Non-Ergodic Nuclear Depolarization in Nano-Cavities

Recently, it has been observed that the effective dipolar interactions between nuclear spins of spin-carrying molecules of a gas in a closed nano-cavities are independent of the spacing between all spins. We derive exact time-dependent polarization for all spins in spin-1/2 ensemble with spatially independent effective dipolar interactions. If the initial polarization is on a single (first) spin,$P_1(0)= 1$ then the exact spin dynamics of the model is shown to exhibit a periodical short pulses of the polarization of the first spin, the effect being typical of the systems having a large number, $N$, of spins. If $N \gg 1$, then within the period $4\pi/g$ ($2\pi/g$) for odd (even) $N$-spin clusters, with $g$ standing for spin coupling, the polarization of spin 1 switches quickly from unity to the time independent value, 1/3, over the time interval about $(g\sqrt{N})^{-1}$, thus, almost all the time, the spin 1 spends in the time independent condition $P_1(t)= 1/3$. The period and the width of the pulses determine the volume and the form-factor of the ellipsoidal cavity. The formalism is adopted to the case of time varying nano-fluctuations of the volume of the cavitation nano-bubbles. If the volume $V(t)$ is varied by the Gaussian-in-time random noise then the envelope of the polarization peaks goes irreversibly to 1/3. The polarization dynamics of the single spin exhibits the Gaussian (or exponential) time dependence when the correlation time of the fluctuations of the nano-volume is larger (or smaller) than the $<(\delta g)^2 >^{-1/2}$, where the $$ is the variance of the $g(V(t))$ coupling. Finally, we report the exact calculations of the NMR line shape for the $N$-spin gaseous aggregate.Comment: 26 pages, 3 figure

In Silico Elucidation of the Recognition Dynamics of Ubiquitin

Elucidation of the mechanism of biomacromolecular recognition events has been a topic of intense interest over the past century. The inherent dynamic nature of both protein and ligand molecules along with the continuous reshaping of the energy landscape during the binding process renders it difficult to characterize this process at atomic detail. Here, we investigate the recognition dynamics of ubiquitin via microsecond all-atom molecular dynamics simulation providing both thermodynamic and kinetic information. The high-level of consistency found with respect to experimental NMR data lends support to the accuracy of the in silico representation of the conformational substates and their interconversions of free ubiquitin. Using an energy-based reweighting approach, the statistical distribution of conformational states of ubiquitin is monitored as a function of the distance between ubiquitin and its binding partner Hrs-UIM. It is found that extensive and dense sampling of conformational space afforded by the µs MD trajectory is essential for the elucidation of the binding mechanism as is Boltzmann sampling, overcoming inherent limitations of sparsely sampled empirical ensembles. The results reveal a population redistribution mechanism that takes effect when the ligand is at intermediate range of 1–2 nm from ubiquitin. This mechanism, which may be depicted as a superposition of the conformational selection and induced fit mechanisms, also applies to other binding partners of ubiquitin, such as the GGA3 GAT domain

A Major Determinant of Cyclophilin Dependence and Cyclosporine Susceptibility of Hepatitis C Virus Identified by a Genetic Approach

Since the advent of genome-wide small interfering RNA screening, large numbers of cellular cofactors important for viral infection have been discovered at a rapid pace, but the viral targets and the mechanism of action for many of these cofactors remain undefined. One such cofactor is cyclophilin A (CyPA), upon which hepatitis C virus (HCV) replication critically depends. Here we report a new genetic selection scheme that identified a major viral determinant of HCV's dependence on CyPA and susceptibility to cyclosporine A. We selected mutant viruses that were able to infect CyPA-knockdown cells which were refractory to infection by wild-type HCV produced in cell culture. Five independent selections revealed related mutations in a single dipeptide motif (D316 and Y317) located in a proline-rich region of NS5A domain II, which has been implicated in CyPA binding. Engineering the mutations into wild-type HCV fully recapitulated the CyPA-independent and CsA-resistant phenotype and four putative proline substrates of CyPA were mapped to the vicinity of the DY motif. Circular dichroism analysis of wild-type and mutant NS5A peptides indicated that the D316E/Y317N mutations (DEYN) induced a conformational change at a major CyPA-binding site. Furthermore, nuclear magnetic resonance experiments suggested that NS5A with DEYN mutations adopts a more extended, functional conformation in the putative CyPA substrate site in domain II. Finally, the importance of this major CsA-sensitivity determinant was confirmed in additional genotypes (GT) other than GT 2a. This study describes a new genetic approach to identifying viral targets of cellular cofactors and identifies a major regulator of HCV's susceptibility to CsA and its derivatives that are currently in clinical trials

Thresholds of Toxicological Concern for Cosmetics-Related Substances: New Database, Thresholds, and Enrichment of Chemical Space

A new dataset of cosmetics-related chemicals for the Threshold of Toxicological Concern (TTC) approach has been compiled, comprising 552 chemicals with 219, 40, and 293 chemicals in Cramer Classes I, II, and III, respectively. Data were integrated and curated to create a database of No-/Lowest-Observed-Adverse-Effect Level (NOAEL/LOAEL) values, from which the final COSMOS TTC dataset was developed. Criteria for study inclusion and NOAEL decisions were defined, and rigorous quality control was performed for study details and assignment of Cramer classes. From the final COSMOS TTC dataset, human exposure thresholds of 42 and 7.9 μg/kg-bw/day were derived for Cramer Classes I and III, respectively. The size of Cramer Class II was insufficient for derivation of a TTC value. The COSMOS TTC dataset was then federated with the dataset of Munro and colleagues, previously published in 1996, after updating the latter using the quality control processes for this project. This federated dataset expands the chemical space and provides more robust thresholds. The 966 substances in the federated database comprise 245, 49 and 672 chemicals in Cramer Classes I, II and III, respectively. The corresponding TTC values of 46, 6.2 and 2.3 μg/kg-bw/day are broadly similar to those of the original Munro dataset

Schweizer HR-Barometer 2009 : Mobilität und Arbeitgeberattraktivität

Im Schweizer HR-Barometer 2009 werden neben allgemeinen Trends die Themen Mobilität und Arbeitgeberattraktivität eingehend untersucht. Erfasst werden das tatsächliche Mobilitätsverhalten und die potenzielle Bereitschaft der Arbeitnehmenden, sich in der Arbeitswelt «mobil» zu verhalten. Weiter wird untersucht,welche Faktoren dazu führen, dass Unternehmen für Arbeitnehmende attraktiv sind und zu «Wahlarbeitgebern» werden. Die Themen der Vorjahre werden, im Hinblick auf die Trendentwicklungen von 2005 bis 2008 und auf den Vergleich zwischen deutsch- und französischsprachiger Schweiz, prägnant präsentiert. Das Schweizer HR-Barometer wird von einem wissenschaftlichen Forschungsteam der ETH und der Universität Zürich im jährlichen Turnus herausgegeben, jeweils mit einem Schwerpunktthema

Hormonaktivität im Trinkwasser

In den letzten Jahren wurden in der Westschweiz einige Fälle von Brustwachstum bei Mädchen vor dem 8. Lebensjahr (prämature Thelarche) beobachtet. Um zu klären, ob hormonaktive Substanzen im Trinkwasser zu diesem Phänomen beitragen, wurde das Wasser in betroffenen und nicht betroffenen Haushalten auf bekannte hormonaktive Stoffe und die totale Hormonaktivität untersucht. Gemäss den Ergebnissen der Studie und dem heutigen Kenntnisstand kann ausgeschlossen werden, dass der Konsum von Trinkwasser zur Entstehung der prämaturen Thelarche beiträgt