Direct time-resolved study of the gas-phase reactions of germylene with ethyl- and diethylgermane: absolute rate constants, temperature dependences, and mechanism

Time-resolved studies of germylene, GeH2, generated by the 193 nm laser flash photolysis of 3,4-dimethyl-1-germacyclopent-3-ene, have been carried out to obtain rate constants for its bimolecular reactions with ethyl- and diethylgermanes in the gas phase. The reactions were studied over the pressure range 1-100 Torr with SF6 as bath gas and at five temperatures in the range 297-564 K. Only slight pressure dependences were found for GeH2 + EtGeH3 (399, 486, and 564 K). The high pressure rate constants gave the following Arrhenius parameters: for GeH2 + EtGeH3, log A = -10.75 +/- 0.08 and E-a = -6.7 +/- 0.6 kJ mol(-1); for GeH2 + Et2GeH2, log A = -10.68 +/- 0.11 and E-a = -6.95 +/- 0.80 kJ mol(-1). These are consistent with fast, near collision-controlled, association processes at 298 K. RRKM modeling calculations are, for the most part, consistent with the observed pressure dependence of GeH2 + EtGeH3. The ethyl substituent effects have been extracted from these results and are much larger than the analogous methyl substituent effects in the SiH2 + methylsilane reaction series. This is consistent with a mechanistic model for Ge-H insertion in which the intermediate complex has a sizable secondary barrier to rearrangement.

First crystallographic signature of an acyclic peptide nanorod: molecular mechanism of nanorod formation by a self-assembled tetrapeptide

A terminally protected acyclic tetrapeptide Boc-Aib-Val-Aib-beta-Ala-OMe 1 (Aib: alpha-aminoisobutyric acid, beta-Ala: beta-Alanine) self-assembles into a continuous hydrogen-bonded supramolecular helix with an average diameter of 10Angstrom (1nm) starting from a double bend molecular conformation in crystals and further self-assembly of this supramolecular architecture leads to the formation of polydisperse nanorods of diameters 10-40 nm.

An insight into the mechanism of protein separation by colloidal gas aphrons (CGA) generated from ionic surfactants

Colloidal gas aphrons (CGA), which are surfactant stabilised microbubbles, have been previously applied for the recovery of proteins from model mixtures and a few studies have demonstrated the potential of these dispersions for the selective recovery of proteins from complex mixtures. However there is a lack of understanding of the mechanism of separation and forces governing the selectivity of the separation. In this paper a mechanistic study is carried out to determine the main factors and forces influencing the selectivity of separation of whey proteins with CGA generated from ionic surfactants. Two different separation strategies were followed: (i) separation of lactoferrin and lactoperoxidase by anionic CGA generated from a solution of sodium bis-(2-ethyl hexyl) sulfosuccinate (AOT); (ii) separation of beta-lactoglobulin by cationic CGA generated from a solution of cetyltrimethylammonium bromide (CTAB). Separation results indicate that electrostatic interactions are the main forces determining the selectivity however these could not completely explain the selectivities obtained following both strategies. Protein-surfactant interactions were studied by measuring the zeta potential changes on individual proteins upon addition of surfactant and at varying pH. Interestingly strongest electrostatic interactions were measured at those pH and surfactant to protein mass ratios which were optimum for protein separation. Effect of surfactant on protein conformation was determined by measuring the change in fluorescence intensity upon addition of surfactant at varying pH. Differences in the fluorescence patterns were detected among proteins which were correlated to differences in their conformational features which could in turn explain their different separation behaviour. The effect of conformation on selectivity was further proven by experiments in which conformational changes were induced by pre-treatment of whey (heating) and by storage at 4 degrees C. Overall it can be concluded that separation of proteins by ionic CGA is driven mainly by electrostatic interactions however conformational features will finally determine the selectivity of the separation with competitive adsorption having also an effect. (c) 2006 Elsevier B.V. All rights reserved.

Selective increases of bifidobacteria in gut microflora improve high-fat-diet-induced diabetes in mice through a mechanism associated with endotoxaemia

Aims/hypothesis Recent evidence suggests that a particular gut microbial community may favour occurrence of the metabolic diseases. Recently, we reported that high-fat (HF) feeding was associated with higher endotoxaemia and lower Bifidobacterium species (spp.) caecal content in mice. We therefore tested whether restoration of the quantity of caecal Bifidobacterium spp. could modulate metabolic endotoxaemia, the inflammatory tone and the development of diabetes. Methods Since bifidobacteria have been reported to reduce intestinal endotoxin levels and improve mucosal barrier function, we specifically increased the gut bifidobacterial content of HF-diet-fed mice through the use of a prebiotic (oligofructose [OFS]). Results Compared with normal chow-fed control mice, HF feeding significantly reduced intestinal Gram-negative and Gram-positive bacteria including levels of bifidobacteria, a dominant member of the intestinal microbiota, which is seen as physiologically positive. As expected, HF-OFS-fed mice had totally restored quantities of bifidobacteria. HF-feeding significantly increased endotoxaemia, which was normalised to control levels in HF-OFS-treated mice. Multiple-correlation analyses showed that endotoxaemia significantly and negatively correlated with Bifidobacterium spp., but no relationship was seen between endotoxaemia and any other bacterial group. Finally, in HF-OFS-treated-mice, Bifidobacterium spp. significantly and positively correlated with improved glucose tolerance, glucose-induced insulin secretion and normalised inflammatory tone (decreased endotoxaemia, plasma and adipose tissue proinflammatory cytokines). Conclusions/interpretation Together, these findings suggest that the gut microbiota contribute towards the pathophysiological regulation of endotoxaemia and set the tone of inflammation for occurrence of diabetes and/or obesity. Thus, it would be useful to develop specific strategies for modifying gut microbiota in favour of bifidobacteria to prevent the deleterious effect of HF-diet-induced metabolic diseases.

Cannabinoids inhibit human keratinocyte proliferation through a non-CB1/CB2 mechanism and have a potential therapeutic value in the treatment of psoriasis

Background: Cannabinoids from cannabis (Cannabis sativa) are anti-inflammatory and have inhibitory effects on the proliferation of a number of tumorigenic cell lines, some of which are mediated via cannabinoid receptors. Cannabinoid (CB) receptors are present in human skin and anandamide, an endogenous CB receptor ligand, inhibits epidermal keratinocyte differentiation. Psoriasis is an inflammatory disease also characterised in part by epidermal keratinocyte hyper-proliferation. Objective: We investigated the plant cannabinoids Delta-9 tetrahydrocannabinol, cannabidiol, cannabinol and cannabigerol for their ability to inhibit the proliferation of a hyper-proliferating human keratinocyte cell line and for any involvement of cannabinoid receptors. Methods: A keratinocyte proliferation assay was used to assess the effect of treatment with cannabinoids. Cell integrity and metabolic competence confirmed using lactate-dehydrogenase and adenosine tri-phosphate assays. To determine the involvement of the receptors, specific agonist and antagonist were used in conjunction with some phytocannabinoids. Western blot and RT-PCR analysis confirmed presence of CB1 and CB2 receptors. Results: The cannabinoids tested all inhibited keratinocyte proliferation in a concentration-dependent manner. The selective CB2 receptor agonists JWH015 and BML190 elicited only partial inhibition, the non-selective CB agonist HU210 produced a concentration-dependent response, the activity of theses agonists were not blocked by either C81 /C82 antagonists. Conclusion: The results indicate that while CB receptors may have a circumstantial role in keratinocyte proliferation, they do not contribute significantly to this process. Our results show that cannabinoids inhibit keratinocyte proliferation, and therefore support a potential role for cannabinoids in the treatment of psoriasis. (c) 2006 Japanese Society for Investigative Dermatology. Published by Elsevier Ireland Ltd. All rights reserved.

Investigating the mechanism of enhanced cytotoxicity of HPMA copolymer-Dox-AGM in breast cancer cells

Recently we have described an HPMA copolymer conjugate carrying both the aromatase inhibitor aminoglutethimide (AGM) and doxorubicin (Dox) as combination therapy. This showed markedly enhanced in vitro cytotoxicity compared to the HPMA copolymer-Dox (FCE28068), a conjugate that demonstrated activity in chemotherapy refractory breast cancer patients during early clinical trials. To better understand the superior activity of HPMA copolymer-Dox-AGM, here experiments were undertaken using MCF-7 and MCF-7ca (aromatase-transfected) breast cancer cell lines to: further probe the synergistic cytotoxic effects of AGM and Dox in free and conjugated form; to compare the endocytic properties of HPMA copolymer-Dox-AGM and HPMA copolymer-Dox (binding, rate and mechanism of cellular uptake); the rate of drug liberation by lysosomal thiol-dependant proteases (i.e. conjugate activation), and also, using immunocytochemistry, to compare their molecular mechanism of action. It was clearly shown that attachment of both drugs to the same polymer backbone was a requirement for enhanced cytotoxicity. FACS studies indicated both conjugates have a similar pattern of cell binding and endocytic uptake (at least partially via a cholesterol-dependent pathway), however, the pattern of enzyme-mediated drug liberation was distinctly different. Dox release from PK1 was linear with time, whereas the release of both Dox and AGM from HPMA copolymer-Dox-AGM was not, and the initial rate of AGM release was much faster than that seen for the anthracycline. Immunocytochemistry showed that both conjugates decreased the expression of ki67. However, this effect was more marked for HPMA copolymer-Dox-AGM and, moreover, only this conjugate decreased the expression of the anti-apoptotic protein bcl-2. In conclusion, the superior in vitro activity of HPMA copolymer-Dox-AGM cannot be attributed to differences in endocytic uptake, and it seems likely that the synergistic effect of Dox and AGM is due to the kinetics of intracellular drug liberation which leads to enhanced activity. (c) 2006 Elsevier B.V All rights reserved.

What neuroimaging and perceptions of self-other similarity can tell us about the mechanism underlying mentalizing

Carruthers' "mindreading is prior" model postulates one unitary mindreading mechanism working identically for self and other. While we agree about shared mindreading mechanisms, there is also evidence from neuroimaging and mentalizing about dissimilar others that suggest factors that differentially affect self-versus-other mentalizing. Such dissociations suggest greater complexity than the mindreading is prior model allows.

Design of redundant drive joint with adjustable stiffness and damping mechanism to improve joint admittance

Improving admittance of robotic joints is the key issue for making rehabilitation robots safe. This paper describes a design of Redundant Drive Joint (RD-Joint) which allows greater flexibility in the design of robotic mechanisms. The design strategy of the RD-Joint employs a systematic approach which consists of 1) adopting a redundant joint mechanism with internal kinematical redundancy to reduce effective joint inertia, and 2) adopting an adjustable admittance mechanism with a novel Cross link Reduction Mechanism and mechanical springs and dampers as a passive second actuator. First, the basic concepts used to construct the redundant drive joint mechanism are explained, in particular the method that allows a reduction in effective inertia at the output joint. The basic structure of the RD-Joint is introduced based on the idea of reduced inertia along with a method to include effective stiffness and damping. Then, the basic design of the adjustable admittance mechanism is described. Finally, a prototype of RD-joint is described and its expected characteristics are discussed.

Phase resetting as a mechanism of ERP generation: evidence from the power spectrum

A Neural Mass model is coupled with a novel method to generate realistic Phase reset ERPs. The power spectra of these synthetic ERPs are compared with the spectra of real ERPs and synthetic ERPs generated via the Additive model. Real ERP spectra show similarities with synthetic Phase reset ERPs and synthetic Additive ERPs.

Proposal of an admittance enhanced redundant joint mechanism to improve backdrivability

This paper describes a proposed admittance enhanced redundant joint mechanism (AERJM) which allows greater flexibility in the design of robotic joints. First, the basic concept of a redundant joint mechanism that reduces joint inertia is explained. Second, the AERJM structure is discussed. AERJM consists of a redundancy introducing mechanism (RIM), the adjustable admittance mechanism (AAM) and an admittance enhancing actuator. The working principles of the AERJM concept are analysed. The design and a working prototype, consisting of a variable reduction mechanism, along with a spring and a damper with constant coefficients, are described.

Pseudogene rescue: an adaptive mechanism of codon reassignment

Alterations to the genetic code – codon reassignments – have occurred many times in life’s history, despite the fact that genomes are coadapted to their genetic codes and therefore alterations are likely to be maladaptive. A potential mechanism for adaptive codon reassignment, which could trigger either a temporary period of codon ambiguity or a permanent genetic code change, is the reactivation of a pseudogene by a nonsense suppressor mutant transfer RNA. I examine the population genetics of each stage of this process and find that pseudogene rescue is plausible and also readily explains some features of extant variability in genetic codes.

Kinetics and mechanism of the interconversion of inverse bicontinuous cubic mesophases

This paper describes time-resolved x-ray diffraction data monitoring the transformation of one inverse bicontinuous cubic mesophase into another, in a hydrated lipid system. The first section of the paper describes a mechanism for the transformation that conserves the topology of the bilayer, based on the work of Charvolin and Sadoc, Fogden and Hyde, and Benedicto and O'Brien in this area. We show a pictorial representation of this mechanism, in terms of both the water channels and the lipid bilayer. The second section describes the experimental results obtained. The system under investigation was 2:1 lauric acid: dilauroylphosphatidylcholine at a hydration of 50% water by weight. A pressure-jump was used to induce a phase transition from the gyroid (Q(II)(G)) to the diamond (Q(II)(D)) bicontinuous cubic mesophase, which was monitored by time-resolved x-ray diffraction. The lattice parameter of both mesophases was found to decrease slightly throughout the transformation, but at the stage where the Q(II)(D) phase first appeared, the ratio of lattice parameters of the two phases was found to be approximately constant for all pressure-jump experiments. The value is consistent with a topology-preserving mechanism. However, the polydomain nature of our sample prevents us from confirming that the specific pathway is that described in the first section of the paper. Our data also reveal signals from two different intermediate structures, one of which we have identified as the inverse hexagonal (H-II) mesophase. We suggest that it plays a role in the transfer of water during the transformation. The rate of the phase transition was found to increase with both temperature and pressure-jump amplitude, and its time scale varied from the order of seconds to minutes, depending on the conditions employed.

Adult skeletal muscle stem cell migration is mediated by a blebbing/amoeboid mechanism

Adult skeletal muscle possesses a resident stem cell population called satellite cells which are responsible for tissue repair following damage. Satellite cell migration is crucial in promoting rapid tissue regeneration but is a poorly understood process. Furthermore, the mechanisms facilitating satellite cell movement have yet to be elucidated. Here the process of satellite cell migration has been investigated revealing that they undergo two distinct phases of movement; firstly under the basal lamina and then rapidly increasing their velocity when on the myofibre surface. Most significantly we show that satellite cells move using a highly dynamic blebbing based mechanism and not via lamellopodia mediated propulsion. We show that nitric oxide and non-canonical Wnt signalling pathways are necessary for regulating the formation of blebs and the migration of satellite cells. In summary, we propose that the formation of blebs and their necessity for satellite cell migration has significant implications in the future development of therapeutic regimes aimed at promoting skeletal muscle regeneration.

A cluster computing implementation of a Monte Carlo simulation of a particle growth mechanism

Clusters of computers can be used together to provide a powerful computing resource. Large Monte Carlo simulations, such as those used to model particle growth, are computationally intensive and take considerable time to execute on conventional workstations. By spreading the work of the simulation across a cluster of computers, the elapsed execution time can be greatly reduced. Thus a user has apparently the performance of a supercomputer by using the spare cycles on other workstations.