tbuckley/cabot-search huggingface dataset:
Arterial Stiffness, Genetic Risk, and Type 2 Diabetes: A Prospective Cohort Study
Authors: Mengying Wang, Jie Huang, Tao Wu, Lu Qi
Journal: Diabetes Care (2022)

We aimed to investigate prospective associations of pulse wave arterial stiffness index (ASI) and pulse pressure (PP) with type 2 diabetes (T2D) and assess the modifying effect of genetics.We included 152,611 participants free of diabetes and cardiovascular disease in the UK Biobank. All participants had ASI and blood pressure measurements collected at baseline visit. In total, 37 single nucleotide polymorphisms were used to calculate the genetic risk score (GRS) of T2D.During a median follow-up of 9.5 years, 3,000 participants developed T2D. Per-SD increase in ASI was associated with a 3% higher T2D risk (95% CI 2-4%). The hazard ratio (HR) (95% CI) of T2D was 1.58 (1.39-1.80) in the highest quintile group compared with the lowest quintile group of ASI. However, the association between PP and T2D was nonlinear. Compared with the lowest quintile group, the risk of T2D in higher quintile groups of PP was 0.91 (0.79-1.04), 0.98 (0.86-1.11), 1.15 (1.01-1.30), and 1.24 (1.10-1.41), respectively. Furthermore, we observed an interaction between ASI and genetic susceptibility to T2D, because the elevated HR of T2D associated with high ASI was more evident among participants with higher GRS of T2D (P interaction = 0.008), whereas the interaction between PP and GRS was nonsignificant (P interaction = 0.55).ASI was associated with an elevated risk of T2D in a dose-response fashion, whereas PP and T2D showed a nonlinear J-shaped association. Additionally, the association between ASI and T2D was partially strengthened by higher genetic susceptibility to T2D.
Thyroid Carcinoma with NSD3::NUTM1 Fusion: a Case with Thyrocyte Differentiation and Colloid Production
Authors: Derek B. Allison, Justin Rueckert, Virgilius Cornea, Cortney Y. Lee, Julie Dueber, Therese Bocklage
Journal: Endocrine Pathology (2022)

Abstract In this report, we present a high-grade thyroid carcinoma with an NSD3::NUTM1 fusion detected on expanded next-generation sequencing testing. Nuclear protein of the testis (NUT) carcinomas comprise high-grade, aggressive tumors characterized by rearrangements of the NUTM1 gene with various partner genes, most commonly the bromodomain protein genes BRD4 and BRD3 . Approximately 10% of NUT carcinomas contain an NSD3::NUTM1 fusion. NUT carcinomas manifest as poorly differentiated or undifferentiated squamous carcinomas, and 33% show areas of mature squamous differentiation. Only exceptionally have NUT carcinomas shown histology discordant from poorly differentiated/undifferentiated squamous carcinoma, and a thyroid NUT carcinoma with histologic thyrocyte differentiation has not been described to date. Our patient’s tumor exhibited mixed cytologic features suggestive of squamoid cells or papillary thyroid carcinoma cells. Overt squamous differentiation was absent, and the tumor produced colloid in poorly formed follicles. Immunophenotypically, the carcinoma was consistent with thyrocyte differentiation with expression of monoclonal PAX8, TTF1, and thyroglobulin (the last predominantly in extracellular colloid). There was zero to &lt; 2% reactivity for proteins typically diffusely expressed in NUT carcinoma: p40, p63, and cytokeratins 5/6. NUT protein expression was equivocal, but fluorescence in situ hybridization confirmed a NUTM1 rearrangement. This exceptional case suggests that NUTM1 fusions may occur in an unknown number of aggressive thyroid carcinomas, possibly with distinctive histologic features but with thyrocyte differentiation. Recognition of this entity potentially has significant prognostic implications. Moreover, thyroid carcinomas with NUTM1 fusions may be amenable to treatment with NUT carcinoma-targeted therapy such as a bromodomain and extraterminal domain protein small molecular inhibitor (BETi).
Murine roseolovirus does not accelerate amyloid-β pathology and human roseoloviruses are not over-represented in Alzheimer disease brains
Authors: Tarin M. Bigley, Monica Xiong, Muhammad Ali, Yun Chen, Chao Wang, Javier Remolina Serrano, Abdallah Eteleeb, Oscar Harari, Liping Yang, Swapneel J. Patel, Carlos Cruchaga, Wayne M. Yokoyama, David M. Holtzman
Journal: Molecular Neurodegeneration (2022)

Abstract Background The role of viral infection in Alzheimer Disease (AD) pathogenesis is an area of great interest in recent years. Several studies have suggested an association between the human roseoloviruses, HHV-6 and HHV-7, and AD. Amyloid-β (Aβ) plaques are a hallmark neuropathological finding of AD and were recently proposed to have an antimicrobial function in response to infection. Identifying a causative and mechanistic role of human roseoloviruses in AD has been confounded by limitations in performing in vivo studies. Recent -omics based approaches have demonstrated conflicting associations between human roseoloviruses and AD. Murine roseolovirus (MRV) is a natural murine pathogen that is highly-related to the human roseoloviruses, providing an opportunity to perform well-controlled studies of the impact of roseolovirus on Aβ deposition. Methods We utilized the 5XFAD mouse model to test whether MRV induces Aβ deposition in vivo. We also evaluated viral load and neuropathogenesis of MRV infection. To evaluate Aβ interaction with MRV, we performed electron microscopy. RNA-sequencing of a cohort of AD brains compared to control was used to investigate the association between human roseolovirus and AD. Results We found that 5XFAD mice were susceptible to MRV infection and developed neuroinflammation. Moreover, we demonstrated that Aβ interacts with viral particles in vitro and, subsequent to this interaction, can disrupt infection. Despite this, neither peripheral nor brain infection with MRV increased or accelerated Aβ plaque formation. Moreover, −omics based approaches have demonstrated conflicting associations between human roseoloviruses and AD. Our RNA-sequencing analysis of a cohort of AD brains compared to controls did not show an association between roseolovirus infection and AD. Conclusion Although MRV does infect the brain and cause transient neuroinflammation, our data do not support a role for murine or human roseoloviruses in the development of Aβ plaque formation and AD.
IL-17RA-signaling in Lgr5+ intestinal stem cells induces expression of transcription factor ATOH1 to promote secretory cell lineage commitment
Authors: Xun Lin, Stephen J Gaudino, Kyung Ku Jang, Tej Bahadur, Ankita Singh, Anirban Banerjee, Michael Beaupre, Timothy Chu, Hoi Tong Wong, Chang-Kyung Kim, Cody Kempen, Jordan Axelrad, Huakang Huang, Saba Khalid, Vyom Shah, Onur Eskiocak, Olivia B Parks, Artan Berisha, Jeremy P McAleer, Misty Good, Miko Hoshino, Richard Blumberg, Agnieszka B Bialkowska, Sarah L Gaffen, Jay K Kolls, Vincent W Yang, Semir Beyaz, Ken Cadwell, Pawan Kumar
Journal: Immunity (2022)
System-wide transcriptome damage and tissue identity loss in COVID-19 patients
Authors: Jiwoon Park, Jonathan Foox, Tyler Hether, David C. Danko, Sarah Warren, Youngmi Kim, Jason Reeves, Daniel J. Butler, Christopher Mozsary, Joel Rosiene, Alon Shaiber, Evan E. Afshin, Matthew MacKay, André F. Rendeiro, Yaron Bram, Vasuretha Chandar, Heather Geiger, Arryn Craney, Priya Velu, Ari M. Melnick, Iman Hajirasouliha, Afshin Beheshti, Deanne Taylor, Amanda Saravia-Butler, Urminder Singh, Eve Syrkin Wurtele, Jonathan Schisler, Samantha Fennessey, André Corvelo, Michael C. Zody, Soren Germer, Steven Salvatore, Shawn Levy, Shixiu Wu, Nicholas P. Tatonetti, Sagi Shapira, Mirella Salvatore, Lars F. Westblade, Melissa Cushing, Hanna Rennert, Alison J. Kriegel, Olivier Elemento, Marcin Imielinski, Charles M. Rice, Alain C. Borczuk, Cem Meydan, Robert E. Schwartz, Christopher E. Mason
Journal: Cell Reports Medicine (2022)

The molecular mechanisms underlying the clinical manifestations of coronavirus disease 2019 (COVID-19), and what distinguishes them from common seasonal influenza virus and other lung injury states such as acute respiratory distress syndrome, remain poorly understood. To address these challenges, we combine transcriptional profiling of 646 clinical nasopharyngeal swabs and 39 patient autopsy tissues to define body-wide transcriptome changes in response to COVID-19. We then match these data with spatial protein and expression profiling across 357 tissue sections from 16 representative patient lung samples and identify tissue-compartment-specific damage wrought by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, evident as a function of varying viral loads during the clinical course of infection and tissue-type-specific expression states. Overall, our findings reveal a systemic disruption of canonical cellular and transcriptional pathways across all tissues, which can inform subsequent studies to combat the mortality of COVID-19 and to better understand the molecular dynamics of lethal SARS-CoV-2 and other respiratory infections.
Human bone marrow mesenchymal stem cell-derived extracellular vesicles inhibit shoulder stiffness via let-7a/Tgfbr1 axis
Authors: Zhiwen Luo, Yaying Sun, Beijie Qi, Jinrong Lin, Yisheng Chen, Yuzhen Xu, Jiwu Chen
Journal: Bioactive Materials (2022)

Shoulder stiffness (SS) is a common shoulder disease characterized by increasing pain and limited range of motion. SS is considered to be an inflammatory and fibrotic disorder pathologically. However, there is no consensus on the most effective conservative treatment for fibrosis. Given that human Bone Marrow Mesenchymal Stem Cell-derived extracellular vesicles (BMSC-EVs) displayed promising therapeutic effects for various tissues, we investigated the therapeutic effect of BMSC-EVs on fibrosis in a mice immobilization model and two cell models. By conducting a series of experiments, we found that BMSC-EVs can significantly inhibit the fibrogenic process both in vitro and in vivo. In detail, BMSC-EVs suppressed the aberrant proliferation, high collagen production capacity, and activation of fibrotic pathways in TGF-β-stimulated fibroblasts in vitro. Besides, in vivo, BMSC-EVs reduced cell infiltration, reduced fibrotic tissue in the shoulder capsule, and improved shoulder mobility. In addition, via exosomal small RNA sequencing and qPCR analysis, let-7a-5p was verified to be the highest expressed miRNA with predicted antifibrotic capability in BMSC-EVs. The antifibrotic capacity of BMSC-EVs was significantly impaired after the knockdown of let-7a-5p. Moreover, we discovered that the mRNA of TGFBR1 (the membrane receptor of transforming growth factor β) was the target of let-7a-5p. Together, these findings elucidated the antifibrotic role of BMSC-EVs in shoulder capsular fibrosis. This study clarifies a new approach using stem cell-derived EVs therapy as an alternative to cell therapy, which may clinically benefit patients with SS in the future.
Cytochrome P450s in algae: Bioactive natural product biosynthesis and light-driven bioproduction
Authors: Shanmin Zheng, Jiawei Guo, Fangyuan Cheng, Zhengquan Gao, Lei Du, Chunxiao Meng, Shengying Li, Xingwang Zhang
Journal: Acta Pharmaceutica Sinica B (2022)

Algae are a large group of photosynthetic organisms responsible for approximately half of the earth's total photosynthesis. In addition to their fundamental ecological roles as oxygen producers and as the food base for almost all aquatic life, algae are also a rich source of bioactive natural products, including several clinical drugs. Cytochrome P450 enzymes (P450s) are a superfamily of biocatalysts that are extensively involved in natural product biosynthesis by mediating various types of reactions. In the post-genome era, a growing number of P450 genes have been discovered from algae, indicating their important roles in algal life-cycle. However, the functional studies of algal P450s remain limited. Benefitting from the recent technical advances in algae cultivation and genetic manipulation, the researches on P450s in algal natural product biosynthesis have been approaching to a new stage. Moreover, some photoautotrophic algae have been developed into "photo-bioreactors" for heterologous P450s to produce high-value added pharmaceuticals and chemicals in a carbon-neutral or carbon-negative manner. Here, we comprehensively review these advances of P450 studies in algae from 2000 to 2021.
Combination of Frailty Status and Comorbidity Score Improves the Prediction of Survival in Patients with Myelodysplastic Syndrome Due to Good Predictive Capability for Infection-Related Mortality
Authors: Kazuki Sakatoku, Yasunobu Takeoka, Taku Araki, Ryosuke Yamamura, Takahiko Nakane, Hirohisa Nakamae, Masayuki Hino, Kensuke Ohta
Journal: Blood (2016)
Association of Ischemic Stroke Incidence, Severity, and Recurrence With Dementia in the Atherosclerosis Risk in Communities Cohort Study
Authors: Silvia Koton, James Russell Pike, Michelle Johansen, David S. Knopman, Kamakshi Lakshminarayan, Thomas Mosley, Shalom Patole, Wayne D. Rosamond, Andrea L. C. Schneider, A. Richey Sharrett, Lisa Wruck, Josef Coresh, Rebecca F. Gottesman
Journal: JAMA Neurology (2022)

Ischemic stroke is associated with increased risk of dementia, but the association of stroke severity and recurrence with risk of impaired cognition is not well known.
Multiple Sclerosis
Authors: Michael J. Olek
Journal: Annals of Internal Medicine (2021)

Many groundbreaking advances have occurred in the field of multiple sclerosis since this series last reviewed the disorder in 2014. The U.S. Food and Drug Administration has approved 7 new medications for relapsing-remitting multiple sclerosis and approved the first medication for primary progressive multiple sclerosis. The McDonald criteria for diagnosing multiple sclerosis were updated in 2017. New blood tests can now differentiate patients with multiple sclerosis from those with neuromyelitis optica spectrum disorder, and 3 new medications have been approved specifically for the latter disorder. Also, new medications for treating the symptoms of multiple sclerosis have been introduced.
An appraisal of the frequency and severity of noninfectious manifestations in primary immunodeficiencies: A study of a national retrospective cohort of 1375 patients over 10 years
Authors: Mickaël Alligon, Nizar Mahlaoui, Virginie Courteille, Laurence Costes, Veronica Afonso, Philippe Randrianomenjanahary, Nathalie de Vergnes, Anja Ranohavimparany, Duy Vo, Inès Hafsa, Perrine Bach, Vincent Benoit, Nicolas Garcelon, Alain Fischer, Wadih Abou-Chahla, Daniel Adoue, Nathalie Aladjidi, Corinne Armari-Alla, Vincent Barlogis, Sophie Bayart, Yves Bertrand, Stéphane Blanche, Damien Bodet, Bernard Bonnotte, Raphaël Borie, Patrick Boutard, David Boutboul, Claire Briandet, Jean-Paul Brion, Jacques Brouard, Liana Carausu, Martin Castelle, Pascal Cathebras, Emilie Catherinot, Nathalie Cheikh, Morgane Cheminant, Sarah Cohen-Beaussant, Thibault Comont, Louis-Jean Couderc, Pierre Cougoul, Gérard Couillault, Lionel Crevon, Elisa Demonchy, Anne Deville, Catherine Devoldere, Eric Dore, Fabienne Dulieu, Isabelle Durieu, Natacha Entz-Werle, Claire Fieschi, Fanny Fouyssac, Pierre Frange, Vincent Gajdos, Lionel Galicier, Virginie Gandemer, Martine Gardembas, Catherine Gaud, Bernard Grosbois, Aurélien Guffroy, Corinne Guitton, Gaëlle Guillerm, Eric Hachulla, Mohamed Hamidou, Sophie Haro, Yves Hatchuel, Olivier Hermine, Cyrille Hoarau, Arnaud Hot, Sébastien Humbert, Arnaud Jaccard, Jean-Philippe Jais, Sarah Jannier, Serge Jacquot, Roland Jaussaud, Pierre-Yves Jeandel, Eric Jeziorski, Kamila Kebaili, Anne-Sophie Korganow, Olivier Lambotte, Fanny Lanternier, Claire Larroche, David Launay, Emmanuelle Le Moigne, Alain Le Quellec, Emmanuelle Le Moigne, Vincent Le Moing, Yvon Lebranchu, Marc Lecuit, Guillaume Lefèvre, Jean-Daniel Lelièvre, Richard Lemal, Valérie Li-Thiao-Te, Olivier Lortholary, Luminita Luca, Coralie Mallebranche, Marion Malphettes, Aude Marie-Cardine, Nicolas Martin-Silva, Agathe Masseau, Françoise Mazingue, Etienne Merlin, Gérard Michel, Frédéric Millot, Charline Miot, Béatrice Monlibert, Fabrice Monpoux, Despina Moshous, Luc Mouthon, Martine Münzer, Robert Navarro, Bénédicte Neven, Dalila Nouar, Raphaële Nove-Josserand, Eric Oksenhendler, Marie Ouachée-Chardin, Anne Pagnier, Marlène Pasquet, Isabelle Pellier, Yves Perel, Antoinette Perlat, Christophe Piguet, Dominique Plantaz, Sophie Rivière, Pascal Roblot, Pierre-Simon Rohrlich, Bruno Royer, Valéry Salle, Françoise Sarrot-Reynauld, Amélie Servettaz, Jean-Louis Stephan, Nicolas Schleinitz, Harry Sokol, Felipe Suarez, Laure Swiader, Sophie Taque, Caroline Thomas, Olivier Tournilhac, Caroline Thumerelle, Jean-Pierre Vannier, Jean-François Viallard
Journal: Journal of Allergy and Clinical Immunology (2022)
Correspondence on ‘Call for action in ANCA-associated vasculitis and lupus nephritis: promises and challenges of SGLT-2 inhibitors’
Authors: Dimitrios Patoulias
Journal: Annals of the Rheumatic Diseases (2022)

Correspondence on 'Call for action in ANCAassociated vasculitis and lupus nephritis: promises and challenges of SGLT-2 inhibitors' by Säemann and Kronbichler Säemann and Kronbichler provided in their published article an excellent perspective on the potential place of sodiumglucose cotransporter-2 (SGLT-2) inhibitors in the treatment armamentarium against antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitis and lupus nephritis (LN). 1 Besides the described mechanisms of action, it seems that their effect against tubular damage and atrophy could also be crucial for the mediated nephroprotection in LN.It has been previously shown that interstitial fibrosis and tubular atrophy are strongly associated with the risk for progression to end-stage renal disease in subjects with LN, also increasing the overall mortality burden. 2 In a previously published trial by Dekkers et al, it was shown that 6-week treatment with dapagliflozin led to a significant decrease in urinary kidney injury molecule-1 (KIM-1) excretion, a marker of tubular injury, which strongly correlated with the change in albuminuria. 3Recently, in a post-hoc analysis of the VERTIS RENAL trial, it was shown that ertugliflozin was associated with a sustained lowering of the plasma levels of KIM-1 regardless of baseline kidney function. 4Such an effect has also been shown in other trials of smaller sample size. 5Thus, it seems that there are more benefits than expected with the use of SGLT-2 inhibitors in patients with LN.Based on the significant cardiovascular and renal burden of those patients, SGLT-2 inhibitors appear to be a promising treatment option, even in the absence of concomitant diabetes mellitus.
Ancestral SARS-CoV-2-specific T cells cross-recognize the Omicron variant
Authors: Yu Gao, Curtis Cai, Alba Grifoni, Thomas R. Müller, Julia Niessl, Anna Olofsson, Marion Humbert, Lotta Hansson, Anders Österborg, Peter Bergman, Puran Chen, Annika Olsson, Johan K. Sandberg, Daniela Weiskopf, David A. Price, Hans-Gustaf Ljunggren, Annika C. Karlsson, Alessandro Sette, Soo Aleman, Marcus Buggert
Journal: Nature Medicine (2022)

Abstract The emergence of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron (B.1.1.529) variant of concern (VOC) has destabilized global efforts to control the impact of coronavirus disease 2019 (COVID-19). Recent data have suggested that B.1.1.529 can readily infect people with naturally acquired or vaccine-induced immunity, facilitated in some cases by viral escape from antibodies that neutralize ancestral SARS-CoV-2. However, severe disease appears to be relatively uncommon in such individuals, highlighting a potential role for other components of the adaptive immune system. We report here that SARS-CoV-2 spike-specific CD4 + and CD8 + T cells induced by prior infection or BNT162b2 vaccination provide extensive immune coverage against B.1.1.529. The median relative frequencies of SARS-CoV-2 spike-specific CD4 + T cells that cross-recognized B.1.1.529 in previously infected or BNT162b2-vaccinated individuals were 84% and 91%, respectively, and the corresponding median relative frequencies for SARS-CoV-2 spike-specific CD8 + T cells were 70% and 92%, respectively. Pairwise comparisons across groups further revealed that SARS-CoV-2 spike-reactive CD4 + and CD8 + T cells were functionally and phenotypically similar in response to the ancestral strain or B.1.1.529. Collectively, our data indicate that established SARS-CoV-2 spike-specific CD4 + and CD8 + T cell responses, especially after BNT162b2 vaccination, remain largely intact against B.1.1.529.
Differential Effects of Cannabis and Tobacco on Lung Function in Mid–Adult Life
Authors: Robert J. Hancox, Andrew R. Gray, Xian Zhang, Richie Poulton, Terrie E. Moffitt, Avshalom Caspi, Malcolm R. Sears
Journal: American Journal of Respiratory and Critical Care Medicine (2022)

Rationale: Evidence suggests that the effects of smoking cannabis on lung function are different from tobacco. However, long-term follow-up data are scarce and mostly based on young adults. Objectives: To assess the effects of cannabis and tobacco on lung function in mid-adult life. Methods: Cannabis and tobacco use were reported at ages 18, 21, 26, 32, 38, and 45 years in a population-based cohort study of 1,037 participants. Spirometry, plethysmography, and carbon monoxide transfer factor were measured at age 45. Associations between lung function and cannabis use were adjusted for tobacco use. Measurements and Main Results: Data were available from 881 (88%) of 997 surviving participants. Cumulative cannabis use was associated with lower FEV1/FVC ratios, owing to a tendency toward higher FVCs. Cannabis use was also associated with higher TLC, FRC, residual volume, and Va along with lower midexpiratory flows, airway conductance, and transfer factor. Quitting regular cannabis use between assessments was not associated with changes in spirometry. Conclusions: Cannabis use is associated with higher lung volumes, suggesting hyperinflation. There is evidence of increased large-airway resistance and lower midexpiratory airflow, but impairment of FEV1/FVC ratio is because of higher FVC. This pattern of effects is different to those of tobacco. We provide the first evidence that lifetime cannabis use may be associated with impairment of gas transfer.