Search Results (10,691)

Cognitive dysfunction is increasingly recognized as a significant complication of chronic kidney disease (CKD), but the clinical relevance of protein-bound uremic toxins (PBUTs) to cognition remains insufficiently characterized. This cross-sectional analysis included 1217 community-dwelling individuals. Cognitive function was assessed using the Mini-Mental State Examination (MMSE), with scores < 28 indicating possible mild cognitive impairment (MCI). Serum concentrations of five PBUTs—indoxyl sulfate, p-cresyl sulfate, phenyl sulfate, indoleacetic acid, and hippuric acid—were measured, and a composite PBUT score was derived using principal component analysis. Multivariable logistic regression was used to examine the associations of MCI with the PBUT score and with each PBUT. Serum PBUT concentrations increased with advancing CKD stage. The mean MMSE score was 26.7 ± 3.4, and scores progressively declined with advancing CKD stage. A higher PBUT score was independently associated with MCI (coefficient, 0.290 ± 0.077; odds ratio, 1.337; 95% confidence interval, 1.151–1.554; p < 0.001). In conclusion, a greater PBUT burden was independently associated with cognitive impairment. These findings identify PBUT burden as a potential correlate of cognitive impairment in CKD. Prospective studies are needed to clarify its temporal relationship with cognitive decline and to assess whether it provides predictive value beyond established measures of kidney function. Full article

Snake venomics and antivenomics approaches have increasingly relied on mass spectrometry to characterize the venom components and to evaluate the antivenom neutralization potential. However, accurate quantification remains essential for distinguishing biologically relevant toxins from snake venom and for translating proteomic data into meaningful clinical interpretations. This review article examines the role of quantitative analysis in snake venomics and antivenomics, with special emphasis on massspectrometry-based strategies used to estimate toxin abundance. This review summarizes the main applications and limitations of mass spectrometry in venom research covering bottom-up and top-down proteomics, venom databases, toxin quantification, and how MS-based quantification determines the efficacy of antivenom through antivenomics approaches. This review also explains why abundance alone cannot determine the biological or therapeutic importance of a toxin. The article discusses label and label-free based quantification, absolute quantification approaches, top-down venomics, mass spectrometry-based antivenomics, and the integration of proteo-transcriptomic workflows in snake venom research. These approaches can be affected by several factors including the problem of measuring toxin isoforms that share similar protein structures and toxin components that are important for antivenom recognition within complex venom samples. A conceptual overview is provided of how inaccurate quantification can influence venom proteome comparisons among similar and different species, as well as the interpretation of antivenom binding and neutralization potential. Reliable mass-spectrometry-based quantification will be critical for linking the venom composition with toxicity, antivenom performance evaluations in preclinical settings, and evidence-based strategies for snake venom research and snakebite management. Full article

Paralytic shellfish toxins (PSTs), potent neurotoxic alkaloids produced by marine dinoflagellates and cyanobacteria, pose severe risks to human health through contaminated seafood and water after absorption into the bloodstream. Current detection methods are limited by matrix interference or ethical concerns. Here, we report a novel screening approach using vanadium pentoxide as an oxidant to convert PSTs into characteristic oxidation products, followed by high-performance liquid chromatography-tandem mass spectrometry (HPLC‒MS/MS) analysis. Under optimized conditions, vanadium pentoxide oxidizes both hydroxylated and non-hydroxylated toxins into distinct major products (P1‒P7), identified by high-performance liquid chromatography‒tandem high-resolution mass spectrometry (HPLC‒HRMS). Vanadium pentoxide oxidation affords excellent product selectivity and, for most PSTs, superior signal intensities, enabling unambiguous differentiation of toxin subgroups. HPLC‒MS/MS method in MRM mode was developed and yielded detection limits of 0.3‒1.5 ng/mL for a broad spectrum of fourteen PSTs in spiked plasma, accuracy of 89.3‒102.2%, and excellent repeatability with intra- and inter-day relative standard deviations (RSDs) ranging from 0.3% to 10.4%. Application of the method to samples from the First Trial OPCW (the Organisation for the Prohibition of Chemical Weapons) Biotoxin Proficiency Test successfully identified STX/neoSTX, confirming its practical utility for trace PSTs detection in complex biological matrices. Full article

Drug-resistant Klebsiella pneumoniae is a serious clinical problem, and bacteriophages are being investigated again as antibacterial agents. This study describes the phenotypic characterization and a preliminary in vivo evaluation of vB_Kpn_NIIPB-V0006, a bacteriophage isolated locally on a drug-resistant clinical K. pneumoniae strain. The genome of the phage was not sequenced. It has therefore not been screened for lysogeny-associated, toxin, virulence or antimicrobial resistance genes, and the results below describe what the phage does, not whether it is suitable for therapy. We assessed plaque morphology, specific lytic activity, titer, host range on a limited non-target panel, particle morphology, adsorption, one-step growth, chloroform exposure, the frequency of phage-resistant host variants, endotoxin reduction, short-term safety in mice and antibacterial effect in guinea pigs. The phage lysed the target strain, with an Appelman activity of 10⁻⁸ and a titer of 1.7 × 10¹¹ PFU/mL. Processing with 1-octanol lowered endotoxin content from 1200 to 12 EU/mL and preserved 80% of infective activity. Mice given the preparation intraperitoneally showed no mortality and no visible acute toxicity over 14 days. In guinea pigs with systemic K. pneumoniae infection, survival was the primary outcome: 0.5 mL three times daily gave 6/6 survivors against 1/6 in untreated controls (p = 0.015). Splenic bacterial burden, a secondary outcome, was also lower in that group (2.64 against 4.41 log₁₀ CFU/g). Two features of the design bias this second comparison in favor of treatment, since survivors and non-survivors were sampled at different times, and phage being carried over into the plating step is likely to have lowered colony counts. The 1.77 log₁₀ difference should therefore be read as an upper bound. The phage merits further study, but whole-genome sequencing, confirmation of the host species, host-range testing against diverse clinical isolates and a controlled comparison with antibiotic treatment are all needed before any therapeutic claim can be made. Full article

Background/Objectives: Multiple organ dysfunction syndrome (MODS) results from dynamic inter-organ interactions rather than isolated organ failures. Among these, kidney–lung crosstalk is a key determinant of outcomes in critically ill patients. Acute kidney injury (AKI) promotes pulmonary dysfunction through hemodynamic, inflammatory, endothelial, and metabolic mechanisms, while acute respiratory failure and mechanical ventilation may aggravate renal injury. Ventilator-associated pneumonia (VAP) may represent a clinical consequence of these interactions, although causality remains uncertain. Renal replacement therapy (RRT) may further influence kidney–lung crosstalk through several physiological mechanisms. To summarize current evidence on kidney–lung crosstalk, evaluate its potential contribution to VAP susceptibility, and examine the role of RRT in modulating these interactions. Methods: Narrative review of experimental, translational, and clinical studies investigating bidirectional kidney–lung interactions in critical illness. Results: Kidney-to-lung crosstalk involves fluid overload, venous congestion, immune activation, endothelial dysfunction, and metabolic disturbances. Lung-to-kidney signaling is driven by mechanical ventilation, ventilator-induced lung injury, hypoxemia, and hypercapnia. Clinical evidence is strongest for fluid overload, venous congestion, and mechanical ventilation, whereas endothelial dysfunction and uremic toxins remain supported mainly by experimental data. AKI-associated immune dysfunction and prolonged mechanical ventilation provide biologically plausible mechanisms linking AKI to VAP, but definitive causal evidence is lacking because of methodological limitations. RRT may influence these interactions through optimized fluid balance, correction of acid–base disorders, improved antimicrobial pharmacokinetics, and potentially extracorporeal immunomodulation. However, no randomized trial has demonstrated a direct reduction in VAP incidence attributable to RRT. Conclusions: Kidney–lung crosstalk is a major driver of organ dysfunction in critical illness, yet translation into targeted therapies remains limited. Current evidence supports integrated organ-protective strategies—including lung-protective ventilation, individualized fluid management, VAP prevention, and optimized antimicrobial therapy—while future advances will rely on biological phenotyping, biomarker-guided risk stratification, and robust causal inference approaches. Full article

Acrolein (ACR) and glyoxal (GO) are highly reactive carbonyls originating from endogenous metabolism, environmental pollution, and thermal food processing. This study compares the toxic mechanisms and redox effects of a 24 h exposure to ACR (30, 60, 90 µM) and GO (2, 5, 10 mM) in PBMCs. We assessed cell viability, lipid membrane fluidity, reactive oxygen/nitrogen species (ROS/RNS), free protein functional groups, reduced glutathione (GSH), non-enzymatic antioxidant capacity (NEAC), antioxidant enzyme activity (CAT, GPx), and protein expression levels (CAT, SOD1). Both aldehydes reduced viability in a concentration-dependent manner (ACR was over 30-fold more toxic than GO based on viability curves). These toxins increased membrane fluidity near the surface, while GO also altered the hydrophobic core. Both triggered a profound accumulation of ROS/RNS. At specific dose thresholds (ACR ≥ 60 µM; GO ≥ 5 mM), both toxins depleted GSH and NEAC, decreased protein thiol/amino groups, and suppressed CAT/GPx catalytic activity and CAT/SOD1 protein expression. In conclusion, ACR emerged as a markedly more potent inducer of oxidative stress and antioxidant failure than GO in PBMCs, disrupting both non-enzymatic (GSH, NEAC) and enzymatic (CAT, GPx, SOD1) defenses. These results support prioritizing ACR in exposure risk assessments and developing biomarkers of carbonyl-induced immune dysfunction. Full article

Alexandrium pacificum is a typical harmful dinoflagellate in aquatic ecosystems that produces paralytic shellfish toxins (PSTs). While PSTs are well known for bioaccumulating in shellfish and posing severe food-safety risks to human consumers, their direct impacts on other aquatic species, such as shrimp, remain poorly studied. The current study investigated the damage caused by A. pacificum to the intestinal tissues of Exopalaemon carinicauda. For this purpose, adult E. carinicauda were divided into a control group and two experimental groups, with the latter involving a seven-day exposure to 0.5 × 10⁴ and 1.0 × 10⁴ A. pacificum cells/mL, respectively. Histological analyses subsequently showed obvious pathological alterations, including an irregular morphology and loosened inter-tissue connections, within the intestinal tissues of the exposure groups. Additionally, oxidative stress-related genes (Sod2, HSP70 12A, HSP90) were significantly upregulated, while cat, Gtpx and GSTM4 were significantly downregulated. The relative expression of Crustin, ALF and proPO3 decreased, whereas that of LGBP, TNFAIP-like and casp3 increased. Finally, analysis of the intestinal microbiota revealed that exposure to A. pacificum could also induce alterations in the intestinal microbial community, as reflected by a lower α-diversity, a high abundance of Proteobacteria and Vibrionaceae as well as functional predictions indicating suppressed metabolic pathways such as energy metabolism. The findings indicated that exposure to A. pacificum may induce histopathological and microbiota changes in E. carinicauda intestines, along with oxidative stress and changes in immune responses. This study reveals the negative impacts of A. pacificum on the intestinal health of E. carinicauda, which should be carefully considered and analyzed in aquaculture practices. Full article

What are the main findings?Migraine care in Italy is characterized by a mismatch between healthcare resource utilization and clinical needs, with limited primary-care involvement, repeated specialist consultations, and healthcare nomadism.Healthcare resource utilization is substantial, including extensive diagnostic testing—predominantly brain imaging—as well as emergency department visits, detoxification cycles, and repeated access to headache centers. Full article

Temporomandibular disorders (TMDs) are heterogeneous musculoskeletal conditions frequently characterized by pain, impaired mandibular function, and reduced quality of life. Botulinum neurotoxin type A (BoNT-A) has emerged as a potential therapeutic option, particularly for persistent myogenous TMDs associated with masticatory muscle hyperactivity. This narrative review critically examines the mechanisms of action, current clinical evidence, therapeutic applications, and safety profile of BoNT-A in TMD management. Available evidence suggests that BoNT-A can reliably reduce masticatory muscle activity and may provide pain relief in selected patients with refractory myogenous TMDs; however, its superiority over placebo or established conservative treatments remains inconsistent. Considerable heterogeneity in patient selection, injected muscles, dosing regimens, injection techniques, and outcome assessment currently prevents the definition of standardized treatment protocols. Although short-term adverse events are generally mild and transient, repeated injections may induce muscle atrophy, reduced bite force, and potentially mandibular skeletal changes, whose long-term clinical relevance remains uncertain. Therefore, BoNT-A should not be considered a first-line treatment but rather a carefully selected adjunct within a multimodal rehabilitation strategy after appropriate conservative management has failed. Future phenotype-stratified comparative trials with standardized protocols and long-term structural safety outcomes are warranted. Full article

Benthic communities are a fundamental component of coastal marine ecosystems, regulating energy flow, mediating trophic transfer, and supporting a wide range of ecological functions closely linked to habitat characteristics. In Marine Protected Areas (MPAs), integrative approaches that simultaneously address trophic and functional dimensions are essential to assess ecosystem functioning and resilience to environmental disturbances. This study aimed to characterize and compare the trophic structure and functional diversity of benthic communities in sub-Antarctic fjords and channels of the Magellan region (southern Chile), all of which are located within MPAs and represent contrasting environmental settings characterized by either proglacial influence or a documented history of recurrent harmful algal bloom (HAB) occurrence and paralytic shellfish toxin (PST) exposure. We hypothesized that benthic communities under these contrasting environmental stressors would differ in carbon assimilation pathways, community isotopic niche breadth, and functional organization. Trophic structure was evaluated using stable isotope analysis (δ¹³C and δ¹⁵N), Bayesian mixing models to estimate basal carbon source contributions, and community-level isotopic metrics. Functional diversity was quantified using biological and ecological traits to calculate community- and species-level functional indices. Our results revealed marked differences in trophic organization among localities, whereas global functional diversity indices were consistently low and similar across environmental settings. Communities from localities characterized by recurrent HAB/PST exposure showed limited trophic reliance on pelagic-derived organic matter, maintaining benthic-based energy pathways, whereas proglacial localities exhibited higher allochthonous subsidies and broader isotopic niches. Functional uniqueness and specialization metrics indicated strong functional redundancy and a high dependence on a small set of functionally distinctive species. These findings establish a baseline for remote MPAs and demonstrate the value of integrating trophic and functional metrics in long-term monitoring and adaptive management frameworks. Full article

Background/Objectives: Maternally transferred antibodies protect infants early in life, but high concentrations can reduce immune responses to primary vaccination. CRM₁₉₇ is a nontoxic mutant of diphtheria toxin that retains antigenic similarity to the native protein. We therefore investigated whether anti-diphtheria antibodies present before vaccination were related to responses against pneumococcal polysaccharides conjugated to CRM₁₉₇. Methods: This post hoc analysis used data from a multicenter, randomized, single-blind phase III trial in which Indian infants received BE-PCV14/PNEUBEVAX 14^® at 6–8, 10–12, and 14–16 weeks of age (commonly referred to as 6–10–14 weeks). Baseline anti-diphtheria toxoid IgG concentrations measured at 6–8 weeks were assessed in relation to serotype-specific pneumococcal IgG responses 28 days after dose 3. We evaluated these associations using categorical and continuous analyses with false-discovery-rate correction for serotype-specific comparisons. Results: Baseline and post-primary results were available for 603 of 650 infants in the co-administration cohort. Post-primary pneumococcal IgG concentrations did not differ significantly across the baseline anti-diphtheria IgG categories. Individual fold rises differed nominally among baseline anti-diphtheria IgG categories for serotype 5, but the difference did not remain significant after multiplicity correction. In the adjusted continuous models, geometric mean ratios (GMRs) associated with each 2-fold increase in baseline anti-diphtheria IgG ranged from 0.978 to 1.011, with no statistically significant associations after false-discovery-rate correction. Analyses stratified by baseline pneumococcal IgG similarly showed no consistent evidence of reduced responses. Conclusions: In this cohort, pre-existing anti-diphtheria toxoid IgG measured before vaccination, which was likely maternally derived, was not associated with a consistent reduction in post-primary serotype-specific pneumococcal IgG responses to CRM₁₉₇-conjugated BE-PCV14. Full article

Temporomandibular disorders (TMDs) represent a heterogeneous group of conditions, including myogenous and arthrogenous, with a significant impact on quality of life. Botulinum toxin type A (BoNT-A) has been proposed as a therapeutic option, particularly for patients with refractory myogenous TMD and bruxism. This systematic review aimed to evaluate the clinical effectiveness of BoNT-A in the management of TMDs overall and bruxism, with particular focus on myogenous TMDs compared to placebo and non-surgical treatments. RCTs published between 2020 and 2025 were identified through PubMed, Scopus, and Google Scholar. Overall, 15 RCTs involving 797 participants were included. The available evidence suggests potential benefits of BoNT-A, particularly in patients with localized myofascial pain, myogenous TMD, or marked masticatory muscle hyperactivity. Interpretation of the findings is limited by substantial heterogeneity in treatment protocols, toxin dosage, diagnostic criteria, outcome measures, and follow-up duration. Current evidence does not support the routine use of BoNT-A as a first-line treatment for TMDs overall. Instead, BoNT-A may represent an adjunctive or second-line option for selected patients with myogenous TMD, localized myofascial pain, or marked masticatory muscle hyperactivity who do not adequately respond to conventional noninvasive treatment. Larger and methodologically rigorous RCTs are needed to establish appropriate indications, duration of treatment effects, and long-term safety across different TMD subtypes. Full article

Diphthamide-specific mono-ADP-ribosylating toxins form a structurally conserved but phylogenetically diverse family of AB-type bacterial toxins, with Pseudomonas exotoxin A (PE) serving as a prototypical member. Here, we expand the known diversity of PE-like toxins (PLTs) through comprehensive genome mining and phylogenetic, structural and sequence analyses of PE, Chx, and their Aeromonas and Vibrio cholerae homologues. Aeromonas toxins separate into two distinct groups: a PE-like cluster (AEI) and a cholix-like cluster (AEII), while a fourth cholix subgroup (ChxIV) is identified within V. cholerae, expanding the previously described ChxI–III classification. Although all newly identified toxins retain the core catalytic architecture and hallmark residues essential for ADP-ribosylation of eEF2, they differ in key functional motifs, including receptor-binding residues, furin cleavage loops, and C-terminal ER-retrieval signals, suggesting variation in host-cell uptake routes and intracellular trafficking. Signal peptides were present in all toxins but varied modestly between clusters, consistent with normal species-level Sec-pathway variation rather than divergent secretion mechanisms. Together, our findings provide a significantly expanded overview of PLT diversity and indicate that Aeromonas-derived toxins comprise at least two evolutionarily and mechanistically distinct groups. These insights offer a framework for future functional studies and highlight PLTs as emerging virulence factors in environmentally and clinically relevant bacteria. Full article

Crystal (Cry) toxins produced by Bacillus thuringiensis are highly specific insecticidal proteins that are widely used as biological insecticides and function through proteolytic activation in insect midguts, which generates a three-domain toxic core responsible for membrane disruption as well as cleaved N- and C-terminal domains. While the structure and function of this core have been extensively characterized, the fate of the cleaved C-terminal region remains poorly understood. Amyloids are protein fibrils with a characteristic cross-β structure that participate in a wide range of functions in bacteria. Here, using bioinformatic approaches, we demonstrated that the C-terminal domains of Cry are rich in potentially amyloidogenic regions. We investigated the aggregation behavior of C-terminal domains from Cry1Ea11 and Cry1Ab12 proteins using a combination of biochemical and structural approaches. We found that the C-terminal domains of Cry1Ea11 and Cry1Ab12 undergo self-assembly in vitro, forming aggregates with fibrillar morphology. These assemblies bind amyloid-associated dyes, exhibit partial resistance to ionic detergents and proteolytic digestion, and display X-ray diffraction patterns confirming their amyloid properties. Functional assessment in insect cells showed that although these amyloids do not induce detectable cytotoxicity, amyloids of the C-terminal domains of Cry1Ea11 alter the readouts of the MTT assay in a manner consistent with previously described amyloid-associated effects on cellular formazan handling. Together, our findings demonstrate that the C-terminal domains of Cry toxins, which are released in the insect midgut as a result of proteolytic cleavage, are able to form bona fide amyloids that affect the metabolism of insect cells. Full article

Background/Objectives: To investigate laryngeal elevation velocity (LEV) as a candidate physiological marker of swallowing safety in post-radiotherapy dysphagia patients with cricopharyngeal muscle dysfunction (CPMD), we examined its association with airway safety and whether the LEV–upper esophageal sphincter (UES) opening relationship differed before versus after botulinum toxin injection, used here as a within-subject physiological perturbation. Methods: This retrospective cohort study included 18 post-radiotherapy patients with nasopharyngeal carcinoma (NPC) and CPMD who underwent botulinum toxin injection into the cricopharyngeal muscle (median total dose, 30 U; range, 20–40 U) and completed videofluoroscopic swallowing studies (VFSSs) before and after intervention. Primary outcomes were the Penetration–Aspiration Scale (PAS) and UES opening diameter; secondary outcomes included the Functional Oral Intake Scale (FOIS), laryngeal elevation (LE) and LEV. Associations were evaluated using generalized estimating equations (GEEs) with LEV × treatment interaction terms to assess whether they differed across pre- and post-injection states. Results: Following botulinum toxin injection, FOIS scores improved significantly (median, 4 to 5; p < 0.001), with concurrent increases in LEV (median, 149.86 to 201.12 C2–4%/s; p = 0.027) and UES diameter (median, 21.10 to 23.30 C2–4%; p = 0.039); PAS scores and laryngeal elevation displacement did not change significantly. Higher LEV was associated with lower odds of unsafe airway invasion (PAS 5–8) in univariate analysis (odds ratio per 100-unit increase, 0.38; 95% confidence interval [CI], 0.17–0.86; p = 0.021). A significant LEV × treatment interaction was observed for UES diameter (p = 0.021). Conclusions: In post-radiotherapy NPC patients with CPMD, higher LEV was associated with airway safety, and the LEV–UES relationship differed across pre- and post-injection states. Although the study design does not permit conclusions about treatment efficacy, LEV may represent a candidate load-sensitive marker of swallowing safety, warranting further investigation. Full article