Local spin Seebeck imaging with scanning thermal probe

In this work we present the results of an experiment to locally resolve the spin Seebeck effect in a high-quality Pt/YIG sample. We achieve this by employing a locally heated scanning thermal probe to generate a highly local non-equilibrium spin current. To support our experimental results, we also present a model based on the non-equilibrium thermodynamic approach which is in a good agreement with experimental findings. To further corroborate our results, we index the locally resolved spin Seebeck effect with that of the local magnetisation texture by MFM and correlate corresponding regions. We hypothesise that this technique allows imaging of magnetisation textures within the magnon diffusion length and hence characterisation of spin caloritronic materials at the nanoscale

Heterochromatic siRNAs and DDM1 Independently Silence Aberrant 5S rDNA Transcripts in Arabidopsis

5S ribosomal RNA gene repeats are arranged in heterochromatic arrays (5S rDNA) situated near the centromeres of Arabidopsis chromosomes. The chromatin remodeling factor DDM1 is known to maintain 5S rDNA methylation patterns while silencing transcription through 5S rDNA intergenic spacers (IGS). We mapped small-interfering RNAs (siRNA) to a composite 5S rDNA repeat, revealing a high density of siRNAs matching silenced IGS transcripts. IGS transcript repression requires proteins of the heterochromatic siRNA pathway, including RNA polymerase IV (Pol IV), RNA-DEPENDENT RNA POLYMERASE 2 (RDR2) and DICER-LIKE 3 (DCL3). Using molecular and cytogenetic approaches, we show that the DDM1 and siRNA-dependent silencing effects are genetically independent. DDM1 suppresses production of the siRNAs, however, thereby limiting RNA-directed DNA methylation at 5S rDNA repeats. We conclude that DDM1 and siRNA-dependent silencing are overlapping processes that both repress aberrant 5S rDNA transcription and contribute to the heterochromatic state of 5S rDNA arrays

Failure of interpolation in the intuitionistic logic of constant domains

This paper shows that the interpolation theorem fails in the intuitionistic logic of constant domains. This result refutes two previously published claims that the interpolation property holds.Comment: 13 pages, 0 figures. Overlaps with arXiv 1202.1195 removed, the text thouroughly reworked in terms of notation and style, historical notes as well as some other minor details adde

Lymphocytic Esophagitis: An Emerging Clinicopathologic Disease Associated with Dysphagia

Lymphocytic Esophagitis (LyE) is a recently described clinicopathological condition, but little is known about its features and clinical associations

Health systems strengthening: a common classification and framework for investment analysis

Significant scale-up of donors' investments in health systems strengthening (HSS), and the increased application of harmonization mechanisms for jointly channelling donor resources in countries, necessitate the development of a common framework for tracking donors' HSS expenditures. Such a framework would make it possible to comparatively analyse donors' contributions to strengthening specific aspects of countries' health systems in multi-donor-supported HSS environments. Four pre-requisite factors are required for developing such a framework: (i) harmonization of conceptual and operational understanding of what constitutes HSS; (ii) development of a common set of criteria to define health expenditures as contributors to HSS; (iii) development of a common HSS classification system; and (iv) harmonization of HSS programmatic and financial data to allow for inter-agency comparative analyses. Building on the analysis of these aspects, the paper proposes a framework for tracking donors' investments in HSS, as a departure point for further discussions aimed at developing a commonly agreed approach. Comparative analysis of financial allocations by the Global Fund to Fight AIDS, Tuberculosis and Malaria and the GAVI Alliance for HSS, as an illustrative example of applying the proposed framework in practice, is also presente

Plasmodium falciparum: linkage disequilibrium between loci in chromosomes 7 and 5 and chloroquine selective pressure in Northern Nigeria.

In view of the recent discovery (Molecular Cell 6, 861-871) of a (Lys76Thr) codon change in gene pfcrt on chromosome 7 which determines in vitro chloroquine resistance in Plasmodium falciparum, we have re-examined samples taken before treatment in our study in Zaria, Northern Nigeria (Parasitology, 119, 343-348). Drug resistance was present in 5/5 cases where the pfcrt 76Thr codon change was seen (100% positive predictive value). Drug sensitivity was found in 26/28 cases where the change was absent (93% negative predictive value). Allele pfcrt 76Thr showed strong linkage disequilibrium with pfmdr1 Tyr86 on chromosome 5, more complete than that between pfcrt and cg2 alleles situated between recombination cross-over points on chromosome 7. Physical linkage of cg2 with pfcrt may account for linkage disequilibrium between their alleles but in the case of genes pfmdr1 and pfcrt, on different chromosomes, it is likely that this is maintained epistatically through the selective pressure of chloroquine

A concerted DNA methylation/histone methylation switch regulates rDNA gene dosage control and nucleolar dominance

Eukaryotes regulate the effective dosage of their ribosomal RNA (rRNA) genes, expressing fewer than half of the genes at any one time. Likewise, genetic hybrids displaying nucleolar dominance transcribe rRNA genes inherited from one parent but silence the other paraental set.We show that rRNA gene dosage control and nucleolar dominance utilize a common mechanis

Minocycline 200 mg or 400 mg versus placebo for mild Alzheimer's disease: the MADE Phase II, three-arm RCT

Background: Minocycline is an anti-inflammatory drug and protects against the toxic effects of β-amyloid in vitro and in animal models of Alzheimer’s disease. To the best of our knowledge, no randomised placebo-controlled clinical trials in patients with Alzheimer’s disease looking at the efficacy and tolerability of minocycline have been carried out. Objectives: The trial investigated whether or not minocycline was superior to placebo in slowing down the rate of decline in cognitive and functional ability over 2 years. The safety and tolerability of minocycline were also assessed. Design: A Phase II, three-arm, randomised, double-blind, multicentre trial with a semifactorial design. Participants continued on trial treatment for up to 24 months. Setting: Patients were identified from memory services, both within the 32 participating NHS trusts and within the network of memory services supported by the Dementias and Neurodegenerative Diseases Research Network (also known as DeNDRoN). Participants: Patients with standardised Mini Mental State Examination scores of > 23 points and with Alzheimer’s disease assessed by the National Institute on Aging–Alzheimer’s Association’s criteria were identified from memory services. Intervention: Patients with mild Alzheimer’s disease were randomly allocated 1 : 1 : 1 to receive one of three treatments: arm 1 – 400 mg per day of minocycline; arm 2 – 200 mg per day of minocycline; or arm 3 – placebo. Patients continued treatment for 24 months. Participants, investigators and outcome assessors were blind to treatment allocation. Main outcome measures: Primary outcome measures were decline in standardised Mini Mental State Examination and Bristol Activities of Daily Living Scale scores of combined minocycline treatment arms versus placebo, as analysed by intention-to-treat repeated measures regression. Results: Between 23 May 2014 and 14 April 2016, 554 participants were randomised. Of the 544 eligible participants, the mean age was 74.3 years and the average standardised Mini Mental State Examination score was 26.4 points. A total of 252 serious adverse events were reported, with the most common categories being neuropsychiatric and cardiocirculatory. Significantly fewer participants completed treatment with 400 mg of minocycline [29% (53/184)] than 200 mg [62% (112/181)] or placebo [64% (114/179)] (p < 0.0001), mainly because of gastrointestinal symptoms (p = 0.0008), dermatological side effects (p = 0.02) and dizziness (p = 0.01). Assessment rates were also lower in the 400-mg treatment arm: 68% (119 of 174 expected) for standardised Mini Mental State Examination scores at 24 months, compared with 82% (144/176) for the 200-mg treatment arm and 84% (140/167) for the placebo arm. Decline in standardised Mini Mental State Examination scores over the 24-month study period in the combined minocycline arms was similar to that in the placebo arm (4.1- vs. 4.3-point reduction; p = 0.9), as was the decline in the 400- and 200-mg treatment arms (3.3 vs. 4.7 points; p = 0.08). Likewise, worsening of Bristol Activities of Daily Living Scale scores over 24 months was similar in all trial arms (5.7, 6.6 and 6.2 points in the 400-mg treatment arm, 200-mg treatment arm and placebo arm, respectively; a p-value of 0.57 for minocycline vs. placebo and a p-value of 0.77 for 400 vs. 200 mg of minocycline). Results were similar in different patient subgroups and in sensitivity analyses adjusting for missing data. Limitations: Potential limitations of the study include that biomarkers were not used to confirm the diagnosis of Alzheimer’s disease, as these and apolipoprotein E (APOE) genotyping are not routinely available within the NHS. Compliance was also worse than expected and differential follow-up rates were observed, with fewer assessments obtained for the 400-mg treatment arm than for the 200-mg treatment and placebo arms. Conclusions: Minocycline does not delay the progress of cognitive or functional impairment in people with mild Alzheimer’s disease over a 2-year period. Minocycline at a dose of 400 mg is poorly tolerated in this population. Future work: The Minocycline in mild Alzheimer’s DiseasE (MADE) study provides a framework for a streamlined trial design that can be usefully applied to test other disease-modifying therapies