Thermal integration of electric power and life support systems for manned space stations

Thermal integration of electric power and life support systems for manned space station

Study of onboard expert systems to augment space shuttle and space station autonomy

The feasibility of onboard crew activity planning was examined. The use of expert systems technology to aid crewmembers in locating stowed equipment was also investigated. The crew activity planning problem, along with a summary of past and current research efforts, was discussed in detail. The requirements and specifications used to develop the crew activity planning system was also defined. The guidelines used to create, develop, and operate the MFIVE Crew Scheduler and Logistics Clerk were discussed. Also discussed is the mathematical algorithm, used by the MFIVE Scheduler, which was developed to aid in optimal crew activity planning

On the K-Winners-Take-All Network

We present and rigorously analyze a generalization of the Winner-Take-All Network: the K-Winners-Take-All Network. This network identifies the K largest of a set of N real numbers. The network model used is the continuous Hopfield model

Current perspectives in fragment based lead discovery (FBLD)

It is over 20 years since the first fragment-based discovery projects were disclosed. The methods are now mature for most ‘conventional’ targets in drug discovery such as enzymes (kinases and proteases) but there has also been growing success on more challenging targets, such as disruption of protein–protein interactions. The main application is to identify tractable chemical startpoints that non-covalently modulate the activity of a biological molecule. In this essay, we overview current practice in the methods and discuss how they have had an impact in lead discovery – generating a large number of fragment-derived compounds that are in clinical trials and two medicines treating patients. In addition, we discuss some of the more recent applications of the methods in chemical biology – providing chemical tools to investigate biological molecules, mechanisms and systems

Expedient synthesis of an atypical oxazolidinone compound library

In order to address the current downturn in the drug discovery pipeline, initiatives are being undertaken to synthesise screening libraries of sp3-rich, low molecular weight compounds. As part of the European Lead Factory initiative, the synthesis and derivatisation of a simple hexahydrooxazolo[5,4-c]pyridin-2(1H)-one bicyclic carbamate has been achieved. The synthetic route employed involved a telescoped hetero-Diels-Alder/[2,3]-sigmatropic rearrangement/cyclisation sequence to deliver the desired core scaffold containing two points for further diversification. When applied, this synthesis was found to be robust and scalable which allowed the production of a 155 compound library

Lack of effect of high-protein vs. high-carbohydrate meal intake on stress-related mood and eating behavior

<p>Abstract</p> <p>Background</p> <p>Consumption of meals with different macronutrients, especially high in carbohydrates, may influence stress-related eating behavior. We aimed to investigate whether consumption of high-protein vs. high-carbohydrate meals influences stress-related mood, food reward, i.e. 'liking' and 'wanting', and post-meal energy intake.</p> <p>Methods</p> <p>Participants (n = 38, 19m/19f, age = 25 ± 9 y, BMI = 25.0 ± 3.3 kg/m²) came to the university four times, fasted, once for a stress session receiving a high-protein meal, once for a rest session receiving a high-protein meal, once for a stress session receiving a high-carbohydrate meal and once for a rest session receiving a high-carbohydrate meal (randomized cross-over design). The high-protein and high-carbohydrate test meals (energy percentage protein/carbohydrate/fat 65/5/30 vs. 6/64/30) matched for energy density (4 kJ/g) and daily energy requirements (30%). Stress was induced using an ego-threatening test. Pre- and post-meal 'liking' and 'wanting' (for bread, filling, drinks, dessert, snacks, stationery (non-food alternative as control)) was measured by means of a computer test. Following the post-meal 'wanting' measurement, participants received and consumed their wanted food items (post-meal energy intake). Appetite profile (visual analogue scales), mood state (Profile Of Mood State and State Trait Anxiety Inventory questionnaires), and post-meal energy intake were measured.</p> <p>Results</p> <p>Participants showed increased feelings of depression and anxiety during stress (P < 0.01). Consumption of the test meal decreased hunger, increased satiety, decreased 'liking' of bread and filling, and increased 'liking' of placebo and drinks (P < 0.0001). Food 'wanting' decreased pre- to post-meal (P < 0.0001). The high-protein vs. high-carbohydrate test meal induced lower subsequent 'wanting' and energy intake (1.7 ± 0.3 MJ vs. 2.5 ± 0.4 MJ) only in individuals characterized by disinhibited eating behavior (factor 2 Three Factor Eating Questionnaire, n = 16), during rest (P ≤ 0.01). This reduction in 'wanting' and energy intake following the high-protein meal disappeared during stress.</p> <p>Conclusions</p> <p>Consumption of a high-protein vs. high-carbohydrate meal appears to have limited impact on stress-related eating behavior. Only participants with high disinhibition showed decreased subsequent 'wanting' and energy intake during rest; this effect disappeared under stress. Acute stress overruled effects of consumption of high-protein foods.</p> <p>Trial registration</p> <p>The study was registered in the Dutch Trial Register (<a href="http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=2040">NTR1904</a>). The protocol described here in this study deviates from the trial protocol approved by the Medical Ethical Committee of the Maastricht University as it comprises only a part of the approved trial protocol.</p

Discovery of High-Affinity Protein Binding Ligands – Backwards

BACKGROUND: There is a pressing need for high-affinity protein binding ligands for all proteins in the human and other proteomes. Numerous groups are working to develop protein binding ligands but most approaches develop ligands using the same strategy in which a large library of structured ligands is screened against a protein target to identify a high-affinity ligand for the target. While this methodology generates high-affinity ligands for the target, it is generally an iterative process that can be difficult to adapt for the generation of ligands for large numbers of proteins. METHODOLOGY/PRINCIPAL FINDINGS: We have developed a class of peptide-based protein ligands, called synbodies, which allow this process to be run backwards--i.e. make a synbody and then screen it against a library of proteins to discover the target. By screening a synbody against an array of 8,000 human proteins, we can identify which protein in the library binds the synbody with high affinity. We used this method to develop a high-affinity synbody that specifically binds AKT1 with a K(d)<5 nM. It was found that the peptides that compose the synbody bind AKT1 with low micromolar affinity, implying that the affinity and specificity is a product of the bivalent interaction of the synbody with AKT1. We developed a synbody for another protein, ABL1 using the same method. CONCLUSIONS/SIGNIFICANCE: This method delivered a high-affinity ligand for a target protein in a single discovery step. This is in contrast to other techniques that require subsequent rounds of mutational improvement to yield nanomolar ligands. As this technique is easily scalable, we believe that it could be possible to develop ligands to all the proteins in any proteome using this approach

Memantine reduces consumption of highly palatable food in a rat model of binge eating

Excessive consumption of highly palatable food has been linked to the development of eating disorders and obesity, and can be modeled in non-food-deprived rats by offering them a limited (2-h daily) access to an optional dietary fat. Since the glutamatergic system has recently emerged as a viable target for binge-eating medication development, we compared the effects of subchronic treatment with glutamatergic receptor antagonists to the effects of a reference appetite-suppressing agent sibutramine on highly palatable food (lard) and normal chow intake. In three separate experiments, the consumption of a standard laboratory chow and lard were measured during 12 days of medication treatment and for 6 days afterwards. Generalized estimating equations analysis demonstrated that sibutramine (7.5 mg/kg, PO) significantly decreased lard consumption, with a concurrent increase in chow consumption. Sibutramine effects disappeared after treatment discontinuation. The NMDA receptor antagonist memantine (5 mg/kg, IP) significantly decreased lard consumption and increased chow consumption, comparable to effects of sibutramine; however, memantine’s effects persisted after treatment discontinuation. The effects of the mGluR5 antagonist MTEP (7.5 mg/kg, IP) on food consumption were in the same direction as seen with memantine, but the observed differences were not significant. In an additional control experiment, sibutramine and memantine reduced unlimited (24 h) chow intake during the treatment phase. Present results provide evidence that glutamatergic neurotransmission might be involved in the regulation of excessive consumption of highly palatable foods, and suggest that NMDA receptor may be an attractive target for developing obesity and disordered eating pharmacotherapies

The Overlap of Small Molecule and Protein Binding Sites within Families of Protein Structures

Protein–protein interactions are challenging targets for modulation by small molecules. Here, we propose an approach that harnesses the increasing structural coverage of protein complexes to identify small molecules that may target protein interactions. Specifically, we identify ligand and protein binding sites that overlap upon alignment of homologous proteins. Of the 2,619 protein structure families observed to bind proteins, 1,028 also bind small molecules (250–1000 Da), and 197 exhibit a statistically significant (p<0.01) overlap between ligand and protein binding positions. These “bi-functional positions”, which bind both ligands and proteins, are particularly enriched in tyrosine and tryptophan residues, similar to “energetic hotspots” described previously, and are significantly less conserved than mono-functional and solvent exposed positions. Homology transfer identifies ligands whose binding sites overlap at least 20% of the protein interface for 35% of domain–domain and 45% of domain–peptide mediated interactions. The analysis recovered known small-molecule modulators of protein interactions as well as predicted new interaction targets based on the sequence similarity of ligand binding sites. We illustrate the predictive utility of the method by suggesting structural mechanisms for the effects of sanglifehrin A on HIV virion production, bepridil on the cellular entry of anthrax edema factor, and fusicoccin on vertebrate developmental pathways. The results, available at http://pibase.janelia.org, represent a comprehensive collection of structurally characterized modulators of protein interactions, and suggest that homologous structures are a useful resource for the rational design of interaction modulators

Neural Correlates of Appetite and Hunger-Related Evaluative Judgments

How much we desire a meal depends on both the constituent foods and how hungry we are, though not every meal becomes more desirable with increasing hunger. The brain therefore needs to be able to integrate hunger and meal properties to compute the correct incentive value of a meal. The present study investigated the functional role of the amygdala and the orbitofrontal cortex in mediating hunger and dish attractiveness. Furthermore, it explored neural responses to dish descriptions particularly susceptible to value-increase following fasting. We instructed participants to rate how much they wanted food menu items while they were either hungry or sated, and compared the rating differences in these states. Our results point to the representation of food value in the amygdala, and to an integration of attractiveness with hunger level in the orbitofrontal cortex. Dishes particularly desirable during hunger activated the thalamus and the insula. Our results specify the functions of evaluative structures in the context of food attractiveness, and point to a complex neural representation of dish qualities which contribute to state-dependent value