Novel antibiotics from DNA adenine methyltransferase inhibitors

The re-emergence of plague as a world-wide health concern and the potential risk posed by bioterrorism has led to an increased interest in available treatments for the disease. The bacterial DNA adenine-N6 methyltransferase, Dam, is involved in the regulation of a range of pathogenic bacteria and has been validated as a target for the development of antimicrobial agents with activity against Yersinia pestis, the causative agent of plague. The lack of a functionally similar enzyme in mammals suggests that highly selective Dam inhibitors could be developed. A coupled, real-time break light Dam activity assay has been optimised for HTS, and assays for the validation and characterisation of screening hits have also been developed. Screening of random and in silico enriched compound libraries, and the subsequent application of counter-screening and hit confirmation assays, resulted in the identification of a single viable lead, (4-(N-(2-hydroxyethyl)sulfamoyl)phenyl) stibonic acid (13776). Screening of compounds analogous to 13776 identified a series of arylstibonic acids with activity against Dam. Kinetic characterisation of the most potent arylstibonic acid, 4-stibonobenzenesulfonic acid (13746), revealed a DNA-competitive mode of action, and a Ki of 6.46 ± 0.07 nM. However, selectivity assays have revealed a potentially non-specific mode of action for the stibonic acids, which have shown activity against a range of DNA and protein binding enzymes. Yersinia cell culture experiments have shown a single compound, (3-((2-hydroxyethyl)carbamoyl)phenyl)stibonic acid (13782), to be capable of penetrating Yersinia cells and partially inhibiting methylation, and mRNA profiling experiments have shown 13782 to induce a statistically significant change in several genes involved in the pathogenicity of Y. pestis. Attempts at resynthesising 13782 have proved challenging, with only a fraction of the activity of the original sample reproduced. HPLC analysis of the original and resynthesised samples has shown the former to comprise two components, with only one present in both samples. The in vitro evaluation of a series of bisubstrate analogues designed to mimic both the methyl donor S-adenosylmethionine (AdoMet), and the methylation target (adenine) has shown that substitution of the AdoMet sulfur for nitrogen results in a significant but not total loss of activity. Furthermore, the addition of a bicyclic heteroaromatic adenine analogue mimic to this scaffold led to an increase in potency and selectivity for Dam over the human cytosine methyltransferase DNMT1 but a reduction in selectivity for Dam over the restriction enzyme DpnI. These results suggest that a selective and potent Dam inhibitor can be obtained by carefully modifying both components of the bisubstrate analogue inhibitor

Effects of Removing the Time Limit on First and Second Language Intelligence Test Performance

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Sharing Success: Expansion of a Tutor-Run Assessment Method to Multiple Courses and Colleges

Objectives: In 2014, data were presented on a successful pilot program using quizzes written by tutors in a single course at Wegmans School of Pharmacy. The objective of this study was to use the methods from the pilot to expand the program to other pharmacology courses at Wegmans School of Pharmacy as well as the University of Arkansas for Medical Sciences College of Pharmacy. Methods: Methods from the previous study were replicated, whereby tutors wrote weekly quizzes administered using ExamSoft®. The optional quizzes were openly accessible to students in preparation for course exams. Performance data were collected from students in one course at each institution and compared to the pilot study. Performance data collected included quiz and course exam scores. All students that utilized quizzes, as well as tutors, were surveyed to assess perceptions of the method. Results: The use and impact of quizzes was similar to the results in the pilot study. However, the magnitude of improvements was slightly lower than what was observed initially. Exam scores were significantly higher than quiz scores on 6/10 exams measured, compared to 5/5 exams in the pilot. Students who utilized the quizzes performed significantly better than those that did not on 3/10 exams (3/5 in the pilot), and earned significantly higher course averages. Student (n=155) and peer instructor (n=13) feedback remained positive after expansion of the program. Implications: This method is a tool that can be translated to different courses and different institutions with a valuable impact on student performance

The Value of Admission Clinical Data for Diagnosing Heart Failure in Long-term Care

Background Heart failure (HF) is common in long-term care (LTC). Diagnostic uncertainty is important barrier to optimal HF management, stemming from inadequate health information transfer upon LTC admission. We determine the utility of admission clinical information to confirm a HF diagnosis in new LTC residents. Methods This was a prospective cohort study. From February 2004 to November 2006, information about new residents from 41 LTC homes in Ontario, Canada, was collected from residents and caregivers, and all available health records. A prior HF diagnosis was confirmed by consensus review of available data by two independent experts. Multivariate modelling was utilized to determine the utility of the admission clinical assessment in confirming a prior HF diagnosis. Results A total of 449 residents were included for analysis, aged84.3±6.5 years, and 21.6% had a prior HF diagnosis. The most useful clinical item for diagnosing HF was a “history of HF”. The final model included “history of HF’ (OR [odds ratio] 13.66, 95% CI 6.61–28.24), “fluid on the lungs” (OR 2.01, 95% CI 1.04–3.89), “orthopnea” (OR 1.76, 95% CI 0.93–3.33), “taking β-blocker” (OR 2.09, 95% CI 1.10– 3.94), “taking loop diuretics” (OR 2.11, 95% CI 1.12–3.98), and “history of coronary artery disease” (OR 2.83, 95% CI 1.42–5.64). Conclusion Elements of the clinical assessment for new LTC residents can help confirm a prior HF diagnosis. An admission history of HF is highly predictiveCanadian Institutes of Health Research (CIHR; Study ID 117947-BCA-CEBA-126289

Potential contribution of lysed bacterial cells to phosphorus solubilisation in two rewetted Australian pasture soils

Soil drying renders considerable amounts of phosphorus soluble upon rewetting, which may be partly derived from lysed microbial cells. Using direct bacterial cell counting in water and tetra-sodium pyrophosphate extracts of two Australian pasture soils, we found that almost all extractable cells were lysed following the rewetting of dry soils. The amounts of phosphorus in the lysed cells corresponded closely to the increases in water-extractable phosphorus following soil drying, suggesting that bacterial cell lysis is a major source of the released phosphorus

The Fifteenth Data Release of the Sloan Digital Sky Surveys: First Release of MaNGA-derived Quantities, Data Visualization Tools, and Stellar Library

Twenty years have passed since first light for the Sloan Digital Sky Survey (SDSS). Here, we release data taken by the fourth phase of SDSS (SDSS-IV) across its first three years of operation (2014 July–2017 July). This is the third data release for SDSS-IV, and the 15th from SDSS (Data Release Fifteen; DR15). New data come from MaNGA—we release 4824 data cubes, as well as the first stellar spectra in the MaNGA Stellar Library (MaStar), the first set of survey-supported analysis products (e.g., stellar and gas kinematics, emission-line and other maps) from the MaNGA Data Analysis Pipeline, and a new data visualization and access tool we call "Marvin." The next data release, DR16, will include new data from both APOGEE-2 and eBOSS; those surveys release no new data here, but we document updates and corrections to their data processing pipelines. The release is cumulative; it also includes the most recent reductions and calibrations of all data taken by SDSS since first light. In this paper, we describe the location and format of the data and tools and cite technical references describing how it was obtained and processed. The SDSS website (www.sdss.org) has also been updated, providing links to data downloads, tutorials, and examples of data use. Although SDSS-IV will continue to collect astronomical data until 2020, and will be followed by SDSS-V (2020–2025), we end this paper by describing plans to ensure the sustainability of the SDSS data archive for many years beyond the collection of data

The 16th Data Release of the Sloan Digital Sky Surveys: First Release from the APOGEE-2 Southern Survey and Full Release of eBOSS Spectra

This paper documents the 16th data release (DR16) from the Sloan Digital Sky Surveys (SDSS), the fourth and penultimate from the fourth phase (SDSS-IV). This is the first release of data from the Southern Hemisphere survey of the Apache Point Observatory Galactic Evolution Experiment 2 (APOGEE-2); new data from APOGEE-2 North are also included. DR16 is also notable as the final data release for the main cosmological program of the Extended Baryon Oscillation Spectroscopic Survey (eBOSS), and all raw and reduced spectra from that project are released here. DR16 also includes all the data from the Time Domain Spectroscopic Survey and new data from the SPectroscopic IDentification of ERosita Survey programs, both of which were co-observed on eBOSS plates. DR16 has no new data from the Mapping Nearby Galaxies at Apache Point Observatory (MaNGA) survey (or the MaNGA Stellar Library "MaStar"). We also preview future SDSS-V operations (due to start in 2020), and summarize plans for the final SDSS-IV data release (DR17)

The 16th Data Release of the Sloan Digital Sky Surveys: First Release from the APOGEE-2 Southern Survey and Full Release of eBOSS Spectra

This paper documents the 16th data release (DR16) from the Sloan Digital Sky Surveys (SDSS), the fourth and penultimate from the fourth phase (SDSS-IV). This is the first release of data from the Southern Hemisphere survey of the Apache Point Observatory Galactic Evolution Experiment 2 (APOGEE-2); new data from APOGEE-2 North are also included. DR16 is also notable as the final data release for the main cosmological program of the Extended Baryon Oscillation Spectroscopic Survey (eBOSS), and all raw and reduced spectra from that project are released here. DR16 also includes all the data from the Time Domain Spectroscopic Survey and new data from the SPectroscopic IDentification of ERosita Survey programs, both of which were co-observed on eBOSS plates. DR16 has no new data from the Mapping Nearby Galaxies at Apache Point Observatory (MaNGA) survey (or the MaNGA Stellar Library "MaStar"). We also preview future SDSS-V operations (due to start in 2020), and summarize plans for the final SDSS-IV data release (DR17)

The 16th Data Release of the Sloan Digital Sky Surveys : First Release from the APOGEE-2 Southern Survey and Full Release of eBOSS Spectra

This paper documents the 16th data release (DR16) from the Sloan Digital Sky Surveys (SDSS), the fourth and penultimate from the fourth phase (SDSS-IV). This is the first release of data from the Southern Hemisphere survey of the Apache Point Observatory Galactic Evolution Experiment 2 (APOGEE-2); new data from APOGEE-2 North are also included. DR16 is also notable as the final data release for the main cosmological program of the Extended Baryon Oscillation Spectroscopic Survey (eBOSS), and all raw and reduced spectra from that project are released here. DR16 also includes all the data from the Time Domain Spectroscopic Survey and new data from the SPectroscopic IDentification of ERosita Survey programs, both of which were co-observed on eBOSS plates. DR16 has no new data from the Mapping Nearby Galaxies at Apache Point Observatory (MaNGA) survey (or the MaNGA Stellar Library "MaStar"). We also preview future SDSS-V operations (due to start in 2020), and summarize plans for the final SDSS-IV data release (DR17).Peer reviewe

The Fifteenth Data Release of the Sloan Digital Sky Surveys: First Release of MaNGA-derived Quantities, Data Visualization Tools, and Stellar Library

Twenty years have passed since first light for the Sloan Digital Sky Survey (SDSS). Here, we release data taken by the fourth phase of SDSS (SDSS-IV) across its first three years of operation (2014 July–2017 July). This is the third data release for SDSS-IV, and the 15th from SDSS (Data Release Fifteen; DR15). New data come from MaNGA—we release 4824 data cubes, as well as the first stellar spectra in the MaNGA Stellar Library (MaStar), the first set of survey-supported analysis products (e.g., stellar and gas kinematics, emission-line and other maps) from the MaNGA Data Analysis Pipeline, and a new data visualization and access tool we call "Marvin." The next data release, DR16, will include new data from both APOGEE-2 and eBOSS; those surveys release no new data here, but we document updates and corrections to their data processing pipelines. The release is cumulative; it also includes the most recent reductions and calibrations of all data taken by SDSS since first light. In this paper, we describe the location and format of the data and tools and cite technical references describing how it was obtained and processed. The SDSS website (www.sdss.org) has also been updated, providing links to data downloads, tutorials, and examples of data use. Although SDSS-IV will continue to collect astronomical data until 2020, and will be followed by SDSS-V (2020–2025), we end this paper by describing plans to ensure the sustainability of the SDSS data archive for many years beyond the collection of data