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

Synthesis of cyclic alpha-diazo-beta-keto sulfoxides in batch and continuous flow

Diazo transfer to beta–keto sulfoxides to form stable isolable alpha-diazo-beta-keto sulfoxides has been achieved for the first time. Both monocyclic and benzofused ketone derived beta-keto sulfoxides were successfully explored as substrates for diazo transfer. Use of continuous flow leads to isolation of the desired compounds in enhanced yields relative to standard batch conditions, with short reaction times, increased safety profile and potential to scale up

miR-199a-5p silencing regulates the unfolded protein response in chronic obstructive pulmonary disease and α1-antitrypsin deficiency.

RATIONALE: Retention of abnormal α1-antitrypsin (AAT) activates the unfolded protein response in AAT-deficient monocytes. The regulatory role of microRNAs (miRNAs) in unfolded protein responses and chronic obstructive pulmonary disease pathogenesis has not been investigated. OBJECTIVES: To investigate miRNA expression and function in MM and ZZ monocytes and identify miRNA(s) regulating the unfolded protein response. METHODS: Peripheral blood monocytes were isolated from asymptomatic and symptomatic MM and ZZ individuals for miRNA expression profiling and pyrosequencing analysis. miRNA/gene and protein expression was measured with quantitative polymerase chain reaction and Western blotting. Overexpression and inhibition studies were performed with pre-miR or anti-miR, respectively. Luciferase reporter genes were used to elucidate direct miRNA-target interactions. Inflammatory cytokines were detected using the Meso Scale Discovery Plex assays. MEASUREMENTS AND MAIN RESULTS: Forty-three miRNAs were differentially expressed, with miR-199a-5p most highly up-regulated in asymptomatic ZZ versus MM monocytes. miR-199a-2 promoter hypermethylation inhibits miR-199a-5p expression and was increased in symptomatic MM and ZZ monocytes compared with asymptomatic counterparts. GRP78, activating transcription factor 6, p50, and p65 were increased in symptomatic versus asymptomatic ZZ monocytes. Reciprocal down- or up-regulation of these markers was observed after miRNA modulation. Direct miR-199a-5p targeting of activating transcription factor 6, p50, and p65 by miR-199a-5p was demonstrated using luciferase reporter systems. Overexpression of miR-199a-5p also decreased other arms of the UPR and expression of cytokines that are not putative targets. CONCLUSIONS: miR-199a-5p is a key regulator of the unfolded protein response in AAT-deficient monocytes, and epigenetic silencing of its expression regulates this process in chronic obstructive pulmonary disease

Comprehensive genetic and epigenetic analysis of sporadic meningioma for macro-mutations on 22q and micro-mutations within the NF2 locus

BACKGROUND: Meningiomas are the most common intracranial neoplasias, representing a clinically and histopathologically heterogeneous group of tumors. The neurofibromatosis type 2 (NF2) tumor suppressor is the only gene known to be frequently involved in early development of meningiomas. The objective of this study was to identify genetic and/or epigenetic factors contributing to the development of these tumors. A large set of sporadic meningiomas were analyzed for presence of 22q macro-mutations using array-CGH in order to identify tumors carrying gene dosage aberrations not encompassing NF2. The NF2 locus was also comprehensively studied for point mutations within coding and conserved non-coding sequences. Furthermore, CpG methylation within the NF2 promoter region was thoroughly analyzed. RESULTS: Monosomy 22 was the predominant finding, detected in 47% of meningiomas. Thirteen percent of the tumors contained interstitial/terminal deletions and gains, present singly or in combinations. We defined at least two minimal overlapping regions outside the NF2 locus that are small enough (~550 kb and ~250 kb) to allow analysis of a limited number of candidate genes. Bialleinactivationo the NF2 gne was detected in 36% of meningiomas. Among the monosomy 22 cases, no additional NF2 mutations could be identified in 35% (17 out of 49) of tumors. Furthermore, the majority of tumors (9 out of 12) with interstitial/terminal deletions did not have any detectable NF2 mutations. Methylation within the NF2 promoter region was only identified at a single CpG site in one tumor sample. CONCLUSION: We confirmed previous findings of pronounced differences in mutation frequency between different histopathological subtypes. There is a higher frequency of biallelic NF2 inactivation in fibroblastic (52%) compared to meningothelial (18%) tumors. The presence of macro-mutations on 22q also shows marked differences between fibroblastic (86%) and meningothelial (39%) subtypes. Thus, inactivation of NF2, often combined with the presence of macro-mutation on 22q, is likely not as important for the development of the meningothelial subtype, as opposed to the fibroblastic form. Analysis of 40 CpG sites distributed within 750 bp of the promoter region suggests that NF2 promoter methylation does not play a major role in meningioma development

Differential DNA methylation patterns define status epilepticus and epileptic tolerance.

Prolonged seizures (status epilepticus) produce pathophysiological changes in the hippocampus that are associated with large-scale, wide-ranging changes in gene expression. Epileptic tolerance is an endogenous program of cell protection that can be activated in the brain by previous exposure to a non-harmful seizure episode before status epilepticus. A major transcriptional feature of tolerance is gene downregulation. Here, through methylation analysis of 34,143 discrete loci representing all annotated CpG islands and promoter regions in the mouse genome, we report the genome-wide DNA methylation changes in the hippocampus after status epilepticus and epileptic tolerance in adult mice. A total of 321 genes showed altered DNA methylation after status epilepticus alone or status epilepticus that followed seizure preconditioning, with \u3e90% of the promoters of these genes undergoing hypomethylation. These profiles included genes not previously associated with epilepsy, such as the polycomb gene Phc2. Differential methylation events generally occurred throughout the genome without bias for a particular chromosomal region, with the exception of a small region of chromosome 4, which was significantly overrepresented with genes hypomethylated after status epilepticus. Surprisingly, only few genes displayed differential hypermethylation in epileptic tolerance. Nevertheless, gene ontology analysis emphasized the majority of differential methylation events between the groups occurred in genes associated with nuclear functions, such as DNA binding and transcriptional regulation. The present study reports select, genome-wide DNA methylation changes after status epilepticus and in epileptic tolerance, which may contribute to regulating the gene expression environment of the seizure-damaged hippocampus

A comparison of two cases of low-latitude thundersnow

http://solberg.snr.missouri.edu/gcc/Two cases of low-latitude snow with lightning are studied to determine their characteristics. Both cases had synoptic-scale origins, but also featured smaller-scale influences (e. g. orographic lift and elevated instability).The first event occurred in the Southern Hemisphere and was a late winter case that developed under the influence of underlying orography. Lightning was plentiful in that event (94 cloud-to-ground flashes in the region), but snow accumulations were not significant. Lightning flashes of negative polarity dominated this case, with a mean peak amplitude of -43.2 kA. The second event was a Northern Hemisphere case of elevated convection, with frontogenesis beneath an extended layer of potential instability. Appreciable lightning occurred with this event as well (706 cloud-to-ground flashes in the region), and snow accumulations were significant over a broad area. Lightning flashes of negative polarity dominated this case also, with a mean peak amplitude of -23.7 kA. Each of these events is worthy of further scrutiny, as studies of such storms do not appear often in the literature. Indeed, such warm, subtropical regions are often unprepared for the effects of just a little snow or ice accumulation. Future forecasters can anticipate better such anomalous events by looking for these broad features: 1) significant and well-defined synoptic-scale weather systems at low latitudes, 2) a strong baroclinic zone with a well-defined (≥60 ms-1) jet structure aloft, 3) cold air of appreciable depth and areal extent drawn much closer to the equator than is typical, and 4) a moist neutral to conditionally unstable layer above the frontal zone

MicroRNA-184 inhibits neuroblastoma cell survival through targeting the serine/threonine kinase AKT2

BACKGROUND: Neuroblastoma is a paediatric cancer of the sympathetic nervous system. The single most important genetic indicator of poor clinical outcome is amplification of the MYCN transcription factor. One of many down-stream MYCN targets is miR-184, which is either directly or indirectly repressed by this transcription factor, possibly due to its pro-apoptotic effects when ectopically over-expressed in neuroblastoma cells. The purpose of this study was to elucidate the molecular mechanism by which miR-184 conveys pro-apoptotic effects. RESULTS: We demonstrate that the knock-down of endogenous miR-184 has the opposite effect of ectopic up-regulation, leading to enhanced neuroblastoma cell numbers. As a mechanism of how miR-184 causes apoptosis when over-expressed, and increased cell numbers when inhibited, we demonstrate direct targeting and degradation of AKT2, a major downstream effector of the phosphatidylinositol 3-kinase (PI3K) pathway, one of the most potent pro-survival pathways in cancer. The pro-apoptotic effects of miR-184 ectopic over-expression in neuroblastoma cell lines is reproduced by siRNA inhibition of AKT2, while a positive effect on cell numbers similar to that obtained by the knock-down of endogenous miR-184 can be achieved by ectopic up-regulation of AKT2. Moreover, co-transfection of miR-184 with an AKT2 expression vector lacking the miR-184 target site in the 3\u27UTR rescues cells from the pro-apoptotic effects of miR-184. CONCLUSIONS: MYCN contributes to tumorigenesis, in part, by repressing miR-184, leading to increased levels of AKT2, a direct target of miR-184. Thus, two important genes with positive effects on cell growth and survival, MYCN and AKT2, can be linked into a common genetic pathway through the actions of miR-184. As an inhibitor of AKT2, miR-184 could be of potential benefit in miRNA mediated therapeutics of MYCN amplified neuroblastoma and other forms of cancer

A study of the norcaradiene-cycloheptatriene equilibrium in a series of azulenones by NMR spectroscopy; the impact of substitution on the position of equilibrium

A systematic investigation of the influence of substitution at positions C-2 and C-3 on the azulenone skeleton, based on NMR characterisation, is discussed with particular focus on the impact of the steric and electronic characteristics of substituents on the position of the norcaradiene-cycloheptatriene (NCD-CHT) equilibrium. Variable temperature (VT) NMR studies, undertaken to enable the resolution of signals for the equilibrating valence tautomers revealed, in addition, interesting shifts in the equilibrium

Global MYCN Transcription Factor Binding Analysis in Neuroblastoma Reveals Association with Distinct E-Box Motifs and Regions of DNA Hypermethylation

BACKGROUND: Neuroblastoma, a cancer derived from precursor cells of the sympathetic nervous system, is a major cause of childhood cancer related deaths. The single most important prognostic indicator of poor clinical outcome in this disease is genomic amplification of MYCN, a member of a family of oncogenic transcription factors. METHODOLOGY: We applied MYCN chromatin immunoprecipitation to microarrays (ChIP-chip) using MYCN amplified/non-amplified cell lines as well as a conditional knockdown cell line to determine the distribution of MYCN binding sites within all annotated promoter regions. CONCLUSION: Assessment of E-box usage within consistently positive MYCN binding sites revealed a predominance for the CATGTG motif (p\u3c0.0016), with significant enrichment of additional motifs CATTTG, CATCTG, CAACTG in the MYCN amplified state. For cell lines over-expressing MYCN, gene ontology analysis revealed enrichment for the binding of MYCN at promoter regions of numerous molecular functional groups including DNA helicases and mRNA transcriptional regulation. In order to evaluate MYCN binding with respect to other genomic features, we determined the methylation status of all annotated CpG islands and promoter sequences using methylated DNA immunoprecipitation (MeDIP). The integration of MYCN ChIP-chip and MeDIP data revealed a highly significant positive correlation between MYCN binding and DNA hypermethylation. This association was also detected in regions of hemizygous loss, indicating that the observed association occurs on the same homologue. In summary, these findings suggest that MYCN binding occurs more commonly at CATGTG as opposed to the classic CACGTG E-box motif, and that disease associated over expression of MYCN leads to aberrant binding to additional weaker affinity E-box motifs in neuroblastoma. The co-localization of MYCN binding and DNA hypermethylation further supports the dual role of MYCN, namely that of a classical transcription factor affecting the activity of individual genes, and that of a mediator of global chromatin structure

Family support in practice : voices from the field

This paper revisits core family support messages for social work practice in working with children and families, linking to findings from high-profile child protection cases in the UK and the Republic of Ireland. Drawing on a comparative study where these identified practice messages were explored through the lens of testimony of family support workers in the UK and Ireland, these core messages are examined. Operating with hard-to-engage children and parents, we hear how families and family support worker colleagues now view the core functions of child and family work across both jurisdictions (Ireland and England). The authors argue that by naming a more detailed set of practices that are deemed as most useful by families, based on the benefits and challenges of intensive family support work, key messages arise that have major resonance for social work and multiagency practice into the future. A basic message from this study is that valuable lessons on engagement and intervention with families can be drawn for professionals by examining the practice elements of this group of paraprofessionals in the child and family arena. This paper adds to debates on the role of support and intervention in social work and family support work