Michael Kosicki, Boyang Zhang, Vivian Hecht, Anusri Pampari, Laura E. Cook, Neil Slaven, Jennifer A. Akiyama, Ingrid Plajzer-Frick, Catherine S. Novak, Momoe Kato, Stella Tran, Riana D. Hunter, Kianna von Maydell, Sarah Barton, Erik Beckman, Yiwen Zhu, Diane E. Dickel, Anshul Kundaje, Axel Visel, Len A. Pennacchio <<<

Abstract All contemporary Eurasians trace most of their ancestry to a small population that dispersed out of Africa about 50,000 years ago (ka)1–9. By contrast, fossil evidence attests to earlier migrations out of Africa10–15. These lines of evidence can only be reconciled if early dispersals made little to no genetic contribution to the later, major wave. A key question therefore concerns what factors facilitated the successful later dispersal that led to long-term settlement beyond Africa. Here we show that a notable expansion in human niche breadth within Africa precedes this later dispersal. We assembled a pan-African database of chronometrically dated archaeological sites and used species distribution models (SDMs) to quantify changes in the bioclimatic niche over the past 120,000 years. We found that the human niche began to expand substantially from 70 ka and that this expansion was driven by humans increasing their use of diverse habitat types, from forests to arid deserts. Thus, humans dispersing out of Africa after 50 ka were equipped with a distinctive ecological flexibility among hominins as they encountered climatically challenging habitats, providing a key mechanism for their adaptive success. <<<

Akanksha Jain, Gilles Gut, Fátima Sanchis-Calleja, Reto Tschannen, Zhisong He, Nicolas Luginbühl, Fides Zenk, Antonius Chrisnandy, Simon Streib, Christoph Harmel, Ryoko Okamoto, Malgorzata Santel, Makiko Seimiya, René Holtackers, Juliane K. Rohland, Sophie Martina Johanna Jansen, Matthias P. Lutolf, J. Gray Camp, Barbara Treutlein <<<

Abstract Brain organoids enable the mechanistic study of human brain development and provide opportunities to explore self-organization in unconstrained developmental systems1–3. Here we establish long-term, live light-sheet microscopy on unguided brain organoids generated from fluorescently labelled human induced pluripotent stem cells, which enables tracking of tissue morphology, cell behaviours and subcellular features over weeks of organoid development4. We provide a novel dual-channel, multi-mosaic and multi-protein labelling strategy combined with a computational demultiplexing approach to enable simultaneous quantification of distinct subcellular features during organoid development. We track actin, tubulin, plasma membrane, nucleus and nuclear envelope dynamics, and quantify cell morphometric and alignment changes during tissue-state transitions including neuroepithelial induction, maturation, lumenization and brain regionalization. On the basis of imaging and single-cell transcriptome modalities, we find that lumenal expansion and cell morphotype composition within the developing neuroepithelium are associated with modulation of gene expression programs involving extracellular matrix pathway regulators and mechanosensing. We show that an extrinsically provided matrix enhances lumen expansion as well as telencephalon formation, and unguided organoids grown in the absence of an extrinsic matrix have altered morphologies with increased neural crest and caudalized tissue identity. Matrix-induced regional guidance and lumen morphogenesis are linked to the WNT and Hippo (YAP1) signalling pathways, including spatially restricted induction of the WNT ligand secretion mediator (WLS) that marks the earliest emergence of non-telencephalic brain regions. Together, our work provides an inroad into studying human brain morphodynamics and supports a view that matrix-linked mechanosensing dynamics have a central role during brain regionalization. <<<

Dirk A. Lamprecht, Richard J. Wall, Annelies Leemans, Barry Truebody, Joke Sprangers, Patricia Fiogbe, Cadi Davies, Jennefer Wetzel, Stijn Daems, William Pearson, Vanessa Pillay, Samantha Saylock, M. Daniel Ricketts, Ellie Davis, Adam Huff, Tsehai Grell, Shiming Lin, Michelle Gerber, Ann Vos, John Dallow, Sam J. Willcocks, Christine Roubert, Stéphanie Sans, Amandine Desorme, Nicolas Chappat, Aurélie Ray, Mariana Pereira Moraes, Tracy Washington, Hope D’Erasmo, Pavankumar Sancheti, Melissa Everaerts, Mario Monshouwer, Jorge Esquivias, Gerald Larrouy-Maumus, Ruxandra Draghia Akli, Helen Fletcher, Alexander S. Pym, Bree B. Aldridge, Jansy P. Sarathy, Kathleen W. Clancy, Bart Stoops, Neeraj Dhar, Adrie J. C. Steyn, Paul Jackson, Clara Aguilar-Pérez, Anil Koul <<<

Yasir Sohail, Chongle Zhang, Dezhen Xue, Jinyu Zhang, Dongdong Zhang, Shaohua Gao, Yang Yang, Xiaoxuan Fan, Hang Zhang, Gang Liu, Jun Sun, En Ma <<<

Hao Huang, Nora R. Balzer, Lea Seep, Iva Splichalova, Nelli Blank-Stein, Maria Francesca Viola, Eliana Franco Taveras, Kerim Acil, Diana Fink, Franzisca Petrovic, Nikola Makdissi, Seyhmus Bayar, Katharina Mauel, Carolin Radwaniak, Jelena Zurkovic, Amir H. Kayvanjoo, Klaus Wunderling, Malin Jessen, Mohamed H. Yaghmour, Lukas Kenner, Thomas Ulas, Stephan Grein, Joachim L. Schultze, Charlotte L. Scott, Martin Guilliams, Zhaoyuan Liu, Florent Ginhoux, Marc D. Beyer, Christoph Thiele, Felix Meissner, Jan Hasenauer, Dagmar Wachten, Elvira Mass <<<

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 <<<