Thazin N. Aung, James Monkman, Jonathan Warrell, Ioannis Vathiotis, Katherine M. Bates, Niki Gavrielatou, Ioannis P. Trontzas, Chin Wee Tan, Aileen I. Fernandez, Myrto Moutafi, Ken O’ Byrne, Kurt A. Schalper, Konstantinos Syrigos, Roy S. Herbst, Arutha Kulasinghe, David L. Rimm <<<

Abstract Non-small cell lung cancer (NSCLC) shows variable responses to immunotherapy, highlighting the need for biomarkers to guide patient selection. We applied a spatial multi-omics approach to 234 advanced NSCLC patients treated with programmed death 1-based immunotherapy across three cohorts to identify biomarkers associated with outcome. Spatial proteomics (n = 67) and spatial compartment-based transcriptomics (n = 131) enabled profiling of the tumor immune microenvironment (TIME). Using spatial proteomics, we identified a resistance cell-type signature including proliferating tumor cells, granulocytes, vessels (hazard ratio (HR) = 3.8, P = 0.004) and a response signature, including M1/M2 macrophages and CD4 T cells (HR = 0.4, P = 0.019). We then generated a cell-to-gene resistance signature using spatial transcriptomics, which was predictive of poor outcomes (HR = 5.3, 2.2, 1.7 across Yale, University of Queensland and University of Athens cohorts), while a cell-to-gene response signature predicted favorable outcomes (HR = 0.22, 0.38 and 0.56, respectively). This framework enables robust TIME modeling and identifies biomarkers to support precision immunotherapy in NSCLC. <<<

Ziqi Dong, Niek Wit, Aastha Agarwal, Adam James Reid, Dnyanesh Dubal, Sina Beier, Krishnaa T. Mahbubani, Kourosh Saeb-Parsy, Jelle van den Ameele, James A. Nathan, Emma L. Rawlins <<<

Yu Chen, Zhixi Chen, Hao Wang, Zhen Cui, Kai-Le Li, Zhiwei Song, Lingjiang Chen, Xiaoxiang Sun, Xiaoyu Xu, Yixue Zhang, Li Tan, Jian Yuan, Rong Tan, Min-Hua Luo, Fang-Lin Sun, Haipeng Liu, Ying Jiang, Zhiyong Mao <<<

Efficient DNA repair might make possible the longevity of naked mole-rats. However, whether they have distinctive mechanisms to optimize functions of DNA repair suppressors is unclear. We find that naked mole-rat cyclic guanosine monophosphate–adenosine monophosphate synthase (cGAS) lacks the suppressive function of human or mouse homologs in homologous recombination repair through the alteration of four amino acids during evolution. The changes enable cGAS to retain chromatin longer upon DNA damage by weakening TRIM41-mediated ubiquitination and interaction with the segregase P97. Prolonged chromatin binding of cGAS enhanced the interaction between repair factors FANCI and RAD50 to facilitate RAD50 recruitment to damage sites, thereby potentiating homologous recombination repair. Moreover, the four amino acids mediate the function of cGAS in antagonizing cellular and tissue aging and extending life span. Manipulating cGAS might therefore constitute a mechanism for life-span extension. <<<

AbstractThe hippocampal cognitive map supports navigation towards, or away from, salient locations in familiar environments1. Although much is known about how the hippocampus encodes location in world-centred coordinates, how it supports flexible navigation is less well understood. We recorded CA1 place cells while rats navigated to a goal on the honeycomb maze2. The maze tests navigation via direct and indirect paths to the goal and allows the directionality of place cells to be assessed at each choice point. Place fields showed strong directional polarization characterized by vector fields that converged to sinks distributed throughout the environment. The distribution of these ‘convergence sinks’ (ConSinks) was centred near the goal location and the population vector field converged on the goal, providing a strong navigational signal. Changing the goal location led to movement of ConSinks and vector fields towards the new goal. The honeycomb maze allows independent assessment of spatial representation and spatial action in place cell activity and shows how the latter relates to the former. The results suggest that the hippocampus creates a vector-based model to support flexible navigation, allowing animals to select optimal paths to destinations from any location in the environment. <<<

Procrastination is considered a result of failed self-regulation. However, could experiencing a sense of successful self-discipline help to boost motivation and reduce procrastination? To explore this question, two studies were conducted to investigate the relationship between the sense of self-discipline, autonomous motivation, and procrastination. Results showed that trait sense of self-discipline negatively predicted general procrastination (Study 1); self-discipline primed participants procrastinated less than the control group (Study 2); autonomous motivation mediated the relationship between sense of self-discipline and procrastination (Study 1 and Study 2). These findings suggest that cultivating a sense of self-discipline can have positive effects on both autonomous motivation and procrastination, and provide useful guidance for interventions aimed at reducing procrastination. <<<