Biology subjects

Nath, P.

Publications and source records attributed to Nath, P..

5 recordsLinked to original sources

bioRxiv2026

mTOR inhibition augments antitumor immune effector response by reprogramming the TP53-mutant, immune-cold HNSCC tumor microenvironment.

IntroductionResistance to immunotherapy remains a major clinical challenge in TP53-mutant head and neck squamous cell carcinoma (HNSCC), a disease subset characterized by immune exclusion, high recurrence, and poor outcomes. Given the constitutive activation of PI3K/AKT/mTOR signaling in TP53-mutant HNSCC and its role in disease progression, we investigated whether the mTOR inhibition (mTORi) could overcome immune resistance and improve outcomes. MethodsWe evaluated the effects of mTOR inhibitor everolimus in TP53-mutant, anti-PD-1-resistant syngeneic HNSCC cell lines and syngeneic tumor models. Tumor microenvironment (TME) changes, including immune cell infiltration, immune checkpoint expression, and key pathways associated with immune suppression and angiogenesis were assessed to define the mechanisms underlying TME remodeling. ResultsEverolimus significantly suppressed tumor growth in syngeneic HNSCC models. At the cellular level, everolimus significantly increased intratumoral CD8+ T cell and dendritic cell (DC) infiltration while reducing the accumulation of regulatory T cells (Tregs). Mechanistically, everolimus induced a cytokine/chemokine response, marked by increased TNF-/CXCL10 expression, leading to enhanced immune infiltration. Everolimus also inhibited the HIF-1/VEGFA angiogenic axis, a central driver of immune exclusion and myeloid-derived suppressor cell (MDSC) recruitment. Furthermore, everolimus treatment attenuated PD-1/PD-L1 signaling by reducing PD-1 and PD-L1 expression, respectively, in T cells and tumor cells, thereby restoring T-cell cytotoxic competence. DiscussionThese findings demonstrate that mTORi with everolimus reverses multiple mechanisms of immune resistance in TP53-mutant HNSCC by promoting immune cell recruitment, suppressing immunosuppressive pathways, and enhancing anti-tumor T cell activity. Collectively, these results support mTORi as a mechanistically rational strategy for reprogramming immune resistance in TP53-mutant HNSCC and provide a strong preclinical rationale for combining everolimus with immune therapy in patients who are likely to fail immunotherapy.

cancer biology↗

bioRxiv2026

Mycobacteriophage D29-Derived LysB Enhances Anti-Tubercular Therapy in Experimental Pulmonary Tuberculosis

Adjunctive therapies that enhance the efficacy of existing antitubercular drugs are needed for drug-resistant tuberculosis. We evaluated the efficacy of intranasally administered recombinant D29 LysB, a mycobacteriophage-derived mycolylarabinogalactan esterase, in murine and guinea pig models of pulmonary tuberculosis. BALB/c mice and guinea pigs were aerosol-infected with Mycobacterium tuberculosis H37Rv and treated for 4 weeks with LysB alone or with standard antitubercular therapy (ATT: rifampicin, isoniazid, pyrazinamide). Outcomes included pulmonary and extrapulmonary bacterial burden (CFU), lung and spleen histopathology, cytokine profiling, and humoral immune responses. LysB monotherapy produced modest pulmonary CFU reductions. When given adjunctively with ATT, LysB produced an additional 0.6-0.7 log10 reduction in lung CFU compared with ATT alone and decreased splenic dissemination in both species. Combination therapy improved tissue pathology, reducing granulomatous involvement and preserving pulmonary architecture. LysB treatment increased TNF- with a moderate rise in IL-10, a profile consistent with enhanced antibacterial immunity without excessive inflammatory damage. Repeated intranasal administration was well tolerated; no IgE-mediated hypersensitivity was detected. LysB-specific IgG developed but did not diminish therapeutic efficacy. These results show that intranasal D29 LysB augments the bactericidal and histopathological effects of standard ATT in vivo and support further development of inhaled phage-derived lysins as adjunctive therapies for drug-resistant tuberculosis. ImportanceTuberculosis remains a major cause of infectious mortality worldwide, and the increasing burden of multidrug-resistant and extensively drug-resistant disease continues to challenge effective treatment. New therapeutic approaches that complement conventional antibiotics are urgently needed. In this study, intranasally delivered recombinant mycobacteriophage-derived LysB was well tolerated and enhanced treatment efficacy in experimental pulmonary tuberculosis. Adjunctive LysB improved bacterial clearance, reduced tissue pathology, and modulated host immune responses in both murine and guinea pig models. These findings highlight phage-derived endolysins as promising inhalable adjunctive therapeutics for drug-resistant tuberculosis.

microbiology↗

bioRxiv2025

Future flooding tolerant rice germplasm: resilience afforded beyond Sub1A gene

Developing high-yielding, flood-tolerant rice varieties is essential for enhancing productivity and livelihoods in flood-prone ecologies. We explored genetic avenues beyond the well-known SUB1A gene to improve flood resilience in rice. We screened a collection of 6,274 elite genotypes from IRRIs germplasm repository for submergence and stagnant flooding tolerance over multiple seasons and years. This rigorous screening identified 89 outstanding elite genotypes, among which thirty-seven exhibited high submergence tolerance, surpassing the survival rate of SUB1A introgression genotypes by 40-50%. Thirty-five genotypes showed significant tolerance to stagnant flooding, and 17 demonstrated dual tolerance capabilities, highlighting their adaptability to varying flood conditions. The genotypes identified have a broader genetic diversity and harbor 86 key QTLs and genes related to traits such as grain quality, grain yield, herbicide resistance, and various biotic and abiotic traits, highlighting the richness of the identified elite collection. Besides germplasm, we introduce an innovative breeding approach called Transition from Trait to Environment (TTE). TTE leverages a parental pool of high-performing genotypes with complete submergence tolerance to drive population improvement and enable genomic selection in the flood breeding program. Our approach of TTE achieved a remarkable 65% increase in genetic gain for submergence tolerance, with the resulting fixed breeding genotypes demonstrating exceptional performance in flood-prone environments of India and Bangladesh. The elite genotypes identified herein represent invaluable genetic resources for the global rice research community. By adopting the TTE approach, which is trait agonistic, we establish a robust framework for developing more resilient genotypes using advanced breeding tools. Plain Language SummaryTo address climate challenges, an urgent focus is necessary to identify and develop flood-tolerant rice varieties, particularly for flood-prone ecosystems across Asia and Africa. We screened 6,274 elite genotypes from IRRIs germplasm and identified 89 promising lines with improved tolerance to submergence and stagnant flooding. Among these, 37 demonstrated 40-50% greater submergence tolerance than SUB1A introgression lines, 35 exhibited stagnant flooding tolerance, and 17 showed dual tolerance. These genotypes contain 86 key QTLs and genes associated with yield, grain quality, and biotic and abiotic tolerance traits. A new breeding strategy, the Transition from Trait to Environment (TTE) approach, was developed. We achieved a genetic gain of 65% for submergence tolerance in rice using this method. The newly identified germplasm provides invaluable genetic resources for the global rice research community to develop flood-tolerant rice genotypes. Core ideas The SUB1A gene, enabling rice to survive underwater for 14 days, marked a significant breakthrough. We have identified elite genotypes with submergence tolerance significantly surpassing the SUB1A gene-mediated tolerance. The diverse elite genotypes identified harbor 86 key genes and QTLs that affect various traits positively. Developed a unique breeding strategy for implementing population improvement in challenging environments. The new breeding strategy demonstrated a genetic gain of 65% for submergence tolerance.

plant biology↗

bioRxiv2025

Epigenetically dynamic human centromeres are maintained within a stable DNA methylation signature

Centromere location is specified by CENP-A, a centromere-specific histone that epigenetically defines centromere identity. How CENP-A is maintained at one location in rapidly evolving centromeric DNA is unknown. Using single-cell-derived clones of human cell lines, we demonstrate single-cell heterogeneity in CENP-A position within cell populations at neocentromeres and a native centromere. CENP-A heterogeneity is accompanied by unique DNA methylation and H3K9me3 patterns, with DNA methylation shifting according to CENP-A position. We further demonstrate centromere epigenetic evolution over prolonged proliferation, with native centromeres maintaining stable heterochromatin boundaries, but neocentromeres exhibiting DNA methylation instability, H3K9me3 gain, boundary loss and fragility. Lastly, prolonged CENP-A and HJURP overexpression leads to centromere and neocentromere expansion, gradual CENP-A depletion, neocentromere destabilization and CENP-A re-localization that is accompanied by local heterochromatin remodeling. This study reveals the naturally evolving epigenetic plasticity of human centromeres and neocentromeres and highlights the importance of repressive chromatin boundaries in maintaining centromere stability.

cell biology↗

bioRxiv2019

Autoimmunity Risk Gene IRGM is a Master Negative Regulator of Interferon Response by Controlling the Activation of cGAS STING and RIG-I-MAVS Signaling Pathways

Activation of type 1 interferon response is extensively connected with the antiviral immunity and pathogenesis of autoimmune diseases. Here, we found that IRGM, whose deficiency is linked with the genesis of several autoimmune disorders, is a master negative regulator of the interferon response. Mechanistically, we show that IRGM interacts with nucleic acid sensor proteins, including cGAS and RIG-I, and mediates their autophagic degradation to restrain activation of interferon signaling. Further, IRGM maintains mitophagy flux, and its deficiency results in the accumulation of defunct leaky mitochondria that releases cytosolic DAMPs triggering activation of interferon responses via cGAS-STING and RIG-I-MAVS signaling axis. Due to an enduring type 1 IFN response in IRGM-deficient cells and mice, they were intrinsically resistant to infection of the Japanese Encephalitis virus, Herpes Simplex virus, and Chikungunya virus. Altogether, this study defines the molecular mechanisms by which IRGM maintains interferon homeostasis and protects from autoimmune diseases. Further, it identifies IRGM as a broad therapeutic target for defense against viruses.\n\nGraphical Abstract\n\nO_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=126 SRC=\"FIGDIR/small/815506v1_ufig1.gif\" ALT=\"Figure 1\">\nView larger version (48K):\norg.highwire.dtl.DTLVardef@1d4822org.highwire.dtl.DTLVardef@6aebbcorg.highwire.dtl.DTLVardef@19a9b72org.highwire.dtl.DTLVardef@1539195_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗