Structural Topology Optimization with Stress Constraint Considering Loading Uncertainties

This paper deals with the consideration of loading uncertainties in topology optimization via a fundamental optimization problem setting. Variability of loading in engineering design is realized e.g. in the action of various load combinations. In this study this phenomenon is modelled by the application of two mutually excluding (i.e. alternating) forces such that the magnitudes and directions are varied parametrically in a range. The optimization problem is stated as to find the minimum volume (i.e. the minimum weight) load-bearing elastic truss structure that transfers such loads acting at a fix point of application to a given line of support provided that stress limits are set. The aim of this paper is to numerically determine the layout, size, and volume of the optimal truss and to support the numerical results by appropriate analytical derivations. We also show that the optimum solution is non-unique, which aects the static determinacy of the structure as well. In this paper we also create a truss-like structure with rigid connections based on the results of the truss optimization and analyse it both as a bar structure (frame model) and a planar continuum (disk) structure to compare with the truss model. The comparative investigation assesses the validity of computational models and proves that the choice aects design negatively since rigidity of connections resulted by usual construction technologies involve extra stresses leading to significant undersizing

Parametric Study on the Element Size Effect for Optimal Topologies

Topology optimization is complex engineering design tool. It needs intensive mathematical, mechanical and computing tools to perform the required design. During its hundred years of history it has become clear that the non-unique solution property of the method is affected by the material parameters (Poisson ratio) and the ways of the discretization. The aim of the paper is to investigate the influence of parameter changes to optimal design property in tasks with great number of degrees of freedom. The parametric study includes influence of material parameter (Poisson ratio) as well as the size of the ground elements which are commonly applied during the discretization. Increasing the size of the ground elements while the total number of the finite elements is constant, the computational time is significantly reduced. Therefore the study on changing accuracy versus ground element resolution may be important factor in choosing ground element size. In addition to it the effective properties of arrangements of the strong and weak materials (black and white elements) in a checkerboard fashion are also investigated. The Michell-type problem is investigated by the minimization of the weight of the structure subjected to a compliance constraint

The fluorescent dye 3,3′-diethylthiatricarbocyanine iodide is unsuitable for in vivo imaging of myelination in the mouse

There is a growing interest to use non-invasive optical imaging methods to study central nervous system diseases. The application of a myelin-binding fluorescent dye, 3,3-diethylthiatricarbocyanine iodide (DBT) was recently described for in vivo optical imaging of demyelination in the mouse. In the present study we aimed at adapting the method to our optical imaging systems, the IVIS Lumina II to measure epifluorescence and the fluorescent molecular tomograph (FMT) for 3-dimensional quantification of the fluorophore. Epifluorescent imaging was performed 5−30 min after DBT injection which was followed by FMT imaging at 40 min. Two mice also underwent micro-CT imaging in the FMT cassette for the purpose of FMT-CT co-registration. Ex vivo imaging of the brain and other tissues of the head and neck was carried out 1 h after injection. Both the FMT-CT co-registration and the ex vivo imaging of organs proved that DBT poorly crossed the blood-brain barrier. The dye did not accumulate in the myelin sheath of the sciatic nerve. In contrast, there was an intense accumulation in the pituitary and salivary glands. The FMT-CT co-registration unequivocally demonstrated that the signal localized to the head did not originate from beyond the blood-brain barrier. No myelin binding was demonstrated by the ex vivo imaging either. In conclusion, DBT is unsuitable for in vivo imaging of myelination due to its poor BBB penetration, accumulation in other structures of the head and neck region and lack of selective binding towards myelin in vivo

Prerequisite Binding Modes Determine the Dynamics of Action of Covalent Agonists of Ion Channel TRPA1

Transient receptor potential ankyrin 1 (TRPA1) is a transmembrane protein channeling the influx of calcium ions. As a polymodal nocisensor, TRPA1 can be activated by thermal, mechanical stimuli and a wide range of chemically damaging molecules including small volatile environmental toxicants and endogenous algogenic lipids. After activation by such compounds, the ion channel opens up, its central pore widens allowing calcium influx into the cytosol inducing signal transduction pathways. Afterwards, the calcium influx desensitizes irritant evoked responses and results in an inactive state of the ion channel. Recent experimental determination of structures of apo and holo forms of TRPA1 opened the way towards the design of new agonists, which can activate the ion channel. The present study is aimed at the elucidation of binding dynamics of agonists using experimental structures of TRPA1-agonist complexes at the atomic level applying molecular docking and dynamics methods accounting for covalent and non-covalent interactions. Following a test of docking methods focused on the final, holo structures, prerequisite binding modes were detected involving the apo forms. It was shown how reversible interactions with prerequisite binding sites contribute to structural changes of TRPA1 leading to covalent bonding of agonists. The proposed dynamics of action allowed a mechanism-based forecast of new, druggable binding sites of potent agonists

A kapszaicin-érzékeny szenzoros neuronok és a gyulladásos sejtek közötti kölcsönhatás vizsgálata normál és transzgenikus egerekben = Investigation of interactions between capsaicin-sensitive sensory neurones and inflammatory cells in normal and transgenic mice

A tranziens receptor potenciál vanilloid 1 (TRPV1) receptor szerepét vizsgáltuk oxazolonnal kiváltott kontakt dermatitisz modellen, egérfülön. Az oxazolon jelentős fülduzzadást okozott 24-72 h alatt, ami a TRPV1 receptor hiányos knockout egerekben szignifikáns mértékben fokozottabb volt. A KO egerek fülében a szövettani vizsgálatok is súlyosabb gyulladásos jeleket mutattak, valamint a TNF-alfa? mennyisége is megemelkedett. Az neurokinin 1 receptor és a calcitonin-gén rokon peptid (CGRP) genetikai hiánya viszont gátolta a gyulladás kifejlődését. Kísérleteinkkel igazoltuk a TRPV1 receptor protektiv hatását az allergiás kontakt dermatitisz kifejlődésére. A TRPV1 receptorok és a CGRP szerepét vizsgáltuk bleomycinnel indukált szkleroderma modellben. A lokális bleomycin kezelés jelentős bőrmegvastagodást és fibrózist okozott egerek hátbőrében a foszfát pufferrrel kezelt kontrollhoz képest. Az összetett szklerózis pontszám 18%-kal, a bőrvastagság 19%-kal, az alfa-SMA-pozitiv sejtek száma 47%-kal, a hydroxyprolin tartalom 57%-kal nagyobb volt a TRPV1 KO állatokban, mint a vadtípusú kontrollokban. Hasonlóan a szklerózis pontszám 47%-kal, a bőrvastagság 29%-kal, az alfa-SMA-pozitiv sejtek száma 76%-kal, a hydroxyprolin tartalom 30%-kal nagyobb volt a CGRP KO, mint a vad egerekben. Az eredmények azt mutatják, hogy a TRPV1 receptor aktivációja olyan neuropeptidek felszabadulását okozza, melyek gátolják a fibrózist. A CGRP protektív szerepét bizonyítottuk a fibrózis kialakulásában. | The purpose of this study was to examine the involvement of the transient receptor potential vanilloid receptor 1 (TRPV1) in inflammatory processes observed in murine allergic contact dermatitis (ACD). Oxazolone-induced ACD evoked a significant ear swelling after 24-72h. It was augmented in TRPV1 knockout mice at all time points and supported by histological analysis and measure of TNF-?. However, tissue swelling and cytokine generation was significantly reduced in both neurokinin 1 receptor and calcitonin gene-related peptide (CGRP) knockout mice. A protective involvement of the TRPV1 receptor was identified of contact dermatitis distinct from mechanisms involving the major pro-inflammatory neuropeptides. Bleomycin treatment induced marked cutaneous thickening and fibrosis compared to the PBS-treated control group. Composite sclerosis score was 18%, dermal thickness 19%, number of ?-SMA-positive cells 47.2%, amount of hydroxyproline 57.5% higher in TRPV1-/- mice than in wild-type counterparts. Similarly, composite sclerosis score was 47%, dermal thickness 29%, number of ?-SMA-positive cells 76%, amount of hydroxyproline 30% higher in CGRP-/- mice than in the respective WT groups. These results suggest that activation of the TRPV1 receptor by inflammatory mediators induces sensory neuropeptide release, which might exert protective action against fibrosis. We confirmed the protective role of CGRP in the development of cutaneous sclerosis

Nitrogén-monoxid, neuropeptidek és más nem-adrenerg, nem-cholinerg átvivőanyagok szerepe zsigeri funkciókban, gyógyszeres befolyásolásuk ép és gyulladásos körülmények közt = Role of nitric oxide, neuropeptides and other non-adrenergic, non-cholinergic mediators in visceral functions; their modulation by drugs under normal and inflammatory conditions

A vállalt munka fő céljai: Izolált szervi kísérletekben megismerni a zsigerek mozgásválaszainak mechanizmusait, az állatokon kapott eredményeket humán preparátumokkal összevetve. Szenzoros és más eredetű nem-adrenerg, nem-kolinerg (NANC) transzmitterek azonosítása (funkcionális vizsgálatok és a transzmitter-felszabadulás mérése). Kóros zsigeri működések modellezése. (Egyes irányokban komplett, másokban tájékozódó kísérletek). Közölt eredmények: Új humán adatok közlése mellett összefoglaltuk a kapszaicin zsigeri hatásaival, transzmittereivel kapcsolatos jelentősebb eredményeket. Alappal fölvetettük annak lehetőségét, hogy emberben?és bizonyos állatfajokban is?az NO szenzoros transzmitter (Barthó et al. 2004?Eur J Pharmac; Benkó et al. 2005?Life Sci). Mind állati, mind (világelsőként) humán GI preparátumokban bizonyítottuk az ATP közvetítő szerepét NANC válaszokban (Undi et al. 2005?Bas Clin Pharmac; 2006?Brain Res Bull; Benkó et al 2006?NS Arch Pharmac, 2007?Neurosci). Nem találtunk bizonyítékot VIP szerepére emberi bél kapszaicinnel kiváltott gátló válaszában, a CO szerepére perisztaltikus reflexben (kongresszusi közlés), ill a CO szerepére a NANC gátló válaszban állati és humán GI preparátumokon (ld. fenti közlemények). Közlésre vár: P-anyag és CGRP-IR felszabadulás bélből; szenzoros izgató mustárolaj és H2S hatásmechanizmusa; a passzív szenzibilizáció/antigén-expozíció hatásainak elemzése állati és emberi GI és légúti simaizomzaton stb. | Aims of the project Experiments on isolated tissues for elucidating the mechanisms behind some evoked movements of viscera of animals and man. Identifying sensory and other non-adrenergic, non-cholinergic (NANC) transmitters. Measuring neurotransmitter release. Modelling pathophysiological processes of viscera. (Planned were complete series of experiments in some and pilot experiments in other directions.) Published results Review, containing original results, on visceral effects of capsaicin and the transmitters thereof. Providing indirect evidence that NO is a sensory neurotransmitter (Bartho et al. 2004?Eur J Pharmac; Benko et al. 2005?Life Sci). Proving the presence of purinergic innervation of human (Undi et al. 2006?Brain Res Bull; Benko et al. 2007?Neurosci) and rat intestine (Benko et al. 2006?NS Arch Pharmac). No evidence for a mediating role of VIP in the inhibitory effect of capsaicin in the human gut, a role of CO in the peristaltic reflex (congress presentations) or in the evoked NANC relaxation in animal or human GI preparations (papers as above). To be published Release of substance P- or CGRP-like IR from the gut; mechanisms of action of the sensory stimulants mustard oil and H2S; effects of passive sensitization/antigen exposure on GI and respiratory smooth muscles of animals and man, etc

Simultaneous detection of BRCA mutations and large genomic rearrangements in germline DNA and FFPE tumor samples

The development of breast and ovarian cancer is strongly connected to the inactivation of the BRCA1 and BRCA2 genes by different germline and somatic alterations, and their diagnosis has great significance in targeted tumor therapy, since recently approved PARP inhibitors show high efficiency in the treatment of BRCA-deficient tumors. This raises the need for new diagnostic methods that are capable of performing an integrative mutation analysis of the BRCA genes not only from germline DNA but also from formalin-fixed and paraffin-embedded (FFPE) tumor samples. Here we describe the development of such a methodology based on next-generation sequencing and a new bioinformatics software for data analysis. The diagnostic method was initially developed on an Illumina MiSeq NGS platform using germline-mutated stem cell lines and then adapted for the Ion Torrent PGM NGS platform as well. We also investigated the usability of NGS coverage data for the detection of copy number variations and exon deletions as a replacement of the conventional MLPA technique. Finally, we tested the developed workflow on FFPE samples from breast and ovarian cancer patients. Our method meets the sensitivity and specificity requirements for the genetic diagnosis of breast and ovarian cancers both from germline and FFPE samples

Novel Drug-Like Somatostatin Receptor 4 Agonists are Potential Analgesics for Neuropathic Pain

Somatostatin released from the capsaicin-sensitive sensory nerves mediates analgesic and anti-inflammatory effects via the somatostatin sst4 receptor without endocrine actions. Therefore, sst4 is considered to be a novel target for drug development in pain including chronic neuropathy, which is an emerging unmet medical need. Here, we examined the in silico binding, the sst4-linked G-protein activation on stable receptor expressing cells (1 nM to 10 μM), and the effects of our novel pyrrolo-pyrimidine molecules in mouse inflammatory and neuropathic pain models. All four of the tested compounds (C1-C4) bind to the same binding site of the sst4 receptor with similar interaction energy to high-affinity reference sst4 agonists, and they all induce G-protein activation. C1 is the more efficacious (γ-GTP-binding: 218.2% ± 36.5%) and most potent (EC50: 37 nM) ligand. In vivo testing of the actions of orally administered C1 and C2 (500 µg/kg) showed that only C1 decreased the resiniferatoxin-induced acute neurogenic inflammatory thermal allodynia and mechanical hyperalgesia significantly. Meanwhile, both of them remarkably reduced partial sciatic nerve ligation-induced chronic neuropathic mechanical hyperalgesia after a single oral administration of the 500 µg/kg dose. These orally active novel sst4 agonists exert potent anti-hyperalgesic effect in a chronic neuropathy model, and therefore, they can open promising drug developmental perspectives