Biology and Life Sciences

Abstract:

The presence of atmospheric carbon dioxide and potential subsurface molecular hydrogen (H₂), in addition to potential subsurface liquid water sources, suggest that the martian subsurface may currently be habitable, particularly to autotrophic chemosynthetic microorganisms. In addition, the widespread nature of clays and other minerals on Mars could provide sufficient nutrients to support microbial life. Here we tested four methanogenic species (Methanosarcina barkeri, Methanobacterium formicicum, Methanothermobacter wolfeii, and Methanococcus maripaludis) in the presence of illite, nontronite, and one martian regolith simulant, Mojave Mars Simulant (MMS), in their optimal growth medium. We aimed to determine whether the presence of certain clay minerals and regolith simulants inhibited, promoted, or had no effect on methane (CH₄) production by these microorganisms. We also tested the same methanogens in the presence of montmorillonite, H₂, sodium sulfide (Na₂S), and bicarbonate buffer to determine if this clay could support growth (as measured by CH₄ production). Results indicated that three of the four methanogens tested, M. barkeri, M. formicicum, and M. wolfeii, were capable of growth in the presence of both clay minerals and MMS, although most cultures demonstrated lower CH₄ production compared to growth in optimal media without clay minerals. Additionally, all three methanogens were capable of CH₄ production in cultures containing only 10% (w/v) montmorillonite, H₂, Na₂S, and bicarbonate buffer. Conversely, M. maripaludis, a halophile, showed the greatest sensitivity of the four methanogens tested, being unable to produce any CH₄ in cultures containing standard methanogenic growth medium and 2% (w/v) illite or in bicarbonate buffer containing H₂, Na₂S, and 10% (w/v) montmorillonite. However, in one experiment assessing the minimum medium requirements for this organism, the presence of 5% (w/v) montmorillonite enabled greater CH₄ production compared to cultures containing the organism’s standard growth medium alone. Overall, these results suggest that the presence of clay minerals on Mars does not preclude the survivability and growth of methanogens in a potential subsurface habitat on the planet. In fact, these geological components may provide sufficient nutrients to support growth and survivability.

Abstract:

Bacteriophages (phages) represent promising therapeutic agents. Their use in treatments is challenged by the rapid rise of resistant bacterial clones. To overcome this problem, phages can be trained in vitro to adapt them to the possible resistance that may arise. Here, we co-evolved phages with their hosts under different conditions and assessed the outcomes using qPCR. The co-evolution experiment yielded a panel of bacterial clones that were either adapted to a phage, a competing phage, or to a cocktail of both. The adaptation of a phage was done either in the continuous presence of an evolutionarily naïve host, or in a cocktail with a competing phage, or both conditions, or neither conditions. We assessed each obtained phage ability to infect evolved bacterial clones in the panel we created, and we used qPCR to enable high-throughput assessment. This allowed us to evaluate 500 phage-bacteria interactions. While all phages benefitted from the presence of evolutionary naïve hosts, the screening suggests that optimal training conditions are phage-specific, based on the four phages tested. For Enterobacter cloacae phages EC151 and EC152, the most extensive infectivity in our experiments was observed when a competing phage and/or an evolutionarily naïve host was included during adaptation. For Stenotrophomonas maltophilia phages StM171 and StenM174, the presence of an evolutionarily naïve hosts appeared beneficial in both replicates; co-adaptation with a competing phage led to a complete loss of StM171 infectivity in both experiments, but benefited StenM174. Phages passaged for 10 passages consistently infected a broader range of bacterial clones than those sampled after 5 passages. Sequencing of 8 phages obtained after adapting EC152 identified recurring mutations in a transcriptional regulator, and in some cases, in the baseplate and tail fiber genes.

Abstract: Neuromyelitis optica spectrum disorder (NMOSD) is a severe autoimmune astrocytopathy of the central nervous system, characterized by recurrent optic neuritis and longitudinally extensive transverse myelitis. Due to overlapping features with multiple sclerosis (MS), misdiagnosis remains common, yet treatment strategies differ fundamentally between these conditions. This narrative review synthesises recent advances in diagnostic and prognostic biomarkers for NMOSD, focusing on serological, cellular, molecular, and microbiological indicators.A targeted literature search was conducted in PubMed, Scopus and Web of Science (January 2015 – June 2025) using keywords related to NMOSD and biomarkers. Of over 500 initially identified articles, 72 key references were selected based on scientific relevance, methodological quality and clinical applicability, consistent with a narrative review approach.Established biomarkers – aquaporin‑4 immunoglobulin G (AQP4‑IgG) and myelin oligodendrocyte glycoprotein antibodies (MOG‑IgG) – remain central to diagnosis and phenotypic classification. Emerging markers, including glial fibrillary acidic protein (GFAP), neurofilament light chain (NfL), cytokines (interleukin‑6, CXCL13, CXCL10), complement components (C3, C4, sC5b‑9), microRNAs, metabolomics profiles, gut microbiome signatures and viral serology (Epstein–Barr virus, human herpesvirus 6), show promise in differentiating NMOSD from MS and MOGAD, predicting relapses, and guiding therapy. Integration of antibody assays with markers of astrocytic and axonal injury, immune activation and microbiological signatures could improve diagnostic accuracy and enable personalised treatment. However, clinical application remains limited by assay variability, lack of standardised cut-offs and small study populations. Future progress requires validated multimarker panels and harmonised measurement platforms across diverse populations.

Abstract: Plague remains a globally significant zoonotic infection maintained in natural foci, with ongoing epizootic activity and periodic human cases reported in different regions of the world. Continuous monitoring of antimicrobial susceptibility of Yersinia pestis is essential due to the potential emergence and spread of resistant strains. A total of 75 Yersinia pestis isolates, including clinical and epizootic strains obtained from plague outbreaks in Kazakhstan, were analyzed. Antimicrobial susceptibility was evaluated using standard phenotypic methods, and molecular screening for resistance determinants was performed by real-time PCR. Genome-level analysis based on whole-genome sequencing (WGS) data from the NCBI BioProject PRJNA1249055 was conducted to assess the presence of acquired antimicrobial resistance genes and chromosomal mutations associated with resistance. All isolates demonstrated high susceptibility to clinically relevant antibiotics. No resistance genes were detected by molecular screening. Genome-based analysis confirmed the absence of acquired antimicrobial resistance determinants, resistance-associated mutations in key loci (rpsL, gyrA, parC), and plasmid-mediated resistance mechanisms. Minor lineage-associated variation in phoP was identified in a limited number of isolates and was not associated with antimicrobial resistance. These findings indicate a stable antimicrobial susceptibility profile of Yersinia pestis in Kazakhstan and confirm the absence of emerging resistance despite long-term circulation in natural plague foci. The results highlight the importance of integrated surveillance and support the continued effectiveness of current therapeutic strategies for plague.

Abstract: Brucellosis and tuberculosis (TB) are chronic infectious diseases of international public health importance, with developing countries being most affected. Co-infection in spite of low prevalence raises a diagnostic challenge due to the common symptoms of infection and immune response. Recently, it has been shown that chronic infections affect cell stress pathways such as oxidative stress and telomere function. The current literature review provides an overview of the relationship between brucellosis and tuberculosis at a molecular level, focusing on telomere biology, oxidative stress and the mechanisms of antimicrobial resistance. Due to chronic immune response in brucellosis and TB patients, an increase in ROS level is observed leading to DNA damage and subsequent telomere shortening and alteration of telomerase activity. These alterations might be responsible for immune senescence, weakened defense response and persistent infection. In addition, different methods of drug resistance have been discovered among brucellae and mycobacteria, such as mutation in target sites, efflux systems and intracellular persistence, making their eradication difficult. Finally, the potential role of telomere-related genes and biomarkers of oxidative stress in diagnosis and prognosis is also highlighted. Insight into these interrelated pathways would allow us to have a better understanding of host-pathogen interaction, and hence offer a possible means of developing new strategies in the fight against co-infection.

Abstract: Background: Colorectal cancer (CRC) continues to be a leading cause of global oncology-related deaths. While mRNA vaccines delivered via lipid nanoparticles (LNPs) have achieved clinical success, challenges regarding systemic inflammatory potential, complex multi-step manufacturing, and cold-chain dependence persist. This study explores an alternative delivery paradigm using Nona-arginine (R9), a cell-penetrating peptide, to stabilise mRNA encoding the Carcinoembryonic Antigen (CEA), providing a biocompatible, LNP-free platform for CRC immunisation. Methods: CEA-encoded mRNA was synthesised through in vitro transcription and complexed with R9 at various Nitrogen-to-Phosphate (N/P) ratios. The resulting polyplexes were characterised using Dynamic Light Scattering (DLS) and Electrophoretic Mobility Shift Assays (EMSA). Molecular docking was employed to elucidate the structural stability of the carrier-cargo interface and the binding kinetics of vaccine-induced antibodies. The therapeutic index was validated in a CT26 murine colorectal tumour model (n=10/group), assessing tumour volume reduction, survival kinetics, and the density of tumour-infiltrating lymphocytes (TILs). Results: Optimal polyplex stability was achieved at an $N/P$ ratio of 10, yielding homogenous particles (142.5 ± 4.2 nm) with a protective zeta potential of +18.6 mV. In vivo evaluation demonstrated a 65% reduction in tumour burden and an $80\%$ survival rate in vaccinated cohorts compared to 0% in control groups. This clinical efficacy was correlated with a 3-fold increase in CD8+ T-cell infiltration, a 7.6-fold upregulation of Granzyme B, and the induction of high-affinity neutralising antibodies (∆∆G = -12.4 kcal/mol) targeting critical metastatic adhesion domains. Conclusion: The R9-mRNA platform serves as a highly effective, lipid-free alternative for CRC vaccination, eliciting a sophisticated "dual-strike" immune response. By bypassing the limitations of LNPs, this strategy offers a streamlined, stable, and potent pathway for the next generation of cancer immunotherapies.

Abstract: Background/Objectives: Induction of anti-SARS-CoV-2 antibodies by COVID-19 vaccination reduces morbidity and mortality, but immune responses may be compromised in people living with HIV (PLWH). The aims of the current study were to determine whether viral suppression (VS) or immune reconstitution (IR) in PLWH directly affected their ability to produce effective levels of anti-SARS-CoV-2 antibodies in mucosal secretions or blood induced by vaccination. Methods: Anti-SARS-CoV-2 spike IgG, IgA and secretory IgA (SIgA) antibodies and their avidities were measured by ELISA in HIV-negative healthy controls (HC; n=49) and PLWH (n=94) using stimulated oral fluid (SOF) and serum. Frequencies of CD4/CD8 T cells and their expression of exhaustion/senescence were determined by flow cytometry. Cytokine levels were measured by cytokine bead arrays. Results: We showed that higher HIV burden negatively impacted the levels of systemic and mucosal anti-SARS-CoV-2 spike IgG antibodies produced. This differential IgG antibody production was unaffected by the IR status, antiretroviral therapy duration or by T cell exhaustion/senescence. PLWH elicited higher anti-SARS-CoV-2 spike IgA antibodies both in peripheral blood and oral mucosa, and secretory IgA (SIgA) antibodies in the oral mucosa. PLWH with higher HIV burdens elicited lower IgG avidity but the IgA avidity indices remained unaffected. PLWH expressed higher levels of innate immunity cytokines irrespective of the HIV burden in the oral mucosa. Conclusions: Significantly fewer breakthrough infections in PLWH compared with HC, along with high IgA/SIgA antibodies and increased innate immunity cytokines in the SOF suggests a potential role for mucosal immunity in the immunopathogenesis of COVID-19.

Abstract: Psoriasis and psoriatic arthritis (PsA) are systemic immune-mediated diseases, but the features that distinguish cutaneous-dominant psoriasis from musculoskeletal involvement remain unclear. We analyzed four core public cross-sectional datasets spanning whole-blood methylation, PBMC single-cell RNA sequencing summarized at the subject level, skin RNA sequencing, and purified CD4+ T-cell methylation, and used two additional public skin cohorts for external contextual checks to define an inflammatory disease axis (DIR) and a contrast-resolved systemic-state coordinate (CRS) representing additional systemic immune-state variation associated with PsA. In whole-blood methylation, DIR primarily separated healthy controls from psoriasis, whereas CRS separated psoriasis from PsA with minimal correlation to DIR. In PBMC single-cell data, CRS was higher in PsA and in the source-defined PSX subgroup (joint pain without CASPAR-classified PsA) than in PsO. Cell-type-resolved analyses localized CRS-related shifts to CD8 naive T cells, NK cells, CD14 monocytes, and regulatory T cells and identified multicompartment pathway-state remodeling along the CRS continuum. In contrast, skin RNA sequencing mainly captured lesional inflammatory burden and showed only limited additional PsA-related separation within the same tissue state. These findings support a model in which PsA is distinguished from psoriasis by an additional systemic immune-state axis rather than by skin inflammatory burden alone.

Abstract: Background/Objectives: Glioblastoma (GBM) remains a lethal primary CNS malignancy with limited response to immunotherapy. Adoptive cellular therapy (ACT) improves survival in preclinical models, yet tumors ultimately recur. While T cell exhaustion is a common mechanism of resistance, the contribution of dendritic cell (DC) dysfunction remains unclear. We aimed to define mechanisms of immune escape following ACT, focusing on DC function and the role of hypoxia. Methods: Using a murine glioma model (KR158B), mice were treated with ACT consisting of tumor RNA–pulsed DC vaccines and adoptively transferred T cells. Tumor-infiltrating immune populations were analyzed by flow cytometry. DC function was assessed using T cell activation assays. Bulk RNA sequencing and gene set enrichment analysis were performed on sorted DCs. Hypoxia was modeled in vitro, and HIF1α was perturbed using CRISPR-mediated knockout. Results: ACT significantly increased survival but did not prevent tumor recurrence. Escaped tumors contained abundant cytotoxic, non-exhausted T cells, indicating that T cell dysfunction was not the primary driver of resistance. Instead, tumor-associated DCs exhibited impaired T cell activation despite preserved antigen uptake. Transcriptomic analyses revealed reduced antigen presentation and co-stimulatory signaling, alongside increased expression of tolerogenic factors. ACT-treated tumors demonstrated heightened hypoxia pathway activation, with elevated HIF1α expression in DCs. Hypoxia induced DC tolerogenic programs and reduced their ability to activate T cells, an effect partially reversed by HIF1α disruption. Increased immune infiltration and inflammation following ACT further amplified hypoxia signaling. Conclusions: DC dysfunction is a key mechanism of immune escape following ACT in glioma. Hypoxia-driven tolerization of DCs impairs sustained anti-tumor immunity, highlighting the hypoxia–DC axis as a promising therapeutic target to enhance immunotherapy efficacy.

Abstract: This article reviews current knowledge in comparative immunology and presents updated hypotheses on the evolution of the immune system in jawed vertebrates. It focuses on the co-option of the RAG transposon in the origin of the V(D)J recombination system, proposed to have occurred in two stages. Initially, the RAG transposon, along with other eukaryote-specific transposon such as HAT, interacted with host genes in early eukaryotes, leading to a new transposition mechanism. Subsequently, RAG and host genes were integrated into the V(D)J recombination system, representing a major evolutionary innovation. The broader implications of this events are also considered. Earlier hypothesis suggest that the establishment of the V(D)J recombination system contributed to MHC polymorphism. Phylogenomic evidence indicates that key immune components, including MHC, T-cell receptors (α,β and γ,δ), and immunoglobulins, existed in ancestors and later expanded through gene duplication, forming multigene families with diverse functions. Their proteins products interact with other immune molecules to regulate immune responses. While some retained original functions, others evolved new roles through neo-functionalization. Overall, the co-option of the RAG transposon played a critical role in shaping the immune system of jawed vertebrates by driving innovation in both adaptive and innate immunity.

Abstract: Irritant contact dermatitis is an inflammatory skin condition caused by exposure of the skin to substances or the environment that damages the skin barrier. Irritant contact dermatitis presents on the skin as a rash accompanied by redness, itching, burning sensation, blisters and cracking of the skin. In babies, it is more commonly known as diaper dermatitis or diaper rash but can also present in older children and adults with incontinence issues. General measures to prevent irritant contact dermatitis in babies includes frequent nappy changes to keep the baby’s skin as dry as possible, regular cleaning to remove urine and feces to maintain a healthy skin pH level and the use of products with minimal chemical irritants (wipes, diapers, barrier creams etc.). This study evaluates the effectiveness of a water-based wipe liquid (WaterWipes®) to reduce urine-induced inflammation in a 3D in vitro human skin model.

Abstract: Adipose tissue is a heterogenous organ with newly identified endocrine function, consisting of immune cells along with main populations of fat storing adipocytes and adipose precursor cells. Dysregulated immune cell function and infiltration cause low grade chronic inflammation in adipose tissue that leads to various metabolic disorders like obesity, insulin resistance, type2 diabetes and cardiovascular disease. Our research showed the role of P311 protein in adipogenesis, amoeboid migration, vascular wall homeostasis, and blood pressure regulation. Studies from our laboratory and other labs showed the potential involvement of P311 in wound healing and predicted immune function. Here we studied the role of P311 on inflammation mainly focusing on macrophage phenotypes and functions as macrophages are predominant immune cells in adipose tissue that switch the inflammatory micro-environment between pro- and anti-inflammatory conditions. For the first time, we show the expression of P311 in macrophages implicating its role in inflammation directly. Further, P311 expression in macrophages induced anti-inflammatory phenotype (M2 macrophages) through phosphorylation of STAT6 of canonical JAK/STAT signaling pathway. The human gastrointestinal (GI) system harbors high populations of both healthier and pathogenic microbial communities that provide immunity, inflammation, nutrients, and GI tract epithelial homeostasis. Given the roles of P311 in macrophage mediated inflammation and metabolic diseases, we verified whether lack of P311 in P311 knockout mice has any effects on GI microbiome compared to wildtype mice. Our studies demonstrate that lack of P311 led to changes in the intestinal microbial strains. Together, current studies implicate a larger role of P311 connecting inflammation and microbiome with obesity.

Abstract: Background/Objectives: The incidence of gastroesophageal reflux disease (GERD) is increasing worldwide; however, the contribution of gastroduodenal microbiota to GERD phenotypes and symptom severity remains incompletely understood. This study profiled mucosa-associated microbiota from the gastric antrum and duodenum across GERD phenotypes and examined site-specific associations with symptom severity. Methods: Forty individuals with erosive reflux disease (ERD), non-erosive reflux disease (NERD), or an endoscopically normal comparator group underwent 16S rRNA gene sequencing of the V3–V4 region. Community differences were assessed using Bray–Curtis dissimilarity, differential taxa were explored by linear discriminant analysis effect size (LEfSe), and correlations with validated symptom questionnaires (GERD-Q and FSSG) were evaluated. Results: Microbial community structure differed significantly between the antrum and duodenum, with Proteobacteria and Firmicutes predominating at both sites. LEfSe suggested enrichment of Streptococcus, Haemophilus, and Enterobacter in the duodenum, whereas Sphingobium, Acinetobacter, and Aquabacterium were more abundant in the antrum. The genus Helicobacter was relatively enriched in the antrum of ERD samples, whereas Streptococcus-dominant signatures were more prominent in the duodenum. Symptom severity showed stronger associations with duodenal taxa, including Prevotella with epigastric pain, throat clearing, and postnasal drip; Veillonella with early satiety; Neisseria with dyspnea; and Helicobacter with hoarseness, whereas gastric associations were fewer. Conclusions: Overall, gastroduodenal microbiota exhibited site-specific differences across GERD phenotypes. These findings highlight the importance of anatomical context in host–microbe interactions and identify site-specific microbial patterns that warrant validation in larger, phenotypically well-characterized cohorts.

Abstract: Neonatal calf diarrhea (NCD) is one of the most important problems of calf breeding across the world. It causes deaths in calves in the first 10 days of their life and it is mainly caused by E. coli, Bovine Rotavirus (BRV) and Bovine Coronavirus (BCoV). Ab-sence of an effective vaccine targeting the main causes of NCD makes disease control highly challenging. The current study aims to design multi-epitope mRNA based vac-cine targeting the major pathogens responsible for NCD using Immunoinformatic tools and molecular modelling approaches. BRV capsid protein VP6, BCoV Spike glycopro-tein and E. coli F5 fimbrial protein were used as antigenic proteins to predict potential epitopes. Fifteen selected epitopes were linked with suitable linkers and conjugated with build adjuvant, resulting in designing of stable, antigenic and non-allergenic vac-cine candidate against NCD pathogens. Furthermore, Molecular docking analysis shows strong binding affinity between the vaccine candidate and bovine Toll-like re-ceptors TLR2 and TLR4 at low energy and high stability. Based on these findings, the proposed multi-epitope vaccine represents a promising approach for prevention and control of neonatal calf diarrhea and provides a solid scientific foundation for future experimental studies to validate its efficacy and safety in vivo.

Abstract: The Caribbean exhibits hyperendemic dengue transmission with near-universal adult seroprevalence in many territories, driven by sustained co-circulation of all four DENV serotypes and the domestic ecology of Aedes aegypti. Serosurveys report adult IgG rates as high as 93–100% in the French West Indies, Puerto Rico, and Jamaica, while children frequently acquire multitypic immunity before adolescence. High inapparent infection rates and population mobility complicate surveillance and mask true transmission intensity. These immunoepidemiological conditions elevate the risk of severe disease via antibody-dependent enhancement and challenge both acute diagnostics and vaccine policy. Effective control demands year-round integrated vector management, improved molecular and neutralization-based surveillance, pediatric-focused prevention strategies, and cautious deployment of balanced tetravalent vaccines informed by serotype-specific and genomic data.

Abstract: Historically, the study of oral fungal species was limited by the inability to cultivate most of them. However, advances in metagenomic techniques have enabled the direct identification of microbial genomes from human samples, markedly broadening our understanding of the oral mycobiome. This literature review aims to analyze the available scientific evidence on the composition and dynamics of the oral mycobiome, as well as its influence on the development of local pathological conditions. The oral mycobiome is highly diverse, with emphasis on genus Candida, followed by Malassezia, Aspergillus, Saccharomyces, Cladosporium, Trichosporon and Geotrichum. Candida albicans remains the most frequently identified species in both health and diseases state. However, individuals with oral candidiasis present a higher detection of Candida dubliniensis, Candida parapsilosis, Pichia kudriavzevii, Antrodiella micra and Cladosporium sphaerospermum. In dental caries, C. albicans and C. dubliniensis are associated with advanced lesions, whereas Malassezia and Rhodotorula may exert protective effects against cariogenic bacteria. In periodontitis, an increase in yeast-bacteria interactions is observed. Additionally, C. albicans has been implicated in oral carcinogenesis through multiple mechanisms. These findings highlight the need for a deeper understanding of the oral mycobiome to enable early detection of oral diseases and the development of therapeutic approaches.

Abstract: Background: The dendritic cell initiates and directs antigen-specific immunity. Three Nobel Prizes frame the system it controls: Steinman (2011) for the dendritic cell as conductor of adaptive immunity; Allison and Honjo (2018) for CTLA-4 and PD-1 checkpoint inhibition; Sakaguchi, Brunkow, and Ramsdell (2025) for Foxp3+ regulatory T cell tolerance. Hypothesis: The evidence reviewed here establishes that these discoveries describe a single bidirectional circuit with the dendritic cell as its fulcrum, and that the tolerogenic default observed in aging, cancer, chronic infection, and senescence represents a correctable failure of dendritic cell instruction driven by a specific molecular chain: SASP–STAT3–DNMT/EZH2–IRF8 silencing. SASP cytokines activate STAT3 in hematopoietic progenitors; STAT3 recruits DNMT1/DNMT3B and EZH2 to silence IRF8 through dual DNA and histone methylation; IRF8 silencing—locked by a BATF3-dependent bistable switch with no stable intermediate within any given lineage, though different lineages have different switching thresholds producing the dose-dependent phenotypes in human IRF8 mutations (90)—simultaneously eliminates IL-12 transcription, disarms target cells against apoptosis, collapses genome surveillance, and installs bilateral disarmament across the immune synapse. STAT3 in parallel drives PD-L1 transcription on tolerogenic DCs and tumor cells. Six molecular locks on IL-12 operate at transcriptional initiation, elongation, post-translational, progenitor fate, biosynthetic, and Polycomb/histone methylation levels, with a seventh lock—the PGE2 chromatin trap—permanently closing the IL-12p35 locus through cAMP-dependent nucleosome stabilization during the maturation window. Seven self-reinforcing loops—including the SOCS3 feed-forward loop, the alpha-ketoglutarate trap blocking TET demethylases, the NAD+/SIRT1 acetylation lock, lactate-derived lysine lactylation, the STAT3-EZH2 Polycomb loop, and the mTOR-STAT3 amplification loop—ensure the tolerogenic default is metabolically as well as epigenetically locked. Proposed correction: The alpha-type-1 polarized dendritic cell (alpha-DC1), manufactured ex vivo with IFN-γ and multi-TLR engagement, escapes this architecture because its maturation commitment occurs outside the STAT3 field. It initiates a self-amplifying four-phase cascade that progressively restores IRF8 expression across the immune surveillance network, simultaneously re-enabling all ten IRF8-dependent surveillance functions, breaking all seven feedback loops by removing their SASP input, and reversing all three dimensions of bilateral disarmament through a single manufactured cell that renders itself unnecessary by correcting the upstream cause of its own requirement. Significance: This framework redefines the alpha-DC1 from an immunotherapy to a biological senolytic—an intervention that clears senescent cells by restoring the immune system’s endogenous capacity to clear them—and redefines the therapeutic target from the effector compartment to the instructor.

Abstract: Current models of microbiome–immune crosstalk center on extracellular receptor-mediated signaling, yet a critical observation challenges this paradigm: intracellular concentrations of gut-derived bacterial metabolites (GDBMs) in CD4⁺ T cells do not correlate with paired plasma levels, and it is intracellular — not circulating — GDBM burden that associates with metabolic pathway disruption and immune senescence. Here we propose the concept of an intracellular microbiome metabolome: a pool of aromatic GDBMs actively accumulated through carrier-mediated transport, retained through transcriptional suppression of efflux transporters, and integrated into host metabolic networks where metabolites directly engage intracellular senescence pathways. Using p-cresol sulfate (PCS) as a mechanistic prototype, we review transcriptomic, proteomic, and metabolomic evidence implicating SLCO4A1/OATP4A1 as the primary entry transporter, whose suppression following PCS exposure creates a feed-forward intracellular retention loop. Once accumulated, PCS functions as a direct agonist of the aryl hydrocarbon receptor (AhR), engaging five downstream effector programs — TGF-β/SMAD signaling, Wnt/β-catenin reprogramming, Foxp3-dependent Treg induction, Notch dysregulation, and PTGS2/COX-2 induction with coordinate HPGD suppression driving PGE₂ excess via EP2/EP4/cAMP/CREM — that converge on mTOR suppression, glycolytic collapse, and mitochondrial dysfunction. This metabolic collapse in turn activates the GCN2/integrated stress response as a downstream consequence, driving p16/CDKN2A and p21/CDKN1A induction and the full immunometabolic signature of accelerated CD4⁺ T cell aging. The plasma–intracellular dissociation explains why circulating GDBM levels have failed to predict immune outcomes in HIV-1 infection, chronic kidney disease, and aging, and positions intracellular GDBM quantification as the biologically relevant exposure metric. We discuss three therapeutic intervention layers: reduction of microbial metabolite production, blockade of SLCO4A1-mediated entry and efflux suppression, and targeting the AhR signaling axis with downstream metabolic and GCN2/ISR consequences.

Abstract: Autophagy, also referred to as the “self-eating machinery”, is a crucial process where organisms maintain intracellular homeostasis through recycling or degrading non-essential and damaged cellular components, especially during starvation conditions. Autophagy is important in numerous biological functions such as cellular differentiation, aging, nutrient sensing, stress response, tissue homeostasis, immunity, and programmed cell death. To induce autophagy, a double-layered membrane structure called “autophagosome” wraps damaged organelles or proteins and transports them to the vacuole or lysosome for degradation. Autophagy is beneficial to organisms, and it should be optimally regulated because elevated or decreased levels are detrimental for survival. To date more than 40 autophagy-related genes (ATGs) have been identified in the budding yeast Saccharomyces cerevisiae, with most having homologs in fungi and higher eukaryotes. Majority of the ATGs in industrial and pathogenic fungal species have been characterized and known to play vital roles in growth, development, and virulence. In this review we provide a comprehensive overview of ATGs in various fungal species and highlight how autophagy is regulated and controls various functions in plant, human, and industrial fungal species.

Abstract:

Pet birds are increasingly recognized as reservoirs of zoonotic and antimicrobial-resistant bacteria, raising concerns within the One Health framework. However, data on bacterial diversity and resistance profiles in clinically affected ornamental birds remain limited. This study, conducted over three years (November 2022–March 2026), included 198 pet birds presenting with digestive and respiratory disorders. Samples were analyzed bacteriologically, with isolates identified by MALDI-TOF mass spectrometry, and antimicrobial susceptibility assessed using the Kirby-Bauer disk diffusion method according to EUCAST and CLSI guidelines. Bacterial growth was detected in 87.9% of cases, yielding 249 isolates across 26 genera. Gram-positive cocci predominated (62.3%), particularly Staphylococcus spp. (33.3%) and Enterococcus spp. (9.6%), while Escherichia coli (9.2%) was the most common Gram-negative species. Polymicrobial infections occurred in 39.1% of cases. High resistance rates were observed for tylosin (71.6%), oxytetracycline (68.4%), and trimethoprim–sulfamethoxazole (63.4%), whereas amikacin showed the highest susceptibility (58%). Overall, 57% of isolates were multidrug-resistant, with Staphylococcus spp. contributing most to this burden. These findings highlight pet birds as important reservoirs of antimicrobial-resistant bacteria and highlight the need for routine diagnostics and improved antimicrobial stewardship in avian medicine.