Are flexibility and muscle-strengthening activities associated with functional limitation?

This retrospective cohort study examined the relationship between self-reported participation in flexibility and muscular strengthening activities and the development of functional limitation (i.e., once an individual has difficulty with or becomes unable to perform activities of daily living). Data were obtained from 1318 adults (mean age 49.5 ​± ​9.7 years; 98.7% Caucasian; 14.9% female) enrolled in the Aerobics Center Longitudinal Study from 1979 to 2004 and free of functional limitation at baseline. Mail-back health surveys were used to prospectively determine incident functional limitation. Participation in muscle-strengthening and flexibility activities was assessed via self-report. Adjusted logistic regression analyses were used to determine the odds ratios (OR) and corresponding 95% confidence intervals for developing functional limitation during follow-up based on participation in general and specific categories of flexibility (‘Stretching’, ‘Calisthenics’, or ‘Exercise Class’) and muscle-strengthening activities (‘Calisthenics’, ‘Free Weights’, ‘Weight Training Machines’, or ‘Other’). Overall, 42.6% of the sample reported incident functional limitation. After adjusting for potential confounders (e.g., age, sex, cardiometabolic risk factors), those who reported performing muscle-strengthening activities in general (n ​= ​685) were at lower risk of developing functional limitation [OR ​= ​0.79 (0.63–1.00)]. In addition, the specific flexibility activities of stretching (n ​= ​491) and calisthenics (n ​= ​122) were associated with 24% and 38% decreased odds of incident functional limitation, respectively. General muscle-strengthening, stretching, and calisthenics activities are prospectively associated with decreased risk of incident functional limitation in generally healthy, middle-aged and older adults. Thus, both public health and rehabilitation programs should highlight the importance of flexibility and muscle-strengthening activities during adulthood to help preserve functional capacity

Constraints on Decaying Dark Matter from Fermi Observations of Nearby Galaxies and Clusters

We analyze the impact of Fermi gamma-ray observations (primarily non-detections) of selected nearby galaxies, including dwarf spheroidals, and of clusters of galaxies on decaying dark matter models. We show that the fact that galaxy clusters do not shine in gamma rays puts the most stringent limits available to-date on the lifetime of dark matter particles for a wide range of particle masses and decay final states. In particular, our results put strong constraints on the possibility of ascribing to decaying dark matter both the increasing positron fraction reported by PAMELA and the high-energy feature in the electron-positron spectrum measured by Fermi. Observations of nearby dwarf galaxies and of the Andromeda Galaxy (M31) do not provide as strong limits as those from galaxy clusters, while still improving on previous constraints in some cases.Comment: 27 pages, 5 figures, submitted to JCAP, revised version with some additions and correction

Residues Clustered in the Light-Sensing Knot of Phytochrome B are Necessary for Conformer-Specific Binding to Signaling Partner PIF3

The bHLH transcription factor, PHYTOCHROME INTERACTING FACTOR 3 (PIF3), interacts specifically with the photoactivated, Pfr, form of Arabidopsis phytochrome B (phyB). This interaction induces PIF3 phosphorylation and degradation in vivo and modulates phyB-mediated seedling deetiolation in response to red light. To identify missense mutations in the phyB N-terminal domain that disrupt this interaction, we developed a yeast reverse-hybrid screen. Fifteen individual mutations identified in this screen, or in previous genetic screens for Arabidopsis mutants showing reduced sensitivity to red light, were shown to also disrupt light-induced binding of phyB to PIF3 in in vitro co-immunoprecipitation assays. These phyB missense mutants fall into two general classes: Class I (eleven mutants) containing those defective in light signal perception, due to aberrant chromophore attachment or photoconversion, and Class II (four mutants) containing those normal in signal perception, but defective in the capacity to transduce this signal to PIF3. By generating a homology model for the three-dimensional structure of the Arabidopsis phyB chromophore-binding region, based on the crystal structure of Deinococcus radiodurans phytochrome, we predict that three of the four Class II mutated phyB residues are solvent exposed in a cleft between the presumptive PAS and GAF domains. This deduction suggests that these residues could be directly required for the physical interaction of phyB with PIF3. Because these three residues are also necessary for phyB-imposed inhibition of hypocotyl elongation in response to red light, they are functionally necessary for signal transfer from photoactivated phyB, not only to PIF3 and other related bHLH transcription factors tested here, but also to other downstream signaling components involved in regulating seedling deetiolation

Comparative Analyses of SUV420H1 Isoforms and SUV420H2 Reveal Differences in Their Cellular Localization and Effects on Myogenic Differentiation

Methylation of histone H4 on lysine 20 plays critical roles in chromatin structure and function via mono- (H4K20me1), di- (H4K20me2), and trimethyl (H4K20me3) derivatives. In previous analyses of histone methylation dynamics in mid-gestation mouse embryos, we documented marked changes in H4K20 methylation during cell differentiation. These changes were particularly robust during myogenesis, both in vivo and in cell culture, where we observed a transition from H4K20me1 to H4K20me3. To assess the significance of this change, we used a gain-of-function strategy involving the lysine methyltransferases SUV420H1 and SUV420H2, which catalyze H4K20me2 and H4K20me3. At the same time, we characterized a second isoform of SUV420H1 (designated SUV420H1_i2) and compared the activity of all three SUV420H proteins with regard to localization and H4K20 methylation.Immunofluorescence revealed that exogenous SUV420H1_i2 was distributed throughout the cell, while a substantial portion of SUV420H1_i1 and SUV420H2 displayed the expected association with constitutive heterochromatin. Moreover, SUV420H1_i2 distribution was unaffected by co-expression of heterochromatin protein-1α, which increased the targeting of SUV420H1_i1 and SUV420H2 to regions of pericentromeric heterochromatin. Consistent with their distributions, SUV420H1_i2 caused an increase in H4K20me3 levels throughout the nucleus, whereas SUV420H1_i1 and SUV420H2 facilitated an increase in pericentric H4K20me3. Striking differences continued when the SUV420H proteins were tested in the C2C12 myogenic model system. Specifically, although SUV420H1_i2 induced precocious appearance of the differentiation marker Myogenin in the presence of mitogens, only SUV420H2 maintained a Myogenin-enriched population over the course of differentiation. Paradoxically, SUV420H1_i1 could not be expressed in C2C12 cells, which suggests it is under post-transcriptional or post-translational control.These data indicate that SUV420H proteins differ substantially in their localization and activity. Importantly, SUV420H2 can induce a transition from H4K20me1 to H4K20me3 in regions of constitutive heterochromatin that is sufficient to enhance myogenic differentiation, suggesting it can act an as epigenetic ‘switch’ in this process

Yeast Two-Hybrid: State of the Art

Genome projects are approaching completion and are saturating sequence databases. This paper discusses the role of the two-hybrid system as a generator of hypotheses. Apart from this rather exhaustive, financially and labour intensive procedure, more refined functional studies can be undertaken. Indeed, by making hybrids of two-hybrid systems, customised approaches can be developed in order to attack specific function-related problems. For example, one could set-up a "differential" screen by combining a forward and a reverse approach in a three-hybrid set-up. Another very interesting project is the use of peptide libraries in two-hybrid approaches. This could enable the identification of peptides with very high specificity comparable to "real" antibodies. With the technology available, the only limitation is imagination

RhoGTPase Regulators Orchestrate Distinct Stages of Synaptic Development

Small RhoGTPases regulate changes in post-synaptic spine morphology and density that support learning and memory. They are also major targets of synaptic disorders, including Autism. Here we sought to determine whether upstream RhoGTPase regulators, including GEFs, GAPs, and GDIs, sculpt specific stages of synaptic development. The majority of examined molecules uniquely regulate either early spine precursor formation or later matura- tion. Specifically, an activator of actin polymerization, the Rac1 GEF β-PIX, drives spine pre- cursor formation, whereas both FRABIN, a Cdc42 GEF, and OLIGOPHRENIN-1, a RhoA GAP, regulate spine precursor elongation. However, in later development, a novel Rac1 GAP, ARHGAP23, and RhoGDIs inactivate actomyosin dynamics to stabilize mature synap- ses. Our observations demonstrate that specific combinations of RhoGTPase regulatory pro- teins temporally balance RhoGTPase activity during post-synaptic spine development