SuperLFV: An SLHA tool for lepton flavor violating observables in supersymmetric models

We introduce SuperLFV, a numerical tool for calculating low-energy observables that exhibit charged lepton flavor violation (LFV) in the context of the minimal supersymmetric standard model (MSSM). As the Large Hadron Collider and MEG, a dedicated μ⁺→e⁺γ${\mu }^{+}\to e^{+}\gamma$ experiment, are presently acquiring data, there is need for tools that provide rapid discrimination of models that exhibit LFV. SuperLFV accepts a spectrum file compliant with the SUSY Les Houches Accord (SLHA), containing the MSSM couplings and masses with complex phases at the supersymmetry breaking scale. In this manner, SuperLFV is compatible with but divorced from existing SLHA spectrum calculators that provide the low energy spectrum. Hence, input spectra are not confined to the LFV sources provided by established SLHA spectrum calculators. Input spectra may be generated by personal code or by hand, allowing for arbitrary models not supported by existing spectrum calculators.     

A tau method approach for the diffusion equation with nonlocal boundary conditions

An approximate method for solving the diffusion equation with nonlocal boundary conditions is proposed. The method is based upon constructing the double shifted Legendre series to approximate the required solution using Legendre tau method. The differential and integral expressions which arise in the diffusion equation with nonlocal boundary conditions are converted into a system of linear algebraic equations which can be solved for the unknown coefficients. Numerical examples are included to demonstrate the validity and applicability of the method and a comparison is made with existing results.     

Domain decomposition and the numerical solution of partial differential equations defined on irregular domains using segmented forms of the tau lines method

The Tau Lines Method, a numerical technique based on the combination of the Tau Method and the Method of Lines is used, in connection with the domain decomposition technique, to solve problems in partial differential equations defined on irregular domains. Two nontrivial problems have been considered. The first is a curved crack defined on a square domain and the second is defined on a kite-shaped domain. The domain of interest is subdivided into appropriate Semidiscretized elements so to efficiently deal with any appearance of boundary and/or interior singularities. Numerical application is carried out on the Poisson's equation. The approximate solutions are sought along segmented lines as finite expansions in terms of a given orthogonal polynomial basis. Two types of orthogonal expansions have been used alongside second and fourth order accurate Finite Difference Approximations. In both cases good and rapid convergence has been achieved.     

The methionine precursor dl-2-hydroxy-(4-methylthio)butanoic acid protects intestinal epithelial barrier function

dl-2-hydroxy-(4-methylthio)butanoic acid (HMTBA) is a source of dietary methionine (Met) that is widely used in poultry nutrition. We have previously shown that HMTBA is preferentially diverted to the transsulfuration pathway, which gives antioxidant metabolites such as taurine and glutathione. Therefore, here we hypothesize that this Met source can protect epithelial barrier function in an in vitro model of intestinal inflammation of Caco-2 cells. The results show that HMTBA prevents the increase in paracellular permeability induced by H₂O₂ or tumour necrosis factor-α. This effect can be attributed to the increased production of taurine and reduced glutathione. Similar results were obtained for dl-Met, although the protective role of the amino acid was less pronounced than that of the hydroxy analogue. In conclusion, the diversion to the transsulfuration pathway means that this Met precursor is of greater value than previously thought, due to its capacity to improve intestinal homeostasis and the quality of poultry products destined for human consumption.     

Deciphering the Effect of Lysine Acetylation on the Misfolding and Aggregation of Human Tau Fragment 171IPAKTPPAPK180 Using Molecular Dynamic Simulation and the Markov State Model

The formation of neurofibrillary tangles (NFT) with β-sheet-rich structure caused by abnormal aggregation of misfolded microtubule-associated protein Tau is a hallmark of tauopathies, including Alzheimer’s Disease. It has been reported that acetylation, especially K174 located in the proline-rich region, can largely promote Tau aggregation. So far, the mechanism of the abnormal acetylation of Tau that affects its misfolding and aggregation is still unclear. Therefore, revealing the effect of acetylation on Tau aggregation could help elucidate the pathogenic mechanism of tauopathies. In this study, molecular dynamics simulation combined with multiple computational analytical methods were performed to reveal the effect of K174 acetylation on the spontaneous aggregation of Tau peptide ¹⁷¹IPAKTPPAPK¹⁸⁰, and the dimerization mechanism as an early stage of the spontaneous aggregation was further specifically analyzed by Markov state model (MSM) analysis. The results showed that both the actual acetylation and the mutation mimicking the acetylated state at K174 induced the aggregation of the studied Tau fragment; however, the effect of actual acetylation on the aggregation was more pronounced. In addition, acetylated K174 plays a major contributing role in forming and stabilizing the antiparallel β-sheet dimer by forming several hydrogen bonds and side chain van der Waals interactions with residues I171, P172, A173 and T175 of the corresponding chain. In brief, this study uncovered the underlying mechanism of Tau peptide aggregation in response to the lysine K174 acetylation, which can deepen our understanding on the pathogenesis of tauopathies.     

Accepting its random coil nature allows a partial NMR assignment of the neuronal Tau protein

A combined strategy to obtain a partial NMR assignment of the neuronal Tau protein is presented. Confronted with the extreme spectral degeneracy that the spectrum of this 441 amino acid long unstructured protein presents, we have introduced a graphical procedure based on residue type-specific product planes. Combining this strategy with the search for pairwise motifs, and combining the spectra of different Tau isoforms and even of peptides derived from the native sequence, we arrive at a partial assignment that is sufficient to map the interactions of Tau with its molecular partners. The obtained assignments equally confirm the absence of regular secondary structure in the isolated protein.     

Taurine ameliorates alcoholic steatohepatitis via enhancing self-antioxidant capacity and alcohol metabolism

Chronic alcohol consumption or alcohol abuse is the main cause of alcoholic steatohepatitis or further cirrhosis. This study was to exam if the antioxidant capacity and alcohol metabolism in livers of chronic alcohol-fed rats were improved by supplementing taurine (Tau). Rats were randomly divided into four groups with five times per week of treatment: 1) isocaloric solution; 2) 3 g alcohol/kg BW/day; 3) 3 g alcohol/kg BW/day + 1 g taurine (Tau)/kg BW/day; and 4) 3 g alcohol/kg BW/day + 2 g Tau/kg BW/day. A 6-week alcohol consumption resulted in lower (p < 0.05) body weight gain and self-antioxidant capacities, as well as increased (p < 0.05) liver size, serum/hepatic lipids, and AST and ALT values. However, alcohol-fed rats co-treated with Tau have decreased (p < 0.05) liver lipid levels via increasing fecal lipid output and cholesterol metabolism. Besides, co-treatment of Tau also enhanced (p < 0.05) self-antioxidant capacities and alcohol metabolism in livers via enhancing GSH contents, CAT, GSH-Px, ADH, and ALDH activities, but decreasing MDA contents. In a histological examination of rat liver, microvesicular steatosis and necrotic cells were observed in alcohol-fed rats without Tau while largely suppressed microvesicular steatosis and no necrotic cells were observed in alcohol-fed rat supplemented with Tau. Therefore, Tau could be an effective hepatoprotective agent against alcohol-induced damage via enhancing self-antioxidant capacity and alcohol metabolism.     

Update rates and fidelity in virtual environments

Interaction is the primary characteristic of a Virtual Environment and update rate is normally taken as an index or measure of the interactivity of the system. The speed of many systems is dictated by the slowest component which is often the Computer Image Generator (CIG). It is common for the workload of the CIG to vary and hence the performance of the system. This paper shows how a variable update rate can produce undesirable results. Two solutions to this problem are presented: service degradation and worst-case. In the case of the CIG, service degradation would require the quality of the image to be reduced such that the time taken never exceeds a given deadline. The worst-case technique works by finding the longest time taken to render any view and then uses that as the deadline for completion. The support of predictive methods is one of several benefits of this approach. An implementation of the worst-case technique is described which takes finer control over the CIG than usual and may be applied to many existing systems with little modification.     

阿尔茨海默病中Tau蛋白聚集抑制剂的研究进展

近年来,以Tau蛋白作为阿尔茨海默病靶点的药物研究受到越来越多的关注。纵观国内外发展状况,基于Tau蛋白磷酸化酶的药物研发居多,部分已进入临床阶段,而关于直接抑制Tau聚集的药物研究尚处于起步阶段。从药物化学的角度,综述了目前关于小分子化合物能够有效抑制Tau蛋白异常聚集的研究进展,系统考察了这些小分子化合物的结构特征,并对其结构和功能的关系作了初步的探讨。     

Non-Canonical Roles of Tau and Their Contribution to Synaptic Dysfunction

Tau plays a central role in a group of neurodegenerative disorders collectively named tauopathies. Despite the wide range of diverse symptoms at the onset and during the progression of the pathology, all tauopathies share two common hallmarks, namely the misfolding and aggregation of Tau protein and progressive synaptic dysfunctions. Tau aggregation correlates with cognitive decline and behavioural impairment. The mechanistic link between Tau misfolding and the synaptic dysfunction is still unknown, but this correlation is well established in the human brain and also in tauopathy mouse models. At the onset of the pathology, Tau undergoes post-translational modifications (PTMs) inducing the detachment from the cytoskeleton and its release in the cytoplasm as a soluble monomer. In this condition, the physiological enrichment in the axon is definitely disrupted, resulting in Tau relocalization in the cell soma and in dendrites. Subsequently, Tau aggregates into toxic oligomers and amyloidogenic forms that disrupt synaptic homeostasis and function, resulting in neuronal degeneration. The involvement of Tau in synaptic transmission alteration in tauopathies has been extensively reviewed. Here, we will focus on non-canonical Tau functions mediating synapse dysfunction.