We demonstrate a novel detection method for the cyclotron resonance frequency of an electron plasma in a Penning-Malmberg trap. With this technique, the electron plasma is used as an in situ ...diagnostic tool for the measurement of the static magnetic field and the microwave electric field in the trap. The cyclotron motion of the electron plasma is excited by microwave radiation and the temperature change of the plasma is measured non-destructively by monitoring the plasma's quadrupole mode frequency. The spatially resolved microwave electric field strength can be inferred from the plasma temperature change and the magnetic field is found through the cyclotron resonance frequency. These measurements were used extensively in the recently reported demonstration of resonant quantum interactions with antihydrogen.
The study aimed to assess the diagnostic properties of electrocardiographic (ECG) criteria for right ventricular hypertrophy (RVH) measured by cardiac magnetic resonance imaging (cMRI) in adults ...without clinical cardiovascular disease.
Current ECG criteria for RVH were based on cadaveric dissection in small studies.
MESA (Multi-Ethnic Study of Atherosclerosis) performed cMRIs with complete right ventricle (RV) interpretation on 4,062 participants without clinical cardiovascular disease. Endocardial margins of the RV were manually contoured on diastolic and systolic images. The ECG screening criteria for RVH from the 2009 American Heart Association Recommendations for Standardization and Interpretation of the ECG were examined in participants with and without left ventricular (LV) hypertrophy or reduced ejection fraction. RVH was defined using sex-specific normative equations based on age, height, and weight.
The study sample with normal LV morphology and function (n = 3,719) was age 61.3 ± 10.0 years, 53.5% female, 39.6% Caucasian, 25.5% African American, 21.9% Hispanic, and 13.0% Asian. The mean body mass index was 27.9 ± 5.0 kg/m(2). A total of 6% had RVH, which was generally mild. Traditional ECG criteria were specific (many >95%) but had low sensitivity for RVH by cMRI. The positive predictive values were not sufficiently high as to be clinically useful (maximum 12%). The results did not differ based on age, sex, race, or smoking status, or with the inclusion of participants with abnormal LV mass or function. Classification and regression tree analysis revealed that no combination of ECG variables was better than the criteria used singly.
The recommended ECG screening criteria for RVH are not sufficiently sensitive or specific for screening for mild RVH in adults without clinical cardiovascular disease.
Multiparameter optimization of a series of 5-((4-aminopyridin-2-yl)amino)pyrazine-2-carbonitriles resulted in the identification of a potent and selective oral CHK1 preclinical development ...candidate with in vivo efficacy as a potentiator of deoxyribonucleic acid (DNA) damaging chemotherapy and as a single agent. Cellular mechanism of action assays were used to give an integrated assessment of compound selectivity during optimization resulting in a highly CHK1 selective adenosine triphosphate (ATP) competitive inhibitor. A single substituent vector directed away from the CHK1 kinase active site was unexpectedly found to drive the selective cellular efficacy of the compounds. Both CHK1 potency and off-target human ether-a-go-go-related gene (hERG) ion channel inhibition were dependent on lipophilicity and basicity in this series. Optimization of CHK1 cellular potency and in vivo pharmacokinetic–pharmacodynamic (PK–PD) properties gave a compound with low predicted doses and exposures in humans which mitigated the residual weak in vitro hERG inhibition.
Human mutations and in vitro studies indicate that DLX3 has a crucial function in bone development, however, the in vivo role of DLX3 in endochondral ossification has not been established. Here, we ...identify DLX3 as a central attenuator of adult bone mass in the appendicular skeleton. Dynamic bone formation, histologic and micro-computed tomography analyses demonstrate that in vivo DLX3 conditional loss of function in mesenchymal cells (Prx1-Cre) and osteoblasts (OCN-Cre) results in increased bone mass accrual observed as early as 2 weeks that remains elevated throughout the lifespan owing to increased osteoblast activity and increased expression of bone matrix genes. Dlx3OCN-conditional knockout mice have more trabeculae that extend deeper in the medullary cavity and thicker cortical bone with an increased mineral apposition rate, decreased bone mineral density and increased cortical porosity. Trabecular TRAP staining and site-specific Q-PCR demonstrated that osteoclastic resorption remained normal on trabecular bone, whereas cortical bone exhibited altered osteoclast patterning on the periosteal surface associated with high Opg/Rankl ratios. Using RNA sequencing and chromatin immunoprecipitation-Seq analyses, we demonstrate that DLX3 regulates transcription factors crucial for bone formation such as Dlx5, Dlx6, Runx2 and Sp7 as well as genes important to mineral deposition (Ibsp, Enpp1, Mepe) and bone turnover (Opg). Furthermore, with the removal of DLX3, we observe increased occupancy of DLX5, as well as increased and earlier occupancy of RUNX2 on the bone-specific osteocalcin promoter. Together, these findings provide novel insight into mechanisms by which DLX3 attenuates bone mass accrual to support bone homeostasis by osteogenic gene pathway regulation.
Although conventional cogeneration systems have been used successfully in the last two decades, most of them have been large units using mainly hydrocarbon fuels that are becoming increasingly ...expensive. New cogeneration systems based on fuel cells and sorption air conditioning systems promise to be an energy-saving alternative for situations when cooling, heating and power are needed at low and medium capacities. Cogeneration Fuel Cell-Sorption Air Conditioning Systems examines the thermodynamic principles of fuel cell performance and sorption air conditioning systems, and gives relevant information about the state of the art of these technologies. It also provides the reader with the theoretical bases and knowledge needed to understand the operation of these new cogeneration systems, as well as discussing the design basis and economical evaluation. Topics covered include: selected fuel cells for cogeneration CHP processes, state-of-the-art sorption refrigeration systems, potential applications in demonstration projects, and profitability assessment of the cogeneration system. Air conditioning and fuel cell engineers, postgraduates and researchers in energy fields, and designers of cooling, heating and power cogeneration systems will find Cogeneration Fuel Cell-Sorption Air Conditioning Systems a useful and informative reference.
The uptake of pre-exposure prophylaxis (PrEP) for HIV prevention remains low. We hypothesized that a high proportion of patients presenting for HIV non-occupational post-exposure prophylaxis (nPEP) ...would be candidates for PrEP based on current CDC guidelines. Outcomes from a comprehensive HIV Prevention Clinic are described. We evaluated all patients who attended the HIV Prevention Clinic for nPEP between January 1, 2013 and September 30, 2014. Each patient was evaluated for PrEP candidacy based on current CDC-guidelines and subjectively based on physician opinion. Patients were then evaluated for initiation of PrEP if they met guideline suggestions. Demographic, social, and behavioral factors were then analyzed with logistic regression for associations with PrEP candidacy and initiation. 99 individuals who attended the nPEP clinic were evaluated for PrEP. The average age was 32 years (range, 18-62), 83 (84%) were male, of whom 46 (55%) men who had have sex with men (MSM). 31 (31%) met CDC guidelines for PrEP initiation, which had very good agreement with physician recommendation (kappa=0.88, 0.78-0.98). Factors associated with PrEP candidacy included sexual exposure to HIV, prior nPEP use, and lack of drug insurance (p<0.05 for all comparisons). Combining nPEP and PrEP services in a dedicated clinic can lead to identification of PrEP candidates and may facilitate PrEP uptake. Strategies to ensure equitable access of PrEP should be explored such that those without drug coverage may also benefit from this effective HIV prevention modality.
Observations of neutral-current nu interactions on deuterium in the Sudbury Neutrino Observatory are reported. Using the neutral current (NC), elastic scattering, and charged current reactions and ...assuming the standard 8B shape, the nu(e) component of the 8B solar flux is phis(e) = 1.76(+0.05)(-0.05)(stat)(+0.09)(-0.09)(syst) x 10(6) cm(-2) s(-1) for a kinetic energy threshold of 5 MeV. The non-nu(e) component is phi(mu)(tau) = 3.41(+0.45)(-0.45)(stat)(+0.48)(-0.45)(syst) x 10(6) cm(-2) s(-1), 5.3sigma greater than zero, providing strong evidence for solar nu(e) flavor transformation. The total flux measured with the NC reaction is phi(NC) = 5.09(+0.44)(-0.43)(stat)(+0.46)(-0.43)(syst) x 10(6) cm(-2) s(-1), consistent with solar models.
Each year diagnostic laboratories in the Netherlands profile thousands of individuals for heritable disease using next‐generation sequencing (NGS). This requires pathogenicity classification of ...millions of DNA variants on the standard 5‐tier scale. To reduce time spent on data interpretation and increase data quality and reliability, the nine Dutch labs decided to publicly share their classifications. Variant classifications of nearly 100,000 unique variants were catalogued and compared in a centralized MOLGENIS database. Variants classified by more than one center were labeled as “consensus” when classifications agreed, and shared internationally with LOVD and ClinVar. When classifications opposed (LB/B vs. LP/P), they were labeled “conflicting”, while other nonconsensus observations were labeled “no consensus”. We assessed our classifications using the InterVar software to compare to ACMG 2015 guidelines, showing 99.7% overall consistency with only 0.3% discrepancies. Differences in classifications between Dutch labs or between Dutch labs and ACMG were mainly present in genes with low penetrance or for late onset disorders and highlight limitations of the current 5‐tier classification system. The data sharing boosted the quality of DNA diagnostics in Dutch labs, an initiative we hope will be followed internationally. Recently, a positive match with a case from outside our consortium resulted in a more definite disease diagnosis.
PDF
