Interferon-α (IFN-α) is essential for antiviral immunity, but in the absence of matrix metalloproteinase-12 (MMP-12) or IκBα (encoded by NFKBIA) we show that IFN-α is retained in the cytosol of ...virus-infected cells and is not secreted. Our findings suggest that activated IκBα mediates the export of IFN-α from virus-infected cells and that the inability of cells in Mmp12(-/-) but not wild-type mice to express IκBα and thus export IFN-α makes coxsackievirus type B3 infection lethal and renders respiratory syncytial virus more pathogenic. We show here that after macrophage secretion, MMP-12 is transported into virus-infected cells. In HeLa cells MMP-12 is also translocated to the nucleus, where it binds to the NFKBIA promoter, driving transcription. We also identified dual-regulated substrates that are repressed both by MMP-12 binding to the substrate's gene exons and by MMP-12-mediated cleavage of the substrate protein itself. Whereas intracellular MMP-12 mediates NFKBIA transcription, leading to IFN-α secretion and host protection, extracellular MMP-12 cleaves off the IFN-α receptor 2 binding site of systemic IFN-α, preventing an unchecked immune response. Consistent with an unexpected role for MMP-12 in clearing systemic IFN-α, treatment of coxsackievirus type B3-infected wild-type mice with a membrane-impermeable MMP-12 inhibitor elevates systemic IFN-α levels and reduces viral replication in pancreas while sparing intracellular MMP-12. These findings suggest that inhibiting extracellular MMP-12 could be a new avenue for the development of antiviral treatments.
The aim of this study was to quantify and predict relationships between rating of perceived exertion (RPE) and GPS training-load (TL) variables in professional Australian football (AF) players using ...group and individualized modeling approaches.
TL data (GPS and RPE) for 41 professional AF players were obtained over a period of 27 wk. A total of 2711 training observations were analyzed with a total of 66 ± 13 sessions/player (range 39-89). Separate generalized estimating equations (GEEs) and artificial-neural-network analyses (ANNs) were conducted to determine the ability to predict RPE from TL variables (ie, session distance, high-speed running HSR, HSR %, m/min) on a group and individual basis.
Prediction error for the individualized ANN (root-mean-square error RMSE 1.24 ± 0.41) was lower than the group ANN (RMSE 1.42 ± 0.44), individualized GEE (RMSE 1.58 ± 0.41), and group GEE (RMSE 1.85 ± 0.49). Both the GEE and ANN models determined session distance as the most important predictor of RPE. Furthermore, importance plots generated from the ANN revealed session distance as most predictive of RPE in 36 of the 41 players, whereas HSR was predictive of RPE in just 3 players and m/min was predictive of RPE in just 2 players.
This study demonstrates that machine learning approaches may outperform more traditional methodologies with respect to predicting athlete responses to TL. These approaches enable further individualization of load monitoring, leading to more accurate training prescription and evaluation.
A high level of participant skill is influential in determining the outcome of many sports. Thus, tests assessing skill outcomes in sport are commonly used by coaches and researchers to estimate an ...athlete's ability level, to evaluate the effectiveness of interventions or for the purpose of talent identification.
The objective of this systematic review was to examine the methodological quality, measurement properties and feasibility characteristics of sporting skill outcome tests reported in the peer-reviewed literature.
A search of both SPORTDiscus and MEDLINE databases was undertaken.
Studies that examined tests of sporting skill outcomes were reviewed. Only studies that investigated measurement properties of the test (reliability or validity) were included. A total of 22 studies met the inclusion/exclusion criteria.
A customised checklist of assessment criteria, based on previous research, was utilised for the purpose of this review.
A range of sports were the subject of the 22 studies included in this review, with considerations relating to methodological quality being generally well addressed by authors. A range of methods and statistical procedures were used by researchers to determine the measurement properties of their skill outcome tests. The majority (95%) of the reviewed studies investigated test-retest reliability, and where relevant, inter and intra-rater reliability was also determined. Content validity was examined in 68% of the studies, with most tests investigating multiple skill domains relevant to the sport. Only 18% of studies assessed all three reviewed forms of validity (content, construct and criterion), with just 14% investigating the predictive validity of the test. Test responsiveness was reported in only 9% of studies, whilst feasibility received varying levels of attention.
In organised sport, further tests may exist which have not been investigated in this review. This could be due to such tests firstly not being published in the peer-review literature and secondly, not having their measurement properties (i.e., reliability or validity) examined formally.
Of the 22 studies included in this review, items relating to test methodological quality were, on the whole, well addressed. Test-retest reliability was determined in all but one of the reviewed studies, whilst most studies investigated at least two aspects of validity (i.e., content, construct or criterion-related validity). Few studies examined predictive validity or responsiveness. While feasibility was addressed in over half of the studies, practicality and test limitations were rarely addressed. Consideration of study quality, measurement properties and feasibility components assessed in this review can assist future researchers when developing or modifying tests of sporting skill outcomes.
Cotadutide, a peptide co-agonist at the glucagon-like peptide-1 (GLP-1) and glucagon (GCG) receptors, has demonstrated robust improvements in body weight, glycemia, and hepatic fat fraction (HFF) in ...patients living with obesity and type 2 diabetes mellitus.
In PROXYMO, a 19-week randomized double-blind placebo-controlled trial, the safety and efficacy of cotadutide (600 μg, 300 μg) or placebo were evaluated in 74 participants with biopsy-proven noncirrhotic metabolic dysfunction-associated steatohepatitis (MASH) with fibrosis. Analyses were performed using intent-to-treat and modified intent-to-treat population data.
Dose- and time-dependent improvements in HFF, alanine aminotransferase (ALT), and aspartate aminotransferase (AST), markers of liver health, and metabolic parameters were observed with significant improvements after 19 weeks with 600 μg (least squares mean difference vs placebo, 95% confidence interval for absolute HFF: –5.0% –8.5 to –1.5; ALT: –23.5 U/L –47.1 to –1.8; AST: –16.8 U/L –33.0 to –0.8). Incidences of any grade treatment-emergent adverse events (TEAEs) were 91.7%, 76.9%, and 37.5% with cotadutide 600 μg, 300 μg, and placebo, respectively. The majority were gastrointestinal, mild to moderate in severity, and generally consistent with other incretins at this stage of development. TEAEs leading to treatment discontinuation were 16.7%, 7.7%, and 4.2% with cotadutide 600 μg, 300 μg, and placebo, respectively.
PROXYMO provides preliminary evidence for the safety and efficacy of GLP-1/GCG receptor co-agonism in biopsy-proven noncirrhotic MASH with fibrosis, supporting further evaluation of this mechanism in MASH. Clinical Trial registration number: NCT04019561.
Summary On-call work is becoming an increasingly common work pattern, yet the human impacts of this type of work are not well established. Given the likelihood of calls to occur outside regular work ...hours, it is important to consider the potential impact of working on-call on stress physiology and sleep. The aims of this review were to collate and evaluate evidence on the effects of working on-call from home on stress physiology and sleep. A systematic search of Ebsco Host, Embase, Web of Science, Scopus and ScienceDirect was conducted. Search terms included: on-call , on call , standby, sleep , cortisol, heart rate , adrenaline , noradrenaline , nor-adrenaline , epinephrine , norepinephrine , nor-epinephrine , salivary alpha amylase and alpha amylase . Eight studies met the inclusion criteria, with only one study investigating the effect of working on-call from home on stress physiology. All eight studies investigated the effect of working on-call from home on sleep. Working on-call from home appears to adversely affect sleep quantity, and in most cases, sleep quality. However, studies did not differentiate between night’s on-call from home with and without calls. Data examining the effect of working on-call from home on stress physiology were not sufficient to draw meaningful conclusions.
The emergence of SARS‐CoV‐2 variants has exacerbated the COVID‐19 global health crisis. Thus far, all variants carry mutations in the spike glycoprotein, which is a critical determinant of viral ...transmission being responsible for attachment, receptor engagement and membrane fusion, and an important target of immunity. Variants frequently bear truncations of flexible loops in the N‐terminal domain (NTD) of spike; the functional importance of these modifications has remained poorly characterised. We demonstrate that NTD deletions are important for efficient entry by the Alpha and Omicron variants and that this correlates with spike stability. Phylogenetic analysis reveals extensive NTD loop length polymorphisms across the sarbecoviruses, setting an evolutionary precedent for loop remodelling. Guided by these analyses, we demonstrate that variations in NTD loop length, alone, are sufficient to modulate virus entry. We propose that variations in NTD loop length act to fine‐tune spike; this may provide a mechanism for SARS‐CoV‐2 to navigate a complex selection landscape encompassing optimisation of essential functionality, immune‐driven antigenic variation and ongoing adaptation to a new host.
Synopsis
The functional importance of the SARS‐CoV‐2 spike N‐terminal domain is poorly understood. This study demonstrates that length variation in flexible loops within the NTD can modulate spike activity to optimise SARS‐CoV‐2 entry.
SARS‐CoV‐2 spike NTD loops are a hotspot of diversity in emergent variants and sarbecoviruses in general.
The NTD determines virus entry efficiency by Alpha and Omicron variants, and by Pangolin coronavirus.
NTD loops may provide a mechanism for evolutionary fine tuning of spike activity.
The functional importance of the SARS‐CoV‐2 spike N‐terminal domain is poorly understood. This study demonstrates that length variation in flexible loops within the NTD can modulate spike activity to optimise SARS‐CoV‐2 entry.
The purpose of this study was to validate peak acceleration data from an accelerometer contained within a wearable tracking device while walking, jogging and running. Thirty-nine participants walked, ...jogged and ran on a treadmill while 10 peak accelerations per movement were obtained (n = 390). A single triaxial accelerometer measured resultant acceleration during all movements. To provide a criterion measure of acceleration, a 12-camera motion analysis (MA) system tracked the position of a retro-reflective marker affixed to the wearable tracking device. Peak raw acceleration recorded by the accelerometer significantly overestimated peak MA acceleration (P < 0.01). Filtering accelerometer data improved the relationship with the MA system (P < 0.01). However, only the 10 Hz and 8 Hz cut-off frequencies significantly reduced the errors found. The walk movement demonstrated the highest accuracy, agreement and precision and the lowest relative errors. Linear increases in error were observed for jog compared with walk and for run compared to both other movements. As the magnitude of acceleration increased, the strength of the relationship between the accelerometer and the criterion measure decreased. These results indicate that filtered accelerometer data provide an acceptable means of assessing peak accelerations, in particular for walking and jogging.
It has been suggested that young people should develop competence in a variety of 'lifelong physical activities' to ensure that they can be active across the lifespan.
The primary aim of this ...systematic review is to report the methodological properties, validity, reliability, and test duration of field-based measures that assess movement skill competency in lifelong physical activities. A secondary aim was to clearly define those characteristics unique to lifelong physical activities.
A search of four electronic databases (Scopus, SPORTDiscus, ProQuest, and PubMed) was conducted between June 2014 and April 2015 with no date restrictions.
Studies addressing the validity and/or reliability of lifelong physical activity tests were reviewed. Included articles were required to assess lifelong physical activities using process-oriented measures, as well as report either one type of validity or reliability.
Assessment criteria for methodological quality were adapted from a checklist used in a previous review of sport skill outcome assessments.
Movement skill assessments for eight different lifelong physical activities (badminton, cycling, dance, golf, racquetball, resistance training, swimming, and tennis) in 17 studies were identified for inclusion. Methodological quality, validity, reliability, and test duration (time to assess a single participant), for each article were assessed. Moderate to excellent reliability results were found in 16 of 17 studies, with 71% reporting inter-rater reliability and 41% reporting intra-rater reliability. Only four studies in this review reported test-retest reliability. Ten studies reported validity results; content validity was cited in 41% of these studies. Construct validity was reported in 24% of studies, while criterion validity was only reported in 12% of studies.
Numerous assessments for lifelong physical activities may exist, yet only assessments for eight lifelong physical activities were included in this review. Generalizability of results may be more applicable if more heterogeneous samples are used in future research.
Moderate to excellent levels of inter- and intra-rater reliability were reported in the majority of studies. However, future work should look to establish test-retest reliability. Validity was less commonly reported than reliability, and further types of validity other than content validity need to be established in future research. Specifically, predictive validity of 'lifelong physical activity' movement skill competency is needed to support the assertion that such activities provide the foundation for a lifetime of activity.
In team sports, tactical periodisation refers to the planned manipulation of training loads with the aim of prioritising athlete readiness for matches of greatest importance. Although monitoring of ...athletes' physical condition is often used to inform this planning, the direct influence of external factors on match difficulty has not been well quantified. In this study, a 'match difficulty index' (MDI) for use in Super Rugby was developed, based on the influence imparted by five external factors on previous match outcomes. Specifically, information relating to match location, days break between matches, time-zone change and opposition ladder position (both current and previous year) were collected for matches played during the 2011-2013 Super Rugby seasons. Logistic regression analyses were used to assess the importance of each of these factors with respect to match outcome (win/loss), with opposition ladder position and match location (home, domestic away or international) exerting the greatest influence on match difficulty. Three separate cross-validated models were constructed, with match outcome classification performance reported as 66.2%, 65.5% and 63.7% respectively. The three MDI models emanating from this study can each be used to inform tactical periodisation program design both prior to and during the regular season.
Understanding the interactions among anthropogenic stressors is critical for effective conservation and management of ecosystems. Freshwater scientists have invested considerable resources in ...conducting factorial experiments to disentangle stressor interactions by testing their individual and combined effects. However, the diversity of stressors and systems studied has hindered previous syntheses of this body of research. To overcome this challenge, we used a novel machine learning framework to identify relevant studies from over 235,000 publications. Our synthesis resulted in a new dataset of 2396 multiple‐stressor experiments in freshwater systems. By summarizing the methods used in these studies, quantifying trends in the popularity of the investigated stressors, and performing co‐occurrence analysis, we produce the most comprehensive overview of this diverse field of research to date. We provide both a taxonomy grouping the 909 investigated stressors into 31 classes and an open‐source and interactive version of the dataset (https://jamesaorr.shinyapps.io/freshwater‐multiple‐stressors/). Inspired by our results, we provide a framework to help clarify whether statistical interactions detected by factorial experiments align with stressor interactions of interest, and we outline general guidelines for the design of multiple‐stressor experiments relevant to any system. We conclude by highlighting the research directions required to better understand freshwater ecosystems facing multiple stressors.
We used a novel machine learning framework to compile a dataset of 2396 multiple‐stressor experiments in freshwater systems and we provide a quantitative summary of this diverse field of research. We also propose a framework to help clarify whether statistical interactions detected by factorial experiments align with stressor interactions of interest, and we outline general guidelines for the design of multiple‐stressor experiments relevant to any system.
PDF
