Genomic determinants of Furin cleavage in diverse European SARS-related bat coronaviruses

The furin cleavage site (FCS) in SARS-CoV-2 is unique within the Severe acute respiratory syndrome–related coronavirus (SrC) species. We re-assessed diverse SrC from European horseshoe bats and analyzed the spike-encoding genomic region harboring the FCS in SARS-CoV-2. We reveal molecular features in SrC such as purine richness and RNA secondary structures that resemble those required for FCS acquisition in avian influenza viruses. We discuss the potential acquisition of FCS through molecular mechanisms such as nucleotide substitution, insertion, or recombination, and show that a single nucleotide exchange in two European bat-associated SrC may suffice to enable furin cleavage. Furthermore, we show that FCS occurrence is variable in bat- and rodent-borne counterparts of human coronaviruses. Our results suggest that furin cleavage sites can be acquired in SrC via conserved molecular mechanisms known in other reservoir-bound RNA viruses and thus support a natural origin of SARS-CoV-2

Estimations of Competence in Neurodevelopmental Conditions: A Review

Estimations of competence paradigms offer methods to help us measure how well we track our performance. Bridging across the clinical research and metacognitive research traditions, we identified the Positive Illusory Bias (PIB), metamemory and meta-reasoning paradigms for assessing estimation of competence in neurodevelopmental conditions. Overall, studies from PIB paradigms suggest that individuals with Attention-Deficit Hyperactivity Disorder, Autism, Intellectual Disability and Learning Disability tend to display a positive bias in their performance relative to other informants. In metamemory paradigms, individuals with these neurodevelopmental conditions tend to show more discrepancy between their subjective judgments and their memory performance relative to comparison controls, but these findings have been less consistent than for PIB. Meta-reasoning has been less well-studied across neurodevelopmental conditions. In order to advance our understanding of whether estimation of competence is a significant domain for understanding neurodevelopmental conditions, consideration must be given to conceptual models for each neurodevelopmental condition, methodological issues (paradigm selection and interpretation of self-report and subjective judgment) and developmental considerations

Estimations of Competence in Neurodevelopmental Conditions: A Review

Estimations of competence paradigms offer methods to help us measure how well we track our performance. Bridging across the clinical research and metacognitive research traditions, we identified the Positive Illusory Bias (PIB), metamemory and meta-reasoning paradigms for assessing estimation of competence in neurodevelopmental conditions. Overall, studies from PIB paradigms suggest that individuals with Attention-Deficit Hyperactivity Disorder, Autism, Intellectual Disability and Learning Disability tend to display a positive bias in their performance relative to other informants. In metamemory paradigms, individuals with these neurodevelopmental conditions tend to show more discrepancy between their subjective judgments and their memory performance relative to comparison controls, but these findings have been less consistent than for PIB. Meta-reasoning has been less well-studied across neurodevelopmental conditions. In order to advance our understanding of whether estimation of competence is a significant domain for understanding neurodevelopmental conditions, consideration must be given to conceptual models for each neurodevelopmental condition, methodological issues (paradigm selection and interpretation of self-report and subjective judgment) and developmental considerations

A quantum theory account of order effects and conjunction fallacies in political judgments

Are our everyday judgments about the world around us normative? Decades of research in the judgment and decision-making literature suggest the answer is no. If people's judgments do not follow normative rules, then what rules if any do they follow? Quantum probability theory is a promising new approach to modeling human behavior that is at odds with normative, classical rules. One key advantage of using quantum theory is that it explains multiple types of judgment errors using the same basic machinery, unifying what have previously been thought of as disparate phenomena. In this article, we test predictions from quantum theory related to the co-occurrence of two classic judgment phenomena, order effects and conjunction fallacies, using judgments about real-world events (related to the U.S. presidential primaries). We also show that our data obeys two a priori and parameter free constraints derived from quantum theory. Further, we examine two factors that moderate the effects, cognitive thinking style (as measured by the Cognitive Reflection Test) and political ideology

Democratized image analytics by visual programming through integration of deep models and small-scale machine learning

Analysis of biomedical images requires computational expertize that are uncommon among biomedical scientists. Deep learning approaches for image analysis provide an opportunity to develop user-friendly tools for exploratory data analysis. Here, we use the visual programming toolbox Orange (http://orange.biolab.si) to simplify image analysis by integrating deep-learning embedding, machine learning procedures, and data visualization. Orange supports the construction of data analysis workflows by assembling components for data preprocessing, visualization, and modeling. We equipped Orange with components that use pre-trained deep convolutional networks to profile images with vectors of features. These vectors are used in image clustering and classification in a framework that enables mining of image sets for both novel and experienced users. We demonstrate the utility of the tool in image analysis of progenitor cells in mouse bone healing, identification of developmental competence in mouse oocytes, subcellular protein localization in yeast, and developmental morphology of social amoebae

Treatment gaps in the implementation of LDL cholesterol control among high- and very high-risk patients in Europe between 2020–2021: the multinational observational SANTORINI study

Background European data pre-2019 suggest statin monotherapy is the most common approach to lipid management for preventing cardiovascular (CV) events, resulting in only one-fifth of high- and very high-risk patients achieving the 2019 ESC/EAS recommended low-density lipoprotein cholesterol (LDL-C) goals. Whether the treatment landscape has evolved, or gaps persist remains of interest. Methods Baseline data are presented from SANTORINI, an observational, prospective study that documents the use of lipid-lowering therapies (LLTs) in patients ≥18 years at high or very high CV risk between 2020 and 2021 across primary and secondary care settings in 14 European countries. Findings Of 9602 enrolled patients, 9044 with complete data were included (mean age: 65.3 ± 10.9 years; 72.6% male). Physicians reported using 2019 ESC/EAS guidelines as a basis for CV risk classification in 52.0% (4706/9044) of patients (overall: high risk 29.2%; very high risk 70.8%). However, centrally re-assessed CV risk based on 2019 ESC/EAS guidelines suggested 6.5% (308/4706) and 91.0% (4284/4706) were high- and very high-risk patients, respectively. Overall, 21.8% of patients had no documented LLTs, 54.2% were receiving monotherapy and 24.0% combination LLT. Median (interquartile range [IQR]) LDL-C was 2.1 (1.6, 3.0) mmol/L (82 [60, 117] mg/dL), with 20.1% of patients achieving risk-based LDL-C goals as per the 2019 ESC/EAS guidelines. Interpretation At the time of study enrolment, 80% of high- and very high-risk patients failed to achieve 2019 ESC/EAS guidelines LDL-C goals. Contributory factors may include CV risk underestimation and underutilization of combination therapies. Further efforts are needed to achieve current guideline-recommended LDL-C goals. Trial registration ClinicalTrials.gov Identifier: NCT04271280. Funding This study is funded by Daiichi Sankyo Europe GmbH, Munich, Germany

Performance deficits of NK1 receptor knockout mice in the 5 choice serial reaction time task: effects of d Amphetamine, stress and time of day.

Background The neurochemical status and hyperactivity of mice lacking functional substance P-preferring NK1 receptors (NK1R-/-) resemble abnormalities in Attention Deficit Hyperactivity Disorder (ADHD). Here we tested whether NK1R-/- mice express other core features of ADHD (impulsivity and inattentiveness) and, if so, whether they are diminished by d-amphetamine, as in ADHD. Prompted by evidence that circadian rhythms are disrupted in ADHD, we also compared the performance of mice that were trained and tested in the morning or afternoon. Methods and Results The 5-Choice Serial Reaction-Time Task (5-CSRTT) was used to evaluate the cognitive performance of NK1R-/- mice and their wildtypes. After training, animals were tested using a long (LITI) and a variable (VITI) inter-trial interval: these tests were carried out with, and without, d-amphetamine pretreatment (0.3 or 1 mg/kg i.p.). NK1R-/- mice expressed greater omissions (inattentiveness), perseveration and premature responses (impulsivity) in the 5-CSRTT. In NK1R-/- mice, perseveration in the LITI was increased by injection-stress but reduced by d-amphetamine. Omissions by NK1R-/- mice in the VITI were unaffected by d-amphetamine, but premature responses were exacerbated by this psychostimulant. Omissions in the VITI were higher, overall, in the morning than the afternoon but, in the LITI, premature responses of NK1R-/- mice were higher in the afternoon than the morning. Conclusion In addition to locomotor hyperactivity, NK1R-/- mice express inattentiveness, perseveration and impulsivity in the 5-CSRTT, thereby matching core criteria for a model of ADHD. Because d-amphetamine reduced perseveration in NK1R-/- mice, this action does not require functional NK1R. However, the lack of any improvement of omissions and premature responses in NK1R-/- mice given d-amphetamine suggests that beneficial effects of this psychostimulant in other rodent models, and ADHD patients, need functional NK1R. Finally, our results reveal experimental variables (stimulus parameters, stress and time of day) that could influence translational studies