Age- and size-corrected kicking speed and accuracy in elite junior soccer players.

Kicking powerfully and accurately is essential in soccer, and players who kick proficiently with both feet are highly sought after. Assessing performance in youth players is often confounded by more physically developed players outperforming their smaller peers. To alleviate such bias, we present a testing protocol and normative data developed with an elite Brazilian soccer academy that controls for players' age and size to assess kick performance with both feet. We measured kick speed and kick accuracy of 178 players and recorded their age (10-20 years), height, and mass. Combining age, height, and mass into an age and size index (ASI), we developed equations describing the relationship between ASI and performance. To determine the underlying predictors of performance, we also measured sprint ability and soccer-specific motor control of each foot with ball dribbling tasks. Kicking speed with the dominant foot was predicted by ASI, sprint speed, and motor control of the nondominant foot, while kicking speed with the nondominant foot was predicted by ASI and motor control of the nondominant foot. Kick accuracy with each foot was predicted by ASI and motor control of the corresponding foot. To improve kicking performance, we suggest training programs focus on motor control.

Genetic and phenotypic variation exhibit both predictable and stochastic patterns across an intertidal fish metapopulation.

Interactions among selection, gene flow, and drift affect the trajectory of adaptive evolution. In natural populations, the direction and magnitude of these processes can be variable across different spatial, temporal, or ontogenetic scales. Consequently, variability in evolutionary processes affects the predictability or stochasticity of microevolutionary outcomes. We studied an intertidal fish, Bathygobius cocosensis (Bleeker, 1854), to understand how space, time, and life stage structure genetic and phenotypic variation in a species with potentially extensive dispersal and a complex life cycle (larval dispersal preceding benthic recruitment). We sampled juvenile and adult life stages, at three sites, over three years. Genome-wide SNPs uncovered a pattern of chaotic genetic patchiness, that is, weak-but-significant patchy spatial genetic structure that was variable through time and between life stages. Outlier locus analyses suggested that targets of spatially divergent selection were mostly temporally variable, though a significant number of spatial outlier loci were shared between life stages. Head shape, a putatively ecologically responsive (adaptive) phenotype in B. cocosensis also exhibited high temporal variability within sites. However, consistent spatial relationships between sites indicated that environmental similarities among sites may generate predictable phenotype distributions across space. Our study highlights the complex microevolutionary dynamics of marine systems, where consideration of multiple ecological dimensions can reveal both predictable and stochastic patterns in the distributions of genetic and phenotypic variation. Such considerations probably apply to species that possess short, complex life cycles, have large dispersal potential and fecundities, and that inhabit heterogeneous environments.

Low-dose aspirin in pregnancy: who? when? how much? and why?

PURPOSE OF REVIEW: The use of low dose aspirin (LDA) has become routine in prenatal care for a variety of diagnoses, most importantly in women with a history of preeclampsia and associated poor pregnancy outcomes. Although LDA is currently indicated in patients considered to be at risk for development of preeclampsia, optimal dosing, timing of treatment initiation, and persons of benefit are under investigation. Several studies have also looked at LDA treatment and its effect on other maternal and fetal outcomes. This review summarizes the current guidelines for the use of LDA, incorporating the most recent research findings, and offers possible future implications of LDA treatment. RECENT FINDINGS: Over 10 years ago, the American College of Obstetricians and Gynecologists, the World Health Organization, and the United States Preventive Service Task Force began publishing guidelines focused on the use of LDA in pregnancy. Since the release of these guidelines, several large studies have re-evaluated the use of LDA with a focus on initiation of treatment and dosing. The combined results of these studies suggest a decreased rate of preeclampsia at aspirin doses >100 mg when treatment is initiated prior to 16 weeks of gestation. SUMMARY: Overall, early initiation of LDA has been shown to decrease the development of preeclampsia in patients considered at increased risk. Current literature suggests increasing the recommended dose to >100 mg to optimize these risk reductions. Although LDA use seems promising for other outcomes like preterm delivery and intrauterine growth restriction, further studies to strengthen recommendations are warranted.

Prevention of preterm birth in multiples.

PURPOSE OF REVIEW: Multifetal pregnancy carries increased risk of preterm delivery, and consensus on management options to prevent early birth in this population has not been reached. This review serves to summarize the most contemporary findings on this controversial topic. RECENT FINDINGS: Examination-indicated cerclage is effective in reducing preterm birth in twin pregnancies, whereas cerclages for other indications are less convincing. Cervical pessary may be beneficial for patients with a short cervix and in those who have had threatened preterm labor. Progesterone supplementation for multifetal gestation alone is not beneficial, but it can be considered in those with a history of prior singleton preterm birth. SUMMARY: Interventions for preterm birth prevention in multiple gestations remain under investigation, and further data is required in order to reach consensus for this high-risk population.

Loss of neutral ceramidase protects cells from nutrient- and energy -deprivation-induced cell death.

Sphingolipids are a family of lipids that regulate the cell cycle, differentiation and cell death. Sphingolipids are known to play a role in the induction of apoptosis, but a role for these lipids in necroptosis is largely unknown. Necroptosis is a programmed form of cell death that, unlike apoptosis, does not require ATP. Necroptosis can be induced under a variety of conditions, including nutrient deprivation and plays a major role in ischaemia/reperfusion injury to organs. Sphingolipids play a role in ischaemia/reperfusion injury in several organs. Thus, we hypothesized that sphingolipids mediate nutrient-deprivation-induced necroptosis. To address this, we utilized mouse embryonic fibroblast (MEFs) treated with 2-deoxyglucose (2DG) and antimycin A (AA) to inhibit glycolysis and mitochondrial electron transport. 2DG/AA treatment of MEFs induced necroptosis as it was receptor- interacting protein (RIP)-1/3 kinase-dependent and caspase-independent. Ceramides, sphingosine (Sph) and sphingosine 1-phosphate (S1P) were increased following 2DG/AA treatment. Cells lacking neutral ceramidase (nCDase(-/-)) were protected from 2DG/AA. Although nCDase(-/-) cells generated ceramides following 2DG/AA treatment, they did not generate Sph or S1P. This protection was stimulus-independent as nCDase(-/-) cells were also protected from endoplasmic reticulum (ER) stressors [tunicamycin (TN) or thapsigargin (TG)]. nCDase(-/-) MEFs had higher autophagic flux and mitophagy than wild-type (WT) MEFs and inhibition of autophagy sensitized them to necroptosis. These data indicate that loss of nCDase protects cells from nutrient- deprivation-induced necroptosis via autophagy, and clearance of damaged mitochondria. Results suggest that nCDase is a mediator of necroptosis and might be a novel therapeutic target for protection from ischaemic injury.

Renal glycosphingolipid metabolism is dysfunctional in lupus nephritis.

Nearly one half of patients with lupus develop glomerulonephritis (GN), which often leads to renal failure. Although nephritis is diagnosed by the presence of proteinuria, the pathology of nephritis can fall into one of five classes defined by different forms of tissue injury, and the mechanisms involved in pathogenesis are not completely understood. Glycosphingolipids are abundant in the kidney, have roles in many cellular functions, and were shown to be involved in other renal diseases. Here, we show dysfunctional glycosphingolipid metabolism in patients with lupus nephritis and MRL/lpr lupus mice. Specifically, we found that glucosylceramide (GlcCer) and lactosylceramide (LacCer) levels are significantly higher in the kidneys of nephritic MRL/lpr lupus mice than the kidneys of non-nephritic lupus mice or healthy controls. This elevation may be, in part, caused by altered transcriptional regulation and/or activity of LacCer synthase (GalT5) and neuraminidase 1, enzymes that mediate glycosphingolipid metabolism. We show increased neuraminidase 1 activity early during the progression of nephritis (before significant elevation of GlcCer and LacCer in the kidney). Elevated levels of urinary LacCer were detected before proteinuria in lupus mice. Notably, LacCer levels were higher in the urine and kidneys of patients with lupus and nephritis than patients with lupus without nephritis or healthy controls. Together, these results show early and significant dysfunction of the glycosphingolipid metabolic pathway in the kidneys of lupus mice and patients with lupus nephritis and suggest that molecules in this pathway may serve as early markers in lupus nephritis.

Cathepsin C inhibitors: property optimization and identification of a clinical candidate.

A lead generation and optimization program delivered the highly selective and potent CatC inhibitor 10 as an in vivo tool compound and potential development candidate. Structural studies were undertaken to generate SAR understanding.

The design of a novel series of muscarinic receptor antagonists leading to AZD8683, a potential inhaled treatment for COPD.

A novel series of muscarinic receptor antagonists was developed, with the aim of identifying a compound with high M3 receptor potency and a reduced risk of dose-limiting side effects with potential for the treatment of COPD. Initial compound modifications led to a novel cycloheptyl series, which was improved by focusing on a quinuclidine sub-series. A wide range of N-substituents was evaluated to determine the optimal substituent providing a high M3 receptor potency, high intrinsic clearance and high human plasma protein binding. Compounds achieving in vitro study criteria were selected for in vivo evaluation. Pharmacokinetic half-lives, inhibition of bronchoconstriction and duration of action, as well as systemic side effects, induced by the compounds were assessed in guinea-pig models. Compounds with a long duration of action and good therapeutic index were identified and AZD8683 was selected for progression to the clinic.

Glycosphingolipids and kidney disease.

Glycosphingolipids, derived from the addition of sugar-moieties to the sphingolipid ceramide, are highly abundant in the kidney. Glycosphingolipids are known to play an important role in organ function at least in part from inherited lipid storage diseases such as Anderson-Fabry disease (Fabry's disease; FD) that results from a mutation in alpha-galactosidase a (α-GLA or α-Gal A), the enzyme responsible for catalyzing the removal of terminal galactose residues from glycosphingolipids. The inactivation in α-GLA in FD results in the accumulation of glycosphingolipids, including globosides and lactosylceramides, which manifests as several common pathologies including end-stage kidney disease. More recently, glycosphingolipids and other sphingolipids have become increasingly recognized for their roles in a variety of other kidney diseases including polycystic kidney disease, acute kidney injury, glomerulonephritis, diabetic nephropathy and kidney cancer. This chapter reviews evidence supporting a mechanistic role for glycosphingolipids in kidney disease and discusses data implicating a role for these lipids in kidney disease resulting from metabolic syndrome. Importantly, inhibitors of glycosphingolipid synthesis are well tolerated in animal models as well as in humans. Thus, an increased understanding of the mechanisms by which altered renal glycosphingolipid metabolism leads to kidney disease has great therapeutic potential.

Molecular evolution of the Bovini tribe (Bovidae, Bovinae): is there evidence of rapid evolution or reduced selective constraint in Domestic cattle?

BACKGROUND: If mutation within the coding region of the genome is largely not adaptive, the ratio of nonsynonymous (dN) to synonymous substitutions (dS) per site (dN/dS) should be approximately equal among closely related species. Furthermore, dN/dS in divergence between species should be equivalent to dN/dS in polymorphisms. This hypothesis is of particular interest in closely related members of the Bovini tribe, because domestication has promoted rapid phenotypic divergence through strong artificial selection of some species while others remain undomesticated. We examined a number of genes that may be involved in milk production in Domestic cattle and a number of their wild relatives for evidence that domestication had affected molecular evolution. Elevated rates of dN/dS were further queried to determine if they were the result of positive selection, low effective population size (N(e)) or reduced selective constraint. RESULTS: We have found that the domestication process has contributed to higher dN/dS ratios in cattle, especially in the lineages leading to the Domestic cow (Bos taurus) and Mithan (Bos frontalis) and within some breeds of Domestic cow. However, the high rates of dN/dS polymorphism within B. taurus when compared to species divergence suggest that positive selection has not elevated evolutionary rates in these genes. Likewise, the low rate of dN/dS in Bison, which has undergone a recent population bottleneck, indicates a reduction in population size alone is not responsible for these observations. CONCLUSION: The effect of selection depends on effective population size and the selection coefficient (N(e)s). Typically under domestication both selection pressure for traits important in fitness in the wild and Ne are reduced. Therefore, reduced selective constraint could be responsible for the observed elevated evolutionary ratios in domesticated species, especially in B. taurus and B. frontalis, which have the highest dN/dS in the Bovini. This may have important implications for tests of selection such as the McDonald-Kreitman test. Surprisingly we have also detected a significant difference in the supposed neutral substitution rate between synonymous and noncoding sites in the Bovine genome, with a 30% higher rate of substitution at synonymous sites. This is due, at least in part, to an excess of the highly mutable CpG dinucleotides at synonymous sites, which will have implications for time of divergence estimates from molecular data.

Cervicofacial and mediastinal emphysema complicating a dental procedure.

Cervicofacial subcutaneous emphysema is an infrequently reported sequela of dental surgery. It may be caused by the inadvertent introduction of air into the soft tissues during procedures using high-speed, air-driven handpieces or air-water syringes. In this paper, we present a case in which subcutaneous emphysema developed in a middle-aged woman following routine restorative treatment. We review the features of the condition and its treatment and discuss means of prevention.

Testing the neutral theory of molecular evolution using genomic data: a comparison of the human and bovine transcriptome.

Despite growing evidence of rapid evolution in protein coding genes, the contribution of positive selection to intra- and interspecific differences in protein coding regions of the genome is unclear. We attempted to see if genes coding for secreted proteins and genes with narrow expression, specifically those preferentially expressed in the mammary gland, have diverged at a faster rate between domestic cattle (Bos taurus) and humans (Homo sapiens) than other genes and whether positive selection is responsible. Using a large data set, we identified groups of genes based on secretion and expression patterns and compared them for the rate of nonsynonymous (dN) and synonymous (dS) substitutions per site and the number of radical (Dr) and conservative (Dc) amino acid substitutions. We found evidence of rapid evolution in genes with narrow expression, especially for those expressed in the liver and mammary gland and for genes coding for secreted proteins. We compared common human polymorphism data with human-cattle divergence and found that genes with high evolutionary rates in human-cattle divergence also had a large number of common human polymorphisms. This argues against positive selection causing rapid divergence in these groups of genes. In most cases dN/dS ratios were lower in human-cattle divergence than in common human polymorphism presumably due to differences in the effectiveness of purifying selection between long-term divergence and short-term polymorphism.