tbuckley/cabot-search huggingface dataset:
Abstract 13664: Membrane Stiffness as a Function of Plakophilin-2 Expression: Implications to Arrhythmogenic Right Ventricular Cardiomyopathy
Authors: Pamela Swiatlowska, Mario Delmar
Journal: Circulation (2020)

Mutations in PKP2 , the gene coding for the desmosomal protein Plakophilin-2 (PKP2), can lead to an inheritable cardiac disease called Arrhythmogenic Right Ventricle Cardiomyopathy (ARVC). Various studies investigated the molecular and electrical properties of cardiomyocytes (CMs) with PKP2 deficiency. However, systematic studies on the mechanical properties of PKP2-deficient CMs, and their relation to the cardiomyopathic phenotype, are lacking. We studied the relation between PKP2 expression, membrane transverse Young’s modulus (tYM; a surrogate measure of membrane stiffness), and their correlation with tubulin expression and with substrate stiffness. Left and right ventricular (LV, RV) CMs were isolated from murine hearts control (ctrl), or with a cardiomyocyte-specific, tamoxifen-activated knockout of PKP2 (PKP2cKO). Three time points were studied: 14, 15 and 21 days post-tamoxifen injection (dpi). The phenotypes at these time points correspond to three disease stages: concealed, arrhythmogenic and cardiomyopathy of RV predominance, respectively. tYM was evaluated by mechanoSICM. Tubulin was visualized by confocal microscopy. tYM in LV myocytes from control hearts showed a tendency toward higher values when compared to RV myocytes (LV 2.9±0.2 kPa vs RV 2.6±0.2 kPa, n=53-59). At 14 dpi, LV and RV PKP2cKO CMs were softer than ctrl (LV 2.1±0.1 kPa, RV 2.1±0.1 kPa vs ctrl, n=30-59). The trend reversed a day later and by 21 dpi there was a clear increase in tYM, particularly in PKP2cKO RV myocytes (LV 4.5±0.3 kPa, RV 4.8±0.6 kPa vs ctrl, n=44-59). Z-groove index, a parameter of membrane organization, decreased in PKP2cKO CMs. Increased tYM at 21 dpi corresponded to upregulation of α-tubulin and particularly, acetylated tubulin, which was reduced at 14dpi but went up in 21dpi. We also observed an inverse correlation between membrane tYM, and substrate stiffness. We conclude that loss of PKP2 expression affects, in a disease stage-specific manner, CM mechanical properties and the MT network organization. Whether these effects are correlative or one is consequence of the other, remains to be determined. We speculate that changes in membrane mechanics at the single cell level are a component of mechanical dysfunction in hearts affected with ARVC.
Guenther Boden, MD (1935–2015): A Pioneer in Human Studies of Nutrition and Obesity—And the Mystery of Insulin Resistance for Handling Glucose
Authors: Kevin Jon Williams, Edward S. Horton, Elias S. Siraj
Journal: Diabetes Care (2020)

Professor Guenther Boden, MD, was drawn to the field of diabetes research through an unconventional route, but in that journey he brought a perpetually fresh set of eyes to help unravel the relationships between nutrition, obesity, and defects in insulin action.



A delighted Guenther Boden in ski gear, Elk Mountain, PA, 1980



Guenther Boden was born on 8 January 1935 to Dr. Alwin Boden, an internist who practiced from a home office, and Irma Boden ( nee Godelmann), a homemaker who had trained as a medical technologist. During his early years, the family lived in Ludwigshafen am Rhein, an industrial city in southwestern Germany. The place and time would leave Guenther with vivid memories of a childhood spent during, and immediately after, World War II.

Guenther once wrote that when Allied bombing of key industrial sites in Ludwigshafen began, the bombs were, from an 8-year-old child’s perspective, “more a matter of excitement than threat for me[,] and together with my friends, we would rush out of the cellar after the air raids to look for bomb shards, which we boys considered a valuable collection item. This lost much of its attraction as the air raids became more frequent… .” When his father was drafted as a medical officer in the Luftwaffe (Air Force), Guenther’s mother took him and his two sisters to the relative safety of her parents’ home in Heidelberg.



Young Guenther Boden with mother Irma and two sisters, Marianne and Ilse, in Durkheim, Germany, 1950



Early life promoted an independent spirit, a healthy skepticism of authority, and remarkable resourcefulness. Rough lessons came at a personal level, from the “sadist” who taught his 3rd and 4th grade classes—using frequent corporal punishment—and from Guenther’s childhood experiences of hunger—today called food insecurity. Hard lessons also came from learning of the genocidal war criminals …
Impact of the COVID-19 pandemic on tuberculosis laboratory services in Europe
Authors: Vladyslav Nikolayevskyy, Yen Holicka, Dick van Soolingen, Marieke J. van der Werf, Csaba Ködmön, Elena Surkova, Doris Hillemann, Ramona Groenheit, Daniela Cirillo
Journal: European Respiratory Journal (2020)

<b>Sustainable support from healthcare bodies is needed to preserve TB laboratory capacity, and maintain personnel and skills, to minimise negative effects of the COVID-19 pandemic on laboratory services severely disrupted in the early months of pandemic</b>https://bit.ly/38camaL
A Phylodynamic Workflow to Rapidly Gain Insights into the Dispersal History and Dynamics of SARS-CoV-2 Lineages
Authors: Simon Dellicour, Keith Durkin, Samuel L Hong, Bert Vanmechelen, Joan Martí-Carreras, Mandev S Gill, Cécile Meex, Sébastien Bontems, Emmanuel André, Marius Gilbert, Conor Walker, Nicola De Maio, Nuno R Faria, James Hadfield, Marie-Pierre Hayette, Vincent Bours, Tony Wawina-Bokalanga, Maria Artesi, Guy Baele, Piet Maes
Journal: Molecular Biology and Evolution (2020)

Abstract Since the start of the COVID-19 pandemic, an unprecedented number of genomic sequences of SARS-CoV-2 have been generated and shared with the scientific community. The unparalleled volume of available genetic data presents a unique opportunity to gain real-time insights into the virus transmission during the pandemic, but also a daunting computational hurdle if analyzed with gold-standard phylogeographic approaches. To tackle this practical limitation, we here describe and apply a rapid analytical pipeline to analyze the spatiotemporal dispersal history and dynamics of SARS-CoV-2 lineages. As a proof of concept, we focus on the Belgian epidemic, which has had one of the highest spatial densities of available SARS-CoV-2 genomes. Our pipeline has the potential to be quickly applied to other countries or regions, with key benefits in complementing epidemiological analyses in assessing the impact of intervention measures or their progressive easement.
Abstract 14695: What Lies Ahead? Project Survival Estimates in the Setting of a ’Low Risk’ Fontan Circulation
Authors: David W Baker, Chris Schilling, Diana Zannino, Mark Dennis, Yves d’Udekem, David Celermajer, Rachael Cordina
Journal: Circulation (2020)

The Fontan procedure has enabled those born with a functionally single ventricle to survive well into early adulthood albeit with high rates of morbidity and mortality. The total cavopulmonary connection (TCPC) has superseded the atriopulmonary connection (APC) and is associated with improved outcomes. However, the chance of survival into late adulthood is unknown and outcomes specifically in young adults without high risk features are not well characterized. We therefore projected the late survival of ‘low risk’ Fontan patients. Patients were included from the Australian and New Zealand Fontan Registry if they survived to age 16y without transplantation, sustained arrhythmia, thromboembolic event, Fontan conversion or takedown, plastic bronchitis, protein losing enteropathy, NYHA class III/IV or ≥ moderate ventricular dysfunction or atrioventricular regurgitation. Estimates of projected survival were obtained via Weibull distribution (Stata software, V15, StataCorp LLC) using current survival curves and extrapolating different modelled scenarios. In ‘optimistic’, Fontan mortality risks continue on current trends until reaching all-cause general population mortality risks. In ‘conservative’, the ratio of mortality risk between Fontan survivors and the general population are maintained from last follow-up. ‘Pessimistic’ was modelled to consider the possibility the TCPC cohort experience significant deterioration, as observed in the APC cohort; here risks were increased to match the APC mortality risk from age 55y. There were 612 ‘low risk’ patients included; 152 APC and 460 TCPC. Survival at 40 years of age was 80% and 89% for APC and TCPC respectively. Projected survival estimates are shown in Table 1 . Projected survival for low-risk TCPC patients is far more encouraging than previously expected, with 49-67% reaching their seventh decade. There is a growing need for enhanced resources in the specialized area of adult congenital heart disease.
Abstract 12918: The Association Between Central Obesity and Myocardial Ageing: Traditional Body Mass Index (bmi) Falls Short of Expectation
Authors: Yen How Tan, Jun Pei Lim, Wee Shiong Lim, Fei Gao, Loon Yee Teo, SEE HOOI EWE, Bryan Keng, Ru San Tan, Woon-Puay Koh, Angela S Koh
Journal: Circulation (2020)

Background: The Asian phenotype of central obesity is intriguing. Current data suggest links between central obesity and cardiovascular (CV) risks. However, age-related sarcopenia (resulting in loss of skeletal muscle) may falsely reduce body mass index (BMI), leading to inaccurate measures of obesity. We aim to determine how waist circumference (WC), would compare against BMI, in differentiating obesity, among older adults. Further, we explore the differential association between each obesity definition and myocardial ageing. Methods: We performed anthropometric and CV examinations on a cohort of asymptomatic aged adults. Myocardial ageing was defined by ratio of peak velocity flow in early diastole E (m/s) to peak velocity flow in late diastole by atrial contraction A (m/s). For BMI, a cut-off of 27.5kg/m 2 was used, and WC cut-offs of &gt;90cm for males and &gt;80cm for females. Results: Among n=970 adults (mean age 73±4 years, 432 (44%) males), 124 (12.8%) were obese by BMI definition while 347 (35.7%) were obese by WC definition. Inter-definitional agreement was fair between BMI and WC (cohen’s κ=0.345). More women (66% vs 50%, p&lt;0.001) and older participants (63±14 vs 65±11 years, p=0.007) were defined as obese by WC definition, while age and gender did not differentiate obese versus non-obese as defined by BMI. There were more hypertension (p&lt;0.001) and diabetes mellitus (p&lt;0.001) among the obese as defined by both definitions, compared to non-obese. Based on either definition, obese participants had significantly lower E/A ratio [(1.13 ± 0.46 vs 0.98 ± 0.35; P &lt; 0.001 using BMI), (1.17 ± 0.49 vs 1.00 ± 0.37; P &lt; 0.001 using WC)] compared to non-obese. Left atrial volume index was larger in obese in both the BMI group (20.5 ± 7.43 vs 22.3 ± 7.90; P = 0.020) and WC group (20.0 ± 6.9 vs 22.1 ± 8.3; P &lt; 0.001). By multivariate regression, WC, but not BMI, was independently associated with E/A (β=-0.114, SE -0.114±0.024, p&lt;0.001). Conclusion: Obesity prevalence varies depending on the definition used. Among Asians, waist circumference identifies higher prevalence of obesity, possibly related to central adiposity. While impact of age-related sarcopenia and BMI in older adults require deeper study, WC may better characterize the impact of obesity on myocardial ageing.
TeleBCI: remote user training, monitoring, and communication with an evoked-potential brain-computer interface
Authors: Andrew Geronimo, Zachary Simmons
Journal: Brain-Computer Interfaces (2020)

ABSTRACT Brain-computer interfaces (BCIs) can serve as a type of augmentative and alternative communication (AAC) for individuals with amyotrophic lateral sclerosis (ALS). One hindrance to BCI adoption is the complexity of providing training and support for users. This paper describes the teleBCI interface used to train end-users in the operation of a virtual keyboard using an evoked potential BCI. Fifteen patients with motor neuron disease and their communication partners were included in the study. Teams completed 8 sessions of P300 BCI training virtually with the researcher. Over time, teams required less help to complete physical, computer, and BCI-specific tasks associated with device use. A subset of users experienced improved performance over sessions, progressing to utilize the full functionality of the speller and communicate with a nurse partner over a telemedicine interface. Integration of telemedicine in ALS care provides new opportunities for how BCI-AAC are deployed and used.
Abstract 14318: Long Noncoding RNA Differentiation Antagonizing Non-protein Coding RNA 201 Ameliorates Endothelial Dysfunction via Sponging MicroRNA-216a
Authors: rongxia li, Shujun Yang, Yu Chen, Weili Zhang
Journal: Circulation (2020)

Background: Endothelial dysfunction contributes to the initiation of atherosclerosis, which has been associated with the long noncoding RNAs (lncRNAs). However, the role of lncRNAs in endothelial function remains largely unknown. This study aimed to investigate whether the differentiation antagonizing non-protein coding RNA 201 (DANCR201) regulated the endothelial function. Methods and Results: The whole transcriptome sequencing was conducted to identify differentially expressed lncRNAs in the peripheral blood from patients with coronary artery diseases who had coronary calcified plaques (n=10), vulnerable plaques (n=5), and control subjects without coronary plaques (n=10). The characteristics of plaques were determined by the coronary computed tomography angiography. The results showed that DANCR201 was significantly downregulated in patients with vulnerable plaques compared to those with calcified plaques and control subjects. The RNA fluorescence in situ hybridization showed that DANCR201 was localized in both cytoplasm and nuclei. Next, we assessed the role of DANCR201 in endothelial function. In the replicative aging model of human umbilical vein endothelial cells (HUVECs), DANCR201 was found to decrease in senescent passage 20 cells compared with young passage 3 cells. Furthermore, DANCR201 overexpression in HUVECs significantly repressed monocytes adhesion to endothelium, inhibited the expression of pro-inflammatory cytokines interleukin 1β, intercellular cell adhesion molecule 1, tumor necrosis factor α, and promoted the abilities of endothelial proliferation and migration, indicating that DANCR201 was a protective factor for endothelial function. Bioinformatics analysis of miRNA-lncRNA interactions indicated that DANCR201 contained a candidate binding sequence of miR-216a which had been reported to promote the endothelial dysfunction through NF-κB pathway. The luciferase assay further showed that DANCR201 specifically combined with miR-216a. Conclusions: Our data indicated that DANCR201 can improve endothelial function via sponging miR-216a, ultimately maintaining vascular normalization. DANCR201 maybe a potential therapeutic target for atherosclerotic plaque progression and instability.
Epigenetics and pulmonary diseases in the horizon of precision medicine: a review
Authors: Giuditta Benincasa, Dawn L. DeMeo, Kimberly Glass, Edwin K. Silverman, Claudio Napoli
Journal: European Respiratory Journal (2020)

Epigenetic mechanisms represent potential molecular routes which could bridge the gap between genetic background and environmental risk factors contributing to the pathogenesis of pulmonary diseases. In patients with COPD, asthma and pulmonary arterial hypertension (PAH), there is emerging evidence of aberrant epigenetic marks, mainly including DNA methylation and histone modifications which directly mediate reversible modifications to the DNA without affecting the genomic sequence. Post-translational events and microRNAs can be also regulated epigenetically and potentially participate in disease pathogenesis. Thus, novel pathogenic mechanisms and putative biomarkers may be detectable in peripheral blood, sputum, nasal and buccal swabs or lung tissue. Besides, DNA methylation plays an important role during the early phases of fetal development and may be impacted by environmental exposures, ultimately influencing an individual's susceptibility to COPD, asthma and PAH later in life. With the advances in omics platforms and the application of computational biology tools, modelling the epigenetic variability in a network framework, rather than as single molecular defects, provides insights into the possible molecular pathways underlying the pathogenesis of COPD, asthma and PAH. Epigenetic modifications may have clinical applications as noninvasive biomarkers of pulmonary diseases. Moreover, combining molecular assays with network analysis of epigenomic data may aid in clarifying the multistage transition from a “pre-disease” to “disease” state, with the goal of improving primary prevention of lung diseases and its subsequent clinical management. We describe epigenetic mechanisms known to be associated with pulmonary diseases and discuss how network analysis could improve our understanding of lung diseases.
Fight fire with fire: Neurobiology of capsaicin-induced analgesia for chronic pain
Authors: Vipin Arora, James N. Campbell, Man-Kyo Chung
Journal: Pharmacology & Therapeutics (2020)

Capsaicin, the pungent ingredient in chili peppers, produces intense burning pain in humans. Capsaicin selectively activates the transient receptor potential vanilloid 1 (TRPV1), which is enriched in nociceptive primary afferents, and underpins the mechanism for capsaicin-induced burning pain. Paradoxically, capsaicin has long been used as an analgesic. The development of topical patches and injectable formulations containing capsaicin has led to application in clinical settings to treat chronic pain conditions, such as neuropathic pain and the potential to treat osteoarthritis. More detailed determination of the neurobiological mechanisms of capsaicin-induced analgesia should provide the logical rationale for capsaicin therapy and help to overcome the treatment's limitations, which include individual differences in treatment outcome and procedural discomfort. Low concentrations of capsaicin induce short-term defunctionalization of nociceptor terminals. This phenomenon is reversible within hours and, hence, likely does not account for the clinical benefit. By contrast, high concentrations of capsaicin lead to long-term defunctionalization mediated by the ablation of TRPV1-expressing afferent terminals, resulting in long-lasting analgesia persisting for several months. Recent studies have shown that capsaicin-induced Ca2+/calpain-mediated ablation of axonal terminals is necessary to produce long-lasting analgesia in a mouse model of neuropathic pain. In combination with calpain, axonal mitochondrial dysfunction and microtubule disorganization may also contribute to the longer-term effects of capsaicin. The analgesic effects subside over time in association with the regeneration of the ablated afferent terminals. Further determination of the neurobiological mechanisms of capsaicin-induced analgesia should lead to more efficacious non-opioidergic analgesic options with fewer adverse side effects.
Abstract 150: Effect of Amplitude Spectral Area on Termination of Fibrillation and Outcomes in Pediatric Cardiac Arrest
Authors: Tia Raymond, Sandeep Pandit, Heather M Griffis, Xuemei Zhang, Richard Hanna, Dana E Niles, Annemarie E Silver, Javier J Lasa, Sarah E Haskell, Dianne L Atkins, Vinay M Nadkarni
Journal: Circulation (2020)

Introduction: Amplitude spectral area (AMSA) predicts termination of fibrillation (TOF) with return of spontaneous circulation (ROSC) and hospital survival in adults, but has not been studied during pediatric cardiac arrest (pCA). Hypothesis: We characterized AMSA during pCA from a pediatric resuscitation quality (pediRES-Q) collaborative and hypothesized that AMSA would be associated with TOF and ROSC. Methods: Children &lt;18 years of age with pCA and VF were studied. AMSA was measured for 2 seconds prior to each shock and also averaged for each subject (AMSA-avg). TOF was defined as termination of VF 10 secs after defibrillation (DF) to any rhythm other than VF. ROSC was defined as &gt;20 mins without chest compressions. Univariate and multivariable logistic regression analyses controlling for weight, current, and illness category (cardiac vs non-cardiac) were performed. Primary endpoints were TOF and ROSC without ECMO. Secondary endpoints were 24-hr survival and survival to hospital discharge. Results: Between 2015-2019, 50 children from 14 hospitals (median age 3.7 years [IQR 0.6, 13.1]; median weight 16.3 kgs [IQR 6.9, 37.2]; 46% male; 73% cardiac illness category) were identified. IHCA occurred in 47 children and OHCA in 3 children. We analyzed 111 shocks with median number of DFs 1.0 [IQR 1.0, 3.0], median DF energy dose 3.27 J/kg [IQR 2.65,5.01], median DF current 0.64 A/kg [IQR 0.38,0.96], median AMSA 12.21 [IQR 7.17,17.03], and median AMSA-avg 14.6 [IQR 8.6,19.2]. TOF was achieved in 72 DFs (65%), ROSC without ECMO in 31 (62%), ROC with ECMO in 11 (22%), 24-hr survival in 40 (80%), and survival to hospital discharge in 26 (52%). Weight (OR 0.91 [0.84, 0.99] P=0.025) and DF current (OR 1.44 [0.97, 2.2] P=0.07), but not AMSA, were significantly associated with TOF for the first shock. Controlling for DF current and illness category, there was a significant association between AMSA-avg (OR 1.11 [1.0, 1.24] P=0.044) and ROSC without ECMO. There was no significant association between AMSA-avg and 24-hr survival or survival to hospital discharge. Conclusions: In pediatric patients, TOF was associated with weight and DF current, but not AMSA, whereas AMSA-avg was associated with ROSC without ECMO, but not 24-hr survival or survival to hospital discharge.
Author Correction: Noncanonical binding of Lck to CD3ε promotes TCR signaling and CAR function
Authors: Frederike A. Hartl, Esmeralda Beck-Garcìa, Nadine M. Woessner, Lea J. Flachsmann, Rubí M.-H. Velasco Cárdenas, Simon M. Brandl, Sanaz Taromi, Gina J. Fiala, Anna Morath, Pankaj Mishra, O. Sascha Yousefi, Julia Zimmermann, Nico Hoefflin, Maja Köhn, Birgitta M. Wöhrl, Robert Zeiser, Kristian Schweimer, Stefan Günther, Wolfgang W. Schamel, Susana Minguet
Journal: Nature Immunology (2020)