Cryogenic Orbital Nitrogen Experiment (CONE): Phase A/B design study

Subcritical cryogenic fluid management (CFM) has long been recognized as an enabling technology for future space missions. Subcritical liquid storage and supply are two of the five CFM technology areas that need to be studied in the low gravity on-orbit environment. The Cryogenic Orbital Nitrogen Experiment (CONE) is a LN2 cryogenic storage and supply system demonstration placed in orbit by the National Space Transportation System (NSTS) Orbiter and operated as an in-bay payload. In-space demonstration of CFM using LN2 with a few well defined areas of focus would provide the confidence level required to implement subcritical cryogen use and is the first step towards the more far reaching issue of cryogen transfer and tankage resupply. A conceptual approach for CONE was developed and an overview of the program is described including the following: (1) a description of the background and scope of the technology objectives; (2) a description of the payload design and operation; and (3) the justification for CONE relating to potential near term benefits and risk mitigation for future systems. Data and criteria is provided to correlate in-space performance with analytical and numerical modeling of CFM systems

Cryogenic On-Orbit Liquid Depot Storage, Acquisition, and Transfer satellite (COLD-SAT) feasibility study

The Cryogenic On-Orbit Liquid Depot Storage, Acquisition, and Transfer Satellite (COLD-SAT) is an experimental spacecraft launched from an expendable launch vehicle which is designed to investigate the systems and technologies required for efficient, effective, and reliable management of cryogenic fluid in the reduced gravity space environment. The COLD-SAT program will provide the necessary data base and provide low-g proving of fluid and thermal models of cryogenic storage, transfer, and resupply concepts and processes. A conceptual approach was developed and an overview of the results of the 24 month COLD-SAT Phase A feasibility is described which includes: (1) a definition of the technology needs and the accompanying experimental 3 month baseline mission; (2) a description of the experiment subsystem, major features and rationale for satisfaction of primary and secondary experiment requirements using liquid hydrogen as the test fluid; and (3) a presentation of the conceptual design of the COLD-SAT spacecraft subsystems which support the on-orbit experiment with emphasis on areas of greatest challenge

Reoperation for coarctation of the aorta

Between 1957 and 1980 reoperation for coarctation of the aorta was performed in 21 patients at one institution for an overall incidence rate of 7.9 percent. The incidence rate of reoperation was 38 percent for patients younger than age 3 years and 1.5 percent for patients 3 years or older at initial repair. Before reoperation 14 of the 21 patients were symptomatic, 19 had systolic hypertension of the upper limbs and 20 had a documented coarctation pressure gradient at rest (mean 42.4 mm Hg). Surgical techniques used at reoperation were patch aortoplasty in 12 patients, graft interposition in 4, end to end anastomosis in 3 and end to side left subclavian to descending aorta bypass graft in 2. There was one surgical death. The 20 survivors have been followed up a mean of 4.3 years. There has been significant symptomatic improvement (p In conclusion, the incidence of reoperation is significantly increased in patients who are younger than age 3 years at initial coarctation repair. Reoperation is a safe and effective procedure. It has a low mortality rate (4.8 percent), relieves symptoms and decreases hypertension and the coarctation pressure gradient. Patch aortoplasty appears to be the operative procedure of choice. Moderate to severe hemodynamic abnormalities may persist during exercise after reoperation for coarctation of the aorta.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/24189/1/0000448.pd

An Artemisinin-Derived Dimer Has Highly Potent Anti-Cytomegalovirus (CMV) and Anti-Cancer Activities

We recently reported that two artemisinin-derived dimers (dimer primary alcohol 606 and dimer sulfone 4-carbamate 832-4) are significantly more potent in inhibiting human cytomegalovirus (CMV) replication than artemisinin-derived monomers. In our continued evaluation of the activities of artemisinins in CMV inhibition, twelve artemisinin-derived dimers and five artemisinin-derived monomers were used. Dimers as a group were found to be potent inhibitors of CMV replication. Comparison of CMV inhibition and the slope parameter of dimers and monomers suggest that dimers are distinct in their anti-CMV activities. A deoxy dimer (574), lacking the endoperoxide bridge, did not have any effect on CMV replication, suggesting a role for the endoperoxide bridge in CMV inhibition. Differences in anti-CMV activity were observed among three structural analogs of dimer sulfone 4-carbamate 832-4 indicating that the exact placement and oxidation state of the sulfur atom may contribute to its anti-CMV activity. Of all tested dimers, artemisinin-derived diphenyl phosphate dimer 838 proved to be the most potent inhibitor of CMV replication, with a selectivity index of approximately 1500, compared to our previously reported dimer sulfone 4-carbamate 832-4 with a selectivity index of about 900. Diphenyl phosphate dimer 838 was highly active against a Ganciclovir-resistant CMV strain and was also the most active dimer in inhibition of cancer cell growth. Thus, diphenyl phosphate dimer 838 may represent a lead for development of a highly potent and safe anti-CMV compound

The Association of Depressive Symptoms with Inflammatory Factors and Adipokines in Middle-Aged and Older Chinese

Studies in Western populations find that depression is associated with inflammation and obesity. The present study aimed to evaluate the relation of depressive symptoms with inflammatory factors and adipose-derived adipokines in middle-aged and older Chinese.Data were from 3289 community residents aged 50-70 from Beijing and Shanghai who participated in the Nutrition and Health of Aging Population in China project. Depressive symptoms were defined as a Center for Epidemiological Studies of Depression Scale (CES-D) score of 16 or higher. Plasma concentrations of C-reactive protein (CRP), interleukin-6 (IL-6), adiponectin, resistin, plasminogen activator inhibitor-1 (PAI-1) and retinol binding protein 4 (RBP4) were measured. Of the 3289 participants, 312 (9.5%) suffered from current depressive symptoms. IL-6 level was higher in participants with depressive symptoms compared to their counterparts in the crude analyses (1.17 vs. 1.05 pg/mL, p = 0.023) and this association lost statistical significance after multiple adjustments (1.13 vs. 1.10 pg/mL, p = 0.520). Depressive symptoms were not associated with increased mean levels of any other inflammatory factors or adipokines in the unadjusted or adjusted analyses.We found no evidence that depressive symptoms were associated with inflammatory factors and adipokines in the middle-aged and older Chinese populations. Prospective studies and studies in clinically diagnosed patients are needed to confirm our results and clarify the relation of depression with inflammatory factors and adipokines

The complex genetics of gait speed:Genome-wide meta-analysis approach

Emerging evidence suggests that the basis for variation in late-life mobility is attributable, in part, to genetic factors, which may become increasingly important with age. Our objective was to systematically assess the contribution of genetic variation to gait speed in older individuals. We conducted a meta-analysis of gait speed GWASs in 31,478 older adults from 17 cohorts of the CHARGE consortium, and validated our results in 2,588 older adults from 4 independent studies. We followed our initial discoveries with network and eQTL analysis of candidate signals in tissues. The meta-analysis resulted in a list of 536 suggestive genome wide significant SNPs in or near 69 genes. Further interrogation with Pathway Analysis placed gait speed as a polygenic complex trait in five major networks. Subsequent eQTL analysis revealed several SNPs significantly associated with the expression of PRSS16, WDSUB1 and PTPRT, which in addition to the meta-analysis and pathway suggested that genetic effects on gait speed may occur through synaptic function and neuronal development pathways. No genome-wide significant signals for gait speed were identified from this moderately large sample of older adults, suggesting that more refined physical function phenotypes will be needed to identify the genetic basis of gait speed in aging

Genome-wide association study in 79,366 European-ancestry individuals informs the genetic architecture of 25-hydroxyvitamin D levels

Vitamin D is a steroid hormone precursor that is associated with a range of human traits and diseases. Previous GWAS of serum 25-hydroxyvitamin D concentrations have identified four genome-wide significant loci (GC, NADSYN1/DHCR7, CYP2R1, CYP24A1). In this study, we expand the previous SUNLIGHT Consortium GWAS discovery sample size from 16,125 to 79,366 (all European descent). This larger GWAS yields two additional loci harboring genome-wide significant variants (P = 4.7x10(-9) at rs8018720 in SEC23A, and P = 1.9x10(-14) at rs10745742 in AMDHD1). The overall estimate of heritability of 25-hydroxyvitamin D serum concentrations attributable to GWAS common SNPs is 7.5%, with statistically significant loci explaining 38% of this total. Further investigation identifies signal enrichment in immune and hematopoietic tissues, and clustering with autoimmune diseases in cell-type-specific analysis. Larger studies are required to identify additional common SNPs, and to explore the role of rare or structural variants and gene-gene interactions in the heritability of circulating 25-hydroxyvitamin D levels.Peer reviewe

Genome-wide interaction study of a proxy for stress-sensitivity and its prediction of major depressive disorder

Individual response to stress is correlated with neuroticism and is an important predictor of both neuroticism and the onset of major depressive disorder (MDD). Identification of the genetics underpinning individual differences in response to negative events (stress-sensitivity) may improve our understanding of the molecular pathways involved, and its association with stress-related illnesses. We sought to generate a proxy for stress-sensitivity through modelling the interaction between SNP allele and MDD status on neuroticism score in order to identify genetic variants that contribute to the higher neuroticism seen in individuals with a lifetime diagnosis of depression compared to unaffected individuals. Meta-analysis of genome-wide interaction studies (GWIS) in UK Biobank (N = 23,092) and Generation Scotland: Scottish Family Health Study (N = 7,155) identified no genome-wide significance SNP interactions. However, gene-based tests identified a genome-wide significant gene, ZNF366, a negative regulator of glucocorticoid receptor function implicated in alcohol dependence (p = 1.48x10-7; Bonferroni-corrected significance threshold p < 2.79x10-6). Using summary statistics from the stress-sensitivity term of the GWIS, SNP heritability for stress-sensitivity was estimated at 5.0%. In models fitting polygenic risk scores of both MDD and neuroticism derived from independent GWAS, we show that polygenic risk scores derived from the UK Biobank stress-sensitivity GWIS significantly improved the prediction of MDD in Generation Scotland. This study may improve interpretation of larger genome-wide association studies of MDD and other stress-related illnesses, and the understanding of the etiological mechanisms underpinning stress-sensitivity