. The mean age was 27.31 ± 3.07, and 138 (57.3%) were female students. Most students (N = 193, 79.4%) agreed to a great degree or to a very great degree that there was a role for cannabis for medical purposes. Most students thought that medical cannabis should be recommended for use by pain specialists (N = 231, 95.1%), by oncologists (N = 208, 85.6%), and by psychiatrists (N = 192, 79%). A little more than half of the participants (N = 127, 52.5%) would agree to be licensed, as future physicians, to prescribe medical cannabis. A logistic regression analysis found that the students strongly agreed with legalization of medical cannabis and students who strongly agreed that medical cannabis should be in the health basket predicted a very strong agreement about its use (OR = 2.623, P ≤ 0.002, and OR = 3.285, P ≤ 0.001, respectively).

Conclusions:
Most medical students support the use of medical cannabis for medical purposes and are in favor of its legalization. As physicians of the future, it is important to assess the attitudes of medical students on medical cannabis.
H5 and H9 avian influenza – potential re-emergent zoonotic threats to humans
Authors: Dabrera Gavin 
Published: July 2024

Purpose of review
This review aims to discuss the current state of human infections with Avian Influenza A (H5) and (H9) viruses, to support awareness of the global epidemiology among clinicians and public health professionals interested in emerging respiratory infections.

Recent findings
Among increasing numbers of detections in avian species of Avian Influenza A(H5N1) clade 2.3.4.4b globally, reported human cases of severe infection have been rare.
Enhanced surveillance of persons exposed to avian species infected with Influenza A (H5N1) clade 2.3.4.4b in different countries has identified small numbers of asymptomatic individuals with Avian Influenza A (H5N1) detected by PCR from the upper respiratory tract; some of these instances have been considered to represent contamination rather than infection.
There have also been recent sporadic human cases of Avian Influenza A(H9N2) internationally, including in China and Cambodia.

Summary
Human infections with Avian Influenza A(H5) and (H9) viruses remain of interest as an emerging infection both to clinicians and public health professionals. While maintaining effective surveillance is essential, one health strategies to control infection in avian species will be key to mitigating these risks.
Effectiveness of Mindfulness-Based Cognitive Therapy on Depressive Symptoms, Brain Potential, and Neuroimmunoinflammatory Factors in Depressed Patients
Authors: Qiu Jiancheng , Gong Yifei , Zhang Xiucui , Mao Weibing 
Published: July 2024

Objective
This study was aimed to investigate the effectiveness of mindfulness-based cognitive therapy (MBCT) on depressive symptoms, brain potential, and neuroimmunoinflammatory factors in patients with depression.

Methods
Sixty-four eligible patients according to the inclusion criteria were randomly divided into the control group and the observation group, with 32 patients in each group. The control group received conventional therapy, while the observation group received MBCT on top of conventional therapy. The depressive symptoms, brain potential, and neuroimmunoinflammatory factors were measured in the two groups.

Results
After treatment, the Hamilton Depression Rating Scale score, tumor necrosis factor α, and interleukin-6 levels were decreased, while the World Health Organization Quality of Life Scale score, total number of response execution score, and 5-hydroxy tryptamine level were increased in both groups. Moreover, the Hamilton Depression Rating Scale score, tumor necrosis factor α, and interleukin-6 levels were decreased more significantly, while the World Health Organization Quality of Life Scale score, total number of response execution score, and 5-hydroxy tryptamine level were increased more significantly in the observation group compare to the control group (P < 0.01). In addition, the latency in the observation group was shorter and the amplitude was longer than those in the control group (P < 0.01).

Conclusions
Compared with conventional therapy, the use of MBCT combined with conventional therapy can effectively reduce depressive symptoms, suppresses inflammatory responses, and optimize attention and response to target stimulation and is worthy of wide clinical implementation.
Evaluation of the efficacy of Cephalosporin antibiotics Sold in Kano Nigeria against Some Clinical Bacterial Isolates.
Authors: Ibrahim Safiyya Atiku , Muhammad Bashir , Rabiu Ismail , Muhammed Abdulazeez 
Published: July 2024

Introduction: The circulation of substandard antibiotics is believed to aggravate the evil effect of Antibiotic resistance (AR) globally. AR knows no boundaries and pose a serious threat to existing antibiotics.
Gap statement: Sabon Gari market is chosen due to several formal and informal reports of substandard antibiotics. It's a major distribution centre for pharmaceuticals, yet research on its impact and extent of substandard drugs is lacking.
Aim: This study aims to evaluate the susceptibility status of some clinical Bacterial isolates (E. coli, K. pneumoniae, S. aureus, S. pneumoniae, P. aeruginosa and Salmonella sp.) to generations of Cephalosporins purchased from drug distributors in Sabon Gari Market Kano.
Methodology: Antimicrobial susceptibility pattern of the test isolates was determined by disc diffusion method. Fourier Transform Infrared Spectroscopy (FT-IR) analysis was used to confirm the functional group of the active ingredients of all the antibiotics tested. Molecular identification of resistant gene (CTX-M1) were carried out using PCR.
Results: Market survey reveals that Cephalexin 61% (first generation), Cefuroxime 72% (Second generation) and Cefixime 68%, Cefpodoxime 79%, Ceftriaxone 63%, Ceftazidime 70% and Cefotaxime 45% (third generation) and Cefepime 84% (fourth generation) were the most commonly sold Cephalosporins, with different brands and company names. In all the antibiotics tested, similar activity was observed in the branded antibiotics as compared with the standard antibiotics, with no significant difference observed. Exactly 20% of E. coli and K. pneumoniae were resistant while 80% of S. aureus, S. pneumoniae, Pseudomonas, and Salmonella sp. were susceptible. CTX-M1 resistant gene was identified E. coli and K. pneumoniae which further confirms their resistance to Cefotaxime and ceftriaxone antibiotics.
Conclusion: Branded cephalosporins sold in Kano were effective as standard antibiotics with good bioavailability and compliance with the standard formulation of medicine, thus fit for human intake.
Proteomics and personalized patient-derived xenograft models identify treatment opportunities for a progressive malignancy within a clinically actionable timeframe and change care
Authors: Barnabas Georgina D. , Bhat Tariq A. , Goebeler Verena , Leclair Pascal , Azzam Nadine , Melong Nicole , Anderson Colleen , Gom Alexis , An Seohee , Ergin Enes K. , Shen Yaoqing , Mungall Andy J. , Mungall Karen L. , Maxwell Christopher A. , Reid Gregor S.D. , Hirst Martin , Jones Steven , Chan Jennifer A. , Senger Donna L. , Berman Jason N. , Parker Seth J. , Bush Jonathan W. , Strahlendorf Caron , Deyell Rebecca J. , Lim Chinten J. , Lange Philipp F. ,   PROFYLE Program
Published: July 2024

AbstractIncreased access to high-throughput DNA sequencing platforms has transformed the diagnostic landscape of pediatric malignancies by identifying and integrating actionable genomic or transcriptional features that refine diagnosis, classification, and treatment. Yet less than 10% of treated patients show a positive response and translating precision oncology data into feasible and effective therapies for hard-to-cure childhood, adolescent, and young adult malignancies remains a significant challenge. Combining the identification of therapeutic targets at the protein and pathway levels with demonstration of treatment response in personalized models holds great promise. Here we present the case for combining proteomics with patient-derived xenograft (PDX) models to identify personalized treatment options that were not apparent at genomic and transcriptomic levels. Proteome analysis with immunohistochemistry (IHC) validation of formalin-fixed paraffin-embedded sections from an adolescent with primary and metastatic spindle epithelial tumor with thymus-like elements (SETTLE) was completed within two weeks of biopsy.The results identified an elevated protein level of SHMT2 as a possible target for therapy with the commercially available anti-depressant sertraline. Within 2 months and ahead of a molecular tumor board, we confirmed a positive drug response in a personalized chick chorioallantoic membrane (CAM) model of the SETTLE tumor (CAM-PDX). Following the failure of cytotoxic chemotherapy and second-line therapy, a treatment of sertraline was initiated for the patient. After 3 months of sertraline treatment the patient showed decreased tumor growth rates, albeit with clinically progressive disease.Significance: Overall, we demonstrate that proteomics and fast-track personalized xenograft models can provide supportive pre-clinical data in a clinically meaningful timeframe to support medical decision-making and impact the clinical practice. By this we show that proteome-guided and functional precision oncology are feasible and valuable complements to the current genome-driven precision oncology practices.
Benchmarking algorithms for spatially variable gene identification in spatial transcriptomics
Authors: Chen Xuanwei , Ran Qinghua , Tang Junjie , Chen Zihao , Huang Siyuan , Shi Xingjie , Xi Ruibin 
Published: July 2024

AbstractThe rapid development of spatial transcriptomics has underscored the importance of identifying spatially variable genes. As a fundamental task in spatial transcriptomic data analysis, spatially variable gene identification has been extensively studied. However, the lack of comprehensive benchmark makes it difficult to validate the effectiveness of various algorithms scattered across a large number of studies with real-world datasets. In response, this article proposes a benchmark framework to evaluate algorithms for identifying spatially variable genes through the analysis of synthesized and real-world datasets, aiming to identify the best algorithms and their corresponding application scenarios. This framework can assist medical and life scientists in selecting suitable algorithms for their research, while also aid bioinformatics scientists in developing more powerful and efficient computational methods in spatial transcriptomic research.
GeneSurfer Enables Transcriptome-wide Exploration and Functional Annotation of Gene Co-expression Modules in 3D Spatial Transcriptomics Data
Authors: Li Chang , Thijssen Julian , Kroes Thomas , van der Burg Ximaine , van der Weerd Louise , Höllt Thomas , Lelieveldt Boudewijn 
Published: July 2024

SummaryGene co-expression provides crucial insights into biological functions, however, there is a lack of exploratory analysis tools for localized gene co-expression in large-scale datasets. We present GeneSurfer, an interactive interface designed to explore localized transcriptome-wide gene co-expression patterns in the 3D spatial domain. Key features of GeneSurfer include transcriptome-wide gene filtering and gene clustering based on spatial local co-expression within transcriptomically similar cells, multi-slice 3D rendering of average expression of gene clusters, and on-the-fly Gene Ontology term annotation of co-expressed gene sets. Additionally, GeneSurfer offers multiple linked views for investigating individual genes or gene co-expression in the spatial domain at each exploration stage. Demonstrating its utility with both spatial transcriptomics and single-cell RNA sequencing data from the Allen Brain Cell Atlas, GeneSurfer effectively identifies and annotates localized transcriptome-wide co-expression, providing biological insights and facilitating hypothesis generation and validation.
Frequent transitions in self-assembly across the evolution of a central metabolic enzyme
Authors: Sendker Franziska L. , Schlotthauer Tabea , Mais Christopher-Nils , Lo Yat Kei , Girbig Mathias , Bohn Stefan , Heimerl Thomas , Schindler Daniel , Weinstein Arielle , Metzger Brain P. , Thornton Joseph W. , Pillai Arvind , Bange Gert , Schuller Jan M. , Hochberg Georg K.A. 
Published: July 2024

AbstractMany enzymes assemble into homomeric protein complexes comprising multiple copies of one protein. Because structural form is usually assumed to follow function in biochemistry, these assemblies are thought to evolve because they provide some functional advantage. In many cases, however, no specific advantage is known and, in some cases, quaternary structure varies among orthologs. This has led to the proposition that self-assembly may instead vary neutrally within protein families. The extent of such variation has been difficult to ascertain because quaternary structure has until recently been difficult to measure on large scales. Here, we employ mass photometry, phylogenetics, and structural biology to interrogate the evolution of homo-oligomeric assembly across the entire phylogeny of prokaryotic citrate synthases – an enzyme with a highly conserved function. We discover a menagerie of different assembly types that come and go over the course of evolution, including cases of parallel evolution and reversions from complex to simple assemblies. Functional experiments in vitro and in vivo indicate that evolutionary transitions between different assemblies do not strongly influence enzyme catalysis. Our work suggests that enzymes can wander relatively freely through a large space of possible assemblies and demonstrates the power of characterizing structure-function relationships across entire phylogenies.
Infant- and child-level predictors of mortality in low-resource settings: the WHO Child Mortality Risk Stratification Multi-Country Pooled Cohort
Authors:   The WHO Risk Stratification Working Group (WHO-RSWG), Schwinger Catherine 
Published: July 2024

SUMMARYBackgroundDespite impressive reductions in overall global child mortality, rates of decline have slowed during the last decade. Current guidelines for the care of at-risk children in low-resource settings mostly focus on broad clinical syndromes or undernutrition rather than children’s individual contextualized risk. We aimed to identify readily assessable child-level characteristics that can predict child mortality risk in a range of community and healthcare settings in high-burden settings.MethodsWe analysed pooled data from 33 cohorts including 75,287 children under five years of age living in low resource settings to estimate the absolute risks of death associated with risk exposures separately and combined with anthropometry. Children were grouped according to population types studied: general population (GP), selected on anthropometric criteria (A-S), and selected on the presence of illness (I-S).FindingsDuring a total of 69,085 child-years of follow-up in the pooled dataset, 2,805 (3.7%) children died. Age <24 months, low anthropometry, preterm birth, low birthweight, and absence of breastfeeding were each associated with increased mortality: risks were additive and declined with increasing age. However, overall mortality and the association between child-level characteristics and mortality differed according to the type of study population and child age.InterpretationRisk assessments combining individual child-level characteristics including anthropometry can enable programmes to identify children at high and lower risk of mortality and, thereafter, differentiate care accordingly. Such a strategy may reduce mortality and optimise health system efficiency and effectiveness.
DeepDrug: An Expert-led Domain-specific AI-Driven Drug-Repurposing Mechanism for Selecting the Lead Combination of Drugs for Alzheimer’s Disease
Authors: Li Victor OK , Han Yang , Kaistha Tushar , Zhang Qi , Downey Jocelyn , Gozes Illana , Lam Jacqueline CK 
Published: July 2024

AbstractAlzheimer’s Disease (AD) significantly aggravates human dignity and quality of life. While newly approved amyloid immunotherapy has been reported, effective AD drugs remain to be identified. Here, we propose a novel AI-driven drug-repurposing method, DeepDrug, to identify a lead combination of approved drugs to treat AD patients. DeepDrug advances drug-repurposing methodology in four aspects. Firstly, it incorporates expert knowledge to extend candidate targets to include long genes, immunological and aging pathways, and somatic mutation markers that are associated with AD. Secondly, it incorporates a signed directed heterogeneous biomedical graph encompassing a rich set of nodes and edges, and node/edge weighting to capture crucial pathways associated with AD. Thirdly, it encodes the weighted biomedical graph through a Graph Neural Network into a new embedding space to capture the granular relationships across different nodes. Fourthly, it systematically selects the high-order drug combinations via diminishing return-based thresholds. A five-drug lead combination, consisting of Tofacitinib, Niraparib, Baricitinib, Empagliflozin, and Doxercalciferol, has been selected from the top drug candidates based on DeepDrug scores to achieve the maximum synergistic effect. These five drugs target neuroinflammation, mitochondrial dysfunction, and glucose metabolism, which are all related to AD pathology. DeepDrug offers a novel AI-and-big-data, expert-guided mechanism for new drug combination discovery and drug-repurposing across AD and other neuro-degenerative diseases, with immediate clinical applications.
Which social media platforms facilitate monitoring the opioid crisis?
Authors: Carpenter Kristy A. , Nguyen Anna T. , Smith Delaney A. , Samori Issah A. , Humphreys Keith , Lembke Anna , Kiang Mathew V. , Eichstaedt Johannes C. , Altman Russ B. 
Published: July 2024

AbstractSocial media can provide real-time insight into trends in substance use, addiction, and recovery. Prior studies have used platforms such as Reddit and X (formerly Twitter), but evolving policies around data access have threatened these platforms’ usability in research. We evaluate the potential of a broad set of platforms to detect emerging trends in the opioid epidemic. From these, we created a shortlist of 11 platforms, for which we documented official policies regulating drug-related discussion, data accessibility, geolocatability, and prior use in opioid-related studies. We quantified their volumes of opioid discussion, capturing informal language by including slang generated using a large language model. Beyond the most commonly used Reddit and X, the platforms with high potential for use in opioid-related surveillance are TikTok, YouTube, and Facebook. Leveraging many different social platforms, instead of a single platform, safeguards against sudden changes to data access and may better capture all populations that use opioids than any single platform.TeaserTikTok, Facebook, and YouTube may complement Reddit and X as text sources to monitor trends in the opioid epidemic.