Promoting a MOSAIC future in science.

Discoveries at the frontiers of science and finding solutions to pressing biomedical problems will be accelerated when talent, which is widely distributed, is better aligned with opportunities. Strategies to enhance a MOSAIC (Maximizing Opportunities for Scientific and Academic Independent Careers) professoriate and diversify the biomedical landscape are discussed.

A repeating fast radio burst source in a globular cluster.

Fast radio bursts (FRBs) are flashes of unknown physical origin1. The majority of FRBs have been seen only once, although some are known to generate multiple flashes2,3. Many models invoke magnetically powered neutron stars (magnetars) as the source of the emission4,5. Recently, the discovery6 of another repeater (FRB 20200120E) was announced, in the direction of the nearby galaxy M81, with four potential counterparts at other wavelengths6. Here we report observations that localized the FRB to a globular cluster associated with M81, where it is 2 parsecs away from the optical centre of the cluster. Globular clusters host old stellar populations, challenging FRB models that invoke young magnetars formed in a core-collapse supernova. We propose instead that FRB 20200120E originates from a highly magnetized neutron star formed either through the accretion-induced collapse of a white dwarf, or the merger of compact stars in a binary system7. Compact binaries are efficiently formed inside globular clusters, so a model invoking them could also be responsible for the observed bursts.

A repeating fast radio burst source localized to a nearby spiral galaxy.

Fast radio bursts (FRBs) are brief, bright, extragalactic radio flashes1,2. Their physical origin remains unknown, but dozens of possible models have been postulated3. Some FRB sources exhibit repeat bursts4-7. Although over a hundred FRB sources have been discovered8, only four have been localized and associated with a host galaxy9-12, and just one of these four is known to emit repeating FRBs9. The properties of the host galaxies, and the local environments of FRBs, could provide important clues about their physical origins. The first known repeating FRB, however, was localized to a low-metallicity, irregular dwarf galaxy, and the apparently non-repeating sources were localized to higher-metallicity, massive elliptical or star-forming galaxies, suggesting that perhaps the repeating and apparently non-repeating sources could have distinct physical origins. Here we report the precise localization of a second repeating FRB source6, FRB 180916.J0158+65, to a star-forming region in a nearby (redshift 0.0337 ± 0.0002) massive spiral galaxy, whose properties and proximity distinguish it from all known hosts. The lack of both a comparably luminous persistent radio counterpart and a high Faraday rotation measure6 further distinguish the local environment of FRB 180916.J0158+65 from that of the single previously localized repeating FRB source, FRB 121102. This suggests that repeating FRBs may have a wide range of luminosities, and originate from diverse host galaxies and local environments.

Incomplete bunyavirus particles can cooperatively support virus infection and spread.

Bunyaviruses lack a specific mechanism to ensure the incorporation of a complete set of genome segments into each virion, explaining the generation of incomplete virus particles lacking one or more genome segments. Such incomplete virus particles, which may represent the majority of particles produced, are generally considered to interfere with virus infection and spread. Using the three-segmented arthropod-borne Rift Valley fever virus as a model bunyavirus, we here show that two distinct incomplete virus particle populations unable to spread autonomously are able to efficiently complement each other in both mammalian and insect cells following co-infection. We further show that complementing incomplete virus particles can co-infect mosquitoes, resulting in the reconstitution of infectious virus that is able to disseminate to the mosquito salivary glands. Computational models of infection dynamics predict that incomplete virus particles can positively impact virus spread over a wide range of conditions, with the strongest effect at intermediate multiplicities of infection. Our findings suggest that incomplete particles may play a significant role in within-host spread and between-host transmission, reminiscent of the infection cycle of multipartite viruses.

Detecting Changes in Tissue Perfusion With Hyperspectral Imaging and Thermal Imaging Following Endovascular Treatment for Peripheral Arterial Disease.

PURPOSE: Hyperspectral imaging (HSI) and thermal imaging allow contact-free tissue perfusion measurements and may help determine the effect of endovascular treatment (EVT) in patients with peripheral arterial disease. This study aimed to detect changes in perfusion with HSI and thermal imaging peri-procedurally and determine whether these changes can identify limbs that show clinical improvement after 6 weeks. METHODS: Patients with Rutherford class 2-6 scheduled for EVT were included prospectively. Hyperspectral imaging and thermal imaging were performed directly before and after EVT. Images were taken from the lateral side of the calves and plantar side of the feet. Concentrations of (de)oxyhemoglobin, oxygen saturation, and skin temperature were recorded. Angiographic results were determined on completion angiogram. Clinical improvement 6 weeks after EVT was defined as a decrease ≥ one Rutherford class. Peri-procedural changes in perfusion parameters were compared between limbs with and without good angiographic results or clinical improvement. To identify limbs with clinical improvement, receiver operating characteristic (ROC) curves were used to determine cutoff values for change in HSI. RESULTS: Included were 23 patients with 29 treated limbs. Change in HSI values and temperature was not significantly different between limbs with good and poor angiographic results. Change in peri-procedural deoxyhemoglobin, determined by HSI, at the calves and feet was significantly different between limbs with and without clinical improvement at 6 week follow-up (p=0.027 and p=0.017, respectively). The ROC curve for change in deoxyhemoglobin at the calves showed a cutoff value of ≤1.0, and ≤-0.5 at the feet, which were discriminative for clinical improvement (sensitivity 77%; specificity 75% and sensitivity 62%; specificity 88%, respectively). CONCLUSIONS: HSI can detect changes in perfusion at the calves after EVT in patients with Rutherford class 2-6. Peri-procedural deoxyhemoglobin changes at the calves and feet are significantly different between limbs with and without clinical improvement. Decrease in deoxyhemoglobin directly after EVT may identify limbs that show clinical improvement 6 weeks after EVT.

Muscle fiber type-specific autophagy responses following an overnight fast and mixed meal ingestion in human skeletal muscle.

The aim of the present study was to investigate the fiber type-specific abundance of autophagy-related proteins after an overnight fast and following ingestion of a mixed meal in human skeletal muscle. Twelve overweight, healthy young male volunteers underwent a 3-h mixed meal tolerance test following an overnight fast. Blood samples were collected in the overnight-fasted state and throughout the 180-min postmeal period. Skeletal muscle biopsies were collected in the fasted state, and at 30 and 90 min after meal ingestion. Protein content of key autophagy markers and upstream signaling responses were measured in whole muscle and pooled single fibers using immunoblotting. In the fasted state, type I fibers displayed lower LC3B-I but higher LC3B-II abundance and higher LC3B-II/LC3B-I ratio compared with type II fibers (P < 0.05). However, there were no fiber type differences in p62/SQSTM1, unc-51 like autophagy activating kinase (ULK1), ATG5, or ATG12 (P > 0.05). Compared with the fasted state, there was a reduction in LC3B-II abundance, indicative of lower autophagosome content, in whole muscle and in both type I and type II fibers following meal ingestion (P < 0.05). This reduction in autophagosome content occurred alongside similar increases in p-AktS473 and p-mTORS2448 in both type I and type II muscle fibers (P < 0.05). In human skeletal muscle, type I fibers have a greater autophagosome content than type II fibers in the overnight-fasted state despite comparable abundance of other key upstream autophagy proteins. Autophagy is rapidly inhibited in both fiber types following the ingestion of a mixed meal.NEW & NOTEWORTHY This study examined the fiber type-specific content of key autophagy proteins in human muscle. We showed that markers of autophagosome content are higher in type I fibers in the overnight-fasted state, whereas autophagy is rapidly inhibited in both type I and type II fibers after the ingestion of a mixed meal.

Colonoscopy Needs for Implementation of a Colorectal Cancer Screening Program in Ukraine.

BACKGROUND: In Ukraine, there is no established colorectal cancer screening program. We aimed to project the number of screening colonoscopies needed for implementation of various CRC screening strategies in Ukraine. METHODS: We modified a previously developed Markov microsimulation model to reflect the natural history of adenoma and CRC progression among average-risk 50-74-year-olds. We simulated colonoscopies needed for the following screening strategies: no screening, fecal occult blood test yearly, FOBT yearly with flexible sigmoidoscopy every 5 years, FS every 5 years, fecal immunohistochemistry test (FIT) yearly, or colonoscopy every 10 years. Assuming 80% screening adherence, we estimated colonoscopies required at 1 and 5 years depending on the implementation rate. In one-way sensitivity analyses, we varied implementation rate, screening adherence, sensitivity, and specificity. RESULTS: Assuming an 80% screening adherence and complete implementation (100%), besides a no screening strategy, the fewest screening colonoscopies are needed with an FOBT program, requiring on average 6,600 and 26,800 colonoscopies per 100,000 persons at 1 and 5 years post-implementation, respectively. The most screening colonoscopies are required with a colonoscopy program, requiring on average 76,600 and 101,000 colonoscopies per 100,000 persons at 1 and 5 years post-implementation, respectively. In sensitivity analyses, the biggest driver of number of colonoscopies needed was screening adherence. CONCLUSIONS: The number of colonoscopies needed and therefore the potential strain on the healthcare system vary substantially by screening test. These findings can provide valuable information for stakeholders on equipment needs when implementing a national screening program in Ukraine.

Reliability assessment of hyperspectral imaging with the HyperView™ system for lower extremity superficial tissue oxygenation in young healthy volunteers.

PURPOSE: Hyperspectral imaging (HSI) is a noninvasive spectroscopy technique for determining superficial tissue oxygenation. The HyperView™ system is a hand-held camera that enables perfusion image acquisition. The evaluation of superficial tissue oxygenation is warranted in the evaluation of patients with peripheral arterial disease. The aim was to determine the reliability of repeated HSI measurements. METHODS: In this prospective cohort study, HSI was performed on 50 healthy volunteers with a mean age of 26.4 ± 2.5 years, at the lower extremity. Two independent observers performed HSI during two subsequent measurement sessions. Short term test-retest reliability and intra- and inter-observer reliability were determined, and generalizability and decision studies were performed. Transcutaneous oxygen pressure (TcPO2) measurements were also performed. RESULTS: The short term test-retest reliability was good for the HSI values determined at the lower extremity, ranging from 0.72 to 0.90. Intra- and inter-observer reliability determined at different days were poor to moderate for both HSI (0.24 to 0.71 and 0.30 to 0.58, respectively) and TcPO2 (0.54 and 0.56, and 0.51 and 0.31, respectively). Reliability can be increased to >0.75 by averaging two measurements on different days. CONCLUSION: This study showed good short term test-retest reliability for HSI measurements, however low intra- and inter-observer reliability was observed for tissue oxygenation measurements with both HSI and TcPO2 performed at separate days in young healthy volunteers. Reliability of HSI can be improved when determined as a mean of two measurements taken on different days.

Health care professionals' motivation, their behaviors, and the quality of hospital care: A mixed-methods systematic review.

BACKGROUND: Health care professionals' work motivation is assumed to be crucial for the quality of hospital care, but it is unclear which type of motivation ought to be stimulated to improve quality. Motivation and similar concepts are aligned along a motivational continuum that ranges from (intrinsic) autonomous motivation to (extrinsic) controlled motivation to provide a framework for this mixed-methods systematic review. PURPOSE: This mixed-methods systematic review aims to link various types of health care professionals' motivation directly and through their work-related behaviors to quality of care. METHODS: Six databases were searched from January 1990 to August 2016. Qualitative and quantitative studies were included if they reported on work motivation in relationship to work behavior and/or quality, and study participants were health care professionals working in hospitals in high-income countries. Study bias was evaluated using the Standard Quality Assessment Criteria for Evaluating Primary Research Papers from a Variety of Fields. The review protocol was registered in the PROSPERO database (CRD42016043284). RESULTS: A total of 84 out of 6,525 unique records met the inclusion criteria. Results show that health care professionals' autonomous motivation improves their quality perceptions and work-related behaviors. Controlled motivation inhibits voicing behavior, but when balanced with autonomous motivation, it stimulates core task and proactive behavior. Proactivity is associated with increased quality of care perceptions. PRACTICE IMPLICATIONS: To improve quality of care, policy makers and managers need to support health care professionals' autonomous motivation and recognize and facilitate proactivity as an essential part of health care professionals' jobs. Incentive-based quality improvements need to be complemented with aspects that stimulate autonomous motivation.

Global Health 101.

Global health is an evolving field that has been broadly defined as the promotion of health for all through transnational collaboration and research. It centers on the concepts of equity and collaboration. The focus of global health has recently undergone a major shift toward emphasizing the importance of a systems-based approach to healthcare delivery, which considers not only the target disease but also the many contextual factors, influencing the ability to deliver care equitably to a population to reduce the burden of any particular disease. Thus, an important global health delivery framework has been established to outline this inter- and multi-disciplinary systems-based to address major global health issues and improve health for all globally. The practice of global health, whether in research or in active intervention, necessitates guiding principles to ensure ethical conduct in the transnational partnerships and efforts to advance the field. With the introduction of the United Nations' Sustainable Development Goals in 2015, there has been a major shift in response to epidemiologic transition to focus on reducing the burden of noncommunicable diseases, including cancer, which disproportionately impact low-to-middle income countries. This is true for colorectal cancer, with care challenged by significant gaps in screening, early detection, and referral systems.

Autophagy is not involved in lipid accumulation and the development of insulin resistance in skeletal muscle.

OBJECTIVE: To investigate the effect of high fat diet-induced insulin resistance on autophagy markers in the liver and skeletal muscle of mice in the fasted state and following an oral glucose bolus. METHODS: Forty C57BL/6J male mice were fed either a high fat, high sucrose (HFSD, n = 20) or standard chow control (CON, n = 20) diet for 16 weeks. Upon trial completion, mice were gavaged with water or glucose and skeletal muscle and liver were collected 15 min post gavage. Protein abundance and gene expression of autophagy markers and activation of related signalling pathways were assessed. RESULTS: Compared to CON, the HFSD intervention increased LC3B-II and p62/SQSTM1 protein abundance in the liver which is indicative of elevated autophagosome content via reduced clearance. These changes coincided with inhibitory autophagy signalling through elevated p-mTOR S2448 and p-ULK1S758. HFSD did not alter autophagy markers in skeletal muscle. Administration of an oral glucose bolus had no effect on autophagy markers or upstream signalling responses in either tissue regardless of diet. CONCLUSION: HFSD induces tissue-specific autophagy impairments, with autophagosome accumulation indicating reduced lysosomal clearance in the liver. In contrast, autophagy markers were unchanged in skeletal muscle, indicating that autophagy is not involved in the development of skeletal muscle insulin resistance.

A Systematic Review and Critical Appraisal of Peri-Procedural Tissue Perfusion Techniques and their Clinical Value in Patients with Peripheral Arterial Disease.

OBJECTIVE: Many techniques have been introduced to enable quantification of tissue perfusion in patients with peripheral arterial disease (PAD). Currently, none of these techniques is widely used to analyse real time tissue perfusion changes during endovascular or surgical revascularisation procedures. The aim of this systematic review was to provide an up to date overview of the peri-procedural applicability of currently available techniques, diagnostic accuracy of assessing tissue perfusion and the relationship with clinical outcomes. DATA SOURCES: MEDLINE, Embase, CINAHL, and the Cochrane Central Register of Controlled Trials. REVIEW METHODS: This systematic review was conducted in accordance with the Preferred Reporting Items for Systematic review and Meta-Analysis (PRISMA) guidelines. Four electronic databases were searched up to 31 12 2020 for eligible articles: MEDLINE, Embase, CINAHL and the Cochrane Central Register of Controlled Trials. Eligible articles describing a perfusion measurement technique, used in a peri-procedural setting before and within 24 hours after the revascularisation procedure, with the aim of determining the effect of intervention in patients with PAD, were assessed for inclusion. The QUADAS-2 tool was used to assess the risk of bias and applicability of the studies. RESULTS: An overview of 10 techniques found in 26 eligible articles focused on study protocols, research goals, and clinical outcomes is provided. Non-invasive techniques included laser speckle contrast imaging, micro-lightguide spectrophotometry, magnetic resonance imaging perfusion, near infrared spectroscopy, skin perfusion pressure, and plantar thermography. Invasive techniques included two dimensional perfusion angiography, contrast enhanced ultrasound, computed tomography perfusion imaging, and indocyanine green angiography. The results of the 26 eligible studies, which were mostly of poor quality according to QUADAS-2, were without exception, not sufficient to substantiate implementation in daily clinical practice. CONCLUSION: This systematic review provides an overview of 10 tissue perfusion assessment techniques for patients with PAD. It seems too early to appoint one of them as a reference standard. The scope of future research in this domain should therefore focus on clinical accuracy, reliability, and validation of the techniques.

A taxonomy to assess the interaction between nurses and children: Development and reliability.

AIMS AND OBJECTIVES: The aim of this study was to develop a valid and reliable instrument to assess the nurse-child interaction during medical or nursing interventions. BACKGROUND: Communication is an important competency for the professional practice of nurses and physicians. The nurse-patient relationship is fundamental for high-quality care. It has been suggested that if nurses have more skills to interact with children, care will be less distressing and less painful for the children. DESIGN: A qualitative observational psychometric study; the GRRAS checklist was used. METHODS: In-depth video-analyses, taxonomy development (19 videos) and testing it is psychometric properties (10 videos). Three observers micro-analysed video recordings of experienced nurses changing children's wound dressing in a specialised Burn Centre. RESULTS: The nurse-child interaction taxonomy (NCIT) was developed to observe and score the interactional behaviour between nurse and child. The taxonomy has three main patterns: being considerate, attuning oneself, and procedural interventions, subdivided in eight dimensions. These dimensions contain 16 elements that can be observed and scored on a 7-point scale. Intra-rater, inter-rater reliability and agreement were good. CONCLUSIONS: This study shows that interaction between nurses and children can be assessed reliably with the NCIT by an experienced observer or alternatively, scoring by two observers is recommended. RELEVANCE TO CLINICAL PRACTICE: The development of the taxonomy is an important step to find evidence for the best way for nurses to interact with children during nursing interventions or medical events and as such, ultimately, contributes to providing the best care possible.

Mechanisms of hyperinsulinaemia in apparently healthy non-obese young adults: role of insulin secretion, clearance and action and associations with plasma amino acids.

AIMS/HYPOTHESIS: This study aimed to examine the metabolic health of young apparently healthy non-obese adults to better understand mechanisms of hyperinsulinaemia. METHODS: Non-obese (BMI < 30 kg/m2) adults aged 18-35 years (N = 254) underwent a stable isotope-labelled OGTT. Insulin sensitivity, glucose effectiveness and beta cell function were determined using oral minimal models. Individuals were stratified into quartiles based on their insulin response during the OGTT, with quartile 1 having the lowest and quartile 4 the highest responses. RESULTS: Thirteen per cent of individuals had impaired fasting glucose (IFG; n = 14) or impaired glucose tolerance (IGT; n = 19), allowing comparisons across the continuum of insulin responses within the spectrum of normoglycaemia and prediabetes. BMI (~24 kg/m2) was similar across insulin quartiles and in those with IFG and IGT. Despite similar glycaemic excursions, fasting insulin, triacylglycerols and cholesterol were elevated in quartile 4. Insulin sensitivity was lowest in quartile 4, and accompanied by increased insulin secretion and reduced insulin clearance. Individuals with IFG had similar insulin sensitivity and beta cell function to those in quartiles 2 and 3, but were more insulin sensitive than individuals in quartile 4. While individuals with IGT had a similar degree of insulin resistance to quartile 4, they exhibited a more severe defect in beta cell function. Plasma branched-chain amino acids were not elevated in quartile 4, IFG or IGT. CONCLUSIONS/INTERPRETATION: Hyperinsulinaemia within normoglycaemic young, non-obese adults manifests due to increased insulin secretion and reduced insulin clearance. Individual phenotypic characterisation revealed that the most hyperinsulinaemic were more similar to individuals with IGT than IFG, suggesting that hyperinsulinaemic individuals may be on the continuum toward IGT. Furthermore, plasma branched-chain amino acids may not be an effective biomarker in identifying hyperinsulinaemia and insulin resistance in young non-obese adults.

Plasma from Volunteers Breathing Helium Reduces Hypoxia-Induced Cell Damage in Human Endothelial Cells-Mechanisms of Remote Protection Against Hypoxia by Helium.

PURPOSE: Remote ischemic preconditioning protects peripheral organs against prolonged ischemia/reperfusion injury via circulating protective factors. Preconditioning with helium protected healthy volunteers against postischemic endothelial dysfunction. We investigated whether plasma from helium-treated volunteers can protect human umbilical vein endothelial cells (HUVECs) against hypoxia in vitro through release of circulating of factors. METHODS: Healthy male volunteers inhaled heliox (79% helium, 21% oxygen) or air for 30 min. Plasma was collected at baseline, directly after inhalation, 6 h and 24 h after start of the experiment. HUVECs were incubated with either 5% or 10% of the plasma for 1 or 2 h and subjected to enzymatically induced hypoxia. Cell damage was measured by LDH content. Furthermore, caveolin 1 (Cav-1), hypoxia-inducible factor (HIF1α), extracellular signal-regulated kinase (ERK)1/2, signal transducer and activator of transcription (STAT3) and endothelial nitric oxide synthase (eNOS) were determined. RESULTS: Prehypoxic exposure to 10% plasma obtained 6 h after helium inhalation decreased hypoxia-induced cell damage in HUVEC. Cav-1 knockdown in HUVEC abolished this effect. CONCLUSIONS: Plasma of healthy volunteers breathing helium protects HUVEC against hypoxic cell damage, possibly involving circulating Cav-1.

Lysine post-translational modification of glyceraldehyde-3-phosphate dehydrogenase regulates hepatic and systemic metabolism.

Reciprocal regulation of hepatic glycolysis and gluconeogenesis contributes to systemic metabolic homeostasis. Recent evidence from lower order organisms has found that reversible post-translational modification of glyceraldehyde-3-phosphate dehydrogenase (GAPDH), particularly acetylation, contributes to the reciprocal regulation of glycolysis/gluconeogenesis. However, whether this occurs in mammalian hepatocytes in vitro or in vivo is unknown. Several proteomics studies have identified 4 lysine residues in critical regions of mammalian GAPDH that are altered by multiple post-translational modifications. In FAO hepatoma cells, mutation of all 4 lysine residues (4K-R GAPDH) to mimic their unmodified state reduced GAPDH glycolytic activity and glycolytic flux and increased gluconeogenic GAPDH activity and glucose production. Hepatic expression of 4K-R GAPDH in mice increased GAPDH gluconeogenic activity and the contribution of gluconeogenesis to endogenous glucose production in the unfed state. Consistent with the increased reliance on the energy-consuming gluconeogenic pathway, plasma free fatty acids and ketones were elevated in mice expressing 4K-R GAPDH, suggesting enhanced lipolysis and hepatic fatty acid oxidation. In normal mice, food withholding and refeeding, as well as hormonal regulators of reciprocal glycolysis/gluconeogenesis, such as insulin, glucagon, and norepinephrine, had no effect on global GAPDH acetylation. However, GAPDH acetylation was reduced in obese and type 2 diabetic db/db mice. These findings show that post-translational modification of GAPDH lysine residues regulates hepatic and systemic metabolism, revealing an unappreciated role for hepatic GAPDH in substrate selection and utilization.-Bond, S. T., Howlett, K. F., Kowalski, G. M., Mason, S., Connor, T., Cooper, A., Streltsov, V., Bruce, C. R., Walder, K. R., McGee, S. L. Lysine post-translational modification of glyceraldehyde-3-phosphate dehydrogenase regulates hepatic and systemic metabolism.

Genetic Kinship Analyses Reveal That Gray's Beaked Whales Strand in Unrelated Groups.

Some marine mammals are so rarely seen that their life history and social structure remain a mystery. Around New Zealand, Gray's beaked whales (Mesoplodon grayi) are almost never seen alive, yet they are a commonly stranded species. Gray's are unique among the beaked whales in that they frequently strand in groups, providing an opportunity to investigate their social organization. We examined group composition and genetic kinship in 113 Gray's beaked whales with samples collected over a 20-year period. Fifty-six individuals stranded in 19 groups (2 or more individuals), and 57 whales stranded individually. Mitochondrial control region haplotypes and microsatellite genotypes (16 loci) were obtained for 103 whales. We estimated pairwise relatedness between all pairs of individuals and average relatedness within, and between, groups. We identified 6 mother-calf pairs and 2 half-siblings, including 2 whales in different strandings 17 years and 1500 km apart. Surprisingly, none of the adults stranding together were related suggesting that groups are not formed through the retention of kin. These data suggest that both sexes may disperse from their mothers, and groups consisting of unrelated subadults are common. We also found no instances of paternity within the groups. Our results provide the first insights into dispersal, social organization, and the mating system in this rarely sighted species. Why whales strand is still unknown but, in Gray's beaked whales, the dead can tell us much about the living.

Effect of helium pre- or postconditioning on signal transduction kinases in patients undergoing coronary artery bypass graft surgery.

BACKGROUND: The noble gas helium induces pre- and postconditioning in animals and humans. Volatile anesthetics induce cardioprotection in humans undergoing coronary artery bypass graft (CABG) surgery. We hypothesized that helium induces pre- and postconditioning in CABG-patients, affecting signaling molecules protein kinase C-epsilon (PKC-ε), p38 mitogen activated protein kinase (p38 MAPK), extracellular signal-regulated kinase 1/2 (ERK-1/2) and heat shock protein 27 (HSP-27) within cardiac tissue, and reducing postoperative troponin levels. METHODS: After ethical approval and informed consent, 125 elective patients undergoing CABG surgery were randomised into this prospective, placebo controlled, investigator blinded, parallel arm single-centre study. Helium preconditioning (3 × 5 min of 70 % helium and 30 % oxygen) was applied before aortic cross clamping; postconditioning (15 min of helium) was applied before release of the aortic cross clamp. Signaling molecules were measured in right atrial appendix specimens. Troponin-T was measured at 4, 12, 24 and 48 h postoperatively. RESULTS: Baseline characteristics of all groups were similar. Helium preconditioning did not significantly alter the primary outcome (molecular levels of kinases PKC-ε and HSP-27, ratio of activated p38 MAPK or ERK ½). Postoperative troponin T was 11 arbitrary units [5, 31; area-under-the-curve (interquartile range)] for controls, and no statistically significant changes were observed after helium preconditioning [He-pre: 11 (6, 18)], helium postconditioning [He-post: 11 (8, 15)], helium pre- and postconditioning [He-PP: 14 (6, 20)] and after sevoflurane preconditioning [APC: 12 (8, 24), p = 0.13]. No adverse effects related to study treatment were observed in this study. CONCLUSIONS: No effect was observed of helium preconditioning, postconditioning or the combination thereof on activation of p38 MAPK, ERK 1/2 or levels of HSP27 and PKC-ε in the human heart. Helium pre- and postconditioning did not affect postoperative troponin release in patients undergoing CABG surgery. Clinical trial number Dutch trial register ( http://www.trialregister.nl/ ) number NTR1226.

Rhodium-Catalyzed Enantioselective Intramolecular Hydroacylation of Trisubstituted Alkenes.

We report the first examples of transition metal-catalyzed enantioselective alkene hydroacylations with 1,1,2-trisubstituted alkenes. DFT and mechanistic studies are consistent with a reaction pathway for these rhodium-catalyzed processes including intramolecular alkene hydroacylation and α-epimerization to generate highly enantioenriched, polycyclic architectures. This reaction sequence enables the hydroacylation of 2-(cyclohex-1-en-1-yl)benzaldehydes to form hexahydro-9H-fluoren-9-ones in moderate to high yields (68-91 %) with high enantioselectivities (up to 99 % ee) and diastereoselectivities (typically >20:1).

Epigenetic regulation of skeletal muscle metabolism.

Normal skeletal muscle metabolism is essential for whole body metabolic homoeostasis and disruptions in muscle metabolism are associated with a number of chronic diseases. Transcriptional control of metabolic enzyme expression is a major regulatory mechanism for muscle metabolic processes. Substantial evidence is emerging that highlights the importance of epigenetic mechanisms in this process. This review will examine the importance of epigenetics in the regulation of muscle metabolism, with a particular emphasis on DNA methylation and histone acetylation as epigenetic control points. The emerging cross-talk between metabolism and epigenetics in the context of health and disease will also be examined. The concept of inheritance of skeletal muscle metabolic phenotypes will be discussed, in addition to emerging epigenetic therapies that could be used to alter muscle metabolism in chronic disease states.