A path toward understanding neurodegeneration

The specter of neurodegenerative disease, particularly Alzheimer's disease, haunts the developed world and exacts a poorly documented toll on underdeveloped countries. With so little progress made toward finding a cure—or, better, a prevention—it is time to rethink the path to progress. This requires a change in perspective on the type of research that will make a difference. The lesson learned from cancer research is that a new commitment means rethinking the fundamental approach to the disease. Cancer research moved from taking potshots with, usually, cytotoxic drugs to a bottom-up, mechanism-based approach in which newly acquired genetic knowledge played the largest role. Today, that effort has produced a platform of knowledge from which academia and industry are drawing. For neurodegenerative disease, the genetic approach remains valid but the problem must concurrently be approached from a complementary, robust cell biological perspective, focusing on the cellular cascade of events that lead to neuronal cell death

Balancing the double‐edged sword effect of increased resistant starch content and its impact on rice texture: its genetics and molecular physiological mechanisms

Resistant starch (RS) is the portion of starch that escapes gastrointestinal digestion and acts as a substrate for fermentation of probiotic bacteria in the gut. Aside from enhancing gut health, RS contributes to a lower glycemic index. A genome‐wide association study coupled with targeted gene association studies was conducted utilizing a diverse panel of 281 resequenced Indica rice lines comprising of ~2.2 million single nucleotide polymorphisms. Low‐to‐intermediate RS phenotypic variations were identified in the rice diversity panel, resulting in novel associations of RS to several genes associated with amylopectin biosynthesis and degradation. Selected rice lines encoding superior alleles of SSIIa with medium RS and inferior alleles with low RS groups were subjected to detailed transcriptomic, metabolomic, non‐starch dietary fibre (DF), starch structural and textural attributes. The gene regulatory networks highlighted the importance of a protein phosphatase alongside multiple genes of starch metabolism. Metabolomics analyses resulted in the identification of several metabolite hubs (carboxylic acid, sugars and polyamines) in the medium RS group. Among DF, mannose and galactose from the water‐insoluble fraction were found to be highly associated with low and medium RS lines, respectively. Starch structural analyses revealed that a moderate increase in RS is also linked to an elevation of amylose 1 and amylose 2 fractions. Although rice lines with medium RS content negatively affected textural and viscosity properties in comparison to low RS, the textural property of medium RS lines was in the same acceptable range as IR64, a rice mega variety popular in Asia

Improving Rice Dietary Fibre Content and Consumption for Human Health

Soft textured rice is the major source of calories in the diet of most South East (SE) Asian countries. However, it is most often consumed after polishing which removes the bran and embryo and hence most of the vitamins, minerals and dietary fibre (DF) are lost. Consequently, white rice comprises over 90% starch with only trace amounts of DF and is rapidly digested in the human gastrointestinal tract, resulting in a high glycaemic index (GI). The excessive consumption of high GI foods is associated with increased risks of a range of chronic diseases including type-2 diabetes, cardiovascular disease (CVD) and some types of cancer. Furthermore, the incidence of these conditions is dramatically increasing in areas where white rice is the staple food, notably Asia, with the prevalence of diabetes in SE Asia alone predicted to reach 120 million by 2030. It is therefore necessary to develop rice lines in which high energy content is combined with low GI. This may be achieved by combining acceptable levels of resistant starch (RS) with an increased content of the cell wall derived-dietary fibre components

A Comprehensive Resource for Induced Pluripotent Stem Cells from Patients with Primary Tauopathies.

Primary tauopathies are characterized neuropathologically by inclusions containing abnormal forms of the microtubule-associated protein tau (MAPT) and clinically by diverse neuropsychiatric, cognitive, and motor impairments. Autosomal dominant mutations in the MAPT gene cause heterogeneous forms of frontotemporal lobar degeneration with tauopathy (FTLD-Tau). Common and rare variants in the MAPT gene increase the risk for sporadic FTLD-Tau, including progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD). We generated a collection of fibroblasts from 140 MAPT mutation/risk variant carriers, PSP, CBD, and cognitively normal controls; 31 induced pluripotent stem cell (iPSC) lines from MAPT mutation carriers, non-carrier family members, and autopsy-confirmed PSP patients; 33 genome engineered iPSCs that were corrected or mutagenized; and forebrain neural progenitor cells (NPCs). Here, we present a resource of fibroblasts, iPSCs, and NPCs with comprehensive clinical histories that can be accessed by the scientific community for disease modeling and development of novel therapeutics for tauopathies

Three Repeat Isoforms of Tau Inhibit Assembly of Four Repeat Tau Filaments

Tauopathies are defined by assembly of the microtubule associated protein tau into filamentous tangles and classified by the predominant tau isoform within these aggregates. The major isoforms are determined by alternative mRNA splicing of exon 10 generating tau with three (3R) or four (4R) ∼32 amino acid imperfect repeats in the microtubule binding domain. In normal adult brains there is an approximately equimolar ratio of 3R and 4R tau which is altered by several disease-causing mutations in the tau gene. We hypothesized that when 4R and 3R tau isoforms are not at equimolar ratios aggregation is favored. Here we provide evidence for the first time that the combination of 3R and 4R tau isoforms results in less in vitro heparin induced polymerization than with 4R preparations alone. This effect was independent of reducing conditions and the presence of alternatively spliced exons 2 and 3 N-terminal inserts. The addition of even small amounts of 3R to 4R tau assembly reactions significantly decreased 4R assembly. Together these findings suggest that co-expression of 3R and 4R tau isoforms reduce tau filament assembly and that 3R tau isoforms inhibit 4R tau assembly. Expression of equimolar amounts of 3R and 4R tau in adult humans may be necessary to maintain proper neuronal microtubule dynamics and to prevent abnormal tau filament assembly. Importantly, these findings indicate that disruption of the normal equimolar 3R to 4R ratio may be sufficient to drive tau aggregation and that restoration of the tau isoform balance may have important therapeutic implications in tauopathies

A point mutation in the kinase domain of CRK10 leads to xylem vessel collapse and activation of defence responses in Arabidopsis

Cysteine-rich receptor-like kinases (CRKs) are a large family of plasma membrane-bound receptors ubiquitous in higher plants. However, despite their prominence, their biological roles have remained largely elusive so far. In this study we report the characterization of an Arabidopsis mutant named crk10-A397T in which alanine 397 has been replaced by a threonine in the αC helix of the kinase domain of CRK10, known to be a crucial regulatory module in mammalian kinases. The crk10-A397T mutant is a dwarf that displays collapsed xylem vessels in the root and hypocotyl, whereas the vasculature of the inflorescence develops normally. In situ phosphorylation assays with His-tagged wild type and crk10-A397T versions of the CRK10 kinase domain revealed that both alleles are active kinases capable of autophosphorylation, with the newly introduced threonine acting as an additional phosphorylation site in crk10-A397T. Transcriptomic analysis of wild type and crk10-A397T mutant hypocotyls revealed that biotic and abiotic stress-responsive genes are constitutively up-regulated in the mutant, and a root-infection assay with the vascular pathogen Fusarium oxysporum demonstrated that the mutant has enhanced resistance to this pathogen compared with wild type plants. Taken together our results suggest that crk10-A397T is a gain-of-function allele of CRK10, the first such mutant to have been identified for a CRK in Arabidopsis

Comparison of Hepatic and Nephric Total Mercury Concentrations Between Feral and Ranch American Mink (Neovison vison) from Northwestern Poland

For many years the American mink (Neovison vison) has been used in North America (where it originates from) as a sensitive indirect bioindicator in assessing the degree of mercury (Hg) contamination in terrestrial ecosystems. The aim of this paper was the determination of total concentrations of Hg in the liver and kidneys of feral and ranch mink from the Warta Mouth National Park (WMNP) and from farms located in northwestern Poland, for comparison with similar data on American mink from North America. In road-killed feral mink from the WMNP, the mean concentrations were 11.8 and 14.1 mg/kg dry weight in the liver and kidney, respectively. Mean Hg concentrations in feral mink were from 240 to 90 times higher in these two respective tissues than in ranch mink. The feral mink from northwestern Poland had concentrations of hepatic and nephric Hg similar to the highest concentrations that have been recorded over the past several decades in wild American mink from certain areas of Canada and the USA

Resistance to autosomal dominant Alzheimer's disease in an APOE3 Christchurch homozygote: a case report.

We identified a PSEN1 (presenilin 1) mutation carrier from the world's largest autosomal dominant Alzheimer's disease kindred, who did not develop mild cognitive impairment until her seventies, three decades after the expected age of clinical onset. The individual had two copies of the APOE3 Christchurch (R136S) mutation, unusually high brain amyloid levels and limited tau and neurodegenerative measurements. Our findings have implications for the role of APOE in the pathogenesis, treatment and prevention of Alzheimer's disease

Erosion, permeation and outgassing performances of tin coating under/after hydrogen plasma iffadiation

An erosion behavior of TiN-coated stainless-steel (SS) surfaces was investigated during biased-limiter experiments within the Uragan-3M torsatron and during simulation experiments, which were performed with plasma-accelerator and glow-discharge (GD) plasmas. For a TiN-coated SS head-plate of a limiter the arc ignition probability was found to be lower than 10-4 per plasma pulse. Possible physical mechanisms of this effect had been discussed. Within special vacuum stands, using thermal-desorption and mass-spectrometry methods, there were performed measurements of an outgassing rate and hydrogen permeability of TiNcoatings. The negligible outgassing from TiN-coated SS samples, during their heating up to 473 K, was observed after a cleaning procedure with a molecular hydrogen inflow under pressure of about 10-4 Torr, on contrary to the considerable increase of (q) rate for the irradiated samples. Measured values of the TiN-film hydrogen permeability were several times lower, and activation energy of the hydrogen permeation was considerably lower than that for the SS films (15 kJ/mole instead of 19.9 kJ/mole). The use of TiN-coated SS and diffusion membranes, for the reduction of the erosion, recycling, and hydrogen isotope inventory control, as well as for improvement of vacuum conditions, has been considered