Multicenter research priorities in pediatric CMR: results of a collaborative wiki survey

Multicenter studies in pediatric cardiovascular magnetic resonance (CMR) improve statistical power and generalizability. However, a structured process for identifying important research topics has not been developed. We aimed to (1) develop a list of high priority knowledge gaps, and (2) pilot the use of a wiki survey to collect a large group of responses. Knowledge gaps were defined as areas that have been either unexplored or under-explored in the research literature. High priority goals were: (1) feasible and answerable from a multicenter research study, and (2) had potential for high impact on the field of pediatric CMR. Seed ideas were contributed by a working group and imported into a pairwise wiki survey format which allows for new ideas to be uploaded and voted upon (https://allourideas.org). Knowledge gaps were classified into 2 categories: ‘Clinical CMR Practice’ (16 ideas) and ‘Disease Specific Research’ (22 ideas). Over a 2-month period, 3,658 votes were cast by 96 users, and 2 new ideas were introduced. The 3 highest scoring sub-topics were myocardial disorders (9 ideas), translating new technology & techniques into clinical practice (7 ideas), and normal reference values (5 ideas). The highest priority gaps reflected strengths of CMR (e.g., myocardial tissue characterization; implementation of technologic advances into clinical practice), and deficiencies in pediatrics (e.g., data on normal reference values). The wiki survey format was effective and easy to implement, and could be used for future surveys

MultiLexNorm: A Shared Task on Multilingual Lexical Normalization

Lexical normalization is the task of transforming an utterance into its standardized form. This task is beneficial for downstream analysis, as it provides a way to harmonize (often spontaneous) linguistic variation. Such variation is typical for social media on which information is shared in a multitude of ways, including diverse languages and code-switching. Since the seminal work of Han and Baldwin (2011) a decade ago, lexical normalization has attracted attention in English and multiple other languages. However, there exists a lack of a common benchmark for comparison of systems across languages with a homogeneous data and evaluation setup. The MultiLexNorm shared task sets out to fill this gap. We provide the largest publicly available multilingual lexical normalization benchmark including 13 language variants. We propose a homogenized evaluation setup with both intrinsic and extrinsic evaluation. As extrinsic evaluation, we use dependency parsing and part-of-speech tagging with adapted evaluation metrics (a-LAS, a-UAS, and a-POS) to account for alignment discrepancies. The shared task hosted at W-NUT 2021 attracted 9 participants and 18 submissions. The results show that neural normalization systems outperform the previous state-of-the-art system by a large margin. Downstream parsing and part-of-speech tagging performance is positively affected but to varying degrees, with improvements of up to 1.72 a-LAS, 0.85 a-UAS, and 1.54 a-POS for the winning system

Replication and shedding kinetics of infectious hematopoietic necrosis virus in juvenile rainbow trout

Viral replication and shedding are key components of transmission and fitness, the kinetics of which are heavily dependent on virus, host, and environmental factors. To date, no studies have quantified the shedding kinetics of infectious hematopoietic necrosis virus (IHNV) in rainbow trout (Oncorhynchus mykiss), or how they are associated with replication, making it difficult to ascertain the transmission dynamics of this pathogen of high agricultural and conservation importance. Here, the replication and shedding kinetics of two M genogroup IHNV genotypes were examined in their naturally co-evolved rainbow trout host. Within host virus replication began rapidly, approaching maximum values by day 3 post-infection, after which viral load was maintained or gradually dropped through day 7. Host innate immune response measured as stimulation of Mx-1 gene expression generally followed within host viral loads. Shedding also began very quickly and peaked within 2 days, defining a generally uniform early peak period of shedding from 1 to 4 days after exposure to virus. This was followed by a post-peak period where shedding declined, such that the majority of fish were no longer shedding by day 12 post-infection. Despite similar kinetics, the average shedding rate over the course of infection was significantly lower in mixed compared to single genotype infections, suggesting a competition effect, however, this did not significantly impact the total amount of virus shed. The data also indicated that the duration of shedding, rather than peak amount of virus shed, was correlated with fish mortality. Generally, the majority of virus produced during infection appeared to be shed into the environment rather than maintained in the host, although there was more retention of within host virus during the post-peak period. Viral virulence was correlated with shedding, such that the more virulent of the two genotypes shed more total virus. This fundamental understanding of IHNV shedding kinetics and variation at the individual fish level could assist with management decisions about how to respond to disease outbreaks when they occur. (C) 2016 Elsevier B.V. All rights reserved

Degradation of Internalized αvβ5 Integrin Is Controlled by uPAR Bound uPA: Effect on β1 Integrin Activity and α-SMA Stress Fiber Assembly

Myofibroblasts (Mfs) that persist in a healing wound promote extracellular matrix (ECM) accumulation and excessive tissue contraction. Increased levels of integrin αvβ5 promote the Mf phenotype and other fibrotic markers. Previously we reported that maintaining uPA (urokinase plasminogen activator) bound to its cell-surface receptor, uPAR prevented TGFβ-induced Mf differentiation. We now demonstrate that uPA/uPAR controls integrin β5 protein levels and in turn, the Mf phenotype. When cell-surface uPA was increased, integrin β5 levels were reduced (61%). In contrast, when uPA/uPAR was silenced, integrin β5 total and cell-surface levels were increased (2–4 fold). Integrin β5 accumulation resulted from a significant decrease in β5 ubiquitination leading to a decrease in the degradation rate of internalized β5. uPA-silencing also induced α-SMA stress fiber organization in cells that were seeded on collagen, increased cell area (1.7 fold), and increased integrin β1 binding to the collagen matrix, with reduced activation of β1. Elevated cell-surface integrin β5 was necessary for these changes after uPA-silencing since blocking αvβ5 function reversed these effects. Our data support a novel mechanism by which downregulation of uPA/uPAR results in increased integrin αvβ5 cell-surface protein levels that regulate the activity of β1 integrins, promoting characteristics of the persistent Mf

Regulation of Signaling at Regions of Cell-Cell Contact by Endoplasmic Reticulum-Bound Protein-Tyrosine Phosphatase 1B

Protein-tyrosine phosphatase 1B (PTP1B) is a ubiquitously expressed PTP that is anchored to the endoplasmic reticulum (ER). PTP1B dephosphorylates activated receptor tyrosine kinases after endocytosis, as they transit past the ER. However, PTP1B also can access some plasma membrane (PM)-bound substrates at points of cell-cell contact. To explore how PTP1B interacts with such substrates, we utilized quantitative cellular imaging approaches and mathematical modeling of protein mobility. We find that the ER network comes in close proximity to the PM at apparently specialized regions of cell-cell contact, enabling PTP1B to engage substrate(s) at these sites. Studies using PTP1B mutants show that the ER anchor plays an important role in restricting its interactions with PM substrates mainly to regions of cell-cell contact. In addition, treatment with PTP1B inhibitor leads to increased tyrosine phosphorylation of EphA2, a PTP1B substrate, specifically at regions of cell-cell contact. Collectively, our results identify PM-proximal sub-regions of the ER as important sites of cellular signaling regulation by PTP1B

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