Age-related differences in adaptation during childhood: The influences of muscular power production and segmental energy flow caused by muscles

Acquisition of skillfulness is not only characterized by a task-appropriate application of muscular forces but also by the ability to adapt performance to changing task demands. Previous research suggests that there is a different developmental schedule for adaptation at the kinematic compared to the neuro-muscular level. The purpose of this study was to determine how age-related differences in neuro-muscular organization affect the mechanical construction of pedaling at different levels of the task. By quantifying the flow of segmental energy caused by muscles, we determined the muscular synergies that construct the movement outcome across movement speeds. Younger children (5-7 years; n = 11), older children (8-10 years; n = 8), and adults (22-31 years; n = 8) rode a stationary ergometer at five discrete cadences (60, 75, 90, 105, and 120 rpm) at 10% of their individually predicted peak power output. Using a forward dynamics simulation, we determined the muscular contributions to crank power, as well as muscular power delivered to the crank directly and indirectly (through energy absorption and transfer) during the downstroke and the upstroke of the crank cycle. We found significant age × cadence interactions for (1) peak muscular power at the hip joint [Wilks' Lambda = 0.441, F(8,42) = 2.65, p = 0.019] indicating that at high movement speeds children produced less peak power at the hip than adults, (2) muscular power delivered to the crank during the downstroke and the upstroke of the crank cycle [Wilks' Lambda = 0.399, F(8,42) = 3.07, p = 0.009] indicating that children delivered a greater proportion of the power to the crank during the upstroke when compared to adults, (3) hip power contribution to limb power [Wilks' Lambda = 0.454, F(8,42) = 2.54, p = 0.023] indicating a cadence-dependence of age-related differences in the muscular synergy between hip extensors and plantarflexors. The results demonstrate that in spite of a successful performance, children construct the task of pedaling differently when compared to adults, especially when they are pushed to their performance limits. The weaker synergy between hip extensors and plantarflexors suggests that a lack of inter-muscular coordination, rather than muscular power production per se, is a factor that limits children's performance ranges

Nutritional supplements and infection in the elderly: why do the findings conflict?

BACKGROUND: Most of the randomized placebo-controlled trials that have examined the clinical effects of multivitamin-mineral supplements on infection in the elderly have shown no significant effect. The exceptions are three such trials, all using a supplement with the same composition, and all claiming dramatic benefits: a frequently cited study published in 1992, which reported a 50% reduction in the number of days of infection (NDI), and two 2002 replication studies. Questions have been raised about the 1992 report; a second report in 2001 based on the same trial, but describing effects of the supplement on cognitive functions, has been retracted by Nutrition. The primary purpose of the present paper is to evaluate the claims about the effects of supplements on NDI in the two replication reports. METHODS: Examination of internal consistency (outcomes of statistical tests versus reported data); comparison of variability of NDI across individuals in these two reports with variability in other trials; estimation of the probability of achieving the reported close agreement with the original finding. RESULTS: The standard deviations of NDI and levels of statistical significance reported are profoundly inconsistent. The reported standard deviations of NDI are consistently below what other studies have found. The reported percent reductions in NDI agree too closely with the original study. CONCLUSION: The claims of reduced NDI in the two replication reports should be questioned, which also adds to concerns about the 1992 study. It follows that there is currently no trustworthy evidence from randomized placebo-controlled clinical trials that favors the use of vitamin-mineral supplements to reduce infection in the elderly

Fusion in the ETS gene family and prostate cancer

It has recently been shown that the majority of prostate cancers harbour a chromosomal rearrangement that fuses the gene for an androgen-regulated prostate-specific serine protease, TMPRSS2, with a member of the ETS family of transcription factors, most commonly ERG. These are among the most common genetic alterations in any human solid tumour. This knowledge may provide us with clues to prostate carcinogenesis, and may lead to the development of important molecular-based biomarkers for patients with localised prostate cancer. The most common variant is fusion between the 5′-untranslated region of TMPRSS2 and the 3′ region of ERG. However, over 20 other fusion variants have now been described (involving over 10 different genes) and the number of variants continues to grow. Fusion products can be identified by several techniques, including FISH, RT–PCR, and expression profiling using exon arrays. The protein products associated with the fusion transcripts have not been characterised, and the phenotypic expression of the various products of gene fusion on prostate cancer histology, or on the clinical course of cancer, are not yet understood. Several early cohort studies suggest that the presence of the TMPRSS2:ERG fusion product is associated with relatively poor cancer-specific survival. Studies that examine how individual variants and their associated phenotypes affect prostate cancer presentation and progression are required

Expression of the TMPRSS2:ERG fusion gene predicts cancer recurrence after surgery for localised prostate cancer

The prostate-specific gene, TMPRSS2 is fused with the gene for the transcription factor ERG in a large proportion of human prostate cancers. The prognostic significance of the presence of the TMPRSS2:ERG gene fusion product remains controversial. We examined prostate cancer specimens from 165 patients who underwent surgery for clinically localised prostate cancer between 1998 and 2006. We tested for the presence of TMPRSS2:ERG gene fusion product, using RT–PCR and direct sequencing. We conducted a survival analysis to determine the prognostic significance of the presence of the TMPRSS2:ERG fusion gene on the risk of prostate cancer recurrence, adjusting for the established prognostic factors. We discovered that the fusion gene was expressed within the prostate cancer cells in 81 of 165 (49.1%) patients. Of the 165 patients, 43 (26.1%) developed prostate-specific antigen (PSA) relapse after a mean follow-up of 28 months. The subgroup of patients with the fusion protein had a significantly higher risk of recurrence (58.4% at 5 years) than did patients who lacked the fusion protein (8.1%, P<0.0001). In a multivariable analysis, the presence of gene fusion was the single most important prognostic factor; the adjusted hazard ratio for disease recurrence for patients with the fusion protein was 8.6 (95% CI=3.6–20.6, P<0.0001) compared to patients without the fusion protein. Among prostate cancer patients treated with surgery, the expression of TMPRSS2:ERG fusion gene is a strong prognostic factor and is independent of grade, stage and PSA level

Topologically Associated Domains Delineate Susceptibility to Somatic Hypermutation

Somatic hypermutation (SHM) introduces point mutations into immunoglobulin (Ig) genes but also causes mutations in other parts of the genome. We have used lentiviral SHM reporter vectors to identify regions of the genome that are susceptible ("hot") and resistant ("cold") to SHM, revealing that SHM susceptibility and resistance are often properties of entire topologically associated domains (TADs). Comparison of hot and cold TADs reveals that while levels of transcription are equivalent, hot TADs are enriched for the cohesin loader NIPBL, super-enhancers, markers of paused/stalled RNA polymerase 2, and multiple important B cell transcription factors. We demonstrate that at least some hot TADs contain enhancers that possess SHM targeting activity and that insertion of a strong Ig SHM-targeting element into a cold TAD renders it hot. Our findings lead to a model for SHM susceptibility involving the cooperative action of cis-acting SHM targeting elements and the dynamic and architectural properties of TADs

World Health Organization Discontinues Its Drinking-Water Guideline for Manganese

Background: The World Health Organization (WHO) released the fourth edition of Guidelines for Drinking-Water Quality in July 2011. In this edition, the 400-µg/L drinking-water guideline for manganese (Mn) was discontinued with the assertion that because “this health-based value is well above concentrations of manganese normally found in drinking water, it is not considered necessary to derive a formal guideline value.

YK-4-279 Inhibits ERG and ETV1 Mediated Prostate Cancer Cell Invasion

Background: Genomic rearrangements involving the ETS family of transcription factors occur in 40–70 % of prostate cancer cases. ERG and ETV1 are the most common ETS members observed in these genetic alterations. The high prevalence of these rearrangements and their biological significance represents a novel therapeutic target for the treatment of prostate cancer. Methods and Findings: We recently reported the development of YK-4-279, a small molecule inhibitor of EWS-FLI1 oncoprotein in Ewing’s Sarcoma. Since ERG and ETV1 belong to the same class of ETS factors as FLI1, we tested the ability of YK-4-279 to inhibit biological functions of ERG and ETV1 proteins in prostate cancer. YK-4-279 inhibited ERG and ETV1 mediated transcriptional activity in a luciferase assay. YK-4-279 also decreased ERG and ETV1 downstream target mRNA and protein expression in ETV1-fusion positive LNCaP and ERG fusion positive VCaP cells. YK-4-279 reduced the motility of LNCaP cells in a scratch assay and the invasive phenotype of both LNCaP and VCaP cells in a HUVEC invasion assay. Fusion-negative PC3 cells were unresponsive to YK-4-279. SiRNA mediated ERG knockdown in VCaP cells resulted in a loss of drug responsiveness. Concurrently, transient ERG expression in PC-3 cells resulted in increased invasive potential, which was reduced by YK-4-279. Conclusion: These data demonstrate that YK-4-279 inhibits ERG and ETV1 biological activity in fusion-positive prostat

Capturing the cloud of diversity reveals complexity and heterogeneity of MRSA carriage, infection and transmission.

Genome sequencing is revolutionizing clinical microbiology and our understanding of infectious diseases. Previous studies have largely relied on the sequencing of a single isolate from each individual. However, it is not clear what degree of bacterial diversity exists within, and is transmitted between individuals. Understanding this 'cloud of diversity' is key to accurate identification of transmission pathways. Here, we report the deep sequencing of methicillin-resistant Staphylococcus aureus among staff and animal patients involved in a transmission network at a veterinary hospital. We demonstrate considerable within-host diversity and that within-host diversity may rise and fall over time. Isolates from invasive disease contained multiple mutations in the same genes, including inactivation of a global regulator of virulence and changes in phage copy number. This study highlights the need for sequencing of multiple isolates from individuals to gain an accurate picture of transmission networks and to further understand the basis of pathogenesis.Thanks to Dr Alex O’Neill, University of Leeds and Dr Matthew Ellington, Public Health England for provision of RN4220 and RN4200mutS. We thank the core sequencing and informatics team at the Wellcome Trust Sanger Institute for sequencing of the isolates described in this study. This work was supported by a Medical Research Council Partnership grant (G1001787/1) held between the Department of Veterinary Medicine, University of Cambridge (M.A.H.), the School of Clinical Medicine, University of Cambridge (S.J.P.), the Moredun Research Institute, and the Wellcome Trust Sanger Institute (J.P. and S.J.P). S.J.P. receives support from the NIHR Cambridge Biomedical Research Centre. M.T.G.H., S.R.H. and J.P. were funded by Wellcome Trust grant no. 098051. G.G.R.M. was funded by an MRC studentship.This is the final version of the article. It first appeared from Nature Publishing Group via http://dx.doi.org/10.1038/ncomms756