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Pre-existing pathogen-specific antibodies shape vaccine outcomes, yet their impact on local reactogenicity and qualitative features of the immune response are not fully defined. In this prospective human cohort receiving seasonal influenza vaccination, high baseline hemagglutinin-specific IgG1 levels were associated with more pronounced local thermal responses at the vaccinated arm and greater vaccine-induced antibody levels. These IgG antibodies formed immune complexes with hemagglutinin, activated complement and enhanced Fc-receptor-dependent monocyte activation and phagocytosis in vitro, connecting pre-existing immunity to innate activation and local reactogenicity. Despite higher antibody levels and early plasmablast responses in subjects with strong thermal reactogenicity after vaccination, we observed lower avidity and hemagglutinin-inhibition capacity, suggesting extrafollicular responses. T cell responses were unaltered. These findings support a model in which pre-existing hemagglutinin-specific IgG may contribute to local thermal reactogenicity and qualitative features of the vaccine response through immune complex-mediated pathways, providing a framework for how prior immunity may shape human vaccine responsiveness.

The Mediterranean Diet (MD) is a dietary pattern associated with reduced chronic disease risk and increased longevity. This systematic review and meta-analysis aimed to evaluate the association between adherence to the MD and frailty and disability among older people. A comprehensive literature search was conducted in PubMed/MEDLINE, Cochrane Library, Embase, and Scopus (search date: February 28, 2024) without date restrictions. Observational and interventional studies examining the association between MD adherence (measured by any validated score) and frailty or disability, using any definition, and their complications were included. Study selection and data extraction were performed independently by pairs of reviewers using Covidence. Risk of bias was assessed using the Newcastle-Ottawa Scale. Random-effects meta-analysis was conducted, estimating pooled relative risks (RRs) per 1-point increment in MD adherence score. Heterogeneity was assessed using the I² statistic, and publication bias was evaluated by funnel plot. Certainty of evidence was graded using the NUTRIGRADE approach. Out of 1361 screened records, 19 observational studies were included. Higher MD adherence was associated with a lower incidence (9 cohort studies, n = 94 072 participants; OR = 0.95, 95% CI: 0.93-0.97; moderate certainty of evidence) and prevalence (6 cross-sectional studies, n = 12 277participants; OR = 0.94, 95% CI: 0.90-0.98; low certainty of evidence) of frailty. The association with disability was present only for prevalence (OR = 0.98; 95% CI: 0.97-0.98). Higher adherence to the MD is associated with a reduced presence of frailty and disability in older adults. These findings support public health strategies promoting the MD as a sustainable dietary model for healthy longevity.

Acute-on-chronic liver failure (ACLF) is a life-threatening condition characterized by acute hepatic decompensation, multi-organ failure, and high short-term mortality in patients with liver cirrhosis. A hallmark of ACLF is profound deterioration of the immune system, which contributes to organ-specific excessive inflammation and immune dysfunction, predisposing patients to infection and multi-organ failure. This review aims to elucidate the cellular and molecular mechanisms underlying systemic immune dysfunction in ACLF, highlighting key pathophysiological pathways and their clinical significance. We provide an overview of ACLF including its global prevalence and clinical significance, against the background of the underlying immune dysfunction in its pathogenesis. The discussion focuses on innate immune alterations, such as impaired neutrophil and monocyte phagocytosis, excessive neutrophil extracellular trap (NET) formation, and monocyte/macrophage dysfunction contributing to immuneparesis and exaggerated inflammation, respectively, which evolve in an organ-specific manner. Dysregulation of natural killer (NK) cell cytotoxicity and adaptive immune dysfunction, including changes in T cell subpopulations and B cell antibody production in ACLF, are discussed. We further dissect the emerging evidence of molecular pathways driving dysfunction of immune cells and their impaired ability to control infections in ACLF, emphasizing the roles of pathogen- and damage-associated molecular patterns (PAMPs/DAMPs), toll-like receptor (TLR) signaling, oxidative stress, mitochondrial dysfunction, epigenetic/metabolic reprogramming and immune checkpoint molecules. The review expands on immune cell communication within the immune system (innate and adaptive), with other non-parenchymal and parenchymal cells and at the inter-organ level, detailing interactions between immune cells of key organs and compartments affected during ACLF, including the liver, circulation, brain, gut and kidney. Finally, we summarize the latest preclinical and clinical findings exploring biomarkers of immune dysfunction and immunomodulatory therapeutic strategies aimed at restoring immune homeostasis in patients with ACLF.

Intrinsic apoptosis is a form of programmed cell death that underpins development, tissue homeostasis and stress responses across Metazoa. In roundworms (nematodes), the pathway was first genetically defined in the free-living nematode Caenorhabditis elegans, yet how it has diversified and operates across the phylum Nematoda, encompassing parasites of humans and animals spanning clades IV, remains incompletely resolved. Here, we synthesise comparative genomic, structural and functional evidence to establish a framework for intrinsic apoptosis in nematodes. Although the core CED-9-CED-4-CED-3 module is broadly retained, regulatory wiring and developmental deployment remain largely uncharacterised beyond C. elegans. Unlike vertebrates, nematodes lack a canonical BAX/BAK-driven mitochondrial permeabilisation system, revealing what we term the "Nematode Apoptosis Paradox" - caspase activation in the absence of the mitochondrial amplification step central to vertebrate intrinsic apoptosis. This alternative regulatory configuration, coupled with structural divergence of nematode BCL-2-like proteins from their vertebrate homologues, suggests a distinctive evolutionary trajectory for apoptotic regulation in Nematoda. By integrating evolutionary cell biology with emerging structural and pharmacological insights, we define a conceptual framework for interrogating apoptosis across clades IV and evaluate its potential as a target for anthelmintic discovery.

Immune checkpoint inhibitors (ICI) have transformed the treatment of metastatic malignancies, yet only 20-40% of unselected patients benefit. Peripheral blood could offer a minimally invasive and dynamic source for predictive biomarkers of ICI therapy.This study evaluated circulating immune cell frequencies and phenotypes before and during ICI therapy to identify tumor-agnostic blood-based biomarkers. We analyzed routine blood immune cell counts in a retrospective cohort of 202 patients treated with ICIs. Next, we investigated the findings in a prospectively collected cohort of 45 patients using multiparametric flow cytometry for characterization of immune cell subsets. We considered early radiological response, progression-free survival (PFS), and overall survival (OS) as clinical outcomes.Higher pre-treatment monocyte and lower lymphocyte counts were consistently associated with inferior PFS and OS but not with early radiological response in the retrospective cohort. In the prospective cohort, detailed immunophenotyping identified elevated pre-treatment frequencies of intermediate (CD14⁺CD16⁺) monocytes as a marker of poorer PFS and OS. Within lymphocyte subsets, higher T cell frequencies were associated with better OS, and a higher pre-treatment frequency of CD226-expressing CD8⁺ memory T cells with better ICI response. ICI therapy induced increase in TIGIT+CD8+ and CD4+ memory T cell subsets, regardless of treatment response.In conclusion, elevated pre-treatment levels of blood monocytes, together with decreased levels lymphocytes, were associated with poor survival of ICI-treated patients. Although detailed immunophenotyping of pre-treatment blood immune cell populations showed limited predictive utility, specific subpopulations, such as intermediate monocytes and CD226⁺CD8⁺ memory T cells, may harbor potential as prognostic/predictive indicators.

To achieve adequate symptom control, patients with allergic rhinitis (AR) often need to increase their medication dose or add other treatments (co-medication). We aimed to perform a systematic review to compare the efficacy and safety of AR medications for increased dose versus co-medication. We searched four bibliographic databases and three trial databases for randomised controlled trials assessing the effect of intranasal and/or oral medications in patients of all ages with seasonal or perennial AR. We performed pairwise meta-analysis based on direct evidence to compare (i) non-standard versus standard treatment doses, and (ii) co-medication strategies versus monotherapy using standard doses. Furthermore, we fitted dose-response network meta-analysis (NMA) to obtain projected estimates for comparisons involving two times the standard dose of AR medications in monotherapy versus co-medication with the standard dose of the same medications. We assessed the certainty of evidence using GRADE for NMA. We included 262 studies. Co-medication schemes involving oral antihistamines (OAH) + intranasal corticosteroids (INCS) resulted in higher improvements of nasal symptoms and quality of life than doubling the dose of OAH. However, doubling the dose of intranasal medications led to better results than having intranasal medications + OAH. Doubling the dose of INCS was associated with higher efficacy than adding intranasal antihistamines (INAH). No relevant safety differences were found between treatment strategies. Results favoured (i) doubling the dose of intranasal medications versus adding OAH, and (ii) adding INCS to OAH over doubling the dose of OAH. This study will inform the ARIA-EAACI 2024-2025 guidelines.

Mesomelic dysplasia Savarirayan-type or ID4-related (MDST) is an ultra-rare skeletal dysplasia caused by chromosome 6p22.3 microdeletions. To date, only four cases have been reported. Here, we report a fifth case, a 9 year-old female with severe mesomelic lower limb shortening and characteristic radiographic findings, highly resembling those identified in previous MDST patients. No deletion was identified by array. However, whole genome sequencing (WGS) revealed a de novo inversion at 6p22.3. As hypothesized for deletions detected in this disorder we predict that the structural variant disrupts several topologically associated domains (TADs) in the region and is likely to place ID4 in closer proximity to more telomerically located limb enhancers, which could result in enhancer adoption and potentially lead to ID4 limb misexpression. Thus, this case broadens the genetic spectrum in MDST and provides further support to the role of ID4 dysregulation as the main underlying molecular mechanism of this ultra-rare skeletal disorder.

Although artificial intelligence (AI) models have demonstrated high accuracy in diagnosing Parkinson's disease (PD) from speech signals, their "black-box" nature prevents mechanistic understanding of vocal impairment, limiting clinical trust and utility. A paradigm shift from correlation-based explanation to causal reasoning is needed to unlock the potential of AI in computational medicine. We propose the Voice Causal Generative Model (VCGM), a novel computational framework designed to infer physiologically plausible causal pathways from observational speech data. The core technical innovation of VCGM is the integration of biophysical knowledge as hard constraints within a linear non-Gaussian acyclic model. We formalize this in Theorem 1, which proves that these domain-specific hierarchical constraints guarantee the unique identifiability of the underlying causal structure, a condition unachievable by unconstrained methods. We implemented VCGM using a constrained DirectLiNGAM algorithm and conducted rigorous validation, including bootstrap analysis for stability, an ablation study, and comparison with traditional causal discovery algorithms. The VCGM uncovered a stable, medically plausible causal pathway for PD dysphonia. The model revealed a hierarchical cascade from disease status to physiological instability (e.g., the robust Shimmer→HNR pathway) and finally to acoustic distortion (e.g., HNR→MFCC2). VCGM reduced physiologically implausible edges by 100% compared to unconstrained LiNGAM (5 implausible edges) and GES (5 implausible edges). while a conventional SHAP-based associative model failed to provide any directional mechanistic insights. The VCGM provides a validated, "white-box" framework for deconstructing pathophysiology from complex biosignals. Its primary technical contribution is a provably identifiable modeling approach that makes causal discovery feasible and reliable in hierarchically structured domains. It marks a critical step from the associative "what" to the causal "why" in computational biomedicine, offering a blueprint for more transparent, trustworthy, and clinically insightful AI systems. To facilitate clinical translation and reproducibility, all code and data are publicly available under an open-source license.

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RNA modifications regulate post transcriptional gene expression, yet most computational methods model each modification independently and overlook competition among modification types at a single site. We present EvoRMD, a biologically contextualized and interpretable framework for RNA modification prediction. EvoRMD combines RNA language model embeddings with structured metadata, including species, organ, cell type, and subcellular localization, and uses attention to identify informative sequence positions. A shared multiclass classifier produces context conditioned predictions across 11 modification types. EvoRMD achieves strong performance and provides interpretable insights through attention patterns and motif analyses, supporting biologically grounded prioritization of candidate RNA modifications.

Photothermal therapy (PTT) holds transformative potential for precision cancer treatment, yet clinical translation remains constrained by the scarcity of molecularly defined, biocompatible, and efficiently NIR-absorbing photothermal agents (PTAs). Here we report a rational donor-acceptor-donor (D-A-D) framework that delivers ultrasmall organic PTAs with record photothermal conversion efficiencies (49.8%) and intrinsic immunogenic cell death (ICD) activity. The design exploits 6,7-diphenyl-[1,2,5]thiadiazolo[3,4-g]quinoxaline as a π-extended, multi-nitrogenated acceptor core flanked by trifluoromethyl groups to deepen the LUMO, while methoxylated triphenylamine donors intensify intramolecular charge-transfer and suppress radiative decay. Nanoprecipitation furnishes monodisperse nanoparticles that exhibit intense NIR-II absorption, exceptional photostability across five hyperthermic cycles, and lysosome-directed uptake. In vitro, single-dose FTPA NPs plus 808-nm laser irradiation trigger mitochondrial depolarization, G0/G1 arrest, and apoptosis in > 70% of 4T1 cells while releasing abundant ATP and surface calreticulin-canonical ICD signals. A prophylactic vaccination model corroborates these molecular cues: mice primed with FTPA-NP-treated tumor cells reject contralateral challenge, achieving > 90% long-term survival, expansion of cytotoxic CD8+ T cells (≈ 70% activation), and suppression of Tregs (≈ 3%). No systemic toxicity or off-target pathology is observed. This study establishes a chemically tunable, metal-free PTA platform that synergizes thermal ablation with systemic anti-tumor immunity, providing a versatile scaffold for next-generation precision immuno-photothermal medicine.

Nonribosomal peptides are diverse natural products with important applications in medicine and agriculture. Bacterial and fungal genomes contain thousands of nonribosomal peptide biosynthetic gene clusters (BGCs) of unknown function, providing a promising resource for peptide discovery. Core structural features of such peptides can be inferred by predicting the substrate(s) of adenylation (A) domains in nonribosomal peptide synthetases (NRPSs). However, existing approaches to A domain prediction rely on limited data sets and often struggle with domains selecting large substrates and domains from underrepresented taxa. Here, we systematically curate and computationally analyze 3653 A domains and present two high-accuracy specificity predictors, PARAS and PARASECT. A type of A domain with unusually high l-tryptophan specificity was identified through the application of PARAS. Cloning and expression of the biosynthetic gene cluster encoding the NRPS showed that it directs the biosynthesis of tryptopeptin-related metabolites in Streptomyces species. Together, these technologies will accelerate the characterization of novel NRPSs and their metabolic products. PARAS and PARASECT are available at https://paras.bioinformatics.nl.

This study evaluates the applicability of the Iscan method to Post-Mortem Computed Tomography (PMCT) for age estimation through morphological analysis of the sternal end of the fourth right rib. Employing a double-blind design, two observers independently assessed a sample of 112 fragments of fourth ribs from individuals of European origin, isolated and processed before CT imaging. The findings indicate that Iscan's method applied via CT scans demonstrates strong reproducibility and substantial inter-operator reliability, as shown by weighted Cohen's kappa values ranging from 0.75 (inter-operator) to 0.92-0.98 (intra-operator). The method exhibited higher accuracy and consistency for middle-aged and older individuals, particularly in phases 3 to 5, whereas younger and elderly age groups showed lower reliability, with phase 8 requiring further refinement due to significant variability. Furthermore, the study introduced and evaluated a new CT-specific parameter-joint fossa sclerosis-to enhance age-at-death predictions. Regression analysis incorporating this parameter demonstrated improved accuracy and refined age-range estimations, particularly highlighting sex-specific variations: in males, sclerosis tended to shift estimates toward higher age phases, while in females, it primarily improved precision within established phase limits without significantly altering phase assignments. These observations underscore potential sex-based differences in bone remodeling dynamics that influence the Iscan phase classification. This research paves the way for future identification, introduction, and refinement of additional morphological parameters aimed at enhancing predictive accuracy. The substantial age-range overlaps inherent to Iscan's traditional method significantly limit its practical forensic applicability, emphasizing the need for methodological advancements to ensure reliable and accurate age estimation in forensic settings.

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The coral holobiont functions as a complex biogeochemical system, sustained by intricate metabolic exchanges between the host and its associated microbiome. While the taxonomic diversity of these communities is well documented, the specific metabolic roles and biogeochemical contributions of microorganisms across distinct coral compartments, particularly within the endolithic habitats, remain poorly understood. Using RNA-seq, we investigated the active microbiome of healthy stony coral Porites lutea, focusing on the coral tissue, the green endolithic algal layer (Ostreobium layer), and the deeper coral skeleton. We identified distinct, metabolically active communities within these compartments and highlight substantial metabolic redundancy across carbon, nitrogen, and sulfur pathways. Our study provides the first transcriptomic evidence of Ostreobium's ability to transfer fixed carbon to other holobiont members and the coral host. We highlight the critical roles of diverse coral holobiont members in nutrient cycling and maintaining homeostasis through scavenging of reactive oxygen and nitrogen species. This study provides a novel molecular-level understanding of the functional roles played by diverse coral holobiont members in their respective compartments and underscores that corals harbor distinct microbiomes with wide-ranging functions. Video Abstract.

Innovative biomaterials are playing an increasingly important role in biomedicine as drug-delivery carriers, tissue-repair scaffolds, and beyond. However, effective approaches for in situ, longitudinal monitoring of lesion initiation and progression in vivo during biomaterial-based interventions remain limited. Magnetic resonance imaging (MRI) offers high spatial resolution and excellent soft-tissue contrast. Here, gadolinium ions (Gd3⁺) were incorporated into a double-network gelatin methacryloyl (GelMA) hydrogel microsphere platform for photothermal-chemotherapy. Monodisperse microspheres were fabricated via microfluidics and photocrosslinking to construct an MRI-visible biomaterial for pancreatic cancer treatment, enabling non-invasive, real-time tracking of both the material and therapeutic response. The microsphere morphology and photothermal performance were characterized by transmission electron microscopy (TEM), scanning electron microscopy (SEM), spectroscopy, and photothermal measurements, and a pancreatic cancer model was established for in vivo evaluation. Following in-situ injection of the hydrogel microspheres, serial MRI was performed to monitor intratumoral distribution and treatment outcomes. The microspheres exhibited an MRI contrast half-life of 32 h and supported continuous MR monitoring for 15 days, allowing clear visualization of tumor evolution. In addition, the system demonstrated favorable in vivo safety with no evident toxicity.

PSD95, a member of the membrane-associated guanylate kinase family, plays a key role in synaptic transmission. In this multidomain protein, the third PDZ domain has a complex regulatory mechanism that modulates its binding of carboxyl-terminal sequences. Phosphorylation of Tyr397, located in the additional α3 helix of this PDZ domain, has been shown to affect the domain's binding affinity. To explore the molecular basis of these changes in affinity, the crystal structure of the mutant Tyr397Glu, a point mutation intended to mimic phosphorylated tyrosine, has been determined. The crystal structure of this mutant reveals conformational changes induced by the introduction of a negative charge into the extra-domain α3 helix, suggesting communication between distant secondary-structure elements that may affect the binding affinity of this domain. Additionally, DSC folding studies show a noticeable decrease in the mutant's stability, indicating significant conformational changes. Altogether, the experimental results included in this work demonstrate that α3 is part of an electrostatic network that regulates stability and conformational changes at distant sites, including the β-hairpin at the binding site.

The synergistic use of silver nanoparticles (AgNPs) and photosensitizer's offers promise biomedical improvements. This study assesses and creates the potential for photosensitizers (Chlorine e6 (Ce6), Methylene Blue (MB)) and Silver Nanoparticles to work together to enhance biological activity. AgNPs were created by the laser ablation method and characterized using methods including scanning electron microscopy (SEM), Fourier transform infrared (FTIR) spectroscopy, and X-ray diffraction (XRD).The antibacterial and anticancer properties of these nanoparticles, both individually and in combination with photosensitizers, were further examined. AgNPs were combined with Methylene Blue and Chlorine e6 to enhance their antibacterial activity against Gram-negative bacteria, such as Salmonella enteritidis, Pseudomonas aeruginosa, and Acinetobacter baumannii, resulting in inhibition zones of up to as large as 0.66 ± 057 mm. The anticancer properties of the combination therapy were also examined against MCF-7 breast cancer cells, where Chlorine e6 alone had an IC50 of approximately 231.2%. Another photosensitizer, Methylene blue, showed a dose-dependent reduction in cell viability, with an IC50 of around 6.52 ± 3.26%. When AgNPs and Methylene Blue combined, the IC50 decreased to 11.42 ± 5.71, indicating a synergistic increase in cytotoxicity. Similarly, Chlorine e6 and AgNPs together significantly decreased the IC50 to 80µM to 100 µM. These findings show that the combined use of Methylene Blue or Chlorine e6 with AgNPs greatly improves anticancer and antibacterial efficacy compared to their individual applications. This research highlights how AgNPs and photosensitizers have the ability to change treatment approaches by providing improved specificity and efficacy in biomedical applications.

Aplastic anemia (AA) results from T-cell-mediated destruction of hematopoietic stem and progenitor cells (HSPCs), driving clonal hematopoiesis via loss of human leukocyte antigen (HLA) risk alleles (HLA loss-of-function mutations or uniparental disomy 6p, UPD6p), paroxysmal nocturnal hemoglobinuria and clonal hematopoiesis of indeterminate potential (CHIP) mutations. Here genomic profiling of 619 patients with AA revealed clonal hematopoiesis in 69% of cases, with ASXL1, BCOR and BCORL1 identified as the most frequent CHIP mutations in pediatric cases. Single-cell multi-omics analysis of 304,902 cells from 48 samples uncovered complex branching clonal architecture, with a median of three HLA loss events per patient, converging to inactivate HLA risk alleles. Single-cell whole-genome sequencing (WGS) resolved up to 15 HLA loss clones per patient and phylogenetic reconstruction indicated that these clones originated years before diagnosis. Long-read WGS precisely mapped UPD6p breakpoints and HLA methylation. HLA loss conferred a protective effect against CHIP, evidenced by their near-absent co-occurrence. Longitudinal single-cell analysis demonstrated that long-lived clones were enriched in the CD34+ HSPC compartment. These findings reveal parallel evolutionary pathways used by hematopoietic cells to evade immune attack.