ALBERT

Description: The recent emergence of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the underlying cause of Coronavirus Disease 2019 (COVID-19), has led to a worldwide pandemic causing substantial morbidity, mortality, and economic devastation. In response, many laboratories have redirected attention to SARS-CoV-2, meaning there is an urgent need for tools that can be used in laboratories unaccustomed to working with coronaviruses. Here we report a range of tools for SARS-CoV-2 research. First, we describe a facile single plasmid SARS-CoV-2 reverse genetics system that is simple to genetically manipulate and can be used to rescue infectious virus through transient transfection (without in vitro transcription or additional expression plasmids). The rescue system is accompanied by our panel of SARS-CoV-2 antibodies (against nearly every viral protein), SARS-CoV-2 clinical isolates, and SARS-CoV-2 permissive cell lines, which are all openly available to the scientific community. Using these tools, we demonstrate here that the controversial ORF10 protein is expressed in infected cells. Furthermore, we show that the promising repurposed antiviral activity of apilimod is dependent on TMPRSS2 expression. Altogether, our SARS-CoV-2 toolkit, which can be directly accessed via our website at https://mrcppu-covid.bio/, constitutes a resource with considerable potential to advance COVID-19 vaccine design, drug testing, and discovery science.

Description: We have gained considerable insight into the mechanisms which recognize and repair DNA damage, but how they adapt to extreme environmental challenges remains poorly understood. Cavefish have proven to be fascinating models for exploring the evolution of DNA repair in the complete absence of UV-induced DNA damage and light. We have previously revealed that the Somalian cavefish Phreatichthys andruzzii, lacks photoreactivation repair via the loss of light, UV and ROS-induced photolyase gene transcription mediated by D-box enhancer elements. Here, we explore whether other systems repairing UV-induced DNA damage have been similarly affected in this cavefish model. By performing a comparative study using P. andruzzii and the surface-dwelling zebrafish, we provide evidence for a conservation of sunlight-regulated Nucleotide Excision Repair (NER). Specifically, the expression of the ddb2 gene which encodes a key NER recognition factor is robustly induced following exposure to light, UV and oxidative stress in both species. As in the case of the photolyase genes, D-boxes in the ddb2 promoter are sufficient to induce transcription in zebrafish. Interestingly, despite the loss of D-box-regulated photolyase gene expression in P. andruzzii, the D-box is required for ddb2 induction by visible light and oxidative stress in cavefish. However, in the cavefish ddb2 gene this D-box-mediated induction requires cooperation with an adjacent, highly conserved E2F element. Furthermore, while in zebrafish UV-induced ddb2 expression results from transcriptional activation accompanied by stabilization of the ddb2 mRNA, in P. andruzzii UV induces ddb2 expression exclusively via an increase in mRNA stability. Thus, we reveal plasticity in the transcriptional and post transcriptional mechanisms regulating the repair of sunlight-induced DNA damage under long-term environmental challenges.

Description: Abstract One known method to reduce vortex shedding from the tip of a blade is the use of end plates or winglets. Although the aerodynamic impact of such end plates has been investigated in the past, no studies exist on the effect of such end plates on the far-field noise. The aeroacoustic noise reduction of three different end-plate geometries is experimentally investigated. The end plates are applied to the free end of a wall-mounted symmetric NACA 0012 airfoil and a cambered NACA 4412 airfoil with an aspect ratio of 2 and natural boundary layer transition. Microphone array measurements are taken in the aeroacoustic open-jet wind tunnel at BTU Cottbus-Senftenberg for chord-based Reynolds numbers between 75,000 and 225,000 and angles of attack from 0$$^circ$$ ∘ to 30$$^circ$$ ∘ . The obtained acoustic spectra show a broad frequency hump for the airfoil base configurations at higher angles of attack that is attributed to tip noise. Hot-wire measurements taken for one configuration show that the application of an end plate diffuses the vorticity at the tip. The aeroacoustic noise contribution of the tip can be reduced when the endplates are applied. This reduction is most effective for higher angles of attack, when the tip vortex is the dominant sound source. Graphic abstract

Description: Background Patients of congenital heart disease surgery have good prospects for reaching old age. Against the backdrop of increasing life expectancies, the question of how well such patients are mastering daily routines and their working life emerges. In our study, the educational and occupational performance of patients over 15 years was examined. Methods Intergenerational social mobility (changes in social positions from the parental generation to the generation of children) was examined in terms of education, and intragenerational social mobility (changes in positions within the same generation, i.e., in individuals over their life courses) was examined in terms of occupational positions. Comparisons were made between patients and a control group drawn from the German Socio-Economic Panel (SOEP). Controls were drawn from respondents who participated in the 2004 and 2018 SOEP surveys. Results The data were from 244 out of 360 patients (68%) with complete social data from the first survey (2003–2004) and who were included in the follow-up (2017–2019), and 238 controls were drawn from the SOEP. At the time of the second survey, subjects’ ages ranged from 28 to 59 years of age (M = 40.1 years). Intergenerational educational mobility did not differ between cases and controls. For intragenerational social mobility, downward changes were more frequent among controls. This latter finding may be explained by patients retiring earlier than the general population. Retirement rates increased over time, particularly among patients with severe congenital malformations. Unemployment rates were also higher among patients. Conclusions Taken together, although a considerable proportion of patients with congenital heart disease retired prematurely or never entered the labour force, their educational and occupational careers proceeded more favourably than expected.

Description: In visual search tasks, repeating features or the position of the target results in faster response times. Such inter-trial ‘priming’ effects occur not just for repetitions from the immediately preceding trial but also from trials further back. A paradigm known to produce particularly long-lasting inter-trial effects–of the target-defining feature, target position, and response (feature)–is the ‘priming of pop-out’ (PoP) paradigm, which typically uses sparse search displays and random swapping across trials of target- and distractor-defining features. However, the mechanisms underlying these inter-trial effects are still not well understood. To address this, we applied a modeling framework combining an evidence accumulation (EA) model with different computational updating rules of the model parameters (i.e., the drift rate and starting point of EA) for different aspects of stimulus history, to data from a (previously published) PoP study that had revealed significant inter-trial effects from several trials back for repetitions of the target color, the target position, and (response-critical) target feature. By performing a systematic model comparison, we aimed to determine which EA model parameter and which updating rule for that parameter best accounts for each inter-trial effect and the associated n-back temporal profile. We found that, in general, our modeling framework could accurately predict the n-back temporal profiles. Further, target color- and position-based inter-trial effects were best understood as arising from redistribution of a limited-capacity weight resource which determines the EA rate. In contrast, response-based inter-trial effects were best explained by a bias of the starting point towards the response associated with a previous target; this bias appeared largely tied to the position of the target. These findings elucidate how our cognitive system continually tracks, and updates an internal predictive model of, a number of separable stimulus and response parameters in order to optimize task performance.

Description: In order to detect the misuse of testosterone (T), urinary steroid concentrations and concentration ratios are quantified and monitored in a longitudinal manner to enable the identification of samples exhibiting atypical test results. These suspicious samples are then forwarded to isotope ratio mass spectrometry (IRMS)–based methods for confirmation. Especially concentration ratios like T over epitestosterone (E) or 5α-androstanediol over E proved to be valuable markers. Unfortunately, depending on the UGT2B17 genotype and/or the gender of the athlete, these markers may fail to provide evidence for T administrations when focusing exclusively on urine samples. In recent years, the potential of plasma steroids has been investigated and were found to be suitable to detect T administrations especially in female volunteers. A current drawback of this approach is the missing possibility to confirm that elevated steroid concentrations are solely derived from an administration of T and cannot be attributed to confounding factors. Therefore, an IRMS method for plasma steroids was developed and validated taking into account the comparably limited sample volume. As endogenous reference compounds, unconjugated cholesterol and dehydroepiandrosterone sulfate were found suitable, while androsterone and epiandrosterone (both sulfo-conjugated) were chosen as target analytes. The developed method is based on multi-dimensional gas chromatography coupled to IRMS in order to optimize the overall assay sensitivity. The approach was validated, and a reference population encompassing n = 65 males and females was investigated to calculate population-based thresholds. As proof-of-concept, samples from volunteers receiving T replacement therapies and excretion study samples were investigated. Graphical abstract