The Most Severe Test for Hydrophobicity Scales: Two Proteins with 88% Sequence Identity but Different Structure and Function

Protein-protein interactions (protein functionalities) are mediated by water, which compacts individual proteins and promotes close and temporarily stable large-area protein-protein interfaces. In their classic paper Kyte and Doolittle (KD) concluded that the "simplicity and graphic nature of hydrophobicity scales make them very useful tools for the evaluation of protein structures". In practice, however, attempts to develop hydrophobicity scales (for example, compatible with classical force fields (CFF) in calculating the energetics of protein folding) have encountered many difficulties. Here we suggest an entirely different approach, based on the idea that proteins are self-organized networks, subject to finite-scale criticality (like some network glasses). We test this proposal against two small proteins that are delicately balanced between alpha and alpha/beta structures, with different functions encoded with only 12% of their amino acids. This example explains why protein structure prediction is so challenging, and it provides a severe test for the accuracy and content of hydrophobicity scales. The new method confirms KD's evaluation, and at the same time suggests that protein structure, dynamics and function can be best discussed without using CFF

Endogeneous Versus Exogeneous Shocks in Systems with Memory

Systems with long-range persistence and memory are shown to exhibit different precursory as well as recovery patterns in response to shocks of exogeneous versus endogeneous origins. By endogeneous, we envision either fluctuations resulting from an underlying chaotic dynamics or from a stochastic forcing origin which may be external or be an effective coarse-grained description of the microscopic fluctuations. In this scenario, endogeneous shocks result from a kind of constructive interference of accumulated fluctuations whose impacts survive longer than the large shocks themselves. As a consequence, the recovery after an endogeneous shock is in general slower at early times and can be at long times either slower or faster than after an exogeneous perturbation. This offers the tantalizing possibility of distinguishing between an endogeneous versus exogeneous cause of a given shock, even when there is no ``smoking gun.'' This could help in investigating the exogeneous versus self-organized origins in problems such as the causes of major biological extinctions, of change of weather regimes and of the climate, in tracing the source of social upheaval and wars, and so on. Sornette, Malevergne and Muzy have already shown how this concept can be applied concretely to differentiate the effects on financial markets of the Sept. 11, 2001 attack or of the coup against Gorbachev on Aug., 19, 1991 (exogeneous) from financial crashes such as Oct. 1987 (endogeneous).Comment: Latex document of 14 pages with 3 eps figure

A full scale comparative study of methods for generation of functional Dendritic cells for use as cancer vaccines

<p/> <p>Background</p> <p>Dendritic cells (DCs) are professional antigen-presenting cells with the ability to induce primary T-cell responses and are commonly produced by culturing monocytes in the presence of IL-4 and GM-CSF for 5–7 days (Standard DC). Recently, Dauer and co-workers presented a modified protocol for differentiation of human monocytes into mature DCs within 48 hours (Fast DC). Here we report a functional comparison of the two strategies for generation of DCs from human monocytes with adaptions for large-scale clinical use.</p> <p>Methods</p> <p>The Elutra Cell Selection System was used to isolate monocytes after collection of leukapheresis product. The enriched monocytes were cultured in gas permeable Teflon bags with IL-4 and GM-CSF for 24 hours (Fast DC) or 5 days (Standard DC) to obtain immature DCs. The cells were then transfected with mRNA from the leukemia cell line Jurkat E6 by electroporation and incubated for additional 24 h or 2 days in the presence of pro-inflammatory cytokines (TNFα, IL-1β, IL-6 and PGE₂) to obtain mature DCs.</p> <p>Results</p> <p>Mature Fast DC and Standard DC displayed comparable levels of many markers expressed on DC, including HLA-DR, CD83, CD86, CD208 and CCR7. However, compared to Standard DC, mature Fast DC was CD14^highCD209^low. Fast DC and Standard DC transfected with Jurkat E6-cell mRNA were equally able to elicit T cell specifically recognizing transfected DCs in vitro. IFNγ-secreting T cells were observed in both the CD4+ and CD8+ subsets.</p> <p>Conclusion</p> <p>Our results indicate that mature Fast DC are functional antigen presenting cells (APCs) capable of inducing primary T-cell responses, and suggest that these cells may be valuable for generation of anti-tumor vaccines.</p

Hydrophobic gating of mechanosensitive channel of large conductance evidenced by single-subunit resolution

Mechanosensitive (MS) ion channels are membrane proteins that detect and respond to membrane tension in all branches of life. In bacteria, MS channels prevent cells from lysing upon sudden hypoosmotic shock by opening and releasing solutes and water. Despite the importance of MS channels and ongoing efforts to explain their functioning, the molecular mechanism of MS channel gating remains elusive and controversial. Here we report a method that allows single-subunit resolution for manipulating and monitoring “mechanosensitive channel of large conductance” from Escherichia coli. We gradually changed the hydrophobicity of the pore constriction in this homopentameric protein by modifying a critical pore residue one subunit at a time. Our experimental results suggest that both channel opening and closing are initiated by the transmembrane 1 helix of a single subunit and that the participation of each of the five identical subunits in the structural transitions between the closed and open states is asymmetrical. Such a minimal change in the pore environment seems ideal for a fast and energy-efficient response to changes in the membrane tension.

Numerical analysis of the thermomechanical behaviour of an integrally water-heated tool for composite manufacturing

Integrally water-heated tooling is one of the technologies available for ‘out-of-autoclave’ processing of advanced thermoset polymer composites. Temperature variation and temperature cycling, during heating and cooling, affect the properties of tool material and may produce undesirable thermal effects that degrade the tool durability and performance, especially when the tool construction involves various materials. Hence, in the current study, the performance and the thermomechanical behaviour of an integrally water-heated tool have been investigated using finite element analysis method. The intended tool, in the current study, consists different materials of composite and metals and is designed to heat up to 90℃. Linear mechanical properties, coefficient of thermal expansions and transient heating curve of each tool part are determined experimentally and set during the numerical analysis of tool structure to calculate the static thermal load effects of deformation, stress and strain. Comparing the numerical thermal effects with the ultimate stresses and strains of the tool, materials concluded that no failure occurs with regard to static thermal loads. However, the calculated stresses are as much as the lowest magnitude of safety relates to the tool mould part made of Alepoxy. </jats:p

Cancer immunotherapy:From the lab to clinical applications - Potential impact on cancer centres' organisation

This report covers the Immunotherapy sessions of the 2016 Organisation of European Cancer Institutes (OECI) Oncology Days meeting, which was held on 15th–17th June 2016 in Brussels, Belgium. Immunotherapy is a potential cancer treatment that uses an individual’s immune system to fight the tumour. In recent years significant advances have been made in this field in the treatment of several advanced cancers. Cancer immunotherapies include monoclonal antibodies that are designed to attack a very specific part of the cancer cell and immune checkpoint inhibitors which are molecules that stimulate or block the inhibition of the immune system. Other cancer immunotherapies include vaccines and T cell infusions. This report will summarise some of the research that is going on in this field and will give us an update on where we are at present