Immune defects in Alzheimer's disease: new medications development

Alzheimer's disease (AD) is a neurodegenerative disease characterized by the accumulation of intracellular and extracellular aggregates. According to the amyloid beta (Aβ) hypothesis, amyloidosis occurring in the brain is a leading cause of neurodegeneration in AD. Defects in the innate immune system may decrease the clearance of Aβ in the brain. Macrophages of most AD patients do not transport Aβ into endosomes and lysosomes, and monocytes from AD patients do not efficiently clear Aβ from AD brain. After stimulation with Aβ, mononuclear cells of normal subjects display up-regulated transcription of MGAT3, which encodes β-1,4-mannosyl-glycoprotein 4-β-N-acetylglucosaminyltransferase, and Toll-like receptor (TLR) genes. Monocytes of AD patients generally down-regulate these genes. A commonly used, naturally occurring material from a spice that enhances certain key functions defective in cells of innate immunity of many AD patients has shown epidemiologic rationale for use in AD treatment. Bisdemethoxycurcumin, a natural curcumin, is a minor constituent of turmeric (curry), and it enhances phagocytosis and clearance of Aβ in cells from most AD patients. We confirmed the effectiveness of a synthetic version of the same compound. In mononuclear cells of most AD patients, bisdemethoxycurcumin enhanced defective phagocytosis of Aβ and increased the transcription of MGAT3 and TLR genes. The potency of bisdemethoxycurcumin as a highly purified compound in facilitating the clearance of Aβ in mononuclear cells suggests the promise of enhanced effectiveness compared to curcuminoid mixtures. Bisdemethoxycurcumin appears to enhance immune function in mononuclear cells of AD patients and may provide a novel approach to AD immunotherapy

DNA insertions distinguish the duplicated renin genes of DBA/2 and M. hortulanus mice

In a survey of inbred and wild mouse DNAs for genetic variation at the duplicate renin loci, Ren-1 and Ren-2 , a variant Not I hybridization pattern was observed in the wild mouse M. hortulanus . To determine the basis for this variation, the structure of the M. hortulanus renin loci has been examined in detail and compared to that of the inbred strain DBA/2. Overall, the gross features of structure in this chromosomal region are conserved in both Mus species. In particular, the sequence at the recombination site between the linked Ren-1 and Ren-2 loci was found to be identical in both DBA/2 and M. hortulanus , indicating that the renin gene duplication occurred prior to the divergence of ancestors of these mice. Renin flanking sequences in M. hortulanus , however, were found to lack four DNA insertions totaling approximately 10.5 kb which reside near the DBA/2 loci. The postduplication evolution of the mouse renin genes in thus characterized by a number of insertion and/or deletion events within nearby flanking sequences. Analysis of renin expression showed little or no difference between these mice in steady state renin RNA levels in most tissues examined, suggesting that these insertions do not influence expression at those sites. A notable exception is the adrenal gland, in which DBA/2 and M. hortulanus mice exhibit different patterns of developmentally regulated renin expression.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/46988/1/335_2004_Article_BF00570438.pd

Lectures on Supersymmetry Breaking

We review the subject of spontaneous supersymmetry breaking. First we consider supersymmetry breaking in a semiclassical theory. We illustrate it with several examples, demonstrating different phenomena, including metastable supersymmetry breaking. Then we give a brief review of the dynamics of supersymmetric gauge theories. Finally, we use this dynamics to present various mechanisms for dynamical supersymmetry breaking. These notes are based on lectures given by the authors in 2007, at various schools.Comment: 47 pages. v2: minor correction

Using DNA pools for genotyping trios

The genotyping of mother–father–child trios is a very useful tool in disease association studies, as trios eliminate population stratification effects and increase the accuracy of haplotype inference. Unfortunately, the use of trios for association studies may reduce power, since it requires the genotyping of three individuals where only four independent haplotypes are involved. We describe here a method for genotyping a trio using two DNA pools, thus reducing the cost of genotyping trios to that of genotyping two individuals. Furthermore, we present extensions to the method that exploit the linkage disequilibrium structure to compensate for missing data and genotyping errors. We evaluated our method on trios from CEPH pedigree 66 of the Coriell Institute. We demonstrate that the error rates in the genotype calls of the proposed protocol are comparable to those of standard genotyping techniques, although the cost is reduced considerably. The approach described is generic and it can be applied to any genotyping platform that achieves a reasonable precision of allele frequency estimates from pools of two individuals. Using this approach, future trio-based association studies may be able to increase the sample size by 50% for the same cost and thereby increase the power to detect associations

Prevalence of Children with Severe Fetal Alcohol Spectrum Disorders in Communities Near Rome, Italy: New Estimated Rates Are Higher than Previous Estimates

Objective: To determine the population-based epidemiology of fetal alcohol syndrome (FAS) and other fetal alcohol spectrum disorders (FASD) in towns representative of the general population of central Italy. Methods: Slightly revised U.S. Institute of Medicine diagnostic methods were used among children in randomly-selected schools near Rome. Consented first grade children (n = 976) were screened in Tier I for height, weight, or head circumference and all childre

Towards an Intelligent Tutor for Mathematical Proofs

Computer-supported learning is an increasingly important form of study since it allows for independent learning and individualized instruction. In this paper, we discuss a novel approach to developing an intelligent tutoring system for teaching textbook-style mathematical proofs. We characterize the particularities of the domain and discuss common ITS design models. Our approach is motivated by phenomena found in a corpus of tutorial dialogs that were collected in a Wizard-of-Oz experiment. We show how an intelligent tutor for textbook-style mathematical proofs can be built on top of an adapted assertion-level proof assistant by reusing representations and proof search strategies originally developed for automated and interactive theorem proving. The resulting prototype was successfully evaluated on a corpus of tutorial dialogs and yields good results.Comment: In Proceedings THedu'11, arXiv:1202.453

System-wide approaches to antimicrobial therapy and antimicrobial resistance in the UK: the AMR-X framework

Antimicrobial resistance (AMR) threatens human, animal, and environmental health. Acknowledging the urgency of addressing AMR, an opportunity exists to extend AMR action-focused research beyond the confines of an isolated biomedical paradigm. An AMR learning system, AMR-X, envisions a national network of health systems creating and applying optimal use of antimicrobials on the basis of their data collected from the delivery of routine clinical care. AMR-X integrates traditional AMR discovery, experimental research, and applied research with continuous analysis of pathogens, antimicrobial uses, and clinical outcomes that are routinely disseminated to practitioners, policy makers, patients, and the public to drive changes in practice and outcomes. AMR-X uses connected data-to-action systems to underpin an evaluation framework embedded in routine care, continuously driving implementation of improvements in patient and population health, targeting investment, and incentivising innovation. All stakeholders co-create AMR-X, protecting the public from AMR by adapting to continuously evolving AMR threats and generating the information needed for precision patient and population care

Precipitation sensitivity to autoconversion rate in a numerical weather-prediction model

Aerosols are known to significantly affect cloud and precipitation patterns and intensity, but these interactions are ignored or very simplistically handled in climate and numerical weather-prediction (NWP) models. A suite of one-way nested Met Office Unified Model (UM) runs, with a single-moment bulk microphysics scheme was used to study two convective cases with contrasting characteristics observed in southern England. The autoconversion process that converts cloud water to rain is directly controlled by the assumed droplet number. The impact of changing cloud droplet number concentration (CDNC) on cloud and precipitation evolution can be inferred through changes to the autoconversion rate. This was done for a range of resolutions ranging from regional NWP (1 km) to high resolution (up to 100 m grid spacing) to evaluate the uncertainties due to changing CDNC as a function of horizontal grid resolution. The first case is characterised by moderately intense convective showers forming below an upper-level potential vorticity anomaly, with a low freezing level. The second case, characterised by one persistent stronger storm, is warmer with a deeper boundary layer. The colder case is almost insensitive to even large changes in CDNC, while in the warmer case a change of a factor of 3 in assumed CDNC affects total surface rain rate by ~17%. In both cases the sensitivity to CDNC is similar at all grid spacings <1 km. The contrasting sensitivities of these cases are induced by their contrasting ice-phase proportion. The ice processes in this model damp the precipitation sensitivity to CDNC. For this model the convection is sensitive to CDNC when the accretion process is more significant than the melting process and vice versa

Localization of the human homolog of the yeast cell division control 27 gene (CDC27) proximal to ITGB3 on human chromosome 17q21.3

The human homolog of the Saccharomyces cerevisiae cell division control 27 gene (CDC27) was mapped to human chromosome 17q12-q21 using a panel of human/rodent somatic cell hybrids and localized distal to the breast cancer susceptibility gene, BRCA1 , using a panel of radiation hybrids. The radiation hybrid panel indicates that the most likely position of human CDC27 on human chromosome 17 is between the marker D17S409 and the beta 3 subunit of integrin (ITGB3). Further confirmation of this localization comes from the sequence tagged site (STS) mapping of human CDC27 to the same yeast artificial chromosomes (YACs) positive for ITGB3 . The estimated distance between ITGB3 and human CDC27 is less than 600 kb.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/45546/1/11188_2005_Article_BF02257470.pd