Biology subjects

Puri, R.

Publications and source records attributed to Puri, R..

6 recordsLinked to original sources

bioRxiv2026

MHC-I downregulation is associated with immune-evasion in breast cancers with heterogeneous activation of epithelial-mesenchymal plasticity

Cancer cell-intrinsic epithelial-mesenchymal plasticity (EMP) drives carcinoma progression through increased intratumoral heterogeneity and an immunosuppressive tumor microenvironment (TME). Specifically, EMP activation in murine mammary carcinomas results in exclusion of CD8+ T-cells and recruitment of immunosuppressive M2-like macrophages, resulting in resistance to anti-CTLA-4 immune checkpoint blockade (ICB) therapy. Notably, mixed E-qM tumors in which only 10% of cancer cells have activated EMP are resistant anti-CTLA-4 immune checkpoint blockade (ICB) therapy. This suggests that minority fractions of qM cancer cells could, in theory, exert immunosuppressive effects on surrounding E cancer and immune cells to shield the entire heterogeneous tumor against immune attack. However, this has not yet been demonstrated. Here, we use spatial transcriptomic profiling to demonstrate that mixed E-qM tumors assemble immunosuppressive cellular niches. Furthermore, E cancer cells within mixed E-qM tumors experience long-term MHC-I downregulation leading to resistance to elimination by CD8+ T-cells. This is associated with the exclusion of T-cells from the tumor core and a dysfunctional phenotype in the remaining CD8+ T-cells. qM cancer cells recruit immunosuppressive M2-like macrophages to mixed tumors, which further downregulates E cancer cell-intrinsic MHC-I levels. Finally, we demonstrate that human triple-negative breast cancers with increased EMP activation exclude T-cells from the tumor core. Together, these findings reveal that qM cancer cells modulate the immune infiltrate of mixed tumors, promoting MHC-I downregulation and evasion of immunological control by CD8+ T-cells.

cancer biology↗

bioRxiv2026

Epstein-Barr virus transformation creates a methionine-dependent ferroptosis vulnerability in B cells

Epstein-Barr virus (EBV) causes over 200,000 cancers annually, including immunoblastic lymphomas in immunosuppressed hosts. Most transformed cells arrest, yet survive when deprived of the essential amino acid methionine. We instead find that EBV transformed lymphoblastoid cell lines (LCLs), which model the EBV latency III program-driven B-cell lymphoproliferative diseases of immunosuppressed hosts, rapidly die upon methionine restriction. Methionine restriction elevated LCL lipid reactive oxygen species and triggered ferroptosis. Whereas methionine restriction hypomethylates the EBV genome and triggers viral reactivation in latency I Burkitt cells by lowering the cellular methylation potential, the LCL latency III program instead redirected methionine toward redox defense, without altering the SAM/SAH ratio. Stable-isotope tracing revealed that latency III strongly induces transsulfuration, synthesizing cysteine de novo to support glutathione pools. The EBV oncoprotein LMP2A, which mimics B-cell receptor signaling, supported newly infected human B cell cystathionine-{beta}-synthase and cystathionine-{gamma}-lyase expression and methionine dependence, phenocopied by immunoglobulin crosslinking. In vivo, dietary methionine restriction impaired LCL xenograft outgrowth and depleted tumor cystine. Combined methioninase and cyst(e)inase administration blocked both cysteine sources, collapsed tumor glutathione levels, and triggered ferroptosis. Our results define methionine metabolism as a targetable ferroptosis vulnerability of EBV-transformed B cells. HighlightsO_LIMethionine restriction triggers EBV-transformed lymphoblastoid B cell ferroptosis C_LIO_LIEBV latency III induces transsulfuration to sustain LCL cysteine and glutathione C_LIO_LIMethioninase or dietary methionine restriction strongly impair LCL growth in vivo C_LIO_LIMethioninase plus cyst(e)inase collapses xenograft GSH levels and drives ferroptosis C_LI

biochemistry↗

bioRxiv2025

The Stop Signal Stepping Task: how action cancellation commands disrupt step initiation in young and healthy older adults

Action cancellation - the ability to rapidly cancel an initiated movement in response to unexpected events - has been extensively studied in the upper limb using the stop signal task (SST). During gait, action cancellation is needed to stop and modify steps to avoid hazards and prevent falls. By adapting the SST to step initiation, this study investigated how the anticipatory postural adjustment (APA) and foot-lift phases of forward stepping were affected by action cancellation commands, and whether this changed with healthy ageing. The SST was performed in stepping, foot tap, and finger button conditions in 27 young (Mage = 28.7 years) and 29 healthy older adults (Mage = 70.1 years). Across conditions, older adults exhibited slower response speed compared to young adults and greater proactive slowing of responses when stop cues were anticipated. However, there was no significant difference in stopping speed between young and older adults. Stopping speed was fastest in the finger tap condition, and slowest in the step condition. When an APA was initiated in a step cancellation trial, the magnitude of the weight shift toward the step leg did not differ between successful and unsuccessful foot-lift cancellations. Foot-lift could be cancelled when stop cues were presented at similar phases of step preparation for young and older adults. These results suggest that the initial loading of the step leg is a ballistic process, however as weight is shifted toward the stance leg, action cancellation commands responding to external stimuli can decouple the APA and foot-lift step phases. Key PointsO_LIThe stop signal task (SST) - which allows an estimation of stopping speed independently of response speed - was applied to voluntary stepping in young and older adults. C_LIO_LIWhile response speed was slower for older than young adults, stopping speed was not significantly different between age groups in the upper limb, lower limb when seated, and during forward stepping. C_LIO_LIWhen stop cues were introduced, response speed slowed more in older than young adults, and more in the upper than the lower limb (i.e., Foot Tap and Step conditions). C_LIO_LIThe initial preparatory weight shift toward the stepping foot was not significantly different between successfully cancelled steps and normal steps, highlighting the ballistic nature of the early phase of step preparation. C_LIO_LIPrior to foot-lift, action cancellation commands could decouple the preparatory weight shift phase from foot-lift at similar stages of step initiation in young and healthy older adults. C_LI

neuroscience↗

bioRxiv2023

Healthy ageing influences how the shape of alpha and beta oscillations change during reaction time tasks.

Age-related changes to the power and frequency of the brains oscillatory activity have been reported by an extensive literature. In contrast, the influence of advancing age on the shape of oscillation waveforms, a characteristic with increasingly recognised physiological and functional relevance, has not been previously investigated. To address this, we examined the shape of alpha and beta band oscillations from electroencephalography (EEG) data recorded during performance of simple and go/no-go reaction time tasks in 33 young (23.3 {+/-} 2.9 years, 27 females) and 27 older (60.0 {+/-} 5.2 years, 23 females) adults. The shape of individual cycles was characterised using instantaneous frequency, and then decomposed into waveform motifs using principal component analysis. This analysis identified four principal components (one from the alpha band, 3 from the beta band) that were uniquely influenced by the different motor tasks and/or age. These each described different dimensions of shape and tended to be modulated during the reaction phase of each task. However, the way in which each facet of shape varied during the task was unrelated to motor performance, indexed via reaction time, in either group or band. Our results suggest that although oscillation shape is task-dependent, the nature of this effect is altered by advancing age. While these outcomes demonstrate the utility of this approach for understanding the neurophysiological effects of ageing, future work that more clearly links these outcomes with function will be critical.

neuroscience↗

bioRxiv2022

Beta tACS over rIFG and preSMA Improves Stopping Ability for Younger but not Older Adults

A growing body of research suggests that changes in both structural and functional connectivity in the aging brain contribute to declines in cognitive functions such as response inhibition. In recent years, transcranial alternating current stimulation (tACS) has garnered substantial research interest as a potential tool for the modulation of functional connectivity. Here, we report the findings from a double-blind crossover study that investigated the effects of dual-site beta tACS over the right inferior frontal gyrus (rIFG) and pre-supplementary motor area (preSMA) on functional connectivity measured with electroencephalography and response inhibition (stop-signal task performance) of healthy young (n = 18, aged 18-34 years) and older (n =15, aged 61-79 years) adults. Two tACS conditions were administered in separate sessions: in-phase tACS, where electrical currents delivered to the rIFG and preSMA had a 0{degrees} phase difference, and anti-phase tACS, where currents had a 180{degrees} phase difference. Stop-signal task performance was assessed before and after tACS. We found significant improvements in response inhibition that were not due to the phase of the tACS applied. There were also no significant changes in rIFG-preSMA phase connectivity in either age group from in- or anti-phase tACS. Furthermore, we did not observe significant differences in rIFG-preSMA phase connectivity between successful and unsuccessful inhibition, which suggests that rIFG-preSMA phase-coupling might not underlie effective response inhibition. The results offer insight into the neurophysiology of response inhibition and contribute to the future development of non-pharmacological interventions aimed at alleviating age-related declines in cognitive function.

neuroscience↗

bioRxiv2022

Methionine Metabolism Controls the B-cell EBV Epigenome and Viral Latency

Epstein-Barr virus (EBV) subverts host epigenetic pathways to switch between viral latency programs, colonize the B-cell compartment and reactivate. Within memory B-cells, the reservoir for lifelong infection, EBV genomic DNA and histone methylation marks restrict gene expression. But, this epigenetic strategy also enables EBV-infected tumors, including Burkitt lymphomas to evade immune detection. Little is known about host cell metabolic pathways that support EBV epigenome landscapes. We therefore used amino acid restriction, metabolomic and CRISPR approaches to identify that an abundant methionine supply, and interconnecting methionine and folate cycles, maintain Burkitt EBV gene silencing. Methionine restriction, or methionine cycle perturbation, hypomethylated EBV genomes, de-repressed latent membrane protein and lytic gene expression. Methionine metabolism also shaped EBV latency gene regulation required for B-cell immortalization. Dietary methionine restriction altered murine Burkitt xenograft metabolomes and de-repressed EBV immunogens in vivo. These results highlight epigenetic/immunometabolism crosstalk supporting the EBV B-cell lifecycle and suggest therapeutic approaches. HighlightsO_LIMethionine metabolism is critical for Epstein-Barr virus B-cell latency C_LIO_LIExtensive cross-talk enables methionine metabolism to control the EBV epigenome C_LIO_LIMethionine restriction also impairs EBV-driven human B-cell immortalization C_LIO_LIDietary methionine restriction unmasks EBV antigens in Burkitt xenografts in vivo C_LI

microbiology↗