tbuckley/cabot-search huggingface dataset:
Systematic optimization and prediction of cre recombinase for precise genome editing in mice
Authors: Valerie Erhardt, Elli Hartig, Kristian Lorenzo, Hannah R Megathlin, Basile Tarchini, Vishnu Hosur
Journal: Genome biology (2025)

The Cre-Lox system is a powerful tool in mouse genetics, enabling precise spatiotemporal control of gene expression and conditional knockout models. Since its development, it has transformed genome editing by facilitating targeted deletions, translocations, inversions, and complex modifications-double-floxed inverse orientation. Its utility extends beyond mice to rats, pigs, and zebrafish. However, challenges such as high costs, lengthy timelines, and unpredictable recombination remain, highlighting the need for ongoing improvements to enhance efficiency, reliability, and applicability across genetic models. In this study, we perform a systematic analysis of Cre-mediated recombination in mice, creating 11 new strains with conditional alleles at the Rosa26 locus, using the C57BL/6J background. Factors influencing recombination efficiency include inter-loxP distance, mutant loxP sites, zygosity, chromosomal location, and breeder age. Our results demonstrate that the choice of Cre-driver strain plays a significant role in recombination efficiency. Optimal recombination is achieved when loxP sites are spaced by less than 4 kb and mutant loxP sites by 3 kb. Complete recombination fails with wildtype loxP sites spaced ≥ 15 kb or mutant lox71/66 sites spaced ≥ 7 kb. The best recombination efficiency is observed in breeders aged 8-20 weeks and when using heterozygous floxed alleles. The Cre-Lox system remains indispensable for genetic engineering, offering flexibility beyond standalone applications by integrating with CRISPR-based methods to expand its utility. Despite challenges, our findings provide a framework for optimizing Cre-mediated recombination. By refining Cre-Lox strategies, this knowledge enhances experimental precision, improves reproducibility, and ultimately reduces the time and cost of genome modification.
Alterations in intestinal bile acid transport provide a therapeutic target in patients with post-bariatric hypoglycaemia
Authors: Snehal N Chaudhari, Yingjia Chen, Rafael Ferraz-Bannitz, Cameron Cummings, Amanda Sheehan, Pilar Casanova Querol, Berkcan Ozturk, Hanna Wang, Gabriel D'Agostino, Fei Ye, Eric G Sheu, A Sloan Devlin, Mary-Elizabeth Patti
Journal: Nature Metabolism (2025)
Stapokibart for moderate-to-severe seasonal allergic rhinitis: a randomized phase 3 trial
Authors: Yuan Zhang, Jingyun Li, Menglin Wang, Xian Li, Bing Yan, Jixiang Liu, Li Shi, Zhiwei Cao, Yan Feng, Weiwei Liu, Zhendong Xu, Ruixia Ma, Xiaoping Gao, Wen Liu, Jinmei Xue, Xiaoyong Ren, Xuezhong Li, Xicheng Song, Yi Yang, Yusheng Wang, Zhimin Xing, Fang Quan, Jing Pan, Yue Sun, Fengpo Shi, Xiaoqiu Chen, Hongyue Yan, Guoqing Zhao, Bo Chen, Chengshuo Wang, Luo Zhang
Journal: Nature Medicine (2025)

Seasonal allergic rhinitis (SAR) places a significant socioeconomic burden, particularly on individuals with poorly managed recurrent and severe symptoms despite standard-of-care treatment. Stapokibart, a humanized monoclonal antibody that targets the interleukin (IL)-4 receptor subunit alpha, inhibits its interaction with both IL-4 and IL-13 in type 2 inflammation. Here we aim to assess the efficacy and safety of stapokibart as an add-on therapy in adults with moderate-to-severe SAR. The study was a phase 3 multicenter, randomized, double-blind, placebo-controlled clinical trial with 108 patients diagnosed with moderate-to-severe SAR and having baseline blood eosinophil counts ≥300 cells μl-1. Participants were randomized (1:1) to receive 600 mg (loading dose) to 300 mg stapokibart subcutaneously or a placebo every 2 weeks for 4 weeks. The primary endpoint was mean change from baseline in daily reflective total nasal symptom score (rTNSS) over the first 2 weeks. Multiplicity-tested secondary endpoints included changes in rTNSS over 4 weeks, reflective total ocular symptom score and Rhinoconjunctivitis Quality of Life Questionnaire score over 2 weeks and 4 weeks. Compared with the placebo, stapokibart led to a significant improvement in the mean change from baseline in daily rTNSS during the 2-week (least-squares mean difference, -1.3; 95% confidence interval, -2.0 to -0.6; P = 0.0008) and 4-week (least-squares mean difference, -1.7; 95% confidence interval, -2.5 to -0.8; P = 0.0002) treatments. Stapokibart significantly improved the multiplicity-tested secondary endpoints. Treatment-emergent adverse events were comparable between the groups. Pharmacodynamics and exploratory analyses indicated that the observed improvements in outcomes during pollen season may be attributed to the reduction of type 2 inflammation in response to stapokibart treatment. The results of this trial show that pollen seasonal administration of stapokibart improved both nasal and ocular symptoms and quality of life in patients with moderate-to-severe SAR. ClinicalTrials.gov registration: NCT05908032 .
Molecular characterization of newly diagnosed acute myeloid leukemia patients aged 60 years or older: a report from the Beat AML clinical trial
Authors: Fieke W Hoff, Ying Huang, Rina Li Welkie, Ronan T Swords, Elie Traer, Eytan M Stein, Tara L Lin, Prapti A Patel, Robert H Collins, Maria R Baer, Vu H Duong, William G Blum, Martha L Arellano, Wendy Stock, Olatoyosi Odenike, Robert L Redner, Tibor Kovacsovics, Michael W Deininger, Joshua F Zeidner, Rebecca L Olin, Catherine C Smith, James M Foran, Gary J Schiller, Emily K Curran, Kristin L Koenig, Nyla A Heerema, Timothy Chen, Molly Martycz, Mona Stefanos, Sonja G Marcus, Leonard Rosenberg, Brian J Druker, Ross L Levine, Amy Burd, Ashley O Yocum, Uma M Borate, Alice S Mims, John C Byrd, Yazan F Madanat
Journal: Blood Cancer Journal (2025)
LILRB1-directed CAR-T cells for the treatment of hematological malignancies
Authors: Katsiaryna Marhelava, Klaudyna Fidyt, Monika Pepek, Marta Krawczyk, Christopher Forcados, Agata Malinowska, Bianka Swiderska, Narcis Fernandez-Fuentes, Natalia Czerwik, Iwona Baranowska, Agnieszka Krzywdzinska, Lukasz Sedek, Lukasz Slota, Bartosz Perkowski, Alicia Villatoro, Thibault Leray, Ewa Lech-Maranda, Pablo Menendez, Else Marit Inderberg, Sébastien Wälchli, Magdalena Winiarska, Malgorzata Firczuk
Journal: Leukemia (2025)

Abstract CD19 CAR-T cells have established a new standard for relapsed/refractory B-cell malignancies. However, the treatment fails in 50% of patients, often due to CD19 antigen loss. Alternative immunotherapies targeting other antigens are being tested but show limited efficacy, especially in cases of lineage switching or loss of B-cell phenotype, highlighting the need for novel targets. Herein, we identified leukocyte-immunoglobulin-like-receptor-B1 (LILRB1, CD85j) as a novel target for CAR-T cells through cell surface proteomics on patient-derived samples of high-risk B-cell acute lymphoblastic leukemia (B-ALL). LILRB1, an immune inhibitory receptor, is normally expressed only on monocytes and B-cells. We observed stable LILRB1 expression in B-ALL and B-cell non-Hodgkin lymphoma (B-NHL), even after CD20/CD19-based immunotherapies. LILRB1 CAR-T cells showed antigen-specific antitumor activity in vitro against B-ALL/B-NHL cells, including those resistant to CD19 CAR-T-cells, and in vivo in B-ALL xenografts. Additionally, we identified LILRB1 in monocytic acute myeloid leukemia (AML) and demonstrated LILRB1 CAR-T cell cytotoxicity against AML cell lines in vitro and in vivo. These findings establish LILRB1 as a novel target for cancer immunotherapy and show evidence for the preclinical efficacy of LILRB1 CAR-T cells against haematological malignancies, including cases resistant to previous lines of immunotherapy, thus holding promise for further clinical development.
Regeneration leads to global tissue rejuvenation in aging sexual planarians
Authors: Xiaoting Dai, Xinghua Li, Alexander Tyshkovskiy, Cassandra Zuckerman, Nan Cheng, Peter Lin, David Paris, Saad Qureshi, Leonid Kruglyak, Xiaoming Mao, Jayakrishnan Nandakumar, Vadim N Gladyshev, Scott Pletcher, Jacob Sobota, Longhua Guo
Journal: Nature Aging (2025)
Glofitamab in refractory or relapsed diffuse large B cell lymphoma after failing CAR-T cell therapy: a phase 2 LYSA study
Authors: Guillaume Cartron, Roch Houot, Yassine Al Tabaa, Fabien Le Bras, Loïc Ysebaert, Sylvain Choquet, Fabrice Jardin, Jacques-Olivier Bay, François-Xavier Gros, Franck Morschhauser, Olivier Casasnovas, Thomas Gastinne, Catherine Thieblemont, Magalie Joris, Laure Ricard, Caroline Regny, Laurianne Drieu La Rochelle, Pierre Feugier, Ambroise Marcais, Samuel Griolet, Karin Tarte, Camille Laurent, Pierre Sesques
Journal: Nature Cancer (2025)
Immune and metabolic effects of African heritage diets versus Western diets in men: a randomized controlled trial
Authors: Godfrey S Temba, Tal Pecht, Vesla I Kullaya, Nadira Vadaq, Mary V Mosha, Thomas Ulas, Sneha Kanungo, Liesbeth van Emst, Lorenzo Bonaguro, Jonas Schulte-Schrepping, Elias Mafuru, Paolo Lionetti, Musa M Mhlanga, Andre J van der Ven, Duccio Cavalieri, Leo A B Joosten, Reginald A Kavishe, Blandina T Mmbaga, Joachim L Schultze, Mihai G Netea, Quirijn de Mast
Journal: Nature Medicine (2025)
Human lifespan changes in the brain’s functional connectome
Authors: Lianglong Sun, Tengda Zhao, Xinyuan Liang, Mingrui Xia, Qiongling Li, Xuhong Liao, Gaolang Gong, Qian Wang, Chenxuan Pang, Qian Yu, Yanchao Bi, Pindong Chen, Rui Chen, Yuan Chen, Taolin Chen, Jingliang Cheng, Yuqi Cheng, Zaixu Cui, Zhengjia Dai, Yao Deng, Yuyin Ding, Qi Dong, Dingna Duan, Jia-Hong Gao, Qiyong Gong, Ying Han, Zaizhu Han, Chu-Chung Huang, Ruiwang Huang, Ran Huo, Lingjiang Li, Ching-Po Lin, Qixiang Lin, Bangshan Liu, Chao Liu, Ningyu Liu, Ying Liu, Yong Liu, Jing Lu, Leilei Ma, Weiwei Men, Shaozheng Qin, Jiang Qiu, Shijun Qiu, Tianmei Si, Shuping Tan, Yanqing Tang, Sha Tao, Dawei Wang, Fei Wang, Jiali Wang, Pan Wang, Xiaoqin Wang, Yanpei Wang, Dongtao Wei, Yankun Wu, Peng Xie, Xiufeng Xu, Yuehua Xu, Zhilei Xu, Liyuan Yang, Huishu Yuan, Zilong Zeng, Haibo Zhang, Xi Zhang, Gai Zhao, Yanting Zheng, Suyu Zhong, Yong He
Journal: Nature Neuroscience (2025)
Adoptively transferred tumor-specific IL-9-producing cytotoxic CD8+ T cells activate host CD4+ T cells to control tumors with antigen loss
Authors: Liuling Xiao, Rui Duan, Wendao Liu, Chuanchao Zhang, Xingzhe Ma, Miao Xian, Qiang Wang, Qi Guo, Wei Xiong, Pan Su, Lingqun Ye, Yabo Li, Ling Zhong, Jianfei Qian, Yong Lu, Zhongming Zhao, Qing Yi
Journal: Nature Cancer (2025)
Syndromic epidermal differentiation disorders: New classification towards pathogenesis-based therapy
Authors: Amy S Paller, Joyce Teng, Juliette Mazereeuw-Hautier, Ángela Hernández-Martín, Céline Granier Tournier, Alain Hovnanian, Mandy Aldwin-Easton, Gianluca Tadini, Schwartz Janice, Eli Sprecher, Kiril Malovitski, Akemi Ishida-Yamamoto, Keith Choate, Masashi Akiyama, Edel A O’Toole, Judith Fischer, Christine Bodemer, Antoni Gostynski, Matthias Schmuth
Journal: British Journal of Dermatology (2025)

Abstract Since the 2010 classification of ichthyoses, our understanding of hereditary epidermal differentiation disorders (EDDs) has markedly increased, allowing consideration of new therapeutic targets based on disease pathogenesis. A new gene- and protein product function-based classification focuses on shared mechanisms of disease pathogenesis, with the possibility that grouped disorders may respond similarly to new therapeutics. These EDDs have been subdivided into syndromic (sEDD), nonsyndromic with features limited to skin and appendages (nEDD), and predominantly palmoplantar skin involvement (pEDD, nonsyndromic and syndromic). The sEDDs have clinically important extracutaneous features related to the gene alteration. Often, recognition based on skin manifestations facilitates early gene-based diagnosis, discussion of prognosis, genetic counseling, and initiation of therapy. All sEDDs are rare, the most common of which are STS-sEDD (formerly known as X-linked ichthyosis) and SPINK5-sEDD (formerly known as Netherton syndrome). Given the rarity, frequent association with early demise, and variable clinical features of sEDDs, their disease natural history with advancing age and genotype-phenotype relationships are poorly defined. Among the 51 sEDDs, associated neurologic (71%) and/or ophthalmologic (49%) findings are most common, and 39% have hair abnormalities. The widespread use of topical lovastatin-cholesterol for cholesterol synthesis-related sEDDs represents the prototype of pathogenesis-based therapy. This concept of upstream inhibition to prevent metabolite accumulation and supplementation with pathway end product potentially applies to other sEDDs, such as those affecting ceramide synthesis and transport. Topical or systemically administered inhibition of activated pathways is another potential approach, exemplified by the emerging treatment with kallikrein inhibitors for SPINK5-sEDD. Many sEDDs may be amenable to gene editing or introduction of functional cDNA. However, even systemic treatments targeting cutaneous diseases may not address extracutaneous manifestations that arise during embryologic development.
Pancreatic Cancer: Pathogenesis and Clinical Studies
Authors: Kexun Zhou, Yingping Liu, Chuanyun Tang, Hong Zhu
Journal: MedComm (2025)

ABSTRACT Pancreatic cancer (PC) is a highly lethal malignancy, with pancreatic ductal adenocarcinoma (PDAC) being the most common and aggressive subtype, characterized by late diagnosis, aggressive progression, and resistance to conventional therapies. Despite advances in understanding its pathogenesis, including the identification of common genetic mutations (e.g., KRAS, TP53, CDKN2A, SMAD4) and dysregulated signaling pathways (e.g., KRAS–MAPK, PI3K–AKT, and TGF‐β pathways), effective therapeutic strategies remain limited. Current treatment modalities including chemotherapy, targeted therapy, immunotherapy, radiotherapy, and emerging therapies such as antibody–drug conjugates (ADCs), chimeric antigen receptor T (CAR‐T) cells, oncolytic viruses (OVs), cancer vaccines, and bispecific antibodies (BsAbs), face significant challenges. This review comprehensively summarizes these treatment approaches, emphasizing their mechanisms, limitations, and potential solutions, to overcome these bottlenecks. By integrating recent advancements and outlining critical challenges, this review aims to provide insights into future directions and guide the development of more effective treatment strategies for PC, with a specific focus on PDAC. Our work underscores the urgency of addressing the unmet needs in PDAC therapy and highlights promising areas for innovation in this field.
Efficacy and safety of individualised versus standard 10-day antibiotic treatment in children with febrile urinary tract infection (INDI-UTI): a pragmatic, open-label, multicentre, randomised, controlled, non-inferiority trial in Denmark
Authors: Naqash Javaid Sethi, Emma Louise Malchau Carlsen, Abdullah Tabassum, Dina Cortes, Simone Mark Øw, Ida Maria Schmidt, Mette Marie Christensen, Ann-Britt Kiholm Kirkedal, Claudia Mau Kai, Charlotte Kjær Bjerre, Lise Heilmann Jensen, Maria Antonova, Signe Sønderkær, Maren Johanne Heilskov Rytter, Gry Tordrup, Tatjana Zaharov, Line Thousig Sehested, Ulrikka Nygaard
Journal: The Lancet Infectious Diseases (2025)
Correction: WDR82-binding long noncoding RNA <i>lncEry</i> controls mouse erythroid differentiation and maturation
Authors: Shangda Yang, Guohuan Sun, Peng Wu, Cong Chen, Yijin Kuang, Ling Liu, Zhaofeng Zheng, Yicheng He, Quan Gu, Ting Lu, Caiying Zhu, Fengjiao Wang, Fanglin Gou, Zining Yang, Xiangnan Zhao, Shiru Yuan, Liu Yang, Shihong Lu, Yapu Li, Xue Lv, Fang Dong, Yanni Ma, Jia Yu, Lai Guan Ng, Lihong Shi, Jing Liu, Lei Shi, Tao Cheng, Hui Cheng
Journal: The Journal of Experimental Medicine (2025)
Eosinophil innate immune memory after bacterial skin infection promotes allergic lung inflammation
Authors: Mariem Radhouani, Asma Farhat, Anna Hakobyan, Sophie Zahalka, Lisabeth Pimenov, Alina Fokina, Anastasiya Hladik, Karin Lakovits, Jessica Brösamlen, Vojtech Dvorak, Natalia Nunes, Andreas Zech, Marco Idzko, Thomas Krausgruber, Jörg Köhl, Ozge Uluckan, Jiri Kovarik, Kai Hoehlig, Axel Vater, Margret Eckhard, Andy Sombke, Nikolaus Fortelny, Jörg Menche, Sylvia Knapp, Philipp Starkl
Journal: Science Immunology (2025)

Microbial exposure at barrier interfaces drives development and balance of the immune system, but the consequences of local infections for systemic immunity and secondary inflammation are unclear. Here, we show that skin exposure to the bacterium Staphylococcus aureus persistently shapes the immune system of mice with specific impact on progenitor and mature bone marrow neutrophil and eosinophil populations. The infection-imposed changes in eosinophils were long-lasting and associated with functional as well as imprinted epigenetic and metabolic changes. Bacterial exposure enhanced cutaneous allergic sensitization and resulted in exacerbated allergen-induced lung inflammation. Functional bone marrow eosinophil reprogramming and pulmonary allergen responses were driven by the alarmin interleukin-33 and the complement cleavage fragment C5a. Our study highlights the systemic impact of skin inflammation and reveals mechanisms of eosinophil innate immune memory and organ cross-talk that modulate systemic responses to allergens.
Skin damage signals mediate allergic sensitization to spatially unlinked antigen
Authors: Daniel A. Waizman, Isabela Brown-Soler, Anjelica L. Martin, Yifan Ma, Kenneth Zhou, Kavita Israni-Winger, Cuiling Zhang, Ruslan Medzhitov, Pierre Launay, Michaël F. Michieletto, Jorge Henao-Mejia, Noah W. Palm, Joe Craft, Anna Eisenstein, Andrew Wang
Journal: Science Immunology (2025)

Our current understanding of immunity to pathogens suggests that anatomic coupling of antigens with danger signals is a required feature for the formation of immune memory. However, in the context of pathogen-independent inflammation, the stringency of this anatomical coupling is unclear. Here, we demonstrate that multiple modes of skin injury were sufficient to induce a humoral response to antigens introduced in the gut. Skin damage induced a narrow subset of endocrine cytokines that were necessary and sufficient for the priming of antigens introduced at various distal tissues. Thus, in addition to “local priming” of antigen entering through damaged skin, there also exists another paradigm of “remote priming” where anatomical coupling is not essential because of the dissemination of damage-associated intermediaries. Our findings have implications for understanding the fundamental mechanisms of the formation of humoral memory with wide implications for diseases such as food allergy and in vaccinology.
Brain sensing of metabolic state regulates circulating monocytes
Authors: Joao Paulo Cavalcanti de Albuquerque, Jenna Hunter, Rita G. Domingues, Erika Harno, Amy A. Worth, Fabrizio Maria Liguori, Aurora D’Alessio, Gabriella Aviello, David Bechtold, Anne White, Simon M. Luckman, Matthew R. Hepworth, Giuseppe D’Agostino
Journal: Science Immunology (2025)

Changes in energy availability alter the dynamics of circulating immune cells. The existing view is that these effects are due to altered nutrient levels affecting peripheral tissue metabolism. Here, using mice and genetic approaches to manipulate the activity of distinct molecularly defined neurons, we show that the brain’s perception of hunger and satiety alone is sufficient to drive these immune changes. Hunger-promoting Agouti-related peptide (AgRP) neurons in the hypothalamus were both sufficient and necessary to reduce circulating Ly6C Hi classical monocytes during fasting. Mechanistically, these neurons suppressed hepatic mammalian target of rapamycin signaling via sympathetic regulation, decreasing circulating chemokine ligand 2 and monocyte numbers. AgRP neuron–induced corticosterone release and glucocorticoid receptor activation played a permissive role in this process. These changes in monocyte dynamics can occur independently of actual nutrient levels, revealing an unexpected brain-mediated control of peripheral immunity in response to perceived variation in energy state.
Precision Omics Initiative Sweden (PROMISE) will integrate research with healthcare
Authors: Anders Kämpe, Sanna Gudmundsson, Colum P Walsh, Kerstin Lindblad-Toh, Åsa Johansson, Anna Clareborn, Adam Ameur, Anders Edsjö, Thoas Fioretos, Hans Ehrencrona, Daniel Eriksson, Tove Fall, Paul W Franks, Ulf Gyllensten, Margareta Haag, Anna Hagwall, Maria Johansson Soller, Janne Lehtiö, Yi Lu, Patrik K E Magnusson, Erik Melén, Beatrice Melin, Karl Michaëlsson, Ann Nordgren, Jessica Nordlund, Lao H Saal, Jochen M Schwenk, Per Sikora, Johan Sundström, Fulya Taylan, Bethany Van Guelpen, Mia Wadelius, Anna Wedell, Valtteri Wirta, Päivi Östling, Bo Jacobsson, Tobias Sjöblom, Bengt Persson, Richard Rosenquist, Anna Lindstrand, Tuuli Lappalainen
Journal: Nature Medicine (2025)
Retrieval augmented generation for 10 large language models and its generalizability in assessing medical fitness
Authors: Yu He Ke, Liyuan Jin, Kabilan Elangovan, Hairil Rizal Abdullah, Nan Liu, Alex Tiong Heng Sia, Chai Rick Soh, Joshua Yi Min Tung, Jasmine Chiat Ling Ong, Chang-Fu Kuo, Shao-Chun Wu, Vesela P Kovacheva, Daniel Shu Wei Ting
Journal: npj Digital Medicine (2025)

Large Language Models (LLMs) hold promise for medical applications but often lack domain-specific expertise. Retrieval Augmented Generation (RAG) enables customization by integrating specialized knowledge. This study assessed the accuracy, consistency, and safety of LLM-RAG models in determining surgical fitness and delivering preoperative instructions using 35 local and 23 international guidelines. Ten LLMs (e.g., GPT3.5, GPT4, GPT4o, Gemini, Llama2, and Llama3, Claude) were tested across 14 clinical scenarios. A total of 3234 responses were generated and compared to 448 human-generated answers. The GPT4 LLM-RAG model with international guidelines generated answers within 20 s and achieved the highest accuracy, which was significantly better than human-generated responses (96.4% vs. 86.6%, p = 0.016). Additionally, the model exhibited an absence of hallucinations and produced more consistent output than humans. This study underscores the potential of GPT-4-based LLM-RAG models to deliver highly accurate, efficient, and consistent preoperative assessments.