Biology subjects

Jack, J.

Publications and source records attributed to Jack, J..

7 recordsLinked to original sources

bioRxiv2026

Continual Learning for Emerging Epitope Landscapes in TCR peptide Binding Prediction

The TCR-peptide binding landscape evolves continuously: novel pathogens (SARS-CoV-2, emerging influenza variants) and newly characterized tumor neoantigens introduce epitope families with no training precedent. Deploying a static model trained on historical data leads to degraded performance on emerging epitopes, while naive fine-tuning on new data causes catastrophic forgetting--erasing performance on previously learned epitopes. We introduce ContinualTCR, a continual learning framework that combines reservoir replay with Elastic Weight Consolidation (EWC) regularization to balance stability (retaining old-epitope performance) and plasticity (adapting to new epitopes). Evaluated on a temporally partitioned VDJdb- IEDB benchmark across four sequential epitope arrival tasks, ContinualTCR achieves new-epitope AUROC 0.812 and old-epitope AUROC 0.781 simultaneously--reducing catastrophic forgetting by 62.9% relative to naive fine-tuning. A streaming evaluation protocol with per-task backward transfer (BWT) reporting reveals that replay alone resolves 30.6% of forgetting, EWC alone resolves 57.3%, and their combination achieves synergistic complementarity. These results establish continual learning as a necessary component of production TCR specificity systems that must adapt to evolving pathogen and neoantigen landscapes without requiring full retraining.

bioinformatics↗

bioRxiv2026

Proximity-Aware Graph Attention Networks for Spatially Resolved Cell-Cell Inference

Cell-cell inference is a fundamental mechanism driving tissue homeostasis, immune regulation, and disease progression. Existing CCC inference tools operate on dissociated single-cell RNA-seq data, discarding the spatial constraints that govern short-range paracrine and juxtacrine signaling. We present SO_SCPLOWPAC_SCPLOWGNN, a proximity-aware graph attention network that jointly encodes physical cell adjacency and ligand-receptor co-expression from spatial transcriptomics data to infer spatially resolved CCC interactions. A heterogeneous cell communication graph is constructed by combining spatial proximity edges with molecular ligand-receptor edges, and a distance-modulated attention mechanism enforces the locality constraint of cell-to-cell signaling. The model is trained with a composite self-supervised objective that integrates spatial co-localization enrichment and downstream target gene activation. We evaluate SO_SCPLOWPAC_SCPLOWGNN on four spatial transcriptomics datasets spanning 10X Visium, MERFISH, and Slide-seq platforms. Compared with state-of-the-art methods including COMMOT, SpaOTsc, CellChat, and NicheNet, our method achieves superior interaction AUROC (0.871 vs. 0.831 for COMMOT), a 3.42x spatial enrichment score, and an F1 of 0.681 in communication hotspot detection. Ablation studies confirm that spatial distance modulation is the single most impactful component, contributing a 0.030 AUROC improvement over a non-spatial baseline.

bioinformatics↗

bioRxiv2023

Combined PI3K and MAPK inhibition synergizes to suppress PDAC

Oncogenic KRAS mutations are nearly ubiquitous in pancreatic ductal adenocarcinoma (PDAC), yet therapeutic attempts to target KRAS as well as its target MAPK pathway effectors have shown limited success due to the difficulty to pharmacologically target KRAS, inherent drug resistance in PDAC cells, and acquired resistance through activation of alternative mitogenic pathways such JAK-STAT and PI3K-AKT. While KRAS canonically drives the MAPK signaling pathway via RAF-MEK-ERK, it is also known to play a role in PI3K-AKT signaling. Our therapeutic study targeted the PI3K-AKT pathway with the drug Omipalisib (p110/{beta}/{delta}/{gamma} and mTORC1/2 inhibitor) in combination with MAPK pathway targeting drug Trametinib (MEK1/2 inhibitor) or SHP099-HCL (SHP099), which is an inhibitor of the KRAS effector SHP2. Western blot analysis demonstrated that application of Trametinib or SHP099 alone selectively blocked ERK phosphorylation (pERK) but failed to suppress phosphorylated AKT (pAKT) and in some instances increased pAKT levels. Conversely, Omipalisib alone successfully inhibited pAKT but failed to suppress pERK. Therefore, we hypothesized that a combination therapeutic comprised of Omipalisib with either Trametinib or SHP099 would inhibit two prominent mitogenic pathways, MEK and PI3K-AKT, to more effectively suppress pancreatic cancer. In vitro studies demonstrated that both Omipalisib/Trametinib and Omipalisib/SHP099 combination therapeutic strategies were generally more effective than treatment with each drug individually at reducing proliferation, colony formation, and cell migration compared to vehicle controls. Additionally, we found that while combination Omipalisib/SHP099 treatment reduced implanted tumor growth in vivo, the Omipalisib/Trametinib treatment was significantly more effective. Therefore, we additionally tested the Omipalisib/Trametinib combination therapeutic in the highly aggressive PKT (Ptf1acre, LSL-KrasG12D, TGFbR2fl/fl) spontaneous mouse model of PDAC. We subsequently found that PKT mice treated with the Omipalisib/Trametinib combination therapeutic survived significantly longer than mice treated with either drug alone, and more than doubled the mean survival time of vehicle control mice. Altogether, our data support the importance of a dual treatment strategy targeting both MAPK and PI3K-AKT pathways.

cancer biology↗

bioRxiv2023

Adipose contributes to CXCL5 regulated immune evasion in pancreatic cancer

BackgroundCXCR1/2 inhibitors are being implemented with immunotherapies in PDAC clinical trials. Cytokines responsible for stimulating these receptors include CXCL ligands, typically secreted by activated immune cells, fibroblasts, and even adipocytes. Obesity has been linked to poor patient outcome and altered anti-tumor immunity. Adipose-derived cytokines and chemokines have been implicated as potential drivers of tumor cell immune evasion, suggesting a possibility of susceptibility to targeting specifically in the context of obesity. MethodsRNA-sequencing of human PDAC cell lines was used to assess differential influences on the cancer cell transcriptome after treatment with conditioned media from peri-pancreatic adipose tissue of lean and obese PDAC patients. The adipose-induced secretome of PDAC cells was then assessed by cytokine arrays and ELISAs. Lentiviral transduction and CRISPR-Cas9 was used to knock out CXCL5 from a murine PDAC cell line for orthotopic tumor studies in diet-induced obese, syngeneic mice. Flow cytometry was used to define the immune profiles of tumors. Anti-PD-1 immune checkpoint blockade therapy was administered to alleviate T cell exhaustion and invoke an immune response, while the mice were monitored at endpoint for differences in tumor size. ResultsThe chemokine CXCL5 was secreted in response to stimulation of PDAC cells with human adipose conditioned media (hAT-CM). PDAC CXCL5 secretion was induced by either IL-1{beta} or TNF, but neutralization of both was required to limit secretion. Ablation of CXCL5 from tumors promoted an immune phenotype susceptible to PD-1 inhibitor therapy. While application of anti-PD-1 treatment to control tumors failed to alter tumor growth, knockout CXCL5 tumors were diminished. ConclusionsIn summary, our findings show that known adipokines TNF and IL-1{beta} can stimulate CXCL5 release from PDAC cells in vitro. In vivo, CXCL5 depletion alone is sufficient to promote T cell infiltration into tumors in an obese setting, but requires checkpoint blockade inhibition to alleviate tumor burden. DATA AVAILABILITY STATEMENTRaw and processed RNAseq data will be further described in the GEO accession database (awaiting approval from GEO for PRJ number). Additional raw data is included in the supplemental material and available upon reasonable request. WHAT IS ALREADY KNOWN ON THIS TOPICObesity is linked to a worsened patient outcome and immunogenic tumor profile in PDAC. CXCR1/2 inhibitors have begun to be implemented in combination with immune checkpoint blockade therapies to promote T cell infiltration under the premise of targeting the myeloid rich TME. WHAT THIS STUDY ADDSUsing in vitro/ex vivo cell and tissue culture-based assays with in vivo mouse models we have identified that adipose derived IL-1{beta} and TNF can promote tumor secretion of CXCL5 which acts as a critical deterrent to CD8 T cell tumor infiltration, but loss of CXCL5 also leads to a more immune suppressive myeloid profile. HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE, OR POLICYThis study highlights a mechanism and emphasizes the efficacy of single CXCR1/2 ligand targeting that could be beneficial to overcoming tumor immune-evasion even in the obese PDAC patient population.

cancer biology↗

bioRxiv2023

ATP-Gated Potassium Channels Contribute to Ketogenic Diet-Mediated Analgesia in Mice.

Chronic pain is a substantial health burden and options for treating chronic pain remain minimally effective. Ketogenic diets are emerging as well-tolerated, effective therapeutic strategies in preclinical models of chronic pain, especially diabetic neuropathy. We tested whether a ketogenic diet is antinociceptive through ketone oxidation and related activation of ATP-gated potassium (KATP) channels in mice. We demonstrate that consumption of a ketogenic diet for one week reduced evoked nocifensive behaviors (licking, biting, lifting) following intraplantar injection of different noxious stimuli (methylglyoxal, cinnamaldehyde, capsaicin, or Yoda1) in mice. A ketogenic diet also decreased the expression of p-ERK, an indicator of neuronal activation in the spinal cord, following peripheral administration of these stimuli. Using a genetic mouse model with deficient ketone oxidation in peripheral sensory neurons, we demonstrate that protection against methylglyoxal-induced nociception by a ketogenic diet partially depends on ketone oxidation by peripheral neurons. Injection of tolbutamide, a KATP channel antagonist, prevented ketogenic diet-mediated antinociception following intraplantar capsaicin injection. Tolbutamide also restored the expression of spinal activation markers in ketogenic diet-fed, capsaicin-injected mice. Moreover, activation of KATP channels with the KATP channel agonist diazoxide reduced pain-like behaviors in capsaicin-injected, chow-fed mice, similar to the effects observed with a ketogenic diet. Diazoxide also reduced the number of p-ERK+ cells in capsaicin-injected mice. These data support a mechanism that includes neuronal ketone oxidation and activation of KATP channels to provide ketogenic diet-related analgesia. This study also identifies KATP channels as a new target to mimic the antinociceptive effects of a ketogenic diet.

neuroscience↗

bioRxiv2023

Ketolysis is Required for the Proper Development and Function of the Somatosensory Nervous System.

Ketogenic diets are emerging as protective interventions in preclinical and clinical models of somatosensory nervous system disorders. Additionally, dysregulation of succinyl-CoA 3-oxoacid CoA-transferase 1 (SCOT, encoded by Oxct1), the fate-committing enzyme in mitochondrial ketolysis, has recently been described in Friedreichs ataxia and amyotrophic lateral sclerosis. However, the contribution of ketone metabolism in the normal development and function of the somatosensory nervous system remains poorly characterized. We generated sensory neuron-specific, Advillin-Cre knockout of SCOT (Adv-KO-SCOT) mice and characterized the structure and function of their somatosensory system. We used histological techniques to assess sensory neuronal populations, myelination, and skin and spinal dorsal horn innervation. We also examined cutaneous and proprioceptive sensory behaviors with the von Frey test, radiant heat assay, rotarod, and grid-walk tests. Adv-KO-SCOT mice exhibited myelination deficits, altered morphology of putative A{delta} soma from the dorsal root ganglion, reduced cutaneous innervation, and abnormal innervation of the spinal dorsal horn compared to wildtype mice. Synapsin 1-Cre-driven knockout of Oxct1 confirmed deficits in epidermal innervation following a loss of ketone oxidation. Loss of peripheral axonal ketolysis was further associated with proprioceptive deficits, yet Adv-KO-SCOT mice did not exhibit drastically altered cutaneous mechanical and thermal thresholds. Knockout of Oxct1 in peripheral sensory neurons resulted in histological abnormalities and severe proprioceptive deficits in mice. We conclude that ketone metabolism is essential for the development of the somatosensory nervous system. These findings also suggest that decreased ketone oxidation in the somatosensory nervous system may explain the neurological symptoms of Friedreichs ataxia.

neuroscience↗

bioRxiv2018

Altered Bile Acid Profile Associates with Cognitive Impairment in Alzheimer’s Disease – An Emerging Role for Gut Microbiome

IntroductionIncreasing evidence suggests a role for the gut microbiome in central nervous system disorders and specific role for the gut-brain axis in neurodegeneration. Bile acids (BA), products of cholesterol metabolism and clearance, are produced in the liver and are further metabolized by gut bacteria. They have major regulatory and signaling functions and seem dysregulated in Alzheimer disease (AD).\n\nMethodsSerum levels of 15 primary and secondary BAs and their conjugated forms were measured in 1,464 subjects including 370 cognitively normal older adults (CN), 284 with early mild cognitive impairment (MCI), 505 with late MCI, and 305 AD cases enrolled in the AD Neuroimaging Initiative. We assessed associations of BA profiles including selected ratios with diagnosis, cognition, and AD-related genetic variants, adjusting for cofounders and multiple testing.\n\nResultsIn AD compared to CN, we observed significantly lower serum concentrations of a primary BA (cholic acid CA) and increased levels of the bacterially produced, secondary BA, deoxycholic acid (DCA), and its glycine and taurine conjugated forms. An increased ratio of DCA:CA, which reflects 7-dehydroxylation of CA by gut bacteria, strongly associated with cognitive decline, a finding replicated in serum and brain samples in the Rush Religious Orders and Memory and Aging Project. Several genetic variants in immune response related genes implicated in AD showed associations with BA profiles.\n\nConclusionWe report for the first time an association between altered BA profile, genetic variants implicated in AD and cognitive changes in disease using a large multicenter study. These findings warrant further investigation of gut dysbiosis and possible role of gut liver brain axis in the pathogenesis of AD.

neuroscience↗