Biology subjects

Patel, S. P.

Publications and source records attributed to Patel, S. P..

10 recordsLinked to original sources

bioRxiv2026

Closed-head injury produces a delayed, region-specific defect in glucose-carbon routing at the pyruvate branchpoint in APP/PS1 KI mice

Traumatic brain injury (TBI) is a risk factor for Alzheimer's disease (AD), and both conditions are associated with impaired glucose metabolism and mitochondrial dysfunction. We previously reported time-dependent mitochondrial dysfunction following closed-head injury (CHI) in amyloid precursor protein/presenilin 1 (APP/PS1) knock-in (KI) mice, but whether glucose-derived carbon labeling showed a corresponding temporal pattern remained unknown. We hypothesized that early deficits would involve tricarboxylic acid (TCA)-cycle metabolites, whereas chronic changes persisted upstream at the pyruvate-lactate branchpoint. Here, oral uniformly 13C-labeled glucose ([U-13C]-glucose) tracing and gas chromatography-mass spectrometry (GC-MS)-based isotopologue analysis were used to quantify first-turn glucose-derived carbon fate in cortex and hippocampus. To distinguish the effects of age at injury from those of post-injury interval, mice were analyzed 1 month after injury either at 7 or 12 months of age or 8 months after injury at 12 months of age. The most pronounced alterations occurred 8 months after CHI, when KI mice exhibited increased pyruvate and lactate labeling in the cortex and broader increases in glycolytic labeling in the hippocampus. These findings suggest that in APP/PS1 KI mice, chronic closed-head injury produced a delayed shift in glucose-derived carbon labeling centered on glycolytic and pyruvate/lactate nodes, with loss of hippocampal precursor-product coupling but without broad reduction of first-turn TCA-linked labeling.

neuroscience↗

bioRxiv2026

Molecular Translators as a Computational Primitive for Biomarker Discovery: Learnability Gains Under Conserved Information Ceilings

Virtual molecular mapping systems such as MISO and GigaTIME introduce a potentially transformative primitive in computational pathology: translation of H&E whole-slide images into biologically structured molecular representations, learned on paired cohorts and deployed as an inference-time map. Despite sustained progress in machine learning, H&E-to-molecular-biomarker (e.g., gene mutation) prediction continues to exhibit recurrent field-level performance plateaus whose drivers remain poorly resolved. It remains unclear whether continued optimization targets a removable methodological limitation or instead presses against an intrinsic ceiling imposed by morphology. We develop a formal framework characterizing what deterministic translators can and cannot change. Histology-based biomarker modeling is governed by two constraints: method-limited gaps (finite labels, weak supervision, structured nuisance) and modality-limited ceilings (intrinsic slide-specific information in morphology). Because deterministic translation introduces no new slide-level measurements at inference, H&E information ceilings are conserved; however, translation can still improve finite-sample learnability, yielding an apparent information-performance paradox that we formalize as learnability gains under conserved information ceilings. We derive falsifiable signatures distinguishing these regimes and characterize them in controlled analytical experiments anchored to representative systems, including MISO and GigaTIME. We introduce an open-source toolkit comprising learning regime diagnosis, information-ceiling estimations, phase analyses, fidelity perturbation tests, and shortcut-confounding stress tests as an operational rubric for identifying and overcoming removable performance plateaus in translator-assisted molecular biomarker discovery and computational pathology.

bioinformatics↗

bioRxiv2025

Traumatic brain injury exacerbates mitochondrial dysfunction in APP/PS1 knock-in mice through time-dependent pathways

Cerebral hypometabolism occurs in both traumatic brain injury (TBI) and Alzheimers disease (AD), but whether these conditions act through distinct or overlapping mechanisms is unclear. TBI disrupts cerebral metabolism via blood-brain barrier damage, altered glucose transporter expression, calcium buffering abnormalities, and oxidative damage to metabolic enzymes. AD-related hypometabolism is linked to amyloid-{beta} (A{beta}) effects on mitochondria, including impaired respiration, oxidative stress, and altered mitophagy, fusion, and fission. We tested whether TBI-induced mitochondrial dysfunction exacerbates A{beta}-mediated impairment using a closed-head injury (CHI) model in APP/PS1 knock-in (KI) mice. Injuries were delivered at 4-5 months of age, before plaque formation and mitochondrial deficits in KI mice. Bioenergetics were measured at 1, 4, and 8 months post-injury in hippocampus and cortex using Seahorse assays on isolated mitochondria. At 1 month, genotype-by-injury interactions revealed greater dysfunction in KI mice than either condition alone, with males more vulnerable than females. At 4-8 months, amyloid-mediated effects predominated, while TBI-specific changes were no longer apparent, suggesting recovery or convergence onto shared mechanisms. These results indicate that TBI can temporarily worsen mitochondrial dysfunction in the context of early amyloidosis, with sex influencing vulnerability. Findings provide insight into the temporal relationship between TBI and amyloid-induced mitochondrial deficits and support the importance of sex as a biological variable in neurodegenerative disease progression. HighlightsTBI and APP/PS1 genotype interact to worsen early mitochondrial dysfunction. Hippocampus exhibits greater susceptibility to combined TBI and amyloid pathology. Sex-specific effects and temporal patterns underscore TBIs role in AD risk. Male mice show heightened vulnerability to TBI-induced mitochondrial dysfunction. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=71 SRC="FIGDIR/small/679790v1_ufig1.gif" ALT="Figure 1"> View larger version (27K): org.highwire.dtl.DTLVardef@198e17org.highwire.dtl.DTLVardef@1bfa6d4org.highwire.dtl.DTLVardef@161c1d0org.highwire.dtl.DTLVardef@fb4dc1_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2025

Decitabine reverses innate immune gene suppression in rare melanomas

Rare melanoma subtypes, including acral, mucosal, and uveal melanomas, exhibit limited responses to immune checkpoint inhibitors (ICIs), yet the molecular mechanisms of immune resistance remain poorly defined. Here, we performed transcriptomic profiling of patient-derived xenografts (PDXs) and publicly available tumor datasets to systematically compare intratumoral gene expression across cutaneous and rare melanoma subtypes. We identified a convergent downregulation of innate immune pathogen sensing (IIPS) and type I interferon signaling pathways in rare melanomas compared to cutaneous, with lower expression also observed in anti-PD-1 non-responder tumors. CIBERSORT deconvolution of immune populations revealed that lower IIPS gene-expressing tumors exhibited reduced CD8 T cell and memory CD4 T cell infiltration, and enrichment of M2 macrophages, consistent with a more immunosuppressive tumor microenvironment. In vitro screening of epigenetic and immunomodulatory compounds revealed that the DNA hypomethylating agent decitabine robustly induced IIPS and adaptive immune gene expression in rare melanoma cell lines. In vivo treatment of mucosal and uveal melanoma xenograft models with decitabine resulted in durable upregulation of IIPS and antigen presentation genes, and whole transcriptome analysis confirmed that IIPS gene re-expression was the dominant transcriptional consequence of decitabine treatment. These findings highlight silencing of IIPS genes as a recurrent immune evasion mechanism in rare melanomas and nominate decitabine as a potential immunomodulatory strategy for enhancing immune responsiveness.

cancer biology↗

bioRxiv2024

Imipridones inhibit tumor growth and improve survival in an orthotopic liver metastasis mouse model of human uveal melanoma

PurposeUveal melanoma (UM) is a highly aggressive disease with very few treatment options. We previously demonstrated that mUM is characterized by high oxidative phosphorylation (OXPHOS). Here we tested the anti-tumor, signaling and metabolic effects of imipridones, CLPP activators which reduce OXPHOS indirectly and have demonstrated safety in patients. Experimental DesignWe assessed CLPP expression in UM patient samples. We tested the effects of imipridones (ONC201, ONC212) on the growth, survival, signaling and metabolism of UM cell lines in vitro, and for therapeutic effects in vivo in UM liver metastasis models. ResultsCLPP expression was confirmed in primary and mUM patient samples. ONC201/212 treatment of UM cell lines in vitro decreased OXPHOS effectors, inhibited cell growth and migration, and induced apoptosis. ONC212 increased metabolic stress and apoptotic pathways, inhibited amino acid metabolism, and induced cell death-related lipids. ONC212 also decreased tumor burden and increased survival in vivo in two UM liver metastasis models. ConclusionImipridones are a promising strategy for further testing and development in mUM.

cancer biology↗

bioRxiv2023

ID transcription factors regulate the ability of Muller glia to become proliferating neurogenic progenitor-like cells

The purpose of this study was to investigate how ID transcription factors (TFs) regulate the ability of Muller glia (MG) to reprogram into proliferating MG-derived progenitor cells (MGPCs) in the chick retina. We found that ID1 is transiently expressed by maturing MG, whereas ID4 is upregulated and maintained in maturing MG in embryonic retinas. In mature retinas, ID4 was prominently expressed by resting MG, but in response to retinal damage ID4 was rapidly upregulated and then downregulated in MGPCs. By contrast, ID1, ID2 and ID3 were low in resting MG and then upregulated by MGPCs. Inhibition of ID TFs following retinal damage decreased numbers of proliferating MGPCs. Inhibition of IDs after the proliferation of MGPCs significantly increased numbers of progeny that differentiate as neurons. In damaged or undamaged retinas inhibition of IDs increased levels of p21Cip1 in MG. In response to damage or insulin+FGF2 levels of CDKN1A message and p21Cip1 protein were decreased, absent in proliferating MGPCs, and elevated in MG returning to a resting phenotype. Inhibition of Notch- or gp130/Jak/Stat-signaling in damaged retinas increased levels of ID4 but not p21Cip1 in MG. Although ID4 is the predominant isoform expressed by MG in the chick retina, id1 and id2a are predominantly expressed by resting MG and downregulated in activated MG and MGPCs in zebrafish retinas. We conclude that ID TFs have a significant impact on regulating the responses of MG to retinal damage, controlling the ability of MG to proliferate by regulating levels of p21Cip1, and suppressing the neurogenic potential of MGPCs.

neuroscience↗

bioRxiv2023

Platelet extracellular vesicles and their mitochondrial content significantly improve survival and cytokine levels when transfused into mice with sepsis or H1N1 infections

BACKGROUNDMitochondrial transplantation has recently gained prominence as a novel technique primarily focused on addressing ischemiareperfusion injuries and rare mitochondrial mutation diseases. Platelets, abundant in the bloodstream, play a crucial role in immune function. Upon activation, platelets release mitochondria encapsulated within extracellular vesicles, here referred to as "mitlets". These mitlets exhibit a preference for being internalized by immune cells circulating in the bloodstream, enhancing their cellular energetics. Herein, we hypothesized that the transplantation of mitlets between young animals and aged animals may exert a significant influence on the progression of infectious diseases. STUDY DESIGN AND METHODSIn this study, murine models of Influenza H1N1 infection and sepsis were employed to investigate disease dynamics. Specifically, mitlets isolated from young and healthy mice were transplanted into cohorts of mice of the same age afflicted by H1N1 infection, or into aged mice subjected to polymicrobial infection and sepsis. Survival outcomes and the quantification of cytokine levels were assessed across experimental groups to elucidate the potential therapeutic effects of mitlet transplantation. RESULTSIn the matched-age H1N1 infection model, as predicted, mitlet transplantation did not yield a statistically significant improvement in survival, although it did show a trend towards a reduction in the circulating inflammatory cytokine burden. In the young-to-old sepsis model, the transplantation of mitlets was associated with a significant enhancement in survival rates and a substantial reduction in bacterial loads and circulating cytokine levels. DISCUSSIONOur findings suggest that mitochondrial transplantation may constitute a safe and promising avenue for enhancing the immune systems capacity to counter infectious threats. This pilot investigation sets the stage for further exploration. It is plausible that in the future, immune senescence resulting from diminished mitochondrial energy production could be ameliorated through such transplantation interventions. As a consequence, this approach holds substantial potential as a novel immunotherapeutic strategy for the management of infectious diseases.

molecular biology↗

bioRxiv2023

Selective effects of estradiol on human corneal endothelial cells

Fuchs endothelial corneal dystrophy (FECD) results from genetic and environmental factors triggering mitochondrial and oxidative stress in corneal endothelial cells (CEnCs) leading to CEnC death and corneal opacification. FECD is more common in women than men, but the basis for this observation is unknown. Because FECD is commonly diagnosed around the time of the menopausal transition in women when estrogen levels decrease precipitously, we studied the effects of the potent estrogen,17-{beta} estradiol (E2) on growth, oxidative stress, and metabolism in primary cultures of human CEnCs (HCEnCs) under conditions of physiologic 2.5% O2 ([O2]2.5) and under hyperoxic stress ([O2]A: room air + 5% CO2). We hypothesized that E2 would counter the stresses of the hyperoxic environment in HCEnCs. HCEnCs were treated {+/-} 10 nM E2 for 7-10 days at [O2]2.5 and [O2]A followed by measurements of cell density, viability, reactive oxygen species (ROS), mitochondrial morphology, oxidative DNA damage, ATP levels, mitochondrial respiration (O2 consumption rate [OCR]), and glycolysis (extracellular acidification rate [ECAR]). There were no significant changes in HCEnC density, viability, ROS levels, oxidative DNA damage, OCR, and ECAR in response to E2 under either O2 condition. We found that E2 disrupted mitochondrial morphology in HCEnCs from female donors but not male donors at the [O2]A condition. ATP levels were significantly higher at [O2]2.5 compared to [O2]A in HCEnCs from female donors only, but were not affected by E2. Our findings demonstrate the overall resilience of primary HCEnCs against hyperoxic stress. The selective detrimental effects of hyperoxia and estradiol on HCEnCs from female but not male donors suggests mechanisms of toxicity based upon cell-sex in addition to hormonal environment.

cell biology↗

bioRxiv2023

Reply to: Caution Regarding the Specificities of Pan-Cancer Microbial Structure

The cancer microbiome field tremendously accelerated following the release of our manuscript nearly three years ago1, including direct validation of our cancer type-specific conclusions in independent, international cohorts2,3 and the tumor microbiomes adoption into the hallmarks of cancer4. Disentangling contamination signals from biological signals is an important consideration for this research field. Therefore, despite numerous, high-impact, peer-reviewed research papers that either validated our conclusions or extended them using data we released2,5-13, we carefully considered criticism raised by Gihawi et al. about potential mishandling of contaminants, batch effects, and machine learning approaches--all of which were central topics in our manuscript. Nonetheless, a close examination of each concern alongside the original manuscript and re-analyses of our published data strongly demonstrates the robustness of the original findings. To remove all doubt, however, we have reproduced all key conclusions from the original manuscript using only overlapping bacterial genera identified in a highly decontaminated, multi-cancer, international cohort (Weizmann Institute of Science, WIS)2, with or without batch correction, and with multiclass machine learning analyses to mitigate class imbalances. Our published pan-cancer mycobiome manuscript3 also affirms these findings using updated, state-of-the-art methods. We also note that every analysis shown here was possible using public data and code that we had already provided.

bioinformatics↗

bioRxiv2021

Germline variants that influence the tumor immune microenvironment also drive response to immunotherapy

With the continued promise of immunotherapy as an avenue for treating cancer, understanding how host genetics contributes to the tumor immune microenvironment (TIME) is essential to tailoring cancer screening and treatment strategies. Approaches that intersect SNP modifiers of molecular phenotype, such as gene expression, with disease phenotypes have shown promise for implicating causal genetic factors. Here we evaluated 194 literature-curated TIME associations and 890 associations detected with 157 immune phenotype (IP) components found using genotypes from over 8,000 individuals in The Cancer Genome Atlas. Of these 1084, 233 associations comprising 219 unique TIME-SNPs were also cancer relevant, associating with cancer risk, survival, and/or immunotherapy treatment response. Many cancer relevant TIME-SNPS overlapped regions of active transcription, and were associated with gene expression in specific immune cell subsets, such as macrophages and dendritic cells. TIME-SNPs associated with cancer risk and response to immunotherapy implicated genes involved in antigen presentation, especially by antigen presenting cells. The strongest associations with survival were with PD-L1 and CTLA-4, suggesting that SNPs modifying the potential for immune evasion could contribute to disease progression. To assess whether our approach could reveal novel cancer immunotherapy targets, we inhibited CTSS, a gene implicated by cancer risk and immunotherapy response-associated TIME-SNPs; CTSS inhibition resulted in slowed tumor growth and extended survival in vivo. These results validate the potential of cancer relevant TIME-SNPs to implicate target genes for countering immune suppressive characteristics of the TIME and set the stage for future host genetics analysis integrating germline variation and TIME characteristics. SignificanceA systematic screen for common germline variants associated with the tumor immune microenvironment across > 8000 tumors reveals novel cancer risk factors and targets for immunotherapy.

cancer biology↗