Long-term in vivo imaging of fibrillar tau in the retina of P301S transgenic mice.

Tauopathies are widespread neurodegenerative disorders characterised by the intracellular accumulation of hyperphosphorylated tau. Especially in Alzheimer's disease, pathological alterations in the retina are discussed as potential biomarkers to improve early diagnosis of the disease. Using mice expressing human mutant P301S tau, we demonstrate for the first time a straightforward optical approach for the in vivo detection of fibrillar tau in the retina. Longitudinal examinations of individual animals revealed the fate of single cells containing fibrillar tau and the progression of tau pathology over several months. This technique is most suitable to monitor therapeutic interventions aimed at reducing the accumulation of fibrillar tau. In order to evaluate if this approach can be translated to human diagnosis, we tried to detect fibrillar protein aggregates in the post-mortem retinas of patients that had suffered from Alzheimer's disease or Progressive Supranuclear Palsy. Even though we could detect hyperphosphorylated tau, we did not observe any fibrillar tau or Aß aggregates. In contradiction to previous studies, our observations do not support the notion that Aβ or tau in the retina are of diagnostic value in Alzheimer's disease

Single-crossover dynamics: finite versus infinite populations

Populations evolving under the joint influence of recombination and resampling (traditionally known as genetic drift) are investigated. First, we summarise and adapt a deterministic approach, as valid for infinite populations, which assumes continuous time and single crossover events. The corresponding nonlinear system of differential equations permits a closed solution, both in terms of the type frequencies and via linkage disequilibria of all orders. To include stochastic effects, we then consider the corresponding finite-population model, the Moran model with single crossovers, and examine it both analytically and by means of simulations. Particular emphasis is on the connection with the deterministic solution. If there is only recombination and every pair of recombined offspring replaces their pair of parents (i.e., there is no resampling), then the {\em expected} type frequencies in the finite population, of arbitrary size, equal the type frequencies in the infinite population. If resampling is included, the stochastic process converges, in the infinite-population limit, to the deterministic dynamics, which turns out to be a good approximation already for populations of moderate size.Comment: 21 pages, 4 figure

Different MAPT haplotypes influence expression of total MAPT in postmortem brain tissue

The MAPT gene, encoding the microtubule-associated protein tau on chromosome 17q21.31, is result of an inversion polymorphism, leading to two allelic variants (H1 and H2). Homozygosity for the more common haplotype H1 is associated with an increased risk for several tauopathies, but also for the synucleinopathy Parkinson's disease (PD). In the present study, we aimed to clarify whether the MAPT haplotype influences expression of MAPT and SNCA, encoding the protein alpha-synuclein (alpha-syn), on mRNA and protein levels in postmortem brains of PD patients and controls. We also investigated mRNA expression of several other MAPT haplotype-encoded genes. Postmortem tissues from cortex of fusiform gyrus (ctx-fg) and of the cerebellar hemisphere (ctx-cbl) of neuropathologically confirmed PD patients (n = 95) and age- and sex-matched controls (n = 81) were MAPT haplotype genotyped to identify cases homozygous for either H1 or H2. Relative expression of genes was quantified using real-time qPCR;soluble and insoluble protein levels of tau and alpha-syn were determined by Western blotting. Homozygosity for H1 versus H2 was associated with increased total MAPT mRNA expression in ctx-fg regardless of disease state. Inversely, H2 homozygosity was associated with markedly increased expression of the corresponding antisense MAPT-AS1 in ctx-cbl. PD patients had higher levels of insoluble 0N3R and 1N4R tau isoforms regardless of the MAPT genotype. The increased presence of insoluble alpha-syn in PD patients in ctx-fg validated the selected postmortem brain tissue. Our findings in this small, but well controlled cohort of PD and controls support a putative biological relevance of tau in PD. However, we did not identify any link between the disease-predisposing H1/H1 associated overexpression of MAPT with PD status. Further studies are required to gain a deeper understanding of the potential regulatory role of MAPT-AS1 and its association to the disease-protective H2/H2 condition in the context of PD

Psychiatric genome-wide association study analyses implicate neuronal, immune and histone pathways

Genome-wide association studies (GWAS) of psychiatric disorders have identified multiple genetic associations with such disorders, but better methods are needed to derive the underlying biological mechanisms that these signals indicate. We sought to identify biological pathways in GWAS data from over 60,000 participants from the Psychiatric Genomics Consortium. We developed an analysis framework to rank pathways that requires only summary statistics. We combined this score across disorders to find common pathways across three adult psychiatric disorders: schizophrenia, major depression and bipolar disorder. Histone methylation processes showed the strongest association, and we also found statistically significant evidence for associations with multiple immune and neuronal signaling pathways and with the postsynaptic density. Our study indicates that risk variants for psychiatric disorders aggregate in particular biological pathways and that these pathways are frequently shared between disorders. Our results confirm known mechanisms and suggest several novel insights into the etiology of psychiatric disorders

Highly sensitive coulometric titration of oxygen for the characterization of solid materials at elevated temperatures

A new setup for characterization of solid material oxygen exchange and conductivity in a broad oxygen partial pressure range and at elevated temperatures is presented. The development target of this setup is directed towards the detection of ultra-low amounts of exchanged oxygen. For this, electrochemical cells made of yttria-stabilized zirconia (YSZ) were optimized and applied in a flow-through arrangement. The design and process measures enable a lower limit of detection below 100&thinsp;pmol of exchanged oxygen. Furthermore, the system characteristics concerning oxygen dispersion, titration efficiency and electrode kinetics are described.</p

Notch1 mutations drive clonal expansion in normal esophageal epithelium but impair tumor growth

NOTCH1 mutant clones occupy the majority of normal human esophagus by middle age but are comparatively rare in esophageal cancers, suggesting NOTCH1 mutations drive clonal expansion but impede carcinogenesis. Here we test this hypothesis. Sequencing NOTCH1 mutant clones in aging human esophagus reveals frequent biallelic mutations that block NOTCH1 signaling. In mouse esophagus, heterozygous Notch1 mutation confers a competitive advantage over wild-type cells, an effect enhanced by loss of the second allele. Widespread Notch1 loss alters transcription but has minimal effects on the epithelial structure and cell dynamics. In a carcinogenesis model, Notch1 mutations were less prevalent in tumors than normal epithelium. Deletion of Notch1 reduced tumor growth, an effect recapitulated by anti-NOTCH1 antibody treatment. Notch1 null tumors showed reduced proliferation. We conclude that Notch1 mutations in normal epithelium are beneficial as wild-type Notch1 favors tumor expansion. NOTCH1 blockade may have therapeutic potential in preventing esophageal squamous cancer

Ornamental plants, 1983: a summary of research

Capital requirements for establishing container nurseries in Ohio - 1982 / Harold H. Kneen, Reed D. Taylor, David E. Hahn, and Elton M. Smith -- Production costs of operating container nurseries in Ohio - 1982 / Harold H. Kneen, Reed D. Taylor, David E. Hahn, and Elton M. Smith -- Pigmented polyethylene films for nursery crop storage / John A. Wynstra and Elton M. Smith -- Micropropagation of Ajuga reptans 'Burgundy Glow' / R. Daniel Lineberger and Audrey Wanstreet -- Effects of fertilizer in the propagation medium and extended photoperiod on growth of Acer rubrum 'Red Sunset' cuttings / Steven M. Still and Bryce H. Lane -- Area of weed control from a single herbicide tablet / M. A. Ruizzo, E. M. Smith, and S. F. Gorske -- Slow release herbicide formulations for container grown landscape crops / M. A. Ruizzo, E. M. Smith, and S. F. Gorske -- Effects of pre-emergence herbicides on selected herbaceous perennials / Elton M. Smith, Gary Gibson, and Sharon A. Treaster -- Controlling weeds in garden lily, gladiolus, and dahlia with pre-emergence herbicides / Elton M. Smith and Sharon A. Treaster -- Root pruning landscape plants produced on sand capillary beds / Elton M. Smith and Sharon A. Treaster -- Genetic variation in wound response among cultivars of Acer platanoides L. / Peter W. Gallagher and T. Davis Sydnor -- A preliminary host preference study for fall webworm (Hyphantria cunea Drury) / T. Davis Sydnor and Daniel Herms -- Evaluation of flowering crabapple susceptibility to apple scab in Ohio - 1982 / Elton M. Smit

The Trem2 R47H Alzheimer's risk variant impairs splicing and reduces Trem2 mRNA and protein in mice but not in humans

BACKGROUND: The R47H variant of the Triggering Receptor Expressed on Myeloid cells 2 (TREM2) significantly increases the risk for late onset Alzheimer's disease. Mouse models accurately reproducing phenotypes observed in Alzheimer' disease patients carrying the R47H coding variant are required to understand the TREM2 related dysfunctions responsible for the enhanced risk for late onset Alzheimer's disease. METHODS: A CRISPR/Cas9-assisted gene targeting strategy was used to generate Trem2 R47H knock-in mice. Trem2 mRNA and protein levels as well as Trem2 splicing patterns were assessed in these mice, in iPSC-derived human microglia-like cells, and in human brains from Alzheimer's patients carrying the TREM2 R47H risk factor. RESULTS: Two independent Trem2 R47H knock-in mouse models show reduced Trem2 mRNA and protein production. In both mouse models Trem2 haploinsufficiency was due to atypical splicing of mouse Trem2 R47H, which introduced a premature stop codon. Cellular splicing assays using minigene constructs demonstrate that the R47H variant induced abnormal splicing only occurs in mice but not in humans. TREM2 mRNA levels and splicing patterns were both normal in iPSC-derived human microglia-like cells and patient brains with the TREM2 R47H variant. CONCLUSIONS: The Trem2 R47H variant activates a cryptic splice site that generates miss-spliced transcripts leading to Trem2 haploinsufficiency only in mice but not in humans. Since Trem2 R47H related phenotypes are mouse specific and do not occur in humans, humanized TREM2 R47H knock-in mice should be generated to study the cellular consequences caused by the human TREM2 R47H coding variant. Currently described phenotypes of Trem2 R47H knock-in mice can therefore not be translated to humans

Metabolic analysis of the interaction between plants and herbivores

Insect herbivores by necessity have to deal with a large arsenal of plant defence metabolites. The levels of defence compounds may be increased by insect damage. These induced plant responses may also affect the metabolism and performance of successive insect herbivores. As the chemical nature of induced responses is largely unknown, global metabolomic analyses are a valuable tool to gain more insight into the metabolites possibly involved in such interactions. This study analyzed the interaction between feral cabbage (Brassica oleracea) and small cabbage white caterpillars (Pieris rapae) and how previous attacks to the plant affect the caterpillar metabolism. Because plants may be induced by shoot and root herbivory, we compared shoot and root induction by treating the plants on either plant part with jasmonic acid. Extracts of the plants and the caterpillars were chemically analysed using Ultra Performance Liquid Chromatography/Time of Flight Mass Spectrometry (UPLCT/MS). The study revealed that the levels of three structurally related coumaroylquinic acids were elevated in plants treated on the shoot. The levels of these compounds in plants and caterpillars were highly correlated: these compounds were defined as the ‘metabolic interface’. The role of these metabolites could only be discovered using simultaneous analysis of the plant and caterpillar metabolomes. We conclude that a metabolomics approach is useful in discovering unexpected bioactive compounds involved in ecological interactions between plants and their herbivores and higher trophic levels.

Novel multiple sclerosis susceptibility loci implicated in epigenetic regulation

We conducted a genome-wide association study (GWAS) on multiple sclerosis (MS) susceptibility in German cohorts with 4888 cases and 10,395 controls. In addition to associations within the major histocompatibility complex (MHC) region, 15 non-MHC loci reached genome-wide significance. Four of these loci are novel MS susceptibility loci. They map to the genes L3MBTL3, MAZ, ERG, and SHMT1. The lead variant at SHMT1 was replicated in an independent Sardinian cohort. Products of the genes L3MBTL3, MAZ, and ERG play important roles in immune cell regulation. SHMT1 encodes a serine hydroxymethyltransferase catalyzing the transfer of a carbon unit to the folate cycle. This reaction is required for regulation of methylation homeostasis, which is important for establishment and maintenance of epigenetic signatures. Our GWAS approach in a defined population with limited genetic substructure detected associations not found in larger, more heterogeneous cohorts, thus providing new clues regarding MS pathogenesis