Conformational study into N-alkyl-N'-aryl ureas to inform drug discovery.

Ureas are an important functional group in small molecule drugs as well as having wider applications in organic chemistry. Understanding of their conformation is of critical importance for rational design of urea-containing bioactive compounds. Whilst the conformational preferences of biaryl ureas have been extensively studied, very little attention has been paid to alkylated analogues. We carried out a systematic study of N-aryl (phenyl and pyridyl)-N'-cyclopentyl ureas with differing N-methylation patterns using Well Tempered Metadynamics at a semi-empirical level in implicit water (GBSA) using Well-Tempered Metadynamics to generate their conformational free-energy landscapes. Geometries and energetics of the most relevant configurations are further refined using DFT level of theory. Validation for the computation was obtained by synthesis of all 8 analogues followed by conformational studies by X-ray crystallography and NMR. These findings reveal that the methylation pattern significantly affects the conformational preference of the system. Most notably, N-phenyl-N'-cyclopentyl urea is shown to adopt both the trans-trans, and cis-trans conformations with equal energy and that the cis-trans conformation can be significantly stabilised by the presence of an internal hydrogen bond to the N'-hydrogen. This study will be of utility for the design of N-alkyl-N'-aryl ureas as drug candidates.

Reactivity of Covalent Fragments and Their Role in Fragment Based Drug Discovery.

Fragment based drug discovery has long been used for the identification of new ligands and interest in targeted covalent inhibitors has continued to grow in recent years, with high profile drugs such as osimertinib and sotorasib gaining FDA approval. It is therefore unsurprising that covalent fragment-based approaches have become popular and have recently led to the identification of novel targets and binding sites, as well as ligands for targets previously thought to be 'undruggable'. Understanding the properties of such covalent fragments is important, and characterizing and/or predicting reactivity can be highly useful. This review aims to discuss the requirements for an electrophilic fragment library and the importance of differing warhead reactivity. Successful case studies from the world of drug discovery are then be examined.

Transnational Migration and Dual Career of Slovenian and Swiss Elite Female Handball Players-A Longitudinal Analysis.

The purpose of this study was to identify the career paths of transnational migrating female elite handball players. Fourteen Slovenian and Suisse national team players were monitored over a 7-year period by means of semi-structured interviews and official handball records. At the end of the examination period, six still-active players were interviewed again. Qualitative thematic analysis was employed to develop a contextualized understanding of participants' careers paths and life trajectories in relation to their athletic migration and dual career. In relation to the limited opportunities offered by small countries with middle-ranking national handball teams, participants highlighted that sport migration coupled with dual career opportunities represented a strategic decision for a successful career development through several key factors: (1) a clear intention towards a professional handball career; (2) the actual fulfilment of professional handball career aspirations; (3) dual career goals as part of the migration process; (4) high personal ambition and emotional connection to handball; (5) the implementation of a successful dual career path; (6) a positive migration experience; and (7) feeling supported and valued during relocation. Sport federations and elite clubs should consider the implementation of a multidimensional approach encompassing dual career paths to facilitate athletes' transnational relocation and career transitions.

Correlation between Employee Performance, Well-Being, Job Satisfaction, and Life Satisfaction in Sedentary Jobs in Slovenian Enterprises.

The purpose of this study was to explore the relationship between employees' work performance and their well-being, job satisfaction, and life satisfaction in sedentary jobs in Slovenian enterprises using a mixed-methods research design. The quantitative component of the research included the responses to four selected questionnaires of 120 employees in 22 identified enterprises (out of 81), with more than 20 employees, having more than 85 percent sedentary jobs. Each of four questionnaires was chosen to cover one area of enquiry under the research foci of work performance, job satisfaction, life satisfaction and well-being. The statistical program STATA was used for data analyses. The analysis shows statistically significant positive correlations between employee performance and job satisfaction (r = 0.35), employee performance and life satisfaction (r = 0.28), life satisfaction and well-being (r = 0.33), and job satisfaction and well-being, whereas the correlation between well-being and work performance did not prove to be statistically significant. The qualitative component of the mixed-methods research design included systematic observation combined with one-to-one discussions. The results indicated that job satisfaction and life satisfaction are more significant in determining work performance in sedentary jobs than employee well-being and that being unwell is still considered a sign of weakness; therefore, employees who are unwell do not want to expose themselves and refuse to cooperate in activities and studies about well-being. Further research examining the impact on work performance of organizational climate measurements in sedentary jobs is recommended.

Fragment-based drug discovery-the importance of high-quality molecule libraries.

Fragment-based drug discovery (FBDD) is now established as a complementary approach to high-throughput screening (HTS). Contrary to HTS, where large libraries of drug-like molecules are screened, FBDD screens involve smaller and less complex molecules which, despite a low affinity to protein targets, display more 'atom-efficient' binding interactions than larger molecules. Fragment hits can, therefore, serve as a more efficient start point for subsequent optimisation, particularly for hard-to-drug targets. Since the number of possible molecules increases exponentially with molecular size, small fragment libraries allow for a proportionately greater coverage of their respective 'chemical space' compared with larger HTS libraries comprising larger molecules. However, good library design is essential to ensure optimal chemical and pharmacophore diversity, molecular complexity, and physicochemical characteristics. In this review, we describe our views on fragment library design, and on what constitutes a good fragment from a medicinal and computational chemistry perspective. We highlight emerging chemical and computational technologies in FBDD and discuss strategies for optimising fragment hits. The impact of novel FBDD approaches is already being felt, with the recent approval of the covalent KRASG12C inhibitor sotorasib highlighting the utility of FBDD against targets that were long considered undruggable.

Multi-national perceptions on challenges, opportunities, and support structures for Dual Career migrations in European student-athletes.

Despite Dual Careers (sports and education) and mobility of students being priorities in the funding policies of the European Commission, migrating student-athletes report severe challenges and decreased performance or dropouts at sport and academic levels. The objective of this study was to depict and assess the perceptions on challenges, support services, and their effectiveness in consideration of specific characteristics of participants and migrations. Based on a meta-synthesis and previous findings, a 50-items questionnaire was developed and completed by 245 student-athletes in 5 European countries. Participants with Dual Careers migration experience (n = 140) were considered for analyses of qualitative and quantitative (ordinal 5pt-Likert-scaled and metric) data on the Dual Career status, migration characteristics, received services, and outcomes. Chi-square-tests were conducted for differences between countries and genders at a significance level of p < .05. Country-related differences were found for experiences and intentions to migrate (X2(12) = 50.52, p<0.001), duration of the migration (X2(16) = 38.20, p = 0.001), financial support (X2(8) = 29.87, p<0.001), and decreased performances in academics (X2(16) = 56.12, p<0.001) and sports (X2(16) = 31.79, p = 0.01). Gender-related difference emerged in financial support (X2(4) = 10.68, p = 0.03), duration of the migration (X2(4) = 14.56, p = 0.01), and decreased academic performance (X2(4) = 10.57, p = 0.03). Tutoring and counselling support was ranked as the most effective support, especially when received from the academic field (4.0±1.0 pt) and others (4.1±0.8 pt), followed by online services from sport and academic sectors (both: 3.9±0.9 pt). Considering the pervasive globalization of sport and education, Dual Career migration can contribute to the development of a European sport culture. The high ratio of migrating student-athletes underlines the relevance of migrations in the field of Dual Careers. This study contributes to the literature by adding insights on practices, challenges, supports, and outcomes perceived by student-athletes migrating in Europe. Moreover, country- and gender-related differences support the consideration of specific characteristics and reveal critical factors in specific target groups. The findings contribute to identifying requirements and effective support measures in Dual Career migrations and can be used to improve support services.

Occupational specifics of elite female handball players in relation to injury recovery, social support and environmental factors.

OBJECTIVES: The aim of the study was to analyze the injury characteristics, satisfaction with social support and environmental factors in elite female handball players in the injury recovery process. MATERIAL AND METHODS: The retrospective study combined quantitative (questionnaire) and qualitative (interview) methods, and presented 3 distinct perspectives, i.e., those of active players, former players and coaching staff members (SMs). The research sample in the first part consisted of 51 active professional female handball players (aged 26.3±2.6 years) with an injury history. The answers from an online questionnaire were processed according to basic statistical parameters (SPSS). The second part of the study included 9 semi-structured interviews, 6 with former players and 3 with coaching SMs. RESULTS: All the 51 active players reported 140 injuries (on average 2.7 injuries/player) in the last 6 years. The recovery time ranged 1 day-10 months. No statistically significant differences were observed between the career length and anterior cruciate ligament tear (χ2-3.18, p = 0.53), and the career length and posterior cruciate ligament tear (χ2-1.87; p = 0.76). The former players' perceptions of social support and environmental factors are similar to the opinions expressed by the coaching SMs, while the active players held high expectations. The highest level of satisfaction with social support was reported for family members (M±SD 4.35±0.814) and the physiotherapist (M±SD 4.12±3.28), whereas the players were not very satisfied with the social support offered by the head coach (M±SD 2.73±0.75). Coaching SMs considered providing social support as something that exceeded their competences. CONCLUSIONS: The analysis of the injury recovery process indicated a need for a new function in handball clubs - an expert with interdisciplinary competencies, who would contribute to faster recovery and general wellbeing of professional handball players. Int J Occup Med Environ Health. 2021;34(1):101-10.

The Structure of Sub-nm Platinum Clusters at Elevated Temperatures.

Little is known about metallic clusters consisting merely of a dozen of atoms or even less, despite of their importance in catalysis and crystal nucleation. Scanning transmission electron microscopy (STEM) provides direct atomic structure information but has inherently suffered from limited time resolution. We employ fast dynamic STEM combined with a spatio-temporal image denoising algorithm to explore the structure and stability of Pt clusters on carbon, which represents a highly relevant catalysis system. At room temperature, dynamic amorphous 2D structures are found, while above ≈300 °C, the clusters transform into a crystalline state. Our experimental and theoretical data reveal an unexpected strong trend of the crystalline clusters to exhibit the face-centered cubic, bulk structure of Pt with cuboidal geometries being most prominent.

Template-Assisted in Situ Synthesis of Ag@Au Bimetallic Nanostructures Employing Liquid-Phase Transmission Electron Microscopy.

Noble metal nanostructure synthesis via seed-mediated route is a widely adopted strategy for a plethora of nanocrystal systems. Ag@Au core-shell nanostructures are radiolytically grown in real-time using in situ liquid-cell (scanning) transmission electron microscopy. Here we employ a capping agent, dimethyl-amine (DMA) and a coordinating complex, potassium iodide (KI) in an organic solvent (methanol) in order to (1) slow down the reaction kinetics to observe mechanistic insights into the overgrowth process and (2) shift the growth regime from galvanic-replacement mode to direct synthesis mode resulting in the conventional synthesis of Ag@Au core-shell structures. A theoretical approach based on classical simulations complements our experiments, providing further insight on the growth modes. In particular, we focus on the shape evolution and chemical ordering, as currently there is an insufficient understanding regarding mixed composition phases at interfaces of alloys even with well-known miscibilities. Furthermore, the comparison of theoretical and experimental data reveals that the final morphology of these nanoalloys is not simply a function of crystallinity of the underlying seed structure but instead is readily modified by extrinsic parameters such as additives, capping agent, and modulation of surface energies of exposed crystal surfaces by the encapsulating solvent. The impact of these additional parameters is systematically investigated using an empirical approach in light of ab initio simulations.

The reaction mechanism of the azide-alkyne Huisgen cycloaddition.

The azide-alkyne Huisgen cycloaddition has a key role in click chemistry and is configured as a powerful tool in pharmaceutical and medicinal chemistry. Although this reaction has already been largely studied, there is an ongoing debate about its mechanism. In this work we study the dynamical aspects of the process using metadynamics computer simulations. We focus on the conformational aspects that determine the course of the reaction and characterize its free energy landscape. To properly capture the thermodynamics of the process we select optimal collective variables using harmonic linear discriminant analysis. The results qualitatively confirm and explain the experimental evidence and give insights into the role of the substituents and the possible transition mechanisms.

Revealing the role of phosphoric acid in all-vanadium redox flow batteries with DFT calculations and in situ analysis.

The present work suggests the use of a mixed water-based electrolyte containing sulfuric and phosphoric acid for both negative and positive electrolytes of a vanadium redox flow battery. Computational and experimental investigations reveal insights on the possible interactions between the vanadium ions in all oxidation states and sulphate, bisulphate, dihydrogen phosphate ions and phosphoric acid. In situ cycling experiments and ion-specific electrochemical impedance measurements confirmed a significant lowering of the charge-transfer resistance for the reduction of V(iii) ions and, consequently, an increase of the voltaic efficiency associated with the negative side of the battery. This increase of performance is attributable to the complexation of this oxidation state by phosphoric acid. So far, mixed acids have mainly been discussed with the focus on V(v) solubility. In this work we rationalize the impact of the mixed acids on the electrochemical efficiency opening new strategies on how to improve the cycling performance with ionic additives.

The El Dorado of Handball? Foreign Female Players Stay, while Domestic Players Return from Abroad.

The main purpose of this research was to study the characteristics of migration in European women's handball based on the Slovenian example and to find the differences between the foreigners coming to Slovenia and the Slovenians transferring to foreign clubs. The research was based on 16 open face-to-face semi-structured interviews (8 Slovenians (age 29.5 ± 6.2 years) and 8 foreigners (age 35.5 ± 8.7 years)). We found out that the most powerful factor in foreigners was the financial one, while within Slovenian players it was their personal desire for progression within their sport, the club's reputation and poor conditions in their previous club. The results confirm that when making a decision on transfer, all players had the support of family and friends, while the clubs of foreign players were not as supportive. Most interviewees considered their careers successful and did not regret going abroad. The research indicates that the largest differences discovered between Slovenians and foreigners were that foreign female players chose to stay in the new country (Slovenia), while domestic players returned home after few years playing abroad. In conclusion, the results show that in top-level handball there are important differences between migration models which are based on nationality and also that the migration models change throughout time, which is largely connected with the socioeconomic events in the country of origin or transfer.

Position-Related Differences in Selected Morphological Body Characteristics of Top-Level Female Handball Players.

The study aimed to establish the main morphological characteristics of Slovenian junior and senior female national handball team players. Morphological characteristics of various player subgroups (goalkeepers, wings, back players and pivots) were also determined so as to establish whether they had distinct profiles. The subjects were 87 handball players who were members of the Slovenian junior and senior female national teams in the period from 2003 to 2009. A standardised anthropometric protocol was used to assess the subjects' morphological characteristics. The measurements included 23 different anthropometric measures. First, basic statistical characteristics of anthropometric measures were obtained for all subjects together and then for each group separately. Somatotypes were determined using Heath-Carter's method. Endomorphic, mesomorphic and ectomorphic components were calculated by computer on the basis of formulas. In order to determine differences in the body composition and anthropometric data of the subjects playing in different positions, a one-way analysis of variance was employed. The results show that, on average, the wings differed the most from the other player groups in terms of their morphological body characteristics. The wings differed most prominently from the other player groups in terms of their morphological body parameters as they were significantly smaller and had a statistically significantly lower body mass than the other groups. In terms of transversal measures of the skeleton and the circumferences, the wings significantly differed mainly from the pivots and goalkeepers and less from the backs. The goalkeepers were the tallest, with high values of body mass and low values of transversal measures compared to P. Their skin folds were the most pronounced among all the groups on average and their share of subcutaneous fat in total body mass was the highest. Consequently, their endomorphic component of the somatotype was pronounced. Players in the Pivot position were significantly taller than the Wplayers but were not significantly different from G and B. They had high values of body mass which were significantly higher than that of W but did not differ significantly from the body mass values of B and G. The average values of their circumferences were the highest among all the player groups and the same is true for transversal measures of the skeleton. It is very interesting that, compared to the players in other playing positions, they achieved low values of subcutaneous fat. Their values of the somatotype revealed an endo-mesomorphic somatotype, with a pronounced mesomorphic component. Back players were tall and had the lowest share of subcutaneous fat of all the player groups. Significant differences were established mainly in terms of the structure of the lower extremities. The values of the somato-type characteristics were very balanced between all three components. The results of our study confirm that groups of handball players occupying different positions differed amongst themselves in terms of many measurements. This is a result of the specific requirements of handball play which are to be met by particular players. The tallest players should thus be oriented to back player positions. As regards pivots, the coaches must, besides body height, consider robustness. For goal-keepers, body height is very important; however, the robustness criteria are slightly lower. For wings, body height is not a decisive factor and smaller players can also occupy this position. Both of the above (also taking other criteria into account) facilitate coaches' decisions when orienting players into their playing positions.

Computational approaches elucidate the allosteric mechanism of human aromatase inhibition: a novel possible route to Small-molecule regulation of CYP450s activities?

Human aromatase (HA) is a P450 cytochrome (CYP) with an essential role in estrogen biosynthesis. Since more than 70% of breast cancers are positive for estrogenic receptor (ER), the reduction of estrogen physiological concentrations through HA inhibition is one of most important therapeutic strategies against this cancer type. Recently, experimental evidence showed that selected taxmoxifen metabolites, which are typically used as estrogen receptor modulators (SERMs), inhibit HA through an allosteric mechanism. In this work, we present a computational protocol to (i) characterize the structural framework and (ii) define the atomistic details of the determinants for the noncompetitive inhibition mechanism. Our calculations identify two putative binding sites able to efficiently bind all tamoxifen metabolites. Analysis of long-scale molecular dynamics simulations reveal that endoxifen, the most effective noncompetitive inhibitor, induces significant enzyme rigidity by binding in one of the possible peripheral sites. The consequence of this binding event is the suppression of one of the functional enzymatic collective motions associated with breathing of the substrate access channel. Moreover, an internal dynamics-based alignment of HA with six other human cytochromes shows that this collective motion is common to other members of the CYP450 protein family. On this basis, our findings may thus be of help for the development of new (pan)inhibitors for the therapeutic treatment of cancer, targeting and modulating the activity of HA and of estrogen receptor, and may also stimulate the development of new drug design strategies for chemoprevention and chemoprotection via allosteric inhibition of CYP450 proteins.

Observation and analysis of large-scale human motion.

Many team sports include complex human movement, which can be observed at different levels of detail. Some aspects of the athlete's motion can be studied in detail using commercially available high-speed, high-accuracy biomechanical measurement systems. However, due to their limitations, these devices are not appropriate for studying large-scale motion during a game (for example, the motion of a player running across the entire playing field). We describe an alternative approach to studying such large-scale motion, and present a video-based, computer-aided system, developed specifically for the purpose of acquiring large-scale motion data. The baseline of our approach consists of sacrificing much of the spatial accuracy and temporal resolution of widely used biomechanical measurement systems, to obtain data on human movement that span large areas and long intervals of time. Data can be obtained for each of the observed athletes with reasonable amount of operator work. The system was developed using the recordings of a handball match. Several field tests were performed to assess measurement error, including comparison to one of the widely available biomechanical measurement systems. With the help of the system presented, we could obtain position data for all 14 handball players on a 40 x 20 m large court with RMS error better than 0.6 m, covering 1 h of action. Several results, obtained during the handball match study are presented, in order to highlight the importance of large-scale motion acquisition.