Jason Guo, Roger Liang, Andrew Chung, Zhijie Li, Boyuan Li, Eric Chen, Lin Li, Jingjing Wang, Meng-Hsiung Hsieh, Ivy Xiangyi Fang, Benjamin Kroger, Yunguan Wang, Min Zhu, Xiongzhao Ren, Greg Mannino, Yuemeng Jia, Yonglong Wei, Stephen Moore, Daniel J. Siegwart, Stephen S. Chung, Zixi Wang, Tripti Sharma, Suman Komjeti, Yi Han, Purva Gopal, Guanghua Xiao, Tao Wang, Hao Zhu <<<

The origin of cancer is poorly understood because premalignant cells are rarely followed in their native environments. While the spatial compartmentalization of metabolic functions is critical for proper liver function, it is unknown if cancers arise from some zones but not others, and if there are metabolic determinants of cancer risk. Zone-specific, mosaic introduction of Ctnnb1 and Arid2 mutations, commonly co-mutated genes in hepatocellular carcinoma (HCC), showed that position and metabolic context determine clone fates. Ctnnb1/Arid2 -driven cancers were much more likely to arise in zone 3. The zone 3 genes Gstm2 and Gstm3 were required for efficient HCC initiation, in part through inhibition of ferroptosis. In the liver, the zonal determinants of HCC development can reveal metabolic vulnerabilities of cancer. <<<

Li Wang, Cheng Wang, Juan A. Moriano, Songcang Chen, Guolong Zuo, Arantxa Cebrián-Silla, Shaobo Zhang, Tanzila Mukhtar, Shaohui Wang, Mengyi Song, Lilian Gomes de Oliveira, Qiuli Bi, Jonathan J. Augustin, Xinxin Ge, Mercedes F. Paredes, Eric J. Huang, Arturo Alvarez-Buylla, Xin Duan, Jingjing Li, Arnold R. Kriegstein <<<

In this paper, we investigate whether better schools can compensate for the effects of children’s genetic differences. To this end, we combine data from the Norwegian Mother, Father, and Child Cohort Study (MoBa) with Norwegian register data to estimate the interaction between measures of children’s predisposition to education and school quality. We use MoBa’s genetic data to compute polygenic indices for educational attainment ( PGI EA ). Importantly, MoBa includes genetic data on mother-father-child trios, allowing us to identify causal genetic effects using within-family variation. We calculate school value-added measures from Norwegian register data, allowing us to causally estimate school quality effects. Leveraging the advantages of both data sources, we provide a causally identified study of gene–environment interactions in the school context. We find evidence for substitutability of PGI EA and school quality in reading but not numeracy: A 1 SD increase of school quality decreases the impact of a 1 SD increase of PGI EA on reading test scores by 6%. The substitutability arises through gains of students at the lower end of the PGI EA distribution. This suggests that investments in school quality may help reduce educational inequalities arising from genetic differences between students. <<<

Aya Ludin, Georgia L Stirtz, Asaf Tal, Ajit J Nirmal, Kathleen L Pfaff, Michael Manos, Naomi Besson, Nebiyat Eskndir, Billie Porter, Stephanie M Jones, Hannah M Faulkner, Qiyu Gong, Sophia Liu, Irving Barrera, Lijian Wu, Cecilia Pessoa Rodrigues, Aditi Sahu, Elizabeth Jerison, Joao V Alessi, Biagio Ricciuti, Douglas S Richardson, Jodi D Weiss, Hadley M Moreau, Meredith E Stanhope, Alexander B Afeyan, James Sefton, Wyatt D McCall, Emily Formato, Song Yang, Yi Zhou, David P Hoytema van Konijnenburg, Hannah L Cole, Miguel Cordova, Liang Deng, Milind Rajadhyaksha, Stephen R Quake, Mark M Awad, Fei Chen, Kai W Wucherpfennig, Peter K Sorger, F Stephen Hodi, Scott J Rodig, George F Murphy, Leonard I Zon <<<

T cell-mediated tumor killing underlies immunotherapy success. Here, we used long-term in vivo imaging and high-resolution spatial transcriptomics of zebrafish endogenous melanoma, as well as multiplex imaging of human melanoma, to identify domains facilitating the immune response during immunotherapy. We identified cancer regions of antigen presentation and T cell engagement and retention (CRATERs) as pockets at the stroma-melanocyte boundaries of zebrafish and human melanoma. CRATERs are rich in antigen-recognition molecules, harboring the highest density of CD8 T cells in tumors. In zebrafish, CD8 T cells formed prolonged interactions with melanoma cells within CRATERs, characteristic of antigen recognition. Following immunostimulatory treatment, CRATERs expanded, becoming the major sites of activated CD8 T cell accumulation and tumor killing. In humans, elevation in CRATER density in biopsies following immune checkpoint blockade (ICB) therapy correlated with a clinical response to therapy. CRATERs are structures that show active tumor killing and may be useful as a diagnostic indicator for immunotherapy success. <<<

Yasuaki Mohri, Jialiang Nie, Hironobu Morinaga, Tomoki Kato, Takahiro Aoto, Takashi Yamanashi, Daisuke Nanba, Hiroyuki Matsumura, Sakura Kirino, Kouji Kobiyama, Ken J. Ishii, Masahiro Hayashi, Tamio Suzuki, Takeshi Namiki, Jun Seita, Emi K. Nishimura <<<

María Bueno Álvez, Sofia Bergström, Josefin Kenrick, Emil Johansson, Mikael Åberg, Murat Akyildiz, Ozlem Altay, Hilda Sköld, Konstantinos Antonopoulos, Emmanouil Apostolakis, Yasin Hasan Balcioglu, Anna Bergström, Göran Bergström, Sophia Björkander, Suzanne Egyhazi Brage, Petter Brodin, Lynn Butler, Sara Cajander, Hanna Danielsson, Murat Dayangac, Gizem Dinler-Doganay, Levent Doğanay, Gunilla Enblad, Malin Enblad, Linn Fagerberg, Sara Falck-Jones, Anna Färnert, Mattias Forsberg, Laura Gonzalez, Anders Gummesson, Karin Gunnarsson, Iva Gunnarsson, Ulf Gyllensten, Göran Hesselager, Andreas Hober, Martin Höglund, Marie Holmqvist, Begum Horuluoglu, Rebecka Hultgren, Maria Jesus Iglesias, Helena Janols, Fredric Johansson, Anette Johnsson, Lars Klareskog, David Kotol, Inger Kull, Marika Kvarnström, Maximilian Julius Lautenbach, Ulrika Liljedahl, Henrik Lindman, Cecilia Lindskog, Miklos Lipcsey, Ingrid E Lundberg, Adil Mardinoglu, Erik Melén, Lingqi Meng, Anne-Sophie Merritt, Jan Mulder, Mai Thi-Huyen Nguyen, Jessica Nordlund, Anna Norrby-Teglund, Antonella Notarnicola, Piotr Nowak, Jacob Odeberg, Per Oksvold, Tomas Olsson, Leonid Padyukov, Karlis Pauksens, Fredrik Piehl, Elisa Pin, Fredrik Pontén, Natallia Rameika, Anton Reepalu, Joy Roy, Jochen M. Schwenk, Meltem Sen, Antti Siika, Oscar E. Simonson, Åsa Sivertsson, Tobias Sjöblom, Evelina Sjöstedt, Lovisa Skoglund, Anna Smed-Sörensen, Klara Sondén, Anders Sönnerborg, Karin Stålberg, Kristoffer Strålin, Jonas Sundén-Cullberg, Christopher Sundling, Thanadol Sutantiwanichkul, Fernanda Costa Svedman, Mattias Svensson, Elisabet Svenungsson, Tadepally Lakshmikanth, Khue Hua Tran-Minh, Hasan Türkez, Christian Unge, Per Venge, Marie Wahren-Herlenius, Jakob Woessmann, Hong Yang, Umit Haluk Yeşilkaya, Meng Yuan, Mujdat Zeybel, Cheng Zhang, Wen Zhong, Martin Zwahlen, Kalle von Feilitzen, Peter Nilsson, Fredrik Edfors, Mathias Uhlén <<<

The human blood proteome provides a holistic readout of health states through the assessment of thousands of circulating proteins. Here, we present a pan-disease resource to enable the study of diverse disease phenotypes within a harmonized proteomics dataset. By profiling protein concentrations across 59 diseases and healthy cohorts, we identified proteins associated with age, sex, and BMI, as well as disease-specific signatures. This study highlights shared and distinct protein patterns across conditions, demonstrating the power of a unified proteomics approach to uncover biological insights. The dataset, covering 8,262 individuals and up to 5,416 proteins, serves as an online resource for exploring disease-specific protein profiles and advancing precision medicine research. <<<

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. <<<

Li Ping Tang, Li Ming Zhai, Jiming Li, Yue Gao, Qiu Li Ma, Rui Li, Qing Fei Liu, Wen Jie Zhang, Wang Jinsong Yao, Bangbang Mu, Chao Qin, Xin Tian, Rahul Shaw, Keke Xia, Jian Xu, Ying Hua Su, Xian Sheng Zhang <<<

Abstract Waddington’s epigenetic landscape has long served as a conceptual framework for understanding cell fate decisions. The landscape’s geometry encodes the molecular mechanisms that guide the gene expression profiles of uncommitted cells toward terminally differentiated cell types. In this study, we demonstrate that applying the concept of intrinsic dimension to single-cell transcriptomic data can effectively capture trends in expression trajectories, supporting this framework. This approach allows us to define a robust cell potency score without relying on prior biological information. By analyzing an extensive collection of datasets from various species, experimental protocols, and differentiation processes, we validate our method and successfully reproduce established hierarchies of cell type potency. Our work provides a direct link between geometric properties of single-cell expression profiles and the level of differentiation of a cell population. <<<

Jinghui Lei, Zijuan Xin, Ning Liu, Taixin Ning, Ying Jing, Yicheng Qiao, Zan He, Mengmeng Jiang, Yuanhan Yang, Zhiyi Zhang, Liyun Zhao, Jingyi Li, Dongliang Lv, Yupeng Yan, Hui Zhang, Lingling Xiao, Baohu Zhang, Haoyan Huang, Shuhui Sun, Fangshuo Zheng, Xiaoyu Jiang, Huifen Lu, Xueda Dong, Shasha Yue, Chencan Ma, Jichen Shuai, Zhejun Ji, Feifei Liu, Yanxia Ye, Kaowen Yan, Qinchao Hu, Gang Xu, Qian Zhao, Ruochen Wu, Yusheng Cai, Yanling Fan, Yaobin Jing, Qiaoran Wang, Pradeep Reddy, Xiaoyong Lu, Zikai Zheng, Beibei Liu, Amin Haghani, Shuai Ma, Keiichiro Suzuki, Concepcion Rodriguez Esteban, Jiayin Yang, Moshi Song, Steve Horvath, Weiqi Zhang, Wei Li, Andy Peng Xiang, Lan Zhu, Xiaobing Fu, Guoguang Zhao, Juan Carlos Izpisua Belmonte, Jing Qu, Si Wang, Guang-Hui Liu <<<

Juan L. Gomez, Christopher J. Magnus, Jordi Bonaventura, Oscar Solis, Fallon P. Curry, Marjorie R. Levinstein, Reece C. Budinich, Meghan L. Carlton, Emilya N. Ventriglia, Sherry Lam, Le Wang, Ingrid Schoenborn, William Dunne, Michael Michaelides, Scott M. Sternson <<<

Abstract Chemical feedback is ubiquitous in physiology but is challenging to study without perturbing basal functions. One example is addictive drugs, which elicit a positive-feedback cycle of drug-seeking and ingestion by acting on the brain to increase dopamine signalling1–3. However, interfering with this process by altering basal dopamine also adversely affects learning, movement, attention and wakefulness4. Here, inspired by physiological control systems, we developed a highly selective synthetic physiology approach to interfere with the positive-feedback cycle of addiction by installing a cocaine-dependent opposing signalling process into this body–brain signalling loop. We used protein engineering to create cocaine-gated ion channels that are selective for cocaine over other drugs and endogenous molecules. Expression of an excitatory cocaine-gated channel in the rat lateral habenula, a brain region that is normally inhibited by cocaine, suppressed cocaine self-administration without affecting food motivation. This artificial cocaine-activated chemogenetic process reduced the cocaine-induced extracellular dopamine rise in the nucleus accumbens. Our results show that cocaine chemogenetics is a selective approach for countering drug reinforcement by clamping dopamine release in the presence of cocaine. In the future, chemogenetic receptors could be developed for additional addictive drugs or hormones and metabolites, which would facilitate efforts to probe their neural circuit mechanisms using a synthetic physiology approach. As these chemogenetic ion channels are specific for cocaine over natural rewards, they may also offer a route towards gene therapies for cocaine addiction. <<<

Iain S. Forrest, Ha My T. Vy, Ghislain Rocheleau, Daniel M. Jordan, Ben O. Petrazzini, Girish N. Nadkarni, Judy H. Cho, Mythily Ganapathi, Kuan-Lin Huang, Wendy K. Chung, Ron Do <<<

Accurate variant penetrance estimation is crucial for precision medicine. We constructed machine learning (ML) models for 10 diseases using 1,347,298 participants with electronic health records, then applied them to an independent cohort with linked exome data. Resulting probabilities were used to evaluate ML penetrance of 1648 rare variants in 31 autosomal dominant disease-predisposition genes. ML penetrance was variable across variant classes, but highest for pathogenic and loss-of-function variants, and was associated with clinical outcomes and functional data. Compared with conventional case-versus-control approaches, ML penetrance provided refined quantitative estimates and aided the interpretation of variants of uncertain significance and loss-of-function variants by delineating clinical trajectories over time. By leveraging ML and deep phenotyping, we present a scalable approach to accurately quantify disease risk of variants. <<<

Penadés JR, Gottweis J, He L, Patkowski JB, Daryin A, Weng WH, Tu T, Palepu A, Myaskovsky A, Pawlosky A, Natarajan V, Karthikesalingam A, Costa TRD <<<

Miranda V. Hunter, Eshita Joshi, Sydney Bowker, Emily Montal, Yilun Ma, Young Hun Kim, Zhifan Yang, Laura Tuffery, Zhuoning Li, Eric Rosiek, Alexander Browning, Reuben Moncada, Itai Yanai, Helen Byrne, Mara Monetti, Elisa de Stanchina, Pierre-Jacques Hamard, Richard P. Koche, Richard M. White <<<

Abstract Phenotype switching is a form of cellular plasticity in which cancer cells reversibly move between two opposite extremes: proliferative versus invasive states1,2. Although it has long been hypothesized that such switching is triggered by external cues, the identity of these cues remains unclear. Here we demonstrate that mechanical confinement mediates phenotype switching through chromatin remodelling. Using a zebrafish model of melanoma coupled with human samples, we profiled tumour cells at the interface between the tumour and surrounding microenvironment. Morphological analysis of interface cells showed elliptical nuclei, suggestive of mechanical confinement by the adjacent tissue. Spatial and single-cell transcriptomics demonstrated that interface cells adopted a gene program of neuronal invasion, including the acquisition of an acetylated tubulin cage that protects the nucleus during migration. We identified the DNA-bending protein HMGB2 as a confinement-induced mediator of the neuronal state. HMGB2 is upregulated in confined cells, and quantitative modelling revealed that confinement prolongs the contact time between HMGB2 and chromatin, leading to changes in chromatin configuration that favour the neuronal phenotype. Genetic disruption of HMGB2 showed that it regulates the trade-off between proliferative and invasive states, in which confined HMGB2high tumour cells are less proliferative but more drug-resistant. Our results implicate the mechanical microenvironment as a mechanism that drives phenotype switching in melanoma. <<<

Elaine Huang, Ting Fu, Ling Zhang, Guanao Yan, Ryo Yamamoto, Sari Terrazas, Thuy Linh Nguyen, Carlos Gonzalez-Figueroa, Armen Khanbabaei, Jae Hoon Bahn, Rajagopal Varada, Kofi Amoah, Jonatan Hervoso, Michelle T. Paulsen, Brian Magnuson, Mats Ljungman, Jingyi Jessica Li, Xinshu Xiao <<<