Search Results (10,468)

Targeted down-modulation of monocytes and macrophages is a promising strategy for controlling excessive inflammatory processes. Bacterial protein toxins are attractive pharmacological modulation tools for this purpose because of their potency and specificity. Here, we combined the specific properties of the two protein toxins C3lim from Clostridium limosum and CyaA from Bordetella pertussis in the preferentially monocyte/macrophage-targeting bioconjugate C2IN-C3lim_E174Q-Cys_His-AC. The enzymatically inactive and monocytic cell-targeting transporter C2IN-C3lim_E174Q-Cys was recombinantly produced and chemically coupled to the isolated adenylate cyclase (AC) domain of CyaA, which mediates down-modulation of monocytic cell functions through intracellular cAMP accumulation Within 1 h, the bioconjugate showed preferential cell association with monocytic cells relative to HeLa cells, which served as the non-target cell model, without impairing overall cellular viability. Intracellular enzymatic activity was successfully confirmed by significantly elevated cAMP levels in all target cell types. Moreover, in migration assays with primary human monocytes, the bioconjugate markedly reduced both general motility and targeted chemotaxis, demonstrating that the delivery of the enzyme moiety translates into a measurable functional response. Therefore, we conclude that the novel bioconjugate C2IN-C3lim_E174Q-Cys_His-AC enables preferential targeting of monocytes and macrophages under the experimental conditions investigated here and provides proof-of-concept for a targeted protein delivery platform for functional modulation of monocytic cells. Full article

The widespread use and improper disposal of plastics have made them ubiquitous contaminants that can potentially adversely affect both the environment and human health. The impact of microplastics (MPs)—plastic particles less than 5 mm in size—has been widely studied in marine and terrestrial environments; however, their potential effects on human health have only recently begun to receive attention. Although once considered inert materials, MPs exposure in laboratory animals is now linked to inflammation, immunological responses, lipid and energy metabolism alterations, mitochondrial damage, and other disorders. Since clearance-associated organs such as the liver, kidneys, spleen, lungs, and the gastrointestinal tract play a critical role in processing, metabolizing, filtering, and excreting toxins and foreign substances, they are particularly vulnerable to MPs exposure and accumulation. The increasing intake of plastics, primarily via ingestion and inhalation, raises concerns regarding their fate and retention in these organs, potentially leading to long-term health impacts. This review provides an overview of recent findings regarding MPs accumulation in clearance-associated organs and possible health impacts, and discusses future outlook and potential strategies for mitigating the health risks associated with nano- and microplastics exposure. Full article

Clostridioides difficile infection (CDI) is a major cause of antibiotic-associated diarrhea and pseudomembranous colitis and remains one of the most common healthcare-associated infections. Clostridioides difficile sequence types 1 and 11 (ST1 and ST11), which belong to multilocus sequence typing (MLST) clades 2 and 5, respectively, are widely recognized as epidemic-associated lineages. Both lineages harbor virulence-associated genetic features, including truncating variants in tcdC and carriage of the binary toxin locus (CdtLoc). ST37 (clade 4) has been an epidemic lineage in East Asia, whereas ST17 (clade 1) has been reported as a predominant lineage in the Republic of Korea and Japan. We performed short-read whole-genome sequencing (WGS) on 61 clinical isolates collected at a university-affiliated hospital in the Republic of Korea between February 2016 and April 2019. Long-read sequencing was additionally performed for 24 isolates, generating complete genomes by hybrid assembly. ST17 was the most prevalent sequence type (n = 16, 26.2%), followed by ST1 (n = 10, 16.4%). ST1 and ST11 isolates harbored the genetic features reported for these lineages, including truncating variants in tcdC. Genomic profiling further identified virulence-associated genes and antimicrobial resistance (AMR) determinants in diverse lineages. These findings characterize the genomic features of co-circulating C. difficile lineages and reveal the local presence of epidemic-associated strains. Full article

Bladder sensory neurons are essential components of lower urinary tract sensory encoding and micturition reflex control. They detect bladder filling, stretch, inflammatory mediators, and pathogen-associated stimuli, and they communicate with urothelial cells, immune cells, and stromal cells through neuropeptides such as calcitonin gene-related peptide (CGRP), substance P (SP), and vasoactive intestinal peptide (VIP). Under physiological conditions, this neuro-immune-urothelial axis contributes to bladder homeostasis. Under pathological conditions, including neural injury, infection, inflammation, or epithelial barrier disruption, TRP channels, purinergic signaling, neurotrophic factors, chemokines, and voltage-gated ion channels can induce peripheral sensitization, increased excitability of dorsal root ganglion (DRG) neurons, spinal plasticity, and central sensitization, thereby contributing to urinary frequency, urgency, bladder pain, and detrusor overactivity in neurogenic bladder and interstitial cystitis/bladder pain syndrome (IC/BPS). This review summarizes the anatomical and functional organization of bladder sensory afferents, sensory neuron-associated molecular signaling, neuro-immune-urothelial interactions, disease-specific mechanisms, and targeted therapeutic strategies. We also discuss the translational potential and limitations of interventions targeting TRPV1/TRPV4/TRPA1, P2X3, CGRP, SP/neurokinin receptors, NGF, ion channels, botulinum toxin, and neuromodulation. These mechanisms provide a framework for understanding neurogenic mechanisms in bladder disorders and for developing targeted interventions. Full article

This study investigated the prevalence and genomic characteristics of Bacillus cereus group organisms in animal-origin foods sold in Guangzhou, China. A total of 505 retail samples, including 117 milk samples and 388 commercially available smoked sausage products, were collected from supermarkets and farmers’ markets. The isolation rates of B. cereus group organisms were 8.5% in milk and 44.9% in smoked sausages. Whole-genome sequencing of 169 isolates showed that antimicrobial-resistance genes, including bacII, fosB and vanZF, and diarrheal virulence-associated genes, including nheA, nheB and nheC, were widely distributed among the isolates. Most representative isolates showed biofilm-forming ability, and three antimicrobial-resistant isolates carrying multiple virulence-associated genes showed pathogenic potential in mice under high-dose experimental administration. These findings indicate that retail smoked sausage products can serve as a reservoir of B. cereus group organisms with antimicrobial-resistance, virulence-associated and biofilm-forming traits. However, the detection of resistance- or virulence-associated genes does not necessarily prove gene expression, toxin production, phenotypic resistance or consumer exposure risk. This study did not directly evaluate growth of B. cereus in sausage matrices during storage. Therefore, the present results indicate a potential microbiological hazard rather than a quantified consumer risk. Product-specific challenge studies under defined storage conditions are required to determine whether B. cereus can proliferate in particular sausage products and reach hazardous levels at consumption. Full article

Leishmaniasis and Chagas disease are neglected tropical diseases that continue to pose significant public health challenges, highlighting the need for new therapeutic strategies. Brazilian snake venoms represent a valuable and underexplored source of bioactive molecules with diverse pharmacological activities and promising therapeutic potential. In this context, the present study aimed to investigate the in vitro antiprotozoal potential of venoms from Bothrops and Crotalus species, including Bothrops jararacussu, Bothrops pauloensis, Bothrops alternatus, Bothrops leucurus, Bothrops atrox, Bothrops jararaca, Crotalus durissus terrificus, and Crotalus durissus ruruima, metalloprotease (MTL)- and crotoxin (CTX)-enriched, against Leishmania spp. and Trypanosoma cruzi. Crude venom protein profiles were analyzed by SDS-PAGE, and cytotoxicity was assessed in differentiated C2C12 myotubes and murine peritoneal macrophages. Antiprotozoal activity was evaluated against extracellular parasite forms, including promastigotes of Leishmania amazonensis and Leishmania infantum and epimastigotes of T. cruzi. Venoms exhibiting the highest selectivity indices (SIs), calculated using murine macrophage cytotoxicity data, were further tested against intracellular amastigotes of L. amazonensis. Among the tested samples, B. jararacussu venom showed activity against promastigotes of both L. amazonensis (IC₅₀ = 2.9 µg mL⁻¹) and L. infantum (IC₅₀ = 2.8 µg mL⁻¹), as well as in epimastigotes of T. cruzi (IC₅₀ = 15.5 µg mL⁻¹). The MTLand CTX pools from C. d. ruruima venom exhibited the highest activity against promastigotes of L. amazonensis, with IC₅₀ values of 1.6 and 3.8 µg mL⁻¹, respectively. Against intracellular amastigotes, MTL and CTX showed IC₅₀ values of 4.1 and 2.5 µg mL⁻¹, respectively, with selectivity indices (SIs) of 73.1 and 120, respectively. Overall, these findings provide preliminary evidence for the antiparasitic potential of snake venom-derived molecules, supporting further characterization and in vivo evaluation. Full article

Pharmacodynamic models of botulinum toxin type A map a mean concentration onto a smooth dose–response curve, yet the outcome is binary and arises from a finite population of near-threshold motor units. We analyse a discrete model in which N units are silenced once local SNAP-25 cleavage exceeds a unit-specific threshold, and a functional block of neuromuscular transmission follows once the silenced fraction exceeds a collective threshold. Whether that collective threshold is a fraction of the population or a fixed count changes the location of the dose–response curve and not its steepness: under a fraction, potency is invariant to unit number at fixed dose–concentration gain, and the transition contracts in absolute dose where fixed-count architectures require it to widen. The width contracts as $N^{-1/2}$, an exponent that is prior and not claimed here. One consequence needs no measurement: a quantal terminal response caps the silenced fraction below unity, so any fixed count fails above a target size it determines, whereas the toxin block targets differ by orders of magnitude. A second reinterprets existing data, flat cohort dose–response curves being what a near-step individual response predicts once convolved with between-subject dispersion. Outcome is accordingly less repeatable in the smallest targets. No parameter is fitted. Full article

Harmful cyanobacterial blooms require control strategies that suppress bloom-forming taxa while limiting effects on non-target primary producers and toxin-related risks. We developed a cationic polyquaternium (P126)-engineered local red-soil composite and evaluated its electrokinetic properties, taxon-dependent photophysiological effects, activity against colonial Microcystis, robustness to water chemistry, short-term Danio rerio responses, and field-scale performance. P126 modification reversed soil surface charge to the range of +20 to +33 mV across a pH range of 6.0–10.0, generating a strong electrostatic contrast with negatively charged cyanobacteria. At 10 mg L⁻¹, the composite suppressed maximum photosystem II quantum yield (F_v/F_m) in Microcystis aeruginosa and Dolichospermum sp., with no statistically detectable effects on the four tested chlorophyte and diatom strains. For Microcystis colonies ≥ 500 μm, 20 mg L⁻¹ of composite achieved >95% MTT-based inhibition within 24 h, versus < 15% for CuSO₄. Suppression persisted across the tested pH and nutrient ranges but was attenuated by high humate concentrations. The maximum unfractionated-sample ELISA microcystin-equivalent signal was approximately 25% lower than with CuSO₄; however, dissolved and particulate fractions were not resolved. No statistically detectable treatment-related differences in zebrafish hatching or larval length were observed up to 10.5 mg L⁻¹. In a physically isolated sub-lake, composite application preceded a decline of more than three orders of magnitude in algal/cyanobacterial density and an increase in Secchi depth from approximately 0.25 to 1.2 m; Vallisneria natans was planted subsequently. These results provide laboratory evidence and field case-study observations consistent with electrostatically favored, selective bloom suppression, while residual-polymer fate, sediment effects, chronic toxicity, and multi-trophic responses require further evaluation. Full article

Enterobacter cloacae (E. cloacae) is an important healthcare-associated pathogen with increasing antimicrobial resistance. Prophages and phage-inducible chromosomal islands (PICIs) are integral components of the E. cloacae genome, yet their contribution to resistance, virulence, and anti-phage defense remains poorly understood. To address this gap, we analyzed 35 complete E. cloacae genomes, identifying 139 intact prophages (10.8–85.7 kb) with an average GC content (~52%) close to that of the host (54–55%). Most prophages (86.6%) were assigned to the families Peduoviridae and Drexlerviridae within the class Caudoviricetes, and proteome-based clustering showed strong relatedness to phages infecting Enterobacteriaceae. The E. cloacae genomes harbored multiple antimicrobial resistance genes, notably fosA (97%), oqxA/oqxB (89%) and blaCMH-3 (77%). However, on genomic-context verification none were genuinely prophage-encoded; they were instead located on the chromosome or plasmids. Virulence profiling revealed universal presence of ompA and high prevalence of csgG (94%), while the only confirmed prophage-encoded virulence determinants were the Shiga toxin genes stxA and stx1B. Additionally, 16 phage satellites were identified, containing conserved integration, replication, and packaging modules together with diverse accessory and anti-phage defense systems. Overall, prophages and phage satellites drive genome diversification in E. cloacae, with satellites notably serving as reservoirs of anti-phage defense, whereas resistance and virulence genes are located outside prophage and satellite regions. Full article

Background/Objectives: Proteus mirabilis is an opportunistic pathogen and a potential reservoir of clinically important antimicrobial resistance genes in animal production. However, mink-derived P. mirabilis remains poorly characterized. This study investigated multidrug-resistant and extended-spectrum β-lactamase (ESBL)-producing isolates from intensive mink farms, focusing on clinically important β-lactamase genes, their genomic backgrounds, and mobile genetic elements (MGEs). Methods:  Among 373 fecal and intestinal-content samples collected from six mink farms in Shandong Province, China, 68 P. mirabilis isolates were recovered. All underwent antimicrobial susceptibility testing, ESBL confirmation, and virulence-associated phenotypic assays. The 39 ESBL-positive isolates underwent whole-genome sequencing, followed by analyses of antimicrobial resistance genes, the pangenome, and MGEs and comparison with 198 publicly available genomes. Results:  Of the 373 sampled mink, 68 (18.2%) were P. mirabilis positive, and 39 (10.5%) carried ESBL-producing isolates. Of the 68 isolates, 63 (92.6%) were multidrug resistant, and 39 (57.4%) were ESBL positive. All exhibited strong biofilm formation and urease activity, while 83.8% showed strong swarming motility. Among the sequenced isolates, bla_CTX-M genes were identified in 32 isolates and bla_NDM-1 in three. Both bla_CTX-M-65- and bla_NDM-1-positive isolates were distributed across multiple genomic lineages, with bla_CTX-M-65 additionally detected in multiple sequence types. This distribution indicates that these genes were not restricted to a single clone but does not demonstrate horizontal gene transfer. MGE-associated features showed same-contig co-occurrence with several resistance genes, notably IS903–bla_CTX-M-65 and ISAba125–bla_NDM-1. The sequenced isolates also exhibited substantial accessory-genome diversity and widely distributed virulence determinants associated with adhesion, motility, iron acquisition, and toxin-related functions. Conclusions:  Mink-derived P. mirabilis exhibited extensive multidrug resistance and carried clinically important β-lactamase genes across diverse genomic backgrounds. These findings support the inclusion of fur-animal production systems in One Health surveillance of antimicrobial-resistant P. mirabilis. Full article

Background: Botulinum toxin type A (BoNT-A) is globally recognized as a standard treatment for post-stroke spasticity (PSS), although its secondary mechanisms remain underinvestigated. The objective of this study was to investigate the neurophysiological mechanisms underlying BoNT-A treatment in PSS and explore their implications for mechanism-based rehabilitation. Methods: A systematic review and meta-analysis (PROSPERO registration number ID: CRD420261352230) of 39 studies involving 760 patients was conducted on 18 August 2026, following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. PubMed, Web of Science, Scopus, and Embase were systematically searched using the PICO framework. Where possible, quantitative data were pooled according to predefined neurophysiological constructs, including passive stretch-evoked activity, voluntary activation of the injected muscle, compound muscle action potential (CMAP), reciprocal motor control, normalized Hmax/Mmax, and specific spinal inhibitory mechanisms. Results: Quantitative synthesis demonstrated construct-specific neurophysiological changes following BoNT-A treatment. Passive stretch-evoked activity showed the largest pooled effect (Hedges’ g = 0.80, 95% CI 0.35–1.24), followed by CMAP amplitude (g = 0.69, 95% CI 0.23–1.14) and reciprocal motor control (g = 0.52, 95% CI 0.23–0.81). Effects on voluntary activation of the injected muscle (g = 0.31, 95% CI −0.38 to 1.00) and normalized Hmax/Mmax (g = 0.22, 95% CI −0.74 to 1.17) were smaller and more heterogeneous. Reciprocal and recurrent inhibition were each represented by single-study estimates, while supraspinal outcomes were synthesized narratively due to methodological heterogeneity. Conclusions: The findings support a predominantly peripheral mechanism of BoNT-A while suggesting possible secondary changes within spinal and supraspinal motor control pathways. However, the certainty of evidence was low to very low. These neurophysiological effects provide a rationale for individualized, mechanism-based rehabilitation during the post-injection therapeutic window, although higher-quality evidence is required to confirm this framework. Full article

In 2017, an unusually large number of live stranded and dead marine birds were found in California, coincident with a large bloom of the diatom Pseudo-nitzschia that produced the toxin domoic acid (DA). The most abundant bird species affected by this large die-off and stranding event were Pacific Loons (Gavia pacifica) and Red-throated Loons (Gavia stellata). International Bird Rescue (IBR; San Pedro, CA) received 117 live loons with suspected DA toxicosis. Many birds that survived the first few days in rehabilitation quickly re-attained suitable health metrics; however, 68 loons (58.1%) died or were considered unreleasable due to ongoing abnormal behavior or injuries that necessitated humane euthanasia. In this descriptive study, both live stranded euthanized birds and dead stranded birds were examined to characterize and better understand the effects of DA toxicosis in the avian brain and body. Utilizing a suite of diagnostics, our analysis revealed novel pathological patterns that divided these birds into three groups: those suspected of having acute, subacute, and chronic DA toxicosis. Domoic Acid was found in all groups, and the severity of the microscopic lesions appeared to correspond with the amount of timeeach bird survived post-stranding. Our investigation is the first known account identifying the pathological progression from acute to chronic DA toxicosis in birds. Full article

Background and Aims: Metabolic dysfunction-associated steatotic liver disease (MASLD) affects over 30% of adults globally; its progressive form, metabolic dysfunction-associated steatohepatitis (MASH), has limited pharmacological options beyond the recently approved resmetirom. The statin–ezetimibe combination, widely co-prescribed for dyslipidemia in patients with MASH, significantly reduces hepatic fat versus statin monotherapy in the ESSENTIAL randomized trial, yet macrophage-driven mechanisms linking this lipid-lowering combination to hepatic inflammation and fibrosis remain poorly characterized. We investigated these mechanisms using in vivo and in vitro approaches. Methods: Male C57BL/6 mice (n = 6/group; 6 groups) received a high-fat diet (HFD; 45% kcal) plus thioacetamide (TAA; 300 mg/kg twice-weekly, 8 weeks) to establish MASH with advanced fibrosis. Simvastatin (5 mg/kg) and/or Ezetimibe (10 mg/kg) were added to the diet for 4 weeks. Blinded hepatic histology (H&E, Picrosirius red, Oil Red-O), qPCR, immunohistochemistry, and Western blot were performed. Macrophage polarization and NF-κB nuclear translocation were assessed in RAW 264.7 cells and thioglycolate-elicited peritoneal macrophages by flow cytometry and immunofluorescence. Results: Combination therapy significantly reduced steatosis, inflammation, and fibrosis versus HFD-TAA controls. Pro-inflammatory (IL-1β, IL-6, TNF-α, iNOS) and fibrosis-related (collagen-I, α-SMA, TGF-β1) markers were markedly suppressed (p < 0.01). In vitro, the combination reduced the proportion of iNOS⁺ macrophages to approximately 50% of the LPS control (normalized to each experiment), although statistical significance was not reached; monotherapies showed weaker and variable trends and inhibited NF-κB p65 nuclear translocation in cultured macrophages (Holm-adjusted p < 0.01); MAPK signaling was not significantly altered under the present conditions. Anti-fibrotic effects were consistent with a macrophage-mediated mechanism, with no direct stellate cell suppression observed by LX-2 assays. Conclusions: Statin–Ezetimibe combination exerts anti-inflammatory and anti-fibrotic effects in a multi-hit murine model of MASH with advanced fibrosis associated with macrophage NF-κB inhibition in vitro and with reduced hepatic inflammatory signaling in vivo. These findings provide mechanistic rationale for the hepatic benefits of this widely used regimen in MASH patients with dyslipidemia, supporting its evaluation as a drug-repurposing strategy. Full article

The cervicovaginal virome remains poorly characterized in relation to human papillomavirus (HPV) infection and bacterial community structure. We performed shotgun metagenomic sequencing of 311 cervicovaginal specimens from a Kazakhstani cohort spanning seven groups defined by HPV status and cervical cytology. Viral community composition differed according to HPV status, with increasing representation of the oncogenic Alphapapillomavirus 9 clade across more abnormal cytological categories. Predicted phage functional profiles also differed between NILM HPV-positive and NILM HPV-negative women. Integrase, excisionase, transcriptional repressor, anti-repressor Ant, and amidase annotations showed differential prevalence after false-discovery-rate correction. Auxiliary metabolic and host-interaction genes associated with nucleotide metabolism, DNA modification, anti-restriction functions, and toxin–antitoxin systems were also differentially represented. Stratification by bacterial community state type revealed contrasting predicted functional repertoires, with toxin–antitoxin-associated annotations enriched in Lactobacillus crispatus-dominated communities and anti-restriction-associated annotations enriched in Gardnerella vaginalis-dominated communities. These findings identify associations between HPV status, bacterial community structure, and cervicovaginal viral composition and predicted phage functions. Longitudinal and experimental studies are required to determine the directionality and biological activity of these associations. Full article