Distributed Atomic Polarizabilities of Amino Acids and their Hydrogen-Bonded Aggregates

With the purpose of rational design of optical materials, distributed atomic polarizabilities of amino acid molecules and their hydrogen-bonded aggregates are calculated in order to identify the most efficient functional groups, able to buildup larger electric susceptibilities in crystals. Moreover, we carefully analyze how the atomic polarizabilities depend on the one-electron basis set or the many-electron Hamiltonian, including both wave function and density functional theory methods. This is useful for selecting the level of theory that best combines high accuracy and low computational costs, very important in particular when using the cluster method to estimate susceptibilities of molecular-based materials.

Proteotoxic stress induces phosphorylation of p62/SQSTM1 by ULK1 to regulate selective autophagic clearance of protein aggregates.

Disruption of proteostasis, or protein homeostasis, is often associated with aberrant accumulation of misfolded proteins or protein aggregates. Autophagy offers protection to cells by removing toxic protein aggregates and injured organelles in response to proteotoxic stress. However, the exact mechanism whereby autophagy recognizes and degrades misfolded or aggregated proteins has yet to be elucidated. Mounting evidence demonstrates the selectivity of autophagy, which is mediated through autophagy receptor proteins (e.g. p62/SQSTM1) linking autophagy cargos and autophagosomes. Here we report that proteotoxic stress imposed by the proteasome inhibition or expression of polyglutamine expanded huntingtin (polyQ-Htt) induces p62 phosphorylation at its ubiquitin-association (UBA) domain that regulates its binding to ubiquitinated proteins. We find that autophagy-related kinase ULK1 phosphorylates p62 at a novel phosphorylation site S409 in UBA domain. Interestingly, phosphorylation of p62 by ULK1 does not occur upon nutrient starvation, in spite of its role in canonical autophagy signaling. ULK1 also phosphorylates S405, while S409 phosphorylation critically regulates S405 phosphorylation. We find that S409 phosphorylation destabilizes the UBA dimer interface, and increases binding affinity of p62 to ubiquitin. Furthermore, lack of S409 phosphorylation causes accumulation of p62, aberrant localization of autophagy proteins and inhibition of the clearance of ubiquitinated proteins or polyQ-Htt. Therefore, our data provide mechanistic insights into the regulation of selective autophagy by ULK1 and p62 upon proteotoxic stress. Our study suggests a potential novel drug target in developing autophagy-based therapeutics for the treatment of proteinopathies including Huntington's disease.

A MORTALITY STUDY OF BUTYL-CHLOROBUTYL RUBBER WORKERS

Worker populations are potentially exposed to multiple chemical substances simultaneously during the performance of routine tasks. The acute health effects from exposure to toxic concentrations of these substances are usually well-described. However, very little is known about the long-term health effects of chronic low dose exposure to all except a few chemical substances. A mortality study was performed on a population of workers employed at a butyl rubber manufacturing plant in Baton Rouge, Louisiana for the period 1943-1978, with special emphasis on potential exposure to methyl chloride.^ The study population was enumerated using company records. The mortality experience among the population was evaluated by comparing the number of observed deaths (total and cause-specific) to the expected number of deaths, based on the U.S. general age, race, sex specific rates. An internal comparison population was assembled to address the issue of lack of comparability when the U.S. rates are used to calculate expected deaths in an employed population.^ There were 18% fewer total observed deaths compared to the expected when the U.S. death rates were used to obtain the expected. Deaths from specific causes were also less than expected except when numbers of observed and expected deaths were small. Similar results were obtained when the population was characterized by intensity and duration of potential exposure to methyl chloride. When the internal comparison population was utilized to evaluate overall mortality of the study population, the relative risk was about 1.2.^ The study results were discussed and conclusions drawn in light of certain limitations of the methodology and study population size. ^