A Proposed Strategy for the U.S. to Develop and Maintain a Mainstream Capability Suite ("Warehouse") for Automated/Autonomous Rendezvous and Docking in Low Earth Orbit and Beyond

The ability of space assets to rendezvous and dock/capture/berth is a fundamental enabler for numerous classes of NASA fs missions, and is therefore an essential capability for the future of NASA. Mission classes include: ISS crew rotation, crewed exploration beyond low-Earth-orbit (LEO), on-orbit assembly, ISS cargo supply, crewed satellite servicing, robotic satellite servicing / debris mitigation, robotic sample return, and robotic small body (e.g. near-Earth object, NEO) proximity operations. For a variety of reasons to be described, NASA programs requiring Automated/Autonomous Rendezvous and Docking/Capture/Berthing (AR&D) capabilities are currently spending an order-of-magnitude more than necessary and taking twice as long as necessary to achieve their AR&D capability, "reinventing the wheel" for each program, and have fallen behind all of our foreign counterparts in AR&D technology (especially autonomy) in the process. To ensure future missions' reliability and crew safety (when applicable), to achieve the noted cost and schedule savings by eliminate costs of continually "reinventing the wheel ", the NASA AR&D Community of Practice (CoP) recommends NASA develop an AR&D Warehouse, detailed herein, which does not exist today. The term "warehouse" is used herein to refer to a toolbox or capability suite that has pre-integrated selectable supply-chain hardware and reusable software components that are considered ready-to-fly, low-risk, reliable, versatile, scalable, cost-effective, architecture and destination independent, that can be confidently utilized operationally on human spaceflight and robotic vehicles over a variety of mission classes and design reference missions, especially beyond LEO. The CoP also believes that it is imperative that NASA coordinate and integrate all current and proposed technology development activities into a cohesive cross-Agency strategy to produce and utilize this AR&D warehouse. An initial estimate indicates that if NASA strategically coordinates the development of a robust AR&D capability across the Agency, the cost of implementing AR&D on a spacecraft could be reduced from roughly $70M per mission to as low as$7M per mission, and the associated development time could be reduced from 4 years to 2 years, after the warehouse is completely developed. Table 1 shows the clear long-term benefits to the Agency in term of costs and schedules for various missions. (The methods used to arrive at the Table 1 numbers is presented in Appendices A and B.

A prognostic model for critically ill children in locations with emerging critical care capacity

Objectives: To develop a clinical prediction model to risk stratify children admitted to PICUs in locations with limited resources, and compare performance of the model to nine existing pediatric severity scores. Design: Retrospective, single-center, cohort study. Setting: PICU of a pediatric hospital in Siem Reap, northern Cambodia. Patients: Children between 28 days and 16 years old admitted nonelectively to the PICU. Interventions: None. Measurements and Main Results: Clinical and laboratory data recorded at the time of PICU admission were collected. The primary outcome was death during PICU admission. One thousand five hundred fifty consecutive nonelective PICU admissions were included, of which 97 died (6.3%). Most existing severity scores achieved comparable discrimination (area under the receiver operating characteristic curves [AUCs], 0.71–0.76) but only three scores demonstrated moderate diagnostic utility for triaging admissions into high- and low-risk groups (positive likelihood ratios [PLRs], 2.65–2.97 and negative likelihood ratios [NLRs], 0.40–0.46). The newly derived model outperformed all existing severity scores (AUC, 0.84; 95% CI, 0.80–0.88; p < 0.001). Using one particular threshold, the model classified 13.0% of admissions as high risk, among which probability of mortality was almost ten-fold greater than admissions triaged as low-risk (PLR, 5.75; 95% CI, 4.57–7.23 and NLR, 0.47; 95% CI, 0.37–0.59). Decision curve analyses indicated that the model would be superior to all existing severity scores and could provide utility across the range of clinically plausible decision thresholds. Conclusions: Existing pediatric severity scores have limited potential as risk stratification tools in resource-constrained PICUs. If validated, our prediction model would be a readily implementable mechanism to support triage of critically ill children at admission to PICU and could provide value across a variety of contexts where resource prioritization is important

Improved Hepatic Function in the 24-Hour Preserved Rat Liver With UW-Lactobionate Solution and SRI 63-441

The present study compares rat liver preservation for 9, 12, and 24 h in the standard Eurocollins solution with preservation for the same time periods in the new UW-Iactobionate solution. Pharmacologic manipulation with a potent plateletactivating factor antagonist, SRI 63-441, was also evaluated. After cold storage in each of the test solutions, the livers underwent 90 min of warm, oxygenated, sanguinous perfusion. A significant increase in liver weight was noted in Eurocollinsstored versus UW-Iactobionate-stored livers. After 90 min of perfusion, livers preserved in UW-lactobionate produced significantly more bile and liberated significantly less glucose and transaminases when compared with Eurocollins-stored livers. Significant augmentation of bile production was observed when donor animals were pretreated with SRI 63-441 and the livers were then stored in UW-lactobionate for 24 h. Eurocollins-stored livers demonstrated increased hepatocyte vacuolization and endothelial disruption when compared with UW-lactobionate-stored livers after 12 and 24 h of preservation. This study demonstrates the superiority of UW-lactobionate solution in liver preservation and suggests that SRI 63-441 may be beneficial in the further reduction of cold ischemic injury. © 1988, American Gastroenterological Association. All rights reserved

Mutation analysis of "Endoglin" and "Activin receptor-like kinase" genes in German patients with hereditary hemorrhagic telangiectasia and the value of rapid genotyping using an allele-specific PCR-technique

<p>Abstract</p> <p>Background</p> <p>Hereditary hemorrhagic telangiectasia (HHT), also known as Rendu-Osler-Weber syndrome, is an autosomal dominant disorder which is clinically characterised by recurrent epistaxis, mucocutaneous telangiectasia and visceral arteriovenous malformations. Genetic linkage studies identified two genes primarily related to HHT: endoglin (<it>ENG</it>) on chromosome 9q33-34 and activin receptor-like kinase1 (<it>ACVRL1</it>) on chromosome 12q13. We have screened a total of 41 unselected German patients with the suspected diagnosis of HHT. Mutation analysis for the <it>ENG </it>and <it>ACVRL1 </it>genes in all patients was performed by PCR amplification. Sequences were then compared to the HHT database <url>http://www.hhtmutation.org</url> sequences of the <it>ENG </it>mRNA (accession no. BC014271.2) and the <it>ACVRL1 </it>mRNA (accession no. NM000020.1).</p> <p>Results</p> <p>We identified 15 different mutations in 18 cases by direct sequencing. Among these mutations, one novel <it>ENG </it>mutation could be detected which has not yet been described in the literature before. The genotype-phenotype correlation was consistent with a higher frequency of pulmonary arteriovenous malformations in patients with <it>ENG </it>mutations than in patients with <it>ACVRL1 </it>mutations in our collective.</p> <p>Conclusion</p> <p>For rapid genotyping of mutations and SNPs (single nucleotide polymorphisms) in <it>ENG </it>and <it>ACVRL1</it>, allele-specific PCR methods with sequence-specific primers (PCR-SSP) were established and their value analysed.</p

M1 muscarinic allosteric modulators slow prion neurodegeneration and restore memory loss.

The current frontline symptomatic treatment for Alzheimer's disease (AD) is whole-body upregulation of cholinergic transmission via inhibition of acetylcholinesterase. This approach leads to profound dose-related adverse effects. An alternative strategy is to selectively target muscarinic acetylcholine receptors, particularly the M1 muscarinic acetylcholine receptor (M1 mAChR), which was previously shown to have procognitive activity. However, developing M1 mAChR-selective orthosteric ligands has proven challenging. Here, we have shown that mouse prion disease shows many of the hallmarks of human AD, including progressive terminal neurodegeneration and memory deficits due to a disruption of hippocampal cholinergic innervation. The fact that we also show that muscarinic signaling is maintained in both AD and mouse prion disease points to the latter as an excellent model for testing the efficacy of muscarinic pharmacological entities. The memory deficits we observed in mouse prion disease were completely restored by treatment with benzyl quinolone carboxylic acid (BQCA) and benzoquinazoline-12 (BQZ-12), two highly selective positive allosteric modulators (PAMs) of M1 mAChRs. Furthermore, prolonged exposure to BQCA markedly extended the lifespan of diseased mice. Thus, enhancing hippocampal muscarinic signaling using M1 mAChR PAMs restored memory loss and slowed the progression of mouse prion disease, indicating that this ligand type may have clinical benefit in diseases showing defective cholinergic transmission, such as AD

The genetic architecture of the human cerebral cortex

The cerebral cortex underlies our complex cognitive capabilities, yet little is known about the specific genetic loci that influence human cortical structure. To identify genetic variants that affect cortical structure, we conducted a genome-wide association meta-analysis of brain magnetic resonance imaging data from 51,665 individuals. We analyzed the surface area and average thickness of the whole cortex and 34 regions with known functional specializations. We identified 199 significant loci and found significant enrichment for loci influencing total surface area within regulatory elements that are active during prenatal cortical development, supporting the radial unit hypothesis. Loci that affect regional surface area cluster near genes in Wnt signaling pathways, which influence progenitor expansion and areal identity. Variation in cortical structure is genetically correlated with cognitive function, Parkinson's disease, insomnia, depression, neuroticism, and attention deficit hyperactivity disorder

The genetic architecture of the human cerebral cortex

The cerebral cortex underlies our complex cognitive capabilities, yet little is known about the specific genetic loci that influence human cortical structure. To identify genetic variants that affect cortical structure, we conducted a genome-wide association meta-analysis of brain magnetic resonance imaging data from 51,665 individuals. We analyzed the surface area and average thickness of the whole cortex and 34 regions with known functional specializations. We identified 199 significant loci and found significant enrichment for loci influencing total surface area within regulatory elements that are active during prenatal cortical development, supporting the radial unit hypothesis. Loci that affect regional surface area cluster near genes in Wnt signaling pathways, which influence progenitor expansion and areal identity. Variation in cortical structure is genetically correlated with cognitive function, Parkinson's disease, insomnia, depression, neuroticism, and attention deficit hyperactivity disorder

Against the Flow: The Colonisation of the Lesotho Highlands by Freshwater Limpets

To date, limited research has taken place on the evolutionary history of biodiversity in the high-altitude zones of southern Africa, particularly the Lesotho Highlands. The few studies that do exist point to similar high-altitude zones being either prolific museums (i.e., refugia and cradles) for cold-evolved species or sinks for temperate species post the Last Glacial Maximum, yet the role this zone has played for freshwater biodiversity is unknown for almost all freshwater taxa. In this study, we address this lack of knowledge by looking at the phylogeography of the freshwater limpet genus, Burnupia, across its southern and eastern African range, but particularly focusing on the Lesotho Highlands. We used COI data to reconstruct the evolutionary history of the genus, quantify phylogenetic species diversity, test both isolation by distance (IBD) and by elevation (IBE) and model ancestral area estimation “in” and “out” of the Highlands to determine: 1) The diversity and endemicity of Burnupia spp. in the Highlands in comparison to the broader southern African region and 2) when did the colonisation of the Highlands happen. Our results showed that at least two of the nine southern African phylogenetic species delimited occur in the Highlands (which appears average for the geographical extent of this area in comparison to the broader southern African region) and that the genus has been present in the Lesotho Highlands for somewhere between 1.38–0.23 million years. However, we found the endemicity of at least one of the two Highland species, supported by weak but significant IBD and IBE in Burnupia. Therefore we favour the notion that the Highlands are likely an important haven for cold-evolved species. As our results also generated a lot of data useful for Burnupia systematics, we discuss some taxonomic implications of our findings

Leg Edema Quantification for Heart Failure Patients via 3D Imaging

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