Synthesis, molecular modelling and CYP24A1 inhibitory activity of novel of (E)-N-(2-(1H-imidazol-1-yl)-2-(phenylethyl)-3/4-styrylbenzamides

CYP24A1 (25-hydroxyvitamin D-24-hydroxylase) is a useful enzyme target for a range of medical conditions including cancer, cardiovascular and autoimmune disease, which show elevated CYP24A1 levels and corresponding reduction of calcitriol (the biologically active form of vitamin D). A series of (E)-N-(2-(1H-imidazol-1-yl)-2-(phenylethyl)-3/4-styrylbenzamides have been synthesised using an efficient synthetic route and shown to be potent inhibitors of CYP24A1 (IC50 0.11–0.35 μM) compared with the standard ketoconazole. Molecular modelling using our CYP24A1 homology model showed the inhibitors to fill the hydrophobic binding site, forming key transition metal interaction between the imidazole nitrogen and the haem Fe3+ and multiple interactions with the active site amino acid residues

Adiabatic Formation of Rydberg Crystals with Chirped Laser Pulses

Ultracold atomic gases have been used extensively in recent years to realize textbook examples of condensed matter phenomena. Recently, phase transitions to ordered structures have been predicted for gases of highly excited, 'frozen' Rydberg atoms. Such Rydberg crystals are a model for dilute metallic solids with tunable lattice parameters, and provide access to a wide variety of fundamental phenomena. We investigate theoretically how such structures can be created in four distinct cold atomic systems, by using tailored laser-excitation in the presence of strong Rydberg-Rydberg interactions. We study in detail the experimental requirements and limitations for these systems, and characterize the basic properties of small crystalline Rydberg structures in one, two and three dimensions.Comment: 23 pages, 10 figures, MPIPKS-ITAMP Tandem Workshop, Cold Rydberg Gases and Ultracold Plasmas (CRYP10), Sept. 6-17, 201

Breast cancer management and outcome according to surgeon's affiliation: a population-based comparison adjusted for patient's selection bias

Background Studies have reported that breast cancer (BC) units could increase the quality of care but none has evaluated the efficacy of alternative options such as private BC networks, which is our study objective. Patients and methods We included all 1404 BC patients operated in the public unit or the private network and recorded at the Geneva Cancer Registry between 2000 and 2005. We compared quality indicators of care between the public BC unit and the private BC network by logistic regression and evaluated the effect of surgeon's affiliation on BC-specific mortality by the Cox model adjusting for the propensity score. Results Both the groups had high care quality scores. For invasive cancer, histological assessment before surgery and axillary lymph node dissection when indicated were less frequent in the public sector (adjusted odds ratio (OR): 0.4, 95% confidence interval (CI) 0.3-0.7, and OR: 0.4, 95% CI 0.2-0.8, respectively), while radiation therapy after breast-conserving surgery was more frequent (OR: 2.5, 95% CI 1.4-4.8). Surgeon affiliation had no substantial effect on BC-specific mortality (adjusted hazard ratio (HR): 0.8, 95% CI 0.5-1.4). Conclusions This study suggests that private BC networks could be an alternative to public BC units with both structures presenting high quality indicators of BC care and similar BC-specific mortalit

Left ventricular pseudo-aneurysm: Do not make the same mistake

The differentiation between left ventricular pseudo-aneurysm and true aneurysm is sometimes difficult and there are some pitfalls in the process of making the right diagnosis. Correct diagnosis has considerable effect on the outcome and management of the patients. We report the case of 59-year-old man who referred to the emergency department with complaints of lower extremity edema and dyspnea on exertion. In his past medical history, he had been diagnosed with post-myocardial infarction and apical true aneurysm four months before his arrival at the emergency ward. The patient was under strict medical follow-up for his condition. Echocardiography was conducted in the emergency ward, and it revealed a huge apical pseudo-aneurysm, which had been miss-diagnosed in the past echocardiographic examination. We herein seek to address this issue and underscore the pitfalls in making the correct and necessary distinction between these two not so uncommon entities

Experimental and mathematical survey of sound absorption performance of date palm fibers

The present study examines the acoustic behavior sample composites made of date palm natural fibers and polyvinyl alcohol. It also provides the comparison between the sound absorption coefficients obtained from the experimental tests and the ones predicted by the mathematical models. An impedance tube system was used to measure the normal sound absorption coefficient of the samples. Using the differential equation algorithm, the predicted sound absorption coefficient for the Johnson-Champoux-Allard model was also calculated. The sound absorption properties of samples increased significantly by increasing the frequency, and increasing the thickness of materials with constant density. Comparison of the data from the experimental tests and mathematical model showed that increasing the thickness of samples will make the predicted and tested values of acoustic absorption coefficient significantly comparable. Date palm fibers have a good potential for dissipating the energy of sound waves particularly when an air gap is introduced behind the sample and can be used as a new source for the fabrication of natural fiber reinforced composites. © 2019 The Author(s

Analysis of the binding sites of vitamin D 1α-hydroxylase (CYP27B1) and vitamin D 24-hydroxylase (CYP24A1) for the design of selective CYP24A1 inhibitors: homology modelling, molecular dynamics simulations and identification of key binding requirements

A homology model of human CYP27B1 was built using MOE and was further optimised by molecular dynamics simulations of the hCYP27B1 homology model and a hCYP27B1-SDZ-88357 complex. Docking results from the hCYP27B1-SDZ-88357 complex showed amino acids Arg107, Asn387 and Asp320 have an important role in binding interaction, with Asp320 part of the important acid-alcohol pair situated in the I-helix with the conserved sequence (A/G) GX (E/D) (T/S), which assumes an essential role in the binding of an oxygen molecule for catalysis. Additional docking experiments with selective hCYP27B1 or hCYP24A1 inhibitors using both the hCYP27B1 model and a triple mutant hCYP24A1 model provided further support for the importance of H-bonding interactions with the three identified active site amino acids. To confirm the role of Arg107, Asn387 and Asp320 in the active site of hCYP27B1 compounds were designed that would form H-bonding interactions, as determined from docking experiments with the hCYP27B1 model. Subsequent synthesis and CYP24A1 and CYP27B1 enzyme assays of the designed compounds 1a and 1b showed a ∼5-fold selectivity for CYP27B1 confirming the importance of Asp320 in particular and also Asn387 and Arg107 as important amino acids for CYP27B1 inhibitory activity

Reduced Nucleus Accumbens SK Channel Activity Enhances Alcohol Seeking during Abstinence

SummaryThe cellular mechanisms underlying pathological alcohol seeking remain poorly understood. Here, we show an enhancement of nucleus accumbens (NAcb) core action potential firing ex vivo after protracted abstinence from alcohol but not sucrose self-administration. Increased firing is associated with reduced small-conductance calcium-activated potassium channel (SK) currents and decreased SK3 but not SK2 subunit protein expression. Furthermore, SK activation ex vivo produces greater firing suppression in NAcb core neurons from alcohol- versus sucrose-abstinent rats. Accordingly, SK activation in the NAcb core significantly reduces alcohol but not sucrose seeking after abstinence. In contrast, NAcb shell and lateral dorsal striatal firing ex vivo are not altered after abstinence from alcohol, and SK activation in these regions has little effect on alcohol seeking. Thus, decreased NAcb core SK currents and increased excitability represents a critical mechanism that facilitates motivation to seek alcohol after abstinence

Employment of the Master of Arts in Mathematics Education Graduates of a University in Northern Philippines

This study aimed to trace the 2015 to 2019 MAME graduates in the College of Teacher Education for Graduate Studies of the University of Northern Philippines in terms of their personal profile, their work-related profile before and after taking their master’s degree, reasons of taking up the program, competency level before and after taking the program, appraisal of the most useful courses offered in the program, evaluation on the contribution of the program to their personal and professional growth and assessment on the features of the program and suggestions of how to improve the program. The researcher utilized mixed method of research. The subjects were the MAME graduates, and a questionnaire and open-ended questions were sent to them thru various online flat forms. Based on the findings of the study, the following conclusions are derived: pursuing graduate studies chooses no sex, civil status or age as long as there is a will to improve one's self; students have math- related educational background and finished the program within the prescribed number of years; having master’s degree could contribute greatly in landing a permanent teaching job in public schools; professional and personal growth and development is the strongest drive to pursue advance education; the program offers subjects that are useful which enhanced the teaching competencies of the graduates and consequently contribute to the holistic development of the graduates; and that there are areas needing improvement in the MAME program

Making a symbolic gesture: a qualitative examination of self-immolation in Iran

Self-immolation is one of the most dramatic methods of committing suicide. Some regions in Iran have a high prevalence of suicide by this method. This study aims to understand and explore the experience of self-immolated women in Iran. Twenty women have interviewed in the burns centers of three different cities immediately the following hospitalization due self-immolation, and the data was analyzed using conventional content analysis. The results were categorized in three main categories: Cultural background and preparing the stage, making a symbolic gesture and events of the day of the incident. Making a symbolic gesture consists of the critical elements of self-immolation, including the presence of significant others, dramatic presentation of misery, bringing an end to misfortune, proof of innocence, creating a sense of compassion or guilt and inspiration from similar cases. The social situation of women in Iran is contributing to self-immolation through feelings of anger and helplessnes