Relating side chain organization of PNIPAm with its conformation in aqueous methanol

Combining nuclear magnetic resonance (NMR), dynamic light scattering (DLS), and μs long all-atom simulations with two million particles, we establish a delicate correlation between increased side chain organization of PNIPAm and its collapse in aqueous methanol mixtures. We find that the preferential binding of methanol with PNIPAm side chains, bridging distal monomers along the polymer backbone, results in increased organization. Furthermore, methanol–PNIPAm preferential binding is dominated by hydrogen bonding. Our findings reveal that the collapse of PNIPAm is dominated by enthalpic interactions and that the standard poor solvent (entropic) effects play no major role

Некоторые результаты применения метода геометрического анализа дизъюнктов для поисков смещенного крыла пласта в Прокопьевском районе Кузбасса

In this paper we present the development of a compact, thermo-optically stable and vibration and mechanical shock resistant mounting technique by soldering of optical components. Based on this technique, new generations of laser pump sources for aerospace applications are designed. In these laser systems the used soldering technique replaces the glued connection between the optical component and its join partner. The main challenges are the alignment accuracy in the arc second range and the realization of the long term stability of every single part in the laser system (e.g. resonator mirrors)

О необходимости прослеживания Балейско-Дарасунского разлома в пределах Борщевочного кряжа

In this paper we present the development of a compact, thermo-optically stable and vibration and mechanical shock resistant mounting technique by soldering of optical components. Based on this technique a new generation of laser sources for aerospace applications is designed. In these laser systems solder technique replaces the glued and bolted connections between optical component, mount and base plate. Alignment precision in the arc second range and realization of long term stability of every single part in the laser system is the main challenge. At the Fraunhofer Institute for Laser Technology ILT a soldering and mounting technique has been developed for high precision packaging. The specified environmental boundary conditions (e.g. a temperature range of -40 °C to +50 °C) and the required degrees of freedom for the alignment of the components have been taken into account for this technique. In general the advantage of soldering compared to gluing is that there is no outgassing. In addition no flux is needed in our special process. The joining process allows multiple alignments by remelting the solder. The alignment is done in the liquid phase of the solder by a 6 axis manipulator with a step width in the nm range and a tilt in the arc second range. In a next step the optical components have to pass the environmental tests. The total misalignment of the component to its adapter after the thermal cycle tests is less than 10 arc seconds. The mechanical stability tests regarding shear, vibration and shock behavior are well within the requirements

A pulsed, mono-energetic and angular-selective UV photo-electron source for the commissioning of the KATRIN experiment

The KATRIN experiment aims to determine the neutrino mass scale with a sensitivity of 200 meV/c^2 (90% C.L.) by a precision measurement of the shape of the tritium $\beta$-spectrum in the endpoint region. The energy analysis of the decay electrons is achieved by a MAC-E filter spectrometer. To determine the transmission properties of the KATRIN main spectrometer, a mono-energetic and angular-selective electron source has been developed. In preparation for the second commissioning phase of the main spectrometer, a measurement phase was carried out at the KATRIN monitor spectrometer where the device was operated in a MAC-E filter setup for testing. The results of these measurements are compared with simulations using the particle-tracking software "Kassiopeia", which was developed in the KATRIN collaboration over recent years.Comment: 19 pages, 16 figures, submitted to European Physical Journal

Explaining differentiation in European Union treaties

Since the early 1990s, European integration has become increasingly differentiated. Analysing the conditions under which member states make use of the opportunity to opt out of, or exclude other countries from, European integration, we argue that different explanations apply to treaty and accession negotiations, respectively. Threatening to block deeper integration, member states with strong national identities secure differentiations in treaty reform. In enlargement, in turn, old member states fear economic disadvantages and low administrative capacity and therefore impose differentiation on poor newcomers. Opt-outs from treaty revisions are limited to the area of core state powers, whereas they also occur in the market in the context of enlargement

Commissioning of the vacuum system of the KATRIN Main Spectrometer

The KATRIN experiment will probe the neutrino mass by measuring the beta-electron energy spectrum near the endpoint of tritium beta-decay. An integral energy analysis will be performed by an electro-static spectrometer (Main Spectrometer), an ultra-high vacuum vessel with a length of 23.2 m, a volume of 1240 m^3, and a complex inner electrode system with about 120000 individual parts. The strong magnetic field that guides the beta-electrons is provided by super-conducting solenoids at both ends of the spectrometer. Its influence on turbo-molecular pumps and vacuum gauges had to be considered. A system consisting of 6 turbo-molecular pumps and 3 km of non-evaporable getter strips has been deployed and was tested during the commissioning of the spectrometer. In this paper the configuration, the commissioning with bake-out at 300{\deg}C, and the performance of this system are presented in detail. The vacuum system has to maintain a pressure in the 10^{-11} mbar range. It is demonstrated that the performance of the system is already close to these stringent functional requirements for the KATRIN experiment, which will start at the end of 2016.Comment: submitted for publication in JINST, 39 pages, 15 figure

Two additive mechanisms impair the differentiation of 'substrate-selective' p38 inhibitors from classical p38 inhibitors in vitro

<p>Abstract</p> <p>Background</p> <p>The success of anti-TNF biologics for the treatment of rheumatoid arthritis has highlighted the importance of understanding the intracellular pathways that regulate TNF production in the quest for an orally-available small molecule inhibitor. p38 is known to strongly regulate TNF production via MK2. The failure of several p38 inhibitors in the clinic suggests the importance of other downstream pathways in normal cell function. Recent work has described a 'substrate-selective' p38 inhibitor that is able to preferentially block the activity of p38 against one substrate (MK2) versus another (ATF2). Using a combined experimental and computational approach, we have examined this mechanism in greater detail for two p38 substrates, MK2 and ATF2.</p> <p>Results</p> <p>We found that in a dual (MK2 and ATF2) substrate assay, MK2-p38 interaction reduced the activity of p38 against ATF2. We further constructed a detailed kinetic mechanistic model of p38 phosphorylation in the presence of multiple substrates and successfully predicted the performance of classical and so-called 'substrate-selective' p38 inhibitors in the dual substrate assay. Importantly, it was found that excess MK2 results in a stoichiometric effect in which the formation of p38-MK2-inhibitor complex prevents the phosphorylation of ATF2, despite the preference of the compound for the p38-MK2 complex over the p38-ATF2 complex. MK2 and p38 protein expression levels were quantified in U937, Thp-1 and PBMCs and found that [MK2] > [p38].</p> <p>Conclusion</p> <p>Our integrated mechanistic modeling and experimental validation provides an example of how systems biology approaches can be applied to drug discovery and provide a basis for decision-making with limited chemical matter. We find that, given our current understanding, it is unlikely that 'substrate-selective' inhibitors of p38 will work as originally intended when placed in the context of more complex cellular environments, largely due to a stoichiometric excess of MK2 relative to p38.</p

Introduction: Connecting with the Electorate? Parliamentary Communication in EU Affairs

ational parliaments have often been described as latecomers to European integration, but there is little doubt that they have developed the institutional means to become more involved over the last few years – and especially since the Lisbon Treaty. Accordingly, the main focus of the literature has been on this institutional adaptation and thus on the relationship between the parliament and the government in European Union (EU) affairs. Other parliamentary functions, and in particular those that relate to their citizens such as the communication function, by contrast, have been largely neglected. Yet democracy depends on a viable public debate on policy choices and political alternatives to allow citizens to make informed political (electoral) choices and to exercise democratic control. This collection therefore investigates whether, and how, individual members of parliament, political parties, or legislatures as institutions ‘link’ with their electorates in EU politics. This introduction discusses why engaging with the public in EU affairs is – or at least should be – an important aspect of parliamentary work, introduces parliamentary means of communication and assesses parliamentary incentives and disincentives ‘to go public’ in EU politics. (author's abstract

Downregulation of the AU-Rich RNA-Binding Protein ZFP36 in Chronic HBV Patients: Implications for Anti-Inflammatory Therapy

Inflammation caused by chronic hepatitis B virus (HBV) infection is associated with the development of cirrhosis and hepatocellular carcinoma; however, the mechanisms by which HBV infection induces inflammation and inflammatory cytokine production remain largely unknown. We analyzed the gene expression patterns of lymphocytes from chronic HBV-infected patients and found that the expression of ZFP36, an AU-rich element (ARE)-binding protein, was dramatically reduced in CD4+ and CD8+ T lymphocytes from chronic HBV patients. ZFP36 expression was also reduced in CD14+ monocytes and in total PBMCs from chronic HBV patients. To investigate the functional consequences of reduced ZFP36 expression, we knocked down ZFP36 in PBMCs from healthy donors using siRNA. siRNA-mediated silencing of ZFP36 resulted in dramatically increased expression of multiple inflammatory cytokines, most of which were also increased in the plasma of chronic HBV patients. Furthermore, we found that IL-8 and RANTES induced ZFP36 downregulation, and this effect was mediated through protein kinase C. Importantly, we found that HBsAg stimulated PBMCs to express IL-8 and RANTES, resulting in decreased ZFP36 expression. Our results suggest that an inflammatory feedback loop involving HBsAg, ZFP36, and inflammatory cytokines may play a critical role in the pathogenesis of chronic HBV and further indicate that ZFP36 may be an important target for anti-inflammatory therapy during chronic HBV infection

Post-transcriptional control during chronic inflammation and cancer: a focus on AU-rich elements

A considerable number of genes that code for AU-rich mRNAs including cytokines, growth factors, transcriptional factors, and certain receptors are involved in both chronic inflammation and cancer. Overexpression of these genes is affected by aberrations or by prolonged activation of several signaling pathways. AU-rich elements (ARE) are important cis-acting short sequences in the 3′UTR that mediate recognition of an array of RNA-binding proteins and affect mRNA stability and translation. This review addresses the cellular and molecular mechanisms that are common between inflammation and cancer and that also govern ARE-mediated post-transcriptional control. The first part examines the role of the ARE-genes in inflammation and cancer and sequence characteristics of AU-rich elements. The second part addresses the common signaling pathways in inflammation and cancer that regulate the ARE-mediated pathways and how their deregulations affect ARE-gene regulation and disease outcome