Design and Discovery of a Potent and Selective Inhibitor of Integrin αvß1.

Selective inhibition of the RGD (Arg-Gly-Asp) integrin αvß1 has been recently identified as an attractive therapeutic approach for the treatment of liver fibrosis given its function, target expression, and safety profile. Our identification of a non-RGD small molecule lead followed by focused, systematic changes to the core structure utilizing a crystal structure, in silico modeling, and a tractable synthetic approach resulted in the identification of a potent small molecule exhibiting a remarkable affinity for αvß1 relative to several other integrin isoforms measured. Azabenzimidazolone 25 demonstrated antifibrotic efficacy in an in vivo rat liver fibrosis model and represents a tool compound capable of further exploring the biological consequences of selective αvß1 inhibition.

Exploiting high-energy hydration sites for the discovery of potent peptide aldehyde inhibitors of the SARS-CoV-2 main protease with cellular antiviral activity.

Small-molecule antivirals that prevent the replication of the SARS-CoV-2 virus by blocking the enzymatic activity of its main protease (Mpro) are and will be a tenet of pandemic preparedness. However, the peptidic nature of such compounds often precludes the design of compounds within favorable physical property ranges, limiting cellular activity. Here we describe the discovery of peptide aldehyde Mpro inhibitors with potent enzymatic and cellular antiviral activity. This structure-activity relationship (SAR) exploration was guided by the use of calculated hydration site thermodynamic maps (WaterMap) to drive potency via displacement of waters from high-energy sites. Thousands of diverse compounds were designed to target these high-energy hydration sites and then prioritized for synthesis by physics- and structure-based Free-Energy Perturbation (FEP+) simulations, which accurately predicted biochemical potencies. This approach ultimately led to the rapid discovery of lead compounds with unique SAR that exhibited potent enzymatic and cellular activity with excellent pan-coronavirus coverage.

Synthetic Approaches to the New Drugs Approved During 2022.

In 2022, 23 new small molecule chemical entities were approved as drugs by the United States FDA, European Union EMA, Japan PMDA, and China NMPA. This review describes the synthetic approach demonstrated on largest scale for each new drug based on patent or primary literature. The synthetic routes highlight practical methods to construct molecules, sometimes on the manufacturing scale, to access the new drugs. Ten additional drugs approved in 2021 and one approved in 2020 are included that were not covered in the previous year's review.

Perspectives on the role of nutrition in influencing academy soccer player development and performance: A qualitative case study of key stakeholders from an English category one soccer academy.

This study aimed to explore player and stakeholder perceptions of the role of nutrition in influencing the development of male academy soccer players. Semi-structured interviews (28 ± 13 mins in length) were conducted with 31 participants from an English category one academy, including players (Youth Development Phase, YDP: n = 6; Professional Development Phase, PDP: n = 4), parents/guardians (n = 10), coaches (n = 3), sport scientists (n = 3), physiotherapists (n = 3), and catering (n = 2). Via reflexive thematic analysis, data demonstrate an apparent lack of understanding and awareness on the role of nutrition in influencing player development, especially in relation to growth, maturation and reducing injury risk. Players highlighted the influence of their parents on their dietary behaviours, whilst parents also called for education to better support their sons. Notably, players and stakeholders perceived that the daily schedule of an academy soccer player presents as "too busy to eat", especially in relation to before school, and before and after training. The results demonstrate the necessity for the co-creation of player and stakeholder specific nutrition education programmes as an initial step towards positively impacting the nutrition culture associated with the academy soccer environment.

Open science discovery of potent noncovalent SARS-CoV-2 main protease inhibitors.

We report the results of the COVID Moonshot, a fully open-science, crowdsourced, and structure-enabled drug discovery campaign targeting the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease. We discovered a noncovalent, nonpeptidic inhibitor scaffold with lead-like properties that is differentiated from current main protease inhibitors. Our approach leveraged crowdsourcing, machine learning, exascale molecular simulations, and high-throughput structural biology and chemistry. We generated a detailed map of the structural plasticity of the SARS-CoV-2 main protease, extensive structure-activity relationships for multiple chemotypes, and a wealth of biochemical activity data. All compound designs (>18,000 designs), crystallographic data (>490 ligand-bound x-ray structures), assay data (>10,000 measurements), and synthesized molecules (>2400 compounds) for this campaign were shared rapidly and openly, creating a rich, open, and intellectual property-free knowledge base for future anticoronavirus drug discovery.

Synthetic Approaches to the New Drugs Approved During 2021.

Each year, new drugs are introduced to the market, representing structures that have affinity for biological targets implicated in human diseases and conditions. These new chemical entities (NCEs), particularly small molecules and antibody-drug conjugates, provide insight into molecular recognition and serve as potential leads for the design of future medicines. This annual review is part of a continuing series highlighting the most likely process-scale synthetic approaches to 35 NCEs that were first approved anywhere in the world during 2021.

An audit of performance nutrition services in English soccer academies: implications for optimising player development.

To audit the current provision of performance nutrition services provided to male adolescent players within academies from the English soccer leagues. Practitioners from all 89 academies (status categorised as one-four according to the Elite Player Performance Plan, EPPP) completed an online survey to audit: a) job role/professional accreditation status of persons delivering nutrition support, b) activities inherent to service provision, c) topics of education, d) on-site food, fluid and supplement provision and e) nutritional related data collected for objective monitoring. More full-time accredited nutritionists are employed within category one (14/26) versus category two (0/18), three (1/41) and four (0/4). Respondents from category one clubs report more hours of monthly service delivery (62 ± 57 h) than category two (12 ± 9 h), three (14 ± 26 h) and four (12 ± 14 h), inclusive of one-to-one player support and stakeholder education programmes. Category one practitioners reported a greater prevalence of on-site food, fluid and supplement provision on training and match days. Across all categories, players from the professional development phase receive more frequent support than players from the youth development phase, despite the latter corresponding to the most rapid phase of growth and maturation. We report distinct differences in the extent of service provision provided between categories. Additionally, players from all categories receive nutrition support from non-specialist staff. Data demonstrate that performance nutrition appears an under-resourced component of academy sport science and medicine programmes in England, despite being an integral component of player development.

Synthetic Approaches to the New Drugs Approved During 2020.

New drugs introduced to the market are privileged structures that have affinities for biological targets implicated in human diseases and conditions. These new chemical entities (NCEs), particularly small molecules and antibody-drug conjugates (ADCs), provide insight into molecular recognition and simultaneously function as leads for the design of future medicines. This Review is part of a continuing series presenting the most likely process-scale synthetic approaches to 44 new chemical entities approved for the first time anywhere in the world during 2020.

Coherent Scattering of Low Mass Dark Matter from Optically Trapped Sensors.

We propose a search for low mass dark matter particles through momentum recoils caused by their scattering from trapped, nanometer-scale objects. Our projections show that even with a modest array of femtogram-mass sensors, parameter space beyond the reach of existing experiments can be explored. The case of smaller, attogram-mass sensors is also analyzed-where dark matter can coherently scatter from the entire sensor-enabling a large enhancement in the scattering cross-section relative to interactions with single nuclei. Large arrays of such sensors have the potential to investigate new parameter space down to dark matter masses as low as 10 keV. If recoils from dark matter are detected by such sensors, their inherent directional sensitivity would allow an unambiguous identification of a dark matter signal.

Trapped Electrons and Ions as Particle Detectors.

Electrons and ions trapped with electromagnetic fields have long served as important high-precision metrological instruments, and more recently have also been proposed as a platform for quantum information processing. Here we point out that these systems can also be used as highly sensitive detectors of passing charged particles, due to the combination of their extreme charge-to-mass ratio and low-noise quantum readout and control. In particular, these systems can be used to detect energy depositions many orders of magnitude below typical ionization scales. As illustrations, we suggest some applications in particle physics. We outline a nondestructive time-of-flight measurement capable of sub-eV energy resolution for slowly moving, collimated particles. We also show that current devices can be used to provide competitive sensitivity to models where ambient dark matter particles carry small electric millicharges ≪e. Our calculations may also be useful in the characterization of noise in quantum computers coming from backgrounds of charged particles.

Synthetic Approaches to the New Drugs Approved during 2019.

New drugs introduced to the market are privileged structures having affinities for biological targets implicated in human diseases and conditions. These new chemical entities (NCEs), particularly small molecules and antibody-drug conjugates, provide insight into molecular recognition and simultaneously function as leads for the design of future medicines. This review is part of a continuing series presenting the most likely process-scale synthetic approaches to 40 NCEs approved for the first time anywhere in the world in 2019.

Prioritizing Injury Prevention: Cause of Injury Text Analysis.

BACKGROUND: Motor vehicle (MVCs) and motorcycle crashes (MCCs) continue to be among the most prevalent mechanisms of trauma injury and mortality. We sought to identify specific populations and factors associated with MVCs and MCCs for local injury prevention efforts. A novel, yet easily performed, research method was utilized-a qualitative content analysis of text narratives describing each patient's cause of injury. OBJECTIVE: To determine target populations for local MVC and MCC injury prevention. METHODS: A retrospective descriptive analysis was performed using registry data from a Level I trauma center. The registry was queried for all trauma patients presenting with MVC or MCC injuries between June 8, 2014, and June 7, 2019. Cases were then reviewed via their respective text narratives of injury causation. Common themes were identified, coded by independent raters, and assessed for interrater reliability using Cohen's κ. Frequencies and proportions are reported for each preventable factor and patient characteristic. RESULTS: There were a total of 2,861 cases studied, of which 2,330 (81.4%) were MVC and 531 (18.6%) were MCC. Demographics varied by mechanism of injury. Driver drug or alcohol use was involved in 97 (3.4%), protective devices were not used in 776 (27.1%), distracted driving was involved in 30 (1%), excessive speeding was involved in 152 (5.3%), and driver sleeping/syncope/medical condition was present in 113 (3.9%) cases. CONCLUSIONS: Content analysis of cause of injury text narratives can detect target populations and preventable factors to direct injury prevention efforts specific to the local population.

Novel High-Throughput Strategy for the Aqueous Solubility Assessment of Peptides and Proteins Exhibiting a Propensity for Gelation: Application to the Discovery of Novel Antibacterial Teixobactin Analogues.

A novel high-throughput aqueous solubility assay was developed for peptides and proteins exhibiting a high gelling propensity (in this case, antibacterial teixobactin analogues). By integrating the assessment of gel formation, as indicated by an increase in the solution viscosity, into the peptide equilibrium solubility screening assay, we were able to estimate the "free-flowing solubility", which is defined as the concentration at which the peptide solution not only is fully dissolved but also is a liquid exhibiting ideal flowing characteristics. In this workflow, peptide solutions passing the turbidity assessment were further screened by viscosity measurements based on nanobead-assisted dynamic light scattering analysis in a 96-well plate. The method is able to effectively detect the initiation of peptide gelation and facilitate compound ranking based on their aqueous solubility. The application of such an approach helped confirm that the substitution of Ser3 in teixobactin led to desired physicochemical improvements and provided a focal point for further chemistry structure-activity relationship exploration.

Energy Requirements of Male Academy Soccer Players from the English Premier League.

PURPOSE: This study aimed to inform the energy requirements of highly trained adolescent soccer players. Total energy expenditure (TEE) was quantified in academy soccer players from the English Premier League (EPL). METHODS: Twenty-four male adolescent soccer players from an EPL academy (under (U) 12/13 (U12/13), n = 8; U15, n = 8; U18, n = 8) were assessed for baseline maturity (maturity offset), body composition (dual-energy x-ray absorptiometry), and resting metabolic rate (indirect calorimetry). Subsequently, TEE, energy intake (EI) and physical loading patterns were assessed over a 14-d in-season period using doubly labeled water, the remote food photographic method, and global positioning system technology, respectively. RESULTS: U18 players presented with greater resting metabolic rate (2236 ± 93 kcal·d) and TEE (3586 ± 487 kcal·d; range, 2542-5172 kcal·d) than did both U15 (2023 ± 162 and 3029 ± 262 kcal·d, respectively; TEE range, 2738-3726 kcal·d) and U12/13 players (1892 ± 211 and 2859 ± 265 kcal·d, respectively; TEE range, 2275-3903 kcal·d; all, P < 0.01), although no difference in TEE was apparent between the U12/13 and U15 age groups. Fat-free mass was significantly different between all comparisons in a hierarchal manner (U18: 57.2 ± 6.1 kg > U15: 42.9 ± 5.8 kg > U12/13: 31.1 ± 3.5 kg; all, P < 0.01). Within age groups, no differences were apparent between EI and TEE (U12/13: -29 ± 277 kcal·d, P = 0.78; U15: -134 ± 327 kcal·d, P = 0.28; U18: -243 ± 724 kcal·d, P = 0.37), whereas U18 players (3180 ± 279 kcal·d) reported higher EI than did both U15 (2821 ± 338 kcal·d; P = 0.05) and U12/13 players (2659 ± 187 kcal·d; P < 0.01). CONCLUSIONS: The TEE of male academy soccer players progressively increase as players progress through the academy age groups. In some individuals (evident in all age groups), TEE was greater than that previously observed in adult EPL soccer players.

Search for Composite Dark Matter with Optically Levitated Sensors.

Results are reported from a search for a class of composite dark matter models with feeble long-range interactions with normal matter. We search for impulses arising from passing dark matter particles by monitoring the mechanical motion of an optically levitated nanogram mass over the course of several days. Assuming such particles constitute the dominant component of dark matter, this search places upper limits on their interaction with neutrons of α_{n}≤1.2×10^{-7} at 95% confidence for dark matter masses between 1 and 10 TeV and mediator masses m_{ϕ}≤0.1 eV. Because of the large enhancement of the cross section for dark matter to coherently scatter from a nanogram mass (∼10^{29} times that for a single neutron) and the ability to detect momentum transfers as small as ∼200 MeV/c, these results provide sensitivity to certain classes of composite dark matter models that substantially exceeds existing searches, including those employing kilogram- or ton-scale targets. Extensions of these techniques can enable directionally sensitive searches for a broad class of previously inaccessible heavy dark matter candidates.

Cross-sectional comparison of body composition and resting metabolic rate in Premier League academy soccer players: Implications for growth and maturation.

For the first time we aimed to: (1) assess fat-free mass (FFM) and RMR in youth soccer players, (2) compare measured RMR to estimated RMR using previously published prediction equations, and (3) develop a novel population-specific prediction equation. In a cross-sectional design, 99 males from a Premier League academy underwent assessments of body composition (DXA) and RMR (indirect-calorimetry). Measured RMR was compared to estimated values from five prediction equations. A novel RMR prediction equation was developed using stepwise multiple regression. FFM increased (P<0.05) between U12 (31.6±4.2 kg) and U16 (56.3±5.3 kg) after which no further increases occurred (P>0.05). RMR in the U12s (1655±195 kcal.day-1), U13s (1720±205 kcal.day-1) and U14s (1846±218kcal.day-1) was significantly lower than the U15s (1957±128 kcal.day-1), U16s (2042±155 kcal.day-1), U18s (1875±180 kcal.day-1) and U23s (1941±197 kcal.day-1) squads (P>0.05). FFM was the single best predictor of RMR (r2=0.43; P<0.01) and was subsequently included in the novel prediction equation: RMR (kcal.day-1) = 1315 + (11.1 x FFM in kg). Both FFM and RMR increase from 12-16 years old, thus highlighting the requirement to adjust daily energy intake to support growth and maturation. The novel prediction RMR equation developed may help to inform daily energy requirements.

Dissecting the Binding Interactions of Teixobactin with the Bacterial Cell-Wall Precursor Lipid†II.

The prevalence of life-threatening, drug-resistant microbial infections has challenged researchers to consider alternatives to currently available antibiotics. Teixobactin is a recently discovered "resistance-proof" antimicrobial peptide that targets the bacterial cell wall precursor lipid II. In doing so, teixobactin exhibits potent antimicrobial activity against a wide range of Gram-positive organisms. Herein we demonstrate that teixobactin and several structural analogues are capable of binding lipid II from both Gram-positive and Gram-negative bacteria. Furthermore, we show that when combined with known outer membrane-disrupting peptides, teixobactin is active against Gram-negative organisms.

Refractometric Sensing with Periodic Nano-Indented Arrays: Effect of Structural Dimensions.

Fabrication and sensor application of a simple plasmonic structure is described in this paper. The sensor element consists of nano-patterned gold film brought about from two-dimensional periodic photoresist templates created by holographic laser interference lithography. Reflectance spectroscopy revealed that the sensor exhibits significant refractive index sensitivity. A linear relationship between shifts in plasmonic resonances and changes in the refractive index were demonstrated. The sensor has a bulk sensitivity (SB) of 880 nm/refractive index unit and work under normal incidence conditions. This sensitivity exceeded that of many common types of plasmonic sensors with more intricate structures. A modeled spectral response was used to study the effect of its geometrical dimensions on plasmonic behavior. A qualitative agreement between the experimental spectra and modeled ones was obtained.

Comparing fracture patterns of younger versus older riders involved in nonfatal motorcycle accidents.

OBJECTIVE: The motorcyclist demographic is shifting to a larger proportion of riders over the age of 40. We sought to identify differences in orthopedic injury distribution and severity between 3 age cohorts and identify independent factors that contribute to fractures following a motorcycle collision (MCC). METHODS: A trauma registry at a level 1 trauma center was queried for motorcycle-related orthopedic injuries between January 1, 2008, and December 31, 2014. Subjects were stratified into 3 age groups: Young (<40 years), middle-aged (40-59 years), and elderly (≥60 years). Age groups were compared with respect to gender, weight, mechanism of collision, helmet use, Glascow Coma Scale (GCS), fracture type and location, Injury Severity Score (ISS), and hospital length of stay (LOS). A logistic regression model was constructed to identify independent factors that contribute to fractures following MCCs. RESULTS: Five hundred sixty-seven patients received care for motorcycle-related injuries (219 young, 264 middle-aged, and 84 elderly). Patients were predominantly male (88.7%), were wearing a helmet at the time of collision (58.0%), and sustained a mean of 1.48 fractures per patient. The primary mechanism of collision was noncollision transport accidents (41.4%). Elderly riders weighed significantly more than middle-aged and young riders (P < .0001). There was a significant difference in mean GCS between age groups (P = .02), with elderly patients demonstrating the highest mean GCS (14.0 ± 3.3). Young patients sustained no fractures most frequently when compared with middle-aged and elderly riders (P = .002). There was a significant difference in the percentage of patients sustaining right-sided, lower body fractures between age groups (P = .02) for elderly, middle-aged, and young patients, respectively. There was also a significant difference between age groups in the percentage of riders sustaining fractures other than those of the extremities, pelvis, or spine (P = .0005). Only age was identified as an independent predictor of sustaining a fracture (P = .008). CONCLUSIONS: Elderly patients sustained fractures more frequently. There was no difference between age groups with respect to injury severity. Mechanism of collision may have more influence than age with respect to fracture type and location. Further research is warranted to develop a more widely generalizable characterization of motorcycle collision injury patterns, risk factors, and patient characteristics.