Effect of Microgravity on the Contraction and Cytoskeletal Remodeling of A7r5 Smooth Muscle Cells

Smooth muscle presents several unique contractile properties when compared to striated muscle. Data suggests that differential remodeling of the alpha-actin and beta-actin and the regulation of such remodeling may play an essential role in smooth muscle contraction. At rest both alpha- and beta-actin both exhibit a cable-like appearance. During contraction, alpha-actin appears to undergo significant remodeling with dissolution on the majority of the cables and the formation of podosomes where it demonstrates co-localization with myosin while beta-actin retains a cable-like appearance. While the remodeling of the two actin domains has been characterized under normal gravity little is known regarding cytoskeletal dynamics in A7r5 smooth muscle cells. A7r5 cells will be subjected to the microgravity environment of the International Space Station. We speculate that the absence of gravity as an organizing force on biological structures may produce different effects than what is observed on Earth. In collaboration with SpaceTango Inc., a cell culturing module has been engineered that will allow the cells to ascend into space and maintain homeostasis while on orbit. The module will also administer phorbol ester, a contractile stimulant, followed by acetone to “fix” the cells in their contracted state so observations can be made about the aforementioned processes when they return from orbit

Exercise and insulin resistance in PCOS: muscle insulin signalling and fibrosis

OBJECTIVE:Mechanisms of insulin resistance in polycystic ovary syndrome (PCOS) remain ill-defined, contributing to sub-optimal therapies. Recognising skeletal muscle plays a key role in glucose homeostasis we investigated early insulin signalling, its association with aberrant transforming growth factor β (TGFβ) regulated tissue fibrosis. We also explored the impact of aerobic exercise on these molecular pathways. METHODS:A secondary analysis from a cross-sectional study was undertaken in women with (n=30) or without (n=29) PCOS across lean and overweight BMIs. A subset of participants with (n=8) or without (n=8) PCOS who were overweight completed 12-weeks of aerobic exercise training. Muscle was sampled before and 30 min into a euglycaemic-hyperinsulinaemic clamp pre- and post-training. RESULTS:We found reduced signalling in PCOS of mechanistic target of rapamycin (mTOR). Exercise training augmented but did not completely rescue this signalling defect in women with PCOS. Genes in the TGFβ signalling network were upregulated in skeletal muscle in the overweight women with PCOS but were unresponsive to exercise training except for genes encoding LOX, collagen 1 and 3. CONCLUSIONS:We provide new insights into defects in early insulin signalling, tissue fibrosis, and hyperandrogenism in PCOS-specific insulin resistance in lean and overweight women. PCOS-specific insulin-signalling defects were isolated to mTOR, while gene expression implicated TGFβ ligand regulating a fibrosis in the PCOS-obesity synergy in insulin resistance and altered responses to exercise. Interestingly, there was little evidence for hyperandrogenism as a mechanism for insulin resistance

Modeled Effect of Coastal Biogeochemical Processes, Climate Variability, and Ocean Acidification on Aragonite Saturation State in the Bering Sea

The Bering Sea is highly vulnerable to ocean acidification (OA) due to naturally cold, poorly buffered waters and ocean mixing processes. Harsh weather conditions within this rapidly changing, geographically remote environment have limited the quantity of carbon chemistry data, thereby hampering efforts to understand underlying spatial-temporal variability and detect long-term trends. We add carbonate chemistry to a regional biogeochemical model of the Bering Sea to explore the underlying mechanisms driving carbon dynamics over a decadal hindcast (2003–2012). The results illustrate that coastal processes generate considerable spatial variability in the biogeochemistry and vulnerability of Bering Sea shelf water to OA. Substantial seasonal biological productivity maintains high supersaturation of aragonite on the outer shelf, whereas riverine freshwater runoff loaded with allochthonous carbon decreases aragonite saturation states (ΩArag) to values below 1 on the inner shelf. Over the entire 2003–2012 model hindcast, annual surface ΩArag decreases by 0.025 – 0.04 units/year due to positive trends in the partial pressure of carbon dioxide (pCO2) in surface waters and dissolved inorganic carbon (DIC). Variability in this trend is driven by an increase in fall phytoplankton productivity and shelf carbon uptake, occurring during a transition from a relatively warm (2003–2005) to cold (2010–2012) temperature regime. Our results illustrate how local biogeochemical processes and climate variability can modify projected rates of OA within a coastal shelf system

Episodic Memory and Appetite Regulation in Humans

Psychological and neurobiological evidence implicates hippocampal-dependent memory processes in the control of hunger and food intake. In humans, these have been revealed in the hyperphagia that is associated with amnesia. However, it remains unclear whether 'memory for recent eating' plays a significant role in neurologically intact humans. In this study we isolated the extent to which memory for a recently consumed meal influences hunger and fullness over a three-hour period. Before lunch, half of our volunteers were shown 300 ml of soup and half were shown 500 ml. Orthogonal to this, half consumed 300 ml and half consumed 500 ml. This process yielded four separate groups (25 volunteers in each). Independent manipulation of the 'actual' and 'perceived' soup portion was achieved using a computer-controlled peristaltic pump. This was designed to either refill or draw soup from a soup bowl in a covert manner. Immediately after lunch, self-reported hunger was influenced by the actual and not the perceived amount of soup consumed. However, two and three hours after meal termination this pattern was reversed - hunger was predicted by the perceived amount and not the actual amount. Participants who thought they had consumed the larger 500-ml portion reported significantly less hunger. This was also associated with an increase in the 'expected satiation' of the soup 24-hours later. For the first time, this manipulation exposes the independent and important contribution of memory processes to satiety. Opportunities exist to capitalise on this finding to reduce energy intake in humans

Biomarkers of hepatic injury and function in neonatal hypoxic ischemic encephalopathy and with therapeutic hypothermia

Therapeutic hypothermia (TH) is now provided as standard care to infants with moderate-severe hypoxic ischemic encephalopathy (HIE). The role of TH in limiting neuronal injury is well recognized, but its effect on hepatic injury which occurs frequently in neonatal HIE is not known. Our objective was to characterize biomarkers of liver injury and function in the setting of neonatal HIE and to describe whether HIE severity and provision of TH influence these hepatic biomarkers. We performed a multicenter retrospective study and compared hepatic biomarkers obtained during the first postnatal week, according to the severity of HIE and whether treated with TH. Of a total of 361 infants with HIE, 223 (62%) received TH and 138 (38%) were managed at normal temperature. Most hepatic biomarkers and C-reactive protein (CRP) were significantly associated with the severity of HIE (p<0.001). Infants treated with TH had lower peak Alanine aminotransferase (ALT) concentrations (p=0.025) and delay in reaching peak CRP concentration (p<0.001).  Conclusion: We observed a significant association between the clinical grade of HIE and biomarkers of liver metabolism and function. Therapeutic hypothermia was associated with delayed CRP responses and with lower ALT concentrations and so may have the potential to modulate hepatic injury

Prediction of peak oxygen uptake in children using submaximal ratings of perceived exertion during treadmill exercise

Purpose: This study assessed the utility of the Children’s Effort Rating Table (CERT) and the Eston-Parfitt (EP) Scale in estimating peak oxygen uptake (V• O2peak) in children, during cardiopulmonary exercise testing (CPET) on a treadmill. Methods: Fifty healthy children (n=21 boys; 9.4 ± 0.9 y) completed a continuous, incremental protocol until the attainment of V• O2peak. Oxygen uptake (V• O2) was measured continuously, and Ratings of Perceived Exertion (RPE) were estimated at the end of each exercise stage using the CERT and the EP Scale. Ratings up to- and including RPE 5 and 7, from both the CERT (CERT 5, CERT 7) and EP Scale (EP 5, EP 7), were linearly regressed against the corresponding V• O2, to both maximal RPE (CERT 10, EP 10) and terminal RPE (CERT 9, EP 9). Results: There were no differences between measured- and predicted V• O2peak from CERT 5, CERT 7, EP 5 and EP 7 when extrapolated to either CERT 9 or EP 9 (P &gt; .05). Pearson’s correlations of r = 0.64-0.86 were observed between measured- and predicted V• O2peak, for all perceptual ranges investigated. However, only EP 7 provided a small difference when considering the Standard Error of Estimate, suggesting that the prediction of V• O2peak from EP 7 would be within 10% of measured V• O2peak. Conclusions: Although robust estimates of V• O2peak may be elicited using both the CERT and EP Scale during a single CPET with children, the most accurate estimates of V• O2peak occur when extrapolating from EP 7

Dissecting the Shared Genetic Architecture of Suicide Attempt, Psychiatric Disorders, and Known Risk Factors

Background Suicide is a leading cause of death worldwide, and nonfatal suicide attempts, which occur far more frequently, are a major source of disability and social and economic burden. Both have substantial genetic etiology, which is partially shared and partially distinct from that of related psychiatric disorders. Methods We conducted a genome-wide association study (GWAS) of 29,782 suicide attempt (SA) cases and 519,961 controls in the International Suicide Genetics Consortium (ISGC). The GWAS of SA was conditioned on psychiatric disorders using GWAS summary statistics via multitrait-based conditional and joint analysis, to remove genetic effects on SA mediated by psychiatric disorders. We investigated the shared and divergent genetic architectures of SA, psychiatric disorders, and other known risk factors. Results Two loci reached genome-wide significance for SA: the major histocompatibility complex and an intergenic locus on chromosome 7, the latter of which remained associated with SA after conditioning on psychiatric disorders and replicated in an independent cohort from the Million Veteran Program. This locus has been implicated in risk-taking behavior, smoking, and insomnia. SA showed strong genetic correlation with psychiatric disorders, particularly major depression, and also with smoking, pain, risk-taking behavior, sleep disturbances, lower educational attainment, reproductive traits, lower socioeconomic status, and poorer general health. After conditioning on psychiatric disorders, the genetic correlations between SA and psychiatric disorders decreased, whereas those with nonpsychiatric traits remained largely unchanged. Conclusions Our results identify a risk locus that contributes more strongly to SA than other phenotypes and suggest a shared underlying biology between SA and known risk factors that is not mediated by psychiatric disorders.Peer reviewe