A Systems Biology Approach Reveals the Role of a Novel Methyltransferase in Response to Chemical Stress and Lipid Homeostasis

Using small molecule probes to understand gene function is an attractive approach that allows functional characterization of genes that are dispensable in standard laboratory conditions and provides insight into the mode of action of these compounds. Using chemogenomic assays we previously identified yeast Crg1, an uncharacterized SAM-dependent methyltransferase, as a novel interactor of the protein phosphatase inhibitor cantharidin. In this study we used a combinatorial approach that exploits contemporary high-throughput techniques available in Saccharomyces cerevisiae combined with rigorous biological follow-up to characterize the interaction of Crg1 with cantharidin. Biochemical analysis of this enzyme followed by a systematic analysis of the interactome and lipidome of CRG1 mutants revealed that Crg1, a stress-responsive SAM-dependent methyltransferase, methylates cantharidin in vitro. Chemogenomic assays uncovered that lipid-related processes are essential for cantharidin resistance in cells sensitized by deletion of the CRG1 gene. Lipidome-wide analysis of mutants further showed that cantharidin induces alterations in glycerophospholipid and sphingolipid abundance in a Crg1-dependent manner. We propose that Crg1 is a small molecule methyltransferase important for maintaining lipid homeostasis in response to drug perturbation. This approach demonstrates the value of combining chemical genomics with other systems-based methods for characterizing proteins and elucidating previously unknown mechanisms of action of small molecule inhibitors

Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries

Abstract Background Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres. Methods This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and low–middle-income countries. Results In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of ‘single-use’ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for low–middle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia. Conclusion This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both high– and low–middle–income countries

Depression is common and precludes accurate assessment of functional status in elderly patients with congestive heart failure.

BACKGROUND: Congestive heart failure (CHF) and depression are independently known to result in physical decline and diminished functional capacity in the general population. The prevalence and relationship of depressive symptoms in CHF to physical limitations has not been objectively examined. METHODS AND RESULTS: The Center for Epidemiological Studies Depression Scale (CES-D) was used to ascertain depressive symptoms in 33 elderly ambulatory individuals with CHF. Self-report assessment of functional status, cardiopulmonary exercise testing (CPX), and measurement of energy expenditure by doubly labeled water and Caltrac Accelerometer (Muscle Dynamics, Torrance, CA) were performed. Depressed and nondepressed groups were compared. Forty-two percent of the patients scored in the depressed range (CES-D score of 16 or greater). There were no differences in demographic variables or severity of illness between the depressed and nondepressed patients. Energy expenditure was comparable across groups. Although obtaining similar maximal heart rate and maximal oxygen consumption (VO2max) on CPX, the depressed group showed less exertion on exercise testing with a significantly lower respiratory quotient (P = .017). CONCLUSION: Depressive symptoms were common and unrelated to the severity of CHF. Although depressed individuals tended to report worse physical functioning than nondepressed individuals, objective assessment of energy expenditure was comparable. Depressed patients appear to underestimate their functional ability. Subsequently, inaccurate assessment of functional status may occur

Effects of exercise training on peak performance and quality of life in congestive heart failure patients.

BACKGROUND: Exercise programs for patients with heart failure have often enrolled and evaluated relatively healthy, young patients. They also have not measured the impact of exercise performance on daily activities and quality of life. METHODS AND RESULTS: We investigated the impact of a 6-month supervised and graded exercise program in 33 elderly patients with moderate to severe heart failure randomized to usual care or an exercise program. Six of 17 patients did not tolerate the exercise program. Of those who did, peak oxygen consumption increased by 2.4 +/- 2.8 mL/kg/min (P \u3c .05) and 6-minute walk increased by 194 ft (P \u3c .05). However, outpatient energy expenditure did not increase, as measured by either the doubly labeled water technique or Caltrac accelerometer. Perceived quality of life also did not improve, as measured by the Medical Outcomes Study, Functional Status Assessment, or Minnesota Living With Heart Failure questionnaires. CONCLUSION: Elderly patients with severe heart failure can safely exercise, with an improvement in peak exercise tolerance. However, not all patients will benefit, and daily energy expenditure and quality of life do not improve to the same extent as peak exercise