tbuckley/cabot-search huggingface dataset:
Single-cell transcriptomics reveals that glial cells integrate homeostatic and circadian processes to drive sleep–wake cycles
Authors: Joana Dopp, Antonio Ortega, Kristofer Davie, Suresh Poovathingal, El-Sayed Baz, Sha Liu
Journal: Nature Neuroscience (2024)

The sleep-wake cycle is determined by circadian and sleep homeostatic processes. However, the molecular impact of these processes and their interaction in different brain cell populations are unknown. To fill this gap, we profiled the single-cell transcriptome of adult Drosophila brains across the sleep-wake cycle and four circadian times. We show cell type-specific transcriptomic changes, with glia displaying the largest variation. Glia are also among the few cell types whose gene expression correlates with both sleep homeostat and circadian clock. The sleep-wake cycle and sleep drive level affect the expression of clock gene regulators in glia, and disrupting clock genes specifically in glia impairs homeostatic sleep rebound after sleep deprivation. These findings provide a comprehensive view of the effects of sleep homeostatic and circadian processes on distinct cell types in an entire animal brain and reveal glia as an interaction site of these two processes to determine sleep-wake dynamics.
Correction: Landscape of mast cell populations across organs in mice and humans
Authors: Marie Tauber, Lilian Basso, Jeremy Martin, Luciana Bostan, Marlene Magalhaes Pinto, Guilhem R. Thierry, Raïssa Houmadi, Nadine Serhan, Alexia Loste, Camille Blériot, Jasper B.J. Kamphuis, Mirjana Grujic, Lena Kjellén, Gunnar Pejler, Carle Paul, Xinzhong Dong, Stephen J. Galli, Laurent L. Reber, Florent Ginhoux, Marc Bajenoff, Rebecca Gentek, Nicolas Gaudenzio
Journal: The Journal of Experimental Medicine (2024)

After publication of the article, some readers reached out to JEM to raise concerns about Figs. 5 and6, specifically regarding the clustering of human mast cells.They highlighted that the analysis did not correct for the influence of donors' gender and/or sequencing technique on the conclusions.At JEM's request, the authors reanalyzed the data to correct for such bias and identified six different mast cell clusters/states with distinct transcriptomic signatures across twelve organs in humans (the previous analysis had identified seven mast cell clusters/states).Accordingly, the clustering of human mast cells and associated mast cell signatures have been revised in the text, in Figs. 5 and6, and in Tables S3-S5.The conclusions regarding the heterogeneity and diversity of human mast cells remain unchanged.The corrected Figs. 5 and 6 are shown here, as well as changes to the text and figure legends (indicated in bold).Tables S3-S5 have been replaced online.
Author Correction: Trimodal single-cell profiling reveals a novel pediatric CD8αα+ T cell subset and broad age-related molecular reprogramming across the T cell compartment
Authors: Zachary Thomson, Ziyuan He, Elliott Swanson, Katherine Henderson, Cole Phalen, Samir Rachid Zaim, Mark-Phillip Pebworth, Lauren Y. Okada, Alexander T. Heubeck, Charles R. Roll, Veronica Hernandez, Morgan Weiss, Palak C. Genge, Julian Reading, Josephine R. Giles, Sasikanth Manne, Jeanette Dougherty, C. J. Jasen, Allison R. Greenplate, Lynne A. Becker, Lucas T. Graybuck, Suhas V. Vasaikar, Gregory L. Szeto, Adam K. Savage, Cate Speake, Jane H. Buckner, Xiao-jun Li, Thomas F. Bumol, E.John Wherry, Troy R. Torgerson, Laura A. Vella, Sarah E. Henrickson, Peter J. Skene, Claire E. Gustafson
Journal: Nature Immunology (2024)
Inhibition of ADAM9 promotes the selective degradation of KRAS and sensitizes pancreatic cancers to chemotherapy
Authors: Yu-Kai Huang, Wei-Chung Cheng, Ting-Ting Kuo, Juan-Cheng Yang, Yang-Chang Wu, Heng-Hsiung Wu, Chia-Chien Lo, Chih-Ying Hsieh, Sze-Ching Wong, Chih-Hao Lu, Wan-Ling Wu, Shih-Jen Liu, Yi-Chuan Li, Ching-Chan Lin, Chia-Ning Shen, Mien-Chie Hung, Jaw-Town Lin, Chun-Chieh Yeh, Yuh-Pyng Sher
Journal: Nature Cancer (2024)
Validating inborn error of immunity prevalence and risk with nationally representative electronic health record data
Authors: Nicholas L Rider, Ahuva Truxton, Tracy Ohrt, Irene Margolin-Katz, Mary Horan, Harold Shin, Roger Davila, Vanessa Tenembaum, Jessica Quinn, Vicki Modell, Fred Modell, Jordan S Orange, Almut Branner, Cynthia Senerchia
Journal: Journal of Allergy and Clinical Immunology (2024)
PRESTO: A Phase III, Open-Label Study of Intensification of Androgen Blockade in Patients With High-Risk Biochemically Relapsed Castration-Sensitive Prostate Cancer (AFT-19)
Authors: Rahul Aggarwal, Glenn Heller, David W. Hillman, Han Xiao, Joel Picus, Mary-Ellen Taplin, Tanya Dorff, Leonard Appleman, Douglas Weckstein, Akash Patnaik, Alan Bryce, Daniel Shevrin, James Mohler, Daniel Anderson, Arpit Rao, Scott Tagawa, Alan Tan, Susan Halabi, Katharine Dooley, Patrick O'Brien, Ronald Chen, Charles J. Ryan, Scott E. Eggener, Michael J. Morris, Rahul Aggarwal, Daniel Shevrin, Scott Tagawa, Charles Kim, Mary-Ellen Taplin, Young Whang, Shaker Dakhil, Raymond Smith, Benjamin Gartrell, Seth Fagbemi, Rex Mowat, Charles Farber, Neda Hashemi, Michael Humeniuk, Charles Ryan, John Ellerton, Mark Olsen, Jennifer Wang, Tanya Dorff, Sheila Karina Pascual, Douglas Weckstein, Douglas Weckstein, Alan Bryce, James Mohler, James Michael Randall, Han Xiao, Akash Patnaik, David King, Joel Picus, Deepak Kilari, Paul Monk, Rhonda Bitting, Leonard Appleman, Jose Eugenio Najera, Kendrith Rowland, Ralph Hauke, Nasfat Shehadeh, Brendan Curti, Gopal Gupta, Alan Tan, Timothy Collins, Tomasz Beer, David Tate, Bryant Sheh, Alina Basnet, James Conway, Howard Gross, Michael Goodman
Journal: Journal of Clinical Oncology (2024)

PURPOSE Patients with biochemically recurrent prostate cancer (BRPC) after radical prostatectomy and a short PSA doubling time are at risk for distant metastases. Apalutamide, an androgen receptor antagonist, and abiraterone acetate plus prednisone (AAP) prolong survival in the metastatic setting. We evaluated whether intensification of androgen-deprivation therapy (ADT) improves outcomes in BRPC. PATIENTS AND METHODS PRESTO is a randomized phase III, open-label trial in patients with BRPC and PSA doubling time ≤9 months (ClinicalTrials.gov identifier: NCT03009981 ). Patients were randomly assigned 1:1:1 to receive a finite 52-week treatment course with ADT control, ADT + apalutamide, or ADT + apalutamide + AAP. The primary end point was PSA progression-free survival (PSA-PFS), defined as serum PSA &gt;0.2 ng/mL after treatment completion. RESULTS Five hundred three patients were enrolled. The median PSA was 1.8 ng/mL (IQR, 1.0-3.6). At the first planned interim analysis, both experimental arms significantly prolonged PSA-PFS compared with the control arm (median, 24.9 months for ADT + apalutamide v 20.3 months for ADT; hazard ratio [HR], 0.52 [95% CI, 0.35 to 0.77]; P = .00047; median, 26.0 months for ADT + apalutamide + AAP v 20.0 months for ADT; HR, 0.48 [95% CI, 0.32 to 0.71]; P = .00008). Median time to testosterone recovery did not differ across treatment arms. The most common grade ≥3 adverse event was hypertension (7.5%, 7.4%, and 18% in ADT, ADT + apalutamide, and ADT + apalutamide + AAP arms, respectively). CONCLUSION Intensified AR blockade for a finite duration prolongs PSA-PFS with a manageable safety profile, without adversely affecting time to testosterone recovery. The addition of apalutamide to ADT should be considered in patients with high-risk BRPC.
Single-nucleus multi-omic profiling of human placental syncytiotrophoblasts identifies cellular trajectories during pregnancy
Authors: Meijiao Wang, Yawei Liu, Run Sun, Fenting Liu, Jiaqian Li, Long Yan, Jixiang Zhang, Xinwei Xie, Dongxu Li, Yiming Wang, Shiwen Li, Xili Zhu, Rong Li, Falong Lu, Zhenyu Xiao, Hongmei Wang
Journal: Nature Genetics (2024)

Abstract The human placenta has a vital role in ensuring a successful pregnancy. Despite the growing body of knowledge about its cellular compositions and functions, there has been limited research on the heterogeneity of the billions of nuclei within the syncytiotrophoblast (STB), a multinucleated entity primarily responsible for placental function. Here we conducted integrated single-nucleus RNA sequencing and single-nucleus ATAC sequencing analyses of human placentas from early and late pregnancy. Our findings demonstrate the dynamic heterogeneity and developmental trajectories of STB nuclei and their correspondence with human trophoblast stem cell (hTSC)-derived STB. Furthermore, we identified transcription factors associated with diverse STB nuclear lineages through their gene regulatory networks and experimentally confirmed their function in hTSC and trophoblast organoid-derived STBs. Together, our data provide insights into the heterogeneity of human STB and represent a valuable resource for interpreting associated pregnancy complications.
TXNRD1 drives the innate immune response in senescent cells with implications for age-associated inflammation
Authors: Xue Hao, Bo Zhao, Martina Towers, Liping Liao, Edgar Luzete Monteiro, Xin Xu, Christina Freeman, Hongzhuang Peng, Hsin-Yao Tang, Aaron Havas, Andrew V. Kossenkov, Shelley L. Berger, Peter D. Adams, David W. Speicher, David Schultz, Ronen Marmorstein, Kenneth S. Zaret, Rugang Zhang
Journal: Nature Aging (2024)
Prophylactic and long-lasting efficacy of senolytic CAR T cells against age-related metabolic dysfunction
Authors: Corina Amor, Inés Fernández-Maestre, Saria Chowdhury, Yu-Jui Ho, Sandeep Nadella, Courtenay Graham, Sebastian E. Carrasco, Emmanuella Nnuji-John, Judith Feucht, Clemens Hinterleitner, Valentin J. A. Barthet, Jacob A. Boyer, Riccardo Mezzadra, Matthew G. Wereski, David A. Tuveson, Ross L. Levine, Lee W. Jones, Michel Sadelain, Scott W. Lowe
Journal: Nature Aging (2024)

Senescent cells, which accumulate in organisms over time, contribute to age-related tissue decline. Genetic ablation of senescent cells can ameliorate various age-related pathologies, including metabolic dysfunction and decreased physical fitness. While small-molecule drugs that eliminate senescent cells ('senolytics') partially replicate these phenotypes, they require continuous administration. We have developed a senolytic therapy based on chimeric antigen receptor (CAR) T cells targeting the senescence-associated protein urokinase plasminogen activator receptor (uPAR), and we previously showed these can safely eliminate senescent cells in young animals. We now show that uPAR-positive senescent cells accumulate during aging and that they can be safely targeted with senolytic CAR T cells. Treatment with anti-uPAR CAR T cells improves exercise capacity in physiological aging, and it ameliorates metabolic dysfunction (for example, improving glucose tolerance) in aged mice and in mice on a high-fat diet. Importantly, a single administration of these senolytic CAR T cells is sufficient to achieve long-term therapeutic and preventive effects.
Oligodendrocyte–axon metabolic coupling is mediated by extracellular K+ and maintains axonal health
Authors: Zoe J. Looser, Zainab Faik, Luca Ravotto, Henri S. Zanker, Ramona B. Jung, Hauke B. Werner, Torben Ruhwedel, Wiebke Möbius, Dwight E. Bergles, L. Felipe Barros, Klaus-Armin Nave, Bruno Weber, Aiman S. Saab
Journal: Nature Neuroscience (2024)

The integrity of myelinated axons relies on homeostatic support from oligodendrocytes (OLs). To determine how OLs detect axonal spiking and how rapid axon-OL metabolic coupling is regulated in the white matter, we studied activity-dependent calcium (Ca
Reversion of ACP Nanoparticles into Prenucleation Clusters via Surfactant for Promoting Biomimetic Mineralization: A Physicochemical Understanding of Biosurfactant Role in Biomineralization Process
Authors: Dongni Shen, Zihuai Zhou, Yuedan Xu, Changyu Shao, Ying Shi, Weijia Zhao, Ruikang Tang, Haihua Pan, Mengfei Yu, Matthias Hannig, Baiping Fu
Journal: Advanced Healthcare Materials (2024)

Amphiphilic biomolecules are abundant in mineralization front of biological hard tissues, which play a vital role in osteogenesis and dental hard tissue formation. Amphiphilic biomolecules function as biosurfactants, however, their biosurfactant role in biomineralization process has never been investigated. This study, for the first time, demonstrates that aggregated amorphous calcium phosphate (ACP) nanoparticles can be reversed into dispersed ultrasmall prenucleation clusters (PNCs) via breakdown and dispersion of the ACP nanoparticles by a surfactant. The reduced surface energy of ACP@TPGS and the electrostatic interaction between calcium ions and the pair electrons on oxygen atoms of C-O-C of D-α-tocopheryl polyethylene glycol succinate (TPGS) provide driving force for breakdown and dispersion of ACP nanoparticles into ultrasmall PNCs which promote in vitro and in vivo biomimetic mineralization. The ACP@TPGS possesses excellent biocompatibility without any irritations to oral mucosa and dental pulp. This study not only introduces surfactant into biomimetic mineralization field, but also excites attention to the neglected biosurfactant role during biomineralization process.
Role of innate host defense proteins in oral cancerogenesis
Authors: Jochen Winter, Søren Jepsen
Journal: Periodontology 2000 (2024)

Abstract It is nowadays well accepted that chronic inflammation plays a pivotal role in tumor initiation and progression. Under this aspect, the oral cavity is predestined to examine this connection because periodontitis is a highly prevalent chronic inflammatory disease and oral squamous cell carcinomas are the most common oral malignant lesions. In this review, we describe how particular molecules of the human innate host defense system may participate as molecular links between these two important chronic noncommunicable diseases (NCDs). Specific focus is directed toward antimicrobial polypeptides, such as the cathelicidin LL‐37 and human defensins, as well as S100 proteins and alarmins. We report in which way these peptides and proteins are able to initiate and support oral tumorigenesis, showing direct mechanisms by binding to growth‐stimulating cell surface receptors and/or indirect effects, for example, inducing tumor‐promoting genes. Finally, bacterial challenges with impact on oral cancerogenesis are briefly addressed.
Diagnostic reasoning prompts reveal the potential for large language model interpretability in medicine
Authors: Thomas Savage, Ashwin Nayak, Robert Gallo, Ekanath Rangan, Jonathan H. Chen
Journal: npj Digital Medicine (2024)

Abstract One of the major barriers to using large language models (LLMs) in medicine is the perception they use uninterpretable methods to make clinical decisions that are inherently different from the cognitive processes of clinicians. In this manuscript we develop diagnostic reasoning prompts to study whether LLMs can imitate clinical reasoning while accurately forming a diagnosis. We find that GPT-4 can be prompted to mimic the common clinical reasoning processes of clinicians without sacrificing diagnostic accuracy. This is significant because an LLM that can imitate clinical reasoning to provide an interpretable rationale offers physicians a means to evaluate whether an LLMs response is likely correct and can be trusted for patient care. Prompting methods that use diagnostic reasoning have the potential to mitigate the “black box” limitations of LLMs, bringing them one step closer to safe and effective use in medicine.
An unusual form of <scp>BRAF‐V600E</scp> mutated hairy cell neoplasm with clinical resistance to <scp>BRAF</scp> inhibition: Challenging precision medicine
Authors: Andrea Marra, Alessia Santi, Alessandra Pucciarini, Alessandra Venanzi, Luca De Carolis, Francesco Zaja, Stefano Ascani, Vincenzo Canzonieri, Stelvio Ballanti, Brunangelo Falini, Enrico Tiacci
Journal: American Journal of Hematology (2024)

Graphical Abstract Distinct outcomes of BRAF inhibition in BRAF-mutated hairy cell neoplasms with wild-type or mutant TP53, and alternative strategies to overcome mutant TP53.
Regulation of immune response genes in the skin of allergic and clinically tolerant individuals exposed to p‐phenylenediamine
Authors: Sanne S. Meisser, Yasutaka Mitamura, Can Altunbulakli, Josefine Bandier, Morten S. Opstrup, Anne‐Sofie Ø. Gadsbøll, Manru Li, Ge Tan, Mubeccel Akdis, Cezmi A. Akdis, Carsten Geisler, Jeanne D. Johansen, Charlotte M. Bonefeld
Journal: Allergy (2024)

Abstract Background p ‐Phenylenediamine (PPD) is a potent contact allergen found in many hair colour products. However, not all individuals develop allergic contact dermatitis (ACD) although they are regularly exposed to PPD. It is unclear whether these asymptomatic individuals are true non‐responders to PPD or whether they mount a response to PPD without showing any symptoms. Methods Skin biopsies were collected from 11 asymptomatic hairdressers regularly exposed to PPD and from 10 individuals with known ACD on day 4 after patch testing with 1% PPD in petrolatum and petrolatum exclusively as control. RNA sequencing and confocal microscopy were performed. Results T cell activation, inflammation and apoptosis pathways were up‐regulated by PPD in both asymptomatic and allergic individuals. Compared to asymptomatic individuals with a negative patch test, individuals with a strong reaction to PPD strongly up‐regulated both pro‐ and anti‐inflammatory cytokines genes. Interestingly, PPD treatment induced significant up‐regulation of several genes for chemokines, classical type 2 dendritic cell markers and regulatory T cell markers in both asymptomatic and allergic individuals. In addition, apoptosis signalling pathway was activated in both non‐responders and allergic individuals. Conclusion This study demonstrates that there are no true non‐responders to PPD but that the immune response elicited by PPD differs between individuals and can lead to either tolerance, subclinical inflammation or allergy.
Circulating micromegakaryocytes in an asplenic patient with post‐polycythemia myelofibrosis
Authors: Albert Borg, Viviene Ballon, Barbara J. Bain
Journal: American Journal of Hematology (2024)

Micromegakaryocytes are usually only seen in the bone marrow of patients with myeloid neoplasms. They are rare in blood films. The images above are from a 55-year-old woman who presented with an upper gastrointestinal hemorrhage related to a bleeding peptic ulcer. She had a background diagnosis of JAK2-mutated polycythemia vera with progression to myelofibrosis. Mutations that had been demonstrated previously included JAK2 p.Val617Phe-variant allele frequency (VAF) 77%, ASXL1 p.Pro808LeufsTer10-VAF 35%, EZH2 p.Arg690His-VAF 40%; p.Arg288Gln-VAF 12%. Two months prior to this presentation the patient had suffered a traumatic splenic rupture requiring splenectomy to control acute bleeding. Spleen pathology showed a capsular breach consistent with the history of trauma and, in addition, extramedullary hematopoiesis in keeping with the known diagnosis of post-polycythemia myelofibrosis. This admission was complicated by aspiration pneumonia requiring intensive care admission for ventilatory support, and concomitant COVID-19. Blood count results at this time showed hemoglobin concentration 95 g/L, mean cell volume 98 fL, white cell count 25.1 × 109/L, platelet count 1967 × 109/L, and mean platelet volume 10.8 fL. A blood film was markedly abnormal: leucoerythroblastic with prominent red cell changes (anisopoikilocytosis, dacrocytes, and ecchinocytes) with marked dyserythropoietic features (binucleated red cells, internuclear bridging, nuclear budding, abnormal hemoglobinization, and siderotic granules); the myeloid series was left shifted, and neutrophils were hypergranular, with pseudo-Pelger–Huët nuclei. The most notable abnormalities, however, were marked thrombocytosis with giant platelets and multiple platelet aggregates (top left), and the presence of numerous circulating megakaryocytes with almost bare nuclei; some of the latter had ragged, almost villous, cytoplasm (top right) and others appeared to be budding platelets (lower images). We attribute the presence of micromegakaryocytes to myelodysplasia associated with disease evolution in polycythemia vera with the large number of these cells in the peripheral circulation resulting from extramedullary hematopoiesis and hyposplenism. The authors declare no conflicts of interest.
Butyrate dietary supplementation promotes tolerant responses in a Pru p 3‐anaphylactic mouse model
Authors: Anyith Cruz‐Amaya, María del Carmen Martín‐Astorga, Clara Lebrón‐Martín, Juan Luis Paris, José Antonio Céspedes, Rafael Núñez, María José Torres, Carlos José Aranda, José Antonio Cañas, Cristobalina Mayorga
Journal: Allergy (2024)

The data that support the findings of this study are available from the corresponding author upon reasonable request. Figure S1 Figure S2 Figure S3 Figure S4 Figure S5 Figure S6 Figure S7 Figure S8 Appendix S1 Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
Plasma protein signatures of adult asthma
Authors: Gordon J. Smilnak, Yura Lee, Abhijnan Chattopadhyay, Annah B. Wyss, Julie D. White, Sinjini Sikdar, Jianping Jin, Andrew J. Grant, Alison A. Motsinger‐Reif, Jian‐Liang Li, Mikyeong Lee, Bing Yu, Stephanie J. London
Journal: Allergy (2024)

Abstract Background Adult asthma is complex and incompletely understood. Plasma proteomics is an evolving technique that can both generate biomarkers and provide insights into disease mechanisms. We aimed to identify plasma proteomic signatures of adult asthma. Methods Protein abundance in plasma was measured in individuals from the Agricultural Lung Health Study (ALHS) (761 asthma, 1095 non‐case) and the Atherosclerosis Risk in Communities study (470 asthma, 10,669 non‐case) using the SOMAScan 5K array. Associations with asthma were estimated using covariate adjusted logistic regression and meta‐analyzed using inverse‐variance weighting. Additionally, in ALHS, we examined phenotypes based on both asthma and seroatopy (asthma with atopy ( n = 207), asthma without atopy ( n = 554), atopy without asthma ( n = 147), compared to neither ( n = 948)). Results Meta‐analysis of 4860 proteins identified 115 significantly (FDR&lt;0.05) associated with asthma. Multiple signaling pathways related to airway inflammation and pulmonary injury were enriched (FDR&lt;0.05) among these proteins. A proteomic score generated using machine learning provided predictive value for asthma (AUC = 0.77, 95% CI = 0.75–0.79 in training set; AUC = 0.72, 95% CI = 0.69–0.75 in validation set). Twenty proteins are targeted by approved or investigational drugs for asthma or other conditions, suggesting potential drug repurposing. The combined asthma‐atopy phenotype showed significant associations with 20 proteins, including five not identified in the overall asthma analysis. Conclusion This first large‐scale proteomics study identified over 100 plasma proteins associated with current asthma in adults. In addition to validating previous associations, we identified many novel proteins that could inform development of diagnostic biomarkers and therapeutic targets in asthma management.