tbuckley/cabot-search huggingface dataset:
Inter-α-trypsin inhibitor heavy chain 4 (ITIH4) as a compensatory protease inhibitor in hereditary angioedema
Authors: Anne Troldborg, Zsofia Godnic-Polai, László Cervenak, Annette G Hansen, Henriette Farkas, Steffen Thiel
Journal: Journal of Allergy and Clinical Immunology (2024)

Hereditary angioedema (HAE) is a genetic disorder that manifests as recurrent angioedema attacks, most frequently due to absent or reduced C1 inhibitor (C1INH) activity. C1INH is a crucial regulator of enzymatic cascades in the complement, fibrinolytic, and contact systems. Inter-α-trypsin inhibitor heavy chain 4 (ITIH4) is an abundant plasma protease inhibitor that can inhibit enzymes in the proteolytic pathways associated with HAE. Nothing is known about its role in HAE. We investigated ITIH4 activation in HAE, establishing it as a potential biomarker, and explored its involvement in HAE-associated proteolytic pathways. Specific immunoassays for noncleaved ITIH4 (intact ITIH4) and an assay detecting both intact and cleaved ITIH4 (total ITIH4) were developed. We initially tested serum samples from HAE patients (n = 20), angiotensin-converting enzyme inhibitor-induced edema patients (ACEI) (n = 20), and patients with HAE of unknown cause (HAE-UNK) (n = 20). Validation involved an extended cohort of 80 HAE patients (60 with HAE-C1INH type 1, 20 with HAE-C1INH type 2), including samples taken during attack and quiescent disease periods, as well as samples from 100 healthy controls. In 63% of HAE patients, intact ITIH4 assay showed lower signals than total ITIH4 assay. This difference was not observed in ACEI and HAE-UNK patients. Western blot analysis confirmed cleaved ITIH4 with low intact ITIH4 samples. In serum samples lacking intact endogenous ITIH4, we observed immediate cleavage of added recombinant ITIH4, suggesting continuous enzymatic activity in the serum. Confirmatory HAE cohort analysis revealed significantly lower intact ITIH4 levels in both type 1 and type 2 HAE patients compared to controls, with consistently low intact/total ITIH4 ratios during clinical HAE attacks. The disease-specific low intact ITIH4 levels highlight its unique nature in HAE. ITIH4 may exhibit compensatory mechanisms in HAE, suggesting its utility as a diagnostic and prognostic biomarker. The variations during quiescent and active disease periods raise intriguing questions about the dynamics of proteolytic pathways in HAE.
Author Correction: Concurrent intrathecal and intravenous nivolumab in leptomeningeal disease: phase 1 trial interim results
Authors: Isabella C. Glitza Oliva, Sherise D. Ferguson, Roland Bassett, Alexandra P. Foster, Ida John, Tarin D. Hennegan, Michelle Rohlfs, Jessie Richard, Masood Iqbal, Tina Dett, Carol Lacey, Natalie Jackson, Theresa Rodgers, Suzanne Phillips, Sheila Duncan, Lauren Haydu, Ruitao Lin, Rodabe N. Amaria, Michael K. Wong, Adi Diab, Cassian Yee, Sapna P. Patel, Jennifer L. McQuade, Grant M. Fischer, Ian E. McCutcheon, Barbara J. O’Brien, Sudhakar Tummala, Matthew Debnam, Nandita Guha-Thakurta, Jennifer A. Wargo, Fernando C. L. Carapeto, Courtney W. Hudgens, Jason T. Huse, Michael T. Tetzlaff, Elizabeth M. Burton, Hussein A. Tawbi, Michael A. Davies
Journal: Nature Medicine (2024)
Error in Reported Number of Countries
Journal: JAMA Network Open (2024)

Error in Reported Number of CountriesIn the Original Investigation titled "Estimated Sustainable Cost-Based Prices for Diabetes Medicines," 1 published March 27, 2024, there was an error in the number of countries reported.Each instance of "13 countries" should have been "12 countries."In the Methods, the listing of countries from which current market prices were collected given as "Indonesia, Morocco, South Africa, and Ukraine" should have omitted Indonesia and Ukraine and added "the Philippines."Data from Indonesia were indeterminate and therefore not included in the final analysis.This article was corrected.
Growth hormone promotes myelin repair after chronic hypoxia via triggering pericyte-dependent angiogenesis
Authors: Shu-Yu Ren, Yu Xia, Bin Yu, Qi-Jing Lei, Peng-Fei Hou, Sheng Guo, Shuang-Ling Wu, Wei Liu, Shao-Fan Yang, Yi-Bin Jiang, Jing-Fei Chen, Kai-Feng Shen, Chun-Qing Zhang, Fei Wang, Mi Yan, Hong Ren, Nian Yang, Jun Zhang, Kuan Zhang, Sen Lin, Tao Li, Qing-Wu Yang, Lan Xiao, Zhang-Xue Hu, Feng Mei
Journal: Neuron (2024)
Integrated drug profiling and CRISPR screening identify BCR::ABL1-independent vulnerabilities in chronic myeloid leukemia
Authors: Shady Adnan Awad, Olli Dufva, Jay Klievink, Ella Karjalainen, Aleksandr Ianevski, Paavo Pietarinen, Daehong Kim, Swapnil Potdar, Maija Wolf, Kourosh Lotfi, Tero Aittokallio, Krister Wennerberg, Kimmo Porkka, Satu Mustjoki
Journal: Cell Reports Medicine (2024)

BCR::ABL1-independent pathways contribute to primary resistance to tyrosine kinase inhibitor (TKI) treatment in chronic myeloid leukemia (CML) and play a role in leukemic stem cell persistence. Here, we perform ex vivo drug screening of CML CD34
Retraction: PKCδ null mutations in a mouse model of osteoarthritis alter osteoarthritic pain independently of joint pathology by augmenting NGF/TrkA-induced axonal outgrowth
Journal: Annals of the Rheumatic Diseases (2024)

Objectives A key clinical paradox in osteoarthritis (OA), a prevalent age-related joint disorder characterised by cartilage degeneration and debilitating pain, is that the severity of joint pain does not strictly correlate with radiographic and histological defects in joint tissues.Here, we determined whether protein kinase Cδ (PKCδ), a key mediator of cartilage degeneration, is critical to the mechanism by which OA develops from an asymptomatic joint-degenerative condition to a painful disease.Methods OA was induced in 10-week-old PKCδ null (PKCδ -/-) and wild-type mice by destabilisation of the medial meniscus (DMM) followed by comprehensive examination of the histology, molecular pathways and knee-pain-related-behaviours in mice, and comparisons with human biopsies.Results In the DMM model, the loss of PKCδ expression prevented cartilage degeneration but exacerbated OAassociated hyperalgesia.Cartilage preservation corresponded with reduced levels of inflammatory cytokines and of cartilage-degrading enzymes in the joints of PKCδ-deficient DMM mice.Hyperalgesia was associated with stimulation of nerve growth factor (NGF) by fibroblast-like synovial cells and with increased synovial angiogenesis.Results from tissue specimens of patients with symptomatic OA strikingly resembled our findings from the OA animal model.In PKCδ null mice, increases in sensory neuron distribution in knee OA synovium and activation of the NGF-tropomyosin receptor kinase (TrkA) axis in innervating dorsal root ganglia were highly correlated with knee OA hyperalgesia.Conclusions Increased distribution of synovial sensory neurons in the joints, and augmentation of NGF/TrkA signalling, causes OA hyperalgesia independently of cartilage preservation.
Loss of GPR75 protects against non-alcoholic fatty liver disease and body fat accumulation
Authors: Alasdair Leeson-Payne, Jean Iyinikkel, Cameron Malcolm, Brian Y.H. Lam, Nadine Sommer, Georgina K.C. Dowsett, Pablo B. Martinez de Morentin, Dawn Thompson, Alasdair Mackenzie, Raffaella Chianese, Katherine Kentistou, Eugene J. Gardner, John R.B. Perry, Felix Grassmann, John R. Speakman, Justin J. Rochford, Giles S.H. Yeo, Fiona Murray, Lora K. Heisler
Journal: Cell Metabolism (2024)

Approximately 1 in 4 people worldwide have non-alcoholic fatty liver disease (NAFLD); however, there are currently no medications to treat this condition. This study investigated the role of adiposity-associated orphan G protein-coupled receptor 75 (GPR75) in liver lipid accumulation. We profiled Gpr75 expression and report that it is most abundant in the brain. Next, we generated the first single-cell-level analysis of Gpr75 and identified a subpopulation co-expressed with key appetite-regulating hypothalamic neurons. CRISPR-Cas9-deleted Gpr75 mice fed a palatable western diet high in fat adjusted caloric intake to remain in energy balance, thereby preventing NAFLD. Consistent with mouse results, analysis of whole-exome sequencing data from 428,719 individuals (UK Biobank) revealed that variants in GPR75 are associated with a reduced likelihood of hepatic steatosis. Here, we provide a significant advance in understanding of the expression and function of GPR75, demonstrating that it is a promising pharmaceutical target for NAFLD treatment.
Assessing phage-host population dynamics by reintroducing virulent viruses to synthetic microbiomes
Authors: Jacob Wilde, Randy Boyes, Avery V. Robinson, Brendan A. Daisley, Alexander J. Botschner, Dylan J.L. Brettingham, Christine V. Macpherson, Elizabeth Mallory, Emma Allen-Vercoe
Journal: Cell Host & Microbe (2024)

Microbiomes feature complex interactions between diverse bacteria and bacteriophages. Synthetic microbiomes offer a powerful way to study these interactions; however, a major challenge is obtaining a representative bacteriophage population during the bacterial isolation process. We demonstrate that colony isolation reliably excludes virulent viruses from sample sources with low virion-to-bacteria ratios such as feces, creating "virulent virus-free" controls. When the virulent dsDNA virome is reintroduced to a 73-strain synthetic gut microbiome in a bioreactor model of the human colon, virulent viruses target susceptible strains without significantly altering community structure or metabolism. In addition, we detected signals of prophage induction that associate with virulent predation. Overall, our findings indicate that dilution-based isolation methods generate synthetic gut microbiomes that are heavily depleted, if not devoid, of virulent viruses and that such viruses, if reintroduced, have a targeted effect on community assembly, metabolism, and prophage replication.
Taking consciousness for real: Increasing the ecological validity of the study of conscious vs. unconscious processes
Authors: Liad Mudrik, Rony Hirschhorn, Uri Korisky
Journal: Neuron (2024)

The study of consciousness has developed well-controlled, rigorous methods for manipulating and measuring consciousness. Yet, in the process, experimental paradigms grew farther away from everyday conscious and unconscious processes, which raises the concern of ecological validity. In this review, we suggest that the field can benefit from adopting a more ecological approach, akin to other fields of cognitive science. There, this approach challenged some existing hypotheses, yielded stronger effects, and enabled new research questions. We argue that such a move is critical for studying consciousness, where experimental paradigms tend to be artificial and small effect sizes are relatively prevalent. We identify three paths for doing so—changing the stimuli and experimental settings, changing the measures, and changing the research questions themselves—and review works that have already started implementing such approaches. While acknowledging the inherent challenges, we call for increasing ecological validity in consciousness studies.
A commentary on “Portal vein thrombosis and liver transplantation: management, matching, and outcomes: a retrospective multicenter cohort study”
Authors: Junjian Wang, Xiaoang Ye, Hongyu Chen
Journal: International Journal of Surgery (2024)

aHangzhou TCM Hospital Affiliated to Zhejiang Chinese Medical University, Hangzhou, Zhejiang, People's Republic of China bThe Second Clinical Medical College of Zhejiang Chinese Medical University, Hangzhou, Zhejiang, People's Republic of China cDepartment of Nephrology, Hangzhou TCM Hospital Affiliated to Zhejiang Chinese Medical University, Hangzhou, Zhejiang,People's Republic of China Junjian Wang and Xiaoang Ye contributed equally to this work and share first authorship. Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article. Published online ■ ■ *Corresponding author. Address: Hangzhou TCM Hospital Affiliated to Zhejiang Chinese Medical University, 453 Stadium Road, West Lake District, Hangzhou, Zhejiang 310007, People's Republic of China. E-mail address: [email protected] (H. Chen). This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms. http://creativecommons.org/licenses/by-nc-sa/4.0/
Differential selection of yield and quality traits has shaped genomic signatures of cowpea domestication and improvement
Authors: Xinyi Wu, Zhongyuan Hu, Yan Zhang, Mao Li, Nanqiao Liao, Junyang Dong, Baogen Wang, Jian Wu, Xiaohua Wu, Ying Wang, Jian Wang, Zhongfu Lu, Yi Yang, Yuyan Sun, Wenqi Dong, Mingfang Zhang, Guojing Li
Journal: Nature Genetics (2024)
Cortical gene expression architecture links healthy neurodevelopment to the imaging, transcriptomics and genetics of autism and schizophrenia
Authors: Richard Dear, Konrad Wagstyl, Jakob Seidlitz, Ross D. Markello, Aurina Arnatkevičiūtė, Kevin M. Anderson, Richard A. I. Bethlehem, Armin Raznahan, Edward T. Bullmore, Petra E. Vértes
Journal: Nature Neuroscience (2024)

Abstract Human brain organization involves the coordinated expression of thousands of genes. For example, the first principal component (C1) of cortical transcription identifies a hierarchy from sensorimotor to association regions. In this study, optimized processing of the Allen Human Brain Atlas revealed two new components of cortical gene expression architecture, C2 and C3, which are distinctively enriched for neuronal, metabolic and immune processes, specific cell types and cytoarchitectonics, and genetic variants associated with intelligence. Using additional datasets (PsychENCODE, Allen Cell Atlas and BrainSpan), we found that C1–C3 represent generalizable transcriptional programs that are coordinated within cells and differentially phased during fetal and postnatal development. Autism spectrum disorder and schizophrenia were specifically associated with C1/C2 and C3, respectively, across neuroimaging, differential expression and genome-wide association studies. Evidence converged especially in support of C3 as a normative transcriptional program for adolescent brain development, which can lead to atypical supragranular cortical connectivity in people at high genetic risk for schizophrenia.
Targeting dysregulated phago-/auto-lysosomes in Sertoli cells to ameliorate late-onset hypogonadism
Authors: Zhiwen Deng, Liangyu Zhao, Sha Li, Xiaoyang Chen, Xiaohan Ling, Jiajun Zheng, Kunkun Yu, Jing Xu, Chencheng Yao, Sha Han, Jiayi Liang, Huimin Feng, Lanlan Wu, Peng Li, Ruhui Tian, Tao Jing, Yuxin Tang, Yingbo Dai, Minbo Yan, Chenchen Wang, Zheng Li, Zhi Zhou
Journal: Nature Aging (2024)
<i>miR‐146a<sup>−/−</sup></i> mice model reveals that <scp>NF‐κB</scp> inhibition reverts <scp>inflammation‐driven</scp> myelofibrosis‐like phenotype
Authors: Ernesto José Cuenca‐Zamora, Pedro J. Guijarro‐Carrillo, María J. López‐Poveda, María Luz Morales, María Luisa Lozano, Rocío Gonzalez‐Conejero, Constantino Martínez, Raúl Teruel‐Montoya, Francisca Ferrer‐Marín
Journal: American Journal of Hematology (2024)

Abstract Emerging evidence shows the crucial role of inflammation (particularly NF‐κB pathway) in the development and progression of myelofibrosis (MF), becoming a promising therapeutic target. Furthermore, tailoring treatment with currently available JAK inhibitors (such as ruxolitinib or fedratinib) does not modify the natural history of the disease and has important limitations, including cytopenias. Since recent studies have highlighted the role of miR‐146a, a negative regulator of the NF‐κB pathway, in the pathogenesis of MF; here we used miR‐146a −/− (KO) mice, a MF‐like model lacking driver mutations, to investigate whether pharmacological inhibition of JAK/STAT and/or NF‐κB pathways may reverse the myelofibrotic phenotype of these mice. Specifically, we tested the JAK1/2 inhibitor, ruxolitinib; the NF‐κB inhibitor via IKKα/β, BMS‐345541; both inhibitors in combination; or a dual inhibitor of both pathways (JAK2/IRAK1), pacritinib. Although all treatments decreased spleen size and partially recovered its architecture, only NF‐κB inhibition, either using BMS‐345541 (alone or in combination) or pacritinib, resulted in a reduction of extramedullary hematopoiesis, bone marrow (BM) fibrosis and osteosclerosis, along with an attenuation of the exacerbated inflammatory state (via IL‐1β and TNFα). However, although dual inhibitor improved anemia and reversed thrombocytopenia, the combined therapy worsened anemia by inducing BM hypoplasia. Both therapeutic options reduced NF‐κB and JAK/STAT signaling in a context of JAK2V617F‐driven clonal hematopoiesis. Additionally, combined treatment reduced both COL1A1 and IL‐6 production in an in vitro model mimicking JAK2 ‐driven fibrosis. In conclusion, NF‐κB inhibition reduces, in vitro and in vivo, disease burden and BM fibrosis, which could provide benefits in myelofibrosis patients.
Mechanisms of ischaemia-induced arrhythmias in hypertrophic cardiomyopathy: a large-scale computational study
Authors: James A Coleman, Ruben Doste, Zakariye Ashkir, Raffaele Coppini, Rafael Sachetto, Hugh Watkins, Betty Raman, Alfonso Bueno-Orovio
Journal: Cardiovascular Research (2024)

Abstract Aims Lethal arrhythmias in hypertrophic cardiomyopathy (HCM) are widely attributed to myocardial ischaemia and fibrosis. How these factors modulate arrhythmic risk remains largely unknown, especially as invasive mapping protocols are not routinely used in these patients. By leveraging multiscale digital twin technologies, we aim to investigate ischaemic mechanisms of increased arrhythmic risk in HCM. Methods and results Computational models of human HCM cardiomyocytes, tissue, and ventricles were used to simulate outcomes of Phase 1A acute myocardial ischaemia. Cellular response predictions were validated with patch-clamp studies of human HCM cardiomyocytes (n = 12 cells, N = 5 patients). Ventricular simulations were informed by typical distributions of subendocardial/transmural ischaemia as analysed in perfusion scans (N = 28 patients). S1-S2 pacing protocols were used to quantify arrhythmic risk for scenarios in which regions of septal obstructive hypertrophy were affected by (i) ischaemia, (ii) ischaemia and impaired repolarization, and (iii) ischaemia, impaired repolarization, and diffuse fibrosis. HCM cardiomyocytes exhibited enhanced action potential and abnormal effective refractory period shortening to ischaemic insults. Analysis of ∼75 000 re-entry induction cases revealed that the abnormal HCM cellular response enabled establishment of arrhythmia at milder ischaemia than otherwise possible in healthy myocardium, due to larger refractoriness gradients that promoted conduction block. Arrhythmias were more easily sustained in transmural than subendocardial ischaemia. Mechanisms of ischaemia–fibrosis interaction were strongly electrophysiology dependent. Fibrosis enabled asymmetric re-entry patterns and break-up into sustained ventricular tachycardia. Conclusion HCM ventricles exhibited an increased risk to non-sustained and sustained re-entry, largely dominated by an impaired cellular response and deleterious interactions with the diffuse fibrotic substrate.
Systemic inflammation and delirium during critical illness
Authors: Nathan E. Brummel, Christopher G. Hughes, J. Brennan McNeil, Pratik P. Pandharipande, Jennifer L. Thompson, Onur M. Orun, Rameela Raman, Lorraine B. Ware, Gordon R. Bernard, Fiona E. Harrison, E. Wesley Ely, Timothy D. Girard
Journal: Intensive Care Medicine (2024)
Inhibition of cyclin-dependent kinase 7 mitigates doxorubicin cardiotoxicity and enhances anticancer efficacy
Authors: Jingrui Chen, Jing Wei, Peng Xia, Yuening Liu, Mahder Dawit Belew, Ryan Toohill, Boyang Jason Wu, Zhaokang Cheng
Journal: Cardiovascular Research (2024)

The anthracycline family of anticancer agents such as doxorubicin (DOX) can induce apoptotic death of cardiomyocytes and cause cardiotoxicity. We previously reported that DOX-induced apoptosis is accompanied by cardiomyocyte cell cycle re-entry. Cell cycle progression requires cyclin-dependent kinase 7 (CDK7)-mediated activation of downstream cell cycle CDKs. This study aims to determine whether CDK7 can be targeted for cardioprotection during anthracycline chemotherapy.
How relevant are eosinophils to chronic spontaneous urticaria? No evidence of clinical benefit from eosinophil depletion with benralizumab
Authors: Clive E H Grattan, Emek Kocatürk
Journal: British Journal of Dermatology (2024)

Journal Article Accepted manuscript How relevant are eosinophils to chronic spontaneous urticaria? No evidence of clinical benefit from eosinophil depletion with benralizumab Get access Clive E H Grattan, Clive E H Grattan St John's Institute of Dermatology, London, UK Correspondence: Clive E.H. Grattan, Email:clive.e.grattan@gstt.nhs.uk Search for other works by this author on: Oxford Academic Google Scholar Emek Kocatürk Emek Kocatürk Koç University School of Medicine, Department of Dermatology, Istanbul, TurkeyInstitute of Allergology, Charité – Universitätsmedizin Berlin, GermanyFraunhofer Institute for Translational Medicine and Pharmacology ITMP, Allergology and Immunology, Berlin, Germany Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, ljae165, https://doi.org/10.1093/bjd/ljae165 Published: 22 April 2024 Article history Received: 13 March 2024 Revision received: 09 April 2024 Accepted: 19 April 2024 Published: 22 April 2024
Chronic neutrophilic leukemia and atypical chronic myeloid leukemia: 2024 update on diagnosis, genetics, risk stratification, and management
Authors: Natasha Szuber, Attilio Orazi, Ayalew Tefferi
Journal: American Journal of Hematology (2024)

Chronic neutrophilic leukemia (CNL) is a rare BCR::ABL1-negative myeloproliferative neoplasm (MPN) defined by persistent mature neutrophilic leukocytosis and bone marrow granulocyte hyperplasia. Atypical chronic myeloid leukemia (aCML) (myelodysplastic "[MDS]/MPN with neutrophilia" per World Health Organization [WHO]) is a MDS/MPN overlap disorder featuring dysplastic neutrophilia and circulating myeloid precursors. Both manifest with frequent hepatosplenomegaly and less commonly, bleeding, with high rates of leukemic transformation and death. The 2022 revised WHO classification conserved CNL diagnostic criteria of leukocytosis ≥25 × 10