julilili42/papers huggingface dataset:
Antiviral and immunomodulatory effect of zapnometinib in animal models and hospitalized COVID-19 patients
2025-09-22

Introduction In severe COVID-19, direct-acting antiviral drugs were not effective in hyperinflammatory stages and steroid treatment may weaken host immunity. The MEK inhibitor zapnometinib, as a host-targeting drug, has demonstrated promising efficacy against severe acute viral infections. Proof-of-concept for the innovative approach was presented in a clinical Phase 2 trial with hospitalized COVID-19 patients. Methods The antiviral and immunomodulatory potential of zapnometinib was investigated in samples obtained from COVID-19 patients enrolled in a Phase 2 clinical trial (RESPIRE), as well as in a SARS-CoV-2 Syrian hamster model, an acute lung injury mouse model, and in cell culture. The antiviral activity of zapnometinib was assessed using viral load reduction assays and RT-qPCR. Cytokines and chemokines were analyzed via ELISA and RT-qPCR. Alterations in T and B cells from COVID-19 patients were analyzed using flow cytometry. Biomarker analysis in hamster serum was conducted to monitor potential toxic effects. Results Zapnometinib reduced SARS-CoV-2 viral load in hospitalized COVID-19 patients, in the hamster model and in various highly pathogenic coronaviruses in vitro . Pro-inflammatory cytokines and chemokines decreased in COVID-19 patients, in a lung injury mouse model, and in vitro in primary human blood cells treated with zapnometinib. In the hamster model, zapnometinib alleviated SARS-CoV-2-mediated lung pathology. In patients with COVID-19, zapnometinib increased T and plasma B cells. Conclusion Unlike direct-acting antivirals, zapnometinib’s dual effect highlights its therapeutic potential in the treatment of severe acute viral infections, with favorable antiviral and immunomodulatory properties.
UCL-MetIsoLib: A Public High-Resolution Tandem Mass Spectrometry Library for HILIC-Based Isomer-Resolved Profiling of Glycolysis, Central Carbon Metabolism, and Beyond in Urine, Plasma, Tissues, Cells, and Patient-Derived Organoids
2025-09-22

We present UCL-MetIsoLib, a publicly accessible high-resolution tandem mass spectrometry (HRMS/MS) library developed for HILIC-based, ion-pairing-free, isomer-resolved metabolomics using a bioinert UHPLC system and the Acquity Premier BEH Amide column. The platform integrates two complementary methods operating under distinct chromatographic conditions (pH 3.5, ESI<sup>+</sup>; pH 11.0, ESI<sup>-</sup>), enabling broad metabolic coverage. A total of 334 metabolites are annotated in the library structure, with thiol derivatization incorporated into the extraction protocol to mitigate redox-driven artifacts. Metabolite identification is supported by 245 authentic reference standards and curated according to MSI Level 1 and Level 2 criteria. Validation followed FDA guidelines for bioanalytical method validation across five biological matrices─urine, plasma, tissues, cells, and patient-derived colorectal organoids. The method demonstrated high precision (<15% RSD intra/inter-day) and recovery (85-115% across all QC levels). To demonstrate biological applicability, UCL-MetIsoLib was applied to a case study comparing healthy and colorectal cancer-derived organoids. The method enabled confident annotation of metabolite isomers, including key glycolytic intermediates such as DHAP and GA3P, as well as sugar phosphates from the glycolysis and pentose phosphate pathways. Metabolic alterations were observed in tumor organoids, including accumulation of nucleotide derivatives and shifts in central carbon metabolism. The library is constantly under expansion and is freely available in its latest version at: https://github.com/kserafimov10/UCLMetIsoLib.
Enhanced Polarity of Sulfonamide Metformin Derivatives Increases Cellular Uptake and Apoptosis-Inducing Effects in Human Breast Cancer Cells
2025-09-22

Multitarget agent metformin, a compound originally developed as an antidiabetic agent, has been extensively studied as a repurposed medicine for various diseases. Over the past few decades, the mechanisms by which metformin is transported across cell membranes have also been identified. These include various solute carriers (SLCs), such as plasma membrane monoamine transporter (PMAT), organic cation transporters 1-3 (OCT1-3), and multidrug and toxin extrusion 1-2 (MATE1-2), which can facilitate the bidirectional transport of metformin depending on the cell type. Since metformin is a highly polar and easily excreted compound, more lipophilic derivatives and prodrugs of metformin have been, in turn,developed to improve the targeted delivery, e.g., into cancer cells. However, the required interactions of novel metformin derivatives with cationic transporters are not yet well understood. In the present study, the cellular uptake of nine metformin sulfonamides with various polar substituents was explored in human breast adenocarcinoma cell lines, MCF-7 and MDA-MB-231. The interactions of the novel derivatives with OCT1 and OCT3 were investigated by docking and molecular dynamics simulations. Curiously, the highest cellular uptake was achieved with a compound that effectively released metformin and thus behaved as a prodrug (compound <b>6</b>). This highlights that despite the molecular interactions with the protein, the greatest driving force into the cancer cells was the intracellular bioconversion. Subsequently, the cell viability and apoptosis-inducing effects of the most effectively uptaken compounds were evaluated, which revealed, in turn, that the prodrug approach may not be the most efficient strategy to attain anticancer effects with metformin. Some more stable metformin derivatives with polar substituents were many times more effective in inducing apoptosis with smaller intracellular concentrations compared with metformin released from the prodrug <b>6</b>. Therefore, the rational design of novel metformin derivatives should focus on analogical structures of metformin with functionalities that can increase apoptosis-inducing effects while maintaining appropriate interactions with transmembrane proteins, and thus, have a balanced cellular uptake. The polar ring substituents in the sulfonamide moiety of metformin sulfonamides may offer a potential solution.
Expression of mecA increases daptomycin tolerance in Staphylococcus aureus
2025-09-22

ABSTRACT Staphylococcus aureus is a leading cause of bacteremia, and infections caused by methicillin-resistant S. aureus (MRSA) strains are especially challenging to treat. MRSA strains are resistant to front-line beta-lactams due to PBP2a, a low-affinity penicillin-binding protein encoded by mecA . Daptomycin is used to treat MRSA infections but is not always effective. While daptomycin resistance has been well studied, the ability of S. aureus to tolerate daptomycin, a feature likely to slow clearance of the bacteria from the bloodstream, is less well understood. Here, using a panel of clinical bacteremia isolates, we show that MRSA strains are more tolerant of daptomycin than methicillin-susceptible S. aureus (MSSA) strains. This difference in tolerance is due to mecA and is independent of any changes in surface properties previously associated with altered daptomycin susceptibility. Instead, using a mecA transposon mutant, we found that a lack of this gene led to higher activity of the Agr quorum sensing system, resulting in an increased release of the phenol-soluble modulin toxins. Increased levels of these surfactant-like toxins prevented daptomycin from being inactivated by lipids released by the bacteria, leading to reduced antibiotic tolerance. Additionally, the clinical MRSA strains tested produced lower levels of toxins than the MSSA strains and inactivated daptomycin to a greater extent, explaining their enhanced tolerance. The expression of mecA in clinical MSSA strains reduced toxin production, increasing daptomycin inactivation and thereby enhancing tolerance. Together, these results demonstrate that mecA not only affects beta-lactam susceptibility but also compromises the efficacy of the last resort antibiotic daptomycin. IMPORTANCE The incidence of Staphylococcus aureus bacteremia is on a steady incline in many parts of the world. Given the associated mortality rates have changed little in the last 10 years, this is a major health concern. One contributing problem is that antibiotics effective against the bacteria in vitro are failing to cure many patients, e.g., the use of daptomycin to treat methicillin-resistant Staphylococcus aureus (MRSA) infections. Here, we present a mechanistic study that may explain why this occurs. The expression of mecA , which confers the methicillin resistance of MRSA, reduces Agr activity, and this decreases the release of phenol-soluble modulins from the bacteria. Without these, the phospholipids that can block daptomycin activity are free to do so, rendering MRSA less sensitive to both antibiotics. This study, bridging clinical and molecular biology, provides an explanation for a significant clinical problem and may inform how antibiotic combinations should be managed in future trials.
Beyond BRCA deficiency: Clinical and molecular predictors of survival in patients with BRCA-deficient tubo-ovarian high-grade serous carcinoma
2025-09-22

ABSTRACT BRCA -associated homologous recombination deficiency (HRD) is present in ∼50% of high-grade serous carcinomas (HGSC) and predicts sensitivity to platinum-based therapy. However, there is little understanding of why some patients with BRCA -deficient tumors experience unexpectedly poor outcomes. We profiled 154 tumors, enriched for patients with BRCA -deficient tumors that experienced short overall survival (≤3 years, n=42), using whole-genome, transcriptome, and methylation analyses. All but one BRCA -deficient tumor exceeded an accepted HRD genomic scarring threshold. However, patients with BRCA1 -deficient HGSC with a more elevated HRD score survived significantly longer. Patients with BRCA2 -deficient HGSC and loss of NF1 survived twice as long as those without NF1 loss, whereas PIK3CA or RAD21 amplification defined BRCA2 -deficient HGSC with exceptionally short survival. BRCA1 -deficient tumors in short survivors had evidence of immunosuppressive c-kit signaling and EMT. In a large HGSC cohort (n=1,389) including 282 individuals with pathogenic germline BRCA variants (g BRCA pv), the location of the mutation within functional domains stratified clinical outcomes. Notably, residual disease after primary surgery had limited prognostic effect in g BRCA pv-carriers compared to non-carriers. Our findings indicate that tumor HR proficiency in the context of therapy response and survival is not a binary property, and highlight genomic and immune modifiers of outcomes in BRCA -deficient HGSC.
Association of habitual diet with skeletal muscle composition in a cross-sectional, population-based imaging study
2025-09-23

Abstract Background Skeletal muscle health influences overall health and functionality. Nutrition is an important contributor to muscle health, however there is insufficient research on the relation between nutrition and muscle composition, i.e. mass and fatty infiltration, on a population-based level. Objective We aimed to investigate the association of habitual dietary intake of energy-providing nutrients (carbohydrates, fat, protein and alcohol) and of essential amino acids with skeletal muscle fat and muscle area derived by magnetic resonance imaging (MRI) in a sample of middle-aged individuals from a population-based cohort. Methods We analyzed N = 294 individuals (45% women, mean age 56.5 years) from the KORA-MRI study, Southern Germany. Muscle fat (%) and muscle area (cm 2 ) were assessed by a multi-echo Dixon sequence on whole-body MRI. Habitual dietary intake was calculated based on repeated 24 h recalls and a food frequency questionnaire. Correlation analyses and adjusted regression models were calculated. Results Alcohol intake was associated with increased skeletal muscle fat, particularly in men (β = 0.28%, 95% confidence interval [0.10%,0.45%]; p = 0.002) per percent of total energy intake). Protein intake was tentatively associated with lower muscle fat (β=-0.33% [-0.68%,0.01%]; p = 0.052). Accounting for overall protein and energy, specific essential amino acids were tentatively associated with lower muscle fat, e.g. leucine (β=-0.63%, [-1.27%,0.01%]; p = 0.054). Conclusion In middle-aged adults, habitual alcohol and protein intake are associated with fatty infiltration of skeletal muscle. Individualized diet adaptations might improve muscle composition and function.
Effectiveness of CRISPR-Cas in sensitizing bacterial populations with plasmid-encoded antimicrobial resistance
2025-09-23

Abstract The spread of bacteria resistant to antibiotics poses a serious threat to human health. Genes that encode antibiotic resistance are often harbored on plasmids, extra-chromosomal DNA molecules found in bacteria. The emergence of multiresistance plasmids is particularly problematic and demands the development of new antibiotics and alternative strategies. CRISPR-Cas derived tools with their sequence specificity offer a promising new approach to combating antibiotic resistance. By introducing CRISPR-Cas encoding plasmids that target antibiotic resistance genes on plasmids, the susceptibility of bacteria to conventional antibiotics can be restored. However, genetic variation within bacterial populations can hinder the effectiveness of such CRISPR-Cas tools by allowing some mutant plasmids to evade CRISPR-mediated cleaving or gene silencing. In this study, we develop a model to test the effectiveness of CRISPR-Cas in sensitizing bacterial populations carrying resistance on nontransmissible plasmids and assess the success probability of a subsequent treatment with conventional antibiotics. We evaluate this probability according to the target interference mechanism, the copy number of the resistance-encoding plasmid, and its compatibility with the CRISPR-Cas encoding plasmid. Our results identify promising approaches to revert antibiotic resistance with CRISPR-Cas encoding plasmids: A DNA-cleaving CRISPR-Cas system on a plasmid incompatible with the targeted plasmid is most effective for low copy numbers, while for resistance plasmids with higher copy numbers gene silencing by CRISPR-Cas systems encoded on compatible plasmids is the superior solution.
High survival rates and patient satisfaction 12 years after medial open wedge HTO surgery: A prospective cohort study
2025-09-23

Abstract Purpose Medial open wedge high tibial osteotomy (HTO) can delay knee arthroplasty (KA) in patients with medial compartment varus knee osteoarthritis (OA). However, prospectively collected long‐term outcomes and survival rates are limited. The purpose of this study was to assess the survival rate and the outcome following HTO. Methods In this prospective cohort study with initially 120 knees from 112 patients treated from 2008 to 2011 with an HTO, 95 knees from 88 patients (age: 47.0 ± 7.6 years; female: n = 28) were followed‐up. The minimum follow‐up was 12 years or an earlier conversion to KA. The 5‐, 10‐ and 12‐year survival rates were calculated. The Lysholm and IKDC scores were assessed preoperatively and 1.5, 6 and 12 years postoperatively. Results At the last follow‐up (12.9 ± 0.8 (12.0–15.1 years), 67.4% ( n = 64) had no conversion to KA. 31 knees (32.6%; 2 unicompartmental KA, 29 total KA) were converted to a KA on average 7.3 ± 3.3 (1.5–13.0) years after the HTO. The 5‐, 10‐ and 12‐year survival rates were 88.2%, 76.3% and 69.7%. Knees without conversion to KA had significantly higher scores at the last follow‐up compared to preoperatively: The Lysholm score increased from 60.4 ± 21.1 (14.0–91.0) preoperatively to 89.1 ± 12.5 (39.0–100.0), 86.5 ± 13.8 (39.0–100.0) and 82.6 ± 18.3 (30.0–100.0). The IKDC score also increased from 51.8 ± 16.6 (15.0–93.0) preoperatively to 77.7 ± 14.8 (21.0–100.0), 70.9 ± 15.3 (26.0–98.0) and 72.5 ± 18.1 (14.0–95.0) at the corresponding postoperative time points 1.5, 6 and 12‐years. Conclusion HTO to treat varus medial OA showed good long‐term outcomes. Most patients can expect no conversion to KA for more than twelve years and a higher subjective knee function than preoperatively. Level of Evidence Level IV.
Adrenergic Ligands-Induced Transinhibition of EGFR by GPR27 and GPR173 Reveals a Novel GPCR Signaling Mechanism
2025-09-23

<title>Abstract</title> G protein-coupled receptors 27 and 173 (GPR27 and GPR173) are part of the "Super Conserved Receptors Expressed in Brain" (SREB) family, alongside GPR85. While the endogenous ligands and functions of SREB receptors are still unknown, GPR27 has been implicated in insulin secretion and tumorigenesis, whereas GPR173 has been proposed to be a receptor mediating biological effects of phoenixin-20 amide. Here, we show that substituting GPR27’s C-terminal domain with that of the β1 adrenergic receptor (β1AR) yields a chimera with β1AR-like ligand selectivity and cellular functions. Interestingly, stimulation of GPR27 with isoproterenol and adrenergic ligands inhibited epidermal growth factor (EGF)-induced serum-responsive element (SRE) activation, independently of G proteins and β-arrestins, and induced GPR27 internalization.Surprisingly, GPR173 responded exclusively to noradrenaline, showing both inhibition of EGF-induced SRE activity and receptor internalisation, whereas GPR85 remained unresponsive to the tested adrenergic ligands. Taken together, these intriguing findings suggest that GPR27 and GPR173 respond to adrenergic ligands to transinhibit EGFR through a unique and atypical signaling mechanism, previously undescribed for any known GPCR. Moreover, we provide the first evidence of ligand-induced functional transinhibition of a receptor tyrosine kinase, such as EGFR, by a GPCR, opening new research lines with translational potential.
Medical Artificial Intelligence
2025-09-23

Abstract As a scientific discipline, medicine has always sought to incorporate new technological and scientific advances from other fields. Computer science is no exception. Breakthroughs in artificial intelligence (AI) are about to revolutionize clinical medicine. Although ethical and epistemic issues raised by AI are gaining increasing traction by philosophers, the relevant debate is still in its infancy. This chapter sets out to navigate the philosophical debate on medical AI by focusing on three problems that currently claim center-stage: opacity, collaboration of AI systems with physicians and patients, and fairness. The chapter also considers what the contribution of philosophy can be—and where the particular challenges for philosophy lie—given the fast-paced research landscape in medical AI.
A Global Speleothem‐Based Assessment of Spontaneous Dansgaard–Oeschger Type Oscillations in Two Isotope‐Enabled General Circulation Models
2025-09-23

Abstract Several general circulation models have now demonstrated the ability to simulate spontaneous millennial‐scale oscillations that resemble Dansgaard–Oeschger (DO) events. It is often unclear how representative of DO events these simulations are, particularly outside of the polar regions. To test this, we directly compare simulated changes from two isotope‐enabled models to a compilation of 111 speleothem records from 67 caves across the low‐ and mid‐latitudes. We find that both models successfully reproduce the observed pattern of changes in Europe and the Mediterranean, Asia, and Central America. However, they perform less well for Western North America, South America, and Oceania, and the simulated changes are also generally too small in their magnitude. Where the models do reproduce the observed changes, we find evidence that the isotopic variability is influenced by both local and remote drivers, but the remote drivers appear more important.
Revealing Plasma Membrane Protein Dynamics in Living Plant Cells with Single-Molecule Tracking
2025-09-23

Abstract The behavior of proteins and other biomolecules in cellular environments is governed by complex molecular processes. Understanding their temporal dynamics and interactions with other biomolecules or cellular structures is essential for elucidating physiological functions. Single-particle tracking photoactivated localization microscopy (sptPALM) has emerged as a powerful single-molecule technique for investigating these processes with exceptional spatial and temporal resolution. In this Expert View, we introduce sptPALM with a special focus on its application in the plasma membrane of plant cells. Key aspects and advances of the technique, including instrumentation and data analysis, are discussed to equip researchers with the foundational knowledge required to establish and execute sptPALM experiments. Recent studies are highlighted to demonstrate the potential of sptPALM to advance our understanding of molecular dynamics in plant cells.
A phase 2b basket trial approach to treat multiple rare and fibrotic skin diseases
2025-09-23

Fibrotic skin diseases are rare, chronic, and often debilitating conditions characterized by excessive extracellular matrix deposition, leading to tissue scarring and functional impairment. Despite their severity, diseases—such as lichen sclerosus et atrophicus (LSA), frontal fibrosing alopecia (FFA), radiation-induced skin fibrosis (RISF), eosinophilic fasciitis (EF), pansclerotic disabling morphea (PDM), and linear circumscript sclerodermia (LCS)—lack approved therapies and are underrepresented in clinical research. This phase 2b multicenter basket trial proposes a novel approach to evaluate a common antifibrotic therapy across these diverse but pathophysiologically related conditions. The trial employs a two-stage Simon design to address the statistical challenges posed by small patient populations, allowing the inclusion of ultra-rare diseases while maintaining analytical rigor. LSA and FFA serve as primary study groups due to higher prevalence, while EF, RISF, PDM, and LCS are included as exploratory arms. The study aims to assess the efficacy, safety, and tolerability of the selected therapy, while also providing mechanistic insights into fibrosis through molecular analyses. The primary endpoint is a ≥ 1-point improvement in the Investigator Global Assessment (IGA) at 24 weeks. Secondary endpoints at 52 weeks encompass quality of life (Dermatological Life Quality Index (DLQI), EuroQol Group Quality of Life Questionnaire (EuroQol five dimensions (EQ-5D))), symptom relief (itch and pain Numeric Rating Scale (NRS)), and disease-specific clinical scores. The trial excludes a placebo arm due to ethical considerations in progressive, untreated diseases but allows rescue therapies for disease progression. This design not only facilitates access to treatment for underserved populations but also leverages shared clinical and molecular features to enhance statistical power. By integrating disease-specific and global outcome measures, the study aims to generate robust evidence for repurposing existing therapies. If successful, this trial could serve as a model for future research in rare fibrotic diseases, accelerating drug development and improving patient outcomes.