A 29 nucleotide deletion in open reading frame 8 (ORF8) is the most obvious genetic change in severe acute respiratory syndrome coronavirus (SARS-CoV) during its emergence in humans. In spite of ...intense study, it remains unclear whether the deletion actually reflects adaptation to humans. Here we engineered full, partially deleted (-29 nt), and fully deleted ORF8 into a SARS-CoV infectious cDNA clone, strain Frankfurt-1. Replication of the resulting viruses was compared in primate cell cultures as well as Rhinolophus bat cells made permissive for SARS-CoV replication by lentiviral transduction of the human angiotensin-converting enzyme 2 receptor. Cells from cotton rat, goat, and sheep provided control scenarios that represent host systems in which SARS-CoV is neither endemic nor epidemic. Independent of the cell system, the truncation of ORF8 (29 nt deletion) decreased replication up to 23-fold. The effect was independent of the type I interferon response. The 29 nt deletion in SARS-CoV is a deleterious mutation acquired along the initial human-to-human transmission chain. The resulting loss of fitness may be due to a founder effect, which has rarely been documented in processes of viral emergence. These results have important implications for the retrospective assessment of the threat posed by SARS.
Survivors of an acute myocardial infarction with diabetes mellitus retain an increased mortality risk. Reliable assessment of individual risk is required for effective and cost-efficient medical care ...in these patients. The Polyscore is a previously established risk predictor consisting of seven autonomic tests derived from electrocardiogram, blood pressure, and respiration. The Polyscore allows classification of survivors of myocardial infarction in groups at low, intermediate and high mortality risk. The aim of this study was to investigate the prognostic value of the Polyscore in diabetic survivors of acute myocardial infarction, which may be impaired by the presence of diabetic autonomic neuropathy. Survivors of an acute myocardial infarction were included in a prospective cohort study during hospitalisation due to the index event at two university hospitals in Munich, Germany. The Polyscore was determined from simultaneous non-invasive 30-min recordings of electrocardiogram, continuous arterial blood pressure, and respiration which were performed in all participants. Patients were followed for 5 years. The primary and secondary outcomes were all-cause mortality and cardiac mortality. 184 of 941 enrolled patients (19.6%) suffered from diabetes mellitus. 5-year-mortality was higher in diabetic patients (15.2%) compared to non-diabetic patients (5.8%). A multivariable Cox regression model confirmed the Polyscore as a strong predictor of mortality in diabetic post-MI patients (intermediate risk: HR 6.56, 95% CI 1.61-26.78, p = 0.004, mortality 22.8%; high risk: HR 18.76, 95% CI 4.35-80.98, p < 0.001, mortality 68.8%). There was no interaction between diabetes mellitus and the Polyscore regarding mortality prediction (p = 0.775). Interestingly, in contrast to the groups at intermediate and high risk (73 patients, 39.7%), the Polyscore identified a majority of diabetic patients (111, 60.3%) with a low mortality risk, comparable to that of low-risk non-diabetic patients (3.6% and 2.1%, respectively, p = 0.339). Consistent results were observed for cardiac mortality. This analysis shows that the Polyscore predicts all-cause and cardiac mortality in diabetic survivors of acute myocardial infarction. Within these patients it identifies a large population not affected by the excess mortality associated with diabetes in this setting. Thus, the Polyscore may facilitate risk-adapted follow-up strategies in diabetic survivors of myocardial infarction.
Chitin and its deacetylated derivative, chitosan, are nontoxic, antibacterial, biodegradable, and biocompatible biopolymers. Due to these properties, they are widely used for biomedical applications ...such as scaffolds for tissue engineering, wound dressings, separation membranes and antibacterial coatings. Unfortunately, there is still a lack of suitable solvent systems for the direct processing of chitin, e.g., into films and coatings. Such solvents must be nontoxic, noncorrosive, nondegrading, and allow for high chitin concentrations. Here, the potential of designed ionic liquids (IL) as solvents for chitin is outlined. Phosphonium‐ and imidazolium‐based ILs are synthesized, characterized and the influence of the cation on the solution process has been evaluated. It is shown that particularly imidazolium carboxylate‐based ILs are appropriate solvents for chitin and are suitable for the production of foils and coatings on both fabrics and foams.
Designed phosphonium‐ and imidazolium‐based ionic liquids are used as solvents for chitin and the influence of the cation on the solution process has been evaluated. In particular imidazolium carboxylate‐based ILs are turned out to be appropriate solvents for chitin and allowed for the production of foils and coatings on both fabrics and foams.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) evades most innate immune responses but may still be vulnerable to some. Here, we systematically analyze the impact of SARS-CoV-2 proteins ...on interferon (IFN) responses and autophagy. We show that SARS-CoV-2 proteins synergize to counteract anti-viral immune responses. For example, Nsp14 targets the type I IFN receptor for lysosomal degradation, ORF3a prevents fusion of autophagosomes and lysosomes, and ORF7a interferes with autophagosome acidification. Most activities are evolutionarily conserved. However, SARS-CoV-2 Nsp15 antagonizes IFN signaling less efficiently than the orthologs of closely related RaTG13-CoV and SARS-CoV-1. Overall, SARS-CoV-2 proteins counteract autophagy and type I IFN more efficiently than type II or III IFN signaling, and infection experiments confirm potent inhibition by IFN-γ and -λ1. Our results define the repertoire and selected mechanisms of SARS-CoV-2 innate immune antagonists but also reveal vulnerability to type II and III IFN that may help to develop safe and effective anti-viral approaches.
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•Numerous SARS-CoV-2 proteins synergize to suppress immune sensing and signaling•Nsp14 targets IFNAR1 for lysosomal degradation•ORF3a and ORF7a block autophagy by different mechanisms•Synergistic treatment with IFN-γ and -λ1 is highly effective against SARS-CoV-2
Hayn et al. analyze the impact of individual SARS-CoV-2 proteins on virus sensing, interferon signaling, and autophagy. They define the repertoire of viral antagonists of innate immune defenses, determine selected underlying mechanisms, and identify remaining vulnerabilities of SARS-CoV-2.
Vegans are at an increased risk for certain micronutrient deficiencies, foremost of vitamin B
. Little is known about the short-term effects of dietary change to plant-based nutrition on vitamin B
...metabolism. Systemic biomarkers of vitamin B
status, namely, serum vitamin B
and holotranscobalamin, may respond quickly to a reduced intake of vitamin B
. To test this hypothesis, 53 healthy omnivore subjects were randomized to a controlled unsupplemented vegan diet (VD,
= 26) or meat-rich diet (MD,
= 27) for 4 weeks. Vitamin B
status was examined by measurement of serum vitamin B
, holotranscobalamin (holo-TC), methylmalonic acid (MMA) and total plasma homocysteine (tHcy). Holo-TC decreased significantly in the VD compared to the MD group after four weeks of intervention, whereas metabolites MMA and tHcy were unaffected. Body weight remained stable in both groups. VD intervention led to a significant reduction of cholesterol intake, and adequate profiles of nutrient and micronutrient status. Lower intake of vitamin B
was observed in VD, which was mirrored by a lower concentration of serum vitamin B
and reduced holo-TC after 4 weeks. Plasma holo-TC may be a fast-responding biomarker to monitor adequate supply of vitamin B
in plant-based individuals.
Nanostructuring has proven to be a successful strategy in overcoming the trade-off between light absorption and hole transport to the solid/electrolyte interface in hematite photoanodes for water ...splitting. The suggestion that poor electron (majority carrier) collection hinders the performance of nanostructured hematite electrodes has led to the emergence of host–guest architectures in which the absorber layer is deposited onto a transparent high-surface-area electron collector. To date, however, state of the art nanostructured hematite electrodes still outperform their host–guest counterparts, and a quantitative evaluation of the benefits of the host–guest architecture is still lacking. In this paper, we examine the impact of host–guest architectures by comparing nanostructured tin-doped hematite electrodes with hematite nanoparticle layers coated onto two types of conducting macroporous SnO2 scaffolds. Analysis of the external quantum efficiency spectra for substrate (SI) and electrolyte side (EI) illumination reveals that the electron diffusion length in the host–guest electrodes based on an undoped SnO2 scaffold is increased substantially relative to the nanostructured hematite electrode without a supporting scaffold. Nevertheless, electron collection is still incomplete for EI illumination. By contrast, an electron collection efficiency of 100% is achieved by fabricating the scaffold using antimony-doped SnO2, showing that the scaffold conductivity is crucial for the device performance.
Objective
To assess the value of a positive family history (FH) as a risk factor for prostate cancer incidence and grade among men undergoing organised prostate‐specific antigen (PSA) screening in a ...population‐based study.
Subjects and Methods
The study cohort comprised all attendees of the Swiss arm of the European Randomised Study of Screening for Prostate Cancer (ERSPC) with systematic PSA level tests every 4 years. Men reporting first‐degree relative(s) diagnosed with prostate cancer were considered to have a positive FH. Biopsy was exclusively PSA triggered at a PSA level threshold of 3 ng/mL. The primary endpoint was prostate cancer diagnosis. Kaplan–Meier and Cox regression analyses were used.
Results
Of 4 932 attendees with a median (interquartile range, IQR) age of 60.9 (57.6–65.1) years, 334 (6.8%) reported a positive FH. The median (IQR) follow‐up duration was 11.6 (10.3–13.3) years. Cumulative prostate cancer incidence was 60/334 (18%, positive FH) and 550/4 598 (12%, negative FH) odds ratio 1.6, 95% confidence interval (CI) 1.2–2.2, P = 0.001). In both groups, most prostate cancer diagnosed was low grade. There were no significant differences in PSA level at diagnosis, biopsy Gleason score or Gleason score on pathological specimen among men who underwent radical prostatectomy between both groups. On multivariable analysis, age (hazard ratio HR 1.04, 95% CI 1.02–1.06), baseline PSA level (HR 1.13, 95% CI 1.12–1.14), and FH (HR 1.6, 95% CI 1.24–2.14) were independent predictors for overall prostate cancer incidence (all P < 0.001). Only baseline PSA level (HR 1.14, 95% CI 1.12–1.16, P < 0.001) was an independent predictor of Gleason score ≥7 prostate cancer on prostate biopsy. The proportion of interval prostate cancer diagnosed in‐between the screening rounds was not significantly different.
Conclusion
Irrespective of the FH status, the current PSA‐based screening setting detects the majority of aggressive prostate cancers and missed only a minority of interval cancers with a 4‐year screening algorithm. Our results suggest that men with a positive FH are at increased risk of low‐grade but not aggressive prostate cancer.
Summary
Phosphatidylethanol (PEth) is a new, highly specific alcohol marker. The aim of this study was to assess its diagnostic value in the liver transplant setting. In 51 pre‐ and 61 ...post‐transplant patients with underlying alcoholic liver disease PEth, ethanol, methanol, carbohydrate‐deficient transferrin (CDT), and ethyl glucuronide in urine (uEtG) and hair (hEtG) were tested and compared with patients’ questionnaire reports. Twenty‐eight (25%) patients tested positive for at least one alcohol marker. PEth alone revealed alcohol consumption in 18% of patients. With respect to detection of alcohol intake in the preceding week, PEth showed a 100% sensitivity. PEth testing was more sensitive than the determination of ethanol, methanol, CDT or uEtG alone sensitivity 25% (confidence interval (CI) 95%, 7–52%), 25% (7–52%), 21% (6–45%) and 71% (41–91%), respectively, or ethanol, methanol and uEtG taken in combination with 73% (45–92%). Specificity of all markers was 92% or higher. Additional testing of hEtG revealed alcohol consumption in seven patients, not being positive for any other marker. Phosphatidylethanol was a highly specific and sensitive marker for detection of recent alcohol consumption in pre‐ and post‐transplant patients. The additional determination of hEtG was useful in disclosing alcohol consumption 3–6 months retrospectively.
Mortality rates in females who survived acute myocardial infarction (AMI) exceed those in males. Differences between sexes in age, cardiovascular risk factors and revascularization therapy have been ...proposed as possible reasons.
To select sets of female and male patients comparable in respect of relevant risk factors in order to compare the sex-specific risk in a systematic manner.
Data of the ISAR-RISK and ART studies were investigated. Patients were enrolled between 1996 and 2005 and suffered from AMI within 4 weeks prior to enrolment. Patients of each sex were selected with 1:1 equivalent age, previous AMI history, sinus-rhythm presence, hypertension, diabetes mellitus, smoking status, left ventricular ejection fraction (LVEF), and revascularization therapy. Survival times were compared between sex groups in the whole study cohort and in the matched cohort.
Of 3840 consecutive AMI survivors, 994 (25.9%) were females and 2846 (74.1%) were males. Females were older and suffered more frequently from hypertension and diabetes mellitus. In the whole cohort, females showed an increased mortality with a hazard ratio (HR) of 1.54 compared to males (p<0.0001). The matched cohort comprised 802 patients of each sex and revealed a trend towards poorer survival in females (HR for female sex 1.14; p = 0.359). However, significant mortality differences with a higher risk in matched females was observed during the first year after AMI (HR = 1.61; p = 0.045) but not during the subsequent years.
Matched sub-groups of post-AMI patients showed a comparable long-term mortality. However, a female excess mortality remained during first year after AMI and cannot be explained by differences in age, cardiovascular risk factors, and modes of acute treatment. Other causal factors, including clinical as well as psychological and social aspects, need to be considered. Female post-AMI patients should be followed more actively particularly during the first year after AMI.
The adverse effects of maternal prenatal stress (PS) on child's neurodevelopment warrant the establishment of biomarkers that enable early interventional therapeutic strategies. We performed a ...prospective matched double cohort study screening 2000 pregnant women in third trimester with Cohen Perceived Stress Scale-10 (PSS-10) questionnaire; 164 participants were recruited and classified as stressed and control group (SG, CG). Fetal cord blood iron parameters of 107 patients were measured at birth. Transabdominal electrocardiograms-based Fetal Stress Index (FSI) was derived. We investigated sex contribution to group differences and conducted causal inference analyses to assess the total effect of PS exposure on iron homeostasis using a directed acyclic graph (DAG) approach. Differences are reported for p < 0.05 unless noted otherwise. Transferrin saturation was lower in male stressed neonates. The minimum adjustment set of the DAG to estimate the total effect of PS exposure on fetal ferritin iron biomarkers consisted of maternal age and socioeconomic status: SG revealed a 15% decrease in fetal ferritin compared with CG. Mean FSI was higher among SG than among CG. FSI-based timely detection of fetuses affected by PS can support early individualized iron supplementation and neurodevelopmental follow-up to prevent long-term sequelae due to PS-exacerbated impairment of the iron homeostasis.
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