The effects of Cstb duplication on APP/amyloid-β pathology and cathepsin B activity in a mouse model

People with Down syndrome (DS), caused by trisomy of chromosome 21 have a greatly increased risk of developing Alzheimer's disease (AD). This is in part because of triplication of a chromosome 21 gene, APP. This gene encodes amyloid precursor protein, which is cleaved to form amyloid-β that accumulates in the brains of people who have AD. Recent experimental results demonstrate that a gene or genes on chromosome 21, other than APP, when triplicated significantly accelerate amyloid-β pathology in a transgenic mouse model of amyloid-β deposition. Multiple lines of evidence indicate that cysteine cathepsin activity influences APP cleavage and amyloid-β accumulation. Located on human chromosome 21 (Hsa21) is an endogenous inhibitor of cathepsin proteases, CYSTATIN B (CSTB) which is proposed to regulate cysteine cathepsin activity in vivo. Here we determined if three copies of the mouse gene Cstb is sufficient to modulate amyloid-β accumulation and cathepsin activity in a transgenic APP mouse model. Duplication of Cstb resulted in an increase in transcriptional and translational levels of Cstb in the mouse cortex but had no effect on the deposition of insoluble amyloid-β plaques or the levels of soluble or insoluble amyloid-β42, amyloid-β40, or amyloid-β38 in 6-month old mice. In addition, the increased CSTB did not alter the activity of cathepsin B enzyme in the cortex of 3-month or 6-month old mice. These results indicate that the single-gene duplication of Cstb is insufficient to elicit a disease-modifying phenotype in the dupCstb x tgAPP mice, underscoring the complexity of the genetic basis of AD-DS and the importance of multiple gene interactions in disease

Periodic magnetorotational dynamo action as a prototype of nonlinear magnetic field generation in shear flows

The nature of dynamo action in shear flows prone to magnetohydrodynamic instabilities is investigated using the magnetorotational dynamo in Keplerian shear flow as a prototype problem. Using direct numerical simulations and Newton's method, we compute an exact time-periodic magnetorotational dynamo solution to the three-dimensional dissipative incompressible magnetohydrodynamic equations with rotation and shear. We discuss the physical mechanism behind the cycle and show that it results from a combination of linear and nonlinear interactions between a large-scale axisymmetric toroidal magnetic field and non-axisymmetric perturbations amplified by the magnetorotational instability. We demonstrate that this large scale dynamo mechanism is overall intrinsically nonlinear and not reducible to the standard mean-field dynamo formalism. Our results therefore provide clear evidence for a generic nonlinear generation mechanism of time-dependent coherent large-scale magnetic fields in shear flows and call for new theoretical dynamo models. These findings may offer important clues to understand the transitional and statistical properties of subcritical magnetorotational turbulence.Comment: 10 pages, 6 figures, accepted for publication in Physical Review

Global bifurcations to subcritical magnetorotational dynamo action in Keplerian shear flow

Magnetorotational dynamo action in Keplerian shear flow is a three-dimensional, non-linear magnetohydrodynamic process whose study is relevant to the understanding of accretion processes and magnetic field generation in astrophysics. Transition to this form of dynamo action is subcritical and shares many characteristics of transition to turbulence in non-rotating hydrodynamic shear flows. This suggests that these different fluid systems become active through similar generic bifurcation mechanisms, which in both cases have eluded detailed understanding so far. In this paper, we build on recent work on the two problems to investigate numerically the bifurcation mechanisms at work in the incompressible Keplerian magnetorotational dynamo problem in the shearing box framework. Using numerical techniques imported from dynamical systems research, we show that the onset of chaotic dynamo action at magnetic Prandtl numbers larger than unity is primarily associated with global homoclinic and heteroclinic bifurcations of nonlinear magnetorotational dynamo cycles. These global bifurcations are found to be supplemented by local bifurcations of cycles marking the beginning of period-doubling cascades. The results suggest that nonlinear magnetorotational dynamo cycles provide the pathway to turbulent injection of both kinetic and magnetic energy in incompressible magnetohydrodynamic Keplerian shear flow in the absence of an externally imposed magnetic field. Studying the nonlinear physics and bifurcations of these cycles in different regimes and configurations may subsequently help to better understand the physical conditions of excitation of magnetohydrodynamic turbulence and instability-driven dynamos in a variety of astrophysical systems and laboratory experiments. The detailed characterization of global bifurcations provided for this three-dimensional subcritical fluid dynamics problem may also prove useful for the problem of transition to turbulence in hydrodynamic shear flows

Reciprocal Effects on Neurocognitive and Metabolic Phenotypes in Mouse Models of 16p11.2 Deletion and Duplication Syndromes.

The 16p11.2 600 kb BP4-BP5 deletion and duplication syndromes have been associated with developmental delay; autism spectrum disorders; and reciprocal effects on the body mass index, head circumference and brain volumes. Here, we explored these relationships using novel engineered mouse models carrying a deletion (Del/+) or a duplication (Dup/+) of the Sult1a1-Spn region homologous to the human 16p11.2 BP4-BP5 locus. On a C57BL/6N inbred genetic background, Del/+ mice exhibited reduced weight and impaired adipogenesis, hyperactivity, repetitive behaviors, and recognition memory deficits. In contrast, Dup/+ mice showed largely opposite phenotypes. On a F1 C57BL/6N × C3B hybrid genetic background, we also observed alterations in social interaction in the Del/+ and the Dup/+ animals, with other robust phenotypes affecting recognition memory and weight. To explore the dosage effect of the 16p11.2 genes on metabolism, Del/+ and Dup/+ models were challenged with high fat and high sugar diet, which revealed opposite energy imbalance. Transcriptomic analysis revealed that the majority of the genes located in the Sult1a1-Spn region were sensitive to dosage with a major effect on several pathways associated with neurocognitive and metabolic phenotypes. Whereas the behavioral consequence of the 16p11 region genetic dosage was similar in mice and humans with activity and memory alterations, the metabolic defects were opposite: adult Del/+ mice are lean in comparison to the human obese phenotype and the Dup/+ mice are overweight in comparison to the human underweight phenotype. Together, these data indicate that the dosage imbalance at the 16p11.2 locus perturbs the expression of modifiers outside the CNV that can modulate the penetrance, expressivity and direction of effects in both humans and mice

PloS one

Down syndrome (DS) results from one extra copy of human chromosome 21 and leads to several alterations including intellectual disabilities and locomotor defects. The transchromosomic Tc1 mouse model carrying an extra freely-segregating copy of human chromosome 21 was developed to better characterize the relation between genotype and phenotype in DS. The Tc1 mouse exhibits several locomotor and cognitive deficits related to DS. In this report we analyzed the contribution of the genetic dosage of 13 conserved mouse genes located between Abcg1 and U2af1, in the telomeric part of Hsa21. We used the Ms2Yah model carrying a deletion of the corresponding interval in the mouse genome to rescue gene dosage in the Tc1/Ms2Yah compound mice to determine how the different behavioral phenotypes are affected. We detected subtle changes with the Tc1/Ms2Yah mice performing better than the Tc1 individuals in the reversal paradigm of the Morris water maze. We also found that Tc1/Ms2Yah compound mutants performed better in the rotarod than the Tc1 mice. This data support the impact of genes from the Abcg1-U2af1 region as modifiers of Tc1-dependent memory and locomotor phenotypes. Our results emphasize the complex interactions between triplicated genes inducing DS features

HENA, heterogeneous network-based data set for Alzheimer's disease.

Alzheimer's disease and other types of dementia are the top cause for disabilities in later life and various types of experiments have been performed to understand the underlying mechanisms of the disease with the aim of coming up with potential drug targets. These experiments have been carried out by scientists working in different domains such as proteomics, molecular biology, clinical diagnostics and genomics. The results of such experiments are stored in the databases designed for collecting data of similar types. However, in order to get a systematic view of the disease from these independent but complementary data sets, it is necessary to combine them. In this study we describe a heterogeneous network-based data set for Alzheimer's disease (HENA). Additionally, we demonstrate the application of state-of-the-art graph convolutional networks, i.e. deep learning methods for the analysis of such large heterogeneous biological data sets. We expect HENA to allow scientists to explore and analyze their own results in the broader context of Alzheimer's disease research

A fast framework construction and visualization method for particle-based fluid

© 2017, The Author(s). Fast and vivid fluid simulation and visualization is a challenge topic of study in recent years. Particle-based simulation method has been widely used in the art animation modeling and multimedia field. However, the requirements of huge numerical calculation and high quality of visualization usually result in a poor computing efficiency. In this work, in order to improve those issues, we present a fast framework for 3D fluid fast constructing and visualization which parallelizes the fluid algorithm based on the GPU computing framework and designs a direct surface visualization method for particle-based fluid data such as WCSPH, IISPH, and PCISPH. Considering on conventional polygonization or adaptive mesh methods may incur high computing costs and detail losses, an improved particle-based method is provided for real-time fluid surface rendering with the screen-space technology and the utilities of the modern graphics hardware to achieve the high performance rendering; meanwhile, it effectively protects fluid details. Furthermore, to realize the fast construction of scenes, an optimized design of parallel framework and interface is also discussed in our paper. Our method is convenient to enforce, and the results demonstrate a significant improvement in the performance and efficiency by being compared with several examples

The impact of Oportunidades on human capital and income distribution in Mexico: A top-down/bottom-up approach

This paper sets a computable general equilibrium model for the Mexican economy and a behavioural microsimulation model for Mexico's Oportunidades social transfers, and links the models in a bi-directional and iterative way. The model results suggest that partial equilibrium analysis may underestimate the effects of the program. Extending the coverage of the program leads to a significant increase in school attendance, which lowers labour supply and increases the equilibrium wages of the children who remain at work. The general equilibrium effect indirectly reduces income inequality and poverty at the national level

EMMA—mouse mutant resources for the international scientific community

The laboratory mouse is the premier animal model for studying human disease and thousands of mutants have been identified or produced, most recently through gene-specific mutagenesis approaches. High throughput strategies by the International Knockout Mouse Consortium (IKMC) are producing mutants for all protein coding genes. Generating a knock-out line involves huge monetary and time costs so capture of both the data describing each mutant alongside archiving of the line for distribution to future researchers is critical. The European Mouse Mutant Archive (EMMA) is a leading international network infrastructure for archiving and worldwide provision of mouse mutant strains. It operates in collaboration with the other members of the Federation of International Mouse Resources (FIMRe), EMMA being the European component. Additionally EMMA is one of four repositories involved in the IKMC, and therefore the current figure of 1700 archived lines will rise markedly. The EMMA database gathers and curates extensive data on each line and presents it through a user-friendly website. A BioMart interface allows advanced searching including integrated querying with other resources e.g. Ensembl. Other resources are able to display EMMA data by accessing our Distributed Annotation System server. EMMA database access is publicly available at http://www.emmanet.org