DNA tape measurements of AraC

A new method for measuring distances between points in the AraC–DNA complex was developed and applied. It utilizes variable lengths of single-stranded DNA that connect double-stranded regions containing the two half-site binding sequences of AraC. These distances plus the protein interdomain linker distances are compatible with two classes of structure for the dimeric AraC gene regulatory protein. In one class, the N-terminal regulatory arm of one dimerization domain is capable of interacting with the DNA-binding domain on the same polypeptide chain for a cis interaction. In the other class, the possible arm-DNA-binding domain interaction is trans, where it adds to the dimerization interface

Point-Focus Concentration Compact Telescoping Array: EESP Option 1 Phase Final Report for Public Release

Orbital ATK, in partnership with Mark ONeill LLC (MOLLC) and SolAero Technologies Corp., has developed a novel solar array platform, PFC-CTA, which provides a significant advance in performance and cost reduction compared to all currently available space solar systems. PFC refers to the Point Focus Concentration of light provided by MOLLCs thin, flat Fresnel optics. These lenses focus light to a point of approximately 100 times the intensity of the ambient light, onto a solar cell of approximately 1/25th the size of the lens. CTA stands for Compact Telescoping Array1, which is the solar array blanket structural platform originally devised by NASA and currently being advanced by Orbital ATK and partners under NASA and AFRL funding to a projected TRL 5+ by late-2018. The NASA Game Changing Development Extreme Environment Solar Power (EESP) Option 1 Phase study has enabled Orbital ATK to generate and refine component designs, perform component level and system performance analyses, and test prototype hardware of the key elements of PFC-CTA, and increased the TRL of PFC-specific technology elements to TRL ~5. Key performance metrics currently projected are as follows: Scalability from 300 kW per wing (AM0); Specific Power > 250 W/kg (BoL, AM0); Stowage Efficiency > 60 kW/m3; 5:1 margin on pointing tolerance vs. capability; >50% launched cost savings; Wide range of operability between Venus and Saturn by active and/or passive thermal management

Repurposing environmental DNA samples—detecting the western pearlshell (Margaritifera falcata) as a proof of concept

Information on the distribution of multiple species in a common landscape is fundamental to effective conservation and management. However, distribution data are expensive to obtain and often limited to high-profile species in a system. A recently developed technique, environmental DNA (eDNA) sampling, has been shown to be more sensitive than traditional detection methods for many aquatic species. A second and perhaps underappreciated benefit of eDNA sampling is that a sample originally collected to determine the presence of one species can be re-analyzed to detect additional taxa without additional field effort. We developed an eDNA assay for the western pearlshell mussel (Margaritifera falcata) and evaluated its effectiveness by analyzing previously collected eDNA samples that were annotated with information including sample location and deposited in a central repository. The eDNA samples were initially collected to determine habitat occupancy by nonbenthic fish species at sites that were in the vicinity of locations recently occupied by western pearlshell. These repurposed eDNA samples produced results congruent with historical western pearlshell surveys and permitted a more precise delineation of the extent of local populations. That a sampling protocol designed to detect fish was also successful for detecting a freshwater mussel suggests that rapidly accumulating collections of eDNA samples can be repurposed to enhance the efficiency and cost-effectiveness of aquatic biodiversity monitoring

Major trends in mobility technology research and development: Overview of the results of the NSF-WTEC European study

Mobility technologies, including wheelchairs, prostheses, joint replacements, assistive devices, and therapeutic exercise equipment help millions of people participate in desired life activities. Yet, these technologies are not yet fully transformative because many desired activities cannot be pursued or are difficult to pursue for the millions of individuals with mobility related impairments. This WTEC study, initiated and funded by the National Science Foundation, was designed to gather information on European innovations and trends in technology that might lead to greater mobility for a wider range of people. What might these transformative technologies be and how might they arise? Based on visits to leading mobility technology research labs in western Europe, the WTEC panel identified eight major trends in mobility technology research. This commentary summarizes these trends, which are then described in detail in companion papers appearing in this special issue

Effect of ligand backbone on the selectivity and stability of rhodium hydroformylation catalysts derived from phospholane-phosphites

We thank the Eastman Chemical Company for funding and permission to publish. M.B. thanks the School of Chemistry and EaStCHEM for support.A study on how ligand backbone structure has an impact on selectivity, rate, and catalyst stability of hydroformylation catalysts was prompted by some longer-term stability issues being discovered for a phospholane-phosphite with a [−CH2O−] backbone. A series of phospholane-phosphite ligands were synthesized. Catalysts made in situ from these ligands and [Rh(acac)(CO)2] were found to give iso-butanal selectivities up to 75% at temperatures between 75 and 105 °C: the latter being a benchmark for iso-selectivity in reactions conducted at industrially meaningful temperatures. A racemic rhodium complex of a bidentate phospholane-phosphite from a tropos-biphenol with an extended backbone showed unusually high stability at high temperatures, combined with even better iso-selectivity in propene hydroformylation relative to the original complex. A related ligand with an electron-withdrawing group maintained the unusually high stability and improved activity. Characterization of the precatalysts of type [RhH(CO)2(L)] was accomplished using in situ HPIR spectroscopy and backed up by density functional theory calculations (B3PW91-D3 level) and by NMR studies; the latter showed that the variation of the backbone also had a pronounced impact on the precatalyst structure. A key finding is that it is now possible to prepare phospholane-phosphite ligands that deliver high iso-butanal selectivity and that show no signs of degradation after several days even above typical reaction temperatures. In one stability test, several kilograms of aldehydes were produced with TOF and selectivity being consistent over several days.PostprintPeer reviewe

Melarsoprol cyclodextrin inclusion complexes as promising oral candidates for the treatment of human African trypanosomiasis

Human African trypanosomiasis (HAT), or sleeping sickness, results from infection with the protozoan parasites <i>Trypanosoma brucei</i> (<i>T.b.</i>) <i>gambiense</i> or <i>T.b.rhodesiense</i> and is invariably fatal if untreated. There are 60 million people at risk from the disease throughout sub-Saharan Africa. The infection progresses from the haemolymphatic stage where parasites invade the blood, lymphatics and peripheral organs, to the late encephalitic stage where they enter the central nervous system (CNS) to cause serious neurological disease. The trivalent arsenical drug melarsoprol (Arsobal) is the only currently available treatment for CNS-stage <i>T.b.rhodesiense</i> infection. However, it must be administered intravenously due to the presence of propylene glycol solvent and is associated with numerous adverse reactions. A severe post-treatment reactive encephalopathy occurs in about 10% of treated patients, half of whom die. Thus melarsoprol kills 5% of all patients receiving it. Cyclodextrins have been used to improve the solubility and reduce the toxicity of a wide variety of drugs. We therefore investigated two melarsoprol cyclodextrin inclusion complexes; melarsoprol hydroxypropyl-͎-cyclodextrin and melarsoprol randomly-methylated-β-cyclodextrin. We found that these compounds retain trypanocidal properties <i>in vitro</i> and cure CNS-stage murine infections when delivered orally, once per day for 7-days, at a dosage of 0.05 mmol/kg. No overt signs of toxicity were detected. Parasite load within the brain was rapidly reduced following treatment onset and magnetic resonance imaging showed restoration of normal blood-brain barrier integrity on completion of chemotherapy. These findings strongly suggest that complexed melarsoprol could be employed as an oral treatment for CNS-stage HAT, delivering considerable improvements over current parenteral chemotherapy

Allopregnanolone preclinical acute pharmacokinetic and pharmacodynamic studies to predict tolerability and efficacy for Alzheimer's disease.

To develop allopregnanolone as a therapeutic for Alzheimer's disease, we investigated multiple formulations and routes of administration in translationally relevant animal models of both sexes. Subcutaneous, topical (transdermal and intranasal), intramuscular, and intravenous allopregnanolone were bolus-administered. Pharmacokinetic analyses of intravenous allopregnanolone in rabbit and mouse indicated that peak plasma and brain levels (3-fold brain/plasma ratios) at 5min were sufficient to activate neuroregenerative responses at sub-sedative doses. Slow-release subcutaneous suspension of allopregnanolone displayed 5-fold brain/plasma ratio at Cmax at 30min. At therapeutic doses by either subcutaneous or intravenous routes, allopregnanolone mouse plasma levels ranged between 34-51ng/ml by 30min, comparable to published endogenous human level in the third trimester of pregnancy. Exposure to subcutaneous, topical, intramuscular, and intravenous allopregnanolone, at safe and tolerable doses, increased hippocampal markers of neurogenesis including BrdU and PCNA in young 3xTgAD and aged wildtype mice. Intravenous allopregnanolone transiently and robustly phosphorylated CREB within 5min and increased levels of neuronal differentiation transcription factor NeuroD within 4h. Neurogenic efficacy was achieved with allopregnanolone brain exposure of 300-500hr*ng/g. Formulations were tested to determine the no observable adverse effect level (NOAEL) and maximally tolerated doses (MTD) in male and female rats by sedation behavior time course. Sex differences were apparent, males exhibited ≥40% more sedation time compared to females. Allopregnanolone formulated in sulfobutyl-ether-beta-cyclodextrin at optimized complexation ratio maximized allopregnanolone delivery and neurogenic efficacy. To establish the NOAEL and MTD for Allo-induced sedation using a once-per-week intravenous regenerative treatment regimen: In female rats the NOAEL was 0.5mg/kg and MTD 2mg/kg. The predicted MTD in human female is 0.37mg/kg. In male rats the NOAEL and MTD were less than those determined for female. Outcomes of these PK/PD studies predict a safe and efficacious dose range for initial clinical trials of allopregnanolone for Alzheimer's disease. These findings have translational relevance to multiple neurodegenerative conditions

Engineering a modular 44Ti/44Sc generator: Eluate evaluation in preclinical models and estimation of human radiation dosimetry

BACKGROUND: METHODS: RESULTS: CONCLUSIONS: A clinical-scal

Epistatic and Combinatorial Effects of Pigmentary Gene Mutations in the Domestic Pigeon

SummaryUnderstanding the molecular basis of phenotypic diversity is a critical challenge in biology, yet we know little about the mechanistic effects of different mutations and epistatic relationships among loci that contribute to complex traits. Pigmentation genetics offers a powerful model for identifying mutations underlying diversity and for determining how additional complexity emerges from interactions among loci. Centuries of artificial selection in domestic rock pigeons (Columba livia) have cultivated tremendous variation in plumage pigmentation through the combined effects of dozens of loci. The dominance and epistatic hierarchies of key loci governing this diversity are known through classical genetic studies [1–6], but their molecular identities and the mechanisms of their genetic interactions remain unknown. Here we identify protein-coding and cis-regulatory mutations in Tyrp1, Sox10, and Slc45a2 that underlie classical color phenotypes of pigeons and present a mechanistic explanation of their dominance and epistatic relationships. We also find unanticipated allelic heterogeneity at Tyrp1 and Sox10, indicating that color variants evolved repeatedly though mutations in the same genes. These results demonstrate how a spectrum of coding and regulatory mutations in a small number of genes can interact to generate substantial phenotypic diversity in a classic Darwinian model of evolution [7]