tbuckley/cabot-search huggingface dataset:
Hippocampal output suppresses orbitofrontal cortex schema cell formation
Authors: Wenhui Zong, Jingfeng Zhou, Matthew P H Gardner, Zhewei Zhang, Kauê Machado Costa, Geoffrey Schoenbaum
Journal: Nature Neuroscience (2025)

Abstract Both the orbitofrontal cortex (OFC) and the hippocampus (HC) are implicated in the formation of cognitive maps and their generalization into schemas. However, how these areas interact in supporting this function remains unclear, with some proposals supporting a serial model in which the OFC draws on task representations created by the HC to extract key behavioral features and others suggesting a parallel model in which both regions construct representations that highlight different types of information. In the present study, we tested between these two models by asking how schema correlates in rat OFC would be affected by inactivating the output of the HC, after learning and during transfer across problems. We found that the prevalence and content of schema correlates were unaffected by inactivating one major HC output area, the ventral subiculum, after learning, whereas inactivation during transfer accelerated their formation. These results favor the proposal that the OFC and HC operate in parallel to extract different features defining cognitive maps and schemas.
Polygenic overlap between subjective well-being and psychiatric disorders and cross-ancestry validation
Authors: Jin Young Jung, Yeeun Ahn, Jung-Wook Park, Kyeongmin Jung, Soyeon Kim, Soohyun Lim, Sang-Hyuk Jung, Hyejin Kim, Beomsu Kim, Mi Yeong Hwang, Young Jin Kim, Woong-Yang Park, Aysu Okbay, Kevin S O'Connell, Ole A Andreassen, Woojae Myung, Hong-Hee Won
Journal: Nature Human Behaviour (2025)
An implantable hydrogel-based phononic crystal for continuous and wireless monitoring of internal tissue strains
Authors: Ye Tian, Yueying Yang, Hanchuan Tang, Jiaxin Wang, Na Li, Yifan Cheng, Tianyu Kang, Jiarui Tang, Mengyuan Zhou, Wei Chen, Yan Yu, Xinqi Liu, Xurui Liu, Liqun Xu, Zhouping Yin, Jianfeng Zang
Journal: Nature Biomedical Engineering (2025)
Protein-responsive gut hormone tachykinin directs food choice and impacts lifespan
Authors: Nadja Ahrentløv, Olga Kubrak, Mette Lassen, Alina Malita, Takashi Koyama, Amalie S Frederiksen, Casper M Sigvardsen, Alphy John, Pernille E H Madsen, Kenneth V Halberg, Stanislav Nagy, Cordelia Imig, Erik A Richter, Michael J Texada, Kim Rewitz
Journal: Nature Metabolism (2025)

Animals select food based on hungers that reflect dynamic macronutrient needs, but the hormonal mechanisms underlying nutrient-specific appetite regulation remain poorly defined. Here, we identify tachykinin (Tk) as a protein-responsive gut hormone in Drosophila and female mice, regulated by conserved environmental and nutrient-sensing mechanisms. Protein intake activates Tk-expressing enteroendocrine cells (EECs), driving the release of gut Tk through mechanisms involving target of rapamycin (TOR) and transient receptor potential A1 (TrpA1). In flies, we delineate a pathway by which gut Tk controls selective appetite and sleep after protein ingestion, mediated by glucagon-like adipokinetic hormone (AKH) signalling to neurons and adipose tissue. This mechanism suppresses protein appetite, promotes sugar hunger and modulates wakefulness to align behaviour with nutritional needs. Inhibiting protein-responsive gut Tk prolongs lifespan through AKH, revealing a role for nutrient-dependent gut hormone signalling in longevity. Our results provide a framework for understanding EEC-derived nutrient-specific satiety signals and the role of gut hormones in regulating food choice, sleep and lifespan.
Longitudinal single-cell multiomic atlas of high-risk neuroblastoma reveals chemotherapy-induced tumor microenvironment rewiring
Authors: Wenbao Yu, Rumeysa Biyik-Sit, Yasin Uzun, Chia-Hui Chen, Anusha Thadi, Jonathan H Sussman, Minxing Pang, Chi-Yun Wu, Liron D Grossmann, Peng Gao, David W Wu, Aliza Yousey, Mei Zhang, Christina S Turn, Zhan Zhang, Shovik Bandyopadhyay, Jeffrey Huang, Tasleema Patel, Changya Chen, Daniel Martinez, Lea F Surrey, Michael D Hogarty, Kathrin Bernt, Nancy R Zhang, John M Maris, Kai Tan
Journal: Nature Genetics (2025)

Abstract High-risk neuroblastoma, a leading cause of pediatric cancer mortality, exhibits substantial intratumoral heterogeneity, contributing to therapeutic resistance. To understand tumor microenvironment evolution during therapy, we longitudinally profiled 22 patients with high-risk neuroblastoma before and after induction chemotherapy using single-nucleus RNA and ATAC sequencing and whole-genome sequencing. This revealed profound shifts in tumor and immune cell subpopulations after therapy and identified enhancer-driven transcriptional regulators of neuroblastoma neoplastic states. Poor outcome correlated with proliferative and metabolically active neoplastic states, whereas more differentiated neuronal-like states predicted better prognosis. Proportions of mesenchymal neoplastic cells increased after therapy and a high proportion correlated with a poorer chemotherapy response. Macrophages significantly expanded towards pro-angiogenic, immunosuppressive and metabolic phenotypes. We identified paracrine signaling networks and validated the HB-EGF–ERBB4 axis between macrophage and neoplastic subsets, which promoted tumor growth through the induction of ERK signaling. These findings collectively reveal intrinsic and extrinsic regulators of therapy response in high-risk neuroblastoma.
Efficacy and Safety of Zimlovisertib, Ritlecitinib and Tofacitinib, Alone and in Combination, in Patients With Moderate to Severe Rheumatoid Arthritis and an Inadequate Response to Methotrexate
Authors: Spencer I. Danto, Mikhail Salganik, Anindita Banerjee, Pawel Hrycaj, Irina Jashi, Negin Shojaee, Ravi Shankar P. Singh, Steven A. Gilbert, Karen Page, Elena Peeva, Michael S. Vincent, Jean S. Beebe
Journal: Arthritis & Rheumatology (2025)

Objective To evaluate the efficacy and safety of zimlovisertib (interleukin‐1 receptor‐associated kinase 4 inhibitor) in combination with ritlecitinib (a Janus kinase [JAK] 3 and tyrosine kinase expressed in hepatocellular carcinoma [TEC] kinase family inhibitors) or tofacitinib (a JAK inhibitor) vs tofacitinib alone. Methods This phase 2 study randomized patients with moderate to severe active RA to zimlovisertib 400 mg+tofacitinib 11 mg, zimlovisertib 400 mg+ritlecitinib 100 mg, zimlovisertib 400 mg, ritlecitinib 100 mg, or tofacitinib 11 mg (4:4:3:3:4) for 24 weeks. The primary endpoint was change from baseline (CFB) in Disease Activity Score in 28 joints, C‐reactive protein (DAS28‐CRP) at week 12. Treatment‐emergent adverse events (TEAEs) were monitored. Results Overall, 460 patients were randomized. At week 12, zimlovisertib+tofacitinib demonstrated a greater magnitude of mean CFB in DAS28‐CRP (−2.65 [90% CI, −2.84, −2.46]) vs tofacitinib (−2.30 [90% CI, −2.49, −2.11]; P value = 0.032); mean CFB with zimlovisertib+ritlecitinib (−2.35 [90% CI, −2.54, −2.15]) was similar to tofacitinib. TEAEs were reported in 246 (53.5%) patients, with the highest aggregate incidence of TEAEs in the tofacitinib group (n = 60 [58.8%]). Most TEAEs were mild; severe TEAEs were reported by nine (2.0%) patients and 10 patients reported serious AEs. One patient receiving tofacitinib died due to severe COVID‐19 infection. Safety profiles were similar across all treatment groups, with no evidence of additive/synergistic issues. Conclusion Zimlovisertib+tofacitinib was more effective than tofacitinib for the primary endpoint, while the efficacy of zimlovisertib+ritlecitinib did not achieve statistical significance vs tofacitinib. All treatments were well tolerated.
Bi-allelic variants in BRF2 are associated with perinatal death and craniofacial anomalies
Authors: Francesca Mattioli, Rún Friðriksdóttir, Anne Hebert, Sissy Bassani, Nazia Ibrahim, Shagufta Naz, Jacqueline Chrast, Clara Pailler-Pradeau, Ásmundur Oddsson, Patrick Sulem, Gisli H Halldorsson, Páll Melsted, Daníel F Guðbjartsson, Flavia Palombo, Tommaso Pippucci, Nayereh Nouri, Marco Seri, Emily G Farrow, Carol J Saunders, Nicolas Guex, Muhammad Ansar, Kari Stefansson, Alexandre Reymond
Journal: Genome Medicine (2025)

Abstract Background Variants in genes encoding multiple subunits of the RNA Polymerase III complex which synthesizes rRNAs, tRNAs, and other small RNAs were previously associated with neurological disorders, such as syndromic hypomyelination leukodystrophies, pontocerebellar hypoplasia, and cerebellofaciodental syndrome. One new such candidate is BRF2 , which encodes a TFIIB-like factor that recruits the RNA polymerase III complex to type 3 promoters to initiate transcription of U6, RnaseP, and 7SK RNAs. Methods We combined sequencing with functional analyses to investigate the effects of BRF2 variants. Results We observe that a previously reported significant underrepresentation of double transmission of a splice variant results in recessive lethality in three large Icelandic families with multiple perinatal losses. Using data aggregation, we identified an additional seven individuals worldwide from three unrelated families carrying biallelic variants in BRF2 . Affected individuals present a variable phenotype ranging from severe craniofacial anomalies with early death to intellectual disability with motor and speech development. In silico 3D modelling and functional analyses showed functional impairment of the identified variants, e.g., differences in target loci occupancy. Zebrafish knocked down for the orthologous brf2 presented with abnormal escape response, reduced swimming velocity and head size, and craniofacial malformations. These defects were complemented by the human wild-type but not mutated BRF2 mRNA further demonstrating their deleteriousness. Conclusions Overall, our results support the association of biallelic BRF2 variants with a novel neurodevelopmental disease and provide an additional link between RNA polymerase III, its targets and craniofacial anomalies.
Virtual urgent care in an integrated value based healthcare system
Authors: Khang Nguyen, Dinh Nguyen, Sinjin Lee, Jin Chang, Yvonne Bach, Kien La, Ferdinand Justus, Tianyuan Shao, Caleb Wang, Mason Kellogg, Raquel Taylor, Alan Evans
Journal: npj Digital Medicine (2025)

Virtual urgent care (VUC) is not well understood when delivered through an integrated value-based healthcare system. The Southern California Permanente Medical Group operates Get Care Now (GCN), a VUC program complementing its urgent care clinics (UCC). Quality and patient experience dimensions are included in this study, comparing GCN and UCC patients. Females and Hispanics/Latinos were predominant in both groups and proportions of patients with chronic conditions were nearly identical within the leading 30-49 age band. Wait times for GCN were 21.19 min lower than for UCC, and positive patient survey results align with GCN's average Net Promoter Score of 87. 3-day return rates to the ED (2.53% GCN vs. 3.26% UCC) and to UCC (5.44% GCN vs. 2.42% UCC) were comparable between GCN and UCC utilizers. Findings demonstrate that 24/7 VUC sustainably supports meeting patient demand for urgent care services in an integrated value-based system.
Correction: Pulmonary herpes simplex virus and cytomegalovirus in patients with acute respiratory distress syndrome related to COVID-19
Authors: Leonoor S Boers, Frank van Someren Gréve, Jarne M van Hattem, Justin de Brabander, Tom Zwaan, Hugo van Willigen, Marion Cornelissen, Menno de Jong, Tom van der Poll, JanWillem Duitman, Janke Schinkel, Lieuwe D J Bos
Journal: Intensive Care Medicine (2025)
Staircase strategy, tier-three therapies, and effects on outcome in traumatic brain injured patients: the Triple-T TBI study
Authors: Edoardo Picetti, Laura Galarza, Marta Arroyo Diez, Rafael Badenes, Maria Angeles Ballesteros Sanz, Jesús A Barea-Mendoza, Romina Georgina Bórtoli, Pierre Bouzat, Giuseppe Citerio, Daniel Agustin Godoy, Paolo Gritti, Sandra Magnoni, Marina Munari, Theveen Tellambura, Mathieu van der Jagt, Fabio Silvio Taccone, Chiara Robba
Journal: Intensive Care Medicine (2025)
The NET-DNA-CCDC25 inhibitor di-Pal-MTO suppresses tumor progression and promotes the innate immune response
Authors: Shun Wang, Xinyan Liang, Heliang Li, Junying Zou, Linxi Xu, Yetong Zhang, Jianghua Lin, Jiayi Zeng, Xiaoming Zhong, Xu Liu, Zhou Liu, Yue Zheng, Man Nie, Linbin Yang
Journal: Cellular and Molecular Immunology (2025)
Effect size estimation in cooperative group and industry sponsored phase 3 oncology trials
Authors: Sonal S Noticewala, Adam Grippin, Ramez Kouzy, Joseph Abi Jaoude, Avital Miller, Alexander Sherry, Ethan B Ludmir
Journal: JNCI Journal of the National Cancer Institute (2025)

Overly optimistic estimations of effect sizes may lead to underpowered studies and risk of erroneously dismissing effective treatments. To understand the prevalence and factors contributing to estimation of effect sizes, we evaluated 385 superiority-design phase 3 oncology randomized controlled trials (RCTs) with pre-specified and observed hazard ratios (HR) in published manuscripts. Of these, 88% were sponsored by industry and 22.6% were sponsored by cooperative groups. Few studies (10%) provided justification of their chosen sample size in the manuscript or available protocol. Overly optimistic estimations of effect sizes were common in cooperative group studies and, by contrast, uncommon in industry-sponsored studies. Moreover, industry-sponsored trials meeting the primary endpoint frequently achieved significantly lower HRs than expected. Together, these data suggest a correlation between study sponsorship, clinical trial power calculations, and subsequent trial outcomes.
Genomic evidence for low genetic diversity but purging of strong deleterious variants in snow leopards
Authors: Lin Yang, Hong Jin, Qien Yang, Andrey Poyarkov, Miroslav Korablev, Viatcheslav Rozhnov, Junjie Shao, Qiaomei Fu, Jose Antonio Hernandez-Blanco, Xiangjiang Zhan, Li Yu, Dmitry Alexandrov, Qingyan Dai, Bariushaa Munkhtsog, Xin Du, Bayaraa Munkhtsog, Liqing Ma, Wanlin Chen, Sergei Malykh, Yipeng Jin, Shunfu He, Tongzuo Zhang, Guosheng Wu, Yonghong Shi, Fuwen Wei, Yibo Hu
Journal: Genome biology (2025)

Long-term persistence of species with low genetic diversity is the focus of widespread attention in conservation biology. The snow leopard, Panthera uncia, is a big cat from high-alpine regions of Asia. However, its subspecies taxonomy, evolutionary history, evolutionary potential, and survival strategy remain unclear, which greatly hampers their conservation. We sequence a high-quality chromosome-level genome of the snow leopard and the genomes of 52 wild snow leopards. Population genomics reveal the existence of two large genetic lineages in global snow leopards, the northern and southern lineages, supported by the biogeography. The Last Glacial Maximum drove the divergence of two lineages. Microclimate differences and large rivers between the western and central Himalayas likely maintain the differentiation of two lineages. EPAS1 is positively selected in the southern lineage with almost fixed amino acid substitutions and shows an increased allele frequency with elevation. Compared to the southern lineage, the northern lineage exhibits a lower level of genomic diversity and higher levels of inbreeding and genetic load, consistent with its recent population decline. We find that snow leopards have extremely low genomic diversity and higher inbreeding than other Carnivora species; however, strong deleterious mutations have been effectively purged in snow leopards by historical population bottlenecks and inbreeding, which may be a vital genetic mechanism for their population survival and viability. Our findings reveal the survival strategy of a species with low genetic diversity and highlight the importance of unveiling both genetic diversity and genetic burden for the conservation of threatened species.
Extracellular vesicle-derived miRNA-mediated cell–cell communication inference for single-cell transcriptomic data with miRTalk
Authors: Xin Shao, Lingqi Yu, Chengyu Li, Jingyang Qian, Xinyu Yang, Haihong Yang, Jie Liao, Xueru Fan, Xiao Xu, Xiaohui Fan
Journal: Genome biology (2025)
Post-cleavage target residence determines asymmetry in non-homologous end joining of Cas12a-induced DNA double strand breaks
Authors: Ruo-Dan Chen, Yi Yang, Kun-Ming Liu, Jing-Zhen Hu, Yi-Li Feng, Chun-Yi Yang, Rui-Rui Jiang, Si-Cheng Liu, Yue Wang, Ping-An Han, Ru-Gang Tian, Yu-Long Wang, Shi-Ming Xu, An-Yong Xie
Journal: Genome biology (2025)

After Cas12a cleaves its DNA target, it generates a DNA double strand break (DSB) with two compatible 5'-staggered ends. The Cas12a-gRNA complex remains at the protospacer adjacent motif (PAM)-proximal end (PPE) while releasing the PAM-distal end (PDE). The effects of this asymmetric retention on DSB repair are currently unknown. Post-cleavage retention of LbCas12a at PPEs suppresses the recruitment of classical non-homologous end joining (c-NHEJ) core factors, leading to longer deletions at PPEs compared to PDEs. This asymmetry in c-NHEJ engagement results in approximately tenfold more accurate ligation between two compatible PDEs induced by paired LbCas12a than ligation involving a compatible PPE. Moreover, ligation to a given end of SpCas9-induced DSBs demonstrates more efficient ligation with a PDE from Cas12a-induced DSBs than with a PPE. In LbCas12a-induced NHEJ-mediated targeted integration, only two compatible PDEs from LbCas12a-induced DSBs-one from donor templates and the other from target sites-promote accurate and directional ligation. Based on these findings, we developed a strategy called Cas12a-induced PDE ligation (CIPDEL) for NHEJ-mediated efficient and precise gene correction and insertion. The asymmetric retention of CRISPR-LbCas12a at DSB ends suppresses c-NHEJ at PPEs, not at PDEs. This unique repair mechanism can be utilized in the CIPDEL strategy, offering a potentially better alternative for homology-directed targeted integration.
Enhanced TLR7-dependent production of type I interferon by pDCs underlies pandemic chilblains
Authors: Fanny Saidoune, Danyel Lee, Jeremy Di Domizio, Corentin Le Floc’h, Raphael Jenelten, Jérémie Le Pen, Vincent Bondet, Ana Joncic, Marie-Anne Morren, Vivien Béziat, Shen-Ying Zhang, Emmanuelle Jouanguy, Darragh Duffy, Charles M. Rice, Curdin Conrad, Jacques Fellay, Jean-Laurent Casanova, Michel Gilliet, Ahmad Yatim
Journal: The Journal of Experimental Medicine (2025)

Outbreaks of chilblains were reported during the COVID-19 pandemic. Given the essential role of type I interferon (I-IFN) in protective immunity against SARS-CoV-2 and the association of chilblains with inherited type I interferonopathies, we hypothesized that excessive I-IFN responses to SARS-CoV-2 might underlie the occurrence of chilblains in this context. We identified a transient I-IFN signature in chilblain lesions, accompanied by an acral infiltration of activated plasmacytoid dendritic cells (pDCs). Patients with chilblains were otherwise asymptomatic or had mild disease without seroconversion. Their leukocytes produced abnormally high levels of I-IFN upon TLR7 stimulation with agonists or ssRNA viruses—particularly SARS-CoV-2—but not with DNA agonists of TLR9 or the dsDNA virus HSV-1. Moreover, the patients’ pDCs displayed cell-intrinsic hyperresponsiveness to TLR7 stimulation regardless of TLR7 levels. Inherited TLR7 or I-IFN deficiency confers a predisposition to life-threatening COVID-19. Conversely, our findings suggest that enhanced TLR7 activity in predisposed individuals could confer innate, pDC-mediated, sterilizing immunity to SARS-CoV-2 infection, with I-IFN–driven chilblains as a trade-off.
CAR T-cell therapy response varies by extranodal disease site in large B-cell lymphoma
Authors: Alejandro Luna, Sean M Devlin, Kai Rejeski, Jessica R Flynn, Magdalena Corona, Efrat Luttwak, Alfredo Rivas-Delgado, Ivan Landego, Giulio Cassanello, Marina Gomez-Llobell, Sandeep S Raj, Parastoo B Dahi, Richard J Lin, Allison Parascondola, M Lia Palomba, Gunjan L Shah, Michael Scordo, Ana Alarcon Tomas, Doris Leithner, Akshay Bedmutha, Heiko Schöder, Brandon S Imber, Gilles Salles, Jae H Park, Miguel-Angel Perales, Roni Shouval
Journal: Blood Cancer Journal (2025)

Abstract The role of extranodal (EN) sites as potential sanctuary regions resistant to CD19-directed chimeric antigen receptor T-cell (CAR-T) therapy in large B-cell lymphoma (LBCL) remains unclear. To investigate this, we retrospectively analyzed 283 adults treated with commercial CD19 CAR-T therapy, assessing 958 PET-CT scans across four time points: pre-apheresis, pre-lymphodepletion, best response, and relapse. EN involvement prior to CAR-T therapy was common (76%). Outcomes for patients with exclusive EN disease were similar to those with nodal (ND) disease alone; however, patients with concomitant EN and ND disease (EN + ND) had lower complete response rates and shorter progression-free survival. Site-specific outcomes varied: lungs/pleura/pericardium and gastrointestinal/peritoneum involvement had the lowest local response rates (48% and 51%, respectively). Notably, the risk of same-site relapse was highest in the lungs/pleura/pericardium (hazard ratio [HR] 7.8) and gastrointestinal/peritoneum (HR 5.97). Among patients relapsing after CAR-T, two-year overall survival rates from time of relapse were significantly lower in those with EN relapse (23% for exclusive EN; 25% for EN + ND) compared to exclusive ND relapse (64%; p = 0.008). These findings underscore the high prevalence of EN disease in CAR-T recipients and its site-specific impact on outcomes, highlighting the need for organ-targeted strategies to enhance treatment efficacy.
Prepregnancy Adiposity, Adverse Pregnancy Outcomes, and Cardiovascular Disease Risk in Midlife
Authors: Jaclyn D Borrowman, Xiaoning Huang, Lucia C Petito, Amanda M Perak, Denise Scholtens, William J Lowe, Donald M Lloyd-Jones, William A Grobman, Sadiya S Khan
Journal: Journal of the American College of Cardiology (2025)
Optimal Medical Therapy Is Associated With Improved Limb Outcomes in PAD Patients
Authors: Vikram S Kashyap, Joshua A Beckman, Gheorghe Doros, Matthew T Menard, Kenneth Rosenfield, Mark A Creager, Katherine R Tuttle, Katharine L McGinigle, Thomas Huber, Scott Kinlay, Alain T Drooz, Michael B Strong, Ido Weinberg, Alik Farber, Michael R Jaff
Journal: Journal of the American College of Cardiology (2025)