Structure-function study of ubiquitin c-terminal hydrolase L1 (UCH-L1) by NMR spectroscopy - insights into UCH-L1 mutation's association with the risk of Parkinson's disease

Poster Presentation: P72Protein ubiquitination and deubiquitination, play important roles in many aspects of cellular mechanisms. Its defective regulation results in diseases that range from developmental abnormalities to neurodegenerative diseases and cancer. Ubiquitin carboxy-terminal hydrolase L1 (UCH-L1) is a protein of 223 amino acids, which is highly abundant in brain, constituting up to 2% of total brain proteins. Although it was originally characterized as a deubiquitinating enzyme, recent studies indicate that it also functions as a ubiquitin ligase and a mono-Ub stabilizer. Down-regulation and extensive oxidative modifications of UCH-L1 have been observed in the brains of Alzheimer’s disease and Parkinson’s disease (PD) patients. Of importance, I93M and S18Y point mutations in the UCH-L1 gene have been reported to be linked to susceptibility to and protection from PD respectively. Hence, the structure of UCH-L1 and the effects of disease associated mutations on the structure and function are of considerable interest. Our circular dichroism studies suggest that the S18Y point mutation only slightly perturbs the structure while a significant decrease in the α-helical content is observed in the I93M mutant. We have determined the solution structure of S18Y and mapping its interaction with ubiquitin by chemical shift perturbation approach. The electrostatic surface potential analysis reveals that the interaction between ubiquitin and UCH-L1-S18Y is primarily electrostatic in nature, with negatively charged residues on the surface of UCH-L1-S18Y interacting with the positively charged residues on the basic face of ubiquitin. Although the active site and the L8 loop in UCH-L1-S18Y adopts conformations similar to that observed in the crystal structure of UCH-L1-WT, both the altered hydrogen bond network and surface charge distributions have demonstrated that the S18Y substitution could lead to profound structural changes. In particular, the difference in the dimeric interfaces of the wild-type and the S18Y mutant has shown that mutation can significantly affect the distribution of the surface-exposed residues involved in the dimeric interface. Such observed difference might weaken the stability of the UCH-L1 dimer and hence may explain the reduced dimerization-dependent ligase activity of UCH-L1-S18Y in comparison to UCH-L1-WT.postprin

An Optimal Binding Number Condition for Bipancyclism

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Muscle synergies in chronic stroke during a robot-assisted wrist training

Author name used in this publication: X. L. HuAuthor name used in this publication: K. Y. TongAuthor name used in this publication: R. SongAuthor name used in this publication: K. H. LuiRefereed conference paper2006-2007 > Academic research: refereed > Refereed conference paperVersion of RecordPublishe

Lycopene protects against hypoxia/reoxygenation-induced apoptosis by preventing mitochondrial dysfunction in primary neonatal mouse cardiomyocytes

BACKGROUND: Hypoxia/reoxygenation(H/R)-induced apoptosis of cardiomyocytes plays an important role in myocardial injury. Lycopene is a potent antioxidant carotenoid that has been shown to have protective properties on cardiovascular system. The aim of the present study is to investigate the potential for lycopene to protect the cardiomyocytes exposed to H/R. Moreover, the effect on mitochondrial function upon lycopene exposure was assessed. METHODS AND FINDINGS: Primary cardiomyocytes were isolated from neonatal mouse and established an in vitro model of H/R which resembles ischemia/reperfusion in vivo. The pretreatment of cardiomyocytes with 5 microM lycopene significantly reduced the extent of apoptosis detected by TUNEL assays. To further study the mechanism underlying the benefits of lycopene, interactions between lycopene and the process of mitochondria-mediated apoptosis were examined. Lycopene pretreatment of cardiomyocytes suppressed the activation of the mitochondrial permeability transition pore (mPTP) by reducing the intracellular reactive oxygen species (ROS) levels and inhibiting the increase of malondialdehyde (MDA) levels caused by H/R. Moreover, the loss of mitochondrial membrane potential, a decline in cellular ATP levels, a reduction in the amount of cytochrome c translocated to the cytoplasm and caspase-3 activation were observed in lycopene-treated cultures. CONCLUSION: The present results suggested that lycopene possesses great pharmacological potential in protecting against H/R-induced apoptosis. Importantly, the protective effects of lycopene may be attributed to its roles in improving mitochondrial function in H/R-treated cardiomyocytes.published_or_final_versio

Snap evaporation of droplets on smooth topographies

Droplet evaporation on solid surfaces is important in many applications including printing, micro-patterning and cooling. While seemingly simple, the configuration of evaporating droplets on solids is difficult to predict and control. This is because evaporation typically proceeds as a “stick-slip” sequence—a combination of pinning and de-pinning events dominated by static friction or “pinning”, caused by microscopic surface roughness. Here we show how smooth, pinning-free, solid surfaces of non-planar topography promote a different process called snap evaporation. During snap evaporation a droplet follows a reproducible sequence of configurations, consisting of a quasi-static phase-change controlled by mass diffusion interrupted by out-of-equilibrium snaps. Snaps are triggered by bifurcations of the equilibrium droplet shape mediated by the underlying non-planar solid. Because the evolution of droplets during snap evaporation is controlled by a smooth topography, and not by surface roughness, our ideas can inspire programmable surfaces that manage liquids in heat- and mass-transfer applications

A Detailed X-Ray Investigation of PSR J2021+4026 and the γ-Cygni Supernova Remnant

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Topology dependent quantities at the Anderson transition

The boundary condition dependence of the critical behavior for the three dimensional Anderson transition is investigated. A strong dependence of the scaling function and the critical conductance distribution on the boundary conditions is found, while the critical disorder and critical exponent are found to be independent of the boundary conditions

The nuclear immune receptor RPS4 is required for RRS1SLH1-dependent constitutive defense activation in Arabidopsis thaliana

Plant nucleotide-binding leucine-rich repeat (NB-LRR) disease resistance (R) proteins recognize specific ‘‘avirulent’’ pathogen effectors and activate immune responses. NB-LRR proteins structurally and functionally resemble mammalian Nod-like receptors (NLRs). How NB-LRR and NLR proteins activate defense is poorly understood. The divergently transcribed Arabidopsis R genes, RPS4 (resistance to Pseudomonas syringae 4) and RRS1 (resistance to Ralstonia solanacearum 1), function together to confer recognition of Pseudomonas AvrRps4 and Ralstonia PopP2. RRS1 is the only known recessive NBLRR R gene and encodes a WRKY DNA binding domain, prompting suggestions that it acts downstream of RPS4 for transcriptional activation of defense genes. We define here the early RRS1-dependent transcriptional changes upon delivery of PopP2 via Pseudomonas type III secretion. The Arabidopsis slh1 (sensitive to low humidity 1) mutant encodes an RRS1 allele (RRS1SLH1) with a single amino acid (leucine) insertion in the WRKY DNA-binding domain. Its poor growth due to constitutive defense activation is rescued at higher temperature. Transcription profiling data indicate that RRS1SLH1-mediated defense activation overlaps substantially with AvrRps4- and PopP2-regulated responses. To better understand the genetic basis of RPS4/RRS1-dependent immunity, we performed a genetic screen to identify suppressor of slh1 immunity (sushi) mutants. We show that many sushi mutants carry mutations in RPS4, suggesting that RPS4 acts downstream or in a complex with RRS1. Interestingly, several mutations were identified in a domain C-terminal to the RPS4 LRR domain. Using an Agrobacterium-mediated transient assay system, we demonstrate that the P-loop motif of RPS4 but not of RRS1SLH1 is required for RRS1SLH1 function. We also recapitulate the dominant suppression of RRS1SLH1 defense activation by wild type RRS1 and show this suppression requires an intact RRS1 P-loop. These analyses of RRS1SLH1 shed new light on mechanisms by which NB-LRR protein pairs activate defense signaling, or are held inactive in the absence of a pathogen effector

Mixed-Model Noise Removal in 3D MRI via Rotation-and-Scale Invariant Non-Local Means

Mixed noise is a major issue influencing quantitative analysis in different forms of magnetic resonance image (MRI), such as T1 and diffusion image like DWI and DTI. Using different filters sequentially to remove mixed noise will severely deteriorate such medical images. We present a novel algorithm called rotation-and-scale invariant nonlocal means filter (RSNLM) to simultaneously remove mixed noise from different kinds of three-dimensional (3D) MRI images. First, we design a new similarity weights, including rank-ordered absolute difference (ROAD), coming from a trilateral filter (TriF) that is obtained to detect the mixed and high-level noise. Then, we present a shape view to consider the MRI data as a 3D operator, with which the similarity between the patches is calculated with the rigid transformation. The translation, rotation and scale have no influence on the similarity. Finally, the adaptive parameter estimation method of ROAD is illustrated, and the effective proof that validates the proposed algorithm is presented. Experiments using synthetic data with impulse noise, Rician noise, and the real MRI data confirm that the proposed method yields superior performance compared with current state-of-the-art methods

On the rotational dynamics of the Rattleback

The Rattleback is a very popular science toy shown to students all over the world to demonstrate the non-triviality of rotational motion. When spun on a horizontal table, this boat-shaped object behaves in a peculiar way. Although the object appears symmetric, the dynamics of its motion seem very asymmetric. When spun in the preferred direction, it spins smoothly, whereas in the other direction it starts to oscillate wildly. The oscillation soon dies out and the rattleback starts to spin in the preferred way. We will construct and go through an analytical model capable of explaining this behaviour in a simple and intelligible way. Although we aim at a semi-pedagogical treatise, we will study the details only when they are necessary to understand the calculation. After presenting the calculations we will discuss the physical validity of our assumptions and take a look at more sophisticated models requiring numerical analysis. We will then improve our model by assuming a simple friction force.Comment: 17 pages and 2 figures, typos corrected, some minor additions and rewording