Weifeng Lin, Xiaohui Jia, Xiaofeng Shi, Qiuya He, Panyu Zhang, Xianglei Zhang, Liping Zhang, Mingqi Wu, Tengfei Ren, Yufei Liu, Haohao Deng, Yanyao Li, Shiqi Liu, Shaoyong Huang, Jingmin Kang, Jun Luo, Ziqing Deng, Wei Wang <<<

Mammals display prominent diversity in the ability to regenerate damaged ear pinna, but the genetic changes underlying the failure of regeneration remain elusive. We performed comparative single-cell and spatial transcriptomic analyses of rabbits and mice recovering from pinna damage. Insufficient retinoic acid (RA) production, caused by the deficiency of rate-limiting enzyme Aldh1a2 and boosted RA degradation, was responsible for the failure of mouse pinna regeneration. Switching on Aldh1a2 or RA supplementation reactivated regeneration. Evolutionary inactivation of multiple Aldh1a2-linked regulatory elements accounted for the deficient Aldh1a2 expression upon injury in mice and rats. Furthermore, the activation of Aldh1a2 by a single rabbit enhancer was sufficient to improve ear pinna regeneration in transgenic mice. Our study identified a genetic switch involved in the evolution of regeneration. <<<

Mingyue Wang, Qinan Hu, Zhencheng Tu, Lingshi Kong, Tengxiang Yu, Zihan Jia, Yuetian Wang, Jiajun Yao, Rong Xiang, Zhan Chen, Yan Zhao, Yanfei Zhou, Qing Ye, Kang Ouyang, Xianzhe Wang, Yinqi Bai, Zhenyu Yang, Hanxiang Wang, Yanru Wang, Hanxiang Jiang, Tao Yang, Jing Chen, Yunting Huang, Ni Yin, Wenyuan Mo, Wenfu Liang, Chang Liu, Xiumei Lin, Chuanyu Liu, Ying Gu, Wei Chen, Longqi Liu, Xun Xu, Yuhui Hu <<<

Lingling Geng, Jiale Ping, Ruochen Wu, Haoteng Yan, Hui Zhang, Yuan Zhuang, Taixin Ning, Jun Wang, Chuqian Liang, Jiachen Zhang, Qingqing Chu, Jing Zhang, Yifan Wen, Yaobin Jing, Shuhui Sun, Qin Qiao, Qian Zhao, Qianzhao Ji, Shuai Ma, Yusheng Cai, Yandong Zheng, Zhiran Zou, Zhiqing Diao, Mingheng Li, Hao Zhang, Jianli Hu, Liangzheng Fu, Wang Kang, Ruijun Bai, Hongkai Zhao, Sheng Zhang, Yingjie Ding, Jinghui Lei, Wei Wang, Yun Ji, Bo Gou, Guoqiang Sun, Jian Yin, Pengze Yan, Hao Li, Zehua Wang, Shikun Ma, Zunpeng Liu, Hezhen Shan, Qiaoran Wang, Tianling Cao, Shanshan Yang, Cui Wang, Ping Yang, Yanling Fan, Yanxia Ye, Jinghao Hu, Mengmeng Jiang, Ye Wang, Kan Liu, Yujing Li, Yuanxiang Li, Jingyi Li, Weimin Ci, Zi-Bing Jin, Xiaobing Fu, Xu Zhang, Guoguang Zhao, Juan Carlos Izpisua Belmonte, Si Wang, Moshi Song, Weiqi Zhang, Jing Qu, Guang-Hui Liu <<<

Deepti Lall, Michael J. Workman, Samuel Sances, Briana N. Ondatje, Shaughn Bell, George Lawless, Amanda Woodbury, Dylan West, Amanda Meyer, Andrea Matlock, Vineet Vaibhav, Jennifer E. Van Eyk, Clive N. Svendsen <<<

The constraints that govern the evolution of gene expression patterns across development remain unclear. Single-cell RNA sequencing can detail these constraints by systematically profiling homologous cells. The conserved invariant embryonic lineage of Caenorhabditis elegans and C. briggsae makes them ideal for comparing cell type gene expression across evolution. Measuring the spatiotemporal divergence of gene expression across embryogenesis, we find a high level of similarity in gene expression programs between species despite tens of millions of years of evolutionary divergence. Nonetheless, thousands of genes show divergence in their cell type specific expression patterns, with enrichment for functions in environmental response and behavior. Neuronal cell types show higher divergence than others such as the intestine and germline. This work identifies likely constraints on the evolution of developmental gene expression. <<<

Joe Sneath Thompson, Laura Madrid, Barbara Hernando, Carolin M. Sauer, Maria Vias, Maria Escobar-Rey, Wing-Kit Leung, Diego Garcia-Lopez, Jamie Huckstep, Magdalena Sekowska, Karen Hosking, Mercedes Jimenez-Linan, Marika A. V. Reinius, Abhipsa Roy, Omar Abdulle, Justina Pangonyte, Harry Dobson, Amy E. Cullen, Dilrini De Silva, David Gómez-Sánchez, Marina Torres, Ángel Fernández-Sanromán, Deborah Sanders, Filipe Correia Martins, Ionut-Gabriel Funingana, Giovanni Codacci-Pisanelli, Miguel Quintela-Fandino, Florian Markowetz, Jason Yip, James D. Brenton, Anna M. Piskorz, Geoff Macintyre <<<

Abstract Chemotherapies are often given without precision biomarkers, exposing patients to toxic side effects without guaranteed benefit. Here we present chromosomal instability signature biomarkers that identify resistance to platinum-, taxane- and anthracycline-based treatments using a single genomic test. In retrospectively emulated randomized-control biomarker clinical trials using real-world cohorts (n = 840), predicted resistant patients had elevated treatment failure risk for taxane (hazard ratio (HR) of 7.44) and anthracycline (HR of 1.88) in ovarian, taxane (HR of 3.98) and anthracycline (HR of 3.69) in metastatic breast and taxane (HR of 5.46) in metastatic prostate. Nonrandomized emulations showed predictive capacity for platinum resistance in ovarian (HR of 1.46) and anthracycline in sarcoma (HR of 3.59). We demonstrate feasibility using whole-genome sequencing, capture-panel sequencing and cell-free DNA. Our findings highlight the clinical value of chromosomal instability signatures in predicting resistance to chemotherapies across multiple cancer types, with the potential to transform the one-size-fits-all chemotherapy approach into precise, tailored treatment. <<<

Zachary H. Walsh, Chris J. Frangieh, Neeharika Kothapalli, Jay Levy, Clarissa K. Heck, Johannes C. Melms, Ron S. Gejman, Parin Shah, Jared M. Pollard, Akul Naik, Sarah L. Grauman, Lei Haley Huang, Ashley Lee, Dusan Bogunovic, Joshua D. Milner, Benjamin Izar <<<

Next-generation sequencing is pivotal for diagnosing inborn errors of immunity (IEI) but predominantly yields variants of uncertain significance (VUS), creating clinical ambiguity. Activated PI3Kδ syndrome (APDS) is caused by gain-of-function (GOF) variants in PIK3CD or PIK3R1, which encode the PI3Kδ heterodimer. We performed massively parallel base editing of PIK3CD/PIK3R1 in human T cells and mapped thousands of variants to a clinically important readout (phospho-AKT/S6), nominating >100 VUS and unannotated variants for functional classification and validating 27 hits. Leniolisib, an FDA-approved PI3Kδ inhibitor, rescued aberrant signaling and dysfunction in GOF-harboring T cells and revealed partially drug-resistant PIK3R1 hotspots that responded to novel combination therapies of leniolisib with mTORC1/2 inhibition. We confirmed these findings in T cells from APDS patients spanning the functional spectrum discovered in the screen. Integrating our screens with population-level genomic studies revealed that APDS may be more prevalent than previously estimated. This work exemplifies a broadly applicable framework for removing ambiguity from sequencing in IEI. <<<

Michelli Faria de Oliveira, Juan Pablo Romero, Meii Chung, Stephen R. Williams, Andrew D. Gottscho, Anushka Gupta, Susan E. Pilipauskas, Seayar Mohabbat, Nandhini Raman, David J. Sukovich, David M. Patterson, , Michelli Faria de Oliveira, Juan Pablo Romero, Stephen R. Williams, David M. Patterson, Sarah E. B. Taylor, Sarah E. B. Taylor <<<

Peng Xie, Juan Shen, Yi Yang, Xinrui Wang, Wei Liu, Hailong Cao, Yanying Zheng, Chen Wu, Guangyao Mao, Linjin Chen, Jingjing He, Weiheng Zheng, Zepu Yang, Xiao Zhang, Xu Jiang, Xianfa Yang, Ke Fang, Zhao Zhang, Xin Xue, Xueting Chen, Chaoyi Wang, Xing Liu, Ling Liu, Xuebiao Yao, Naihe Jing, Wei Xie, Jin Liu, Hua Cao, Zhuojuan Luo, Xiaodong Fang, Chengqi Lin <<<

Mika Kivimäki, Jaana Pentti, Philipp Frank, Fangyu Liu, Acer Blake, Solja T. Nyberg, Jussi Vahtera, Archana Singh-Manoux, Tony Wyss-Coray, Keenan A. Walker, Linda Partridge, Joni V. Lindbohm <<<

Abstract Social disadvantage, like advanced age, is a risk factor for a broad range of health conditions; however, whether it influences the aging process remains unclear. Here, using a multicohort approach, we investigated the associations of social disadvantage with age-related plasma proteins and age-related diseases. We found proteomic signatures of accelerated immune aging and 14 specific age-related proteins linked to social disadvantage during both early and later life. Individuals experiencing social disadvantage had an increased risk of 66 age-related diseases, with up to 39% of these associations mediated by the 14 age-related proteins (for example, DNAJB9, F2, HSPA1A, BGN). The main enriched pathway involved the upregulation of the pro-inflammatory regulator NF-κB24 and its downstream factor interleukin-8. Our findings support the hypothesis that social disadvantage throughout the life course may accelerate aging, a biological mechanism that could explain why social stratification plays such a fundamental role in determining human health. <<<

Ahyeon Hwang, Mario Skarica, Siwei Xu, Jensine Coudriet, Che Yu Lee, Lin Lin, Rosemarie Terwilliger, Alexa-Nicole Sliby, Jiawei Wang, Tuan Nguyen, Hongyu Li, Min Wu, Yi Dai, Ziheng Duan, Shushrruth Sai Srinivasan, Xiangyu Zhang, Yingxin Lin, Dianne Cruz, P J Michael Deans, Traumatic Stress Brain Research Group, Bertrand R Huber, Daniel Levey, Jill R Glausier, David A Lewis, Joel Gelernter, Paul E Holtzheimer, Matthew J Friedman, Mark Gerstein, Nenad Sestan, Kristen J Brennand, Ke Xu, Hongyu Zhao, John H Krystal, Keith A Young, Douglas E Williamson, Alicia Che, Jing Zhang, Matthew J Girgenti <<<

Post-traumatic stress disorder (PTSD) is a polygenic disorder occurring after extreme trauma exposure. Recent studies have begun to detail the molecular biology of PTSD. However, given the array of PTSD-perturbed molecular pathways identified so far, it is implausible that a single cell type is responsible. Here we profile the molecular responses in over two million nuclei from the dorsolateral prefrontal cortex of 111 human brains, collected post-mortem from individuals with and without PTSD and major depressive disorder. We identify neuronal and non-neuronal cell-type clusters, gene expression changes and transcriptional regulators, and map the epigenomic regulome of PTSD in a cell-type-specific manner. Our analysis revealed PTSD-associated gene alterations in inhibitory neurons, endothelial cells and microglia and uncovered genes and pathways associated with glucocorticoid signalling, GABAergic transmission and neuroinflammation. We further validated these findings using cell-type-specific spatial transcriptomics, confirming disruption of key genes such as SST and FKBP5. By integrating genetic, transcriptomic and epigenetic data, we uncovered the regulatory mechanisms of credible variants that disrupt PTSD genes, including ELFN1, MAD1L1 and KCNIP4, in a cell-type-specific context. Together, these findings provide a comprehensive characterization of the cell-specific molecular regulatory mechanisms that underlie the persisting effects of traumatic stress response on the human prefrontal cortex. <<<

Gustaw Eriksson, Congru Li, Tina Gorsek Sparovec, Anja Dekanski, Sara Torstensson, Sanjiv Risal, Claes Ohlsson, Angelica Lindén Hirschberg, Sophie Petropoulos, Qiaolin Deng, Elisabet Stener-Victorin <<<

Abstract Polycystic ovary syndrome (PCOS) has a negative effect on the receptivity of the endometrium to embryo implantation and increases the risk of miscarriage and endometrial cancer. The cellular and molecular heterogeneity of the endometrium in women with PCOS has not been well studied. Our study presents a comprehensive cellular atlas of the endometrium during the proliferative phase in women with PCOS characterized by overweight and obesity, hyperandrogenism and insulin resistance compared with controls of similar age, weight and body mass index. Analysis of 247,791 isolated endometrial nuclei from 27 biopsies (5 controls and 12 PCOS cases at baseline and 7 after 16 weeks of metformin and 3 after lifestyle intervention) revealed cell-type-specific disease signatures and variations in cellular composition and localization. Samples taken after 16 weeks of metformin treatment and lifestyle management showed extensive recovery of disease-specific endometrial signatures. We linked the specific role of each cell type to clinical features such as hyperandrogenism and insulin resistance, and specific cell types to risk of endometrial and metabolic disease. In addition, potential therapeutic targets such as integrin inhibitors were identified and the role of metformin in restoring endometrial health in patients with PCOS was highlighted. Our findings lay the groundwork to significantly advance the understanding of PCOS-specific endometrial dysfunction for future targeted therapies. <<<

Matthias Diebold, Patrick T. Gauthier, Katharina A. Mayer, Martina Mackova, Christian Hinze, Jessica Chang, Uptal D. Patel, Ekkehard Schütz, Bernd Jilma, Eva Schrezenmeier, Klemens Budde, Georg A. Böhmig, Philip F. Halloran <<<

Abstract A recent randomized controlled trial demonstrated that treatment with anti-CD38 monoclonal antibody felzartamab suppressed antibody-mediated rejection (ABMR) in kidney transplant patients but with recurrence after treatment in some patients. Here we examined the molecular effects of 6 months of felzartamab treatment on biopsies from the trial using genome-wide microarray analysis, comparing pretreatment, end-of-treatment (week 24) and posttreatment (week 52) biopsies from ten patients treated with felzartamab and ten patients in the placebo group. Felzartamab reduced molecular ABMR activity scores in all nine patients with baseline ABMR activity, selectively suppressing interferon gamma-inducible and natural killer cell transcripts, with minimal effect on ABMR stage-related endothelial transcripts. Suppression was often incomplete when ABMR activity was intense, and molecular recurrence was nearly universal by week 52. However, we also found that felzartamab had parenchymal benefits at week 52, slowing the trajectories of molecular injury scores beyond the treatment period, suggesting that suppression of ABMR activity could potentially slow future progression to kidney failure. These data provide preliminary molecular insights into the effects of CD38-directed treatment for ABMR, which have the potential to inform future therapeutic strategies. <<<

Anne-Julie Tessier, Fenglei Wang, Andres Ardisson Korat, A. Heather Eliassen, Jorge Chavarro, Francine Grodstein, Jun Li, Liming Liang, Walter C. Willett, Qi Sun, Meir J. Stampfer, Frank B. Hu, Marta Guasch-Ferré <<<