Regulation of CLC-1 chloride channel biosynthesis by FKBP8 and Hsp90β.

Mutations in human CLC-1 chloride channel are associated with the skeletal muscle disorder myotonia congenita. The disease-causing mutant A531V manifests enhanced proteasomal degradation of CLC-1. We recently found that CLC-1 degradation is mediated by cullin 4 ubiquitin ligase complex. It is currently unclear how quality control and protein degradation systems coordinate with each other to process the biosynthesis of CLC-1. Herein we aim to ascertain the molecular nature of the protein quality control system for CLC-1. We identified three CLC-1-interacting proteins that are well-known heat shock protein 90 (Hsp90)-associated co-chaperones: FK506-binding protein 8 (FKBP8), activator of Hsp90 ATPase homolog 1 (Aha1), and Hsp70/Hsp90 organizing protein (HOP). These co-chaperones promote both the protein level and the functional expression of CLC-1 wild-type and A531V mutant. CLC-1 biosynthesis is also facilitated by the molecular chaperones Hsc70 and Hsp90β. The protein stability of CLC-1 is notably increased by FKBP8 and the Hsp90β inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG) that substantially suppresses cullin 4 expression. We further confirmed that cullin 4 may interact with Hsp90β and FKBP8. Our data are consistent with the idea that FKBP8 and Hsp90β play an essential role in the late phase of CLC-1 quality control by dynamically coordinating protein folding and degradation

Dynamic scaling in the 2D Ising spin glass with Gaussian couplings

We carry out simulated annealing and employ a generalized Kibble-Zurek scaling hypothesis to study the 2D Ising spin glass with normal-distributed couplings. The system has an equilibrium glass transition at temperature $T=0$. From a scaling analysis when $T\rightarrow 0$ at different annealing velocities, we extract the dynamic critical exponent $z$, i.e., the exponent relating the relaxation time $\tau$ to the system length $L$; $\tau\sim L^z$. We find $z=13.6 \pm 0.4$ for both the Edwards-Anderson spin-glass order parameter and the excess energy. This is different from a previous study of the system with bimodal couplings [S. J. Rubin, N. Xu, and A. W. Sandvik, Phys. Rev. E {\bf 95}, 052133 (2017)] where the dynamics is faster and the above two quantities relax with different exponents (and that of the energy is larger). We here argue that the different behaviors arise as a consequence of the different low-energy landscapes---for normal-distributed couplings the ground state is unique (up to a spin reflection) while the system with bimodal couplings is massively degenerate. Our results reinforce the conclusion of anomalous entropy-driven relaxation behavior in the bimodal Ising glass. In the case of a continuous coupling distribution, our results presented here indicate that, although Kibble-Zurek scaling holds, the perturbative behavior normally applying in the slow limit breaks down, likely due to quasi-degenerate states, and the scaling function takes a different form.Comment: 10 pages, 5 figure

Large scale simulation of watershed mass transport – a case study of Tsengwen reservoir watershed

The Tenth International Symposium on Mitigation of Geo-disasters in Asia Matsue Symposium Place: Shimane Civil Center, Matsue Date: 8 October 2012We present the large scale simulation of watershed mass transport, including landslide, debris-flow and sediment transport. A case study of Tsengwen reservoir watershed under the extreme rainfall triggered by typhoon Morakot is simulated for verification. This approach starts with volume-area relationship formula with inventory method to predict temporal and regional landslide volume production and distribution. Then, debris flow model, Debris-2D, is used to simulate the mass transport of debris-flow from hillslope to fluvial channel. Finally a sediment transport model, NETSTARS, is used for hydraulic and sediment routing in river and reservoir. The integrated simulation for the whole watershed gives a very good agreement with the temporal variation of sediment concentration recorded at the very downstream location

Modeling the tradeoff between inventory and capacity to optimize return on assets in production scheduling

Thesis (M. Eng. in Logistics)--Massachusetts Institute of Technology, Engineering Systems Division, 2013.Cataloged from PDF version of thesis.Includes bibliographical references (p. 51-52).In the agrochemical industry, companies are challenged with an extreme seasonality in demand driven by the crops' growing cycles. Therefore, balancing supply with such fluctuating demand has been a struggle for most companies due to their capacity constraints. One way to accommodate the demand is to stock enough inventory ahead of the peak seasons, while the other is to increase the production capacity so that the companies can react to the changing demand more quickly. However, either alternative comes at a significant cost. This paper examines the optimal mix of production capacity and inventory for a company to meet customers' demand at the highest net present value (NPV) of operating assets value add (OAVA). We use a multi-period, multi-stage, multi-product mixed integer linear optimization model to determine the best combination of resources. Viable resource options include stocking inventory ahead of the peak seasons, enhancing output through overtime, outsourcing production activities to a third party, and acquiring new assets for a particular production stage. The results show that the optimal OAVA comes from a combination of all these viable resources. Additionally, the master production schedule, the resulting inventory levels, and the recommended timings for external resources and asset acquisition are important takeaways from our model. They serve not only as the guidance of the company's day-to-day operations, but also as the quantitative analysis necessary to communicate with stakeholders across different functional teams with potentially conflicting interests.by Cindy (Hsin-ying) Wu and José Antonio González Duhart Muñoz de Cote.M.Eng.in Logistic

Applying Theory of Planned Behavior to Predict Nurses' Intention and Volunteering to Care for Sars Patients in Southern Taiwan

Severe acute respiratory syndrome (SARS) spread worldwide after an outbreak in Guangdong Province, China, in mid-November 2002. Health care workers were at highest risk of infection. The purpose of this study, which was based on Ajzen's theory of planned behavior (TPB), was to determine the extent to which personal attitudes, subjective norms, and perceived control influence nurses' intention and volunteering to care for SARS patients. After the SARS outbreak, a total of 750 staff nurses (response rate 90%) at one hospital completed a questionnaire assessing their intention to provide care to SARS patients. Overall, 42.7% of nurses had a positive intention to provide care to SARS patients, and 25.4% of nurses would volunteer to care for SARS patients. Four factors explaining 35% of the variance in nurses' intention to care for SARS patients were self-efficacy (β = 0.39, p < 0.001), attitude (β = 0.25, p < 0.001), years of working in the study hospital (β = −0.15, p < 0.001), and receiving resources from the hospital (β = 0.13, p < 0.001). Two factors explaining 15% of the variance in nurses' volunteering to care for SARS patients were intention (β = 0.31, p < 0.001) and attitude (β = 0.15, p < 0.001). The final model shows that the variables of the TPB contributed significantly to the explanation of a portion of variance in nurses' intention and volunteering to care for SARS patients. The results are helpful for human resources managers facing a new contagious disease

Structural insights into the gating of DNA passage by the topoisomerase II DNA-gate.

Type IIA topoisomerases (Top2s) manipulate the handedness of DNA crossovers by introducing a transient and protein-linked double-strand break in one DNA duplex, termed the DNA-gate, whose opening allows another DNA segment to be transported through to change the DNA topology. Despite the central importance of this gate-opening event to Top2 function, the DNA-gate in all reported structures of Top2-DNA complexes is in the closed state. Here we present the crystal structure of a human Top2 DNA-gate in an open conformation, which not only reveals structural characteristics of its DNA-conducting path, but also uncovers unexpected yet functionally significant conformational changes associated with gate-opening. This structure further implicates Top2's preference for a left-handed DNA braid and allows the construction of a model representing the initial entry of another DNA duplex into the DNA-gate. Steered molecular dynamics calculations suggests the Top2-catalyzed DNA passage may be achieved by a rocker-switch-type movement of the DNA-gate