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Dietary Methionine Restriction Regulates Liver Protein Synthesis and Gene Expression Independently of Eukaryotic Initiation Factor 2 Phosphorylation in Mice

Background: The phosphorylation of eukaryotic initiation factor 2 (p-eIF2) during dietary amino acid insufficiency reduces protein synthesis and alters gene expression via the integrated stress response (ISR).Objective: We explored whether a Met-restricted (MR) diet activates the ISR to reduce body fat and regulate protein balance.Methods: Male and female mice aged 3-6 mo with either whole-body deletion of general control nonderepressible 2 (Gcn2) or liver-specific deletion of protein kinase R-like endoplasmic reticulum kinase (Perk) alongside wild-type or floxed control mice were fed an obesogenic diet sufficient in Met (0.86%) or an MR (0.12% Met) diet for ≤5 wk. Ala enrichment with deuterium was measured to calculate protein synthesis rates. The guanine nucleotide exchange factor activity of eIF2B was measured alongside p-eIF2 and hepatic mRNA expression levels at 2 d and 5 wk. Metabolic phenotyping was conducted at 4 wk, and body composition was measured throughout. Results were evaluated with the use of ANOVA (P < 0.05).Results: Feeding an MR diet for 2 d did not increase hepatic p-eIF2 or reduce eIF2B activity in wild-type or Gcn2-/- mice, yet many genes transcriptionally regulated by the ISR were altered in both strains in the same direction and amplitude. Feeding an MR diet for 5 wk increased p-eIF2 and reduced eIF2B activity in wild-type but not Gcn2-/- mice, yet ISR-regulated genes altered in both strains similarly. Furthermore, the MR diet reduced mixed and cytosolic but not mitochondrial protein synthesis in both the liver and skeletal muscle regardless of Gcn2 status. Despite the similarities between strains, the MR diet did not increase energy expenditure or reduce body fat in Gcn2-/- mice. Finally, feeding the MR diet to mice with Perk deleted in the liver increased hepatic p-eIF2 and altered body composition similar to floxed controls.Conclusions: Hepatic activation of the ISR resulting from an MR diet does not require p-eIF2. Gcn2 status influences body fat loss but not protein balance when Met is restricted

Ethnic inequalities in mental health and socioeconomic status among older women living with HIV: results from the PRIME Study.

OBJECTIVES: Women living with HIV in the UK are an ethnically diverse group with significant psychosocial challenges. Increasing numbers are reaching older age. We describe psychological and socioeconomic factors among women with HIV in England aged 45-60 and explore associations with ethnicity. METHODS: Analysis of cross-sectional data on 724 women recruited to the PRIME Study. Psychological symptoms were measured using the Patient Health Questionnaire 4 and social isolation with a modified Duke-UNC Functional Social Support Scale. RESULTS: Black African (BA) women were more likely than Black Caribbean or White British (WB) women to have a university education (48.3%, 27.0%, 25.7%, respectively, p<0.001), but were not more likely to be employed (68.4%, 61.4%, 65.2%, p=0.56) and were less likely to have enough money to meet their basic needs (56.4%, 63.0%, 82.9%, p<0.001). BA women were less likely to report being diagnosed with depression than WB women (adjusted odds ratio (aOR) 0.40, p<0.001) but more likely to report current psychological distress (aOR 3.34, p<0.05). CONCLUSIONS: We report high levels of poverty, psychological distress and social isolation in this ethnically diverse group of midlife women with HIV, especially among those who were BA. Despite being more likely to experience psychological distress, BA women were less likely to have been diagnosed with depression suggesting a possible inequity in access to mental health services. Holistic HIV care requires awareness of the psychosocial needs of older women living with HIV, which may be more pronounced in racially minoritised communities, and prompt referral for support including psychology, peer support and advice about benefits

The Dimer Interfaces of Protease and Extra-Protease Domains Influence the Activation of Protease and the Specificity of GagPol Cleavage

Activation of the human immunodeficiency virus type 1 (HIV-1) protease is an essential step in viral replication. As is the case for all retroviral proteases, enzyme activation requires the formation of protease homodimers. However, little is known about the mechanisms by which retroviral proteases become active within their precursors. Using an in vitro expression system, we have examined the determinants of activation efficiency and the order of cleavage site processing for the protease of HIV-1 within the full-length GagPol precursor. Following activation, initial cleavage occurs between the viral p2 and nucleocapsid proteins. This is followed by cleavage of a novel site located in the transframe domain. Mutational analysis of the dimer interface of the protease produced differential effects on activation and specificity. A subset of mutations produced enhanced cleavage at the amino terminus of the protease, suggesting that, in the wild-type precursor, cleavages that liberate the protease are a relatively late event. Replacement of the proline residue at position 1 of the protease dimer interface resulted in altered cleavage of distal sites and suggests that this residue functions as a cis-directed specificity determinant. In summary, our studies indicate that interactions within the protease dimer interface help determine the order of precursor cleavage and contribute to the formation of extended-protease intermediates. Assembly domains within GagPol outside the protease domain also influence enzyme activation

Emergence: Key physical issues for deeper philosophical inquiries

A sketch of three senses of emergence and a suggestive view on the emergence of time and the direction of time is presented. After trying to identify which issues philosophers interested in emergent phenomena in physics view as important I make several observations pertaining to the concepts, methodology and mechanisms required to understand emergence and describe a platform for its investigation. I then identify some key physical issues which I feel need be better appreciated by the philosophers in this pursuit. I end with some comments on one of these issues, that of coarse-graining and persistent structures.Comment: 16 pages. Invited Talk at the Heinz von Foerster Centenary International Conference on Self-Organization and Emergence: Emergent Quantum Mechanics (EmerQuM11). Nov. 10-13, 2011, Vienna, Austria. Proceedings to appear in J. Phys. (Conf. Series

Emergence: Key physical issues for deeper philosophical inquiries

A sketch of three senses of emergence and a suggestive view on the emergence of time and the direction of time is presented. After trying to identify which issues philosophers interested in emergent phenomena in physics view as important I make several observations pertaining to the concepts, methodology and mechanisms required to understand emergence and describe a platform for its investigation. I then identify some key physical issues which I feel need be better appreciated by the philosophers in this pursuit. I end with some comments on one of these issues, that of coarse-graining and persistent structures.Comment: 16 pages. Invited Talk at the Heinz von Foerster Centenary International Conference on Self-Organization and Emergence: Emergent Quantum Mechanics (EmerQuM11). Nov. 10-13, 2011, Vienna, Austria. Proceedings to appear in J. Phys. (Conf. Series