Biology subjects

Good, J.

Publications and source records attributed to Good, J..

8 recordsLinked to original sources

bioRxiv2025

Tumor-Initiating Cells Fine-tune the Plasticity of Neutrophils to Sculpt a Protective Niche

The abundant accumulation of neutrophils in various solid cancers has been well recognized, but the functions of tumor-associated neutrophils (TANs) remain controversial. TANs have long been believed to be immune suppressive and have thus been referred to as "myeloid-derived suppressor cells". However, effective tumor control induced by immunotherapy was recently found to be associated with strong neutrophil signatures. These seemingly contradictory findings highlight the unexpected degree of plasticity and heterogeneity unique to TANs. How the cellular plasticity and functional heterogeneity of TANs are regulated remains unknown. Here, we show that, while anti-PDL1/CD40 agonist immunotherapy can induce interferon responses to reprogram many TANs, allowing them to become plastic and regain anti-tumor activities in squamous cell carcinomas, a subset of TANs residing at the tumor-stroma interface can preserve their immune suppressive state. Importantly, by designing a reverse genetic screening, we identified a group of Sox2Hi tumor-initiating cells (TICs) at the tumor-stroma interface that could upregulate Fatty Acid Desaturase 1 (Fads1) to produce arachidonic acid. This TIC-specific pathway can disrupt the interferon responsive potentials of TANs, preventing the interferon-mediated reprogramming. Thus, by fine-tuning the plasticity of neutrophils, TICs shape neutrophil heterogeneity and sculpt a protective micro-niche to survive from immunotherapy and drive cancer relapse.

cancer biology↗

bioRxiv2025

Avid lysosomal acidification in fibroblasts of the Mediterranean mouse Mus spretus

Failures of the lysosome-autophagy system are a hallmark of aging and many disease states. As a consequence, interventions that enhance lysosome function are of keen interest in the context of drug development. Throughout the biomedical literature, evolutionary biologists have found cases in which challenges faced by humans in clinical settings have been resolved by non-model organisms adapting to wild environments. Here, we used a primary cell culture approach to survey lysosomal characteristics in species of the genus Mus. We found that fibroblasts from M. spretus, a wild Mediterranean mouse, exhibited elevated lysosomal mass and enzyme activity along with reduced activity of {beta}-galactosidase, a classical marker of cellular senescence, compared to those from M. musculus, a related species adapted to human-associated environments. We propose that classic laboratory models of lysosome function and senescence may reflect characters that diverge from the phenotypes of wild mice. The M. spretus phenotype may ultimately serve as a blueprint for interventions that ameliorate lysosomal dysfunction under conditions of stress and disease.

evolutionary biology↗

bioRxiv2024

Species limits and hybridization in Andean leaf-eared mice (Phyllotis)

Leaf-eared mice (genus Phyllotis) are among the most widespread and abundant small mammals in the Andean Altiplano, but species boundaries and distributional limits are often poorly delineated due to sparse survey data from remote mountains and high-elevation deserts. Here we report a combined analysis of mitochondrial DNA variation and whole-genome sequence (WGS) variation in Phyllotis mice to delimit species boundaries, to assess the timescale of diversification of the group, and to examine evidence for interspecific hybridization. Estimates of divergence dates suggest that most diversification of Phyllotis occurred during the past 3 million years. Consistent with the Pleistocene Aridification hypothesis, our results suggest that diversification of Phyllotis largely coincided with climatically induced environmental changes in the mid- to late Pleistocene. Contrary to the Montane Uplift hypothesis, most diversification in the group occurred well after the major phase of uplift of the Central Andean Plateau. Species delimitation analyses revealed surprising patterns of cryptic diversity within several nominal forms, suggesting the presence of much undescribed alpha diversity in the genus. Results of genomic analyses revealed evidence of ongoing hybridization between the sister species Phyllotis limatus and P. vaccarum and suggest that the contemporary zone of range overlap between the two species represents an active hybrid zone.

evolutionary biology↗

bioRxiv2023

Dietary Pyruvate Targets Cytosolic Phospholipase A2 to Mitigate Inflammation and Obesity in Mice

Obesity has a multifactorial etiology and is known to be a state of chronic low-grade inflammation, known as meta-inflammation. This state is associated with the development of metabolic disorders such as glucose intolerance and nonalcoholic fatty liver disease. Pyruvate is a glycolytic metabolite and a crucial node in various metabolic pathways. However, its role and molecular mechanism in obesity and associated complications are obscure. In this study, we reported that pyruvate substantially inhibited adipogenic differentiation in vitro and its administration significantly prevented HFD-induced weight gain, white adipose tissue inflammation, and metabolic dysregulation. To identify the target proteins of pyruvate, drug affinity responsive target stability was employed with proteomics, cellular thermal shift assay, and isothermal drug response to detect the interactions between pyruvate and its molecular targets. Consequently, we identified cytosolic phospholipase A2 (cPLA2) as a novel molecular target of pyruvate and demonstrated that pyruvate restrained diet-induced obesity, white adipose tissue inflammation, and hepatic steatosis in a cPLA2-dependent manner. Studies with global ablation of cPLA2 in mice showed that the protective effects of pyruvate were largely abrogated, confirming the importance of pyruvate/cPLA2 interaction in pyruvate attenuation of inflammation and obesity. Overall, our study not only establishes pyruvate as an antagonist of cPLA2 signaling and a potential therapeutic option for obesity, but it also sheds light on the mechanism of its action. Pyruvates prior clinical use indicates that it can be considered a safe and viable alternative for obesity, whether consumed as a dietary supplement or as part of a regular diet.

cell biology↗

bioRxiv2023

Extreme high-elevation mammal surveys reveal unexpectedly high upper range limits of Andean mice

In the worlds highest mountain ranges, uncertainty about the upper elevational range limits of alpine animals represents a critical knowledge gap regarding the environmental limits of life and presents a problem for detecting range shifts in response to climate change. Here we report results of mountaineering mammal surveys in the Central Andes, which led to the discovery of multiple species of mice living at extreme elevations that far surpass previously assumed range limits for mammals. We live-trapped small mammals from ecologically diverse sites spanning >6700 m of vertical relief, from the desert coast of northern Chile to the summits of the highest volcanoes in the Andes. We used molecular sequence data and whole-genome sequence data to confirm the identities of species that represent new elevational records and to test hypotheses regarding species limits. These discoveries contribute to a new appreciation of the environmental limits of vertebrate life.

evolutionary biology↗

bioRxiv2022

A natural variation-based screen in mouse cells reveals USF2 as a regulator of the DNA damage response and cellular senescence

Cellular senescence is a program of cell cycle arrest, apoptosis resistance, and cytokine release induced by stress exposure in metazoan cells. Landmark studies in laboratory mice have characterized a number of master senescence regulators, including p16INK4a, p21, NF-kB, p53, and C/EBP{beta}. To discover other molecular players in senescence, we developed a screening approach to harness the evolutionary divergence between mouse species. We found that primary cells from the Mediterranean mouse Mus spretus, when treated with DNA damage to induce senescence, produced less cytokine and had less-active lysosomes than cells from laboratory M. musculus. We used allele-specific expression profiling to catalog senescence-dependent cis-regulatory variation between the species at thousands of genes. We then tested for correlation between these expression changes and interspecies sequence variants in the binding sites of transcription factors. Among the emergent candidate senescence regulators, we chose a little-studied cell cycle factor, USF2, for molecular validation. In acute irradiation experiments, cells lacking USF2 had compromised DNA damage repair and response. Longer-term senescent cultures without USF2 mounted an exaggerated senescence regulatory program--shutting down cell cycle and DNA repair pathways, and turning up cytokine expression, more avidly than wild-type. We interpret these findings under a model of pro-repair, anti-senescence regulatory function by USF2. Our study affords new insights into the mechanisms by which cells commit to senescence, and serves as a validated proof of concept for natural variation-based regulator screens.

genomics↗

bioRxiv2021

Single-cell Multiomics Reveals Clonal T-cell Expansions and Exhaustion in Blastic Plasmacytoid Dendritic Cell Neoplasm

The immune system represents a major barrier to cancer progression, driving the evolution of immunoregulatory interactions between malignant cells and T-cells in the tumor environment. Blastic plasmacytoid dendritic cell neoplasms (BPDCN), a rare acute leukemia with plasmacytoid dendritic cell (pDC) differentiation, provides a unique opportunity to study these interactions. pDCs are key producers of interferon alpha (IFNA) that play an important role in T-cell activation at the interface between the innate and adaptive immune system. To assess how uncontrolled proliferation of malignant BPDCN cells affects the tumor environment, we catalog immune cell heterogeneity in the bone marrow (BM) of five healthy controls and five BPDCN patients by analyzing 52,803 single-cell transcriptomes, including 18,779 T-cells. We test computational techniques for robust cell type classification and find that T-cells in BPDCN patients consistently upregulate interferon alpha (IFNA) response and downregulate tumor necrosis factor alpha (TNFA) pathways. Integrating transcriptional data with T-cell receptor sequencing via shared barcodes reveals significant T-cell exhaustion in BPDCN that is positively correlated with T-cell clonotype expansion. By highlighting new mechanisms of T-cell exhaustion and immune evasion in BPDCN, our results demonstrate the value of single-cell multiomics to understand immune cell interactions in the tumor environment.

immunology↗

bioRxiv2019

Correlates of resting and exertional dyspnea among older adults with obstructive lung disease: a cross-sectional analysis of the Canadian Longitudinal Study on Aging

IntroductionIn patients with chronic obstructive pulmonary disease (COPD), the perception of dyspnea is related to quality of life, and is a better predictor of mortality than the severity of airway obstruction. The purpose of the current study was to use population-level data from the Canadian Longitudinal Study on Aging (CLSA) to identify potential correlates of dyspnea in adults with obstructive lung disease.\n\nMethodsData from participants with a self-reported obstructive lung disease (asthma or COPD) were used for analysis (n=2,854). Four outcome variables were assessed: self-reported dyspnea at 1) rest, 2) walking on a flat surface, 3) walking uphill/climbing stairs, 4) following strenuous activity. Potential sociodemographic, health, and health behaviour correlates were entered in to logistic regression models.\n\nResultsHigher body fat percentage, and worse forced expiratory volume in one second were associated with higher odds of reporting dyspnea. Females with an anxiety disorder (OR=1.91, CI: 1.29, 2.83) and males with a mood disorder (OR=2.67, CI: 1.53, 4.68) reported higher odds of experiencing dyspnea walking on a flat surface, independent of lung function and other correlates. Dyspnea while walking uphill/climbing stairs was associated with a slower timed up and go time in females (e.g. OR=1.18, CI: 1.10) and males (OR=1.19, CI: 1.09, 1.30).\n\nConclusionsIn addition to traditional predictors such as lung function and body composition, we found that anxiety and mood disorders, as well as functional fitness were correlates of dyspnea. Further research is needed to understand whether targeting these correlates leads to improvements in perceptions of dyspnea.

epidemiology↗