Stoichiometries and Affinities of Interacting Proteins from Concentration Series of Solution Scattering Data: Decomposition by Least Squares and Quadratic Optimization

In studying interacting proteins, complementary insights are provided by analyzing both the association model (the stoichiometry and affinity constants of the intermediate and final complexes) and the quaternary structure of the resulting complexes. Many current methods for analyzing protein interactions either give a binary answer to the question of association and no information about quaternary structure or at best provide only part of the complete picture. Presented here is a method to extract both types of information from X-ray or neutron scattering data for a series of equilibrium mixtures containing the initial components at different concentrations. The method determines the association pathway and constants, along with the scattering curves of the individual members of the mixture, so as to best explain the scattering data for the mixtures. The derived curves then enable reconstruction of the intermediate and final complexes. Using simulated solution scattering data for four hetero-oligomeric complexes with different structures, molecular weights and association models, it is demonstrated that this method accurately determines the simulated association model and scattering profiles for the initial components and complexes. Recognizing that experimental mixtures contain static contaminants and nonspecific complexes with the lowest affinities (inter-particle interference) as well as the desired specific complex(es), a new analytical method is also employed to extend this approach to evaluating the association models and scattering curves in the presence of static contaminants, testing both a nonparticipating monomer and a large homo-oligomeric aggregate. It is demonstrated that the method is robust to both random noise and systematic noise from such contaminants, and the treatment of nonspecific complexes is discussed. Finally, it is shown that this method is applicable over a large range of weak association constants typical of specific but transient protein-protein complexes

Jefferson Village Downtown District Plan

Jefferson Village is an incorporated municipality in Northeastern Ohio, with a population in 2000 of about 4000 residents. Originally founded in 1803 and incorporated in 1836, the Village has been the county seat for Ashtabula County since 1807. The Village is centrally located in Ashtabula County, 10 miles south of Lake Erie, and 10 miles west of the Pennsylvania border. Interstate highway 90 runs parallel to the lake shore, about 6 miles north of the village; and State Route 11 is a major north-south connector located about 2 miles east of the village. The primary employment locations in the Village are the downtown County administration and the independent professional offices that serve county-related needs, and a light industrial park to the southeast of downtown. The County fairground is also located within the village limits. While residential, commercial and retail growth have occurred over the years, the village still retains much of its original Western Reserve town character. Over 25% of the buildings in the downtown district have historic merit, and both Chestnut and Jefferson Streets are lined with older brick commercial buildings, as well as large, well-kept residences of Western Reserve, Georgian and Victorian architectural styles. Village administration is still based in the original Town Hall, and residents take much pride in the small town charm of the community. In 2006, new commercial development was proposed for Chestnut Street that would have required removal of a residence of historic character, replacing it with a new, generic commercial structure and a typical street-frontage parking lot. Residents were concerned, and public discourse in the local newspaper and at Town Hall led to withdrawal of the proposal. Village leadership felt that it was time to explore the historic character and economic future of the downtown district, and establish policy that could guide future decision making for the downtown

Jefferson Village Downtown District Plan

Jefferson Village is an incorporated municipality in Northeastern Ohio, with a population in 2000 of about 4000 residents. Originally founded in 1803 and incorporated in 1836, the Village has been the county seat for Ashtabula County since 1807. The Village is centrally located in Ashtabula County, 10 miles south of Lake Erie, and 10 miles west of the Pennsylvania border. Interstate highway 90 runs parallel to the lake shore, about 6 miles north of the village; and State Route 11 is a major north-south connector located about 2 miles east of the village. The primary employment locations in the Village are the downtown County administration and the independent professional offices that serve county-related needs, and a light industrial park to the southeast of downtown. The County fairground is also located within the village limits. While residential, commercial and retail growth have occurred over the years, the village still retains much of its original Western Reserve town character. Over 25% of the buildings in the downtown district have historic merit, and both Chestnut and Jefferson Streets are lined with older brick commercial buildings, as well as large, well-kept residences of Western Reserve, Georgian and Victorian architectural styles. Village administration is still based in the original Town Hall, and residents take much pride in the small town charm of the community. In 2006, new commercial development was proposed for Chestnut Street that would have required removal of a residence of historic character, replacing it with a new, generic commercial structure and a typical street-frontage parking lot. Residents were concerned, and public discourse in the local newspaper and at Town Hall led to withdrawal of the proposal. Village leadership felt that it was time to explore the historic character and economic future of the downtown district, and establish policy that could guide future decision making for the downtown

The AllWISE Motion Survey, Part 2

We use the AllWISE Data Release to continue our search for WISE-detected motions. In this paper, we publish another 27,846 motion objects, bringing the total number to 48,000 when objects found during our original AllWISE motion survey are included. We use this list, along with the lists of confirmed WISE-based motion objects from the recent papers by Luhman and by Schneider et al. and candidate motion objects from the recent paper by Gagne et al. to search for widely separated, common-proper-motion systems. We identify 1,039 such candidate systems. All 48,000 objects are further analyzed using color-color and color-mag plots to provide possible characterizations prior to spectroscopic follow-up. We present spectra of 172 of these, supplemented with new spectra of 23 comparison objects from the literature, and provide classifications and physical interpretations of interesting sources. Highlights include: (1) the identification of three G/K dwarfs that can be used as standard candles to study clumpiness and grain size in nearby molecular clouds because these objects are currently moving behind the clouds, (2) the confirmation/discovery of several M, L, and T dwarfs and one white dwarf whose spectrophotometric distance estimates place them 5-20 pc from the Sun, (3) the suggestion that the Na 'D' line be used as a diagnostic tool for interpreting and classifying metal-poor late-M and L dwarfs, (4) the recognition of a triple system including a carbon dwarf and late-M subdwarf, for which model fits of the late-M subdwarf (giving [Fe/H] ~ -1.0) provide a measured metallicity for the carbon star, and (5) a possible 24-pc-distant K5 dwarf + peculiar red L5 system with an apparent physical separation of 0.1 pc.Comment: 62 pages with 80 figures, accepted for publication in The Astrophysical Journal Supplement Series, 23 Mar 2016; second version fixes a few small typos and corrects the footnotes for Table

CELLObration

https://dc.ewu.edu/music_performances/1683/thumbnail.jp

Explorations, Vol. 3, No. 3

Cover: Artwork by Marcia Spencer, University of Maine art student. Articles include: Characterization of Normal and Carcinogen Induced Neoplastic Cells of Teleost Origin, by Tim Lyden Attitutdes and Opinions of Maine Dairy Farmers, by John Muth and James Leiby Background: the quest for the eighteen month oyster, by Kevin Scully The Quest for the Eighteen Month Oyster, by Kevin Scully Measurement of Surface Tension of Kraft Black Liquor, by Jayalakshmi Jaya Krishnagopalan From the former student, by Jayalakshmi Krishnagopalan From the faculty advisor, by Ivar H. Stockel Aquatic Fungal Decomposers in Two Adjacent Maine Lakes of Different Acidity, by Peter Wagner Studies on a New Mouse Mutation, by Luanne L. Peters Opportunities for Students: Maine Agricultural Experiment Station Research Programs, by Mark W. Anderson Experimental Embryogenesis in Red Pine, by Judy C. Gates The V-Notched Lobster in Maine, by Cheryl Waltz Undernutrition in a Pediatric Population, by Paula Quatromoni From the Advisor Archaeology of the Central Maine Coast, by Douglas Kellogg Marketing Strategies for Computer Consultants in Small Business, by Kimberly Dagher Our Cover Artist From the Advisor, by James Lineha

An integrated general practice and pharmacy-based intervention to promote the use of appropriate preventive medications among individuals at high cardiovascular disease risk: protocol for a cluster randomized controlled trial

Background: Cardiovascular diseases (CVD) are responsible for significant morbidity, premature mortality, and economic burden. Despite established evidence that supports the use of preventive medications among patients at high CVD risk, treatment gaps remain. Building on prior evidence and a theoretical framework, a complex intervention has been designed to address these gaps among high-risk, under-treated patients in the Australian primary care setting. This intervention comprises a general practice quality improvement tool incorporating clinical decision support and audit/feedback capabilities; availability of a range of CVD polypills (fixed-dose combinations of two blood pressure lowering agents, a statin ± aspirin) for prescription when appropriate; and access to a pharmacy-based program to support long-term medication adherence and lifestyle modification. Methods: Following a systematic development process, the intervention will be evaluated in a pragmatic cluster randomized controlled trial including 70 general practices for a median period of 18 months. The 35 general practices in the intervention group will work with a nominated partner pharmacy, whereas those in the control group will provide usual care without access to the intervention tools. The primary outcome is the proportion of patients at high CVD risk who were inadequately treated at baseline who achieve target blood pressure (BP) and low-density lipoprotein cholesterol (LDL-C) levels at the study end. The outcomes will be analyzed using data from electronic medical records, utilizing a validated extraction tool. Detailed process and economic evaluations will also be performed. Discussion: The study intends to establish evidence about an intervention that combines technological innovation with team collaboration between patients, pharmacists, and general practitioners (GPs) for CVD prevention. Trial registration: Australian New Zealand Clinical Trials Registry ACTRN1261600023342

Hepatitis B Sero-Prevalence and Risk Behaviors Among Immigrant Men in a Population-Based Household Survey in Low-Income Neighborhoods of Northern California

Background Despite an effective vaccine, 60,000 new HBV infections were reported in the US in 2004; 95% in adults. We evaluate HBV sero-prevalence, risk behaviors and self-reported vaccination among Latino immigrant, Asian immigrant and US born low income men in five northern California counties. Methods Population based, cross sectional survey of HBV sero-prevalence and risk behaviors in men aged 18 to 35 years. Results Among 1,512 men screened, Asian immigrants were most likely to have had prior HBV infection (15.1%) and chronic infection (3.8%) compared to US born (prior 5.1%, chronic 0.6%) and Latino immigrant men (prior 2.0%, chronic 0.3%.) Reported HBV vaccination was lowest for Latino immigrants (12%) compared to Asian immigrants and US born men (35% in both.) Latino immigrants reported less educational attainment, medical insurance coverage and access to a physician in the last six months. Discussion Healthcare providers should routinely screen Asian immigrants for HBV regardless of their self reported vaccination status. Latino immigrants may comprise an important group of under-vaccinated, at risk persons in California. HBV testing and vaccination of immigrants soon after US arrival should be encouraged

A Real-Time PCR Antibiogram for Drug-Resistant Sepsis

Current molecular diagnostic techniques for susceptibility testing of septicemia rely on genotyping for the presence of known resistance cassettes. This technique is intrinsically vulnerable due to the inability to detect newly emergent resistance genes. Traditional phenotypic susceptibility testing has always been a superior method to assay for resistance; however, relying on the multi-day growth period to determine which antimicrobial to administer jeopardizes patient survival. These factors have resulted in the widespread and deleterious use of broad-spectrum antimicrobials. The real-time PCR antibiogram, described herein, combines universal phenotypic susceptibility testing with the rapid diagnostic capabilities of PCR. We have developed a procedure that determines susceptibility by monitoring pathogenic load with the highly conserved 16S rRNA gene in blood samples exposed to different antimicrobial drugs. The optimized protocol removes heme and human background DNA from blood, which allows standard real-time PCR detection systems to be employed with high sensitivity (<100 CFU/mL). Three strains of E. coli, two of which were antimicrobial resistant, were spiked into whole blood and exposed to three different antibiotics. After real-time PCR-based determination of pathogenic load, a ΔCt<3.0 between untreated and treated samples was found to indicate antimicrobial resistance (P<0.01). Minimum inhibitory concentration was determined for susceptible bacteria and pan-bacterial detection was demonstrated with 3 Gram-negative and 2 Gram-positive bacteria. Species identification was performed via analysis of the hypervariable amplicons. In summary, we have developed a universal diagnostic phenotyping technique that assays for the susceptibility of drug-resistant septicemia with the speed of PCR. The real-time PCR antibiogram achieves detection, susceptibility testing, minimum inhibitory concentration determination, and identification in less than 24 hours

Polygenic hazard score to guide screening for aggressive prostate cancer: development and validation in large scale cohorts.

OBJECTIVES: To develop and validate a genetic tool to predict age of onset of aggressive prostate cancer (PCa) and to guide decisions of who to screen and at what age. DESIGN: Analysis of genotype, PCa status, and age to select single nucleotide polymorphisms (SNPs) associated with diagnosis. These polymorphisms were incorporated into a survival analysis to estimate their effects on age at diagnosis of aggressive PCa (that is, not eligible for surveillance according to National Comprehensive Cancer Network guidelines; any of Gleason score ≥7, stage T3-T4, PSA (prostate specific antigen) concentration ≥10 ng/L, nodal metastasis, distant metastasis). The resulting polygenic hazard score is an assessment of individual genetic risk. The final model was applied to an independent dataset containing genotype and PSA screening data. The hazard score was calculated for these men to test prediction of survival free from PCa. SETTING: Multiple institutions that were members of international PRACTICAL consortium. PARTICIPANTS: All consortium participants of European ancestry with known age, PCa status, and quality assured custom (iCOGS) array genotype data. The development dataset comprised 31 747 men; the validation dataset comprised 6411 men. MAIN OUTCOME MEASURES: Prediction with hazard score of age of onset of aggressive cancer in validation set. RESULTS: In the independent validation set, the hazard score calculated from 54 single nucleotide polymorphisms was a highly significant predictor of age at diagnosis of aggressive cancer (z=11.2, P98th centile) were compared with those with average scores (30th-70th centile), the hazard ratio for aggressive cancer was 2.9 (95% confidence interval 2.4 to 3.4). Inclusion of family history in a combined model did not improve prediction of onset of aggressive PCa (P=0.59), and polygenic hazard score performance remained high when family history was accounted for. Additionally, the positive predictive value of PSA screening for aggressive PCa was increased with increasing polygenic hazard score. CONCLUSIONS: Polygenic hazard scores can be used for personalised genetic risk estimates that can predict for age at onset of aggressive PCa