Protein Misdirection Inside and Outside Motor Neurons in Amyotrophic Lateral Sclerosis (ALS): A Possible Clue for Therapeutic Strategies

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease characterized by progressive muscle wasting and weakness with no effective cure. Emerging evidence supports the notion that the abnormal conformations of ALS-linked proteins play a central role in triggering the motor neuron degeneration. In particular, mutant types of superoxide dismutase 1 (SOD1) and TAR DNA binding protein 43kDa (TDP-43) are key molecules involved in the pathogenesis of familial and sporadic ALS, respectively. The commonalities of the two proteins include a propensity to aggregate and acquire detrimental conformations through oligomerization, fragmentation, or post-translational modification that may drive abnormal subcellular localizations. Although SOD1 is a major cytosolic protein, mutated SOD1 has been localized to mitochondria, endoplasmic reticulum, and even the extracellular space. The nuclear exclusion of TDP-43 is a pathological hallmark for ALS, although the pathogenic priority remains elusive. Nevertheless, these abnormal behaviors based on the protein misfolding are believed to induce diverse intracellular and extracellular events that may be tightly linked to non-cell-autonomous motor neuron death. The generation of mutant- or misfolded protein-specific antibodies would help to uncover the distribution and propagation of the ALS-linked proteins, and to design a therapeutic strategy to clear such species. Herein we review the literature regarding the mislocalization of ALS-linked proteins, especially mutant SOD1 and TDP-43 species, and discuss the rationale of molecular targeting strategies including immunotherapy.     

The effect of airflow pattern on filter breakthrough in physical adsorption

The Wheeler-Jonas (WJ) model for prediction of the protection capacity of organic vapor filters under a fixed airflow was extended to breathing-simulation, pulsating flow. Breakthrough curves of dimethyl-methyl phosphonate (DMMP) and decane were measured under fixed flow and sinusoidal flow. A linear dependence of ln(C_X/C₀) on the breakthrough time (t_B) was observed in all the experiments, indicating that the concepts of critical bed weight (W_C) and dynamic adsorption capacity (W_E) as defined by the WJ model are applicable to pulsating flow as well. W_E was found to be almost unchanged by the flow pattern, whereas W_C was considerably larger (by 7-44%) at pulsating flow compared to fixed flow with the same average rate. Thus, shifting from fixed flow to pulsating flow may shorten t_B significantly. The effect of the flow type on t_B increases with the ratio of the critical weight to the total bed weight. For a high protection level (C₀/C_X=60?000), the protection capacity of personal NBC canisters was reduced by up to 15% upon shifting from fixed to pulsating flow.     

Characterization of a Large-Scale Nondoped YBa2Cu3O7−x Superconductor Prepared by Plastic Forming Without High-Pressure Molding

A slurry containing YBa₂Cu₃O_{7− x} particles and a fine YBa₂Cu₃(OH) _x colloid solution was prepared, and a large-scale bulk YBa₂Cu₃O_{7− x} superconductor (about 50 mm × 35 mm × 2 mm) was produced by plastic forming without high-pressure molding. The samples molded from the slurry were dried and then fired at 1223 K in air. X-ray diffraction data indicated that the samples had the characteristic orthorhombic YBa₂Cu₃O_{7− x} structure. Measurements of electrical resistance were carried out between 300 and 50 K by the standard four-probe DC electrical measurement. The samples began superconducting at an onset temperature around 92 K, and the full-transition temperature (critical temperature) ( T _c) was 88.7±1.4 K. The critical current density ( J _c) measured at 77 K was about 440 A/cm², the value of J _c was improved by the heat treatment under an oxygen atmosphere, and J _c=1.6 × 10³ A/cm² was observed. Under the magnetic field (B=1 T), the sample held its superconductivity, and demonstrated that this method can be used to produce the magnetic shielding used in magnetic resonance imaging diagnosis.     

Modification of Odor Investigation and Discrimination in Female Opossums (Monodelphis domestica) Following the Ablation of the Accessory Olfactory Bulbs.

To determine whether the vomeronasal system of the Brazilian short-tailed opossum (Monodelphis domestica) is important to the response to conspecific chemical signals, the authors tested female opossums with conspecific odors, before and after ablation of their accessory olfactory bulbs (AOBs). Anesthesia and sham treatments did not modify females' discrimination of conspecific odors when tested against water, between male and female odors, or between different odors from the same male donors. Odor investigation was partially diminished following partial ablation of the AOB, and complete ablation of the AOBs further impaired the ability of females to discriminate between certain odors. These findings provide the first evidence for the importance of the vomeronasal system in the detection of chemosignals of known origin in opossums. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Metabolic Remodeling with Hepatosteatosis Induced Vascular Oxidative Stress in Hepatic ERK2 Deficiency Mice with High Fat Diets

We previously demonstrated the marked hepatosteatosis and endothelial dysfunction in hepatocyte-specific ERK2 knockout mice (LE2KO) with a high-fat/high-sucrose diet (HFHSD), but detailed metabolic changes and the characteristics in insulin-sensitive organs were not tested. This study aimed to characterize metabolic remodeling with changes in insulin-sensitive organs, which could induce endothelial dysfunction in HFHSD-LE2KO. The serum glucose and fatty acid (FA) were modestly higher in HFHSD-LE2KO than HFHSD-Control. FA synthesis genes were up-regulated, which was associated with the decreased phosphorylation of AMPK and ACC, and with the up-regulation of SREBP-1 in the liver from HFHSD-LE2KO. In FA and amino acids fraction analysis, arachidonic acid/eicosapentaenoic acid ratio, L-ornithine/arginine ratio, asymmetric dimethylarginine and homocysteine levels were elevated in HFHSD-LE2KO. Insulin-induced phosphorylation of AKT was blunted in skeletal muscle. Serum leptin and IL-1β were elevated, and serum adiponectin was decreased with the enlargement of epididymal adipocytes. Finally, the enhanced superoxide levels in the aorta, which were blunted with CCCP, apocynin, and tempol, were observed in HFHSD-LE2KO. A pre-incubation of aortic rings with tempol improved endothelial dysfunction in HFHSD-LE2KO. HFHSD-LE2KO revealed an acceleration of FA synthesis in the liver leading to insulin resistance in skeletal muscle and the enlargement of visceral adipocytes. Global metabolic remodeling such as changes in arginine metabolism, ω3/ω6 ratio, and adipocytokines, could affect the vascular oxidative stress and endothelial dysfunction in HFHSD-LE2KO.     

4D printing shape memory polymers for dynamic jewellery and fashionwear

4D printing is a novel approach that enables dynamic functionality in ordinary static object. We used a methacrylated semicrystalline polymer to print objects exhibiting thermally triggered shape memory behaviour. By exploring various molecular weights, it was found that a methacrylated polycaprolactone polymer with a number average molecular weight of 10,000?g?mol^?1 exhibited the best thermal and mechanical behaviour. The effect of dyes’ addition to the ink formulation on the photopolymerisation and on the printing processes was evaluated. The ink was utilised for demonstrating fabrication of dynamic jewellery and a shoe accessory by Digital Light Processing printing.     

Mean shift trackers with cross-bin metrics

Cross-bin metrics have been shown to be more suitable than bin-by-bin metrics for measuring the distance between histograms in various applications. In particular, a visual tracker that minimizes the earth mover's distance (EMD) between the candidate and reference feature histograms has recently been proposed. This tracker was shown to be more robust than the Mean Shift tracker, which employs a bin-by-bin metric. In each frame, the former tracker iteratively shifts the candidate location by one pixel in the direction opposite to the EMD's gradient until no improvement is made. This optimization process involves the clustering of the candidate feature density in feature space, as well as the computation of the EMD between the candidate and reference feature histograms after each shift of the candidate location. In this paper, alternative trackers that employ cross-bin metrics as well, but that are based on Mean Shift (MS) iterations, are derived. The proposed trackers are simpler and faster due to 1) the use of MS-based optimization, which is not restricted to single pixel shifts, 2) abstention from any clustering of feature densities, and 3) abstention from EMD computations in multidimensional spaces.     

Studies on peroxidized lipids. V. Formation and characterization of 1,4-dihydropyridine-3,5-dicarbaldehydes as model of fluorescent components in lipofuscin

We investigated fluorescence properties of 1,4-dihydropyridine-3,5-dicarbaldehydes and their formation in mild reaction of primary amines and malonaldehyde, in order to clarify the role of malonaldehyde in the formation of fluorescent components of lipofuscin. The compounds exhibited fluorescence with excitation maxima at 375–405 nm and emission maxima at 435–465 nm, which was similar to those of lipofuscin and the fluorescent substances derived from the reaction of oxidized fatty acids with primary amines. Fluorescence of the compounds was greatly affected in acidic medium and little influenced in alkaline medium or by the metal chelator. The compounds lost fluorescence by treatment with sodium borohydride. They were inert to thiobarbituric acid reaction. Some of the fluorescence properties of the compounds were different from those of lipofuscin and the related fluorescent substances. Mild reaction of methylamine with pure malonaldehyde gave a single fluorescent compound, 1,4-dimethyl-1,4-dihydropyridine-3,5-dicarbaldehyde (Ia), and the reaction with the acid hydrolysate of tetramethoxypropane gave Ia and 1-methyl-4-(dimethoxyethyl)-1,4-dihydropyridine-3,5-dicarbaldehyde (IIa), the latter being produced from the impurity in the hydrolysate. These reactions produced a non-fluorescent Schiff base, a 1∶1-adduct of methylamine and malonaldehyde (IIIa), as a major product. It looks unlikely that malonaldehyde is the only product of lipid oxidation that produces fluorescent components in lipofuscin complex.     

Essential Amino Acid Composition of Fleshy Fruits Versus Maintenance Requirements of Passerine Birds

Nutritional analyses were performed on 27 fruit species that are eaten by frugivorous birds in east Mediterranean habitats in Israel. The essential amino acid (EAA) profile [compared by principal component analysis (PCA)] of these fruits indicated two distinct groups of fruits. The main group consisted of 23 species that were similar in their relatively low total EAA quantities and unbalanced EAA profiles. On average, the EAAs phenylalanine and tyrosine were most concentrated and histidine least (tryptophan was not measured). Comparing the relative amounts of EAAs in fruits with required amounts for maintenance of granivorous passerine birds revealed that these fruits are deficient in all or most EAAs. The sulfur-containing amino acids (methionine and cystine) were most limiting relative to the required amount (41–61% below requirement), while four others (arginine, lysine, isoleucine, and leucine) were severely deficient (30–37% below requirement). These results complement reports suggesting that frugivorous birds have lower total protein demands than granivores. The second group of four fruit species had relatively high total EAA contents. Each of these fruits appeared to contain especially large quantities of some EAAs, but it was uncertain whether some high concentrations could have resulted from interactions in the pulp during preparation and chemical analysis.     

Random low-degree polynomials are hard to approximate

We study the problem of how well a typical multivariate polynomial can be approximated by lower-degree polynomials over mathbb F{mathbb F} . We prove that almost all degree d polynomials have only an exponentially small correlation with all polynomials of degree at most d − 1, for all degrees d up to Θ(n). That is, a random degree d polynomial does not admit a good approximation of lower degree. In order to prove this, we prove far tail estimates on the distribution of the bias of a random low-degree polynomial. Recently, several results regarding the weight distribution of Reed–Muller codes were obtained. Our results can be interpreted as a new large deviation bound on the weight distribution of Reed–Muller codes.