Youth Single-Sport Specialization in Professional Baseball Players.

Background: An increasing number of youth baseball athletes are specializing in playing baseball at younger ages. Purpose: The purpose of our study was to describe the age and prevalence of single-sport specialization in a cohort of current professional baseball athletes. In addition, we sought to understand the trends surrounding single-sport specialization in professional baseball players raised within and outside the United States (US). Study Design: Cross-sectional study; Level of evidence, 3. Methods: A survey was distributed to male professional baseball athletes via individual team athletic trainers. Athletes were asked if and at what age they had chosen to specialize in playing baseball at the exclusion of other sports, and data were then collected pertaining to this decision. We analyzed the rate and age of specialization, the reasons for specialization, and the athlete\u27s perception of injuries related to specialization. Results: A total of 1673 professional baseball athletes completed the survey, representing 26 of the 30 Major League Baseball (MLB) organizations. Less than half (44.5%) of professional athletes specialized in playing a single sport during their childhood/adolescence. Those who reported specializing in their youth did so at a mean age of 14.09 ± 2.79 years. MLB players who grew up outside the US specialized at a significantly earlier age than MLB players native to the US (12.30 ± 3.07 vs 14.89 ± 2.24 years, respectively; Conclusion: This study challenges the current trends toward early youth sport specialization, finding that the majority of professional baseball athletes studied did not specialize as youth and that those who did specialize did so at a mean age of 14 years. With the potential cumulative effects of pitching and overhead throwing on an athlete\u27s arm, the trend identified in this study toward earlier specialization within baseball is concerning

Long-term climatic stability drives accumulation and maintenance of divergent freshwater fish lineages in a temperate biodiversity hotspot

Anthropogenic climate change is forecast to drive regional climate disruption and instability across the globe. These impacts are likely to be exacerbated within biodiversity hotspots, both due to the greater potential for species loss but also to the possibility that endemic lineages might not have experienced significant climatic variation in the past, limiting their evolutionary potential to respond to rapid climate change. We assessed the role of climatic stability on the accumulation and persistence of lineages in an obligate freshwater fish group endemic to the southwest Western Australia (SWWA) biodiversity hotspot. Using 19,426 genomic (ddRAD-seq) markers and species distribution modelling, we explored the phylogeographic history of western (Nannoperca vittata) and little (Nannoperca pygmaea) pygmy perches, assessing population divergence and phylogenetic relationships, delimiting species and estimating changes in species distributions from the Pliocene to 2100. We identified two deep phylogroups comprising three divergent clusters, which showed no historical connectivity since the Pliocene. We conservatively suggest these represent three isolated species with additional intraspecific structure within one widespread species. All lineages showed long-term patterns of isolation and persistence owing to climatic stability but with significant range contractions likely under future climate change. Our results highlighted the role of climatic stability in allowing the persistence of isolated lineages in the SWWA. This biodiversity hotspot is under compounding threat from ongoing climate change and habitat modification, which may further threaten previously undetected cryptic diversity across the region

Ожирение – фактор риска развития неуточненной инфекции подкожно-жировой клетчатки

Представлено результати дослідження С-пептиду, інсуліну та лептину, а також розраховано індекс маси тіла у хворих з неуточненою інфекцією підшкірної клітковини. У 47,62 % хворих ожиріння I-III ступеня, що збільшує ліпогенез, який провокує гіпертрофію адипоцитів.The results of C-peptide, insulin and leptin exploration are presented; also the body weight index among the ill with the subcutaneous cellular tissue unspecified infection has been calculated. 47,62 % of the ill has adiposity of levels I-III, which increases lipogenesis provoking the adepocites hypertrophy

Computationally-designed miniproteins showing neutralization activity against SARS-CoV-2

As the COVID-19 pandemic demonstrated, the need for robust antiviral therapies against SARS-CoV-2 remains substantial. A promising strategy to meet this demand is through the development of proteins tailored for enhanced binding affinity to crucial viral targets, such as epitopes located on their fusion proteins. Among these targets is the Spike proteins receptor binding domain (RBD), which interacts with the human receptor ACE2 protein, initiating the viral entry process. Targeting the RBD epitope that binds to ACE2 is a promising strategy to fight COVID-19 and is used here as a model target to validate our approach. In this work, we implemented a computational pipeline leveraging artificial intelligence-based computational design methodologies, RFDiffusion and ProteinMPNN, to de novo design miniproteins targeting the RBD epitope that interacts with ACE2. The most promising designs were selected based on a combination of relevant criteria, including metrics derived from the protein structure prediction tool AlphaFold2 and properties like surface hydrophobicity and shape complementarity to the target. We expressed in vitro selected designs and evaluated their binding affinity to the RBD using Bio-layer Interferometry and Yeast Display assays. Proteins demonstrating favourable binding affinity to the RBD were subsequently subjected to neutralization assays, evaluating the proteins ability to inhibit SARS-CoV-2 infection. We observed that two of the selected designs can bind to the RBD and neutralize viral infection, thus successfully demonstrating that this computational framework is able to design proteins that are tailor-made to interact with specific epitopes. This paves the way for the next round of design, where the most promising candidates are being optimized using strategies that consider the oligomerization tendency observed in some of the designs tested.info:eu-repo/semantics/publishedVersio

Zero Botnets: An Observe-Pursue-Counter Approach

Adversarial Internet robots (botnets) represent a growing threat to the safe use and stability of the Internet. Botnets can play a role in launching adversary reconnaissance (scanning and phishing), influence operations (upvoting), and financing operations (ransomware, market manipulation, denial of service, spamming, and ad click fraud) while obfuscating tailored tactical operations. Reducing the presence of botnets on the Internet, with the aspirational target of zero, is a powerful vision for galvanizing policy action. Setting a global goal, encouraging international cooperation, creating incentives for improving networks, and supporting entities for botnet takedowns are among several policies that could advance this goal. These policies raise significant questions regarding proper authorities/access that cannot be answered in the abstract. Systems analysis has been widely used in other domains to achieve sufficient detail to enable these questions to be dealt with in concrete terms. Defeating botnets using an observe-pursue-counter architecture is analyzed, the technical feasibility is affirmed, and the authorities/access questions are significantly narrowed. Recommended next steps include: supporting the international botnet takedown community, expanding network observatories, enhancing the underlying network science at scale, conducting detailed systems analysis, and developing appropriate policy frameworks.Comment: 26 pages, 13 figures, 2 tables, 72 references, submitted to PlosOn

Obituary for Paul Bacon

Paul Bacon, Emeritus Professor of Rheumatology and the first Professor of Rheumatology in Birmingham UK, died peacefully on Friday 12 January 2018 after a short illness. Positive and organized until the end, he was able to say goodbye to his family and friends who came to visit him and his wife Jean over the Christmas period at their retirement home in Lancashire

Archaeometric evidence for the earliest exploitation of lignite from the bronze age Eastern Mediterranean

This paper presents the earliest evidence for the exploitation of lignite (brown coal) in Europe and sheds new light on the use of combustion fuel sources in the 2nd millennium BCE Eastern Mediterranean. We applied Thermal Desorption/Pyrolysis-Gas Chromatography-Mass Spectrometry and Polarizing Microscopy to the dental calculus of 67 individuals and we identified clear evidence for combustion markers embedded within this calculus. In contrast to the scant evidence for combustion markers within the calculus samples from Egypt, all other individuals show the inhalation of smoke from fires burning wood identified as Pinaceae, in addition to hardwood, such as oak and olive, and/ or dung. Importantly, individuals from the Palatial Period at the Mycenaean citadel of Tiryns and the Cretan harbour site of Chania also show the inhalation of fire-smoke from lignite, consistent with the chemical signature of sources in the northwestern Peloponnese and Western Crete respectively. This first evidence for lignite exploitation was likely connected to and at the same time enabled Late Bronze Age Aegean metal and pottery production, significantly by both male and female individuals

Structural and Atropisomeric Factors Governing the Selectivity of Pyrimido-benzodiazipinones as Inhibitors of Kinases and Bromodomains

This is the author accepted manuscript. The final version is available from American Chemical Society via the DOI in this recordBromodomains have been pursued intensively over the past several years as emerging targets for the devel-opment of anti-cancer and anti-inflammatory agents. It has recently been shown that some kinase inhibitors are able to potently inhibit the bromodomains of BRD4. The clinical activities of PLK inhibitor BI-2536 and JAK2-FLT3 inhibitor TG101348 have been attributed to this unexpected poly-pharmacology, indicating that dual-kinase/bromodomain activity may be advantageous in a therapeutic context. However, for target validation and biological investigation, a more selec-tive target profile is desired. Here we report that benzo[e]pyrimido-[5,4-b]diazepine-6(11H)-ones, versatile ATP-site di-rected kinase pharmacophores utilized in the development of inhibitors of multiple kinases including a number of previ-ously reported kinase chemical probes, are also capable of exhibiting potent BRD4-dependent pharmacology. Using a dual kinase-bromodomain inhibitor of the kinase domains of ERK5 and LRRK2, and the bromodomain of BRD4 as a case study, we define the structure-activity relationships required to achieve dual kinase/BRD4 activity as well as how to di-rect selectivity towards inhibition of either ERK5 or BRD4. This effort resulted in identification of one of the first report-ed kinase-selective chemical probes for ERK5 (JWG-071), a BET selective inhibitor with 1 μM BRD4 IC50 (JWG-115), and additional inhibitors with rationally designed polypharmacology (JWG-047, JWG-069). Co-crystallography of seven representative inhibitors with the first bromodomain of BRD4 demonstrate that distinct atropisomeric conformers rec-ognize the kinase ATP-site and the BRD4 acetyl lysine binding site, conformational preferences supported by rigid dock-ing studies.This work was supported by NIH (Grant No. U54HL127365, to N.S.G. and J.W.; No. NIH P50 GM107618, to X.X. and S.C.B.; Nos. NIH U54 HD093540 and P01 CA066996, to J.Q.), the Medical Research Council (No. MC_UU_12016/2, to D.R.A.), the Spanish Ministerio de Economia y Competitividad (MINECO) (Grant No. SAF2015-60268R, to J.M.L.), and Fondo Europeo de Desarrollo Regional (FEDER) funds (to J.M.L.). D.L.B. was supported as a Merck Fellow of Damon Runyon Cancer Research Foundation (No. DRG-2196-14)

Simplified Models for LHC New Physics Searches

This document proposes a collection of simplified models relevant to the design of new-physics searches at the LHC and the characterization of their results. Both ATLAS and CMS have already presented some results in terms of simplified models, and we encourage them to continue and expand this effort, which supplements both signature-based results and benchmark model interpretations. A simplified model is defined by an effective Lagrangian describing the interactions of a small number of new particles. Simplified models can equally well be described by a small number of masses and cross-sections. These parameters are directly related to collider physics observables, making simplified models a particularly effective framework for evaluating searches and a useful starting point for characterizing positive signals of new physics. This document serves as an official summary of the results from the "Topologies for Early LHC Searches" workshop, held at SLAC in September of 2010, the purpose of which was to develop a set of representative models that can be used to cover all relevant phase space in experimental searches. Particular emphasis is placed on searches relevant for the first ~50-500 pb-1 of data and those motivated by supersymmetric models. This note largely summarizes material posted at http://lhcnewphysics.org/, which includes simplified model definitions, Monte Carlo material, and supporting contacts within the theory community. We also comment on future developments that may be useful as more data is gathered and analyzed by the experiments.Comment: 40 pages, 2 figures. This document is the official summary of results from "Topologies for Early LHC Searches" workshop (SLAC, September 2010). Supplementary material can be found at http://lhcnewphysics.or

A single cell atlas of frozen shoulder capsule identifies features associated with inflammatory fibrosis resolution

Frozen shoulder is a spontaneously self-resolving chronic inflammatory fibrotic human disease, which distinguishes the condition from most fibrotic diseases that are progressive and irreversible. Using single-cell analysis, we identify pro-inflammatory MERTKlowCD48+ macrophages and MERTK + LYVE1 + MRC1+ macrophages enriched for negative regulators of inflammation which co-exist in frozen shoulder capsule tissues. Micro-cultures of patient-derived cells identify integrin-mediated cell-matrix interactions between MERTK+ macrophages and pro-resolving DKK3+ and POSTN+ fibroblasts, suggesting that matrix remodelling plays a role in frozen shoulder resolution. Cross-tissue analysis reveals a shared gene expression cassette between shoulder capsule MERTK+ macrophages and a respective population enriched in synovial tissues of rheumatoid arthritis patients in disease remission, supporting the concept that MERTK+ macrophages mediate resolution of inflammation and fibrosis. Single-cell transcriptomic profiling and spatial analysis of human foetal shoulder tissues identify MERTK + LYVE1 + MRC1+ macrophages and DKK3+ and POSTN+ fibroblast populations analogous to those in frozen shoulder, suggesting that the template to resolve fibrosis is established during shoulder development. Crosstalk between MerTK+ macrophages and pro-resolving DKK3+ and POSTN+ fibroblasts could facilitate resolution of frozen shoulder, providing a basis for potential therapeutic resolution of persistent fibrotic diseases