Rare Titin (TTN) Variants in Diseases Associated with Sudden Cardiac Death

A leading cause of death in western countries is sudden cardiac death, and can be associated with genetic disease. Next-generation sequencing has allowed thorough analysis of genes associated with this entity, including, most recently, titin. We aimed to identify potentially pathogenic genetic variants in titin. A total of 1126 samples were analyzed using a custom sequencing panel including major genes related to sudden cardiac death. Our cohort was divided into three groups: 432 cases from patients with cardiomyopathies, 130 cases from patients with channelopathies, and 564 post-mortem samples from individuals showing anatomical healthy hearts and non-conclusive causes of death after comprehensive autopsy. None of the patients included had definite pathogenic variants in the genes analyzed by our custom cardio-panel. Retrospective analysis comparing the in-house database and available public databases also was performed. We identified 554 rare variants in titin, 282 of which were novel. Seven were previously reported as pathogenic. Of these 554 variants, 493 were missense variants, 233 of which were novel. Of all variants identified, 399 were unique and 155 were identified at least twice. No definite pathogenic variants were identified in any of genes analyzed. We identified rare, mostly novel, titin variants that seem to play a potentially pathogenic role in sudden cardiac death. Additional studies should be performed to clarify the role of these variants in sudden cardiac death.     

Inhibitors against Fungal Cell Wall Remodeling Enzymes

Fungal β‐1,3‐glucan glucanosyltransferases are glucan‐remodeling enzymes that play important roles in cell wall integrity, and are essential for the viability of pathogenic fungi and yeasts. As such, they are considered possible drug targets, although inhibitors of this class of enzymes have not yet been reported. Herein we report a multidisciplinary approach based on a structure‐guided design using a highly conserved transglycosylase from Sacharomyces cerevisiae, that leads to carbohydrate derivatives with high affinity for Aspergillus fumigatus Gel4. We demonstrate by X‐ray crystallography that the compounds bind in the active site of Gas2/Gel4 and interact with the catalytic machinery. The topological analysis of noncovalent interactions demonstrates that the combination of a triazole with positively charged aromatic moieties are important for optimal interactions with Gas2/Gel4 through unusual pyridinium cation–π and face‐to‐face π–π interactions. The lead compound is capable of inhibiting AfGel4 with an IC₅₀ value of 42 μm .     

Inroads to Predict in Vivo Toxicology-An Introduction to the eTOX Project

There is a widespread awareness that the wealth of preclinical toxicity data that the pharmaceutical industry has generated in recent decades is not exploited as efficiently as it could be. Enhanced data availability for compound comparison ("read-across"), or for data mining to build predictive tools, should lead to a more efficient drug development process and contribute to the reduction of animal use (3Rs principle). In order to achieve these goals, a consortium approach, grouping numbers of relevant partners, is required. The eTOX ("electronic toxicity") consortium represents such a project and is a public-private partnership within the framework of the European Innovative Medicines Initiative (IMI). The project aims at the development of in silico prediction systems for organ and in vivo toxicity. The backbone of the project will be a database consisting of preclinical toxicity data for drug compounds or candidates extracted from previously unpublished, legacy reports from thirteen European and European operation-based pharmaceutical companies. The database will be enhanced by incorporation of publically available, high quality toxicology data. Seven academic institutes and five small-to-medium size enterprises (SMEs) contribute with their expertise in data gathering, database curation, data mining, chemoinformatics and predictive systems development. The outcome of the project will be a predictive system contributing to early potential hazard identification and risk assessment during the drug development process. The concept and strategy of the eTOX project is described here, together with current achievements and future deliverables.     

Palladium(II) complexes bearing the new pincer ligand 3,5-bis(indazol-2-ylmethyl)toluene; synthesis and catalytic properties

The reaction of 3,5-bis(bromomethyl)toluene with 1H-indazole in toluene, in the presence of triethylamine, yields the ligand 3,5-bis(indazol-2-ylmethyl)toluene (1). Compound 1 reacts with Pd(OAc)₂ in refluxing acetic acid, followed by a metathetic reaction with lithium chloride and with [PdCl₂(cod)] (cod = 1,5-cyclooctadiene) in refluxing acetonitrile to give the complexes [PdCl{3,5-bis(indazol-2-ylmethyl)tolyl-N,C,N}] (2) and [PdCl₂{3,5-bis(indazol-2-ylmethyl)toluene-N,N}] (3), respectively. Compounds 1–3 were characterized by elemental analyses, mass spectra and IR and NMR (¹H, ¹³C) spectroscopies. The molecular structure of 1 was also determined by single-crystal X-ray diffraction. The palladium(II) complexes (2,3) were tested as catalysts in ethylene polymerization and in C–C coupling reactions involving aryl halides substrates.     

Identification of phases and precipitates by AFM in duplex stainless steel unions

ABSTRACT

Atomic Force Microscopy (AFM), a characterization technique that generates topographic images of surfaces at very high resolutions, works by recording the surface relief details of the material with a cantilever which moves over the sample, while a piezoelectric sensor monitors changes in height. This technique is useful for identifying phases, particles and precipitates on a nanoscale and is therefore proposed for identifying them in the fusion zone of welded components and for early identification of faults due to cracking. This is a technique that does not require conductive samples, or special metallographic preparation of specimens as is the case with electron microscopy. The material studied is a duplex 2205 stainless steel, welded by means of gas tungsten arc welding (GTAW). The welded material was subjected to stress tests. The test specimens were characterized using optical microscopy, scanning electron microscopy, atomic force microscopy and nanoindentation tests. The results focus on the identification of the specific magnetic, topographic and hardness characteristics of each of the phases, particles and areas present in the base metal, the fusion zone and the zone deformed by the fracture.     

Characterization of Urine Stem Cell-Derived Extracellular Vesicles Reveals B Cell Stimulating Cargo

Elucidation of the biological functions of extracellular vesicles (EVs) and their potential roles in physiological and pathological processes is an expanding field of research. In this study, we characterized USC–derived EVs and studied their capacity to modulate the human immune response in vitro. We found that the USC–derived EVs are a heterogeneous population, ranging in size from that of micro–vesicles (150 nm–1 μm) down to that of exosomes (60–150 nm). Regarding their immunomodulatory functions, we found that upon isolation, the EVs (60–150 nm) induced B cell proliferation and IgM antibody secretion. Analysis of the EV contents unexpectedly revealed the presence of BAFF, APRIL, IL–6, and CD40L, all known to play a central role in B cell stimulation, differentiation, and humoral immunity. In regard to their effect on T cell functions, they resembled the function of mesenchymal stem cell (MSC)–derived EVs previously described, suppressing T cell response to activation. The finding that USC–derived EVs transport a potent bioactive cargo opens the door to a novel therapeutic avenue for boosting B cell responses in immunodeficiency or cancer.     

The Peculiar Structure of Acetobacter pasteurianus CIP103108 LPS Core Oligosaccharide

Acetobacter pasteurianus, a member of the Alphaproteobacteria, is an acetic acid-producing bacterium present on sugar-rich substrates such as such as fruits, flowers and vegetables and traditionally used in the production of fermented food. The preferred living habitat associated with acid conditions makes the structure of the bacterial cell wall interesting to study, due to expected uncommon features. We have used a combination of chemical, analytical and NMR spectroscopy approaches to define the complete structure of the core oligosaccharide from A. pasteurianus CIP103108 LPS. Interestingly, the core oligosaccharide displays a high concentration of negatively charged groups, structural features that might contribute to reinforcing the bacterial membrane.     

Electrospun fibers based on porcine plasma: a rheological and morphological study

Iranian Polymer Journal - The present work focuses on the assessment of the ability of porcine plasma protein (PPP) to be electrospun satisfactorily to form fibre mats, and their rheological and...     

Chemical Desensitization of Explosives. Part 1. Effect of Ethyl Centralite on the Properties of an RDX-Based PBX

The effects of the addition of ethyl centralite, a commonly used stabilizer in double-base propellants, on a cyclotrimethylenetrinitramine (RDX)-based polymer-bonded explosive (PBX) were investigated. A reduction in sensitivity to impact was observed with increasing ethyl centralite content along with a reduction in explosiveness. Small-scale gap tests also show a reduction in sensitivity to shock initiation. High-performance liquid chromatography (HPLC) analysis of impact-stressed samples showed traces of 4-nitro- and 2-nitro-ethyl centralite and N-ethyl-N-nitrosoaniline; these results indicate the possibility that the mechanism of desensitization may, at least partially, be chemical in nature.