Future Challenges in Managing Human Health and Performance Risks for Space Flight

The global economy forces many nations to consider their national investments and make difficult decisions regarding their investment in future exploration. To enable safe, reliable, and productive human space exploration, we must pool global resources to understand and mitigate human health & performance risks prior to embarking on human exploration of deep space destinations. Consensus on the largest risks to humans during exploration is required to develop an integrated approach to mitigating risks. International collaboration in human space flight research will focus research on characterizing the effects of spaceflight on humans and the development of countermeasures or systems. Sharing existing data internationally will facilitate high quality research and sufficient power to make sound recommendations. Efficient utilization of ISS and unique ground-based analog facilities allows greater progress. Finally, a means to share results of human research in time to influence decisions for follow-on research, system design, new countermeasures and medical practices should be developed. Although formidable barriers to overcome, International working groups are working to define the risks, establish international research opportunities, share data among partners, share flight hardware and unique analog facilities, and establish forums for timely exchange of results. Representatives from the ISS partnership research and medical communities developed a list of the top ten human health & performance risks and their impact on exploration missions. They also drafted a multilateral data sharing plan to establish guidelines and principles for sharing human spaceflight data. Other working groups are also developing methods to promote international research solicitations. Collaborative use of analog facilities and shared development of space flight research and medical hardware continues. Establishing a forum for exchange of results between researchers, aerospace physicians and program managers takes careful consideration of researcher concerns and decision maker needs. Active participation by researchers in the development of this forum is essential, and the benefit can be tremendous. The ability to rapidly respond to research results without compromising publication rights and intellectual property will facilitate timely reduction in human health and performance risks in support of international exploration missions

Evaluation of phenoxybenzamine in the CFA model of pain following gene expression studies and connectivity mapping

<p>Abstract</p> <p>Background</p> <p>We have previously used the rat 4 day Complete Freund's Adjuvant (CFA) model to screen compounds with potential to reduce osteoarthritic pain. The aim of this study was to identify genes altered in this model of osteoarthritic pain and use this information to infer analgesic potential of compounds based on their own gene expression profiles using the Connectivity Map approach.</p> <p>Results</p> <p>Using microarrays, we identified differentially expressed genes in L4 and L5 dorsal root ganglia (DRG) from rats that had received intraplantar CFA for 4 days compared to matched, untreated control animals. Analysis of these data indicated that the two groups were distinguishable by differences in genes important in immune responses, nerve growth and regeneration. This list of differentially expressed genes defined a "CFA signature". We used the Connectivity Map approach to identify pharmacologic agents in the Broad Institute Build02 database that had gene expression signatures that were inversely related ('negatively connected') with our CFA signature. To test the predictive nature of the Connectivity Map methodology, we tested phenoxybenzamine (an alpha adrenergic receptor antagonist) - one of the most negatively connected compounds identified in this database - for analgesic activity in the CFA model. Our results indicate that at 10 mg/kg, phenoxybenzamine demonstrated analgesia comparable to that of Naproxen in this model.</p> <p>Conclusion</p> <p>Evaluation of phenoxybenzamine-induced analgesia in the current study lends support to the utility of the Connectivity Map approach for identifying compounds with analgesic properties in the CFA model.</p

Microbial liberation of N-methylserotonin from orange fiber in gnotobiotic mice and humans

Plant fibers in byproduct streams produced by non-harsh food processing methods represent biorepositories of diverse, naturally occurring, and physiologically active biomolecules. To demonstrate one approach for their characterization, mass spectrometry of intestinal contents from gnotobiotic mice, plus in vitro studies, revealed liberation of N-methylserotonin from orange fibers by human gut microbiota members including Bacteroides ovatus. Functional genomic analyses of B. ovatus strains grown under permissive and non-permissive N-methylserotonin mining conditions revealed polysaccharide utilization loci that target pectins whose expression correlate with strain-specific liberation of this compound. N-methylserotonin, orally administered to germ-free mice, reduced adiposity, altered liver glycogenesis, shortened gut transit time, and changed expression of genes that regulate circadian rhythm in the liver and colon. In human studies, dose-dependent, orange-fiber-specific fecal accumulation of N-methylserotonin positively correlated with levels of microbiome genes encoding enzymes that digest pectic glycans. Identifying this type of microbial mining activity has potential therapeutic implications

Albuminuria in a remote South Australian Aboriginal community: results of a community based screening program for renal disease

Australi

Mechanisms by which sialylated milk oligosaccharides impact bone biology in a gnotobiotic mouse model of infant undernutrition

Undernutrition in children is a pressing global health problem, manifested in part by impaired linear growth (stunting). Current nutritional interventions have been largely ineffective in overcoming stunting, emphasizing the need to obtain better understanding of its underlying causes. Treating Bangladeshi children with severe acute malnutrition with therapeutic foods reduced plasma levels of a biomarker of osteoclastic activity without affecting biomarkers of osteoblastic activity or improving their severe stunting. To characterize interactions among the gut microbiota, human milk oligosaccharides (HMOs), and osteoclast and osteoblast biology, young germ-free mice were colonized with cultured bacterial strains from a 6-mo-old stunted infant and fed a diet mimicking that consumed by the donor population. Adding purified bovine sialylated milk oligosaccharides (S-BMO) with structures similar to those in human milk to this diet increased femoral trabecular bone volume and cortical thickness, reduced osteoclasts and their bone marrow progenitors, and altered regulators of osteoclastogenesis and mediators of Th2 responses. Comparisons of germ-free and colonized mice revealed S-BMO-dependent and microbiota-dependent increases in cecal levels of succinate, increased numbers of small intestinal tuft cells, and evidence for activation of a succinate-induced tuft cell signaling pathway linked to Th2 immune responses. A prominent fucosylated HMO, 2'-fucosyllactose, failed to elicit these changes in bone biology, highlighting the structural specificity of the S-BMO effects. These results underscore the need to further characterize the balance between, and determinants of, osteoclastic and osteoblastic activity in stunted infants/children, and suggest that certain milk oligosaccharides may have therapeutic utility in this setting

A shared group of bacterial taxa in the duodenal microbiota of undernourished Pakistani children with environmental enteric dysfunction

Environmental enteric dysfunction (EED) is a subclinical syndrome of altered small intestinal function postulated to be an important contributor to childhood undernutrition. The role of small intestinal bacterial communities in the pathophysiology of EED is poorly defined due to a paucity of studies where there has been a direct collection of small intestinal samples from undernourished children. Sixty-three members of a Pakistani cohort identified as being acutely malnourished between 3 and 6 months of age and whose wasting (weight-for-lengt

Right Ventricular Tissue Doppler in Space Flight

Tissue Doppler (TD) registers movement of a given sample of cardiac tissue throughout the cardiac cycle. TD spectra of the right ventricle (RV) were obtained from a long-duration ISS crewmember as a portion of an ongoing experiment ("Braslet" test objective). To our knowledge, this is the first report of RV TD conducted in space flight, and the data represent reproducibility and fidelity of this application in space and serve as the first "space normal" data set. Methods RV TD was performed by astronaut scientists remotely guided by an ultrasound expert from Mission Control Center, Houston, TX. In four of the subjects, RV TD was acquired from the free wall near the tricuspid annulus in two separate sessions 4 to 7 days apart. A fifth subject had only one session. All digital DICOM frames were exported for off-line analysis. Systolic (S ), early diastolic (E ) and late diastolic (A ) velocities were measured. RV Tei-index was calculated using diastolic and systolic time intervals as a combined measure of myocardial performance. Results and Discussion The mean values from the first 4 subjects (8 sessions) were used as the on-orbit reference data, and subject 5 was considered as a hypothetical patient for comparison (see Table). The greatest difference was in the early diastolic A (31 %) yet the standard deviation (a) for A amongst the reference subjects was 2.25 (mean = 16.02). Of interest is the Tei index, a simple and feasible indicator of overall ventricular function; it was similar amongst all the subjects. The late diastolic A seems to compensate for the variance in E . Normal Tei index for the RV is < 0.3, yet our data show all but one subject consistently above this level, notwithstanding their nominal responses to daily exercise in microgravity. These data remind us that the physiology of RV preload in altered gravity environments is still not completely understood

Alkynyl Benzoxazines and Dihydroquinazolines as Cysteine Targeting Covalent Warheads and Their Application in Identification of Selective Irreversible Kinase Inhibitors.

With a resurgence in interest in covalent drugs, there is a need to identify new moieties capable of cysteine bond formation that are differentiated from commonly employed systems such as acrylamide. Herein, we report on the discovery of new alkynyl benzoxazine and dihydroquinazoline moieties capable of covalent reaction with cysteine. Their utility as alternative electrophilic warheads for chemical biological probes and drug molecules is demonstrated through site-selective protein modification and incorporation into kinase drug scaffolds. A potent covalent inhibitor of JAK3 kinase was identified with superior selectivity across the kinome and improvements in in vitro pharmacokinetic profile relative to the related acrylamide-based inhibitor. In addition, the use of a novel heterocycle as a cysteine reactive warhead is employed to target Cys788 in c-KIT, where acrylamide has previously failed to form covalent interactions. These new reactive and selective heterocyclic warheads supplement the current repertoire for cysteine covalent modification while avoiding some of the limitations generally associated with established moieties