Design and Discovery of a Potent and Selective Inhibitor of Integrin αvβ1.

Selective inhibition of the RGD (Arg-Gly-Asp) integrin αvβ1 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, modeling, and a tractable synthetic approach resulted in the identification of a potent small molecule exhibiting a remarkable affinity for αvβ1 relative to several other integrin isoforms measured. Azabenzimidazolone demonstrated antifibrotic efficacy in an rat liver fibrosis model and represents a tool compound capable of further exploring the biological consequences of selective αvβ1 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.

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.

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:  = 6; Professional Development Phase, PDP:  = 4), parents/guardians ( = 10), coaches ( = 3), sport scientists ( = 3), physiotherapists ( = 3), and catering ( = 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.

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.

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.

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).

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.

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.

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.

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.

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).

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.

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.

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.

Infrared Quantum Information.

We discuss information-theoretic properties of low-energy photons and gravitons in the S matrix. Given an incoming n-particle momentum eigenstate, we demonstrate that unobserved soft photons decohere nearly all outgoing momentum superpositions of charged particles, while the universality of gravity implies that soft gravitons decohere nearly all outgoing momentum superpositions of all the hard particles. Using this decoherence, we compute the entanglement entropy of the soft bosons and show that it is infrared-finite when the leading divergences are resummed in the manner of Bloch and Nordsieck.

Vinblastine 20' Amides: Synthetic Analogues That Maintain or Improve Potency and Simultaneously Overcome Pgp-Derived Efflux and Resistance.

A series of 180 vinblastine 20' amides were prepared in three steps from commercially available starting materials, systematically exploring a typically inaccessible site in the molecule enlisting a powerful functionalization strategy. Clear structure-activity relationships and a structural model were developed in the studies which provided many such 20' amides that exhibit substantial and some even remarkable enhancements in potency, many that exhibit further improvements in activity against a Pgp overexpressing resistant cancer cell line, and an important subset of the vinblastine analogues that display little or no differential in activity against a matched pair of vinblastine sensitive and resistant (Pgp overexpressing) cell lines. The improvements in potency directly correlated with target tubulin binding affinity, and the reduction in differential functional activity against the sensitive and Pgp overexpressing resistant cell lines was found to correlate directly with an impact on Pgp-derived efflux.

Ultrapotent vinblastines in which added molecular complexity further disrupts the target tubulin dimer-dimer interface.

Approaches to improving the biological properties of natural products typically strive to modify their structures to identify the essential pharmacophore, or make functional group changes to improve biological target affinity or functional activity, change physical properties, enhance stability, or introduce conformational constraints. Aside from accessible semisynthetic modifications of existing functional groups, rarely does one consider using chemical synthesis to add molecular complexity to the natural product. In part, this may be attributed to the added challenge intrinsic in the synthesis of an even more complex compound.

A Conformationally Constrained Cyclic Acyldepsipeptide Is Highly Effective in Mice Infected with Methicillin-Susceptible and -Resistant Staphylococcus aureus.

Background: Cyclic acyldepsipeptides (ADEPs) are a novel class of antibacterial agents, some of which (e.g., ADEP 4) are highly active against Gram-positive bacteria.

Developmental delays in phonological recoding among children and adolescents with Down syndrome and Williams syndrome.

This study examined the development of phonological recoding in short-term memory (STM) span tasks among two clinical groups with contrasting STM and language profiles: those with Down syndrome (DS) and Williams syndrome (WS). Phonological recoding was assessed by comparing: (1) performance on phonologically similar and dissimilar items (phonological similarity effects, PSE); and (2) items with short and long names (word length effects, WLE). Participant groups included children and adolescents with DS (n=29), WS (n=25) and typical development (n=51), all with average mental ages around 6 years.