1,810 research outputs found
A novel design concept for connections in glass: structural Integrity of glass reinforced with externally–bonded GFRP laminates
No full textThe paper reports experimental results of the load response and failure behaviour of open-hole annealed glass tensile test specimens reinforced with adhesively-bonded GFRP laminates. The results show that the bonded GFRP has potential to strengthen stress concentration features in glass by either arresting the cracks developed in the critical zone or eliminating the failure from the vicinity of the critical area. It is anticipated that the findings of this research could be effectively used to develop reinforcement strategies for critical joints in glass structures
CRIME AS AN OBJECT OF INQUIRY IN RUSSIAN CRIMINALISTICS ALEKSEY BESSONOV,
No full textThis article deals with the definition of the subject and objects of modern Russian criminalistics. It is aimed at sensitizing world public opinion to the necessity of inquiry into the criminalistic essence of crime and encouraging criminalists to study new techniques of crime investigation in order to mitigate risks and reduce errors arising in the criminal investigation process.One of the main objects that is constantly undergoing research in Russian criminalistics is criminal activity. The subject of Russian criminalistics is the regularities of criminal activity. When investigating crimes scientists are interested in the information that allows the successful investigation of the crimes and determination of the offender. The information about different types of crimes, which is necessary for crime investigation, is accumulated in the criminalistic characteristic of crimes. The Criminalistic Characteristic of Crimes is a scientific theory of modern Russian criminalistics that makes it possible to fully examine the specific features of crimes of all kinds, i.e. the forensic nature (essence) of crime, the system of crime elements with their characteristics, and the relationship between those elements. In U.S. and European criminalistics, the regularities of criminal activity are not defined as an object of study of this science. Yet, in the U.S. and European countries criminal profilers investigating criminal cases study the criminal links between crimes to identify crime series and crimes committed by similar offenders (or to determine co-offenders)
Finding consensus after two decades of breast implant-associated anaplastic large cell lymphoma
No full textBreast implant-associated anaplastic large cell lymphoma (BIA-ALCL) is an emerging and indolent, but potentially fatal cancer of the immune system that can develop around textured-surface breast implants. The World Health Organization first recognized BIA-ALCL as a unique clinical entity in 2016. To date, over 600 confirmed cases have been reported worldwide. BIA-ALCL most commonly presents with disease confined to the capsule, as a seroma or a mass adjacent to the implant. While BIA-ALCL has a fairly indolent clinical course, with an excellent prognosis in early stage disease, disseminated cancer and death have also been reported. In this review, the authors focus on the early diagnosis and treatment, including reconstructing the breast following BIA-ALCL, and also discuss recently updated National Comprehensive Cancer Network guidelines. They also review the current epidemiology and risk factors associated with BIA-ALCL. Finally, they discuss important medicolegal considerations and the bioethics surrounding the continued use of textured-surface breast implants
Solution Nuclear Magnetic Resonance Structure and Molecular Dynamics Simulations of a Murine 18.5 kDa Myelin Basic Protein Segment (S72-S107) in Association with Dodecylphosphocholine Micelles.
No full textpeer reviewedThe 18.5 kDa myelin basic protein (MBP), the most abundant splice isoform in adult mammalian myelin, is a multifunctional, intrinsically disordered protein involved in the development and compaction of the myelin sheath in the central nervous system. A highly conserved central segment comprises a membrane-anchoring amphipathic alpha-helix followed by a proline-rich segment that represents a ligand for SH3 domain-containing proteins. Here, we have determined using solution nuclear magnetic resonance spectroscopy the structure of a 36-residue peptide fragment of MBP (murine 18.5 kDa residues S72-S107, denoted the alpha2-peptide) comprising these two structural motifs, in association with dodecylphosphocholine (DPC) micelles. The structure was calculated using CS-ROSETTA (version 1.01) because the nuclear Overhauser effect restraints were insufficient for this protein. The experimental studies were complemented by molecular dynamics simulations of a corresponding 24-residue peptide fragment (murine 18.5 kDa residues E80-G103, denoted the MD-peptide), also in association with a DPC micelle in silico. The experimental and theoretical results agreed well with one another, despite the independence of the starting structures and analyses, both showing membrane association via the amphipathic alpha-helix, and a sharp bend in the vicinity of the Pro93 residue (murine 18.5 kDa sequence numbering). Overall, the conformations elucidated here show how the SH3 ligand is presented to the cytoplasm for interaction with SH3 domain-containing proteins such as Fyn and contribute to our understanding of myelin architecture at the molecular level
Glass–GFRP hybrids: from brittle glass to ductile and high strength structural glass
No full textThis paper presents selected findings from a research programme that aimed to exploit the use of adhesively-bonded Glass Fibre Reinforced Polymer (GFRP) laminates as a mean of improving strength and ductility of glass structural elements. In the first half of the paper, using the results of an experimental investigation of the load response and failure behaviour of annealed glass beams reinforced with GFRP laminates, it is shown that the load resistance and the ductility of the glass beams can be enhanced. In the latter half of the paper, it is shown that the stress concentration geometries and bolted joints in annealed glass can sustain greater loads with greater ductility, even after microcracks formed, if the glass is reinforced with adhesively-bonded GFRP laminates
Towards screening for antibiotics with enhanced permeation properties through bacterial porins
No full textGram-negative bacteria are protected by an outer membrane barrier, and to reach their periplasmic target, penicillins have to diffuse through outer membrane porins such as OmpF. Here we propose a structure-dynamics-based strategy for improving such antibiotic uptake. Using a variety of experiments (high-resolution single channel recording, Minimum Inhibitory Concentration (MIC), liposome swelling assay) and accelerated molecular simulations, we decipher the subtle balance of interactions governing ampicillin diffusion through the porin OmpF. This suggests mutagenesis of a hot spot residue of OmpF for which additional simulations reveal drastic changes in the molecular and energetic pathway of ampicillin's diffusion. Inverting the problem, we predict and describe how benzylpenicillin diffuses with a lower effective energy barrier by interacting differently with OmpF. The thorough comparison between the theoretical predictions and the three independent experiments, which were set up to measure the kinetics of transport and biological activity, gives insights on how to combine such different investigation techniques with the aim of providing complementary validation. Our study illustrates the importance of microscopic interactions at the constriction region of the biological channel to control the antibiotic flux through it. We conclude by providing a complete inventory of the channel and antibiotic hot spots and discuss the implications in terms of antibacterial screening and design
The effects of threonine phosphorylation on the stability and dynamics of the central molecular switch region of 18.5-kDa myelin basic protein.
No full textThe classic isoforms of myelin basic protein (MBP) are essential for the formation and maintenance of myelin in the central nervous system of higher vertebrates. The protein is involved in all facets of the development, compaction, and stabilization of the multilamellar myelin sheath, and also interacts with cytoskeletal and signaling proteins. The predominant 18.5-kDa isoform of MBP is an intrinsically-disordered protein that is a candidate auto-antigen in the human demyelinating disease multiple sclerosis. A highly-conserved central segment within classic MBP consists of a proline-rich region (murine 18.5-kDa sequence -T92-P93-R94-T95-P96-P97-P98-S99-) containing a putative SH3-ligand, adjacent to a region that forms an amphipathic α-helix (P82-I90) upon interaction with membranes, or under membrane-mimetic conditions. The T92 and T95 residues within the proline-rich region can be post-translationally modified through phosphorylation by mitogen-activated protein (MAP) kinases. Here, we have investigated the structure of the α-helical and proline-rich regions in dilute aqueous buffer, and have evaluated the effects of phosphorylation at T92 and T95 on the stability and dynamics of the α-helical region, by utilizing four 36-residue peptides (S72-S107) with differing phosphorylation status. Nuclear magnetic resonance spectroscopy reveals that both the α-helical as well as the proline-rich regions are disordered in aqueous buffer, whereas they are both structured in a lipid environment (cf., Ahmed et al., Biochemistry 51, 7475-9487, 2012). Thermodynamic analysis of trifluoroethanol-titration curves monitored by circular dichroism spectroscopy reveals that phosphorylation, especially at residue T92, impedes formation of the amphipathic α-helix. This conclusion is supported by molecular dynamics simulations, which further illustrate that phosphorylation reduces the folding reversibility of the α-helix upon temperature perturbation and affect the global structure of the peptides through altered electrostatic interactions. The results support the hypothesis that the central conserved segment of MBP constitutes a molecular switch in which the conformation and/or intermolecular interactions are mediated by phosphorylation/dephosphorylation at T92 and T95
Screening for antibiotics with enhanced permeation properties: proof of concept using molecular simulations
No full textBridging time and length scales: from macroscopic flux to molecular mechanism of antibiotics diffusion through porins
No full textOur aim in this study was to provide an atomic description of ampicillin translocation through OmpF, the major outer membrane channel in Escherichia coli and main entry point for beta-lactam antibiotics. By applying metadynamics simulations, we also obtained the energy barriers along the diffusion pathway We then studied the effect of mutations that affect the charge and size at the channel constriction zone, and found that in comparison to the wild-type, much lower energy barriers are required for translocation The expected higher translocation rates were confirmed on the macroscopic scale by liposome-swelling assays. A microscopic view on the millisecond timescale was obtained by analysis of temperature-dependent ion current fluctuations in the presence of ampicillin and provide the enthalpic part of the energy barrier. By studying antibiotic translocation over various timescales and length scales, we were able to discern its molecular mechanism and rate-limiting interactions, and draw biologically relevant conclusions that may help in the design of drugs with enhanced permeation rates
- …
