AMPK Is a Negative Regulator of the Warburg Effect and Suppresses Tumor Growth In Vivo

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Highlights? Loss of AMPKα1 cooperates with the Myc oncogene to accelerate lymphomagenesis ? AMPKα dysfunction enhances aerobic glycolysis (Warburg effect) ? Inhibiting HIF-1α reverses the metabolic effects of AMPKα loss ? HIF-1α mediates the growth advantage of tumors with reduced AMPK signaling     

Cutaneous heat flux models do not reliably predict metabolic rates of marine mammals

Heat flux models have been used to predict metabolic rates of marine mammals, generally by estimating conductive heat transfer through their blubber layer. Recently, Kvadsheim et al. (1997) found that such models tend to overestimate metabolic rates, and that such errors probably result from the asymmetrical distribution of blubber. This problem may be avoided if reliable estimates of heat flux through the skin of the animals are obtained by using models that combine calculations of conductive heat flux through the skin and fur, and convective heat flux from the surface of the animal to the environment. We evaluated this approach based on simultaneous measurements of metabolic rates and of input parameters necessary for heat flux calculations, as obtained from four harp seals (Phoca groenlandica) resting in cold water. Heat flux estimates were made using two free convection models (double-flat-plate and cylindrical geometry) and one forced convection model (single-flat-plate geometry). We found that heat flux estimates generally underestimated metabolic rates, on average by 26-58%, and that small variations in input parameters caused large variations in these estimates. We conclude that cutaneous heat flux models are too inaccurate and sensitive to small errors in input parameters to provide reliable estimates of metabolic rates of marine mammals.     

The protective effect of licofelone on experimental osteoarthritis is correlated with the downregulation of gene expression and protein synthesis of several major cartilage catabolic factors: MMP-13, cathepsin K and aggrecanases

This study sought to evaluate the levels of mRNA expression and protein synthesis of MMP-13, cathepsin K, aggrecanase-1 (ADAMTS-4), aggrecanase-2 (ADAMTS-5) and 5-lipoxygenase (5-LOX) in cartilage in the experimental anterior cruciate ligament (ACL) dog model of osteoarthritis (OA), and to examine the effects of treatment with licofelone, a 5-lipoxygenase (LOX)/cyclooxygenase (COX) inhibitor, on the levels of these catabolic factors. Sectioning of the ACL of the right knee was performed in three experimental groups: group 1 received no active treatment (placebo group); and groups 2 and 3 received therapeutic concentrations of licofelone (2.5 or 5.0 mg/kg/day orally, respectively) for 8 weeks, beginning the day following surgery. A fourth group consisted of untreated dogs that were used as normal controls. Specimens of cartilage were selected from lesional areas of OA femoral condyles and tibial plateaus, and were processed for real-time quantitative PCR and immunohistochemical analyses. The levels of MMP-13, cathepsin K, ADAMTS-4, ADAMTS-5 and 5-LOX were found to be significantly increased in OA cartilage. Licofelone treatment decreased the levels of both mRNA expression and protein synthesis of the factors studied. Of note was the marked reduction in the level of 5-LOX gene expression. The effects of the drug were about the same at both tested dosages. In vivo treatment with therapeutic dosages of licofelone has been found to reduce the degradation of OA cartilage in experimental OA. This, coupled with the results of the present study, indicates that the effects of licofelone are mediated by the inhibition of the major cartilage catabolic pathways involved in the destruction of cartilage matrix macromolecules. Moreover, our findings also indicate the possible auto-regulation of 5-LOX gene expression by licofelone in OA cartilage.     

Sex-specific homeodomain proteins Sxi1alpha and Sxi2a coordinately regulate sexual development in Cryptococcus neoformans

Homeodomain proteins are central regulators of development in eukaryotes. In fungi, homeodomain proteins have been shown to control cell identity and sexual development. Cryptococcus neoformans is a human fungal pathogen with a defined sexual cycle that produces spores, the suspected infectious particles. Previously, only a single homeodomain regulatory protein involved in sexual development, Sxi1alpha, had been identified. Here we present the discovery of Sxi2a, a predicted but heretofore elusive cell-type-specific homeodomain protein essential for the regulation of sexual development. Our studies reveal that Sxi2a is necessary for proper sexual development and sufficient to drive this development in otherwise haploid alpha cells. We further show that Sxi1alpha and Sxi2a interact with one another and impart similar expression patterns for two key mating genes. The discovery of Sxi2a and its relationship with Sxi1alpha leads to a new model for how the sexual cycle is controlled in C. neoformans, with implications for virulence.     

Effect of body mass and water temperature on the standard metabolic rate of juvenile yellow perch, Perca flavescens (Mitchill)

Fish respiration rates that are presumed to represent standard metabolic rates (SMR) may sometimes include an unspecified energy expenditure associated with activity and digestion. This situation may introduce a bias in bioenergetics models because standard metabolism, digestion, and activity may not be affected by the same environmental conditions. The aim of this study was to (1) develop a SMR model for juvenile yellow perch, Perca flavescens (Mitchill), that represent the minimum energy expenditure required to maintain life and (2) compare the results of this study with published perch metabolic rates and bioenergetics models. SMR was estimated for yellow perch over a range of body␣mass (4.4–24.7 g) and water temperature (12–20°C). The intercept of the relationship between fish respiration and swimming velocity obtained during forced swimming experiments was used to determine SMR. SMR estimated by the present study were comparable to values presented by two published studies on Eurasian perch, Perca fluviatilis L. However, estimated SMR were 4.1–20.9 times lower than values of a third respirometry study and predictions of bioenergetics models for perch. The present study suggests that published SMR models may sometimes include a significant fraction of energy expenditures (39.2–75.9%) associated with digestion and activity. This may complicate the implementation and the interpretation of fish bioenergetics models. The present study indicates that the intercept of respiration-velocity relationships and long-term respiration rates during starvation experiments may provide similar and reliable SMR values.     

HIV Treatment as Prevention: Considerations in the Design, Conduct, and Analysis of Cluster Randomized Controlled Trials of Combination HIV Prevention

The rigorous evaluation of the impact of combination HIV prevention packages at the population level will be critical for the future of HIV prevention. In this review, we discuss important considerations for the design and interpretation of cluster randomized controlled trials (C-RCTs) of combination prevention interventions. We focus on three large C-RCTs that will start soon and are designed to test the hypothesis that combination prevention packages, including expanded access to antiretroviral therapy, can substantially reduce HIV incidence. Using a general framework to integrate mathematical modelling analysis into the design, conduct, and analysis of C-RCTs will complement traditional statistical analyses and strengthen the evaluation of the interventions. Importantly, even with combination interventions, it may be challenging to substantially reduce HIV incidence over the 2- to 3-y duration of a C-RCT, unless interventions are scaled up rapidly and key populations are reached. Thus, we propose the innovative use of mathematical modelling to conduct interim analyses, when interim HIV incidence data are not available, to allow the ongoing trials to be modified or adapted to reduce the likelihood of inconclusive outcomes. The preplanned, interactive use of mathematical models during C-RCTs will also provide a valuable opportunity to validate and refine model projections.     

Hibernation and daily torpor in an armadillo, the pichi (Zaedyus pichiy).

Hibernation and daily torpor are physiological strategies to cope with energetic challenges that occur in many mammalian and avian taxa, but no reliable information exists about daily torpor or hibernation for any xenarthran. Our objective was to determine whether the pichi (Zaedyus pichiy), a small armadillo (Xenarthra, Dasypodidae) that inhabits arid and semi-arid habitats in central and southern Argentina and Chile, enters shallow daily torpor or prolonged deep hibernation during winter when environmental temperature and food availability are low. We studied body temperature changes during winter in semi-captive pichis by means of temperature dataloggers implanted subcutaneously. All individuals entered hibernation, characterized by torpor events of 75+/-20 h during which the subcutaneous temperature (T(sc)) decreased to 14.6+/-2.1 degrees C. These events were interrupted by periods of euthermia of 44+/-38 h with a T(sc) of 29.1+/-0.7 degrees C. After the hibernation season, daily torpor bouts of 4 to 6 h occurred irregularly, with T(sc) dropping to as low as 24.5 degrees C. We conclude that the pichi is a true hibernator and can enter daily torpor outside of the hibernation season.     

Antiretroviral Therapy Uptake,Attrition, Adherence and Outcomes among HIV-Infected Female Sex Workers: A Systematic Review and Meta-Analysis

Purpose

We aimed to characterize the antiretroviral therapy (ART) cascade among female sex workers (FSWs) globally.

Methods

We systematically searched PubMed, Embase and MEDLINE in March 2014 to identify studies reporting on ART uptake, attrition, adherence, and outcomes (viral suppression or CD4 count improvements) among HIV-infected FSWs globally. When possible, available estimates were pooled using random effects meta-analyses (with heterogeneity assessed using Cochran''s Q test and I² statistic).

Results

39 studies, reporting on 21 different FSW study populations in Asia, Africa, North America, South America, and Central America and the Caribbean, were included. Current ART use among HIV-infected FSWs was 38% (95% CI: 29%–48%, I² = 96%, 15 studies), and estimates were similar between high-, and low- and middle-income countries. Ever ART use among HIV-infected FSWs was greater in high-income countries (80%; 95% CI: 48%–94%, I² = 70%, 2 studies) compared to low- and middle-income countries (36%; 95% CI: 7%–81%, I² = 99%, 3 studies). Loss to follow-up after ART initiation was 6% (95% CI: 3%–11%, I² = 0%, 3 studies) and death after ART initiation was 6% (95% CI: 3%–11%, I² = 0%, 3 studies). The fraction adherent to ≥95% of prescribed pills was 76% (95% CI: 68%–83%, I² = 36%, 4 studies), and 57% (95% CI: 46%–68%, I² = 82%, 4 studies) of FSWs on ART were virally suppressed. Median gains in CD4 count after 6 to 36 months on ART, ranged between 103 and 241 cells/mm³ (4 studies).

Conclusions

Despite global increases in ART coverage, there is a concerning lack of published data on HIV treatment for FSWs. Available data suggest that FSWs can achieve levels of ART uptake, retention, adherence, and treatment response comparable to that seen among women in the general population, but these data are from only a few research settings. More routine programme data on HIV treatment among FSWs across settings should be collected and disseminated.     

A novel approach to investigate tissue-specific trinucleotide repeat instability

Background

In Huntington's disease (HD), an expanded CAG repeat produces characteristic striatal neurodegeneration. Interestingly, the HD CAG repeat, whose length determines age at onset, undergoes tissue-specific somatic instability, predominant in the striatum, suggesting that tissue-specific CAG length changes could modify the disease process. Therefore, understanding the mechanisms underlying the tissue specificity of somatic instability may provide novel routes to therapies. However progress in this area has been hampered by the lack of sensitive high-throughput instability quantification methods and global approaches to identify the underlying factors.

Results

Here we describe a novel approach to gain insight into the factors responsible for the tissue specificity of somatic instability. Using accurate genetic knock-in mouse models of HD, we developed a reliable, high-throughput method to quantify tissue HD CAG repeat instability and integrated this with genome-wide bioinformatic approaches. Using tissue instability quantified in 16 tissues as a phenotype and tissue microarray gene expression as a predictor, we built a mathematical model and identified a gene expression signature that accurately predicted tissue instability. Using the predictive ability of this signature we found that somatic instability was not a consequence of pathogenesis. In support of this, genetic crosses with models of accelerated neuropathology failed to induce somatic instability. In addition, we searched for genes and pathways that correlated with tissue instability. We found that expression levels of DNA repair genes did not explain the tissue specificity of somatic instability. Instead, our data implicate other pathways, particularly cell cycle, metabolism and neurotransmitter pathways, acting in combination to generate tissue-specific patterns of instability.

Conclusion

Our study clearly demonstrates that multiple tissue factors reflect the level of somatic instability in different tissues. In addition, our quantitative, genome-wide approach is readily applicable to high-throughput assays and opens the door to widespread applications with the potential to accelerate the discovery of drugs that alter tissue instability.