On the performance of non-conforming finite elements for the upper bound limit analysis of plates

This is a preprint version of an article accepted for publication in International Journal for Numerical Methods in Engineering Copyright © 2012 John Wiley & Sons, Ltd.International audienceIn this paper, the upper bound limit analysis of thin plates in bending is addressed using various types of triangular finite elements for the generation of velocity fields and second order cone programming (SOCP) for the minimization problem. Three different C1-discontinuous finite elements are considered : the quadratic 6 node Lagrange triangle (T6), an enhanced T6 element with a cubic bubble function at centroid (T6b) and the cubic Hermite triangle (H3). Through numerical examples involving Johansen and von Mises yield criteria, it is shown that cubic elements (H3) give far better results in terms of convergence rate and precision than fully conforming elements found in the literature, especially for problems involving clamped boundaries

Residence Time (RT), a new parameter to predict neurosteroidogenic efficacy of Translocator Protein (TSPO) ligands: N,N-dialkyl-2-arylindol-3-ylglyoxylamides, a case study

Targeting neuroactive steroid biosynthetic pathway by specific 18 kDa Translocator Protein (TSPO) ligands may represent a therapeutic approach in a variety of neurodegenerative and neuropsychiatric diseases. However, the lack of correlation between the binding affinity and the in vitro steroidogenic efficacy has limited the identification of lead compounds by a traditional affinity-based drug discovery strategy. Our recent researches indicate that the key factor for robust steroidogenic TSPO ligand efficacy is not the binding affinity per se, but rather the time the compound spends into the target, namely its Residence Time (RT). The assessment of this kinetic parameter during the in vitro characterization of compounds appears mandatory in order to obtain structure-efficacy relationships suitable for the future development of novel molecules with promising pharmacological properties

TSPO: kaleidoscopic 18-kDa amid biochemical pharmacology, control and targeting of mitochondria

The 18-kDa translocator protein (TSPO) localizes in the outer mitochondrial membrane (OMM) of cells and is readily up-regulated under various pathological conditions such as cancer, inflammation, mechanical lesions and neurological diseases. Able to bind with high affinity synthetic and endogenous ligands, its core biochemical function resides in the translocation of cholesterol into the mitochondria influencing the subsequent steps of (neuro-)steroid synthesis and systemic endocrine regulation. Over the years, however, TSPO has also been linked to core cellular processes such as apoptosis and autophagy. It interacts and forms complexes with other mitochondrial proteins such as the voltage-dependent anion channel (VDAC) via which signalling and regulatory transduction of these core cellular events may be influenced. Despite nearly 40 years of study, the precise functional role of TSPO beyond cholesterol trafficking remains elusive even though the recent breakthroughs on its high-resolution crystal structure and contribution to quality-control signalling of mitochondria. All this along with a captivating pharmacological profile provides novel opportunities to investigate and understand the significance of this highly conserved protein as well as contribute the development of specific therapeutics as presented and discussed in the present review

A TSPO-related protein localizes to the early secretory pathway in Arabidopsis, but is targeted to mitochondria when expressed in yeast

AtTSPO is a TspO/MBR domain-protein potentially involved in multiple stress regulation in Arabidopsis. As in most angiosperms, AtTSPO is encoded by a single, intronless gene. Expression of AtTSPO is tightly regulated both at the transcriptional and post-translational levels. It has been shown previously that overexpression of AtTSPO in plant cell can be detrimental, and the protein was detected in the endoplasmic reticulum (ER) and Golgi stacks, contrasting with previous findings and suggesting a mitochondrial subcellular localization for this protein. To ascertain these findings, immunocytochemistry and ABA induction were used to demonstrate that, in plant cells, physiological levels of AtTSPO colocalized with AtArf1, a mainly Golgi-localized protein in plant cells. In addition, fluorescent protein-tagged AtTSPO was targeted to the secretory pathway and did not colocalize with MitoTracker-labelled mitochondria. These results suggest that the polytopic membrane protein AtTSPO is cotranslationally targeted to the ER in plant cells and accumulates in the Trans-Golgi Network. Heterologous expression of AtTSPO in Saccharomyces cerevisiae, yeast devoid of TSPO-related protein, resulted in growth defects. However, subcellular fractionation and immunoprecipitation experiments showed that AtTSPO was targeted to mitochondria where it colocalized and interacted with the outer mitochondrial membrane porin VDAC1p, reminiscent of the subcellular localization and activity of mammalian translocator protein 18 kDa TSPO. The evolutionarily divergent AtTSPO appears therefore to be switching its sorting mode in a species-dependent manner, an uncommon peculiarity for a polytopic membrane protein in eukaryotic cells. These results are discussed in relation to the recognition and organelle targeting mechanisms of polytopic membrane proteins in eukaryotic cells

Anxiolytic activity of pyridoindole derivatives SMe1EC2 and SMe1M2: behavioral analysis using rat model

Anxiety and mood disorders have become very significant affections in the last decades. According to WHO at least one mental disease occurred per year in 27% of EU inhabitants (more than 82 mil. people). It is estimated that by 2020, depression will be the main cause of morbidity in the developed countries. These circumstances call for research for new prospective drugs with anxiolytic and antidepressive properties exhibiting no toxicity and withdrawal effect and possessing beneficial properties, like antioxidant and/or neuroprotective effects. The aim of this study was to obtain information about psychopharmacological properties of pyridoindole derivatives SMe1EC2 and SMe1M2, using non-invasive behavioral methods in rats

Synthesis of fluorine-18 labeled GABA uptake inhibitors

The first syntheses of fluorine-18 labeled inhibitors of GABA reuptake [(R,S)-1-{2-{4-[18F]fluorophenyl}phenyl}methoxyethyl]piperidine-3-carboxylic acid, (R,S)-1-{2-(4-[18F]fluorophenyl)(4-fluorophenyl)methoxyethyl}piperidine-3-carboxylic acid, and (R,S)-1-[2-{(4-[18F]trifluoromethyl)phenyl} {(4-trifluoromethyl)phenyl}-methoxyethyl]piperidine-3-carboxylic acid] are described. These N-substituted nipecotic acid derivatives were prepared in no-carrier-added form by the condensation of the appropriately substituted [18F]benzhydryl chlorides (prepared in three steps from [18F]fluoride ion) with N-(2-hydroxyethyl)nipecotic acid ethyl ester, followed by ester hydrolysis. Overall radiochemical yields were 17-28% (corrected, 150 min synthesis time). A simple new method for synthesis of a [18F]trifluoromethyl group by the nucleophilic substitution of a bromodifluoromethyl substituent has also been developed.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/28921/1/0000758.pd

Rats that differentially respond to cocaine differ in their dopaminergic storage capacity of the nucleus accumbens

Cocaine (COC) inhibits the re-uptake of dopamine. However, the dopamine response to COC also depends on dopamine inside storage vesicles. The aim of this study was to investigate whether rats that differentially respond to COC differ in their dopaminergic storage capacity of the nucleus accumbens. Total and vesicular levels of accumbal dopamine as well as accumbal vesicular monoamine transporter-2 levels were established in high (HR) and low responders (LR) to novelty rats. Moreover, the effects of reserpine (RES) on the COC-induced increase of extracellular accumbal dopamine were investigated. HR displayed higher accumbal levels of total and vesicular dopamine than LR. Moreover, HR displayed more accumbal vesicular monoamine transporters-2 than LR. COC increased extracellular accumbal dopamine more strongly in HR than in LR. A low dose of RES prevented the COC-induced increase of accumbal dopamine in LR, but not in HR. A higher dose of RES was required to inhibit the COC-induced increase of accumbal dopamine in HR. These data demonstrate that HR were marked by a larger accumbal dopaminergic storage pool than LR. It is hypothesized that HR are more sensitive to COC than LR, because COC can release more dopamine from accumbal storage vesicles in HR than in LR

The 18 kDa Translocator Protein (Peripheral Benzodiazepine Receptor) Expression in the Bone of Normal, Osteoprotegerin or Low Calcium Diet Treated Mice

The presence of the translocator protein (TSPO), previously named as the mitochondrial or peripheral benzodiazepine receptor, in bone cells was studied in vitro and in situ using RT-qPCR, and receptor autoradiography using the selective TSPO ligand PK11195

A Steered Molecular Dynamics Study of Binding and Translocation Processes in the GABA Transporter

The entire substrate translocation pathway in the human GABA transporter (GAT-1) was explored for the endogenous substrate GABA and the anti-convulsive drug tiagabine. Following a steered molecular dynamics (SMD) approach, in which a harmonic restraining potential is applied to the ligand, dissociation and re-association of ligands were simulated revealing events leading to substrate (GABA) translocation and inhibitor (tiagabine) mechanism of action. We succeeded in turning the transporter from the outward facing occluded to the open-to-out conformation, and also to reorient the transporter to the open-to-in conformation. The simulations are validated by literature data and provide a substrate pathway fingerprint in terms of which, how, and in which sequence specific residues are interacted with. They reveal the essential functional roles of specific residues, e.g. the role of charged residues in the extracellular vestibule including two lysines (K76 (TM1) and K448 (TM10)) and a TM6-triad (D281, E283, and D287) in attracting and relocating substrates towards the secondary/interim substrate-binding site (S2). Likewise, E101 is highlighted as essential for the relocation of the substrate from the primary substrate-binding site (S1) towards the cytoplasm

The Influence of Coastal Access on Isotope Variation in Icelandic Arctic Foxes

To quantify the ecological effects of predator populations, it is important to evaluate how population-level specializations are dictated by intra- versus inter-individual dietary variation. Coastal habitats contain prey from the terrestrial biome, the marine biome and prey confined to the coastal region. Such habitats have therefore been suggested to better support predator populations compared to habitats without coastal access. We used stable isotope data on a small generalist predator, the arctic fox, to infer dietary strategies between adult and juvenile individuals with and without coastal access on Iceland. Our results suggest that foxes in coastal habitats exhibited a broader isotope niche breadth compared to foxes in inland habitats. This broader niche was related to a greater diversity of individual strategies rather than to a uniform increase in individual niche breadth or by individuals retaining their specialization but increasing their niche differentiation. Juveniles in coastal habitats exhibited a narrower isotope niche breadth compared to both adults and juveniles in inland habitats, and juveniles in inland habitats inhabited a lower proportion of their total isotope niche compared to adults and juveniles from coastal habitats. Juveniles in both habitats exhibited lower intra-individual variation compared to adults. Based on these results, we suggest that foxes in both habitats were highly selective with respect to the resources they used to feed offspring, but that foxes in coastal habitats preferentially utilized marine resources for this purpose. We stress that coastal habitats should be regarded as high priority areas for conservation of generalist predators as they appear to offer a wide variety of dietary options that allow for greater flexibility in dietary strategies