tbuckley/cabot-search huggingface dataset:
Tissue-specific RNA Polymerase II promoter-proximal pause release and burst kinetics in a Drosophila embryonic patterning network
Authors: George Hunt, Roshan Vaid, Sergei Pirogov, Alexander Pfab, Christoph Ziegenhain, Rickard Sandberg, Johan Reimegård, Mattias Mannervik
Journal: Genome biology (2024)

Formation of tissue-specific transcriptional programs underlies multicellular development, including dorsoventral (DV) patterning of the Drosophila embryo. This involves interactions between transcriptional enhancers and promoters in a chromatin context, but how the chromatin landscape influences transcription is not fully understood.
Single-cell transcriptomic analysis reveals tumor cell heterogeneity and immune microenvironment features of pituitary neuroendocrine tumors
Authors: Nan Yan, Weiyan Xie, Dongfang Wang, Qiuyue Fang, Jing Guo, Yiyuan Chen, Xinqi Li, Lei Gong, Jialin Wang, Wenbo Guo, Xuegong Zhang, Yazhuo Zhang, Jin Gu, Chuzhong Li
Journal: Genome Medicine (2024)

Pituitary neuroendocrine tumors (PitNETs) are one of the most common types of intracranial tumors. Currently, the cellular characteristics of normal pituitary and various other types of PitNETs are still not completely understood.
Proteolytic activation of fatty acid synthase signals pan-stress resolution
Authors: Hai Wei, Yi M. Weaver, Chendong Yang, Yuan Zhang, Guoli Hu, Courtney M. Karner, Matthew Sieber, Ralph J. DeBerardinis, Benjamin P. Weaver
Journal: Nature Metabolism (2024)

Chronic stress and inflammation are both outcomes and major drivers of many human diseases. Sustained responsiveness despite mitigation suggests a failure to sense resolution of the stressor. Here we show that a proteolytic cleavage event of fatty acid synthase (FASN) activates a global cue for stress resolution in Caenorhabditis elegans. FASN is well established for biosynthesis of the fatty acid palmitate. Our results demonstrate FASN promoting an anti-inflammatory profile apart from palmitate synthesis. Redox-dependent proteolysis of limited amounts of FASN by caspase activates a C-terminal fragment sufficient to downregulate multiple aspects of stress responsiveness, including gene expression, metabolic programs and lipid droplets. The FASN C-terminal fragment signals stress resolution in a cell non-autonomous manner. Consistent with these findings, FASN processing is also seen in well-fed but not fasted male mouse liver. As downregulation of stress responses is critical to health, our findings provide a potential pathway to control diverse aspects of stress responses.
A candidate antibody drug for prevention of malaria
Authors: Katherine L. Williams, Steve Guerrero, Yevel Flores-Garcia, Dongkyoon Kim, Kevin S. Williamson, Christine Siska, Pauline Smidt, Sofia Z. Jepson, Kan Li, S. Moses Dennison, Shamika Mathis-Torres, Xiaomu Chen, Ulrike Wille-Reece, Randall S. MacGill, Michael Walker, Erik Jongert, C. Richter King, Christian Ockenhouse, Jacob Glanville, James E. Moon, Jason A. Regules, Yann Chong Tan, Guy Cavet, Shaun M. Lippow, William H. Robinson, Sheetij Dutta, Georgia D. Tomaras, Fidel Zavala, Randal R. Ketchem, Daniel E. Emerling
Journal: Nature Medicine (2024)

Abstract Over 75% of malaria-attributable deaths occur in children under the age of 5 years. However, the first malaria vaccine recommended by the World Health Organization (WHO) for pediatric use, RTS,S/AS01 (Mosquirix), has modest efficacy. Complementary strategies, including monoclonal antibodies, will be important in efforts to eradicate malaria. Here we characterize the circulating B cell repertoires of 45 RTS,S/AS01 vaccinees and discover monoclonal antibodies for development as potential therapeutics. We generated &gt;28,000 antibody sequences and tested 481 antibodies for binding activity and 125 antibodies for antimalaria activity in vivo. Through these analyses we identified correlations suggesting that sequences in Plasmodium falciparum circumsporozoite protein, the target antigen in RTS,S/AS01, may induce immunodominant antibody responses that limit more protective, but subdominant, responses. Using binding studies, mouse malaria models, biomanufacturing assessments and protein stability assays, we selected AB-000224 and AB-007088 for advancement as a clinical lead and backup. We engineered the variable domains (Fv) of both antibodies to enable low-cost manufacturing at scale for distribution to pediatric populations, in alignment with WHO’s preferred product guidelines. The engineered clone with the optimal manufacturing and drug property profile, MAM01, was advanced into clinical development.
Synaptic-like transmission between neural axons and arteriolar smooth muscle cells drives cerebral neurovascular coupling
Authors: Dongdong Zhang, Jiayu Ruan, Shiyu Peng, Jinze Li, Xu Hu, Yiyi Zhang, Tianrui Zhang, Yaping Ge, Zhu Zhu, Xian Xiao, Yunxu Zhu, Xuzhao Li, Tingbo Li, Lili Zhou, Qingzhu Gao, Guoxiao Zheng, Bingrui Zhao, Xiangqing Li, Yanming Zhu, Jinsong Wu, Wensheng Li, Jingwei Zhao, Woo-Ping Ge, Tian Xu, Jie-Min Jia
Journal: Nature Neuroscience (2024)

Abstract Neurovascular coupling (NVC) is important for brain function and its dysfunction underlies many neuropathologies. Although cell-type specificity has been implicated in NVC, how active neural information is conveyed to the targeted arterioles in the brain remains poorly understood. Here, using two-photon focal optogenetics in the mouse cerebral cortex, we demonstrate that single glutamatergic axons dilate their innervating arterioles via synaptic-like transmission between neural–arteriolar smooth muscle cell junctions (NsMJs). The presynaptic parental–daughter bouton makes dual innervations on postsynaptic dendrites and on arteriolar smooth muscle cells (aSMCs), which express many types of neuromediator receptors, including a low level of glutamate NMDA receptor subunit 1 ( Grin1 ). Disruption of NsMJ transmission by aSMC-specific knockout of GluN1 diminished optogenetic and whisker stimulation-caused functional hyperemia. Notably, the absence of GluN1 subunit in aSMCs reduced brain atrophy following cerebral ischemia by preventing Ca 2+ overload in aSMCs during arteriolar constriction caused by the ischemia-induced spreading depolarization. Our findings reveal that NsMJ transmission drives NVC and open up a new avenue for studying stroke.
The Dhaka Call to Action to accelerate the control of cardiovascular diseases in South-East Asia
Authors: Pradeep Joshi, Mohammad Robed Amin, Farzana Akter Dorin, Laigden Dzed, Pema Lethro, Sunny Swarnkar, Yutaro Setoya, Eva Susanti, Lubna Bhatti, Hassan Mohamed, Fathimath Hudha, Dinesh Jeyakumaran, Phanindra Prasad Baral, Gampo Dorji, S. Sridharan, Farrukh Qureshi, Krisada Hanbunjerd, Olivia Corazon Nieveras, Helder J. N. da Silva, Leoneto Pinto, Angela De Silva, Jagdish Kaur, Nalika Gunawardena, Cherian Varghese
Journal: Nature Medicine (2024)
Perioperative toripalimab and chemotherapy in locally advanced gastric or gastro-esophageal junction cancer: a randomized phase 2 trial
Authors: Shu-Qiang Yuan, Run-Cong Nie, Ying Jin, Cheng-Cai Liang, Yuan-Fang Li, Rui Jian, Xiao-Wei Sun, Ying-Bo Chen, Wen-Long Guan, Zi-Xian Wang, Hai-Bo Qiu, Wei Wang, Shi Chen, Dong-Sheng Zhang, Yi-Hong Ling, Shao-Yan Xi, Mu-Yan Cai, Chun-Yu Huang, Qiu-Xia Yang, Zhi-Min Liu, Yuan-Xiang Guan, Yong-Ming Chen, Ji-Bin Li, Xiong-Wen Tang, Jun-Sheng Peng, Zhi-Wei Zhou, Rui-Hua Xu, Feng Wang
Journal: Nature Medicine (2024)
A decentralized delivery program for rheumatic heart disease treatment and prevention in Uganda
Authors: Doreen Nakagaayi, Jafesi Pulle, Isaac Otim, Oyoo Charles Akiya, Okello Henry Otto, Kristen Danforth, Chris T Longenecker, Nicholas Ollberding, Rachel Sarnacki, Miriam Nakitto, Samantha Buonfiglio, Joselyn Rwebembera, Craig Sable, Kenneth Sherr, Yanfang Su, Allison Webel, Andrea Beaton, Emmy Okello, David Watkins
Journal: Nature Medicine (2024)
Disentangling the effects of PTSD from Gulf War Illness in male veterans via a systems-wide analysis of immune cell, cytokine, and symptom measures
Authors: Esha Sultana, Nandan Shastry, Rishabh Kasarla, Jacob Hardy, Fanny Collado, Kristina Aenlle, Maria Abreu, Emily Sisson, Kimberly Sullivan, Nancy Klimas, Travis J A Craddock
Journal: Military Medical Research (2024)

Abstract Background One-third of veterans returning from the 1990–1991 Gulf War reported a myriad of symptoms including cognitive dysfunction, skin rashes, musculoskeletal discomfort, and fatigue. This symptom cluster is now referred to as Gulf War Illness (GWI). As the underlying mechanisms of GWI have yet to be fully elucidated, diagnosis and treatment are based on symptomatic presentation. One confounding factor tied to the illness is the high presence of post-traumatic stress disorder (PTSD). Previous research efforts have demonstrated that both GWI and PTSD are associated with immunological dysfunction. As such, this research endeavor aimed to provide insight into the complex relationship between GWI symptoms, cytokine presence, and immune cell populations to pinpoint the impact of PTSD on these measures in GWI. Methods Symptom measures were gathered through the Multidimensional fatigue inventory (MFI) and 36-item short form health survey (SF-36) scales and biological measures were obtained through cytokine &amp; cytometry analysis. Subgrouping was conducted using Davidson Trauma Scale scores and the Structured Clinical Interview for Diagnostic and statistical manual of mental disorders (DSM)-5, into GWI with high probability of PTSD symptoms (GWI H ) and GWI with low probability of PTSD symptoms (GWI L ). Data was analyzed using Analysis of variance (ANOVA) statistical analysis along with correlation graph analysis. We mapped correlations between immune cells and cytokine signaling measures, hormones and GWI symptom measures to identify patterns in regulation between the GWI H , GWI L , and healthy control groups. Results GWI with comorbid PTSD symptoms resulted in poorer health outcomes compared with both Healthy control (HC) and the GWI L subgroup. Significant differences were found in basophil levels of GWI compared with HC at peak exercise regardless of PTSD symptom comorbidity (ANOVA F = 4.7, P = 0.01,) indicating its potential usage as a biomarker for general GWI from control. While the unique identification of GWI with PTSD symptoms was less clear, the GWI L subgroup was found to be delineated from both GWI H and HC on measures of IL-15 across an exercise challenge (ANOVA F &gt; 3.75, P &lt; 0.03). Additional differences in natural killer (NK) cell numbers and function highlight IL-15 as a potential biomarker of GWI in the absence of PTSD symptoms. Conclusion We conclude that disentangling GWI and PTSD by defining trauma-based subgroups may aid in the identification of unique GWI biosignatures that can help to improve diagnosis and target treatment of GWI more effectively.
Presence of onco-fetal neighborhoods in hepatocellular carcinoma is associated with relapse and response to immunotherapy
Authors: Ziyi Li, Rhea Pai, Saurabh Gupta, Jennifer Currenti, Wei Guo, Anna Di Bartolomeo, Hao Feng, Zijie Zhang, Zhizhen Li, Longqi Liu, Abhishek Singh, Yinqi Bai, Bicheng Yang, Archita Mishra, Katharine Yang, Liang Qiao, Michael Wallace, Yujia Yin, Qiang Xia, Jerry Kok Yen Chan, Jacob George, Pierce Kah-Hoe Chow, Florent Ginhoux, Ankur Sharma
Journal: Nature Cancer (2024)
Artificial Intelligence Detected the Relationship Between Nuclear Morphological Features and Molecular Abnormalities of Papillary Thyroid Carcinoma
Authors: Toui Nishikawa, Ibu Matsuzaki, Ayata Takahashi, Iwamoto Ryuta, Fidele Yambayamba Musangile, Kanako Sagan, Mizuki Nishikawa, Yurina Mikasa, Yuichi Takahashi, Fumiyoshi Kojima, Shin-ichi Murata
Journal: Endocrine Pathology (2024)
Traditional risk factors and premature acute coronary syndromes in South Eastern Europe: a multinational cohort study
Authors: Raffaele Bugiardini, Edina Cenko, Jinsung Yoon, Maria Bergami, Zorana Vasiljevic, Guiomar Mendieta, Marija Zdravkovic, Marija Vavlukis, Sasko Kedev, Davor Miličić, Lina Badimon, Olivia Manfrini
Journal: The Lancet Regional Health - Europe (2024)

The age-standardized death rates under 65 years from ischemic heart disease in South Eastern Europe are approximately twice as high than the Western Europe average, but the reasons are not completely recognized. The aim of the present study was to address this issue by collecting and analyzing data from a large, multinational cohort.
Efficacy and safety of transcranial direct current stimulation to the ipsilesional motor cortex in subacute stroke (NETS): a multicenter, randomized, double-blind, placebo-controlled trial
Authors: Diana Cordes, Christian Gerloff, Kirstin-Friederike Heise, Friedhelm C. Hummel, Robert Schulz, Silke Wolf, Kerstin Haevernick, Heike Krüger, Linda Krause, Anna Suling, Karl Wegscheider, Antonia Zapf, Jürgen Dressnandt, Barbara Schäpers, Christoph Schrödl, Björn Hauptmann, Anja Kirchner, Anna Brault, Alexander Gutschalk, Constanze Richter, Dennis A. Nowak, Jitka Veldema, Giacomo Koch, Michele Maiella, Christian Dohle, Katrin Jettkowski, Mario Pilz, Farsin Hamzei, Lydia Olischer, Caroline Renner, Marcus Groß, Michael Jöbges, Bernhard Voller
Journal: The Lancet Regional Health - Europe (2024)
Blocking methionine catabolism induces senescence and confers vulnerability to GSK3 inhibition in liver cancer
Authors: Fuming Li, Pingyu Liu, Wen Mi, Liucheng Li, Nicole M Anderson, Nicholas P Lesner, Michelle Burrows, Jacqueline Plesset, Ariana Majer, Guanlin Wang, Jinyang Li, Lingzhi Zhu, Brian Keith, M Celeste Simon
Journal: Nature Cancer (2024)
Phase <scp>I</scp> study of zoledronic acid combined with escalated doses of interleukine‐2 for early in vivo generation of <scp>Vγ9Vδ2 T</scp>‐cells after haploidentical stem cell transplant with posttransplant cyclophosphamide
Authors: Maxime Jullien, Thierry Guillaume, Amandine Le Bourgeois, Pierre Peterlin, Alice Garnier, Marion Eveillard, Yannick Le Bris, Simon Bouzy, Benoît Tessoulin, Thomas Gastinne, Viviane Dubruille, Cyrille Touzeau, Béatrice Mahé, Nicolas Blin, Anne Lok, Sophie Vantyghem, Clara Sortais, Chloé Antier, Philippe Moreau, Emmanuel Scotet, Marie C. Béné, Patrice Chevallier
Journal: American Journal of Hematology (2024)

Abstract The presence of donor Vγ9Vδ2 T‐cells after haploidentical hematopoietic stem cell transplant (h‐HSCT) has been associated with improved disease‐free survival. These cells kill tumor cells in a non‐MHC restricted manner, do not induce graft‐versus‐host disease (GVHD), and can be generated by stimulation with zoledronic acid (ZA) in combination with interleukin‐2 (IL‐2). This monocentric phase I, open‐label, dose‐escalating study (ClinicalTrials.gov: NCT03862833) aimed at evaluating the safety and possibility to generate Vγ9Vδ2 T‐cells early after h‐HSCT. It applied a standard 3 + 3 protocol to determine the maximum tolerated dose (MTD) of increasing low‐doses of IL‐2 (5 days [d] per week, 4 weeks) in combination with a single dose of ZA, starting both the first Monday after d + 15 posttransplant. Vγ9Vδ2 T‐cell monitoring was performed by multiparameter flow cytometry on blood samples and compared with a control cohort of h‐HSCT recipients. Twenty‐six patients were included between April 2019 and September 2022, 16 of whom being ultimately treated and seven being controls who received h‐HSCT only. At the three dose levels tested, 1, 0, and 1 dose‐limiting toxicities were observed. MTD was not reached. A significantly higher number of Vγ9Vδ2 T‐cells was observed during IL‐2 treatment compared with controls. In conclusion, early in vivo generation of Vγ9Vδ2 T‐cells is feasible after h‐HSCT by using a combination of ZA and repeated IL‐2 infusions. This study paves the way to a future phase 2 study, with the hope to document lesser posttransplant relapse with this particular adaptive immunotherapy.
Propionate alleviates itch in murine models of atopic dermatitis by modulating sensory <scp>TRP</scp> channels of dorsal root ganglion
Authors: Yao Xu, Zhuoqiong Qiu, Chaoying Gu, Su Yu, Shangshang Wang, Changlin Li, Xu Yao, Wei Li
Journal: Allergy (2024)

Abstract Background Itch is the most common symptom of atopic dermatitis (AD) and significantly decreases the quality of life. Skin microbiome is involved in AD pathogenesis, whereas its role in the regulation of itch remains elusive. In this study, we aimed to investigate the effects of skin microbial metabolite propionate on acute and chronic pruritus and to explore the mechanism. Methods Using various mouse models of itch, the roles of propionate were explored by behavioral tests and histopathology/immunofluorescent analysis. Primary‐cultured dorsal root ganglion neurons and HEK293 cells expressing recombinant human TRP channels were utilized for in vitro calcium imaging/in vivo miniature two‐photon imaging in combination with electrophysiology and molecular docking approaches for investigation of the mechanism. Results Propionate significantly alleviated itch and alloknesis in various mouse models of pruritus and AD and decreased the density of intraepidermal nerve fibers. Propionate reduced the responsiveness of dorsal root ganglion neurons to pruritogens in vitro, attenuated the hyper‐excitability in sensory neurons in MC903‐induced AD model, and inhibited capsaicin‐evoked hTRPV1 currents (IC 50 = 20.08 ± 1.11 μM) via interacting with the vanilloid binding site. Propionate also decreased the secretion of calcitonin gene‐related peptide by nerves in MC903‐induced AD mouse model, which further attenuated itch and skin inflammation. Conclusion Our study revealed a protective effect of propionate against persistent itch through direct modulation of sensory TRP channels and neuropeptide production in neurons. Regulation of itch via the skin microbiome might be a novel strategy for the treatment of AD.
Complex karyotype but not other cytogenetic abnormalities is associated with worse posttransplant survival of patients with nucleophosmin 1‐mutated acute myeloid leukemia: A study from the European Society for Blood and Marrow Transplantation Acute Leukemia Working Party
Authors: Nour Moukalled, Myriam Labopin, Jurjen Versluis, Gérard Socié, Didier Blaise, Urpu Salmenniemi, Alessandro Rambaldi, Tobias Gedde‐Dahl, Eleni Tholouli, Nicolaus Kröger, Jean‐Henri Bourhis, Peter Von Dem Borne, Etienne Daguindau, Edouard Forcade, Arnon Nagler, Jordi Esteve, Fabio Ciceri, Ali Bazarbachi, Mohamad Mohty
Journal: American Journal of Hematology (2024)

Abstract In the 2022 European LeukemiaNet classification, patients with nucleophosmin 1 (NPM1) ‐mutated acute myeloid leukemia (AML) were classified in the adverse‐risk category in the presence of high‐risk cytogenetics (CG). Nonetheless, the impact of various CG aberrations on posttransplant outcomes remains to be unraveled. This registry study analyzed adult patients with NPM1 ‐mutated de novo AML who underwent their first allogeneic hematopoietic cell transplantation in the first complete remission from 2005 to 2021. A total of 3275 patients were identified, 2782 had normal karyotype, 493 had chromosomal aberrations including 160 with adverse‐risk CG, 72 patients had complex karyotype (CK), and 66 monosomal karyotype (MK). Overall, 2377 (73%) patients had FLT3 ‐ITD. On univariate analysis, only FLT3 ‐ITD, minimal/measurable residual disease (MRD) positivity and CK, but not abnormal CG, affected posttransplant outcomes. On multivariable analysis, CK was associated with lower overall survival (OS) (hazard ratio [HR] 1.72, p = .009). In the subgroup of 493 patients with aberrant CG, the 2‐year leukemia‐free survival (LFS) and OS were around 61% and 68%, respectively. On multivariable analysis for this subgroup, CK and MRD positivity were associated with increased risk of relapse (HR 1.7, p = .025; and 1.99, p = .003 respectively) and worse LFS (HR 1.62, p = .018; and 1.64, p = .011 respectively) while FLT3‐ ITD, MK, or other CG abnormalities had no significant effect. Importantly, CK negatively affected OS (HR 1.91, p = .002). In the first complete remission transplant setting, CK was found as the only cytogenetic risk factor for worse outcomes in NPM1 ‐mutated AML. Nevertheless, even for this subgroup, a significant proportion of patients can achieve long‐term posttransplant survival.
Lung function trajectories in a cohort of patients with moderate‐to‐severe asthma on mepolizumab, omalizumab, or dupilumab
Authors: Tanawin Nopsopon, Nora A. Barrett, Wanda Phipatanakul, Tanya M. Laidlaw, Scott T. Weiss, Ayobami Akenroye
Journal: Allergy (2024)

Abstract Background Lung function is an independent predictor of mortality. We evaluated the lung function trajectories of a cohort of patients with asthma receiving biologic therapy. Methods We identified 229 monoclonal antibody‐naïve adult patients with moderate‐to‐severe asthma who initiated omalizumab, mepolizumab, or dupilumab between 2010 and 2022 in a large healthcare system in Boston, MA. Generalized additive mixed models were used to estimate the lung function trajectories during the 156 weeks following biologic initiation. Response was defined as an improvement in FEV 1 or a decrease of ≤0.5% per year. The Kaplan–Meier estimator was used to assess time to no additional improvement in FEV 1 in responders. All models were adjusted for age, sex, body mass index, smoking status, baseline exacerbation rate, and baseline blood eosinophil count. Results Eighty‐eight patients initiated mepolizumab, 76 omalizumab, and 65 dupilumab. Baseline eosinophil count was highest in the mepolizumab group (405 cells/mcL) and lowest for omalizumab (250 cells/mcL). Both FEV 1 and FVC improved in the mepolizumab group (FEV 1 + 20 mL/year; FVC +43 mL/year). For omalizumab, there was an initial improvement in the first year followed by decline with an overall FEV 1 loss of −44 mL/year and FVC −32 mL/year. For dupilumab, both FEV 1 (+61 mL/year) and FVC (+74 mL/year) improved over time. Fifty percent of the mepolizumab group, 58% omalizumab, and 72% of dupilumab were responders. The median time to no additional FEV 1 improvement in responders was 24 weeks for omalizumab, 48 weeks for mepolizumab, and 57 weeks for dupilumab. Conclusion In this clinical cohort, mepolizumab, omalizumab, and dupilumab had beneficial effects on FEV 1 and FVC with distinct post‐initiation trajectories.
Optimizing Interventions for Early Childhood Development
Authors: Wafaie W. Fawzi, Uttara Partap
Journal: JAMA (2024)

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