Making the invisible enemy visible.

Structural biology plays a crucial role in the fight against COVID-19, permitting us to ‘see’ and understand SARS-CoV-2. However, the macromolecular structures of SARS-CoV-2 proteins that were solved with great speed and urgency can contain errors that may hinder drug design. The Coronavirus Structural Task Force has been working behind the scenes to evaluate and improve these structures, making the results freely available at https://insidecorona.net/

Erectile dysfunction, physical activity and metabolic syndrome: differences in markers of atherosclerosis

<p>Abstract</p> <p>Background</p> <p>Erectile dysfunction (ED), impaired arterial elasticity, elevated resting heart rate as well as increased levels of oxidized LDL and fibrinogen associate with future cardiovascular events. Physical activity is crucial in the prevention of cardiovascular diseases (CVD), while metabolic syndrome (MetS) comprises an increased risk for CVD events. The aim of this study was to assess whether markers of subclinical atherosclerosis are associated with the presence of ED and MetS, and whether physical activity is protective of ED.</p> <p>Methods</p> <p>57 MetS (51.3 ± 8.0 years) and 48 physically active (PhA) (51.1 ± 8.1 years) subjects participated in the study. ED was assessed by the International Index of Erectile Function (IIEF) questionnaire, arterial elasticity by a radial artery tonometer (HDI/PulseWave™ CR-2000) and circulating oxLDL by a capture ELISA immunoassay. Fibrinogen and lipids were assessed by validated methods. The calculation of mean daily energy expenditure of physical exercise was based on a structured questionnaire.</p> <p>Results</p> <p>ED was more often present among MetS compared to PhA subjects, 63.2% and 27.1%, respectively (p < 0.001). Regular physical exercise at the level of > 400 kcal/day was protective of ED (OR 0.12, 95% CI 0.017-0.778, p = 0.027), whereas increased fibrinogen (OR 4.67, 95% CI 1.171-18.627, p = 0.029) and elevated resting heart rate (OR 1.07, 95% CI 1.003-1.138, p = 0.04) were independently associated with the presence of ED. In addition, large arterial elasticity (ml/mmHgx10) was lower among MetS compared to PhA subjects (16.6 ± 4.0 <it>vs</it>. 19.6 ± 4.2, p < 0.001), as well as among ED compared to non-ED subjects (16.7 ± 4.6 <it>vs</it>. 19.0 ± 3.9, p = 0.008). Fibrinogen and resting heart rate were highest and large arterial elasticity lowest among subjects with both MetS and ED.</p> <p>Conclusions</p> <p>Markers of subclinical atherosclerosis associated with the presence of ED and were most evident among subjects with both MetS and ED. Thus, especially MetS patients presenting with ED should be considered at high risk for CVD events. Physical activity, on its part, seems to be protective of ED.</p> <p>Trial registration</p> <p>ClinicalTrials.gov <a href="http://www.clinicaltrials.gov/ct2/show/NCT01119404">NCT01119404</a></p

The Blood Pressure "Uncertainty Range" – a pragmatic approach to overcome current diagnostic uncertainties (II)

A tremendous amount of scientific evidence regarding the physiology and physiopathology of high blood pressure combined with a sophisticated therapeutic arsenal is at the disposal of the medical community to counteract the overall public health burden of hypertension. Ample evidence has also been gathered from a multitude of large-scale randomized trials indicating the beneficial effects of current treatment strategies in terms of reduced hypertension-related morbidity and mortality. In spite of these impressive advances and, deeply disappointingly from a public health perspective, the real picture of hypertension management is overshadowed by widespread diagnostic inaccuracies (underdiagnosis, overdiagnosis) as well as by treatment failures generated by undertreatment, overtreatment, and misuse of medications. The scientific, medical and patient communities as well as decision-makers worldwide are striving for greatest possible health gains from available resources. A seemingly well-crystallised reasoning is that comprehensive strategic approaches must not only target hypertension as a pathological entity, but rather, take into account the wider environment in which hypertension is a major risk factor for cardiovascular disease carrying a great deal of our inheritance, and its interplay in the constellation of other, well-known, modifiable risk factors, i.e., attention is to be switched from one's "blood pressure level" to one's absolute cardiovascular risk and its determinants. Likewise, a risk/benefit assessment in each individual case is required in order to achieve best possible results. Nevertheless, it is of paramount importance to insure generalizability of ABPM use in clinical practice with the aim of improving the accuracy of a first diagnosis for both individual treatment and clinical research purposes. Widespread adoption of the method requires quick adjustment of current guidelines, development of appropriate technology infrastructure and training of staff (i.e., education, decision support, and information systems for practitioners and patients). Progress can be achieved in a few years, or in the next 25 years

Assessment of protein-protein interfaces in cryo-EM derived assemblies

Structures of macromolecular assemblies derived from cryo-EM maps often contain errors that become more abundant with decreasing resolution. Despite efforts in the cryo-EM community to develop metrics for map and atomistic model validation, thus far, no specific scoring metrics have been applied systematically to assess the interface between the assembly subunits. Here, we comprehensively assessed protein–protein interfaces in macromolecular assemblies derived by cryo-EM. To this end, we developed Protein Interface-score (PI-score), a density-independent machine learning-based metric, trained using the features of protein–protein interfaces in crystal structures. We evaluated 5873 interfaces in 1053 PDB-deposited cryo-EM models (including SARS-CoV-2 complexes), as well as the models submitted to CASP13 cryo-EM targets and the EM model challenge. We further inspected the interfaces associated with low-scores and found that some of those, especially in intermediate-to-low resolution (worse than 4 Å) structures, were not captured by density-based assessment scores. A combined score incorporating PI-score and fit-to-density score showed discriminatory power, allowing our method to provide a powerful complementary assessment tool for the ever-increasing number of complexes solved by cryo-EM

Racial analysis of patients with myocardial infarction complicated by heart failure and/or left ventricular dysfunction treated with valsartan, captopril, or both

African Americans have a high incidence of heart failure (HF). Limited retrospective observational subgroup analyses of patients with left ventricular systolic dysfunction (LVSD) suggest marginal benefit of angiotensin-converting enzyme inhibitors in the prevention of HF hospitalizations or total mortality in African Americans