The origins of directed acyclic graphs (DAGs) date back to the emergence of ‘graph theory’ in the early 1700s (Biggs et al. 1986). DAGs are conceptual or literal, diagrammatic representations of causal paths between variables which are constructed – as their name suggests – on the basis of two over-riding principles: first, that all causal paths are ‘directed’ (i.e. for each pair of variables, only one can represent the cause, while the other must be its consequence); and second, that no direct cyclical paths, or indirect cyclical pathways (comprising sequences of consecutive paths) are allowed, such that no consequence can be considered its own direct or indirect cause (hence ‘acyclic’; Law et al., 2012). As such DAGs reflect the knowledge, presumptions, assumptions and/or speculation of the analyst(s) concerned regarding the causal relationships between each of the variables included therein. Current convention dictates that variables are represented as nodes/vertices, and that any causal paths between variables are represented as directed arcs/edges/lines, often in the form of arrows (see Figure 1). Although each arc indicates the presence and direction of a known/presumed/assumed/speculative causal relationship between the two variables concerned, drawing an arc does not require the sign, magnitude, precision or shape of the relationship to be known or declared (Tennant et al., 2021). In this respect, DAGs provide a simple, uncomplicated, accessible and entirely nonparametric approach for postulating causal relationships amongst any variables of interest even when these are uncertain, unknown or entirely speculative (Ellison, 2020). Nonetheless, as a result of the parametric constraints imposed by the presence/absence of possible arcs within any given DAG, these also reflect and support a number of more sophisticated statistical applications which make it possible to use DAGs to inform the design of multivariable statistical models that reflect the causal structure(s) involved – albeit without the need to know or understand the mathematical technicalities on which these are based (Lewis and Kuerbis, 2016). These features make DAGs attractive cognitive, educational and analytical tools for strengthening the epistemological, theoretical and empirical basis of causal inference, and there has been a recent proliferation in the use of DAGs across a range of applied scientific disciplines (e.g. Knight and Winship, 2013), and an associated upsurge in analytical methods training (e.g. Elwert, 2011; Gilthorpe, 2017; Hernán 2018; Roy, 2021; Hünermund, 2021). This Chapter reflects on a decade of delivering medical statistics training to undergraduate medical students at the University of Leeds between 2012-2021 in which the third year research, evaluation and special studies module (‘RESS3’) has used DAGs to support the development of applied statistical skills relevant to the extended student-selected research and evaluation projects (ESREP) students undertake in their fourth and final years (Ellison, 2021; Ellison et al., 2014a,b). Based on successive iterations of the structure and content of the RESS3 module, together with notes made during formal and informal planning and review meetings with module leads, lecturers, tutors and students, we draw on the claims and criticisms made of DAGs in the epidemiological literature to identify a number of explicit strengths (and associated, often implicit. weaknesses) that are central to their use in prediction and causal inference modelling. While using DAGs requires (and benefits from) a clear understanding of their non-parametric nature and parametric implications, the weaknesses of DAGs seem likely to reflect both: the challenges inherent in the modelling of data generating processes when these are imperfectly understood; and troublesome cognitive and heuristic tendencies common to all analytical tools – in which the tool facilitates the task in hand by reducing the necessity (and benefits of) exploring uncertainties and identifying assumptions. These, more epistemological considerations appear particularly challenging for medical undergraduates to grasp (Ellison, 2021), but also appear poorly understood by many established analysts and clinical epidemiologists (Ellison, 2020).

Directed acyclic graphs (DAGs) are nonparametric causal path diagrams that have substantial utility as principled representations of disease and healthcare pathways, and of the underlying ‘data generating mechanisms’ these pathways involve. As such, DAGs provide a valuable bridge between: the aetiological knowledge, operational insight and professional experience on which clinical training and practice depend; and the more abstract epistemological and analytical considerations required to extract robust statistical insight from health and healthcare data. DAGs are nonetheless vulnerable to imperfect biomedical paradigms, partial clinical knowledge and limited empirical data. DAGs drawn under such circumstances offer limited scope for statistical insight free from cognitive, analytical or inferential bias if: they misrepresent the data generating mechanisms involved; or ignore the important role that omitted variables (whether measured, unmeasured or unacknowledged) might play therein. To address these weaknesses and broaden the appeal and application of DAGs, this chapter provides ten simple steps that educators can use to improve the analytical competence and statistical confidence of the healthcare students, qualified practitioners and experienced researchers they support. These steps use temporal logic to draw DAGs so as to: reduce reliance on uncertain knowledge, incomplete information, flawed assumptions or guesswork; and avoid, mitigate or acknowledge the errors and biases that each of these incur. The chapter comprises an accessible, non-technical overview of the perspective and thoughtfulness required to generate temporally coherent DAGs as objective representations of the probabilistic causal paths involved in context-specific data generating mechanisms. It encourages a focus on those variables operating as potential sources of analytical or inferential bias when estimating the plausible, probabilistic causal relationship between two pre-specified variables; and specifically addresses the challenges posed by: omitted; time-variant; non-asynchronous; and temporally obscure variables. The chapter includes a worked example based on a published clinical study to demonstrate how each of the steps required to generate temporally-informed DAGs can be applied to: critically appraise the analytical decisions made during applied healthcare research; and inform the decisions required when designing, undertaking and analysing primary and secondary, prospective and retrospective research. The appendices include a summary of ten recommendations for improving the reporting and interrogability of DAGs and DAG-informed analyses.

Using Directed Transfer Function (DTF) and Partial Directed Coherence (PDC) in their information version, this paper extends their theoretical framework to incorporate instantaneous Granger Causality (iGC)’s frequency domain description into a single unified perspective. We show that standard vector autoregressive models allow portraying iGC’s repercussions associated with Granger Connectivity where interactions mediated without delay between time series can be easily detected.

We present a new computing package Flagser, designed to construct the directed flag complex of a finite directed graph, and compute persistent homology for flexibly defined filtrations on the graph and the resulting complex. The persistent homology computation part of Flagser is based on the program Ripser [2], but is optimised specifically for large computations. The construction of the directed flag complex is done in a way that allows easy parallelisation by arbitrarily many cores. Flagser also has the option of working with undirected graphs. For homology computations Flagser has an Approximate option, which shortens compute time with remarkable accuracy. We demonstrate the power of Flagser by applying it to the construction of the directed flag complex of digital reconstructions of brain microcircuitry by the Blue Brain Project and several other examples. In some instances we perform computation of homology. For a more complete performance analysis, we also apply Flagser to some other data collections. In all cases the hardware used in the computation, the use of memory and the compute time are recorded.

In a previous paper we defined the Black-and-White SAT problem which has exactly two solutions, where each variable is either true or false. We showed that Black-and-White $2$-SAT problems represent strongly connected directed graphs. We presented also the strong model of communication graphs. In this work we introduce two new models, the weak model, and the Balatonbogl\'{a}r model of communication graphs. A communication graph is a directed graph, where no self loops are allowed. In this work we show that the weak model of a strongly connected communication graph is a Black-and-White SAT problem. We prove a powerful theorem, the so called Transitions Theorem. This theorem states that for any model which is between the strong and the weak model, we have that this model represents strongly connected communication graphs as Blask-and-White SAT problems. We show that the Balatonbogl\'{a}r model is between the strong and the weak model, and it generates $3$-SAT problems, so the Balatonbogl\'{a}r model represents strongly connected communication graphs as Black-and-White $3$-SAT problems. Our motivation to study these models is the following: The strong model generates a $2$-SAT problem from the input directed graph, so it does not give us a deep insight how to convert a general SAT problem into a directed graph. The weak model generates huge models, because it represents all cycles, even non-simple cycles, of the input directed graph. We need something between them to gain more experience. From the Balatonbogl\'{a}r model we learned that it is enough to have a subset of a clause, which represents a cycle in the weak model, to make the Balatonbogl\'{a}r model more compact. We still do not know how to represent a SAT problem as a directed graph, but this work gives a strong link between two prominent fields of formal methods: SAT problem and directed graphs.

This letter attempts to find splashing height of liquid-filled container drop impact to a solid surface by dimensional analysis (DA). Two solutions were obtained by both traditional DA and directed DA without solving any governing equations. It is found that the directed DA can provide much more useful information than the traditional one. This study shows that the central controlling parameter is called splash number $\mathrm{Sp}=\mathrm{Ga} \mathrm{La}^\beta=(\frac{gR^3}{\nu^2})(\frac{\sigma R}{\rho \nu^2})^\beta$, which is the collective performance of each quantity. The splash height is given by $ \frac{h}{H}=(\frac{\rho\nu^2}{\sigma R})^\alpha f[\frac{gR^3}{\nu^2}(\frac{R\sigma}{\rho\nu^2})^\beta]=\frac{1}{\mathrm{La}^\alpha}f(\mathrm{Ga}\cdot \mathrm{La}^\beta)$. From the physics of the splashing number, we can have a fair good picture on the physics of the liquid splashing as follows: the jets propagation will generate vortex streets from the container bottom due to sudden pressure increasing from drop impact (water-hammer effect), which will travel along the container sidewall to the centre of the container and subsequently excite a gravity wave on the liquid surface. The interaction between the gravitational force, surface force and viscous force is responsible for creating droplet splash at the liquid surface.

Zika virus (ZIKV), a mosquito-borne flavivirus, was an almost neglected pathogen until its introduction in the Americas in 2015, where it has been responsible for a threat to global health, causing a great social and sanitary alarm due to its increased virulence, rapid spread, and an association with severe neurological and ophthalmological complications. Currently, no specific antiviral therapy against ZIKV is available, and treatments are palliative and mainly directed to symptoms relief, such as fever and rash, by administering antipyretics, anti-histamines, and fluids for dehydration. Nevertheless, lately, a great effort has been made to search for antiviral candidates using different approaches and methodologies, ranging from repurposing of specific compounds with known antiviral activity to the screening of libraries and of natural compounds. The identified antiviral candidates include drugs targeting viral components (structural proteins and enzymes), as well as cellular ones. Here, we present an updated review of current knowledge about anti-ZIKV strategies, focusing on host-directed antivirals as a realistic alternative to combat ZIKV infection.

Viruses with spindle or lemon-shaped virions are rare in the world of viruses, but are common in viruses of archaeal extremophiles, possibly due to the extreme conditions in which they thrive. However, the structural and genetic basis for the unique spindle shape is unknown. The best-studied spindle-shaped virus, SSV1, is composed mostly of the major capsid protein VP1. Similar to many other viruses, proteolytic cleavage of VP1 is thought to be critical for virion formation. Unlike half of the genes in SSV1, including the minor capsid protein gene vp3, the vp1 gene does not tolerate deletion or transposon insertion. In order determine the role of the vp1 gene and its proteolysis for virus function, we developed techniques for site-directed mutagenesis of the SSV1 genome and complemented deletion mutants with vp1 genes from other SSVs. By analyzing these mutants we demonstrate that the N-terminus of the VP1 protein is required, but the N-terminus, or entire SSV1 VP1 protein, can be exchanged with VP1s from other SSVs. However, the conserved glutamate at the cleavage site is not essential for infectivity. Interestingly, viruses containing point mutations at this position generate mostly abnormal virions.

Extraversion, a Big Five personality trait, has been identified as a significant factor in COVID-19 positive coping—yet, relevant research is conflicting. Studies have not situated the influence of extraversion within a geographical and historical context. Thus, a sound base is lacking for assessing when opposing results regarding extraversion and COVID-19 positive coping are likely to result. Furthermore, extraversion with respect to COVID-19 coping has not been considered concerning other-directed learning in contrast to self-directed learning. To establish a sufficiently sound base, an examination of the range of high-ranking Google Scholar results on extraversion and COVID-19 coping from different countries during the pandemic’s various waves—pre and post vaccine introduction—is undertaken. The same are then considered for insights into public opinion. Following, extraversion is compared with other-directed learning and differentiated from self-directed learning. An understanding is thus presented for assessing when extraversion will necessarily be an effective personality trait for COVID-19 positive coping and when it will not. Extraversion’s effect will be found inherently inconsistent for identifying COVID-19 positive coping as a result, because of its dependence on other-directed learning. The conclusion: COVID-19 positive coping stability is contingent on personal values that guide self-directed learning, rather than other-directed extraversion.

Routing a person through a traffic network presents a tension between selecting a fixed route that is easy to navigate and selecting an aggressively adaptive route that minimizes the expected travel time. We propose to create non-aggressive adaptive routes in the middle-ground seeking the best of both these extremes. Specifically, these routes still adapt to changing traffic conditions, however we limit the number of adjustments made in the route. This improves the user experience, by providing a continuum of options between saving travel time and minimizing navigation. We design strategies to model single and multiple route adjustments, and investigate enumerative techniques to solve these models. To alleviate the intractability with handling real-life traffic data, we develop efficient algorithms with easily computable lower and upper bounds. We finally present computational experiments highlighting the benefits of limited adaptability in terms of reducing the expected travel time.

Re-shaping of thermodynamics with the graph theory and Ramsey theory is suggested. Maps built of thermodynamic states are addressed. Thermodynamic states may be attainable and non-attainable by the thermodynamic process in the system of constant mass. We address the following question how large should be a graph describing connections between discrete thermodynamic states to guarantee the appearance of thermodynamic cycles? The Ramsey theory supplies the answer to this question. Direct graphs emerging from the chains of irreversible thermodynamic processes are considered. In any complete directed graph, representing the thermodynamic states of the system the Hamiltonian path is found. Transitive thermodynamic tournaments are addressed. The entire transitive thermodynamic tournament built of irreversible processes does not contain a cycle of length 3, or in other words, the transitive thermodynamic tournament is acyclic and contains no directed thermodynamic cycles.

For any positive integer n ≥ 2, the Erdős-Straus Conjecture claims that the Diophantine equation 4/n = 1/x + 1/y + 1/z has a solution where x, y, z are also positive integers. In this paper, a directed network based on this equation is generated, with properties such as its average clustering coefficient, average path length, degree distributions, and largest strongly connected component analysed to reveal some underlying trends about the nature of the conjecture. Potential connections between different numbers, that result from satisfying a source-solution relationship for this equation, are described using the appropriate number-theoretic interpretations wherever possible, while conjectures backed by these trends are made in other instances. Additionally, a directed configuration model is used to show that the origin of several results is the degree sequence of the network. Metrics relating to the prime number nodes, specifically their in and out degrees, are also explored to yield some intriguing observations. On the whole, the aim is to highlight the viability of complex networks as a computational tool to study this general class of problems pertaining to fixed-length unit fraction splits.

High-frequency neuroelectric signals like electroencephalography (EEG) or magnetoencephalography (MEG) provide a unique opportunity to infer causal relationships between local activity of brain areas. While causal inference is commonly performed through Classical Granger causality (GC) based on multivariate autoregressive models, this method may encounter important limitations (e.g. data paucity) in the case of high dimensional data from densely connected systems like the brain. Additionally, physiological signals often present long-range dependencies which commonly require high autoregressive model orders / number of parameters. We present a generalization of autoregressive models for GC estimation based on Wiener-Volterra decompositions with Laguerre polynomials as basis functions. In this basis, the introduction of only one additional global parameter allows to capture arbitrary long dependencies without increasing model order, hence retaining model simplicity, linearity and ease of parameters estimation. We validate our method in synthetic data generated from families of complex, densely connected networks and demonstrate superior performance as compared to classical GC. Additionally, we apply our framework to studying the directed human brain connectome through MEG data from 89 subjects drawn from the Human Connectome Project (HCP) database, showing that it is able to reproduce current knowledge as well as to uncover previously unknown directed influences between cortical and limbic brain regions.

The contemporary landscape of education is witnessing a paradigm shift towards innovative instructional methods, with the flipped learning approach gaining considerable attention. The purpose of this research was to investigate the impact of the flipped learning approach on students' perception and acceptance throughout an entire semester in the 'Introduction to Programming with Java' course, using a research design with a quantitative approach, ultimately aiming to inform educational practice and advance our knowledge of innovative teaching methods in higher education. This study was conducted at a university with 174 students involved, divided into two groups, 87 students in the experimental group and 87 students in the control group. The data collected through the scales were analyzed by using descriptive and inferential statistical analysis techniques in statistical software. At the end of the measurements, the technology acceptance level and self-directed learning perceptions of engineering students who received education with flipped learning were high. The results suggest that educators should consider students' readiness for self-directed learning when implementing the flipped learning approach and focus on creating an environment that supports their autonomy and engagement. This research offers valuable guidance for instructors, curriculum designers, and educational policymakers seeking to enhance the effectiveness of flipped learning in higher education courses.

Defects in low-density lipoprotein receptor (LDLR) are associated with familial hypercholesterolemia (FH), manifested by atherosclerosis and cardiovascular disease. Defective LDLR in hepatocytes leads to increased blood cholesterol level that damage vascular cells, especially endothelial cells, through oxidative stress and inflammation. However, the distinctions between endothelial cells from individuals with normal and defective LDLR are not yet fully comprehended. In this study, we obtained and examined endothelial derivatives of induced pluripotent stem cells (iPSC) generated previously from conditionally healthy donors and compound heterozygous FH patients carrying pathogenic LDLR alleles. In normal iPSC-derived endothelial cells (iPSC-EC), we detected the LDLR protein predominantly in its mature form, while iPSC-EC from patients with FH display reduced level of mature LDLR and show abolished low-density lipoprotein uptake. RNA-seq of iPSC-EC with mutant LDLR revealed a unique transcriptome profile comprising downregulated genes related to monocarboxylic acid transport, exocytosis and cell adhesion, as well as upregulated signaling pathways of cell secretion and leukocyte activation. Overall, these findings suggest that LDLR defects increases susceptibility of endothelial cells to inflammation and oxidative stress. This, combined with elevated extrinsic cholesterol levels, may result in accelerated endothelial dysfunction, contributing to early progression of atherosclerosis and other cardiovascular pathologies related to FH.

The term new genomic techniques (NGTs), is an umbrella term to describe a variety of techniques that can alter the genetic material of an organism and that have emerged or have been developed since 2001, when the existing genetically modified organism (GMO) legislation was adopted. The analytical framework to detect GMOs in Europe is a established single harmonized procedure which is mandatory for authorization of GM food and feed, thus generating reliable, transparent and effective labelling scheme for GMO products. However, NGT products challenge the implementation and enforcement of the current regulatory system in the EU, relating in particular to the detection of NGT products that contain no foreign genetic material. Consequently, current detection methods will fail to meet minimum performance requirements. Although existing detection methods may be able to detect and quantify even small alterations in the genome, this does not necessarily confirm the distinction between products resulting from NGTs subject to the GMO legislation and other products. Therefore, this study provides a stepwise approach for the in silico prediction of PCR systems specificity by testing a bioinformatics pipeline for amplicon and primer set searches in current genomic databases. We have tested our methodology in two mutant genotypes produced by CRISPR/Cas9 in Arabidopsis thaliana. Overall, our results demonstrated that the single PCR system developed for the identification of a nucleotide insertion in the grf1-3 genotype has sufficient hits in the databases that would not allow discrimination of this mutanted event. Differently, the second mutated genotype grf8-61 which contains a -3bp deletion, found no matches in the sequence variant database. Our approach is the first step in decision making on PCR system and modification of them for empirical testings.

Directed energy deposition (DED) is an efficient method to fabricate functionally graded materials (FGMs) with gradient composition and complex structures, allowing for local tailoring of properties instead of the costly need for extraneous welds and joints. In this study, a FGM from stainless steel to Inconel alloy was successfully fabricated using the powder-based laser DED. A very refined grain structure has been observed in at the composition with 75 wt.% Inconel alloy content, which also exhibits the highest (entropy). For the first time, the post heat treatments, microstructure and aging precipitation behaviors of FGMs were systematically studied via experimental characterization and computation, to elucidate their effects on the gradient smoothing and mechanical properties. The diffusion and segregation of Ni, Nb and Ti elements underly the transformation mechanism between Laves, δ, γ’ and γ’’ phases during precipitation. Homogenization on FGMs not only eliminates the heterogeneity inherited from the AM process, but also provides a practical way to smoothen the gradient on composition and microstructure for the eventual good gradient properties. It has a direct influence on the following precipitation behaviors in the FGM, which highly relies on the diffusion degree of the elements in the matrix and grain boundaries. The high-throughput thermodynamic modeling and kinetic modeling were exploited to evaluate the experimental microstructure and address computational uncertainty using different thermodynamic conditions and databases, which enables an accelerated design through local tailoring of process-structure-property relationships to develop new functional materials.

Background: High coronary thrombus burden has been associated with unfavorable outcomes in patients with ST-segment elevation myocardial infarction (STEMI), the optimal management of which has not yet to be established. Methods: We evaluated the safety and efficacy of adjunctive catheter-directed thrombolysis (CDT) during primary percutaneous coronary intervention (PCI) in patients with STEMI and high thrombus burden. Results: Among the 1,849 consecutive patients with STEMI, 263 had high thrombus burden. Moreover, 41 patients received intracoronary infusion of tissue plasminogen activator during primary PCI (CDT group), whereas 222 did not receive (non-CDT group). No significant differences in bleeding complications and in-hospital and long-term mortalities were observed (9.8% vs. 7.2%, p=0.53; 7.3% vs. 2.3%, p=0.11; and 12.6% vs. 17.5%, p=0.84, CDT vs. non-CDT). In patients who underwent antecedent aspiration thrombectomy during PCI (75.6%; CDT group and 87.4%; non-CDT group), thrombolysis in myocardial infarction grade 2 or 3 flow rate after thrombectomy was significantly lower in the CDT group than in the non-CDT group (32.2% vs. 61.0%, p<0.01). However, the final rates improved considerably without significant difference (90.3% vs. 97.4%, p=0.14). Conclusions: For STEMI patients with high thrombus burden, adjunctive CDT is safe and effective for improving coronary flow. CDT resulted in favorable coronary flow even after unsatisfactory aspiration thrombectomy.

Genetic switches can be utilized for many purposes in synthetic biology including the assembly of complex genetic circuits to achieve sophisticated cellular systems and the construction of biosensors for real-time monitoring of intracellular metabolite concentrations. Although genetic switches have mainly been developed in prokaryotes to date, eukaryotic genetic switches are increasingly being reported as both rational and irrational engineering technologies mature. In this review, we describe genetic switches in yeast based on synthetic transcription factors and/or synthetic promoters. We also discuss directed evolution technologies for the rapid and robust construction of yeast genetic switches.

Complex systems can be described as the network of interactions between their components. In directed networks, information, energy and matter flow in dominant directions. Undirected networks, on the other hand, cannot easily capture these asymmetries. The local flow of information depends on the node spin, which is a function of the number of incoming and outgoing links attached to it. And yet, how the heterogeneous association between in-degree and out-degree constraints global dynamics remains poorly understood. Here, we develop a new theoretical model to study the relationship between node directionality and global flow dynamics. Our computational analysis of random and scale-free directed networks indicates that structural diversity constrains the dimensionality of reachable dynamical space. These results suggest how local directionality might be an universal driver of global dynamics in many systems, from social networks, to technological systems to the connectome.

Organizational skills are a set of cognitive abilities responsible for goal-directed behaviors. While they are moderately studied in clinical settings, the assessment of organizational skills in the general population remains under-studied. This paper presents the new Durand Organizational Skills Questionnaire (DOSQ), which was developed to examine the factors associated with organizational abilities in the general population. Exploratory factor analysis, validated by a confirmatory factor analysis, suggests eight factors: Work Organization, Communication Clarity, Punctuality, Goal-Oriented Behavior, Assiduity, Workspace Organization, Strategies, and Attentiveness. Three studies using samples from the general population provided evidence for the reliability and validity of the DOSQ’s scores. Overall, the results suggest that the DOSQ offers a valid approach to measuring organizational skills in the general population.

The combination of wet-lab experimental data on multi-site combinatorial mutations and machine learning is an innovative method in protein engineering. In this study, we present an improved innovative sequence–activity relationship (innov'SAR) methodology based on novel descriptors and digital signal processing (DSP) to construct a predictive model. In this improved approach, 21 experimental (R)-selective amine transaminases from Aspergillus terreus (AT-ATA) were used as an input to predict higher thermostability than that predicted using the existing data. We successfully improved the determination coefficient (R2) of the model from 0.66 to 0.92. In addition, root mean square deviation (RMSD) and root mean square fluctuation (RMSF) were estimated and conformation analysis based on molecular dynamics simulations was performed to verify the enhanced thermal stability of the screened mutants. The improved innov'SAR algorithm enhanced the predictive accuracy, suggesting a method for modifying the stability of AT-ATA, which may help in directed evolutionary screening and open up new avenues for protein engineering.

Despite of over 20 years of community directed treatment with ivermectin (CDTI), a high prevalence of onchocerciasis and onchocerciasis-associated epilepsy were observed in rural villages in Mahenge, Tanzania. Therefore, we assessed the knowledge, attitude and practice about onchocerciasis in four rural villages in the Mahenge area. This was a qualitative study conducted between June and July 2019. Eleven focus group discussions were organized with persons with epilepsy and their caretakers, community resource persons, and community drug distributors (CDDs), and two in-depth interviews with district programme coordinators of neglected tropical diseases (NTD). Most participants were aware about symptoms of onchocerciasis using local terminologies such as “ukurutu/rough dry skin” and “kuwashwa/itching”. A small proportion of people did not take ivermectin during CDTI for fear of adverse reactions such as itching and swelling. Some men believed that ivermectin may decrease libido. Challenges for high CDTI coverage included, long walking distance by CDDs to deliver drugs to households, persons being away for farming, low awareness of the disease and limited supervision by the NTD coordinators. In conclusion, ivermectin uptake in Mahenge should be optimised by continuous advocacy about the importance of taking ivermectin to prevent onchocerciasis-associated morbidity and by improving supervision during CDTI.

A large variety of molecular interactions occurs between biomolecular components in cells. When one or a cascade of molecular interactions results in a regulatory effect, by one component onto a downstream component, a so-called ‘causal interaction’ takes place. Causal interactions constitute the building blocks in our understanding of larger regulatory networks in cells. These causal interactions and the biological processes they enable (e.g., gene regulation) need to be described with a careful appreciation of molecular interactions that occur between entities. A proper description of this information enables archiving, sharing, and reuse by humans and for computational science. Various representations of causal relationships between biological components are currently used in a variety of resources. Here, we propose a checklist that accommodates current representations, and call it the Minimum Information about a Molecular Interaction CAusal STatement (MI2CAST). This checklist defines both the required core information, as well as a comprehensive set of other contextual details valuable to the end user and relevant for reusing and reproducing causal molecular interaction information. The MI2CAST checklist can be used as reporting guidelines when annotating and curating causal statements, while assuring uniformity and interoperability of the data across resources.

Cholesterol biosynthesis inhibitors (statins) protect hypercholesterolemic patients from developing active tuberculosis, suggesting that these drugs could help the host to control the pathogen at the initial stages of the disease. This work studies the effect of fluvastatin on the early response of healthy peripheral blood mononuclear cells (PBMC) to inactivated Mycobacterium tuberculosis (Mtb) H37Ra. We found that in fluvastatin-treated PBMC, most monocytes/macrophages became foamy cells that overproduce NLRP3 inflammasome components in the absence of immune stimulation, evidencing important cholesterol metabolism/immunity connections. When both fluvastatin-treated and untreated PBMC were exposed to Mtb, a subset of macrophages quickly captured large amounts of bacilli and died, concentrating the bacteria in necrotic areas. In fluvastatin-untreated cultures, most of the remaining macrophages became epithelioid cells that isolated these areas of cell death in granulomatous structures that barely produced IFN-gamma. By contrast, in fluvastatin-treated cultures, foamy macrophages surrounded the accumulated bacteria to degrade them, markedly activated caspase-1 and elicited a potent IFNgamma/cytotoxic response. In rabb-gammaits immunized with the same bacteria, fluvastatin therapy increased the tuberculin test response. We conclude that statins enhance macrophage effectiveness to control Mtb supported by adaptive immunity, offering a promising tool in the design of alternative therapies to fight tuberculosis.

Recent results have shown that the human malaria-resistant hemoglobin S mutation originates de novo more frequently in the gene and in the population where it is of adaptive significance, namely, in the hemoglobin subunit beta gene compared to the non-resistant but otherwise identical 20A>T mutation in the hemoglobin subunit delta gene, and in sub-Saharan Africans, who have been subject to intense malarial pressure for many generations, compared to Northern Europeans, who have not. This finding raises a fundamental challenge to the traditional notion of accidental mutation. Here we address this finding with the replacement hypothesis, according to which pre-existing genetic interactions can lead directly and mechanistically to mutations that simplify and replace them. Thus, a gradual evolutionary process under selection can hone in on interactions of importance for the currently evolving adaptations, from which large-effect mutations follow that are relevant to these adaptations. We exemplify this hypothesis using multiple types of mutation, including gene fusion mutations, gene duplication mutations, A>G mutations in RNA-edited sites and transcription-associated mutations, and place it in the broader context of a system-level view of mutation origination called Interaction-based Evolution. Potential consequences include that similarity of mutation pressures may contribute to parallel evolution in genetically related species, that the evolution of genome organization may be driven by mutational mechanisms, that transposable element movements may also be explained by replacement, and that long-term directional mutational responses to specific environmental pressures are possible. Such responses need to be further tested by future studies in natural and artificial settings.

Solidification cracking is a major obstacle when joining dissimilar alloys using additive manufacturing. In this work, location-specific solidification cracking susceptibility has been investigated using an integrated computational materials engineering (ICME) approach for a graded alloy formed by mixing P91 steel and Inconel 740H superalloy. An alloy derived from a mixture of 26 wt.% P91 steel and 74 wt.% Inconel 740H, with high configurational and total entropy, was fabricated using wire-arc additive manufacturing. Microstructure characterization revealed intergranular solidification cracks, which increased in length along with the build height. With inputs from experiments, such as secondary dendrite arm spacing, the DICTRA (diffusion-controlled transformations) module within the Thermo-Calc software was used to model location-specific solidification cracking susceptibility. The top region, with the highest cooling rate, has the highest solidification cracking susceptibility and is in good agreement with the experimentally observed crack length. From Scheil simulations, it was deduced that pronounced segregation of Nb and Cu within the cracks increased the solidification range by suppressing the solidus temperature. The overall solidification cracking susceptibility and freezing range was highest for the 26 wt.% P91 alloy amongst the mixed compositions between P91 steel and 740H superalloy, proving that solidification characteristics play a major role in alloy design for additive manufacturing.

This study is a synthesis of 159 articles that were selected for their relevance to comprehend key aspects of the Massive Open Online Courses (MOOCs) phenomenon, from a discourse analysis perspective. Since 2011, MOOCs are expanding worldwide so that the number of subscribers outpointed 101 million at the end of 2018. This paper explores the question whether the MOOCs are the embodiment of the global one-world classroom or whether, instead, they represent a low-cost alternative tailored to a segment that doesn´t have enough time or resources to attend a brick-and-mortar college. In addition, the review tackles the link between motivation and low completion rates. Finally, we discuss the need to devise better methods to assess the pedagogical value of MOOCs.

The research proposes a self-directed paradigm with self-design using the existing technology with LMS modules, discussions, and self-tests. The research establishes its criteria for assurance of teaching and learning known as 7x2C for the compliance of content, and appearance along with other criteria for the analysis. The above technology of web and LMS is tested for a business course that is technology-oriented in creating an experiential learning system for Covid-19 awareness. Similarly, among other ideas, an environment for educating learners about diabetes and obesity has been designed. The project is known as Sunchoke with its theme of Grow, Eat, and Heal. The educators can use their technology and apply self-directed pedagogy to transform this approach to their customized ways by using their content and rubrics.

Infection with Zika virus (ZIKV), a member of the Flavivirus genus of the Flaviviridae family, typically results in mild self-limited illness, but severe neurological disease occurs in a limited subset of patients. In contrast, serious outcomes commonly occur in pregnancy that affect the developing fetus, including microcephaly and other major birth defects. The genetic similarity of ZIKV to other widespread flaviviruses, such as dengue virus (DENV), presents a challenge to the development of specific ZIKV diagnostic assays. Nonstructural protein 1 (NS1) is established for use in immunodiagnostic assays for flaviviruses. To address the cross-reactivity of ZIKV NS1 with proteins from other flaviviruses we used site-directed mutagenesis to modified putative epitopes. Goat polyclonal antibodies to variant ZIKV NS1 were affinity-purified to remove antibodies binding to the closely related NS1 protein of DENV. An antigen-capture ELISA configured with the affinity-purified polyclonal antibody showed a linear dynamic range between approximately 500 to 30 ng/mL, with a limit of detection of between 1.95 and 7.8 ng/mL. NS1 proteins from DENV, yellow fever virus, St. Louis encephalitis virus and West Nile virus showed significantly reduced reactivity in the ZIKV antigen-capture ELISA. Refinement of approaches similar to those employed here could lead to development of ZIKV-specific immunoassays suitable for use in areas where infections with related flaviviruses are common.

Myxobacteria represent a viable source of chemically diverse and biologically active secondary metabolites. The myxochelins are a well-studied family of catecholate-type siderophores produced by various myxobacterial strains. Here, we report the discovery, isolation and structure elucidation of three new myxochelins N1–N3 from the terrestrial myxobacterium Corallococcus sp. MCy9049, featuring an unusual nicotinic acid moiety. Precursor-directed biosynthesis (PDB) experiments and total synthesis were performed in order to confirm structures, improve access to pure compounds for bioactivity testing and to devise a biosynthesis proposal. The combined evaluation of metabolome and genome data covering myxobacteria supports the notion that the new myxochelin congeners reported here are in fact frequent side products of the known myxochelin A biosynthetic pathway in myxobacteria.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is characterized by a high mortality of elderly men with age-related comorbidities. In most of these patients, uncontrolled local and systemic hyperinflammation induces severe and often lethal outcomes. The aging process is characterized by the gradual development of a chronic subclinical systemic inflammation (inflamm-aging) and by acquired immune system impairment (immune senescence). Here, we advance the hypothesis that some key features of aging contribute to the disproportionate SARS-CoV-2 mortality suffered by elderly men. At least four well-recognized aging-related characteristics that are strongly expressed in older men go some way towards explaining why these patients account for the vast majority of fatalities: i. the presence of subclinical systemic inflammation without overt disease, ii. a blunted acquired immune system and type I interferon response due to the chronic inflammation; iii. the downregulation of ACE2 (SARS-CoV-2 receptor), which triggers inflammation, particularly in patients with age-related comorbid diseases such as type II diabetes; and iv. accelerated biological aging, as measured by epigenetic and senescence markers (e.g. telomere shortening) associated to the chronic inflammatory state. Though typical of the aged, especially of elderly men, it is conceivable that these features are also shared by some subsets of the younger population. The high mortality rate of SARS-CoV-2 infection suggests that clarification of the mechanisms of inflamm-aging and immune senescence can help combat not only age-related disorders but also SARS-CoV-2 infection.

Hybrid machine tools combining additive and subtractive processes have arisen as a solution to the increasing manufacture requirements, boosting the potentials of both technologies, while compensating and minimizing their limitations. Nevertheless, the idea of hybrid machines is relatively new and there is a notable lack of knowledge in the field. Therefore, in the present paper, an insight into the advancements of hybrid machines is given, identifying their real capabilities, together with the latest developments from an industrial context. In addition, the current situation and future perspectives of hybrid machines from the point of view of process planning, monitoring and inspection are discussed. Finally, the challenges that must be overcome and the opportunities that the hybrid machines will provide in the forthcoming years are presented.

The article outlines a creative approach by fusing ideas from fuzzy contractions, graph mappings, and Kannan mappings to create a brand-new notion known as "Kannan-graph-fuzzy contraction." This combination of concepts makes it possible to create a unique framework for resolving real-world issues controlled by nonlinear models. It is anticipated that using Kannan-graph-fuzzy contractions will offer a fresh approach to discussing solution existence in situations where these ideas overlap. This strategy might have a significant impact on a lot of real-world applications, proving how practical multidisciplinary techniques are for tackling issues in the real world originating from technology and engineering. The article includes several illustrated examples based on computer simulations, making the results more explicit.

Background: Coronavirus disease (COVID-19) has caused one of the worst global pandemics in recent decades. It has disrupted education systems worldwide, leading to a forced shift from traditional face-to-face to blended or fully distanced learning, requiring a higher level of student readiness for self-directed learning (SDL) and a more internal locus of control (LOC). Objective: This study explored the relationship between locus of control and level of readiness for SDL among Saudi nursing students and whether the COVID-19 pandemic has impacted this relation-ship. Methods: a cross-sectional correlational descriptive study was conducted to survey 277 Saudi nursing students enrolled in the bachelor program at one of the reputable universities in Saudi Arabia. An E-questionnaire containing two scales, the Self-Directed Learning Readiness Scale for Nursing Education, and the Locus of Control Scale, was used to collect data in addition to the selected participants’ characteristics. Results: Nursing students had a moderate-to-low level of readiness for SDL (mean = 144.0), and the majority had an external LOC. There was a significant association between the locus of control and level of readiness for self-directed learning (r = 0.19*, p = 0.001), and the internal locus of control was more significantly associated with self-directed learning (r = 0.22*, p = 0.0001) than with external locus of control. Conclusion: The study findings indicate a propensity of respondents towards an external locus of control, whereas most of the respondents’ reported levels of readiness ranged between low and moderate across all dimensions of self-directed learning. This study was not registered.

Alzheimer's disease is a multifactorial neurodegenerative disorder, with Acetylcholinesterase, Butyrylcholinesterase, Beta secretase, Glycogen Synthase Kinase beta and Monoamine oxidase B playing central role in it's pathogenesis. Therefore, this research aims to discover potential curative multitarget drugs derived from African natural products capable of addressing the multifactorial characteristics of the disease. In silico approaches were used to filter a 880 african natural compounds library based on selected pharmacokinetic properties. Molecular docking against the five aforementioned proteins, followed by Molecular Mechanics with Generalised Born and Surface Area Solvation scoring for the top compounds were used to assess binding. Density Functional Theory studies were used to assess electronic transitions. Pharmacokinetic filters resulted in 200 compounds, of which only five were selected after molecular docking. Density Functional Theory and Molecular Mechanics with Generalised Born and Surface Area Solvation scoring resulted in 3 potential multitarget compounds. Compound 157 (ZINC000095485950) showed triple-target inhibitory activity against Butyrylcholinesterase, Glycogen Synthase Kinase beta and Beta-secretase, while compounds 159 (ZINC000095485952) and 696 (ZINC000039144622) showed dual-target inhibitory activity against Butyrylcholinesterase and Glycogen Synthase Kinase beta. Molecular dynamics simulation and further experimental assessments are suggested.

Laser Powder Directed Energy Deposition (LP-DED) is an Additive Manufacturing process in which a laser beam is used to generate a melt pool onto a substrate. The additional material, in form of powder material, is fed into the generated melt pool and a raised track is obtained. The LP-DED process is very powerful for different applications such as the repair operations and the production of functionally graded material, however the application is still limited and one of the main reasons is related to the lack of knowledge in the physics of the process mechanisms. The process is influenced by a huge number of parameters and three main mechanisms can be identi-fied. These mechanisms are the powder flow, the generation of the molten pool and the solidifica-tion process and for each of these mechanisms the process parameters have a different relevance. In this paper, a review of the main mechanisms and the relationship between the process parame-ters and the outcome of each step of the process is presented.

Abstract: Background and objectives: Symptomatic walled-off pancreatic necrosis is a serious local complication of acute necrotising pancreatitis. The endoscopic step-up approach is the standard treatment for symptomatic walled-off pancreatic necrosis; however, adjunctive radiologic percu-taneous drainage for this condition is controversial. This study compared the clinical and radio-logic resolution of walled-off pancreatic necrosis achieved with the endoscopic step-up approach with or without radiology-guided percutaneous drainage. Material and Methods: This retrospective, single-center cohort study enrolled patients with symp-tomatic walled-off pancreatic necrosis who underwent endoscopic transmural drainage (ETD) followed by directed endoscopic necrosectomy (DEN) with or without radiology-guided drainage. A total of 34 patients (endoscopic approach, n=22; combined modality approach, n=12) underwent the endoscopic step-up approach (ETD followed by DEN). Baseline characteristics, clinical success, and resolution of necrosis were compared between groups. Results: All patients achieved symptom resolution from walled-off pancreatic necrosis. The mean patient age was 58.4 years, and 21 (61.8%) were men. After treatment with the endoscopic approach and combined modality approach, clinical success was achieved in 90.9% of patients within 11.5 days, and 66.7% of patients within 16.5 days, respectively. Both the total hospital stay (55 days vs 71 days; p=0.071) and time to complete radiologic resolution were shorter (93 days vs 124 days; p=0.23) in the endoscopic approach group. Conclusion: The endoscopic step-up approach resulted in the clinical resolution of symptomatic walled-off pancreatic necrosis comparable to that of the combined modality drainage. However, the endoscopic approach alone allows higher clinical success, early clinical and radiologic resolution, and a shorter hospital stay.

The ability to self-direct a research program determines graduate degree completion. Yet, research on incompletion of graduate physics programs assume students’ present level of self-direction adequate and neglects to recognize a lack of self-directed learning as key. One theoretical mathematical physicist focused on changing this challenge of physics graduate education by promoting self-directed learning through the type research flow that has been found to bring the greatest satisfaction to researchers with respect to their insights. This he provided through his space, time, open mindedness and theoretical contributions with his students and in collaboration with his colleagues. A self-directed learner himself, David J. Rowe developed methods of mentoring for encouraging physics graduate students to recognize symmetry as valuable in identifying solutions to problems quickly—helping these students take the lead in finding insightful resolutions to complex, multidimensional, mathematical physics uncertainties. How Rowe set about supporting self-directed learning in his graduate physics education interactions will be examined with the use of narrative research to interpret the texts and conversations with the author he made available. His techniques will be presented and recommendations made regarding how Rowe’s work in this regard can be modeled to improve self-direction in STEM graduate education.

Within the oligometastatic state, oligo-recurrent lymph node disease in prostate cancer represents an interesting clinical entity characterized by a relatively indolent biology that makes it unique: it can be treated radically, and its treatment is usually associated with a long period of control and excellent survival. Additionally it is an emergent situation that we are facing more frequently, mainly due to: a) the incorporation into clinical practice of the PSMA PET that provides strikingly increase superior images in comparison to conventional imaging, with higher sensitivity and specificity; b) the higher detection rates of bone and node disease with extremely low levels of PSA; and c) the availability of high-precision technology in radiotherapy treatments with the incorporation of stereotaxic body radiotherapy (SBRT) or stereotaxic ablative radiotherapy (SABR) technology that allows the safe administration of high doses of radiation in a very limited number of fractions with low toxicity and excellent tolerance. This approach of new image-guided patient management is compelling for doctors and patients since it can potentially contribute to improve the clinical outcome. In this work we discuss the available evidence, areas of debate, and potential future directions concerning the utilization of new imaging guided SBRT for the treatment of nodal recurrence in prostate cancer.

The cardiac sodium ion channel (NaV1.5) is a protein with four domains (DI-DIV), each with six transmembrane segments. Its opening and subsequent inactivation results in the brief rapid influx of Na+ ions resulting in the depolarization of cardiomyocytes. The neurotoxin veratridine (VTD) inhibits NaV1.5 inactivation resulting in longer channel opening times, and potentially fatal action potential prolongation. VTD is predicted to bind at the channel pore, but alternative binding sites have not been ruled out. To determine the binding site of VTD on NaV1.5, we performed docking calculations and high-throughput electrophysiology experiments. The docking calculations identified two distinct binding regions. The first site was in the pore, close to the binding site of NaV1.4 and NaV1.5 blocking drugs in experimental structures. The second site was at the “mouth” of the pore at the cytosolic side, partly solvent-exposed. Mutations at this site (L409, E417, and I1466) had large effects on VTD binding, while residues deeper in the pore had no effect, consistent with VTD binding at the mouth site. Overall, our results suggest a VTD binding site close to the cytoplasmic mouth of the channel pore. Binding at this alternative site might indicate an allosteric inactivation mechanism for VTD at NaV1.5.

Biological technologies are fundamentally unlike any other because biology evolves. Bioengineering therefore requires novel design methodologies with evolution at their core. Knowledge about evolution is currently applied to the design of biosystems ad hoc. Unless we have a unified engineering theory of evolution, we will neither be able to meet evolution’s potential as a design tool, nor understand or limit its unintended consequences on our designs. Our concept of the evotype offers a conceptual framework for engineering the evolutionary potential of biosystems. We show how a biosystem’s evolutionary properties might be rationally designed by engineering aspects of genetic variation, designed function, and natural selection. This idea could apply to all biosystems – from individual proteins to communities of whole-cells or even entire ecosystems – whether the goal is to direct evolution in the design process, or to limit its impacts during application. These principles could even be used beyond the realm of bioengineering to design entirely synthetic evolving auto-adaptive technologies.

In line with Pomeau’s conjecture about the relevance of directed percolation (DP) to turbulence onset/decay in wall-bounded flows, we propose a minimal stochastic model dedicated to the interpretation of the spatially intermittent regimes observed in channel flow before its return to laminar flow. Numerical simulations show that a regime with bands obliquely drifting in two stream-wise symmetrical directions bifurcates into an asymmetrical regime, before ultimately decaying to laminar flow. The model is expressed in terms of a probabilistic cellular automaton evolving von Neumann neighbourhoods with probabilities educed from a close examination of simulation results. It implements band propagation and the two main local processes: longitudinal splitting involving bands with the same orientation, and transversal splitting giving birth to a daughter band with orientation opposite to that of its mother. The ultimate decay stage observed to display one-dimensional DP properties in a two-dimensional geometry is interpreted as resulting from the irrelevance of lateral spreading in the single-orientation regime. The model also reproduces the bifurcation restoring the symmetry upon variation of the probability attached to transversal splitting, which opens the way to a study of the critical properties of that bifurcation, in analogy with thermodynamic phase transitions.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has resulted in the current COVID-19 pandemic. Worldwide this disease has infected around 1.5 million individuals with a mortality rate ranging from 5 to 10%. It has also imposed extreme challenges on global health, economy, and social behavior. Due to the unavailability of therapeutics, several efforts are going on in the drug discovery to control the SARS-CoV-2 viral infection. The main protease (M^Pro) plays a critical role in viral replication and maturation, thus can serve as the primary drug target. To understand the structural evolution of M^Pro, we have performed phylogenetic and SSN analysis, that depicted divergence of Coronaviridae M^Pro in five clusters specific to viral hosts. This clustering was also corroborated with the comparison of M^Pro structures. Furthermore, it has been observed that backbone and binding site conformations are conserved despite variation in some of the residues. This conservation can be exploited to repurpose available viral protease inhibitors against SARS-CoV-2 M^Pro. In agreement with this, we performed screening of the custom-made library of ~7100 molecules including active ingredients present in the Ayurvedic anti-tussive medicines, anti-viral phytochemicals and synthetic anti-virals against SARS-CoV-2 M^Pro as the primary target. We identified several natural molecules that strongly binds to SARS-CoV-2 M^Pro among which top seven molecules are d-Viniferin, Myricitrin, Taiwanhomoflavone A, Lactucopicrin 15-oxalate, Nympholide A, Biorobin and Phyllaemblicin B. Most of the predicted lead molecules are from Vitis vinifera, also reported for anti-tussive and/or antiviral activities. These molecules also showed strong binding with other main targets RdRp and hACE-2. We anticipate that our approach for identification of multi-target-directed ligand will provide new avenues for drug discovery against SARS-CoV-2 infection.

Background: Kidney transplantation is considered the first-choice therapy in ESRD patients. Despite recent improvements in terms of outcomes and graft survival in recipients, postoperative complications still concern health-care providers involved in the management of those patients. Particularly challenging are cardiovascular complications. Perioperative goal-directed fluid-therapy (PGDT) and hemodynamic optimization are widely used in high-risk surgical patients, and are associated with a significant reduction in postoperative complication rates and length of stay (LOS). The aim of this work is to compare the effects of perioperative goal-directed therapy (PGDT) with conventional fluid therapy (CFT), and to determine whether there are any differences in major postoperative complications rates and delayed graft function (DGF) outcomes. Methods: Prospective study with historical controls. Two groups, a PGDT- and a CFT- group were used: the stroke volume (SV) optimization protocol was applied in PGDT group throughout the procedure. Conventional fluid therapy with fluids titration at a central venous pressure (CVP) 8-12 mmHg and mean arterial pressure (MAP) >80mmHg was applied to the control-group. Postoperative data collection including vital signs, weight, urinary output, serum creatinine, blood urea nitrogen, serum potassium, and assessement of volemic status and the signs and symptoms of major postoperative complications occurred at 24h, 72h, 7 days and 30 days after transplantation. Results: Among the 66 patients enrolled, 33 were in each group and both groups had similar physical characteristics. Good fuctional recovery was evident in the 94% of patients. The statistical analysis has showed a difference in postoperative complications as follows: significant reduction of cardiovascular complications, DGF episodes (p<0.05) and surgical complications (p<0.01). There were no significant differences in pulmonary or other complication. Conclusions: PGDT and SV optimization effectively influenced the rate of major postoperative complications, reducing the overall morbidity and thus the mortality in patients receiving kidney transplantation.

As distinct human societies, three unique intentional communities are investigated regarding their preferred consensus decision-making practices. It is Identified that each has adopted a different form of consensus decision-making to solve potential group-wide interpersonal conflict. The individual attributes of these three consensus decision-making practices are considered, both from the perspective of maintaining group stability and in relation to individual member's mental health. The communities are a Canadian self-directed public senior elementary and secondary school, an annual English conference for those self-identifying as on the autistic spectrum, and a self-producing Korean popular music (K-pop) group. It is found that the intentional community and participants’ mental health are sustained regarding each of the three consensus decision-making practices. Nevertheless, the resulting decisions generate various stresses within the communities, both as a whole and concerning the individual members. To retain group cohesion and maintain individual mental health, these stresses must be recognized and understood by participants. The novel finding of this research is that, dependent on the time available for decision-making, and the members’ perspective adopted, intentional communities might practice more than one form of consensus decision-making and still support both group cohesion and individual mental health, maintaining the democracy of these distinct societies.

Hemolysin II (HlyII) – one of the pathogenic factors of Bacillus cereus, a pore-forming β-barrel toxin – possesses a C-terminal extension of 94 amino acid residues, designated as the C-terminal domain of HlyII (HlyIICTD), which plays an important role in the functioning of the toxin. Our previous work described a monoclonal antibody (HlyIIC-20), capable of strain-specific inhibi-tion of hemolysis caused by HlyII, and demonstrated the dependence of the efficiency of hemol-ysis on the presence of proline at position 324 in HlyII outside the conformational antigenic de-terminant. In this work, we studied 16 mutant forms of HlyIICTD. Each of the mutations, ob-tained by multiple site-directed mutagenesis leading to the replacement of amino acid residues lying on the surface of the 3D structure of HlyIICTD, led to a decrease in the interaction of HlyIIC-20 with the mutant form of the protein. Changes in epitope structure confirm the high conformational mobility of HlyIICTD required for the functioning of HlyII. Comparison of the effect of the introduced mutations on the effectiveness of interaction between HlyIICTD and HlyIIC-20 and a control antibody recognizing a non-overlapping epitope enabled identifying the amino acid residues N339, K340 included in the conformational antigenic determinant rec-ognized by HlyIIC-20.

A variety of techniques have been utilized in metal additive manufacturing (AM) for melt pool size management, including modeling and feed-forward approaches. In a few cases, closed-loop control has been demonstrated. In this research, closed-loop melt pool size control for large-scale, laser-wire based Directed Energy Deposition is demonstrated with a novel modification: site-specific changes to the controller set-point were commanded at trigger points, the locations of which were generated by the projection of a secondary geometry onto the primary 3D-printed component geometry. The present work shows that, through this technique, it is possible to print a specific geometry that occurs beyond the actual toolpath of the print head. This is denoted as an extra-toolpath geometry and is fundamentally different from other methods of generating component features in metal AM. A proof-of-principle experiment is presented in which a complex oak leaf geometry was embossed on an otherwise ordinary double-bead wall made from Ti-6Al-4V. The process is introduced and characterized primarily from a controls perspective with reports on the performance of the control system, the melt pool size response, and the resulting geometry. The implications of this capability, which extend beyond localized control of bead geometry to the potential mitigations of defects and functional grading of component properties, are discussed.

This study explores the relationship between job satisfaction, employee loyalty and two types of flexible employment arrangements; teleworking and flexi-time. The analysis relies on data derived by the Workplace Employee Relations Survey (WERS) in 2004 and 2011. A propensity score matching and least squares regressions are applied. Furthermore, Bayesian Networks (BN) and Directed Acyclic Graphs (DAGs) are employed in order to confirm the causality between employment types explored and the outcomes of interest. Finally, an instrumental variables (IV) approach based on the BN framework is proposed and applied in this study. The results support that there is a positive causal effect from these employment arrangements on job satisfaction and employee loyalty.

The online learning necessitated by COVID-19 social distancing limitations has resulted in the utilization of hybrid online formats focused on maintaining visual contact among learners and teachers. The preferred option of video conferencing for academic meetings has become that of Zoom. The needs of one voluntary, democratic, self-reflective university research group—grounded in responses to writing prompts—differed in learning focus. Demanding a safe space to encourage and record both self-reflection and creative questioning of other participants, the private Facebook group was chosen over video conferencing to maintain the concentration on group members’ written responses rather than how they saw themselves (and thought others saw them) on screen. A narrative research model initiated in 2015, the 2020/21 interaction of the group in the year’s worth of Facebook entries, and the yearend feedback received from group participants, will be compared with previous years when the weekly group met in-person. The results in relation to COVID-19 limitations indicate that an important aspect of self-directed learning related to trust that comes from team mindfulness is lost when face-to-face interaction is eliminated regarding the democratic nature of these meetings. With online meetings the new standard, maintaining trust requires improvements to online virtual meeting spaces.

Good health and the promotion of well-being for all is the third of the 17 Global Goals included in the 2030 Agenda for Sustainable Development. Contributing to this goal, the current study aimed to examine the relationships between one kind of athletes’ well-being, namely state organic self-talk, with personality traits, and basic psychological need satisfaction and frustration within their sport. Athletes (N = 691; mean age 21.65) from a variety of individual (n = 270) and team sports (n = 421) completed a multisection questionnaire capturing the targeted variables. Three-step hierarchical regression analyses revealed that: In step 1, all personality traits were to some extent a significant predictor of athletes’ organic, spontaneous self-talk dimensions and goal-directed self-talk functions. In step 2, need satisfaction significantly contributed to all spontaneous self-talk dimensions and goal-directed self-talk functions (except for creating functional deactivated states) over and above personality. Finally, in step 3, need frustration significantly contributed to negative spontaneous self-talk dimensions, and to all goal-directed self-talk functions (except for instruction) over and above personality and need satisfaction. Overall, our results indicate the importance of personality traits as personal antecedents, and perceptions of basic psychological need satisfaction and frustration as social-environmental antecedents, in shaping athletes’ state organic self-talk.

Negative mental health in students currently is classified as a global crisis with the highest and lowest student achievers recognized at greatest risk. Public schooling, in reproducing accepted psychosocial beliefs through standardized learning, developed separately from necessitating student mental health, in contrast to self-directed learning. Differing from standardized learning, the objective of self-directed learning in public schools is the creation of relevant support structures for student mental health, promoting positive psychosocial outcomes. The designed separation of public schooling from both mental health and self-directed learning was first acknowledged—and lamented—by John Dewey, over 100 years ago, in anticipating today’s mental health crisis. Yet, in responding effectively to the limitations of COVID-19, self-directed learning became an acknowledged learning method in public schools, potentially able to be accommodated by them regularly in support of mental health through the use of online technology. This study investigates the COVID-19 results of self-directed online learning in public schools through a Google Scholar search of peer reviewed research regarding self-directed learning, online learning, and mental health during COVID-19, recommending support for self-initiated self-directed online learning so that self-directed learning can continue, post COVID-19, improving student mental health in public schools, leading to positive psychosocial outcomes.

Labelling techniques such as electron paramagnetic resonance spectroscopy and single-molecule fluorescence resonance energy transfer, allow access to distances in the range of tens of angstroms, corresponding to the size of proteins and small to medium-sized protein complexes. Such measurements do not require long-range ordering and are therefore applicable to systems with partial disorder. Data from spin-label-based measurements can be processed into distance distributions that provide information about the extent of such disorder. Using such information in modelling presents several challenges, including a small number of restraints, the influence of the label itself on the measured distance and distribution width, and balancing the fitting quality of the long-range restraints with the fitting quality of other restraint subsets. Starting with general considerations about integrative and hybrid structural modelling, this review provides an overview of recent approaches to these problems and identifies where further progress is needed.

Chikungunya virus (CHIKV) is a mosquito-transmitted alphavirus that has re-emerged in recent decades, causing large-scale epidemics in many parts of the world. CHIKV infection leads to a febrile disease known as chikungunya fever (CHIKF), which is characterised by severe joint pain and myalgia. As many patients develop a painful chronic stage and neither antiviral drugs nor vaccines are available, the development of a potent CHIKV inhibiting drug is crucial for CHIKF treatment. A comprehensive summary of current antiviral research and development of small-molecule inhibitor against CHIKV is presented in this review. We highlight different approaches used for the identification of such compounds and further discuss the identification and application of promising viral and host targets.

The actions of many drugs involve enzyme inhibition. This is exemplified by the inhibitors of monoamine oxidases (MAO) and the cholinsterases (ChE) that have been used for several pharmacological purposes. This review describes key principles and approaches for the reliable determination of enzyme activities and inhibition as well as some of the methods that are in current use for such studies with these two enzymes. Their applicability and potential pitfalls arising from their inappropriate use are discussed. Since inhibitor potency is frequently assessed in terms of the quantity necessary to give 50% inhibition (the IC50 value), the relationships between this and the mode of inhibition is also considered, in terms of the misleading information that it may provide. Incorporation of more than one functionality into the same molecule to give a multi-target-directed ligands (MTDLs) requires careful assessment to ensure that the specific target effects are not significantly altered and that the kinetic behaviour remains as favourable with the MTDL as it does with the individual components. Such factors will be considered in terms of recently developed MTDLs that combine MAO and ChE inhibitory functions.

Descriptive geometry has indispensable applications in many engineering activities, some of which are presented in the first chapter of this paper in order to place the development presented here among them. As a result of the continuous variability of the technological environment according to various optimization aspects, the engineering activities must also be continuously adapted to the changes, which an appropriate approach and formulation are required from the practitioners of descriptive geometry, and can even lead to improvement in the field of descriptive geometry. The imaging procedures are always based on the methods and theorems of descriptive geometry. Resolving contradictions in spatial geometry reconstruction research is a constant challenge, to which a possible answer in many cases is the search for the right projection direction. A special method of enumerating the possible infinite viewpoints for the representation of the surface edge curves is presented in another part of the paper. The procedure for determining the correct directions in a mathematically exact way is also presented through examples. The analysis and some of the results of the Monge mapping, which is suitable for the solution of a mechanical engineering task to be solved in a specific technical environment, are also presented.

Recent brain imaging findings by using different methods (e.g., fMRI and PET) have suggested that social anxiety disorder (SAD) is correlated with alterations in regional or network-level brain function. However, due to many limitations associated with these methods, such as poor temporal resolution and limited number of samples per second, neuroscientists could not quantify the fast dynamic connectivity of causal information networks in SAD. In this study, SAD-related changes in brain connections within the default mode network (DMN) were investigated using eight electroencephalographic (EEG) regions of interest. Partial directed coherence (PDC) was used to assess the causal influences of DMN regions on each other and indicate the changes in the DMN effective network related to SAD severity. The DMN is a large-scale brain network basically composed of the mesial prefrontal cortex (mPFC), posterior cingulate cortex (PCC)/precuneus, and lateral parietal cortex (LPC). The EEG data were collected from 88 subjects (22 control, 22 mild, 22 moderate, 22 severe) and used to estimate the effective connectivity between DMN regions at different frequency bands: delta (1–3 Hz), theta (4–8 Hz), alpha (8–12 Hz), low beta (13–21 Hz), and high beta (22–30 Hz). Among the healthy control (HC) and the three considered levels of severity of SAD, the results indicated a higher level of causal interactions for the mild and moderate SAD groups than for the severe and HC groups. Between the control and the severe SAD groups, the results indicated a higher level of causal connections for the control throughout all the DMN regions. We found significant increases in the mean PDC in the delta (p = 0.009) and alpha (p = 0.001) bands between the SAD groups. Among the DMN regions, the precuneus exhibited a higher level of causal influence than other regions. Therefore, it was suggested to be a major source hub that contributes to the mental exploration and emotional content of SAD. In contrast to the severe group, HC exhibited higher resting-state connectivity at the mPFC, providing evidence for mPFC dysfunction in the severe SAD group. Furthermore, the total Social Interaction Anxiety Scale (SIAS) was positively correlated with the mean values of the PDC of the severe SAD group, r (22) = 0.576, p = 0.006 and negatively correlated with those of the HC group, r (22) = −0.689, p = 0.001. The reported results may facilitate greater comprehension of the underlying potential SAD neural biomarkers and can be used to characterize possible targets for further medication.

The aim of this paper is to present a comprehensive overview of the main aims and scopes in screening of botanicals, a task which thin-layer chromatography (TLC) is on an everyday basis confronted with and engaged in. Stunning omnipresence of this modest analytical technique (both in its standard format (TLC) and the high-performance one (HPTLC), either hyphenated or not) for many analysts might at a first glance appear chaotic and random, with an auxiliary rather than leading role in research, and not capable of issuing meaningful final statements. Based on these reflections, our purpose is not to present a general review paper on TLC in screening of botanicals, but a blueprint rather (illustrated with a selection of practical examples), which highlights a sovereign and important role of TLC in accomplishing the following analytical tasks: (i) solving puzzles related to chemotaxonomy of plants, (ii) screening a wide spectrum of biological properties of plants, (iii) providing quality control of herbal medicines and alimentary and cosmetic products of biological origin, and (iv) tracing psychoactive plants under forensic surveillance.