Biology subjects

Ghosh, S.

Publications and source records attributed to Ghosh, S..

At least 19 recordsLinked to original sources

bioRxiv2026

Transient noradrenergic signals act as online controllers of perceptual computation

Neuromodulatory signals influence perception, arousal and learning, but their effects on behavioral performance can arise from fundamentally different computations. A transient signal could alter a persistent operating state, control an ongoing computation, or provide a teaching signal that modifies future behavior. These mechanisms make distinct predictions about the time course of neuromodulatory influence on behavior within and across trials. Here we applied temporally randomized white-noise optogenetic activation of locus coeruleus (LC) noradrenergic neurons while monkeys performed a visual match-to-sample discrimination task. Computational simulations established that reverse correlation could distinguish the temporal signatures of the modeled persistent-state, controller and outcome-dependent teaching mechanisms based on behavioral choices. LC activation selectively increased perceptual sensitivity for contralateral stimuli during a narrow time window preceding sensory input, without a detectable change in decision criterion. Cross-trial effects were smaller than predicted by the persistent-state and teaching models, despite sufficient sensitivity to detect the predicted effects. After accounting for the measured LC spiking response to optical stimulation, we estimated that behaviorally effective LC activity occurred approximately 50 ms before sensory input. The temporal weighting of optical stimulation predicted contralateral perceptual outcomes on held-out individual trials. Together, these findings support a temporally and spatially selective controller-like contribution of transient LC activation to ongoing perception among the mechanisms tested. More broadly, they demonstrate how the temporal structure of causal effects can distinguish computational roles of neuromodulatory signals that are difficult to resolve from average behavioral performance.

neuroscience↗

bioRxiv2026

A Computational Framework for Understanding HCV Infection and Associated Lipid Dynamics

Hepatitis C virus (HCV) infection is strongly intertwined with host lipid metabolism and is frequently associated with hepatic steatosis, particularly in genotype-specific cases where lipid accumulation reflects direct viral effects rather than host metabolic comorbidities. Despite extensive clinical and experimental evidence, a quantitative framework capturing the bidirectional coupling between viral dynamics and lipid metabolism remains lacking. In this work, we develop a comprehensive mathematical model that integrates HCV infection dynamics with intracellular lipid regulation. The framework combines a reaction diffusion system for spatial viral spread with a coupled metabolic module describing lipid influx. Numerical simulations highlight the role of lipid feedback in shifting infection outcomes toward persistence and recurrent oscillations, demonstrating that lipid accumulation acts as a critical driver of viral amplification. The model also highlights the critical role of immune memory to study acute and chronic phase and successfully reproduces observed viral RNA trajectories. Overall, the framework provides mechanistic insights into HCV dynamics and offers a general modeling approach for studying virus metabolism interactions in liver disease.

cell biology↗

bioRxiv2026

Interleukin-4 suppresses TIMP-2 transcription during endometriosis: Allele-specific regulation of the TIMP-2 -418G/C promoter by SP1

Abstract Tissue inhibitor of metalloproteinase-2 (TIMP-2) is a critical regulator of extracellular matrix (ECM) homeostasis in inflammatory disorder, but the mechanisms underlying its dysregulation in endometriosis remain poorly understood. Furthermore, whether inflammatory cytokine signaling and functional genetic variants within the TIMP-2 promoter contribute to its altered expression during disease progression is unknown. This study investigated the regulation of TIMP-2 expression by interleukin-4 (IL-4) signaling and the functional significance of the TIMP-2 -418G/C promoter polymorphism in endometriosis. We found that TIMP-2 expression was significantly reduced in ectopic lesions and serum samples from endometriosis patients in comparison to normal. Functional promoter analyses revealed that the -418C allele exhibited higher basal transcriptional activity than the G allele while displayed greater sensitivity to IL-4-mediated repression. IL-4 activated STAT6 signaling concomitant with SP1 and TIMP-2 downregulation, whereas SP1 overexpression restored TIMP-2 expression and SP1 silencing further suppressed its transcription, identifying SP1 as a positive regulator of TIMP-2. Single-cell transcriptomic analyses identified fibroblasts and mesenchymal populations as the major TIMP-2-expressing cell types and revealed enhanced inflammatory signaling and ECM remodeling networks in endometriosis. Collectively, these findings identify an IL-4-SP1-TIMP-2 regulatory axis that contributes to aberrant ECM turnover in endometriosis. Furthermore, the TIMP-2 -418G/C promoter polymorphism influences cytokine-mediated transcriptional regulation of TIMP-2, providing new mechanistic insights into the interplay between inflammatory signaling, genetic variation, and ECM homeostasis during endometriosis progression.

molecular biology↗

bioRxiv2026

Scan field rotation with a K-mirror for fast two-photon imaging along curved planes

In contrast to the curved geometry of biological structures, the imaging plane of conventional microscopes is flat. In principle, axial scanning can adjust the focus to follow curved structures. In resonant scanning microscopes, which are broadly used for video-rate functional imaging, however, such focus adjustment is typically possible at rates faster than the slow (~30 Hz) scan axis but not as fast as the fast (~8000 Hz) resonant axis. The fixed direction of the fast resonant axis therefore constrains how the imaging plane can be tilted or curved using axial scanning, and limits how well it can be aligned with biological structures of interest. Here, we present an optical modification that overcomes this constraint. Specifically, we combine scan field rotation using a K-mirror with fast axial scanning using an electrically tunable lens. We demonstrate the versatility of our approach for calcium imaging by aligning the imaging plane with the curved pyramidal cell layer in mouse hippocampus, increasing the number of simultaneously imaged neurons. In addition, we image dendritic arbors of hippocampal and cortical pyramidal neurons that would otherwise be only partially accessible for fast imaging, and we apply our method to the curved layers of cerebellar Purkinje cells. Furthermore, we demonstrate how scan field rotation can be used to optimally orient a dendritic branch for high-speed subcellular glutamate imaging. Our approach is based on a single module and can therefore be retrofitted to standard two-photon systems. We openly share design specifications, 3D-printed parts, and custom ScanImage-compatible code to facilitate rapid adoption.

neuroscience↗

bioRxiv2026

Mathematical modeling of SUMOylation reveals tissue-specific and dynamic responses to abiotic stress

SUMOylation is an essential and evolutionarily conserved post-translational modification that enables rapid cellular adaptation to environmental stress. Despite its importance, how the SUMOylation machinery controls its dynamics remains poorly understood. Here, we integrated a mathematical model of the plant SUMO cycle with quantitative imaging and biochemical data to decode the regulatory logic of SUMOylation dynamics. The model reveals a fundamental principle: steady-state SUMOylation levels are determined not by the full complement of SUMO-cycle components, but by the abundance of SUMO modifier proteins and E1 enzymes, together with SUMO protease abundance and activity. Strikingly, when we integrated fluorescence measurements from reporters for SUMO-cycle components in Arabidopsis roots after three hours of abiotic stress, the model predicted decreased SUMOylation levels across several tissues, contrary to prevailing evidence. Motivated by this unexpected prediction, we performed time-resolved imaging to better characterize the dynamics of key SUMO-cycle components after salt and osmotic stress. These data revealed highly dynamic component levels within the first three hours of stress that were not captured in the previous measurements. Incorporating this temporal data into the model uncovered a twin-peaked SUMOylation response to salt stress: an early surge underpinned by protease dynamics, followed by a decline and a second peak driven by elevated SUMO modifier and E2 levels. Western blot analysis revealed a corresponding twin-peaked pattern of SUMOylation. Together, our findings demonstrate that the plant SUMO cycle is a highly dynamic system that achieves tissue- and stress-specific control of SUMOylation through the coordinated interplay of multiple SUMO-cycle components.

plant biology↗

bioRxiv2026

The bacterial iron sensor IdeR distinguishes DNA sequences by applying stress to non-cognate DNA

The transcription factor IdeR regulates iron homeostasis in many gram-positive bacteria. It primarily functions as a repressor of iron uptake genes by binding to their promoters and blocking RNA polymerase access. IdeR recognizes a highly conserved DNA sequence consisting of four palindromic 5'-C1C2T3A4A5 repeats. For target site recognition, IdeR requires a thymine in position 3 of the repeat and at least one cytosine in the first two positions, while the identity of the bases in positions 4 and 5 is less important. We have previously shown that IdeR recognizes its target sequences through indirect or shape readout, rather than direct interactions with the bases. However, the mechanism of indirect recognition is unknown. Here we employed molecular dynamics simulations, X-ray crystallography, and DNA-binding assays to investigate the thermodynamic principles underlying accurate pyrimidine recognition by IdeR. We found that the recognition helix of IdeR forms a differential dielectric cleft that accommodates the C-H edge of the 5'-C1C2T3 sequence, with a polar pocket for the first two bases and a non-polar pocket for the third. The local dielectric environment of IdeR applies strain to non-cognate DNA, leading to non-productive binding and thereby ensuring the fidelity of target DNA reading.

biochemistry↗

bioRxiv2026

Conserved mycobacteriophage protein uses structural mimicry to displace host initiation factors

Compact viral genomes encode sophisticated strategies to reprogram host gene expression, often by co-opting rather than replacing the host RNA polymerase. How bacteriophages achieve such control in Mycobacteria remains largely unknown. Here, time-resolved interaction proteomics of mycobacteriophage D29 infection identifies a conserved two-protein module, gp53-gp52, that binds the host RNA polymerase. Affinity purification confirmed association of both proteins with the polymerase, while native mass spectrometry demonstrated that gp53 displaces the host sigma factor. Structural modelling places gp53 at the sigma-binding surface of RNA polymerase, consistent with molecular mimicry of sigma-factor engagement. The module is conserved throughout Cluster A mycobacteriophages and occurs in fused or split genomic architectures. These findings suggest sigma-factor displacement as a mechanism of transcriptional takeover in viruses of mycobacteria and show how a compact viral module can repurpose an essential host molecular machine

microbiology↗

bioRxiv2026

LIF-LIFR/gp130 Survival Signaling and Connexin 47 Dysregulation upon Murine-β-Coronavirus Infection: Discovery of a Novel ERK2 Phosphorylation Site at Cx47 C-Terminal Domain

Oligodendrocyte (OLG) injury and loss are increasingly recognized as major determinants of demyelination and remyelination failure in multiple sclerosis (MS), alongside conventional immune-mediated processes. However, the mechanism underlying OLG injury and remyelination failure remains incompletely understood. Astrocyte-oligodendrocyte interactions mediated by Connexin (Cx)-43-Cx47 gap junction (GJ) communication and leukemia inhibitory factor (LIF)-LIFR/gp130 signaling are critical for oligodendroglial survival, homeostasis, and myelination. Despite their established role, how these pathways are altered during neuroinflammatory diseases remains unclear. To address this, we integrated a murine {beta}-coronavirus (RSA59)-induced in vivo model with enriched primary oligodendrocyte precursor cell (OPC) and mature OLG cultures to investigate the effect of RSA59 infection on OLGs, Cx47-mediated GJ communication, and LIF-LIFR/gp130 Signaling. We observed that RSA59 directly targets oligodendroglial lineage cells, including OPCs and mature OLGs, and induces apoptosis in mature OLGs. Despite increased OPC abundance, RSA59 infection reduces the expression of mature and myelinating markers CNPase and MBP, raising the possibility of impaired oligodendrocyte maturation and myelination. RSA59 infection also differentially regulates Cx47-mediated GJ communication and LIF-LIFR/gp130 signaling, crucial for OLG survival and homeostasis. Furthermore, our studies demonstrate that extracellular signal-regulated kinase (ERK), a downstream effector of LIF signaling, phosphorylates the Cx47 C-terminal domain (Cx47CT) at Serine-372 residue, identifying a previously unreported mechanism. Collectively, these findings reveal that RSA59 infection disrupts interconnected oligodendroglial communication and survival pathways, providing mechanistic insights into virus-induced chronic demyelination pathology. The study further identifies Cx47-mediated GJ communication and LIF-LIFR/gp130 signaling as crucial therapeutic targets, and highlights ERK-dependent Cx47CT phosphorylation as a potential regulatory mechanism.

neuroscience↗

bioRxiv2026

Pathogenic variants of the mitochondrial copper chaperones SCO1 and SCO2 reshape their respective interactomes and disrupt cellular phospholipid metabolism

SCO1 and SCO2 are required for copper delivery to COX2, a copper-containing subunit of cytochrome c oxidase (COX), yet how mutations in these genes cause distinct, tissue-specific forms of human disease remains poorly understood. To gain further insight into the molecular underpinnings of this clinical heterogeneity, we used BioID to map the interactomes of four pathogenic SCO variants (SCO1 G132S, SCO1 P174L, SCO1 M294V and SCO2 E140K) and the wild-type proteins. While this approach identified many proteins common to both wild-type neighbourhoods, several potential interacting partners unique to each SCO protein were also observed that were consistent with their known roles in COX assembly. Follow-up analyses revealed that SCO1 interacts with COX16 and that this interaction is stabilized within the membrane by a coiled-coil helix-helix interface, with the soluble C-terminal region of COX16 physically bridging SCO1 and COX2 within a ternary complex to facilitate copper delivery. We further observed that COX16 abundance is relatively low in the brain and its association with SCO1 is most severely impaired by the M294V substitution associated with a fatal encephalopathy. Intriguingly, our BioID analyses also detected significant enrichment in each SCO neighbourhood for biosynthetic enzymes and lipases critical to phospholipid metabolism and found that the affinity for these candidate interactors was uniquely perturbed by various pathogenic variants of SCO1 and SCO2. Collectively, our data emphasize the potential of proximity labelling to further define the molecular roles of disease-causing variants that perturb mitochondrial function and suggest that SCO proteins impinge upon phospholipid metabolism.

molecular biology↗

bioRxiv2026

CX3CR1+ microglia/macrophages, activated T cells, and IFN-γ-driven stimulation confer age-dependent protective immunity in young-adult mice following β-coronavirus infection.

Age-dependent variation in the immune response is a critical determinant of host susceptibility, disease severity, and long-term sequelae in coronavirus infections, a principle strikingly demonstrated by the COVID-19 pandemic caused by SARS-CoV-2. Although primarily pneumotropic, coronaviruses carry significant neurotropic potential, driving neurological complications whose severity is profoundly determined by host age. Elderly individuals and often children suffer disproportionately severe disease, whereas young adults relatively mount protective responses; yet the cellular and molecular determinants of this age-dependent neuroprotection remain poorly characterized. Using juvenile and young-adult C57BL/6 mice intracranially inoculated with {beta}-coronavirus MHV-RSA59, a murine equivalent of human coronaviruses, we examined immune dynamics at days 5 (innate-acute), 7 (innate-to-adaptive transition), and 30 (chronic) post-infection. Young-adult mice exhibited only occasional demyelination, in stark contrast to the extensive demyelination observed across all spinal cord levels in juveniles. This differential outcome was attributable to enhanced age-dependent immune maturation, characterized by efficient T cell-microglia/macrophage crosstalk enabling effective viral control by day 7 post-infection. Young adults displayed greater glial activation, heightened cytokine release, CX3CR1+ microglia activation, and augmented CNS trafficking of CX3CR1+ and MHC II+ monocytes/macrophages, IFN-{gamma}+ CD4+/CD8+ T cells, and CXCR3+ effector T cells relative to juveniles. Reduced naive T cell frequencies and elevated effector/central memory T cell populations in cervical lymph nodes further indicate a robust adaptive memory response conferring long-term protection. Additionally, greater regulatory T cell accumulation in young adults facilitates timely suppression of excessive neuroinflammation as viral burden subsides. Together, these findings define the age-dependent immune landscape that underpins neuroprotection in {beta}-coronavirus infection.

immunology↗

bioRxiv2026

Bacterial vitamin sharing emerges from a balance between release and uptake

Vitamin availability often shapes microbial communities, as many microbes use vitamins they cannot synthesize. Yet how vitamins become available to users remains poorly understood. To explore this process, we quantified vitamin B12 synthesis, uptake, and extracellular accumulation across hundreds of diverse soil, freshwater, and marine bacterial isolates. These measurements revealed distinct source-sink phenotypes and showed that producers vary substantially in the amount of B12 they provide extracellularly. B12 synthesis was predictable across divergent bacterial lineages from genome content, whereas uptake and extracellular accumulation were not. Controlled cell-death experiments and independently parameterized models showed that extracellular B12 could be quantitatively predicted from release by dead cells and reuptake by surviving cells. Thus, extracellular B12 availability is governed not by synthesis alone, but by the balance between release and uptake, with producer reuptake acting as a previously overlooked sink.

microbiology↗

bioRxiv2026

A mathematical investigation of the interplay between vasculature and intratumoral cellular heterogeneity during tumor progression

Tumors consist of heterogeneous phenotypic cells, such as normoxic cells, which are highly proliferative, and hypoxic cells, which are less proliferative. Their phenotypic switching depends on tumor microenvironmental factors, such as oxygen and nutrient concentrations supplied by local blood vessels. However, during ongoing angiogenesis, the process of sprouting new blood vessels at the tumor site from pre-existing blood vessels, and how this phenotypic switching affects and impacts tumor growth, remains poorly understood. In this article, we formulate a mathematical model to elucidate the crosstalk between vasculature and tumor cellular heterogeneity during tumor progression. The model results show a strong agreement with the experimental data. Our simulation results demonstrate that ongoing angiogenesis increases tumor growth rate. In addition, we observe that the influence of hypoxic cells on phenotypic switching from normoxic to hypoxic is more pronounced than their influence on the transition from hypoxic to normoxic. Furthermore, we perform a global sensitivity analysis using the Sobol's method to assess the importance of the model's parameters. It highlights that the volume at which blood vessels attain half-maximal rate has the maximum effect on the model.

systems biology↗

bioRxiv2026

IRES-mediated translation of delta160p53 regulates p53 functions and fine-tunes cancer homeostasis

Mutations in p53 and its 12 isoforms can alter its functions. As N-terminally truncated isoforms of p53 (delta40p53, delta133p53, and delta160p53) participate in tetramer formation, they are important regulators of cancer fate. Although delta40p53- and delta133p53-mediated regulation of cancer is well reported, the mechanism underlying delta160p53 production and its functional role remains unclear. We investigated the internal ribosomal entry site (IRES)-mediated translation of {Delta}160p53 and its role in cancer regulation. As differential synthesis of delta160p53 was observed under different stress conditions, IRES-mediated translation of this isoform was demonstrated using bicistronic luciferase constructs. No cryptic promoters or splicing sites were detected in the IRES sequence. Cell death and late apoptosis were significantly decreased, while proliferation, the number of cells in the S phase, and drug resistance were induced by delta160p53. Furthermore, delta160p53 did not induce p53-responsive promoters. RNA sequencing analysis of delta160p53 overexpression showed similar results, along with the inhibition of other tumor suppressor genes. Overall, our results provide insights into IRES-mediated translation of delta160p53, which can be considered a novel target for cancer treatment.

molecular biology↗

bioRxiv2026

Differential Impact of Isoflurane and Propofol on Apoptotic Regulation of Helper T cells

BackgroundAnesthetic agents administered during surgery are one of the key perioperative factors affecting immune modulation in cancer patients. This comparative study elucidated the mechanisms by which the volatile anesthetic, isoflurane and the intravenous anesthetic, propofol impacted apoptosis signaling in CD4+ helper T (Th) cells. MethodsFlow cytometry was used to analyze apoptosis, mitochondrial function and reactive oxygen species (ROS) generation, while Western blotting, ELISA and RT-qPCR were employed to study protein/gene expression in sorted CD4{square} Th cells from perioperative breast cancer female patients (anesthetized with isoflurane or propofol, n=15 per group) and Jurkat T cells. ResultsPatient-derived CD4{square} Th cells and Jurkat T cells exhibited that isoflurane at clinically relevant concentrations triggered apoptosis through mitochondrial depolarization, ROS generation, DNA damage, and activation of caspase-3/7. Specific use of caspase-3/7 inhibitor, Z-DEVD-FMK and antioxidant N-acetyl cysteine rescued isoflurane-induced apoptosis. Further, isoflurane relative to propofol, activated p38 mitogen-activated protein kinase (MAPK), and use of p38 inhibitor, SB203580 suppressed isoflurane-induced apoptosis. Collectively, these findings validated the involvement of the ROS-p38-caspase-3/7 axis in isoflurane-associated apoptosis signaling. On the other hand, propofol conserved mitochondrial integrity, reduced oxidative stress, and maintained higher proliferative capacity. Interestingly, isoflurane-associated apoptosis was transient, with postoperative recovery in patients and similar rescue from apoptosis was evident in Jurkat T cells within 24-48 h of drug removal. ConclusionsBy integrating analyses of patient-derived CD4+ Th cells with mechanistic validations in Jurkat T cells, this study identified the ROS-p38-caspase-3/7 signaling axis and the reversible nature of isoflurane-induced apoptosis.

cancer biology↗

bioRxiv2026

Loss of PTPRB function remodels VEGFR1 activation in tumors overexpressing the receptor tyrosine kinase

The VEGF Receptor-1 (VEGFR1) is a deceptive receptor tyrosine kinase (RTK). In early embryonic development, VEGFR1 negatively regulates angiogenesis by acting like a decoy receptor. Ligand binding transiently phosphorylates the receptor and induces a weak activation, even at high receptor density. Yet, in multiple cancers, overexpression of VEGFR1 plays a central role in tumor vascularization and growth. Unlike many pro-oncogenic RTKs, extensive patient data analysis revealed no somatic mutation in VEGFR1 that may spontaneously activate the tyrosine kinase. The mechanism by which VEGFR1 is activated in cancers has remained an open question for more than two decades. Here, we evaluated the multi-omics profiles of VEGFR1 and its regulators in a pan-cancer database. We observed an inverse correlation between VEGFR1 and PTPRB phosphatase expression in KIRC patients and disease outcome. We observed that patients overexpressing VEGFR1 and deficient in PTPRB expression have a lower likelihood of survival. Using super-resolution single-cell imaging, we discovered that inhibiting PTPRB spontaneously activates VEGFR1 by inducing ligand-independent dimerization, possibly by shifting the equilibrium toward the active state. PTPRB inhibition induces sustained, ligand-dependent phosphorylation of VEGFR1, which may promote tumor vascularization. We conclude that a subtle phosphatase imbalance is fundamental in determining VEGFR1s role in pathological angiogenesis in tumors.

biochemistry↗

bioRxiv2026

Mutation of charged inner pore residues reduce E. coli β clamp residency and increase sliding rates on DNA

Sliding clamp proteins play central roles in DNA metabolism, including replication and repair. The ring-shaped E. coli beta clamp accommodates double-stranded DNA and serves as a platform for proteins involved in multiple DNA transactions. The inner pore of the beta clamp harbors a series of positively charged and polar residues that can bind to the negatively charged backbone of the DNA. These residues are arrayed so that they do not align with the charged phosphates of the DNA backbone. It is hypothesized that this arrangement of these residues provides for the movement of the clamp on DNA as it alternates which residues are bound to the DNA backbone. In this work, we mutated specific charged and polar residues that project into the inner pore of the beta clamp. The beta clamp variants are dimers and have similar thermal stability and in general a similar ability to complement a temperature sensitive strain for growth. One exception was beta-Q149A, which appeared as higher-order species on a native gel although its hydrogen-deuterium exchange pattern measured by mass spectrometry was overall similar to WT beta. These variants all had decreased binding to DNA after loading. Optical tweezers experiments were used to monitor loading on single DNA molecules and measure the rate of beta clamp sliding on DNA. Consistent with the hypothesized role of positively charged residues in the beta inner pore, mutation of one residue resulted in a faster rate of sliding on DNA.

biochemistry↗

bioRxiv2026

Targeting glucocorticoid signalling in dendritic cells for glioblastoma treatment

Glioblastoma (GBM) remains a devastating disease with few meaningful therapeutic advances over the past three decades. Dendritic cell (DC) vaccination is a promising immunotherapeutic strategy for GBM, but its efficacy is limited by the clinical use of dexamethasone to control cerebral oedema and associated symptoms. Here we show that steroid signalling is a central regulator of DC dysfunction in GBM. Through targeted metabolomics of primary GBM samples, we identified a steroid-rich tumour microenvironment in which dexamethasone is present at high levels. Across bulk and single-cell transcriptomic and epigenomic datasets, NR3C1 emerged as the dominant steroid receptor in GBM immune cells and was negatively associated with activated DC states. In patient-derived DCs, dexamethasone altered NR3C1 chromatin occupancy, induced broad transcriptional and chromatin remodelling, and suppressed co-stimulatory antigen-presentation and cytokine programmes. DC-specific deletion of Nr3c1 restricted syngeneic glioblastoma growth, enhanced DC activation, promoted cytotoxic CD8+ T cell responses and remodelled myeloid states in vivo. In GBM patient-derived DCs, pharmacological or non-viral CRISPR-mediated disruption of NR3C1 restored inflammatory, antigen presentation and T cell-stimulatory programmes, enhanced antigen-specific CD8+ T cell priming, and improved tumour lysate-loaded DC vaccination. Together, these findings identify glucocorticoid signalling as a key barrier to DC immunotherapy in GBM and establish NR3C1-targeted, steroid-resistant DCs as a potential therapeutic strategy.

immunology↗

bioRxiv2026

Plasma Metabolomic Profiling of COPD Patients Stratified by Smoking Status: A GC-MS- Based Approach

BackgroundChronic obstructive pulmonary disease, primarily caused by exposure to cigarette smoke, is a heterogeneous lung condition characterized by complex metabolic alterations. The metabolic changes associated with smoking status have not been thoroughly investigated. Our study aims to explore the metabolite profile of COPD patients categorised by their smoking habits, including smokers, ex-smokers, and non-smokers. MethodsIn this study, the plasma metabolome of smoking stratified COPD patients were assessed using gas chromatography coupled to mass spectrometry. We applied multivariate and univariate statistical analysis to identify the differentially abundant metabolites. ResultsWe identified 23 altered metabolites in the smokers and 36 in the ex-smokers COPD subgroups. Interestingly, in comparison to the control group, no significant alteration was observed in the plasma of non-smoker COPD patients. Additionally, pathway enrichment analysis revealed top dysregulated metabolic pathways, including biosynthesis of unsaturated fatty acids, galactose metabolism, phenylalanine, tyrosine, and tryptophan biosynthesis, and glycosylphosphatidylinositol (GPI)-anchor biosynthesis. The receiver operating characteristic curve screened five metabolites, such as tetradecanoic acid, 2,4-di-tert-butylphenol, chloroxylenol, tetradecanal, and 1-dodecene, with the highest diagnostic performance (AUC > 0.8). ConclusionThis study reveals distinct plasma metabolic signatures across COPD subgroups categorized by cigarette smoking history.

biochemistry↗