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Bacterial Outer Membrane Vesicles in Colorectal Cancer: Interdomain Communication Hubs in Pathogenesis and Immunotherapy.

The complex interaction between the intestinal microbiota and host mucosal immunity plays a defining role in colorectal cancer (CRC) development and therapeutic outcomes. Recently, bacterial outer membrane vesicles (OMVs)-nano-sized, lipid-bilayered extracellular particulates released by both commensal and pathogenic microorganisms-have emerged as critical long-range signaling vehicles within the gut. This review provides a comprehensive synthesis of the dual functionalities of OMVs in CRC pathogenesis and oncology. Mechanistically, pathogenic OMVs cross compromised mucosal barriers to drive horizontal gene transfer (HGT) of chimeric episomes, such as SPHINX DNAs and Bovine Meat and Milk Factors (BMMFs), thereby promoting genomic instability and neoplastic transformation. Conversely, there is a paradigm shift toward exploiting next-generation probiotic and engineered OMVs as highly tunable therapeutic platforms. By combining cutting-edge bioengineering strategies-such as biomimetic mineralization to neutralize local tissue acidity and chemotherapeutic packaging-these nanovectors effectively reprogram the immunosuppressive tumor microenvironment (TME). Specifically, optimized OMVs modulate macrophage polarization from an M2 to an M1 phenotype and stimulate CXCL10-mediated CD8+ T-cell infiltration, effectively turning immunologically "cold" tumors "hot." Finally, the great translational challenges regarding systemic endotoxicity, scalability, and target delivery, providing a strategic approach for the integration of OMV-based platforms into synergistic immune checkpoint inhibition regimens.

Colon cancer

Exerkine dysregulation links visceral adiposity to skeletal muscle impairment in end-stage heart failure with reduced ejection fraction: proteomic evidence for a cardio-adipose-muscle axis.

BACKGROUND: Heart failure with reduced ejection fraction (HFrEF) is associated with profound alterations in body composition, skeletal muscle dysfunction, and impaired exercise capacity. Exerkines representing exercise-responsive signaling molecules released by skeletal muscle, adipose tissue, and other organs may mediate systemic metabolic communication between tissues. However, their role in advanced HFrEF and their relationship with adiposity and skeletal muscle characteristics remain poorly understood. METHODS: We studied 73 patients with end-stage HFrEF and 16 healthy controls. Body composition was assessed using computed tomography, including visceral (VAT), subcutaneous (SAT), and epicardial adipose tissue (EAT), as well as skeletal muscle quantity (psoas muscle index, PMI) and quality (psoas muscle density, PMD). Functional performance was evaluated using handgrip strength (HGT) and the 6-min walk test (6MWT). Circulating exerkines were quantified using the Olink technology. Associations between proteins and clinical variables were assessed using age- and creatinine-adjusted linear models with false discovery rate correction. RESULTS: Among patients with HFrEF, 36% were obese and 38% exhibited central obesity independent of BMI. Muscle strength and muscle quality were strongly associated with functional capacity. VAT correlated with muscle mass but not with muscle quality or performance. Compared with controls, HFrEF patients demonstrated elevated inflammatory and metabolic stress-related exerkines including CXCL8, CCL2, IL-6, TNF, IL-15, GDF15, FGF21, ANGPTL4, CTSB, DCN, and resistin. In contrast, proteins associated with muscle integrity and regenerative signaling (myostatin, BDNF, IL-7, SPARC) were significantly reduced. In HFrEF patients leptin strongly correlated with adiposity measures. Metabolic stress mediators (GDF15, IL-15, FGF21, CTSB) were inversely associated with muscle quality and functional performance, whereas myostatin positively correlated with muscle quality, strength, and exercise capacity. BDNF was inversely associated with frailty. CONCLUSIONS: Advanced HFrEF is characterized by a dysregulated exerkine network linking adiposity, skeletal muscle quality, and functional performance. Four biologically coherent axes were identified: a leptin-driven adiposity axis, a metabolic stress-muscle quality axis, a myostatin-related muscle function axis, and a neurotrophic frailty axis. These findings support the presence of a systemic cardio-adipose-muscle signaling network in end-stage HFrEF and identify candidate molecular mediators of sarcopenia and functional decline.

Humans

An Evolutionary Framework Exploiting Virologs and Their Host Origins to Inform Poxvirus Protein Functions.

Poxviruses represent evolutionary successful infectious agents. As a family, poxviruses can infect a wide variety of species including humans, fish, and insects. While many other viruses are species-specific, an individual poxvirus species is often capable of infecting diverse hosts and cell types. For example, the prototypical poxvirus, vaccinia, is well known to infect numerous human cell types but can also infect cells from divergent hosts like frog neurons. Notably, poxvirus infections result in both detrimental human and animal diseases. The most infamous disease linked to a poxvirus is smallpox caused by variola virus. Poxviruses are large double-stranded DNA viruses, which uniquely replicate in the cytoplasm of cells. The model poxvirus genome encodes ~200 nonoverlapping protein-coding open reading frames (ORFs). Poxvirus gene products impact various biological processes like the production of virus particles, the host range of infectivity, and disease pathogenesis. In addition, poxviruses and their gene products have biomedical application with several species commonly engineered for use as vaccines and oncolytic virotherapy. Nevertheless, we still have an incomplete understanding of the functions associated with many poxvirus genes. In this chapter, we outline evolutionary insights that can complement ongoing studies of poxvirus gene functions and biology, which may serve to elucidate new molecular activities linked to this biomedically relevant class of viruses.

Animals

Dating the origin of a viral domestication event in parasitoid wasps attacking Diptera.

Over the course of evolution, hymenopteran parasitoids have developed a close relationship with heritable viruses, sometimes integrating viral genes into their chromosomes. For example, in Drosophila parasitoids belonging to the Leptopilina genus, 13 viral genes from the Filamentoviridae family have been domesticated to deliver immunosuppressive factors to host immune cells, thereby protecting parasitoid offspring from the host immune response. The present study aims to comprehensively characterize this domestication event in terms of the viral genes involved, the wasp diversity affected by this event and its chronology. Our genomic analysis of 41 Cynipoidea wasps from six subfamilies revealed 18 viral genes that were endogenized during the early radiation of the Eucoilini/Trichoplastini clade around 75 million years ago. Wasps from this highly diverse clade develop not only from Drosophila but also from a variety of Schizophora. This event coincides with the radiation of Schizophora, a highly speciose Diptera clade, suggesting that viral domestication facilitated wasp diversification in response to host diversification. Additionally, in one of the species, at least one viral gene was replaced by another gene derived from a related filamentovirus. This study highlights the impact of viral domestication on the diversification of parasitoid wasps.

Animals

Comprehensive genomic analysis of antibiotic resistance plasmids in animal-associated Staphylococcus aureus in France.

UNLABELLED: In Staphylococcus aureus, an animal pathogen and zoonotic agent, plasmids play a pivotal role in the acquisition and spread of antibiotic resistance genes (ARGs). This study investigated the plasmid content of 329 S. aureus isolates from livestock and companion animals collected in France between 2010 and 2021. Plasmids (n = 211) were identified from 139 isolates. The major families identified-rep7a, rep20, and rep10-were associated with specific resistance genes (str, cat, blaZ, erm(C)) and exhibited widespread horizontal transfer across different S. aureus sequence types (STs) and animal hosts. In temporal analysis, the rep7a/str and rep7a/cat plasmids circulating in horses were progressively replaced by a rep7a plasmid carrying both str and cat genes. The study also highlighted the presence of mosaic plasmids, which combined elements from different bacterial species/genera, confirming the broad host range of S. aureus plasmids and their ability to acquire ARGs from diverse sources. Moreover, the occurrence of hybrid plasmids (carrying multiple rep genes) underscores the plasticity of these vectors of ARGs. This study emphasizes the need to investigate the mechanisms driving the spread and persistence of antibiotic-resistant plasmids in S. aureus, with a view to developing strategies aimed at combating antibiotic resistance. IMPORTANCE: The spread of antibiotic resistance in Staphylococcus aureus is a growing concern, particularly in animals that can serve as reservoirs for resistant strains. This study highlights the crucial role of plasmids in transmitting resistance genes among different animal hosts and S. aureus lineages. The characterization of 329 isolates collected over 10 years revealed how certain plasmid families are associated with specific resistance genes and how they evolve over time. The occurrence of mosaic and hybrid plasmids further underscores the ability of S. aureus to acquire resistance from diverse bacterial sources. These findings provide key insights into the mechanisms shaping antibiotic resistance in this pathogen and emphasize the fact that understanding plasmid-driven resistance is essential for developing effective interventions to limit the spread of multidrug-resistant S. aureus in both veterinary and human medicine.

Animals