蛋白质组学面临的新问题

蛋白质组学领域仅仅经历了十年的发展历程。虽然它还有许多棘手的问题尚待解决，但是研究人员坚信蛋白质组学能够发现新的药靶和生物标记物，从而可以改进诊断和治疗过程。本文选择此领域内几家瑞士公司的工作进行评述。     

Contribution to DEMO reactor RH maintenance assessment

The scope of this paper is a preliminary assessment of the maintenance scheme in support of the European study for the next generation of fusion reactor: DEMO. Despite other fusion machine requiring remote handling maintenance operations, DEMO is supposed to work under steady state operational conditions. Therefore, requirement on the maintenance scheme is stronger. To target a good availability of the machine along machine operation plan, it is necessary to draw an adequate maintenance scheme. Indeed, due to the high fluxes generated by the plasma in the vacuum vessel, the first wall lifetime is limited, so the frequent replacement is necessary. On current fusion experimental machine, as first wall load conditions are less severe, DEMO condition implies high level of requirement on maintenance time. During DEMO lifetime, several full first wall replacements are expected. To provide access to the vacuum vessel machine for first wall removal, preparatory work is required to set the machine to adequate maintenance conditions and to open the machine properly, the same situation at the end of the maintenance period. Shutdown duration for first wall replacement should be as short as possible to reach the availability target of the machine. From this statement, the maintenance duration should not exceed 20% of the total lifetime of the reactor operation. First wall segmentation (i.e. total number of component to replace) has a high impact onto the replacement time. Considering the number of feasible designs for the first wall segmentation, we concentrate remote handling concept assessments one type of segmentation, the one minimizing the numbers of modules to replace [4], [5], [6]. Assumption on Divertor segmentation for these DEMO studies have similarities with Divertor ITER design; therefore ITER design output is relevant [1], [2]. We assume divertor removal performed in shadow time, while removing the other first wall modules.     

Conformational Stabilization of Gp41-Mimetic Miniproteins Opens Up New Ways of Inhibiting HIV-1 Fusion

Inhibition of the HIV-1 fusion process constitutes a promising strategy to neutralize the virus at an early stage before it enters the cell. In this process, the envelope glycoprotein (Env) plays a central role by promoting membrane fusion. We previously identified a vulnerability at the flexible C-terminal end of the gp41 C-terminal heptad repeat (CHR) region to inhibition by a single-chain miniprotein (named covNHR-N) that mimics the first half of the gp41 N-terminal heptad repeat (NHR). The miniprotein exhibited low stability, moderate binding to its complementary CHR region, both as an isolated peptide and in native trimeric Envs, and low inhibitory activity against a panel of pseudoviruses. The addition of a disulfide bond stabilizing the miniprotein increased its inhibitory activity, without altering the binding affinity. Here, to further study the effect of conformational stability on binding and inhibitory potency, we additionally stabilized these miniproteins by engineering a second disulfide bond stapling their N-terminal end, The new disulfide-bond strongly stabilizes the protein, increases binding affinity for the CHR target and strongly improves inhibitory activity against several HIV-1 strains. Moreover, high inhibitory activity could be achieved without targeting the preserved hydrophobic pocket motif of gp41. These results may have implications in the discovery of new strategies to inhibit HIV targeting the gp41 CHR region.     

Investigation of Trypanothione Reductase as a Drug Target in Trypanosoma brucei

There is an urgent need for new drugs for the treatment of tropical parasitic diseases such as human African trypanosomiasis, which is caused by Trypanosoma brucei. The enzyme trypanothione reductase (TryR) is a potential drug target within these organisms. Herein we report the screening of a 62 000 compound library against T. brucei TryR. Further work was undertaken to optimise potency and selectivity of two novel‐compound series arising from the enzymatic and whole parasite screens and mammalian cell counterscreens. Both of these series, containing either a quinoline or pyrimidinopyrazine scaffold, yielded low micromolar inhibitors of the enzyme and growth of the parasite. The challenges of inhibiting TryR with druglike molecules is discussed.     

Silica Colloidal Membranes with Enantioselective Permeability

Robust mesoporous membranes composed of silica spheres were surface-modified with chiral selector moieties, including small molecules, macrocycles, and polymers. Diffusion rates of enantiomers of a chiral dye through the resulting asymmetrically modified colloidal membranes were measured and the corresponding permselectivities were calculated. The membranes showed enantioselectivities in the range of 1.2–1.8, which were not significantly affected by the structure of the surface-immobilized chiral electors. This selectivity is on par with most reported polymer-based solid membranes and bulk liquid membranes. The enantioselectivity results from the surface-facilitated mechanism of transport of enantiomers through the mesopores.     

High frequency response to the impedance complex properties of Nb-doped CaCu3Ti4O12 electroceramics

Impedance analyses was performed on undoped and Nb-doped CaCu₃Ti₄O₁₂ (CaCu₃Ti_4−xNb_xO_12+x/2; x = 0, 0.01, 0.03, 0.05, 0.1) to investigate their electrical properties. The pellet samples were prepared using the solid state reaction method. Silver electrode was deposited on both pellets’ surfaces for electrical measurement. The thermally etched samples showed tiny bumped domains within the grains. The existence of both domain and grain boundaries are believed to strongly influence the dielectric constant of CaCu₃Ti₄O₁₂ (CCTO). Undoped CCTO showed two arcs of impedance complex plane while Nb-doped samples have three arcs. Each arc represents the constituent elements of the CCTO. The highest frequency arc is evidence that CCTO consists of conductive domains which measure about 1 Ω and are insulated by two types of barriers, i.e. domain boundary and grain boundary.     

Is a sense of inequity an ancestral primate trait? Testing social inequity in cotton top tamarins (Saguinus oedipus).

To address a controversy in the literature concerning whether monkeys show an aversion to inequity, individuals of a New World monkey species, cotton top tamarins (Saguinus oedipus) were tested in an offering task and in a bartering task. At issue was whether the monkeys rejected rewards because of a violation of expectancy of the preferred reward, or whether they rejected rewards because of a sensitivity to socially mediated inequity. The data from both tasks indicated that the subjects were more likely to reject when preferred rewards were presented, either because of another animal eating the reward (the social condition) or because of rewards being presented but inaccessible. The bartering task led to the only behavioral indication of aversion due specifically to social inequity, which was demonstrated when tamarins' sensitivity to the difference in rewards increased with exposure to other tamarins working to receive the preferred rewards. The results suggest that social inequity aversion will be assessed by tamarins, and possibly by other primates, only under conditions of limited resources and a requirement of work, which may make the situation a bit more competitive and thus drives attention toward both social and reward evaluation. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Invention from War: a circumstantial modernism for Australian architecture

Between 1942 and 1945, Australian architects and engineers within the Allied Works Council and the US Army Corps of Engineers undertook a vast programme of building works to assist the campaign to drive Japanese forces northward through the Southwest Pacific and avoid invasion.¹ Huge distances, lack of time and the need to wage a campaign from the air lay behind US General Douglas Macarthur’s phrase that it would be an ‘engineer’s war’. By necessity, buildings such as airfields, hospitals, camps, warehouses, and other structures had to be light weight, constructed quickly, and inevitably dropped in by air as easily handled pre-cut packages. With the lack of American and European softwoods in the Australasian region, an unlikely local material was pressed into war service – unseasoned or ‘green’ Australian hardwood. It was a material choice that would have profound implications for two reasons. First, in the years of conflict, circumstances dictated the unprecedented innovation and experiment in light-weight timber structures. Second, in an echo of Lewis Mumford’s poignant maxim that ‘war is the health of the machine’², the systematisation and ruthless economy inherent in wartime timber buildings would influence the development and practice of a particular form of modern architecture in Australia in the late 1940s and the 1950s.