Biology subjects

Raz, D.

Publications and source records attributed to Raz, D..

5 recordsLinked to original sources

bioRxiv2026

Locomotor adaptation can persistently reorganize stride-to-stride regulation of centre of mass error dynamics

Locomotor learning in novel environments relies on a gradual alteration of motor output to achieve a desired state. Changes in gait outcomes such as step-length asymmetry are typically used to describe this process. Recently, stability-relevant adaptations, quantified by scalar metrics such as the margin of stability, have also attracted interest. Yet humans, in part, regulate walking stability from stride-to-stride. Scalar metrics only provide instantaneous snapshots of stability and fail to capture rules governing fluctuations from one stride to the next. Here, we investigate whether locomotor adaptation changes how movement regulation evolves across strides using a multidimensional, dynamical systems model of centre-of-mass (CoM) based locomotion error. We apply this approach to split-belt locomotor adaptation, where participants walk on a treadmill with a separate belt for each foot. One belt moves faster than the other, driving participants to adapt compensatory gait patterns due to asymmetry. Using our stride-to-stride model, we find that, in addition to reducing CoM error while adapting, multidimensional error regulation dynamics are also adapted. This structural adaptation persists upon re-exposure to split-belt conditions. Our findings show that split-belt locomotor adaptation includes an adaptation of the structure of stride-to-stride CoM movement regulation and that this structure may be rapidly recalled.

neuroscience↗

bioRxiv2025

Chryseobacterium indologenes mediates resistance to osimertinib by activating the IGF1R pathway in EGFR-mutant lung adenocarcinoma

IntroductionLung cancers harboring sensitizing epidermal growth factor receptor (EGFR) mutations typically exhibit an initial response to osimertinib; however, the development of resistance is inevitable, and there are currently no approved targeted therapies available once resistance emerges. Accumulating evidence indicates that intra-tumoral bacteria can influence tumor biology and contribute to therapy resistance in several cancer types, including pancreatic and colorectal cancer. Despite these findings, whether intra-tumoral bacteria play a role in modulating response and resistance to osimertinib in EGFR-mutant lung adenocarcinoma remains largely unexplored. This study aims to investigate the contribution of intra-tumoral bacteria to osimertinib resistance, thereby providing new insights into resistance mechanisms and identifying potential therapeutic strategies. MethodsBacteria previously identified in lung cancer tissue samples were cultured in liquid growth medium, and their preconditioned medium (PCM) was collected. PC9 cells were treated with PCM in the presence or absence of osimertinib to screen for bacteria capable of mediating resistance. Cell viability was assessed using Cell Counting Kit-8 assays. To investigate potential mechanisms, Western blotting and receptor tyrosine kinase (RTK) phosphorylation arrays were performed. Control groups included cells treated with osimertinib alone, PCM alone, or vehicle. Statistical analyses were conducted using Students t-test as appropriate, with p < 0.05 considered statistically significant. Data represent mean {+/-} SD from at least three independent experiments. ResultsThe addition of PCM from Chryseobacterium indologenes restored cell viability in EGFR-mutant lung adenocarcinoma cells treated with osimertinib. PCM exposure markedly increased insulin-like growth factor-1 receptor (IGF1R) phosphorylation levels. PCM did not enhance cell viability when IGF1R was silenced or inhibited with linsitinib, demonstrating the pathways essential role. Proteinase K treatment abolished the ability of PCM to protect cells from osimertinib, and removal of proteins potentially interacting with IGF1R further diminished its efficacy. Finally, PCM also conferred resistance to osimertinib in patient-derived EGFR-mutant lung adenocarcinoma cell lines. ConclusionOur study demonstrates that the intra-tumoral bacteria C. indologenes may significantly influence sensitivity to osimertinib or impart resistance in EGFR-mutant lung adenocarcinoma by activating the IGF1R signaling pathway.

cancer biology↗

bioRxiv2024

Cell of origin alters myeloid-mediated immunosuppression in lung adenocarcinoma

Solid carcinomas are often highly heterogenous cancers, arising from multiple epithelial cells of origin. Yet, how the cell of origin influences the response of the tumor microenvironment is poorly understood. Lung adenocarcinoma (LUAD) arises in the distal alveolar epithelium which is populated primarily by alveolar epithelial type I (AT1) and type II (AT2) cells. It has been previously reported that Gramd2+ AT1 cells can give rise to a histologically-defined LUAD that is distinct in pathology and transcriptomic identity from that arising from Sftpc+ AT2 cells1,2. To determine how cells of origin influence the tumor immune microenvironment (TIME) landscape, we comprehensively characterized transcriptomic, molecular, and cellular states within the TIME of Gramd2+ AT1 and Sftpc+ AT2-derived LUAD using KRASG12D oncogenic driver mouse models. Myeloid cells within the Gramd2+AT1-derived LUAD TIME were increased, specifically, immunoreactive monocytes and tumor associated macrophages (TAMs). In contrast, the Sftpc+ AT2 LUAD TIME was enriched for Arginase-1+ myeloid derived suppressor cells (MDSC) and TAMs expressing profiles suggestive of immunosuppressive function. Validation of immune infiltration was performed using flow cytometry, and intercellular interaction analysis between the cells of origin and major myeloid cell populations indicated that cell-type specific markers SFTPD in AT2 cells and CAV1 in AT1 cells mediated unique interactions with myeloid cells of the differential immunosuppressive states within each cell of origin mouse model. Taken together, Gramd2+ AT1-derived LUAD presents with an anti-tumor, immunoreactive TIME, while the TIME of Sftpc+ AT2-derived LUAD has hallmarks of immunosuppression. This study suggests that LUAD cell of origin influences the composition and suppression status of the TIME landscape and may hold critical implications for patient response to immunotherapy.

cancer biology↗

bioRxiv2019

A Non-genetic Mechanism for Chemoresistance in Lung Cancer: The Role of Integrin β4/Paxillin Axis

Tumor heterogeneity and cisplatin resistance are a major cause of tumor relapse and poor survival. Here we show that in lung adenocarcinoma (LUAD), paxillin (PXN) and integrin beta 4 (ITGB4) are associated with tumor progression, and cisplatin resistance. Silencing PXN and ITGB4 render cisplatin tolerant cells sensitive, and immunologically neutralizing ITGB4 improves sensitivity. The N-terminal half of PXN is intrinsically disordered and interacts with ITGB4 to regulate expression of USP1 and VDAC1 which are required for maintaining genomic stability and mitochondrial function in LUAD. By virtual screening an FDA-approved compound library, we identified compounds that interact with PXN in silico and attenuate cisplatin resistance in LUAD cells. RNAseq analysis identified a double negative feedback loop between ITGB4 and microRNA miR-1-3p, suggesting that bistability could lead to stochastic switching between cisplatin-sensitive and resistant states in these cells. The data highlight an alternate, non-genetic, mechanism underlying chemoresistance in lung cancer.

cancer biology↗

bioRxiv2019

Gene Activation and repression by the glucocorticoid receptor are mediated by sequestering Ep300 and two modes of chromatin binding

The transcription factor glucocorticoid receptor (GR) is a key mediator of stress response and a broad range of physiological processes. How can GR rapidly activate the expression of some genes while repress others, remains an open question due to the challenge to associate GR binding sites (GBSs) to their distant gene targets. Mapping the full 3D scope of GR-responsive promoters using high-resolution 4C-seq unravelled spatial separation between chromatin interaction networks of GR-activated and repressed genes. Analysing GR binding sites and other regulatory loci in their functional 3D context revealed that GR sequesters the co-activator Ep300 from active non-GBS enhancers in both activated and repressed gene compartments. While this is sufficient for rapid gene repression, gene activation is countered by productive recruitment of Ep300 to GBS. Importantly, in GR-activated compartments Klf4 binding at non-GBS regulatory elements cluster in 3D with GBS and antagonizes GR activation. In addition, we revealed ROR and Rev-erb transcription factors as novel co-regulators for GR-mediated gene expression.

molecular biology↗