tbuckley/cabot-search huggingface dataset:
JAM-A Acts via C/EBP-α to Promote Claudin-5 Expression and Enhance Endothelial Barrier Function
Authors: Nikolaos Kakogiannos, Laura Ferrari, Costanza Giampietro, Anna Agata Scalise, Claudio Maderna, Micol Ravà, Andrea Taddei, Maria Grazia Lampugnani, Federica Pisati, Matteo Malinverno, Emanuele Martini, Ilaria Costa, Michela Lupia, Ugo Cavallaro, Galina V. Beznoussenko, Alexander A. Mironov, Bethania Fernandes, Noemi Rudini, Elisabetta Dejana, Monica Giannotta
Journal: Circulation Research (2020)

Intercellular tight junctions are crucial for correct regulation of the endothelial barrier. Their composition and integrity are affected in pathological contexts, such as inflammation and tumor growth. JAM-A (junctional adhesion molecule A) is a transmembrane component of tight junctions with a role in maintenance of endothelial barrier function, although how this is accomplished remains elusive.We aimed to understand the molecular mechanisms through which JAM-A expression regulates tight junction organization to control endothelial permeability, with potential implications under pathological conditions.Genetic deletion of JAM-A in mice significantly increased vascular permeability. This was associated with significantly decreased expression of claudin-5 in the vasculature of various tissues, including brain and lung. We observed that C/EBP-α (CCAAT/enhancer-binding protein-α) can act as a transcription factor to trigger the expression of claudin-5 downstream of JAM-A, to thus enhance vascular barrier function. Accordingly, gain-of-function for C/EBP-α increased claudin-5 expression and decreased endothelial permeability, as measured by the passage of fluorescein isothiocyanate (FITC)-dextran through endothelial monolayers. Conversely, C/EBP-α loss-of-function showed the opposite effects of decreased claudin-5 levels and increased endothelial permeability. Mechanistically, JAM-A promoted C/EBP-α expression through suppression of β-catenin transcriptional activity, and also through activation of EPAC (exchange protein directly activated by cAMP). C/EBP-α then directly binds the promoter of claudin-5 to thereby promote its transcription. Finally, JAM-A-C/EBP-α-mediated regulation of claudin-5 was lost in blood vessels from tissue biopsies from patients with glioblastoma and ovarian cancer.We describe here a novel role for the transcription factor C/EBP-α that is positively modulated by JAM-A, a component of tight junctions that acts through EPAC to up-regulate the expression of claudin-5, to thus decrease endothelial permeability. Overall, these data unravel a regulatory molecular pathway through which tight junctions limit vascular permeability. This will help in the identification of further therapeutic targets for diseases associated with endothelial barrier dysfunction. Graphic Abstract: An graphic abstract is available for this article.
Acute SARS-CoV-2 Infection Impairs Dendritic Cell and T Cell Responses
Authors: Runhong Zhou, Kelvin Kai-Wang To, Yik-Chun Wong, Li Liu, Biao Zhou, Xin Li, Haode Huang, Yufei Mo, Tsz-Yat Luk, Thomas Tsz-Kan Lau, Pauline Yeung, Wai-Ming Chan, Alan Ka-Lun Wu, Kwok-Cheung Lung, Owen Tak-Yin Tsang, Wai-Shing Leung, Ivan Fan-Ngai Hung, Kwok-Yung Yuen, Zhiwei Chen
Journal: Immunity (2020)
Simplification of Ribosomes in Bacteria with Tiny Genomes
Authors: Daria D Nikolaeva, Mikhail S Gelfand, Sofya K Garushyants
Journal: Molecular Biology and Evolution (2020)

The ribosome is an essential cellular machine performing protein biosynthesis. Its structure and composition are highly conserved in all species. However, some bacteria have been reported to have an incomplete set of ribosomal proteins. We have analyzed ribosomal protein composition in 214 small bacterial genomes (<1 Mb) and found that although the ribosome composition is fairly stable, some ribosomal proteins may be absent, especially in bacteria with dramatically reduced genomes. The protein composition of the large subunit is less conserved than that of the small subunit. We have identified the set of frequently lost ribosomal proteins and demonstrated that they tend to be positioned on the ribosome surface and have fewer contacts to other ribosome components. Moreover, some proteins are lost in an evolutionary correlated manner. The reduction of ribosomal RNA is also common, with deletions mostly occurring in free loops. Finally, the loss of the anti-Shine-Dalgarno sequence is associated with the loss of a higher number of ribosomal proteins.
Tumor Microenvironment-Derived NRG1 Promotes Antiandrogen Resistance in Prostate Cancer
Authors: Zeda Zhang, Wouter R. Karthaus, Young Sun Lee, Vianne R. Gao, Chao Wu, Joshua W. Russo, Menghan Liu, Jose Mauricio Mota, Wassim Abida, Eliot Linton, Eugine Lee, Spencer D. Barnes, Hsuan-An Chen, Ninghui Mao, John Wongvipat, Danielle Choi, Xiaoping Chen, Huiyong Zhao, Katia Manova-Todorova, Elisa de Stanchina, Mary-Ellen Taplin, Steven P. Balk, Dana E. Rathkopf, Anuradha Gopalan, Brett S. Carver, Ping Mu, Xuejun Jiang, Philip A. Watson, Charles L. Sawyers
Journal: Cancer Cell (2020)
Effects of 4- and 6-h Time-Restricted Feeding on Weight and Cardiometabolic Health: A Randomized Controlled Trial in Adults with Obesity
Authors: Sofia Cienfuegos, Kelsey Gabel, Faiza Kalam, Mark Ezpeleta, Eric Wiseman, Vasiliki Pavlou, Shuhao Lin, Manoela Lima Oliveira, Krista A. Varady
Journal: Cell Metabolism (2020)
Royal college aims to tackle racism in obstetrics and gynaecology with new taskforce
Authors: Abi Rimmer
Journal: BMJ (2020)

A race equality taskforce has been launched by the Royal College of Obstetricians and Gynaecologists to explore racial disparities in women’s healthcare and racism within the obstetric and gynaecology workforce.

Statistics show that black women are five times more likely to die in pregnancy, childbirth, or in the six month postpartum period compared with white women and the risk for Asian women is twice as …
Treatment of Fractures and Dislocations
Authors: Edwin F. Cave, Carter R. Rowe, Donald P. Todd
Journal: New England Journal of Medicine (1951)

The AnkleStandard x-ray technic has aided in demonstrating the extent of bone injury and ligamentous damage in ankle fractures. Anterior-posterior views of both ankles, inverted 20° to 25°, on the same film will demonstrate a true mortise view. "Stress films,"98 , 99 taken with the patient anesthetized, may be indicated to determine more accurately the extent of ligamentous injury.Accurate closed reduction of the fracture elements and maintenance of reduction should produce union of the fractures and repair of ligamentous injury. However, if reduction is not maintained open reduction is indicated. For the malleoli, a small stainless-steel screw, approximately half the . . .
Host immune genetic variations influence the risk of developing acute myeloid leukaemia: results from the NuCLEAR consortium
Authors: J. M. Sánchez-Maldonado, D. Campa, J. Springer, J. Badiola, Y. Niazi, A. Moñiz-Díez, F. Hernández-Mohedo, P. González-Sierra, R. Ter Horst, A. Macauda, S. Brezina, C. Cunha, M. Lackner, M. A. López-Nevot, L. Fianchi, L. Pagano, E. López-Fernández, L. Potenza, M. Luppi, L. Moratalla, J. J. Rodríguez-Sevilla, J. E. Fonseca, M. Tormo, C. Solano, E. Clavero, A. Romero, Y. Li, C. Lass-Flörl, H. Einsele, L. Vazquez, J. Loeffler, K. Hemminki, A. Carvalho, M. G. Netea, A. Gsur, C. Dumontet, F. Canzian, A. Försti, M. Jurado, J. Sainz
Journal: Blood Cancer Journal (2020)

The purpose of this study was to conduct a two-stage case control association study including 654 acute myeloid leukaemia (AML) patients and 3477 controls ascertained through the NuCLEAR consortium to evaluate the effect of 27 immune-related single nucleotide polymorphisms (SNPs) on AML risk. In a pooled analysis of cohort studies, we found that carriers of the IL13rs1295686A/A genotype had an increased risk of AML (PCorr = 0.0144) whereas carriers of the VEGFArs25648T allele had a decreased risk of developing the disease (PCorr = 0.00086). In addition, we found an association of the IL8rs2227307 SNP with a decreased risk of developing AML that remained marginally significant after multiple testing (PCorr = 0.072). Functional experiments suggested that the effect of the IL13rs1295686 SNP on AML risk might be explained by its role in regulating IL1Ra secretion that modulates AML blast proliferation. Likewise, the protective effect of the IL8rs2227307 SNP might be mediated by TLR2-mediated immune responses that affect AML blast viability, proliferation and chemorresistance. Despite the potential interest of these results, additional functional studies are still warranted to unravel the mechanisms by which these variants modulate the risk of AML. These findings suggested that IL13, VEGFA and IL8 SNPs play a role in modulating AML risk.
Altered proximal tubular cell glucose metabolism during acute kidney injury is associated with mortality
Authors: David Legouis, Sven-Erick Ricksten, Anna Faivre, Thomas Verissimo, Karim Gariani, Charles Verney, Pierre Galichon, Lena Berchtold, Eric Feraille, Marylise Fernandez, Sandrine Placier, Kari Koppitch, Alexandre Hertig, Pierre-Yves Martin, Maarten Naesens, Jérôme Pugin, Andrew P. McMahon, Pietro E. Cippà, Sophie de Seigneux
Journal: Nature Metabolism (2020)
99mTc-RBC SPECT/CT for Duodenal Bleeding Point Detection
Authors: Seo Young Kang, Byung Seok Moon, Hye Ok Kim, Hai-Jeon Yoon, Bom Sahn Kim
Journal: Clinical Nuclear Medicine (2020)

Abstract This is a case of a 63-year-old man who presented with acute melena and low hemoglobin. Upper and lower gastrointestinal evaluations failed to localize the bleeding focus. 99m Tc-RBC planar scintigraphy identified 2 sites of suspected bleeding in the lower abdomen area. Subsequent SPECT/CT was performed and identified the precise main focus of active bleeding, the second and third parts of the duodenum, and also described the blood accumulation in the jejunum. Esophagogastroduodenoscopy was immediately performed, and results confirmed spurting blood from the small vessel with multiple ulcers in the second part of the duodenum.
Association of Hearing Loss With Psychological Distress and Utilization of Mental Health Services Among Adults in the United States
Authors: Robin T. Bigelow, Nicholas S. Reed, Katharine K. Brewster, Alison Huang, George Rebok, Bret R. Rutherford, Frank R. Lin
Journal: JAMA Network Open (2020)

Psychological distress affects health and health care utilization. Hearing loss (HL) is highly prevalent and undertreated, and it may be a potentially modifiable risk factor for psychological distress.To investigate the association between HL, psychological distress, and mental health care utilization among adults in the United States.This cross-sectional study included 25 665 individuals aged 18 years and older who participated in the 2017 National Health Interview Survey, a home-based nationally representative cross-sectional survey of noninstitutionalized US adults conducted by trained interviewers.Self-reported hearing and hearing aid use.Kessler psychological distress scale (scores ≥5 indicating moderate distress), self-reported use of medication to treat depression or anxiety symptoms, and use of mental health services in the past year.A total of 25 665 adults (mean [SD] age 47.0 [18.1] years, 51.7% [95% CI, 51.0%-52.5%] women, weighted to be representative of the US adult population) were included in the analysis. Compared with 11 558 participants (49.3%; 95% CI, 48.2%-50.5%) with no HL, the 9390 (35.3%; 95% CI, 34.4%-36.2%) with mild HL and 4717 (15.4%; 95% CI, 14.8%-16.0%) with moderate or worse HL had increased odds of moderate psychological distress (mild HL: odds ratio [OR], 1.49; 95% CI, 1.35-1.62; moderate HL: OR, 2.12; 95% CI, 1.87-2.41) and were more likely to report antidepressant medication use (mild HL: OR, 1.39; 95% CI, 1.17-1.67; moderate HL: OR, 2.07; 95% CI, 1.70-2.57), and antianxiety medication use (mild HL: OR, 1.39; 95% CI, 1.16-1.67; moderate HL: OR, 1.94; 95% CI, 1.57-2.39). Moderate HL was associated with increased odds of use of mental health services (moderate HL: OR, 1.53; 95% CI, 1.30-1.79). Among individuals with moderate HL, those with hearing aids (1066 [22.6%]) were less likely to experience psychological distress than those without hearing aids (3651 [77.4%]; OR, 0.66; 95% CI, 0.53-0.83).In a large nationally representative sample of US adults, self-reported HL was associated with both greater psychological distress and increased rates of antidepressant and antianxiety medication use and utilization of mental health services. Further research is needed to investigate whether HL may be a modifiable risk factor for these outcomes.
Time-distanced gates in long short-term memory networks
Authors: Riqiang Gao, Yucheng Tang, Kaiwen Xu, Yuankai Huo, Shunxing Bao, Sanja L. Antic, Emily S. Epstein, Steve Deppen, Alexis B. Paulson, Kim L. Sandler, Pierre P. Massion, Bennett A. Landman
Journal: Medical Image Analysis (2020)
Heart Regeneration by Endogenous Stem Cells and Cardiomyocyte Proliferation
Authors: Lingjuan He, Ngoc B. Nguyen, Reza Ardehali, Bin Zhou
Journal: Circulation (2020)

Ischemic heart disease is the leading cause of death worldwide. Myocardial infarction results in an irreversible loss of cardiomyocytes with subsequent adverse remodeling and heart failure. Identifying new sources for cardiomyocytes and promoting their formation represents a goal of cardiac biology and regenerative medicine. Within the past decade, many types of putative cardiac stem cells (CSCs) have been reported to regenerate the injured myocardium by differentiating into new cardiomyocytes. Some of these CSCs have been translated from bench to bed with reported therapeutic effectiveness. However, recent basic research studies on stem cell tracing have begun to question their fundamental biology and mechanisms of action, raising serious concerns over the myogenic potential of CSCs. We review the history of different types of CSCs within the past decade and provide an update of recent cell tracing studies that have challenged the origin and existence of CSCs. In addition to the potential role of CSCs in heart regeneration, proliferation of preexisting cardiomyocytes has recently gained more attention. This review will also evaluate the methodologic and technical aspects of past and current studies on CSCs and cardiomyocyte proliferation, with emphasis on technical strengths, advantages, and potential limitations of research approaches. While our understanding of cardiomyocyte generation and regeneration continues to evolve, it is important to address the shortcomings and inaccuracies in this field. This is best achieved by embracing technological advancements and improved methods to label single cardiomyocytes/progenitors and accurately investigate their developmental potential and fate/lineage commitment.
Abstract 16202: Early Intervention in a Novel Early-Phase Pulmonary Hypertension Animal Model, Exercise-Induced Pulmonary Arterial Hypertension in Rat
Authors: Zhongkai Zhu, Wei Huang
Journal: Circulation (2018)

Introduction: The patients with pulmonary arterial hypertension (PAH) are commonly diagnosed at late stage with right heart failure, results in poor prognosis. Invasive cardiopulmonary exercise tes...
Identification of Effective Combinations of Targeted Drugs for DNMT3A and NPM1 Mutated Acute Myeloid Leukemia
Authors: Stephen E Kurtz, Christopher A. Eide, Andy Kaempf, Samantha L Savage, Anna M. Reister Schultz, Beth Wilmot, Shannon Mcweeney, Motomi Mori, Elie Traer, Brian J. Druker, Jeffrey W. Tyner
Journal: Blood (2017)
PRMT5 Inhibition Modulates E2F1 Methylation and Gene-Regulatory Networks Leading to Therapeutic Efficacy in JAK2V617F-Mutant MPN
Authors: Friederike Pastore, Neha Bhagwat, Alessandro Pastore, Aliaksandra Radzisheuskaya, Abdul Karzai, Aishwarya Krishnan, Bing Li, Robert L. Bowman, Wenbin Xiao, Aaron D. Viny, Anouar Zouak, Young C. Park, Keith B. Cordner, Stephanie Braunstein, Jesper L. Maag, Alexander Grego, Jaanvi Mehta, Min Wang, Hong Lin, Benjamin H. Durham, Richard P. Koche, Raajit K. Rampal, Kristian Helin, Peggy Scherle, Kris Vaddi, Ross L. Levine
Journal: Cancer Discovery (2020)

We investigated the role of PRMT5 in myeloproliferative neoplasm (MPN) pathogenesis and aimed to elucidate key PRMT5 targets contributing to MPN maintenance. PRMT5 is overexpressed in primary MPN cells, and PRMT5 inhibition potently reduced MPN cell proliferation ex vivo. PRMT5 inhibition was efficacious at reversing elevated hematocrit, leukocytosis, and splenomegaly in a model of JAK2V617F+ polycythemia vera and leukocyte and platelet counts, hepatosplenomegaly, and fibrosis in the MPLW515L model of myelofibrosis. Dual targeting of JAK and PRMT5 was superior to JAK or PRMT5 inhibitor monotherapy, further decreasing elevated counts and extramedullary hematopoiesis in vivo. PRMT5 inhibition reduced expression of E2F targets and altered the methylation status of E2F1 leading to attenuated DNA damage repair, cell-cycle arrest, and increased apoptosis. Our data link PRMT5 to E2F1 regulatory function and MPN cell survival and provide a strong mechanistic rationale for clinical trials of PRMT5 inhibitors in MPN. SIGNIFICANCE: Expression of PRMT5 and E2F targets is increased in JAK2V617F+ MPN. Pharmacologic inhibition of PRMT5 alters the methylation status of E2F1 and shows efficacy in JAK2V617F/MPLW515L MPN models and primary samples. PRMT5 represents a potential novel therapeutic target for MPN, which is now being clinically evaluated.This article is highlighted in the In This Issue feature, p. 1611.
Urgent endoscopic retrograde cholangiopancreatography with sphincterotomy versus conservative treatment in predicted severe acute gallstone pancreatitis (APEC): a multicentre randomised controlled trial
Authors: Nicolien J Schepers, Nora D L Hallensleben, Marc G Besselink, Marie-Paule G F Anten, Thomas L Bollen, David W da Costa, Foke van Delft, Sven M van Dijk, Hendrik M van Dullemen, Marcel G W Dijkgraaf, Casper H J van Eijck, G Willemien Erkelens, Nicole S Erler, Paul Fockens, Erwin J M van Geenen, Janneke van Grinsven, Robbert A Hollemans, Jeanin E van Hooft, Rene W M van der Hulst, Jeroen M Jansen, Frank J G M Kubben, Sjoerd D Kuiken, Robert J F Laheij, Rutger Quispel, Rogier J J de Ridder, Marno C M Rijk, Tessa E H Römkens, Carola H M Ruigrok, Erik J Schoon, Matthijs P Schwartz, Xavier J N M Smeets, B W Marcel Spanier, Adriaan C I T L Tan, Willem J Thijs, Robin Timmer, Niels G Venneman, Robert C Verdonk, Frank P Vleggaar, Wim van de Vrie, Ben J Witteman, Hjalmar C van Santvoort, Olaf J Bakker, Marco J Bruno
Journal: The Lancet (2020)
AB1268 ONLINE EDUCATION YIELDS SIGNIFICANT GAINS IN RHEUMATOLOGISTS’ KNOWLEDGE OF THE ROLE OF JAK INHIBITORS IN THE MANAGEMENT OF RA
Authors: E. Bell, M. Calle, R. Van Vollenhoven
Journal: Annals of the Rheumatic Diseases (2020)

Background: The treatment armamentarium for rheumatoid arthritis (RA) has expanded rapidly in recent years, making it challenging for rheumatologists to stay up to date with key advances. The most recently available treatment options for RA are the JAK inhibitors. Objectives: Our goal with this activity was to assess whether online CME can improve rheumatologists’ knowledge of the role of JAK inhibitors in the management of RA. Methods: Rheumatologists participated in an online CME activity entitled ‘Advancing patient care in rheumatoid arthritis: role of JAK inhibitors’. This was a 30-minute video roundtable discussion between 3 experts, with accompanying slides. This CME activity launched on April 30 2019 with data collection through September 13 2019. The educational effect was assessed using a repeated-pair design, pre-/post-assessment. A Chi-square test of independence determined if a statistically significant improvement (5% significance level, P &lt;.05) existed in the number of correct responses between the pretest and posttest scores. Cramer’s V estimated the effect size of the education. Results: •Significant improvement in average percentage of correct responses, rising from a relatively high baseline of 67% to 81% post-activity ( P = .0006) •Increase in percentage of rheumatologists (n=68) answering all 3 questions correctly (37% at baseline rising to 66% post assessment) •Significant improvement in knowledge of clinical trial safety data for JAK inhibitors (43% improvement, P = .0079) •Numerical improvement from relatively high baseline for understanding of unmet needs in RA patients (74% at baseline, 87% post-activity) and the advantages of JAK inhibitors versus TNF inhibitors for a specific patient case (75% at baseline, 84% post-activity) •Considerable educational impact (Cramer’s V = 0.167) with 35% of rheumatologists reporting greater confidence in describing the mechanism of action of current and emerging JAK inhibitors (noteable average confidence shift of 15%) Conclusion: A positive and significant effect on physician knowledge and confidence regarding JAK inhibitors for RA was achieved following this online CME activity. The extent of this educational impact is likely to lead to better patient outcomes since physicians are better equipped to consider JAK inhibitors for appropriate patients. The results also revealed that physicians would benefit from additional education to reinforce their knowledge of key clinical data for JAK inhibitors and on the use of JAK inhibitors in clinical practice. Disclosure of Interests: : Elaine Bell: None declared, Marinella Calle: None declared, Ronald van Vollenhoven Grant/research support from: AbbVie, Arthrogen, Bristol-Myers Squibb, GlaxoSmithKline, Lilly, Pfizer, and UCB, Consultant of: AbbVie, AstraZeneca, Biotest, Bristol-Myers Squibb, Celgene, GSK, Janssen, Lilly, Medac, Merck, Novartis, Pfizer, Roche, and UCB
Morning Report—
Authors: Brenda J. Butka
Journal: JAMA (2020)

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