The Use of Isomeric Testosterone Dimers to Explore Allosteric Effects in Substrate Binding to Cytochrome P450 CYP3A4

Abstract: Cytochrome P450 CYP3A4 is the main drug-metabolizing enzyme in the human liver, being responsible for oxidation of 50% of all pharmaceuticals metabolized by human P450 enzymes. Possessing a large substrate binding pocket, it can simultaneously bind several substrate molecules and often exhibits a complex pattern of drug–drug interactions. In order to better understand structural and functional aspects of binding of multiple substrate molecules to CYP3A4 we used resonance Raman and UV–VIS spectroscopy to document the effects of binding of synthetic testosterone dimers of different configurations, cis-TST2 and trans-TST2. We directly demonstrate that the binding of two steroid molecules, which can assume multiple possible configurations inside the substrate binding pocket of monomeric CYP3A4, can lead to active site structural changes that affect functional properties. Using resonance Raman spectroscopy, we have documented perturbations in the ferric and Fe-CO states by these substrates, and compared these results with effects caused by binding of monomeric TST. While the binding of trans-TST2 yields results similar to those obtained with monomeric TST, the binding of cis-TST2 is much tighter and results in significantly more pronounced conformational changes of the porphyrin side chains and Fe-CO unit. In addition, binding of an additional monomeric TST molecule in the remote allosteric site significantly improves binding affinity and the overall spin shift for CYP3A4 with trans-TST2 dimer bound inside the substrate binding pocket. This result provides the first direct evidence for an allosteric effect of the peripheral binding site at the protein-membrane interface on the functional properties of CYP3A4. Graphical abstract: Synthetic dimers of the steroid testosterone are used to address directly the mechanisms of multiple substrate binding at the active site of cytochrome P450 3A4 and the role of substrate binding at a distal site in the control of allostery in this central enzyme of human drug metabolism

Cluster analysis of wind turbine alarms for characterising and classifying stoppages

Turbine alarm systems can give useful information to remote technicians on the cause of a fault or stoppage. However, alarms are generally generated at much too high a rate to gain meaningful insight from on their own, so generally require extensive domain knowledge to interpret. By grouping together commonly occurring alarm sequences, the burden of analysis can be reduced. Instead of analysing many individual alarms that occur during a stoppage, the stoppage can be linked to a commonly occurring sequence of alarms. Hence, maintenance technicians can be given information about the shared characteristics or root causes of stoppages where that particular alarm sequence appeared in the past. This research presents a methodology to identify relevant alarms from specific turbine assemblies and group together similar alarm sequences as they appear during stoppages. Batches of sequences associated with 456 different stoppages are created, and features are extracted from these batches representing the order the alarms appeared in. The batches are grouped together using clustering techniques, and evaluated using silhouette analysis and manual inspection. Results show that almost half of all stoppages can be attributed to one of 15 different clusters of alarm sequences

Finite element approximation of the p(⋅)p(\cdot)-Laplacian

We study a~priori estimates for the Dirichlet problem of the $p(\cdot)$-Laplacian, $$-\mathrm{div}(|\nabla v|^{p(\cdot)-2} \nabla v) = f.$$ We show that the gradients of the finite element approximation with zero boundary data converges with rate $O(h^\alpha)$ if the exponent $p$ is $\alpha$-H\"{o}lder continuous. The error of the gradients is measured in the so-called quasi-norm, i.e. we measure the $L^2$-error of $|\nabla v|^{\frac{p-2}{2}} \nabla v$

Correlation between body mass index and waist circumference in Nigerian adults: implication as indicators of health status

Background. Anthropometric measures have been widely used for body weight classification in humans. Waist circumference has been advanced as a useful parameter for measuring adiposity. This study evaluated the correlation between body mass index (BMI) and waist circumference and examined their significance as indicators of health status in adults. Design and Methods. The subject included 489 healthy adults from Ota, Nigeria, aged between 20 and 75 years, grouped into early adulthood (20-39 years), middle adulthood (40-59 years) and advanced adulthood (60 years and above). Weight, height and abdominal circumference were measured. BMI was calculated as weight kg/height2 (m2) and World Health Organization cut-offs were used to categorize them into normal, underweight, overweight and obese. Results. Abnormal weight categories accounted for 60 % of the subjects (underweight 11 %, overweight 31%, and obese 18%). The waist circumference of overweight and obese categories were significantly (P<0.05) higher than the normal weight category. There was no significant difference between waist circumference of underweight and normal subjects. The correlation coefficient values of BMI with waist circumference (r=0.63), body weight (r=0.76) and height (r=-0.31) were significant (P<0.01) for the total subjects. Conclusions. The study indicates that waist circumference can serve as a positive indicator of overweight and obesity in the selected communities; however, it may not be used to determine underweight in adults. Regular BMI and waist circumference screening is recommended as an easy and effective means of assessing body weight and in the prevention of weight related diseases in adults

Automatically identifying and predicting unplanned wind turbine stoppages using SCADA and alarms system data: case study and results

Using 10-minute wind turbine SCADA data for fault prediction offers an attractive way of gaining additional prognostic capabilities without needing to invest in extra hardware. To use these data-driven methods effectively, the historical SCADA data must be labelled with the periods when the turbine was in faulty operation as well the sub-system the fault was attributed to. Manually identifying faults using maintenance logs can be effective, but is also highly time consuming and tedious due to the disparate nature of these logs across manufacturers, operators and even individual maintenance events. Turbine alarm systems can help to identify these periods, but the sheer volume of alarms and false positives generated makes analysing them on an individual basis ineffective. In this work, we present a new method for automatically identifying historical stoppages on the turbine using SCADA and alarms data. Each stoppage is associated with either a fault in one of the turbine's sub-systems, a routine maintenance activity, a grid-related event or a number of other categories. This is then checked against maintenance logs for accuracy and the labelled data fed into a classifier for predicting when these stoppages will occur. Results show that the automated labelling process correctly identifies each type of stoppage, and can be effectively used for SCADA-based prediction of turbine fault

Klinička evaluacija inlej-retiniranih adhezivnih mostova tokom dvogodišnjeg opservacionog perioda

Introduction. Inlay retained adhesive restorations present a conservative approach when a single tooth is missing in the posterior region. Material and methods. Twenty five restorations were included in the clinical study. Patient selection, preparation technique as well as denture fabrication followed current principles in this area. Patients were examined every 6 months over a 2 year examination period. Results were statistically analyzed. Results. The success rate for the first year comes to 91.1%, while cumulative success probability during the second year (24 months) was 86.6%. Furthermore, colour, texture and marginal staining were satisfactory during the observation period. Conclusion. Fibre-reinforced composite adhesive dentures are a tooth preserving, minimally invasive, aesthetic and reliable treatment option for single tooth replacement in the posterior area.Uvod. Inlej retinirani adhezivni mostovi predstavljaju konzervativni modalitet tretmana nedostatka pojedinačnog zuba u bočnoj regiji. Materijal i metod. U kliničku studiju, uključeno je 25 adhezivnih nadoknada. Odabir pacijenata, principi preparacije, kao i tehnika izrade mostova urađeni su prema važećim standardima u ovoj oblasti. Pacijenti su praćeni na svakih 6 meseci tokom dvogodišnjeg perioda. Rezultati su statistički obrađeni. Rezultati. Uspešnost nadoknada u prvoj godini iznosi 91.1%, dok kumulativna uspešnost tokom druge godine (24 meseca) iznosi 86.6%. Takođe, ocena boje, teksture i marginalnog prebojavanja daje zadovoljavajuće rezulate tokom perioda praćenja. Zaključak. Kompozitne nadoknade ojačane vlaknima su minimalno invazivni, estetski i pouzdan način tretmana minimalne krezubosti bočnog segmenta denticije

E. coli O157 on Scottish cattle farms: evidence of local spread and persistence using repeat cross-sectional data

&lt;b&gt;Background&lt;/b&gt;&lt;p&gt;&lt;/p&gt; Escherichia coli (E. coli) O157 is a virulent zoonotic strain of enterohaemorrhagic E. coli. In Scotland (1998-2008) the annual reported rate of human infection is 4.4 per 100,000 population which is consistently higher than other regions of the UK and abroad. Cattle are the primary reservoir. Thus understanding infection dynamics in cattle is paramount to reducing human infections.&lt;p&gt;&lt;/p&gt; A large database was created for farms sampled in two cross-sectional surveys carried out in Scotland (1998 - 2004). A statistical model was generated to identify risk factors for the presence of E. coli O157 on farms. Specific hypotheses were tested regarding the presence of E. coli O157 on local farms and the farms previous status. Pulsed-field gel electrophoresis (PFGE) profiles were further examined to ascertain whether local spread or persistence of strains could be inferred.&lt;p&gt;&lt;/p&gt; &lt;b&gt;Results&lt;/b&gt;&lt;p&gt;&lt;/p&gt; The presence of an E. coli O157 positive local farm (average distance: 5.96km) in the Highlands, North East and South West, farm size and the number of cattle moved onto the farm 8 weeks prior to sampling were significant risk factors for the presence of E. coli O157 on farms. Previous status of a farm was not a significant predictor of current status (p = 0.398). Farms within the same sampling cluster were significantly more likely to be the same PFGE type (p &#60; 0.001), implicating spread of strains between local farms. Isolates with identical PFGE types were observed to persist across the two surveys, including 3 that were identified on the same farm, suggesting an environmental reservoir. PFGE types that were persistent were more likely to have been observed in human clinical infections in Scotland (p &#60; 0.001) from the same time frame.&lt;p&gt;&lt;/p&gt; &lt;b&gt;Conclusions&lt;/b&gt;&lt;p&gt;&lt;/p&gt; The results of this study demonstrate the spread of E. coli O157 between local farms and highlight the potential link between persistent cattle strains and human clinical infections in Scotland. This novel insight into the epidemiology of Scottish E. coli O157 paves the way for future research into the mechanisms of transmission which should help with the design of control measures to reduce E. coli O157 from livestock-related sources

Health care effects and medical benefits of a smartphone-based diabetes self-management application : study protocol for a randomized controlled trial

Background: Diabetes self-management is a mainstay of diabetes care, but the implementation of self-management regimens into daily life is complex and often results in discouragement and distress. Modern approaches such as smartphone-based self-management applications are therefore needed to support people with diabetes. Since reimbursability would increase the availability of such digital applications to people with diabetes, we designed a study that meets all scientific and methodological requirements set by the German Digital Healthcare Act to allow reimbursement for a specific application (mySugr PRO). Here, we report the protocol of this study that aims at evaluating the efficacy of the digital self-management application with regard to patient-reported outcomes and medical benefits. Methods/design: This multicenter, open-label, randomized, parallel-group, controlled trial will evaluate the health care effects and medical benefits of mySugr PRO. A total of 466 people with diabetes will be randomly allocated (2:1 randomization) to the interventional group (n = 311) that will use the digital self-management application during the 12-week study period or the control group (n = 155; no usage of the application). Baseline and follow-up examinations will assess diabetes distress as the primary endpoint as well as empowerment, HbA1c, blood glucose data, self-management, general well-being, and treatment satisfaction as secondary endpoints. Statistical analyses will use an intention-to-treat procedure (using multiple imputation for missing values) as well as a per-protocol approach for sensitivity analysis. Discussion: To the best of our knowledge, this study will be one of the largest diabetes-specific evaluations of a digital health application supporting people with diabetes in their diabetes self-management that follow the requirements of the German Digital Healthcare Act. Trial registration: German Clinical Trial Register DRKS00022923. Registered on 22 October 2020

Generally Covariant Actions for Multiple D-branes

We develop a formalism that allows us to write actions for multiple D-branes with manifest general covariance. While the matrix coordinates of the D-branes have a complicated transformation law under coordinate transformations, we find that these may be promoted to (redundant) matrix fields on the transverse space with a simple covariant transformation law. Using these fields, we define a covariant distribution function (a matrix generalization of the delta function which describes the location of a single brane). The final actions take the form of an integral over the curved space of a scalar single-trace action built from the covariant matrix fields, tensors involving the metric, and the covariant distribution function. For diagonal matrices, the integral localizes to the positions of the individual branes, giving N copies of the single-brane action.Comment: 34 pages, LaTeX. v2: comments and refs adde