Small‐Molecule Inhibitors Targeting Sterol 14α‐Demethylase (CYP51): Synthesis, Molecular Modelling and Evaluation Against Candida albicans

Fungal infections are a global issue affecting over 150 million people worldwide annually, with 750 000 of these caused by invasive Candida infections. Azole drugs are the frontline treatment against fungal infections; however, resistance to current azole antifungals in C. albicans poses a threat to public health. Two series of novel azole derivatives, short and extended derivatives, have been designed, synthesised and investigated for CYP51 inhibitory activity, binding affinity and minimum inhibitory concentration (MIC) against C. albicans strains. The short derivatives were more potent against the C. albicans strains (e. g., MIC 2‐(4‐chlorophenyl)‐N‐(2,4‐dichlorobenzyl)‐3‐(1H‐imidazol‐1‐yl)propanamide (5 f ) <0.03 μg/mL, N‐(4‐((4‐chlorophenyl)sulfonamido)benzyl)‐2‐phenyl‐3‐(1H‐1,2,4‐triazol‐1‐yl)propanamide (12 c ), 1 μg/mL, fluconazole 0.125 μg/mL) but both displayed comparable enzyme binding and inhibition (5 f K d 62±17 nM, IC50 0.46 μM; 12 c K d 43±18 nM, IC50 0.33 μM, fluconazole K d 41±13 nM, IC50 0.31 μM, posaconazole K d 43±11 nM, IC50 0.2 μM). The short series had poor selectivity for CaCYP51 over the human homologue, whereas the selectivity of the extended series, for example, compound 12 c , was higher (21.5‐fold) than posaconazole (4.7‐fold) based on K d values, although posaconazole was more selective (615‐fold) than 12 c (461‐fold) based on IC50 values. Based on inhibitory activity and selectivity profile, the extended series are the better of the two series for further development

An Analysis of Resting-State Functional Transcranial Doppler Recordings from Middle Cerebral Arteries

Functional transcrannial Doppler (fTCD) is used for monitoring the hemodynamics characteristics of major cerebral arteries. Its resting-state characteristics are known only when considering the maximal velocity corresponding to the highest Doppler shift (so called the envelope signals). Significantly more information about the resting-state fTCD can be gained when considering the raw cerebral blood flow velocity (CBFV) recordings. In this paper, we considered simultaneously acquired envelope and raw CBFV signals. Specifically, we collected bilateral CBFV recordings from left and right middle cerebral arteries using 20 healthy subjects (10 females). The data collection lasted for 15 minutes. The subjects were asked to remain awake, stay silent, and try to remain thought-free during the data collection. Time, frequency and time-frequency features were extracted from both the raw and the envelope CBFV signals. The effects of age, sex and body-mass index were examined on the extracted features. The results showed that the raw CBFV signals had a higher frequency content, and its temporal structures were almost uncorrelated. The information-theoretic features showed that the raw recordings from left and right middle cerebral arteries had higher content of mutual information than the envelope signals. Age and body-mass index did not have statistically significant effects on the extracted features. Sex-based differences were observed in all three domains and for both, the envelope signals and the raw CBFV signals. These findings indicate that the raw CBFV signals provide valuable information about the cerebral blood flow which can be utilized in further validation of fTCD as a clinical tool. © 2013 Sejdić et al

Does controlling for epicurean eating or the tendency to supersize food portions change the relationship between mindful eating and grazing?

The study examines the potential for Epicurean eating to offer fresh perspectives on the predictive value of mindful eating. This research seeks to ascertain whether accounting for Epicurean eating (or its antithesis, supersizing), could influence the previously identified negative relationship between mindful eating and grazing habits. In a cross-sectional study, 419 participants completed questionnaires on epicurean eating, grazing, and mindful eating. The findings suggested mindful eating and epicurean eating were significantly associated with grazing, with both variables accounting for a significant amount of variance in grazing. Further analysis of the mindful eating subscales showed that eating without distraction, eating with awareness, and hunger and satiety cues accounted for this association with grazing when epicurean eating was included. Finally, whilst eating without distraction, eating with awareness, and hunger and satiety cues were associated with grazing, preference for supersizing did not account for a significant amount of variance in the relationship with grazing. The complex interplay between grazing and mindful eating becomes more apparent when considering the influence of epicurean eating. Exploring cross-cultural factors through additional research could provide valuable insights into the dynamics of epicurean eating and grazing. Simultaneously, incorporating alternative mindful eating scales may yield a more nuanced interpretation of mindful eating. Collectively, these avenues of inquiry warrant further investigation. Limitations and future directions are discussed

Dielectric relaxations in PEEK by combined dynamic dielectric spectroscopy and thermally stimulated current

The molecular dynamics of a quenched poly (ether ether ketone) (PEEK) was studied over a broad frequency range from 10-3 to 106 Hz by combining dynamic dielectric spectroscopy (DDS) and thermo-stimulated current (TSC) analysis. The dielectric relaxation losses e00 KK has been determined from the real part e0 T(x) thanks to Kramers–Kronig transform. In this way, conduction and relaxation processes can be analyzed independently. Two secondary dipolar relaxations, the c and the b modes, corresponding to non-cooperative localized molecular mobility have been pointed out. The main a relaxation appeared close to the glass transition temperature as determined by DSC; it has been attributed to the delocalized cooperative mobility of the free amorphous phase. The relaxation times of dielectric relaxations determined with TSC at low frequency converge with relaxation times extracted from DDS at high frequency. This correlation emphasized continuity of mobility kinetics between vitreous and liquid state. The dielectric spectroscopy exhibits the ac relaxation, near 443 K, which has been associated with the rigid amorphous phase confined by crystallites. This present experiment demonstrates coherence of the dynamics of the PEEK heterogeneous amorphous phase between glassy and liquid state and significantly improve the knowledge of molecular/dynamic structure relationships

From the Guest Editors: the legitimacy and impact of business schools—key issues and a research agenda

It is an appropriate moment to review research into the legitimacy and impact of business schools. It is more than a decade now since Pfeffer and Fong's (2002) provocative paper challenging the perceived orthodoxy of business school success in the very first edition of the Academy of Management Learning & Education

Genetic Testing to Inform Epilepsy Treatment Management From an International Study of Clinical Practice

IMPORTANCE: It is currently unknown how often and in which ways a genetic diagnosis given to a patient with epilepsy is associated with clinical management and outcomes. OBJECTIVE: To evaluate how genetic diagnoses in patients with epilepsy are associated with clinical management and outcomes. DESIGN, SETTING, AND PARTICIPANTS: This was a retrospective cross-sectional study of patients referred for multigene panel testing between March 18, 2016, and August 3, 2020, with outcomes reported between May and November 2020. The study setting included a commercial genetic testing laboratory and multicenter clinical practices. Patients with epilepsy, regardless of sociodemographic features, who received a pathogenic/likely pathogenic (P/LP) variant were included in the study. Case report forms were completed by all health care professionals. EXPOSURES: Genetic test results. MAIN OUTCOMES AND MEASURES: Clinical management changes after a genetic diagnosis (ie, 1 P/LP variant in autosomal dominant and X-linked diseases; 2 P/LP variants in autosomal recessive diseases) and subsequent patient outcomes as reported by health care professionals on case report forms. RESULTS: Among 418 patients, median (IQR) age at the time of testing was 4 (1-10) years, with an age range of 0 to 52 years, and 53.8% (n = 225) were female individuals. The mean (SD) time from a genetic test order to case report form completion was 595 (368) days (range, 27-1673 days). A genetic diagnosis was associated with changes in clinical management for 208 patients (49.8%) and usually (81.7% of the time) within 3 months of receiving the result. The most common clinical management changes were the addition of a new medication (78 [21.7%]), the initiation of medication (51 [14.2%]), the referral of a patient to a specialist (48 [13.4%]), vigilance for subclinical or extraneurological disease features (46 [12.8%]), and the cessation of a medication (42 [11.7%]). Among 167 patients with follow-up clinical information available (mean [SD] time, 584 [365] days), 125 (74.9%) reported positive outcomes, 108 (64.7%) reported reduction or elimination of seizures, 37 (22.2%) had decreases in the severity of other clinical signs, and 11 (6.6%) had reduced medication adverse effects. A few patients reported worsening of outcomes, including a decline in their condition (20 [12.0%]), increased seizure frequency (6 [3.6%]), and adverse medication effects (3 [1.8%]). No clinical management changes were reported for 178 patients (42.6%). CONCLUSIONS AND RELEVANCE: Results of this cross-sectional study suggest that genetic testing of individuals with epilepsy may be materially associated with clinical decision-making and improved patient outcomes

La cohérence interne dans les enquêtes par interviews

International audienceEn marge des problèmes traditionnels de fidélité et validité de la mesure en marketing, la cohérence interne des réponses apportées par les répondants dans une enquête par interview est étudiée. Confrontés à des questions complexes portant sur des produits très nouveaux, les répondants font preuve d'un certain degré d'incohérence dans leurs réponses. La mesure et les facteurs explicatifs de cette incohérence doivent être examinés pour redresser les biais éventuels. Lorsqu'il pressent un danger d'incohérence sur un sujet, le chercheur en marketing doit impérativement multiplier les formulations des questions relatives à ce sujet

TMR system of feeding dairy cows in terms of precision agriculture

Wykonano analizę poprawności żywienia krów mlecznych pod względem energetycznym i białkowym. Materiał badawczy stanowiły wyniki użytkowości stada 250 krów za 6 miesięcy, od listopada 2010 r. do kwietnia 2011 r. Stado podzielono na 3 grupy technologiczno-żywieniowe na podstawie wydajności mlecznej krów. Zmian składu grup dokonywano raz w miesiącu. Grupa A, o najwyższej wydajności mleka, otrzymywała dawkę obliczoną na 38 kg mleka. Dawkę pokarmową dla grupy B zaplanowano na 28 kg, a dla grupy C - przed zasuszeniem na 19 kg mleka. Przeciętne wydajności grup w kolejnych miesiącach badań były dość stabilne. Różnice w wydajności mlecznej w obrębie grup były bardzo duże i przekraczały 20 kg. W grupie A u 34% krów zaobserwowano niedobór energii pobranej w paszy w stosunku do aktualnych potrzeb, natomiast w grupach B i C - nadmiar energii w pobranej paszy, odpowiednio u 62% i 75% krów. Niedobór białka w pobranej paszy wystąpił u 11% krów w grupie A, u 10% krów w grupie B i 24% w grupie C, a nadmiar odpowiednio - u 28, 19 i 22%.Correctness of feeding dairy cows was analysed in terms of sufficient energy and protein quantities supplied in the diet. As the source data for research, production results over 6 months (since November 2010 till April 2011) for the herd of 250 dairy cows were used. The herd was divided into 3 technological-nutrition groups of cows on the basis of milk yields. Once a month the structure of groups was corrected. The group A, of highest milk yielding cows, was fed with a diet provided for 38 kg milk production. Diet B was provided for group of cows yielding 28 kg milk, whereas for group C - the cows just before drying off - diet for 19 kg milk production. Average milk yields of particular groups in succeeding months of experiment were quite stable. However, the differences in milk yielding within particular groups were considerable and exceeded 20 kg. Shortage of energy in diets, in relation to the actual demands, was observed in 34% cows of group A; instead, in groups B and C the surplus of energy in diets fed - was noted in 62% and 75% cows. Protein deficiency in uptaken feed occurred in 11% cows of group A, in 10% cows of group B and in 24% cows of group C, while the excess in 28, 19 and 22% cows, respectively

Relation between structure and gas transport properties of polyethylene oxide networks based on crosslinked bisphenol A ethoxylate diacrylate

Poly(ethylene oxide) (PEO) networks prepared from the photopolymerization of bisphenol A ethoxylate diacrylate (BPA-EDA) have been investigated as a function of crosslinker molecular weight and copolymer composition. Dynamic mechanical and dielectric methods have been used to elucidate the thermal relaxation characteristics of the polymers as a function of network composition and architecture, and these properties were related to measured gas transport for CO2 separations. Copolymerization strategies involving the insertion of flexible PEG side chains along the network backbone proved effective in enhancing network free volume and increasing permeability. The gas transport performance of rubbery amorphous membranes based on the n=15 BPA-EDA crosslinker (i.e., crosslinker encompassing 30 ethylene oxide repeat units between crosslinks) compared favorably to model polymers synthesized from poly(ethylene glycol) diacrylate. © 2008 Elsevier Ltd. All rights reserved

Poly(curcumin &beta;-amino ester)-Based Tablet Formulation for a Sustained Release of Curcumin

Oral drug delivery remains the most common and well tolerated method for drug administration. However, its applicability is often limited due to low drug solubility and stability. One approach to overcome the solubility and stability limitations is the use of amorphous polymeric prodrug formulations, such as poly(&beta;-amino ester) (PBAE). PBAE hydrogels, which are biodegradable and pH responsive, have shown promising results for the controlled release of drugs by improving the stability and increasing the solubility of these drugs. In this work, we have evaluated the potential use of PBAE prodrugs in an oral tablet formulation, studying their sustained drug release potential and storage stability. Curcumin, a low solubility, low stability antioxidant drug was used as a model compound. Poly(curcumin &beta;-amino ester) (PCBAE), a crosslinked amorphous network, was synthesized by a previously published method using a commercial diacrylate and a primary diamine, in combination with acrylate-functionalized curcumin. PCBAE-based tablets were made and exhibited a sustained release for 16 h, following the hydrolytic degradation of PCBAE particles into native curcumin. In addition to the release studies, preliminary storage stability was assessed using standard and accelerated stability conditions. As PCBAE degradation is hydrolysis driven, tablet stability was found to be sensitive to moisture