The Location and Nature of General Anesthetic Binding Sites on the Active Conformation of Firefly Luciferase; A Time Resolved Photolabeling Study

Firefly luciferase is one of the few soluble proteins that is acted upon by a wide variety of general anesthetics and alcohols; they inhibit the ATP–driven production of light. We have used time–resolved photolabeling to locate the binding sites of alcohols during the initial light output, some 200 ms after adding ATP. The photolabel 3-azioctanol inhibited the initial light output with an IC50 of 200 µM, close to its general anesthetic potency. Photoincorporation of [3H]3-azioctanol into luciferase was saturable but weak. It was enhanced 200 ms after adding ATP but was negligible minutes later. Sequencing of tryptic digests by HPLC–MSMS revealed a similar conformation–dependence for photoincorporation of 3-azioctanol into Glu-313, a residue that lines the bottom of a deep cleft (vestibule) whose outer end binds luciferin. An aromatic diazirine analog of benzyl alcohol with broader side chain reactivity reported two sites. First, it photolabeled two residues in the vestibule, Ser-286 and Ile-288, both of which are implicated with Glu-313 in the conformation change accompanying activation. Second, it photolabeled two residues that contact luciferin, Ser-316 and Ser-349. Thus, time resolved photolabeling supports two mechanisms of action. First, an allosteric one, in which anesthetics bind in the vestibule displacing water molecules that are thought to be involved in light output. Second, a competitive one, in which anesthetics bind isosterically with luciferin. This work provides structural evidence that supports the competitive and allosteric actions previously characterized by kinetic studies

PANC Study (Pancreatitis: A National Cohort Study): national cohort study examining the first 30 days from presentation of acute pancreatitis in the UK

Abstract Background Acute pancreatitis is a common, yet complex, emergency surgical presentation. Multiple guidelines exist and management can vary significantly. The aim of this first UK, multicentre, prospective cohort study was to assess the variation in management of acute pancreatitis to guide resource planning and optimize treatment. Methods All patients aged greater than or equal to 18 years presenting with acute pancreatitis, as per the Atlanta criteria, from March to April 2021 were eligible for inclusion and followed up for 30 days. Anonymized data were uploaded to a secure electronic database in line with local governance approvals. Results A total of 113 hospitals contributed data on 2580 patients, with an equal sex distribution and a mean age of 57 years. The aetiology was gallstones in 50.6 per cent, with idiopathic the next most common (22.4 per cent). In addition to the 7.6 per cent with a diagnosis of chronic pancreatitis, 20.1 per cent of patients had a previous episode of acute pancreatitis. One in 20 patients were classed as having severe pancreatitis, as per the Atlanta criteria. The overall mortality rate was 2.3 per cent at 30 days, but rose to one in three in the severe group. Predictors of death included male sex, increased age, and frailty; previous acute pancreatitis and gallstones as aetiologies were protective. Smoking status and body mass index did not affect death. Conclusion Most patients presenting with acute pancreatitis have a mild, self-limiting disease. Rates of patients with idiopathic pancreatitis are high. Recurrent attacks of pancreatitis are common, but are likely to have reduced risk of death on subsequent admissions. </jats:sec

Prominence of Filtering Techniques for Harmonics Mitigation in Advanced Power Electronics Systems

With the advancement in technology, non-linear loads, continue to increase, and the enigma of harmonics is getting more and more serious. The huge addition of electronic loads in power systems has formed the problem of harmonic generation that has resulted in many associated drawbacks. This paper aims to analyze the harmonics in advanced power electronics-based systems and describes a solution to mitigate them through two distinguished filtering techniques. A rigorous analysis is done concerning the generation of harmonic distortion through different types of loads and harmonic mitigation by employing passive and active power filters. The active power (adaptive) filtering method mitigates all sorts of undesirable frequency components using artificial intelligence (AI) based algorithms by calculating the weight of the fundamental component and generating a harmonics replica to subtract it from the original periodic wave. The simulations that were done show that the indicated techniques can mitigate undesirable harmonics and can lower the total harmonic distortion (THD) effectively according to the statutory limit of the IEEE 519-2014 standard, thus lowering the associated drawbacks of harmonic generation in advanced power electronics systems

Prominence of Filtering Techniques for Harmonics Mitigation in Advanced Power Electronics Systems

With the advancement in technology, non-linear loads, continue to increase, and the enigma of harmonics is getting more and more serious. The huge addition of electronic loads in power systems has formed the problem of harmonic generation that has resulted in many associated drawbacks. This paper aims to analyze the harmonics in advanced power electronics-based systems and describes a solution to mitigate them through two distinguished filtering techniques. A rigorous analysis is done concerning the generation of harmonic distortion through different types of loads and harmonic mitigation by employing passive and active power filters. The active power (adaptive) filtering method mitigates all sorts of undesirable frequency components using artificial intelligence (AI) based algorithms by calculating the weight of the fundamental component and generating a harmonics replica to subtract it from the original periodic wave. The simulations that were done show that the indicated techniques can mitigate undesirable harmonics and can lower the total harmonic distortion (THD) effectively according to the statutory limit of the IEEE 519-2014 standard, thus lowering the associated drawbacks of harmonic generation in advanced power electronics systems

Carboetomidate: A Pyrrole Analog of Etomidate Designed Not to Suppress Adrenocortical Function

Background: Etomidate is a sedative-hypnotic that is often used in critically ill patients because it provides superior hemodynamic stability. However it also binds with high affinity to 11?-hydroxylase, potently suppressing synthesis of steroids by the adrenal gland that are necessary for survival. We report the results of studies to define the pharmacology of (R)-ethyl 1-(1-phenylethyl)-1H-pyrrole-2-carboxylate (carboetomidate), a pyrrole analogue of etomidate specifically designed not to bind with high affinity to 11?-hydroxylase. Methods: The hypnotic potency of carboetomidate was defined in tadpoles and rats using loss of righting reflex assays. Its ability to enhance wild-type ?1?2?2L and etomidate-insensitive mutant ?1?2(M286W)?2L human ?-aminobutyric acid type A receptor activities was assessed using electrophysiological techniques. Its potency for inhibiting in vitro cortisol synthesis was defined using a human adrenocortical cell assay. Its effects on in vivo hemodynamic and adrenocortical function were defined in rats. Results: Carboetomidate was a potent hypnotic in tadpoles and rats. It increased currents mediated by wild-type, but not etomidate-insensitive mutant ?-aminobutyric acid type A receptors. Carboetomidate was three orders of magnitude less potent an inhibitor of in vitro cortisol synthesis by adrenocortical cells than was etomidate. In rats, carboetomidate caused minimal hemodynamic changes and did not suppress adrenocortical function at hypnotic doses. Conclusions: Carboetomidate is an etomidate analogue that retains many of etomidate’s beneficial properties, but is dramatically less potent as an inhibitor of adrenocortical steroid synthesis. Carboetomidate is a promising new sedative-hypnotic for potential use in critically ill patients in whom adrenocortical suppression is undesirable