Inflatable Re-entry Vehicle Experiment (IRVE-4) Overview

The suite of Inflatable Re-Entry Vehicle Experiments (IRVE) is designed to further our knowledge and understanding of Hypersonic Inflatable Aerodynamic Decelerators (HIADs). Before infusion into a future mission, three challenges need to be addressed: surviving the heat pulse during re-entry, demonstrating system performance at relevant scales, and demonstrating controllability in the atmosphere. IRVE-4 will contribute to a better understanding of controllability by characterizing how a HIAD responds to a set of controlled inputs. The ability to control a HIAD is vital for missions that are g-limited, require precision targeting and guidance for aerocapture or entry, descent, and landing. The IRVE-4 flight test will focus on taking a first look into controlling a HIAD. This paper will give an overview of the IRVE-4 mission including the control response portion of the flight test sequence, and will provide a review of the mission s development

The rhesus macaque is three times as diverse but more closely equivalent in damaging coding variation as compared to the human

Abstract Background As a model organism in biomedicine, the rhesus macaque (Macaca mulatta) is the most widely used nonhuman primate. Although a draft genome sequence was completed in 2007, there has been no systematic genome-wide comparison of genetic variation of this species to humans. Comparative analysis of functional and nonfunctional diversity in this highly abundant and adaptable non-human primate could inform its use as a model for human biology, and could reveal how variation in population history and size alters patterns and levels of sequence variation in primates. Results We sequenced the mRNA transcriptome and H3K4me3-marked DNA regions in hippocampus from 14 humans and 14 rhesus macaques. Using equivalent methodology and sampling spaces, we identified 462,802 macaque SNPs, most of which were novel and disproportionately located in the functionally important genomic regions we had targeted in the sequencing. At least one SNP was identified in each of 16,797 annotated macaque genes. Accuracy of macaque SNP identification was conservatively estimated to be >90%. Comparative analyses using SNPs equivalently identified in the two species revealed that rhesus macaque has approximately three times higher SNP density and average nucleotide diversity as compared to the human. Based on this level of diversity, the effective population size of the rhesus macaque is approximately 80,000 which contrasts with an effective population size of less than 10,000 for humans. Across five categories of genomic regions, intergenic regions had the highest SNP density and average nucleotide diversity and CDS (coding sequences) the lowest, in both humans and macaques. Although there are more coding SNPs (cSNPs) per individual in macaques than in humans, the ratio of dN/dS is significantly lower in the macaque. Furthermore, the number of damaging nonsynonymous cSNPs (have damaging effects on protein functions from PolyPhen-2 prediction) in the macaque is more closely equivalent to that of the human. Conclusions This large panel of newly identified macaque SNPs enriched for functionally significant regions considerably expands our knowledge of genetic variation in the rhesus macaque. Comparative analysis reveals that this widespread, highly adaptable species is approximately three times as diverse as the human but more closely equivalent in damaging variation.http://deepblue.lib.umich.edu/bitstream/2027.42/112453/1/12863_2011_Article_1004.pd

Genetic polymorphisms associated with the inflammatory response in bacterial meningitis

BACKGROUND Bacterial meningitis (BM) is an infectious disease that results in high mortality and morbidity. Despite efficacious antibiotic therapy, neurological sequelae are often observed in patients after disease. Currently, the main challenge in BM treatment is to develop adjuvant therapies that reduce the occurrence of sequelae. In recent papers published by our group, we described the associations between the single nucleotide polymorphisms (SNPs) AADAT +401C > T, APEX1 Asn148Glu, OGG1 Ser326Cys and PARP1 Val762Ala and BM. In this study, we analyzed the associations between the SNPs TNF -308G > A, TNF -857C > T, IL-8 -251A > T and BM and investigated gene-gene interactions, including the SNPs that we published previously. METHODS The study was conducted with 54 BM patients and 110 healthy volunteers (as the control group). The genotypes were investigated via primer-introduced restriction analysis-polymerase chain reaction (PIRA-PCR) or polymerase chain reaction-based restriction fragment length polymorphism (PCR-RFLP) analysis. Allelic and genotypic frequencies were also associated with cytokine and chemokine levels, as measured with the x-MAP method, and cell counts. We analyzed gene-gene interactions among SNPs using the generalized multifactor dimensionality reduction (GMDR) method. RESULTS We did not find significant association between the SNPs TNF -857C > T and IL-8 -251A > T and the disease. However, a higher frequency of the variant allele TNF -308A was observed in the control group, associated with changes in cytokine levels compared to individuals with wild type genotypes, suggesting a possible protective role. In addition, combined inter-gene interaction analysis indicated a significant association between certain genotypes and BM, mainly involving the alleles APEX1 148Glu, IL8 -251 T and AADAT +401 T. These genotypic combinations were shown to affect cyto/chemokine levels and cell counts in CSF samples from BM patients. CONCLUSIONS In conclusion, this study revealed a significant association between genetic variability and altered inflammatory responses, involving important pathways that are activated during BM. This knowledge may be useful for a better understanding of BM pathogenesis and the development of new therapeutic approaches

Adenine Nucleotide Pool Perturbation Is a Metabolic Trigger for AMP Deaminase Inhibitor-Based Herbicide Toxicity

AMP deaminase (AMPD) is essential for plant life, but the underlying mechanisms responsible for lethality caused by genetic and herbicide-based limitations in catalytic activity are unknown. Deaminoformycin (DF) is a synthetic modified nucleoside that is taken up by plant cells and 5′-phosphorylated into a potent transition state-type inhibitor of AMPD. Systemic exposure of Arabidopsis (Arabidopsis thaliana) seedlings to DF results in dose-dependent (150–450 nm) and time-dependent decreases in plant growth that are accompanied by 2- to 5-fold increases in the intracellular concentrations of all adenine ribonucleotides. No measurable rescue is observed with either hypoxanthine or xanthine (250 μm), indicating that downstream effects of AMPD inhibition, such as limitations in adenine-to-guanine nucleotide conversion or ureide synthesis, do not play important roles in DF toxicity. However, adenine (250 μm) acts synergistically with a nontoxic dose of DF (150 nm) to produce growth inhibition and adenine nucleotide pool expansion comparable to that observed with a toxic concentration of the herbicide alone (300 nm). Conversely, adenine alone (60–250 μm) has no measurable effects on these parameters. These combined results support the hypothesis that AMPD is the primary intracellular target for this class of herbicides and strongly suggest that adenine nucleotide accumulation is a metabolic trigger for DF toxicity. AMP binds to 14-3-3 proteins and can interrupt client interactions that appear to drive their distributions. Trichome subcellular localization of the phi isoform is disrupted within 8 to 24 h after seedlings are semisubmersed in a solution of DF (100 nm), further suggesting that disrupted 14-3-3 protein function plays a role in the associated herbicidal activity

Synthesis of 3-(carboxyarylalkyl)imidazo[2,1-f][1,2,4]triazines as potential inhibitors of AMP deaminase

C-Ribosyl 1,2,4-triazolo[1,2,4]triazines which are able to undergo covalent hydration are of interest as potential inhibitors of AMP deaminase. In a search for compounds with improved bioavailability we have synthesized compounds in which the sugar has been replaced by carboxyarylalkyl based ribose phosphate mimics. The target carboxyarylalkyl imidazotriazines 11 and 12 were synthesized using a linear seven step sequence starting from simple benzoate derivatives. Alternatively, the hydroxyethyl imidazotriazine 39 is available in five steps and this synthon was used to prepare the imidazotriazines 34 and 48 in a short convergent manner.</p