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464 papers

The LAV-BPIFB4-Platelet-CD47 Axis: A Novel Mechanism Associated With Immune Resilience in Longevity.

Ciaglia E et al. · Jul 1, 2026

Long-living individuals (LLIs) possess remarkable genetic resilience, characterized by protective variants that confer immune robustness and resistance to age-related diseases. The longevity-associated variant of BPIFB4 (LAV-BPIFB4), enriched in centenarians, demonstrated pleiotropic benefits including reduced inflammation, cardiovascular protection, and immune system rejuvenation. However, the molecular mechanisms underlying these protective effects remain incompletely understood. Here, we revealed that LAV-BPIFB4 fundamentally reshaped the immune features of platelets to establish enhanced immunomodulatory capacity through CD47 upregulation. Of note, centenarians displayed an elevated percentage of circulating CD47 + reticulated platelets (RPs), a condition mimicked by LAV-BPIFB4 carriers which exhibited significantly elevated CD47 levels both on RPs and mature platelets' surface. In agreement with an early acquirement of CD47 overexpression, MEG-01 megakaryoblastic cells overexpressing LAV-BPIFB4 produced CD47-high platelet-sized particles. Functionally, platelets from LAV carriers suppressed monocyte activation and inflammatory cytokine production through CD47-dependent mechanisms, selectively reducing p38 MAPK activation while leaving NF-κB signaling largely unaffected in response to LPS. rhLAV-BPIFB4 administration in vivo increased CD47 on murine platelets and reduced, ex vivo, LPS-induced monocyte activation, validating cross-species therapeutic potential. Critically, rhLAV-BPIFB4 protein phenocopies genetic effects, rapidly increasing CD47 expression on wild-type platelets through cytoskeleton-dependent trafficking mechanisms and conferring enhanced anti-inflammatory capacity. This might represent a translatable strategy to replicate some of the biological features associated with a longevity-associated variant beyond genetic carriers. Our findings establish the platelet-CD47-monocyte axis as a pivotal pathway for healthy aging and reveal recombinant LAV-BPIFB4 as a promising therapeutic approach for managing inflammaging and cardiovascular disease by harnessing the immune-tuning capacity characteristic of exceptional longevity.

Immunology and Microbiology

Population Pharmacokinetics and Pharmacodynamics of Paracetamol in Malaysian Patients With Plasmodium knowlesi Malaria.

Wattanakul T et al. · Jul 1, 2026

Paracetamol may improve renal function in patients with severe Plasmodium knowlesi malaria, particularly in those with acute kidney injury and hemolysis, via inhibition of cell-free hemoglobin mediated oxidative kidney damage. We developed a population pharmacokinetic/pharmacodynamic (PK/PD) model to assess effects of paracetamol on creatinine, hepatotoxicity, fever clearance, and parasite clearance among Malaysian patients with predominantly non-severe knowlesi malaria using data from the PACKNOW trial (Clinical Trials Registration: NCT03056391). A total of 372 patients were included in the PK/PD analyses (paracetamol: n = 183, control: n = 189). Paracetamol PK was described using a prior PK model published in patients with falciparum malaria. The PK/PD demonstrated that higher paracetamol exposures were associated with a faster decline in both creatinine and fever clearance time, supporting its renoprotective and antipyretic effects. Increased paracetamol exposure was not associated with hepatotoxicity or serious adverse events, despite a weak positive association with liver transaminases over time. No significant relationship was observed between paracetamol exposure and parasite clearance. Overall, these findings highlight an exposure-response relationship for paracetamol and a decline in creatinine, supporting its use as a renoprotective drug in treating Plasmodium knowlesi malaria.

Medicine

Unraveling the complex web of acute kidney injury: pathways, biomarkers, and future directions.

Zha C et al. · Jul 1, 2026

Acute kidney injury (AKI), a widespread severe acute condition caused by several factors and characterized by a rapid decline in renal function over a short time, is associated with high incidence and mortality rates worldwide. Investigating AKI signaling pathways is crucial for elucidating its pathogenesis, optimizing diagnostic and therapeutic approaches, and developing novel therapeutic agents. This article comprehensively examines AKI pathophysiological mechanisms, apoptosis-related signaling pathways, and inflammatory response pathways. It analyzes clinical signaling pathways associated with epidemiology, diagnostic technologies, and therapeutic strategies, explores advancements in novel biomarker applications, drug development, and gene editing technologies, and discusses current hot topics and controversies. The study further outlines future research trends, personalized treatment prospects, and potential challenges and opportunities, aiming to provide comprehensive insights into AKI signaling pathway research and lay the foundation for further exploration in related fields.

Medicine

Fragmentation of Long Reads Enables Reliable Mitogenome Assembly From Whole-Genome Amplification Data With Pervasive Palindromic Reads.

Vecchi M et al. · Jul 1, 2026

Whole genome amplification (WGA), and in particular multiple displacement amplification (MDA), has become a key technique for genomic sequencing of microscopic organisms, yet it introduces artefacts such as palindromic (inverted chimeric) reads that may compromise downstream analyses. We assessed how pervasive palindromic reads generated by MDA impact the assembly of tardigrade (Acutuncus giovanniniae and A. mecnuffi) mitogenomes sequenced with Oxford Nanopore technology. We show that the MDA produces a high proportion of palindromic reads, often exceeding one-third of mitochondrial reads and frequently exhibiting complex multi-inversion structures. These artefacts severely impair long-read assembly, leading to low success rates and inconsistent genome reconstruction. To solve this issue, a strategy based on in silico fragmentation of long reads into short, high-quality fragments, followed by short-read assembly, consistently produced complete and accurate circularised mitochondrial genomes. Our results demonstrate that palindromic read formation can be, in some cases, a limitation of MDA coupled with long-read sequencing, but this issue can be mitigated through read fragmentation. This approach provides a simple, robust and scalable solution for mitogenome assembly from data heavily affected by amplification artefacts, particularly in microscopic taxa where whole genome amplification is often unavoidable.

Agricultural and Biological Sciences

COVID-19 Mortality in Swedish Intensive Care Units: A Multicenter Survival Analysis.

Forsberg G et al. · Jul 1, 2026

Background Mortality among critically ill COVID-19 patients has varied globally. In Sweden, geographic differences in mortality have also been observed. The current study aimed to determine whether mortality differences persist after adjusting for differences in case-mix, and to identify potential independent factors contributing to regional variations in mortality. Methods We conducted a multicenter cohort study including adult patients admitted to seven hospital ICUs across three Swedish healthcare counties between March 1, 2020 and July 31, 2021. These ICUs include one university hospital, three county hospitals and three local hospitals, and cover the intensive care infrastructure for approximately one million inhabitants. Patients were assigned to the hospital of initial ICU admission, even if transferred later during the course. Patient characteristics, disease severity, respiratory support, and treatments were registered. Primary outcome was 90-day mortality. A mixed-effects Cox proportional hazards model was used. Results Seven hundred and forty seven patients were included. The unadjusted 90-day mortality varied significantly, with the highest rate at 30%, and the lowest at 8.5% (p Conclusion Among patients admitted to ICU due to COVID-19, we observed a difference in mortality related to the hospital of first ICU admission. This difference persisted after adjustment for calendar time, baseline confounders, and healthcare county. Potential explanations are lacking within the current study. Future studies should focus on comprehensive evaluation of both organizational and contextual determinants of mortality. Editorial comment This analysis from 3 Swedish counties (7 hospitals) for COVID ICU cases presents factors and relations to mortality risk, including factors for first admission to university-larger-, or smaller hospital. An association was observed for higher risk if the first ICU admission was in a smaller hospital, though recognizing that this is a dataset coming from a small set of hospitals.

Medicine

Linking the Pre-Assessment Information Form (PIF) to the ICF: Enhancing Standardized Functional Assessment in Parkinson's Disease.

Rogatto FBT et al. · Jul 1, 2026

Background and purpose Systematic documentation of functioning in people with Parkinson's disease (pwPD) requires a standardized language to enable comparability across services and countries. The International Classification of Functioning, Disability and Health (ICF) provides this framework; however, instruments recommended by the European Physiotherapy Guideline for Parkinson's disease have not previously been linked to its categories. This study aimed to link items from the Pre-Assessment Information Form (PIF) to ICF categories using the refined linking rules. Methods Methodological study. Two independent evaluators with extensive knowledge of the ICF taxonomic framework applied 10 refined linking rules to 26 PIF items, working independently and blindly. Disagreements were resolved by a third evaluator with prior ICF experience. Inter-rater agreement was assessed using the Kappa coefficient (95% confidence interval). Results Initial inter-rater agreement was moderate across all ICF taxonomy levels (k = 0.42-0.54; p Discussion The resulting set of 25 ICF categories provides a structured description of the mobility and body function domains represented in the instrument. The application of ICF qualifiers to grade the severity of patient-reported limitations represents a potential next step, subject to implementation and validation in applied clinical settings.

Medicine

How Hazards Turn Into Disasters: Perspectives of Emergency Responders.

Bhattacharyya A et al. · Jul 1, 2026

Natural hazards like floods, storms, or earthquakes turn into disasters if they hit vulnerable communities and societies. In policy and academia, this understanding has led to a surge of models and risk reduction policies that aim to reduce vulnerability and strengthen resilience. However, it remains unclear which vulnerabilities are the most important, and what stakeholders in different contexts prioritize. To address this gap, this article identifies critical exposure, vulnerability, and coping capacity factors, elicits their priority among emergency responders from different contexts, and analyses their perceived interdependences to understand their cascading potentials. To do that, we conducted a stakeholder survey with experienced disaster and emergency management professionals around the world. The results are used to analyze the perceived relationships between the priority factors via a fuzzy cognitive map. The professionals identified the level of preparedness, exposure to hazard, risk and crisis communication, community engagement, and disaster risk financing as the most important factors. The results show that the most catastrophic disasters are perceived to be caused by a combination of multiple factors and their interdependences. It was also found that practitioners thought that active civil protection agencies and available disaster risk financing have the greatest potential to prevent disasters.

Social Sciences

Getting It Right the Second Time: How Can we Optimize First-Generation Cephalosporin Dosing for Skin and Soft Tissue Infections in the 21st Century?

Ryder JH et al. · Jul 1, 2026

Optimal cephalexin and cefadroxil dosing for skin and soft tissue infections (SSTIs) is unclear. We summarize clinical and pharmacokinetic/pharmacodynamic (PK/PD) data that compare dosing strategies for SSTIs. Additionally, we conduct population PK target attainment simulations for varying doses of cephalexin and cefadroxil for Staphylococcus aureus and Group A Streptococcus. Although some clinical data support lower doses in mild SSTIs, higher doses optimize PK/PD parameters in moderate-severe SSTIs, especially due to Staphylococcus aureus. Further prospective clinical and PK/PD studies, especially in obese adults, would be beneficial.

Medicine

Analytical Robustness and Competing Interpretations in Violent Video Game Research: A Response to Teng and Bushman's (2026) Reanalysis of Lacko et al. (2024).

Lacko D et al. · Jul 1, 2026

Recent debates on violent video game (VVG) effects highlight the importance of analytical robustness and transparency in longitudinal research. Teng and Bushman reanalyzed our prior study, identifying several methodological concerns and arguing that our conclusions were unwarranted. In this response, we examine their reanalysis and assess whether their conclusions hold across alternative analytical specifications and operational decisions. Through comprehensive robustness checks available on OSF, we address concerns regarding model specification, missing data, measurement decisions, and time constraints. We further examine the unexpected empathy-aggression association and alternative VVG operationalizations. While some inconsistencies emerge across different specifications, the results do not consistently support General Aggression Model (GAM) interpretations in this dataset. We further identify inconsistencies and incomplete reporting in Teng and Bushman's presentation of results, data processing procedures, and interpretation of effect sizes. Finally, we argue that the current debate reveals a fundamental theoretical problem: without precise specifications of mechanisms, developmental patterns, and falsifiable predictions, GAM risks unfalsifiability when contradictory findings can all be accommodated as supporting evidence. We advocate for formal modeling approaches to enhance theoretical rigor and predictive specificity in violent media research.

Psychology

Mex-3 RNA-binding family member A limits macrophage ferroptosis-associated injury linked to the SLC7A11/GPX4 pathway in diabetic atherosclerosis.

Ma Y et al. · Jul 1, 2026

Background Diabetes accelerates atherosclerotic plaque expansion and loss of stability, but the plaque-resident mechanisms through which the diabetic milieu promotes macrophage lipid-oxidative injury are not fully understood. Methods We used apolipoprotein E-deficient (ApoE -/- ) mice with Mex-3 RNA-binding family member A (MEX3A) deficiency and primary bone marrow-derived macrophage (BMDM) experiments under diabetic conditions to investigate the role of MEX3A in diabetic atherosclerosis and macrophage lipid-peroxidation injury. Results MEX3A loss worsened diabetic atherosclerosis while leaving body weight, glycaemia and lipid measurements largely unchanged relative to diabetes alone. MEX3A deficiency enlarged aortic lesions, enhanced lipid deposition, increased macrophage content, expanded necrotic cores and thinned fibrous caps, while reducing collagen content. In lesional macrophages, loss of MEX3A coincided with increased lipid reactive oxygen species, malondialdehyde, increased labile iron, 4-hydroxynonenal, a disturbed glutathione redox state, mitochondrial abnormalities compatible with ferroptotic stress, lower GPX4/SLC7A11 and higher ACSL4. CRISPR/Cas9-mediated Mex3a knockout in BMDMs recapitulated this phenotype, whereas restoring MEX3A blunted it. RNA immunoprecipitation-qPCR together with actinomycin D decay analyses demonstrated preferential recovery of Slc7a11 and Gpx4 transcripts with MEX3A and decreased stability of Slc7a11 and Gpx4 mRNAs after Mex3a knockout. GPX4 or SLC7A11 overexpression reduced lipid-peroxidation injury in Mex3a-knockout macrophages, whereas Gpx4 or Slc7a11 knockdown weakened the protection conferred by MEX3A re-expression. Ferrostatin-1 partially attenuated macrophage lipid peroxidation and plaque injury. Conclusions Together, these results place MEX3A among the protective regulators of diabetic plaque stability and support a MEX3ASLC7A11/GPX4-linked ferroptosis-associated mechanism in plaque macrophages. Key points MEX3A deficiency worsens diabetic atherosclerosis without further aggravating systemic metabolic indices. Loss of MEX3A promotes plaque lipid deposition, macrophage accumulation, necrotic core expansion and fibrous cap thinning. MEX3A limits macrophage lipid-peroxidation injury linked to the SLC7A11/GPX4 pathway. Ferrostatin-1 partially attenuates macrophage lipid peroxidation and plaque injury associated with MEX3A deficiency.

Medicine