Apoptosis facilitates antigen presentation to T lymphocytes through MHC-I and CD1 in tuberculosis

Protective immunity against Mycobacterium tuberculosis involves major histocompatibility complex class I (MHC-I)- and CD1-restricted CD8 T cells, but the mechanisms underlying antigen delivery to antigen-presenting molecules remain enigmatic. Macrophages, the primary host cells for mycobacteria, are CD1-negative. Here we show that M. tuberculosis phagosomes are secluded from the cytosolic MHC-I processing pathway and that mycobacteria-infected cells lose their antigen-presenting capacity. We also show that mycobacteria induce apoptosis in macrophages, causing the release of apoptotic vesicles that carry mycobacterial antigens to uninfected antigen-presenting cells (APCs). Inhibition of apoptosis reduced transfer of antigens to bystander cells and activation of CD8 T cells. Uninfected dendritic cells, which engulfed extracellular vesicles, were indispensable for subsequent cross-presentation of antigens, through MHC-I and CD1b, to T cells from mycobacteria-sensitized donors. This new 'detour' pathway for presentation of antigens from a phagosome-contained pathogen shows the functional significance of infection-induced apoptosis in the activation of CD8 T cells specific for both protein and glycolipid antigens in tuberculosis.     

Impact of participant and interventionist race concordance on weight loss outcomes

Objective:

We have previously shown that racial composition of behavioral intervention groups does not affect achieved weight loss. However, it is unclear if the race of the interventionist affects intervention outcomes. The objective of this analysis is to estimate the impact of race concordance between participant and interventionist on weight change in the initial weight loss phase (phase I) of the Weight Loss Maintenance trial (WLM).

Design and Methods:

A total of 1,685 overweight or obese adults (BMI 25‐45 kg/m²) who were taking medication for hypertension and/or dyslipidemia participated in phase I of the WLM trial. All participants received a 6‐month intensive behavioral intervention in groups of 15‐20 facilitated by a trained interventionist. The main outcome is change in weight at 6 months.

Results:

Participants were on average 55 years of age, 67% female and 44% African American (AA). Three of seventeen interventionists were AA, 14 were non‐AA. Seventy‐three percent of participants shared race concordance with the interventionist. There was a small but statistically significant difference in weight change of participants who were the same race as the interventionist (?5.84 kg, s.e. 0.17) as compared with those who were not race concordant (?5.04 kg, s.e. 0.33), a difference of 0.8 kg, (P = 0.04). The impact of concordance on weight change differed by race (i.e., interaction of race and concordance was significant, P = 0.02).

Conclusions:

In a post hoc analysis of a group‐based behavioral intervention, race concordance for non‐AA participants was associated with slightly greater weight loss. Race concordance was not associated with weight loss for AA participants.

     

Community-level relaxation of plant defenses against herbivores at high elevation

Ecological gradients shape the evolution of plant functional traits through variation in climate, abiotic factors, and biological processes. While recent observations highlight elevation clines in functional trait variation, several traits vary independently of others and vary in species-specific manner, thereby hindering community-level generalization. In this study, we examined whether whole plant communities at different elevations independently converge to elevation-specific trait values. Using a combination of field-derived trait quantification and a literature survey, we analyzed eight functional traits relating to plant palatability [specific leaf area (SLA), leaf dry matter content, carbon-to-nitrogen ratio], and defenses (spines, trichomes, silica, and the relative importance of phenolic- or non-phenolic-based chemical defenses in plants) of plants growing along several mountain transects in Switzerland, and computed community-level means for each trait. We observed a general decline of most defense traits in communities at high elevations. The individual traits’ patterns underlined a concerted decline of the physico-chemical defense syndrome at high elevation, and low SLA values at high elevation also indicate investment in the production of leaves with slow turnover rates. In addition, we found that high-elevation plant trait values tend to converge, while at low elevation, to diverge within communities. Our data suggest that community-level defense syndromes along elevation gradients are influenced by ecological filtering. Lower herbivore pressures select for reduced plant defenses, while harsh environmental conditions select for investment in tolerance-related traits. Secondly, since species are highly variable in their functional trait space within communities, niche-partitioning theory might explain which variabilities of the defense functional space are selected within communities, particularly at low elevation.     

The direction of mothers' and daughters' preferences and the heritability of male ornaments in red jungle fowl (Gallus gallus)

We used a breeding design involving 18 sires and 108 dams tostudy the heritabilities of male ornaments in red jungle fowl(Gallus gallus). Ornaments used by females to choose mates showedlow heritabilities, with the exception of comb and wattle measures.The general absence of heritability suggests that a geneticcovariance did not exist at the time of this study between mostmale ornaments and female preferences for those ornaments. Thisresult is contrary to a key prediction of the arbitrary or Fisherianhypothesis of sexual selection. Comb size and color are condition-dependenttraits that reflect short-term changes in health, and comb sizeof males was positively correlated with offspring weight. Ourresults are consistent with the expectation of good-genes hypothesesthat male ornaments reflect the ability of males to withstandenvironmental stresses.     

WASH‐driven actin polymerization is required for efficient mycobacterial phagosome maturation arrest

Pathogenic mycobacteria survive in phagocytic host cells primarily as a result of their ability to prevent fusion of their vacuole with lysosomes, thereby avoiding a bactericidal environment. The molecular mechanisms to establish and maintain this replication compartment are not well understood. By combining molecular and microscopical approaches we show here that after phagocytosis the actin nucleation‐promoting factor WASH associates and generates F‐actin on the mycobacterial vacuole. Disruption of WASH or depolymerization of F‐actin leads to the accumulation of the proton‐pumping V‐ATPase around the mycobacterial vacuole, its acidification and reduces the viability of intracellular mycobacteria. This effect is observed for M. marinum in the model phagocyte Dictyostelium but also for M. marinum and M. tuberculosis in mammalian phagocytes. This demonstrates an evolutionarily conserved mechanism by which pathogenic mycobacteria subvert the actin‐polymerization activity of WASH to prevent phagosome acidification and maturation, as a prerequisite to generate and maintain a replicative niche.     

Fasting and postprandial overproduction of intestinally derived lipoproteins in an animal model of insulin resistance. Evidence that chronic fructose feeding in the hamster is accompanied by enhanced intestinal de novo lipogenesis and ApoB48-containing lipoprotein overproduction

Insulin-resistant states are characterized by hypertriglyceridemia, predominantly because of overproduction of hepatic very low density lipoprotein particles. The additional contribution of intestinal lipoprotein overproduction to the dyslipidemia of insulin-resistant states has not been previously appreciated. Here, we have investigated intestinal lipoprotein production in a fructose-fed hamster model of insulin resistance previously documented to have whole body and hepatic insulin resistance, and hepatic very low density lipoprotein overproduction. Chronic fructose feeding for 3 weeks induced significant oversecretion of apolipoprotein B48 (apoB48)-containing lipoproteins in the fasting state and during steady state fat feeding, based on (a) in vivo Triton WR1339 studies of apoB48 production as well as (b) ex vivo pulse-chase labeling of intestinal enterocytes from fasted and fed hamsters. ApoB48 particle overproduction was accompanied by increased intracellular apoB48 stability, enhanced lipid synthesis, higher abundance of microsomal triglyceride transfer protein mass, and a significant shift toward the secretion of larger chylomicron-like particles. ApoB48 particle overproduction was not observed with short-term fructose feeding or in vitro incubation of enterocytes with fructose. Secretion of intestinal apoB48 and triglyceride was closely linked to intestinal enterocyte de novo lipogenesis, which was up-regulated in fructose-fed hamsters. Inhibition of fatty acid synthesis by cerulenin, a fatty acid synthase inhibitor, resulted in a dose-dependent decrease in intestinal apoB48 secretion. Overall, these findings further suggest that intestinal overproduction of apoB48 lipoproteins should also be considered as a major contributor to the fasting and postprandial dyslipidemia observed in response to chronic fructose feeding and development of an insulin-resistant state.     

The PhoU Protein from Escherichia coli Interacts with PhoR,PstB, and Metals To Form a Phosphate-Signaling Complex at the Membrane

Robust growth in many bacteria is dependent upon proper regulation of the adaptive response to phosphate (P_i) limitation. This response enables cells to acquire P_i with high affinity and utilize alternate phosphorous sources. The molecular mechanisms of P_i signal transduction are not completely understood. PhoU, along with the high-affinity, P_i-specific ATP-binding cassette transporter PstSCAB and the two-component proteins PhoR and PhoB, is absolutely required for P_i signaling in Escherichia coli. Little is known about the role of PhoU and its function in regulation. We have demonstrated using bacterial two-hybrid analysis and confirmatory coelution experiments that PhoU interacts with PhoR through its PAS (Per-ARNT-Sim) domain and that it also interacts with PstB, the cytoplasmic component of the transporter. We have also shown that the soluble form of PhoU is a dimer that binds manganese and magnesium. Alteration of highly conserved residues in PhoU by site-directed mutagenesis shows that these sites play a role in binding metals. Analysis of these phoU mutants suggests that metal binding may be important for PhoU membrane interactions. Taken together, these results support the hypothesis that PhoU is involved in the formation of a signaling complex at the cytoplasmic membrane that responds to environmental P_i levels.     

Myosin Phosphatase Target Subunit 1 (MYPT1) Regulates the Contraction and Relaxation of Vascular Smooth Muscle and Maintains Blood Pressure

Myosin light chain phosphatase with its regulatory subunit, myosin phosphatase target subunit 1 (MYPT1) modulates Ca²⁺-dependent phosphorylation of myosin light chain by myosin light chain kinase, which is essential for smooth muscle contraction. The role of MYPT1 in vascular smooth muscle was investigated in adult MYPT1 smooth muscle specific knock-out mice. MYPT1 deletion enhanced phosphorylation of myosin regulatory light chain and contractile force in isolated mesenteric arteries treated with KCl and various vascular agonists. The contractile responses of arteries from knock-out mice to norepinephrine were inhibited by Rho-associated kinase (ROCK) and protein kinase C inhibitors and were associated with inhibition of phosphorylation of the myosin light chain phosphatase inhibitor CPI-17. Additionally, stimulation of the NO/cGMP/protein kinase G (PKG) signaling pathway still resulted in relaxation of MYPT1-deficient mesenteric arteries, indicating phosphorylation of MYPT1 by PKG is not a major contributor to the relaxation response. Thus, MYPT1 enhances myosin light chain phosphatase activity sufficient for blood pressure maintenance. Rho-associated kinase phosphorylation of CPI-17 plays a significant role in enhancing vascular contractile responses, whereas phosphorylation of MYPT1 in the NO/cGMP/PKG signaling module is not necessary for relaxation.     

Hibernation patterns of Turkish hamsters: influence of sex and ambient temperature

Turkish hamsters (Mesocricetus brandti) are a model organism for studies of hibernation, yet a detailed account of their torpor characteristics has not been undertaken. This study employed continuous telemetric monitoring of body temperature (T _b) in hibernating male and female Turkish hamsters at ambient temperatures (T _as) of 5 and 13 °C to precisely characterize torpor bout depth, duration, and frequency, as well as rates of entry into and arousal from torpor. Hamsters generated brief intervals of short (<12 h), shallow test bouts (T _b > 20 °C), followed by deep torpor bouts lasting 4–6 days at T _a = 5 °C and 2–3 days at T _a = 13 °C. Females at T _a = 5 °C had longer bouts than males, but maintained higher torpor T _b; there were no sex differences at T _a = 13 °C. Neither body mass loss nor food intake differed between the two T _as. Hamsters entered torpor primarily during the scotophase (subjective night), but timing of arousals was highly variable. Hamsters at both T _as generated short, shallow torpor bouts between deep bouts, suggesting that this species may be capable of both hibernation and daily torpor.     

Comparing land surface phenology derived from satellite and GPS network microwave remote sensing

The land surface phenology (LSP) start of season (SOS) metric signals the seasonal onset of vegetation activity, including canopy growth and associated increases in land-atmosphere water, energy and carbon (CO₂) exchanges influencing weather and climate variability. The vegetation optical depth (VOD) parameter determined from satellite passive microwave remote sensing provides for global LSP monitoring that is sensitive to changes in vegetation canopy water content and biomass, and insensitive to atmosphere and solar illumination constraints. Direct field measures of canopy water content and biomass changes desired for LSP validation are generally lacking due to the prohibitive costs of maintaining regional monitoring networks. Alternatively, a normalized microwave reflectance index (NMRI) derived from GPS base station measurements is sensitive to daily vegetation water content changes and may provide for effective microwave LSP validation. We compared multiyear (2007–2011) NMRI and satellite VOD records at over 300 GPS sites in North America, and their derived SOS metrics for a subset of 24 homogenous land cover sites to investigate VOD and NMRI correspondence, and potential NMRI utility for LSP validation. Significant correlations (P?<?0.05) were found at 276 of 305 sites (90.5 %), with generally favorable correspondence in the resulting SOS metrics (r ²?=?0.73, P?<?0.001, RMSE = 36.8 days). This study is the first attempt to compare satellite microwave LSP metrics to a GPS network derived reflectance index and highlights both the utility and limitations of the NMRI data for LSP validation, including spatial scale discrepancies between local NMRI measurements and relatively coarse satellite VOD retrievals.