The Effects of Endurance Running Training on Young Adult Bone: Densitometry vs. Biomaterial Properties

Densitometric measurement of bone mineral parameters has been developed in recent decades. Since bone strength is associated with bone mineral density (BMD) and/or bone mineral content (BMC), densitometric measurement is widely accepted and used as one golden standard in clinical settings to determine bone health. Based on this concept, some human studies have suggested that endurance training, such as long distance running, provides no benefit and may even be harmful to bone health or bone mineral accretion during development, since long distance runners often have low BMD and/or BMC and may even exhibit conditions associated with bone loss or osteopenia.1, 2 Conversely, serum bone marker assays in healthy distance runners show normal or positive bone metabolism status.3, 4 Therefore, the definite role of endurance running training (ERT) on bone health remains a controversial issue. It would be valuable to further clarify whether ERT benefits bone health through a pathway other than absolutely increasing BMD or BMC. Clinical observations of human subjects require further basic studies to investigate possible mechanisms. Animal studies can provide unique ways not feasible in studies using human subjects of assessing the effects of endurance running on bone. Generally, previous animal studies further verified benefits of ERT to bone health. However, the limitations of animal studies must be clarified before applying their findings to human beings. The present article reviews the phenomena shown in bone of adolescent or young adult distance runners. Moreover, previous animal studies which adopted growing and young adult rats as subjects are reviewed, and the applicability of the findings to humans is also discussed

Persistent Oscillations of X-ray Speckles: Pt (001) Step Flow

We have performed coherent x-ray scattering experiments on the hexagonally reconstructed Pt (001) surface to study the temperature-dependent surface dynamics. By correlating speckle patterns collected at the (001) anti-Bragg position we are able to measure surface dynamics when the averaged incoherent x-ray scattering appears static. In the temperature range above the rotational epitaxy transition and below the roughening transition (1750 K - 1830 K), we have observed well-defined oscillatory autocorrelations of speckles that persist for tens of minutes, in addition to the expected thermal decorrelation. The observed oscillations indicate surface dynamics due to "step-flow" motion. This is shown with a simple model in which the phase of the scattered x-rays from the steps within the illumination area is retained in the coherent x-ray scattering. This demonstrates a possibility that x-ray speckles can be used to monitor the real-space real-time evolution of surfaces in addition to the traditional decorrelation measurements.Comment: 12 pages, 3 figure

Autophagy Is Required for Glucose Homeostasis and Lung Tumor Maintenance

Macroautophagy (autophagy hereafter) recycles intracellular components to sustain mitochondrial metabolism that promotes the growth, stress tolerance, and malignancy of lung cancers, suggesting that autophagy inhibition may have antitumor activity. To assess the functional significance of autophagy in both normal and tumor tissue, we conditionally deleted the essential autophagy gene, autophagy related 7 (Atg7), throughout adult mice. Here, we report that systemic ATG7 ablation caused susceptibility to infection and neurodegeneration that limited survival to 2 to 3 months. Moreover, upon fasting, autophagy-deficient mice suffered fatal hypoglycemia. Prior autophagy ablation did not alter the efficiency of non–small cell lung cancer (NSCLC) initiation by activation of oncogenic KrasG12D and deletion of the Trp53 tumor suppressor. Acute autophagy ablation in mice with preexisting NSCLC, however, blocked tumor growth, promoted tumor cell death, and generated more benign disease (oncocytomas). This antitumor activity occurred before destruction of normal tissues, suggesting that acute autophagy inhibition may be therapeutically beneficial in cancer. Significance: We systemically ablated cellular self-cannibalization by autophagy in adult mice and determined that it is dispensable for short-term survival, but required to prevent fatal hypoglycemia and cachexia during fasting, delineating a new role for autophagy in metabolism. Importantly, acute, systemic autophagy ablation was selectively destructive to established tumors compared with normal tissues, thereby providing the preclinical evidence that strategies to inhibit autophagy may be therapeutically advantageous for RAS-driven cancers.Val Skinner FoundationNational Institutes of Health (U.S.) (RC1 CA147961)Rutgers Cancer Institute of New JerseyRutgers Cancer Institute of New Jersey (P30 CA072720)National Institutes of Health (U.S.) (R01 CA163591)National Institutes of Health (U.S.) (R37 CA53370)National Institutes of Health (U.S.) (R01 CA130893

The Two Variables in The Triple System HR 6469=V819 Her: One Eclipsing, One Spotted

A complete BV light curve, from 14 nights of good data obtained with the Vanderbilt University-Tennessee State University (VU-TSU) automatic telescope, are presented and solved with the Wilson-Devinney program. Third light is evaluated, with the companion star brighter by 0.58m in V and 0.11m in B. The eclipses are partial. Inferred color indices yield F2 V and F8 V for the eclipsing pair and G8 IV-III for the distant companion star. After removing the variability due to eclipses, we study the residual variability of the G8 IV-III star over the ten years 1982 to 1992. Each yearly light curve is fit with a two-spot model. Three relatively long-lived spots are identified, with rotation periods of 85.9d, 85.9d, and 86.1d. The weak and intermittent variability is understood because the G8 IV-III star has a Rossby number at the threshold for the onset of heavy spottedness

BRIT1/MCPH1 Is Essential for Mitotic and Meiotic Recombination DNA Repair and Maintaining Genomic Stability in Mice

BRIT1 protein (also known as MCPH1) contains 3 BRCT domains which are conserved in BRCA1, BRCA2, and other important molecules involved in DNA damage signaling, DNA repair, and tumor suppression. BRIT1 mutations or aberrant expression are found in primary microcephaly patients as well as in cancer patients. Recent in vitro studies suggest that BRIT1/MCPH1 functions as a novel key regulator in the DNA damage response pathways. To investigate its physiological role and dissect the underlying mechanisms, we generated BRIT1−/− mice and identified its essential roles in mitotic and meiotic recombination DNA repair and in maintaining genomic stability. Both BRIT1−/− mice and mouse embryonic fibroblasts (MEFs) were hypersensitive to γ-irradiation. BRIT1−/− MEFs and T lymphocytes exhibited severe chromatid breaks and reduced RAD51 foci formation after irradiation. Notably, BRIT1−/− mice were infertile and meiotic homologous recombination was impaired. BRIT1-deficient spermatocytes exhibited a failure of chromosomal synapsis, and meiosis was arrested at late zygotene of prophase I accompanied by apoptosis. In mutant spermatocytes, DNA double-strand breaks (DSBs) were formed, but localization of RAD51 or BRCA2 to meiotic chromosomes was severely impaired. In addition, we found that BRIT1 could bind to RAD51/BRCA2 complexes and that, in the absence of BRIT1, recruitment of RAD51 and BRCA2 to chromatin was reduced while their protein levels were not altered, indicating that BRIT1 is involved in mediating recruitment of RAD51/BRCA2 to the damage site. Collectively, our BRIT1-null mouse model demonstrates that BRIT1 is essential for maintaining genomic stability in vivo to protect the hosts from both programmed and irradiation-induced DNA damages, and its depletion causes a failure in both mitotic and meiotic recombination DNA repair via impairing RAD51/BRCA2's function and as a result leads to infertility and genomic instability in mice

A highly conserved transcriptional repressor controls a large regulon involved in lipid degradation in Mycobacterium smegmatis and Mycobacterium tuberculosis

The Mycobacterium tuberculosis TetR-type regulator Rv3574 has been implicated in pathogenesis as it is induced in vivo, and genome-wide essentiality studies show it is required for infection. As the gene is highly conserved in the mycobacteria, we deleted the Rv3574 orthologue in Mycobacterium smegmatis (MSMEG_6042) and used real-time quantitative polymerase chain reaction and microarray analyses to show that it represses the transcription both of itself and of a large number of genes involved in lipid metabolism. We identified a conserved motif within its own promoter (TnnAACnnGTTnnA) and showed that it binds as a dimer to 29 bp probes containing the motif. We found 16 and 31 other instances of the motif in intergenic regions of M. tuberculosis and M. smegmatis respectively. Combining the results of the microarray studies with the motif analyses, we predict that Rv3574 directly controls the expression of 83 genes in M. smegmatis, and 74 in M. tuberculosis. Many of these genes are known to be induced by growth on cholesterol in rhodococci, and palmitate in M. tuberculosis. We conclude that this regulator, designated elsewhere as kstR, controls the expression of genes used for utilizing diverse lipids as energy sources, possibly imported through the mce4 system

Protomers of Benzocaine: Solvent and Permittivity Dependence

The immediate environment of a molecule can have a profound influence on its properties. Benzocaine, the ethyl ester of para-aminobenzoic acid, which finds an application as a local anesthetic (LA), is found to adopt in its protonated form at least two populations of distinct structures in the gas phase and their relative intensities strongly depend on the properties of the solvent used in the electrospray ionization (ESI) process. Here we combine IR-vibrational spectroscopy with ion mobility-mass spectrometry (IM-MS) to yield gas-phase IR spectra of simultaneously m/z and drift-time resolved species of benzocaine. The results allow for an unambiguous identification of two protomeric species - the N- and O-protonated form. Density functional theory (DFT) calculations link these structures to the most stable solution and gas-phase structures, respectively, with the electric properties of the surrounding medium being the main determinant for the preferred protonation site. The fact that the N-protonated form of benzocaine can be found in the gas phase is owed to kinetic trapping of the solution phase structure during transfer into the experimental setup. These observations confirm earlier studies on similar molecules where N- and O-protonation has been suggested

Viperin mRNA is a novel target for the human RNase MRP/RNase P endoribonuclease

RNase MRP is a conserved endoribonuclease, in humans consisting of a 267-nucleotide RNA associated with 7–10 proteins. Mutations in its RNA component lead to several autosomal recessive skeletal dysplasias, including cartilage-hair hypoplasia (CHH). Because the known substrates of mammalian RNase MRP, pre-ribosomal RNA, and RNA involved in mitochondrial DNA replication are not likely involved in CHH, we analyzed the effects of RNase MRP (and the structurally related RNase P) depletion on mRNAs using DNA microarrays. We confirmed the upregulation of the interferon-inducible viperin mRNA by RNAi experiments and this appeared to be independent of the interferon response. We detected two cleavage sites for RNase MRP/RNase P in the coding sequence of viperin mRNA. This is the first study providing direct evidence for the cleavage of a mRNA by RNase MRP/RNase P in human cells. Implications for the involvement in the pathophysiology of CHH are discussed

Pathologic and biologic response to preoperative endocrine therapy in patients with ER-positive ductal carcinoma in situ

Abstract Background Endocrine therapy is commonly recommended in the adjuvant setting for patients as treatment for ductal carcinoma in situ (DCIS). However, it is unknown whether a neoadjuvant (preoperative) anti-estrogen approach to DCIS results in any biological change. This study was undertaken to investigate the pathologic and biomarker changes in DCIS following neoadjuvant endocrine therapy compared to a group of patients who did not undergo preoperative anti-estrogenic treatment to determine whether such treatment results in detectable histologic alterations. Methods Patients (n = 23) diagnosed with ER-positive pure DCIS by stereotactic core biopsy were enrolled in a trial of neoadjuvant anti-estrogen therapy followed by definitive excision. Patients on hormone replacement therapy, with palpable masses, or with histologic or clinical suspicion of invasion were excluded. Premenopausal women were treated with tamoxifen and postmenopausal women were treated with letrozole. Pathologic markers of proliferation, inflammation, and apoptosis were evaluated at baseline and at three months. Biomarker changes were compared to a cohort of patients who had not received preoperative treatment. Results Median age of the cohort was 53 years (range 38–78); 14 were premenopausal. Following treatment, predominant morphologic changes included increased multinucleated histiocytes and degenerated cells, decreased duct extension, and prominent periductal fibrosis. Two postmenopausal patients had ADH only with no residual DCIS at excision. Postmenopausal women on letrozole had significant reduction of PR, and Ki67 as well as increase in CD68-positive cells. For premenopausal women on tamoxifen treatment, the only significant change was increase in CD68. No change in cleaved caspase 3 was found. Two patients had invasive cancer at surgery. Conclusion Preoperative therapy for DCIS is associated with significant pathologic alterations. These changes may be clinically significant. Further work is needed to identify which women may be the best candidates for such treatment for DCIS, and whether best responders may safely avoid surgical intervention. Trial Registration ClinicalTrials.gov NCT0029074