Structures of synaptic vesicle protein 2A and 2B bound to anticonvulsants.

Epilepsy is a common neurological disorder characterized by abnormal activity of neuronal networks, leading to seizures. The racetam class of anti-seizure medications bind specifically to a membrane protein found in the synaptic vesicles of neurons called synaptic vesicle protein 2 (SV2) A (SV2A). SV2A belongs to an orphan subfamily of the solute carrier 22 organic ion transporter family that also includes SV2B and SV2C.

Titanium dioxide particles frequently present in face masks intended for general use require regulatory control.

Although titanium dioxide (TiO) is a suspected human carcinogen when inhaled, fiber-grade TiO (nano)particles were demonstrated in synthetic textile fibers of face masks intended for the general public. STEM-EDX analysis on sections of a variety of single use and reusable face masks visualized agglomerated near-spherical TiO particles in non-woven fabrics, polyester, polyamide and bi-component fibers. Median sizes of constituent particles ranged from 89 to 184 nm, implying an important fraction of nano-sized particles (< 100 nm).

Designing Out PXR Activity on Drug Discovery Projects: A Review of Structure-Based Methods, Empirical and Computational Approaches.

This perspective discusses the role of pregnane xenobiotic receptor (PXR) in drug discovery and the impact of its activation on CYP3A4 induction. The use of structural biology to reduce PXR activity on drug discovery projects has become more common in recent years. Analysis of this work highlights several important molecular interactions, and the resultant structural modifications to reduce PXR activity are summarized.

Teaching humanitarian surgery: Filling the gap between NGO needs and subspecialized surgery through a novel inter-university certificate.

Access to surgical care is a global health burden. A broad spectrum of surgical competences is required in the humanitarian context whereas current occidental surgical training is oriented towards subspecialties. We proposed to design a course addressing the specificities of surgery in the humanitarian setting and austere environment.

The Major Envelope Glycoprotein of Murid Herpesvirus 4 Promotes Sexual Transmission.

Gammaherpesviruses are important human and animal pathogens. Infection control has proven difficult because the key process of transmission is ill understood. Murid herpesvirus 4 (MuHV-4), a gammaherpesvirus of mice, is transmitted sexually.

Towards a KCC2 blocker pharmacophore model.

A multi-disciplinary approach was used to identify the first pharmacophore model for KCC2 blockers: several physico-chemical studies such as XRD and NMR were combined to molecular modelling techniques, SAR analysis and synthesis of constrained analogues in order to determine a minimal conformational space regrouping few potential bioactive conformations. These conformations were further compared to the conformational space of a different series of KCC2 blockers in order to identify the common pharmacophoric features. The synthesis of more potent analogues in this second series confirmed the usefulness of this KCC2 blocker pharmacophore model.

Analysis of the interactions taking place in the recognition site of a bimetallic Mg(II)-Zn(II) enzyme, isopentenyl diphosphate isomerase. a parallel quantum-chemical and polarizable molecular mechanics study.

Using the SIBFA polarizable molecular mechanics procedure, we analyze the binding energy of a bimetallic Mg(II)/Zn(II) enzyme, isopentenyl diphosphate isomerase, to an inhibitor built up of a trianionic diphosphate and of a cationic ethyldimethylammonium (EDMA) moiety. The analyses are performed on the protein recognition site, which totals 13 residues, as well as on some "mutants" in which one selected residue is removed at a time. They are also carried out for the individual recognition sites, namely, EDMA, Mg(II), and Zn(II).

Ligand-based and structure-based virtual screening to identify carbonic anhydrase IX inhibitors.

A three-dimensional pharmacophore model of CA IX inhibitors was generated and used to screen the ZINC database of commercially available compounds. The hits were docked in a CA IX homology model. By visualizing the binding mode and score of these compounds, six derivatives were selected and evaluated for their inhibitory potency against CA IX.

Synthesis and biological evaluation of a new family of anti-benzylanilinosulfonamides as CA IX inhibitors.

We report the synthesis and the pharmacological evaluation of a new class of human carbonic anhydrase (hCA) inhibitors prepared regio- and stereoselectively by reacting sulfanilamide with ethyl trans-phenylglycidate in the presence of cobalt(II) chloride. Various derivatizations of the ester moiety in the parent compound led to a small library of derivatives (2R,3R and 2S,3S) which displayed interesting inhibitory activities towards the human tumor-associated isoform CA IX. One of the new compounds shows high selectivity in inhibiting hCA IX compared to the two physiologically relevant, cytosolic isozymes hCA I and hCA II.

Indanesulfonamides as carbonic anhydrase inhibitors. Toward structure-based design of selective inhibitors of the tumor-associated isozyme CA IX.

Carbonic anhydrases are ubiquitous metalloenzymes which are involved in fundamental processes (i.e., acid-base regulation, respiration, calcification, etc.

Metal-organic compounds: a new approach for drug discovery. N1-(4-methyl-2-pyridyl)-2,3,6-trimethoxybenzamide copper(II) complex as an inhibitor of human immunodeficiency virus 1 protease.

The use of metal-organic complexes is a potentially fruitful approach for the development of novel enzyme inhibitors. They hold the attractive promise of forming stronger attachments with the target by combining the co-ordination ability of metals with the unique stereoelectronic properties of the ligand. We demonstrated that this approach can be successfully used to inhibit the protease of the human immunodeficiency virus (type 1).

Synthesis and structural analysis of the copper(II) complexes of N2-(2-pyridylmethyl)-2-pyridinecarboxamide.

Previous investigations of the potential of metal-organic compounds as inhibitors of human immunodeficiency virus type I protease (HIV-1 PR) showed that the copper(II) complex diaqua [bis(2-pyridylcarbonyl)amido] copper(II) nitrate dihydrate and the complex bis[N2-(2,3,6-trimethoxybenzyl)-4-2-pyridinecarboxamide] copper(II) behaved as inhibitors of HIV-1 PR. In a search for similar readily accessible ligands, we synthesised and studied the structural properties of N2-(2-pyridylmethyl)-2-pyridinecarboxamide (L) copper(II) complexes. Three different crystal structures were obtained.

Approaches to the design of effective HIV-1 protease inhibitors.

Recently, western countries have recorded a decrease in the death rate imputed to AIDS. This success has been largely attributed to the presence on the market of chemotherapies that inhibit the infectivity of the predominant causative agent, the HIV-1 virus, by targeting essential viral enzymes. One of these is the protease (HIV-1 PR) whose activity is a prerequisite for viral replication.

Postoperative acalculous cholecystitis. A five-case study and a literature review.

The study reports five cases of postoperative acute acalculous cholecystitis. Clinical symptoms are upper abdominal pain, fever, jaundice or an unexplained septic shock. Biology orients the diagnosis but only gallbladder ultrasonography and, to a lesser degree, hepatobiliary scintigraphy are really diagnostic.

[Primary inguinal hernia: Lichtenstein's ambulatory hernioplasty: early clinical results and economic implications. Study of the initial 130 surgical cases].

The authors report their preliminary experience of 130 ambulatory treatment under local anesthesia of primary inguinal hernia. This method of treatment is very well accepted by the patients. There are few early recurrences.

[Transsection of the cervical trachea secondary to a closed injury. Apropos of a case].

The successful surgical management of a case of complete blunt traumatic transection of the cervical trachea is reported. The management of this rare pathology is a real challenge for the surgeon with regard to early recognition of the lesion and proper therapeutic strategy. Except in case of respiratory distress and/or major laryngotracheal lesions, where urgent tracheotomy is recommended, diagnostic fiberoptic bronchoscopy should be performed to assess the lesions.