Synthesis and Evaluation of Mixed Efficacy Mu Opioid Receptor (MOR), Delta Opioid Receptor (DOR) Peptidomimetic Ligands.

Reported here is a structure activity relationship (SAR) study on a series of mixed efficacy mu opioid receptor (MOR) agonist/delta opioid receptor (DOR) antagonist ligands featuring a tetrahydroquinoline (THQ) scaffold. A diverse set of substitutions at the 6-position of the THQ core has revealed a number of important trends. Attachment of this pendant at a basic nitrogen resulted in a number of analogues that showed superior binding affinity and potency at MOR, with improved binding affinity at the kappa opioid receptor (KOR). In particular, N-acetylated, tetrahydroisoquinoline analogue 102 showed equal, subnanomolar binding affinity for MOR, DOR and KOR, with a low nanomolar EC50 at MOR and no stimulation at DOR. 102, in addition to isoindoline analogue 86, were also shown to produce dose dependent antinociception in the mouse warm water tail withdrawal (WWTW) assay, with both compounds having a total duration of action comparable to morphine, an improvement on lead peptidomimetic 1. Substitution of the THQ aniline with a variety of heteroatoms was found to maintain subnanomolar MOR binding affinity and high efficacy, although only thiochroman analogue 214 was found to produce a dose dependent antinociceptive effect in the WWTW assay, with a duration of action comparable to 86 and 102. Expansion or contraction of the THQ ring system was detrimental to the overall desired MOR agonist/DOR antagonist profile, with MOR potency being particularly affected. A 3-step synthesis of Boc-2’,6’-dimethyl-L-tyrosine featuring a microwave-assisted Negishi coupling is also described, which led to the expedient synthesis of novel tyrosine analogues that were incorporated into the peptidomimetic scaffold. Of particular interest is 2’,6’-dichloro-L-tyrosine intermediate 243, which may be useful for the development of peptidomimetics with reduced liability for oxidative metabolism on the aryl methyl groups, and carboxamido peptidomimetic 251, which shows a total duration of action in vivo that is comparable to lead compound 1. An alternative series of peptidomimetics featuring a piperidine or piperazine core is also discussed. In this series, it was found that an increase in the length of the hydrophobic chain at position 4 corresponds to an improved efficacy at MOR.PhDMedicinal ChemistryUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/120867/1/ambender_1.pd

Environmentally Responsible Aviation N plus 2 Advanced Vehicle Study

This is the Northrop Grumman final report for the Environmentally Responsible Aviation (ERA) N+2 Advanced Vehicle Study performed for the National Aeronautics and Space Administration (NASA). Northrop Grumman developed advanced vehicle concepts and associated enabling technologies with a high potential for simultaneously achieving significant reductions in emissions, airport area noise, and fuel consumption for transport aircraft entering service in 2025. A Preferred System Concept (PSC) conceptual design has been completed showing a 42% reduction in fuel burn compared to 1998 technology, and noise 75dB below Stage 4 for a 224- passenger, 8,000 nm cruise transport aircraft. Roadmaps have been developed for the necessary technology maturation to support the PSC. A conceptual design for a 55%-scale demonstrator aircraft to reduce development risk for the PSC has been completed

The C. elegans CHP1 homolog, pbo-1, functions in innate immunity by regulating the pH of the intestinal lumen

This work is licensed under a Creative Commons Attribution 4.0 International License.Caenorhabditis elegans are soil-dwelling nematodes and models for understanding innate immunity and infection. Previously, we developed a novel fluorescent dye (KR35) that accumulates in the intestine of C. elegans and reports a dynamic wave in intestinal pH associated with the defecation motor program. Here, we use KR35 to show that mutations in the Ca2+-binding protein, PBO-1, abrogate the pH wave, causing the anterior intestine to be constantly acidic. Surprisingly, pbo-1 mutants were also more susceptible to infection by several bacterial pathogens. We could suppress pathogen susceptibility in pbo-1 mutants by treating the animals with pH-buffering bicarbonate, suggesting the pathogen susceptibility is a function of the acidity of the intestinal pH. Furthermore, we use KR35 to show that upon infection by pathogens, the intestinal pH becomes neutral in a wild type, but less so in pbo-1 mutants. C. elegans is known to increase production of reactive oxygen species (ROS), such as H2O2, in response to pathogens, which is an important component of pathogen defense. We show that pbo-1 mutants exhibited decreased H2O2 in response to pathogens, which could also be partially restored in pbo-1 animals treated with bicarbonate. Ultimately, our results support a model whereby PBO-1 functions during infection to facilitate pH changes in the intestine that are protective to the host

Constraints on H_0 from the Central Velocity Dispersions of Lens Galaxies

We employ Schwarzschild's method of orbit modeling to constrain the mass profiles of the central lens galaxies in Q0957+561 and PG 1115+080. We combine the measured central projected stellar velocity dispersions of these galaxies with the self-similar radial profiles of the rms velocity and of the Gauss-Hermite moment h_4 observed in nearby galaxies for 0 < R < 2 R_eff. For Q0957+561, we find a 16% uncertainty in the galaxy mass, and formal 2-sigma limits on the Hubble constant of H_0 = (61 +13/-15) km/s/Mpc. For PG 1115+080, we find that none of the viable lens models can be ruled out, so that H_0 is not yet strongly constrained by this system.Comment: Revised version accepted by ApJ: slightly modified results for both lens sytems. 18 pages, with 7 inline Postscript figures, LaTeX, aaspp4.sty; postscript paper w/figs (490 kb) also available at http://cfa-www.harvard.edu/~romanow/orbit.post.v2.ps.g

An Approach to Measuring Step Excrescence Effects in the Presence of a Pressure Gradient

An experimental study was undertaken to determine the effects of step excrescences on boundary layer transition using a unique ground test facility in which the test model was propelled though still air. The models used were designed to have a nominally constant pressure gradient so that the results would be relevant to laminar flow aircraft whose wings often have long runs of mildly favorable pressure gradient. The models had an integrated continuously adjustable two-dimensional step, which could be adjusted to be forward-facing or aft-facing. The large model was used to increase the Reynolds numbers examined so that the results are applicable to laminar flow flight vehicles. Multiple measurement methods, including Preston tubes, hot wires, accelerometers, a boundary layer traverse, and static pressure taps were used to provide comparison data, and to add to the physical understanding of the results. The propelled-model test approach required that the instrumentation be self-contained and ride along with the model as the carrier vehicle moved down the test track. Due to the relatively short times available for data-taking (approximately 15-30 seconds per run), the initialization and data analysis techniques had to be tailored for this application

Mild inborn errors of metabolism in commonly used inbred mouse strains.

Inbred mouse strains are a cornerstone of translational research but paradoxically many strains carry mild inborn errors of metabolism. For example, alpha-aminoadipic acidemia and branched-chain ketoacid dehydrogenase deficiency are known in C57BL/6J mice. Using RNA sequencing, we now reveal the causal variants in Dhtkd1 and Bckdhb, and the molecular mechanism underlying these metabolic defects. C57BL/6J mice have decreased Dhtkd1 mRNA expression due to a solitary long terminal repeat (LTR) in intron 4 of Dhtkd1. This LTR harbors an alternate splice donor site leading to a partial splicing defect and as a consequence decreased total and functional Dhtkd1 mRNA, decreased DHTKD1 protein and alpha-aminoadipic acidemia. Similarly, C57BL/6J mice have decreased Bckdhb mRNA expression due to an LTR retrotransposon in intron 1 of Bckdhb. This transposable element encodes an alternative exon 1 causing aberrant splicing, decreased total and functional Bckdhb mRNA and decreased BCKDHB protein. Using a targeted metabolomics screen, we also reveal elevated plasma C5-carnitine in 129 substrains. This biochemical phenotype resembles isovaleric acidemia and is caused by an exonic splice mutation in Ivd leading to partial skipping of exon 10 and IVD protein deficiency. In summary, this study identifies three causal variants underlying mild inborn errors of metabolism in commonly used inbred mouse strains

Garbage In, Garbage Out? Do Machine Learning Application Papers in Social Computing Report Where Human-Labeled Training Data Comes From?

Many machine learning projects for new application areas involve teams of humans who label data for a particular purpose, from hiring crowdworkers to the paper's authors labeling the data themselves. Such a task is quite similar to (or a form of) structured content analysis, which is a longstanding methodology in the social sciences and humanities, with many established best practices. In this paper, we investigate to what extent a sample of machine learning application papers in social computing --- specifically papers from ArXiv and traditional publications performing an ML classification task on Twitter data --- give specific details about whether such best practices were followed. Our team conducted multiple rounds of structured content analysis of each paper, making determinations such as: Does the paper report who the labelers were, what their qualifications were, whether they independently labeled the same items, whether inter-rater reliability metrics were disclosed, what level of training and/or instructions were given to labelers, whether compensation for crowdworkers is disclosed, and if the training data is publicly available. We find a wide divergence in whether such practices were followed and documented. Much of machine learning research and education focuses on what is done once a "gold standard" of training data is available, but we discuss issues around the equally-important aspect of whether such data is reliable in the first place.Comment: 18 pages, includes appendi

Food-Web Models Predict Species Abundances in Response to Habitat Change

Plant and animal population sizes inevitably change following habitat loss, but the mechanisms underlying these changes are poorly understood. We experimentally altered habitat volume and eliminated top trophic levels of the food web of invertebrates that inhabit rain-filled leaves of the carnivorous pitcher plant Sarracenia purpurea. Path models that incorporated food-web structure better predicted population sizes of food-web constituents than did simple keystone species models, models that included only autecological responses to habitat volume, or models including both food-web structure and habitat volume. These results provide the first experimental confirmation that trophic structure can determine species abundances in the face of habitat loss

Is it possible to diagnose the therapeutic adherence of patients with COPD in clinical practice? A cohort study

<p>Abstract</p> <p>Background</p> <p>Therapeutic adherence of patients with chronic obstructive pulmonary disease (COPD) is poor. It is therefore necessary to determine the magnitude of non-adherence to develop strategies to correct this behaviour. The purpose of this study was to analyse the diagnostic validity of indirect adherence methods.</p> <p>Methods</p> <p>Sample: 195 COPD patients undergoing scheduled inhaled treatment attending 5 Primary Care Centres of Malaga, Spain. Variables: Sociodemographic profile, illness data, spirometry, quality of life (St. George Respiratory Questionnaire: SGRQ), and inhaled medication counting (count of dose/pill or electronic monitoring) were collected. The patient's knowledge of COPD (Batalla test:BT),their attitude towards treatment (Morisky-Green test: MGT) and their self-reported therapeutic adherence (Haynes-Sackett test: HST) were used as methods of evaluating adherence. The follow-up consisted four visits over one year (the recruitment visit: V0; and after 1 month:V1; 6 months:V2; and 1 year:V3).</p> <p>Results</p> <p>The mean age was 69.59 (95% CI, 68.29-70.89) years old and 93.8% were male. Other findings included: 85.4% had a low educational level, 23.6% were smokers, 71.5% mild-moderate COPD stage with a FEV1 = 56.86 (SD = 18.85); exacerbations per year = 1.41(95% CI, 1-1.8). The total SGRQ score was 44.96 (95% CI, 42.46-47.46), showing a mild self-perceived impairment in health. The prevalence of adherence (dose/pill count) was 68.1% (95% CI, 60.9-75.3) at V1, 80% (95% CI, 73-87) at V2 and 84% (95% CI, 77.9) at V3. The MGT showed a specificity of 67.34% at V1, 76.19% at V2 and 69.62% at V3. The sensitivity was 53.33% at V1, 66.66% at V2 and 33.33% at V3.The BT showed a specificity of 55.1% at V1, 70.23% at V2 and 67.09% at V3. The sensitivity was 68.88% at V1, 71.43% at V2 and 46.66% at V3. Considering both tests together, the specificity was 86.73% at V1, 94.04% at V2 and 92.49% at V3 and the sensitivity was 37.77% at V1, 47.62% at V2 and 13.3% at V3.</p> <p>Conclusions</p> <p>The prevalence of treatment adherence changes over time. Indirect methods (dose/pill count and self-reported) can be useful to detect non-adherence in COPD patients. The combination of MGT and BT is the best approach to test self-reported adherence.</p