The synucleins.

PMC ID: PMC150459. The author can archive publisher's version/PDF.SUMMARY: Synucleins are small, soluble proteins expressed primarily in neural tissue and in certain tumors. The family includes three known proteins: alpha-synuclein, beta-synuclein, and gamma-synuclein. All synucleins have in common a highly conserved alpha-helical lipid-binding motif with similarity to the class-A2 lipid-binding domains of the exchangeable apolipoproteins. Synuclein family members are not found outside vertebrates, although they have some conserved structural similarity with plant 'late-embryo-abundant' proteins. The alpha- and beta-synuclein proteins are found primarily in brain tissue, where they are seen mainly in presynaptic terminals. The gamma-synuclein protein is found primarily in the peripheral nervous system and retina, but its expression in breast tumors is a marker for tumor progression. Normal cellular functions have not been determined for any of the synuclein proteins, although some data suggest a role in the regulation of membrane stability and/or turnover. Mutations in alpha-synuclein are associated with rare familial cases of early-onset Parkinson's disease, and the protein accumulates abnormally in Parkinson's disease, Alzheimer's disease, and several other neurodegenerative illnesses. The current challenge is to understand the normal cellular function of these proteins and how they might contribute to the development of human disease

Fluid and Diffusion Limits for Bike Sharing Systems

Bike sharing systems have rapidly developed around the world, and they are served as a promising strategy to improve urban traffic congestion and to decrease polluting gas emissions. So far performance analysis of bike sharing systems always exists many difficulties and challenges under some more general factors. In this paper, a more general large-scale bike sharing system is discussed by means of heavy traffic approximation of multiclass closed queueing networks with non-exponential factors. Based on this, the fluid scaled equations and the diffusion scaled equations are established by means of the numbers of bikes both at the stations and on the roads, respectively. Furthermore, the scaling processes for the numbers of bikes both at the stations and on the roads are proved to converge in distribution to a semimartingale reflecting Brownian motion (SRBM) in a $N^{2}$-dimensional box, and also the fluid and diffusion limit theorems are obtained. Furthermore, performance analysis of the bike sharing system is provided. Thus the results and methodology of this paper provide new highlight in the study of more general large-scale bike sharing systems.Comment: 34 pages, 1 figure

Hepato-Protective Potential of Methanol Extract of Leaf of Ziziphus mucronata (zmlm) against Dimethoate Toxicity: Biochemical and Histological Approach

Background: The leaves of Ziziphus mucronata are used locally as food and a health drink; the leaf paste can also be used in the treatment of boils. The root of the plant is usually used in the treatment of a wide range of pains.Objective: The study was carried out to evaluate the hepatoprotective potential of the methanol leaf extract of Ziziphus mucronata (ZMLM).Method: The extract was prepared by soaking in 70% methanol/water and rotary evaporation. The phenol content of extract was then estimated. Twenty five adult male Sprague dawley rats (aged 21 weeks) were divided into five groups of five rats each and treated as follows; normal control (NC) received distilled water. Dimethoate control (DC) (received 6 mg/kg.bw.day-1 dimethoate dissolved in distilled water). Experimental Groups (E1) received dimethoate (6mg/kg.bw) + ZMLM (100 mg/kg.bw-1); (E2) received dimethoate (6 mg/kg.bw) + ZMLM (200 mg/kg.bw-1) and (E3) received dimethoate (6 mg/kg.bw) + ZMLM (300 mg/kg.bw-1). In both the cases a normal control and dimethoate control were kept to compare the results. After 90 days, blood was collected and rats were sacrificed to collect the liver tissue for biochemical assays and histological estimations.Results: The results of E1 did not show much change from the normal control group but was significantly different from the dimethoate control group (P≤ 0.05). The preventive effect which was tested in E2 and E3 proved that the extract could almost retain the normal condition in 90 days time. Histological observations also agreed with the results obtained in biochemical parameters.Conclusions: Ziziphus mucronata methanol leaf extract possesses a preventive effect against dimethoate induced oxidative stress as observed in male albino Sprague Dawley rats.Keywords: Leaf methanol extract, hepatoprotective, Ziziphus mucronata, oxidative stress, phenol conten

Dynamic transport and localization of alpha-synuclein in primary hippocampal neurons.

BACKGROUND: Alpha-synuclein is a presynaptic protein with a proposed role in neurotransmission and dopamine homeostasis. Abnormal accumulation of alpha-synuclein aggregates in dopaminergic neurons of the substantia nigra is diagnostic of sporadic Parkinson's disease, and mutations in the protein are linked to early onset forms of the disease. The folded conformation of the protein varies depending upon its environment and other factors that are poorly understood. When bound to phospholipid membranes, alpha-synuclein adopts a helical conformation that mediates specific interactions with other proteins. RESULTS: To investigate the role of the helical domain in transport and localization of alpha-synuclein, eGFP-tagged constructs were transfected into rat primary hippocampal neurons at 7 DIV. A series of constructs were analyzed in which each individual exon was deleted, for comparison to previous studies of lipid affinity and alpha-helix content. A53T and A30P substitutions, representing Parkinson's disease-associated variants, were analyzed as well. Single exon deletions within the lipid-binding N-terminal domain of alpha-synuclein (exons 2, 3, and 4) partially disrupted its presynaptic localization at 17-21 DIV, resulting in increased diffuse labeling of axons. Similar results were obtained for A30P, which exhibits decreased lipid binding, but not A53T. To examine whether differences in presynaptic enrichment were related to deficiencies in transport velocity, transport was visualized via live cell microscopy. Tagged alpha-synuclein migrated at a rate of 1.85 +/- 0.09 mum/s, consistent with previous reports, and single exon deletion mutants migrated at similar rates, as did A30P. Deletion of the entire N-terminal lipid-binding domain (Delta234GFP) did not significantly alter rates of particle movement, but decreased the number of moving particles. Only the A53TGFP mutant exhibited a significant decrease in transport velocity as compared to ASGFP. CONCLUSIONS: These results support the hypothesis that presynaptic localization involves a mechanism that requires helical conformation and lipid binding. Conversely, the rate of axonal transport is not determined by lipid affinity and is not sufficient to account for differences in presynaptic localization of alpha-synuclein-eGFP variants.This study was funded by the Branfman Family Foundation, including salary support for MLY, LH, and WSW

The active site structure and catalytic mechanism of arsenite oxidase

Arsenite oxidase is thought to be an ancient enzyme, originating before the divergence of the Archaea and the Bacteria. We have investigated the nature of the molybdenum active site of the arsenite oxidase from the Alphaproteobacterium Rhizobium sp. str. NT-26 using a combination of X-ray absorption spectroscopy and computational chemistry. Our analysis indicates an oxidized Mo(VI) active site with a structure that is far from equilibrium. We propose that this is an entatic state imposed by the protein on the active site through relative orientation of the two molybdopterin cofactors, in a variant of the Rây-Dutt twist of classical coordination chemistry, which we call the pterin twist hypothesis. We discuss the implications of this hypothesis for other putatively ancient molybdopterin-based enzymes

Dynamic variation of CD5 surface expression levels within individual chronic lymphocytic leukemia clones.

Chronic lymphocytic leukemia (CLL) is characterized by the accumulation of clonally derived mature CD5high B cells; however, the cellular origin of CLL is still unknown. Patients with CLL also harbor variable numbers of CD5low B cells, but the clonal relationship of these cells to the bulk disease is unknown and can have important implications for monitoring, treating, and understanding the biology of CLL. Here, we use B-cell receptors (BCRs) as molecular barcodes to first show by single-cell BCR sequencing that the great majority of CD5low B cells in the blood of CLL patients are clonally related to CD5high CLL B cells. We investigate whether CD5 state switching was likely to occur continuously as a common event or as a rare event in CLL by tracking somatic BCR mutations in bulk CLL B cells and using them to reconstruct the phylogenetic relationships and evolutionary history of the CLL in four patients. Using statistical methods, we show that there is no parsimonious route from a single or low number of CD5low switch events to the CD5high population, but rather, large-scale and/or dynamic switching between these CD5 states is the most likely explanation. The overlapping BCR repertoires between CD5high and CD5low cells from CLL patient peripheral blood reveal that CLL exists in a continuum of CD5 expression. The major proportion of CD5low B cells in patients are leukemic, thus identifying CD5low B cells as an important component of CLL, with implications for CLL pathogenesis, clinical monitoring, and the development of anti-CD5-directed therapies

Gluon Scattering Amplitudes in Finite Temperature Gauge/Gravity Dualities

We examine the gluon scattering amplitude in N=4 super Yang-Mills at finite temperature with nonzero R-charge densities, and in Non-Commutative gauge theory at finite temperature. The gluon scattering amplitude is defined as a light-like Wilson loop which lives at the horizon of the T-dual black holes of the backgrounds we consider. We study in detail a special amplitude, which corresponds to forward scattering of a low energy gluon off a high energy one. For this kinematic configuration in the considered backgrounds, we find the corresponding minimal surface which is directly related to the gluon scattering amplitude. We find that for increasing the chemical potential or the non-commutative parameter, the on-shell action corresponding to our Wilson loop in the T-dual space decreases. For all of our solutions the length of the short side of the Wilson loop is constrained by an upper bound which depends on the temperature, the R-charge density and the non-commutative parameter. Due to this constraint, in the limit of zeroth temperature our approach breaks down since the upper bound goes to zero, while by keeping the temperature finite and letting the chemical potential or the non-commutative parameter to approach to zero the limit is smooth.Comment: 30 pages, 16 figures, minor corrections (plus improved numerical computation for the non-commutative case

Accelerating Oxygen Reduction Catalysts through Preventing Poisoning with Non-Reactive Species by Using Hydrophobic Ionic Liquids

Poster presentation given at the 68th Annual Meeting of the International Society of Electrochemistr

Identifying Treatment Effect Modifiers in the STarT Back Trial: A Secondary Analysis

Identification of patient characteristics influencing treatment outcomes is a top low back pain (LBP) research priority. Results from the STarT Back Trial support the effectiveness of prognostic stratified care for LBP compared to current best care, however patient characteristics associated with treatment response have not yet been explored. The purpose of this secondary analysis was to identify treatment-effect modifiers within the STarT Back Trial at 4 months follow-up (n=688). Treatment response was dichotomized using back-specific physical disability measured by the Roland-Morris Disability Questionnaire (≥7). Candidate modifiers were identified using previous literature and evaluated using logistic regression with statistical interaction terms to provide preliminary evidence of treatment-effect modification. Socioeconomic status (SES) was identified as an effect modifier for disability outcomes (OR = 1.71, P=.028). High SES patients receiving prognostic stratified care were 2.5 times less likely to have a poor outcome compared to low SES patients receiving best current care (OR = 0.40, P=.006). Education level (OR = 1.33, P=.109) and number of pain medications (OR = 0.64, P=.140) met our criteria for effect modification with weaker evidence (0.20>P≥0.05). These findings provide preliminary evidence for SES, education, and number of pain medications as treatment-effect modifiers of prognostic stratified care delivered in the STarT Back Trial