The COVID-19 pandemic began in early 2020 with major health consequences. While a need to disseminate information to the medical community and general public was paramount, concerns have been raised ...regarding the scientific rigor in published reports. We performed a systematic review to evaluate the methodological quality of currently available COVID-19 studies compared to historical controls. A total of 9895 titles and abstracts were screened and 686 COVID-19 articles were included in the final analysis. Comparative analysis of COVID-19 to historical articles reveals a shorter time to acceptance (13.0IQR, 5.0-25.0 days vs. 110.0IQR, 71.0-156.0 days in COVID-19 and control articles, respectively; p < 0.0001). Furthermore, methodological quality scores are lower in COVID-19 articles across all study designs. COVID-19 clinical studies have a shorter time to publication and have lower methodological quality scores than control studies in the same journal. These studies should be revisited with the emergence of stronger evidence.
Cancer-associated fibroblasts (CAFs) are a key component of the tumour microenvironment with diverse functions, including matrix deposition and remodelling, extensive reciprocal signalling ...interactions with cancer cells and crosstalk with infiltrating leukocytes. As such, they are a potential target for optimizing therapeutic strategies against cancer. However, many challenges are present in ongoing attempts to modulate CAFs for therapeutic benefit. These include limitations in our understanding of the origin of CAFs and heterogeneity in CAF function, with it being desirable to retain some antitumorigenic functions. On the basis of a meeting of experts in the field of CAF biology, we summarize in this Consensus Statement our current knowledge and present a framework for advancing our understanding of this critical cell type within the tumour microenvironment.
Existing approaches to solving combinatorial optimization problems on graphs suffer from the need to engineer each problem algorithmically, with practical problems recurring in many instances. The ...practical side of theoretical computer science, such as computational complexity, then needs to be addressed. Relevant developments in machine learning research on graphs are surveyed for this purpose. We organize and compare the structures involved with learning to solve combinatorial optimization problems, with a special eye on the telecommunications domain and its continuous development of live and research networks.
This paper provides a review of empirical studies published with a decolonial epistemic approach in psychology. Our goal was to better understand how decolonial approaches are being practiced ...empirically in psychology, with an emphasis on community‐social psychology. We first discuss the context of colonization and coloniality in the research process as orienting information. We identified 17 peer‐reviewed empirical articles with a decolonial approach to psychology scholarship and discerned four waves that characterize the articles: relationally‐based research to transgress fixed hierarchies and unsettle power, research from the heart, sociohistorical intersectional consciousness, and desire‐based future‐oriented research to rehumanize and seek utopia. Community‐social psychology research with a decolonial approach has the potential to remember grassroots efforts, decolonizing our world.
TDP‐43 is an RNA‐binding protein active in splicing that concentrates into membraneless ribonucleoprotein granules and forms aggregates in amyotrophic lateral sclerosis (ALS) and Alzheimer's disease. ...Although best known for its predominantly disordered C‐terminal domain which mediates ALS inclusions, TDP‐43 has a globular N‐terminal domain (NTD). Here, we show that TDP‐43 NTD assembles into head‐to‐tail linear chains and that phosphomimetic substitution at S48 disrupts TDP‐43 polymeric assembly, discourages liquid–liquid phase separation (LLPS) in vitro, fluidizes liquid–liquid phase separated nuclear TDP‐43 reporter constructs in cells, and disrupts RNA splicing activity. Finally, we present the solution NMR structure of a head‐to‐tail NTD dimer comprised of two engineered variants that allow saturation of the native polymerization interface while disrupting higher‐order polymerization. These data provide structural detail for the established mechanistic role of the well‐folded TDP‐43 NTD in splicing and link this function to LLPS. In addition, the fusion‐tag solubilized, recombinant form of TDP‐43 full‐length protein developed here will enable future phase separation and in vitro biochemical assays on TDP‐43 function and interactions that have been hampered in the past by TDP‐43 aggregation.
Synopsis
The N‐terminal globular domain (NTD) of TDP‐43 forms linear polymers whose disruption by phosphomimetic substitution reduces TDP‐43 liquid‐liquid phase separation and RNA splicing function.
TDP‐43 NTD polymerization is disrupted by the phosphomimetic substitution at S48.
NTD forms a linear polymer through low‐affinity head‐to‐tail intermolecular contacts.
TDP‐43 NTD polymerization‐disrupting mutations destabilize phase separation of full‐length TDP‐43 in vitro and in cells.
Disrupting NTD polymerization impedes TDP‐43's role in RNA splicing in cells.
Structural and functional analyses of ALS‐related protein TDP43 illustrates its higher order organisation and links splicing activity with the ability to undergo liquid–liquid phase separation.
Smartwatch electrocardiograms (ECGs) could facilitate the detection of sudden cardiac arrest (SCA)-associated abnormalities. We evaluated the feasibility of using smartwatch-derived ECGs for ...detecting SCA-associated abnormalities in young adults and its agreement with 12-lead ECGs.
Twelve-lead and Apple Watch ECGs were registered in 155 healthy volunteers and 67 patients aged 18-45 years with diagnosis and ECG signs of long-QT syndrome (n = 10), Brugada syndrome (n = 12), ventricular pre-excitation (n = 19), hypertrophic cardiomyopathy (HCM, n = 13), and arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVC/D, n = 13). Cardiologists separately analysed 12-lead ECGs and the smartwatch ECGs taken from the left wrist (AW-I) and then from chest positions V1, V3, and V6 (AW-4). Compared with AW-I, AW-4 improved the classification of ECGs as 'abnormal', increasing the sensitivity from 64% to 89% (P < 0.01). Pre-excitation was detected in most cases using AW-I (sensitivity 89%) and in all cases using AW-4 (sensitivity 100%, P = 0.48 compared with AW-I, specificity 100% for both). Brugada was missed using AW-I but was detected in 11/12 patients using AW-4 (sensitivity 92%, specificity 100%, P = 0.003). Long QT was detected in 8/10 cases using AW-I (sensitivity 80%, specificity 100%) and in 9 patients using AW-4 (sensitivity 90%, specificity 100%, P > 0.99). Hypertrophic cardiomyopathy was correctly suspected using AW-I and AW-4 (sensitivity 92% and 85%, specificity 85%, and 100%, P > 0.99). AW-I was mostly (62%) considered normal in ARVC/D whereas AW-4 was useful in suspecting ARVC/D (100% sensitivity, 99% specificity, P = 0.004).
Detection of SCA-associated ECG abnormalities (pre-excitation, Brugada patterns, long QT, and signs suggestive of HCM and ARVC/D) is possible with an ECG smartwatch.
Introduction
Human atria comprise distinct layers. One layer can bypass another, and lead to a downstream centrifugal propagation at their interface. We sought to characterize anatomical substrates, ...electrophysiological properties, and ablation outcomes of "pseudo‐focal" atrial tachycardias (ATs), defined as macroreentrant ATs mimicking focal ATs.
Methods and Results
We retrospectively analyzed left atrial ATs showing centrifugal propagation with postpacing intervals (PPIs) after entrainment pacing suggestive of a macroreentrant mechanism. A total of 22 patients had pseudo‐focal ATs consisting of 15 perimitral and 7 roof‐dependent flutters. A low‐voltage area was consistently found at the collision site and colocalized with distinct anatomical structures like the: (1) coronary sinus‐great cardiac vein bundle (27%), (2) vein of Marshall bundle (18%), (3) Bachmann bundle (27%), (4) septopulmonary bundle (18%), and (5) fossa ovalis (9%). The mean missing tachycardia cycle length (TCL) was 65 ± 31 ms (22%) on the endocardial activation map. PPI was 0 0–15 ms and 0 0–21 ms longer than TCL at the breakthrough site and the opposite site, respectively. While feasible in 21 pseudo‐focal ATs (95%), termination was better achieved by blocking the anatomical isthmus than ablating the breakthrough site 20/21 (95%) vs. 1/5 (20%); p < .001.
Conclusion
Perimitral and roof‐dependent flutters with centrifugal propagation are favored by a low‐voltage area located at well‐identified anatomical structures. Comprehensive entrainment pacing maneuvers are crucial to distinguish pseudo‐focal ATs from true focal ATs. Blocking the anatomical isthmus is a better therapeutic option than ablating the breakthrough site.
With an increasing demand for efficacious, safe, and affordable vaccines for human and animal use, process intensification in cell culture-based viral vaccine production demands advanced process ...strategies to overcome the limitations of conventional batch cultivations. However, the use of fed-batch, perfusion, or continuous modes to drive processes at high cell density (HCD) and overextended operating times has so far been little explored in large-scale viral vaccine manufacturing. Also, possible reductions in cell-specific virus yields for HCD cultivations have been reported frequently. Taking into account that vaccine production is one of the most heavily regulated industries in the pharmaceutical sector with tough margins to meet, it is understandable that process intensification is being considered by both academia and industry as a next step toward more efficient viral vaccine production processes only recently. Compared to conventional batch processes, fed-batch and perfusion strategies could result in ten to a hundred times higher product yields. Both cultivation strategies can be implemented to achieve cell concentrations exceeding 10⁷ cells/mL or even 10⁸ cells/mL, while keeping low levels of metabolites that potentially inhibit cell growth and virus replication. The trend towards HCD processes is supported by development of GMP-compliant cultivation platforms, i.e., acoustic settlers, hollow fiber bioreactors, and hollow fiber-based perfusion systems including tangential flow filtration (TFF) or alternating tangential flow (ATF) technologies. In this review, these process modes are discussed in detail and compared with conventional batch processes based on productivity indicators such as space-time yield, cell concentration, and product titers. In addition, options for the production of viral vaccines in continuous multi-stage bioreactors such as two- and three-stage systems are addressed. While such systems have shown similar virus titers compared to batch cultivations, keeping high yields for extended production times is still a challenge. Overall, we demonstrate that process intensification of cell culture-based viral vaccine production can be realized by the consequent application of fed-batch, perfusion, and continuous systems with a significant increase in productivity. The potential for even further improvements is high, considering recent developments in establishment of new (designer) cell lines, better characterization of host cell metabolism, advances in media design, and the use of mathematical models as a tool for process optimization and control.
This article presents an extension to the nonlinear model predictive control (MPC) for tracking scheme able to guarantee convergence even in cases of nonconvex output admissible sets. This is ...achieved by incorporating a convexifying homeomorphism in the optimization problem, allowing it to be solved in the convex space. A novel class of nonconvex sets is also defined for which a systematic procedure to construct a convexifying homeomorphism is provided. This homeomorphism is then embedded in the MPC optimization problem in such a way that the homeomorphism is no longer required in closed form. Finally, the effectiveness of the proposed method is showcased through an illustrative example.
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