Amino Acid Restriction Triggers Angiogenesis via GCN2/ATF4 Regulation of VEGF and H2S Production

Angiogenesis, the formation of new blood vessels by endothelial cells (ECs), is an adaptive response to oxygen/nutrient deprivation orchestrated by vascular endothelial growth factor (VEGF) upon ischemia or exercise. Hypoxia is the best-understood trigger of VEGF expression via the transcription factor HIF1 alpha. Nutrient deprivation is inseparable from hypoxia during ischemia, yet its role in angiogenesis is poorly characterized. Here, we identified sulfur amino acid restriction as a proangiogenic trigger, promoting increased VEGF expression, migration and sprouting in ECs in vitro, and increased capillary density in mouse skeletal muscle in vivo via the GCN2/ATF4 amino acid starvation response pathway independent of hypoxia or HIF1 alpha. We also identified a requirement for cystathionine-gamma-lyase in VEGF-dependent angiogenesis via increased hydrogen sulfide (H2S) production. H2S mediated its proangiogenic effects in part by inhibiting mitochondrial electron transport and oxidative phosphorylation, resulting in increased glucose uptake and glycolytic ATP production.11Ysciescopu

Plasma Hydrogen Sulfide Is Positively Associated With Post-operative Survival in Patients Undergoing Surgical Revascularization.

Objective: Hydrogen sulfide (H <sub>2</sub> S) is a gaseous signaling molecule and redox factor important for cardiovascular function. Deficiencies in its production or bioavailability are implicated in atherosclerotic disease. However, it is unknown if circulating H <sub>2</sub> S levels differ between vasculopaths and healthy individuals, and if so, whether H <sub>2</sub> S measurements can be used to predict surgical outcomes. Here, we examined: (1) Plasma H <sub>2</sub> S levels in patients undergoing vascular surgery and compared these to healthy controls, and (2) the association between H <sub>2</sub> S levels and mortality in a cohort of patients undergoing surgical revascularization. Methods: One hundred and fifteen patients undergoing carotid endarterectomy, open lower extremity revascularization or lower leg amputation were enrolled at a single institution. Peripheral blood was also collected from a matched control cohort of 20 patients without peripheral or coronary artery disease. Plasma H <sub>2</sub> S production capacity and sulfide concentration were measured using the lead acetate and monobromobimane methods, respectively. Results: Plasma H <sub>2</sub> S production capacity and plasma sulfide concentrations were reduced in patients with PAD (p < 0.001, p = 0.013, respectively). Patients that underwent surgical revascularization were divided into high vs. low H <sub>2</sub> S production capacity groups by median split. Patients in the low H <sub>2</sub> S production group had increased probability of mortality (p = 0.003). This association was robust to correction for potentially confounding variables using Cox proportional hazard models. Conclusion: Circulating H <sub>2</sub> S levels were lower in patients with atherosclerotic disease. Patients undergoing surgical revascularization with lower H <sub>2</sub> S production capacity, but not sulfide concentrations, had increased probability of mortality within 36 months post-surgery. This work provides insight on the role H <sub>2</sub> S plays as a diagnostic and potential therapeutic for cardiovascular disease

Thigh-length compression stockings and DVT after stroke

Controversy exists as to whether neoadjuvant chemotherapy improves survival in patients with invasive bladder cancer, despite randomised controlled trials of more than 3000 patients. We undertook a systematic review and meta-analysis to assess the effect of such treatment on survival in patients with this disease

Developing Digital Records: Early Experiences of Record and Replay.

In this paper we consider the development of ‘digital records’ to support ethnographic study of interaction and collaboration in ubiquitous computing environments and articulate the core concept of ‘record and replay’ through two case studies. One focuses on the utility of digital records, or records of interaction generated by a computer system, to ethnographic inquiry and highlights the mutually supportive nature of digital records and ethnographic methods. The other focuses on the work it takes to make digital records support ethnography, particularly the work of description and representation that is required to reconcile the fragmented character of interaction in ubiquitous computing environments. The work involved in ‘making digital records work’ highlights requirements for the design of tools to support the endeavour and informs the development of a Replay Tool. This tool enables ethnographers to visualize the data content of digital records; to extract sequences of relevance to analysis and remove non-relevant features; to marry recorded content with external resources, such as video; to add content from internal and external resources through annotation; and to reorder digital records to reflect the interactional order of events rather than the recorded order of events

Hypothalamic-pituitary axis regulates hydrogen sulfide production

Decreased growth hormone (GH) and thyroid hormone (TH) signaling are associated with longevity and metabolic fitness. The mechanisms underlying these benefits are poorly understood, but may overlap with those of dietary restriction (DR), which imparts similar benefits. Recently we discovered that hydrogen sulfide (H2S) is increased upon DR and plays an essential role in mediating DR benefits across evolutionary boundaries. Here we found increased hepatic H2S production in long-lived mouse strains of reduced GH and/or TH action, and in a cell-autonomous manner upon serum withdrawal in vitro. Negative regulation of hepatic H2S production by GH and TH was additive and occurred via distinct mechanisms, namely direct transcriptional repression of the H2S-producing enzyme cystathionine g-lyase (CGL) by TH, and substrate-level control of H2S production by GH. Mice lacking CGL failed to downregulate systemic T4 metabolism and circulating IGF-1, revealing an essential role for H2S in the regulation of key longevity-associated hormones.117Nsciescopu