Structural characterization of angiotensin I-converting enzyme in complex with a selenium analogue of captopril

Human somatic angiotensin I-converting enzyme (ACE), a zinc-dependent dipeptidyl carboxypeptidase, is central to the regulation of the renin–angiotensin aldosterone system. It is a well-known target for combating hypertension and related cardiovascular diseases. In a recent study by Bhuyan and Mugesh [Org. Biomol. Chem. (2011) 9, 1356–1365], it was shown that the selenium analogues of captopril (a well-known clinical inhibitor of ACE) not only inhibit ACE, but also protect against peroxynitrite-mediated nitration of peptides and proteins. Here, we report the crystal structures of human testis ACE (tACE) and a homologue of ACE, known as AnCE, from Drosophila melanogaster in complex with the most promising selenium analogue of captopril (SeCap) determined at 2.4 and 2.35 Å resolution, respectively. The inhibitor binds at the active site of tACE and AnCE in an analogous fashion to that observed for captopril and provide the first examples of a protein–selenolate interaction. These new structures of tACE–SeCap and AnCE–SeCap inhibitor complexes presented here provide important information for further exploration of zinc coordinating selenium-based ACE inhibitor pharmacophores with significant antioxidant activity

Simulation of a pre-structure device for fountain-like magnetorheological elastomer via Finite Element Magnetic Method (FEMM)

The ability of a pre-structure device for curing the fountain-like alignment of CIPs in a magnetorheological elastomer (MRE) is simulated in this study. In order to generate the fountain-like magnetic flux in the device, the device was equipped with an electromagnet coil and a cylindrical permanent magnet to pick-up the pass magnetic flux trough the MRE mould. While the electromagnetic coil is utilised to control the generated magnetic flux density in the device via manipulating induced currents for different magnetic fields. The analysis then was conducted by using Finite Element Magnetic Method (FEMM) software to determine the magnetic flux density in the device as well as the fountain-like shape of magnetic flux lines that flew in the MRE mould. In the simulation, the primary factor in determining the strength of the magnetic field across the mould is the change in current. The simulation has found that the current required to generate around 0.24T is about 1A comprise of electromagnetic coil and permanent magnet

Water retention properties of a fused deposition modeling based 3D printed polylactic acid vessel

The applications of fused deposition modelling (FDM) based 3D printing have gone beyond merely simple prototypes to where functionalities are expected. One of such functionalities is the water retention properties, especially for fluid handling products, either completely waterproof or deliberately porous. Issues arise especially in determining crucial parameters and their optimization to achieve the desired water retention properties. This study established the relationship among printing parameters (layer thickness and wall thickness) and water temperature with leakage flow rate. A series of 3D printed polylactic acid (PLA) vessels were fabricated at various layer height and wall thickness. Then, the volumetric loss of water at various temperatures was measured, elapsed time was recorded, and the leakage flow rate was calculated for each 3D printed vessel. It has been found that the leakage flow rate decreased when layer height decreased, wall thickness increased, and water temperature decreased. Based on multilinear regression analysis, the magnitude of influence for the layer height was the highest, which could reach at a point where variation in wall thickness and water temperature had no effect. A regression model having 81.27% fitness that provided a quantitative relationship among all parameters had also been obtained. ANOVA analysis revealed that all parameters were statistically significant in optimizing as well as predicting the value of the leakage flow rate

Novel mechanism of inhibition of human angiotensin-I-converting enzyme (ACE) by a highly specific phosphinic tripeptide

Human ACE (angiotensin-I-converting enzyme) has long been regarded as an excellent target for the treatment of hypertension and related cardiovascular diseases. Highly potent inhibitors have been developed and are extensively used in the clinic. To develop inhibitors with higher therapeutic efficacy and reduced side effects, recent efforts have been directed towards the discovery of compounds able to simultaneously block more than one zinc metallopeptidase (apart from ACE) involved in blood pressure regulation in humans, such as neprilysin and ECE-1 (endothelin-converting enzyme-1). In the present paper, we show the first structures of testis ACE [C-ACE, which is identical with the C-domain of somatic ACE and the dominant domain responsible for blood pressure regulation, at 1.97Å (1 Å=0.1 nm)] and the N-domain of somatic ACE (N-ACE, at 2.15Å) in complex with a highly potent and selective dual ACE/ECE-1 inhibitor. The structural determinants revealed unique features of the binding of two molecules of the dual inhibitor in the active site of C-ACE. In both structures, the first molecule is positioned in the obligatory binding site and has a bulky bicyclic P1′ residue with the unusual R configuration which, surprisingly, is accommodated by the large S2′ pocket. In the C-ACE complex, the isoxazole phenyl group of the second molecule makes strong pi–pi stacking interactions with the amino benzoyl group of the first molecule locking them in a ‘hand-shake’ conformation. These features, for the first time, highlight the unusual architecture and flexibility of the active site of C-ACE, which could be further utilized for structure-based design of new C-ACE or vasopeptidase inhibitors

Infected pancreatic necrosis: outcomes and clinical predictors of mortality. A post hoc analysis of the MANCTRA-1 international study

: The identification of high-risk patients in the early stages of infected pancreatic necrosis (IPN) is critical, because it could help the clinicians to adopt more effective management strategies. We conducted a post hoc analysis of the MANCTRA-1 international study to assess the association between clinical risk factors and mortality among adult patients with IPN. Univariable and multivariable logistic regression models were used to identify prognostic factors of mortality. We identified 247 consecutive patients with IPN hospitalised between January 2019 and December 2020. History of uncontrolled arterial hypertension (p = 0.032; 95% CI 1.135-15.882; aOR 4.245), qSOFA (p = 0.005; 95% CI 1.359-5.879; aOR 2.828), renal failure (p = 0.022; 95% CI 1.138-5.442; aOR 2.489), and haemodynamic failure (p = 0.018; 95% CI 1.184-5.978; aOR 2.661), were identified as independent predictors of mortality in IPN patients. Cholangitis (p = 0.003; 95% CI 1.598-9.930; aOR 3.983), abdominal compartment syndrome (p = 0.032; 95% CI 1.090-6.967; aOR 2.735), and gastrointestinal/intra-abdominal bleeding (p = 0.009; 95% CI 1.286-5.712; aOR 2.710) were independently associated with the risk of mortality. Upfront open surgical necrosectomy was strongly associated with the risk of mortality (p < 0.001; 95% CI 1.912-7.442; aOR 3.772), whereas endoscopic drainage of pancreatic necrosis (p = 0.018; 95% CI 0.138-0.834; aOR 0.339) and enteral nutrition (p = 0.003; 95% CI 0.143-0.716; aOR 0.320) were found as protective factors. Organ failure, acute cholangitis, and upfront open surgical necrosectomy were the most significant predictors of mortality. Our study confirmed that, even in a subgroup of particularly ill patients such as those with IPN, upfront open surgery should be avoided as much as possible. Study protocol registered in ClinicalTrials.Gov (I.D. Number NCT04747990)

Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries

Abstract Background Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres. Methods This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and low–middle-income countries. Results In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of ‘single-use’ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for low–middle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia. Conclusion This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both high– and low–middle–income countries

η\eta-RICCI SOLITONS AND GRADIENT RICCI SOLITONS ON δ\delta- LORENTZIAN TRANS-SASAKIAN MANIFOLDS

The objective of the present research article is to study the $\delta$-Lorentzian trans-Sasakian manifolds conceding the $\eta$-Ricci solitons and gradient Ricci soliton. We shown that a symmetric second order covariant tensor in a $\delta$-Lorentzian trans-Sasakian manifold is a constant multiple of metric tensor. Also, we furnish an example of $\eta$-Ricci soliton on 3-diemsional $\delta$-Lorentzian trans-Sasakian manifold is provide in the region where $\delta$-Lorentzian trans-Sasakian manifold is expanding. Furthermore, we discuss some results based on gradient Ricci solitons on $3$-dimensional $\delta$- Lorentzian trans-Sasakian manifold

Feature Selection and Radial Basis Function Network for Parkinson Disease Classification

Recently, several works have focused on detection of a different disease using computational intelligence techniques. In this paper, we applied feature selection method and radial basis function neural network (RBFN) to classify the diagnosis of Parkinson’s disease. The feature selection (FS) method used to reduce the number of attributes in Parkinson disease data. The Parkinson disease dataset is acquired from UCI repository of large well-known data sets. The experimental results have revealed significant improvement to detect Parkinson’s disease using feature selection method and RBF network

<i>η</i>-Ricci–Yamabe Solitons along Riemannian Submersions

In this paper, we investigate the geometrical axioms of Riemannian submersions in the context of the η-Ricci–Yamabe soliton (η-RY soliton) with a potential field. We give the categorization of each fiber of Riemannian submersion as an η-RY soliton, an η-Ricci soliton, and an η-Yamabe soliton. Additionally, we consider the many circumstances under which a target manifold of Riemannian submersion is an η-RY soliton, an η-Ricci soliton, an η-Yamabe soliton, or a quasi-Yamabe soliton. We deduce a Poisson equation on a Riemannian submersion in a specific scenario if the potential vector field ω of the soliton is of gradient type =:grad(γ) and provide some examples of an η-RY soliton, which illustrates our finding. Finally, we explore a number theoretic approach to Riemannian submersion with totally geodesic fibers