Dysregulation of Na+/K+ ATPase by amyloid in APP+PS1 transgenic mice

Background  

The pathology of Alzheimer's disease (AD) is comprised of extracellular amyloid plaques, intracellular tau tangles, dystrophic neurites and neurodegeneration. The mechanisms by which these various pathological features arise are under intense investigation. Here, expanding upon pilot gene expression studies, we have further analyzed the relationship between Na+/K+ ATPase and amyloid using APP+PS1 transgenic mice, a model that develops amyloid plaques and memory deficits in the absence of tangle formation and neuronal or synaptic loss.     

Tissue-specific and neural activity-regulated expression of human BDNF gene in BAC transgenic mice

Background  

Brain-derived neurotrophic factor (BDNF) is a small secreted protein that has important roles in the developing and adult nervous system. Altered expression or changes in the regulation of the BDNF gene have been implicated in a variety of human nervous system disorders. Although regulation of the rodent BDNF gene has been extensively investigated, in vivo studies regarding the human BDNF gene are largely limited to postmortem analysis. Bacterial artificial chromosome (BAC) transgenic mice harboring the human BDNF gene and its regulatory flanking sequences constitute a useful tool for studying human BDNF gene regulation and for identification of therapeutic compounds modulating BDNF expression.     

Cocaine reward and locomotion stimulation in mice with reduced dopamine transporter expression

Background  

The dopamine transporter (DAT) plays a critical role in regulating dopamine neurotransmission. Variations in DAT or changes in basal dopaminergic tone have been shown to alter behavior and drug responses. DAT is one of the three known high affinity targets for cocaine, a powerful psychostimulant that produces reward and stimulates locomotor activity in humans and animals. We have shown that cocaine no longer produces reward in knock-in mice with a cocaine insensitive mutant DAT (DAT-CI), suggesting that cocaine inhibition of DAT is critical for its rewarding effect. However, in DAT-CI mice, the mutant DAT has significantly reduced uptake activity resulting in elevated basal dopaminergic tone, which might cause adaptive changes that alter responses to cocaine. Therefore, the objective of this study is to determine how elevated dopaminergic tone affects how mice respond to cocaine.     

Genetically-increased taste cell population with Gα-gustducin-coupled sweet receptors is associated with increase of gurmarin-sensitive taste nerve fibers in mice

Background  

The peptide gurmarin is a selective sweet response inhibitor for rodents. In mice, gurmarin sensitivity differs among strains with gurmarin-sensitive C57BL and gurmarin-poorly-sensitive BALB strains. In C57BL mice, sweet-responsive fibers of the chorda tympani (CT) nerve can be divided into two distinct populations, gurmarin-sensitive (GS) and gurmarin-insensitive (GI) types, suggesting the existence of two distinct reception pathways for sweet taste responses. By using the dpa congenic strain (dpa CG) whose genetic background is identical to BALB except that the gene(s) controlling gurmarin sensitivity are derived from C57BL, we previously found that genetically-elevated gurmarin sensitivity in dpa CG mice, confirmed by using behavioral response and whole CT nerve response analyses, was linked to a greater taste cell population co-expressing sweet taste receptors and a Gα protein, Gα-gustducin. However, the formation of neural pathways from the increased taste cell population to nerve fibers has not yet been examined.     

Phase diagrams of quasispecies theory with recombination and horizontal gene transfer

We consider how transfer of genetic information between individuals influences the phase diagram and mean fitness of both the Eigen and the parallel, or Crow-Kimura, models of evolution. In the absence of genetic transfer, these physical models of evolution consider the replication and point mutation of the genomes of independent individuals in a large population. A phase transition occurs, such that below a critical mutation rate an identifiable quasispecies forms. We show how transfer of genetic information changes the phase diagram and mean fitness and introduces metastability in quasispecies theory, via an analytic field theoretic mapping.     

The genetic control of neocortex volume and covariation with neocortical gene expression in mice

Background  

The size of the cerebral cortex varies widely within human populations, and a large portion of this variance is modulated by genetic factors. The discovery and characterization of these genes and their variants can contribute to an understanding of individual differences in brain development, behavior, and disease susceptibility. Here we use unbiased stereological techniques to map quantitative trait loci (QTLs) that modulate the volume of neocortex.     

Characterization of Fe,Cu and Zn in organs of PDAPP transgenic mice by XRF spectrometry

A large body of evidence indicates that abnormalities in the levels of iron, copper and zinc and their metabolism are associated with neurodegenerative diseases. However, it is difficult to decide whether any observed changes of trace elements reflect the primary disease process or are secondary to a primary process or mechanism. In the present study, Fe, Cu and Zn in organs of transgenic mice which express the familial Alzheimer's disease (AD) gene and normal mice of the same species and ages were determined by X‐ray fluorescence (XRF) spectrometry. The results show that Fe concentrations in a variety of organs and tissues were significantly increased whereas Zn concentrations decreased in the transgenic mice as compared with the ‘normals’. The levels of Cu in transgenic mice were also altered. Data obtained in the present study suggest that expression of the familial AD gene in mice results in altered homeostasis of Fe, Cu and Zn in organs of the animals, which may in turn accelerate the process of neurodegeneration. Copyright © 2006 John Wiley & Sons, Ltd.     

The behavioral response of mice to gaps in noise depends on its spectral components and its bandwidth

The purpose of these experiments was to determine whether detecting brief decrements in noise level ("gaps") varies with the spectral content and bandwidth of noise in mice as it does in humans. The behavioral effect of gaps was quantified by their inhibiting a subsequent acoustic startle reflex. Gap durations from 1 to 29 ms were presented in five adjacent 1-octave noise bands and one 5-octave band, their range being 2 kHz to 64 kHz. Gaps ended 60 ms before the startle stimulus (experiment 1) or at startle onset (experiment 2). Asymptotic inhibition was greater for higher-frequency 1-octave bands and highest for the 5-octave band in both experiments, but time constants were related to frequency only in experiment 1. For the lowest band (2-4 kHz) neither noise decrements (experiment 1 and 2) nor increments (experiment 3) had any behavioral consequence, but this band was effective when presented as a pulse in quiet (experiment 4). The lowest frequencies in the most effective 1-octave band were one octave above the spectral region where mice have their best absolute thresholds. These effects are similar to those obtained in humans, and reveal a special contribution of wide band, high-frequency stimulation to temporal acuity.     

Assessment of health risk associated with natural gamma dose rate levels and isodose mapping of Jordan

ABSTRACT

As a pioneering study in Jordan, an extensive measurement for external gamma dose rate (GDR) was conducted. A portable gamma radiation detector was used to perform these measurements at 1?m above the soil surface. A geographical positioning system Garmin was used to record a total of 823 measured points. The GDRs’ measurement ranged from 35 to 470?nGy?h^?1 giving a mean value of 90?nGy?h^?1, which was found to be one and half times higher than the world average of 59?nGy?h^?1. The lowest mean GDR 72?nGy?h^?1 was found in the Albalqa governate, while the highest mean GDR 131?nGy?h^?1 was found to be for the Alkarak governate. The mean annual effective dose was found to be 0.551?mSv, which is higher than the world average value of 0.48?mSv. This is a pivotal study evaluating the risks associated with GDR levels in Jordan that were the relative excess lifetime cancer risk, the mean collective effective dose, the mean weighted GDR and the mean lifetime dose that are 2.24?×?10^?3, 5538manSv?y^?1, 0.531?mSv and 39?mSv, respectively. The cosmic rays mean GDR was determined to be 20?nGy?h^?1. This study focuses on constructing GDRs’ baseline data in Jordan, which will be used to determine the possible change in the natural radiation due to other human activities in the future. ArcGIS software was employed to generate an isodose map to characterise exposure rates caused by GDR in Jordan.     

Anti-depressant and anxiolytic like behaviors in PKCI/HINT1 knockout mice associated with elevated plasma corticosterone level

Background  

Protein kinase C interacting protein (PKCI/HINT1) is a small protein belonging to the histidine triad (HIT) family proteins. Its brain immunoreactivity is located in neurons and neuronal processes. PKCI/HINT1 gene knockout (KO) mice display hyper-locomotion in response to D-amphetamine which is considered a positive symptom of schizophrenia in animal models. Postmortem studies identified PKCI/HINT1 as a candidate molecule for schizophrenia and bipolar disorder. We investigated the hypothesis that the PKCI/HINT1 gene may play an important role in regulating mood function in the CNS. We submitted PKCI/HINT1 KO mice and their wild type (WT) littermates to behavioral tests used to study anti-depressant, anxiety like behaviors, and goal-oriented behavior. Additionally, as many mood disorders coincide with modifications of hypothalamic-pituitary-adrenal (HPA) axis function, we assessed the HPA activity through measurement of plasma corticosterone levels.     

Formation of leptofibrils is associated with remodelling of muscle cells and myofibrillogenesis in the border zone of myocardial infarction

Leptofibrils, or leptomeres, remain the least studied cytoskeletal structures in muscle cells, and their function and mechanism of assembly are still poorly understood. Our ultrastructural study of the surviving cardiac myocytes located in the perinecrotic border zone of the infarcted left ventricle in rats revealed intense formation of leptofibrils and leptofibrillar clusters during 4-15 days following experimental myocardial infarction. In the perinecrotic myocytes, leptofibrils developed predominantly in the subsarcolemmal areas, near disassembled intercalated discs and at the sites of intense myofibrillogenesis in the peripheral zones of the sarcoplasm. We found that the development of these structures occurred before or at the time of assembly of myofibrils. In our material, leptofibrils consisted of longitudinally oriented filamentous bundles inserted in electron dense Z-band-like material and periodically crossed by 3-8 bands of this material with the period of cross-striation of 120-210 nm. The presence of leptofibrils in growing cytoplasmic processes and ruffles developing in the border zone in the areas of lost intercellular contacts indicates their formation de novo during post-infarction period. We observed four major morphological types of localization of these structures: (1) direct contact of one end of leptofibrils with Z bands of nascent, mature or disassembling myofibrils; (2) direct contact with the sarcolemma: (a) multifocal attachment of leptofibrils to the sarcolemma through the lateral surfaces of their minute Z band-like structures; (b) attachment of one or both ends of leptofibrils to the sarcolemma without contacts or in contact with myofibrils; (3) attachment of leptofibrils to subsarcolemmal accumulations of electron dense Z-band material in newly formed fasciae adherentes of the remodeled intercalated disks; (4) clustering and contacts of leptofibrils with one another predominantly at the level of their Z bands. Interestingly, most leptofibrils of all four types were topographically associated with the system of T-tubules, the sarcoplasmic reticulum and subsarcolemmal vesicles. Serial sections through the areas containing leptofibrils indicate their spindle-like or nearly cylindrical shape. Thus, we found that leptofibrils assemble in terminally differentiated cardiac myocytes following destabilization of their differentiated state and partial dedifferentiation induced by myocardial infarction. The results of this study demonstrate that formation of leptofibrils, earlier described mainly in the developing and malignant muscle, is temporally associated with adaptive structural remodelling and the activation of myofibrillogenesis in functionally overloaded cardiac myocytes of adult animals. Our findings suggest that re-expression of some structural characteristics of the embryonic muscle appear to represent one of the mechanisms that underlie adaptive plasticity of the myocardium following injury and under conditions of hyperfunction.     

Airy传递矩阵法与偏压下多势垒结构的准束缚能级

使用Airy函数和传递矩阵方法精确计算了一维定态薛定谔方程，并推广到多势垒结构，求解出有/无偏压作用的2,3势垒结构的准束缚能级，进一步研究了有/无偏压作用的2,3势垒结构的准束缚能级与有效质量和外加电压的关系，并对结论的正确性进行了验证． 另外，文中 还指出了有些文章中关于Airy传递矩阵法与计算偏压下多势垒结构的准束缚能级的错误陈述 . 关键词： 准束缚能级 有/无偏压作用的多势垒结构 Airy函数 透射系数     

Generation of spin currents and spin densities in systems with reduced symmetry

We show that the spin-current response of a semiconductor crystal to an external electric field is considerably more complex than previously assumed. While in systems of high symmetry only the spin-Hall components are allowed, in systems of lower symmetry other non-spin-Hall components may be present. We argue that, when spin-orbit interactions are present only in the band structure, the distinction between intrinsic and extrinsic contributions to the spin current is not useful. We show that the generation of spin currents and that of spin densities in an electric field are closely related, and that our general theory provides a systematic way to distinguish between them in experiment. We discuss also the meaning of vertex corrections in systems with spin-orbit interactions.     

Dyskinesia and brain-derived neurotrophic factor levels after long-term levodopa and nicotinic receptor agonist treatments in female mice with near-total unilateral dopaminergic denervation

Background

The treatment of Parkinson’s disease is often complicated by levodopa-induced dyskinesia (LID). Nicotinic acetylcholine receptor agonists can alleviate LID in animal models but may be less effective in conditions of severe dopaminergic denervation. While the mechanisms of LID remain incompletely understood, elevated corticostriatal levels of the brain-derived neurotrophic factor (BDNF) have been suggested to play a role. Here, female mice with near-total unilateral 6-hydroxydopamine-induced nigrostriatal lesions were chronically treated with levodopa, and the effects of the α7 nicotinic receptor partial agonist AZD0328 and nicotine on LID were assessed. At the end of the experiment, BDNF protein levels in the prefrontal cortex and striatum were measured.

Results

Five-day treatments with three escalating doses of AZD0328 and a 10-week treatment with nicotine failed to alleviate LID. BDNF levels in the lesioned striatum correlated positively with LID severity, but no evidence was found for a levodopa-induced elevation of corticostriatal BDNF in the lesioned hemisphere. The nicotine treatment decreased BDNF levels in the prefrontal cortex but had no effect on striatal BDNF.

Conclusions

The findings suggest that treatment of LID with nicotinic agonists may lose its effectiveness as the disease progresses, represent further evidence for a role for BDNF in LID, and expand previous knowledge on the effects of long-term nicotine treatment on BDNF.

     

Aging is associated with increased collagen type IV accumulation in the basal lamina of human cerebral microvessels

Background  

Microvascular alterations contribute to the development of stroke and vascular dementia. The goal of this study was to evaluate age and hypertension related changes of the basal lamina in cerebral microvessels of individuals, who died from non-cerebral causes.