tbuckley/cabot-search huggingface dataset:
Covid-19: now is not the time to judge the UK’s response
Authors: Mary Slingo
Journal: BMJ (2020)

<h3>SUMMARY</h3> Autosomal recessive mutations in PINK1 and Parkin cause Parkinson’s disease. How activation of PINK1 and Parkin leads to elimination of damaged mitochondria by mitophagy is largely based on cell culture studies with few molecular studies in neurons. Herein we have undertaken a global proteomic-analysis of mitochondria from mouse neurons to identify ubiquitylated substrates of endogenous Parkin activation. Comparative analysis with human iNeuron datasets revealed a subset of 49 PINK1-dependent diGLY sites upregulated upon mitochondrial depolarisation in 22 proteins conserved across mouse and human systems. These proteins were exclusively localised at the mitochondrial outer membrane (MOM) including, CISD1, CPT1α, ACSL1, and FAM213A. We demonstrate that these proteins can be directly ubiquitylated by Parkin <i>in vitro</i>. We also provide evidence for a subset of cytoplasmic proteins recruited to mitochondria that undergo PINK1 and Parkin independent ubiquitylation including SNX3, CAMK2α and CAMK2β indicating the presence of alternate ubiquitin E3 ligase pathways that are activated by mitochondrial depolarisation in neurons. Finally we have developed an online resource to visualise mitochondrial ubiquitin sites in neurons and search for ubiquitin components recruited to mitochondria upon mitochondrial depolarisation, MitoNUb. This analysis will aid in future studies to understand Parkin activation in neuronal subtypes. Our findings also suggest that monitoring ubiquitylation status of the 22 identified MOM proteins may represent robust biomarkers for PINK1 and Parkin activity <i>in vivo</i>.
Publisher Correction: Long-distance modulation of bystander tumor cells by CD8+ T-cell-secreted IFN-γ
Authors: Mirjam E. Hoekstra, Laura Bornes, Feline E. Dijkgraaf, Daisy Philips, Iris N. Pardieck, Mireille Toebes, Daniela S. Thommen, Jacco van Rheenen, Ton N. M. Schumacher
Journal: Nature Cancer (2020)
Association Between Common Variants in <i>RBFOX1</i>, an RNA-Binding Protein, and Brain Amyloidosis in Early and Preclinical Alzheimer Disease
Authors: Neha S. Raghavan, Logan Dumitrescu, Elizabeth Mormino, Emily R. Mahoney, Annie J. Lee, Yizhe Gao, Murat Bilgel, David Goldstein, Theresa Harrison, Corinne D. Engelman, Andrew J. Saykin, Christopher D. Whelan, Jimmy Z. Liu, William Jagust, Marilyn Albert, Sterling C. Johnson, Hyun-Sik Yang, Keith Johnson, Paul Aisen, Susan M. Resnick, Reisa Sperling, Philip L. De Jager, Julie Schneider, David A. Bennett, Matthew Schrag, Badri Vardarajan, Timothy J. Hohman, Richard Mayeux
Journal: JAMA Neurology (2020)

Genetic studies of Alzheimer disease have focused on the clinical or pathologic diagnosis as the primary outcome, but little is known about the genetic basis of the preclinical phase of the disease.
Abstracting abstraction in development and cognitive ability
Authors: Andreas Demetriou
Journal: Behavioral and Brain Sciences (2020)

Abstract We focus on the theory of abstraction proposed by the target article. We suggest that abstraction varies at different levels of learning, cognitive development, or cognitive ability. We argue that this theory does not specify how abstraction is done at each of these levels. Because of these weaknesses, the theory cannot explicate how individuals differ in mental time travel at different phases of life or different levels of cognitive ability.
Laryngeal elevation for endoscopic submucosal dissection in cervical superficial esophageal cancer at esophageal entrance
Authors: Takahiro Inoue, Satoki Shichijo, Hironori Cho, Ayaka Shoji, Kotaro Waki, Takashi Fujii, Ryu Ishihara
Journal: Endoscopy (2020)

Endoscopic submucosal dissection (ESD) for cervical superficial esophageal cancer (CSEC) is an effective and safe procedure [1] [2]. However, in CSEC extending to the esophageal entrance, ESD is technically challenging because of upper sphincter muscle tightening, a narrow working space, and the pharyngeal reflex. General anesthesia relaxes the sphincter muscle and aids endoscope maneuverability. Laryngeal elevation using a laryngoscope facilitates a wider working space and is generally used in ESD for pharyngeal superficial cancer [3], but has not previously been reported in ESD for CSEC.
3D printing preview for stereo-lithography based on photopolymerization kinetic models
Authors: Yi Gao, Lei Xu, Yang Zhao, Zhengwei You, Qingbao Guan
Journal: Bioactive Materials (2020)

The diversity of biomedical applications makes stereolithographic (SL) three-dimensional (3D) printing process complex. A strategy was developed to simulate the layer-by-layer fabrication of 3D printed products combining polymerization kinetic with reaction conditions to realize print preview. As a representative example, the typical UV-curable dental materials based on epoxy acrylate and photoinitiator with different molar ratios was exposed under varying intensity of UV light to verify the simulation results. A theoretical kinetics model containing oxygen inhibition was established. In-situ FTIR was employed to measure propagation and termination constants while coupled UV/vis was performed to examine the law of light attenuation during cure reaction, even with various colours and additives. Simulation results showed that the correlation coefficient square between the experiments and simulations of epoxy acrylate with 1%, 2% and 3% initiator upon 20 mW/cm2 UV light are 0.8959, 0.9324 and 0.9337, respectively. Consequently, our simulation of photopolymerization for SL 3D printing successfully realized visualization of printing quality before practically printing the targeted biomedical objects with complex topology structures.
Do Smoking and Socioeconomic Factors Influence Imaging Outcomes in Axial Spondyloarthritis? Five‐Year Data From the DESIR Cohort
Authors: Elena Nikiphorou, Sofia Ramiro, Alexandre Sepriano, Adeline Ruyssen‐Witrand, Robert B. M. Landewé, Désirée van der Heijde
Journal: Arthritis & Rheumatology (2020)

Objective To investigate the relationship between smoking and imaging outcomes over 5 years in axial spondyloarthritis (SpA) and to assess whether socioeconomic factors influence these relationships. Methods Axial SpA patients from the Devenir des Spondylarthropathies Indifferérenciées Récentes cohort were included. The following 4 imaging outcomes were assessed by 3 central readers at baseline, 2 years, and 5 years: spine radiographs (using the modified Stoke Ankylosing Spondylitis Spine Score [mSASSS]), sacroiliac (SI) joint radiographs (using the modified New York criteria), magnetic resonance imaging (MRI) of the spine (using the Spondyloarthritis Research Consortium of Canada [SPARCC] score), and MRI of the SI joint (using the SPARCC score). The explanatory variable of interest was smoking status at baseline. Interactions between smoking and socioeconomic factors (i.e., job type [blue‐collar or manual work versus white‐collar or nonmanual work] and education [low versus high]) were first tested, and if significant, analyses were run using separate strata. Generalized estimating equations models were used, with adjustments for confounders. Results In total, 406 axial SpA patients were included (52% male, 40% smokers, and 18% blue collar). Smoking was independently associated with more MRI‐detected SI joint inflammation at each visit over the 5 years, an effect that was seen only in patients with blue‐collar professions (β = 5.41 [95% confidence interval (95% CI) 1.35, 9.48]) and in patients with low education levels (β = 2.65 [95% CI 0.42,4.88]), using separate models. Smoking was also significantly associated with spinal inflammation (β = 1.69 [95% CI 0.45, 2.93]) and SI joint damage (β = 0.57 [95% CI 0.18, 0.96]) across all patients, irrespective of socioeconomic factors and other potential confounders. Conclusion Strong associations were found between smoking at baseline and MRI‐detected SI joint inflammation at each visit over a time period of 5 years in axial SpA patients with a blue‐collar job or low education level. These findings suggest a possible role for mechanical stress amplifying the effect of smoking on axial inflammation in axial SpA.
PD-L1 expression by dendritic cells is a key regulator of T-cell immunity in cancer
Authors: Soyoung A. Oh, Dai-Chen Wu, Jeanne Cheung, Armando Navarro, Huizhong Xiong, Rafael Cubas, Klara Totpal, Henry Chiu, Yan Wu, Laetitia Comps-Agrar, Andrew M. Leader, Miriam Merad, Merone Roose-Germa, Soren Warming, Minhong Yan, Jeong M. Kim, Sascha Rutz, Ira Mellman
Journal: Nature Cancer (2020)
SAT0582 RISK OF INTERSTITIAL LUNG DISEASE IN SYSTEMIC AUTOIMMUNE RHEUMATIC DISEASES: A NATIONWIDE, POPULATION-BASED COHORT STUDY
Authors: H. H. Chen, K. H. Ng, W. C. Chao, C. H. Lin
Journal: Annals of the Rheumatic Diseases (2020)

Background: To date, very few studies had investigated the epidemiology of interstitial lung disease (ILD) among patients with systemic autoimmune rheumatic disease (SARD). Objectives: To study the risk of interstitial lung disease (ILD) among patients with various systemic autoimmune rheumatic diseases (SARDs) including rheumatoid arthritis (RA), dermatomyositis (DMtis), polymyositis (PM), systemic sclerosis (SSc), systemic lupus erythematosus (SLE), and primary Sjögren’s syndrome (pSS). Methods: Using 1997–2013 claims data from the Taiwanese National Health Insurance Research Database, we identified 63,277 newly diagnosed patients with various SARDs after excluding those with overlapping SARD diagnoses from 2001-2013 and randomly selected 253,108 non-SARD subjects matching (1:4) SARD patients for SARD diagnosis, age, sex and the year of the index date. We calculated the incidence rates (IRs) of ILD (ICD-9 code 515) in various SARD groups and the corresponding non-SARD comparison groups and estimated the IR ratios (IRRs) with 95% confidence intervals (CI) of ILD development. Using multivariable cox regression analyses, we estimated hazard ratios (HRs) with 95% CIs of ILD in various SARD groups compared with their comparison groups after adjusting for age, sex, Charlson comorbidity index, amiodarone use and methotrexate use. Sensitivity analyses were conducted by using a narrow definition of ILD. Results: As shown in Table 1, the IRs of ILD were greatest in SSc patients (2,523 per 10 5 years), followed by patients with DMtis (2,463 per 10 5 years), PM (1,956 per 10 5 years), SS (601 per 10 5 years), RA (279 per 10 5 years), and SLE (276 per 10 5 years). Multivariable analyses showed that the risks of ILD were significantly increased in patients with SSc (HR, 66.01; 95% CI, 32.73—133.13), DMtis (128.74, 95% CI, 40.19—412.47), PM (HR, 30.39; 95% CI, 11.24—82.15), pSS (HR, 8.76; 95% CI, 7.03—10.90), RA (HR, 4.22; 95% CI, 3.51—5.08), and SLE (HR, 13.98; 95% CI, 9.25—21.14). Conclusion: This nationwide, population-based, matched cohort study demonstrated that the risks of ILD were significantly increased in patients with SARDs. References: [1]Su R, Bennett M, Jacobs S, Hunter T, Bailey C, Krishnan E, et al. An analysis of connective tissue disease-associated interstitial lung disease at a US Tertiary Care Center: better survival in patients with systemic sclerosis. The Journal of rheumatology. 2011;38(4):693-701. [2]Hu Y, Wang LS, Wei YR, Du SS, Du YK, He X, et al. Clinical Characteristics of Connective Tissue Disease-Associated Interstitial Lung Disease in 1,044 Chinese Patients. Chest. 2016;149(1):201-8.Araki T, Putman RK, Hatabu H, Gao W, Dupuis J, Latourelle JC, et al. Development and Progression of Interstitial Lung Abnormalities in the Framingham Heart Study. Am J Respir Crit Care Med 2016;194:1514-1522. Disclosure of Interests: None declared
DNA damage repair pathway alterations in metastatic clear cell renal cell carcinoma and implications on systemic therapy
Authors: Yasser Ged, Joshua L Chaim, Renzo G DiNatale, Andrea Knezevic, Ritesh R Kotecha, Maria I Carlo, Chung-Han Lee, Ashley Foster, Darren R Feldman, Min Yuen Teo, Gopakumar Iyer, Timothy Chan, Sujata Patil, Robert J Motzer, A Ari Hakimi, Martin H Voss
Journal: Journal for ImmunoTherapy of Cancer (2020)

Background Loss-of-function alterations in DNA damage repair (DDR) genes are associated with human tumorigenesis and may determine benefit from immune-oncology (I/O) agents as shown in colon cancer. However, biologic significance and relevance to I/O in metastatic clear cell RCC (ccRCC) are unknown. Methods Genomic data and treatment outcomes were retrospectively collected for patients with metastatic ccRCC. Tumor and germline DNA were subject to targeted next generation sequencing across &gt;400 genes of interest, including 34 DDR genes. Patients were dichotomized according to underlying DDR gene alteration into (1) deleterious DDR gene alterations present (Del DDR); (2) wild-type (WT) and variants of unknown significance (VUS) DDR gene alterations present (WT/VUS DDR). Association between DDR status and therapeutic benefit was investigated separately for I/O and vascular endothelial growth factor (VEGF) tyrosine kinase inhibitor (TKI) therapy. Results Del DDR were detected in 43/229 patients (19%). The most frequently altered genes were CHEK2 and ATM . Clonality analysis was performed in 27 somatic DDR mutations and 17 were clonal (63%). For patients with I/O treatment, Del DDR status was associated with superior overall survival (log-rank p=0.049); after adjusting for International Metastatic Renal Cell Carcinoma Database Consortium risks and extent of prior therapy, the HR for Del DDR was 0.41 (95% CI: 0.14–1.14; p=0.09). No association was seen with VEGF-TKI treatment (log-rank p=0.903). Conclusion Del DDR alterations are recurrent genomic events in patients with advanced RCC and were mostly clonal in this cohort. Loss-of-function events in these genes may affect outcome with I/O therapy in metastatic RCC, and these hypothesis-generating results deserve further study.
Reactive Oxygen-Forming Nox5 Links Vascular Smooth Muscle Cell Phenotypic Switching and Extracellular Vesicle-Mediated Vascular Calcification
Authors: Malgorzata Furmanik, Martijn Chatrou, Rick van Gorp, Asim Akbulut, Brecht Willems, Harald Schmidt, Guillaume van Eys, Marie-Luce Bochaton-Piallat, Diane Proudfoot, Erik Biessen, Ulf Hedin, Ljubica Perisic, Barend Mees, Catherine Shanahan, Chris Reutelingsperger, Leon Schurgers
Journal: Circulation Research (2020)

Rationale: Vascular calcification, the formation of calcium phosphate crystals in the vessel wall, is mediated by vascular smooth muscle cells (VSMCs). However, the underlying molecular mechanisms remain elusive, precluding mechanism-based therapies. Objective: Phenotypic switching denotes a loss of contractile proteins and an increase in migration and proliferation, whereby VSMCs are termed synthetic. We examined how VSMC phenotypic switching influences vascular calcification and the possible role of the uniquely calcium-dependent reactive oxygen species (ROS)-forming Nox5 (NADPH oxidase 5). Methods and Results: In vitro cultures of synthetic VSMCs showed decreased expression of contractile markers CNN-1 (calponin 1), α-SMA (α-smooth muscle actin), and SM22-α (smooth muscle protein 22α) and an increase in synthetic marker S100A4 (S100 calcium binding protein A4) compared with contractile VSMCs. This was associated with increased calcification of synthetic cells in response to high extracellular Ca 2+ . Phenotypic switching was accompanied by increased levels of ROS and Ca 2+ -dependent Nox5 in synthetic VSMCs. Nox5 itself regulated VSMC phenotype as siRNA knockdown of Nox5 increased contractile marker expression and decreased calcification, while overexpression of Nox5 decreased contractile marker expression. ROS production in synthetic VSMCs was cytosolic Ca 2+ -dependent, in line with it being mediated by Nox5. Treatment of VSMCs with Ca 2+ loaded extracellular vesicles (EVs) lead to an increase in cytosolic Ca 2+ . Inhibiting EV endocytosis with dynasore blocked the increase in cytosolic Ca 2+ and VSMC calcification. Increased ROS production resulted in increased EV release and decreased phagocytosis by VSMCs. Conclusions: We show here that contractile VSMCs are resistant to calcification and identify Nox5 as a key regulator of VSMC phenotypic switching. Additionally, we describe a new mechanism of Ca 2+ uptake via EVs and show that Ca 2+ induces ROS production in VSMCs via Nox5. ROS production is required for release of EVs, which promote calcification. Identifying molecular pathways that control Nox5 and VSMC-derived EVs provides potential targets to modulate vascular remodeling and calcification in the context of mineral imbalance. Graphic Abstract: A graphic abstract is available for this article.
Gene therapies for transfusion dependent β‐thalassemia: Current status and critical criteria for success
Authors: Sandeep Soni
Journal: American Journal of Hematology (2020)

Thalassemia is one of the most prevalent monogenic diseases usually caused by quantitative defects in the production of β-globin leading to severe anemia. Technological advances in genome sequencing, stem cell selection, viral vector development, transduction and gene editing strategies now allow for efficient exvivo genetic manipulation of human stem cells that can lead to production of hemoglobin, leading to a meaningful clinical benefit in thalassemia patients. In this review, the status of the gene-therapy approaches available for transfusion dependent thalassemia are discussed, along with the critical criteria that affect efficacy and lessons that have been learned from the early phase clinical trials. Salient steps necessary for the clinical development, manufacturing, and regulatory approvals of gene therapies for thalassemia are also highlighted, so that the potential of these therapies can be realized. It is highly anticipated that gene therapies will soon become a treatment option for patients lacking compatible donors for hematopoietic stem cell transplant and will offer an alternative for definitive treatment of β-thalassemia.
Myelodysplastic Syndromes: Iron Overload Consequences and Current Chelating Therapies
Authors: Peter L. Greenberg
Journal: Journal of the National Comprehensive Cancer Network (2006)

Chronic red blood cell transfusion support in patients with myelodysplastic syndromes (MDS) is often necessary but may cause hemosiderosis and its consequences. The pathophysiologic effects of iron overload relate to increased non-transferrin bound iron generating toxic oxygen free radicals. Studies in patients with MDS and thalassemia major have shown adverse clinical effects of chronic iron overload on cardiac function in patients who underwent polytransfusion. Iron chelation therapy in patients with thalassemia who were effectively chelated has prevented or partially reversed some of these consequences. A small group of patients with MDS who had undergone effective subcutaneous desferrioxamine (DFO) chelation for 1 to 4 years showed substantial hematologic improvements, including transfusion independence. However, because chronic lengthy subcutaneous infusions of DFO in elderly patients have logistic difficulties, this chelation therapy is generally instituted late in the clinical course. Two oral iron chelators, deferiprone (L1) and deferasirox (ICL670), provide potentially useful treatment for iron overload. This article reviews data indicating that both agents are relatively well tolerated, were at least as effective as DFO for decreasing iron burdens in comparative thalassemia trials, and (for deferiprone) were associated with improved cardiac outcomes. These outcomes could potentially alter the tissue siderosis-associated morbidity of patients with MDS, particularly those with pre-existing cardiac disease.
CARM1 inhibition reduces histone acetyltransferase activity causing synthetic lethality in CREBBP/EP300-mutated lymphomas
Authors: Kylee J. Veazey, Donghang Cheng, Kevin Lin, Oscar D. Villarreal, Guozhen Gao, Mabel Perez-Oquendo, Hieu T. Van, Sabrina A. Stratton, Michael Green, Han Xu, Yue Lu, Mark T. Bedford, Margarida Almeida Santos
Journal: Leukemia (2020)
Abstractions, predictions, and speech sound representations
Authors: Mathias Scharinger
Journal: Behavioral and Brain Sciences (2020)

Gilead et al. provide a unified account of predictive cognition in which abstract representations play an essential role. Although acknowledging the similarity to linguistic concepts toward the higher end of the proposed abstraction gradient, Gilead et al. do not consider the potential of their account to embrace phonetic and phonological speech sound representations and their neural bases.
Endoscopic ultrasonography can detect a cause in the majority of patients with idiopathic acute pancreatitis: a systematic review and meta-analysis
Authors: Devica S. Umans, Carlos K. Rangkuti, Christa J. Sperna Weiland, Hester C. Timmerhuis, Stefan A. W. Bouwense, Paul Fockens, Marc G. Besselink, Robert C. Verdonk, Jeanin E. van Hooft
Journal: Endoscopy (2020)

Background Idiopathic acute pancreatitis (IAP) has a 25 % pancreatitis recurrence rate. Endoscopic ultrasonography (EUS) may diagnose treatable causes of IAP and hence prevent recurrence. The goal of this systematic review with meta-analysis is to determine the diagnostic yield of EUS and its impact on recurrence. Methods PubMed, EMBASE and the Cochrane Library were systematically searched for English studies on EUS in adults with IAP. The primary outcome was diagnostic yield. Secondary outcomes included recurrence. Methodological quality was assessed using the QUADAS-2 score. Meta-analysis was performed to calculate the pooled diagnostic yield and risk ratio with 95 % confidence intervals (CI) using a random-effects model with inverse variance method. Results 22 studies were included, with 1490 IAP patients who underwent EUS. Overall diagnostic yield was 59 % (874 /1490; 95 %CI 52 % – 66 %). The most common etiologies were biliary (429 /1490; 30 %, 95 %CI 21 % – 41 %) and chronic pancreatitis (271 /1490; 12 %, 95 %CI 8 % – 19 %). In 2 % of patients, neoplasms were detected (45 /1490; 95 %CI 1 % – 4 %). There was no difference in yield between patients with or without recurrent IAP before EUS (risk ratio 0.89, 95 %CI 0.71 – 1.11). Conclusions EUS is able to identify a potential etiology in the majority of patients with IAP, detecting mostly biliary origin or chronic pancreatitis, but also neoplasms in 2 % of patients. EUS may be associated with a reduction of recurrence rate. Future studies should include complete diagnostic work-up and preferably include patients with a first episode of IAP only.
Pandemic publishing poses a new COVID-19 challenge
Authors: Adam Palayew, Ole Norgaard, Kelly Safreed-Harmon, Tue Helms Andersen, Lauge Neimann Rasmussen, Jeffrey V. Lazarus
Journal: Nature Human Behaviour (2020)

The scientific community's response to COVID-19 has resulted in a large volume of research moving through the publication pipeline at extraordinary speed, with a median time from receipt to acceptance of 6 days for journal articles. Although the nature of this emergency warrants accelerated publishing, measures are required to safeguard the integrity of scientific evidence.
Bcl-6 is the nexus transcription factor of T follicular helper cells via repressor-of-repressor circuits
Authors: Jinyong Choi, Huitian Diao, Caterina E. Faliti, Jacquelyn Truong, Meghan Rossi, Simon Bélanger, Bingfei Yu, Ananda W. Goldrath, Matthew E. Pipkin, Shane Crotty
Journal: Nature Immunology (2020)
Countering Islamic conservatism on being transgender: Clarifying Tantawi's and Khomeini’s fatwas from the progressive Muslim standpoint
Authors: Aisya Aymanee M. Zaharin, Maria Pallotta-Chiarolli
Journal: International Journal of Transgender Health (2020)

In the late 1980s, prompted by an actual case of an assigned male-at-birth (AMAB) transgender person who was allowed to have genital reconstructive surgery, two fatwas1 were issued. One was by the ...