Inhibitors of Activin Receptor-like Kinase 5 Interfere with SARS-CoV-2 S-Protein Processing and Spike-Mediated Cell Fusion via Attenuation of Furin Expression

Screening of a protein kinase inhibitor library identified SB431542, targeting activin receptor-like kinase 5 (ALK5), as a compound interfering with SARS-CoV-2 replication. Since ALK5 is implicated in transforming growth factor β (TGF-β) signaling and regulation of the cellular endoprotease furin, we pursued this research to clarify the role of this protein kinase for SARS-CoV-2 infection. We show that TGF-β1 induces the expression of furin in a broad spectrum of cells including Huh-7 and Calu-3 that are permissive for SARS-CoV-2. The inhibition of ALK5 by incubation with SB431542 revealed a dose-dependent downregulation of both basal and TGF-β1 induced furin expression. Furthermore, we demonstrate that the ALK5 inhibitors SB431542 and Vactosertib negatively affect the proteolytic processing of the SARS-CoV-2 Spike protein and significantly reduce spike-mediated cell–cell fusion. This correlated with an inhibitory effect of ALK5 inhibition on the production of infectious SARS-CoV-2. Altogether, our study shows that interference with ALK5 signaling attenuates SARS-CoV-2 infectivity and cell–cell spread via downregulation of furin which is most pronounced upon TGF-β stimulation. Since a TGF-β dominated cytokine storm is a hallmark of severe COVID-19, ALK5 inhibitors undergoing clinical trials might represent a potential therapy option for COVID-19.     

Attacking Key Performance Indicators in Soccer: Current Practice and Perceptions from the Elite to Youth Academy Level

Key Performance Indicators (KPIs) are used to evaluate the offensive success of a soccer team (e.g. penalty box entries) or player (e.g. pass completion rate). However, knowledge transfer from research to applied practice is understudied. The current study queried practitioners (n = 145, mean ± SD age: 36 ± 9 years) from 42 countries across different roles and levels of competition (National Team Federation to Youth Academy levels) on various forms of data collection, including an explicit assessment of twelve attacking KPIs. 64.3% of practitioners use data tools and applications weekly (predominately) to gather KPIs during matches. 83% of practitioners use event data compared to only 52% of practitioners using positional data, with a preference for shooting related KPIs. Differences in the use and value of metrics derived from positional tracking data (including Ball Possession Metrics) were evident between job role and level of competition. These findings demonstrate that practitioners implement KPIs and gather tactical information in a variety of ways with a preference for simpler metrics related to shots. The low perceived value of newer KPIs afforded by positional data could be explained by low buy-in, a lack of education across practitioners, or insufficient translation of findings by experts towards practice.Key points

• Soccer practitioners collect data and evaluate performance in a variety of ways depending on the level of competition and their role within a club or federation.
• Practitioners reported a preference for shooting related metrics gathered by event data compared to KPIs offered by optical positional tracking technology.
• Despite increased interest and the capability to measure contextual aspects of passing performance with tracking technology, most practitioners still rely on more easily computed metrics (e.g. Pass Completion Percentage) and ball possession KPIs (e.g. Total Duration of Possession).
• This study highlights a gap in knowledge transfer between research and practice, encouraging increased education and collaborative efforts between data/sport scientists and practitioners to progress the field of analytics towards practical use in soccer.

Key words: Football, soccer, match analysis, performance analysis, applied data-science     

Paraoxonase polymorphisms PON1 192 and 55 and longevity in Italian centenarians and Irish nonagenarians. A pooled analysis

BACKGROUND: PON1, an arylesterase, associated with high density lipoprotein (HDL), protects low density lipoprotein (LDL) against oxidative modification. Common polymorphisms PON1 55 (L/M) and 192 (Q/R) in the PON1 gene associate with atherosclerosis and heart disease. Because long-lived people seem protected from premature vascular death, we conducted a pooled statistical analysis to assess any association between these polymorphisms and longevity in a large combined group of Italian centenarians and octo/nonagenarians from Northern Ireland (NI). MATERIALS AND METHODS: Separated DNA was available from 1479 subjects from Italy and Northern Ireland (NI). In Italy 308 centenarians (males 67, females 241, mean age 100.8, SD2.1 years) and 579 young controls (males 347, females 232, mean age 40.7, SD 12.7 years) were included in the study. In NI, 296 octo/nonagenarians (males 92, females 204, mean age 89.8, SD 5.7 years) and 296 young sex-matched subjects (mean age 13.0, SD 1.4 years) had available DNA. PON1 55 (L/M) and 192 (Q/R) polymorphisms were studied using a PCR-RFLP approach. RESULTS: There was a significant difference in PON1 192 genotypes in Italian centenarians compared to younger controls (X(2)= 6.8, df = 2 p= 0.03) and a similar but non significant trend between octo/nonagenarian and young subjects in NI (X(2) = 4.0, df=2, p=0.14). Using logistic regression analysis on the combined Italian and Irish datasets, there was a small survival advantage for centenarian and octo/nonagenarian subjects who were heterozygous for PON1 192 R allele, (OR 1.3, CI 1-1.6; p=0.04 with a stepwise increase for RR homozygous subjects (OR 1.7, CI 1.1-2.6; p = 0.02) compared to QQ subjects. Comparing R and Q alleles there was a survival advantage for octo/nonagenarian/centenarian subjects who carried the R allele (OR 1.3, CI 1.1-1.5; p = 0.007) but there was no sex-specific effect p =0.77) LL, LM and MM genotypes of PON 55 polymorphisms showed similar frequencies in Italy (39.9, 47.0, 13.1%) and Ireland (39.5, 48.6, 11.9%) with no age or sex-related differences. The PON1 192R/Q and PON55L/M loci were in strong linkage disequilibrium with a Lewontin's D' coefficient -0.928 (elderly) and -0.965 (young). There was a significant difference in haplotype frequency of these linked loci in older compared to younger subjects (Likelihood Ratio X(2) = 9.60, df = 3, p= 0.02). CONCLUSION: These data suggest a modest association between the 192R allele and longevity in two very elderly populations in two European countries. Being homozygous for 192 RR further enhances survival advantage but this effect was not found to be sex specific. This finding is of interest because the 192R allele has previously been associated with increased risk of coronary heart disease. On the other hand, the 192R allele shows higher enzymatic activity, using paraoxon as substrate, and we postulate that its role in the metabolism of potentially toxic chemicals or other metabolic pathways may be important in survival to very old age.     

Incidence,consequences, and risk factors for anastomotic dehiscence after colorectal surgery: a prospective monocentric study

Background Anastomotic dehiscence is the most severe surgical complication after large bowel resection. This study was designed to assess the incidence, to observe the consequences, and to identify the risk factors associated with anastomotic leakage after colorectal surgery. Materials and methods All procedures involving anastomoses of the colon or the rectum, which were performed between November 2002 and February 2006 in a single institution, were prospectively entered into a computerized database. Results One thousand eighteen colorectal resections and 811 anastomoses were performed over this 40-month period. The most frequent procedures were sigmoid (276) and right colectomies (217). The overall anastomotic leak rate was 3.8%. The mortality rate associated with anastomotic leak was 12.9%. In univariate analysis, the following parameters were associated with an increased risk for anastomotic dehiscence: (1) ASA score ≥ 3 (p = 0.004), (2) prolonged (>3 h) operative time (p = 0.02), (3) rectal location of the disease (p < 0.001), (4) and a body mass index > 25 (p = 0.04). In multivariate analysis, ASA score ≥ 3 (OR = 2.5; 95% CI 1.5–4.3, p < 0.001), operative time > 3 h [OR = 3.0; 95% CI 1.1–8.0, p = 0.02), and rectal location of the disease (OR = 3.75; 95% CI 1.5–9.0 (vs left colon), p = 0.003; OR = 7.69; 95% CI 2.2–27.3 (vs right colon), p = 0.001] were factors significantly associated with a higher risk of anastomotic dehiscence. Conclusions Three risk factors for anastomotic leak have been identified, one is patient-related (ASA score), one is disease-related (rectal location), the third being surgery-related (prolonged operative time). These factors should be considered in perioperative decision-making regarding defunctioning stoma formation.     

Epidemiological patterns of meningococcal meningitis in Niger in 2003 and 2004: under the threat of N. meningitidis serogroup W135

Since the Neisseria meningitidis serogroup W135 epidemic in Burkina Faso in 2002, the neighbouring countries dread undergoing outbreaks. Niger has strongly enhanced the microbiological surveillance, especially by adding the polymerase chain reaction (PCR) assay to the national framework of the surveillance system. During the 2003 epidemic season, 8113 clinically suspected cases of meningitis were notified and nine districts of the 42 crossed the epidemic threshold, while during the 2004 season, the number of cases was 3521 and four districts notified epidemics. In 2003 and 2004, serogroup A was identified in most N. meningitidis from cerebrospinal fluid (CSF) specimens (89.7% of 759 and 87.2% of 406, respectively). Although serogroup W135 represented only 8.3% of the meningococcal meningitis in 2003 and 7.9% in 2004, and was not involved in outbreaks, it was widespread in various areas of the country. In the regions that notified epidemics, the proportion of serogroup W135 was tiny while it exceeded 40% in several non-epidemic regions. Despite the wide distribution of W135 serogroup in Niger and the fears expressed in 2001, the threat of a large epidemic caused by N. meningitidis W135 seems to have been averted in Niger so far. There is no clear indication whether this serogroup will play a lasting role in the epidemiology of meningococcal meningitis or not. As early as in the 1990s, a significant but transient increase in the incidence of N. meningitidis serogroup X was observed. Close microbiological surveillance is crucial for monitoring the threat and for identifying at the earliest the serogroups involved in epidemics.     

The Rheology of Liquids: A Comparison of Clinicians’ Subjective Impressions and Objective Measurement

Texture-modified diets are commonly prescribed for patients with dysphagia; it is therefore important to demonstrate that clinicians form accurate impressions of the rheological (flow) properties of the items that they recommend for their clients. We explored the correlation between objective rheological measurement and clinicians subjective impressions of liquid consistency, rated on the bases of product labeling and sampling. Ten liquids, ranging from thin through nectar-thick and honey-thick to spoon-thick consistencies, were selected for study. Rheological analysis was conducted using a Carri-Med CSL Controlled Stress Rheometer. Fifty speech-language pathologists ranked the liquids in order of perceived viscosity, based on their interpretation of the product packaging and label. Product nomenclature proved insufficient to accurately represent the consistency class to which each liquid belonged. A second group of 16 speech-language pathologists rated the perceived relative viscosity and density of nectar-thick and honey-thick juice items in blinded two-point discrimination tests of stirring-resistance, oral manipulation, and vessel weight. Physical sampling of these two products enabled clinicians to reliably perceive relative viscosity and density differences between the nectar- and honey-thick items.