Sabri Saeed Sanabani

Background: Acute viral infections trigger overlapping but virus‐specific blood transcriptional responses; however, current analyses rarely quantify the mechanistic depth of activation across pathways, regulators, and immune cell compositions. Methods: RNA‐seq data from GSE157240 were reanalyzed to infer transcription factor (TF) activity using DoRothEA/decoupleR, signaling pathway activity using PROGENy, and stress pathway and transcriptional perturbation breadth metrics. These four components were integrated into a viral host perturbation score (VHPS), a proof‐of‐concept framework designed to quantify the magnitude of host transcriptional perturbation. Differential expression analysis, Gene Ontology enrichment, module scoring, and CIBERSORTx‐based immune deconvolution were used to compare respiratory and systemic viral infections. Results: VHPS‐stratified viruses along an axis of host transcriptional perturbation, with DNA viruses showing the highest median perturbation, followed by dengue and enterovirus/rhinovirus, whereas influenza A and other respiratory RNA viruses were intermediate and healthy controls were lowest. Upregulated genes revealed virus‐specific and shared signatures, and immune/stress GO terms showed stronger T cell and interferon enrichment for respiratory viruses. A 26‐gene “shared respiratory antiviral” module correlated with VHPS and TF/stress components but not PROGENy activity. Immune deconvolution revealed virus‐specific leukocyte remodeling, with marked Treg depletion and elevated neutrophils in respiratory viruses, monocyte skewing in dengue, and the lowest Treg fractions in DNA viruses. Conclusions: Together, VHPS and immune deconvolution delineate shared and virus‐specific regulatory programs in acute viral infections, but the generalizability of VHPS requires evaluation in independent datasets.

Chronic diabetic foot ulcers represent a persistent clinical challenge characterized by a “locked” inflammatory phase, biofilm‐mediated infection, and impaired tissue regeneration. Because conventional antibiotic and debridement therapies fail to resolve dysbiosis or stimulate healing, microbial antagonism has emerged as a potent biological principle for wound restoration. This narrative review integrates ecological evidence and mechanistic insights from animal models and early human studies to explore how beneficial microorganisms, including probiotics, bacteriophages, and competitive consortia, actively reshape diabetic wound environments. We examined the multifaceted mechanisms of these interactions, ranging from direct pathogen inhibition to host immunomodulation and metabolic signaling via conserved pathways such as the p40/epidermal growth factor receptor (EGFR)/PI3K axis. To address significant translational barriers, we introduce a “Regenerative Microbiology” framework that emphasizes spatiotemporal coordination and precision stratification. By tailoring the use of live biotherapeutics or metabolically independent postbiotics to a patient's vascular and microbial profiles, this approach offers a strategic roadmap for transforming the management of infection‐driven tissue damage in chronic diseases.

Neurofibromatosis Type 1 (NF1), an autosomal dominant genetic disorder, is characterized by extensive clinical variability, posing significant challenges for prognosis and patient management. Despite being caused by mutations in a single gene, NF1 , the expressivity of the disease ranges from mild cutaneous manifestations to severe, life-threatening complications, including malignant tumors, skeletal deformities, and cognitive impairments. This paper provides a comprehensive review of the genetic determinants underlying this phenotypic heterogeneity. We begin by elucidating the molecular genetics of NF1, detailing the structure and function of the NF1 gene and its protein product, neurofibromin, and the diverse spectrum of mutations that cause the disorder. Neurofibromin’s critical role as a negative regulator of the Ras signaling pathway is central to understanding the pathophysiology of NF1. Subsequently, the paper explores the primary mechanisms driving phenotypic variation, including established genotype-phenotype correlations, the influence of genetic modifiers, the impact of somatic mosaicism and second-hit mutations, and the emerging role of epigenetic and environmental factors. By synthesizing current knowledge, this review aims to construct a holistic view of the complex interplay between the primary NF1 mutation and the broader genetic landscape that ultimately shapes the clinical presentation of NF1. Understanding these determinants is crucial for advancing diagnostic capabilities, developing personalized therapeutic strategies, and improving clinical outcomes for individuals affected by this complex disorder.

Background: Lung cancer remains a leading cause of mortality, mainly due to aggressive metastasis and therapeutic resistance. Snake venom metalloproteinases (svMPs), particularly the P-I class, are promising sources for novel antitumor agents. Objectives: This study investigated the impacts of BthMP, a P-I svMPs from Bothrops moojeni venom, on human lung carcinoma (A549) cells in comparison to non-cancerous human bronchial epithelial cells (BEAS-2B). Methods and Results: BthMP demonstrated potent and selective anti-cancer activity. It significantly inhibited key metastatic processes in A549 cells, including adhesion, migration, and invasion, while suppressing long-term proliferation, as shown by reduced colony formation and increased lactate dehydrogenase (LDH) release. Mechanistically, BthMP induced a massive increase in intracellular reactive oxygen species (ROS) by over 2000% and elevated nitric oxide (NO) by 35% in A549 cells, driving a state of lethal oxidative stress. Crucially, these cytotoxic and anti-metastatic effects were minimal in BEAS-2B cells; BthMP even suppressed basal ROS and NO levels in this non-cancerous line. The anti-migratory effects of BthMP were completely dependent on its zinc-based catalytic activity, as they were abolished by pretreatment with ethylenediaminetetraacetic acid. By simultaneously disrupting cell–matrix interactions and inducing selective, catastrophic oxidative stress in cancer cells, BthMP presents a dual-pronged anti-metastatic mechanism. Conclusions: These findings establish BthMP as a promising therapeutic scaffold for developing novel treatments against lung cancer progression.

Human T-cell lymphotropic virus type 1 (HTLV-1) can cause HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), a progressive neuroinflammatory disease that lacks noninvasive biomarkers. We used untargeted urine metabolomics with machine learning to profile 113 participants (39 with HAM, 17 with intermediate syndrome, 33 asymptomatic carriers, and 24 healthy controls). Gas chromatography–mass spectrometry identified 175 metabolites, 86 of which showed significant differences (fold change > 2, FDR p < 0.05). Multivariate analyses revealed distinct but partially overlapping metabolic profiles: sPLS-DA captured a reproducible yet moderately discriminative signal, while nonlinear machine learning models (Random Forest and SVM) achieved robust group separation, with HAM displaying a distinct metabolic signature. Key discriminators included Unknown_151, Unknown_127, histidine, alanine, and 4-hydroxyphenylacetic acid, which showed marked reductions in HAM and yielded ROC AUCs of 0.855–0.871. Pathway and disease enrichment analyses highlighted disturbances in amino acid metabolism, particularly beta-alanine and aromatic amino acids, along with disease signatures related to inherited amino acid handling disorders such as hyperlysinemia. These results demonstrate that urinary metabolomics combined with machine learning can identify potential noninvasive biomarkers for HAM and provide novel insights into HTLV-1-associated pathophysiology.

The considerable HIV-1 genetic diversity has several implications for viral adaptive and evolutionary capabilities. Its genetic diversity is due to its high mutational rates derived from the error-prone viral reverse transcriptase activity, which generates highly heterogeneous viral populations. Moreover, genetic diversity can also increase due to intra- or intersubtype viral genomic recombination following multiple infections. This study examines HIV-1 intersubtype recombinant viruses and their increased genomic diversity over a 12-month period in five individuals from São Paulo state, Brazil. We collected peripheral blood mononuclear cells once every three months from selected participants at five distinct visits. Molecular clones of 1.15 Kbp fragments of the Pol polyprotein, spanning the protease and a portion of the reverse transcriptase (RT) genes, were generated by bulk PCR. Pol sequences were used for evolutionary analysis, including phylogenetics (using TnT), genetic diversity (using Highlighter), and hypermutation frequency (using Hypermut). Recombination detection experiments were conducted with a jumping profile-hidden Markov model (jpHMM), SimPlot++, and RDP5. We observed great genetic diversity and frequent recombination events in all patients. Furthermore, most of the patients presented hypermutations. These findings highlight the dynamic nature of HIV-1 genetic diversity, driven by frequent recombination and hypermutation, which can accelerate viral adaptation and diversification, underscoring the challenges for treatment, prevention, and disease control.

Human T‐lymphotropic virus type 1 (HTLV‐1)‐associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a chronic neuroinflammatory disease. Given the established role of the gut‐brain axis in other neurological diseases such as multiple sclerosis, the role of the gut microbiome in the pathogenesis of HAM/TSP remains a critical unexplored area. The aim of this study was to characterize alterations in the gut microbiome associated with HTLV‐1 infection and its clinical stages. We performed a cross‐sectional analysis of the gut microbiome from 112 Brazilian individuals, including 24 healthy controls and 88 HTLV‐1‐infected individuals at different disease stages: 38 HAM patients, 17 patients with intermediate syndromes, and 33 asymptomatic carriers. Fecal samples were collected and analyzed using Illumina MiSeq sequencing to assess bacterial composition and diversity. Functional analysis was performed to identify differentially enriched gene categories and Kyoto Encyclopedia of Genes and Genomes (KEGG) modules. Significant dysbiosis was observed in HTLV‐1‐infected individuals, characterized by reduced bacterial diversity, an inverted Firmicutes/Bacteroidetes ratio, and specific changes in bacterial genera. Notably, HAM patients exhibited decreased Faecalibacterium and increased Ruminococcus_g2 abundance. These associations should be interpreted with caution, as patient cohorts were significantly older and differed in sex distribution from healthy controls. Functional analysis revealed 13 differentially enriched gene categories and five KEGG modules that were more abundant in HAM patients, indicating alterations in metabolic processes. These findings provide the first comprehensive insight into gut microbiome changes associated with HTLV‐1 infection and disease progression. This study provides the first comprehensive insight into gut microbiome changes associated with HTLV‐1 infection and disease progression. The identified microbial signatures and functional alterations highlight potential diagnostic and therapeutic targets for HTLV‐1‐associated diseases, particularly HAM. These findings open new avenues for further research and clinical applications.

Human T-lymphotropic virus type 1 (HTLV-1) infection is associated with a spectrum of clinical outcomes, ranging from lifelong asymptomatic carriage to severe conditions such as HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) and adult T-cell leukemia/lymphoma (ATLL). Although antibody responses are known to shape immune regulation, the functional relevance of IgG idiotype repertoires in HTLV-1 pathogenesis remains poorly understood. This study investigated the immunomodulatory effects of IgG from individuals with distinct HTLV-1 clinical outcomes. IgG was purified from pooled serum samples of asymptomatic carriers (ACs), HAM/TSP, and ATLL patients and used to stimulate peripheral blood mononuclear cells (PBMCs) from healthy donors. Cytokine production in CD4⁺, CD8⁺, and γδ T cells was assessed by flow cytometry. Additionally, proteome-wide IgG reactivity was evaluated using a human protein microarray encompassing over 21,000 proteins, and bioinformatic analyses were conducted to identify protein–protein interaction networks and tissue-specific autoreactivity. HAM/TSP-derived IgG selectively enhanced IFN-γ production in all T-cell subsets and suppressed IL-4 in CD4⁺ T cells. ATLL-derived IgG induced IL-9 and IL-13 production in CD4⁺ T cells, and both HAM/TSP and ATLL IgG elevated IL-13 levels in CD8⁺ T cells. Microarray data revealed distinct autoreactive IgG profiles across clinical groups, targeting immune-related proteins, apoptotic regulators, and proteins expressed in T cells, monocytes, and non-immune tissues such as brain and testis. Notably, no functional or structural clustering was observed in protein–protein interaction networks, suggesting these reactivities reflect complex, idiotype-specific immune alterations rather than compensatory responses. The present findings suggest that HTLV-1 infection may be associated with the development of distinct IgG repertoires that potentially modulate cytokine responses and exhibit broad reactivity toward human proteins. Such patterns could contribute to immune dysregulation and may partially explain the divergent clinical trajectories observed in HAM/TSP and ATLL. Further investigations are warranted to validate these observations at the individual level and to clarify their mechanistic relevance in disease progression.

Endometriosis is a chronic gynecological disease characterized by the presence of endometrial-like tissue outside the uterus, leading to pain and infertility. Recent research has highlighted the important role of the microbiome in various health conditions, including endometriosis. The aim of this review is to examine the central role of the microbiome in the development and treatment of endometriosis. Key findings include the influence of the gut microbiota on estrogen metabolism, whereby certain bacteria can increase estrogen levels and systemic inflammation and exacerbate endometriosis. Changes in the vaginal and endometrial microbiota are also associated with the disease, as they influence inflammatory and estrogen-dependent metabolic pathways. Dysbiosis in various microbiomes can affect inflammatory pathways, with a shift in the vaginal microbiota to the upper reproductive tract affecting endometriosis without symptoms. Probiotic interventions show promise in restoring a healthy microbiota and improving outcomes, with clinical trials demonstrating the efficacy of lactobacilli-based medications for pain relief. In addition, diet and lifestyle changes can directly impact the gastrointestinal microbiome, reducing inflammation and potentially influencing endometriosis. Future research should focus on establishing comprehensive microbiome profiles, mechanistic studies and longitudinal studies to discover new therapeutic targets and improve clinical outcomes for women with endometriosis.