Brief Report: Long‐Term Functional Engraftment of Mesenchymal Progenitor Cells in a Mouse Model of Accelerated Aging

Age‐related osteoporosis is characterized by a decrease in bone‐forming capacity mediated by defects in the number and function of osteoblasts. An important cellular mechanism that may in part explain osteoblast dysfunction that occurs with aging is senescence of mesenchymal progenitor cells (MPCs). In the telomere‐based Wrn −/− Terc −/− model of accelerated aging, the osteoporotic phenotype of these mice is also associated with a major decline in MPC differentiation into osteoblasts. To investigate the role of MPC aging as a cell‐autonomous mechanism in senile bone loss, transplantation of young wild‐type whole bone marrow into Wrn −/− Terc −/− mutants was performed and the ability of engrafted cells to differentiate into cells of the osteoblast lineage was assessed. We found that whole bone marrow transplantation in Wrn −/− Terc −/− mice resulted in functional engraftment of MPCs up to 42 weeks, which was accompanied by a survival advantage as well as delays in microarchitectural features of skeletal aging. S TEM C ELLS 2013;31:607–611Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/96667/1/sc-12-0760_sm_SupplFigure1.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/96667/2/1294_ftp.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/96667/3/sc-12-0760_sm_SupplFigure2.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/96667/4/sc-12-0760_sm_SupplFigure3.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/96667/5/sc-12-0760_sm_SupplInform.pd

Conserved and Differential Effects of Dietary Energy Intake on the Hippocampal Transcriptomes of Females and Males

The level of dietary energy intake influences metabolism, reproductive function, the development of age-related diseases, and even cognitive behavior. Because males and females typically play different roles in the acquisition and allocation of energy resources, we reasoned that dietary energy intake might differentially affect the brains of males and females at the molecular level. To test this hypothesis, we performed a gene array analysis of the hippocampus in male and female rats that had been maintained for 6 months on either ad libitum (control), 20% caloric restriction (CR), 40% CR, intermittent fasting (IF) or high fat/high glucose (HFG) diets. These diets resulted in expected changes in body weight, and circulating levels of glucose, insulin and leptin. However, the CR diets significantly increased the size of the hippocampus of females, but not males. Multiple genes were regulated coherently in response to energy restriction diets in females, but not in males. Functional physiological pathway analyses showed that the 20% CR diet down-regulated genes involved in glycolysis and mitochondrial ATP production in males, whereas these metabolic pathways were up-regulated in females. The 40% CR diet up-regulated genes involved in glycolysis, protein deacetylation, PGC-1α and mTor pathways in both sexes. IF down-regulated many genes in males including those involved in protein degradation and apoptosis, but up-regulated many genes in females including those involved in cellular energy metabolism, cell cycle regulation and protein deacetylation. Genes involved in energy metabolism, oxidative stress responses and cell death were affected by the HFG diet in both males and females. The gender-specific molecular genetic responses of hippocampal cells to variations in dietary energy intake identified in this study may mediate differential behavioral responses of males and females to differences in energy availability

Deconvolution of Images from BLAST 2005: Insight into the K3-50 and IC 5146 Star-Forming Regions

We present an implementation of the iterative flux-conserving Lucy-Richardson (L-R) deconvolution method of image restoration for maps produced by the Balloon-borne Large Aperture Submillimeter Telescope (BLAST). We have analyzed its performance and convergence extensively through simulations and cross-correlations of the deconvolved images with available highresolution maps. We present new science results from two BLAST surveys, in the Galactic regions K3-50 and IC 5146, further demonstrating the benefits of performing this deconvolution. We have resolved three clumps within a radius of 4.'5 inside the star-forming molecular cloud containing K3-50. Combining the well-resolved dust emission map with available multi-wavelength data, we have constrained the Spectral Energy Distributions (SEDs) of five clumps to obtain masses (M), bolometric luminosities (L), and dust temperatures (T). The L-M diagram has been used as a diagnostic tool to estimate the evolutionary stages of the clumps. There are close relationships between dust continuum emission and both 21-cm radio continuum and 12CO molecular line emission. The restored extended large scale structures in the Northern Streamer of IC 5146 have a strong spatial correlation with both SCUBA and high resolution extinction images. A dust temperature of 12 K has been obtained for the central filament. We report physical properties of ten compact sources, including six associated protostars, by fitting SEDs to multi-wavelength data. All of these compact sources are still quite cold (typical temperature below ~ 16 K) and are above the critical Bonner-Ebert mass. They have associated low-power Young Stellar Objects (YSOs). Further evidence for starless clumps has also been found in the IC 5146 region.Comment: 13 pages, 12 Figures, 3 Table

SRT1720 improves survival and healthspan of obese mice

Sirt1 is an NAD+-dependent deacetylase that extends lifespan in lower organisms and improves metabolism and delays the onset of age-related diseases in mammals. Here we show that SRT1720, a synthetic compound that was identified for its ability to activate Sirt1 in vitro, extends both mean and maximum lifespan of adult mice fed a high-fat diet. This lifespan extension is accompanied by health benefits including reduced liver steatosis, increased insulin sensitivity, enhanced locomotor activity and normalization of gene expression profiles and markers of inflammation and apoptosis, all in the absence of any observable toxicity. Using a conditional SIRT1 knockout mouse and specific gene knockdowns we show SRT1720 affects mitochondrial respiration in a Sirt1- and PGC-1α-dependent manner. These findings indicate that SRT1720 has long-term benefits and demonstrate for the first time the feasibility of designing novel molecules that are safe and effective in promoting longevity and preventing multiple age-related diseases in mammals

The High-Energy Radiation Environment Around a 10 Gyr M Dwarf: Habitable at Last?

High levels of X-ray and UV activity on young M dwarfs may drive rapid atmospheric escape on temperate, terrestrial planets orbiting within the liquid water habitable zone. However, secondary atmospheres on planets orbiting older, less active M dwarfs may be stable and present more promising candidates for biomarker searches. We present new HST and Chandra observations of Barnard's Star (GJ 699), a 10 Gyr old M3.5 dwarf, acquired as part of the Mega-MUSCLES program. Despite the old age and long rotation period of Barnard's star, we observe two FUV ($\delta_{130}$ $\approx$ 5000s; $E_{130}$ $\approx$ 10$^{29.5}$ erg each) and one X-ray ($E_{X}$ $\approx$ 10$^{29.2}$ erg) flares, and estimate a high-energy flare duty cycle (defined here as the fraction of the time the star is in a flare state) of $\sim$ 25\%. A 5 A - 10 $\mu$m SED of GJ 699 is created and used to evaluate the atmospheric stability of a hypothetical, unmagnetized terrestrial planet in the habitable zone ($r_{HZ}$ $\sim$ 0.1 AU). Both thermal and non-thermal escape modeling indicate (1) the $quiescent$ stellar XUV flux does not lead to strong atmospheric escape: atmospheric heating rates are comparable to periods of high solar activity on modern Earth, and (2) the $flare$ environment could drive the atmosphere into a hydrodynamic loss regime at the observed flare duty cycle: sustained exposure to the flare environment of GJ 699 results in the loss of $\approx$ 87 Earth atmospheres Gyr$^{-1}$ through thermal processes and $\approx$ 3 Earth atmospheres Gyr$^{-1}$ through ion loss processes, respectively. These results suggest that if rocky planet atmospheres can survive the initial $\sim$ 5 Gyr of high stellar activity, or if a second generation atmosphere can be formed or acquired, the flare duty cycle may be the controlling stellar parameter for the stability of Earth-like atmospheres around old M stars.Comment: Accepted to A

Domestication-induced reduction in eye size revealed in multiple common garden experiments: The case of Atlantic salmon (Salmo salar L.)

Domestication leads to changes in traits that are under directional selection in breeding programmes, though unintentional changes in nonproduction traits can also arise. In offspring of escaping fish and any hybrid progeny, such unintentionally altered traits may reduce fitness in the wild. Atlantic salmon breeding programmes were established in the early 1970s, resulting in genetic changes in multiple traits. However, the impact of domestication on eye size has not been studied. We measured body size corrected eye size in 4000 salmon from six common garden experiments conducted under artificial and natural conditions, in freshwater and saltwater environments, in two countries. Within these common gardens, offspring of domesticated and wild parents were crossed to produce 11 strains, with varying genetic backgrounds (wild, domesticated, F1 hybrids, F2 hybrids and backcrosses). Size-adjusted eye size was influenced by both genetic and environmental factors. Domesticated fish reared under artificial conditions had smaller adjusted eye size when compared to wild fish reared under identical conditions, in both the freshwater and marine environments, and in both Irish and Norwegian experiments. However, in parr that had been introduced into a river environment shortly after hatching and sampled at the end of their first summer, differences in adjusted eye size observed among genetic groups were of a reduced magnitude and were nonsignificant in 2-year-old sea migrating smolts sampled in the river immediately prior to sea entry. Collectively, our findings could suggest that where natural selection is present, individuals with reduced eye size are maladapted and consequently have reduced fitness, building on our understanding of the mechanisms that underlie a well-documented reduction in the fitness of the progeny of domesticated salmon, including hybrid progeny, in the wild

Immunogenicity of Self-Associated Aggregates and Chemically Cross-Linked Conjugates of the 42 kDa Plasmodium falciparum Merozoite Surface Protein-1

Self-associated protein aggregates or cross-linked protein conjugates are, in general, more immunogenic than oligomeric or monomeric forms. In particular, the immunogenicity in mice of a recombinant malaria transmission blocking vaccine candidate, the ookinete specific Plasmodium falciparum 25 kDa protein (Pfs25), was increased more than 1000-fold when evaluated as a chemical cross-linked protein-protein conjugate as compared to a formulated monomer. Whether alternative approaches using protein complexes improve the immunogenicity of other recombinant malaria vaccine candidates is worth assessing. In this work, the immunogenicity of the recombinant 42 kDa processed form of the P. falciparum merozoite surface protein 1 (MSP142) was evaluated as a self-associated, non-covalent aggregate and as a chemical cross-linked protein-protein conjugate to ExoProtein A, which is a recombinant detoxified form of Pseudomonas aeruginosa exotoxin A. MSP142 conjugates were prepared and characterized biochemically and biophysically to determine their molar mass in solution and stoichiometry, when relevant. The immunogenicity of the MSP142 self-associated aggregates, cross-linked chemical conjugates and monomers were compared in BALB/c mice after adsorption to aluminum hydroxide adjuvant, and in one instance in association with the TLR9 agonist CPG7909 with an aluminum hydroxide formulation. Antibody titers were assessed by ELISA. Unlike observations made for Pfs25, no significant enhancement in MSP142 specific antibody titers was observed for any conjugate as compared to the formulated monomer or dimer, except for the addition of the TLR9 agonist CPG7909. Clearly, enhancing the immunogenicity of a recombinant protein vaccine candidate by the formation of protein complexes must be established on an empirical basis

A genome-wide CRISPR screen identifies a restricted set of HIV host dependency factors

Host proteins are essential for HIV entry and replication and can be important nonviral therapeutic targets. Large-scale RNA interference (RNAi)-based screens have identified nearly a thousand candidate host factors, but there is little agreement among studies and few factors have been validated. Here we demonstrate that a genome-wide CRISPR-based screen identifies host factors in a physiologically relevant cell system. We identify five factors, including the HIV co-receptors CD4 and CCR5, that are required for HIV infection yet are dispensable for cellular proliferation and viability. Tyrosylprotein sulfotransferase 2 (TPST2) and solute carrier family 35 member B2 (SLC35B2) function in a common pathway to sulfate CCR5 on extracellular tyrosine residues, facilitating CCR5 recognition by the HIV envelope. Activated leukocyte cell adhesion molecule (ALCAM) mediates cell aggregation, which is required for cell-to-cell HIV transmission. We validated these pathways in primary human CD4 + T cells through Cas9-mediated knockout and antibody blockade. Our findings indicate that HIV infection and replication rely on a limited set of host-dispensable genes and suggest that these pathways can be studied for therapeutic intervention

Postexercise High-Fat Feeding Supresses p70S6K1 Activity in Human Skeletal Muscle.

PURPOSE: To examine the effects of reduced CHO but high post-exercise fat availability on cell signalling and expression of genes with putative roles in regulation of mitochondrial biogenesis, lipid metabolism and muscle protein synthesis (MPS). METHODS: Ten males completed a twice per day exercise model (3.5 h between sessions) comprising morning high-intensity interval (HIT) (8 x 5-min at 85% VO2peak) and afternoon steady-state (SS) running (60 min at 70% VO2peak). In a repeated measures design, runners exercised under different isoenergetic dietary conditions consisting of high CHO (HCHO: 10 CHO, 2.5 Protein and 0.8 Fat g.kg per whole trial period) or reduced CHO but high fat availability in the post-exercise recovery periods (HFAT: 2.5 CHO, 2.5 Protein and 3.5 Fat g.kg per whole trial period). RESULTS: Muscle glycogen was lower (P<0.05) at 3 (251 vs 301 mmol.kgdw) and 15 h (182 vs 312 mmol.kgdw) post-SS exercise in HFAT compared to HCHO. AMPK-α2 activity was not increased post-SS in either condition (P=0.41) though comparable increases (all P<0.05) in PGC-1α, p53, CS, Tfam, PPAR and ERRα mRNA were observed in HCHO and HFAT. In contrast, PDK4 (P=0.003), CD36 (P=0.05) and CPT1 (P=0.03) mRNA were greater in HFAT in the recovery period from SS exercise compared with HCHO. p70S6K activity was higher (P=0.08) at 3 h post-SS exercise in HCHO versus HFAT (72.7 ± 51.9 vs 44.7 ± 27 fmol.min mg). CONCLUSION: Post-exercise high fat feeding does not augment mRNA expression of genes associated with regulatory roles in mitochondrial biogenesis though it does increase lipid gene expression. However, post-exercise p70S6K1 activity is reduced under conditions of high fat feeding thus potentially impairing skeletal muscle remodelling processes