Fifteen-day cessation of training on selected physiological and performance variables in women runners

This study examined the effects of a 15-day cessation of training on maximal oxygen consumption and selected physiological variables (maximal heart rate, cardiac output [Q], stroke volume [SV], arteriovenous oxygen difference [(a-v)O2 diff], blood plasma concentration) in 15 women middle-distance competitive runners (.VO2max: 49.8 +/- 1.1 ml.kg(-1).min(-1)). Subjects were randomly assigned to a cessation training (CT, n = 7) or maintenance training (MT, n = 8) group and tested every 5 days. Q was measured by CO2 rebreathing from which SV and (a-v)O2 diff were calculated. No significant changes were found at day 5. After 10 days there was a significant decrement in .VO2max (3.8 ml.kg(-1).min(-1)) in the CT group, being significantly lower than MT but no changes thereafter in any physiological variables. Performance (2,400 m) times did not change for MT but was significantly slower (21.5 +/- 7.1 seconds) for the CT group after 15 days, corresponding to the 7.8% decrease in .VO2max. These findings suggest that in competitive women middle-distance runners, actual performance decrements found after 15 days of CT most likely are due to declines in .VO2max.     

Partial 7q Isochromosome in Bone Marrow Following Treatment of Hodgkin's Disease

We report on a 29-year-old female followed for relapsed Hodgkin's disease. She had been diagnosed with Hodgkin's disease at 20 years of age and had been treated with chemotherapy. She had been in remission for six years when she relapsed, at which time she received chemotherapy for bone marrow transplant (BMT). After failure of BMT, she received additional chemotherapies with growth factors and radiation treatment. A bone marrow biopsy showed moderate hypercellularity with erythroid hyperplasia, but the karyotype had an abnormal clone containing an isochromosome derived from a 7q22 deletion.     

Wild type and mutant p53 differentially regulate the gene expression of human collagenase-3 (hMMP-13)

Matrix metalloproteinases (MMPs) are a family of secreted or transmembrane proteins that can degrade all the proteins of the extracellular matrix and have been implicated in many abnormal physiological conditions including arthritis and cancer metastasis. Recently we have shown for the first time that the human MMP-1 gene is a p53 target gene subject to repression by wild type p53 (Sun, Y., Sun, Y. I., Wenger, L., Rutter, J. L., Brinckerhoff, C. E., and Cheung, H. S. (1999) J. Biol. Chem. 274, 11535-11540). Here, we report that cotransfection of fibroblast-like synoviocytes with p53 expression and hMMP13CAT reporter plasmids revealed that (i) hMMP13, another member of the human MMP family, was down-regulated by wild type p53, whereas all six of the p53 mutants tested lost the wild type p53 repressor activity in fibroblast-like synoviocytes; (ii) this repression of hMMP-13 gene expression by wild type p53 could be reversed by overexpression of p53 mutants p53-143A, p53-248W, p53-273H, and p53-281G; (iii) the dominant effect of p53 mutants over wild type p53 appears to be a promoter- and mutant-specific effect. An intriguing finding was that p53 mutant p53-281G could conversely stimulate the promoter activity of hMMP13 up to 2-4-fold and that it was dominant over wild type p53. Northern analysis confirmed these findings. Although the significance of these findings is currently unknown, they suggest that in addition to the effect of cytokines activation, the gene expression of hMMP13 could be dysregulated during the disease progression of rheumatoid arthritis (or cancer) associated with p53 inactivation. Since hMMP13 is 5-10 times as active as hMMP1 in its ability to digest type II collagen, the dysregulation or up-modulation of MMP13 gene expression due to the inactivation of p53 may contribute to the joint degeneration in rheumatoid arthritis.     

Stem cells act through multiple mechanisms to benefit mice with neurodegenerative metabolic disease

Intracranial transplantation of neural stem cells (NSCs) delayed disease onset, preserved motor function, reduced pathology and prolonged survival in a mouse model of Sandhoff disease, a lethal gangliosidosis. Although donor-derived neurons were electrophysiologically active within chimeric regions, the small degree of neuronal replacement alone could not account for the improvement. NSCs also increased brain beta-hexosaminidase levels, reduced ganglioside storage and diminished activated microgliosis. Additionally, when oral glycosphingolipid biosynthesis inhibitors (beta-hexosaminidase substrate inhibitors) were combined with NSC transplantation, substantial synergy resulted. Efficacy extended to human NSCs, both to those isolated directly from the central nervous system (CNS) and to those derived secondarily from embryonic stem cells. Appreciating that NSCs exhibit a broad repertoire of potentially therapeutic actions, of which neuronal replacement is but one, may help in formulating rational multimodal strategies for the treatment of neurodegenerative diseases.     

RUN and FYVE domain–containing protein 4 enhances autophagy and lysosome tethering in response to Interleukin-4

Autophagy is a key degradative pathway coordinated by external cues, including starvation, oxidative stress, or pathogen detection. Rare are the molecules known to contribute mechanistically to the regulation of autophagy and expressed specifically in particular environmental contexts or in distinct cell types. Here, we unravel the role of RUN and FYVE domain–containing protein 4 (RUFY4) as a positive molecular regulator of macroautophagy in primary dendritic cells (DCs). We show that exposure to interleukin-4 (IL-4) during DC differentiation enhances autophagy flux through mTORC1 regulation and RUFY4 induction, which in turn actively promote LC3 degradation, Syntaxin 17–positive autophagosome formation, and lysosome tethering. Enhanced autophagy boosts endogenous antigen presentation by MHC II and allows host control of Brucella abortus replication in IL-4–treated DCs and in RUFY4-expressing cells. RUFY4 is therefore the first molecule characterized to date that promotes autophagy and influences endosome dynamics in a subset of immune cells.     

COMPASS: a suite of pre- and post-search proteomics software tools for OMSSA

Here we present the Coon OMSSA Proteomic Analysis Software Suite (COMPASS): a free and open-source software pipeline for high-throughput analysis of proteomics data, designed around the Open Mass Spectrometry Search Algorithm. We detail a synergistic set of tools for protein database generation, spectral reduction, peptide false discovery rate analysis, peptide quantitation via isobaric labeling, protein parsimony and protein false discovery rate analysis, and protein quantitation. We strive for maximum ease of use, utilizing graphical user interfaces and working with data files in the original instrument vendor format. Results are stored in plain text comma-separated value files, which are easy to view and manipulate with a text editor or spreadsheet program. We illustrate the operation and efficacy of COMPASS through the use of two LC-MS/MS data sets. The first is a data set of a highly annotated mixture of standard proteins and manually validated contaminants that exhibits the identification workflow. The second is a data set of yeast peptides, labeled with isobaric stable isotope tags and mixed in known ratios, to demonstrate the quantitative workflow. For these two data sets, COMPASS performs equivalently or better than the current de facto standard, the Trans-Proteomic Pipeline.     

The hypoxic testis and post-meiotic expression of PAS domain proteins

Spermatogenesis in the seminiferous tubuli of the testis occurs under a high proliferation rate, suggesting considerable oxygen consumption. Because of the lack of blood vessels, the oxygen partial pressure in the lumen of the tubuli is very low. However, the consequences of these environmental conditions on spermatogenesis are unknown. The PAS domain is found in environmental protein sensors involved in the perception of oxygen partial pressure, light intensity, redox potentials, voltage and certain ligands. We previously identified two PAS proteins highly expressed in the testis: a novel isoform of the hypoxia-inducible factor (HIF)-1alpha and PASKIN, a PAS-Ser/Thr kinase related to bacterial oxygen sensing PAS-domain proteins.