Miracle-dz/UniFAR-FTUs huggingface dataset:
3D Co-culture of hiPSC-Derived Cardiomyocytes With Cardiac Fibroblasts Improves Tissue-Like Features of Cardiac Spheroids

Purpose: Both cardiomyocytes and cardiac fibroblasts (CF) play essential roles in cardiac development, function, and remodeling. Properties of 3D co-cultures are incompletely understood. Hence, 3D co-culture of cardiomyocytes and CF was characterized, and selected features compared with single-type and 2D culture conditions. Methods: Human cardiomyocytes derived from induced-pluripotent stem cells (hiPSC-CMs) were obtained from Cellular Dynamics or Ncardia, and primary human cardiac fibroblasts from ScienCell. Cardiac spheroids were investigated using cryosections and whole-mount confocal microscopy, video motion analysis, scanning-, and transmission-electron microscopy (SEM, TEM), action potential recording, and quantitative PCR (qPCR). Results: Spheroids formed in hanging drops or in non-adhesive wells showed spontaneous contractions for at least 1 month with frequent media changes. SEM of mechanically opened spheroids revealed a dense inner structure and no signs of blebbing. TEM of co-culture spheroids at 1 month showed myofibrils, intercalated disc-like structures and mitochondria. Ultrastructural features were comparable to fetal human myocardium. We then assessed immunostained 2D cultures, cryosections of spheroids, and whole-mount preparations by confocal microscopy. CF in co-culture spheroids assumed a small size and shape similar to the situation in ventricular tissue. Spheroids made only of CF and cultured for 3 weeks showed no stress fibers and strongly reduced amounts of alpha smooth muscle actin compared to early spheroids and 2D cultures as shown by confocal microscopy, western blotting, and qPCR. The addition of CF to cardiac spheroids did not lead to arrhythmogenic effects as measured by sharp-electrode electrophysiology. Video motion analysis showed a faster spontaneous contraction rate in co-culture spheroids compared to pure hiPSC-CMs, but similar contraction amplitudes and kinetics. Spontaneous contraction rates were not dependent on spheroid size. Applying increasing pacing frequencies resulted in decreasing contraction amplitudes without positive staircase effect. Gene expression analysis of selected cytoskeleton and myofibrillar proteins showed more tissue-like expression patterns in co-culture spheroids than with cardiomyocytes alone or in 2D culture. Conclusion: We demonstrate that the use of 3D co-culture of hiPSC-CMs and CF is superior over 2D culture conditions for co-culture models and more closely mimicking the native state of the myocardium with relevance to drug development as well as for personalized medicine.
Pacing for Patients Suffering From Cardioinhibitory Vasovagal Syncope Using the Closed-Loop System

One in three vasovagal syncope (VVS) patients has syncopal recurrence after diagnosis, despite the standard recommendations for the avoidance of a recurrence, and one in five patients has more than one syncopal recurrence in the medium term. Given the high prevalence of VVS, there is a large population that continues to need effective treatment. There are numerous studies that use the implantable loop recorder (ILR) to document a cardioinhibitory response during VVS, with one study, ISSUE-3, demonstrating the efficacy of pacing using the rate-drop-response algorithm to trigger pacing and prevent syncopal recurrence in this population. There are more uncertainties in the studies that have used head-up tilt test (HUT) to select the population for pacing. We have recently performed the SPAIN randomized, controlled clinical trial using HUT to select the patients for pacing. The conclusion of the study was that, with the closed-loop system to introduce pacing, there was a significant reduction in the burden of syncope and a seven-fold increase in the time to first recurrence of syncope, which was greater than in the ISSUE-3 study. Since the completion of the SPAIN trial and its inclusion in the European guidelines, in our daily clinical practice, the use of this therapy is still recommended with caution in the context of the available literature, but it has increased our confidence in so doing. One in five patients with VVS needs treatment because of a high syncopal load. If an ILR is used to select the patients for pacing, the rate-drop-response algorithm can be recommended. In patients who have asystole on HUT, pacing with the closed-loop system has higher success and must now be considered as a tenable option for VVS patients.
NS5 Conservative Site Is Required for Zika Virus to Restrict the RIG-I Signaling

During host–virus co-evolution, cells develop innate immune systems to inhibit virus invasion, while viruses employ strategies to suppress immune responses and maintain infection. Here, we reveal that Zika virus (ZIKV), a re-emerging arbovirus causing public concerns and devastating complications, restricts host immune responses through a distinct mechanism. ZIKV nonstructural protein 5 (NS5) interacts with the host retinoic acid-inducible gene I (RIG-I), an essential signaling molecule for defending pathogen infections. NS5 subsequently represses K63-linked polyubiquitination of RIG-I, attenuates the phosphorylation and nuclear translocation of interferon regulatory factor 3 (IRF3), and inhibits the expression and production of interferon-β (IFN-β), thereby restricting the RIG-I signaling pathway. Interestingly, we demonstrate that the methyltransferase (MTase) domain of NS5 is required for the repression of RIG-I ubiquitination, IRF3 activation, and IFN-β production. Detailed studies further reveal that the conservative active site D146 of NS5 is critical for the suppression of the RIG-I signaling. Therefore, we uncover an essential role of NS5 conservative site D146 in ZIKV-mediated repression of innate immune system, illustrate a distinct mechanism by which ZIKV evades host immune responses, and discover a potential target for anti-viral infection.
High Glucose-Induced TRPC6 Channel Activation Decreases Glutamate Uptake in Rat Retinal Müller Cells

High glucose (HG) increases the production of reactive oxygen species (ROS), leading to decreased glutamate uptake in Müller cells. The transient receptor potential cation channel 6 (TRPC6) channel, an oxidative stress-sensitive Ca2+-permeable cationic channel, is readily detected in Müller cells and highly expressed under HG conditions. Yet, the effect of high glucose-induced TRPC6 channel activation in Müller cells is poorly understood. We hypothesized that TRPC6 channel activation mediates high glucose-induced decreases in Müller cell glutamate uptake. We found RNA interference (RNAi) of the TRPC6 channel abolished HG-induced decreases in glutamate uptake and cell death. HG also decreased the expression of the glutamate-aspartate transporter (GLAST), which is the most important transporter involved in glutamate uptake. The mRNA level of ciliary neurotrophic factor (CNTF) in rMC-1 cells and the release of CNTF in the culture media was decreased, but the mRNA levels of IL-6 and vascular endothelial growth factor (VEGF) were increased under HG conditions. After RNAi silencing in rMC-1 cells, the mRNA levels of CNTF increased, but IL-6 and VEGF levels decreased. Furthermore, TRPC6 knockdown (KD) decreased expression of glial fibrillary acidic protein (GFAP) and increased expression of Kir4.1, pointing to inhibition of HG-induced gliosis in rMC-1 cells. ROS and intracellular Ca2+ levels decreased after TRPC6 knockdown. Exposure to Hyp9 (10 μM), a highly selective TRPC6 channel agonist, can aggravate HG-induced pathological changes. Collectively, our results suggest TRPC6 channel activation is involved in HG-induced decreases in glutamate uptake in rMC-1 cells. These findings provide novel insights into the role of TRPC6 in HG-induced retinal neurovasculopathy and suggest TRPC6 is a promising target for drug development for diabetic retinopathy (DR).
Microbenthic Net Metabolism Along Intertidal Gradients (Cadiz Bay, SW Spain): Spatio-Temporal Patterns and Environmental Factors

Microphytobenthos (MPB), the photosynthetic primary producing component of microbenthos, shows variable patterns in its biomass distribution along the intertidal gradient as a result of the interactions of factors such as light, tides, temperature, and grazing pressure. These patterns have been studied more extensively in northern European estuaries than southern European coastal systems. Even less information is available regarding temporal changes in MPB primary production rates in these systems. For this reason, we followed the seasonal changes in net production in light and dark respiration rates (determined by oxygen microelectrodes) and MPB biomass (estimated by sediment chlorophyll a) along the intertidal gradient of the inner Cadiz Bay during a year. Sediment cores were collected along two transects (five sampling stations per transect) with distinct sediment granulometry: one muddy [Puerto Real (PR)] and one muddy-sandy transect [San Fernando (SF)]. Our results show that MPB biomass and net production increased seawards reaching their maxima in winter. In contrast to what is observed in northern European systems, the higher solar irradiance and temperatures occurring in summer in southern Spain likely inhibit MPB production. In Cadiz Bay, spatial patterns of MPB biomass and net production depended on season and location due to the environmental heterogeneity observed. Environmental variables, analyzed by principal component analysis (PCA), were used to explain the variability of MPB metabolism by multiple regression. Selected principal component (PC) axes explained 60% of the net production in light and 41% of the dark respiration rates variability in PR, while they only accounted for 25% of the same rates in SF. The differences observed between transects and the variability in the environmental variables explaining them highlight the importance of considering the spatial heterogeneity of our system to estimate the contribution of MPB to the inner Cadiz Bay productivity. In our case, this contribution is significant accounting for up to 49% of the total benthic production of the inner Cadiz Bay intertidal sediments, confirming previous global estimates.
Generative Modeling of InSAR Interferograms

Interferometric synthetic aperture radar (InSAR) has become an essential technique to detect surface variations due to volcanoes, earthquakes, landslides, glaciers, and aquifers. However, Earth's ionosphere, atmosphere, vegetation, surface runoff, etc., introduce noise that requires post‐processing to separate its components. This work defines a generator to create interferograms that include each of those components. Our approach leverages deformation models with real data, either directly or through machine learning using geostatistical methods. These methods result from previous developments to more efficiently and better simulate spatial variables and could replace some statistical approaches used in InSAR processing. We illustrate the use of the generator to simulate an artificial interferogram based on the 2015 Illapel earthquake and discuss the improved performance offered by geostatistical approaches compared with classical statistical ones. The generator establishes a tool for multiple applications (1) to evaluate InSAR correction workflows in controlled scenarios with known ground truth; (2) to develop training sets and generative methods for machine learning algorithms; and (3) to educate on InSAR and its principles.
Factor Xa Inhibition Reduces Coagulation Activity but Not Inflammation Among People With HIV: A Randomized Clinical Trial

Abstract Background Coagulation activity among persons with HIV is associated with end-organ disease risk, but the pathogenesis is not well characterized. We tested a hypothesis that hypercoagulation contributes to disease risk, in part, via upregulation of inflammation. Methods Treatment effects of edoxaban (30 mg), a direct factor Xa inhibitor, vs placebo were investigated in a randomized, double-blind crossover trial among participants with HIV and viral suppression and D-dimer levels ≥100 ng/mL. During each 4-month crossover period, blood measures of coagulation, inflammation, and immune activation were assessed. Analyses of change on edoxaban vs change on placebo used linear mixed models. Results Forty-four participants were randomized, and 40 completed at least 1 visit during each study period. The mean age was 49 years, and the CD4+ count was 739 cells/mm3. Edoxaban treatment led to declines in D-dimer (44%) and thrombin-antithrombin complex (26%) but did not lower inflammatory or immune activation measures. More bruising or bleeding events occurred during edoxaban (n = 28) than during placebo or no drug periods (n = 15). Conclusions The direct factor Xa inhibitor edoxaban led to a substantial reduction in coagulation but no effect on inflammation or immune activation. These results do not support that hypercoagulation contributes to ongoing inflammation during chronic antiretroviral therapy–treated HIV disease.
Epidemiology of cardiomyopathy - A clinical and genetic study of hypertrophic cardiomyopathy: The EPOCH-H study

Background: Hypertrophic cardiomyopathy (HCM) is a genetic disorder with the prevalence of 1 in 500 globally. HCM is clinically characterized by thickening of the wall of the heart, predominantly left ventricle (LV), and interventricular septum (IVS). Our study aims to report the demographical, clinical and genetic profile of Indian HCM patients. Methods: HCM patients were recruited on the basis of WHO criteria. The clinical phenotypes were analyzed using electrocardiography, two-dimensional electrocardiography, and hotspot region of the MYH7 gene was sequenced for all patients as well as for controls. Results: There were 59 patients with a clinical diagnosis of HCM with a preponderance of disease in males with a ratio (men, women) of 5.5:1. Average age of onset of the disease was late 30 s (39.2 ± 14.5) with familial HCM accounting for 18% (n = 9) for total HCM families (n = 50). Nonobstructive kind of HCM was more prevalent as compared to obstructive HCM (66.1% vs. 33.9%). Average posterior wall LV thickness of the HCM patients was 16 ± 4.8 mm and IVS thickness was 21 ± 8.3 mm with familial patients having greater wall thickness as compared to sporadic patients. Sequencing of hotspot region of MYH7 identified three mutations in three different patients. Two mutations were found to be segregating in familial cases. Conclusion: HCM is more prevalent in males with a predominance of hypertrophic nonobstructive cardiomyopathy form. Eighteen percent of cases were familial and showed an early onset of the disease and worse prognosis as compared to sporadic cases. Hotspot sequencing of MYH7 only explains 6% of its genetic basis. More of the candidate genes need to be screened through advanced techniques like next generation sequencing to identify the causal genes which could make us understand the mechanistic pathways.
Performance of pulmonary artery dimensions measured on high-resolution computed tomography scan for identifying pulmonary hypertension

Background On high-resolution computed tomography (HRCT), pulmonary artery (PA) dimensions may hint at the presence of pulmonary hypertension. We aimed to determine how accurately various measures of the PA, as viewed on HRCT, predict right heart catheterisation (RHC)-confirmed pulmonary hypertension. Methods We retrospectively reviewed patients who had HRCT and RHC between 2010 and 2018. Analyses considered respiratory cycle, pulmonary hypertension diagnostic criteria, time between HRCT and RHC, and subgroup analysis in interstitial lung disease (ILD) and chronic obstructive pulmonary disease (COPD). Results Of 620 patients, 375 had pulmonary hypertension. For pulmonary hypertension (defined as mean PA pressure (mPAP) ≥25 mmHg) and from HRCT performed within 60 days of RHC, main PA diameter (MPAD) ≥29 mm had a sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of 88%, 42%, 0.70 and 0.70, respectively, while ratio of the diameter of the PA to the diameter of the ascending aorta (PA:Ao) ≥1.0 showed 53%, 85%, 0.84 and 0.54, respectively. In general, results were similar when the interval between HRCT and RHC varied from 7 to 60 days and when measured on expiratory images. In ILD, the sensitivity of MPAD was higher; in COPD, the specificity of PA:Ao was higher. There was moderately positive correlation between mPAP and inspiratory MPAD, PA:Ao, right PA diameter (RPAD), left PA diameter (LPAD) and (RPAD+LPAD)/2 (r=0.48, 0.51, 0.34, 0.34 and 0.36, respectively), whereas there was weak negative correlation between mPAP and PA angle (r= −0.24). Conclusions Findings on HRCT may assist in the diagnosis of RHC-confirmed pulmonary hypertension. MPAD ≥29 mm had high sensitivity and PA:Ao ≥1.0 had high specificity. Compared with the entire cohort, MPAD had greater sensitivity in ILD and PA:Ao had higher specificity in COPD. Findings on HRCT may assist in the diagnosis of RHC-confirmed pulmonary hypertension. MPAD ≥29 mm has high sensitivity, whereas PA:Ao ≥1.0 has high specificity. MPAD has greater sensitivity in ILD and PA:Ao has higher specificity in COPD. http://bit.ly/2EcrEUY
Herbivore‐mediated negative frequency‐dependent selection underlies a trichome dimorphism in nature

Negative frequency‐dependent selection (NFDS) has been shown to maintain polymorphism in a diverse array of traits. The action of NFDS has been confirmed through modeling, experimental approaches, and genetic analyses. In this study, we investigated NFDS in the wild using morph‐frequency changes spanning a 20‐year period from over 30 dimorphic populations of Datura wrightii. In these populations, plants either possess glandular (sticky) or non‐glandular (velvety) trichomes, and the ratio of these morphs varies substantially among populations. Our method provided evidence that NFDS, rather than drift or migration, is the primary force maintaining this dimorphism. Most populations that were initially dimorphic remained dimorphic, and the overall mean and variance in morph frequency did not change over time. Furthermore, morph‐frequency differences were not related to geographic distances. Together, these results indicate that neither directional selection, drift, or migration played a substantial role in determining morph frequencies. However, as predicted by negative frequency‐dependent selection, we found that the rare morph tended to increase in frequency, leading to a negative relationship between the change in the frequency of the sticky morph and its initial frequency. In addition, we found that morph‐frequency change over time was significantly correlated with the damage inflicted by two herbivores: Lema daturaphila and Tupiochoris notatus. The latter is a specialist on the sticky morph and damage by this herbivore was greatest when the sticky morph was common. The reverse was true for L. daturaphila, such that damage increased with the frequency of the velvety morph. These findings suggest that these herbivores contribute to balancing selection on the observed trichome dimorphism.
Live-case demonstrations in pediatric urology: Ethics, patient safety, and clinical outcomes from an 8-year institutional experience

Purpose Live case demonstrations have become a common occurrence at surgical meetings around the world. These demonstrations are meant to serve as an educational medium for teaching techniques, promote discussion, improve interventions and outcomes. Despite the valuable educational benefits, many authors still question the ethics of this approach. We present our 8-year experience in live surgery, discuss the ethical issues, and provide recommendations. Materials and Methods We reviewed records of patients who underwent live robotic surgery during broadcasting events. Procedures performed were robot-assisted laparoscopic pyeloplasty (RAL-P), ureteral reimplantation (RALUR), and hemi-nephrectomy (RAL-HN). Peri- and post-operative outcomes were compared to our previously published case series. Results From October 2011 to May 2019, the senior author (MSG) performed all live surgery demonstrations on 22 patients: 9 RAL-P, 9 RALUR, and 4 RAL-HN. Live RAL-Ps had a 100% success rate and lower 30-day Clavien-Dindo grade (CDG) III complications when compared to our previous case series (11.1% vs. 21.2%). RALURs performed during live demonstrations had a higher success rate than our previously published cohort (100% vs. 82%). RAL-HN operative time and length of stay were comparable to our non-live control group. Conclusions Live surgery is a valuable didactic tool, but even experienced surgeons may be adversely affected by inappropriate case selection, technical difficulty, and anxiety associated with particular settings, such as operating at different institutions or working with unfamiliar surgical teams. We suggest consultation of an ethics review board and formulation of standard guidelines for patient selection, surgical equipment, and operative team.
Iranian Health Information Technology Acceptance Model (IHITAM) from Users’ Views

Introduction: Information technology (IT) is an important component of medical informatics. Information needs to be accepted by users to function effectively. At different ages and from different views, several models have been proposed and used to show factors affecting users’ IT acceptance. However, such models are in need of frequent revision and development due to variable conditions. Aim: The present research aims to design a new health IT acceptance model from Iranian users’ views. The research aims both to design a model for status quo by reviewing previous models and consider features of Iranian users. Methods: This is a correlative, cross-sectional study. Firstly, the primary model was presented by studying important IT acceptance models. Then, a structured questionnaire was designed and, after confirmation of validity and reliability of the questionnaire, it was given to users of information and health IT systems in different wards of hospitals in Iran. Data were analyzed by SPSS and Lisrel and the final model was designed by structural equations. Results: The model showed that there are six key factors which are effective on attitude and use intention including performance expectancy, observability, effort expectancy, facilitating conditions, empowerment and subjective norms via three interface factors of perceived usefulness, perceived ease of use, self-efficacy. The size of technology use is an important factor in technology acceptance and application as well. Conclusion: The present model has more details compared to the other models and can show a new image of important factors in technology acceptance and their relationships.