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Sample records for ad model mice

  1. Small molecule LX2343 ameliorates cognitive deficits in AD model mice by targeting both amyloid β production and clearance

    PubMed Central

    Guo, Xiao-dan; Sun, Guang-long; Zhou, Ting-ting; Xu, Xin; Zhu, Zhi-yuan; Rukachaisirikul, Vatcharin; Hu, Li-hong; Shen, Xu

    2016-01-01

    Aim: Streptozotocin (STZ) is widely used to induce oxidative damage and to impair glucose metabolism, apoptosis, and tau/Aβ pathology, eventually leading to cognitive deficits in both in vitro and in vivo models of Alzheimer's disease (AD). In this study, we constructed a cell-based platform using STZ to induce stress conditions mimicking the complicated pathologies of AD in vitro, and evaluated the anti-amyloid effects of a small molecule, N-(1,3-benzodioxol-5-yl)-2-[5-chloro-2-methoxy(phenylsulfonyl)anilino]acetamide (LX2343) in the amelioration of cognitive deficits in AD model mice. Methods: Cell-based assays for screening anti-amyloid compounds were established by assessing Aβ accumulation in HEK293-APPsw and CHO-APP cells, and Aβ clearance in primary astrocytes and SH-SY5Y cells after the cells were treated with STZ in the presence of the test compounds. Autophagic flux was observed using confocal laser scanning microscopy. APP/PS1 transgenic mice were administered LX2343 (10 mg·kg−1·d−1, ip) for 100 d. After LX2343 administration, cognitive ability of the mice was evaluated using Morris water maze test, and senile plaques in the brains were detected using Thioflavine S staining. ELISA assay was used to evaluate Aβ and sAPPβ levels, while Western blot analysis was used to measure the signaling proteins in both cell and animal brains. Results: LX2343 (5–20 μmol/L) dose-dependently decreased Aβ accumulation in HEK293-APPsw and CHO-APP cells, and promoted Aβ clearance in SH-SY5Y cells and primary astrocytes. The anti-amyloid effects of LX2343 were attributed to suppressing JNK-mediated APPThr668 phosphorylation, thus inhibiting APP cleavage on one hand, and inhibiting BACE1 enzymatic activity with an IC50 value of 11.43±0.36 μmol/L, on the other hand. Furthermore, LX2343 acted as a non-ATP competitive PI3K inhibitor to negatively regulate AKT/mTOR signaling, thus promoting autophagy, and increasing Aβ clearance. Administration of LX2343 in APP

  2. Sex steroid levels and AD-like pathology in 3xTgAD mice.

    PubMed

    Overk, C R; Perez, S E; Ma, C; Taves, M D; Soma, K K; Mufson, E J

    2013-02-01

    Decreases in testosterone and 17β-oestradiol (E(2)) are associated with an increased risk for Alzheimer's disease (AD), which has been attributed to an increase in β-amyloid and tau pathological lesions. Although recent studies have used transgenic animal models to test the effects of sex steroid manipulations on AD-like pathology, almost none have systematically characterised the associations between AD lesions and sex steroid levels in the blood or brain in any mutant model. The present study evaluated age-related changes in testosterone and E(2) concentrations, as well as androgen receptor (AR) and oestrogen receptor (ER) α and β expression, in brain regions displaying AD pathology in intact male and female 3xTgAD and nontransgenic (ntg) mice. We report for the first time that circulating and brain testosterone levels significantly increase in male 3xTgAD mice with age, but without changes in AR-immunoreactive (IR) cell number in the hippocampal CA1 or medial amygdala. The age-related increase in hippocampal testosterone levels correlated positively with increases in the conformational tau isoform, Alz50. These data suggest that the over-expression of human tau up-regulate the hypothalamic-pituitary-gonadal axis in these mice. Although circulating and brain E(2) levels remained stable with age in both male and female 3xTgAD and ntg mice, ER-IR cell number in the hippocampus and medial amygdala decreased with age in female transgenic mice. Furthermore, E(2) levels were significantly higher in the hippocampus than in serum, suggesting local production of E(2). Although triple transgenic mice mimic AD-like pathology, they do not fully replicate changes in human sex steroid levels, and may not be the best model for studying the effects of sex steroids on AD lesions.

  3. Cholinotrophic basal forebrain system alterations in 3xTg-AD transgenic mice.

    PubMed

    Perez, Sylvia E; He, Bin; Muhammad, Nadeem; Oh, Kwang-Jin; Fahnestock, Margaret; Ikonomovic, Milos D; Mufson, Elliott J

    2011-02-01

    The cholinotrophic system, which is dependent upon nerve growth factor and its receptors for survival, is selectively vulnerable in Alzheimer's disease (AD). But, virtually nothing is known about how this deficit develops in relation to the hallmark lesions of this disease, amyloid plaques and tau containing neurofibrillary tangles. The vast majority of transgenic models of AD used to evaluate the effect of beta amyloid (Aβ) deposition upon the cholinotrophic system over-express the amyloid precursor protein (APP). However, nothing is known about how this system is affected in triple transgenic (3xTg)-AD mice, an AD animal model displaying Aβ plaque- and tangle-like pathology in the cortex and hippocampus, which receive extensive cholinergic innervation. We performed a detailed morphological and biochemical characterization of the cholinotrophic system in young (2-4 months), middle-aged (13-15 months) and old (18-20 months) 3xTg-AD mice. Cholinergic neuritic swellings increased in number and size with age, and were more conspicuous in the hippocampal-subicular complex in aged female than in 3xTg-AD male mice. Stereological analysis revealed a reduction in choline acetyltransferase (ChAT) positive cells in the medial septum/vertical limb of the diagonal band of Broca in aged 3xTg-AD mice. ChAT enzyme activity levels decreased significantly in the hippocampus of middle-aged 3xTg-AD mice compared to age-matched non-transgenic (or wild type) mice. ProNGF protein levels increased in the cortex of aged 3xTg-AD mice, whereas TrkA protein levels were reduced in a gender-dependent manner in aged mutant mice. In contrast, p75(NTR) protein cortical levels were stable but increased in the hippocampus of aged 3xTg-AD mice. These data demonstrate that cholinotrophic alterations in 3xTg-AD mice are age- and gender-dependent and more pronounced in the hippocampus, a structure more severely affected by Aβ plaque pathology. PMID:20937383

  4. Tanshinone IIA Alleviates the AD Phenotypes in APP and PS1 Transgenic Mice

    PubMed Central

    Li, Fengling; Han, Guosheng; Wu, Kexiang

    2016-01-01

    Therapeutic approach for Alzheimer's disease (AD) is still deficient. To find active compounds from herbal medicine is of interest in the alleviation of AD symptoms. This study aimed to investigate the protective effects of Tanshinone IIA (TIIA) on memory performance and synaptic plasticity in a transgenic AD model at the early phase. 25–100 mg/kg TIIA (intraperitoneal injection, i.p.) was administered to the six-month-old APP and PS1 transgenic mice for 30 consecutive days. After treatment, spatial memory, synaptic plasticity, and related mechanisms were investigated. Our result showed that memory impairment in AD mice was mitigated by 50 and 100 mg/kg TIIA treatments. Hippocampal long-term potentiation was impaired in AD model but rescued by 100 mg/kg TIIA treatment. Mechanically, TIIA treatment reduced the accumulations of beta-amyloid 1–42, C-terminal fragments (CTFs), and p-Tau in the AD model. TIIA did not affect basal BDNF but promoted depolarization-induced BDNF synthesis in the AD mice. Taken together, TIIA repairs hippocampal LTP and memory, likely, through facilitating the clearance of AD-related proteins and activating synaptic BDNF synthesis. TIIA might be a candidate drug for AD treatment. PMID:27274990

  5. Influence of Genetic Background on Apathy-Like Behavior in Triple Transgenic AD Mice.

    PubMed

    Pardossi-Piquard, R; Lauritzen, I; Bauer, C; Sacco, G; Robert, P; Checler, F

    2016-01-01

    Apathy is an early and common neuropsychiatric syndrome in Alzheimer's disease (AD) patients. In clinical trials, apathy is associated with decreased motor activity that can be monitored by actigraphy. The triple transgenic mouse AD model (3xTgAD) has been shown to recapitulate the biochemical lesions as well as many of the synaptic and cognitive alterations associated with AD. In the present work we found that these mice also develop an early and consistent apathy-like behavior as evidenced by a drastic decrease in spontaneous activity measured by actimetry. We recently established that these mice also display an intraneuronal accumulation of the β-secretase-derived βAPP fragment (C99) appearing early, in absence of Aβ. Interestingly, we found that the apathy-like behavior observed in 3xTgAD mice was temporally associated with C99 accumulation and synaptic alterations. Since it is well known that the genetic background can strongly influence behavior and can induce transcriptional variability in animal models, we decided to determine the influence of genetic background on the above-described alterations. We backcrossed 3xTgAD mice to C57BL/6 and found that the genetic background had no influence on either C99 accumulation or synaptic plasticity alterations, but strongly affected the apathy-like behavior. PMID:27040141

  6. Aromatase Expression in the Hippocampus of AD Patients and 5xFAD Mice

    PubMed Central

    Prange-Kiel, Janine; Dudzinski, Danuta A.; Pröls, Felicitas; Glatzel, Markus; Matschke, Jakob; Rune, Gabriele M.

    2016-01-01

    Numerous studies show that 17β-estradiol (E2) protects against Alzheimer's disease (AD) induced neurodegeneration. The E2-synthesizing enzyme aromatase is expressed in healthy hippocampi, but although the hippocampus is severely affected in AD, little is known about the expression of hippocampal aromatase in AD. To better understand the role of hippocampal aromatase in AD, we studied its expression in postmortem material from patients with AD and in a mouse model for AD (5xFAD mice). In human hippocampi, aromatase-immunoreactivity was observed in the vast majority of principal neurons and signal quantification revealed higher expression of aromatase protein in AD patients compared to age- and sex-matched controls. The tissue-specific first exons of aromatase I.f, PII, I.3, and I.6 were detected in hippocampi of controls and AD patients by RT-PCR. In contrast, 3-month-old, female 5xFAD mice showed lower expression of aromatase mRNA and protein (measured by qRT-PCR and semiquantitative immunohistochemistry) than WT controls; no such differences were observed in male mice. Our findings stress the importance of hippocampal aromatase expression in neurodegenerative diseases. PMID:27298742

  7. Impairment of nesting behaviour in 3xTg-AD mice.

    PubMed

    Torres-Lista, Virginia; Giménez-Llort, Lydia

    2013-06-15

    Deterioration in executive functions and daily life activities (DLA) are early signs of Alzheimer's disease (AD) that signal the need for caregiver attention. We have addressed this issue in the 3xTg-AD mice model for AD and studied nesting behaviour as a natural DLA of parental structures as well as at early- (6 month-old) and advanced-stages (12 month-old) of the disease in isolated animals. The results show genetic, gender and age-dependent impairment of nesting behaviour but also aware about the relevance of factors such as the temporal course of nest construction and the nesting material. Paper towel consistently showed the impairment of nesting behavior in 3xTg-AD mice since early stages of the disease and in both social conditions. Their nest construction was slow temporal pattern and of poor quality, especially in females and advanced stages of the disease where the deficits were shown from the first day. In all cases, cotton elicited an intense behaviour that lead to perfect nesting during the first 48 h. Genotype, gender and age differences were found in the onset of nesting behaviour, with a time delay in the 3xTg-AD mice, particularly in females. The reported impairment of nesting behaviour in 3xTg-AD provides another behavioral tool to assess the benefits of preventive and/or therapeutic strategies, as well as the potential action of risk factors of AD, in this animal model. PMID:23523959

  8. 3xTgAD mice exhibit altered behavior and elevated Aβ after chronic mild social stress

    PubMed Central

    Rothman, Sarah M.; Herdener, Nathan; Camandola, Simonetta; Texel, Sarah J.; Mughal, Mohamed R.; Cong, Wei-Na; Martin, Bronwen; Mattson, Mark P

    2014-01-01

    Chronic stress may be a risk factor for developing Alzheimer’s disease (AD), but most studies of the effects of stress in models of AD utilize acute adverse stressors of questionable clinical relevance. The goal of this work was to determine how chronic psychosocial stress affects behavioral and pathological outcomes in an animal model of AD, and to elucidate underlying mechanisms. A triple-transgenic mouse model of AD (3xTgAD mice) and nontransgenic control mice were used to test for an affect of chronic mild social stress on blood glucose, plasma glucocorticoids, plasma insulin, anxiety and hippocampal Aβ, ptau and BDNF levels. Despite the fact that both control and 3xTgAD mice experienced rises in corticosterone during episodes of mild social stress, at the end of the 6 week stress period 3xTgAD mice displayed increased anxiety, elevated levels of Aβ oligomers and intraneuronal Aβ, and decreased BDNF levels, whereas control mice did not. Findings suggest 3xTgAD mice are more vulnerable than control mice to chronic psychosocial stress, and that such chronic stress exacerbates Aβ accumulation and impairs neurotrophic signaling. PMID:21855175

  9. Alterations in synaptic plasticity coincide with deficits in spatial working memory in presymptomatic 3xTg-AD mice.

    PubMed

    Clark, Jason K; Furgerson, Matthew; Crystal, Jonathon D; Fechheimer, Marcus; Furukawa, Ruth; Wagner, John J

    2015-11-01

    Alzheimer's disease is a neurodegenerative condition believed to be initiated by production of amyloid-beta peptide, which leads to synaptic dysfunction and progressive memory loss. Using a mouse model of Alzheimer's disease (3xTg-AD), an 8-arm radial maze was employed to assess spatial working memory. Unexpectedly, the younger (3month old) 3xTg-AD mice were as impaired in the spatial working memory task as the older (8month old) 3xTg-AD mice when compared with age-matched NonTg control animals. Field potential recordings from the CA1 region of slices prepared from the ventral hippocampus were obtained to assess synaptic transmission and capability for synaptic plasticity. At 3months of age, the NMDA receptor-dependent component of LTP was reduced in 3xTg-AD mice. However, the magnitude of the non-NMDA receptor-dependent component of LTP was concomitantly increased, resulting in a similar amount of total LTP in 3xTg-AD and NonTg mice. At 8months of age, the NMDA receptor-dependent LTP was again reduced in 3xTg-AD mice, but now the non-NMDA receptor-dependent component was decreased as well, resulting in a significantly reduced total amount of LTP in 3xTg-AD compared with NonTg mice. Both 3 and 8month old 3xTg-AD mice exhibited reductions in paired-pulse facilitation and NMDA receptor-dependent LTP that coincided with the deficit in spatial working memory. The early presence of this cognitive impairment and the associated alterations in synaptic plasticity demonstrate that the onset of some behavioral and neurophysiological consequences can occur before the detectable presence of plaques and tangles in the 3xTg-AD mouse model of Alzheimer's disease.

  10. Gender differences of peripheral plasma and liver metabolic profiling in APP/PS1 transgenic AD mice.

    PubMed

    Wu, Junfang; Fu, Bin; Lei, Hehua; Tang, Huiru; Wang, Yulan

    2016-09-22

    Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive cognitive impairment. Currently, there is less knowledge of the involvement of the peripheral biofluid/organ in AD, compared with the central nervous system. In addition, with reported high morbidity in women in particular, it has become very important to explore whether gender difference in the peripheral metabolome is associated with AD. Here, we investigated metabolic responses of both plasma and liver tissues using an APP/PS1 double mutant transgenic mouse model with NMR spectroscopy, as well as analysis from serum biochemistry and histological staining. Fatty acid composition from plasma and liver extracts was analyzed using GC-FID/MS. We found clear gender differences in AD transgenic mice when compared with their wild-type counterparts. Female AD mice displayed more intensive responses, which were highlighted by higher levels of lipids, 3-hydroxybutyrate and nucleotide-related metabolites, together with lower levels of glucose. These observations indicate that AD induces oxidative stress and impairs cellular energy metabolism in peripheral organs. Disturbances in AD male mice were milder with depletion of monounsaturated fatty acids. We also observed a higher activity of delta-6-desaturate and suppressed activity of delta-5-desaturate in female mice, whereas inhibited stearoyl-CoA-desaturase in male mice suggested that AD induced by the double mutant genes results in different fatty acids catabolism depending on gender. Our results provide metabolic clues into the peripheral biofluid/organs involved in AD, and we propose that a gender-specific scheme for AD treatment in men and women may be required. PMID:27393253

  11. PAK Inactivation Impairs Social Recognition in 3xTg-AD Mice without Increasing Brain Deposition of Tau and Aβ

    PubMed Central

    Arsenault, Dany; Dal-Pan, Alexandre; Tremblay, Cyntia; Bennett, David A.; Guitton, Matthieu J.; De Koninck, Yves; Tonegawa, Susumu

    2013-01-01

    Defects in p21-activated kinase (PAK) are suspected to play a role in cognitive symptoms of Alzheimer's disease (AD). Dysfunction in PAK leads to cofilin activation, drebrin displacement from its actin-binding site, actin depolymerization/severing, and, ultimately, defects in spine dynamics and cognitive impairment in mice. To determine the role of PAK in AD, we first quantified PAK by immunoblotting in homogenates from the parietal neocortex of subjects with a clinical diagnosis of no cognitive impairment (n = 12), mild cognitive impairment (n = 12), or AD (n = 12). A loss of total PAK, detected in the cortex of AD patients (−39% versus controls), was correlated with cognitive impairment (r2 = 0.148, p = 0.027) and deposition of total and phosphorylated tau (r2 = 0.235 and r2 = 0.206, respectively), but not with Aβ42 (r2 = 0.056). Accordingly, we found a decrease of total PAK in the cortex of 12- and 20-month-old 3xTg-AD mice, an animal model of AD-like Aβ and tau neuropathologies. To determine whether PAK dysfunction aggravates AD phenotype, 3xTg-AD mice were crossed with dominant-negative PAK mice. PAK inactivation led to obliteration of social recognition in old 3xTg-AD mice, which was associated with a decrease in cortical drebrin (−25%), but without enhancement of Aβ/tau pathology or any clear electrophysiological signature. Overall, our data suggest that PAK decrease is a consequence of AD neuropathology and that therapeutic activation of PAK may exert symptomatic benefits on high brain function. PMID:23804095

  12. Fitting Value-Added Models in R

    ERIC Educational Resources Information Center

    Doran, Harold C.; Lockwood, J. R.

    2006-01-01

    Value-added models of student achievement have received widespread attention in light of the current test-based accountability movement. These models use longitudinal growth modeling techniques to identify effective schools or teachers based upon the results of changes in student achievement test scores. Given their increasing popularity, this…

  13. Equine strangles modelled in mice.

    PubMed

    Chanter, N; Smith, K C; Mumford, J A

    1995-02-01

    Small animal models of Streptococcus equi infection have been confined to parenteral injection of mice which subsequently develop a septicaemia. To devise a model of infection more closely resembling strangles, 4.9 x 10(6) cfu of S. equi were placed on the nares of C3H and Balb/c mice (fifteen of each). Compared with ten uninfected controls, infected mice sneezed more often and their daily weight gain was significantly reduced. Histopathological examination seven days after infection revealed varying degrees of nasopharyngeal and regional lymphoid pathology in twenty two mice. Eleven mice had an early or mild rhinitis in which the nasal epithelium presented microabscesses containing polymorphonuclear leucocytes. Another eleven mice had a suppurative rhinitis or pharyngitis associated in most with regional lymphadenitis; in two mice, abscessated lymph nodes had erupted into perinodal connective tissues. Two mice had a vestibular abscess. The suppurative rhinitis was associated with extensive necrosis of nasal propria which occasionally extended to conchal bone, resulting in osteomyelitis. Multiple bacterial abscesses were seen in the spleen of one mouse. Histological lesions were not detected in control mice or in eight infected mice. S. equi was re-isolated from the nares of fourteen of the twenty two affected mice but not from the eight unaffected challenged mice or control mice. The close resemblance of this model to strangles in horses may justify its further use for the investigation of pathogenesis and protective immunity.

  14. AdS5×S(5) mirror model as a string sigma model.

    PubMed

    Arutyunov, Gleb; van Tongeren, Stijn J

    2014-12-31

    Doing a double Wick rotation in the world sheet theory of the light cone AdS5×S(5) superstring results in an inequivalent, so-called mirror theory that plays a central role in the field of integrability in the AdS-CFT correspondence. We show that this mirror theory can be interpreted as the light cone theory of a free string on a different background. This background is related to dS5×H(5) by a double T-duality, and has hidden supersymmetry. The geometry can also be extracted from an integrable deformation of the AdS5×S(5) sigma model, and we prove the observed mirror duality of these deformed models at the bosonic level as a byproduct. While we focus on AdS5×S(5), our results apply more generally. PMID:25615306

  15. AdS5×S(5) mirror model as a string sigma model.

    PubMed

    Arutyunov, Gleb; van Tongeren, Stijn J

    2014-12-31

    Doing a double Wick rotation in the world sheet theory of the light cone AdS5×S(5) superstring results in an inequivalent, so-called mirror theory that plays a central role in the field of integrability in the AdS-CFT correspondence. We show that this mirror theory can be interpreted as the light cone theory of a free string on a different background. This background is related to dS5×H(5) by a double T-duality, and has hidden supersymmetry. The geometry can also be extracted from an integrable deformation of the AdS5×S(5) sigma model, and we prove the observed mirror duality of these deformed models at the bosonic level as a byproduct. While we focus on AdS5×S(5), our results apply more generally.

  16. Value-Added Modeling in Physical Education

    ERIC Educational Resources Information Center

    Hushman, Glenn; Hushman, Carolyn

    2015-01-01

    The educational reform movement in the United States has resulted in a variety of states moving toward a system of value-added modeling (VAM) to measure a teacher's contribution to student achievement. Recently, many states have begun using VAM scores as part of a larger system to evaluate teacher performance. In the past decade, only "core…

  17. Early and sustained altered expression of aging-related genes in young 3xTg-AD mice

    PubMed Central

    Gatta, V; D'Aurora, M; Granzotto, A; Stuppia, L; Sensi, S L

    2014-01-01

    Alzheimer's disease (AD) is a multifactorial neurological condition associated with a genetic profile that is still not completely understood. In this study, using a whole gene microarray approach, we investigated age-dependent gene expression profile changes occurring in the hippocampus of young and old transgenic AD (3xTg-AD) and wild-type (WT) mice. The aim of the study was to assess similarities between aging- and AD-related modifications of gene expression and investigate possible interactions between the two processes. Global gene expression profiles of hippocampal tissue obtained from 3xTg-AD and WT mice at 3 and 12 months of age (m.o.a.) were analyzed by hierarchical clustering. Interaction among transcripts was then studied with the Ingenuity Pathway Analysis (IPA) software, a tool that discloses functional networks and/or pathways associated with sets of specific genes of interest. Cluster analysis revealed the selective presence of hundreds of upregulated and downregulated transcripts. Functional analysis showed transcript involvement mainly in neuronal death and autophagy, mitochondrial functioning, intracellular calcium homeostasis, inflammatory response, dendritic spine formation, modulation of synaptic functioning, and cognitive decline. Thus, overexpression of AD-related genes (such as mutant APP, PS1, and hyperphosphorylated tau, the three genes that characterize our model) appears to favor modifications of additional genes that are involved in AD development and progression. The study also showed overlapping changes in 3xTg-AD at 3 m.o.a. and WT mice at 12 m.o.a., thereby suggesting altered expression of aging-related genes that occurs earlier in 3xTg-AD mice. PMID:24525730

  18. Autoimmune Manifestations in the 3xTg-AD Model of Alzheimer's Disease

    PubMed Central

    Marchese, Monica; Cowan, David; Head, Elizabeth; Ma, Donglai; Karimi, Khalil; Ashthorpe, Vanessa; Kapadia, Minesh; Zhao, Hui; Davis, Paulina; Sakic, Boris

    2015-01-01

    Background Immune system activation is frequently reported in patients with Alzheimer's disease (AD). However, it remains unknown whether this is a cause, a consequence, or an epiphenomenon of brain degeneration. Objective The present study examines whether immunological abnormalities occur in a well-established murine AD model and if so, how they relate temporally to behavioral deficits and neuropathology. Methods A broad battery of tests was employed to assess behavioral performance and autoimmune/inflammatory markers in 3xTg-AD (AD) mice and wild type controls from 1.5 to 12 months of age. Results Aged AD mice displayed severe manifestations of systemic autoimmune/inflammatory disease, as evidenced by splenomegaly, hepatomegaly, elevated serum levels of anti-nuclear/anti-dsDNA antibodies, low hematocrit, and increased number of double-negative T splenocytes. However, anxiety-related behavior and altered spleen function were evident as early as 2 months of age, thus preceding typical AD-like brain pathology. Moreover, AD mice showed altered olfaction and impaired “cognitive” flexibility in the first 6 months of life, suggesting mild cognitive impairment-like manifestations before general learning/memory impairments emerged at an older age. Interestingly, all of these features were present in 3xTg-AD mice prior to significant amyloid-β or tau pathology. Conclusion The results indicate that behavioral deficits in AD mice develop in parallel with systemic autoimmune/inflammatory disease. These changes antedate AD-like neuropathology, thus supporting a causal link between autoimmunity and aberrant behavior. Consequently, 3xTg-AD mice may be a useful model in elucidating the role of immune system in the etiology of AD. PMID:24150111

  19. Zileuton restores memory impairments and reverses amyloid and tau pathology in aged AD mice

    PubMed Central

    Di Meco, Antonio; Lauretti, Elisabetta; Vagnozzi, Alana N.; Praticò, Domenico

    2014-01-01

    The enzyme 5-lipoxygenase (5LO) is up-regulated in Alzheimer’s disease (AD), and its pharmacological blockade with zileuton slows down the development of the AD-like phenotype in young AD mice. However, its efficacy after the AD pathology is established is unknown. To this end, starting at 12-months of age triple transgenic mice (3xTg) received zileuton, a selective 5LO inhibitor, or placebo for 3 months, and then the effect of this treatment on behavior, amyloid and tau pathology assessed. While mice on placebo showed worsening of their memory, treated mice performed even better than at baseline. Compared with placebo, treated mice had significant less Aβ deposits and tau phosphorylation secondary to reduced γ-secretase and CDK-5 activation, respectively. Our data provide novel insights into the disease-modifying action of pharmacologically inhibiting 5LO as a viable AD therapeutic approach. They represent the successful completion of preclinical studies for the development of this class of drug as clinically applicable therapy for the disease. PMID:24973121

  20. Marble-burying is enhanced in 3xTg-AD mice, can be reversed by risperidone and it is modulable by handling.

    PubMed

    Torres-Lista, Virginia; López-Pousa, Secundino; Giménez-Llort, Lydia

    2015-07-01

    Translational research on behavioural and psychological symptoms of dementia (BPSD) is relevant to the study the neuropsychiatric symptoms that strongly affect the quality of life of the human Alzheimer's disease (AD) patient and caregivers, frequently leading to early institutionalization. Among the ethological behavioural tests for rodents, marble burying is considered to model the spectrum of anxiety, psychotic and obsessive-compulsive like symptoms. The present work was aimed to study the behavioural interactions of 12 month-old male 3xTg-AD mice with small objects using the marble-burying test, as compared to the response elicited in age-matched non-transgenic (NTg) mice. The distinction of the classical 'number of buried marbles' but also those left 'intact' and those 'changed' of position of marbles or partially buried (the transitional level of interaction) provided new insights into the modelling of BPSD-like alterations in this AD model. The analysis revealed genotype differences in the behavioural patterns and predominant behaviors. In the NTg mice, predominance was shown in the 'changed or partially buried', while interactions with marble were enhanced in 3xTg-AD mice resulting in an increase of marble burying. Besides, genotype-dependent meaningful correlations were found, with the marble test pattern of 3xTg-AD mice being directly related to neophobia in the corner tests. In both genotypes, the increase of burying was reversed by chronic treatment with risperidone (1mg/kg, s.c.). In 3xTg-AD mice, the repetitive handling of animals during the treatment also exerted modulatory effects. These distinct patterns further characterize the modelling of BPSD-like symptoms in the 3xTg-AD mice, and provide another behavioural tool to assess the benefits of preventive and/or therapeutic strategies, as well as the potential action of risk factors for AD, in this animal model.

  1. Persistence of behaviours in the Forced Swim Test in 3xTg-AD mice at advanced stages of disease.

    PubMed

    Torres-Lista, Virginia; Giménez-Llort, Lydia

    2014-07-01

    Forced Swimming Test (FST) models behavioural despair in animals by loss of motivation to respond or the refusal to escape. The present study characterizes the behavioural responses of 12-month-old male 3xTg-AD mice in FST as compared to age-matched no-transgenic (NTg) mice. Paradoxical results were consistently found from what would be expected from their BPSD (Behavioural and Psychological Symptoms of Dementia)-like profile. The comprehensive analysis of the ethogram shown in the FST considered the intervals of the test (0-2 and 2-6min), all the elicited behavioural responses (immobility, swimming and climbing) and their features (total duration, frequency of episodes and mean duration). Both genotypes showed equal number of swimming episodes and climbing attempts during the first interval, that resulted in high swimming times, short climbing and scarce immobility. Thereafter, the NTg mice showed a behavioural shift over time and the immobility response showed up. In contrast, all the measures consistently evidenced that 3xTg-AD persisted with the previous behavioural pattern. Genotype differences consisted in less number of episodes of immobility and swimming, and a low immobility time in favour of swimming. No differences were found in 'climbing' attempts. The behavioural response observed is discussed as a lack of ability of 3xTg-AD mice to shift behaviour over time that may result of poorest cognitive flexibility and copying with stress strategies more than behavioural despair per se.

  2. Enrichment improves cognition in AD mice by amyloid-related and unrelated mechanisms.

    PubMed

    Costa, David A; Cracchiolo, Jennifer R; Bachstetter, Adam D; Hughes, Tiffany F; Bales, Kelly R; Paul, Steven M; Mervis, Ronald F; Arendash, Gary W; Potter, Huntington

    2007-06-01

    Lifelong cognitive stimulation is associated with a lower risk of Alzheimer's disease (AD), but causality is difficult to prove. We therefore sought to investigate the preventative potential of environmental enrichment (EE) using mice expressing both human mutant presenilin-1 and the amyloid precursor protein (PS1/PDAPP). At weaning, mice were placed into either an enriched or standard housing environment. Behavioral testing at 4.5-6 months showed that environmentally enriched PS1/PDAPP mice outperformed mice in standard housing, and were behaviorally indistinguishable from non-transgenic mice across multiple cognitive domains. PS1/PDAPP mice exposed to both environmental enrichment and behavioral testing, but not to EE alone, showed 50% less brain beta-amyloid without improved dendritic morphology. Microarray analysis revealed large enrichment-induced changes in hippocampal expression of genes/proteins related to Abeta sequestration and synaptic plasticity. These results indicate that EE protects against cognitive impairment in AD transgenic mice through a dual mechanism, including both amyloid dependent and independent mechanisms.

  3. Human-relevant levels of added sugar consumption increase female mortality and lower male fitness in mice.

    PubMed

    Ruff, James S; Suchy, Amanda K; Hugentobler, Sara A; Sosa, Mirtha M; Schwartz, Bradley L; Morrison, Linda C; Gieng, Sin H; Shigenaga, Mark K; Potts, Wayne K

    2013-01-01

    Consumption of added sugar has increased over recent decades and is correlated with numerous diseases. Rodent models have elucidated mechanisms of toxicity, but only at concentrations beyond typical human exposure. Here we show that comparatively low levels of added sugar consumption have substantial negative effects on mouse survival, competitive ability, and reproduction. Using Organismal Performance Assays--in which mice fed human-relevant concentrations of added sugar (25% kcal from a mixture of fructose and glucose, modeling high fructose corn syrup) and control mice compete in seminatural enclosures for territories, resources and mates--we demonstrate that fructose/glucose-fed females experience a twofold increase in mortality while fructose/glucose-fed males control 26% fewer territories and produce 25% less offspring. These findings represent the lowest level of sugar consumption shown to adversely affect mammalian health. Clinical defects of fructose/glucose-fed mice were decreased glucose clearance and increased fasting cholesterol. Our data highlight that physiological adversity can exist when clinical disruptions are minor, and suggest that Organismal Performance Assays represent a promising technique for unmasking negative effects of toxicants.

  4. Human-relevant levels of added sugar consumption increase female mortality and lower male fitness in mice.

    PubMed

    Ruff, James S; Suchy, Amanda K; Hugentobler, Sara A; Sosa, Mirtha M; Schwartz, Bradley L; Morrison, Linda C; Gieng, Sin H; Shigenaga, Mark K; Potts, Wayne K

    2013-01-01

    Consumption of added sugar has increased over recent decades and is correlated with numerous diseases. Rodent models have elucidated mechanisms of toxicity, but only at concentrations beyond typical human exposure. Here we show that comparatively low levels of added sugar consumption have substantial negative effects on mouse survival, competitive ability, and reproduction. Using Organismal Performance Assays--in which mice fed human-relevant concentrations of added sugar (25% kcal from a mixture of fructose and glucose, modeling high fructose corn syrup) and control mice compete in seminatural enclosures for territories, resources and mates--we demonstrate that fructose/glucose-fed females experience a twofold increase in mortality while fructose/glucose-fed males control 26% fewer territories and produce 25% less offspring. These findings represent the lowest level of sugar consumption shown to adversely affect mammalian health. Clinical defects of fructose/glucose-fed mice were decreased glucose clearance and increased fasting cholesterol. Our data highlight that physiological adversity can exist when clinical disruptions are minor, and suggest that Organismal Performance Assays represent a promising technique for unmasking negative effects of toxicants. PMID:23941916

  5. Age-dependent impairment of glucose tolerance in the 3xTg-AD mouse model of Alzheimer's disease.

    PubMed

    Vandal, Milene; White, Phillip J; Chevrier, Geneviève; Tremblay, Cyntia; St-Amour, Isabelle; Planel, Emmanuel; Marette, Andre; Calon, Frederic

    2015-10-01

    Alzheimer's disease (AD) has been associated with type II diabetes (T2D) and obesity in several epidemiologic studies. To determine whether AD neuropathology can cause peripheral metabolic impairments, we investigated metabolic parameters in the triple-transgenic (3xTg)-AD mouse model of AD, compared with those in nontransgenic (non-Tg) controls, at 6, 8, and 14 mo of age. We found a more pronounced cortical Aβ accumulation (2- and 3.5-fold increase in Aβ42 in the soluble and insoluble protein fractions, respectively) in female 3xTg-AD mice than in the males. Furthermore, female 3xTg-AD mice displayed a significant deterioration in glucose tolerance (AUC, +118% vs. non-Tg mice at 14 mo). Fasting plasma insulin levels rose 2.5-fold from 6 to 14 mo of age in female 3xTg-AD mice. Glucose intolerance and cortical amyloid pathology worsened with age, and both were more pronounced in the females. Pancreatic amyloidopathy was revealed and could underlie the observed deficit in glycemic response in 3xTg-AD mice. The present results suggest that AD-like neuropathology extends to the pancreas in the 3xTg-AD mouse, leading to glucose intolerance and contributing to a pathologic self-amplifying loop between AD and T2D. PMID:26108977

  6. Massive quiver matrix models for massive charged particles in AdS

    DOE PAGES

    Asplund, Curtis T.; Denef, Frederik; Dzienkowski, Eric

    2016-01-11

    Here, we present a new class of N = 4 supersymmetric quiver matrix models and argue that it describes the stringy low-energy dynamics of internally wrapped D-branes in four-dimensional anti-de Sitter (AdS) flux compactifications. The Lagrangians of these models differ from previously studied quiver matrix models by the presence of mass terms, associated with the AdS gravitational potential, as well as additional terms dictated by supersymmetry. These give rise to dynamical phenomena typically associated with the presence of fluxes, such as fuzzy membranes, internal cyclotron motion and the appearance of confining strings. We also show how these models can bemore » obtained by dimensional reduction of four-dimensional supersymmetric quiver gauge theories on a three-sphere.« less

  7. Behavioral defects in chaperone-deficient Alzheimer's disease model mice.

    PubMed

    Ojha, Juhi; Karmegam, Rajalakshmi V; Masilamoni, J Gunasingh; Terry, Alvin V; Cashikar, Anil G

    2011-01-01

    Molecular chaperones protect cells from the deleterious effects of protein misfolding and aggregation. Neurotoxicity of amyloid-beta (Aβ) aggregates and their deposition in senile plaques are hallmarks of Alzheimer's disease (AD). We observed that the overall content of αB-crystallin, a small heat shock protein molecular chaperone, decreased in AD model mice in an age-dependent manner. We hypothesized that αB-crystallin protects cells against Aβ toxicity. To test this, we crossed αB-crystallin/HspB2 deficient (CRYAB⁻/⁻HSPB2⁻/⁻) mice with AD model transgenic mice expressing mutant human amyloid precursor protein. Transgenic and non-transgenic mice in chaperone-sufficient or deficient backgrounds were examined for representative behavioral paradigms for locomotion and memory network functions: (i) spatial orientation and locomotion was monitored by open field test; (ii) sequential organization and associative learning was monitored by fear conditioning; and (iii) evoked behavioral response was tested by hot plate method. Interestingly, αB-crystallin/HspB2 deficient transgenic mice were severely impaired in locomotion compared to each genetic model separately. Our results highlight a synergistic effect of combining chaperone deficiency in a transgenic mouse model for AD underscoring an important role for chaperones in protein misfolding diseases. PMID:21379584

  8. Behavioral defects in chaperone-deficient Alzheimer's disease model mice.

    PubMed

    Ojha, Juhi; Karmegam, Rajalakshmi V; Masilamoni, J Gunasingh; Terry, Alvin V; Cashikar, Anil G

    2011-01-01

    Molecular chaperones protect cells from the deleterious effects of protein misfolding and aggregation. Neurotoxicity of amyloid-beta (Aβ) aggregates and their deposition in senile plaques are hallmarks of Alzheimer's disease (AD). We observed that the overall content of αB-crystallin, a small heat shock protein molecular chaperone, decreased in AD model mice in an age-dependent manner. We hypothesized that αB-crystallin protects cells against Aβ toxicity. To test this, we crossed αB-crystallin/HspB2 deficient (CRYAB⁻/⁻HSPB2⁻/⁻) mice with AD model transgenic mice expressing mutant human amyloid precursor protein. Transgenic and non-transgenic mice in chaperone-sufficient or deficient backgrounds were examined for representative behavioral paradigms for locomotion and memory network functions: (i) spatial orientation and locomotion was monitored by open field test; (ii) sequential organization and associative learning was monitored by fear conditioning; and (iii) evoked behavioral response was tested by hot plate method. Interestingly, αB-crystallin/HspB2 deficient transgenic mice were severely impaired in locomotion compared to each genetic model separately. Our results highlight a synergistic effect of combining chaperone deficiency in a transgenic mouse model for AD underscoring an important role for chaperones in protein misfolding diseases.

  9. Stress inoculation modeled in mice

    PubMed Central

    Brockhurst, J; Cheleuitte-Nieves, C; Buckmaster, C L; Schatzberg, A F; Lyons, D M

    2015-01-01

    Stress inoculation entails intermittent exposure to mildly stressful situations that present opportunities to learn, practice and improve coping in the context of exposure psychotherapies and resiliency training. Here we investigate behavioral and hormonal aspects of stress inoculation modeled in mice. Mice randomized to stress inoculation or a control treatment condition were assessed for corticosterone stress hormone responses and behavior during open-field, object-exploration and tail-suspension tests. Stress inoculation training sessions that acutely increased plasma levels of corticosterone diminished subsequent immobility as a measure of behavioral despair on tail-suspension tests. Stress inoculation also decreased subsequent freezing in the open field despite comparable levels of thigmotaxis in mice from both treatment conditions. Stress inoculation subsequently decreased novel-object exploration latencies and reduced corticosterone responses to repeated restraint. These results demonstrate that stress inoculation acutely stimulates glucocorticoid signaling and then enhances subsequent indications of active coping behavior in mice. Unlike mouse models that screen for the absence of vulnerability to stress or presence of traits that occur in resilient individuals, stress inoculation training reflects an experience-dependent learning-like process that resembles interventions designed to build resilience in humans. Mouse models of stress inoculation may provide novel insights for new preventive strategies or therapeutic treatments of human psychiatric disorders that are triggered and exacerbated by stressful life events. PMID:25826112

  10. Modeling cancer in mice.

    PubMed

    Jackson-Grusby, Laurie

    2002-08-12

    The laboratory mouse is one of the most powerful tools for both gene discovery and validation in cancer genetics. Recent technological advances in engineering the mouse genome with chromosome translocations, latent alleles, and tissue-specific and temporally regulated mutations have provided more exacting models of human disease. The marriage of mouse tumor models with rapidly evolving methods to profile genetic and epigenetic alterations in tumors, and to finely map genetic modifier loci, will continue to provide insight into the key pathways leading to tumorigenesis. These discoveries hold great promise for identifying relevant drug targets for treating human cancer.

  11. Increased Hippocampal Excitability in the 3xTgAD Mouse Model for Alzheimer's Disease In Vivo

    PubMed Central

    Davis, Katherine E.; Fox, Sarah; Gigg, John

    2014-01-01

    Mouse Alzheimer's disease (AD) models develop age- and region-specific pathology throughout the hippocampal formation. One recently established pathological correlate is an increase in hippocampal excitability in vivo. Hippocampal pathology also produces episodic memory decline in human AD and we have shown a similar episodic deficit in 3xTg AD model mice aged 3–6 months. Here, we tested whether hippocampal synaptic dysfunction accompanies this cognitive deficit by probing dorsal CA1 and DG synaptic responses in anaesthetized, 4–6 month-old 3xTgAD mice. As our previous reports highlighted a decline in episodic performance in aged control mice, we included aged cohorts for comparison. CA1 and DG responses to low-frequency perforant path stimulation were comparable between 3xTgAD and controls at both age ranges. As expected, DG recordings in controls showed paired-pulse depression; however, paired-pulse facilitation was observed in DG and CA1 of young and old 3xTgAD mice. During stimulus trains both short-latency (presumably monosynaptic: ‘direct’) and long-latency (presumably polysynaptic: ‘re-entrant’) responses were observed. Facilitation of direct responses was modest in 3xTgAD animals. However, re-entrant responses in DG and CA1 of young 3xTgAD mice developed earlier in the stimulus train and with larger amplitude when compared to controls. Old mice showed less DG paired-pulse depression and no evidence for re-entrance. In summary, DG and CA1 responses to low-frequency stimulation in all groups were comparable, suggesting no loss of synaptic connectivity in 3xTgAD mice. However, higher-frequency activation revealed complex change in synaptic excitability in DG and CA1 of 3xTgAD mice. In particular, short-term plasticity in DG and CA1 was facilitated in 3xTgAD mice, most evidently in younger animals. In addition, re-entrance was facilitated in young 3xTgAD mice. Overall, these data suggest that the episodic-like memory deficit in 3xTgAD mice could be

  12. Cognitive and emotional profiles of aged Alzheimer's disease (3×TgAD) mice: effects of environmental enrichment and sexual dimorphism.

    PubMed

    Blázquez, Gloria; Cañete, Toni; Tobeña, Adolf; Giménez-Llort, Lydia; Fernández-Teruel, Alberto

    2014-07-15

    Alzheimer's disease is a neurodegenerative disorder associated with age which represents the most common cause of dementia. It is characterized by an accelerated memory loss compared to normal aging, and deterioration of other cognitive abilities that interfere with mood, reason, judgment and language. The main neuropathological hallmarks of the disorder are β-amyloid (βA) plaques and neurofibrillary Tau tangles. Triple transgenic 3×TgAD mouse model develops βA and Tau pathologies in a progressive manner, with a specific temporal and anatomic profile mimicking the pattern that takes place in the human brain with AD, and showing cognitive alterations characteristic of the disease. Environmental enrichment treatment in mice induces behavioral and emotional reactivity changes, including cognitive improvements in some AD-related transgenic mice. The present work intended to characterize the behavioral profile of 3×TgAD mice at advanced stages of neuropathological development (12 and 15 months of age) and to investigate whether environmental enrichment administered during adulthood was able to modify some of their behavioral and cognitive alterations. Results show that, at advanced stages of the disease 3×TgAD mice show deficits of spatial learning acquisition, as well as short-term and working memory deficits, while displaying increased levels of anxiety/fearfulness and normal sensorimotor functions. 3×TgAD mice also show sexual dimorphism, as reflected by increased cognitive deficits in females and increased levels of novelty-induced behavioral inhibition in males. Environmental enrichment exerts some slight positive effects, by mainly improving the initial acquisition of the spatial learning and working memory in 12-month-old 3×TgAD mice. Such effects vary depending on the gender.

  13. AdS black disk model for small-x DIS

    NASA Astrophysics Data System (ADS)

    Cornalba, Lorenzo; Costa, Miguel S.; Penedones, João

    2011-05-01

    Using the approximate conformal invariance of QCD at high energies we consider a simple AdS black disk model to describe saturation in DIS. Deep inside saturation the structure functions have the same power law scaling, FT˜FL˜x-ω, where ω is related to the expansion rate of the black disk with energy. Furthermore, the ratio FL/FT is given by the universal value 1+ω/3+ω, independently of the target.

  14. Chronic Anatabine Treatment Reduces Alzheimer’s Disease (AD)-Like Pathology and Improves Socio-Behavioral Deficits in a Transgenic Mouse Model of AD

    PubMed Central

    Verma, Megha; Beaulieu-Abdelahad, David; Ait-Ghezala, Ghania; Li, Rena; Crawford, Fiona; Mullan, Michael; Paris, Daniel

    2015-01-01

    Anatabine is a minor tobacco alkaloid, which is also found in plants of the Solanaceae family and displays a chemical structure similarity with nicotine. We have shown previously that anatabine displays some anti-inflammatory properties and reduces microgliosis and tau phosphorylation in a pure mouse model of tauopathy. We therefore investigated the effects of a chronic oral treatment with anatabine in a transgenic mouse model (Tg PS1/APPswe) of Alzheimer’s disease (AD) which displays pathological Aβ deposits, neuroinflammation and behavioral deficits. In the elevated plus maze, Tg PS1/APPswe mice exhibited hyperactivity and disinhibition compared to wild-type mice. Six and a half months of chronic oral anatabine treatment, suppressed hyperactivity and disinhibition in Tg PS1/APPswe mice compared to Tg PS1/APPswe receiving regular drinking water. Tg PS1/APPswe mice also elicited profound social interaction and social memory deficits, which were both alleviated by the anatabine treatment. We found that anatabine reduces the activation of STAT3 and NFκB in the vicinity of Aβ deposits in Tg PS1/APPswe mice resulting in a reduction of the expression of some of their target genes including Bace1, iNOS and Cox-2. In addition, a significant reduction in microgliosis and pathological deposition of Aβ was observed in the brain of Tg PS1/APPswe mice treated with anatabine. This is the first study to investigate the impact of chronic anatabine treatment on AD-like pathology and behavior in a transgenic mouse model of AD. Overall, our data show that anatabine reduces β-amyloidosis, neuroinflammation and alleviates some behavioral deficits in Tg PS1/APPswe, supporting further exploration of anatabine as a possible disease modifying agent for the treatment of AD. PMID:26010758

  15. Age-Dependent Modifications of AMPA Receptor Subunit Expression Levels and Related Cognitive Effects in 3xTg-AD Mice.

    PubMed

    Cantanelli, Pamela; Sperduti, Samantha; Ciavardelli, Domenico; Stuppia, Liborio; Gatta, Valentina; Sensi, Stefano Luca

    2014-01-01

    GluA1, GluA2, GluA3, and GluA4 are the constitutive subunits of amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs), the major mediators of fast excitatory transmission in the mammalian central nervous system. Most AMPARs are Ca(2+)-impermeable because of the presence of the GluA2 subunit. GluA2 mRNA undergoes an editing process that results in a Q-R substitution, a key factor in the regulation of AMPAR Ca(2+)-permeability. AMPARs lacking GluA2 or containing the unedited subunit are permeable to Ca(2+) and Zn(2+). The phenomenon physiologically modulates synaptic plasticity while, in pathologic conditions, leads to increased vulnerability to excitotoxic neuronal death. Given the importance of these subunits, we have therefore evaluated possible associations between changes in expression levels of AMPAR subunits and development of cognitive deficits in 3xTg-AD mice, a widely investigated transgenic mouse model of Alzheimer's disease (AD). With quantitative real-time PCR analysis, we assayed hippocampal mRNA expression levels of GluA1-4 subunits occurring in young [3 months of age (m.o.a.)] and old (12 m.o.a) Tg-AD mice and made comparisons with levels found in age-matched wild type (WT) mice. Efficiency of GluA2 RNA editing was also analyzed. All animals were cognitively tested for learning short- and long-term spatial memory with the Morris Water Maze (MWM) navigation task. 3xTg-AD mice showed age-dependent decreases of mRNA levels for all the AMPAR subunits, with the exception of GluA2. Editing remained fully efficient with aging in 3xTg-AD and WT mice. A one-to-one correlation analysis between MWM performances and GluA1-4 mRNA expression profiles showed negative correlations between GluA2 levels and MWM performances in young 3xTg-AD mice. On the contrary, positive correlations between GluA2 mRNA and MWM performances were found in young WT mice. Our data suggest that increases of AMPARs that contain GluA1, GluA3, and GluA4 subunits may help in

  16. High-fat diet-induced memory impairment in triple-transgenic Alzheimer's disease (3xTgAD) mice is independent of changes in amyloid and tau pathology.

    PubMed

    Knight, Elysse M; Martins, Isaura V A; Gümüsgöz, Sarah; Allan, Stuart M; Lawrence, Catherine B

    2014-08-01

    Obesity and consumption of a high-fat diet are known to increase the risk of Alzheimer's disease (AD). Diets high in fat also increase disease neuropathology and/or cognitive deficits in AD mouse models. However, the effect of a high-fat diet on both the neuropathology and memory impairments in the triple-transgenic mouse model of AD (3xTgAD) is unknown. Therefore, groups of 2-month-old male 3xTgAD and control (non-Tg) mice were maintained on a high-fat or control diet and memory was assessed at the age of 3-4, 7-8, 11-12, and 15-16 months using a series of behavioral tests. A comparable increase in body weight was observed in non-Tg and 3xTgAD mice after high-fat feeding at all ages tested but a significantly greater increase in epididymal adipose tissue was observed in 3xTgAD mice at the age of 7-8, 11-12, and 15-16 months. A high-fat diet caused memory impairments in non-Tg control mice as early as the age of 3-4 months. In 3xTgAD mice, high-fat consumption led to a reduction in the age of onset and an increase in the extent of memory impairments. Some of these effects of high-fat diet on cognition in non-Tg and 3xTgAD mice were transient, and the age at which cognitive impairment was detected depended on the behavioral test. The effect of high-fat diet on memory in the 3xTgAD mice was independent of changes in AD neuropathology as no significant differences in (plaques, oligomers) or tau neuropathology were observed. An acute increase in microglial activation was seen in high-fat fed 3xTgAD mice at the age of 3-4 months but in non-Tg control mice microglial activation was not observed until the age of 15-16 months. These data indicate therefore that a high-fat diet has rapid and long-lasting negative effects on memory in both control and AD mice that are associated with neuroinflammation, but independent of changes in beta amyloid and tau neuropathology in the AD mice.

  17. Null-polygonal minimal surfaces in AdS4 from perturbed W minimal models

    NASA Astrophysics Data System (ADS)

    Hatsuda, Yasuyuki; Ito, Katsushi; Satoh, Yuji

    2013-02-01

    We study the null-polygonal minimal surfaces in AdS4, which correspond to the gluon scattering amplitudes/Wilson loops in {N} = 4 super Yang-Mills theory at strong coupling. The area of the minimal surfaces with n cusps is characterized by the thermodynamic Bethe ansatz (TBA) integral equations or the Y-system of the homogeneous sine-Gordon model, which is regarded as the SU( n - 4)4 /U(1) n-5 generalized parafermion theory perturbed by the weight-zero adjoint operators. Based on the relation to the TBA systems of the perturbed W minimal models, we solve the TBA equations by using the conformal perturbation theory, and obtain the analytic expansion of the remainder function around the UV/regular-polygonal limit for n = 6 and 7. We compare the rescaled remainder function for n = 6 with the two-loop one, to observe that they are close to each other similarly to the AdS3 case.

  18. Early inflammation and immune response mRNAs in the brain of AD11 anti-NGF mice.

    PubMed

    D'Onofrio, Mara; Arisi, Ivan; Brandi, Rossella; Di Mambro, Alessandra; Felsani, Armando; Capsoni, Simona; Cattaneo, Antonino

    2011-06-01

    We characterized the gene expression profile of brain regions at an early stage of the Alzheimer's like neurodegeneration in the anti-NGF AD11 model. Total RNA was extracted from hippocampus, cortex and basal forebrain of postnatal day 30 (P30) and postnatal day 90 (P90) mice and expression profiles were studied by microarray analysis, followed by qRT-PCR validation of 243 significant candidates. Wide changes in gene expression profiles occur already at P30. As expected, cholinergic system and neurotrophins related genes expression were altered. Interestingly, the most significantly affected clusters of mRNAs are linked to inflammation and immune response, as well as to Wnt signaling. mRNAs encoding for different complement factors show a large differential expression. This is noteworthy, since these complement cascade proteins are involved in CNS synapse elimination, during normal brain developing and in neurodegenerative diseases. This gene expression pattern highlights that an early event in AD11 neurodegeneration is represented, together with neurotrophic deficits and synaptic remodeling, by an inflammatory response and an unbalance in the immunotrophic state of the brain. These might be key events in the pathogenesis and development of AD.

  19. Early detection of cognitive deficits in the 3xTg-AD mouse model of Alzheimer's disease.

    PubMed

    Stover, Kurt R; Campbell, Mackenzie A; Van Winssen, Christine M; Brown, Richard E

    2015-08-01

    Which behavioral test is the most sensitive for detecting cognitive deficits in the 3xTg-AD at 6.5 months of age? The 3xTg-AD mouse model of Alzheimer's disease (AD) has three transgenes (APPswe, PS1M146V, and Tau P301L) which cause the development of amyloid beta plaques, neurofibrillary tangles, and cognitive deficits with age. In order to determine which task is the most sensitive in the early detection of cognitive deficits, we compared male and female 3xTg-AD and B6129SF2 wildtype mice at 6.5 months of age on a test battery including spontaneous alternation in the Y-Maze, novel object recognition, spatial memory in the Barnes maze, and cued and contextual fear conditioning. The 3xTg-AD mice had impaired learning and memory in the Barnes maze but performed better than B6129SF2 wildtype mice in the Y-Maze and in contextual fear conditioning. Neither genotype demonstrated a preference in the novel object recognition task nor was there a genotype difference in cued fear conditioning but females performed better than males. From our results we conclude that the 3xTg-AD mice have mild cognitive deficits in spatial learning and memory and that the Barnes maze was the most sensitive test for detecting these cognitive deficits in 6.5-month-old mice.

  20. Exenatide promotes cognitive enhancement and positive brain metabolic changes in PS1-KI mice but has no effects in 3xTg-AD animals.

    PubMed

    Bomba, M; Ciavardelli, D; Silvestri, E; Canzoniero, L M T; Lattanzio, R; Chiappini, P; Piantelli, M; Di Ilio, C; Consoli, A; Sensi, S L

    2013-05-02

    Recent studies have shown that type 2 diabetes mellitus (T2DM) is a risk factor for cognitive dysfunction or dementia. Insulin resistance is often associated with T2DM and can induce defective insulin signaling in the central nervous system as well as increase the risk of cognitive impairment in the elderly. Glucagone like peptide-1 (GLP-1) is an incretin hormone and, like GLP-1 analogs, stimulates insulin secretion and has been employed in the treatment of T2DM. GLP-1 and GLP-1 analogs also enhance synaptic plasticity and counteract cognitive deficits in mouse models of neuronal dysfunction and/or degeneration. In this study, we investigated the potential neuroprotective effects of long-term treatment with exenatide, a GLP-1 analog, in two animal models of neuronal dysfunction: the PS1-KI and 3xTg-AD mice. We found that exenatide promoted beneficial effects on short- and long-term memory performances in PS1-KI but not in 3xTg-AD animals. In PS1-KI mice, the drug increased brain lactate dehydrogenase activity leading to a net increase in lactate levels, while no effects were observed on mitochondrial respiration. On the contrary, exenatide had no effects on brain metabolism of 3xTg-AD mice. In summary, our data indicate that exenatide improves cognition in PS1-KI mice, an effect likely driven by increasing the brain anaerobic glycolysis rate.

  1. Exenatide promotes cognitive enhancement and positive brain metabolic changes in PS1-KI mice but has no effects in 3xTg-AD animals

    PubMed Central

    Bomba, M; Ciavardelli, D; Silvestri, E; Canzoniero, L MT; Lattanzio, R; Chiappini, P; Piantelli, M; Di Ilio, C; Consoli, A; Sensi, S L

    2013-01-01

    Recent studies have shown that type 2 diabetes mellitus (T2DM) is a risk factor for cognitive dysfunction or dementia. Insulin resistance is often associated with T2DM and can induce defective insulin signaling in the central nervous system as well as increase the risk of cognitive impairment in the elderly. Glucagone like peptide-1 (GLP-1) is an incretin hormone and, like GLP-1 analogs, stimulates insulin secretion and has been employed in the treatment of T2DM. GLP-1 and GLP-1 analogs also enhance synaptic plasticity and counteract cognitive deficits in mouse models of neuronal dysfunction and/or degeneration. In this study, we investigated the potential neuroprotective effects of long-term treatment with exenatide, a GLP-1 analog, in two animal models of neuronal dysfunction: the PS1-KI and 3xTg-AD mice. We found that exenatide promoted beneficial effects on short- and long-term memory performances in PS1-KI but not in 3xTg-AD animals. In PS1-KI mice, the drug increased brain lactate dehydrogenase activity leading to a net increase in lactate levels, while no effects were observed on mitochondrial respiration. On the contrary, exenatide had no effects on brain metabolism of 3xTg-AD mice. In summary, our data indicate that exenatide improves cognition in PS1-KI mice, an effect likely driven by increasing the brain anaerobic glycolysis rate. PMID:23640454

  2. Assumptions of Value-Added Models for Estimating School Effects

    ERIC Educational Resources Information Center

    Reardon, Sean F.; Raudenbush, Stephen W.

    2009-01-01

    The ability of school (or teacher) value-added models to provide unbiased estimates of school (or teacher) effects rests on a set of assumptions. In this article, we identify six assumptions that are required so that the estimands of such models are well defined and the models are able to recover the desired parameters from observable data. These…

  3. Effects of long-term treatment with pioglitazone on cognition and glucose metabolism of PS1-KI, 3xTg-AD, and wild-type mice.

    PubMed

    Masciopinto, F; Di Pietro, N; Corona, C; Bomba, M; Pipino, C; Curcio, M; Di Castelnuovo, A; Ciavardelli, D; Silvestri, E; Canzoniero, L M T; Sekler, I; Pandolfi, A; Sensi, S L

    2012-12-20

    In this study, we investigated the effects of long-term (9-month) treatment with pioglitazone (PIO; 20 mg/kg/d) in two animal models of Alzheimer's disease (AD)-related neural dysfunction and pathology: the PS1-KI(M146V) (human presenilin-1 (M146V) knock-in mouse) and 3xTg-AD (triple transgenic mouse carrying AD-linked mutations) mice. We also investigated the effects on wild-type (WT) mice. Mice were monitored for body mass changes, fasting glycemia, glucose tolerance, and studied for changes in brain mitochondrial enzyme activity (complexes I and IV) as well as energy metabolism (lactate dehydrogenase (LDH)). Cognitive effects were investigated with the Morris water maze (MWM) test and the object recognition task (ORT). Behavioral analysis revealed that PIO treatment promoted positive cognitive effects in PS1-KI female mice. These effects were associated with normalization of peripheral gluco-regulatory abnormalities that were found in untreated PS1-KI females. PIO-treated PS1-KI females also showed no statistically significant alterations in brain mitochondrial enzyme activity but significantly increased reverse LDH activity.PIO treatment produced no effects on cognition, glucose metabolism, or mitochondrial functioning in 3xTg-AD mice. Finally, PIO treatment promoted enhanced short-term memory performance in WT male mice, a group that did not show deregulation of glucose metabolism but that showed decreased activity of complex I in hippocampal and cortical mitochondria. Overall, these results indicate metabolically driven cognitive-enhancing effects of PIO that are differentially gender-related among specific genotypes.

  4. DHA diet reduces AD pathology in young APPswe/PS1 Delta E9 transgenic mice: possible gender effects.

    PubMed

    Perez, Sylvia E; Berg, Brian M; Moore, Kenneth A; He, Bin; Counts, Scott E; Fritz, Jason J; Hu, Yuan-Shih; Lazarov, Orly; Lah, James J; Mufson, Elliott J

    2010-04-01

    Epidemiological and clinical trial findings suggest that consumption of docosahexaenoic acid (DHA) lowers the risk of Alzheimer's disease (AD). We examined the effects of short-term (3 months) DHA enriched diet on plaque deposition and synaptic defects in forebrain of young APPswe/PS1 Delta E9 transgenic (tg) and non-transgenic (ntg) mice. Gas chromatography revealed a significant increase in DHA concomitant with a decrease of arachidonic acid in both brain and liver in mice fed with DHA. Female tg mice consumed relatively more food daily than ntg female mice, independent of diet. Plaque load was significantly reduced in the cortex, ventral hippocampus and striatum of female APPswe/PS1 Delta E9 tg mice on DHA diet compared to female tg mice on control diet. Immunoblot quantitation of the APOE receptor, LR11, which is involved in APP trafficking and A beta production, were unchanged in mice on DHA or control diets. Moreover drebrin levels were significantly increased in the hippocampus of tg mice on the DHA diet. Finally, in vitro DHA treatment prevented amyloid toxicity in cell cultures. Our findings support the concept that increased DHA consumption may play and important role in reducing brain insults in female AD patients. PMID:19859965

  5. Cognitive and emotional alterations in young Alzheimer's disease (3xTgAD) mice: effects of neonatal handling stimulation and sexual dimorphism.

    PubMed

    Cañete, T; Blázquez, G; Tobeña, A; Giménez-Llort, L; Fernández-Teruel, A

    2015-03-15

    Alzheimer disease is the most common neurodegenerative disorder and cause of senile dementia. It is characterized by an accelerated memory loss, and alterations of mood, reason, judgment and language. The main neuropathological hallmarks of the disorder are β-amyloid (βA) plaques and neurofibrillary Tau tangles. The triple transgenic 3xTgAD mouse model develops βA and Tau pathologies in a progressive manner which mimicks the pattern that takes place in the human brain with AD, and showing cognitive alterations characteristic of the disease. The present study intended to examine whether 3xTgAD mice of both sexes present cognitive, emotional and other behavioral alterations at the early age of 4 months, an age in which only some intraneuronal amyloid accumulation is found. Neonatal handling (H) is an early-life treatment known to produce profound and long-lasting behavioral and neurobiological effects in rodents, as well as improvements in cognitive functions. Therefore, we also aimed at evaluating the effects of H on the behavioral/cognitive profile of 4-month-old male and female 3xTgAD mice. The results indicate that, (1) 3xTgAD mice present spatial learning/memory deficits and emotional alterations already at the early age of 4 months, (2) there exists sexual dimorphism effects on several behavioral variables at this age, (3) neonatal handling exerts a preventive effect on some cognitive (spatial learning) and emotional alterations appearing in 3xTgAD mice already at early ages, and 4) H treatment appears to produce stronger positive effects in females than in males in several spatial learning measures and in the open field test.

  6. Matrix model maps and reconstruction of AdS supergravity interactions

    SciTech Connect

    Cremonini, Sera; Mello Koch, Robert de; Jevicki, Antal

    2008-05-15

    We consider the question of reconstructing (cubic) SUGRA interactions in AdS/CFT. The method we introduce is based on the matrix model maps (MMP) which were previously successfully employed at the linearized level. The strategy is to start with the map for 1/2 BPS configurations, which is exactly known (to all orders) in the Hamiltonian framework. We then use the extension of the matrix model map with the corresponding Ward identities to completely specify the interaction. A central point in this construction is the nonvanishing of off-shell interactions (even for highest-weight states)

  7. Matrix model maps in AdS/CFT correspondence

    SciTech Connect

    Donos, Aristomenis; Jevicki, Antal; Rodrigues, Joao P.

    2005-12-15

    We discuss an extension of a map between BPS states and free fermions. The extension involves states associated with a full two matrix problem which are constructed using a sequence of integral equations. A two parameter set of matrix model eigenstates is then related to states in SUGRA. Their wave functions are characterized by nontrivial dependence on the radial coordinate of AdS and of the Sphere, respectively. A kernel defining a one to one map between these states is then constructed.

  8. What's the Value of VAM (Value-Added Modeling)?

    ERIC Educational Resources Information Center

    Scherrer, Jimmy

    2012-01-01

    The use of value-added modeling (VAM) in school accountability is expanding, but deciding how to embrace VAM is difficult. Various experts say it's too unreliable, causes more harm than good, and has a big margin for error. Others assert VAM is imperfect but useful, and provides valuable feedback. A closer look at the models, and their use,…

  9. Modelling Precursor Decay in AD-99.5 Alumnina

    NASA Astrophysics Data System (ADS)

    Manoj Simha, C. Hari; Bless, Stephan J.; Bedford, Anthony M.

    1997-07-01

    In this paper we present a simple model to explain the absence of precursor decay in the Coor's AD-99.5 Alumina ceramic, as shown by Grady in his plate impact experiments. The model is incorporated in the WONDY finite difference code. The simulations of Grady's experiments compare well with the results.

  10. Modelling precursor decay in AD-99.5 Alumina

    SciTech Connect

    Simha, C. Hari Manoj; Bless, S. J.; Bedford, A.

    1998-07-10

    In this paper we present a simple model to explain the absence of precursor decay in the Coor's AD-99 5 Alumina ceramic, as shown by Grady in his plate impact experiments. The model is incorporated into the Research EPIC 95 finite element code. The simulations compare well with Grady's results.

  11. Modelling precursor decay in AD-99.5 Alumina

    NASA Astrophysics Data System (ADS)

    Simha, C. Hari Manoj; Bless, S. J.; Bedford, A.

    1998-07-01

    In this paper we present a simple model to explain the absence of precursor decay in the Coor's AD-99 5 Alumina ceramic, as shown by Grady in his plate impact experiments. The model is incorporated into the Research EPIC 95 finite element code. The simulations compare well with Grady's results.

  12. The Preventive Effects of Nanopowdered Peanut Sprout-added Caciocavallo Cheese on Collagen-induced Arthritic Mice

    PubMed Central

    Chang, Yoon Hyuk

    2014-01-01

    The present study was carried out to investigate the effects of nanopowdered peanut sprout-added Caciocavallo cheese (NPCC) on the prevention and treatment of rheumatoid arthritis in DBA/IJ mice immunized with type II collagen. After the induction of arthritis, the mice were being divided into five groups: (1) normal, no immunization; (2) CIA, collagen-induced arthritis; (3) MTX, collagen-induced arthritis treated with methotrexate (0.3 mg/kg body weight); (4) CC, collagen-induced arthritis treated with Caciocavallo cheese (0.6 g/d); (5) NPCC, collagen-induced arthritis treated with nanopowdered peanut sprout-added Caciocavallo cheese (0.6 g/d). Nanopowdered peanut sprout was ranged from 300 to 350 nm, while regular powdered peanut sprouts were ranged from 50 to 150 μm. The NPCC group had considerable reductions of clinical scores and paw thicknesses at the end of experiment as compared to the CIA group. In the serum analysis, the TNF-α, IL-1β, IL- 6 and IgG1 levels in the NPCC group have decreased by 69.4, 75.9, 66.6, and 61.9%, respectively, when compared to the CIA group. The histological score and spleen index of the NPCC group were significantly lower than the CIA group. In conclusion, the feeding NPCC method could delay and/or prevent the rheumatoid arthritis in the collagen-induced arthritis mouse model. Based on this study, nanopowdered peanut sprouts could be applied to various functional cheeses. PMID:26760745

  13. Myelin injury induces axonal transport impairment but not AD-like pathology in the hippocampus of cuprizone-fed mice

    PubMed Central

    Sun, Junjun; Zhou, Hong; Bai, Feng; Ren, Qingguo; Zhang, Zhijun

    2016-01-01

    Both multiple sclerosis (MS) and Alzheimer's disease (AD) are progressive neurological disorders with myelin injury and memory impairment. However, whether myelin impairment could cause AD-like neurological pathology remains unclear. To explore neurological pathology following myelin injury, we assessed cognitive function, the expression of myelin proteins, axonal transport-associated proteins, axonal structural proteins, synapse-associated proteins, tau and beta amyloid and the status of neurons, using the cuprizone mouse model of demyelination. We found the mild impairment of learning ability in cuprizone-fed mice and the decreased expression of myelin basic protein (MBP) in the hippocampus. And anti-LINGO-1 improved learning ability and partly restored MBP level. Furthermore, we also found kinesin light chain (KLC), neurofilament light chain (NFL) and neurofilament heavy chain (NF200) were declined in demyelinated hippocampus, which could be partly improved by treatment with anti-LINGO-1. However, we did not observe the increased expression of beta amyloid, hyperphosphorylation of tau and loss of neurons in demyelinated hippocampus. Our results suggest that demyelination might lead to the impairment of neuronal transport, but not cause increased level of hyperphosphorylated tau and beta amyloid. Our research demonstrates remyelination might be an effective pathway to recover the function of neuronal axons and cognition in MS. PMID:27129150

  14. Myelin injury induces axonal transport impairment but not AD-like pathology in the hippocampus of cuprizone-fed mice.

    PubMed

    Sun, Junjun; Zhou, Hong; Bai, Feng; Ren, Qingguo; Zhang, Zhijun

    2016-05-24

    Both multiple sclerosis (MS) and Alzheimer's disease (AD) are progressive neurological disorders with myelin injury and memory impairment. However, whether myelin impairment could cause AD-like neurological pathology remains unclear. To explore neurological pathology following myelin injury, we assessed cognitive function, the expression of myelin proteins, axonal transport-associated proteins, axonal structural proteins, synapse-associated proteins, tau and beta amyloid and the status of neurons, using the cuprizone mouse model of demyelination. We found the mild impairment of learning ability in cuprizone-fed mice and the decreased expression of myelin basic protein (MBP) in the hippocampus. And anti-LINGO-1 improved learning ability and partly restored MBP level. Furthermore, we also found kinesin light chain (KLC), neurofilament light chain (NFL) and neurofilament heavy chain (NF200) were declined in demyelinated hippocampus, which could be partly improved by treatment with anti-LINGO-1. However, we did not observe the increased expression of beta amyloid, hyperphosphorylation of tau and loss of neurons in demyelinated hippocampus. Our results suggest that demyelination might lead to the impairment of neuronal transport, but not cause increased level of hyperphosphorylated tau and beta amyloid. Our research demonstrates remyelination might be an effective pathway to recover the function of neuronal axons and cognition in MS. PMID:27129150

  15. The Ratio of Macronutrients, Not Caloric Intake, Dictates Cardiometabolic Health, Aging, and Longevity in Ad Libitum-Fed Mice

    PubMed Central

    Solon-Biet, Samantha M.; McMahon, Aisling C.; Ballard, J. William O.; Ruohonen, Kari; Wu, Lindsay E.; Cogger, Victoria C.; Warren, Alessandra; Huang, Xin; Pichaud, Nicolas; Melvin, Richard G.; Gokarn, Rahul; Khalil, Mamdouh; Turner, Nigel; Cooney, Gregory J.; Sinclair, David A.; Raubenheimer, David; Le Couteur, David G.; Simpson, Stephen J.

    2016-01-01

    Summary The fundamental questions of what represents a macronutritionally balanced diet and how this maintains health and longevity remain unanswered. Here, the Geometric Framework, a state-space nutritional modeling method, was used to measure interactive effects of dietary energy, protein, fat, and carbohydrate on food intake, cardiometabolic phenotype, and longevity in mice fed one of 25 diets ad libitum. Food intake was regulated primarily by protein and carbohydrate content. Longevity and health were optimized when protein was replaced with carbohydrate to limit compensatory feeding for protein and suppress protein intake. These consequences are associated with hepatic mammalian target of rapamycin (mTOR) activation and mitochondrial function and, in turn, related to circulating branched-chain amino acids and glucose. Calorie restriction achieved by high-protein diets or dietary dilution had no beneficial effects on lifespan. The results suggest that longevity can be extended in ad libitum-fed animals by manipulating the ratio of macronutrients to inhibit mTOR activation. PMID:24606899

  16. Progress report for the ASCI AD resistance weld process modeling project AD2003-15.

    SciTech Connect

    Brown, Arthur A.; Winters, William S.; Bammann, Douglas J.; Ortega, Arthur R.; Foulk, James W., III

    2005-05-01

    This report documents activities related to the ASCI AD Resistance Weld Process Modeling Project AD2003-15. Activities up to and including FY2004 are discussed. This was the third year for this multi year project, the objective of which is to position the SIERRA computational tools for the solution of resistance welding problems. The process of interest is a three-way coupled problem involving current flow, temperature buildup and large plastic deformation. The DSW application is the reclamation stem weld used in the manufacture of high pressure gas bottles. This is the first year the CALAGIO suite of codes (eCALORE, CALORE, and ADAGIO) was used to successfully solve a three-way coupled problem in SIERRA. This report discusses the application of CALAGIO to the tapered bar acceptance problem and a similar but independent tapered bar simulation of a companion C6 experiment. New additions to the EMMI constitutive model and issues related to CALAGIO performance are also discussed.

  17. Nobiletin, a citrus flavonoid, improves cognitive impairment and reduces soluble Aβ levels in a triple transgenic mouse model of Alzheimer's disease (3XTg-AD).

    PubMed

    Nakajima, Akira; Aoyama, Yuki; Shin, Eun-Joo; Nam, Yunsung; Kim, Hyoung-Chun; Nagai, Taku; Yokosuka, Akihito; Mimaki, Yoshihiro; Yokoi, Tsuyoshi; Ohizumi, Yasushi; Yamada, Kiyofumi

    2015-08-01

    Alzheimer's disease (AD), the most common form of dementia among the elderly, is characterized by the progressive decline of cognitive function. Increasing evidence indicates that the production and accumulation of amyloid β (Aβ), particularly soluble Aβ oligomers, is central to the pathogenesis of AD. Our recent studies have demonstrated that nobiletin, a polymethoxylated flavone from citrus peels, ameliorates learning and memory impairment in olfactory-bulbectomized mice, amyloid precursor protein transgenic mice, NMDA receptor antagonist-treated mice, and senescence-accelerated mouse prone 8. Here, we present evidence that this natural compound improves cognitive impairment and reduces soluble Aβ levels in a triple transgenic mouse model of AD (3XTg-AD) that progressively develops amyloid plaques, neurofibrillary tangles, and cognitive impairments. Treatment with nobiletin (30 mg/kg) for 3 months reversed the impairment of short-term memory and recognition memory in 3XTg-AD mice. Our ELISA analysis also showed that nobiletin reduced the levels of soluble Aβ1-40 in the brain of 3XTg-AD mice. Furthermore, nobiletin reduced ROS levels in the hippocampus of 3XTg-AD as well as wild-type mice. These results suggest that this natural compound has potential to become a novel drug for the treatment and prevention of AD.

  18. Period adding cascades: experiment and modeling in air bubbling.

    PubMed

    Pereira, Felipe Augusto Cardoso; Colli, Eduardo; Sartorelli, José Carlos

    2012-03-01

    Period adding cascades have been observed experimentally/numerically in the dynamics of neurons and pancreatic cells, lasers, electric circuits, chemical reactions, oceanic internal waves, and also in air bubbling. We show that the period adding cascades appearing in bubbling from a nozzle submerged in a viscous liquid can be reproduced by a simple model, based on some hydrodynamical principles, dealing with the time evolution of two variables, bubble position and pressure of the air chamber, through a system of differential equations with a rule of detachment based on force balance. The model further reduces to an iterating one-dimensional map giving the pressures at the detachments, where time between bubbles come out as an observable of the dynamics. The model has not only good agreement with experimental data, but is also able to predict the influence of the main parameters involved, like the length of the hose connecting the air supplier with the needle, the needle radius and the needle length.

  19. Deregulation of miRNA-181c potentially contributes to the pathogenesis of AD by targeting collapsin response mediator protein 2 in mice.

    PubMed

    Zhou, Huimin; Zhang, Rui; Lu, Kang; Yu, Wenjun; Xie, Bing; Cui, Dongsheng; Jiang, Lei; Zhang, Qingfu; Xu, Shunjiang

    2016-08-15

    Alzheimer's disease (AD) is a progressive neurodegenerative disorder that is usually accompanied by abnormal gene expression. The 20 to 25 nucleotide (nt) tiny regulators, known as micro ribonucleic acids (miRNAs), have been found to play important roles in the etiology and pathogenesis of various biological processes. The purpose of the current study was to identify the aberrant expression of microRNAs in the hippocampus of an AD mouse model and to investigate its potential role during the progression of AD. The results from microarray analysis showed that several miRNAs were deregulated in the hippocampus tissue of SAMP8 mice compared to SAMR1 mice. Among the deregulated miRNAs, a significant decrease in miR-181c was validated by quantitative real-time PCR. Bioinformatic analysis revealed that miR-181c might be involved in the regulation of axon guidance, MAPK signaling, dorso-ventral axis formation and long-term depression. Moreover, the results of a luciferase activity assay, western blot analysis and immunofluorescent staining showed that over-expression of miR-181c targets the 3'-untranslated region (3'-UTR) of collapsin response mediator protein 2 (crmp2) through its binding sites and down-regulates crmp2 protein abundance at the post-transcriptional level. Taken together, these findings suggested that crmp2 is a target of miR-181c and that the abnormally low expression of miR-181c in the hippocampus of SAMP8 mice could lead to an increase of the crmp2 protein level in AD mice, which might potentially play a role in the pathogenesis of Alzheimer's disease. PMID:27423553

  20. Tail-flick test response in 3×Tg-AD mice at early and advanced stages of disease.

    PubMed

    Baeta-Corral, Raquel; Defrin, Ruti; Pick, Chagi G; Giménez-Llort, Lydia

    2015-07-23

    Despite the impact of pain in cognitive dysfunctions and affective disorders has been largely studied, the research that examines pain dimensions in cognitive impairment or dementia is still scarce. In patients with Alzheimer's disease (AD) and related dementias, management of pain is challenging. While the sensory-discriminative dimension of pain is preserved, the cognitive-evaluative and the affective-motivational pain dimensions are affected. Due to the complexity of the disease and the poor self-reports, pain is underdiagnosed and undertreated. In confluence with an impaired thermoregulatory behavior, the patients' ability to confront environmental stressors such as cold temperature can put them at risk of fatal accidental hypothermia. Here, 3xTg-AD mice demonstrate that the sensorial-discriminative threshold to a noxious cold stimulus, as measured by the latency of tail-flicking, was preserved at early and advances stages of disease (7 and 11 month-old, respectively) as compared to age-matched (adulthood and middle aged, respectively) non-transgenic mice (NTg). In both genotypes, the sensory deterioration and poor thermoregulatory behavior associated to age was observed as an increase of tail-flick response and poor sensorimotor performance. At both stages studied, 3xTg-AD mice exhibited BPSD (Behavioral and Psychological Symptoms of Dementia)-like alterations in the corner, open-field, dark-light box and the T-maze tests. In the adult NTg mice, this nociceptive withdrawal response was correlated with copying with stress-related behaviors. This integrative behavioral profile was lost in both groups of 3xTg-AD mice and middle aged controls, suggesting derangements in their subjacent networks and the complex interplay between the pain dimensions in the elderly with dementia. PMID:26091881

  1. Influence of Asian Dust Particles on Immune Adjuvant Effects and Airway Inflammation in Asthma Model Mice

    PubMed Central

    Kurai, Jun; Watanabe, Masanari; Tomita, Katsuyuki; Yamasaki, Hiroyuki Sano Akira; Shimizu, Eiji

    2014-01-01

    Objective An Asian dust storm (ADS) contains airborne particles that affect conditions such as asthma, but the mechanism of exacerbation is unclear. The objective of this study was to compare immune adjuvant effects and airway inflammation induced by airborne particles collected on ADS days and the original ADS soil (CJ-1 soil) in asthma model mice. Methods Airborne particles were collected on ADS days in western Japan. NC/Nga mice were co-sensitized by intranasal instillation with ADS airborne particles and/or Dermatophagoides farinae (Df), and with CJ-1 soil and/or Df for 5 consecutive days. Df-sensitized mice were stimulated with Df challenge intranasally at 7 days after the last Df sensitization. At 24 hours after challenge, serum allergen specific antibody, differential leukocyte count and inflammatory cytokines in bronchoalveolar lavage fluid (BALF) were measured, and airway inflammation was examined histopathologically. Results Co-sensitization with ADS airborne particles and Df increased the neutrophil and eosinophil counts in BALF. Augmentation of airway inflammation was also observed in peribronchiolar and perivascular lung areas. Df-specific serum IgE was significantly elevated by ADS airborne particles, but not by CJ-1 soil. Levels of interleukin (IL)-5, IL-13, IL-6, and macrophage inflammatory protein-2 were higher in BALF in mice treated with ADS airborne particles. Conclusion These results suggest that substances attached to ADS airborne particles that are not in the original ADS soil may play important roles in immune adjuvant effects and airway inflammation. PMID:25386753

  2. Entropic information of dynamical AdS/QCD holographic models

    NASA Astrophysics Data System (ADS)

    Bernardini, Alex E.; da Rocha, Roldão

    2016-11-01

    The Shannon based conditional entropy that underlies five-dimensional Einstein-Hilbert gravity coupled to a dilaton field is investigated in the context of dynamical holographic AdS/QCD models. Considering the UV and IR dominance limits of such AdS/QCD models, the conditional entropy is shown to shed some light onto the meson classification schemes, which corroborate with the existence of light-flavor mesons of lower spins in Nature. Our analysis is supported by a correspondence between statistical mechanics and information entropy which establishes the physical grounds to the Shannon information entropy, also in the context of statistical mechanics, and provides some specificities for accurately extending the entropic discussion to continuous modes of physical systems. From entropic informational grounds, the conditional entropy allows one to identify the lower experimental/phenomenological occurrence of higher spin mesons in Nature. Moreover, it introduces a quantitative theoretical apparatus for studying the instability of high spin light-flavor mesons.

  3. Impaired thermoregulation and beneficial effects of thermoneutrality in the 3×Tg-AD model of Alzheimer's disease.

    PubMed

    Vandal, Milene; White, Philip J; Tournissac, Marine; Tremblay, Cyntia; St-Amour, Isabelle; Drouin-Ouellet, Janelle; Bousquet, Melanie; Traversy, Marie-Thérèse; Planel, Emmanuel; Marette, Andre; Calon, Frederic

    2016-07-01

    The sharp rise in the incidence of Alzheimer's disease (AD) at an old age coincides with a reduction in energy metabolism and core body temperature. We found that the triple-transgenic mouse model of AD (3×Tg-AD) spontaneously develops a lower basal body temperature and is more vulnerable to a cold environment compared with age-matched controls. This was despite higher nonshivering thermogenic activity, as evidenced by brown adipose tissue norepinephrine content and uncoupling protein 1 expression. A 24-hour exposure to cold (4 °C) aggravated key neuropathologic markers of AD such as: tau phosphorylation, soluble amyloid beta concentrations, and synaptic protein loss in the cortex of 3×Tg-AD mice. Strikingly, raising the body temperature of aged 3×Tg-AD mice via exposure to a thermoneutral environment improved memory function and reduced amyloid and synaptic pathologies within a week. Our results suggest the presence of a vicious cycle between impaired thermoregulation and AD-like neuropathology, and it is proposed that correcting thermoregulatory deficits might be therapeutic in AD. PMID:27255814

  4. Triptolide treatment reduces Alzheimer's disease (AD)-like pathology through inhibition of BACE1 in a transgenic mouse model of AD.

    PubMed

    Wang, Qi; Xiao, Bing; Cui, Shuqin; Song, Hailong; Qian, Yanjing; Dong, Lin; An, Haiting; Cui, Yanqiu; Zhang, Wenjing; He, Yi; Zhang, Jianliang; Yang, Jian; Zhang, Feilong; Hu, Guanzheng; Gong, Xiaoli; Yan, Zhen; Zheng, Yan; Wang, Xiaomin

    2014-12-01

    The complex pathogenesis of Alzheimer's disease (AD) involves multiple contributing factors, including amyloid β (Aβ) peptide accumulation, inflammation and oxidative stress. Effective therapeutic strategies for AD are still urgently needed. Triptolide is the major active compound extracted from Tripterygium wilfordii Hook.f., a traditional Chinese medicinal herb that is commonly used to treat inflammatory diseases. The 5-month-old 5XFAD mice, which carry five familial AD mutations in the β-amyloid precursor protein (APP) and presenilin-1 (PS1) genes, were treated with triptolide for 8 weeks. We observed enhanced spatial learning performances, and attenuated Aβ production and deposition in the brain. Triptolide also inhibited the processing of amyloidogenic APP, as well as the expression of βAPP-cleaving enzyme-1 (BACE1) both in vivo and in vitro. In addition, triptolide exerted anti-inflammatory and anti-oxidative effects on the transgenic mouse brain. Triptolide therefore confers protection against the effects of AD in our mouse model and is emerging as a promising therapeutic candidate drug for AD.

  5. Maternal High-Fat Diet Worsens Memory Deficits in the Triple-Transgenic (3xTgAD) Mouse Model of Alzheimer’s Disease

    PubMed Central

    Martin, Sarah A. L.; Jameson, Christine H.; Allan, Stuart M.; Lawrence, Catherine B.

    2014-01-01

    Alzheimer’s disease (AD) is not normally diagnosed until later in life, although evidence suggests that the disease starts at a much earlier age. Risk factors for AD, such as diabetes, hypertension and obesity, are known to have their affects during mid-life, though events very early in life, including maternal over-nutrition, can predispose offspring to develop these conditions. This study tested whether over-nutrition during pregnancy and lactation affected the development of AD in offspring, using a transgenic AD mouse model. Female triple-transgenic AD dam mice (3xTgAD) were exposed to a high-fat (60% energy from fat) or control diet during pregnancy and lactation. After weaning (at 3 weeks of age), female offspring were placed on a control diet and monitored up until 12 months of age during which time behavioural tests were performed. A transient increase in body weight was observed in 4-week-old offspring 3xTgAD mice from dams fed a high-fat diet. However, by 5 weeks of age the body weight of 3xTgAD mice from the maternal high-fat fed group was no different when compared to control-fed mice. A maternal high-fat diet led to a significant impairment in memory in 2- and 12-month-old 3xTgAD offspring mice when compared to offspring from control fed dams. These effects of a maternal high-fat diet on memory were accompanied by a significant increase (50%) in the number of tau positive neurones in the hippocampus. These data demonstrate that a high-fat diet during pregnancy and lactation increases memory impairments in female 3xTgAD mice and suggest that early life events during development might influence the onset and progression of AD later in life. PMID:24918775

  6. Animal models of anxiety in mice.

    PubMed

    Bourin, Michel; Petit-Demoulière, Benoit; Dhonnchadha, Brid Nic; Hascöet, Martine

    2007-12-01

    Among the multiple possibilities to study human pathologies, animal models remain one of the most used pathways. They allow to access to unavailable answers in human patients and to learn about mechanisms of action of drugs. Primarily developed with rats, animal models in anxiety have been adapted with a mixed success for mice, an easy-to-use mammal with better genetic possibilities than rats. In this review, we have focused on the most used animal models in anxiety in mice. Both conditioned and unconditioned models are described, to represent all types of animal models of anxiety. Behavioural studies require strong care for variable parameters, linked to environment, handling or paradigm; we have discussed about this topic. Finally, we focused on the consequences of re-exposure to the apparatus. Test-retest procedures can bring in new answers, but should be deeply studied, to revalidate the whole paradigm as an animal model of anxiety.

  7. APP/PS1 transgenic mice treated with aluminum: an update of Alzheimer's disease model.

    PubMed

    Zhang, Q L; Jia, L; Jiao, X; Guo, W L; Ji, J W; Yang, H L; Niu, Q

    2012-01-01

    There is still no animal model available that can mimic all the cognitive, behavioral, biochemical, and histopathological abnormalities observed in patients with Alzheimer's disease (AD). We undertook to consider the interaction between genetic factors, including amyloid precursor protein (APP) and presenilin-1 (PS1), and environmental factors, such as Aluminum (Al) in determining susceptibility outcomes when studying the pathogenesis of AD. In this article, we provide an AD model in APP/PS1 transgenic mice triggered by Al. The animal model was established via intracerebral ventricular microinjection of aluminum chloride once a day for 5 days in APP/PS1 transgenic mice. Twenty wild type (WT) mice and 20 APP/PS1 transgenic (TG) mice were separately divided into 2 groups (control and Al group), and a stainless steel injector with stopper was used for microinjection into the left-lateral cerebral ventricle of each mouse. The Morris water maze task was used to evaluate behavioral function of learning and memory ability on the 20th day after the last injection. This AD model's brain was analyzed by: (1) amyloid beta immunohistochemical staining; (2) Tunnel staining; (3) apoptotic rates; (4) caspase-3 gene expression. Here, decrease of cognitive ability and neural cells loss were shown in APP/PS1 transgenic mice exposed to Al, which were more extensive than those in APP/PS1 TG alone and WT mice exposed to Al alone. These findings indicate that there is a close relationship between over-expression of APP and PS1 genes and Al overload. It is also suggested that APP/PS1 TG mice exposed to Al have potential value for improving AD models.

  8. Preferential survival in models of complex ad hoc networks

    NASA Astrophysics Data System (ADS)

    Kong, Joseph S.; Roychowdhury, Vwani P.

    2008-05-01

    There has been a rich interplay in recent years between (i) empirical investigations of real-world dynamic networks, (ii) analytical modeling of the microscopic mechanisms that drive the emergence of such networks, and (iii) harnessing of these mechanisms to either manipulate existing networks, or engineer new networks for specific tasks. We continue in this vein, and study the deletion phenomenon in the web by the following two different sets of websites (each comprising more than 150,000 pages) over a one-year period. Empirical data show that there is a significant deletion component in the underlying web networks, but the deletion process is not uniform. This motivates us to introduce a new mechanism of preferential survival (PS), where nodes are removed according to the degree-dependent deletion kernel, D(k)∝k, with α≥0. We use the mean-field rate equation approach to study a general dynamic model driven by Preferential Attachment (PA), Double PA (DPA), and a tunable PS (i.e., with any α>0), where c nodes ( c<1) are deleted per node added to the network, and verify our predictions via large-scale simulations. One of our results shows that, unlike in the case of uniform deletion (i.e., where α=0), the PS kernel when coupled with the standard PA mechanism, can lead to heavy-tailed power-law networks even in the presence of extreme turnover in the network. Moreover, a weak DPA mechanism, coupled with PS, can help to make the network even more heavy-tailed, especially in the limit when deletion and insertion rates are almost equal, and the overall network growth is minimal. The dynamics reported in this work can be used to design and engineer stable ad hoc networks and explain the stability of the power-law exponents observed in real-world networks.

  9. Suppression of atopic dermatitis in mice model by reducing inflammation utilizing phosphatidylserine-coated biodegradable microparticles.

    PubMed

    Kumar, Purnima; Hosain, Md Zahangir; Kang, Jeong-Hun; Takeo, Masafumi; Kishimura, Akihiro; Mori, Takeshi; Katayama, Yoshiki

    2015-01-01

    Controlling inflammatory response is important to avoid chronic inflammation in many diseases including atopic dermatitis (AD). In this research, we tried using a phosphatidylserine (PS)-coated microparticles in the AD mouse model for achieving the modulation of the macrophage phenotype to an anti-inflammatory state. Here, we prepared poly (D,L-lactic acid) microparticle coated with PS on the outside shell. We confirmed the cellular uptake of the PS-coated microparticle, which leads to the significant downregulation of the inflammatory cytokine production. In the mouse model of AD, the PS-coated microparticle was injected subcutaneously for a period of 12 days. The mice showed significant reduction in the development of AD symptoms comparing with the mice treated with the PC-coated microparticle. PMID:26414796

  10. A model of the two-dimensional quantum harmonic oscillator in an AdS_3 background

    NASA Astrophysics Data System (ADS)

    Frick, R.

    2016-10-01

    In this paper we study a model of the two-dimensional quantum harmonic oscillator in a three-dimensional anti-de Sitter background. We use a generalized Schrödinger picture in which the analogs of the Schrödinger operators of the particle are independent of both the time and the space coordinates in different representations. The spacetime independent operators of the particle induce the Lie algebra of Killing vector fields of the AdS_3 spacetime. In this picture, we have a metamorphosis of the Heisenberg uncertainty relations.

  11. DK-26 model added to Daihastu product line

    SciTech Connect

    1996-12-01

    Adding to the company`s modern-design DK series of medium-speed engines, Daihatsu Diesel has introduced the DK-26 diesel. With a rated power output of 1681 kW at 720 or 750 r/min, the new six-cylinder engine fits nicely between the DK-20 and DK-28 models introduced over the last three years. Daihatsu`s recent diesel engine developments have focused on meeting market requirements in the years to come for prime movers in marine propulsion, marine auxiliary power generation and stationary power plant applications. The newly developed DK series aims to meet these requirements with high reliability and durability, reduced maintenance costs, and high operational economy. Other design goals were for the engines to be environmentally friendly, as well as light and compact. With three different bore sizes available, the DK series covers a power range from 400kW to 2500 kW, meeting most power requirements for marine generators, as well as propulsion systems for ferries, fishing boats and freighters. The engines are rated for operation on diesel oil, as well as heavy fuel to 180 cSt/50{degree}C. 2 figs., 1 tab.

  12. Peripherally administered sera antibodies recognizing amyloid-β oligomers mitigate Alzheimer's disease-like pathology and cognitive decline in aged 3× Tg-AD mice.

    PubMed

    Wang, Hai-Chao; Yu, Yun-Zhou; Liu, Si; Zhao, Meng; Xu, Qing

    2016-04-01

    Active and passive immunotherapy targeting amyloid-β (Aβ) may be the most promising strategy to prevent or treat Alzheimer's disease (AD). Previously, immunization with the recombinant 6Aβ15-T antigen generated robust anti-Aβ serum antibodies that strongly recognized Aβ42 oligomers in different mice, markedly reduced the amyloid burden, and improved behavioral performance of immunized older AD mice. Here, we further determined that these anti-6Aβ15-T serum antibodies from different strains of mice displayed anti-Aβ antibody responses against the same epitopes in the Aβ1-15 region. Peripheral administration of anti-6Aβ15-T serum antibodies was also effective to mitigate AD-like pathology and cognitive decline in aged 3× Tg-AD mice. Specifically, the levels of Aβ and tau in the brains of 3× Tg-AD mice were significantly reduced after passive immunotherapy, which seemed necessary or beneficial to ameliorate memory impairment. In addition, our results showed that this immunotherapy also prevented presynaptic dynamin 1 degradation, which might help to further protect synaptic functions and allow functional recovery of cognition. Moreover, immunization with 6Aβ15-T in rabbits induced a similar antibody response as that in mice, and the rabbit serum antibodies reacted strongly with Aβ42 oligomers and inhibited oligomer-mediated neurotoxicity. We concluded that passive immunization with Aβ42 oligomer conformation-sensitive anti-6Aβ15-T serum antibodies is effective in providing potentially therapeutic effects in aged 3× Tg-AD mice by reducing Aβ and tau.

  13. AdS Black Disk Model for Small-x Deep Inelastic Scattering

    NASA Astrophysics Data System (ADS)

    Cornalba, Lorenzo; Costa, Miguel S.; Penedones, João

    2010-08-01

    Using the approximate conformal invariance of QCD at high energies we consider a simple anti-de Sitter black disk model to describe saturation in deep inelastic scattering. Deep inside saturation the structure functions have the same power law scaling, FT˜FL˜x-ω, where ω is related to the expansion rate of the black disk with energy. Furthermore, the ratio FL/FT is given by the universal value (1+ω)/(3+ω), independently of the target. For γ*-γ* scattering at high energies we obtain explicit expressions and ratios for the total cross sections of transverse and longitudinal photons in terms of the single parameter ω.

  14. Defensive effect of lansoprazole in dementia of AD type in mice exposed to streptozotocin and cholesterol enriched diet.

    PubMed

    Sodhi, Rupinder K; Singh, Nirmal

    2013-01-01

    The present study investigates the potential of lansoprazole (a proton pump inhibitor and agonist of liver x receptors) in experimental dementia of AD type. Streptozotocin [STZ, 3 mg/kg, injected intracerebroventricular (i.c.v), and high fat diet (HFD, administered for 90 days)] were used to induce dementia in separate groups of Swiss mice. Morris water maze (MWM) test was performed to assess learning and memory of the animals. A battery of biochemical and histopathological studies were also performed. Extent of oxidative stress was measured by estimating the levels of brain reduced glutathione (GSH) and thiobarbituric acid reactive species (TBARS). Brain acetylcholinestrase (AChE) activity and serum cholesterol levels were also estimated. The brain level of myeloperoxidase (MPO) was measured as a marker of inflammation. STZ and HFD produced a marked decline in MWM performance of the animals, reflecting impairment of learning and memory. STZ/HFD treated mice exhibited a marked accentuation of AChE activity, TBARS and MPO levels along with a fall in GSH levels. Further, the stained micrographs of STZ/HFD treated mice indicated pathological changes, severe neutrophilic infiltration and amyloid deposition. Lansoprazole treatment significantly attenuated STZ and HFD -induced memory deficits, biochemical and histopathological alterations. It also prevented HFD-induced rise in the cholesterol level. Therefore, the findings demonstrate potential of lansoprazole in memory dysfunctions which may probably be attributed to its anti-cholinesterase, anti-oxidative and anti-inflammatory effects. Moreover, both cholesterol-dependent as well as cholesterol-independent effects of lansoprazole appear to play a role. In addition study indicates the role of liver x receptors in dementia.

  15. Spontaneous scratching behaviour in DS-Nh mice as a possible model for pruritus in atopic dermatitis

    PubMed Central

    Yoshioka, T; Hikita, I; Asakawa, M; Hirasawa, T; Deguchi, M; Matsutani, T; Oku, H; Horikawa, T; Arimura, A

    2006-01-01

    Itching is one of the major clinical symptoms in atopic dermatitis (AD) and complicates the management of this pathological condition. An animal model of AD-like pruritus would contribute to a better understanding of AD and could lead to the development of safe and effective antipruritic agents. DS non-hair (DS-Nh) mice raised under conventional conditions spontaneously develop pruritus, which is associated with a dermatitis similar to human AD. There is a significant positive correlation between disease severity and the period of scratching behaviour in DS-Nh mice. In the present study, we found that levels of histamine and nerve growth factor (NGF) in serum and/or skin tissue were higher in DS-Nh mice with AD-like dermatitis than in age-matched mice without dermatitis. The histopathological data indicated that nerve fibres extend into and mast cells infiltrate the surrounding area of the skin lesion. NGF production by XB-2 cells, which was derived from mouse keratinocytes, was enhanced by histamine via the H1 receptor. We also found that prolonged treatment with an H1-antagonist was effective against pruritus through depression of the production of NGF, which is thought to be generated by keratinocytes. We conclude that DS-Nh mice can serve as a suitable model for gaining a better understanding of pruritus in AD, and that prolonged treatment with an H1-antagonist may be beneficial in patients with AD-associated pruritus. PMID:16827890

  16. Effects of CX3CR1 and Fractalkine Chemokines in Amyloid Beta Clearance and p-Tau Accumulation in Alzheimer's Disease (AD) Rodent Models: Is Fractalkine a Systemic Biomarker for AD?

    PubMed

    Merino, José Joaquín; Muñetón-Gómez, Vilma; Alvárez, María-Isabel; Toledano-Díaz, Adolfo

    2016-01-01

    Microglia and astrocytes are the major source of cytokines in Alzheimer,s disease (AD). CX3CR1 is a delta chemokine receptor found in microglia and its neuronal ligand, Fractalkine, has two isoforms: an anchored-membrane isoform, and a soluble isoform. The reduced soluble fractalkine levels found in the brain (cortex/hippocampus) of aged rats, may be a consequence of neuronal loss. This soluble fractalkine maintains microglia in an appropiate state by interacting with CX3CR1. The ablation of the CX3CR1 gene in mice overexpressing human amyloid precursor protein (APP/PS-1) increased cytokine levels, enhanced Tau pathology and worsened behavioural performance in these mice. However, CX3CR1 deficiency resulted in a gene dose-dependent Aβ clearance in the brain, and induced microglial activation. In addition, CX3CR1 deficiency can have benefical effects by preventing neuronal loss in the 3xTg model. In fact, CX3CR1 deficiency increases microglial phagocytosome activity by inducing selective protofibrillar amyloid-beta phagocytosis in microglial cells in transgenic AD models. On the other hand, the fractalkine membrane isoform plays a differential role in amyloid beta clearance and Tau deposition. This anchored membrane FKN signalling might increase amyloid pathology while soluble fractalkine levels could prevent taupathies. However, in human AD, the only published study has reported higher systemic fractalkine levels in AD patients with cognitive impairment. In mouse models, inflammatory activation of microglia accelerates Tau pathology. Studies in transgenic mice with fractalkine null mice suggest that APP/PS-1 mice deficient for the anchored membrane-fractalkine isoform exhibited enhanced neuronal MAPT phosphorylation despite their reduced amyloid burden. The soluble fractalkine overexpression with adenoviral vectors reduced tau pathology and prevented neurodegeneration in a Tg4510 model of taupathy Finally, animals with Aβ (1-42) infused by lentivirus (cortex) or

  17. Studies on the correlation with olfactory dysfunction in a transgenic mice model of Alzheimer's disease

    NASA Astrophysics Data System (ADS)

    Rasheed, Ameer; Lee, Ji Hye; Suh, Yoo-Hun; Moon, Cheil

    2013-05-01

    Alzheimer's disease (AD) is a progressively debilitating neurodegenerative disorder characterized by the presence of proteinaceous deposits in the brain. AD often results in olfactory dysfunction and impaired olfactory perceptual acuity may be a potential biomarker for early diagnosis of AD. Until recently, there is no Alzheimer's nanoscope or any other high-end microscope developed to be capable of seeing buried feature of AD clearly. Modern neuroimaging techniques are more effective only after the occurrence of cognitive impairment. Therefore, early detection of Alzheimer's disease is critical in developing effective treatment of AD. H and E (Haematoxyline and Eosin) staining is performed for examining gross morphological changes, while TUNEL (transferase (TdT)-mediated dUTP nick end labeling) staining for monitoring neuronal death in the olfactory epithelium (OE). Furthermore, immunohistochemistry and western blot are performed to examine β-amyloid protein expression. AD model animals were Tg2576 (transgenic mice that overexpress a mutated form of the Aβ precursor protein), and 6 month (before onset of AD symptoms) and 14 month (after onset of AD symptoms) old WT (wild type) and transgenic mice were compared in their olfactory system. We found that in OE of Tg2576 mice, thickness and total number of cells were decreased, while the numbers of TUNEL-positive neurons, caspase-3 activation were significantly increased compared with age-matched WT. Our results demonstrate that the olfactory system may get deteriorated before onset of AD symptoms. Our findings imply that an olfactory biopsy could be served as an early and relatively simple diagnostic tool for potential AD patients.

  18. Evaluation of the effects of testosterone and luteinizing hormone on regulation of β-amyloid in male 3xTg-AD mice.

    PubMed

    Rosario, Emily R; Carroll, Jenna C; Pike, Christian J

    2012-07-23

    During normal aging, men experience a significant decline in testosterone levels and a compensatory elevation in levels of gonadotropin luteinizing hormone (LH). Both low testosterone and elevated LH have been identified as significant risk factors for the development of Alzheimer's disease (AD) in men. It is unclear whether changes in testosterone or LH primarily underlie the relationship with AD, and therefore may be a more suitable therapeutic target. To examine this issue, we compared levels of β-amyloid (Aβ) immunoreactivity in male 3xTg-AD mice under varying experimental conditions associated with relatively low or high levels of testosterone and/or LH. In gonadally intact mice, Aβ accumulation increased after treatment with the gonadotropin-releasing hormone agonist leuprolide, which inhibits the hypothalamic-pituitary-gonadal (HPG) axis and reduces both testosterone and LH levels. In gonadectomized (GDX) mice with low testosterone and high LH, we also observed increased Aβ levels. Treatment of GDX mice with testosterone significantly reduced Aβ levels. In contrast, leuprolide did not significantly decrease Aβ levels and moreover, inhibited the Aβ-lowering effect of testosterone. Evaluation of hippocampal-dependent behavior revealed parallel findings, with performance in GDX mice improved by testosterone but not leuprolide. These data suggest that Aβ-lowering actions of testosterone are mediated directly by androgen pathways rather than indirectly via regulation of LH and the HPG axis. These findings support the clinical evaluation of androgen therapy in the prevention and perhaps treatment of AD in hypogonadal men.

  19. Fyn knock-down increases Aβ, decreases phospho-tau, and worsens spatial learning in 3xTg-AD mice

    PubMed Central

    Minami, S. Sakura; Clifford, Thomas G.; Hoe, Hyang-Sook; Matsuoka, Yasuji; Rebeck, G. William

    2011-01-01

    Fyn kinase phosphorylates tau and exacerbates Aβ-mediated synaptic dysfunction. However, Fyn also increases the non-pathological cleavage of amyloid precursor protein (APP), suggesting opposing roles for Fyn in the pathogenesis of Alzheimer’s disease (AD). To determine the effect of Fyn on both Aβ and tau pathologies, we crossed homozygous AD triple transgenic (3xTg) mice harboring mutations in APP, presenilin-1, and tau with wild-type or Fyn knock-out mice to generate Fyn+/+3xTg+/− or Fyn+/−3xTg+/− mice. We found that Fyn+/−3xTg+/− mice had increased soluble and intracellular Aβ, and these changes were accompanied by impaired performance on the Morris water maze at 18 months. Fyn+/−3xTg+/− mice had decreased phosphorylated tau at 15–18 months (as did Fyn knock-out mice), but Fyn+/−3xTg+/− mice had increased phosphorylated tau by 24 months. In addition, we observed that Fyn+/−3xTg+/− males were delayed in developing Aβ pathology compared to females, and displayed better spatial learning performance at 18 months. Overall, these findings suggest that loss of Fyn at early stages of disease increases soluble A accumulation and worsens spatial learning in the absence of changes in tau phosphorylation. PMID:21741124

  20. The Plate Paradigm; the Standard Model Reductio ~ ad ~Absurdum

    NASA Astrophysics Data System (ADS)

    Anderson, D. L.

    2003-12-01

    Midplate volcanism, volcanic chains, diffuse boundaries and variable chemistry basalts are usually considered to be outside the plate tectonic hypothesis and to need separate explanations. This is true only for the instantaneous, steady state, kinematic and hard plate versions of the hypothesis. In the more general plate paradigm (with fewer restrictive adjectives), melting `anomalies', seamount chains, and LIPs are by-products of plate tectonics. This assumes that the shallow mantle is close to the (variable) melting point and that athermal and episodic processes are important. Cooling of the surface generates forces that drive, break and reorganize plates; global reorganizations (including new plate boundaries) are intrinsic; regions of intense, long-lived magmatism and shallow tensile stress are (usually but not always) plate boundaries. Plates are regions of lateral compression. Plate boundaries have shallow extensional or strike-slip earthquakes; where the mantle is near the melting point the buoyancy of magma generates dikes and volcanoes. When compressional forces dominate, upwelling magmas pond beneath the plate until released by extensional stresses. Large melting anomalies are episodic and associated with changes in plate stress and new plate boundaries (often triple-junctions). Incipient boundaries can be extensional and volcanic, as can abandoned ones. Ridges, island arcs, seamount fields and chains, and reactivated and incipient boundaries, are part of a single process. The plate paradigm thereby reverses the assumptions of current geodynamic and geochemical reservoir models : Locations of volcanoes are controlled by lithospheric stress and fabric ( not mantle temperature ).The volumes of magma are controlled by lithospheric extension and shallow mantle fertility (not by conditions at the core mantle boundary).The stress-, fertility- and thermal-states are controlled by plate tectonics and upper mantle recycling (not by infusions from the deep mantle

  1. β-Secretase 1’s Targeting Reduces Hyperphosphorilated Tau, Implying Autophagy Actors in 3xTg-AD Mice

    PubMed Central

    Piedrahita, Diego; Castro-Alvarez, John Fredy; Boudreau, Ryan L.; Villegas-Lanau, Andres; Kosik, Kenneth S.; Gallego-Gomez, Juan Carlos; Cardona-Gómez, Gloria Patricia

    2016-01-01

    β-site APP cleaving enzyme 1 (BACE1) initiates APP cleavage, which has been reported to be an inducer of tau pathology by altering proteasome functions in Alzheimer’s disease (AD). However, the exact relationship between BACE1 and PHF (Paired Helical Filaments) formation is not clear. In this study, we confirm that BACE1 and Hsc70 are upregulated in the brains of AD patients, and we demonstrate that both proteins show enhanced expression in lipid rafts from AD-affected triple transgenic mouse brains. BACE1 targeting increased Hsc70 levels in the membrane and cytoplasm fractions and downregulated Hsp90 and CHIP in the nucleus in the hippocampi of 3xTg-AD mice. However, these observations occurred in a proteasome-independent manner in vitro. The BACE1miR-induced reduction of soluble hyperphosphorylated tau was associated with a decrease in MAPK activity. However, the BACE1 RNAi-mediated reduction of hyperphosphorylated tau was only blocked by 3-MA (3-methyladenine) in vitro, and it resulted in the increase of Hsc70 and LAMP2 in lipid rafts from hippocampi of 3xTg-AD mice, and upregulation of survival and homeostasis signaling. In summary, our findings suggest that BACE1 silencing neuroprotects reducing soluble hyperphosphorylated tau, modulating certain autophagy-related proteins in aged 3xTg-AD mice. PMID:26778963

  2. Arctigenin effectively ameliorates memory impairment in Alzheimer's disease model mice targeting both β-amyloid production and clearance.

    PubMed

    Zhu, Zhiyuan; Yan, Jianming; Jiang, Wei; Yao, Xin-gang; Chen, Jing; Chen, Lili; Li, Chenjing; Hu, Lihong; Jiang, Hualiang; Shen, Xu

    2013-08-01

    Alzheimer's disease (AD) chiefly characterizes a progressively neurodegenerative disorder of the brain, and eventually leads to irreversible loss of intellectual abilities. The β-amyloid (Aβ)-induced neurodegeneration is believed to be the main pathological mechanism of AD, and Aβ production inhibition or its clearance promotion is one of the promising therapeutic strategies for anti-AD research. Here, we report that the natural product arctigenin from Arctium lappa (L.) can both inhibit Aβ production by suppressing β-site amyloid precursor protein cleavage enzyme 1 expression and promote Aβ clearance by enhancing autophagy through AKT/mTOR signaling inhibition and AMPK/Raptor pathway activation as investigated in cells and APP/PS1 transgenic AD model mice. Moreover, the results showing that treatment of arctigenin in mice highly decreased Aβ formation and senile plaques and efficiently ameliorated AD mouse memory impairment strongly highlight the potential of arctigenin in anti-AD drug discovery.

  3. Arctigenin effectively ameliorates memory impairment in Alzheimer's disease model mice targeting both β-amyloid production and clearance.

    PubMed

    Zhu, Zhiyuan; Yan, Jianming; Jiang, Wei; Yao, Xin-gang; Chen, Jing; Chen, Lili; Li, Chenjing; Hu, Lihong; Jiang, Hualiang; Shen, Xu

    2013-08-01

    Alzheimer's disease (AD) chiefly characterizes a progressively neurodegenerative disorder of the brain, and eventually leads to irreversible loss of intellectual abilities. The β-amyloid (Aβ)-induced neurodegeneration is believed to be the main pathological mechanism of AD, and Aβ production inhibition or its clearance promotion is one of the promising therapeutic strategies for anti-AD research. Here, we report that the natural product arctigenin from Arctium lappa (L.) can both inhibit Aβ production by suppressing β-site amyloid precursor protein cleavage enzyme 1 expression and promote Aβ clearance by enhancing autophagy through AKT/mTOR signaling inhibition and AMPK/Raptor pathway activation as investigated in cells and APP/PS1 transgenic AD model mice. Moreover, the results showing that treatment of arctigenin in mice highly decreased Aβ formation and senile plaques and efficiently ameliorated AD mouse memory impairment strongly highlight the potential of arctigenin in anti-AD drug discovery. PMID:23926267

  4. Value-Added Models and the Measurement of Teacher Productivity. CALDER Working Paper No. 54

    ERIC Educational Resources Information Center

    Harris, Douglas; Sass, Tim; Semykina, Anastasia

    2010-01-01

    Research on teacher productivity, and recently developed accountability systems for teachers, rely on value-added models to estimate the impact of teachers on student performance. The authors test many of the central assumptions required to derive value-added models from an underlying structural cumulative achievement model and reject nearly all…

  5. Human apolipoprotein E4 worsens acute axonal pathology but not amyloid-β immunoreactivity after traumatic brain injury in 3xTG-AD mice.

    PubMed

    Bennett, Rachel E; Esparza, Thomas J; Lewis, Hal A; Kim, Eddie; Mac Donald, Christine L; Sullivan, Patrick M; Brody, David L

    2013-05-01

    Apolipoprotein E4 (APOE4) genotype is a risk factor for poor outcome after traumatic brain injury (TBI), particularly in young patients, but the underlying mechanisms are not known. By analogy to effects of APOE4 on the risk of Alzheimer disease (AD), the APOE genotype may influence β-amyloid (Aβ) and tau deposition after TBI. To test this hypothesis, we crossed 3xTG-AD transgenic mice carrying 3 human familial AD mutations (PS1(M146V), tauP(301)L, and APP(SWE)) to human ApoE2-, ApoE3-, and ApoE4-targeted replacement mice. Six- to 8-month-old 3xTG-ApoE mice were assayed by quantitative immunohistochemistry for amyloid precursor protein (APP), Aβ(1-40) (Aβ40), Aβ(1-42) (Aβ42), total human tau, and phospho-serine 199 (pS199) tau at 24 hours after moderate controlled cortical impact. There were increased numbers of APP-immunoreactive axonal varicosities in 3xTG-ApoE4 mice versus the other genotypes. This finding was repeated in a separate cohort of ApoE4-targeted replacement mice without human transgenes compared with ApoE3 and ApoE2 mice. There were no differences between genotypes in the extent of intra-axonal Aβ40 and Aβ42; none of the mice had extracellular Aβ deposition. Regardless of injury status, 3xTG-ApoE4 mice had more total human tau accumulation in both somatodendritic and intra-axonal compartments than other genotypes. These results suggest that the APOE4 genotype may have a primary effect on the severity of axonal injury in acute TBI.

  6. Early postnatal handling and environmental enrichment improve the behavioral responses of 17-month-old 3xTg-AD and non-transgenic mice in the Forced Swim Test in a gender-dependent manner.

    PubMed

    Torres-Lista, Virginia; Giménez-Llort, Lydia

    2015-11-01

    Forced Swimming Test (FST) models behavioural despair in animals by loss of motivation to respond or the refusal to escape. The present study was aimed at characterizing genetic (genotype and gender) and environmental factors (age/stage of disease and rearing conditions: C, standard; H, early postnatal handling; EE, environmental enrichment consisting in physical exercise as well as social and object enrichment) that may modulate the poor behavioural and cognitive flexibility response we have recently described in 12-month-old male 3xTg-AD mice in the FST. The comprehensive analysis of the ethogram shown in the FST considered the intervals of the test (0-2 and 2-6min), all the elicited behavioural responses (immobility, swimming and climbing) and their features (total duration and frequency of episodes). The long persistence of behaviours found in 17-month-old (late-stages of disease) 3xTg-AD mice was comparable to that recently described in males at 12 months of age (beginning of advanced stages) but also suggested increased age-dependent frailty in both genotypes. The poor behavioral flexibility of 3xTg-AD mice to elicit the behavioural despair shown by the NTg mice, was also found in the female gender. Finally, the present work demonstrates that early-life interventions were able to improve the time and frequency of episodes of immobility, being more evident in the female gender of both old NTg and 3xTg-AD mice. Ontogenic modulation by early-postnatal handling resulted in a more effective long-term improvement of the elicited behaviours in the FST than that achieved by environmental enrichment. The results talk in favor of the beneficence of early-life interventions on ageing in both healthy and disease conditions.

  7. IVIg protects the 3xTg-AD mouse model of Alzheimer’s disease from memory deficit and Aβ pathology

    PubMed Central

    2014-01-01

    Background Intravenous immunoglobulin (IVIg) is currently in clinical study for Alzheimer’s disease (AD). However, preclinical investigations are required to better understand AD-relevant outcomes of IVIg treatment and develop replacement therapies in case of unsustainable supply. Methods We investigated the effects of IVIg in the 3xTg-AD mouse model, which reproduces both Aβ and tau pathologies. Mice were injected twice weekly with 1.5 g/kg IVIg for 1 or 3 months. Results IVIg induced a modest but significant improvement in memory in the novel object recognition test and attenuated anxiety-like behavior in 3xTg-AD mice. We observed a correction of immunologic defects present in 3xTg-AD mice (−22% CD4/CD8 blood ratio; −17% IL-5/IL-10 ratio in the cortex) and a modulation of CX3CR1+ cell population (−13% in the bone marrow). IVIg treatment led to limited effects on tau pathology but resulted in a 22% reduction of the soluble Aβ42/Aβ40 ratio and a 60% decrease in concentrations of 56 kDa Aβ oligomers (Aβ*56). Conclusion The memory-enhancing effect of IVIg reported here suggests that Aβ oligomers, effector T cells and the fractalkine pathway are potential pharmacological targets of IVIg in AD. PMID:24655894

  8. Data on the phospholipid fatty acyl composition of retroperitoneal white adipose tissue in ad libitum fed and fasted mice

    PubMed Central

    Marks, Kristin A.; Marvyn, Phillip M.; Henao, Juan J. Aristizabal; Bradley, Ryan M.; Stark, Ken D.; Duncan, Robin E.

    2016-01-01

    Data are presented on the fatty acyl composition of phospholipid from retroperitoneal white adipose tissue of female mice that were either given ad libitum access to food or fasted for 16 h overnight prior to sacrifice. Our data show that total adipose phospholipid concentrations were more than 2-fold higher in the fasted animals compared with the fed animals (33.48±7.40 versus 16.57±4.43 μg phospholipid fatty acids/100 mg tissue). Concentrations of several individual phospholipid fatty acyl species, including palmitic acid (16:0), vaccenic acid (18:1n-7), linoleic acid (18:2n-6), dihomo-gamma-linolenic acid (20:3n-6), arachidonic acid (20:4n-6), eicosapentaenoic acid (20:5n-3) and docosahexaenoic acid (22:6n-3), as well as total phospholipid saturated fatty acids, n-6 polyunsaturated fatty acids and n-3 polyunsaturated fatty acids, were significantly higher in adipose tissue from the fasted animals compared with the fed animals. However, when the relative abundance of phospholipid fatty acyl species was analyzed, only 20:4n-6 was specifically enriched (by ~2.5-fold) in adipose phospholipid with fasting. PMID:27014729

  9. Mice as a model for homeopathy research.

    PubMed

    Khuda-Bukhsh, Anisur Rahman

    2009-10-01

    Mice (Mus musculus) have been used as a model for homeopathy research in relation to cytotoxicity, genotoxicity and carcinogenesis in our laboratory for the last three decades. Initially, anti-radiation activities of several potentized homeopathic drugs were tested against suitable controls by taking into consideration several cytogenetic endpoints. Subsequently, anti-cytotoxic, anti-genotoxic and anti-oxidative stress effects of some homeopathic drugs were tested against several chemical toxic metalloids and metal compounds. Modern techniques including Western blot, immunofluorescence, electron microscopy, UV-spectroscopy, HPLC, FTIR, NMR, RT-PCR etc were deployed to understand the possible mechanisms and pathways of action of potentized homeopathic drugs. We hypothesise that one way by which potentized homeopathic drugs act is through regulatory action on gene expression.

  10. Value-Added Models of Assessment: Implications for Motivation and Accountability

    ERIC Educational Resources Information Center

    Anderman, Eric M.; Anderman, Lynley H.; Yough, Michael S.; Gimbert, Belinda G.

    2010-01-01

    In this article, we examine the relations of value-added models of measuring academic achievement to student motivation. Using an achievement goal orientation theory perspective, we argue that value-added models, which focus on the progress of individual students over time, are more closely aligned with research on student motivation than are more…

  11. Modeling HIV-1 Mucosal Transmission and Prevention in Humanized Mice.

    PubMed

    Veselinovic, Milena; Charlins, Paige; Akkina, Ramesh

    2016-01-01

    The new generation humanized mice (hu-mice) that permit continuous de novo generation of human hematopoietic cells have led to novel strategies in studying HIV-1 pathogenesis, prevention and therapies. HIV-1 infection of hu-mice results in chronic viremia and CD4+ T cell loss, thus mimicking key aspects of the disease progression. In addition, the new generation hu-mice are permissive for HIV-1 sexual transmission by vaginal and rectal routes thus allowing in vivo efficacy testing of new anti-HIV-1 drugs for prevention. Two leading models are currently being used, namely the hu-HSC mice and the BLT mice. Here we describe the methodology for generating both hu-HSC and BLT mice and their use in the study of HIV-1 transmission and prevention of infection by topical and oral administration of anti-retroviral drugs. Practical aspects of the methodologies are emphasized.

  12. Strategies for fitting nonlinear ecological models in R, AD Model Builder, and BUGS

    USGS Publications Warehouse

    Bolker, Benjamin M.; Gardner, Beth; Maunder, Mark; Berg, Casper W.; Brooks, Mollie; Comita, Liza; Crone, Elizabeth; Cubaynes, Sarah; Davies, Trevor; de Valpine, Perry; Ford, Jessica; Gimenez, Olivier; Kéry, Marc; Kim, Eun Jung; Lennert-Cody, Cleridy; Magunsson, Arni; Martell, Steve; Nash, John; Nielson, Anders; Regentz, Jim; Skaug, Hans; Zipkin, Elise

    2013-01-01

    1. Ecologists often use nonlinear fitting techniques to estimate the parameters of complex ecological models, with attendant frustration. This paper compares three open-source model fitting tools and discusses general strategies for defining and fitting models. 2. R is convenient and (relatively) easy to learn, AD Model Builder is fast and robust but comes with a steep learning curve, while BUGS provides the greatest flexibility at the price of speed. 3. Our model-fitting suggestions range from general cultural advice (where possible, use the tools and models that are most common in your subfield) to specific suggestions about how to change the mathematical description of models to make them more amenable to parameter estimation. 4. A companion web site (https://groups.nceas.ucsb.edu/nonlinear-modeling/projects) presents detailed examples of application of the three tools to a variety of typical ecological estimation problems; each example links both to a detailed project report and to full source code and data.

  13. Interpreting incremental value of markers added to risk prediction models.

    PubMed

    Pencina, Michael J; D'Agostino, Ralph B; Pencina, Karol M; Janssens, A Cecile J W; Greenland, Philip

    2012-09-15

    The discrimination of a risk prediction model measures that model's ability to distinguish between subjects with and without events. The area under the receiver operating characteristic curve (AUC) is a popular measure of discrimination. However, the AUC has recently been criticized for its insensitivity in model comparisons in which the baseline model has performed well. Thus, 2 other measures have been proposed to capture improvement in discrimination for nested models: the integrated discrimination improvement and the continuous net reclassification improvement. In the present study, the authors use mathematical relations and numerical simulations to quantify the improvement in discrimination offered by candidate markers of different strengths as measured by their effect sizes. They demonstrate that the increase in the AUC depends on the strength of the baseline model, which is true to a lesser degree for the integrated discrimination improvement. On the other hand, the continuous net reclassification improvement depends only on the effect size of the candidate variable and its correlation with other predictors. These measures are illustrated using the Framingham model for incident atrial fibrillation. The authors conclude that the increase in the AUC, integrated discrimination improvement, and net reclassification improvement offer complementary information and thus recommend reporting all 3 alongside measures characterizing the performance of the final model.

  14. Adding ecosystem function to agent-based land use models

    PubMed Central

    Yadav, V.; Del Grosso, S.J.; Parton, W.J.; Malanson, G.P.

    2015-01-01

    The objective of this paper is to examine issues in the inclusion of simulations of ecosystem functions in agent-based models of land use decision-making. The reasons for incorporating these simulations include local interests in land fertility and global interests in carbon sequestration. Biogeochemical models are needed in order to calculate such fluxes. The Century model is described with particular attention to the land use choices that it can encompass. When Century is applied to a land use problem the combinatorial choices lead to a potentially unmanageable number of simulation runs. Century is also parameter-intensive. Three ways of including Century output in agent-based models, ranging from separately calculated look-up tables to agents running Century within the simulation, are presented. The latter may be most efficient, but it moves the computing costs to where they are most problematic. Concern for computing costs should not be a roadblock. PMID:26191077

  15. Exercise Does Not Protect against Peripheral and Central Effects of a High Cholesterol Diet Given Ad libitum in Old ApoE−/− Mice

    PubMed Central

    Di Cataldo, Vanessa; Géloën, Alain; Langlois, Jean-Baptiste; Chauveau, Fabien; Thézé, Benoît; Hubert, Violaine; Wiart, Marlène; Chirico, Erica N.; Rieusset, Jennifer; Vidal, Hubert; Pialoux, Vincent; Canet-Soulas, Emmanuelle

    2016-01-01

    Aim: Advanced atherosclerosis increases inflammation and stroke risk in the cerebral vasculature. Exercise is known to improve cardio-metabolic profiles when associated with a caloric restriction, but it remains debated whether it is still beneficial without the dietary control. The aim of this study was to determine both the peripheral and central effects of exercise training combined with a cholesterol-rich diet given ad libitum in old ApoE−/− mice. Methods: Forty-five-weeks old obese ApoE−/− mice fed with a high cholesterol diet ad libitum were divided into Exercise-trained (EX; running wheel free access) and Sedentary (SED) groups. Insulin tolerance and brain imaging were performed before and after the twelve-weeks training. Tissue insulin resistance, oxidative stress, and inflammation markers in plasma, aorta, and brain were then assessed. Results: In EX ApoE−/− mice, no beneficial effect of exercise was observed on weight, abdominal fat, metabolic parameters, oxidative stress, or inflammation compared to SED. Despite the regular exercise training in ApoE−/− EX mice (mean of 12.5 km/week during 12 weeks), brain inflammation imaging score was significantly associated with increased blood brain barrier (BBB) leakage evaluated by imaging follow-up (r2 = 0.87; p = 0.049) with a faster evolution compared to SED ApoE−/−mice. Conclusion: We conclude that in a context of high cardio-metabolic risk, exercise does not provide any protective effect in old ApoE−/− animals under high cholesterol diet given ad libitum. Peripheral (insulin sensitivity and oxidative/inflammatory status) but also central features (BBB preservation and protection against inflammation) did not show any benefits of exercise. Indeed, there was a fast induction of irreversible brain damage that was more pronounced in exercise-trained ApoE−/− mice. PMID:27766082

  16. Loss of deep cerebellar nuclei neurons in the 3xTg-AD mice and protection by an anti-amyloid β antibody fragment.

    PubMed

    Esquerda-Canals, Gisela; Marti, Joaquim; Rivera-Hernández, Geovanny; Giménez-Llort, Lydia; Villegas, Sandra

    2013-01-01

    The therapeutic potential of scFv-h3D6 has recently been shown in the 3xTg-AD mice. A clear effect on amyloid β (Aβ) oligomers and certain apolipoproteins in the brain was found, but no effect was seen in the cerebellum. Here, cellular vulnerability of the 3xTg-AD cerebellum is described for the first time, together with its protection by scFv-h3D6. Neuron depletion in the DCN was regionally variable and followed a mediolateral axis of involvement that was greatest in the fastigial nucleus, lesser in the interpositus and negligible in the dentate nucleus. A sole and low intraperitoneal dose of scFv-h3D6 protected 3xTg-AD DCN neurons from death. Further studies might provide interesting information about both the potential of scFv-h3D6 as a therapeutic agent and the role of the cerebellum in AD.

  17. Evaluating Special Educator Effectiveness: Addressing Issues Inherent to Value-Added Modeling

    ERIC Educational Resources Information Center

    Steinbrecher, Trisha D.; Selig, James P.; Cosbey, Joanna; Thorstensen, Beata I.

    2014-01-01

    States are increasingly using value-added approaches to evaluate teacher effectiveness. There is much debate regarding whether these methods should be employed and, if employed, what role such methods should play in comprehensive teacher evaluation systems. In this article, we consider the use of value-added modeling (VAM) to evaluate special…

  18. The Politics and Statistics of Value-Added Modeling for Accountability of Teacher Preparation Programs

    ERIC Educational Resources Information Center

    Lincove, Jane Arnold; Osborne, Cynthia; Dillon, Amanda; Mills, Nicholas

    2014-01-01

    Despite questions about validity and reliability, the use of value-added estimation methods has moved beyond academic research into state accountability systems for teachers, schools, and teacher preparation programs (TPPs). Prior studies of value-added measurement for TPPs test the validity of researcher-designed models and find that measuring…

  19. Oxidatively modified proteins in Alzheimer’s disease (AD), mild cognitive impairment and animal models of AD: role of Abeta in pathogenesis

    PubMed Central

    Sultana, Rukhsana; Perluigi, Marzia

    2009-01-01

    Oxidative stress has been implicated in the pathogenesis of a number of diseases including Alzheimer’s disease (AD). The oxidative stress hypothesis of AD pathogenesis, in part, is based on β-amyloid peptide (Aβ)-induced oxidative stress in both in vitro and in vivo studies. Oxidative modification of the protein may induce structural changes in a protein that might lead to its functional impairment. A number of oxidatively modified brain proteins were identified using redox proteomics in AD, mild cognitive impairment (MCI) and Aβ models of AD, which support a role of Aβ in the alteration of a number of biochemical and cellular processes such as energy metabolism, protein degradation, synaptic function, neuritic growth, neurotransmission, cellular defense system, long term potentiation involved in formation of memory, etc. All the redox proteomics-identified brain proteins fit well with the appearance of the three histopathological hallmarks of AD, i.e., synapse loss, amyloid plaque formation and neurofibrillary tangle formation and suggest a direct or indirect association of the identified proteins with the pathological and/or biochemical alterations in AD. Further, Aβ models of AD strongly support the notion that oxidative stress induced by Aβ may be a driving force in AD pathogenesis. Studies conducted on arguably the earliest stage of AD, MCI, may elucidate the mechanism(s) leading to AD pathogenesis by identifying early markers of the disease, and to develop therapeutic strategies to slow or prevent the progression of AD. In this review, we summarized our findings of redox proteomics identified oxidatively modified proteins in AD, MCI and AD models. PMID:19288120

  20. Bifurcation and Spike Adding Transition in Chay-Keizer Model

    NASA Astrophysics Data System (ADS)

    Lu, Bo; Liu, Shenquan; Liu, Xuanliang; Jiang, Xiaofang; Wang, Xiaohui

    Electrical bursting is an activity which is universal in excitable cells such as neurons and various endocrine cells, and it encodes rich physiological information. As burst delay identifies that the signal integration has reached the threshold at which it can generate an action potential, the number of spikes in a burst may have essential physiological implications, and the transition of bursting in excitable cells is associated with the bifurcation phenomenon closely. In this paper, we focus on the transition of the spike count per burst of the pancreatic β-cells within a mathematical model and bifurcation phenomenon in the Chay-Keizer model, which is utilized to simulate the pancreatic β-cells. By the fast-slow dynamical bifurcation analysis and the bi-parameter bifurcation analysis, the local dynamics of the Chay-Keizer system around the Bogdanov-Takens bifurcation is illustrated. Then the variety of the number of spikes per burst is discussed by changing the settings of a single parameter and bi-parameter. Moreover, results on the number of spikes within a burst are summarized in ISIs (interspike intervals) sequence diagrams, maximum and minimum, and the number of spikes under bi-parameter value changes.

  1. Reduced Uterine Perfusion Pressure (RUPP) Model of Preeclampsia in Mice

    PubMed Central

    Fushima, Tomofumi; Sekimoto, Akiyo; Minato, Takahiro; Ito, Takuya; Oe, Yuji; Kisu, Kiyomi; Sato, Emiko; Funamoto, Kenichi; Hayase, Toshiyuki; Kimura, Yoshitaka; Ito, Sadayoshi; Sato, Hiroshi; Takahashi, Nobuyuki

    2016-01-01

    Preeclampsia (PE) is a pregnancy-induced hypertension with proteinuria that typically develops after 20 weeks of gestation. A reduction in uterine blood flow causes placental ischemia and placental release of anti-angiogenic factors such as sFlt-1 followed by PE. Although the reduced uterine perfusion pressure (RUPP) model is widely used in rats, investigating the role of genes on PE using genetically engineered animals has been problematic because it has been difficult to make a useful RUPP model in mice. To establish a RUPP model of PE in mice, we bilaterally ligated ovarian vessels distal to ovarian branches, uterine vessels, or both in ICR-strain mice at 14.5 days post coitum (dpc). Consequently, these mice had elevated BP, increased urinary albumin excretion, severe endotheliosis, and mesangial expansion. They also had an increased incidence of miscarriage and premature delivery. Embryonic weight at 18.5 dpc was significantly lower than that in sham mice. The closer to the ligation site the embryos were, the higher the resorption rate and the lower the embryonic weight. The phenotype was more severe in the order of ligation at the ovarian vessels < uterine vessels < both. Unlike the RUPP models described in the literature, this model did not constrict the abdominal aorta, which allowed BP to be measured with a tail cuff. This novel RUPP model in mice should be useful for investigating the pathogenesis of PE in genetically engineered mice and for evaluating new therapies for PE. PMID:27187738

  2. NSG Mice Provide a Better Spontaneous Model of Breast Cancer Metastasis than Athymic (Nude) Mice

    PubMed Central

    Puchalapalli, Madhavi; Zeng, Xianke; Mu, Liang; Anderson, Aubree; Hix Glickman, Laura; Zhang, Ming; Sayyad, Megan R.; Mosticone Wangensteen, Sierra; Clevenger, Charles V.; Koblinski, Jennifer E.

    2016-01-01

    Metastasis is the most common cause of mortality in breast cancer patients worldwide. To identify improved mouse models for breast cancer growth and spontaneous metastasis, we examined growth and metastasis of both estrogen receptor positive (T47D) and negative (MDA-MB-231, SUM1315, and CN34BrM) human breast cancer cells in nude and NSG mice. Both primary tumor growth and spontaneous metastases were increased in NSG mice compared to nude mice. In addition, a pattern of metastasis similar to that observed in human breast cancer patients (metastases to the lungs, liver, bones, brain, and lymph nodes) was found in NSG mice. Furthermore, there was an increase in the metastatic burden in NSG compared to nude mice that were injected with MDA-MB-231 breast cancer cells in an intracardiac experimental metastasis model. This data demonstrates that NSG mice provide a better model for studying human breast cancer metastasis compared to the current nude mouse model. PMID:27662655

  3. A Lean Neck Mass Clinic Model: Adding Value to Care

    PubMed Central

    Tillman, Brittny N.; Glazer, Tiffany A.; Ray, Amrita; Brenner, J. Chad; Spector, Matthew E.

    2016-01-01

    Objective To demonstrate that ultrasound guided fine needle aspiration (USFNA) with on-site cytopathologic analysis eliminates unnecessary diagnostic testing, return visits, repeat procedures and optimizes quality of care. Study Design Retrospective Cohort Methods 61 new patients (28 female; 33 male; age range 19-85) were seen in our dedicated neck mass clinic over a one-year period. All patients underwent USFNA of masses located in neck levels I-VI (40), parotid gland (20), or parapharyngeal space (1). Each patient underwent two USFNA passes followed by on-site cytopathologic analysis with additional passes if required for diagnosis. Results Diagnosis was made in 93.4% (57) of patients allowing for counseling and treatment planning at the first visit. In order to obtain a diagnosis, more than half (57.4%, 35) of our patients required additional passes which implies that they would have required an additional visit without on-site cytopathologic analysis. Treatment included: Observation in 42.6% (26) of patients, surgery in 32.8 % (20) of patients and nonsurgical treatment (chemotherapy, radiation, other) in 24.6% (15) of patients. The average time from check-in to checkout including the clinic visit, biopsy and treatment counseling was 103 minutes, and the average round trip mileage traveled per patient was 127.6 miles. Conclusion The adult neck mass is a commonly encountered scenario in otolaryngology. For the patient this can be a stressful situation in which timely and accurate diagnosis is critical. A dedicated lean neck mass clinic model with USFNA and on-site cytopathologic analysis can be both an efficient part of one's practice and a valuable addition to patient care. PMID:26256915

  4. Behavioral abnormalities in APPSwe/PS1dE9 mouse model of AD-like pathology: comparative analysis across multiple behavioral domains.

    PubMed

    Janus, Christopher; Flores, Abigail Y; Xu, Guilian; Borchelt, David R

    2015-09-01

    Alzheimer's disease (AD) is characterized by dysfunction in cognitive and noncognitive domains with clinical diagnosis based on multiple neuropsychological tests. Here, we evaluated cognitive and noncognitive behaviors in 2 age cohorts (8 and 14 months at the start of the study) of APPSwe/PS1dE9 transgenic mice that model AD-like amyloidosis. We used a battery of tests that included fear-conditioned context and tone memories, swimming activity, and orientation to a proximal cue in a visible platform water maze test and burrowing and nest building activity. To compare the performance of mice across all tests, we used z-score normalization of data. The analyses revealed that the behavior of the transgenic mice was significantly compromised in cognitive as well as in noncognitive domains. Combining scores across multiple behavioral tests produced an integrated index characterizing the overall phenotypic abnormality in this model of AD-like amyloidosis. Assessing multiple behavioral domains provides a broader view of the breadth of impairments in multiple behavioral systems. Greater implementation of such approaches could enable reliable and clinically predictive evaluation of therapeutics in mouse models of amyloidosis.

  5. Reduction of the immunostainable length of the hippocampal dentate granule cells' primary cilia in 3xAD-transgenic mice producing human A{beta}{sub 1-42} and tau

    SciTech Connect

    Chakravarthy, Balu; Gaudet, Chantal; Menard, Michel; Brown, Leslie; Atkinson, Trevor; LaFerla, Frank M.; Ito, Shingo; Armato, Ubaldo; Dal Pra, Ilaria; Whitfield, James

    2012-10-12

    Highlights: Black-Right-Pointing-Pointer A{beta} and tau-induced neurofibrillary tangles play a key role in Alzheimer's disease. Black-Right-Pointing-Pointer A{beta}{sub 1-42} and mutant tau protein together reduce the primary cilium length. Black-Right-Pointing-Pointer This shortening likely reduces cilium-dependent neurogenesis and memory function. Black-Right-Pointing-Pointer This provides a model of an A{beta}/tau targeting of a neuronal signaling organelle. -- Abstract: The hippocampal dentate gyrus is one of the two sites of continuous neurogenesis in adult rodents and humans. Virtually all dentate granule cells have a single immobile cilium with a microtubule spine or axoneme covered with a specialized cell membrane loaded with receptors such as the somatostatin receptor 3 (SSTR3), and the p75 neurotrophin receptor (p75{sup NTR}). The signals from these receptors have been reported to stimulate neuroprogenitor proliferation and the post-mitotic maturation of newborn granule cells into functioning granule cells. We have found that in 6-24-months-old triple transgenic Alzheimer's disease model mice (3xTg-AD) producing both A{beta}{sub 1-42} and the mutant human tau protein tau{sub P301L,} the dentate granule cells still had immunostainable SSTR3- and p75{sup NTR}-bearing cilia but they were only half the length of the immunostained cilia in the corresponding wild-type mice. However, the immunostainable length of the granule cell cilia was not reduced either in 2xTg-AD mice accumulating large amounts of A{beta}{sub 1-42} or in mice accumulating only a mutant human tau protein. Thus it appears that a combination of A{beta}{sub 1-42} and tau protein accumulation affects the levels of functionally important receptors in 3xTg-AD mice. These observations raise the important possibility that structural and functional changes in granule cell cilia might have a role in AD.

  6. Behavioral and neuropathological consequences of transient global ischemia in APP/PS1 Alzheimer model mice.

    PubMed

    Kemppainen, S; Hämäläinen, E; Miettinen, P O; Koistinaho, J; Tanila, H

    2014-12-15

    Alzheimer's disease (AD) typically manifests in elderly people with several co-morbidities, especially cardiovascular, whereas transgenic mouse models of this disease usually employ middle-aged animals that have a good general health status. To assess the combined effect of compromised cerebral blood circulation and brain amyloid pathology we induced transient (17min) global ischemia (TGI) to young adult APPswe/PS1dE9 (APdE9) mice modeling AD amyloid pathology, and assessed the outcome on behavior two weeks and on histopathology five weeks after the ischemic insult. Ischemic injury resulted in reduced motor coordination and impaired spatial learning and memory. Neuropathological examination revealed circumscribed sites of neuronal loss in ischemic mice, including hippocampal CA2, lateral CA3 and medial CA1 pyramidal cell layer, and superficial layers of cortical patches. Notably, Fluoro-Jade staining revealed dying neurons as late as five weeks after the initial insult, and staining for active microglia and astrocytes confirmed the presence of inflammatory reaction. The extent of neuronal loss in CA2 and CA1 correlated significantly with impairment in spatial memory. There was no genotype difference in either behavioral or neuropathological consequences of TGI. However, the post-operative survival of transgenic animals was greatly reduced compared to wild type animals. APdE9 mice at a pre-plaque age appear to be more sensitive than wild-type mice to TGI in terms of post-operative recovery but the surviving APdE9 mice do not display more severe neurological deficits than wild-type mice.

  7. Cross-Sectional Comparison of Small Animal [18F]-Florbetaben Amyloid-PET between Transgenic AD Mouse Models

    PubMed Central

    Brendel, Matthias; Jaworska, Anna; Grießinger, Eric; Rötzer, Christina; Burgold, Steffen; Gildehaus, Franz-Josef; Carlsen, Janette; Cumming, Paul; Baumann, Karlheinz; Haass, Christian; Steiner, Harald; Bartenstein, Peter; Herms, Jochen; Rominger, Axel

    2015-01-01

    We aimed to compare [18F]-florbetaben PET imaging in four transgenic mouse strains modelling Alzheimer’s disease (AD), with the main focus on APPswe/PS2 mice and C57Bl/6 mice serving as controls (WT). A consistent PET protocol (N = 82 PET scans) was used, with cortical standardized uptake value ratio (SUVR) relative to cerebellum as the endpoint. We correlated methoxy-X04 staining of β-amyloid with PET results, and undertook ex vivo autoradiography for further validation of a partial volume effect correction (PVEC) of PET data. The SUVR in APPswe/PS2 increased from 0.95±0.04 at five months (N = 5) and 1.04±0.03 (p<0.05) at eight months (N = 7) to 1.07±0.04 (p<0.005) at ten months (N = 6), 1.28±0.06 (p<0.001) at 16 months (N = 6) and 1.39±0.09 (p<0.001) at 19 months (N = 6). SUVR was 0.95±0.03 in WT mice of all ages (N = 22). In APPswe/PS1G384A mice, the SUVR was 0.93/0.98 at five months (N = 2) and 1.11 at 16 months (N = 1). In APPswe/PS1dE9 mice, the SUVR declined from 0.96/0.96 at 12 months (N = 2) to 0.91/0.92 at 24 months (N = 2), due to β-amyloid plaques in cerebellum. PVEC reduced the discrepancy between SUVR-PET and autoradiography from −22% to +2% and increased the differences between young and aged transgenic animals. SUVR and plaque load correlated highly between strains for uncorrected (R = 0.94, p<0.001) and PVE-corrected (R = 0.95, p<0.001) data. We find that APPswe/PS2 mice may be optimal for longitudinal amyloid-PET monitoring in planned interventions studies. PMID:25706990

  8. A novel recombinant 6Aβ15-THc-C chimeric vaccine (rCV02) mitigates Alzheimer’s disease-like pathology, cognitive decline and synaptic loss in aged 3 × Tg-AD mice

    PubMed Central

    Yu, Yun-Zhou; Liu, Si; Wang, Hai-Chao; Shi, Dan-Yang; Xu, Qing; Zhou, Xiao-Wei; Sun, Zhi-Wei; Huang, Pei-Tang

    2016-01-01

    Alzheimer’s disease (AD) is a neurodegenerative disorder that impairs memory and cognition. Targeting amyloid-β (Aβ) may be currently the most promising immunotherapeutic strategy for AD. In this study, a recombinant chimeric 6Aβ15-THc-C immunogen was formulated with alum adjuvant as a novel Aβ B-cell epitope candidate vaccine (rCV02) for AD. We examined its efficacy in preventing the cognitive deficit and synaptic impairment in 3 × Tg-AD mice. Using a toxin-derived carrier protein, the rCV02 vaccine elicited robust Aβ-specific antibodies that markedly reduced AD-like pathology and improved behavioral performance in 3 × Tg-AD mice. Along with the behavioral improvement in aged 3 × Tg-AD mice, rCV02 significantly decreased calpain activation concurrent with reduced soluble Aβ or oligomeric forms of Aβ, probably by preventing dynamin 1 and PSD-95 degradation. Our data support the hypothesis that reducing Aβ levels in rCV02-immunized AD mice increases the levels of presynaptic dynamin 1 and postsynaptic PSD-95 allowing functional recovery of cognition. In conclusion, this novel and highly immunogenic rCV02 shows promise as a new candidate prophylactic vaccine for AD and may be useful for generating rapid and strong Aβ-specific antibodies in AD patients with pre-existing memory Th cells generated after immunization with conventional tetanus toxoid vaccine. PMID:27255752

  9. A novel recombinant 6Aβ15-THc-C chimeric vaccine (rCV02) mitigates Alzheimer's disease-like pathology, cognitive decline and synaptic loss in aged 3 × Tg-AD mice.

    PubMed

    Yu, Yun-Zhou; Liu, Si; Wang, Hai-Chao; Shi, Dan-Yang; Xu, Qing; Zhou, Xiao-Wei; Sun, Zhi-Wei; Huang, Pei-Tang

    2016-01-01

    Alzheimer's disease (AD) is a neurodegenerative disorder that impairs memory and cognition. Targeting amyloid-β (Aβ) may be currently the most promising immunotherapeutic strategy for AD. In this study, a recombinant chimeric 6Aβ15-THc-C immunogen was formulated with alum adjuvant as a novel Aβ B-cell epitope candidate vaccine (rCV02) for AD. We examined its efficacy in preventing the cognitive deficit and synaptic impairment in 3 × Tg-AD mice. Using a toxin-derived carrier protein, the rCV02 vaccine elicited robust Aβ-specific antibodies that markedly reduced AD-like pathology and improved behavioral performance in 3 × Tg-AD mice. Along with the behavioral improvement in aged 3 × Tg-AD mice, rCV02 significantly decreased calpain activation concurrent with reduced soluble Aβ or oligomeric forms of Aβ, probably by preventing dynamin 1 and PSD-95 degradation. Our data support the hypothesis that reducing Aβ levels in rCV02-immunized AD mice increases the levels of presynaptic dynamin 1 and postsynaptic PSD-95 allowing functional recovery of cognition. In conclusion, this novel and highly immunogenic rCV02 shows promise as a new candidate prophylactic vaccine for AD and may be useful for generating rapid and strong Aβ-specific antibodies in AD patients with pre-existing memory Th cells generated after immunization with conventional tetanus toxoid vaccine. PMID:27255752

  10. Differential immunogenicity between HAdV-5 and chimpanzee adenovirus vector ChAdOx1 is independent of fiber and penton RGD loop sequences in mice

    PubMed Central

    Dicks, Matthew D. J.; Spencer, Alexandra J.; Coughlan, Lynda; Bauza, Karolis; Gilbert, Sarah C.; Hill, Adrian V. S.; Cottingham, Matthew G.

    2015-01-01

    Replication defective adenoviruses are promising vectors for the delivery of vaccine antigens. However, the potential of a vector to elicit transgene-specific adaptive immune responses is largely dependent on the viral serotype used. HAdV-5 (Human adenovirus C) vectors are more immunogenic than chimpanzee adenovirus vectors from species Human adenovirus E (ChAdOx1 and AdC68) in mice, though the mechanisms responsible for these differences in immunogenicity remain poorly understood. In this study, superior immunogenicity was associated with markedly higher levels of transgene expression in vivo, particularly within draining lymph nodes. To investigate the viral factors contributing to these phenotypes, we generated recombinant ChAdOx1 vectors by exchanging components of the viral capsid reported to be principally involved in cell entry with the corresponding sequences from HAdV-5. Remarkably, pseudotyping with the HAdV-5 fiber and/or penton RGD loop had little to no effect on in vivo transgene expression or transgene-specific adaptive immune responses despite considerable species-specific sequence heterogeneity in these components. Our results suggest that mechanisms governing vector transduction after intramuscular administration in mice may be different from those described in vitro. PMID:26576856

  11. Generation of gene-targeted mice using embryonic stem cells derived from a transgenic mouse model of Alzheimer's disease.

    PubMed

    Yamamoto, Satoshi; Ooshima, Yuki; Nakata, Mitsugu; Yano, Takashi; Matsuoka, Kunio; Watanabe, Sayuri; Maeda, Ryouta; Takahashi, Hideki; Takeyama, Michiyasu; Matsumoto, Yoshio; Hashimoto, Tadatoshi

    2013-06-01

    Gene-targeting technology using mouse embryonic stem (ES) cells has become the "gold standard" for analyzing gene functions and producing disease models. Recently, genetically modified mice with multiple mutations have increasingly been produced to study the interaction between proteins and polygenic diseases. However, introduction of an additional mutation into mice already harboring several mutations by conventional natural crossbreeding is an extremely time- and labor-intensive process. Moreover, to do so in mice with a complex genetic background, several years may be required if the genetic background is to be retained. Establishing ES cells from multiple-mutant mice, or disease-model mice with a complex genetic background, would offer a possible solution. Here, we report the establishment and characterization of novel ES cell lines from a mouse model of Alzheimer's disease (3xTg-AD mouse, Oddo et al. in Neuron 39:409-421, 2003) harboring 3 mutated genes (APPswe, TauP301L, and PS1M146V) and a complex genetic background. Thirty blastocysts were cultured and 15 stable ES cell lines (male: 11; female: 4) obtained. By injecting these ES cells into diploid or tetraploid blastocysts, we generated germline-competent chimeras. Subsequently, we confirmed that F1 mice derived from these animals showed similar biochemical and behavioral characteristics to the original 3xTg-AD mice. Furthermore, we introduced a gene-targeting vector into the ES cells and successfully obtained gene-targeted ES cells, which were then used to generate knockout mice for the targeted gene. These results suggest that the present methodology is effective for introducing an additional mutation into mice already harboring multiple mutated genes and/or a complex genetic background.

  12. Value-Added Models for Teacher Preparation Programs: Validity and Reliability Threats, and a Manageable Alternative

    ERIC Educational Resources Information Center

    Brady, Michael P.; Heiser, Lawrence A.; McCormick, Jazarae K.; Forgan, James

    2016-01-01

    High-stakes standardized student assessments are increasingly used in value-added evaluation models to connect teacher performance to P-12 student learning. These assessments are also being used to evaluate teacher preparation programs, despite validity and reliability threats. A more rational model linking student performance to candidates who…

  13. The Promise and Peril of Using Value-Added Modeling to Measure Teacher Effectiveness. Research Brief

    ERIC Educational Resources Information Center

    RAND Corporation, 2004

    2004-01-01

    Value-added modeling offers the possibility of estimating the effects of teachers and schools on student performance, a potentially important contribution in the current environment of concern for accountability in education. These techniques, however, are susceptible to a number of sources of bias, depending on decisions about how the modeling is…

  14. Loss of Tau Elicits Axonal Degeneration in a Mouse Model of AD

    PubMed Central

    Cantillana, Viviana; Vitek, Michael P.; Wilcock, Donna M.; Lynch, John R.; Laskowitz, Daniel T.

    2010-01-01

    A central issue in the pathogenesis of tauopathy is the question of how tau protein dysfunction leads to neurodegeneration. We have previously demonstrated that the absence of tau protein is associated with destabilization of microtubules and impaired neurite outgrowth (Dawson et al., 2001, Rapoport et al., 2002). We now hypothesize that the absence of functional tau protein may render the central nervous system more vulnerable to secondary insults such as the overexpression of mutated beta amyloid precursor protein (APP) and traumatic brain injury. We therefore crossed tau knockout mice (Dawson et al., 2001) to mice overexpressing a mutated human APP (APP670,671, Asw) (Hsiao et al., 1996) and created a mouse model (Asw/mTau−/−) that provides evidence that the loss of tau causes degeneration of neuronal processes. The overexpression of APP670,671 in tau knockout mice, elicits the extensive formation of axonal spheroids. While spheroids are only found associated with Aβ plaques in mice expressing APP670,671 on an endogenous mouse tau background (Irizarry et al., 1997), Asw/mTau−/− mice have spheroids not only surrounding Aβ plaques but also in white matter tracts and in the neuropil. Plaque associated and neuropil dystrophic neurites and spheroids are prominent features of Alzheimer’s disease (Masliah et al., 1993, Terry, 1996, Stokin et al., 2005). Thus our current data suggests that loss of tau may lead to neurodegeneration. PMID:20434528

  15. Lamellipodin-Deficient Mice: A Model of Rectal Carcinoma

    PubMed Central

    Miller, Cassandra L.; Muthupalani, Sureshkumar; Shen, Zeli; Drees, Frauke; Ge, Zhongming; Feng, Yan; Chen, Xiaowei; Gong, Guanyu; Nagar, Karan K.; Wang, Timothy C.; Gertler, Frank B.; Fox, James G.

    2016-01-01

    During a survey of clinical rectal prolapse (RP) cases in the mouse population at MIT animal research facilities, a high incidence of RP in the lamellipodin knock-out strain, C57BL/6-Raph1tm1Fbg (Lpd-/-) was documented. Upon further investigation, the Lpd-/- colony was found to be infected with multiple endemic enterohepatic Helicobacter species (EHS). Lpd-/- mice, a transgenic mouse strain produced at MIT, have not previously shown a distinct immune phenotype and are not highly susceptible to other opportunistic infections. Predominantly male Lpd-/- mice with RP exhibited lesions consistent with invasive rectal carcinoma concomitant to clinically evident RP. Multiple inflammatory cytokines, CD11b+Gr1+ myeloid-derived suppressor cell (MDSC) populations, and epithelial cells positive for a DNA damage biomarker, H2AX, were elevated in affected tissue, supporting their role in the neoplastic process. An evaluation of Lpd-/- mice with RP compared to EHS-infected, but clinically normal (CN) Lpd-/- animals indicated that all of these mice exhibit some degree of lower bowel inflammation; however, mice with prolapses had significantly higher degree of focal lesions at the colo-rectal junction. When Helicobacter spp. infections were eliminated in Lpd-/- mice by embryo transfer rederivation, the disease phenotype was abrogated, implicating EHS as a contributing factor in the development of rectal carcinoma. Here we describe lesions in Lpd-/- male mice consistent with a focal inflammation-induced neoplastic transformation and propose this strain as a mouse model of rectal carcinoma. PMID:27045955

  16. New operant model of nicotine-seeking behaviour in mice.

    PubMed

    Martín-García, Elena; Barbano, Maria Flavia; Galeote, Lola; Maldonado, Rafael

    2009-04-01

    Nicotine addiction represents a major health problem in the world with dramatic socio-economic consequences. Recent studies using genetically modified mice have provided a better understanding of the neurobiological mechanisms involved in nicotine responses. However, the study of nicotine addiction requires sophisticated behavioural models that are still not fully developed in mice. Here, we report the validation of a new reliable operant model of nicotine-seeking behaviour in mice. C57BL/6 mice were trained to self-administer nicotine (0.03 mg/kg per infusion) under a fixed ratio 1 schedule of reinforcement for 10 d. A light cue was contingently associated with the nicotine infusion. After reaching the acquisition criteria of nicotine self-administration, mice were exposed to extinction sessions similar to the self-administration training except that nicotine was not available and the associated cues were not presented. Nicotine-seeking behaviour was then reinstated by exposure to nicotine-associated environment cues, a priming injection of nicotine or stress, the three main conditions leading to nicotine relapse in humans. The exposure to the cues associated with nicotine infusion was the most effective stimulus reinstating nicotine-seeking behaviour in 90% of mice. A priming injection of nicotine (0.18 mg/kg) produced nicotine reinstatement in 30% of the animals, whereas stress exposure (0.22 mA footshock) reinstated nicotine-seeking behaviour in 50% of mice. The validation of this new model of nicotine-seeking behaviour and reinstatement in mice provides an important tool to help clarify the genetic and neurochemical bases of nicotine addiction.

  17. Synaptic plasticity defect following visual deprivation in Alzheimer disease model transgenic mice

    PubMed Central

    William, Christopher M.; Andermann, Mark L.; Goldey, Glenn J.; Roumis, Demetris K.; Reid, R. Clay; Shatz, Carla J.; Albers, Mark W.; Frosch, Matthew P.; Hyman, Bradley T.

    2012-01-01

    Amyloid-beta (Aβ)-induced changes in synaptic function in experimental models of Alzheimer disease (AD) suggest that Aβ generation and accumulation may affect fundamental mechanisms of synaptic plasticity. To test this hypothesis, we examined the effect of amyloid precursor protein (APP) overexpression on a well-characterized, in vivo, developmental model of systems-level plasticity, ocular dominance plasticity (ODP). Following monocular visual deprivation during the critical period, mice that express mutant alleles of amyloid precursor protein (APPswe) and Presenilin1 (PS1dE9), as well as mice that express APPswe alone, lack ocular dominance plasticity in visual cortex. Defects in the spatial extent and magnitude of the plastic response are evident using two complementary approaches, Arc induction and optical imaging of intrinsic signals in awake mice. This defect in a classic paradigm of systems level synaptic plasticity shows that Aβ overexpression, even early in postnatal life, can perturb plasticity in cerebral cortex, and supports the idea that decreased synaptic plasticity due to elevated Aβ exposure contributes to cognitive impairment in AD. PMID:22674275

  18. Low Concentrations of Anti-Aβ Antibodies Generated in Tg2576 Mice by DNA Epitope Vaccine Fused with 3C3d Molecular Adjuvant Do Not Affect AD Pathology

    PubMed Central

    Movsesyan, Nina; Davtyan, Hayk; Mkrtichyan, Mikayel; Petrushina, Irina; Tiraturyan, Tigran; Ross, Ted; Agadjanyan, Michael G.

    2010-01-01

    Abstract It has been demonstrated that an active vaccination strategy with protein- or DNA-based epitope vaccines composed of the immunodominant self B cell epitope of amyloid-β42 (Aβ42) and a non-self T helper (Th) cell epitope is an immunotherapeutic approach to preventing or treating Alzheimer's disease (AD). As a DNA-based epitope vaccine, we used a plasmid encoding three copies of Aβ1–11 and Th cell epitope, PADRE (p3Aβ1–11-PADRE). We have previously reported that three copies of component of complement C3d (3C3d) acts as a molecular adjuvant significantly enhancing immune responses in wild-type mice of the H2b haplotype immunized with p3Aβ1–11-PADRE. Here, we tested the efficacy of p3Aβ1–11-PADRE and the same vaccine fused with 3C3d (p3Aβ1–11-PADRE-3C3d) in a transgenic (Tg) mouse model of AD (Tg2576) of the H2bxs immune haplotype. The overall responses to both vaccines were very weak in Tg2576 mice despite the fact that the 3C3d molecular adjuvant significantly enhanced the anti-Aβ response to 3Aβ1–11-PADRE. Importantly, generation of low antibody responses was associated with the strain of amyloid precursor protein Tg mice rather than with a molecular adjuvant, as a p3Aβ1–11-PADRE-3C3d vaccine induced significantly higher antibody production in another AD mouse model, 3xTg-AD of the H2b haplotype. Finally, this study demonstrated that low concentrations of antibodies generated by both DNA vaccines were not sufficient for the reduction of Aβ pathology in the brains of vaccinated Tg2576 animals, confirming previous reports from preclinical studies and the AN-1792 clinical trials, which concluded that the concentration of anti-Aβ antibodies may be essential for the reduction of AD pathology. PMID:20528468

  19. Family of dilatons and metrics for AdS/QCD models

    NASA Astrophysics Data System (ADS)

    Vega, Alfredo; Cabrera, Paulina

    2016-06-01

    We explore some possibilities for obtaining useful metrics and dilatons for anti-de Sitter (AdS)/QCD models. As a guideline, we consider dilatons and/or metrics that on the one hand reproduce the mesonic spectrum, and that on the other hand allow us a correct implementation of chiral symmetry breaking in AdS/QCD models. We discuss two procedures: one is based on supersymmetric quantum mechanics techniques and the other considers the interpolation between some limits on dilatons and/or metrics.

  20. A noninflammatory immune response in aged DNA Aβ42-immunized mice supports its safety for possible use as immunotherapy in AD patients.

    PubMed

    Lambracht-Washington, Doris; Rosenberg, Roger N

    2015-03-01

    Aging in the immune system results in tendency to proinflammatory responses. Intradermal DNA immunization showed Th2 polarized noninflammatory immune responses. We tested here 18-month-old mice which were immunized with Aβ42 peptide, DNA Aβ42 trimer, or 2 different prime boost protocols identical to previous experiments. High Aβ42 antibody levels were found in aged mice which had received peptide immunizations (900 μg/mL plasma), and in mice which had received peptide prime and DNA boost immunizations (500 μg/mL), compared with antibodies in DNA Aβ42 immunized mice with 50 μg/mL. Although we found T-cell proliferation and inflammatory cytokines in mice which had received peptide or prime boost immunization, these were not found in DNA-immunized mice. The results are concordant with proinflammatory responses because of immunosenescence and contraindicate the use of Aβ42 peptide immunizations or prime boost immunization protocols for the use in elderly Alzheimer's disease patients. DNA Aβ42 immunization only on the other hand does lead to effective levels of antibodies without inflammatory cytokine or T-cell responses in the aged animal model tested. PMID:25725942

  1. A noninflammatory immune response in aged DNA Aβ42-immunized mice supports its safety for possible use as immunotherapy in AD patients.

    PubMed

    Lambracht-Washington, Doris; Rosenberg, Roger N

    2015-03-01

    Aging in the immune system results in tendency to proinflammatory responses. Intradermal DNA immunization showed Th2 polarized noninflammatory immune responses. We tested here 18-month-old mice which were immunized with Aβ42 peptide, DNA Aβ42 trimer, or 2 different prime boost protocols identical to previous experiments. High Aβ42 antibody levels were found in aged mice which had received peptide immunizations (900 μg/mL plasma), and in mice which had received peptide prime and DNA boost immunizations (500 μg/mL), compared with antibodies in DNA Aβ42 immunized mice with 50 μg/mL. Although we found T-cell proliferation and inflammatory cytokines in mice which had received peptide or prime boost immunization, these were not found in DNA-immunized mice. The results are concordant with proinflammatory responses because of immunosenescence and contraindicate the use of Aβ42 peptide immunizations or prime boost immunization protocols for the use in elderly Alzheimer's disease patients. DNA Aβ42 immunization only on the other hand does lead to effective levels of antibodies without inflammatory cytokine or T-cell responses in the aged animal model tested.

  2. Brain areas involved in the acupuncture treatment of AD model rats: a PET study

    PubMed Central

    2014-01-01

    Background Acupuncture may effectively treat certain symptoms of Alzheimer’s disease (AD). Although several studies have used functional brain imaging to investigate the mechanisms of acupuncture treatment on AD, these mechanisms are still poorly understood. We therefore further explored the mechanism by which needling at ST36 may have a therapeutic effect in a rat AD model. Methods A total of 80 healthy Wistar rats were divided into healthy control (n = 15) and pre-model (n = 65) groups. After inducing AD-like disease, a total of 45 AD model rats were randomly divided into three groups: the model group (n = 15), the sham-point group (n = 15), and the ST36 group (n = 15). The above three groups underwent PET scanning. PET images were processed with SPM2. Results The brain areas that were activated in the sham-point group relative to the model group were primarily centred on the bilateral limbic system, the right frontal lobe, and the striatum, whereas the activated areas in the ST36 group were primarily centred on the bilateral limbic system (pyriform cortex), the bilateral temporal lobe (olfactory cortex), the right amygdala and the right hippocampus. Compared with the sham-point group, the ST36 group showed greater activation in the bilateral amygdalae and the left temporal lobe. Conclusion We concluded that needling at a sham point or ST36 can increase blood perfusion and glycol metabolism in certain brain areas, and thus may have a positive influence on the cognition of AD patients. PMID:24886495

  3. Scurfy mice: A model for autoimmune disease

    SciTech Connect

    Godfrey, V.L.

    1993-01-01

    Autoimmune disease-the condition in which the body attacks its own tissue-has been an object of public concern recently. Former President George Bush and his wife Barbara both are afflicted with Graves' disease in which the body's own immune system attakcs the thyroid gland. The safety of breast implants was called into question because of evidence that some recipients had developed autoimmune disorders such a rheumatoid arthritis, systemic lupus erythematosus, and scleroderma. Women, the media pointed out, have a higher-than-average incidence of many autoimmune disorders. These events suggest the need to know more about what makes the immune system work so well and what makes it go awry. At ORNL's Biology Division, progress is being in understanding the underlying causes of immune disease by studying mice having a disease that causes them to be underdeveloped; to have scaly skin, small ears, and large spleens; to open their eyes late; and to die early. These [open quotes]scurfy[close quotes]mice are helping us better understand the role of the thymus gland in autoimmune disease.

  4. Loss of deep cerebellar nuclei neurons in the 3xTg-AD mice and protection by an anti-amyloid β antibody fragment

    PubMed Central

    Esquerda-Canals, Gisela; Marti, Joaquim; Rivera-Hernández, Geovanny; Giménez-Llort, Lydia; Villegas, Sandra

    2013-01-01

    The therapeutic potential of scFv-h3D6 has recently been shown in the 3xTg-AD mice. A clear effect on amyloid β (Aβ) oligomers and certain apolipoproteins in the brain was found, but no effect was seen in the cerebellum. Here, cellular vulnerability of the 3xTg-AD cerebellum is described for the first time, together with its protection by scFv-h3D6. Neuron depletion in the DCN was regionally variable and followed a mediolateral axis of involvement that was greatest in the fastigial nucleus, lesser in the interpositus and negligible in the dentate nucleus. A sole and low intraperitoneal dose of scFv-h3D6 protected 3xTg-AD DCN neurons from death. Further studies might provide interesting information about both the potential of scFv-h3D6 as a therapeutic agent and the role of the cerebellum in AD. PMID:23884149

  5. Mesenchymal Stem Cells Preserve Working Memory in the 3xTg-AD Mouse Model of Alzheimer’s Disease

    PubMed Central

    Ruzicka, Jiri; Kulijewicz-Nawrot, Magdalena; Rodrigez-Arellano, Jose Julio; Jendelova, Pavla; Sykova, Eva

    2016-01-01

    The transplantation of stem cells may have a therapeutic effect on the pathogenesis and progression of neurodegenerative disorders. In the present study, we transplanted human mesenchymal stem cells (MSCs) into the lateral ventricle of a triple transgenic mouse model of Alzheimer´s disease (3xTg-AD) at the age of eight months. We evaluated spatial reference and working memory after MSC treatment and the possible underlying mechanisms, such as the influence of transplanted MSCs on neurogenesis in the subventricular zone (SVZ) and the expression levels of a 56 kDa oligomer of amyloid β (Aβ*56), glutamine synthetase (GS) and glutamate transporters (Glutamate aspartate transporter (GLAST) and Glutamate transporter-1 (GLT-1)) in the entorhinal and prefrontal cortices and the hippocampus. At 14 months of age we observed the preservation of working memory in MSC-treated 3xTg-AD mice, suggesting that such preservation might be due to the protective effect of MSCs on GS levels and the considerable downregulation of Aβ*56 levels in the entorhinal cortex. These changes were observed six months after transplantation, accompanied by clusters of proliferating cells in the SVZ. Since the grafted cells did not survive for the whole experimental period, it is likely that the observed effects could have been transiently more pronounced at earlier time points than at six months after cell application. PMID:26821012

  6. Mesenchymal Stem Cells Preserve Working Memory in the 3xTg-AD Mouse Model of Alzheimer's Disease.

    PubMed

    Ruzicka, Jiri; Kulijewicz-Nawrot, Magdalena; Rodrigez-Arellano, Jose Julio; Jendelova, Pavla; Sykova, Eva

    2016-01-25

    The transplantation of stem cells may have a therapeutic effect on the pathogenesis and progression of neurodegenerative disorders. In the present study, we transplanted human mesenchymal stem cells (MSCs) into the lateral ventricle of a triple transgenic mouse model of Alzheimer's disease (3xTg-AD) at the age of eight months. We evaluated spatial reference and working memory after MSC treatment and the possible underlying mechanisms, such as the influence of transplanted MSCs on neurogenesis in the subventricular zone (SVZ) and the expression levels of a 56 kDa oligomer of amyloid β (Aβ*56), glutamine synthetase (GS) and glutamate transporters (Glutamate aspartate transporter (GLAST) and Glutamate transporter-1 (GLT-1)) in the entorhinal and prefrontal cortices and the hippocampus. At 14 months of age we observed the preservation of working memory in MSC-treated 3xTg-AD mice, suggesting that such preservation might be due to the protective effect of MSCs on GS levels and the considerable downregulation of Aβ*56 levels in the entorhinal cortex. These changes were observed six months after transplantation, accompanied by clusters of proliferating cells in the SVZ. Since the grafted cells did not survive for the whole experimental period, it is likely that the observed effects could have been transiently more pronounced at earlier time points than at six months after cell application.

  7. Oral TNFα Modulation Alters Neutrophil Infiltration, Improves Cognition and Diminishes Tau and Amyloid Pathology in the 3xTgAD Mouse Model

    PubMed Central

    Gabbita, S. Prasad; Johnson, Ming F.; Kobritz, Naomi; Eslami, Pirooz; Poteshkina, Aleksandra; Varadarajan, Sridhar; Turman, John; Zemlan, Frank; Harris-White, Marni E.

    2015-01-01

    Cytokines such as TNFα can polarize microglia/macrophages into different neuroinflammatory types. Skewing of the phenotype towards a cytotoxic state is thought to impair phagocytosis and has been described in Alzheimer’s Disease (AD). Neuroinflammation can be perpetuated by a cycle of increasing cytokine production and maintenance of a polarized activation state that contributes to AD progression. In this study, 3xTgAD mice, age 6 months, were treated orally with 3 doses of the TNFα modulating compound isoindolin-1,3 dithione (IDT) for 10 months. We demonstrate that IDT is a TNFα modulating compound both in vitro and in vivo. Following long-term IDT administration, mice were assessed for learning & memory and tissue and serum were collected for analysis. Results demonstrate that IDT is safe for long-term treatment and significantly improves learning and memory in the 3xTgAD mouse model. IDT significantly reduced paired helical filament tau and fibrillar amyloid accumulation. Flow cytometry of brain cell populations revealed that IDT increased the infiltrating neutrophil population while reducing TNFα expression in this population. IDT is a safe and effective TNFα and innate immune system modulator. Thus small molecule, orally bioavailable modulators are promising therapeutics for Alzheimer’s disease. PMID:26436670

  8. Loss of neprilysin alters protein expression in the brain of Alzheimer's disease model mice.

    PubMed

    Nilsson, Per; Loganathan, Krishnapriya; Sekiguchi, Misaki; Winblad, Bengt; Iwata, Nobuhisa; Saido, Takaomi C; Tjernberg, Lars O

    2015-10-01

    Alzheimer's disease (AD) is a neurodegenerative disease displaying extracellular plaques formed by the neurotoxic amyloid β-peptide (Aβ), and intracellular neurofibrillary tangles consisting of protein tau. However, how these pathologies relate to the massive neuronal death that occurs in AD brains remain elusive. Neprilysin is the major Aβ-degrading enzyme and a lack thereof increases Aβ levels in the brain twofold. To identify altered protein expression levels induced by increased Aβ levels, we performed a proteomic analysis of the brain of the AD mouse model APPsw and compared it to that of APPsw mice lacking neprilysin. To this end we established an LC-MS/MS method to analyze brain homogenate, using an (18) O-labeled internal standard to accurately quantify the protein levels. To distinguish between alterations in protein levels caused by increased Aβ levels and those induced by neprilysin deficiency independently of Aβ, the brain proteome of neprilysin deficient APPsw mice was also compared to that of neprilysin deficient mice. By this approach we identified approximately 600 proteins and the levels of 300 of these were quantified. Pathway analysis showed that many of the proteins with altered expression were involved in neurological disorders, and that tau, presenilin and APP were key regulators in the identified networks. The data have been deposited to the ProteomeXchange Consortium with identifiers PXD000968 and PXD001786 (http://proteomecentral.proteomexchange.org/dataset/PXD000968 and (http://proteomecentral.proteomexchange.org/dataset/PXD001786). Interestingly, the levels of several proteins, including some not previously reported to be linked to AD, were associated with increased Aβ levels.

  9. Small molecule TBTC as a new selective retinoid X receptor α agonist improves behavioral deficit in Alzheimer's disease model mice.

    PubMed

    Sun, Yanyan; Fan, Jun; Zhu, Zhiyuan; Guo, Xiaodan; Zhou, Tingting; Duan, Wenhu; Shen, Xu

    2015-09-01

    Alzheimer's disease (AD) is a neurodegenerative disease, which is characterized by progressive cognitive impairments. The β-amyloid (Aβ)-induced neurodegeneration is determined as the main pathogenesis of AD, and either decrease of Aβ production or increase of Aβ clearance is beneficial in the treatment of AD, while Aβ clearance regulation seems to be more attractive as a promising therapeutic strategy against AD based on the fact that the insufficient clearance of Aβ is tightly associated with the late onset of AD that is represented as the majority of AD cases. Here, we report that the small molecular compound, methyl 2-amino-6-(tert-butyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate (TBTC), as a selective agonist of retinoid X receptor α (RXRα) can effectively activate the heterodimerization of RXRα with either liver X receptor α (LXRα) or peroxisome proliferator activated receptor γ (PPARγ), stimulate the expressions of the genes of apoE, ABCA1 and ABCG1, and decrease Aβ content both in cells and animal models. In addition, administration of TBTC (30mg/kg/day) in the transgenic APP-PS1 mice could also reduce the formation of senile plaques and improve the daily living activity of the mice. Therefore, our findings have suggested that TBTC might hold the potential as a drug lead compound for the treatment of AD.

  10. A Reanalysis of the Effects of Teacher Replacement Using Value-Added Modeling

    ERIC Educational Resources Information Center

    Yeh, Stuart S.

    2013-01-01

    Background: In principle, value-added modeling (VAM) might be justified if it can be shown to be a more reliable indicator of teacher quality than existing indicators for existing low-stakes decisions that are already being made, such as the award of small merit bonuses. However, a growing number of researchers now advocate the use of VAM to…

  11. Measuring Teacher Effectiveness Using Value-Added Models of High School Achievement

    ERIC Educational Resources Information Center

    Gawade, Nandita G.; Meyer, Robert H.

    2016-01-01

    This article uses empirical data to consider the consequences of particular characteristics of instruction and testing in high school for the modeling and estimation of value-added measures of school or teacher effectiveness. Unlike Mathematics and Reading for most elementary and middle school grades, there is a lack of annual testing of students…

  12. Estimating Teacher and School Effectiveness in Pittsburgh: Value-Added Modeling and Results. Final Report

    ERIC Educational Resources Information Center

    Lipscomb, Stephen; Gill, Brian; Booker, Kevin; Johnson, Matthew

    2010-01-01

    At the request of Pittsburgh Public Schools (PPS) and the Pittsburgh Federation of Teachers (PFT), Mathematica is developing value-added models (VAMs) that aim to estimate the contributions of individual teachers, teams of teachers, and schools to the achievement growth of their students. The analyses described in this report are intended as an…

  13. Methods for Accounting for Co-Teaching in Value-Added Models. Working Paper

    ERIC Educational Resources Information Center

    Hock, Heinrich; Isenberg, Eric

    2012-01-01

    Isolating the effect of a given teacher on student achievement (value-added modeling) is complicated when the student is taught the same subject by more than one teacher. We consider three methods, which we call the Partial Credit Method, Teacher Team Method, and Full Roster Method, for estimating teacher effects in the presence of co-teaching.…

  14. Using Value-Added Models to Measure Teacher Effects on Students' Motivation and Achievement

    ERIC Educational Resources Information Center

    Ruzek, Erik A.; Domina, Thurston; Conley, AnneMarie M.; Duncan, Greg J.; Karabenick, Stuart A.

    2015-01-01

    Value-added (VA) models measure teacher contributions to student learning and are increasingly employed in educational reform efforts. Using data from 35 seventh-grade teachers and 2,026 students across seven schools, we employ VA methods to measure teacher contributions to students' motivational orientations (mastery and performance achievement…

  15. What Are Error Rates for Classifying Teacher and School Performance Using Value-Added Models?

    ERIC Educational Resources Information Center

    Schochet, Peter Z.; Chiang, Hanley S.

    2013-01-01

    This article addresses likely error rates for measuring teacher and school performance in the upper elementary grades using value-added models applied to student test score gain data. Using a realistic performance measurement system scheme based on hypothesis testing, the authors develop error rate formulas based on ordinary least squares and…

  16. Teacher Value-Added at the High-School Level: Different Models, Different Answers?

    ERIC Educational Resources Information Center

    Goldhaber, Dan D.; Goldschmidt, Pete; Tseng, Fannie

    2013-01-01

    This article reports on findings based on analyses of a unique dataset collected by ACT that includes information on student achievement in a variety of subjects at the high-school level. The authors examine the relationship between teacher effect estimates derived from value-added model (VAM) specifications employing different student learning…

  17. A study of presynaptic alpha2-autoreceptors in alpha2A/D-, alpha2B- and alpha2C-adrenoceptor-deficient mice.

    PubMed

    Trendelenburg, A U; Klebroff, W; Hein, L; Starke, K

    2001-08-01

    The function of presynaptic alpha2-autoreceptors was studied in the hippocampus, occipito-parietal cortex, atria and vas deferens of NMRI mice, mice in which the alpha2A/D-, the alpha2B- or alpha2c-adrenoceptor gene had been disrupted (alpha2A/DKO, alpha2BKO and alpha2CKO, respectively), and the wildtype mice from which the knockout animals had been generated. Tissue pieces were preincubated with 3H-noradrenaline and then superfused and stimulated electrically. The alpha2-adrenoceptor agonist medetomidine reduced the electrically evoked overflow of tritium in all tissues from all mouse strains (stimulation with single pulses or single high-frequency pulse trains, called POPs, i.e. pulse patterns leading to minimal autoinhibition). The effects of medetomidine did not differ in NMRI, wildtype, alpha2BKO and alpha2CKO mice but were greatly reduced in alpha2A/DKO brain preparations and to a lesser extent in alpha2A/DKO atria and vasa deferentia. Six drugs were tested as antagonists against medetomidine. Their pKd values indicated that the hippocampal and occipito-parietal alpha2-autoreceptors in NMRI and wildtype mice were alpha2D (the rodent variant of the alpha2A/D-adrenoceptor) whereas the atrial and vas deferens alpha2-autoreceptors in NMRI and wildtype mice could not be identified with a single alpha2 subtype. Deletion of the alpha2A/D gene changed the pKd values in all tissues so that they now reflected alpha2C properties, whereas deletion of the alpha2C gene changed the pKd values in atria and vasa deferentia so that they now had alpha2D properties (as they had in NMRI and wildtype brain preparations). Autoinhibition by released noradrenaline was created using trains of up to 64 pulses or up to 4 POPs, and the overflow-enhancing effect of the alpha2 antagonist rauwolscine was determined. Results did not differ, irrespective of whether preparations were obtained from NMRI, wildtype, alpha2BKO or alpha2CKO mice: the overflow of tritium elicited by p pulses or POPs

  18. Aluminum exposure through the diet: metal levels in AbetaPP transgenic mice, a model for Alzheimer's disease.

    PubMed

    Gómez, Mercedes; Esparza, José L; Cabré, María; García, Tania; Domingo, José L

    2008-07-30

    Aluminum (Al), iron (Fe), copper (Cu), and zinc (Zn) cause have been implicated in the etiology of certain neurodegenerative disorders. Moreover, these elements cause the conformational changes of Alzheimer's amyloid beta protein. In this study, we determined the concentrations of Al, Cu, Zn, Fe, and Mn in various tissues of Tg 2576 (AbetaPP transgenic) Al-treated mice. Female Tg 2576 mice and wild-type littermates were exposed through the diet to 1mg Al/g for 6 months. At 11 months of age, metal concentrations were measured in various tissues. In brain, Al levels were higher in hippocampus than in cortex and cerebellum. In hippocampus, Cu concentrations decreased in non-treated Tg 2576 mice, while Zn levels were higher in Al-treated mice. Copper, Zn, Mn and Fe concentrations in liver, kidney and bone were not affected by Al exposure. The current results show that Al exposure of Tg 2576 and wild-type mice did not produce important metal changes related with the genotype, responding similarly both groups of animals. As Tg 2576 mice have been considered as a potential model for Alzheimer's disease (AD), the present results would not support the hypothetical role of Al in the etiology of AD.

  19. Effect of epidermal growth factor (EGF) on (/sup 3/H)TdR incorporation into DNA in ad lib fed and fasted CD2F1 mice

    SciTech Connect

    Scheving, L.A.; Tsai, T.H.; Scheving, L.E.; Hoke, W.S.

    1987-03-01

    The effect of EGF on the incorporation of (/sup 3/H)TdR into DNA (DNA synthesis) was determined in the esophagus, liver, pancreas, and kidney in mice standardized to 12 hours (hr) of light alternating with 12 hr of darkness. A question asked was whether intraperitoneally administered EGF could alter the circadian patterns of DNA synthesis in these organs. The most marked effects of EGF were: an increase in DNA synthesis but only after a specific duration of time after treatment, ranging from 8 to 23 hr, which differed for each tissue, a similarity in the response of the esophagus in both ad lib fed and fasted mice, but not in the response of the liver, where the stimulatory effect of EGF observed in fed mice was dramatically reduced in fasted ones, and an advance in the phasing of the circadian rhythm in DNA synthesis of the esophagus by about 12 hr. In addition, no sex differences in fasted animals were found under the conditions of this study.

  20. An Ad-Hoc Adaptive Pilot Model for Pitch Axis Gross Acquisition Tasks

    NASA Technical Reports Server (NTRS)

    Hanson, Curtis E.

    2012-01-01

    An ad-hoc algorithm is presented for real-time adaptation of the well-known crossover pilot model and applied to pitch axis gross acquisition tasks in a generic fighter aircraft. Off-line tuning of the crossover model to human pilot data gathered in a fixed-based high fidelity simulation is first accomplished for a series of changes in aircraft dynamics to provide expected values for model parameters. It is shown that in most cases, for this application, the traditional crossover model can be reduced to a gain and a time delay. The ad-hoc adaptive pilot gain algorithm is shown to have desirable convergence properties for most types of changes in aircraft dynamics.

  1. 5-Lipoxygenase gene transfer worsens memory, amyloid and tau brain pathologies in a mouse model of AD

    PubMed Central

    Chu, Jin; Giannopoulos, Phillip F.; Ceballos-Diaz, Carolina; Golde, Todd E.; Pratico, Domenico

    2012-01-01

    Objective The 5-lipoxygenase (5LO) enzyme is up-regulated in Alzheimer’s disease (AD), and its genetic absence reduces Aβ levels in APP mice. However, its functional role in modulating tau neuropathology remains to be elucidated. Methods To this end, we generated triple transgenic mice (3xTg-AD) over-expressing neuronal 5LO and investigated their phenotype. Results Compared with controls, 3xTg-AD mice over-expressing 5LO manifested an exacerbation of memory deficits, plaques and tangles pathologies. The elevation in Aβ was secondary to an up-regulation of γ-secretase pathway, whereas tau hyperphosphorylation resulted from an activation of the Cdk5 kinase. In vitro study confirmed the involvement of this kinase in the 5-LO-dependent tau phosphorylation, which was independent of the effect on Aβ. Interpretation Our findings highlight the novel functional role that neuronal 5LO plays in exacerbating AD-related tau pathologies. They provide critical preclinical evidence to justify testing selective 5LO inhibitors for AD treatment. PMID:23034916

  2. Cerebral dopamine neurotrophic factor improves long-term memory in APP/PS1 transgenic mice modeling Alzheimer's disease as well as in wild-type mice.

    PubMed

    Kemppainen, Susanna; Lindholm, Päivi; Galli, Emilia; Lahtinen, Hanna-Maija; Koivisto, Henna; Hämäläinen, Elina; Saarma, Mart; Tanila, Heikki

    2015-09-15

    Cerebral dopamine neurotrophic factor (CDNF) protects and repairs dopamine neurons in animal models of Parkinson's disease, which motivated us to investigate its therapeutic effect in an animal model of Alzheimer's disease (AD). We employed an established APP/PS1 mouse model of AD and gave intrahippocampal injections of CDNF protein or CDNF transgene in an AAV2 viral vector to 1-year-old animals. We performed a behavioral test battery 2 weeks after the injections and collected tissue samples after the 3-week test period. Intrahippocampal CDNF-therapy improved long-term memory in both APP/PS1 mice and wild-type controls, but did not affect spontaneous exploration, object neophobia or early stages of spatial learning. The memory improvement was not associated with decreased brain amyloid load or enhanced hippocampal neurogenesis. Intracranial CDNF treatment has beneficial effects on long-term memory and is well tolerated. The CDNF molecular mechanisms of action on memory await further studies.

  3. Mobile agent and multilayer integrated distributed intrusion detection model for clustering ad hoc networks

    NASA Astrophysics Data System (ADS)

    Feng, Jianxin; Wang, Guangxing

    2004-04-01

    Ad hoc networks do not depend on any predefined infrastructure or centralized administration to operate. Their security characters require more complex security preventions. As the second line of defense, Intrusion detection is the necessary means of getting the high survivability. In this paper the security characters of ad hoc networks and the related contents of intrusion detection are discussed. Mobile Agent and Multi-layer Integrated Distributed Intrusion Detection Model (MAMIDIDM) and a heuristic global detection algorithm are proposed tentatively by combining the mobile agent technology with the multi-layer conception. This heuristic global detection algorithm combines the mobile agent detection engine with the multi-layer detection engines and analyzes the results obtained by the corresponding detection engines. MAMIDIDM has the better flexibility and extensibility, can execute the intrusion detection in clustering ad hoc networks effectively.

  4. Vaccination to conserved influenza antigens in mice using a novel Simian adenovirus vector, PanAd3, derived from the bonobo Pan paniscus.

    PubMed

    Vitelli, Alessandra; Quirion, Mary R; Lo, Chia-Yun; Misplon, Julia A; Grabowska, Agnieszka K; Pierantoni, Angiolo; Ammendola, Virginia; Price, Graeme E; Soboleski, Mark R; Cortese, Riccardo; Colloca, Stefano; Nicosia, Alfredo; Epstein, Suzanne L

    2013-01-01

    Among approximately 1000 adenoviruses from chimpanzees and bonobos studied recently, the Pan Adenovirus type 3 (PanAd3, isolated from a bonobo, Pan paniscus) has one of the best profiles for a vaccine vector, combining potent transgene immunogenicity with minimal pre-existing immunity in the human population. In this study, we inserted into a replication defective PanAd3 a transgene expressing a fusion protein of conserved influenza antigens nucleoprotein (NP) and matrix 1 (M1). We then studied antibody and T cell responses as well as protection from challenge infection in a mouse model. A single intranasal administration of PanAd3-NPM1 vaccine induced strong antibody and T cell responses, and protected against high dose lethal influenza virus challenge. Thus PanAd3 is a promising candidate vector for vaccines, including universal influenza vaccines.

  5. Genetic reductions of BACE1 and amyloid-β ameliorate impairment of conditioned taste aversion memory in 5XFAD Alzheimer model mice

    PubMed Central

    Devi, Latha; Ohno, Masuo

    2010-01-01

    Although transgenic mouse models of Alzheimer’s disease (AD) recapitulate amyloid-β (Aβ)-related pathologies and cognitive impairments, previous studies have mainly evaluated their hippocampus-dependent memory dysfunctions using behavioral tasks such as the water maze and fear conditioning. However, multiple memory systems become impaired in AD as disease progresses, and it is important to test whether other forms of memory are affected in AD models. This study was designed to use conditioned taste aversion (CTA) and contextual fear conditioning paradigms to compare the phenotypes of hippocampus-independent and dependent memory functions, respectively, in 5XFAD APP/PS1 transgenic mice that harbor five familial AD (FAD) mutations. While both types of memory were significantly impaired in 5XFAD mice, the onset of CTA memory deficits (~9 months of age) was delayed compared to that of contextual memory deficits (~6 months of age). Furthermore, 5XFAD mice genetically engineered to have reduced levels of β-site APP-cleaving enzyme 1 (BACE1+/−·5XFAD) exhibited improved CTA memory, which was equivalent to the performance of wild-type controls. Importantly, elevated levels of cerebral β-secretase-cleaved C-terminal fragment (C99) and Aβ peptides in 5XFAD mice were significantly reduced in BACE1+/−·5XFAD mice. Furthermore, Aβ deposition in the insular cortex and basolateral amygdala, two brain regions critically involved in CTA performance, was also reduced in BACE1+/−·5XFAD mice compared to 5XFAD mice. Our findings indicate that the CTA paradigm is useful for evaluating a hippocampus-independent form of memory defects in AD model mice, which is sensitive to rescue by partial reductions of the β-secretase BACE1 and consequently of cerebral Aβ. PMID:20092558

  6. Value-Added Teacher Estimates as Part of Teacher Evaluations: Exploring the Effects of Data and Model Specifications on the Stability of Teacher Value-Added Scores

    ERIC Educational Resources Information Center

    Kersting, Nicole B.; Chen, Mei-kuang; Stigler, James W.

    2013-01-01

    If teacher value-added estimates (VAEs) are to be used as indicators of individual teacher performance in teacher evaluation and accountability systems, it is important to understand how much VAEs are affected by the data and model specifications used to estimate them. In this study we explored the effects of three conditions on the stability of…

  7. Exploring Female Mice Interstrain Differences Relevant for Models of Depression

    PubMed Central

    de Sá-Calçada, Daniela; Roque, Susana; Branco, Carlos; Monteiro, Susana; Cerqueira-Rodrigues, Bruno; Sousa, Nuno; Palha, Joana A.; Correia-Neves, Margarida

    2015-01-01

    Depression is an extremely heterogeneous disorder. Diverse molecular mechanisms have been suggested to underlie its etiology. To understand the molecular mechanisms responsible for this complex disorder, researchers have been using animal models extensively, namely mice from various genetic backgrounds and harboring distinct genetic modifications. The use of numerous mouse models has contributed to enrich our knowledge on depression. However, accumulating data also revealed that the intrinsic characteristics of each mouse strain might influence the experimental outcomes, which may justify some conflicting evidence reported in the literature. To further understand the impact of the genetic background, we performed a multimodal comparative study encompassing the most relevant parameters commonly addressed in depression, in three of the most widely used mouse strains: Balb/c, C57BL/6, and CD-1. Moreover, female mice were selected for this study taken into account the higher prevalence of depression in women and the fewer animal studies using this gender. Our results show that Balb/c mice have a more pronounced anxious-like behavior than CD-1 and C57BL/6 mice, whereas C57BL/6 animals present the strongest depressive-like trait. Furthermore, C57BL/6 mice display the highest rate of proliferating cells and brain-derived neurotrophic factor (Bdnf) expression levels in the hippocampus, while hippocampal dentate granular neurons of Balb/c mice show smaller dendritic lengths and fewer ramifications. Of notice, the expression levels of inducible nitric oxide synthase (iNos) predict 39.5% of the depressive-like behavior index, which suggests a key role of hippocampal iNOS in depression. Overall, this study reveals important interstrain differences in several behavioral dimensions and molecular and cellular parameters that should be considered when preparing and analyzing experiments addressing depression using mouse models. It further contributes to the literature by revealing

  8. Diffractive deep inelastic scattering in an AdS/CFT inspired model: A phenomenological study

    SciTech Connect

    Betemps, M. A.; Goncalves, V. P.; Santana Amaral, J. T. de

    2010-05-01

    The analytical treatment of the nonperturbative QCD dynamics is one of the main open questions of the strong interactions. Currently, it is only possible to get some qualitative information about this regime considering other QCD-like theories, as, for example, the N=4 super Yang-Mills theory, where one can perform calculations in the nonperturbative limit of large 't Hooft coupling using the anti-de Sitter space/conformal field theory (AdS/CFT). Recently, the high energy scattering amplitude was calculated in the AdS/CFT approach, applied to deep-inelastic scattering and confronted with the F{sub 2} HERA data. In this work we extend the nonperturbative AdS/CFT inspired model for diffractive processes and compare its predictions with a perturbative approach based on the Balitsky-Kovchegov equation. We demonstrate that the AdS/CFT inspired model is not able to describe the current F{sub 2}{sup D(3)} HERA data and predicts a similar behavior to that from the Balitsky-Kovchegov equation in the range 10{sup -7} < or approx. x{sub P} < or approx. 10{sup -4}. At smaller values of x{sub P} the diffractive structure function is predicted to be energy independent.

  9. Modeling Zika Virus Infection in Mice.

    PubMed

    Rossi, Shannan L; Vasilakis, Nikos

    2016-07-01

    Understanding the link between Zika virus (ZIKV) infection and microcephaly requires in vivo models of ZIKV infection in pregnant adults and fetuses. Three studies recently generated such mouse models of ZIKV infection, which corroborate previous in vitro evidence linking ZIKV infection and apoptosis induction in neurons and progenitors to microcephaly. PMID:27392219

  10. Modeling Zika Virus Infection in Mice.

    PubMed

    Rossi, Shannan L; Vasilakis, Nikos

    2016-07-01

    Understanding the link between Zika virus (ZIKV) infection and microcephaly requires in vivo models of ZIKV infection in pregnant adults and fetuses. Three studies recently generated such mouse models of ZIKV infection, which corroborate previous in vitro evidence linking ZIKV infection and apoptosis induction in neurons and progenitors to microcephaly.

  11. Self-assembling nanofibers improve cognitive impairment in a transgenic mice model of Alzheimer's disease.

    PubMed

    Yang, Hongna; Qu, Tingyu; Yang, Hui; Wei, Lifei; Xie, Zhaohong; Wang, Ping; Bi, Jianzhong

    2013-11-27

    The peptide amphiphile (PA) with a laminin epitope IKVAV (IKVAV-PA) can be trigged into three-dimensional nanostructures in vivo. Application of IKVAV-PA to the injured spinal cord resulted in significant functional improvement in rodents with remarkable axonal regeneration at the lesion site. Here we showed that injection of IKVAV-PA into the hippocampus of a transgenic (Tg) mice model of Alzheimer's disease (AD) significantly improved cognitive impairment, accompanied by an enhanced neurogenesis in the hippocampus. Further examination demonstrated that IKVAV-PA injections also significantly reduced the levels of soluble Aβ1-40, Aβ1-42, and amyloid-beta (Aβ) plaques in these brains. Our data suggest that IKVAV-PA may serve as a potential therapeutic intervention for the learning and memory losses in AD.

  12. Effectiveness Measures for Cross-Sectional Studies: A Comparison of Value-Added Models and Contextualised Attainment Models

    ERIC Educational Resources Information Center

    Lenkeit, Jenny

    2013-01-01

    Educational effectiveness research often appeals to "value-added models (VAM)" to gauge the impact of schooling on student learning net of the effect of student background variables. A huge amount of cross-sectional studies do not, however, meet VAM's requirement for longitudinal data. "Contextualised attainment models (CAM)" measure the influence…

  13. Enhanced inflammation and immunosuppression by ultraviolet radiation in xeroderma pigmentosum group A (XPA) model mice.

    PubMed

    Miyauchi-Hashimoto, H; Tanaka, K; Horio, T

    1996-09-01

    Xeroderma pigmentosum group A (XPA) gene-deficient mice were developed by gene targeting in mouse embryonic stem cells. To examine whether these XPA-model mice display photodermatologic abnormalities similar to those in human xeroderma pigmentosum, we investigated the effects of acute ultraviolet radiation on the homozygous (-/-) mice compared to the wild type (+/+) and heterozygous (+/-) mice. A single irradiation with ultraviolet B or topical psoralen plus ultraviolet A treatment induced stronger and longer lasting ear swelling in the (-/-) mice than in the (+/+) and (+/-) mice. Histologic changes including epidermal necrosis, cell infiltration, and sunburn cell formation after ultraviolet B radiation were more prominent in the (-/-) model mice than in the control mice. The (-/-) model mice showed damage of ADPase(+)Langerhans cells at a lower ultraviolet B dose than did the control mice. Moreover, the reappearance of ADPase(+)Langerhans cells after ultraviolet B radiation was delayed in the (-/-) mice compared to the control mice. Although contact hypersensitivity was induced equally in all mice, ultraviolet B-induced local and systemic immunosuppression were greatly enhanced in the (-/-) model mice. The data suggest that the XPA gene-deficient mice may be a useful model of human XPA, because the responses to UV radiation in the mice were very similar to those in the patients with XPA. Moreover, it is possible that enhanced ultraviolet immunosuppression is involved in the development of skin cancers in xeroderma pigmentosum. PMID:8751968

  14. Full vector archaeomagnetic data and Bayesian modelling for 1300 to 1750 AD

    NASA Astrophysics Data System (ADS)

    Schnepp, E.; Lanos, P.; Chauvin, A.

    2009-04-01

    The data base of geomagnetic palaeointensities obtained from archaeological artefacts is poor and very scattered for Western and Central Europe. High precision palaeointensities have been determined from a single archaeological site in Lübeck (Germany) where a sequence of 25 bread-oven-floors has been preserved in a bakery from medieval times until today. Age dating confines the time interval from about 1300 AD to about 1750 AD. Palaeomagnetic directions have been determined from each oven-floor (Schnepp et al., JGR, 2003). Palaeointensity was measured from selected specimens with the double-heating Thellier method and reliable palaeointensity results have been obtained. Tests for thermoremanent magnetisation anisotropy have been performed, but did not show a significant change, while a cooling rate correction was not necessary. 22 mean palaeointensity values derived from the oven-floors show maxima in the 15th and early 17th century AD, followed by a decrease of palaeointensity of about 25% until 1750 AD. The Thellier experiments provided also new characteristic remanent magnetisation directions which were included in the data set. Mean directions have been recalculated. Palaeointensity together with the directions represent a record of about 450 years full vector secular variation. From this full vector data set a secular variation curve has been calculated using a Bayesian modelling taking dating errors, all errors on the field vector and stratigraphy into account. A smooth curve with an error envelope was obtained which compares very well with the gufm1 geomagnetic model (Jackson et al., Phil. Trans. R. Soc. Lond. A, 2000) obtained from historical observations starting at 1600 AD. Comparison of the marginal curve obtained for palaeointensity with a selected data set of archaeomagnetic intensities from Western and Central Europe will be discussed.

  15. Modelling tsunami sedimentation associated with the AD 1755 event in Algarve (Portugal)

    NASA Astrophysics Data System (ADS)

    Costa, P. J. M.; Gelfenbaum, G. R.; La Selle, S.; Costas, S.; Andrade, C.; Cascalho, J.; Freitas, M. C.

    2015-12-01

    Numerical models of tsunami inundation and sedimentation can provide useful insights into the dynamics of palaeotsunamis. We applied a coupled field data and numerical modelling approach for the AD1755 tsunami, the most destructive tsunami to affect the Atlantic coast of Europe in historical times. At Salgados, a lowland on the south coast of Portugal, tsunami deposits from AD1755 mostly consist of massive or normally-graded, landward thinning layers of shell-rich sand with an erosive base within the mud-dominated lowlands. Landward of the foredune, the AD1755 deposit is roughly 10cm thick and thins in the landward and alongshore directions. It is possible to ascribe the sediment source of this deposit to the dune and/or beach based on mineralogical and grain-size comparisons with modern surface samples. The present dune crest height is 6 m above MSL (mean sea level) near the seasonally-closed inlet of the lagoon, and rises alongshore towards the west up to 17m above MSL. From the combination of the spatial distribution of the deposit thickness landward of the sloping dune, and GPR data, which shows an erosional surface at approximately 6m above MSL, we infer that the maximum tsunami water level at the coast was between 6 and 10m. Regional tsunami historical records, however, suggest higher heights, up to 12m above MSL at the coast. We simulated tsunami inundation and sediment transport using Delft3D to examine these discrepancies. A 1D cross shore model was used to test flow height controls on deposit thickness and also to identify the sediment source of the AD1755 deposit. Four possible sediment sources were tested (nearshore, beach, dune and lagoon) using synthetic, long-period waves to simulate the AD1755 tsunami. The combination of geological studies with numerical modeling of inundation and sediment transport produces a better description of the AD1755 tsunami and its effects in coastal areas in the Algarve that will contribute to better hazard assessments.

  16. Craniofacial statistical deformation models of wild-type mice and Crouzon mice

    NASA Astrophysics Data System (ADS)

    Ólafsdóttir, Hildur; Darvann, Tron A.; Ersbøll, Bjarne K.; Hermann, Nuno V.; Oubel, Estanislao; Larsen, Rasmus; Frangi, Alejandro F.; Larsen, Per; Perlyn, Chad A.; Morriss-Kay, Gillian M.; Kreiborg, Sven

    2007-03-01

    Crouzon syndrome is characterised by premature fusion of cranial sutures and synchondroses leading to craniofacial growth disturbances. The gene causing the syndrome was discovered approximately a decade ago and recently the first mouse model of the syndrome was generated. In this study, a set of Micro CT scans of the heads of wild-type (normal) mice and Crouzon mice were investigated. Statistical deformation models were built to assess the anatomical differences between the groups, as well as the within-group anatomical variation. Following the approach by Rueckert et al. we built an atlas using B-spline-based nonrigid registration and subsequently, the atlas was nonrigidly registered to the cases being modelled. The parameters of these registrations were then used as input to a PCA. Using different sets of registration parameters, different models were constructed to describe (i) the difference between the two groups in anatomical variation and (ii) the within-group variation. These models confirmed many known traits in the wild-type and Crouzon mouse craniofacial anatomy. However, they also showed some new traits.

  17. Value-Added Modeling of Teacher Effectiveness: An Exploration of Stability across Models and Contexts

    ERIC Educational Resources Information Center

    Newton, Xiaoxia A.; Darling-Hammond, Linda; Haertel, Edward; Thomas, Ewart

    2010-01-01

    Recent policy interest in tying student learning to teacher evaluation has led to growing use of value-added methods for assessing student learning gains linked to individual teachers. VAM analyses rely on complex assumptions about the roles of schools, multiple teachers, student aptitudes and efforts, homes and families in producing measured…

  18. The VIS-AD data model: Integrating metadata and polymorphic display with a scientific programming language

    NASA Technical Reports Server (NTRS)

    Hibbard, William L.; Dyer, Charles R.; Paul, Brian E.

    1994-01-01

    The VIS-AD data model integrates metadata about the precision of values, including missing data indicators and the way that arrays sample continuous functions, with the data objects of a scientific programming language. The data objects of this data model form a lattice, ordered by the precision with which they approximate mathematical objects. We define a similar lattice of displays and study visualization processes as functions from data lattices to display lattices. Such functions can be applied to visualize data objects of all data types and are thus polymorphic.

  19. A Leasing Model to Deal with Partial Failures in Mobile Ad Hoc Networks

    NASA Astrophysics Data System (ADS)

    Gonzalez Boix, Elisa; van Cutsem, Tom; Vallejos, Jorge; de Meuter, Wolfgang; D'Hondt, Theo

    In mobile ad hoc networks (MANETs) many partial failures are the result of temporary network partitions due to the intermittent connectivity of mobile devices. Some of these failures will be permanent and require application-level failure handling. However, it is impossible to distinguish a permanent from a transient failure. Leasing provides a solution to this problem based on the temporal restriction of resources. But to date no leasing model has been designed specifically for MANETs. In this paper, we identify three characteristics required for a leasing model to be usable in a MANET, discuss the issues with existing leasing models and then propose the leased object references model, which integrates leasing with remote object references. In addition, we describe an implementation of the model in the programming language AmbientTalk. Leased object references provide an extensible framework that allows programmers to express their own leasing patterns and enables both lease holders (clients) and lease grantors (services) to deal with permanent failures.

  20. A 1D model of the arterial circulation in mice.

    PubMed

    Aslanidou, Lydia; Trachet, Bram; Reymond, Philippe; Fraga-Silva, Rodrigo A; Segers, Patrick; Stergiopulos, Nikolaos

    2016-01-01

    At a time of growing concern over the ethics of animal experimentation, mouse models are still an indispensable source of insight into the cardiovascular system and its most frequent pathologies. Nevertheless, reference data on the murine cardiovascular anatomy and physiology are lacking. In this work, we developed and validated an in silico, one dimensional model of the murine systemic arterial tree consisting of 85 arterial segments. Detailed aortic dimensions were obtained in vivo from contrast-enhanced micro-computed tomography in 3 male, C57BL/6J anesthetized mice and 3 male ApoE(-/-) mice, all 12-weeks old. Physiological input data were gathered from a wide range of literature data. The integrated form of the Navier-Stokes equations was solved numerically to yield pressures and flows throughout the arterial network. The resulting model predictions have been validated against invasive pressure waveforms and non-invasive velocity and diameter waveforms that were measured in vivo on an independent set of 47 mice. In conclusion, we present a validated one-dimensional model of the anesthetized murine cardiovascular system that can serve as a versatile tool in the field of preclinical cardiovascular research.

  1. Quercetin stabilizes apolipoprotein E and reduces brain Aβ levels in amyloid model mice.

    PubMed

    Zhang, Xilin; Hu, Jin; Zhong, Li; Wang, Na; Yang, Longyu; Liu, Chia-Chen; Li, Huifang; Wang, Xin; Zhou, Ying; Zhang, Yunwu; Xu, Huaxi; Bu, Guojun; Zhuang, Jiangxing

    2016-09-01

    Apolipoprotein E (apoE) is a major cholesterol carrier that regulates lipid homeostasis by mediating lipid transport from one tissue or cell type to another. In the central neural system (CNS), apoE is mainly produced by astrocytes, and transports cholesterol to neurons via apoE receptors, which are members of the low-density lipoprotein receptor family. The APOEε4 gene is a strong genetic risk factor for late-onset sporadic Alzheimer's disease (AD), likely through its strong effect on the accumulation of amyloid-β (Aβ) peptide. ApoE protein levels in cerebrospinal fluid (CSF) and plasma are reduced in APOEε4 carriers and in patients with AD. Furthermore, altered cholesterol levels are also associated with the risk of AD. Aβ accumulation, oligomerization and deposition in the brain are central to the pathogenesis of AD. Mounting evidence demonstrates that apoE and apoE receptors play important roles in these processes. Astrocyte-derived apoE is pivotal for cerebral cholesterol metabolism and clearance of Aβ. Thus, we hypothesized that increased apoE in the brain may be an effective therapeutic strategy for AD. We report here that quercetin can significantly increase apoE levels by inhibiting apoE degradation in immortalized astrocytes. Importantly, we show that oral administration of quercetin significantly increased brain apoE and reduced insoluble Aβ levels in the cortex of 5xFAD amyloid model mice. Our results demonstrate that quercetin increases apoE levels through a novel mechanism and can be explored as a novel class of drug for AD therapy. PMID:27114256

  2. Early phenotypical diagnoses in Trembler-J mice model.

    PubMed

    Rosso, Gonzalo; Cal, Karina; Canclini, Lucía; Damián, Juan Pablo; Ruiz, Paul; Rodríguez, Héctor; Sotelo, José Roberto; Vazquez, Cristina; Kun, Alejandra

    2010-06-30

    Pmp-22 mutant mice (Trembler-J: B6.D2-Pmp22/J), are used as a model to study Charcot-Marie-Tooth type 1A (CMT1A). The identification of individual genotypes is a routine in the management of the Tr(J) colony. The earliest phenotypic manifestation of the pmp-22 mutation is just about 20th postnatal days, when pups begin to tremble. In this study, a rapid and simple diagnostic method was developed by modifying the Tail Suspension Test (MTST) to determine the difference between the Tr(J) and the wild-type mice phenotype. The animal behavioral phenotypes generated during the test were consistent with the specific genotype of each animal. The MTST allowed us to infer the heterozygous genotype in early postnatal stages, at 11 days after birth. The motor impairment of Tr(J) mice was also analyzed by a Fixed Bar Test (FBT), which revealed the disease evolution according to age. The main advantages of MTST are its objectivity, simplicity, and from the viewpoint of animal welfare, it is a non-invasive technique that combined with his rapidity show its very well applicability for use from an early age in these mice.

  3. Hierarchical Interactions Model for Predicting Mild Cognitive Impairment (MCI) to Alzheimer's Disease (AD) Conversion

    PubMed Central

    Li, Han; Liu, Yashu; Gong, Pinghua; Zhang, Changshui; Ye, Jieping

    2014-01-01

    Identifying patients with Mild Cognitive Impairment (MCI) who are likely to convert to dementia has recently attracted increasing attention in Alzheimer's disease (AD) research. An accurate prediction of conversion from MCI to AD can aid clinicians to initiate treatments at early stage and monitor their effectiveness. However, existing prediction systems based on the original biosignatures are not satisfactory. In this paper, we propose to fit the prediction models using pairwise biosignature interactions, thus capturing higher-order relationship among biosignatures. Specifically, we employ hierarchical constraints and sparsity regularization to prune the high-dimensional input features. Based on the significant biosignatures and underlying interactions identified, we build classifiers to predict the conversion probability based on the selected features. We further analyze the underlying interaction effects of different biosignatures based on the so-called stable expectation scores. We have used 293 MCI subjects from Alzheimer's Disease Neuroimaging Initiative (ADNI) database that have MRI measurements at the baseline to evaluate the effectiveness of the proposed method. Our proposed method achieves better classification performance than state-of-the-art methods. Moreover, we discover several significant interactions predictive of MCI-to-AD conversion. These results shed light on improving the prediction performance using interaction features. PMID:24416143

  4. Test of the antiorthostatic suspension model on mice: effects on the inflammatory cell response.

    PubMed

    Fleming, S D; Rosenkrans, C F; Chapes, S K

    1990-04-01

    We tested the antiorthostatic suspension model for use as a 1G model to study the effects of factors that will be encountered during space travel on inflammation. We found no differences in inflammatory cells induced in antiorthostatically suspended mice. However, the superoxide response (used for oxidative killing of bacteria such as S. aureus) was impaired in antiorthostatically oriented mice compared to control mice. Elevated corticosterone levels were found in antiorthostatically suspended mice and indicate that stress may be a factor in the model. If the stress factor of the model correlates with the physiological stress of space flight, antiorthostatic suspension may be an acceptable model for studying inflammatory responses in mice.

  5. Test of the antiorthostatic suspension model on mice - Effects on the inflammatory cell response

    NASA Technical Reports Server (NTRS)

    Rosenkrans, Charles F., Jr.; Chapes, Stephen K.; Fleming, Sherry D.

    1990-01-01

    The antiorthostatic suspension model was tested for use as a 1G model to study the effects of factors that will be encountered during space travel on inflammation. No differences were found in inflammatory cells induced in antiorthostatically suspended mice. However, the superoxide response (used for oxidative killing of bacteria such as S. aureus) was impaired in antiorthostatically oriented mice compared to control mice. Elevated corticosterone levels were found in antiorthostatically suspended mice, indicating that stress may be a factor in the model. If the stress factor of the model correlates with the physiological stress of space flight, antiorthostatic suspension may be an acceptable model for studying inflammatory responses in mice.

  6. Open-Space Forced Swim Model of Depression for Mice

    PubMed Central

    Stone, Eric A.; Lin, Yan

    2011-01-01

    This protocol describes a simplified method for inducing a chronic depression-like state in mice that is based on the repeated open-space forced swim method for rats originally developed by Sun and Alkon (2003). The method consists of swimming mice daily in lukewarm water (32-34°C) in rat tub cages 24 × 43 × 23 cm w × h × l, for 15 min/day for 4 days, and thereafter once per week. This procedure produces a progressive decrease in distance swum and a concomitant increase in immobility (floating) in about 70 percent of the mice (Swiss Webster males), both of which persist unaltered for weeks and generalize to other tests of depression (tail suspension). The model has predictive, face and construct validity in that it is responsive to chronic antidepressants and coping responses but not to anxiolytics or antipsychotics, represents an inescapable stress that produces generalized passivity, and is accompanied by changes in neural activity and brain cell proliferation that are characteristic of depression and believed to contribute to the disorder. It is less effective in producing anhedonia than other models probably because it is less stressful. The model has a number of advantages over previous methods in that it utilizes very mild stress, is short in duration, is easily standardized, requires only a video camera and either a manual or automatic behavioral scoring system to measure immobility and distance swum, and can be readily used for time course studies of onset of drug action. Moreover, since it utilizes a greater swimming area than the traditional (Porsolt) method it can be used to study interactions of depressive behavior with behavioral flexibility and perseveration. Finally, its use of mice makes it readily amenable to genetic and molecular analyses. PMID:21207368

  7. Charm structure functions and gluon shadowing effects with the AdS/CFT model

    NASA Astrophysics Data System (ADS)

    Wang, Hong-Min; Hou, Zhao-Yu; Liu, Jia-Fu; Sun, Xian-Jing

    2012-08-01

    By means of the UGD function extracted from an AdS/CFT inspired saturation model, the charm and bottom structure functions are studied in fixed-order perturbation theory. It is shown that the theoretical results are in good agreement with the recent HERA data. Then, this UGD function is also used to investigate net-kaon rapidity distribution in Au+Au collisions at RHIC energies and the theoretical results fit well to the BRAHMS data. In the end of this paper, we give the predicted results for nuclear charm structure function at very small x where the popular shadowing parameterizations are invalid.

  8. Mutant mice: experimental organisms as materialised models in biomedicine.

    PubMed

    Huber, Lara; Keuck, Lara K

    2013-09-01

    Animal models have received particular attention as key examples of material models. In this paper, we argue that the specificities of establishing animal models-acknowledging their status as living beings and as epistemological tools-necessitate a more complex account of animal models as materialised models. This becomes particularly evident in animal-based models of diseases that only occur in humans: in these cases, the representational relation between animal model and human patient needs to be generated and validated. The first part of this paper presents an account of how disease-specific animal models are established by drawing on the example of transgenic mice models for Alzheimer's disease. We will introduce an account of validation that involves a three-fold process including (1) from human being to experimental organism; (2) from experimental organism to animal model; and (3) from animal model to human patient. This process draws upon clinical relevance as much as scientific practices and results in disease-specific, yet incomplete, animal models. The second part of this paper argues that the incompleteness of models can be described in terms of multi-level abstractions. We qualify this notion by pointing to different experimental techniques and targets of modelling, which give rise to a plurality of models for a specific disease.

  9. Using mice to model Alzheimer's dementia: an overview of the clinical disease and the preclinical behavioral changes in 10 mouse models

    PubMed Central

    Webster, Scott J.; Bachstetter, Adam D.; Nelson, Peter T.; Schmitt, Frederick A.; Van Eldik, Linda J.

    2014-01-01

    The goal of this review is to discuss how behavioral tests in mice relate to the pathological and neuropsychological features seen in human Alzheimer's disease (AD), and present a comprehensive analysis of the temporal progression of behavioral impairments in commonly used AD mouse models that contain mutations in amyloid precursor protein (APP). We begin with a brief overview of the neuropathological changes seen in the AD brain and an outline of some of the clinical neuropsychological assessments used to measure cognitive deficits associated with the disease. This is followed by a critical assessment of behavioral tasks that are used in AD mice to model the cognitive changes seen in the human disease. Behavioral tests discussed include spatial memory tests [Morris water maze (MWM), radial arm water maze (RAWM), Barnes maze], associative learning tasks (passive avoidance, fear conditioning), alternation tasks (Y-Maze/T-Maze), recognition memory tasks (Novel Object Recognition), attentional tasks (3 and 5 choice serial reaction time), set-shifting tasks, and reversal learning tasks. We discuss the strengths and weaknesses of each of these behavioral tasks, and how they may correlate with clinical assessments in humans. Finally, the temporal progression of both cognitive and non-cognitive deficits in 10 AD mouse models (PDAPP, TG2576, APP23, TgCRND8, J20, APP/PS1, TG2576 + PS1 (M146L), APP/PS1 KI, 5×FAD, and 3×Tg-AD) are discussed in detail. Mouse models of AD and the behavioral tasks used in conjunction with those models are immensely important in contributing to our knowledge of disease progression and are a useful tool to study AD pathophysiology and the resulting cognitive deficits. However, investigators need to be aware of the potential weaknesses of the available preclinical models in terms of their ability to model cognitive changes observed in human AD. It is our hope that this review will assist investigators in selecting an appropriate mouse model, and

  10. The fate of added alkalinity in model scenarios of ocean alkalinization

    NASA Astrophysics Data System (ADS)

    Ferrer González, Miriam; Ilyina, Tatiana

    2014-05-01

    The deliberate large-scale manipulation of the Earth's climate (geo-engineering) has been proposed to mitigate climate change and ocean acidification. Whilst the mitigation potential of these technologies could sound promising, they may also pose many environmental risks. Our research aims at exploring the ocean-based carbon dioxide removal method of alkalinity enhancement. Its mitigation potential to reduce atmospheric CO2 and counteract the consequences of ocean acidification, risks and unintended consequences are studied. In order to tackle these questions, different scenarios are implemented in the state-of-the-art Earth system model of the Max Planck Institute for Meteorology. The model configuration is based on the 5th phase of the coupled model intercomparison project following a high CO2 future climate change scenario RCP8.5 (in which radiative forcing rises to 8.5 W/m² in 2100). Two different scenarios are performed where the alkalinity is artificially added globally uniformly in the upper ocean. In the first scenario, alkalinity is increased as a pulse by doubling natural values of the first 12 meters. In the second scenario we add alkalinity into the same ocean layer such that the atmospheric CO2 concentration is reduced from RCP8.5 to RCP4.5 levels (with the radiative forcing of 4.5 W/m² in 2100). We investigate the fate of the added alkalinity in these two scenarios and compare the differences in alkalinity budgets. In order to increase oceanic CO2 uptake from the atmosphere, enhanced alkalinity has to stay in the upper ocean. Once the alkalinity is added, it will become part of the biogeochemical cycles and it will be distributed with the ocean currents. Therefore, we are particularly interested in the residence time of the added alkalinity at the surface. Variations in CO2 partial pressure, seawater pH and saturation state of carbonate minerals produced in the implemented scenarios will be presented. Collateral changes in ocean biogeochemistry and

  11. The value of adding optics to ecosystem models: a case study

    NASA Astrophysics Data System (ADS)

    Fujii, M.; Boss, E.; Chai, F.

    2007-05-01

    matter to the modeled properties. Coupling explicit optics to an ecosystem model provides several advantages in generating: (1) a more accurate subsurface light-field, which is important for light sensitive biogeochemical processes such as photosynthesis and photo-oxidation, (2) added constraints on model parameters that help to reduce uncertainties in ecosystem model simulations, and (3) model output which is comparable to basic remotely-sensed properties. In addition, the coupling of biogeochemical models and optics paves the road for future assimilation of ocean color and in-situ measured optical properties into the models.

  12. A climate simulation of the first millennium AD using a comprehensive Earth System Model

    NASA Astrophysics Data System (ADS)

    Wagner, Sebastian; Zorita, Eduardo

    2014-05-01

    Investigations of past climate using fully coupled comprehensive Earth System Models are restricted by the large computational costs of these simulations. Here we present first results from an on-going simulation with the MPI-ESM-P starting in year 100 BC. The simulation is forced with changes in orbital forcing and long-term solar variations augmented by a synthetic 11-year cycle including an interactive ozone cycle. For the first time also changes in volcanic activity are implemented based on the reconstruction method by Crowley and Unterman (2012). The basis of the extended volcanic forcing in terms of aerosol optical depth and effective radius are new sulfate estimations from ice cores from Greenland (NEEM) and Antarctica (WAIS) presented by Sigl et al. (2013). Because the NEEM record only reaches back as far as 79 AD, the time until 100 BC was filled by earlier information contained in the Dye 3 and GRIP record (Clausen et al., 1997). Compared to the 2nd millennium AD, the first millennium does however show a considerably reduced amount of large explosive tropical eruptions. On hemispheric and global scale the large outbreaks around the years 530 and 740 AD are well reflected as negative temperature anomalies. The 79 AD Vesuvius eruption does not however produce a pronounced hemispheric signal. The amount of sulphate ejected into the stratosphere may have been too low for a sustained hemispheric-scale cooling. The large eruption of 530 AD (so called 'mystic cloud') is however well reflected within the temperature evolution and is more pronounced over the northern hemisphere during summertime. On longer, multi-centennial, time scales, global temperatures show a slight decrease. This decrease is more pronounced over the NH hemisphere during JJA and is caused by the decline in the TOA short wave incoming radiation. Over the extratropical SH changes in orbital forcing are not reflected in temperature trends as clearly as over the NH due to the larger oceanic and

  13. Inhalational model of cocaine exposure in mice: neuroteratological effects.

    PubMed

    He, Fang; Lidow, Irina A; Lidow, Michael S

    2006-01-01

    We developed a novel inhalation-based mouse model of prenatal cocaine exposure. This model approximates cocaine abuse via smoking, the preferred route of cocaine administration by heavy drug users. The model is also characterized by (i) absence of procedural stress from drug administration, (ii) long-term drug exposure starting weeks before pregnancy and continuing throughout the entire gestation, and (iii) self-administration of cocaine in multi-hour daily sessions reminiscent of drug binges, which allows animals to set up the levels of their own drug consumption. The offspring of female mice inhaling cocaine in our model displayed no gross alterations in their cortical cytoarchitecture. These offspring, however, showed significant impairments in sustained attention and spatial working memory. We hope that the introduction of the present model will lead to a significant increase in our understanding of outcomes of prenatal cocaine exposure. PMID:16414242

  14. Homoclinic chaos in axisymmetric Bianchi-IX cosmological models with an ad hoc quantum potential

    SciTech Connect

    Correa, G. C.; Stuchi, T. J.; Joras, S. E.

    2010-04-15

    In this work we study the dynamics of the axisymmetric Bianchi-IX cosmological model with a term of quantum potential added. As it is well known, this class of Bianchi-IX models is homogeneous and anisotropic with two scale factors, A(t) and B(t), derived from the solution of Einstein's equation for general relativity. The model we use in this work has a cosmological constant and the matter content is dust. To this model we add a quantum-inspired potential that is intended to represent short-range effects due to the general relativistic behavior of matter in small scales and play the role of a repulsive force near the singularity. We find that this potential restricts the dynamics of the model to positive values of A(t) and B(t) and alters some qualitative and quantitative characteristics of the dynamics studied previously by several authors. We make a complete analysis of the phase space of the model finding critical points, periodic orbits, stable/unstable manifolds using numerical techniques such as Poincare section, numerical continuation of orbits, and numerical globalization of invariant manifolds. We compare the classical and the quantum models. Our main result is the existence of homoclinic crossings of the stable and unstable manifolds in the physically meaningful region of the phase space [where both A(t) and B(t) are positive], indicating chaotic escape to inflation and bouncing near the singularity.

  15. A Correlated Random Effects Model for Nonignorable Missing Data in Value-Added Assessment of Teacher Effects

    ERIC Educational Resources Information Center

    Karl, Andrew T.; Yang, Yan; Lohr, Sharon L.

    2013-01-01

    Value-added models have been widely used to assess the contributions of individual teachers and schools to students' academic growth based on longitudinal student achievement outcomes. There is concern, however, that ignoring the presence of missing values, which are common in longitudinal studies, can bias teachers' value-added scores.…

  16. Does Student Sorting Invalidate Value-Added Models of Teacher Effectiveness? An Extended Analysis of the Rothstein Critique

    ERIC Educational Resources Information Center

    Koedel, Cory; Betts, Julian R.

    2011-01-01

    Value-added modeling continues to gain traction as a tool for measuring teacher performance. However, recent research questions the validity of the value-added approach by showing that it does not mitigate student-teacher sorting bias (its presumed primary benefit). Our study explores this critique in more detail. Although we find that estimated…

  17. Erythroid progenitor cells (CFU-E*) from Friend virus-infected mice undergo VVFe suicide in vitro in the absence of added erythropoietin

    SciTech Connect

    Del Rizzo, D.F.; Axelrad, A.A.

    1985-11-01

    The authors have investigated the effect of VVFe on the survival in suspension of erythropoietin (epo)-independent erythroid progenitor cells (CFU-E*) induced by Friend polycythemia virus (FV). Spleen cells from C3Hf/Bi mice previously infected with FV were exposed to carrier-free VVFe, and the survival of CFU-E* as a function of time in liquid medium was determined from the number of erythroid colonies that developed from these cells seeded in plasma cultures without added epo. The results showed that spleen CFU-E* were highly vulnerable to VVFe. Marrow CFU-E* behaved in a similar manner. The VVFe responsible for their suicide had been presented to the progenitor cells only during the 4-h period of incubation, after which they were washed and plated in excess nonradioactive iron. They therefore conclude that CFU-E* themselves, and not only their progeny, are capable of actively incorporating iron. Under the same conditions in the absence of added epo, the effect of VVFe on the survival of normal spleen or marrow CFU-E could not be assessed because two few normal CFU-E survived the incubation period. Normal bone marrow cells incubated in complete medium containing epo retained their capacity for erythrocytic colony formation, and CFU-E could then be shown to be vulnerable to VVFe. Thus, either the iron-incorporating system of normal CFU-E was inducible by epo, or else epo permitted survival of the CFU-E so that the activity of a constitutive iron-incorporating system could be recognized.

  18. Chronic consumption of a western diet induces robust glial activation in aging mice and in a mouse model of Alzheimer's disease.

    PubMed

    Graham, Leah C; Harder, Jeffrey M; Soto, Ileana; de Vries, Wilhelmine N; John, Simon W M; Howell, Gareth R

    2016-01-01

    Studies have assessed individual components of a western diet, but no study has assessed the long-term, cumulative effects of a western diet on aging and Alzheimer's disease (AD). Therefore, we have formulated the first western-style diet that mimics the fat, carbohydrate, protein, vitamin and mineral levels of western diets. This diet was fed to aging C57BL/6J (B6) mice to identify phenotypes that may increase susceptibility to AD, and to APP/PS1 mice, a mouse model of AD, to determine the effects of the diet in AD. Astrocytosis and microglia/monocyte activation were dramatically increased in response to diet and was further increased in APP/PS1 mice fed the western diet. This increase in glial responses was associated with increased plaque burden in the hippocampus. Interestingly, given recent studies highlighting the importance of TREM2 in microglia/monocytes in AD susceptibility and progression, B6 and APP/PS1 mice fed the western diet showed significant increases TREM2+ microglia/monocytes. Therefore, an increase in TREM2+ microglia/monocytes may underlie the increased risk from a western diet to age-related neurodegenerative diseases such as Alzheimer's disease. This study lays the foundation to fully investigate the impact of a western diet on glial responses in aging and Alzheimer's disease. PMID:26888450

  19. Chronic consumption of a western diet induces robust glial activation in aging mice and in a mouse model of Alzheimer’s disease

    PubMed Central

    Graham, Leah C.; Harder, Jeffrey M.; Soto, Ileana; de Vries, Wilhelmine N.; John, Simon W. M.; Howell, Gareth R.

    2016-01-01

    Studies have assessed individual components of a western diet, but no study has assessed the long-term, cumulative effects of a western diet on aging and Alzheimer’s disease (AD). Therefore, we have formulated the first western-style diet that mimics the fat, carbohydrate, protein, vitamin and mineral levels of western diets. This diet was fed to aging C57BL/6J (B6) mice to identify phenotypes that may increase susceptibility to AD, and to APP/PS1 mice, a mouse model of AD, to determine the effects of the diet in AD. Astrocytosis and microglia/monocyte activation were dramatically increased in response to diet and was further increased in APP/PS1 mice fed the western diet. This increase in glial responses was associated with increased plaque burden in the hippocampus. Interestingly, given recent studies highlighting the importance of TREM2 in microglia/monocytes in AD susceptibility and progression, B6 and APP/PS1 mice fed the western diet showed significant increases TREM2+ microglia/monocytes. Therefore, an increase in TREM2+ microglia/monocytes may underlie the increased risk from a western diet to age-related neurodegenerative diseases such as Alzheimer’s disease. This study lays the foundation to fully investigate the impact of a western diet on glial responses in aging and Alzheimer’s disease. PMID:26888450

  20. Chronic consumption of a western diet induces robust glial activation in aging mice and in a mouse model of Alzheimer's disease.

    PubMed

    Graham, Leah C; Harder, Jeffrey M; Soto, Ileana; de Vries, Wilhelmine N; John, Simon W M; Howell, Gareth R

    2016-02-18

    Studies have assessed individual components of a western diet, but no study has assessed the long-term, cumulative effects of a western diet on aging and Alzheimer's disease (AD). Therefore, we have formulated the first western-style diet that mimics the fat, carbohydrate, protein, vitamin and mineral levels of western diets. This diet was fed to aging C57BL/6J (B6) mice to identify phenotypes that may increase susceptibility to AD, and to APP/PS1 mice, a mouse model of AD, to determine the effects of the diet in AD. Astrocytosis and microglia/monocyte activation were dramatically increased in response to diet and was further increased in APP/PS1 mice fed the western diet. This increase in glial responses was associated with increased plaque burden in the hippocampus. Interestingly, given recent studies highlighting the importance of TREM2 in microglia/monocytes in AD susceptibility and progression, B6 and APP/PS1 mice fed the western diet showed significant increases TREM2+ microglia/monocytes. Therefore, an increase in TREM2+ microglia/monocytes may underlie the increased risk from a western diet to age-related neurodegenerative diseases such as Alzheimer's disease. This study lays the foundation to fully investigate the impact of a western diet on glial responses in aging and Alzheimer's disease.

  1. Rupture models for the A.D. 900-930 Seattle fault earthquake from uplifted shorelines

    USGS Publications Warehouse

    ten Brink, U.S.; Song, J.; Bucknam, R.C.

    2006-01-01

    A major earthquake on the Seattle fault, Washington, ca. A.D. 900-930 was first inferred from uplifted shorelines and tsunami deposits. Despite follow-up geophysical and geological investigations, the rupture parameters of the earthquake and the geometry of the fault are uncertain. Here we estimate the fault geometry, slip direction, and magnitude of the earthquake by modeling shoreline elevation change. The best fitting model geometry is a reverse fault with a shallow roof ramp consisting of at least two back thrusts. The best fitting rupture is a SW-NE ohlique reverse slip with horizontal shortening of 15 m, rupture depth of 12.5 km, and magnitude Mw = 7.5. ?? 2006 Geological Society of America.

  2. Myocardial Infarction in Neonatal Mice, A Model of Cardiac Regeneration.

    PubMed

    Blom, Jessica N; Lu, Xiangru; Arnold, Paul; Feng, Qingping

    2016-01-01

    Myocardial infarction induced by coronary artery ligation has been used in many animal models as a tool to study the mechanisms of cardiac repair and regeneration, and to define new targets for therapeutics. For decades, models of complete heart regeneration existed in amphibians and fish, but a mammalian counterpart was not available. The recent discovery of a postnatal window during which mice possess regenerative capabilities has led to the establishment of a mammalian model of cardiac regeneration. A surgical model of mammalian cardiac regeneration in the neonatal mouse is presented herein. Briefly, postnatal day 1 (P1) mice are anesthetized by isoflurane and placed on an ice pad to induce hypothermia. After the chest is opened, and the left anterior descending coronary artery (LAD) is visualized, a suture is placed around the LAD to inflict myocardial ischemia in the left ventricle. The surgical procedure takes 10-15 min. Visualizing the coronary artery is crucial for accurate suture placement and reproducibility. Myocardial infarction and cardiac dysfunction are confirmed by triphenyl-tetrazolium chloride (TTC) staining and echocardiography, respectively. Complete regeneration 21 days post myocardial infarction is verified by histology. This protocol can be used to as a tool to elucidate mechanisms of mammalian cardiac regeneration after myocardial infarction. PMID:27286473

  3. Hybrid Mice as Genetic Models of High Alcohol Consumption

    PubMed Central

    Ozburn, A. R.; Walker, D.; Ahmed, S.; Belknap, J. K.; Harris, R. A.

    2011-01-01

    We showed that F1 hybrid genotypes may provide a broader variety of ethanol drinking phenotypes than the inbred progenitor strains used to create the hybrids (Blednov et al. in Alcohol Clin Exp Res 29:1949–1958–2005). To extend this work, we characterized alcohol consumption as well as intake of other tastants (saccharin, quinine and sodium chloride) in five inbred strains of mice (FVB, SJL, B6, BUB, NZB) and in their reciprocal F1 hybrids with B6 (FVBxB6; B6xFVB; NZBxB6; B6xNZB; BUBxB6; B6xBUB; SJLxB6; B6xSJL). We also compared ethanol intake in these mice for several concentrations before and after two periods of abstinence. F1 hybrid mice derived from the crosses of B6 and FVB and also B6 and SJL drank higher levels of ethanol than their progenitor strains, demonstrating overdominance for two-bottle choice drinking test. The B6 and NZB hybrid showed additivity in two-bottle choice drinking, whereas the hybrid of B6 and BUB demonstrated full or complete dominance. Genealogical origin, as well as non-alcohol taste preferences (sodium chloride), predicted ethanol consumption. Mice derived from the crosses of B6 and FVB showed high sustained alcohol preference and the B6 and NZB hybrids showed reduced alcohol preference after periods of abstinence. These new genetic models offer some advantages over inbred strains because they provide high, sustained, alcohol intake, and should allow mapping of loci important for the genetic architecture of these traits. PMID:19798565

  4. Banana resistant starch and its effects on constipation model mice.

    PubMed

    Wang, Juan; Huang, Ji Hong; Cheng, Yan Feng; Yang, Gong Ming

    2014-08-01

    Banana resistant starch (BRS) was extracted to investigate the structural properties of BRS, its effects on the gastrointestinal transit, and dejecta of normal and experimentally constipated mice. The mouse constipation model was induced by diphenoxylate administration. The BRS administered mice were divided into three groups and gavaged with 1.0, 2.0, or 4.0 g/kg body weight BRS per day. The small intestinal movement, time of the first black dejecta, dejecta granules, weight and their moisture content, body weight, and food intake of mice were studied. Results showed that the BRS particles were oval and spindly and some light cracks and pits were in the surface. The degree of crystallinity of BRS was 23.13%; the main diffraction peaks were at 2(θ) 15.14, 17.38, 20.08, and 22.51. The degree of polymerization of BRS was 81.16 and the number-average molecular weight was 13147.92 Da, as determined by the reducing terminal method. In animal experiments, BRS at the dose of 4.0 g/kg body weight per day was able to increase the gastrointestinal propulsive rate, and BRS at the doses of 2.0 and 4.0 g/kg body weight per day was found to shorten the start time of defecation by observing the first black dejecta exhaust. However, there were no influences of BRS on the dejecta moisture content, the dejecta granules and their weight, body weight, or daily food intake in mice. BRS was effective in accelerating the movement of the small intestine and in shortening the start time of defecation, but did not impact body weight and food intake. Therefore, BRS had the potential to be useful for improving intestinal motility during constipation.

  5. Dietary Mercury Exposure Resulted in Behavioral Differences in Mice Contaminated with Fish-Associated Methylmercury Compared to Methylmercury Chloride Added to Diet

    PubMed Central

    Bourdineaud, Jean-Paul; Marumoto, Masumi; Yasutake, Akira; Fujimura, Masatake

    2012-01-01

    Methylmercury (MeHg) is a potent neurotoxin, and humans are mainly exposed to this pollutant through fish consumption. However, in classical toxicological studies, pure methylmercury chloride (MeHgCl) is injected, given to drink or incorporated within feed assuming that its effects are identical to those of MeHg naturally associated to fish. In the present study, we wanted to address the question whether a diet containing MeHg associated to fish could result in observable adverse effects in mice as compared to a diet containing the same concentration of MeHg added pure to the diet and whether beneficial nutriments from fish were able to counterbalance the deleterious effects of fish-associated mercury, if any. After two months of feeding, the fish-containing diet resulted in significant observable effects as compared to the control and MeHg-containing diets, encompassing altered behavioral performances as monitored in a Y-shaped maze and an open field, and an increased dopamine metabolic turnover in hippocampus, despite the fact that the fish-containing diet was enriched in polyunsaturated fatty acids and selenium compared to the fish-devoid diets. PMID:22899888

  6. A sensitivity assessment of the TOPKAPI model with an added infiltration module

    NASA Astrophysics Data System (ADS)

    Sinclair, S.; Pegram, G. G. S.

    2013-02-01

    SummaryIn this paper we extend the usefulness of the TOPKAPI model by adding a Green-Ampt infiltration module and make the model and source code freely available on the internet as PyTOPKAPI. Then, we investigate the sensitivity of the PyTOPKAPI hydrological model to systematic bias in the variables rainfall and evapotranspiration, as well as the physically based soil properties that describe the model behaviour. The model sensitivity is assessed in terms of relative changes in the Soil Saturation Index (SSI), which is defined as the percentage of soil pore space filled by water. The volumetric soil moisture content, can be calculated from SSI using location dependent soil properties, if required. The model sensitivity is calculated at 7200 sites in South Africa, for a 2.5 year simulation period with a time-step of three hours. This large spatial extent gives results for a wide array of climates and land properties. Overall, the sensitivity of the model turns out to be a closely linear function of, and the same order of magnitude as (or less than), the forcing/parameter bias. This indicates that the model is robust to errors in forcing/parameters. The results also show that the best estimates of soil water can be obtained by improving estimates of the storage parameters and rainfall forcing. However, the storage parameters must be obtained from static soil property data-sets and we show that there is value in making improvements to the rainfall forcing (in this case TRMM 3B42RT) for places where it is biased relative to observed rainfall. This work is particularly relevant for model application in ungauged basins, where the quality of forcing variables and physical parameters cannot be calibrated.

  7. SOA-Based Model for Value-Added ITS Services Delivery

    PubMed Central

    Herrera-Quintero, Luis Felipe; Maciá-Pérez, Francisco; Marcos-Jorquera, Diego; Gilart-Iglesias, Virgilio

    2014-01-01

    Integration is currently a key factor in intelligent transportation systems (ITS), especially because of the ever increasing service demands originating from the ITS industry and ITS users. The current ITS landscape is made up of multiple technologies that are tightly coupled, and its interoperability is extremely low, which limits ITS services generation. Given this fact, novel information technologies (IT) based on the service-oriented architecture (SOA) paradigm have begun to introduce new ways to address this problem. The SOA paradigm allows the construction of loosely coupled distributed systems that can help to integrate the heterogeneous systems that are part of ITS. In this paper, we focus on developing an SOA-based model for integrating information technologies (IT) into ITS to achieve ITS service delivery. To develop our model, the ITS technologies and services involved were identified, catalogued, and decoupled. In doing so, we applied our SOA-based model to integrate all of the ITS technologies and services, ranging from the lowest-level technical components, such as roadside unit as a service (RSUAAS), to the most abstract ITS services that will be offered to ITS users (value-added services). To validate our model, a functionality case study that included all of the components of our model was designed. PMID:25019101

  8. The added value of high-resolution climate modeling of the Greenland Ice Sheet

    NASA Astrophysics Data System (ADS)

    van de Berg, Willem Jan; van Meijgaard, Erik; van Ulft, Bert; Machguth, Horst; Noël, Brice; van den Broeke, Michiel

    2016-04-01

    The local surface mass balance (SMB) of glaciers and ice sheets is to a very high extent related to topography. Subsequently, spatial variability in the SMB is also related to the spatial scales in the topography. The typical topographic length scales on the Greenland Ice Sheet are from several to over hundred kilometers. Therefore, regional climate models with resolutions between 5 and 25 kilometers normally capture the SMB of the Greenland Ice Sheet well. In this study, we analyze the added value of high-resolution regional climate simulations compared to statistical downscaling. For this aim, the regional climate model RACMO2 has been run for South Greenland for the period 2007-2014 using resolutions of 60, 20, 6.6 and 2.2 kilometer. Modeled and downscaled SMB from these four simulations are analyzed and evaluated against ablation observations. Our results show that the strong correlation of runoff to elevation makes statistical downscaling a robust tool to refine modeled spatial SMB patterns. However, only high-resolution climate modeling can improve the physical representation of the SMB in lower ablation zone, because the summertime interaction between the warm air over the tundra and the colder air over the ice sheet starts to be resolved. As a result, the runoff in the lower ablation zone is more enhanced compared to lower resolution simulations and statistical downscaled SMB.

  9. Stochastic modelling of tumorigenesis in p53 deficient mice.

    PubMed Central

    Mao, J. H.; Lindsay, K. A.; Balmain, A.; Wheldon, T. E.

    1998-01-01

    Stochastic models of tumorigenesis have been developed to investigate the implications of experimental data on tumour induction in wild-type and p53-deficient mice for tumorigenesis mechanisms. Conventional multistage models in which inactivation of each p53 allele represents a distinct stage predict excessively large numbers of tumours in p53-deficient genotypes, allowing this category of model to be rejected. Multistage multipath models, in which a p53-mediated pathway co-exists with one or more p53-independent pathways, are consistent with the data, although these models require unknown pathways and do not enable age-specific curves of tumour appearance to be computed. An alternative model that fits the data is the 'multigate' model in which tumorigenesis results from a small number of gate-pass (enabling) events independently of p53 status. The role of p53 inactivation is as a rate modifier that accelerates the gate-pass events. This model implies that wild-type p53 acts as a 'caretaker' to maintain genetic uniformity in cell populations, and that p53 inactivation increases the probability of occurrence of a viable cellular mutant by a factor of about ten. The multigate model predicts a relationship between the time pattern of tumour occurrence and tumour genotype that should be experimentally testable. Stochastic modelling may help to distinguish 'gatekeeper' and 'caretaker' genes in other tumorigenic pathays. PMID:9460995

  10. Monoacylglycerol Lipase Inhibitor JZL184 Improves Behavior and Neural Properties in Ts65Dn Mice, a Model of Down Syndrome

    PubMed Central

    Lysenko, Larisa V.; Kim, Jeesun; Henry, Cassandra; Tyrtyshnaia, Anna; Kohnz, Rebecca A.; Madamba, Francisco; Simon, Gabriel M.; Kleschevnikova, Natalia E.; Nomura, Daniel K.; Ezekowitz, R . Alan B.; Kleschevnikov, Alexander M.

    2014-01-01

    Genetic alterations or pharmacological treatments affecting endocannabinoid signaling have profound effects on synaptic and neuronal properties and, under certain conditions, may improve higher brain functions. Down syndrome (DS), a developmental disorder caused by triplication of chromosome 21, is characterized by deficient cognition and inevitable development of the Alzheimer disease (AD) type pathology during aging. Here we used JZL184, a selective inhibitor of monoacylglycerol lipase (MAGL), to examine the effects of chronic MAGL inhibition on the behavioral, biochemical, and synaptic properties of aged Ts65Dn mice, a genetic model of DS. In both Ts65Dn mice and their normosomic (2N) controls, JZL184-treatment increased brain levels of 2-arachidonoylglycerol (2-AG) and decreased levels of its metabolites such as arachidonic acid, prostaglandins PGD2, PGE2, PGFα, and PGJ2. Enhanced spontaneous locomotor activity of Ts65Dn mice was reduced by the JZL184-treatement to the levels observed in 2N animals. Deficient long-term memory was also improved, while short-term and working types of memory were unaffected. Furthermore, reduced hippocampal long-term potentiation (LTP) was increased in the JZL184-treated Ts65Dn mice to the levels observed in 2N mice. Interestingly, changes in synaptic plasticity and behavior were not observed in the JZL184-treated 2N mice suggesting that the treatment specifically attenuated the defects in the trisomic animals. The JZL184-treatment also reduced the levels of Aβ40 and Aβ42, but had no effect on the levels of full length APP and BACE1 in both Ts65Dn and 2N mice. These data show that chronic MAGL inhibition improves the behavior and brain functions in a DS model suggesting that pharmacological targeting of MAGL may be considered as a perspective new approach for improving cognition in DS. PMID:25474204

  11. AdS and stabilized extra dimensions in multi-dimensional gravitational models with nonlinear scalar curvature terms R-1 and R4

    NASA Astrophysics Data System (ADS)

    Günther, Uwe; Zhuk, Alexander; Bezerra, Valdir B.; Romero, Carlos

    2005-08-01

    We study multi-dimensional gravitational models with scalar curvature nonlinearities of types R-1 and R4. It is assumed that the corresponding higher dimensional spacetime manifolds undergo a spontaneous compactification to manifolds with a warped product structure. Special attention has been paid to the stability of the extra-dimensional factor spaces. It is shown that for certain parameter regions the systems allow for a freezing stabilization of these spaces. In particular, we find for the R-1 model that configurations with stabilized extra dimensions do not provide a late-time acceleration (they are AdS), whereas the solution branch which allows for accelerated expansion (the dS branch) is incompatible with stabilized factor spaces. In the case of the R4 model, we obtain that the stability region in parameter space depends on the total dimension D = dim(M) of the higher dimensional spacetime M. For D > 8 the stability region consists of a single (absolutely stable) sector which is shielded from a conformal singularity (and an antigravity sector beyond it) by a potential barrier of infinite height and width. This sector is smoothly connected with the stability region of a curvature-linear model. For D < 8 an additional (metastable) sector exists which is separated from the conformal singularity by a potential barrier of finite height and width so that systems in this sector are prone to collapse into the conformal singularity. This second sector is not smoothly connected with the first (absolutely stable) one. Several limiting cases and the possibility of inflation are discussed for the R4 model.

  12. Assessing the effect of adding interactive modeling to the geoscience curriculum

    NASA Astrophysics Data System (ADS)

    Castillo, A.; Marshall, J.; Cardenas, M.

    2013-12-01

    Technology and computer models enhance the learning experience when appropriately utilized. Moreover, learning is significantly improved when effective visualization is combined with models of processes allowing for inquiry-based problem solving. Still, hands-on experiences in real scenarios result in better contextualization of related problems compared to virtual laboratories. Therefore, the role of scientific visualization, technology, and computer modeling is to enhance, not displace, the learning experience by supplementing real-world problem solving and experiences, although in some circumstances, they can adequately serve to take the place of reality. The key to improving scientific education is to embrace an inquiry-based approach that favorably uses technology. This study will attempt to evaluate the effect of adding interactive modeling to the geological sciences curriculum. An assessment tool, designed to assess student understanding of physical hydrology, was used to evaluate a curriculum intervention based on student learning with a data- and modeling-driven approach using COMSOL Multiphysics software. This intervention was implemented in an upper division and graduate physical hydrology course in fall 2012. Students enrolled in the course in fall 2011 served as the control group. Interactive modeling was added to the curriculum in fall 2012 to replace the analogous mathematical modeling done by hand in fall 2011. Pre- and post-test results were used to assess and report its effectiveness. Student interviews were also used to probe student reactions to both the experimental and control curricula. The pre- and post-tests asked students to describe the significant processes in the hydrological cycle and describe the laws governing these processes. Their ability to apply their knowledge in a real-world problem was also assessed. Since the pre- and post-test data failed to meet the assumption of normality, a non-parametric Kruskal-Wallis test was run to

  13. Modelling a crime scene in 3D and adding thermal information

    NASA Astrophysics Data System (ADS)

    van Iersel, Miranda; Veerman, Henny; van der Mark, Wannes

    2009-09-01

    Once a crime has been perpetrated, forensic traces will only be persevered in the crime scene for a limited time frame. It is therefore necessary to record a crime scene meticulously. Usually, photographs and/or videos are taken at the scene to document it, so that later on one will know the exact place of an object. Another possibility is to construct a three dimensional (3D) model of the crime scene. A 3D model has the advantage that you can change the perspective and view the scene from all directions. We use a stereo camera to record the crime scene and use these images to construct a 3D model. A drawback of conventional (color) cameras is that they only capture features that belong to the visible part of electromagnetic spectrum. Interesting traces with strong signatures in other parts of the spectrum could be overlooked. For example; has a lamp or computer screen been turned on previously, is there some fluid on the carpet? Such traces can be observed with an infrared (IR) camera that captures images in the IR part of the spectrum. However, it is not well understood if these traces stay visible for a sufficient amount time. Therefore, a first set of experiments was conducted to gain some insight in the visibility degradation of different IR traces over time. The results are discussed in this paper. Furthermore, it will be shown how adding thermal information to the 3D model can improve crime scene understanding.

  14. The Will, Skill, Tool Model of Technology Integration: Adding Pedagogy as a New Model Construct

    ERIC Educational Resources Information Center

    Knezek, Gerald; Christensen, Rhonda

    2015-01-01

    An expansion of the Will, Skill, Tool Model of Technology Integration to include teacher's pedagogical style is proposed by the authors as a means of advancing the predictive power for level of classroom technology integration to beyond 90%. Suggested advantages to this expansion include more precise identification of areas to be targeted for…

  15. Generation of Pediatric Leukemia Xenograft Models in NSG-B2m Mice: Comparison with NOD/SCID Mice.

    PubMed

    Gopalakrishnapillai, Anilkumar; Kolb, E Anders; Dhanan, Priyanka; Bojja, Aruna Sri; Mason, Robert W; Corao, Diana; Barwe, Sonali P

    2016-01-01

    Generation of orthotopic xenograft mouse models of leukemia is important to understand the mechanisms of leukemogenesis, cancer progression, its cross talk with the bone marrow microenvironment, and for preclinical evaluation of drugs. In these models, following intravenous injection, leukemic cells home to the bone marrow and proliferate there before infiltrating other organs, such as spleen, liver, and the central nervous system. Moreover, such models have been shown to accurately recapitulate the human disease and correlate with patient response to therapy and prognosis. Thus, various immune-deficient mice strains have been used with or without recipient preconditioning to increase engraftment efficiency. Mice homozygous for the severe combined immune deficiency (SCID) mutation and with non-obese diabetic background (NOD/SCID) have been used in the majority of leukemia xenograft studies. Later, NOD/SCID mice deficient for interleukin 2 receptor gamma chain (IL2Rγ) gene called NSG mice became the model of choice for leukemia xenografts. However, engraftment of leukemia cells without irradiation preconditioning still remained a challenge. In this study, we used NSG mice with null alleles for major histocompatibility complex class I beta2-microglobulin (β2m) called NSG-B2m. This is a first report describing the 100% engraftment efficiency of pediatric leukemia cell lines and primary samples in NSG-B2m mice in the absence of host preconditioning by sublethal irradiation. We also show direct comparison of the engraftment efficiency and growth rate of pediatric acute leukemia cells in NSG-B2m and NOD/SCID mice, which showed 80-90% engraftment efficiency. Secondary and tertiary xenografts in NSG-B2m mice generated by injection of cells isolated from the spleens of leukemia-bearing mice also behaved similar to the primary patient sample. We have successfully engrafted 25 acute lymphoblastic leukemia (ALL) and 5 acute myeloid leukemia (AML) patient samples with

  16. Generation of Pediatric Leukemia Xenograft Models in NSG-B2m Mice: Comparison with NOD/SCID Mice.

    PubMed

    Gopalakrishnapillai, Anilkumar; Kolb, E Anders; Dhanan, Priyanka; Bojja, Aruna Sri; Mason, Robert W; Corao, Diana; Barwe, Sonali P

    2016-01-01

    Generation of orthotopic xenograft mouse models of leukemia is important to understand the mechanisms of leukemogenesis, cancer progression, its cross talk with the bone marrow microenvironment, and for preclinical evaluation of drugs. In these models, following intravenous injection, leukemic cells home to the bone marrow and proliferate there before infiltrating other organs, such as spleen, liver, and the central nervous system. Moreover, such models have been shown to accurately recapitulate the human disease and correlate with patient response to therapy and prognosis. Thus, various immune-deficient mice strains have been used with or without recipient preconditioning to increase engraftment efficiency. Mice homozygous for the severe combined immune deficiency (SCID) mutation and with non-obese diabetic background (NOD/SCID) have been used in the majority of leukemia xenograft studies. Later, NOD/SCID mice deficient for interleukin 2 receptor gamma chain (IL2Rγ) gene called NSG mice became the model of choice for leukemia xenografts. However, engraftment of leukemia cells without irradiation preconditioning still remained a challenge. In this study, we used NSG mice with null alleles for major histocompatibility complex class I beta2-microglobulin (β2m) called NSG-B2m. This is a first report describing the 100% engraftment efficiency of pediatric leukemia cell lines and primary samples in NSG-B2m mice in the absence of host preconditioning by sublethal irradiation. We also show direct comparison of the engraftment efficiency and growth rate of pediatric acute leukemia cells in NSG-B2m and NOD/SCID mice, which showed 80-90% engraftment efficiency. Secondary and tertiary xenografts in NSG-B2m mice generated by injection of cells isolated from the spleens of leukemia-bearing mice also behaved similar to the primary patient sample. We have successfully engrafted 25 acute lymphoblastic leukemia (ALL) and 5 acute myeloid leukemia (AML) patient samples with

  17. Generation of Pediatric Leukemia Xenograft Models in NSG-B2m Mice: Comparison with NOD/SCID Mice

    PubMed Central

    Gopalakrishnapillai, Anilkumar; Kolb, E. Anders; Dhanan, Priyanka; Bojja, Aruna Sri; Mason, Robert W.; Corao, Diana; Barwe, Sonali P.

    2016-01-01

    Generation of orthotopic xenograft mouse models of leukemia is important to understand the mechanisms of leukemogenesis, cancer progression, its cross talk with the bone marrow microenvironment, and for preclinical evaluation of drugs. In these models, following intravenous injection, leukemic cells home to the bone marrow and proliferate there before infiltrating other organs, such as spleen, liver, and the central nervous system. Moreover, such models have been shown to accurately recapitulate the human disease and correlate with patient response to therapy and prognosis. Thus, various immune-deficient mice strains have been used with or without recipient preconditioning to increase engraftment efficiency. Mice homozygous for the severe combined immune deficiency (SCID) mutation and with non-obese diabetic background (NOD/SCID) have been used in the majority of leukemia xenograft studies. Later, NOD/SCID mice deficient for interleukin 2 receptor gamma chain (IL2Rγ) gene called NSG mice became the model of choice for leukemia xenografts. However, engraftment of leukemia cells without irradiation preconditioning still remained a challenge. In this study, we used NSG mice with null alleles for major histocompatibility complex class I beta2-microglobulin (β2m) called NSG-B2m. This is a first report describing the 100% engraftment efficiency of pediatric leukemia cell lines and primary samples in NSG-B2m mice in the absence of host preconditioning by sublethal irradiation. We also show direct comparison of the engraftment efficiency and growth rate of pediatric acute leukemia cells in NSG-B2m and NOD/SCID mice, which showed 80–90% engraftment efficiency. Secondary and tertiary xenografts in NSG-B2m mice generated by injection of cells isolated from the spleens of leukemia-bearing mice also behaved similar to the primary patient sample. We have successfully engrafted 25 acute lymphoblastic leukemia (ALL) and 5 acute myeloid leukemia (AML) patient samples with

  18. Ad Hoc modeling, expert problem solving, and R&T program evaluation

    NASA Technical Reports Server (NTRS)

    Silverman, B. G.; Liebowitz, J.; Moustakis, V. S.

    1983-01-01

    A simplified cost and time (SCAT) analysis program utilizing personal-computer technology is presented and demonstrated in the case of the NASA-Goddard end-to-end data system. The difficulties encountered in implementing complex program-selection and evaluation models in the research and technology field are outlined. The prototype SCAT system described here is designed to allow user-friendly ad hoc modeling in real time and at low cost. A worksheet constructed on the computer screen displays the critical parameters and shows how each is affected when one is altered experimentally. In the NASA case, satellite data-output and control requirements, ground-facility data-handling capabilities, and project priorities are intricately interrelated. Scenario studies of the effects of spacecraft phaseout or new spacecraft on throughput and delay parameters are shown. The use of a network of personal computers for higher-level coordination of decision-making processes is suggested, as a complement or alternative to complex large-scale modeling.

  19. The Sciatic Nerve Cuffing Model of Neuropathic Pain in Mice

    PubMed Central

    Yalcin, Ipek; Megat, Salim; Barthas, Florent; Waltisperger, Elisabeth; Kremer, Mélanie; Salvat, Eric; Barrot, Michel

    2014-01-01

    Neuropathic pain arises as a consequence of a lesion or a disease affecting the somatosensory system. This syndrome results from maladaptive changes in injured sensory neurons and along the entire nociceptive pathway within the central nervous system. It is usually chronic and challenging to treat. In order to study neuropathic pain and its treatments, different models have been developed in rodents. These models derive from known etiologies, thus reproducing peripheral nerve injuries, central injuries, and metabolic-, infectious- or chemotherapy-related neuropathies. Murine models of peripheral nerve injury often target the sciatic nerve which is easy to access and allows nociceptive tests on the hind paw. These models rely on a compression and/or a section. Here, the detailed surgery procedure for the "cuff model" of neuropathic pain in mice is described. In this model, a cuff of PE-20 polyethylene tubing of standardized length (2 mm) is unilaterally implanted around the main branch of the sciatic nerve. It induces a long-lasting mechanical allodynia, i.e., a nociceptive response to a normally non-nociceptive stimulus that can be evaluated by using von Frey filaments. Besides the detailed surgery and testing procedures, the interest of this model for the study of neuropathic pain mechanism, for the study of neuropathic pain sensory and anxiodepressive aspects, and for the study of neuropathic pain treatments are also discussed. PMID:25078668

  20. The sciatic nerve cuffing model of neuropathic pain in mice.

    PubMed

    Yalcin, Ipek; Megat, Salim; Barthas, Florent; Waltisperger, Elisabeth; Kremer, Mélanie; Salvat, Eric; Barrot, Michel

    2014-07-16

    Neuropathic pain arises as a consequence of a lesion or a disease affecting the somatosensory system. This syndrome results from maladaptive changes in injured sensory neurons and along the entire nociceptive pathway within the central nervous system. It is usually chronic and challenging to treat. In order to study neuropathic pain and its treatments, different models have been developed in rodents. These models derive from known etiologies, thus reproducing peripheral nerve injuries, central injuries, and metabolic-, infectious- or chemotherapy-related neuropathies. Murine models of peripheral nerve injury often target the sciatic nerve which is easy to access and allows nociceptive tests on the hind paw. These models rely on a compression and/or a section. Here, the detailed surgery procedure for the "cuff model" of neuropathic pain in mice is described. In this model, a cuff of PE-20 polyethylene tubing of standardized length (2 mm) is unilaterally implanted around the main branch of the sciatic nerve. It induces a long-lasting mechanical allodynia, i.e., a nociceptive response to a normally non-nociceptive stimulus that can be evaluated by using von Frey filaments. Besides the detailed surgery and testing procedures, the interest of this model for the study of neuropathic pain mechanism, for the study of neuropathic pain sensory and anxiodepressive aspects, and for the study of neuropathic pain treatments are also discussed.

  1. Modeling Prostate Cancer in Mice: Limitations and Opportunities

    PubMed Central

    Hensley, Patrick J.; Kyprianou, Natasha

    2013-01-01

    The complex dynamics of the tumor microenvironment and prostate cancer heterogeneity have confounded efforts to establish suitable preclinical mouse models to represent human cancer progression from early proliferative phenotypes to aggressive, androgen-independent, and invasive metastatic tumors. Current models have been successful in capitulating individual characteristics of the aggressive tumors. However, none of these models comprehensively mimics human cancer progression, establishing the challenge in their exploitation to study human disease. The ability to tailor phenotypic outcomes in mice by compounding mutations to target specific molecular pathways provides a powerful tool toward disruption of signaling pathways contributing to the initiation and progression of castration-resistant prostate cancer. Each model is characterized by unique features contributing to the understanding of prostate tumorigenesis, as well as limitations challenging our knowledge of the mechanisms of cancer development and progression. Emerging strategies utilize genomic manipulation technology to circumvent these limitations toward the formulation of attractive, physiologically relevant models of prostate cancer progression to advanced disease. This review discusses the current value of the widely used and well-characterized mouse models of prostate cancer progression to metastasis, as well as the opportunities begging exploitation for the development of new models for testing the antitumor efficacy of therapeutic strategies and identifying new biomarkers of disease progression. PMID:21680808

  2. Modeling mania: Further validation for Black Swiss mice as model animals.

    PubMed

    Hannah-Poquette, Chelsey; Anderson, Grant W; Flaisher-Grinberg, Shlomit; Wang, Jia; Meinerding, Tonya M; Einat, Haim

    2011-09-30

    The paucity of appropriate animal models for bipolar disorder hinders the research of the disorder and its treatments. Previous work suggests that Black Swiss (BS) mice may be a suitable model animal for behavioral domains of mania including reward-seeking, risk-taking, vigor, aggression and sensitivity to psychostimulants. These behaviors are high in BS mice compared with other strains and are responsive to the mood stabilizers lithium and valproate but not to the antidepressant imipramine. The current study evaluated the etiological validity of this model by assessing brain expression of two proteins implicated in affective disorders, β-catenin and BDNF, in BS mice versus C57bl/6, A/J and CBA/J mice. Additionally, pharmacological validity was further tested by assessing the effects of risperidone in a behavioral battery of tests. β-catenin and BDNF expression were evaluated in the frontal cortex and hippocampus of untreated BS, CBA/J, A/J and C57bl/6 mice by western blot. Subchronic 0.1 and 0.3mg/kg doses of risperidone were tested in a battery of behavioral tests for domains of mania. Expression of β-catenin was found to be lower in the hippocampus of BS mice compared with the other strains. Reduced β-catenin expression was not observed in the frontal cortex. BDNF expression levels were similar between strains in both the hippocampus and frontal cortex. In the behavioral tests, risperidone ameliorated amphetamine-induced hyperactivity without affecting other tests in the battery. These results offer additional pharmacological and possible etiological validity supporting the utilization of Black Swiss mice as a model for domains of mania. PMID:21570428

  3. Modeling cognition and disease using human glial chimeric mice.

    PubMed

    Goldman, Steven A; Nedergaard, Maiken; Windrem, Martha S

    2015-08-01

    As new methods for producing and isolating human glial progenitor cells (hGPCs) have been developed, the disorders of myelin have become especially compelling targets for cell-based therapy. Yet as animal modeling of glial progenitor cell-based therapies has progressed, it has become clear that transplanted hGPCs not only engraft and expand within murine hosts, but dynamically outcompete the resident progenitors so as to ultimately dominate the host brain. The engrafted human progenitor cells proceed to generate parenchymal astrocytes, and when faced with a hypomyelinated environment, oligodendrocytes as well. As a result, the recipient brains may become inexorably humanized with regards to their resident glial populations, yielding human glial chimeric mouse brains. These brains provide us a fundamentally new tool by which to assess the species-specific attributes of glia in modulating human cognition and information processing. In addition, the cellular humanization of these brains permits their use in studying glial infectious and inflammatory disorders unique to humans, and the effects of those disorders on the glial contributions to cognition. Perhaps most intriguingly, by pairing our ability to construct human glial chimeras with the production of patient-specific hGPCs derived from pluripotential stem cells, we may now establish mice in which a substantial proportion of resident glia are both human and disease-derived. These mice in particular may provide us new opportunities for studying the human-specific contributions of glia to psychopathology, as well as to higher cognition. As such, the assessment of human glial chimeric mice may provide us new insight into the species-specific contributions of glia to human cognitive evolution, as well as to the pathogenesis of human neurological and neuropsychiatric disease.

  4. Oleocanthal enhances amyloid-β clearance from the brains of TgSwDI mice and in vitro across a human blood-brain barrier model.

    PubMed

    Qosa, Hisham; Batarseh, Yazan S; Mohyeldin, Mohamed M; El Sayed, Khalid A; Keller, Jeffrey N; Kaddoumi, Amal

    2015-11-18

    Numerous clinical and preclinical studies have suggested several health promoting effects for the dietary consumption of extra-virgin olive oil (EVOO) that could protect and decrease the risk of developing Alzheimer's disease (AD). Moreover, recent studies have linked this protective effect to oleocanthal, a phenolic secoiridoid component of EVOO. This protective effect of oleocanthal against AD has been related to its ability to prevent amyloid-β (Aβ) and tau aggregation in vitro, and enhance Aβ clearance from the brains of wild type mice in vivo; however, its effect in a mouse model of AD is not known. In the current study, we investigated the effect of oleocanthal on pathological hallmarks of AD in TgSwDI, an animal model of AD. Mice treatment for 4 weeks with oleocanthal significantly decreased amyloid load in the hippocampal parenchyma and microvessels. This reduction was associated with enhanced cerebral clearance of Aβ across the blood-brain barrier (BBB). Further mechanistic studies demonstrated oleocanthal to increase the expression of important amyloid clearance proteins at the BBB including P-glycoprotein and LRP1, and to activate the ApoE-dependent amyloid clearance pathway in the mice brains. The anti-inflammatory effect of oleocanthal in the brains of these mice was also obvious where it was able to reduce astrocytes activation and IL-1β levels. Finally, we could recapitulate the observed protective effect of oleocanthal in an in vitro human-based model, which could argue against species difference in response to oleocanthal. In conclusion, findings from in vivo and in vitro studies provide further support for the protective effect of oleocanthal against the progression of AD. PMID:26348065

  5. Oleocanthal Enhances Amyloid-β Clearance from the Brains of TgSwDI Mice and in Vitro across a Human Blood-Brain Barrier Model

    PubMed Central

    2015-01-01

    Numerous clinical and preclinical studies have suggested several health promoting effects for the dietary consumption of extra-virgin olive oil (EVOO) that could protect and decrease the risk of developing Alzheimer’s disease (AD). Moreover, recent studies have linked this protective effect to oleocanthal, a phenolic secoiridoid component of EVOO. This protective effect of oleocanthal against AD has been related to its ability to prevent amyloid-β (Aβ) and tau aggregation in vitro, and enhance Aβ clearance from the brains of wild type mice in vivo; however, its effect in a mouse model of AD is not known. In the current study, we investigated the effect of oleocanthal on pathological hallmarks of AD in TgSwDI, an animal model of AD. Mice treatment for 4 weeks with oleocanthal significantly decreased amyloid load in the hippocampal parenchyma and microvessels. This reduction was associated with enhanced cerebral clearance of Aβ across the blood-brain barrier (BBB). Further mechanistic studies demonstrated oleocanthal to increase the expression of important amyloid clearance proteins at the BBB including P-glycoprotein and LRP1, and to activate the ApoE-dependent amyloid clearance pathway in the mice brains. The anti-inflammatory effect of oleocanthal in the brains of these mice was also obvious where it was able to reduce astrocytes activation and IL-1β levels. Finally, we could recapitulate the observed protective effect of oleocanthal in an in vitro human-based model, which could argue against species difference in response to oleocanthal. In conclusion, findings from in vivo and in vitro studies provide further support for the protective effect of oleocanthal against the progression of AD. PMID:26348065

  6. Improving Accuracy in Arrhenius Models of Cell Death: Adding a Temperature-Dependent Time Delay.

    PubMed

    Pearce, John A

    2015-12-01

    The Arrhenius formulation for single-step irreversible unimolecular reactions has been used for many decades to describe the thermal damage and cell death processes. Arrhenius predictions are acceptably accurate for structural proteins, for some cell death assays, and for cell death at higher temperatures in most cell lines, above about 55 °C. However, in many cases--and particularly at hyperthermic temperatures, between about 43 and 55 °C--the particular intrinsic cell death or damage process under study exhibits a significant "shoulder" region that constant-rate Arrhenius models are unable to represent with acceptable accuracy. The primary limitation is that Arrhenius calculations always overestimate the cell death fraction, which leads to severely overoptimistic predictions of heating effectiveness in tumor treatment. Several more sophisticated mathematical model approaches have been suggested and show much-improved performance. But simpler models that have adequate accuracy would provide useful and practical alternatives to intricate biochemical analyses. Typical transient intrinsic cell death processes at hyperthermic temperatures consist of a slowly developing shoulder region followed by an essentially constant-rate region. The shoulder regions have been demonstrated to arise chiefly from complex functional protein signaling cascades that generate delays in the onset of the constant-rate region, but may involve heat shock protein activity as well. This paper shows that acceptably accurate and much-improved predictions in the simpler Arrhenius models can be obtained by adding a temperature-dependent time delay. Kinetic coefficients and the appropriate time delay are obtained from the constant-rate regions of the measured survival curves. The resulting predictions are seen to provide acceptably accurate results while not overestimating cell death. The method can be relatively easily incorporated into numerical models. Additionally, evidence is presented

  7. Improving Accuracy in Arrhenius Models of Cell Death: Adding a Temperature-Dependent Time Delay.

    PubMed

    Pearce, John A

    2015-12-01

    The Arrhenius formulation for single-step irreversible unimolecular reactions has been used for many decades to describe the thermal damage and cell death processes. Arrhenius predictions are acceptably accurate for structural proteins, for some cell death assays, and for cell death at higher temperatures in most cell lines, above about 55 °C. However, in many cases--and particularly at hyperthermic temperatures, between about 43 and 55 °C--the particular intrinsic cell death or damage process under study exhibits a significant "shoulder" region that constant-rate Arrhenius models are unable to represent with acceptable accuracy. The primary limitation is that Arrhenius calculations always overestimate the cell death fraction, which leads to severely overoptimistic predictions of heating effectiveness in tumor treatment. Several more sophisticated mathematical model approaches have been suggested and show much-improved performance. But simpler models that have adequate accuracy would provide useful and practical alternatives to intricate biochemical analyses. Typical transient intrinsic cell death processes at hyperthermic temperatures consist of a slowly developing shoulder region followed by an essentially constant-rate region. The shoulder regions have been demonstrated to arise chiefly from complex functional protein signaling cascades that generate delays in the onset of the constant-rate region, but may involve heat shock protein activity as well. This paper shows that acceptably accurate and much-improved predictions in the simpler Arrhenius models can be obtained by adding a temperature-dependent time delay. Kinetic coefficients and the appropriate time delay are obtained from the constant-rate regions of the measured survival curves. The resulting predictions are seen to provide acceptably accurate results while not overestimating cell death. The method can be relatively easily incorporated into numerical models. Additionally, evidence is presented

  8. Effects of aging and genotype on circadian rhythms, sleep, and clock gene expression in APPxPS1 knock-in mice, a model for Alzheimer's disease.

    PubMed

    Duncan, Marilyn J; Smith, J Tyler; Franklin, Kathleen M; Beckett, Tina L; Murphy, M Paul; St Clair, Daret K; Donohue, Kevin D; Striz, Martin; O'Hara, Bruce F

    2012-08-01

    Profound disruptions of circadian rhythms and sleep/wake cycles constitute a major cause of institutionalization of AD patients. This study investigated whether a rodent model of AD, APP(NLH/NLH)/PS-1(P264L/264L) (APPxPS1) mice, exhibits circadian alterations. The APPxPS1 mice were generated using CD-1/129 mice and Cre-lox knock-in technology to "humanize" the mouse amyloid (A)β sequence and create a presenilin-1 mutation identified in familial early-onset AD patients. APPxPS1 and WT mice of several ages (~4, 11, and 15 months) were monitored for circadian rhythms in wheel running, cage activity, and sleep:wake behavior. After rhythm assessment, the mice were euthanized at zeitgeber time (ZT) 2 or 10 (i.e., 2 or 10 h after lights-on) and brains were dissected. Amyloidβ levels were measured in cortical samples and brain sections of the hypothalamus and hippocampus were prepared and used for in situ hybridization of circadian or neuropeptide genes. The most significant effects of the APPxPS1 transgenes were phase delays of ~2 h in the onset of daytime wakefulness bouts (P<0.005) and peak wakefulness (P<0.02), potentially relevant to phase delays previously reported in AD patients. However, genotype did not affect the major activity peaks or phases of wheel running, wake, or general movement, which were bimodal with dominant dawn and dusk activity. Expression of Period 2 in the suprachiasmatic nucleus was affected by ZT (P<0.0001) with a marginal interaction effect of age, genotype, and ZT (P<0.08). A separate analysis of the old animals indicated a robust interaction between ZT and genotype, as well as main effects of these parameters. Aging also altered sleep (e.g., bout length and amount of daytime sleep) and the amount of wheel running and cage activity. In conclusion, the APPxPS1 knock-in mice exhibit some alterations in their sleep:wake rhythm and clock gene expression, but do not show robust, genotype-related changes in activity rhythms. The prominent daytime

  9. A PHYSIOLOGICALLY BASED PHARMACOKINETIC (PBPK) MODEL FOR intravenous and ingested DIMETHYLARSINIC ACID (DMAV) IN MICE.

    EPA Science Inventory

    A physiologically based pharmacokinetic (PBPK) model for the organoarsenical dimethylarsinic acid (DMA(V)) was developed in mice. The model was calibrated using tissue time course data from multiple tissues in mice administered DMA(V) intravenously. The final model structure was ...

  10. Fabrication, Testing and Modeling of the MICE Superconducting Spectrometer Solenoids

    SciTech Connect

    Virostek, S.P.; Green, M.A.; Trillaud, F.; Zisman, M.S.

    2010-05-16

    The Muon Ionization Cooling Experiment (MICE), an international collaboration sited at Rutherford Appleton Laboratory in the UK, will demonstrate ionization cooling in a section of realistic cooling channel using a muon beam. A five-coil superconducting spectrometer solenoid magnet will provide a 4 tesla uniform field region at each end of the cooling channel. Scintillating fiber trackers within the 400 mm diameter magnet bore tubes measure the emittance of the beam as it enters and exits the cooling channel. Each of the identical 3-meter long magnets incorporates a three-coil spectrometer magnet section and a two-coil section to match the solenoid uniform field into the other magnets of the MICE cooling channel. The cold mass, radiation shield and leads are currently kept cold by means of three two-stage cryocoolers and one single-stage cryocooler. Liquid helium within the cold mass is maintained by means of a re-condensation technique. After incorporating several design changes to improve the magnet cooling and reliability, the fabrication and acceptance testing of the spectrometer solenoids have proceeded. The key features of the spectrometer solenoid magnets, the development of a thermal model, the results of the recently completed tests, and the current status of the project are presented.

  11. BDNF restricted knockout mice as an animal model for aggression

    PubMed Central

    Ito, Wataru; Chehab, Mahmoud; Thakur, Siddarth; Li, Jiayang; Morozov, Alexei

    2011-01-01

    Mice with global deletion of one BDNF allele, or with forebrain-restricted deletion of both alleles show elevated aggression, but this phenotype is accompanied by other behavioral changes, including increases in anxiety and deficits in cognition. Here, we performed behavioral characterization of conditional BDNF knockout mice generated using a Cre recombinase driver line, KA1-Cre, which expresses Cre in few areas of brain: highly at hippocampal area CA3, moderately in dentate gyrus, cerebellum and facial nerve nucleus. The mutant animals exhibited elevated conspecific aggression and social dominance, but did not show changes in anxiety-like behaviors assessed using the elevated plus maze and open field test. There were no changes in depression like behaviors tested in the forced swim test, but small increase in immobility in the tail suspension test. In cognitive tasks, mutants showed normal social recognition and normal spatial and fear memory, but exhibited a deficit in object recognition. Thus, this knockout can serve as a robust model of BDNF-dependent aggression and object recognition deficiency. PMID:21255268

  12. Quantum self-consistency of AdS×Σ brane models

    NASA Astrophysics Data System (ADS)

    Flachi, Antonino; Pujolàs, Oriol

    2003-07-01

    Continuing our previous work, we consider a class of higher dimensional brane models with the topology of AdSD1+1×Σ, where Σ is a one-parameter compact manifold and two branes of codimension one are located at the orbifold fixed points. We consider a setup where such a solution arises from Einstein-Yang-Mills theory and evaluate the one-loop effective potential induced by gauge fields and by a generic bulk scalar field. We show that this type of brane model resolves the gauge hierarchy between the Planck and electroweak scales through redshift effects due to the warp factor a=e-πkr. The value of a is then fixed by minimizing the effective potential. We find that, as in the Randall-Sundrum case, the gauge field contribution to the effective potential stabilizes the hierarchy without fine-tuning as long as the Laplacian ΔΣ on Σ has a zero eigenvalue. Scalar fields can stabilize the hierarchy depending on the mass and the nonminimal coupling. We also address the quantum self-consistency of the solution, showing that the classical brane solution is not spoiled by quantum effects.

  13. Short-term treadmill exercise increased tau insolubility and neuroinflammation in tauopathy model mice.

    PubMed

    Elahi, Montasir; Motoi, Yumiko; Matsumoto, Shin-Ei; Hasan, Zafrul; Ishiguro, Koichi; Hattori, Nobutaka

    2016-01-01

    Physical exercise has been identified as a preventive measure for Alzheimer's disease (AD), one of the neuropathological hallmarks of which, neurofibrillary tangles, consist of hyperphosphorylated insoluble tau. Previous studies demonstrated that long-term treadmill exercise reduced tau hyperphosphorylation and insolubility; however, whether short-term treadmill exercise (STE) alters tau modifications currently remains unknown. In the present study, we attempted to characterize the effects of STE on tau solubility and determine its relationship with neuroinflammation using tauopathy model mice (Tg601), which express wild-type human tau. The results obtained showed that 3 weeks of non-shock treadmill exercise in Tg601 and non-transgenic female mice markedly increased insoluble tau. An analysis of phosphorylation patterns indicated that changes in tau solubility were related to an increase in phosphorylation at the tau C-terminal end. The results of immunohistochemical analyses revealed that STE increased the number of Iba-1-positive microglial cells in the hippocampus. Elevations in the levels of the lipid peroxidation markers, 4-hydroxy-trans-2-noneal and malondialdehyde, indicated the presence of oxidative stress. Moreover, higher levels of cytokines, IL-1β and IL-18, and chemokines, CXCL-1 and CXCL-12, supported neuroinflammation. PMID:26592481

  14. Age-dependent inverse correlations in CSF and plasma amyloid-β(1–42) concentrations prior to amyloid plaque deposition in the brain of 3xTg-AD mice

    PubMed Central

    Cho, Soo Min; Lee, Sejin; Yang, Seung-Hoon; Kim, Hye Yun; Lee, Michael Jisoo; Kim, Hyunjin Vincent; Kim, Jiyoon; Baek, Seungyeop; Yun, Jin; Kim, Dohee; Kim, Yun Kyung; Cho, Yakdol; Woo, Jiwan; Kim, Tae Song; Kim, YoungSoo

    2016-01-01

    Amyloid-β (Aβ) plays a critical role as a biomarker in Alzheimer’s disease (AD) diagnosis. In addition to its diagnostic potential in the brain, recent studies have suggested that changes of Aβ level in the plasma can possibly indicate AD onset. In this study, we found that plasma Aβ(1–42) concentration increases with age, while the concentration of Aβ(1–42) in the cerebrospinal fluid (CSF) decreases in APPswe, PS1M146V and TauP301L transgenic (3xTg-AD) mice, if measurements were made before formation of ThS-positive plaques in the brain. Our data suggests that there is an inverse correlations between the plasma and CSF Aβ(1–42) levels until plaques form in transgenic mice’s brains and that the plasma Aβ concentration possesses the diagnostic potential as a biomarker for diagnosis of early AD stages. PMID:26830653

  15. Whole body exposure to 2.4 GHz WIFI signals: effects on cognitive impairment in adult triple transgenic mouse models of Alzheimer's disease (3xTg-AD).

    PubMed

    Banaceur, Sana; Banasr, Sihem; Sakly, Mohsen; Abdelmelek, Hafedh

    2013-03-01

    The present investigation aimed at evaluating the effects of long-term exposure to WIFI type radiofrequency (RF) signals (2.40 GHz), two hours per day during one month at a Specific Absorption Rate (SAR) of 1.60 W/kg. The effects of RF exposure were studied on wildtype mice and triple transgenic mice (3xTg-AD) destined to develop Alzheimer's-like cognitive impairment. Mice were divided into four groups: two sham groups (WT, TG; n=7) and two exposed groups (WTS, TGS; n=7). The cognitive interference task used in this study was designed from an analogous human cognitive interference task including the Flex field activity system test, the two-compartment box test and the Barnes maze test. Our data demonstrate for the first time that RF improves cognitive behavior of 3xTg-AD mice. We conclude that RF exposure may represent an effective memory-enhancing approach in Alzheimer's disease.

  16. Discounting Testimony with the Argument Ad Hominem and a Bayesian Congruent Prior Model

    ERIC Educational Resources Information Center

    Bhatia, Jaydeep-Singh; Oaksford, Mike

    2015-01-01

    When directed to ignore evidence of a witness's previous bad character because of a violation of the rules of evidence, are jurors' beliefs still affected? The intuition is that they will be because in everyday argumentation, fallacies, like the ad hominem, are effective argumentative strategies. An ad hominem argument (against the person)…

  17. Peromyscus mice as a model for studying natural variation

    PubMed Central

    Bedford, Nicole L; Hoekstra, Hopi E

    2015-01-01

    The deer mouse (genus Peromyscus) is the most abundant mammal in North America, and it occupies almost every type of terrestrial habitat. It is not surprising therefore that the natural history of Peromyscus is among the best studied of any small mammal. For decades, the deer mouse has contributed to our understanding of population genetics, disease ecology, longevity, endocrinology and behavior. Over a century's worth of detailed descriptive studies of Peromyscus in the wild, coupled with emerging genetic and genomic techniques, have now positioned these mice as model organisms for the study of natural variation and adaptation. Recent work, combining field observations and laboratory experiments, has lead to exciting advances in a number of fields—from evolution and genetics, to physiology and neurobiology. DOI: http://dx.doi.org/10.7554/eLife.06813.001 PMID:26083802

  18. Peromyscus mice as a model for studying natural variation.

    PubMed

    Bedford, Nicole L; Hoekstra, Hopi E

    2015-01-01

    The deer mouse (genus Peromyscus) is the most abundant mammal in North America, and it occupies almost every type of terrestrial habitat. It is not surprising therefore that the natural history of Peromyscus is among the best studied of any small mammal. For decades, the deer mouse has contributed to our understanding of population genetics, disease ecology, longevity, endocrinology and behavior. Over a century's worth of detailed descriptive studies of Peromyscus in the wild, coupled with emerging genetic and genomic techniques, have now positioned these mice as model organisms for the study of natural variation and adaptation. Recent work, combining field observations and laboratory experiments, has lead to exciting advances in a number of fields-from evolution and genetics, to physiology and neurobiology. PMID:26083802

  19. Early intervention in the 3xTg-AD mice with an amyloid β-antibody fragment ameliorates first hallmarks of Alzheimer disease.

    PubMed

    Giménez-Llort, Lydia; Rivera-Hernández, Geovanny; Marin-Argany, Marta; Sánchez-Quesada, José L; Villegas, Sandra

    2013-01-01

    The single-chain variable fragment, scFv-h3D6, has been shown to prevent in vitro toxicity induced by the amyloid β (Aβ) peptide in neuroblastoma cell cultures by withdrawing Aβ oligomers from the amyloid pathway. Present study examined the in vivo effects of scFv-h3D6 in the triple-transgenic 3xTg-AD mouse model of Alzheimer disease. Prior to the treatment, five-month-old female animals, corresponding to early stages of the disease, showed the first behavioral and psychological symptoms of dementia -like behaviors. Cognitive deficits included long- and short-term learning and memory deficits and high swimming navigation speed. After a single intraperitoneal dose of scFv-h3D6, the swimming speed was reversed to normal levels and the learning and memory deficits were ameliorated. Brain tissues of these animals revealed a global decrease of Aβ oligomers in the cortex and olfactory bulb after treatment, but this was not seen in the hippocampus and cerebellum. In the untreated 3xTg-AD animals, we observed an increase of both apoJ and apoE concentrations in the cortex, as well as an increase of apoE in the hippocampus. Treatment significantly recovered the non-pathological levels of these apolipoproteins. Our results suggest that the benefit of scFv-h3D6 occurs at both behavioral and molecular levels.

  20. A Simple Critical-sized Femoral Defect Model in Mice

    PubMed Central

    Clough, Bret H.; McCarley, Matthew R.; Gregory, Carl A.

    2015-01-01

    While bone has a remarkable capacity for regeneration, serious bone trauma often results in damage that does not properly heal. In fact, one tenth of all limb bone fractures fail to heal completely due to the extent of the trauma, disease, or age of the patient. Our ability to improve bone regenerative strategies is critically dependent on the ability to mimic serious bone trauma in test animals, but the generation and stabilization of large bone lesions is technically challenging. In most cases, serious long bone trauma is mimicked experimentally by establishing a defect that will not naturally heal. This is achieved by complete removal of a bone segment that is larger than 1.5 times the diameter of the bone cross-section. The bone is then stabilized with a metal implant to maintain proper orientation of the fracture edges and allow for mobility. Due to their small size and the fragility of their long bones, establishment of such lesions in mice are beyond the capabilities of most research groups. As such, long bone defect models are confined to rats and larger animals. Nevertheless, mice afford significant research advantages in that they can be genetically modified and bred as immune-compromised strains that do not reject human cells and tissue. Herein, we demonstrate a technique that facilitates the generation of a segmental defect in mouse femora using standard laboratory and veterinary equipment. With practice, fabrication of the fixation device and surgical implantation is feasible for the majority of trained veterinarians and animal research personnel. Using example data, we also provide methodologies for the quantitative analysis of bone healing for the model. PMID:25867551

  1. Traumatic Brain Injury Precipitates Cognitive Impairment and Extracellular Aβ Aggregation in Alzheimer's Disease Transgenic Mice

    PubMed Central

    Shimizu, Toru; Arendash, Gary W.; Borlongan, Cesar V.

    2013-01-01

    Traumatic brain injury (TBI) has become a signature wound of the wars in Iraq and Afghanistan. Many American soldiers, even those undiagnosed but likely suffering from mild TBI, display Alzheimer's disease (AD)-like cognitive impairments, suggesting a pathological overlap between TBI and AD. This study examined the cognitive and neurohistological effects of TBI in presymptomatic APP/PS1 AD-transgenic mice. AD mice and non-transgenic (NT) mice received an experimental TBI on the right parietal cortex using the controlled cortical impact model. Animals were trained in a water maze task for spatial memory before TBI, and then reevaluated in the same task at two and six weeks post-TBI. The results showed that AD mice with TBI made significantly more errors in the task than AD mice without TBI and NT mice regardless of TBI. A separate group of AD mice and NT mice were evaluated neurohistologically at six weeks after TBI. The number of extracellular beta-amyloid (Aβ)-deposits significantly increased by at least one fold in the cortex of AD mice that received TBI compared to the NT mice that received TBI or the AD and NT mice that underwent sham surgery. A significant decrease in MAP2 positive cells, indicating neuronal loss, was observed in the cortex of both the AD and NT mice that received TBI compared to the AD and NT mice subjected to sham surgery. Similar changes in extracellular Aβ deposits and MAP2 positive cells were also seen in the hippocampus. These results demonstrate for the first time that TBI precipitates cognitive impairment in presymptomatic AD mice, while also confirming extracellular Aβ deposits following TBI. The recognition of this pathological link between TBI and AD should aid in developing novel treatments directed at abrogating cellular injury and extracellular Aβ deposition in the brain. PMID:24223856

  2. Traumatic brain injury precipitates cognitive impairment and extracellular Aβ aggregation in Alzheimer's disease transgenic mice.

    PubMed

    Tajiri, Naoki; Kellogg, S Leilani; Shimizu, Toru; Arendash, Gary W; Borlongan, Cesar V

    2013-01-01

    Traumatic brain injury (TBI) has become a signature wound of the wars in Iraq and Afghanistan. Many American soldiers, even those undiagnosed but likely suffering from mild TBI, display Alzheimer's disease (AD)-like cognitive impairments, suggesting a pathological overlap between TBI and AD. This study examined the cognitive and neurohistological effects of TBI in presymptomatic APP/PS1 AD-transgenic mice. AD mice and non-transgenic (NT) mice received an experimental TBI on the right parietal cortex using the controlled cortical impact model. Animals were trained in a water maze task for spatial memory before TBI, and then reevaluated in the same task at two and six weeks post-TBI. The results showed that AD mice with TBI made significantly more errors in the task than AD mice without TBI and NT mice regardless of TBI. A separate group of AD mice and NT mice were evaluated neurohistologically at six weeks after TBI. The number of extracellular beta-amyloid (Aβ)-deposits significantly increased by at least one fold in the cortex of AD mice that received TBI compared to the NT mice that received TBI or the AD and NT mice that underwent sham surgery. A significant decrease in MAP2 positive cells, indicating neuronal loss, was observed in the cortex of both the AD and NT mice that received TBI compared to the AD and NT mice subjected to sham surgery. Similar changes in extracellular Aβ deposits and MAP2 positive cells were also seen in the hippocampus. These results demonstrate for the first time that TBI precipitates cognitive impairment in presymptomatic AD mice, while also confirming extracellular Aβ deposits following TBI. The recognition of this pathological link between TBI and AD should aid in developing novel treatments directed at abrogating cellular injury and extracellular Aβ deposition in the brain. PMID:24223856

  3. A Primer on Value-Added Models: Towards a Better Understanding of the Quantitative Analysis of Student Achievement

    ERIC Educational Resources Information Center

    Nakamura, Yugo

    2013-01-01

    Value-added models (VAMs) have received considerable attention as a tool to transform our public education system. However, as VAMs are studied by researchers from a broad range of academic disciplines who remain divided over the best methods in analyzing the models and stakeholders without the extensive statistical background have been excluded…

  4. Spectral energy distributions and model atmosphere parameters of the quadruple system ADS11061.

    NASA Astrophysics Data System (ADS)

    Al-Wardat, M. A.

    2002-06-01

    The spectral energy distribution between λ 3700 Å, and λ 8100 Å, of the two subsystems 41Dra and 40Dra of the multiple system ADS11061 has been introduced with a description of methodology of getting the spectra on Carl-Zeiss-Jena 1 m telescope of Special Astrophysical Observatory. The spectral type and luminosity class for each of them have been deduced and compared with earlier investigations, the B,V, and R magnitudes and B-V colour indices have been computed, the interstellar reddening of both subsystems have been calculated and an envelope around 40Dra has been suggested, model atmosphere parameters of the subsystem 40Dra' components have been derived: TeffBa =6100 degr K, TeffBb =6100 degr K, lg gBa=4.03, lg gBb=4.20, RBa=1.82R⊙, RBb=1.44R⊙, and finally the formation and evolution of the system have been discussed depending on the filament fragmentation process.

  5. Adding-Point Strategy for Reduced-Order Hypersonic Aerothermodynamics Modeling Based on Fuzzy Clustering

    NASA Astrophysics Data System (ADS)

    Chen, Xin; Liu, Li; Zhou, Sida; Yue, Zhenjiang

    2016-04-01

    Reduced order models(ROMs) based on the snapshots on the CFD high-fidelity simulations have been paid great attention recently due to their capability of capturing the features of the complex geometries and flow configurations. To improve the efficiency and precision of the ROMs, it is indispensable to add extra sampling points to the initial snapshots, since the number of sampling points to achieve an adequately accurate ROM is generally unknown in prior, but a large number of initial sampling points reduces the parsimony of the ROMs. A fuzzy-clustering-based adding-point strategy is proposed and the fuzzy clustering acts an indicator of the region in which the precision of ROMs is relatively low. The proposed method is applied to construct the ROMs for the benchmark mathematical examples and a numerical example of hypersonic aerothermodynamics prediction for a typical control surface. The proposed method can achieve a 34.5% improvement on the efficiency than the estimated mean squared error prediction algorithm and shows same-level prediction accuracy.

  6. Adding Value by Regional Climate Models: Lessons Learned and Ways Forward Using Ensembles

    NASA Astrophysics Data System (ADS)

    Christensen, J. H.; Rummukainen, M.; Christensen, O. B.; Kjellstrom, E.; Boberg, F.; Drews, M.

    2013-12-01

    It has for long been understood that running the same model with slightly different conditions (such as a slightly different initial state) would generate a different trajectory of the model simulation, particularly at the regional scale. To overcome this limitation the solution is to use multiple realizations of otherwise identical simulations or to study simulations covering a very long time span, whether trying to isolate the effect of a new parameterization or assessing climate change due to changes in atmospheric forcings. This insight had important consequences for the strategy to validate global climate models and to determine the response of such models to some prescribed experimental modifications, an area that has not yet fully developed within the regional modeling community. In contrast, many regional modelers, even up to this day, considered one simulation of a short duration sufficient to determine either the quality of the model in reproducing 'reality' as well as the sensitivity to changing components of the model. Given the constraint suppressed by the boundary conditions, it is often more or less assumed that internal variability would be over ruled by the large scale forcing. But ensemble-studies from analyzing multiple RCMs have been published since the late 1990s (e.g. Takle et. al., 1999), and the need to address the chaotic nature of regional climate dynamics has been taken up as a central theme in the last decade (e.g. Denis et al., 2003). Both research themes have been leading to considerable insight into fundamental basics of dynamical down scaling. In parallel, several large scale collaborative projects have developed (e.g. PRUDENCE, ENSEMBLES and NARCCAP) culminating with the WCRP supported CORDEX (Giorgi et al., 2009). However, there have only been few attempts to capitalize on these efforts in trying to extract the overall information, which scientifically must be addressed by these initiatives; do we actually demonstrate added value

  7. Mottled Mice and Non-Mammalian Models of Menkes Disease

    PubMed Central

    Lenartowicz, Małgorzata; Krzeptowski, Wojciech; Lipiński, Paweł; Grzmil, Paweł; Starzyński, Rafał; Pierzchała, Olga; Møller, Lisbeth Birk

    2015-01-01

    Menkes disease is a multi-systemic copper metabolism disorder caused by mutations in the X-linked ATP7A gene and characterized by progressive neurodegeneration and severe connective tissue defects. The ATP7A protein is a copper (Cu)-transporting ATPase expressed in all tissues and plays a critical role in the maintenance of copper homeostasis in cells of the whole body. ATP7A participates in copper absorption in the small intestine and in copper transport to the central nervous system (CNS) across the blood-brain-barrier (BBB) and blood–cerebrospinal fluid barrier (BCSFB). Cu is essential for synaptogenesis and axonal development. In cells, ATP7A participates in the incorporation of copper into Cu-dependent enzymes during the course of its maturation in the secretory pathway. There is a high degree of homology (>80%) between the human ATP7A and murine Atp7a genes. Mice with mutations in the Atp7a gene, called mottled mutants, are well-established and excellent models of Menkes disease. Mottled mutants closely recapitulate the Menkes phenotype and are invaluable for studying Cu-metabolism. They provide useful models for exploring and testing new forms of therapy in Menkes disease. Recently, non-mammalian models of Menkes disease, Drosophila melanogaster and Danio rerio mutants were used in experiments which would be technically difficult to carry out in mammals. PMID:26732058

  8. Abnormal Population Responses in the Somatosensory Cortex of Alzheimer’s Disease Model Mice

    PubMed Central

    Maatuf, Yossi; Stern, Edward A.; Slovin, Hamutal

    2016-01-01

    Alzheimer’s disease (AD) is the most common form of dementia. One of the neuropathological hallmarks of AD is the accumulation of amyloid-β plaques. Overexpression of human amyloid precursor protein in transgenic mice induces hippocampal and neocortical amyloid-β accumulation and plaque deposition that increases with age. The impact of these effects on neuronal population responses and network activity in sensory cortex is not well understood. We used Voltage Sensitive Dye Imaging, to investigate at high spatial and temporal resolution, the sensory evoked population responses in the barrel cortex of aged transgenic (Tg) mice and of age-matched non-transgenic littermate controls (Ctrl) mice. We found that a whisker deflection evoked abnormal sensory responses in the barrel cortex of Tg mice. The response amplitude and the spatial spread of the cortical responses were significantly larger in Tg than in Ctrl mice. At the network level, spontaneous activity was less synchronized over cortical space than in Ctrl mice, however synchronization during evoked responses induced by whisker deflection did not differ between the two groups. Thus, the presence of elevated Aβ and plaques may alter population responses and disrupts neural synchronization in large-scale networks, leading to abnormalities in sensory processing. PMID:27079783

  9. Murine model of pulmonary mucormycosis in cortisone-treated mice.

    PubMed

    Waldorf, A R; Halde, C; Vedros, N A

    1982-09-01

    Intranasal inoculation of Rhizomucor pusillus sporangiospores into cortisone-treated mice produced pulmonary and disseminated mucormycosis (phycomycosis). Evidence for infection in cortisone treated mice was obtained by recovery of Rh. pusillus from homogenates of tissue. Confirmation of infection was shown histologically. The 50% infectious dose was 2.4 x 10(2) colony forming units for lung infections and 2.7 x 10(5) colony forming units for brain infections. No evidence of sporangiospore germination was found in tissues of non-cortisone-treated mice although sporangiospores were found throughout pulmonary tissues. In infected tissues of cortisone-treated mice, hyphae were covered with leukocytes and tissue necrosis was extensive.

  10. Early alterations in blood and brain RANTES and MCP-1 expression and the effect of exercise frequency in the 3xTg-AD mouse model of Alzheimer's disease.

    PubMed

    Haskins, Morgan; Jones, Terry E; Lu, Qun; Bareiss, Sonja K

    2016-01-01

    Exercise has been shown to protect against cognitive decline and Alzheimer's disease (AD) progression, however the dose of exercise required to protect against AD is unknown. Recent studies show that the pathological processes leading to AD cause characteristic alterations in blood and brain inflammatory proteins that are associated with the progression of AD, suggesting that these markers could be used to diagnosis and monitor disease progression. The purpose of this study was to determine the impact of exercise frequency on AD blood chemokine profiles, and correlate these findings with chemokine brain expression changes in the triple transgenic AD (3xTg-AD) mouse model. Three month old 3xTg-AD mice were subjected to 12 weeks of moderate intensity wheel running at a frequency of either 1×/week or 3×/week. Blood and cortical tissue were analyzed for expression of monocyte chemotactic protein-1 (MCP-1) and regulated and normal T cell expressed and secreted (RANTES). Alterations in blood RANTES and MCP-1 expression were evident at 3 and 6 month old animals compared to WT animals. Three times per week exercise but not 1×/week exercise was effective at reversing serum and brain RANTES and MCP-1 expression to the levels of WT controls, revealing a dose dependent response to exercise. Analysis of these chemokines showed a strong negative correlation between blood and brain expression of RANTES. The results indicate that alterations in serum and brain inflammatory chemokines are evident as early signs of Alzheimer's disease pathology and that higher frequency exercise was necessary to restore blood and brain inflammatory expression levels in this AD mouse model.

  11. A Robust Deep Model for Improved Classification of AD/MCI Patients.

    PubMed

    Li, Feng; Tran, Loc; Thung, Kim-Han; Ji, Shuiwang; Shen, Dinggang; Li, Jiang

    2015-09-01

    Accurate classification of Alzheimer's disease (AD) and its prodromal stage, mild cognitive impairment (MCI), plays a critical role in possibly preventing progression of memory impairment and improving quality of life for AD patients. Among many research tasks, it is of a particular interest to identify noninvasive imaging biomarkers for AD diagnosis. In this paper, we present a robust deep learning system to identify different progression stages of AD patients based on MRI and PET scans. We utilized the dropout technique to improve classical deep learning by preventing its weight coadaptation, which is a typical cause of overfitting in deep learning. In addition, we incorporated stability selection, an adaptive learning factor, and a multitask learning strategy into the deep learning framework. We applied the proposed method to the ADNI dataset, and conducted experiments for AD and MCI conversion diagnosis. Experimental results showed that the dropout technique is very effective in AD diagnosis, improving the classification accuracies by 5.9% on average as compared to the classical deep learning methods. PMID:25955998

  12. A Robust Deep Model for Improved Classification of AD/MCI Patients

    PubMed Central

    Li, Feng; Tran, Loc; Thung, Kim-Han; Ji, Shuiwang; Shen, Dinggang; Li, Jiang

    2015-01-01

    Accurate classification of Alzheimer’s Disease (AD) and its prodromal stage, Mild Cognitive Impairment (MCI), plays a critical role in possibly preventing progression of memory impairment and improving quality of life for AD patients. Among many research tasks, it is of particular interest to identify noninvasive imaging biomarkers for AD diagnosis. In this paper, we present a robust deep learning system to identify different progression stages of AD patients based on MRI and PET scans. We utilized the dropout technique to improve classical deep learning by preventing its weight co-adaptation, which is a typical cause of over-fitting in deep learning. In addition, we incorporated stability selection, an adaptive learning factor, and a multi-task learning strategy into the deep learning framework. We applied the proposed method to the ADNI data set and conducted experiments for AD and MCI conversion diagnosis. Experimental results showed that the dropout technique is very effective in AD diagnosis, improving the classification accuracies by 5.9% on average as compared to the classical deep learning methods. PMID:25955998

  13. Vascular pathology of 20-month-old hypercholesterolemia mice in comparison to triple-transgenic and APPSwDI Alzheimer’s disease mouse models

    PubMed Central

    Hohsfield, Lindsay A.; Daschil, Nina; Orädd, Greger; Strömberg, Ingrid; Humpel, Christian

    2015-01-01

    Several studies have shown that elevated plasma cholesterol levels (i.e. hypercholesterolemia) serve as a risk factor for late-onset Alzheimer’s disease (AD). However, it remains unclear how hypercholesterolemia may contribute to the onset and progression of AD pathology. In order to determine the role of hypercholesterolemia at various stages of AD, we evaluated the effects of high cholesterol diet (5% cholesterol) in wild-type (WT; C57BL6) and triple-transgenic AD (3xTg-AD; Psen1, APPSwe, tauB301L) mice at 7, 14, and 20 months. The transgenic APP-Swedish/Dutch/Iowa AD mouse model (APPSwDI) was used as a control since these animals are more pathologically-accelerated and are known to exhibit extensive plaque deposition and cerebral amyloid angiopathy. Here, we describe the effects of high cholesterol diet on: (1) cognitive function and stress, (2) AD-associated pathologies, (3) neuroinflammation, (4) blood–brain barrier disruption and ventricle size, and (5) vascular dysfunction. Our data show that high dietary cholesterol increases weight, slightly impairs cognitive function, promotes glial cell activation and complement-related pathways, enhances the infiltration of blood-derived proteins and alters vascular integrity, however, it does not induce AD-related pathologies. While normal-fed 3xTg-AD mice display a typical AD-like pathology in addition to severe cognitive impairment and neuroinflammation at 20 months of age, vascular alterations are less pronounced. No microbleedings were seen by MRI, however, the ventricle size was enlarged. Triple-transgenic AD mice, on the other hand, fed a high cholesterol diet do not survive past 14 months of age. Our data indicates that cholesterol does not markedly potentiate AD-related pathology, nor does it cause significant impairments in cognition. However, it appears that high cholesterol diet markedly increases stress-related plasma corticosterone levels as well as some vessel pathologies. Together, our findings

  14. Disease course in mdx:utrophin+/- mice: comparison of three mouse models of Duchenne muscular dystrophy.

    PubMed

    McDonald, Abby A; Hebert, Sadie L; Kunz, Matthew D; Ralles, Steven J; McLoon, Linda K

    2015-04-01

    The mdx mouse model of Duchenne muscular dystrophy (DMD) is used to study disease mechanisms and potential treatments, but its pathology is less severe than DMD patients. Other mouse models were developed to more closely mimic the human disease based on knowledge that upregulation of utrophin has a protective effect in mdx muscle. An mdx:utrophin(-/-) (dko) mouse was created, which had a severe disease phenotype and a shortened life span. An mdx:utrophin(+/-) mouse was also created, which had an intermediate disease phenotype compared to the mdx and dko mice. To determine the usefulness of mdx:utrophin(+/-) mice for long-term DMD studies, limb muscle pathology and function were assessed across the life span of wild-type, mdx, mdx:utrophin(+/-), and dko mice. Muscle function assessment, specifically grip duration and rotarod performance, demonstrated that mdx:utrophin(+/-) mice were weaker for a longer time than mdx mice. Mean myofiber area was smaller in mdx:utrophin(+/-) mice compared to mdx mice at 12 months. Mdx:utrophin(+/-) mice had a higher percentage of centrally nucleated myofibers compared to mdx mice at 6 and 12 months. Collagen I and IV density was significantly higher in mdx:utrophin(+/-) muscle compared to mdx at most ages examined. Generally, mdx:utrophin(+/-) mice showed an intermediate disease phenotype over a longer time course compared to the mdx and dko mice. While they do not genetically mirror human DMD, mdx:utrophin(+/-) mice may be a more useful animal model than mdx or dko mice for investigating long-term efficacy of potential treatments when fibrosis or muscle function is the focus.

  15. Gastroesophageal reflux leads to esophageal cancer in a surgical model with mice

    PubMed Central

    2009-01-01

    Background Esophago-gastroduodenal anastomosis with rats mimics the development of human Barrett's esophagus and esophageal adenocarcinoma by introducing mixed reflux of gastric and duodenal contents into the esophagus. However, use of this rat model for mechanistic and chemopreventive studies is limited due to lack of genetically modified rat strains. Therefore, a mouse model of esophageal adenocarcinoma is needed. Methods We performed reflux surgery on wild-type, p53A135V transgenic, and INK4a/Arf+/- mice of A/J strain. Some mice were also treated with omeprazole (1,400 ppm in diet), iron (50 mg/kg/m, i.p.), or gastrectomy plus iron. Mouse esophagi were harvested at 20, 40 or 80 weeks after surgery for histopathological analysis. Results At week 20, we observed metaplasia in wild-type mice (5%, 1/20) and p53A135V mice (5.3%, 1/19). At week 40, metaplasia was found in wild-type mice (16.2%, 6/37), p53A135V mice (4.8%, 2/42), and wild-type mice also receiving gastrectomy and iron (6.7%, 1/15). Esophageal squamous cell carcinoma developed in INK4a/Arf+/- mice (7.1%, 1/14), and wild-type mice receiving gastrectomy and iron (21.4%, 3/14). Among 13 wild-type mice which were given iron from week 40 to 80, twelve (92.3%) developed squamous cell carcinoma at week 80. None of these mice developed esophageal adenocarcinoma. Conclusion Surgically induced gastroesophageal reflux produced esophageal squamous cell carcinoma, but not esophageal adenocarcinoma, in mice. Dominant negative p53 mutation, heterozygous loss of INK4a/Arf, antacid treatment, iron supplementation, or gastrectomy failed to promote esophageal adenocarcinoma in these mice. Further studies are needed in order to develop a mouse model of esophageal adenocarcinoma. PMID:19627616

  16. Therapeutic Effects of Microbubbles Added to Combined High-Intensity Focused Ultrasound and Chemotherapy in a Pancreatic Cancer Xenograft Model

    PubMed Central

    Yu, Mi Hye; Kim, Hae Ri; Kim, Bo Ram; Park, Eun-Joo; Kim, Hoe Suk; Han, Joon Koo; Choi, Byung Ihn

    2016-01-01

    Objective To investigate whether high-intensity focused ultrasound (HIFU) combined with microbubbles enhances the therapeutic effects of chemotherapy. Materials and Methods A pancreatic cancer xenograft model was established using BALB/c nude mice and luciferase-expressing human pancreatic cancer cells. Mice were randomly assigned to five groups according to treatment: control (n = 10), gemcitabine alone (GEM; n = 12), HIFU with microbubbles (HIFU + MB, n = 11), combined HIFU and gemcitabine (HIGEM; n = 12), and HIGEM + MB (n = 13). After three weekly treatments, apoptosis rates were evaluated using the terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling assay in two mice per group. Tumor volume and bioluminescence were monitored using high-resolution 3D ultrasound imaging and in vivo bioluminescence imaging for eight weeks in the remaining mice. Results The HIGEM + MB group showed significantly higher apoptosis rates than the other groups (p < 0.05) and exhibited the slowest tumor growth. From week 5, the tumor-volume-ratio relative to the baseline tumor volume was significantly lower in the HIGEM + MB group than in the control, GEM, and HIFU + MB groups (p < 0.05). Despite visible distinction, the HIGEM and HIGEM + MB groups showed no significant differences. Conclusion High-intensity focused ultrasound combined with microbubbles enhances the therapeutic effects of gemcitabine chemotherapy in a pancreatic cancer xenograft model. PMID:27587968

  17. The flavonoid quercetin ameliorates Alzheimer’s disease pathology and protects cognitive and emotional function in aged triple transgenic Alzheimer’s disease model mice

    PubMed Central

    Maria, Sabogal-Guáqueta Angélica; Ignacio, Muñoz-Manco Juan; Ramírez-Pineda Jose, R; Marisol, Lamprea-Rodriguez; Edison, Osorio; Patricia, Cardona-Gómez Gloria

    2015-01-01

    Alzheimer’s disease (AD) is the most common senile dementia in the world. Although important progress has been made in understanding the pathogenesis of AD, current therapeutic approaches provide only modest symptomatic relief. In this study, we evaluated the neuroprotective effect of quercetin (25 mg/kg) administration via i.p. injection every 48 hours for 3 months on aged (21–24 months old) triple transgenic AD model (3xTg-AD) mice. Our data show that quercetin decreases extracellular β-amyloidosis, tauopathy, astrogliosis and microgliosis in the hippocampus and the amygdala. These results were supported by a significant reduction in the paired helical filament (PHF), β-amyloid (βA) 1–40 and βA 1–42 levels and a decrease in BACE1-mediated cleavage of APP (into CTFβ). Additionally, quercetin induced improved performance on learning and spatial memory tasks and greater risk assessment behavior based on the elevated plus maze test. Together, these findings suggest that quercetin reverses histological hallmarks of AD and protects cognitive and emotional function in aged 3xTg-AD mice. PMID:25666032

  18. Focal brain trauma in the cryogenic lesion model in mice.

    PubMed

    Raslan, Furat; Albert-Weißenberger, Christiane; Ernestus, Ralf-Ingo; Kleinschnitz, Christoph; Sirén, Anna-Leena

    2012-01-01

    The method to induce unilateral cryogenic lesions was first described in 1958 by Klatzo. We describe here an adaptation of this model that allows reliable measurement of lesion volume and vasogenic edema by 2, 3, 5-triphenyltetrazolium chloride-staining and Evans blue extravasation in mice. A copper or aluminium cylinder with a tip diameter of 2.5 mm is cooled with liquid nitrogen and placed on the exposed skull bone over the parietal cortex (coordinates from bregma: 1.5 mm posterior, 1.5 mm lateral). The tip diameter and the contact time between the tip and the parietal skull determine the extent of cryolesion. Due to an early damage of the blood brain barrier, the cryogenic cortical injury is characterized by vasogenic edema, marked brain swelling, and inflammation. The lesion grows during the first 24 hours, a process involving complex interactions between endothelial cells, immune cells, cerebral blood flow, and the intracranial pressure. These contribute substantially to the damage from the initial injury. The major advantage of the cryogenic lesion model is the circumscribed and highly reproducible lesion size and location. PMID:22480252

  19. Modeling the Study of DNA Damage Responses in Mice

    PubMed Central

    Specks, Julia; Nieto-Soler, Maria; Lopez-Contreras, Andres J; Fernandez-Capetillo, Oscar

    2016-01-01

    Summary Damaged DNA has a profound impact on mammalian health and overall survival. In addition to being the source of mutations that initiate cancer, the accumulation of toxic amounts of DNA damage can cause severe developmental diseases and accelerate ageing. Therefore, understanding how cells respond to DNA damage has become one of the most intense areas of biomedical research in the recent years. However, whereas most mechanistic studies derive from in vitro or in cellulo work, the impact of a given mutation on a living organism is largely unpredictable. For instance, why BRCA1 mutations preferentially lead to breast cancer whereas mutations compromising mismatch repair drive colon cancer is still not understood. In this context, evaluating the specific physiological impact of mutations that compromise genome integrity has become crucial for a better dimensioning of our knowledge. We here describe the various technologies that can be used for modeling mutations in mice, and provide a review of the genes and pathways that have been modeled so far in the context of DNA damage responses. PMID:25636482

  20. Peromyscus leucopus mice: a potential animal model for haematological studies.

    PubMed

    Sun, Yu; Desierto, Marie J; Ueda, Yasutaka; Kajigaya, Sachiko; Chen, Jichun; Young, Neal S

    2014-10-01

    Peromyscus leucopus mice share physical similarities with laboratory mice Mus musculus (MM) but have higher agility and longer lifespan. We compared domesticated P. leucopus linville (PLL) and M. musculus C57BL/6 (MMB6) mice for cellular composition of peripheral blood (PB), bone marrow (BM) and spleen. PLL mice had significantly fewer platelets and significantly more monocytes in the blood, and notably fewer megakaryocytes in the BM. Spleens of PLL mice were significantly smaller, with 50% fewer cells and reduced 'red pulp'. There was no obvious haematological change in PLL mice between 2-8 and 16-26 months of age, except for a significant increase in blood monocytes. Cellular reactive oxygen species (ROS) content showed no change with age but differed significantly between different cell types. Treating two to eight month-old PLL mice with antioxidant N-acetylcysteine in drinking water for three months did not affect cellular ROS content, but increased blood leucocytes especially the concentration of monocytes. The low platelets, low megakaryocytes, high monocytes and low splenic erythropoiesis in PLL mice resemble human measurements better than the values seen in MMB6. PMID:25116892

  1. Peromyscus leucopus mice: a potential animal model for haematological studies.

    PubMed

    Sun, Yu; Desierto, Marie J; Ueda, Yasutaka; Kajigaya, Sachiko; Chen, Jichun; Young, Neal S

    2014-10-01

    Peromyscus leucopus mice share physical similarities with laboratory mice Mus musculus (MM) but have higher agility and longer lifespan. We compared domesticated P. leucopus linville (PLL) and M. musculus C57BL/6 (MMB6) mice for cellular composition of peripheral blood (PB), bone marrow (BM) and spleen. PLL mice had significantly fewer platelets and significantly more monocytes in the blood, and notably fewer megakaryocytes in the BM. Spleens of PLL mice were significantly smaller, with 50% fewer cells and reduced 'red pulp'. There was no obvious haematological change in PLL mice between 2-8 and 16-26 months of age, except for a significant increase in blood monocytes. Cellular reactive oxygen species (ROS) content showed no change with age but differed significantly between different cell types. Treating two to eight month-old PLL mice with antioxidant N-acetylcysteine in drinking water for three months did not affect cellular ROS content, but increased blood leucocytes especially the concentration of monocytes. The low platelets, low megakaryocytes, high monocytes and low splenic erythropoiesis in PLL mice resemble human measurements better than the values seen in MMB6.

  2. A Recombinant Chimeric Ad5/3 Vector Expressing a Multistage Plasmodium Antigen Induces Protective Immunity in Mice Using Heterologous Prime-Boost Immunization Regimens.

    PubMed

    Cabrera-Mora, Monica; Fonseca, Jairo Andres; Singh, Balwan; Zhao, Chunxia; Makarova, Natalia; Dmitriev, Igor; Curiel, David T; Blackwell, Jerry; Moreno, Alberto

    2016-10-01

    An ideal malaria vaccine should target several stages of the parasite life cycle and induce antiparasite and antidisease immunity. We have reported a Plasmodium yoelii chimeric multistage recombinant protein (P. yoelii linear peptide chimera/recombinant modular chimera), engineered to express several autologous T cell epitopes and sequences derived from the circumsporozoite protein and the merozoite surface protein 1. This chimeric protein elicits protective immunity, mediated by CD4(+) T cells and neutralizing Abs. However, experimental evidence, from pre-erythrocytic vaccine candidates and irradiated sporozoites, has shown that CD8(+) T cells play a significant role in protection. Recombinant viral vectors have been used as a vaccine platform to elicit effective CD8(+) T cell responses. The human adenovirus (Ad) serotype 5 has been tested in malaria vaccine clinical trials with excellent safety profile. Nevertheless, a major concern for the use of Ad5 is the high prevalence of anti-vector neutralizing Abs in humans, hampering its immunogenicity. To minimize the impact of anti-vector pre-existing immunity, we developed a chimeric Ad5/3 vector in which the knob region of Ad5 was replaced with that of Ad3, conferring partial resistance to anti-Ad5 neutralizing Abs. Furthermore, we implemented heterologous Ad/protein immunization regimens that include a single immunization with recombinant Ad vectors. Our data show that immunization with the recombinant Ad5/3 vector induces protective efficacy indistinguishable from that elicited by Ad5. Our study also demonstrates that the dose of the Ad vectors has an impact on the memory profile and protective efficacy. The results support further studies with Ad5/3 for malaria vaccine development. PMID:27574299

  3. DIS in AdS

    SciTech Connect

    Albacete, Javier L.; Kovchegov, Yuri V.; Taliotis, Anastasios

    2009-03-23

    We calculate the total cross section for the scattering of a quark-anti-quark dipole on a large nucleus at high energy for a strongly coupled N = 4 super Yang-Mills theory using AdS/CFT correspondence. We model the nucleus by a metric of a shock wave in AdS{sub 5}. We then calculate the expectation value of the Wilson loop (the dipole) by finding the extrema of the Nambu-Goto action for an open string attached to the quark and antiquark lines of the loop in the background of an AdS{sub 5} shock wave. We find two physically meaningful extremal string configurations. For both solutions we obtain the forward scattering amplitude N for the quark dipole-nucleus scattering. We study the onset of unitarity with increasing center-of-mass energy and transverse size of the dipole: we observe that for both solutions the saturation scale Q{sub s} is independent of energy/Bjorken-x and depends on the atomic number of the nucleus as Q{sub s}{approx}A{sup 1/3}. Finally we observe that while one of the solutions we found corresponds to the pomeron intercept of {alpha}{sub P} = 2 found earlier in the literature, when extended to higher energy or larger dipole sizes it violates the black disk limit. The other solution we found respects the black disk limit and yields the pomeron intercept of {alpha}{sub P} = 1.5. We thus conjecture that the right pomeron intercept in gauge theories at strong coupling may be {alpha}{sub P} = 1.5.

  4. A novel mice model of metabolic syndrome: the high-fat-high-fructose diet-fed ICR mice

    PubMed Central

    Zhuhua, Zhang; Zhiquan, Wang; Zhen, Yang; Yixin, Niu; Weiwei, Zhang; Xiaoyong, Li; Yueming, Liu; Hongmei, Zhang; Li, Qin; Qing, Su

    2015-01-01

    Currently, the metabolic syndrome (MS) is occurring at growing rates worldwide, raising extensive concerns on the mechanisms and therapeutic interventions for this disorder. Herein, we described a novel method of establishing MS model in rodents. Male Institute of Cancer Research (ICR) mice were fed with high-fat-high-fructose (HFHF) diet or normal chow (NC) respectively for 12 weeks. Metabolic phenotypes were assessed by glucose tolerance test, insulin tolerance test and hyperinsulinemic-euglycemic clamp. Blood pressure was measured by a tail-cuff system. At the end of the experiment, mice were sacrificed, and blood and tissues were harvested for subsequent analysis. Serum insulin levels were measured by ELISA, and lipid profiles were determined biochemically. The HFHF diet-fed ICR mice exhibited obvious characteristics of the components of MS, including obvious obesity, severe insulin resistance, hyperinsulinemia, dislipidemia, significant hypertension and hyperuricemia. Our data suggest that HFHF diet-fed ICR mice may be a robust and efficient animal model that could well mimic the basic pathogenesis of human MS. PMID:26134356

  5. Modelling Patterns of Improvement over Time: Value Added Trends in English Secondary School Performance across Ten Cohorts

    ERIC Educational Resources Information Center

    Thomas, Sally; Peng, Wen Jung; Gray, John

    2007-01-01

    This paper looks at underlying patterns of school effectiveness through analysing a GCSE examination data-set over a period of ten cohorts (1993-2002) in one very large English school district. Both value added and raw score approaches were explored by employing different statistical multilevel models to examine time trends of school and pupil…

  6. Legal Issues in the Use of Student Test Scores and Value-Added Models (VAM) to Determine Educational Quality

    ERIC Educational Resources Information Center

    Pullin, Diana

    2013-01-01

    A growing number of states and local schools across the country have adopted educator evaluation and accountability programs based on the use of student test scores and value-added models (VAM). A wide array of potential legal issues could arise from the implementation of these programs. This article uses legal analysis and social science evidence…

  7. Propensity Score Methods as Alternatives to Value-Added Modeling for the Estimation of Teacher Contributions to Student Achievement

    ERIC Educational Resources Information Center

    Davison, Kimberlee Kaye Callister

    2012-01-01

    The purpose of this study was to examine the potential for using propensity score-based matching methods to estimate teacher contributions to student learning. Value-added models are increasingly used in teacher accountability systems in the United States in spite of ongoing qualms about the validity of teacher quality estimates resulting from…

  8. SENCAR mouse skin tumorigenesis model versus other strains and stocks of mice

    SciTech Connect

    Slaga, T.J.

    1986-09-01

    The SENCAR mouse stock was selectively bred for eight generations for sensitivity to skin tumor induction by the two-stage tumorigenesis protocol using 7,12-dimethylbenz(a)anthracene (DMBA) as the initiator and 12-O-tetradecanoylphorbol-13-acetate (TPA) as the promoter. The SENCAR mouse was derived by crossing Charles River CD-1 mice with skin-tumor-sensitive mice (STS). The SENCAR mice are much more sensitive to both DMBA tumor initiation and TPA tumor promotion than CD-1, BALB/c, and DBA/2 mice. An even greater difference in the sensitivity to two-stage skin tumorigenesis is apparent between SENCAR and C57BL/6 mice when using DMBA-TPA treatment. However, the SENCAR and C57BL/6 mice have a similar tumor response to DMBA-benzoyl peroxide treatment, suggesting that TPA is not an effective promoter in C57BL/6 mice. The DBA/2 mice respond in a similar manner to the SENCAR mice when using N-methyl-N-nitro-N-nitrosoguanidine (MNNG)-TPA treatment. The SENCAR mouse model provides a good dose-response relationship for many carcinogens used as tumor initiators and for many compounds used as tumor promoter. When compared to other stocks and strains of mice, the SENCAR mouse has one of the largest data bases for carcinogens and promoters.

  9. Hairy AdS solitons

    NASA Astrophysics Data System (ADS)

    Anabalón, Andrés; Astefanesei, Dumitru; Choque, David

    2016-11-01

    We construct exact hairy AdS soliton solutions in Einstein-dilaton gravity theory. We examine their thermodynamic properties and discuss the role of these solutions for the existence of first order phase transitions for hairy black holes. The negative energy density associated to hairy AdS solitons can be interpreted as the Casimir energy that is generated in the dual filed theory when the fermions are antiperiodic on the compact coordinate.

  10. Modeling Myocardial Infarction in Mice: Methodology, Monitoring, Pathomorphology

    PubMed Central

    Ovsepyan, A.A.; Panchenkov, D.N.; Prokhortchouk, E.B.; Telegin, G.B.; Zhigalova, N.A.; Golubev, E.P.; Sviridova, T.E.; Matskeplishvili, S.T.; Skryabin, K.G.; Buziashvili, U.I.

    2011-01-01

    Myocardial infarction is one of the most serious and widespread diseases in the world. In this work, a minimally invasive method for simulating myocardial infarction in mice is described in the Russian Federation for the very first time; the procedure is carried out by ligation of the coronary heart artery or by controlled electrocoagulation. As a part of the methodology, a series of anesthetic, microsurgical and revival protocols are designed, owing to which a decrease in the postoperational mortality from the initial 94.6 to 13.6% is achieved. ECG confirms the development of large-focal or surface myocardial infarction. Postmortal histological examination confirms the presence of necrosis foci in the heart muscles of 87.5% of animals. Altogether, the medical data allow us to conclude that an adequate mouse model for myocardial infarction was generated. A further study is focused on the standardization of the experimental procedure and the use of genetically modified mouse strains, with the purpose of finding the most efficient therapeutic approaches for this disease. PMID:22649679

  11. Intraplacental gene therapy with Ad-IGF-1 corrects naturally occurring rabbit model of intrauterine growth restriction.

    PubMed

    Keswani, Sundeep G; Balaji, Swathi; Katz, Anna B; King, Alice; Omar, Khaled; Habli, Mounira; Klanke, Charles; Crombleholme, Timothy M

    2015-03-01

    Intrauterine growth restriction (IUGR) due to placental insufficiency is a leading cause of perinatal complications for which there is no effective prenatal therapy. We have previously demonstrated that intraplacental injection of adenovirus-mediated insulin-like growth factor-1 (Ad-IGF-1) corrects fetal weight in a murine IUGR model induced by mesenteric uterine artery branch ligation. This study investigated the effect of intraplacental Ad-IGF-1 gene therapy in a rabbit model of naturally occurring IUGR (runt) due to placental insufficiency, which is similar to the human IUGR condition with onset in the early third trimester, brain sparing, and a reduction in liver weight. Laparotomy was performed on New Zealand White rabbits on day 21 of 30 days of gestation and litters were divided into five groups: Control (first position)+phosphate-buffered saline (PBS), control+Ad-IGF-1, runt (third position)+PBS, runt+Ad-IGF-1, and runt+Ad-LacZ. The effect of IGF-1 gene therapy on fetal, placental, liver, heart, lung, and musculoskeletal weights of the growth-restricted pups was examined. Protein expression after gene transfer was seen along the maternal-fetal placenta interface (n=12) 48 hr after gene therapy. There was minimal gene transfer detected in the pups or maternal organs. At term, compared with the normally grown first-position control, the runted third-position pups demonstrated significantly lower fetal, placental, liver, lung, and musculoskeletal weights. The fetal, liver, and musculoskeletal weights were restored to normal by intraplacental Ad-IGF-1 gene therapy (p<0.01), with no change in the placental weight. Intraplacental gene therapy is a novel strategy for the treatment of IUGR caused by placental insufficiency that takes advantage of an organ that will be discarded at birth. Development of nonviral IGF-1 gene delivery using placenta-specific promoters can potentially minimize toxicity to the mother and fetus and facilitate clinical translation of

  12. [BEHAVIOR, MEMORY AND IMMUNOLOGICAL STATUS IN MICE MODEL OF DESYNCHRONOSIS].

    PubMed

    Dubrovina, N I; Shurlygina, A V; Litvinenko, G I; Melnikova, E V; Tenditnik, M V; Chasovskich, M I; Trufakin, V A

    2015-05-01

    Interstrain differences in behavior and parameters of the immune system of CBA and C57BL/6 mice with round the clock coverage (KO) were investigated. Open field, light/dark, acoustic startle response, forced swimming, elevated plus-maze, passive avoidance were used for measuring emotional behavior and memory. The number of lymphocyte subpopulations CD3+, CD4+8-, CD4-8+, CD4+8+, CD19+, CD3+hi spleen and thymus, the ratio of cells in different phases of the cell cycle was determined by flow cytometry. C57BL/6J mice strictly increased anxiety in response to the KO compared to CBA mice. Moreover, KO-treated C57BL/6J mice impaired the passive avoidance learning. We found that KO evoked significant changes in the cellular composition of the thymus and decrease of thymocytes proliferation in C57BL/6J mice. In opposite KO-treated CBA mice showed change of splenic cellular structure with increased % CD19+ cells and the proliferation of splenocytes. Our study demonstrated genotype-dependent reactions of the nervous and immune systems in response chronic constant light.

  13. [Synapse maturation and autism: learning from neuroligin model mice].

    PubMed

    Tabuchi, Katsuhiko; Chang, WenHsin; Hang, WenHsin; Asgar, Nur Farehan; Asgar, Nur Farehan Mohamed; Pramanik, Gopal

    2014-02-01

    Autism is a neurodevelopmental disorder characterized by impairments in social interaction, communication, and restricted and repetitive behavior. Synaptic defects have been implicated in autism; nevertheless, the cause is still largely unknown. A mutation that substitutes cysteine for arginine at residue 451 of Neuroligin-3 (R451C) is the first monogenic mutation identified in idiopathic autism patients. To study the relationship between this mutation and autism, we generated knock-in mice that recapitulated this mutation. The knock-in mice were born and grew up normally without showing any major physical phenotypes, but showed a deficit in social interaction. We studied synaptic function in the layer II/III pyramidal neurons in the somatosensory cortex and found inhibitory synaptic transmission was enhanced in the knock-in mice. The administration of GABA blocker rescued social interaction, suggesting that this caused autistic behavior in these mice. We also found, by Morris water maze test, that spatial learning and memory were significantly enhanced in the knock-in mice. Electrophysiology in the CA1 region of the hippocampus revealed that LTP, the NMDA/AMPA ratio, and NR2B function were enhanced, indicating that synaptic maturation was impaired in the knock-in mice. This may cause the deficit in social behavior and extraordinary memory ability occasionally seen in autistic patients.

  14. Chronic GluN2B antagonism disrupts behavior in wild-type mice without protecting against synapse loss or memory impairment in Alzheimer's disease mouse models.

    PubMed

    Hanson, Jesse E; Meilandt, William J; Gogineni, Alvin; Reynen, Paul; Herrington, James; Weimer, Robby M; Scearce-Levie, Kimberly; Zhou, Qiang

    2014-06-11

    Extensive evidence implicates GluN2B-containing NMDA receptors (GluN2B-NMDARs) in excitotoxic-insult-induced neurodegeneration and amyloid β (Aβ)-induced synaptic dysfunction. Therefore, inhibiting GluN2B-NMDARs would appear to be a potential therapeutic strategy to provide neuroprotection and improve cognitive function in Alzheimer's disease (AD). However, there are no reports of long-term in vivo treatment of AD mouse models with GluN2B antagonists. We used piperidine18 (Pip18), a potent and selective GluN2B-NMDAR antagonist with favorable pharmacokinetic properties, for long-term dosing in AD mouse models. Reduced freezing behavior in Tg2576 mice during fear conditioning was partially reversed after subchronic (17 d) Pip18 treatment. However, analysis of freezing behavior in different contexts indicated that this increased freezing likely involves elevated anxiety or excessive memory generalization in both nontransgenic (NTG) and Tg2576 mice. In PS2APP mice chronically fed with medicated food containing Pip18 for 4 months, spatial learning and memory deficits were not rescued, plaque-associated spine loss was not affected, and synaptic function was not altered. At the same time, altered open field activity consistent with increased anxiety and degraded performance in an active avoidance task were observed in NTG after chronic treatment. These results indicate that long-term treatment with a GluN2B-NMDAR antagonist does not provide a disease-modifying benefit and could cause cognitive liabilities rather than symptomatic benefit in AD mouse models. Therefore, these results challenge the expectation of the therapeutic potential for GluN2B-NMDAR antagonists in AD.

  15. HOW GAS-DYNAMIC FLARE MODELS POWERED BY PETSCHEK RECONNECTION DIFFER FROM THOSE WITH AD HOC ENERGY SOURCES

    SciTech Connect

    Longcope, D. W.; Klimchuk, J. A.

    2015-11-10

    Aspects of solar flare dynamics, such as chromospheric evaporation and flare light curves, have long been studied using one-dimensional models of plasma dynamics inside a static flare loop, subjected to some energy input. While extremely successful at explaining the observed characteristics of flares, all such models so far have specified energy input ad hoc, rather than deriving it self-consistently. There is broad consensus that flares are powered by magnetic energy released through reconnection. Recent work has generalized Petschek’s basic reconnection scenario, topological change followed by field line retraction and shock heating, to permit its inclusion in a one-dimensional flare loop model. Here we compare the gas dynamics driven by retraction and shocking to those from more conventional static loop models energized by ad hoc source terms. We find significant differences during the first minute, when retraction leads to larger kinetic energies and produces higher densities at the loop top, while ad hoc heating tends to rarify the loop top. The loop-top density concentration is related to the slow magnetosonic shock, characteristic of Petschek’s model, but persists beyond the retraction phase occurring in the outflow jet. This offers an explanation for observed loop-top sources of X-ray and EUV emission, with advantages over that provided by ad hoc heating scenarios. The cooling phases of the two models are, however, notably similar to one another, suggesting that observations at that stage will yield little information on the nature of energy input.

  16. Multi-tissue computational modeling analyzes pathophysiology of type 2 diabetes in MKR mice.

    PubMed

    Kumar, Amit; Harrelson, Thomas; Lewis, Nathan E; Gallagher, Emily J; LeRoith, Derek; Shiloach, Joseph; Betenbaugh, Michael J

    2014-01-01

    Computational models using metabolic reconstructions for in silico simulation of metabolic disorders such as type 2 diabetes mellitus (T2DM) can provide a better understanding of disease pathophysiology and avoid high experimentation costs. There is a limited amount of computational work, using metabolic reconstructions, performed in this field for the better understanding of T2DM. In this study, a new algorithm for generating tissue-specific metabolic models is presented, along with the resulting multi-confidence level (MCL) multi-tissue model. The effect of T2DM on liver, muscle, and fat in MKR mice was first studied by microarray analysis and subsequently the changes in gene expression of frank T2DM MKR mice versus healthy mice were applied to the multi-tissue model to test the effect. Using the first multi-tissue genome-scale model of all metabolic pathways in T2DM, we found out that branched-chain amino acids' degradation and fatty acids oxidation pathway is downregulated in T2DM MKR mice. Microarray data showed low expression of genes in MKR mice versus healthy mice in the degradation of branched-chain amino acids and fatty-acid oxidation pathways. In addition, the flux balance analysis using the MCL multi-tissue model showed that the degradation pathways of branched-chain amino acid and fatty acid oxidation were significantly downregulated in MKR mice versus healthy mice. Validation of the model was performed using data derived from the literature regarding T2DM. Microarray data was used in conjunction with the model to predict fluxes of various other metabolic pathways in the T2DM mouse model and alterations in a number of pathways were detected. The Type 2 Diabetes MCL multi-tissue model may explain the high level of branched-chain amino acids and free fatty acids in plasma of Type 2 Diabetic subjects from a metabolic fluxes perspective.

  17. Multi-Tissue Computational Modeling Analyzes Pathophysiology of Type 2 Diabetes in MKR Mice

    PubMed Central

    Kumar, Amit; Harrelson, Thomas; Lewis, Nathan E.; Gallagher, Emily J.; LeRoith, Derek; Shiloach, Joseph; Betenbaugh, Michael J.

    2014-01-01

    Computational models using metabolic reconstructions for in silico simulation of metabolic disorders such as type 2 diabetes mellitus (T2DM) can provide a better understanding of disease pathophysiology and avoid high experimentation costs. There is a limited amount of computational work, using metabolic reconstructions, performed in this field for the better understanding of T2DM. In this study, a new algorithm for generating tissue-specific metabolic models is presented, along with the resulting multi-confidence level (MCL) multi-tissue model. The effect of T2DM on liver, muscle, and fat in MKR mice was first studied by microarray analysis and subsequently the changes in gene expression of frank T2DM MKR mice versus healthy mice were applied to the multi-tissue model to test the effect. Using the first multi-tissue genome-scale model of all metabolic pathways in T2DM, we found out that branched-chain amino acids' degradation and fatty acids oxidation pathway is downregulated in T2DM MKR mice. Microarray data showed low expression of genes in MKR mice versus healthy mice in the degradation of branched-chain amino acids and fatty-acid oxidation pathways. In addition, the flux balance analysis using the MCL multi-tissue model showed that the degradation pathways of branched-chain amino acid and fatty acid oxidation were significantly downregulated in MKR mice versus healthy mice. Validation of the model was performed using data derived from the literature regarding T2DM. Microarray data was used in conjunction with the model to predict fluxes of various other metabolic pathways in the T2DM mouse model and alterations in a number of pathways were detected. The Type 2 Diabetes MCL multi-tissue model may explain the high level of branched-chain amino acids and free fatty acids in plasma of Type 2 Diabetic subjects from a metabolic fluxes perspective. PMID:25029527

  18. Mice selected for high versus low stress reactivity: a new animal model for affective disorders.

    PubMed

    Touma, Chadi; Bunck, Mirjam; Glasl, Lisa; Nussbaumer, Markus; Palme, Rupert; Stein, Hendrik; Wolferstätter, Michael; Zeh, Ramona; Zimbelmann, Marina; Holsboer, Florian; Landgraf, Rainer

    2008-07-01

    -related behavior, exploratory drive, locomotor activity, and depression-like behavior point to phenotypic similarities with behavioral changes observed in depressive patients. In general, HR males and females were 'hyperactive' in some behavioral paradigms, resembling symptoms of restlessness and agitation often seen in melancholic depression. LR mice, on the other hand, showed more passive-aggressive coping styles, corresponding to signs of retardation and retreat observed in atypical depression. Several morphometric and neuroendocrine findings further support this view. For example, monitoring the circadian rhythm of glucocorticoid secretion revealed clearly increased trough levels in HR mice, resulting in a flattened diurnal rhythm, again adding to the neuroendocrine similarities to patients suffering from melancholic depression. Taken together, our results suggest that distinct mechanisms influencing the function and regulation of the HPA axis are involved in the respective behavioral and neurobiological endophenotypes. Thus, the generated HR/IR/LR mouse lines can be a valuable model to elucidate molecular genetic, neuroendocrine, and behavioral parameters associated with altered stress reactivity, thereby improving our understanding of affective disorders, presumably including the symptomatology and pathophysiology of specific subtypes of major depression.

  19. [Preliminary establishment of transplanted human chronic myeloid leukemia model in nude mice].

    PubMed

    Li, Xian-Min; Ding, Xin; Zhang, Long-Zhen; Cen, Jian-Nong; Chen, Zi-Xing

    2011-12-01

    Chronic myeloid leukemia (CML) is a malignant clonal disease derived from hematopoietic stem cells. CML stem cells were thought to be the root which could lead disease development and ultimately rapid change. However, a stable animal model for studying the characteristics of CML stem cells is currently lacking. This study was aimed to establish a transplanted human CML nude-mice model to further explore the biological behavior of CML stem cells in vivo, and to enrich CML stem cells in nude mice by series transplantation. The 4 - 6 weeks old BALB/c nude mice pretreated by splenectomy (S), cytoxan intraperitoneal injection (C) and sublethal irradiation (I) were transplanted intravenously with (5 - 7) × 10(7) of bone marrow mononuclear cells from CML patients in chronic phase. Alternatively, 4 - 6 weeks old BALB/c nude mice pretreated by lethal irradiation were transplanted intravenously with 5 × 10(6) homologous bone marrow cells of BALB/c nude mice together with (5 - 7) × 10(7) of bone marrow mononuclear cells from CML patients in chronic phase simultaneously. The leukemic cells engrafted and infiltrated in organs and bone marrow of the mice were tracked by reverse transcription-polymerase chain reaction (RT-PCR), plastic-embedded biopsy and flow cytometry. The results of these two methods were compared. The results showed that human CML cells engrafted and infiltrating into the bone marrow of two nude mice pretreated with SCI could be detected. In spite of the low successful rate, results suggested the feasibility of this method by using BALB/c nude mice as a human CML animal model. In contrast, in nude mice pretreated by the lethal dose irradiation, CML cells in the bone marrow could not be found. It is concluded that human bone marrow CML cells can results in leukemia in nude mice pretreated by SCI. Thus this study provides a new strategy for establishment of CML animal models which deserves further elaboration.

  20. Characterization of 7- and 19-month-old Tg2576 mice using multimodal in vivo imaging: limitations as a translatable model of Alzheimer's disease.

    PubMed

    Luo, Feng; Rustay, Nathan R; Ebert, Ulrich; Hradil, Vincent P; Cole, Todd B; Llano, Daniel A; Mudd, Sarah R; Zhang, Yumin; Fox, Gerard B; Day, Mark

    2012-05-01

    With 90% of neuroscience clinical trials failing to see efficacy, there is a clear need for the development of disease biomarkers that can improve the ability to predict human Alzheimer's disease (AD) trial outcomes from animal studies. Several lines of evidence, including genetic susceptibility and disease studies, suggest the utility of fluorodeoxyglucose positron emission tomography (FDG-PET) as a potential biomarker with congruency between humans and animal models. For example, early in AD, patients present with decreased glucose metabolism in the entorhinal cortex and several regions of the brain associated with disease pathology and cognitive decline. While several of the commonly used AD mouse models fail to show all the hallmarks of the disease or the limbic to cortical trajectory, there has not been a systematic evaluation of imaging-derived biomarkers across animal models of AD, contrary to what has been achieved in recent years in the Alzheimer's Disease Neuroimaging Initiative (ADNI) (Miller, 2009). If animal AD models were found to mimic endpoints that correlate with the disease onset, progression, and relapse, then the identification of such markers in animal models could afford the field a translational tool to help bridge the preclinical-clinical gap. Using a combination of FDG-PET and functional magnetic resonance imaging (fMRI), we examined the Tg2576 mouse for global and regional measures of brain glucose metabolism at 7 and 19 months of age. In experiment 1 we observed that at younger ages, when some plaque burden and cognitive deficits have been reported, Tg2576 mice showed hypermetabolism as assessed with FDG-PET. This hypermetabolism decreased with age to levels similar to wild type (WT) counterparts such that the 19-month-old transgenic (Tg) mice did not differ from age matched WTs. In experiment 2, using cerebral blood volume (CBV) fMRI, we demonstrated that the hypermetabolism observed in Tg mice at 7 months could not be explained by

  1. Value Added?

    ERIC Educational Resources Information Center

    UCLA IDEA, 2012

    2012-01-01

    Value added measures (VAM) uses changes in student test scores to determine how much "value" an individual teacher has "added" to student growth during the school year. Some policymakers, school districts, and educational advocates have applauded VAM as a straightforward measure of teacher effectiveness: the better a teacher, the better students…

  2. Using ICR and SCID mice as animal models for smallpox to assess antiviral drug efficacy.

    PubMed

    Titova, Ksenya A; Sergeev, Alexander A; Zamedyanskaya, Alena S; Galahova, Darya O; Kabanov, Alexey S; Morozova, Anastasia A; Bulychev, Leonid E; Sergeev, Artemiy A; Glotova, Tanyana I; Shishkina, Larisa N; Taranov, Oleg S; Omigov, Vladimir V; Zavjalov, Evgenii L; Agafonov, Alexander P; Sergeev, Alexander N

    2015-09-01

    The possibility of using immunocompetent ICR mice and immunodeficient SCID mice as model animals for smallpox to assess antiviral drug efficacy was investigated. Clinical signs of the disease did not appear following intranasal (i.n.) challenge of mice with strain Ind-3a of variola virus (VARV), even when using the highest possible dose of the virus (5.2 log10 p.f.u.). The 50 % infective doses (ID50) of VARV, estimated by the virus presence or absence in the lungs 3 and 4 days post-infection, were 2.7 ± 0.4 log10 p.f.u. for ICR mice and 3.5 ± 0.7 log10 p.f.u. for SCID mice. After i.n. challenge of ICR and SCID mice with VARV 30 and 50 ID50, respectively, steady reproduction of the virus occurred only in the respiratory tract (lungs and nose). Pathological inflammatory destructive changes were revealed in the respiratory tract and the primary target cells for VARV (macrophages and epithelial cells) in mice, similar to those in humans and cynomolgus macaques. The use of mice to assess antiviral efficacies of NIOCH-14 and ST-246 demonstrated the compliance of results with those described in scientific literature, which opens up the prospect of their use as an animal model for smallpox to develop anti-smallpox drugs intended for humans. PMID:26067292

  3. Using ICR and SCID mice as animal models for smallpox to assess antiviral drug efficacy.

    PubMed

    Titova, Ksenya A; Sergeev, Alexander A; Zamedyanskaya, Alena S; Galahova, Darya O; Kabanov, Alexey S; Morozova, Anastasia A; Bulychev, Leonid E; Sergeev, Artemiy A; Glotova, Tanyana I; Shishkina, Larisa N; Taranov, Oleg S; Omigov, Vladimir V; Zavjalov, Evgenii L; Agafonov, Alexander P; Sergeev, Alexander N

    2015-09-01

    The possibility of using immunocompetent ICR mice and immunodeficient SCID mice as model animals for smallpox to assess antiviral drug efficacy was investigated. Clinical signs of the disease did not appear following intranasal (i.n.) challenge of mice with strain Ind-3a of variola virus (VARV), even when using the highest possible dose of the virus (5.2 log10 p.f.u.). The 50 % infective doses (ID50) of VARV, estimated by the virus presence or absence in the lungs 3 and 4 days post-infection, were 2.7 ± 0.4 log10 p.f.u. for ICR mice and 3.5 ± 0.7 log10 p.f.u. for SCID mice. After i.n. challenge of ICR and SCID mice with VARV 30 and 50 ID50, respectively, steady reproduction of the virus occurred only in the respiratory tract (lungs and nose). Pathological inflammatory destructive changes were revealed in the respiratory tract and the primary target cells for VARV (macrophages and epithelial cells) in mice, similar to those in humans and cynomolgus macaques. The use of mice to assess antiviral efficacies of NIOCH-14 and ST-246 demonstrated the compliance of results with those described in scientific literature, which opens up the prospect of their use as an animal model for smallpox to develop anti-smallpox drugs intended for humans.

  4. Establishment of a model of acetaminophen-induced hepatotoxicity in different weekly-aged ICR mice.

    PubMed

    Taguchi, K; Tokuno, M; Yamasaki, K; Kadowaki, D; Seo, H; Otagiri, M

    2015-10-01

    Acetaminophen (APAP), a widely used analgesic and antipyretic drug, has the potential to cause lethal hepatotoxicity. Mice are widely used for developing murine models of APAP-induced hepatotoxicity, and many researchers have used these models for APAP-related studies including the fields of biology, pharmacology and toxicology. Although drug-induced hepatotoxicity is dependent on a number of factors (species, gender and age), very few studies have investigated the effect of aging on APAP hepatotoxicity. In this study, we evaluated the effect of age on APAP-induced hepatotoxicity in different weekly-aged mice to establish a model of APAP-induced hepatotoxicity that is an accurate reflection of general experimental conditions. Male ICR mice 4, 6, 8, 10 and 12 weeks old were given APAP intraperitoneally, and mortality, hepatic damage and the plasma concentration of APAP metabolites were evaluated. It was found that younger male ICR mice were relatively resistant to hepatotoxicity induced by intraperitoneal APAP administration. In addition, the APAP-glucuronide concentration in plasma remained essentially the same among the differently-aged mice, while APAP-sulfate levels were dramatically decreased in an age-dependent manner. Thus, it is recommended that mice of the same ages be used in studies related to APAP-induced hepatotoxixity. These results provide evidence in support of not only the age-related changes in susceptibility to APAP-derived hepatotoxicity in mice but also in developing mouse models for APAP-related studies.

  5. A high throughput MATLAB program for automated force-curve processing using the AdG polymer model.

    PubMed

    O'Connor, Samantha; Gaddis, Rebecca; Anderson, Evan; Camesano, Terri A; Burnham, Nancy A

    2015-02-01

    Research in understanding biofilm formation is dependent on accurate and representative measurements of the steric forces related to brush on bacterial surfaces. A MATLAB program to analyze force curves from an AFM efficiently, accurately, and with minimal user bias has been developed. The analysis is based on a modified version of the Alexander and de Gennes (AdG) polymer model, which is a function of equilibrium polymer brush length, probe radius, temperature, separation distance, and a density variable. Automating the analysis reduces the amount of time required to process 100 force curves from several days to less than 2min. The use of this program to crop and fit force curves to the AdG model will allow researchers to ensure proper processing of large amounts of experimental data and reduce the time required for analysis and comparison of data, thereby enabling higher quality results in a shorter period of time.

  6. [Specific features of the anticonvulsant effect of memantine in mice intoxicated with a model organic phosphate].

    PubMed

    Iudin, M A; Chepur, S V; Bykov, V N; Kurpiakova, A F; Subbotina, S N; Nikiforov, A S; Ivanov, I M

    2013-01-01

    The effect of memantine administration has been studied on the model of mice poisoning with an anticholinesterase compound. It is established that the memantine action is due to its influence on the cholinesterase activity in the brain, blood plasma, and erythrocytes in addition to its NMDA-blocking action. Memantine promotes oxime-induced erythrocyte enzyme reactivation on the model of mice poisoning with anticholinesterase compound (0.8 LD50).

  7. Electromagnetic waves of 900 MHz in acute pentylenetetrazole model in ontogenesis in mice.

    PubMed

    Erdinc, O O; Baykul, M C; Ozdemir, O; Ozkan, S; Sirmagul, B; Oner, S D; Ozdemir, G

    2003-10-01

    The purpose of this study was to measure the effects of electromagnetic waves (EMW) at 900 MHz. EMW were produced by a signal generator and were administered to mice via an antenna. The frequency of the waves was tested by a spectrum analyser and a frequency-meter. The emitted power was 0.25 mW. A total of 117 mice (59 prepubertal and 58 adult) was used. Mice were exposed to EMW or sham radiation for 2 h and 20 h before an injection of pentylenetetrazole (PTZ). A statistically significant difference was found between the latency measurements within 20 h for prepubertal mice in stages 1 and 2 ( p<0.05). The effects on prepubertal mice of long-term 900 MHz EMW in a PTZ model may be an indication of possible problems in developing brains. PMID:14600821

  8. Modeling Energy Dynamics in Mice with Skeletal Muscle Hypertrophy Fed High Calorie Diets

    PubMed Central

    Bond, Nichole D.; Guo, Juen; Hall, Kevin D.; McPherron, Alexandra C.

    2016-01-01

    Retrospective and prospective studies show that lean mass or strength is positively associated with metabolic health. Mice deficient in myostatin, a growth factor that negatively regulates skeletal muscle mass, have increased muscle and body weights and are resistant to diet-induced obesity. Their leanness is often attributed to higher energy expenditure in the face of normal food intake. However, even obese animals have an increase in energy expenditure compared to normal weight animals suggesting this is an incomplete explanation. We have previously developed a computational model to estimate energy output, fat oxidation and respiratory quotient from food intake and body composition measurements to more accurately account for changes in body composition in rodents over time. Here we use this approach to understand the dynamic changes in energy output, intake, fat oxidation and respiratory quotient in muscular mice carrying a dominant negative activin receptor IIB expressed specifically in muscle. We found that muscular mice had higher food intake and higher energy output when fed either chow or a high-fat diet for 15 weeks compared to WT mice. Transgenic mice also matched their rate of fat oxidation to the rate of fat consumed better than WT mice. Surprisingly, when given a choice between high-fat diet and Ensure® drink, transgenic mice consumed relatively more calories from Ensure® than from the high-fat diet despite similar caloric intake to WT mice. When switching back and forth between diets, transgenic mice adjusted their intake more rapidly than WT to restore normal caloric intake. Our results show that mice with myostatin inhibition in muscle are better at adjusting energy intake and output on diets of different macronutrient composition than WT mice to maintain energy balance and resist weight gain. PMID:27076790

  9. Osteoprotegerin-deficient male mice as a model for severe alveolar bone loss: comparison with RANKL-overexpressing transgenic male mice.

    PubMed

    Koide, Masanori; Kobayashi, Yasuhiro; Ninomiya, Tadashi; Nakamura, Midori; Yasuda, Hisataka; Arai, Yoshinori; Okahashi, Nobuo; Yoshinari, Nobuo; Takahashi, Naoyuki; Udagawa, Nobuyuki

    2013-02-01

    Periodontitis, an inflammatory disease of periodontal tissues, is characterized by excessive alveolar bone resorption. An increase in the receptor activator of nuclear factor-κB ligand (RANKL) to osteoprotegerin (OPG) ratio is thought to reflect the severity of periodontitis. Here, we examined alveolar bone loss in OPG-deficient (OPG(-/-)) mice and RANKL-overexpressing transgenic (RANKL-Tg) mice. Alveolar bone loss in OPG(-/-) mice at 12 weeks was significantly higher than that in RANKL-Tg mice. OPG(-/-) but not RANKL-Tg mice exhibited severe bone resorption especially in cortical areas of the alveolar bone. An increased number of osteoclasts was observed in the cortical areas in OPG(-/-) but not in RANKL-Tg mice. Immunohistochemical analyses showed many OPG-positive signals in osteocytes but not osteoblasts. OPG-positive osteocytes in the cortical area of alveolar bones and long bones were abundant in both wild-type and RANKL-Tg mice. This suggests the resorption in cortical bone areas to be prevented by OPG produced locally. To test the usefulness of OPG(-/-) mice as an animal model for screening drugs to prevent alveolar bone loss, we administered an antimouse RANKL antibody or risedronate, a bisphosphonate, to OPG(-/-) mice. They suppressed alveolar bone resorption effectively. OPG(-/-) mice are useful for screening therapeutic agents against alveolar bone loss.

  10. Proteasome inhibitor model of Parkinson's disease in mice is confounded by neurotoxicity of the ethanol vehicle.

    PubMed

    Landau, Anne M; Kouassi, Edouard; Siegrist-Johnstone, Rosmarie; Desbarats, Julie

    2007-02-15

    Defects in the ubiquitin-proteasome system have been implicated in Parkinson's Disease (PD). Recently, a rat model of PD was developed using a synthetic proteasome inhibitor (PSI), (Z-lle-Glu(OtBu)-Ala-Leu-al). We attempted to transfer this model to mouse studies, where genetics can be more readily investigated due to the availability of genetically modified mice. We treated C57BL/6 (B6) mice with six intraperitoneal injections of 6 mg/kg PSI in 50 mul of 70% ethanol over a 2-week-period. We found significant decreases in nigrostriatal dopamine in PSI-treated mice compared with saline-treated mice. However, we observed similar decreases in the ethanol-treated vehicle control group. Administration of ethanol alone led to significant long-term alterations in dopamine levels. Ethanol significantly eclipses the effects of PSI in the dopamine system, and therefore is a confounding vehicle for this model. PMID:17230468

  11. The value of adding optics to ecosystem models: a case study

    NASA Astrophysics Data System (ADS)

    Fujii, M.; Boss, E.; Chai, F.

    2007-10-01

    Many ecosystem models have been developed to study the ocean's biogeochemical properties, but most of these models use simple formulations to describe light penetration and spectral quality. Here, an optical model is coupled with a previously published ecosystem model that explicitly represents two phytoplankton (picoplankton and diatoms) and two zooplankton functional groups, as well as multiple nutrients and detritus. Surface ocean color fields and subsurface light fields are calculated by coupling the ecosystem model with an optical model that relates biogeochemical standing stocks with inherent optical properties (absorption, scattering); this provides input to a commercially available radiative transfer model (Ecolight). We apply this bio-optical model to the equatorial Pacific upwelling region, and find the model to be capable of reproducing many measured optical properties and key biogeochemical processes in this region. Our model results suggest that non-algal particles largely contribute to the total scattering or attenuation (>50% at 660 nm) but have a much smaller contribution to particulate absorption (<20% at 440 nm), while picoplankton dominate the total phytoplankton absorption (>95% at 440 nm). These results are consistent with the field observations. In order to achieve such good agreement between data and model results, however, key model parameters, for which no field data are available, have to be constrained. Sensitivity analysis of the model results to optical parameters reveals a significant role played by colored dissolved organic matter through its influence on the quantity and quality of the ambient light. Coupling explicit optics to an ecosystem model provides advantages in generating: (1) a more accurate subsurface light-field, which is important for light sensitive biogeochemical processes such as photosynthesis and photo-oxidation, (2) additional constraints on model parameters that help to reduce uncertainties in ecosystem model

  12. Proteomic Alterations in B Lymphocytes of Sensitized Mice in a Model of Chemical-Induced Asthma

    PubMed Central

    De Vooght, Vanessa; Schoofs, Liliane; Nemery, Benoit; Clynen, Elke; Hoet, Peter H. M.

    2015-01-01

    Introduction and Aim The role of B-lymphocytes in chemical-induced asthma is largely unknown. Recent work demonstrated that transferring B lymphocytes from toluene diisocyanate (TDI)-sensitized mice into naïve mice, B cell KO mice and SCID mice, triggered an asthma-like response in these mice after a subsequent TDI-challenge. We applied two-dimensional difference gel electrophoresis (2D-DIGE) to describe the “sensitized signature” of B lymphocytes comparing TDI-sensitized mice with control mice. Results Sixteen proteins were identified that were significantly up- or down-regulated in B lymphocytes of sensitized mice. Particularly differences in the expression of cyclophilin A, cofilin 1 and zinc finger containing CCHC domain protein 11 could be correlated to the function of B lymphocytes as initiators of T lymphocyte independent asthma-like responses. Conclusion This study revealed important alterations in the proteome of sensitized B cells in a mouse model of chemical-induced asthma, which will have an important impact on the B cell function. PMID:26398101

  13. Effects of chronic doxepin and amitriptyline administration in naïve mice and in neuropathic pain mice model.

    PubMed

    Mika, J; Jurga, A M; Starnowska, J; Wasylewski, M; Rojewska, E; Makuch, W; Kwiatkowski, K; Malek, N; Przewlocka, B

    2015-05-21

    Neuropathic pain is a severe clinical problem, often appearing as a co-symptom of many diseases or manifesting as a result of damage to the nervous system. Many drugs and agents are currently used for the treatment of neuropathic pain, such as tricyclic antidepressants (TCAs). The aims of this paper were to test the effects of two classic TCAs, doxepin and amitriptyline, in naïve animals and in a model of neuropathic pain and to determine the role of cytokine activation in the effects of these drugs. All experiments were carried out with Albino-Swiss mice using behavioral tests (von Frey test and the cold plate test) and biochemical analyses (qRT-PCR and Western blot). In the mice subjected to chronic constriction injury (CCI), doxepin and amitriptyline attenuated the symptoms of neuropathic pain and diminished the CCI-induced increase in the levels of spinal interleukin (IL)-6 and -1β mRNA, but not the protein levels of these cytokines, measured on day 12. Unexpectedly, chronic administration of doxepin or amitriptyline for 12 days produced allodynia and hyperalgesia in naïve mice. The treatment with these drugs did not influence the spinal levels of IL-1β and IL-6 mRNA, however, the protein levels of these pronociceptive factors were increased. The administration of ondansetron (5-HT3 receptor antagonist) significantly weakened the allodynia and hyperalgesia induced by both antidepressants in naïve mice; in contrast, yohimbine (α2-adrenergic receptors antagonist) did not influence these effects. Allodynia and hyperalgesia induced in naïve animals by amitriptyline and doxepin may be associated with an increase in the levels of pronociceptive cytokines resulting from 5-HT3-induced hypersensitivity. Our results provide new and important information about the possible side effects of antidepressants. Further investigation of these mechanisms may help to guide decisions about the use of classic TCAs for therapy. PMID:25769941

  14. Enriched endogenous n-3 polyunsaturated fatty acids alleviate cognitive and behavioral deficits in a mice model of Alzheimer's disease.

    PubMed

    Wu, Kefeng; Gao, Xiang; Shi, Baoyan; Chen, Shiyu; Zhou, Xin; Li, Zhidong; Gan, Yuhong; Cui, Liao; Kang, Jing Xuan; Li, Wende; Huang, Ren

    2016-10-01

    Alzheimer's disease (AD) is a progressive neurodegenerative disorder that accompanied by memory deficits and neuropsychiatric dysfunction. Omega-3 polyunsaturated fatty acids (n-3 PUFAs) have seemly therapeutic potential in AD, but the benefit of n-3 PUFAs is still in debates. Here, we employed a transgenic mice carry fat-1 gene to encode n-3 desaturase from Caenorhabditis elegans, which increase endogenous n-3 PUFAs by converting n-6 PUFAs to n-3 PUFAs crossed with amyloid precursor protein (APP) Tg mice to evaluate the protective effects of endogenous n-3 PUFAs on cognitive and behavioral deficits of APP Tg mice. We fed APP, APP/fat-1 and fat-1 mice with n-6 PUFAs rich diet. Brain tissues were collected at 3, 9 and 12 months for fatty acid and gene expression analysis, histology and protein assays. Morris Water Maze Test, open field test and elevated plus maze test were performed to measure the behavior capability. From the results, the expression of fat-1 transgene increased cortical n-3: n-6 PUFAs ratio and n-3 PUFAs concentrations, and sensorimotor dysfunction and cognitive deficits in AD were significantly less severe in APP/fat-1 mice with endogenous n-3 PUFAs than in APP mice controls. The protection against disturbance of spontaneous motor activity and cognitive deficits in AD was strongly correlated with increased n-3: n-6 PUFAs ratio and endogenous n-3 PUFAs, reduced APP generation, inhibited amyloid β peptide aggregation, suppressed nuclear factor-kappa B and astroglia activation, and reduced death of neurons in the cortex of APP/fat-1 mice compared with APP mice controls. In conclusion, our study demonstrates that an available medication with the maintenance of enriched n-3 PUFAs in the brain could slow down cognitive decline and prevent neuropsychological disorder in AD. PMID:27474225

  15. Intraplacental Gene Therapy with Ad-IGF-1 Corrects Naturally Occurring Rabbit Model of Intrauterine Growth Restriction

    PubMed Central

    Keswani, Sundeep G.; Balaji, Swathi; Katz, Anna B.; King, Alice; Omar, Khaled; Habli, Mounira; Klanke, Charles

    2015-01-01

    Abstract Intrauterine growth restriction (IUGR) due to placental insufficiency is a leading cause of perinatal complications for which there is no effective prenatal therapy. We have previously demonstrated that intraplacental injection of adenovirus-mediated insulin-like growth factor-1 (Ad-IGF-1) corrects fetal weight in a murine IUGR model induced by mesenteric uterine artery branch ligation. This study investigated the effect of intraplacental Ad-IGF-1 gene therapy in a rabbit model of naturally occurring IUGR (runt) due to placental insufficiency, which is similar to the human IUGR condition with onset in the early third trimester, brain sparing, and a reduction in liver weight. Laparotomy was performed on New Zealand White rabbits on day 21 of 30 days of gestation and litters were divided into five groups: Control (first position)+phosphate-buffered saline (PBS), control+Ad-IGF-1, runt (third position)+PBS, runt+Ad-IGF-1, and runt+Ad-LacZ. The effect of IGF-1 gene therapy on fetal, placental, liver, heart, lung, and musculoskeletal weights of the growth-restricted pups was examined. Protein expression after gene transfer was seen along the maternal–fetal placenta interface (n=12) 48 hr after gene therapy. There was minimal gene transfer detected in the pups or maternal organs. At term, compared with the normally grown first-position control, the runted third-position pups demonstrated significantly lower fetal, placental, liver, lung, and musculoskeletal weights. The fetal, liver, and musculoskeletal weights were restored to normal by intraplacental Ad-IGF-1 gene therapy (p<0.01), with no change in the placental weight. Intraplacental gene therapy is a novel strategy for the treatment of IUGR caused by placental insufficiency that takes advantage of an organ that will be discarded at birth. Development of nonviral IGF-1 gene delivery using placenta-specific promoters can potentially minimize toxicity to the mother and fetus and facilitate clinical

  16. A Model of Adding Relations in Multi-levels to a Formal Organization Structure with Two Subordinates

    NASA Astrophysics Data System (ADS)

    Sawada, Kiyoshi; Amano, Kazuyuki

    2009-10-01

    This paper proposes a model of adding relations in multi-levels to a formal organization structure with two subordinates such that the communication of information between every member in the organization becomes the most efficient. When edges between every pair of nodes with the same depth in L (L = 1, 2, …, H) levels are added to a complete binary tree of height H, an optimal set of depths {N1, N2, …, NL} (H⩾N1>N2> …>NL⩾1) is obtained by maximizing the total shortening path length which is the sum of shortening lengths of shortest paths between every pair of all nodes in the complete binary tree. It is shown that {N1, N2, …, NL}* = {H, H-1, …, H-L+1}.

  17. Transgenic Mice Expressing Human Transferrin as a Model for Meningococcal Infection▿

    PubMed Central

    Zarantonelli, Maria-Leticia; Szatanik, Marek; Giorgini, Dario; Hong, Eva; Huerre, Michel; Guillou, Florian; Alonso, Jean-Michel; Taha, Muhamed-Kheir

    2007-01-01

    The pathogenesis of meningococcal disease is poorly understood due to the lack of a relevant animal model. Moreover, the use of animal models is not optimal as most meningococcal virulence determinants recognize receptors that are specifically expressed in human tissues. One major element of the host specificity is the system of meningococcal iron uptake by transferrin-binding proteins that bind specifically human transferrin but not murine transferrin. We developed a new mouse model for experimental meningococcal infection using transgenic mice expressing human transferrin. Intraperitoneal challenge of transgenic mice induced bacteremia for at least 48 h with an early stage of multiplication, whereas the initial inoculum was rapidly cleared from blood in wild-type mice. Inflammation in the subarachnoidal space with a high influx of polymorphonuclear cells was observed only in transgenic mice. Meningococcal mutants that were unable to use transferrin as a source of iron were rapidly cleared from both wild-type and transgenic mice. Thus, transgenic mice expressing human transferrin may represent an important advance as a new mouse model for in vivo studies of meningococcal virulence and immunogenicity factors. PMID:17893132

  18. Two new ad-hoc models of detection physics and their evaluation for navigated beta probe surface imaging

    NASA Astrophysics Data System (ADS)

    Shakir, Dzhoshkun I.; Hartl, Alexander; Schneider, Florian R.; Pulko, Jozef; Ziegler, Sibylle I.; Navab, Nassir; Lasser, Tobias

    2012-02-01

    Intra-operative surface imaging with navigated beta probes in conjunction with positron-emitting radiotracers like 18F-FDG has been shown to enable control of tumor resection borders. We showed previously that employing iterative reconstruction (MLEM) in conjunction with an ad-hoc model of the detection physics (based on solid-angle geometry, SA) improves the image quality. In this study, we sampled the beta probe readings of a point source using a precision step-motor to generate a look-up-table (LUT) model. We also generated a simplified geometrical model (SG) based on this data set. To see how these two models influence the image quality compared to the old SA model, we reconstructed images from sparsely sampled datasets of a phantom with three hotspots using each model. The images yielded 76% (SA), 81% (SG), and 81% (LUT) mean NCC compared to the ground truth. The SG and LUT models, however, could resolve the hotspots better in the datasets where the detector-to-phantom distance was larger. Additionally, we compared the deviations of the SA and SG analytical models to the measured LUT model, where we found that the SG model gives estimates substantially closer to the actual beta probe readings than the previous SA model.

  19. Efficacy of Sustained-Release Buprenorphine in an Experimental Laparotomy Model in Female Mice.

    PubMed

    Kendall, Lon V; Wegenast, Daniel J; Smith, Brian J; Dorsey, Kathryn M; Kang, Sooah; Lee, Na Young; Hess, Ann M

    2016-01-01

    Mice purportedly require dosing with the opioid buprenorphine (Bup-HCl) at least every 8 to 12 h to maintain an adequate plane of analgesia. Here we used an experimental laparotomy model to determine the clinical efficacy of sustained-release formulations of buprenorphine (Bup-SR) after surgery in mice. Female CD1 mice underwent laparotomy and received either Bup-SR (0.6 mg/kg), Bup-HCl (0.1 mg/kg every 12 h), or saline (every 12 h). Pain was assessed at 1, 3, 6, 12, 24, 48, and 72 h according to the frequency of several behaviors (general activity, wheel-running activity, rearing, grooming, wound licking, orbital tightening, and percentage of integrated nest material) and daily body weight. Over time, wheel running was increased and wound licking was decreased in Bup-SR-treated mice compared with Bup-HCl- and saline-treated mice. Compared with Bup-HCl- and saline-treated mice, Bup-SR-treated mice had increased general activity and percentage of integrated nest material and decreased orbital tightening for 1 to 6 h after surgery. The Bup-HCl- and saline-treated mice had similar general activity, orbital tightening scores, and wheel running activity. Rearing activity and body weight did not differ throughout the study, and none of the observed behaviors differed between groups at 24, 48, and 72 h after surgery. These results suggest that Bup-SR at 0.6 mg/kg provides adequate analgesia after laparotomy in mice and can be used as an alternative analgesic in this context. Furthermore, Bup-HCl at 0.1 mg/kg every 12 h may be inadequate in providing analgesia for abdominal procedures in mice.

  20. Efficacy of Sustained-Release Buprenorphine in an Experimental Laparotomy Model in Female Mice

    PubMed Central

    Kendall, Lon V; Wegenast, Daniel J; Smith, Brian J; Dorsey, Kathryn M; Kang, Sooah; Lee, Na Young; Hess, Ann M

    2016-01-01

    Mice purportedly require dosing with the opioid buprenorphine (Bup-HCl) at least every 8 to 12 h to maintain an adequate plane of analgesia. Here we used an experimental laparotomy model to determine the clinical efficacy of sustained-release formulations of buprenorphine (Bup-SR) after surgery in mice. Female CD1 mice underwent laparotomy and received either Bup-SR (0.6 mg/kg), Bup-HCl (0.1 mg/kg every 12 h), or saline (every 12 h). Pain was assessed at 1, 3, 6, 12, 24, 48, and 72 h according to the frequency of several behaviors (general activity, wheel-running activity, rearing, grooming, wound licking, orbital tightening, and percentage of integrated nest material) and daily body weight. Over time, wheel running was increased and wound licking was decreased in Bup-SR–treated mice compared with Bup-HCl– and saline-treated mice. Compared with Bup-HCl– and saline-treated mice, Bup-SR–treated mice had increased general activity and percentage of integrated nest material and decreased orbital tightening for 1 to 6 h after surgery. The Bup-HCl– and saline-treated mice had similar general activity, orbital tightening scores, and wheel running activity. Rearing activity and body weight did not differ throughout the study, and none of the observed behaviors differed between groups at 24, 48, and 72 h after surgery. These results suggest that Bup-SR at 0.6 mg/kg provides adequate analgesia after laparotomy in mice and can be used as an alternative analgesic in this context. Furthermore, Bup-HCl at 0.1 mg/kg every 12 h may be inadequate in providing analgesia for abdominal procedures in mice. PMID:26817982

  1. Interferon α/β receptor knockout mice as a model to study bluetongue virus infection.

    PubMed

    Ortego, Javier; de la Poza, Francisco; Marín-López, Alejandro

    2014-03-01

    Bluetongue is an arthropod-borne disease caused by a virus of the genus Orbivirus, the bluetongue virus (BTV), which affects ruminant livestock such as cattle, sheep, and goats and wild ruminants such as deer, and camelids. Recently, adult mice with gene knockouts of the interferon α/β receptor (IFNAR-/-) have been described as a model of lethal BTV infection. IFNAR(-/-) mice are highly susceptible to BTV-1, BTV-4 and BTV-8 infection when the virus is administered intravenously or subcutaneosuly. Disease progression and pathogenesis closely mimics signs of bluetongue disease in ruminants. In the present paper we review the studies where IFNAR(-/-) mice have been used as an animal model to study BTV transmission, pathogenesis, virulence, and protective efficacy of inactivated and new recombinant marker BTV vaccines. Furthermore, we report new data on protective efficacy of different strategies of BTV vaccination and also on induction of interferon α/β and proinflammatory immune responses in IFNAR(-/-) mice infected with BTV.

  2. [Establishment of EV71 animal models with 2-week-old BALB/c mice].

    PubMed

    Wang, Hui-Qiang; Jiang, Jian-Dong; Li, Yu-Huan

    2013-03-01

    Animal model is very important for anti-EV71 (enterovirus 71) drug and vaccine development. 1-day-old suckling EV71 mouse model is the main in vivo model used in China. 1-day-old suckling EV71 mouse is too small to perform antiviral experiment. And the route of administration and dosage capacity are also restricted. A strong virulence EV71 virus strain was selected after screening from five EV71 strains with 1-day-old suckling mice. A mouse-adapted EV71 strain with increased virulence in 12-day-old suckling mice, EV71-M5, was generated after five serial passages of the parental EV71 strain in mice. Virus titers of EV71 infected mice heart, liver, spleen, lung, kidney, small intestine, brain and muscle tissue were determined by cytopathic effect (CPE) assay. The virus used in this model is the first isolated EV71 strain in China. And 2-week-old suckling mice were used in this model. This is a supplement for the EV71 animal model in China. Establishment of this EV71 model will provide an attractive platform for anti-EV71 vaccine and drug development.

  3. Multiscale Snow/Icemelt Discharge Simulations into Alpine Reservoirs: adding Glacier Dynamics to a Hydrological Model

    NASA Astrophysics Data System (ADS)

    Schueller, Felix; Förster, Kristian; Hanzer, Florian; Huttenlau, Matthias; Marzeion, Ben; Strasser, Ulrich; Achleitner, Stefan; Kirnbauer, Robert

    2015-04-01

    Glacier and snow runoff in high alpine regions is an essential process in hydrological research for its high relevance on lower altitude areas and hydro-power generation. MUSICALS II (Multiscale Snow/Icemelt Discharge Simulations into Alpine Reservoirs) seeks to identify and quantify water availability and runoff in alpine headwater catchments. The focus is on future changes due to glacier retreat, altering the multi-day and seasonal runoff available for hydropower operations. Our aim is to investigate and improve runoff forecasts by coupling the semi-distributed hydrological model HQSim with a simple glacier evolution model. The glacier model MMBM (Marzeion Mass Balance Model) with its statistical nature allows for fast modelling of the dynamical properties of glaciers. We present the design of the coupled hydrological application for different hydro power headwater catchments in Tyrol. The capabilities of the glacier model to simulate the selected glaciers is shown. Simulated discharge with the original and the coupled model are compared to downstream gauge measurements. Using the multi-objective optimization algorithm AMALGAM (A Multi-ALgorithm, Genetically Adaptive Multiobjective model), we optimize the glacier module parameters fully automatically. The results show the improvements in runoff modelling for past periods, when altering of glaciated catchment parts is considered. This indicates consideration of this process is mandatory for simulating future developments.

  4. An experimental seasonal hydrological forecasting system over the Yellow River basin - Part 2: The added value from climate forecast models

    NASA Astrophysics Data System (ADS)

    Yuan, Xing

    2016-06-01

    This is the second paper of a two-part series on introducing an experimental seasonal hydrological forecasting system over the Yellow River basin in northern China. While the natural hydrological predictability in terms of initial hydrological conditions (ICs) is investigated in a companion paper, the added value from eight North American Multimodel Ensemble (NMME) climate forecast models with a grand ensemble of 99 members is assessed in this paper, with an implicit consideration of human-induced uncertainty in the hydrological models through a post-processing procedure. The forecast skill in terms of anomaly correlation (AC) for 2 m air temperature and precipitation does not necessarily decrease over leads but is dependent on the target month due to a strong seasonality for the climate over the Yellow River basin. As there is more diversity in the model performance for the temperature forecasts than the precipitation forecasts, the grand NMME ensemble mean forecast has consistently higher skill than the best single model up to 6 months for the temperature but up to 2 months for the precipitation. The NMME climate predictions are downscaled to drive the variable infiltration capacity (VIC) land surface hydrological model and a global routing model regionalized over the Yellow River basin to produce forecasts of soil moisture, runoff and streamflow. And the NMME/VIC forecasts are compared with the Ensemble Streamflow Prediction method (ESP/VIC) through 6-month hindcast experiments for each calendar month during 1982-2010. As verified by the VIC offline simulations, the NMME/VIC is comparable to the ESP/VIC for the soil moisture forecasts, and the former has higher skill than the latter only for the forecasts at long leads and for those initialized in the rainy season. The forecast skill for runoff is lower for both forecast approaches, but the added value from NMME/VIC is more obvious, with an increase of the average AC by 0.08-0.2. To compare with the observed

  5. Experience-dependent reduction of soluble β-amyloid oligomers and rescue of cognitive abilities in middle-age Ts65Dn mice, a model of Down syndrome.

    PubMed

    Sansevero, Gabriele; Begenisic, Tatjana; Mainardi, Marco; Sale, Alessandro

    2016-09-01

    Down syndrome (DS) is the most diffused genetic cause of intellectual disability and, after the age of forty, is invariantly associated with Alzheimer's disease (AD). In the last years, the prolongation of life expectancy in people with DS renders the need for intervention paradigms aimed at improving mental disability and counteracting AD pathology particularly urgent. At present, however, there are no effective therapeutic strategies for DS and concomitant AD in mid-life people. The most intensively studied mouse model of DS is the Ts65Dn line, which summarizes the main hallmarks of the DS phenotype, included severe learning and memory deficits and age-dependent AD-like pathology. Here we report for the first time that middle-age Ts65Dn mice display a marked increase in soluble Aβ oligomer levels in their hippocampus. Moreover, we found that long-term exposure to environmental enrichment (EE), a widely used paradigm that increases sensory-motor stimulation, reduces Aβ oligomers and rescues spatial memory abilities in trisomic mice. Our findings underscore the potential of EE procedures as a non-invasive paradigm for counteracting brain aging processes in DS subjects. PMID:27288239

  6. A dynamic CSTT model for the effects of added nutrients in Loch Creran, a shallow fjord

    NASA Astrophysics Data System (ADS)

    Laurent, Céline; Tett, Paul; Fernandes, Teresa; Gilpin, Linda; Jones, Ken

    2006-07-01

    Despite a tendency for the complexity of physical-biological models to increase, simple coupled models remain useful for some applications and can provide insights into crucial links between physical and biological processes. This argument is illustrated with an account of a simple 3-box model intended to help assess the capacity of fjords to assimilate nutrients from fish farms. The model, a dynamic version of the UK "Comprehensive Studies Task Team" (CSTT) steady-state model for eutrophication, was applied to Loch Creran (Scottish Western Highlands) and was implemented using Stella 8 and tested using historical data from 1975 (before the installation of a salmon farm) and field data collected in 2003, during the period of operation of the farm. The model's biological state variables are chlorophyll, dissolved inorganic nitrogen (DIN) and dissolved inorganic phosphorus (DIP), and it includes a simple run-off model to convert rainfall into river discharge. The physical processes involved in exchange between the loch and the adjacent waters of the Firth of Lorne were parameterised as a constant daily exchange rate. Between 1975 and 2003, local inputs of nutrient increased but, despite this, there was little apparent increase in nutrient concentrations in the loch, and observed chlorophyll concentrations decreased substantially. Model simulations of chlorophyll and DIN agreed well with observations in 1975, as did DIN simulations in 2003. However, simulated chlorophyll was overestimated in 2003. Some of the agreement between observations and simulations come from the use of observed boundary conditions to force the model. However, even when boundary conditions are subtracted from simulations and observations, the simulations in most cases retain a significant correlation with observations, demonstrating that the model's 'interior' processes do add to its ability to replicate conditions in the loch.

  7. Prolonged diet induced obesity has minimal effects towards brain pathology in mouse model of cerebral amyloid angiopathy: implications for studying obesity-brain interactions in mice.

    PubMed

    Zhang, Le; Dasuri, Kalavathi; Fernandez-Kim, Sun-Ok; Bruce-Keller, Annadora J; Freeman, Linnea R; Pepping, Jennifer K; Beckett, Tina L; Murphy, M Paul; Keller, Jeffrey N

    2013-09-01

    Cerebral amyloid angiopathy (CAA) occurs in nearly every individual with Alzheimer's disease (AD) and Down's syndrome, and is the second largest cause of intracerebral hemorrhage. Mouse models of CAA have demonstrated evidence for increased gliosis contributing to CAA pathology. Nearly two thirds of Americans are overweight or obese, with little known about the effects of obesity on the brain, although increasingly the vasculature appears to be a principle target of obesity effects on the brain. In the current study we describe for the first time whether diet induced obesity (DIO) modulates glial reactivity, amyloid levels, and inflammatory signaling in a mouse model of CAA. In these studies we identify surprisingly that DIO does not significantly increase Aβ levels, astrocyte (GFAP) or microglial (IBA-1) gliosis in the CAA mice. However, within the hippocampal gyri a localized increase in reactive microglia were increased in the CA1 and stratum oriens relative to CAA mice on a control diet. DIO was observed to selectively increase IL-6 in CAA mice, with IL-1β and TNF-α not increased in CAA mice in response to DIO. Taken together, these data show that prolonged DIO has only modest effects towards Aβ in a mouse model of CAA, but appears to elevate some localized microglial reactivity within the hippocampal gyri and selective markers of inflammatory signaling. These data are consistent with the majority of the existing literature in other models of Aβ pathology, which surprisingly show a mixed profile of DIO effects towards pathological processes in mouse models of neurodegenerative disease. The importance for considering the potential impact of ceiling effects in pathology within mouse models of Aβ pathogenesis, and the current experimental limitations for DIO in mice to fully replicate metabolic dysfunction present in human obesity, are discussed. This article is part of a Special Issue entitled: Animal Models of Disease.

  8. Rapamycin Increases Mortality in db/db Mice, a Mouse Model of Type 2 Diabetes.

    PubMed

    Sataranatarajan, Kavithalakshmi; Ikeno, Yuji; Bokov, Alex; Feliers, Denis; Yalamanchili, Himabindu; Lee, Hak Joo; Mariappan, Meenalakshmi M; Tabatabai-Mir, Hooman; Diaz, Vivian; Prasad, Sanjay; Javors, Martin A; Ghosh Choudhury, Goutam; Hubbard, Gene B; Barnes, Jeffrey L; Richardson, Arlan; Kasinath, Balakuntalam S

    2016-07-01

    We examined the effect of rapamycin on the life span of a mouse model of type 2 diabetes, db/db mice. At 4 months of age, male and female C57BLKSJ-lepr (db/db) mice (db/db) were placed on either a control diet, lacking rapamycin or a diet containing rapamycin and maintained on these diets over their life span. Rapamycin was found to reduce the life span of the db/db mice. The median survival of male db/db mice fed the control and rapamycin diets was 349 and 302 days, respectively, and the median survival of female db/db mice fed the control and rapamycin diets was 487 and 411 days, respectively. Adjusting for gender differences, rapamycin increased the mortality risk 1.7-fold in both male and female db/db mice. End-of-life pathological data showed that suppurative inflammation was the main cause of death in the db/db mice, which is enhanced slightly by rapamycin treatment.

  9. Strain Differences in the Chronic Mild Stress Animal Model of Depression and Anxiety in Mice

    PubMed Central

    Jung, Yang-Hee; Hong, Sa-Ik; Ma, Shi-Xun; Hwang, Ji-Young; Kim, Jun-Sup; Lee, Ju-Hyun; Seo, Jee-Yeon; Lee, Seok-Yong; Jang, Choon-Gon

    2014-01-01

    Chronic mild stress (CMS) has been reported to induce an anhedonic-like state in mice that resembles some of the symptoms of human depression. In the present study, we used a chronic mild stress animal model of depression and anxiety to examine the responses of two strains of mice that have different behavioral responsiveness. An outbred ICR and an inbred C57BL/6 strain of mice were selected because they are widely used strains in behavioral tests. The results showed that the inbred C57BL/6 and outbred ICR mice were similarly responsive to CMS treatment in sucrose intake test (SIT) and open field test (OFT). However, the two strains showed quite different responses in forced swimming test (FST) and novelty-suppressed feeding (NSF) test after 3 weeks of CMS treatment. Only C57BL/6 mice displayed the depression- and anxiety-like behavioral effects in response to CMS treatment in FST and NSF test. Our results suggest that there are differences in responsiveness to CMS according to the different types of strain of mice and behavioral tests. Therefore, these results provide useful information for the selection of appropriate behavioral methods to test depression- and anxiety-like behaviors using CMS in ICR and C57BL/6 mice. PMID:25414777

  10. Use of Numerical Models as Data Proxies for Approximate Ad-Hoc Query Processing

    SciTech Connect

    Kamimura, R; Abdulla, G; Baldwin, C; Critchlow, T; Lee, B; Lozares, I; Musick, R; Tang, N

    2003-05-19

    As datasets grow beyond the gigabyte scale, there is an increasing demand to develop techniques for dealing/interacting with them. To this end, the DataFoundry team at the Lawrence Livermore National Laboratory has developed a software prototype called Approximate Adhoc Query Engine for Simulation Data (AQSim). The goal of AQSim is to provide a framework that allows scientists to interactively perform adhoc queries over terabyte scale datasets using numerical models as proxies for the original data. The advantages of this system are several. The first is that by storing only the model parameters, each dataset occupies a smaller footprint compared to the original, increasing the shelf-life of such datasets before they are sent to archival storage. Second, the models are geared towards approximate querying as they are built at different resolutions, allowing the user to make the tradeoff between model accuracy and query response time. This allows the user greater opportunities for exploratory data analysis. Lastly, several different models are allowed, each focusing on a different characteristic of the data thereby enhancing the interpretability of the data compared to the original. The focus of this paper is on the modeling aspects of the AQSim framework.

  11. Cold temperature improves mobility and survival in Drosophila models of autosomal-dominant hereditary spastic paraplegia (AD-HSP).

    PubMed

    Baxter, Sally L; Allard, Denise E; Crowl, Christopher; Sherwood, Nina Tang

    2014-08-01

    Autosomal-dominant hereditary spastic paraplegia (AD-HSP) is a crippling neurodegenerative disease for which effective treatment or cure remains unknown. Victims experience progressive mobility loss due to degeneration of the longest axons in the spinal cord. Over half of AD-HSP cases arise from loss-of-function mutations in spastin, which encodes a microtubule-severing AAA ATPase. In Drosophila models of AD-HSP, larvae lacking Spastin exhibit abnormal motor neuron morphology and function, and most die as pupae. Adult survivors display impaired mobility, reminiscent of the human disease. Here, we show that rearing pupae or adults at reduced temperature (18°C), compared with the standard temperature of 24°C, improves the survival and mobility of adult spastin mutants but leaves wild-type flies unaffected. Flies expressing human spastin with pathogenic mutations are similarly rescued. Additionally, larval cooling partially rescues the larval synaptic phenotype. Cooling thus alleviates known spastin phenotypes for each developmental stage at which it is administered and, notably, is effective even in mature adults. We find further that cold treatment rescues larval synaptic defects in flies with mutations in Flower (a protein with no known relation to Spastin) and mobility defects in flies lacking Kat60-L1, another microtubule-severing protein enriched in the CNS. Together, these data support the hypothesis that the beneficial effects of cold extend beyond specific alleviation of Spastin dysfunction, to at least a subset of cellular and behavioral neuronal defects. Mild hypothermia, a common neuroprotective technique in clinical treatment of acute anoxia, might thus hold additional promise as a therapeutic approach for AD-HSP and, potentially, for other neurodegenerative diseases.

  12. Augmenting 3d City Model Components by Geodata Joins to Facilitate Ad-Hoc Geometric-Topologically Sound Integration

    NASA Astrophysics Data System (ADS)

    Kaden, R.; Kolbe, T. H.

    2012-07-01

    Virtual 3D city models are integrated complex compositions of spatial data of different themes, origin, quality, scale, and dimensions. Within this paper, we address the problem of spatial compatibility of geodata aiming to provide support for ad-hoc integration of virtual 3D city models including geodata of different sources and themes like buildings, terrain, and city furniture. In contrast to related work which is dealing with the integration of redundant geodata structured according to different data models and ontologies, we focus on the integration of complex 3D models of the same representation (here: CityGML) but regarding to the geometric-topological consistent matching of non-homologous objects, e.g. a building is connected to a road, and their geometric homogenisation. Therefore, we present an approach including a data model for a Geodata Join and the general concept of an integration procedure using the join information. The Geodata Join aims to bridge the lack of information between fragmented geodata by describing the relationship between adjacent objects from different datasets. The join information includes the geometrical representation of those parts of an object, which have a specific/known topological or geometrical relationship to another object. This part is referred to as a Connector and is either described by points, lines, or surfaces of the existing object geometry or by additional join geometry. In addition, the join information includes the specification of the connected object in the other dataset and the description of the topological and geometrical relationship between both objects, which is used to aid the matching process. Furthermore, the Geodata Join contains object-related information like accuracy values and restrictions of movement and deformation which are used to optimize the integration process. Based on these parameters, a functional model including a matching algorithm, transformation methods, and conditioned adjustment

  13. Morphological Alterations in Gastrocnemius and Soleus Muscles in Male and Female Mice in a Fibromyalgia Model

    PubMed Central

    Oezel, Lisa; Schwarzbach, Hans; Ocker, Matthias; Thieme, Kati; Di Fazio, Pietro; Kinscherf, Ralf

    2016-01-01

    Background Fibromyalgia (FM) is a chronic musculoskeletal pain disorder, characterized by chronic widespread pain and bodily tenderness and is often accompanied by affective disturbances, however often with unknown etiology. According to recent reports, physical and psychological stress trigger FM. To develop new treatments for FM, experimental animal models for FM are needed to be development and characterized. Using a mouse model for FM including intermittent cold stress (ICS), we hypothesized that ICS leads to morphological alterations in skeletal muscles in mice. Methods Male and female ICS mice were kept under alternating temperature (4°C/room temperature [22°C]); mice constantly kept at room temperature served as control. After scarification, gastrocnemius and soleus muscles were removed and snap-frozen in liquid nitrogen–cooled isopentane or fixed for electron microscopy. Results In gastrocnemius/soleus muscles of male ICS mice, we found a 21.6% and 33.2% decrease of fiber cross sectional area (FCSA), which in soleus muscle concerns the loss of type IIa and IIx FCSA. This phenomenon was not seen in muscles of female ICS mice. However, this loss in male ICS mice was associated with an increase in gastrocnemius of the density of MIF+ (8.6%)-, MuRF+ (14.7%)-, Fbxo32+ (17.8%)-cells, a 12.1% loss of capillary contacts/muscle fiber as well as a 30.7% increase of damaged mitochondria in comparison with male control mice. Moreover, significant positive correlations exist among densities (n/mm2) of MIF+, MuRF+, Fbxo32+-cells in gastrocnemius/ soleus muscles of male ICS mice; these cell densities inversely correlate with FCSA especially in gastrocnemius muscle of male ICS mice. Conclusion The ICS-induced decrease of FCSA mainly concerns gastrocnemius muscle of male mice due to an increase of inflammatory and atrogenic cells. In soleus muscle of male ICS and soleus/gastrocnemius muscles of female ICS mice morphological alterations seem to occur not at all or

  14. Ad Hoc Modeling of Root Zone Soil Water with Landsat Imagery and Terrain and Soils Data

    PubMed Central

    Sankey, Joel B.; Lawrence, Rick L.; Wraith, Jon M.

    2008-01-01

    Agricultural producers require knowledge of soil water at plant rooting depths, while many remote sensing studies have focused on surface soil water or mechanistic models that are not easily parameterized. We developed site-specific empirical models to predict spring soil water content for two Montana ranches. Calibration data sample sizes were based on the estimated variability of soil water and the desired level of precision for the soil water estimates. Models used Landsat imagery, a digital elevation model, and a soil survey as predictor variables. Our objectives were to see whether soil water could be predicted accurately with easily obtainable calibration data and predictor variables and to consider the relative influence of the three sources of predictor variables. Independent validation showed that multiple regression models predicted soil water with average error (RMSD) within 0.04 mass water content. This was similar to the accuracy expected based on a statistical power test based on our sample size (n = 41 and n = 50). Improved prediction precision could be achieved with additional calibration samples, and range managers can readily balance the desired level of precision with the amount of effort to collect calibration data. Spring soil water prediction effectively utilized a combination of land surface imagery, terrain data, and subsurface soil characterization data. Ranchers could use accurate spring soil water content predictions to set stocking rates. Such management can help ensure that water, soil, and vegetation resources are used conservatively in irrigated and non-irrigated rangeland systems.

  15. Extreme rainfall in South East France: added value of a convection-permitting regional climate model

    NASA Astrophysics Data System (ADS)

    Alias, Antoinette; Déqué, Michel; Somot, Samuel

    2016-04-01

    EURO-CORDEX simulations are based on 12 km numerical model. They represent with some accuracy, compared to global coupled models used in CMIP, the surface elevation in mountainous regions. As a consequence, the geographical distribution of precipitation is better at regional scale, and the frequency of high precipitation is more realistic. However these models do not explicitly resolve the convective phenomena which are responsible for the heavy accumulated rainfall. Arome model is derived from Aladin model (used in EURO-CORDEX) but uses non-hydrostatic equations, 2.5 km horizontal resolution, and a dedicated set of physical parameterizations. Its domain covers South-East France, a region which undergoes severe rainfall events in autumn. We present ERA-interim driven simulations with Aladin (12 km) driving Arome (2.5 km). The analysis is focussed on daily and hourly precipitation in extended autumn (ASOND) in the central part of the domain. We compare Aladin (i.e. EURO-CORDEX) and Arome simulations in their ability to simulate observed data.

  16. Prednison provokes serum and vasoactive substances in a mice model of immune thrombocytopenia

    PubMed Central

    Zhang, Ling; Chen, Ke; Li, Tiantian; He, Hao; Hou, Li; Wu, Xiaoyong; Sun, Yanping; Zheng, Lei; Chen, Zhixiong; Qin, Bei; Chen, Xinyi; Tian, Shaodan

    2016-01-01

    Objective(s): The main objective of this study was to investigate the variations of β-endorphin (β-EP), vasoactive intestinal peptide (VIP), serotonin (5-HT) and norepinephrine (NE) of immune thrombocytopenia (ITP) mice as well as the regulatory mechanism of prednison. Materials and Methods: Sixty BALB/c mice were randomly divided into control group, model group and prednison intervention group. ITP mice model was duplicated by injecting with glycoprotein-antiplatelet serum (GP-APS) except in control group. After ITP disease model was successful established, prednison was used in prednison intervention group. The β-EP, VIP, 5-HT and NE contents of ITP mice were detected by enzyme linked immunosorbent assay (ELISA). Results: Compared with the values in control group, the detection values of VIP and 5-HT in model group declined, while the detection values of β-EP and NE increased. Compared with prednison intervention group, the detection values of VIP and 5-HT in model group increased, while the detection values of β-EP and NE showed no significant change. Conclusion: In this study, the β-EP, VIP, 5-HT and NE contents in ITP mice injected with GP-APS were changed by prednison. It shows that prednison as the first-line therapy for ITP with effective hemostasis function is likely to increasing the contents of VIP and 5-HT. These results suggest the therapeutic value of prednison for the treatment of ITP. PMID:27803789

  17. Motivational disturbances and effects of L-dopa administration in neurofibromatosis-1 model mice.

    PubMed

    Wozniak, David F; Diggs-Andrews, Kelly A; Conyers, Sara; Yuede, Carla M; Dearborn, Joshua T; Brown, Jacquelyn A; Tokuda, Kazuhiro; Izumi, Yukitoshi; Zorumski, Charles F; Gutmann, David H

    2013-01-01

    Children with neurofibromatosis type 1 (NF1) frequently have cognitive and behavioral deficits. Some of these deficits have been successfully modeled in Nf1 genetically-engineered mice that develop optic gliomas (Nf1 OPG mice). In the current study, we show that abnormal motivational influences affect the behavior of Nf1 OPG mice, particularly with regard to their response to novel environmental stimuli. For example, Nf1 OPG mice made fewer spontaneous alternations in a Y-maze and fewer arm entries relative to WT controls. However, analysis of normalized alternation data demonstrated that these differences were not due to a spatial working memory deficit. Other reported behavioral results (e.g., open-field test, below) suggest that differential responses to novelty and/or other motivational influences may be more important determinants of these kinds of behavior than simple differences in locomotor activity/spontaneous movements. Importantly, normal long-term depression was observed in hippocampal slices from Nf1 OPG mice. Results from elevated plus maze testing showed that differences in exploratory activity between Nf1 OPG and WT control mice may be dependent on the environmental context (e.g., threatening or non-threatening) under which exploration is being measured. Nf1 OPG mice also exhibited decreased exploratory hole poking in a novel holeboard and showed abnormal olfactory preferences, although L-dopa (50 mg/kg) administration resolved the abnormal olfactory preference behaviors. Nf1 OPG mice displayed an attenuated response to a novel open field in terms of decreased ambulatory activity and rearing but only during the first 10 min of the session. Importantly, Nf1 OPG mice demonstrated investigative rearing deficits with regard to a novel hanging object suspended on one side of the field which were not rescued by L-dopa administration. Collectively, our results provide new data important for evaluating therapeutic treatments aimed at ameliorating NF1

  18. Adding Value through Program Integration: A Kayaking Model (Rental, Retail, Repair, Clinics and Outings).

    ERIC Educational Resources Information Center

    Poff, Raymond

    Outdoor programs can offset initial investment costs in services and products by developing integrated program areas. The experience of Outdoors Unlimited, a recently created kayaking program at Brigham Young University (Utah), is provided as a model. The purchase of 11 kayaks for rental was followed by the introduction of retail sales, repair…

  19. Energy and time modelling of kerbside waste collection: Changes incurred when adding source separated food waste.

    PubMed

    Edwards, Joel; Othman, Maazuza; Burn, Stewart; Crossin, Enda

    2016-10-01

    The collection of source separated kerbside municipal FW (SSFW) is being incentivised in Australia, however such a collection is likely to increase the fuel and time a collection truck fleet requires. Therefore, waste managers need to determine whether the incentives outweigh the cost. With literature scarcely describing the magnitude of increase, and local parameters playing a crucial role in accurately modelling kerbside collection; this paper develops a new general mathematical model that predicts the energy and time requirements of a collection regime whilst incorporating the unique variables of different jurisdictions. The model, Municipal solid waste collect (MSW-Collect), is validated and shown to be more accurate at predicting fuel consumption and trucks required than other common collection models. When predicting changes incurred for five different SSFW collection scenarios, results show that SSFW scenarios require an increase in fuel ranging from 1.38% to 57.59%. There is also a need for additional trucks across most SSFW scenarios tested. All SSFW scenarios are ranked and analysed in regards to fuel consumption; sensitivity analysis is conducted to test key assumptions. PMID:27396681

  20. Assessing the Dynamics of Nuclear Glucocorticoid-Receptor Complex: Adding Flexibility to Gene Expression Modeling1

    PubMed Central

    Hazra, Anasuya; DuBois, Debra C.; Almon, Richard R.; Jusko, William J.

    2014-01-01

    A retrospective analysis was performed to modify our fourth-generation pharmacodynamic model for glucocorticoid receptor (GR) dynamics with incorporation of more physiological features. This modified model was developed by integrating previously reported free cytosolic GR and GR mRNA data following single (10, 50 mg/kg) and dual (50 mg/kg at 0 and 24 hr) intravenous doses of methylprednisolone (MPL) in adrenalectomized (ADX) male Wistar rats with several in vitro studies describing real-time kinetics of the transfer of rat steroid-receptor complex from the cell cytosol to the nucleus. Additionally, free hepatic cytosolic GR and its mRNA data from a chronic infusion dosing study of MPL (0.1 and 0.3 mg/kg/hr) in male ADX Wistar rats were used to verify the predictability of the model. Incorporation of information regarding in vitro receptor kinetics allowed us to describe the receptor-mediated pharmacogenomic effects of MPL for a larger variety of genes in rat liver from microarray studies. These included early responsive gene like CCAAT/enhancer binding protein-β (CEBP-β), a transcription factor, as well as the later responsive gene for tyrosine aminotransferase (TAT), a classical biomarker of glucocorticoid (GC) genomic effects. This more mechanistic model of GR dynamics can be applied to characterize profiles for a greater number of genes in liver. PMID:17285360

  1. Deterministic Three-Half-Order Kinetic Model for Microbial Degradation of Added Carbon Substrates in Soil

    PubMed Central

    Brunner, Walter; Focht, Dennis D.

    1984-01-01

    The kinetics of mineralization of carbonaceous substrates has been explained by a deterministic model which is applicable to either growth or nongrowth conditions in soil. The mixed-order nature of the model does not require a priori decisions about reaction order, discontinuity period of lag or stationary phase, or correction for endogenous mineralization rates. The integrated equation is simpler than the integrated form of the Monod equation because of the following: (i) only two, rather than four, interdependent constants have to be determined by nonlinear regression analysis, (ii) substrate or product formation can be expressed explicitly as a function of time, (iii) biomass concentration does not have to be known, and (iv) the required initial estimate for the nonlinear regression analysis can be easily obtained from a linearized form rather than from an interval estimate of a differential equation. 14CO2 evolution data from soil have been fitted to the model equation. All data except those from irradiated soil gave better fits by residual sum of squares (RSS) by assuming growth in soil was linear (RSS = 0.71) as opposed to exponential (RSS = 2.87). The underlying reasons for growth (exponential versus linear), no growth, and relative degradation rates of substrates are consistent with the basic mechanisms from which the model is derived. PMID:16346454

  2. Mellin transforming the minimal model CFTs: AdS/CFT at strong curvature

    NASA Astrophysics Data System (ADS)

    Lowe, David A.

    2016-09-01

    Mack has conjectured that all conformal field theories are equivalent to string theories. We explore the example of the two-dimensional minimal model CFTs and confirm that the Mellin transformed amplitudes have the desired properties of string theory in three-dimensional anti-de Sitter spacetime.

  3. Energy and time modelling of kerbside waste collection: Changes incurred when adding source separated food waste.

    PubMed

    Edwards, Joel; Othman, Maazuza; Burn, Stewart; Crossin, Enda

    2016-10-01

    The collection of source separated kerbside municipal FW (SSFW) is being incentivised in Australia, however such a collection is likely to increase the fuel and time a collection truck fleet requires. Therefore, waste managers need to determine whether the incentives outweigh the cost. With literature scarcely describing the magnitude of increase, and local parameters playing a crucial role in accurately modelling kerbside collection; this paper develops a new general mathematical model that predicts the energy and time requirements of a collection regime whilst incorporating the unique variables of different jurisdictions. The model, Municipal solid waste collect (MSW-Collect), is validated and shown to be more accurate at predicting fuel consumption and trucks required than other common collection models. When predicting changes incurred for five different SSFW collection scenarios, results show that SSFW scenarios require an increase in fuel ranging from 1.38% to 57.59%. There is also a need for additional trucks across most SSFW scenarios tested. All SSFW scenarios are ranked and analysed in regards to fuel consumption; sensitivity analysis is conducted to test key assumptions.

  4. A probabilistic dynamic energy model for ad-hoc wireless sensors network with varying topology

    NASA Astrophysics Data System (ADS)

    Al-Husseini, Amal

    In this dissertation we investigate the behavior of Wireless Sensor Networks (WSNs) from the degree distribution and evolution perspective. In specific, we focus on implementation of a scale-free degree distribution topology for energy efficient WSNs. WSNs is an emerging technology that finds its applications in different areas such as environment monitoring, agricultural crop monitoring, forest fire monitoring, and hazardous chemical monitoring in war zones. This technology allows us to collect data without human presence or intervention. Energy conservation/efficiency is one of the major issues in prolonging the active life WSNs. Recently, many energy aware and fault tolerant topology control algorithms have been presented, but there is dearth of research focused on energy conservation/efficiency of WSNs. Therefore, we study energy efficiency and fault-tolerance in WSNs from the degree distribution and evolution perspective. Self-organization observed in natural and biological systems has been directly linked to their degree distribution. It is widely known that scale-free distribution bestows robustness, fault-tolerance, and access efficiency to system. Fascinated by these properties, we propose two complex network theoretic self-organizing models for adaptive WSNs. In particular, we focus on adopting the Barabasi and Albert scale-free model to fit into the constraints and limitations of WSNs. We developed simulation models to conduct numerical experiments and network analysis. The main objective of studying these models is to find ways to reducing energy usage of each node and balancing the overall network energy disrupted by faulty communication among nodes. The first model constructs the wireless sensor network relative to the degree (connectivity) and remaining energy of every individual node. We observed that it results in a scale-free network structure which has good fault tolerance properties in face of random node failures. The second model considers

  5. Vitamin E and diabetic nephropathy in mice model and humans.

    PubMed

    Farid, Nakhoul; Inbal, Dahan; Nakhoul, Nakhoul; Evgeny, Farber; Miller-Lotan, Rachel; Levy, Andrew P; Rabea, Asleh

    2013-11-01

    Diabetes mellitus (DM) is associated with increased oxidative stress due to elevated glucose levels in the plasma. Glucose promotes glycosylation of both plasma and cellular proteins with increased risk for vascular events. Diabetic patients suffer from a higher incidence of cardiovascular complications such as diabetic nephropathy. Haptoglobin (Hp) is an antioxidant plasma protein which binds free hemoglobin, thus preventing heme-iron mediated oxidation. Two alleles exist at the Hp gene locus (1 and 2) encoding three possible Hp genotypes that differ in their antioxidant ability, and may respond differently to vitamin E treatment. Several clinical studies to have shown that Hp 1-1 genotype is a superior antioxidant to the Hp 2-2 genotype and Hp 2-2 genotype is associated with a higher incidence of cardiovascular disease. Vitamin E was found to have beneficial effect in patient and mice with Hp 2-2 genotype. In this review we have summarized the results of our studies in patients with diabetic nephropathy treated with vitamin E and in diabetic mice with different haptoglobin genotypes. PMID:24255894

  6. Adding geochemical and isotope tracers to models of hillslope evolution: valuable constraints or monumental headache?

    NASA Astrophysics Data System (ADS)

    Mudd, S. M.; Yoo, K.; Hurst, M. D.; Weinman, B. A.; Maher, K.

    2011-12-01

    Landscapes evolve through time, both in terms of their geomorphology and their geochemistry. Past studies have highlighted that topography suffers from the problem of equifinality: the topographic configuration of landscapes can be the result of many different, yet equally plausible, erosion histories. In hillslope soils the properties and chemistry of the soils themselves could provide additional constraints on landscape evolution. Here we present results from a combination of modelling and field studies that seek to quantify the co-evolution of hillslope morphology and the solid state chemistry of hillslope soils. The models follow large numbers of individual particles as they are entrained into a physically mobile soil layer, weathered, and accumulate isotopes such as 10Be and 21Ne. We demonstrate that multiple hillslope properties mitigate (but do not eliminate) the problem of equifinality and demonstrate the importance of accounting for individual particle residence times and ages in interpretation of both isotope and weathering data.

  7. Situated learning theory: adding rate and complexity effects via Kauffman's NK model.

    PubMed

    Yuan, Yu; McKelvey, Bill

    2004-01-01

    For many firms, producing information, knowledge, and enhancing learning capability have become the primary basis of competitive advantage. A review of organizational learning theory identifies two approaches: (1) those that treat symbolic information processing as fundamental to learning, and (2) those that view the situated nature of cognition as fundamental. After noting that the former is inadequate because it focuses primarily on behavioral and cognitive aspects of individual learning, this paper argues the importance of studying learning as interactions among people in the context of their environment. It contributes to organizational learning in three ways. First, it argues that situated learning theory is to be preferred over traditional behavioral and cognitive learning theories, because it treats organizations as complex adaptive systems rather than mere information processors. Second, it adds rate and nonlinear learning effects. Third, following model-centered epistemology, it uses an agent-based computational model, in particular a "humanized" version of Kauffman's NK model, to study the situated nature of learning. Using simulation results, we test eight hypotheses extending situated learning theory in new directions. The paper ends with a discussion of possible extensions of the current study to better address key issues in situated learning.

  8. Ad HOC Model Generation Using Multiscale LIDAR Data from a Geospatial Database

    NASA Astrophysics Data System (ADS)

    Gordon, M.; Borgmann, B.; Gehrung, J.; Hebel, M.; Arens, M.

    2015-08-01

    Due to the spread of economically priced laser scanning technology nowadays, especially in the field of topographic surveying and mapping, ever-growing amounts of data need to be handled. Depending on the requirements of the specific application, airborne, mobile or terrestrial laser scanners are commonly used. Since visualizing this flood of data is not feasible with classical approaches like raw point cloud rendering, real time decision making requires sophisticated solutions. In addition, the efficient storage and recovery of 3D measurements is a challenging task. Therefore we propose an approach for the intelligent storage of 3D point clouds using a spatial database. For a given region of interest, the database is queried for the data available. All resulting point clouds are fused in a model generation process, utilizing the fact that low density airborne measurements could be used to supplement higher density mobile or terrestrial laser scans. The octree based modeling approach divides and subdivides the world into cells of varying size and fits one plane per cell, once a specified amount of points is present. The resulting model exceeds the completeness and precision of every single data source and enables for real time visualization. This is especially supported by data compression ratios of about 90%.

  9. Dietary DHA supplementation causes selective changes in phospholipids from different brain regions in both wild type mice and the Tg2576 mouse model of Alzheimer's disease.

    PubMed

    Bascoul-Colombo, Cécile; Guschina, Irina A; Maskrey, Benjamin H; Good, Mark; O'Donnell, Valerie B; Harwood, John L

    2016-06-01

    Alzheimer's disease (AD) is of major concern in ageing populations and we have used the Tg2576 mouse model to understand connections between brain lipids and amyloid pathology. Because dietary docosahexaenoic acid (DHA) has been identified as beneficial, we compared mice fed with a DHA-supplemented diet to those on a nutritionally-sufficient diet. Major phospholipids from cortex, hippocampus and cerebellum were separated and analysed. Each phosphoglyceride had a characteristic fatty acid composition which was similar in cortex and hippocampus but different in the cerebellum. The biggest changes on DHA-supplementation were within ethanolamine phospholipids which, together with phosphatidylserine, had the highest proportions of DHA. Reciprocal alterations in DHA and arachidonate were found. The main diet-induced alterations were found in ethanolamine phospholipids, (and included their ether derivatives), as were the changes observed due to genotype. Tg mice appeared more sensitive to diet with generally lower DHA percentages when on the standard diet and higher relative proportions of DHA when the diet was supplemented. All four major phosphoglycerides analysed showed age-dependent decreases in polyunsaturated fatty acid contents. These data provide, for the first time, a detailed evaluation of phospholipids in different brain areas previously shown to be relevant to behaviour in the Tg2576 mouse model for AD. The lipid changes observed with genotype are consistent with the subtle alterations found in AD patients, especially for the ethanolamine phospholipid molecular species. They also emphasise the contrasting changes in fatty acid content induced by DHA supplementation within individual phospholipid classes.

  10. A novel model of rheumatoid arthritis-associated interstitial lung disease in SKG mice.

    PubMed

    Keith, Rebecca C; Powers, Jennifer L; Redente, Elizabeth F; Sergew, Amen; Martin, Richard J; Gizinski, Alison; Holers, V Michael; Sakaguchi, Shimon; Riches, David W H

    2012-03-01

    Rheumatoid arthritis-associated interstitial lung disease (RA-ILD) is associated with increased mortality in up to 10% of patients with rheumatoid arthritis. Lung exposure to cigarette smoke has been implicated in disease development. Little is known about the mechanisms underlying the development of RA-ILD, in part due to the lack of an appropriate mouse model. The objectives of this study were (i) to test the suitability of SKG mice as a model of cellular and fibrotic interstitial pneumonia in the setting of autoimmune arthritis, and (ii) to determine the role of lung injury in the development of arthritis in SKG mice. Lung tissues were evaluated in arthritic SKG mice by quantifying cell accumulation in bronchoalveolar lavage, static compliance, collagen levels, and infiltrating cell phenotypes by flow cytometry and histology. Lung injury was induced by exposure to cigarette smoke or bleomycin. Arthritic SKG mice developed a patchy cellular and fibrotic interstitial pneumonia associated with reduced static compliance, increased collagen levels, and accumulation of inflammatory cells. Infiltrating cells comprised CD4+ T cells, B cells, macrophages, and neutrophils. Chronic exposure to cigarette smoke or initiation of lung injury with bleomycin did not cause arthritis. The pattern of lung disease suggests that arthritic SKG mice represent an authentic model of nonspecific interstitial pneumonia in RA-ILD patients. The lack of arthritis development after cigarette smoke or lung injury suggests that a model where breaches in immunologic tolerance are induced by lung inflammation and injury alone may be overly simplistic.

  11. Assessment of Behaviors Modeling Aspects of Schizophrenia in Csmd1 Mutant Mice

    PubMed Central

    Distler, Margaret G.; Opal, Mark D.; Dulawa, Stephanie C.; Palmer, Abraham A.

    2012-01-01

    Schizophrenia is a debilitating psychotic disorder that affects up to 1.5% of the population worldwide. Two recent studies in humans identified genome-wide significant associations between schizophrenia and single-nucleotide polymorphisms (SNPs) in an intron of CSMD1. The effect of deleting CSMD1 on mouse behavior is unknown. The present study utilized mice with a mutant Csmd1 allele in which the first exon had been ablated (KO mice). All Csmd1 transcripts that included the first exon were absent in the brains of KO mice, but there was persistent expression of at least one other transcript that does not include the first exon. Wild type (WT), heterozygous (HET), and KO mice were assessed using several well-established behavioral paradigms that model aspects of schizophrenia. Csmd1 KO mice did not differ from wild-type littermates for sensorimotor gating (measured as prepulse inhibition), social interaction, anhedonia (measured by sucrose preference), or sensitivity to the locomotor stimulant effects of the dopaminergic agent d-amphetamine. These data demonstrate that loss of Csmd1 transcripts that include the first exon does not alter multiple well-established behaviors that model aspects of schizophrenia. The SNP most strongly associated with schizophrenia in humans is between exons 3 and 4; therefore, ablation of exon 1 appeared to be a logical animal model. Nevertheless, future studies should consider alternative mouse models including gain-of-function mutations, and loss-of-function mutations that target alternative transcripts of Csmd1. PMID:23284669

  12. Thermodynamics and jet-quenching in the quark-gluon plasma from an AdS/QCD model

    NASA Astrophysics Data System (ADS)

    Lilleskov, Elias; Bartz, Sean

    2015-10-01

    The Anti-de Sitter Space/Conformal Field Theory Correspondence (AdS/CFT) has been used to study both hadronic dynamics and the thermodynamics and jet quenching behavior of the quark-gluon plasma created in heavy ion collisions. We attempt to connect the two regimes by adapting an AdS/QCD model previously used to study meson spectra to apply to the quark-gluon plasma. The model includes three fields: a dilaton to introduce confinement, and chiral and glueball condensates to reflect the zero-temperature dynamics. We dynamically solve the Einstein field equations to numerically determine the metric, which asymptotically describes an anti-de Sitter-Schwarzschild black hole solution. We then numerically calculate the temperature as a function of the black hole horizon location. Next, we determine the behavior of the entropy density, the speed of sound, and the jet quenching parameter as functions of the temperature. These quantities approach the behavior of a conformal plasma in the high temperature limit. The minimum of the temperature-horizon plot is interpreted as the plasma's deconfinement temperature, found to be 104 MeV.

  13. Design of Value-Added Models for IMPACT and TEAM in DC Public Schools, 2010-2011 School Year. Final Report

    ERIC Educational Resources Information Center

    Isenberg, Eric; Hock, Heinrich

    2011-01-01

    This report presents the value-added models that will be used to measure school and teacher effectiveness in the District of Columbia Public Schools (DCPS) in the 2010-2011 school year. It updates the earlier technical report, "Measuring Value Added for IMPACT and TEAM in DC Public Schools." The earlier report described the methods used…

  14. Does Student Sorting Invalidate Value-Added Models of Teacher Effectiveness? An Extended Analysis of the Rothstein Critique. Working Paper 2009-01

    ERIC Educational Resources Information Center

    Koedel, Cory; Betts, Julian R.

    2009-01-01

    Value-added modeling continues to gain traction as a tool for measuring teacher performance. However, recent research (Rothstein, 2009a, 2009b) questions the validity of the value-added approach by showing that it does not mitigate student teacher sorting bias (its presumed primary benefit). Our study explores this critique in more detail.…

  15. Adding Biotic Interactions into Paleodistribution Models: A Host-Cleptoparasite Complex of Neotropical Orchid Bees

    PubMed Central

    Silva, Daniel Paiva; Varela, Sara; Nemésio, André; De Marco, Paulo

    2015-01-01

    Orchid bees compose an exclusive Neotropical pollinators group, with bright body coloration. Several of those species build their own nests, while others are reported as nest cleptoparasites. Here, the objective was to evaluate whether the inclusion of a strong biotic interaction, such as the presence of a host species, improved the ability of species distribution models (SDMs) to predict the geographic range of the cleptoparasite species. The target species were Aglae caerulea and its host species Eulaema nigrita. Additionally, since A. caerulea is more frequently found in the Amazon rather than the Cerrado areas, a secondary objective was to evaluate whether this species is increasing or decreasing its distribution given South American past and current climatic conditions. SDMs methods (Maxent and Bioclim), in addition with current and past South American climatic conditions, as well as the occurrences for A. caerulea and E. nigrita were used to generate the distribution models. The distribution of A. caerulea was generated with and without the inclusion of the distribution of E. nigrita as a predictor variable. The results indicate A. caerulea was barely affected by past climatic conditions and the populations from the Cerrado savanna could be at least 21,000 years old (the last glacial maximum), as well as the Amazonian ones. On the other hand, in this study, the inclusion of the host-cleptoparasite interaction complex did not statistically improve the quality of the produced models, which means that the geographic range of this cleptoparasite species is mainly constrained by climate and not by the presence of the host species. Nonetheless, this could also be caused by unknown complexes of other Euglossini hosts with A. caerulea, which still are still needed to be described by science. PMID:26069956

  16. Adding Biotic Interactions into Paleodistribution Models: A Host-Cleptoparasite Complex of Neotropical Orchid Bees.

    PubMed

    Silva, Daniel Paiva; Varela, Sara; Nemésio, André; De Marco, Paulo

    2015-01-01

    Orchid bees compose an exclusive Neotropical pollinators group, with bright body coloration. Several of those species build their own nests, while others are reported as nest cleptoparasites. Here, the objective was to evaluate whether the inclusion of a strong biotic interaction, such as the presence of a host species, improved the ability of species distribution models (SDMs) to predict the geographic range of the cleptoparasite species. The target species were Aglae caerulea and its host species Eulaema nigrita. Additionally, since A. caerulea is more frequently found in the Amazon rather than the Cerrado areas, a secondary objective was to evaluate whether this species is increasing or decreasing its distribution given South American past and current climatic conditions. SDMs methods (Maxent and Bioclim), in addition with current and past South American climatic conditions, as well as the occurrences for A. caerulea and E. nigrita were used to generate the distribution models. The distribution of A. caerulea was generated with and without the inclusion of the distribution of E. nigrita as a predictor variable. The results indicate A. caerulea was barely affected by past climatic conditions and the populations from the Cerrado savanna could be at least 21,000 years old (the last glacial maximum), as well as the Amazonian ones. On the other hand, in this study, the inclusion of the host-cleptoparasite interaction complex did not statistically improve the quality of the produced models, which means that the geographic range of this cleptoparasite species is mainly constrained by climate and not by the presence of the host species. Nonetheless, this could also be caused by unknown complexes of other Euglossini hosts with A. caerulea, which still are still needed to be described by science. PMID:26069956

  17. Adding ecology to particle capture models: numerical simulations of capture on a moving cylinder in crossflow.

    PubMed

    Krick, Julian; Ackerman, Josef Daniel

    2015-03-01

    The particle capture efficiency, η, of systems that remove suspended particles from ambient flow (e.g. suspension feeding, abiotic pollination) has been studied using static collectors in steady flows. Particle deposition on collectors moving due to fluid flow remains largely unknown, despite its ecological relevance. We used numerical modeling to simulate particle deposition on a 2D circular cylinder subject to flow-induced oscillation in a cross flow. Using parameter values relevant to wind pollination and other natural biological systems, we examined the influence of the direction, amplitude and frequency of the oscillation, the Stokes number (Stk=0.01-5, characterizing particle behavior), as well as the Reynolds number (Re=662 and 3309, characterizing flow regime) in steady and unsteady flow, on η. The numerical model was validated with empirical results for parts of the parameter space. Particle capture occurred via "inertial impaction", "direct interception" and "leeward deposition", as well as via a new mechanism, "collector chasing" for moving collectors. The η of an oscillating cylinder varied significantly relative to a static cylinder, depending on the parameters used, and on the magnitude of a numerical error that caused loss of particles. This variance of η was due to a change in relative momentum between the particle and the moving collector, which depends on Re, Stk and the oscillation parameters. Collector oscillation transverse to oncoming flow direction strongly increased η, whereas collector motion parallel to flow had little effect on capture efficiency. The oscillation also changed leeward capture significantly in some cases. For most conditions, however, leeward deposition was small. Results suggest that collector motion could have significant influence on the particle capture efficiency of natural systems, which indicates the need to incorporate these ecologically more relevant findings into current models. Empirical studies, however

  18. Adding ecology to particle capture models: numerical simulations of capture on a moving cylinder in crossflow.

    PubMed

    Krick, Julian; Ackerman, Josef Daniel

    2015-03-01

    The particle capture efficiency, η, of systems that remove suspended particles from ambient flow (e.g. suspension feeding, abiotic pollination) has been studied using static collectors in steady flows. Particle deposition on collectors moving due to fluid flow remains largely unknown, despite its ecological relevance. We used numerical modeling to simulate particle deposition on a 2D circular cylinder subject to flow-induced oscillation in a cross flow. Using parameter values relevant to wind pollination and other natural biological systems, we examined the influence of the direction, amplitude and frequency of the oscillation, the Stokes number (Stk=0.01-5, characterizing particle behavior), as well as the Reynolds number (Re=662 and 3309, characterizing flow regime) in steady and unsteady flow, on η. The numerical model was validated with empirical results for parts of the parameter space. Particle capture occurred via "inertial impaction", "direct interception" and "leeward deposition", as well as via a new mechanism, "collector chasing" for moving collectors. The η of an oscillating cylinder varied significantly relative to a static cylinder, depending on the parameters used, and on the magnitude of a numerical error that caused loss of particles. This variance of η was due to a change in relative momentum between the particle and the moving collector, which depends on Re, Stk and the oscillation parameters. Collector oscillation transverse to oncoming flow direction strongly increased η, whereas collector motion parallel to flow had little effect on capture efficiency. The oscillation also changed leeward capture significantly in some cases. For most conditions, however, leeward deposition was small. Results suggest that collector motion could have significant influence on the particle capture efficiency of natural systems, which indicates the need to incorporate these ecologically more relevant findings into current models. Empirical studies, however

  19. Pion Form Factor in Chiral Limit of Hard-Wall AdS/QCD Model

    SciTech Connect

    Anatoly Radyushkin; Hovhannes Grigoryan

    2007-12-01

    We develop a formalism to calculate form factor and charge density distribution of pion in the chiral limit using the holographic dual model of QCD with hard-wall cutoff. We introduce two conjugate pion wave functions and present analytic expressions for these functions and for the pion form factor. They allow to relate such observables as the pion decay constant and the pion charge electric radius to the values of chiral condensate and hard-wall cutoff scale. The evolution of the pion form factor to large values of the momentum transfer is discussed, and results are compared to existing experimental data.

  20. Decentralized Opportunistic Spectrum Resources Access Model and Algorithm toward Cooperative Ad-Hoc Networks.

    PubMed

    Liu, Ming; Xu, Yang; Mohammed, Abdul-Wahid

    2016-01-01

    Limited communication resources have gradually become a critical factor toward efficiency of decentralized large scale multi-agent coordination when both system scales up and tasks become more complex. In current researches, due to the agent's limited communication and observational capability, an agent in a decentralized setting can only choose a part of channels to access, but cannot perceive or share global information. Each agent's cooperative decision is based on the partial observation of the system state, and as such, uncertainty in the communication network is unavoidable. In this situation, it is a major challenge working out cooperative decision-making under uncertainty with only a partial observation of the environment. In this paper, we propose a decentralized approach that allows agents cooperatively search and independently choose channels. The key to our design is to build an up-to-date observation for each agent's view so that a local decision model is achievable in a large scale team coordination. We simplify the Dec-POMDP model problem, and each agent can jointly work out its communication policy in order to improve its local decision utilities for the choice of communication resources. Finally, we discuss an implicate resource competition game, and show that, there exists an approximate resources access tradeoff balance between agents. Based on this discovery, the tradeoff between real-time decision-making and the efficiency of cooperation using these channels can be well improved. PMID:26727504

  1. Decentralized Opportunistic Spectrum Resources Access Model and Algorithm toward Cooperative Ad-Hoc Networks

    PubMed Central

    Liu, Ming; Xu, Yang; Mohammed, Abdul-Wahid

    2016-01-01

    Limited communication resources have gradually become a critical factor toward efficiency of decentralized large scale multi-agent coordination when both system scales up and tasks become more complex. In current researches, due to the agent’s limited communication and observational capability, an agent in a decentralized setting can only choose a part of channels to access, but cannot perceive or share global information. Each agent’s cooperative decision is based on the partial observation of the system state, and as such, uncertainty in the communication network is unavoidable. In this situation, it is a major challenge working out cooperative decision-making under uncertainty with only a partial observation of the environment. In this paper, we propose a decentralized approach that allows agents cooperatively search and independently choose channels. The key to our design is to build an up-to-date observation for each agent’s view so that a local decision model is achievable in a large scale team coordination. We simplify the Dec-POMDP model problem, and each agent can jointly work out its communication policy in order to improve its local decision utilities for the choice of communication resources. Finally, we discuss an implicate resource competition game, and show that, there exists an approximate resources access tradeoff balance between agents. Based on this discovery, the tradeoff between real-time decision-making and the efficiency of cooperation using these channels can be well improved. PMID:26727504

  2. M2M modelling of the Galactic disc via PRIMAL: fitting to Gaia error added data

    NASA Astrophysics Data System (ADS)

    Hunt, Jason A. S.; Kawata, Daisuke

    2014-09-01

    We have adapted our made-to-measure (M2M) algorithm PRIMAL to use mock Milky Way like data constructed from an N-body barred galaxy with a boxy bulge in a known dark matter potential. We use M0 giant stars as tracers, with the expected error of the ESA (European Space Agency) space astrometry mission Gaia. We demonstrate the process of constructing mock Gaia data from an N-body model, including the conversion of a galactocentric Cartesian coordinate N-body model into equatorial coordinates and how to add error to it for a single stellar type. We then describe the modifications made to PRIMAL to work with observational error. This paper demonstrates that PRIMAL can recover the radial profiles of the surface density, radial velocity dispersion, vertical velocity dispersion and mean rotational velocity of the target disc, along with the pattern speed of the bar, to a reasonable degree of accuracy despite the lack of accurate target data. We also construct mock data which take into account dust extinction and show that PRIMAL recovers the structure and kinematics of the disc reasonably well. In other words, the expected accuracy of the Gaia data is good enough for PRIMAL to recover these global properties of the disc, at least in a simplified condition, as used in this paper.

  3. Decentralized Opportunistic Spectrum Resources Access Model and Algorithm toward Cooperative Ad-Hoc Networks.

    PubMed

    Liu, Ming; Xu, Yang; Mohammed, Abdul-Wahid

    2016-01-01

    Limited communication resources have gradually become a critical factor toward efficiency of decentralized large scale multi-agent coordination when both system scales up and tasks become more complex. In current researches, due to the agent's limited communication and observational capability, an agent in a decentralized setting can only choose a part of channels to access, but cannot perceive or share global information. Each agent's cooperative decision is based on the partial observation of the system state, and as such, uncertainty in the communication network is unavoidable. In this situation, it is a major challenge working out cooperative decision-making under uncertainty with only a partial observation of the environment. In this paper, we propose a decentralized approach that allows agents cooperatively search and independently choose channels. The key to our design is to build an up-to-date observation for each agent's view so that a local decision model is achievable in a large scale team coordination. We simplify the Dec-POMDP model problem, and each agent can jointly work out its communication policy in order to improve its local decision utilities for the choice of communication resources. Finally, we discuss an implicate resource competition game, and show that, there exists an approximate resources access tradeoff balance between agents. Based on this discovery, the tradeoff between real-time decision-making and the efficiency of cooperation using these channels can be well improved.

  4. n-3 PUFA added to high-fat diets affect differently adiposity and inflammation when carried by phospholipids or triacylglycerols in mice

    PubMed Central

    2013-01-01

    Background Dietary intake of n-3 polyunsaturated fatty acids (PUFA) is primarily recognized to protect against cardiovascular diseases, cognitive dysfunctions and the onset of obesity and associated metabolic disorders. However, some of their properties such as bioavailability can depend on their chemical carriers. The objective of our study was to test the hypothesis that the nature of n-3 PUFA carrier results in different metabolic effects related to adiposity, oxidative stress and inflammation. Methods 4 groups of C57BL/6 mice were fed for 8 weeks low fat (LF) diet or high-fat (HF, 20%) diets. Two groups of high-fat diets were supplemented with long-chain n-3 PUFA either incorporated in the form of phospholipids (HF-ω3PL) or triacylglycerols (HF-ω3TG). Results Both HF-ω3PL and HF-ω3TG diets reduced the plasma concentrations of (i) inflammatory markers such as monocyte chemoattractant protein-1 (MCP-1) and interleukin 6 (IL-6), (ii) leptin and (iii) 4-hydroxy-2-nonenal (4-HNE), a marker of n-6 PUFA-derived oxidative stress compared with the control HF diet. Moreover, in both HF-ω3PL and HF-ω3TG groups, MCP-1 and IL-6 gene expressions were decreased in epididymal adipose tissue and the mRNA level of gastrointestinal glutathione peroxidase GPx2, an antioxidant enzyme, was decreased in the jejunum compared with the control HF diet. The type of n-3 PUFA carrier affected other outcomes. The phospholipid form of n-3 PUFA increased the level of tocopherols in epididymal adipose tissue compared with HF-ω3TG and resulted in smaller adipocytes than the two others HF groups. Adipocytes in the HF-ω3PL and LF groups were similar in size distribution. Conclusion Supplementation of mice diet with long-chain n-3 PUFA during long-term consumption of high-fat diets had the same lowering effects on inflammation regardless of triacyglycerol or phospholipid carrier, whereas the location of these fatty acids on a PL carrier had a major effect on decreasing the size of

  5. An assessment of the added value from data assimilation on modelled Nordic Seas hydrography and ocean transports

    NASA Astrophysics Data System (ADS)

    Lien, Vidar S.; Hjøllo, Solfrid S.; Skogen, Morten D.; Svendsen, Einar; Wehde, Henning; Bertino, Laurent; Counillon, Francois; Chevallier, Matthieu; Garric, Gilles

    2016-03-01

    The Nordic Seas is a hotspot both in terms of climate related processes, such as Atlantic-Arctic heat exchange, and natural marine resources. A sustainable management of the marine resources within the Nordic Seas, including the co-existence between fisheries and petroleum industries, requires detailed information on the state of the ocean within an operational framework and beyond what is obtainable from observations only. Numerical ocean models applying data assimilation techniques are utilized to address this need. Subsequently, comprehensive comparisons between model results and observations are required in order to assess the model performance. Here, we apply a set of objective statistics to quantitatively assess the added value of data assimilation in numerical ocean models that are currently used operationally. The results indicate that the inclusion of data assimilation improves the model performance both in terms of hydrographic properties and volume and heat transports. Furthermore, we find that increasing the resolution towards eddy resolving resolution performs similarly to coarser resolution models applying data assimilation in shelf areas.

  6. Modeling appetitive Pavlovian-instrumental interactions in mice.

    PubMed

    O'Connor, Eoin C; Stephens, David N; Crombag, Hans S

    2010-10-01

    In appetitive Pavlovian associative learning, a stimulus (conditioned stimulus, CS) that has been associated with the delivery of a reinforcing event (unconditioned stimulus, US; e.g., food) can subsequently elicit or modulate goal-directed instrumental behaviors. For example, a Pavlovian CS can serve to reinforce (novel) instrumental behavior (conditioned reinforcement or CRf), or it can energize and potentiate ongoing instrumental responses when presented non-contingently (Pavlovian-instrumental transfer or PIT). Notably, these different effects of a Pavlovian CS on instrumental behavior are mediated by dissociable psychological and neurobiological mechanisms. Given the critical role that Pavlovian-instrumental interactions play in regulating motivated behavior and maladaptive manifestations of motivation such as eating disorders and addictions, understanding the underlying psychological and neurobiological mechanisms will be important. This unit describes behavioral protocols that produce robust and reliable PIT and CRf in mice and that open the door for future studies using transgenic approaches into the molecular mechanisms underlying associative learning and motivation.

  7. Continuous observation on heart-disease-model mice using biomagnetic measurement system

    NASA Astrophysics Data System (ADS)

    Kasai, Y.; Oikawa, T.; Saitoh, Y.; Ono, Y.; Ishiyama, A.; Kasai, N.; Odawara, A.; Chinone, K.

    2008-02-01

    Magnetocardiography (MCG) is a non-invasive method that can contribute to elucidating heart disease mechanisms and the verification of pharmacological effects. The object of our study is to show the potential of MCG for such study in mice. By using the developed MCG system, which adopts a single channel superconducting quantum interference device (SQUID) magnetometer with the spatial resolution of 500 μm, we continuously measured MCGs for 2 heart-disease-model mice with a high incidence of cardiac infarction from 7-weeks-old to death. An abnormal MCG appeared 1 or 2 weeks before death. The abnormal MCG changes indicate that the damaged place in the ventricles was different for each individual. In addition, we have developed a method to obtain MCGs for newborn mice in particular because they are small and frail. The MCGs of newborn mice were similar to those of adult mice. This study proved the potential of MCG for detecting abnormal cardiac excitation at the early stage of cardiac infarction and monitoring the progress of heart disease in detail from infancy to old age in mice.

  8. Amelioration of inflammation and tissue damage in sickle cell model mice by Nrf2 activation

    PubMed Central

    Keleku-Lukwete, Nadine; Suzuki, Mikiko; Otsuki, Akihito; Tsuchida, Kouhei; Katayama, Saori; Hayashi, Makiko; Naganuma, Eriko; Moriguchi, Takashi; Tanabe, Osamu; Engel, James Douglas; Imaizumi, Masue; Yamamoto, Masayuki

    2015-01-01

    Sickle cell disease (SCD) is an inherited disorder caused by a point mutation in the β-globin gene, leading to the production of abnormally shaped red blood cells. Sickle cells are prone to hemolysis and thereby release free heme into plasma, causing oxidative stress and inflammation that in turn result in damage to multiple organs. The transcription factor Nrf2 (nuclear factor erythroid 2-related factor 2) is a master regulator of the antioxidant cell-defense system. Here we show that constitutive Nrf2 activation by ablation of its negative regulator Keap1 (kelch-like ECH-associated protein 1) significantly improves symptoms in SCD model mice. SCD mice exhibit severe liver damage and lung inflammation associated with high expression levels of proinflammatory cytokines and adhesion molecules compared with normal mice. Importantly, these symptoms subsided after Nrf2 activation. Although hemolysis and stress erythropoiesis did not change substantially in the Nrf2-activated SCD mice, Nrf2 promoted the elimination of plasma heme released by sickle cells’ hemolysis and thereby reduced oxidative stress and inflammation, demonstrating that Nrf2 activation reduces organ damage and segregates inflammation from prevention of hemolysis in SCD mice. Furthermore, administration of the Nrf2 inducer CDDO-Im (2-cyano-3, 12 dioxooleana-1, 9 diene-28-imidazolide) also relieved inflammation and organ failure in SCD mice. These results support the contention that Nrf2 induction may be an important means to protect organs from the pathophysiology of sickle cell-induced damage. PMID:26371321

  9. Amelioration of inflammation and tissue damage in sickle cell model mice by Nrf2 activation.

    PubMed

    Keleku-Lukwete, Nadine; Suzuki, Mikiko; Otsuki, Akihito; Tsuchida, Kouhei; Katayama, Saori; Hayashi, Makiko; Naganuma, Eriko; Moriguchi, Takashi; Tanabe, Osamu; Engel, James Douglas; Imaizumi, Masue; Yamamoto, Masayuki

    2015-09-29

    Sickle cell disease (SCD) is an inherited disorder caused by a point mutation in the β-globin gene, leading to the production of abnormally shaped red blood cells. Sickle cells are prone to hemolysis and thereby release free heme into plasma, causing oxidative stress and inflammation that in turn result in damage to multiple organs. The transcription factor Nrf2 (nuclear factor erythroid 2-related factor 2) is a master regulator of the antioxidant cell-defense system. Here we show that constitutive Nrf2 activation by ablation of its negative regulator Keap1 (kelch-like ECH-associated protein 1) significantly improves symptoms in SCD model mice. SCD mice exhibit severe liver damage and lung inflammation associated with high expression levels of proinflammatory cytokines and adhesion molecules compared with normal mice. Importantly, these symptoms subsided after Nrf2 activation. Although hemolysis and stress erythropoiesis did not change substantially in the Nrf2-activated SCD mice, Nrf2 promoted the elimination of plasma heme released by sickle cells' hemolysis and thereby reduced oxidative stress and inflammation, demonstrating that Nrf2 activation reduces organ damage and segregates inflammation from prevention of hemolysis in SCD mice. Furthermore, administration of the Nrf2 inducer CDDO-Im (2-cyano-3, 12 dioxooleana-1, 9 diene-28-imidazolide) also relieved inflammation and organ failure in SCD mice. These results support the contention that Nrf2 induction may be an important means to protect organs from the pathophysiology of sickle cell-induced damage.

  10. Lethal graft-versus-host disease in nude mice. I. Establishment of model systems

    SciTech Connect

    Kuribayashi, K.; Masuda, T.; Hanaoka, M.

    1988-08-01

    We examined whether nude mice, which are deficient in T cell function, could be used as a model for induction of lethal graft-versus-host disease. Nude mice injected with MHC-disparate spleen cells exhibited only transient GVH reaction such as splenomegaly. Inoculation of B6 spleen cells into BALB/c nude mice produced high titers of alloantibodies to the donor cells. These alloantibodies eliminated host-MHC-reactive donor T cells from the host. After abolition by 400 rads irradiation of the capacity of nude mice to produce antibody, lethal GVHD could be induced by allogeneic spleen cell transfer and was mediated by donor T cells. This lethal GVHD was prevented by prior administration of antidonor alloantibody to the irradiated recipients at least 24 hr before donor-cell grafting. The role of alloantibody was substantiated in 2 other combinations in which little or no alloantibodies to donor spleen cells were produced. Engraftment of either MHC-identical but non-MHC disparate donor spleen cells into BALB/c nude mice or of parental spleen cells into F1 nude mice resulted in death mediated by T cells. In addition, irradiated BALB/c nude mice inoculated with non-MHC-incompatible B10.D2 spleen cells were much more sensitive to alloaggression by the donor cells than were nonirradiated hosts, indicating the presence of some radiation-sensitive component(s) acting in nude mice against GVHD induction by donor T cells. Thus the nude mouse is considered to be a useful recipient for clarifying the basic mechanisms involved in lethal GVHD.

  11. Mitochondrial Superoxide Contributes to Hippocampal Synaptic Dysfunction and Memory Deficits in Angelman Syndrome Model Mice

    PubMed Central

    Santini, Emanuela; Turner, Kathryn L.; Ramaraj, Akila B.; Murphy, Michael P.

    2015-01-01

    Angelman syndrome (AS) is a neurodevelopmental disorder associated with developmental delay, lack of speech, motor dysfunction, and epilepsy. In the majority of the patients, AS is caused by the deletion of small portions of maternal chromosome 15 harboring the UBE3A gene. This results in a lack of expression of the UBE3A gene because the paternal allele is genetically imprinted. The UBE3A gene encodes an enzyme termed ubiquitin ligase E3A (E6-AP) that targets proteins for degradation by the 26S proteasome. Because neurodegenerative disease and other neurodevelopmental disorders have been linked to oxidative stress, we asked whether mitochondrial reactive oxygen species (ROS) played a role in impaired synaptic plasticity and memory deficits exhibited by AS model mice. We discovered that AS mice have increased levels of superoxide in area CA1 of the hippocampus that is reduced by MitoQ 10-methanesuflonate (MitoQ), a mitochondria-specific antioxidant. In addition, we found that MitoQ rescued impairments in hippocampal synaptic plasticity and deficits in contextual fear memory exhibited by AS model mice. Our findings suggest that mitochondria-derived oxidative stress contributes to hippocampal pathophysiology in AS model mice and that targeting mitochondrial ROS pharmacologically could benefit individuals with AS. SIGNIFICANCE STATEMENT Oxidative stress has been hypothesized to contribute to the pathophysiology of neurodevelopmental disorders, including autism spectrum disorders and Angelman syndrome (AS). Herein, we report that AS model mice exhibit elevated levels of mitochondria-derived reactive oxygen species in pyramidal neurons in hippocampal area CA1. Moreover, we demonstrate that the administration of MitoQ (MitoQ 10-methanesuflonate), a mitochondria-specific antioxidant, to AS model mice normalizes synaptic plasticity and restores memory. Finally, our findings suggest that antioxidants that target the mitochondria could be used therapeutically to ameliorate

  12. Influence of the ionospheric model on DCB computation and added value of LEO satellites

    NASA Astrophysics Data System (ADS)

    Wautelet, Gilles; Lestarquit, Laurent; Loyer, Sylvain; Mercier, Flavien; Perosanz, Félix

    2016-04-01

    In order to compute inter-frequency Differential Code Biases (DCBs), the Geometry-Free combination of a GNSS signal pair needs to be corrected from the ionospheric refraction effect. Such information is obtained using either Global Ionospheric Maps (GIMs) or local models. In this work we investigate the influence of GIMs on the final value and precision of DCB solution. The study covers different ionospheric conditions, ranging from very quiet ionospheric background up to a severe ionospheric storm. In a first step, the Slant Total Electron Content (STEC) between GIMs is assessed as a function of receiver latitude, elevation mask and ionospheric conditions. Then, daily DCBs are estimated using these different GIMs, receiver and satellite contributions being separated using a zero-mean constraint. If the precision of satellite DCBs is clearly dependent on ionospheric conditions and of the observing network, the choice of the GIM seems also to have a non negligible impact. At last, an independent estimation of DCBs is performed using Low Earth Orbit (LEO) observations (such as JASON's GPS data). This solution is compared with our ground network solution and with DCBs coming from the International GNSS Service.

  13. Adding Emulsified Isoflurane to Cardioplegia Solution Produces Cardiac Protection in a Dog Cardiopulmonary Bypass Model

    PubMed Central

    Huang, Han; Zhou, Cheng; Liu, Jin; Song, Haibo; Qiu, Yan

    2016-01-01

    This study investigated whether caridoplegia solution with Emulsified Isoflurane (EI) could improve cardiaoprotection in a dog CPB model of great similarity to clinical settings. Adult dogs were randomly assigned to receive one of the following cardioplegia solutions: St. Thomas with EI (group ST+EI), St. Thomas with 30% Intralipid (group ST+EL) and St. Thomas alone (group ST). The aorta was cross-clamped for two hours followed by reperfusion for another two hours, during which cardiac output was measured and dosages of positive inotropic agent to maintain normal hemodynamics were recorded. Serum level of cardiac troponin I (cTnI) and CK-MB were measured. Deletion of cardiac mitochondrial DNA was examined at the end of reperfusion. Compared with ST, ST+EI decreased the requirement of dopamine support while animals receiving ST+EI had a significantly larger cardiac output. ST+EI reduced post-CPB release of cTnI and CK-MB. Mitochondrial DNA loss was observed in only one of the tested animals from group ST+EI while it was seen in all the tested animals from group ST+EL and ST. Addition of emulsified isoflurane into cardioplegia solution protects against myocardial ischemia reperfusion injury. This protective effect might be mediated by preserving mitochondrial ultrastructure and DNA integrity. PMID:27121996

  14. Autoimmunity to Uroplakin II Causes Cystitis in Mice: A Novel Model of Interstitial Cystitis

    PubMed Central

    Altuntas, Cengiz Z.; Daneshgari, Firouz; Sakalar, Cagri; Goksoy, Esen; Gulen, M. Fatih; Kavran, Michael; Qin, Jun; Li, Xiaoxia; Tuohy, Vincent K.

    2011-01-01

    Background The pathophysiology of interstitial cystitis (IC) is unknown. Deficits in urothelial cell layers and autoimmune mechanisms may play a role. Objective To examine whether immunization of mice with recombinant mouse uroplakin II (rmUPK2), a bladder-specific protein, would provoke an autoimmune response sufficient to create an IC phenotype. Design, setting, and participants RmUPK2 complementary DNA was generated, transferred into a bacterial expression vector, and the generated protein was purified. Eight-week-old SWXJ female mice were immunized with rmUPK2 protein via subcutaneous injection of 200 µg of rmUPK2 protein in 200 µl of an emulsion. Measurements Mice were euthanized 5 wk after immunization. Axillary and inguinal lymph node cells were tested for antigen-specific responsiveness and cytokine production, serum isotype antibody titers against rmUPK2 were determined, and gene expression of inflammatory mediators was measured in the bladder and other organs. For functional analysis, mice were placed in urodynamic chambers for 24-h micturition frequency and total voided urine measurements. Results and limitations Immunization with rmUPK2 resulted in T-cell infiltration of the bladder urothelium and increased rmUPK2-specific serum antibody responses in the experimental autoimmune cystitis (EAC) mice models compared with controls. The ratio of bladder to body weight was increased in EAC mice. Quantitative reverse transcriptase polymerase chain reaction analysis showed elevated gene expression of tumor necrosis factor α, interferon γ, interleukin (IL)-17A, and IL-1β in bladder urothelium but not in other organs. Evaluation of 24-h micturition habits of EAC mice showed significantly increased urinary frequency (p < 0.02) and significantly decreased urine output per void (p < 0.021) when compared with control mice. Conclusions Our study showed that a bladder-specific autoimmune response sufficient to induce inflammation and EAC occurs in mice following

  15. Evaluation of GCM Column Radiation Models Under Cloudy Conditions with The Arm BBHRP Value Added Product

    SciTech Connect

    Oreopoulos, Lazaros; Norris, Peter M.

    2010-03-14

    The overarching goal of the project was to improve the transfer of solar and thermal radiation in the most sophisticated computer tools that are currently available for climate studies, namely Global Climate Models (GCMs). This transfer can be conceptually separated into propagation of radiation under cloudy and under cloudless conditions. For cloudless conditions, the factors that affect radiation propagation are gaseous absorption and scattering, aerosol particle absorption and scattering and surface albedo and emissivity. For cloudy atmospheres the factors are the various cloud properties such as cloud fraction, amount of cloud condensate, the size of the cloud particles, and morphological cloud features such as cloud vertical location, cloud horizontal and vertical inhomogeneity and cloud shape and size. The project addressed various aspects of the influence of the above contributors to atmospheric radiative transfer variability. In particular, it examined: (a) the quality of radiative transfer for cloudless and non-complex cloudy conditions for a substantial number of radiation algorithms used in current GCMs; (b) the errors in radiative fluxes from neglecting the horizontal variabiity of cloud extinction; (c) the statistical properties of cloud horizontal and vertical cloud inhomogeneity that can be incorporated into radiative transfer codes; (d) the potential albedo effects of changes in the particle size of liquid clouds; (e) the gaseous radiative forcing in the presence of clouds; and (f) the relative contribution of clouds of different sizes to the reflectance of a cloud field. To conduct the research in the various facets of the project, data from both the DOE ARM project and other sources were used. The outcomes of the project will have tangible effects on how the calculation of radiative energy will be approached in future editions of GCMs. With better calculations of radiative energy in GCMs more reliable predictions of future climate states will be

  16. Final report for the ASC gas-powder two-phase flow modeling project AD2006-09.

    SciTech Connect

    Evans, Gregory Herbert; Winters, William S.

    2007-01-01

    This report documents activities performed in FY2006 under the ''Gas-Powder Two-Phase Flow Modeling Project'', ASC project AD2006-09. Sandia has a need to understand phenomena related to the transport of powders in systems. This report documents a modeling strategy inspired by powder transport experiments conducted at Sandia in 2002. A baseline gas-powder two-phase flow model, developed under a companion PEM project and implemented into the Sierra code FUEGO, is presented and discussed here. This report also documents a number of computational tests that were conducted to evaluate the accuracy and robustness of the new model. Although considerable progress was made in implementing the complex two-phase flow model, this project has identified two important areas that need further attention. These include the need to compute robust compressible flow solutions for Mach numbers exceeding 0.35 and the need to improve conservation of mass for the powder phase. Recommendations for future work in the area of gas-powder two-phase flow are provided.

  17. Mild cold-stress depresses immune responses: Implications for cancer models involving laboratory mice

    PubMed Central

    Messmer, Michelle N.; Kokolus, Kathleen M.; Eng, Jason W.-L.; Abrams, Scott I.; Repasky, Elizabeth A.

    2014-01-01

    Physiologically accurate mouse models of cancer are critical in the pre-clinical development of novel cancer therapies. However, current standardized animal-housing temperatures elicit chronic cold-associated stress in mice, which is further increased in the presence of tumor. This cold-stress significantly impacts experimental outcomes. Data from our lab and others suggests standard housing fundamentally alters murine physiology, and this can produce altered immune baselines in tumor and other disease models. Researchers may thus underestimate the efficacy of therapies that are benefitted by immune responses. A potential mediator, norepinephrine, also underlies stress pathways common in mice and humans. Therefore, research into mechanisms connecting cold-stress and norepinephrine signaling with immune-depression in mice could highlight new combination therapies for humans to simultaneously target stress while stimulating anti-tumor immunity. PMID:25066924

  18. Andrographolide suppresses thymic stromal lymphopoietin in phorbol myristate acetate/calcium ionophore A23187-activated mast cells and 2,4-dinitrofluorobenzene-induced atopic dermatitis-like mice model

    PubMed Central

    Li, Chun-xiao; Li, Hua-guo; Zhang, Hui; Cheng, Ru-hong; Li, Ming; Liang, Jian-ying; Gu, Yan; Ling, Bo; Yao, Zhi-rong; Yu, Hong

    2016-01-01

    Background Atopic dermatitis (AD) is one of the most common inflammatory cutaneous diseases. Thymic stromal lymphopoietin (TSLP) has been demonstrated to be an important immunologic factor in the pathogenesis of AD. The production of TSLP can be induced by a high level of intracellular calcium concentration and activation of the receptor-interacting protein 2/caspase-1/NF-κB pathway. Andrographolide (ANDRO), a natural bicyclic diterpenoid lactone, has been found to exert anti-inflammatory effects in gastrointestinal inflammatory disorders through suppressing the NF-κB pathway. Objective To explore the effect of ANDRO on the production of TSLP in human mast cells and AD mice model. Methods We utilized enzyme-linked immunosorbent assay, real-time reverse transcription polymerase chain reaction analysis, Western blot analysis, and immunofluorescence staining assay to investigate the effects of ANDRO on AD. Results ANDRO ameliorated the increase in the intracellular calcium, protein, and messenger RNA levels of TSLP induced by phorbol myristate acetate/calcium ionophore A23187, through the blocking of the receptor-interacting protein 2/caspase-1/NF-κB pathway in human mast cell line 1 cells. ANDRO, via oral or local administration, also attenuated clinical symptoms in 2,4-dinitrofluorobenzene-induced AD mice model and suppressed the levels of TSLP in lesional skin. Conclusion Taken together, ANDRO may be a potential therapeutic agent for AD through suppressing the expression of TSLP. PMID:26929603

  19. Modeling of the ascent of magma during the plinian eruption of Vesuvius in A.D. 79

    NASA Astrophysics Data System (ADS)

    Papale, Paolo; Dobran, Flavio

    1993-11-01

    The ascent of magma during the A.D. 79 eruption of Vesuvius was studied by a steady-state, one-dimensional, and nonequilibrium two-phase flow model. The gas exsolution process was modeled by assuming a chemical equilibrium between the exsolved and dissolved gas, whereas the magma density and viscosity were modeled by accounting for the crystal content in magma. The exsolution, density, and viscosity models consider the effect of different compositions of the white and gray magmas. By specifying the conduit geometry and magma composition, and employing the model to search for the maximum discharge rate of magma which is consistent with the specified geometry and magma composition, the model was then used to establish the two-phase flow parameters along the conduit. It was found that for all considered conditions the magma pressure in the conduit decreases below the lithostatic pressure near the magma fragmentation level, and that in the deep regions of the conduit the white magma pressure is larger and the gray magma pressure is lower than the lithostatic one. The exsolution and fragmentation levels were found to be deeper for the white than for the gray magma, and the changing composition during the eruption causes an increase of the exit pressure and decrease of the exit gas volumetric fraction. The model also predicted a minimum conduit diameter which is consistent with the white and gray magma compositions and mass flow-rates. The predictions of the model were shown to be consistent with column collapses during the gray eruption phase, large presence of carbonate lithics in the gray pumice fall deposit, and magma-water interaction during a late stage of the eruption.

  20. Generating double knockout mice to model genetic intervention for diabetic cardiomyopathy in humans.

    PubMed

    Chavali, Vishalakshi; Nandi, Shyam Sundar; Singh, Shree Ram; Mishra, Paras Kumar

    2014-01-01

    Diabetes is a rapidly increasing disease that enhances the chances of heart failure twofold to fourfold (as compared to age and sex matched nondiabetics) and becomes a leading cause of morbidity and mortality. There are two broad classifications of diabetes: type1 diabetes (T1D) and type2 diabetes (T2D). Several mice models mimic both T1D and T2D in humans. However, the genetic intervention to ameliorate diabetic cardiomyopathy in these mice often requires creating double knockout (DKO). In order to assess the therapeutic potential of a gene, that specific gene is either overexpressed (transgenic expression) or abrogated (knockout) in the diabetic mice. If the genetic mice model for diabetes is used, it is necessary to create DKO with transgenic/knockout of the target gene to investigate the specific role of that gene in pathological cardiac remodeling in diabetics. One of the important genes involved in extracellular matrix (ECM) remodeling in diabetes is matrix metalloproteinase-9 (Mmp9). Mmp9 is a collagenase that remains latent in healthy hearts but induced in diabetic hearts. Activated Mmp9 degrades extracellular matrix (ECM) and increases matrix turnover causing cardiac fibrosis that leads to heart failure. Insulin2 mutant (Ins2+/-) Akita is a genetic model for T1D that becomes diabetic spontaneously at the age of 3-4 weeks and show robust hyperglycemia at the age of 10-12 weeks. It is a chronic model of T1D. In Ins2+/- Akita, Mmp9 is induced. To investigate the specific role of Mmp9 in diabetic hearts, it is necessary to create diabetic mice where Mmp9 gene is deleted. Here, we describe the method to generate Ins2+/-/Mmp9-/- (DKO) mice to determine whether the abrogation of Mmp9 ameliorates diabetic cardiomyopathy. PMID:25064116

  1. Generating double knockout mice to model genetic intervention for diabetic cardiomyopathy in humans.

    PubMed

    Chavali, Vishalakshi; Nandi, Shyam Sundar; Singh, Shree Ram; Mishra, Paras Kumar

    2014-01-01

    Diabetes is a rapidly increasing disease that enhances the chances of heart failure twofold to fourfold (as compared to age and sex matched nondiabetics) and becomes a leading cause of morbidity and mortality. There are two broad classifications of diabetes: type1 diabetes (T1D) and type2 diabetes (T2D). Several mice models mimic both T1D and T2D in humans. However, the genetic intervention to ameliorate diabetic cardiomyopathy in these mice often requires creating double knockout (DKO). In order to assess the therapeutic potential of a gene, that specific gene is either overexpressed (transgenic expression) or abrogated (knockout) in the diabetic mice. If the genetic mice model for diabetes is used, it is necessary to create DKO with transgenic/knockout of the target gene to investigate the specific role of that gene in pathological cardiac remodeling in diabetics. One of the important genes involved in extracellular matrix (ECM) remodeling in diabetes is matrix metalloproteinase-9 (Mmp9). Mmp9 is a collagenase that remains latent in healthy hearts but induced in diabetic hearts. Activated Mmp9 degrades extracellular matrix (ECM) and increases matrix turnover causing cardiac fibrosis that leads to heart failure. Insulin2 mutant (Ins2+/-) Akita is a genetic model for T1D that becomes diabetic spontaneously at the age of 3-4 weeks and show robust hyperglycemia at the age of 10-12 weeks. It is a chronic model of T1D. In Ins2+/- Akita, Mmp9 is induced. To investigate the specific role of Mmp9 in diabetic hearts, it is necessary to create diabetic mice where Mmp9 gene is deleted. Here, we describe the method to generate Ins2+/-/Mmp9-/- (DKO) mice to determine whether the abrogation of Mmp9 ameliorates diabetic cardiomyopathy.

  2. Kinetic modeling of hyperpolarized 13C 1-pyruvate metabolism in normal rats and TRAMP mice

    NASA Astrophysics Data System (ADS)

    Zierhut, Matthew L.; Yen, Yi-Fen; Chen, Albert P.; Bok, Robert; Albers, Mark J.; Zhang, Vickie; Tropp, Jim; Park, Ilwoo; Vigneron, Daniel B.; Kurhanewicz, John; Hurd, Ralph E.; Nelson, Sarah J.

    2010-01-01

    PurposeTo investigate metabolic exchange between 13C 1-pyruvate, 13C 1-lactate, and 13C 1-alanine in pre-clinical model systems using kinetic modeling of dynamic hyperpolarized 13C spectroscopic data and to examine the relationship between fitted parameters and dose-response. Materials and methodsDynamic 13C spectroscopy data were acquired in normal rats, wild type mice, and mice with transgenic prostate tumors (TRAMP) either within a single slice or using a one-dimensional echo-planar spectroscopic imaging (1D-EPSI) encoding technique. Rate constants were estimated by fitting a set of exponential equations to the dynamic data. Variations in fitted parameters were used to determine model robustness in 15 mm slices centered on normal rat kidneys. Parameter values were used to investigate differences in metabolism between and within TRAMP and wild type mice. ResultsThe kinetic model was shown here to be robust when fitting data from a rat given similar doses. In normal rats, Michaelis-Menten kinetics were able to describe the dose-response of the fitted exchange rate constants with a 13.65% and 16.75% scaled fitting error (SFE) for kpyr→lac and kpyr→ala, respectively. In TRAMP mice, kpyr→lac increased an average of 94% after up to 23 days of disease progression, whether the mice were untreated or treated with casodex. Parameters estimated from dynamic 13C 1D-EPSI data were able to differentiate anatomical structures within both wild type and TRAMP mice. ConclusionsThe metabolic parameters estimated using this approach may be useful for in vivo monitoring of tumor progression and treatment efficacy, as well as to distinguish between various tissues based on metabolic activity.

  3. Interferon α/β Receptor-Deficient Mice as a Model for Ebola Virus Disease.

    PubMed

    Brannan, Jennifer M; Froude, Jeffery W; Prugar, Laura I; Bakken, Russell R; Zak, Samantha E; Daye, Sharon P; Wilhelmsen, Catherine E; Dye, John M

    2015-10-01

    A major obstacle in ebolavirus research is the lack of a small-animal model for Sudan virus (SUDV), as well as other wild-type (WT) ebolaviruses. Here, we expand on research by Bray and by Lever et al suggesting that WT ebolaviruses are pathogenic in mice deficient for the type 1 interferon (IFN) α/β receptor (IFNα/βR-/-). We examined the disease course of several WT ebolaviruses: Boneface (SUDV/Bon) and Gulu variants of SUDV, Ebola virus (EBOV), Bundibugyo virus (BDBV), Taï Forest virus, and Reston virus (RESTV). We determined that exposure to WT SUDV or EBOV results in reproducible signs of disease in IFNα/βR-/- mice, as measured by weight loss and partial lethality. Vaccination with the SUDV or EBOV glycoprotein (GP)-expressing Venezuelan equine encephalitis viral replicon particle vaccine protected these mice from SUDV/Bon and EBOV challenge, respectively. Treatment with SUDV- or EBOV-specific anti-GP antibodies protected mice from challenge when delivered 1-3 days after infection. Serial sampling experiments revealed evidence of disseminated intravascular coagulation in the livers of mice infected with the Boneface variant of SUDV, EBOV, and BDBV. Taken together, these data solidify the IFNα/βR-/- mouse as an important and useful model for the study of WT EBOV disease.

  4. Influence of coagulation factor x on in vitro and in vivo gene delivery by adenovirus (Ad) 5, Ad35, and chimeric Ad5/Ad35 vectors.

    PubMed

    Greig, Jenny A; Buckley, Suzanne Mk; Waddington, Simon N; Parker, Alan L; Bhella, David; Pink, Rebecca; Rahim, Ahad A; Morita, Takashi; Nicklin, Stuart A; McVey, John H; Baker, Andrew H

    2009-10-01

    The binding of coagulation factor X (FX) to the hexon of adenovirus (Ad) 5 is pivotal for hepatocyte transduction. However, vectors based on Ad35, a subspecies B Ad, are in development for cancer gene therapy, as Ad35 utilizes CD46 (which is upregulated in many cancers) for transduction. We investigated whether interaction of Ad35 with FX influenced vector tropism using Ad5, Ad35, and Ad5/Ad35 chimeras: Ad5/fiber(f)35, Ad5/penton(p)35/f35, and Ad35/f5. Surface plasmon resonance (SPR) revealed that Ad35 and Ad35/f5 bound FX with approximately tenfold lower affinities than Ad5 hexon-containing viruses, and electron cryomicroscopy (cryo-EM) demonstrated a direct Ad35 hexon:FX interaction. The presence of physiological levels of FX significantly inhibited transduction of vectors containing Ad35 fibers (Ad5/f35, Ad5/p35/f35, and Ad35) in CD46-positive cells. Vectors were intravenously administered to CD46 transgenic mice in the presence and absence of FX-binding protein (X-bp), resulting in reduced liver accumulation for all vectors. Moreover, Ad5/f35 and Ad5/p35/f35 efficiently accumulated in the lung, whereas Ad5 demonstrated poor lung targeting. Additionally, X-bp significantly reduced lung genome accumulation for Ad5/f35 and Ad5/p35/f35, whereas Ad35 was significantly enhanced. In summary, vectors based on the full Ad35 serotype will be useful vectors for selective gene transfer via CD46 due to a weaker FX interaction compared to Ad5.

  5. Finite temperature effect in infrared-improved AdS/QCD model with back reaction of bulk vacuum

    NASA Astrophysics Data System (ADS)

    Cui, Ling-Xiao; Fang, Zhen; Wu, Yue-Liang

    2016-06-01

    Based on an IR-improved soft-wall AdS/QCD model for mesons, which provides a consistent prediction for the mass spectra of resonance scalar, pseudoscalar, vector and axial-vector mesons, we investigate its finite temperature effect. By analyzing the spectral function of mesons and fitting it with a Breit-Wigner form, we perform an analysis for the critical temperature of mesons. The back-reaction effects of bulk vacuum are considered and the thermal mass spectral function of resonance mesons is calculated based on the back-reaction improved action. A reasonable melting temperature is found to be T c ≈ 150 ± 7 MeV, which is consistent with the recent results from lattice QCD simulations. Supported by National Nature Science Foundation of China (NSFC)(10975170, 10905084, 10821504), and Project of Knowledge Innovation Program (PKIP) of Chinese Academy of Science

  6. Stress-induced hyperlocomotion as a confounding factor in anxiety and depression models in mice.

    PubMed

    Strekalova, T; Spanagel, R; Dolgov, O; Bartsch, D

    2005-05-01

    Chronic stress is broadly used to model anxiety and depression. However, in chronic stress models, anxiety- and depression-like behaviors might be masked by unspecific effects of stress. We tested whether chronic stress in mice can induce unspecific changes in locomotion, and whether these changes interfere with the measurement of anxiety and forced-swimming behaviors. Also, we studied these latter behaviors in relation to the duration of stress, the lighting conditions during testing, and after the injection of diazepam. We employed a 4-week chronic stress paradigm, adopted from a model of stress-induced anhedonia and a 1-week subchronic stress, both consisting of rat exposure, restraint stress and tail suspension. Chronically stressed mice, tested under bright and moderate illumination, exhibited 'anxiolytic-like' behavior along with prolonged swimming and hyperactivity. These behaviors were not detectable under weak illumination or after the injection of diazepam (0.25 mg/kg). Instead, normal locomotion, increased anxiety and inhibited swimming were revealed under these conditions. Thus, chronic stress can induce hyperlocomotion in mice, which is triggered by acute stressors such as light, and interferes with the evaluation of anxiety and forced swimming. One week of stress did not change locomotion and forced swimming, and increased anxiety irrespective of illumination applied during testing. Our data can possibly explain previously reported contradictions in the behavioral testing of mice with chronic stress models of anxiety and depression.

  7. Evaluation of Mecp2(R308/Y) mutant mice as a model to study fetal programming

    Technology Transfer Automated Retrieval System (TEKTRAN)

    DNA (CpG) methylation is altered at candidate loci after prenatal modification of dietary methyl donor supply. Mecp2(R308/Y) mutant mice, with a truncating mutation of the methyl-CpG-binding protein 2 gene which models Rett syndrome, have increased weight gain on a high methyl donor diet. Rett syndr...

  8. Hypoxia facilitates neurogenic dural plasma protein extravasation in mice: a novel animal model for migraine pathophysiology

    PubMed Central

    Hunfeld, Anika; Segelcke, Daniel; Bäcker, Ingo; Mecheri, Badreddine; Hemmer, Kathrin; Dlugosch, Elisabeth; Andriske, Michael; Paris, Frank; Zhu, Xinran; Lübbert, Hermann

    2015-01-01

    Migraine animal models generally mimic the onset of attacks and acute treatment processes. A guinea pig model used the application of meta-chlorophenylpiperazine (mCPP) to trigger immediate dural plasma protein extravasation (PPE) mediated by 5-HT2B receptors. This model has predictive value for antimigraine drugs but cannot explain the delayed onset of efficacy of 5-HT2B receptor antagonists when clinically used for migraine prophylaxis. We found that mCPP failed to induce dural PPE in mice. Considering the role 5-HT2B receptors play in hypoxia-induced pulmonary vessel muscularization, we were encouraged to keep mice under hypoxic conditions and tested whether this treatment will render them susceptible to mCPP-induced dural PPE. Following four-week of hypoxia, PPE, associated with increased transendothelial transport, was induced by mCPP. The effect was blocked by sumatriptan. Chronic application of 5-HT2B receptor or nitric oxide synthase blockers during hypoxia prevented the development of susceptibility. Here we present a migraine model that distinguishes between a migraine-like state (hypoxic mice) and normal, normoxic mice and mimics processes that are related to chronic activation of 5-HT2B receptors under hypoxia. It seems striking, that chronic endogenous activation of 5-HT2B receptors is crucial for the sensitization since 5-HT2B receptor antagonists have strong, albeit delayed migraine prophylactic efficacy. PMID:26644235

  9. Non-obese diabetic mice rapidly develop dramatic sympathetic neuritic dystrophy: a new experimental model of diabetic autonomic neuropathy.

    PubMed

    Schmidt, Robert E; Dorsey, Denise A; Beaudet, Lucie N; Frederick, Kathy E; Parvin, Curtis A; Plurad, Santiago B; Levisetti, Matteo G

    2003-11-01

    To address the pathogenesis of diabetic autonomic neuropathy, we have examined the sympathetic nervous system in non-obese diabetic (NOD) and streptozotocin (STZ)-induced diabetic mice, two models of type 1 diabetes, and the db/db mouse, a model of type 2 diabetes. After only 3 to 5 weeks of diabetes, NOD mice developed markedly swollen axons and dendrites ("neuritic dystrophy") in the prevertebral superior mesenteric and celiac ganglia (SMG-CG), similar to the pathology described in diabetic STZ- and BBW-rat and man. Comparable changes failed to develop in the superior cervical ganglia of the NOD mouse or in the SMG-CG of non-diabetic NOD siblings. STZ-induced diabetic mice develop identical changes, although at a much slower pace and to a lesser degree than NOD mice. NOD-SCID mice, which are genetically identical to NOD mice except for the absence of T and B cells, do not develop diabetes or neuropathology comparable to diabetic NOD mice. However, STZ-treated NOD-SCID mice develop severe neuritic dystrophy, evidence against an exclusively autoimmune pathogenesis for autonomic neuropathy in this model. Chronically diabetic type 2 db/db mice fail to develop neuritic dystrophy, suggesting that hyperglycemia alone may not be the critical and sufficient element. The NOD mouse appears to be a valuable model of diabetic sympathetic autonomic neuropathy with unambiguous, rapidly developing neuropathology which corresponds closely to the characteristic pathology of other rodent models and man. PMID:14578206

  10. Non-obese diabetic mice rapidly develop dramatic sympathetic neuritic dystrophy: a new experimental model of diabetic autonomic neuropathy.

    PubMed

    Schmidt, Robert E; Dorsey, Denise A; Beaudet, Lucie N; Frederick, Kathy E; Parvin, Curtis A; Plurad, Santiago B; Levisetti, Matteo G

    2003-11-01

    To address the pathogenesis of diabetic autonomic neuropathy, we have examined the sympathetic nervous system in non-obese diabetic (NOD) and streptozotocin (STZ)-induced diabetic mice, two models of type 1 diabetes, and the db/db mouse, a model of type 2 diabetes. After only 3 to 5 weeks of diabetes, NOD mice developed markedly swollen axons and dendrites ("neuritic dystrophy") in the prevertebral superior mesenteric and celiac ganglia (SMG-CG), similar to the pathology described in diabetic STZ- and BBW-rat and man. Comparable changes failed to develop in the superior cervical ganglia of the NOD mouse or in the SMG-CG of non-diabetic NOD siblings. STZ-induced diabetic mice develop identical changes, although at a much slower pace and to a lesser degree than NOD mice. NOD-SCID mice, which are genetically identical to NOD mice except for the absence of T and B cells, do not develop diabetes or neuropathology comparable to diabetic NOD mice. However, STZ-treated NOD-SCID mice develop severe neuritic dystrophy, evidence against an exclusively autoimmune pathogenesis for autonomic neuropathy in this model. Chronically diabetic type 2 db/db mice fail to develop neuritic dystrophy, suggesting that hyperglycemia alone may not be the critical and sufficient element. The NOD mouse appears to be a valuable model of diabetic sympathetic autonomic neuropathy with unambiguous, rapidly developing neuropathology which corresponds closely to the characteristic pathology of other rodent models and man.

  11. Optimization of an Image-Guided Laser-Induced Choroidal Neovascularization Model in Mice.

    PubMed

    Gong, Yan; Li, Jie; Sun, Ye; Fu, Zhongjie; Liu, Chi-Hsiu; Evans, Lucy; Tian, Katherine; Saba, Nicholas; Fredrick, Thomas; Morss, Peyton; Chen, Jing; Smith, Lois E H

    2015-01-01

    The mouse model of laser-induced choroidal neovascularization (CNV) has been used in studies of the exudative form of age-related macular degeneration using both the conventional slit lamp and a new image-guided laser system. A standardized protocol is needed for consistent results using this model, which has been lacking. We optimized details of laser-induced CNV using the image-guided laser photocoagulation system. Four lesions with similar size were consistently applied per eye at approximately double the disc diameter away from the optic nerve, using different laser power levels, and mice of various ages and genders. After 7 days, the mice were sacrificed and retinal pigment epithelium/choroid/sclera was flat-mounted, stained with Isolectin B4, and imaged. Quantification of the area of the laser-induced lesions was performed using an established and constant threshold. Exclusion criteria are described that were necessary for reliable data analysis of the laser-induced CNV lesions. The CNV lesion area was proportional to the laser power levels. Mice at 12-16 weeks of age developed more severe CNV than those at 6-8 weeks of age, and the gender difference was only significant in mice at 12-16 weeks of age, but not in those at 6-8 weeks of age. Dietary intake of omega-3 long-chain polyunsaturated fatty acid reduced laser-induced CNV in mice. Taken together, laser-induced CNV lesions can be easily and consistently applied using the image-guided laser platform. Mice at 6-8 weeks of age are ideal for the laser-induced CNV model.

  12. Optimization of an Image-Guided Laser-Induced Choroidal Neovascularization Model in Mice

    PubMed Central

    Sun, Ye; Fu, Zhongjie; Liu, Chi-Hsiu; Evans, Lucy; Tian, Katherine; Saba, Nicholas; Fredrick, Thomas; Morss, Peyton; Chen, Jing; Smith, Lois E. H.

    2015-01-01

    The mouse model of laser-induced choroidal neovascularization (CNV) has been used in studies of the exudative form of age-related macular degeneration using both the conventional slit lamp and a new image-guided laser system. A standardized protocol is needed for consistent results using this model, which has been lacking. We optimized details of laser-induced CNV using the image-guided laser photocoagulation system. Four lesions with similar size were consistently applied per eye at approximately double the disc diameter away from the optic nerve, using different laser power levels, and mice of various ages and genders. After 7 days, the mice were sacrificed and retinal pigment epithelium/choroid/sclera was flat-mounted, stained with Isolectin B4, and imaged. Quantification of the area of the laser-induced lesions was performed using an established and constant threshold. Exclusion criteria are described that were necessary for reliable data analysis of the laser-induced CNV lesions. The CNV lesion area was proportional to the laser power levels. Mice at 12-16 weeks of age developed more severe CNV than those at 6-8 weeks of age, and the gender difference was only significant in mice at 12-16 weeks of age, but not in those at 6-8 weeks of age. Dietary intake of omega-3 long-chain polyunsaturated fatty acid reduced laser-induced CNV in mice. Taken together, laser-induced CNV lesions can be easily and consistently applied using the image-guided laser platform. Mice at 6-8 weeks of age are ideal for the laser-induced CNV model. PMID:26161975

  13. Ischemia-reperfusion Model of Acute Kidney Injury and Post Injury Fibrosis in Mice

    PubMed Central

    Skrypnyk, Nataliya I.; Harris, Raymond C.; de Caestecker, Mark P.

    2013-01-01

    Ischemia-reperfusion induced acute kidney injury (IR-AKI) is widely used as a model of AKI in mice, but results are often quite variable with high, often unreported mortality rates that may confound analyses. Bilateral renal pedicle clamping is commonly used to induce IR-AKI, but differences between effective clamp pressures and/or renal responses to ischemia between kidneys often lead to more variable results. In addition, shorter clamp times are known to induce more variable tubular injury, and while mice undergoing bilateral injury with longer clamp times develop more consistent tubular injury, they often die within the first 3 days after injury due to severe renal insufficiency. To improve post-injury survival and obtain more consistent and predictable results, we have developed two models of unilateral ischemia-reperfusion injury followed by contralateral nephrectomy. Both surgeries are performed using a dorsal approach, reducing surgical stress resulting from ventral laparotomy, commonly used for mouse IR-AKI surgeries. For induction of moderate injury BALB/c mice undergo unilateral clamping of the renal pedicle for 26 min and also undergo simultaneous contralateral nephrectomy. Using this approach, 50-60% of mice develop moderate AKI 24 hr after injury but 90-100% of mice survive. To induce more severe AKI, BALB/c mice undergo renal pedicle clamping for 30 min followed by contralateral nephrectomy 8 days after injury. This allows functional assessment of renal recovery after injury with 90-100% survival. Early post-injury tubular damage as well as post injury fibrosis are highly consistent using this model. PMID:23963468

  14. Differential Fmo3 Gene Expression in Various Liver Injury Models Involving Hepatic Oxidative Stress in Mice

    PubMed Central

    Rudraiah, Swetha; Moscovitz, Jamie E.; Donepudi, Ajay C.; Campion, Sarah N.; Slitt, Angela L.; Aleksunes, Lauren M.; Manautou, José E.

    2015-01-01

    Flavin-containing monooxygenase-3 (FMO3) catalyzes metabolic reactions similar to cytochrome P450 monooxygenase however, most metabolites of FMO3 are considered non-toxic. Recent findings in our laboratory demonstrated Fmo3gene induction following toxic acetaminophen (APAP) treatment in mice.The goal of this study was to evaluate Fmo3gene expression in diverseother mouse models of hepatic oxidative stress and injury. Fmo3 gene regulation by Nrf2 was also investigated using Nrf2 knockout (Nrf2 KO) mice. In our studies, male C57BL/6J mice were treated with toxic dosesof hepatotoxicants or underwent bile duct ligation (BDL, 10d). Hepatotoxicants included APAP (400 mg/kg, 24 to 72h), alpha-naphthylisothiocyanate (ANIT; 50 mg/kg, 2 to 48h), carbontetrachloride (CCl4;10 or 30 μL/kg, 24 and 48h) and allyl alcohol (AlOH; 30 or 60 mg/kg, 6 and 24h). Because oxidative stress activates nuclear factor (erythroid-derived 2)-like 2 (Nrf2), additional studies investigated Fmo3 gene regulation by Nrf2 using Nrf2 knockout (Nrf2 KO) mice. At appropriate time-points, blood and liver samples were collected for assessment of plasma alanine aminotransferase (ALT) activity, plasma and hepatic bile acid levels, as well as liver Fmo3 mRNA and protein expression. Fmo3 mRNA expression increased significantly by 43-fold at 12h after ANIT treatment,and this increase translates to a 4-fold change in protein levels. BDL also increased Fmo3 mRNA expression by 1899-fold, but with no change in protein levels. Treatment of mice with CCl4decreased liver Fmo3gene expression, whileno change in expression was detected with AlOH treatment. Nrf2 KO mice are more susceptible to APAP (400 mg/kg, 72h) treatment compared to their wild-type (WT) counterparts, which is evidenced by greater plasma ALT activity. Fmo3 mRNA and protein expression increased in Nrf2 KO mice after APAP treatment. Collectively, not all hepatotoxicantsthat produce oxidative stress alter Fmo3gene expression. Along with APAP, toxic ANIT

  15. Thromboembolic Model of Cerebral Ischemia and Reperfusion in Mice.

    PubMed

    Alawieh, Ali; Wang, Wenxue; Narang, Aarti; Tomlinson, Stephen

    2016-01-01

    Ischemic stroke is the fourth leading cause of death in the USA and a prominent cause of death globally. Besides thrombolytic therapy used in a small subset of patients, no alternative therapeutic strategy has been shown to improve the outcome of stroke patients. Preclinical models of ischemic stroke are an essential tool for investigating pathogenic processes that happen after the ischemic insult, as well as to screen for candidate therapeutic interventions. There are several models of rodent ischemic stroke including mechanical occlusion, thromboembolic stroke, and photothrombotic stroke. However, models that permit studying stroke in the context of thrombolytic therapy, such as thromboembolic models, are becoming of increasing interest to the research community. In this chapter, we describe a thromboembolic model of ischemic stroke with and without tissue-plasminogen activator-induced reperfusion. We describe protocols for microemboli preparation, surgical procedure, and post-stroke assessment of animals. PMID:27604728

  16. Seizure susceptibility of neuropeptide-Y null mutant mice in amygdala kindling and chemical-induced seizure models.

    PubMed

    Shannon, Harlan E; Yang, Lijuan

    2004-01-01

    Neuropeptide Y (NPY) administered exogenously is anticonvulsant, and, NPY null mutant mice are more susceptible to kainate-induced seizures. In order to better understand the potential role of NPY in epileptogenesis, the present studies investigated the development of amygdala kindling, post-kindling seizure thresholds, and anticonvulsant effects of carbamazepine and levetiracetam in 129S6/SvEv NPY(+/+) and NPY(-/-) mice. In addition, susceptibility to pilocarpine- and kainate-induced seizures was compared in NPY(+/+) and (-/-) mice. The rate of amygdala kindling development did not differ in the NPY(-/-) and NPY(+/+) mice either when kindling stimuli were presented once daily for at least 20 days, or, 12 times daily for 2 days. However, during kindling development, the NPY(-/-) mice had higher seizure severity scores and longer afterdischarge durations than the NPY(+/+) mice. Post-kindling, the NPY(-/-) mice had markedly lower afterdischarge thresholds and longer afterdischarge durations than NPY (+/+) mice. Carbamazepine and levetiracetam increased the seizure thresholds of both NPY (-/-) and (+/+) mice. In addition, NPY (-/-) mice had lower thresholds for both kainate- and pilocarpine-induced seizures. The present results in amygdala kindling and chemical seizure models suggest that NPY may play a more prominent role in determining seizure thresholds and severity of seizures than in events leading to epileptogenesis. In addition, a lack of NPY does not appear to confer drug-resistance in that carbamazepine and levetiracetam were anticonvulsant in both wild type (WT) and NPY null mutant mice.

  17. Mucin model for group B type III streptococcal infection in mice.

    PubMed Central

    Fleming, D O

    1980-01-01

    An experimental murine infection was established by the intraperitoneal injection of a log-phase culture of a laboratory reference strain of Streptococcus agalactiae, Lancefield group B, type III (strain SS620), suspended in sterile hog gastric mucin. The enhancement of streptococcal virulence was measured by a significantly increased mortality in outbred ICR Swiss mice. An inbred C57BL6 strain of mice was resistant to the mucin-bacterial combination. Mucin, treated with Desferal to chelate the iron, did not lose the capacity to enhance the virulence of group B, type III streptococci in ICR Swiss mice. Iron-dextran was not a suitable substitute for mucin and failed to enhance the virulence of group B, type III streptococci. The results of these studies indicate that iron is not the resistance-lowering factor in this group B, type III streptococci-mucin model. PMID:6155334

  18. APP transgenic mice for modelling behavioral and psychological symptoms of dementia (BPSD)

    PubMed Central

    Lalonde, R.; Fukuchi, K.; Strazielle, C.

    2012-01-01

    The discovery of gene mutations responsible for autosomal dominant Alzheimer's disease has enabled researchers to reproduce in transgenic mice several hallmarks of this disorder, notably Aβ accumulation, though in most cases without neurofibrillary tangles. Mice expressing mutated and wild-type APP as well as C-terminal fragments of APP exhibit variations in exploratory activity reminiscent of behavioral and psychological symptoms of Alzeimer dementia (BPSD). In particular, open-field, spontaneous alternation, and elevated plus-maze tasks as well as aggression are modified in several APP transgenic mice relative to non-transgenic controls. However, depending on the precise murine models, changes in open-field and elevated plus-maze exploration occur in either direction, either increased or decreased relative to controls. It remains to be determined which neurotransmitter changes are responsible for this variability, in particular with respect to GABA, 5HT, and dopamine. PMID:22373961

  19. Disease course in mdx:utrophin+/− mice: comparison of three mouse models of Duchenne muscular dystrophy

    PubMed Central

    McDonald, Abby A; Hebert, Sadie L; Kunz, Matthew D; Ralles, Steven J; McLoon, Linda K

    2015-01-01

    The mdx mouse model of Duchenne muscular dystrophy (DMD) is used to study disease mechanisms and potential treatments, but its pathology is less severe than DMD patients. Other mouse models were developed to more closely mimic the human disease based on knowledge that upregulation of utrophin has a protective effect in mdx muscle. An mdx:utrophin−/− (dko) mouse was created, which had a severe disease phenotype and a shortened life span. An mdx:utrophin+/− mouse was also created, which had an intermediate disease phenotype compared to the mdx and dko mice. To determine the usefulness of mdx:utrophin+/− mice for long-term DMD studies, limb muscle pathology and function were assessed across the life span of wild-type, mdx, mdx:utrophin+/−, and dko mice. Muscle function assessment, specifically grip duration and rotarod performance, demonstrated that mdx:utrophin+/− mice were weaker for a longer time than mdx mice. Mean myofiber area was smaller in mdx:utrophin+/− mice compared to mdx mice at 12 months. Mdx:utrophin+/− mice had a higher percentage of centrally nucleated myofibers compared to mdx mice at 6 and 12 months. Collagen I and IV density was significantly higher in mdx:utrophin+/− muscle compared to mdx at most ages examined. Generally, mdx:utrophin+/− mice showed an intermediate disease phenotype over a longer time course compared to the mdx and dko mice. While they do not genetically mirror human DMD, mdx:utrophin+/− mice may be a more useful animal model than mdx or dko mice for investigating long-term efficacy of potential treatments when fibrosis or muscle function is the focus. PMID:25921779

  20. FUS/TLS acts as an aggregation-dependent modifier of polyglutamine disease model mice

    PubMed Central

    Kino, Yoshihiro; Washizu, Chika; Kurosawa, Masaru; Yamada, Mizuki; Doi, Hiroshi; Takumi, Toru; Adachi, Hiroaki; Katsuno, Masahisa; Sobue, Gen; Hicks, Geoffrey G.; Hattori, Nobutaka; Shimogori, Tomomi; Nukina, Nobuyuki

    2016-01-01

    FUS/TLS is an RNA/DNA-binding protein associated with neurodegenerative diseases including amyotrophic lateral sclerosis and frontotemporal lobar degeneration. Previously, we found that a prion-like domain in the N-terminus of FUS/TLS mediates co-aggregation between FUS/TLS and mutant huntingtin, the gene product of Huntington’s disease (HD). Here, we show that heterozygous knockout of FUS/TLS worsened the phenotypes of model mice of (HD, but not spinal and bulbar muscular atrophy (SBMA). This difference was correlated with the degree of pathological association between disease proteins and FUS/TLS. Co-aggregation between FUS/TLS and mutant huntingtin resulted in the depletion of free FUS/TLS protein in HD mice that was detected as a monomer in SDS-PAGE analysis. Recently, we found that FUS/TLS paralogs, TAF15 and EWS, were up-regulated in homozygous FUS/TLS knockout mice. These two proteins were up-regulated in both HD and FUS/TLS heterozygote mice, and were further elevated in HD-TLS+/− double mutant mice, consistent with the functional impairment of FUS/TLS. These results suggest that FUS/TLS sequestration by co-aggregation is a rate-limiting factor of disease phenotypes of HD and that inclusions may have an adverse aspect, rather than being simply benign or protective. In addition, our results highlight inclusions as repositories of potential modifiers of neurodegeneration. PMID:27739513

  1. Calpain Activation in Alzheimer's Model Mice Is an Artifact of APP and Presenilin Overexpression

    PubMed Central

    Saito, Takashi; Matsuba, Yukio; Yamazaki, Naomi; Hashimoto, Shoko

    2016-01-01

    Intraneuronal calcium stimulates the calpain-dependent conversion of p35 to p25, a CDK5 activator. It is widely believed that amyloid β peptide (Aβ) induces this conversion that, in turn, has an essential role in Alzheimer's disease pathogenesis. However, in vivo studies on p25 generation used transgenic mice overexpressing mutant amyloid precursor protein (APP) and presenilin (PS). Here, using single App knock-in mice, we show that p25 generation is an artifact caused by membrane protein overexpression. We show that massive Aβ42 accumulation without overexpression of APP or presenilin does not produce p25, whereas p25 generation occurred with APP/PS overexpression and in postmortem mouse brain. We further support this finding using mice deficient for calpastatin, the sole calpain-specific inhibitor protein. Thus, the intracerebral environment of the APP/PS mouse brain and postmortem brain is an unphysiological state. SIGNIFICANCE STATEMENT We recently estimated using single App knock-in mice that accumulate amyloid β peptide without transgene overexpression that 60% of the phenotypes observed in Alzheimer's model mice overexpressing mutant amyloid precursor protein (APP) or APP and presenilin are artifacts (Saito et al., 2014). The current study further supports this estimate by invalidating key results from papers that were published in Cell. These findings suggest that more than 3000 publications based on APP and APP/PS overexpression must be reevaluated. PMID:27656030

  2. Chronic and progressive Parkinson's disease MPTP model in adult and aged mice.

    PubMed

    Muñoz-Manchado, Ana B; Villadiego, Javier; Romo-Madero, Sonia; Suárez-Luna, Nela; Bermejo-Navas, Alfonso; Rodríguez-Gómez, José A; Garrido-Gil, Pablo; Labandeira-García, José L; Echevarría, Miriam; López-Barneo, José; Toledo-Aral, Juan J

    2016-01-01

    Despite the different animal models of Parkinson's disease developed during the last years, they still present limitations modelling the slow and progressive process of neurodegeneration. Here, we undertook a histological, neurochemical and behavioural analysis of a new chronic parkinsonian mouse model generated by the subcutaneous administration of low doses of MPTP (20 mg/kg, 3 times per week) for 3 months, using both young adult and aged mice. The MPTP-induced nigrostriatal neurodegeneration was progressive and was accompanied by a decrease in striatal dopamine levels and motor impairment. We also demonstrated the characteristic neuroinflammatory changes (microglial activation and astrogliosis) associated with the neurodegenerative process. Aged animals showed both a faster time course of neurodegeneration and an altered neuroinflammatory response. The long-term systemic application of low MPTP doses did not induce any increase in mortality in either young adult or aged mice and better resembles the slow evolution of the neurodegenerative process. This treatment could be useful to model different stages of Parkinson's disease, providing a better understanding of the pathophysiology of the disease and facilitating the testing of both protective and restorative treatments. Here, we show a new chronic and progressive parkinsonian mouse model, in young and aged mice. This model produces a stable degeneration of the dopaminergic nigrostriatal pathway, continuous neuroinflammatory reaction and motor deficits. Aged animals showed a faster neurodegeneration and an altered neuroinflammatory response. This treatment could be useful to model different stages of PD and to test both protective and restorative therapeutic approaches.

  3. Characterization of oral ulcer and pathological scar in nude mice model.

    PubMed

    Sukhitashvili, N; Imnadze, I; Tabaghua, G; Gogilashvili, Q; Amiranashvili, I

    2012-04-01

    Ulceration of mouth mucosa is frequently occurs after injuries in oral cavity. Oral ulcers are relatively common and these lesions cause strong pain and discomfort. Frequently, injury of the oral tissues results in abnormal fibroblast activation and keloid formation. This pathological scar formation is often associates with pain and malfunction of the organ. To understand these phenomena and develop effective treatment, reproducible animal models have to be introduced. Athymic nude mice where used to create animal models. 1% HCl acid solution was used for chemical damage of the mucosa tissue. Surgical operation was performed to create traumatic injury in the mouse oral cavity. Tissues were analyzed using immunohistochemistry methods. All of the HCl treated animals developed ulcers on the skin and mucosa of the oral cavity. Most of the mice on the place of surgical wound developed keloid tissue. Mice in which we induced pathological processes of the oral tissue, did not gain body weight. Moreover their mass had tendency to decrease. Hematoxilyn-eosin staining of the ulcerated mice tissues revealed extended coagulation necrosis - covering all tissue layers of the oral cavity. Strong local inflammatory cell infiltration and absence of proliferative cells has been demonstrated in these ulcerated and adjusted oral tissues. Morphological analysis of scar tissue revealed fibrotic hypertrophy of the injured oral tissues in these animals with the expressed infiltration of inflammatory cells. Our animal models reflect morphology of the specific injury and functionally imitate the disease.

  4. Infection of SCID mice with Montana Myotis leukoencephalitis virus as a model for flavivirus encephalitis.

    PubMed

    Charlier, Nathalie; Leyssen, Pieter; Paeshuyse, Jan; Drosten, Christian; Schmitz, Herbert; Van Lommel, Alfons; De Clercq, Erik; Neyts, Johan

    2002-08-01

    We have established a convenient animal model for flavivirus encephalitis using Montana Myotis leukoencephalitis virus (MMLV), a bat flavivirus. This virus has the same genomic organization, and contains the same conserved motifs in genes that encode potential antiviral targets, as flaviviruses that cause disease in man (N. Charlier et al., accompanying paper), and has a similar particle size (approximately 40 nm). MMLV replicates well in Vero cells and appears to be equally as sensitive as yellow fever virus and dengue fever virus to a selection of experimental antiviral agents. Cells infected with MMLV show dilation of the endoplasmic reticulum, a characteristic of flavivirus infection. Intraperitoneal, intranasal or direct intracerebral inoculation of SCID mice with MMLV resulted in encephalitis ultimately leading to death, whereas immunocompetent mice were refractory to either intranasal or intraperitoneal infection with MMLV. Viral RNA and/or antigens were detected in the brain and serum of MMLV-infected SCID mice, but not in any other organ examined: MMLV was detected in the olfactory lobes, the cerebral cortex, the limbic structures, the midbrain, cerebellum and medulla oblongata. Infection was confined to neurons. Treatment with the interferon-alpha/beta inducer poly(I).poly(C) protected SCID mice against MMLV-induced morbidity and mortality, and this protection correlated with a reduction in infectious virus titre and viral RNA load. This validates the MMLV model for use in antiviral drug studies. The MMLV SCID model may, therefore, be attractive for the study of chemoprophylactic or chemotherapeutic strategies against flavivirus infections causing encephalitis.

  5. Development of a physiologically based pharmacokinetic model for bisphenol A in pregnant mice

    SciTech Connect

    Kawamoto, Yuko; Matsuyama, Wakoto; Wada, Masahiro; Hishikawa, Junko; Chan, Melissa Pui Ling; Nakayama, Aki; Morisawa, Shinsuke

    2007-10-15

    Bisphenol A (BPA) is a weakly estrogenic monomer used to produce polymers for food contact and other applications, so there is potential for oral exposure of humans to trace amounts via ingestion. To date, no physiologically based pharmacokinetic (PBPK) model has been located for BPA in pregnant mice with or without fetuses. An estimate by a mathematical model is essential since information on humans is difficult to obtain experimentally. The PBPK model was constructed based on the pharmacokinetic data of our experiment following single oral administration of BPA to pregnant mice. The risk assessment of bisphenol A (BPA) on the development of human offspring is an important issue. There have been limited data on the exposure level of human fetuses to BPA (e.g. BPA concentration in cord blood) and no information is available on the pharmacokinetics of BPA in humans with or without fetuses. In the present study, we developed a physiologically based pharmacokinetic (PBPK) model describing the pharmacokinetics of BPA in a pregnant mouse with the prospect of future extrapolation to humans. The PBPK model was constructed based on the pharmacokinetic data of an experiment we executed on pregnant mice following single oral administration of BPA. The model could describe the rapid transfer of BPA through the placenta to the fetus and the slow disappearance from fetuses. The simulated time courses after three-time repeated oral administrations of BPA by the constructed model fitted well with the experimental data, and the simulation for the 10 times lower dose was also consistent with the experiment. This suggested that the PBPK model for BPA in pregnant mice was successfully verified and is highly promising for extrapolation to humans who are expected to be exposed more chronically to lower doses.

  6. Down Syndrome Cognitive Phenotypes Modeled in Mice Trisomic for All HSA 21 Homologues

    PubMed Central

    Belichenko, Pavel V.; Kleschevnikov, Alexander M.; Becker, Ann; Wagner, Grant E.; Lysenko, Larisa V.; Yu, Y. Eugene; Mobley, William C.

    2015-01-01

    Down syndrome (DS), trisomy for chromosome 21, is the most common genetic cause of intellectual disability. The genomic regions on human chromosome 21 (HSA21) are syntenically conserved with regions on mouse chromosomes 10, 16, and 17 (Mmu10, Mmu16, and Mmu17). Recently, we created a genetic model of DS which carries engineered duplications of all three mouse syntenic regions homologous to HSA21. This ‘triple trisomic’ or TTS model thus represents the most complete and accurate murine model currently available for experimental studies of genotype-phenotype relationships in DS. Here we extended our initial studies of TTS mice. Locomotor activity, stereotypic and repetitive behavior, anxiety, working memory, long-term memory, and synaptic plasticity in the dentate gyrus were examined in the TTS and wild-type (WT) control mice. Changes in locomotor activity were most remarkable for a significant increase in ambulatory time and a reduction in average velocity of TTS mice. No changes were detected in repetitive and stereotypic behavior and in measures of anxiety. Working memory showed no changes when tested in Y-maze, but deficiency in a more challenging T-maze test was detected. Furthermore, long-term object recognition memory was significantly reduced in the TTS mice. These changes were accompanied by deficient long-term potentiation in the dentate gyrus, which was restored to the WT levels following blockade of GABAA receptors with picrotoxin (100 μM). TTS mice thus demonstrated a number of phenotypes characteristic of DS and may serve as a new standard by which to evaluate and direct findings in other less complete models of DS. PMID:26230397

  7. Omega-3 polyunsaturated fatty acids ameliorate the severity of ileitis in the senescence accelerated mice (SAM)P1/Yit mice model

    PubMed Central

    Matsunaga, H; Hokari, R; Kurihara, C; Okada, Y; Takebayashi, K; Okudaira, K; Watanabe, C; Komoto, S; Nakamura, M; Tsuzuki, Y; Kawaguchi, A; Nagao, S; Miura, S

    2009-01-01

    Clinical studies using omega-3 polyunsaturated fatty acids (ω3-PUFA) to Crohn's disease (CD) are conflicting. Beneficial effects of dietary ω3-PUFA intake in various experimental inflammatory bowel disease (IBD) models have been reported. However, animal models of large intestinal inflammation have been used in all previous studies, and the effect of ω3 fat in an animal model of small intestinal inflammation has not been reported. We hypothesized that the effects of ω3 fat are different between large and small intestine. The aim of this study was to determine whether the direct effect of ω3 fat is beneficial for small intestinal inflammation. Senescence accelerated mice (SAM)P1/Yit mice showed remarkable inflammation of the terminal ileum spontaneously. The numbers of F4/80-positive monocyte–macrophage cells as well as β7-integrin-positive lymphocytes in the intestinal mucosa were increased significantly compared with those in the control mice (AKR-J mice). The area of mucosal addressin cell adhesion molecule-1 (MAdCAM-1)-positive vessels was also increased. The degree of expression levels of monocyte chemoattractant protein-1 (MCP-1), interleukin (IL)-6 and interferon (IFN)-γ mRNA were increased significantly compared with those in the control mice. The feeding of two different kinds of ω3 fat (fish-oil-rich and perilla-oil-rich diets) for 16 weeks to SAMP1/Yit mice ameliorated inflammation of the terminal ileum significantly. In both the ω3-fat-rich diet groups, enhanced infiltration of F4/80-positive monocytes/macrophages in intestinal mucosa of SAMP1/Yit mice cells and the increased levels of MCP-1, IL-6 and IFN-γ mRNA expression were ameliorated significantly compared with those in the control diet group. The results suggest that ω3 fat is beneficial for small intestinal inflammation by inhibition of monocyte recruitment to inflamed intestinal mucosa. PMID:19793338

  8. SAMHD1 knockout mice: modeling retrovirus restriction in vivo.

    PubMed

    Wu, Li

    2013-11-20

    The host dNTP hydrolase SAMHD1 acts as a viral restriction factor to inhibit the replication of several retroviruses and DNA viruses in non-cycling human immune cells. However, understanding the physiological role of mammalian SAMHD1 has been elusive due to the lack of an animal model. Two recent studies reported the generation of samhd1 knockout mouse models for investigating the restriction of HIV-1 vectors and endogenous retroviruses in vivo. Both studies suggest that SAMHD1 is important for regulating the intracellular dNTP pool and the intrinsic immunity against retroviral infection, despite different outcomes of HIV-1 vector transduction in these mouse models. Here I discuss the significance of these new findings and the future directions in studying SAMHD1-mediated retroviral restriction.

  9. Geospatial modeling approach to monument construction using Michigan from A.D. 1000-1600 as a case study.

    PubMed

    Howey, Meghan C L; Palace, Michael W; McMichael, Crystal H

    2016-07-01

    Building monuments was one way that past societies reconfigured their landscapes in response to shifting social and ecological factors. Understanding the connections between those factors and monument construction is critical, especially when multiple types of monuments were constructed across the same landscape. Geospatial technologies enable past cultural activities and environmental variables to be examined together at large scales. Many geospatial modeling approaches, however, are not designed for presence-only (occurrence) data, which can be limiting given that many archaeological site records are presence only. We use maximum entropy modeling (MaxEnt), which works with presence-only data, to predict the distribution of monuments across large landscapes, and we analyze MaxEnt output to quantify the contributions of spatioenvironmental variables to predicted distributions. We apply our approach to co-occurring Late Precontact (ca. A.D. 1000-1600) monuments in Michigan: (i) mounds and (ii) earthwork enclosures. Many of these features have been destroyed by modern development, and therefore, we conducted archival research to develop our monument occurrence database. We modeled each monument type separately using the same input variables. Analyzing variable contribution to MaxEnt output, we show that mound and enclosure landscape suitability was driven by contrasting variables. Proximity to inland lakes was key to mound placement, and proximity to rivers was key to sacred enclosures. This juxtaposition suggests that mounds met local needs for resource procurement success, whereas enclosures filled broader regional needs for intergroup exchange and shared ritual. Our study shows how MaxEnt can be used to develop sophisticated models of past cultural processes, including monument building, with imperfect, limited, presence-only data.

  10. Geospatial modeling approach to monument construction using Michigan from A.D. 1000–1600 as a case study

    PubMed Central

    Howey, Meghan C. L.; Palace, Michael W.; McMichael, Crystal H.

    2016-01-01

    Building monuments was one way that past societies reconfigured their landscapes in response to shifting social and ecological factors. Understanding the connections between those factors and monument construction is critical, especially when multiple types of monuments were constructed across the same landscape. Geospatial technologies enable past cultural activities and environmental variables to be examined together at large scales. Many geospatial modeling approaches, however, are not designed for presence-only (occurrence) data, which can be limiting given that many archaeological site records are presence only. We use maximum entropy modeling (MaxEnt), which works with presence-only data, to predict the distribution of monuments across large landscapes, and we analyze MaxEnt output to quantify the contributions of spatioenvironmental variables to predicted distributions. We apply our approach to co-occurring Late Precontact (ca. A.D. 1000–1600) monuments in Michigan: (i) mounds and (ii) earthwork enclosures. Many of these features have been destroyed by modern development, and therefore, we conducted archival research to develop our monument occurrence database. We modeled each monument type separately using the same input variables. Analyzing variable contribution to MaxEnt output, we show that mound and enclosure landscape suitability was driven by contrasting variables. Proximity to inland lakes was key to mound placement, and proximity to rivers was key to sacred enclosures. This juxtaposition suggests that mounds met local needs for resource procurement success, whereas enclosures filled broader regional needs for intergroup exchange and shared ritual. Our study shows how MaxEnt can be used to develop sophisticated models of past cultural processes, including monument building, with imperfect, limited, presence-only data. PMID:27330115

  11. Geospatial modeling approach to monument construction using Michigan from A.D. 1000-1600 as a case study.

    PubMed

    Howey, Meghan C L; Palace, Michael W; McMichael, Crystal H

    2016-07-01

    Building monuments was one way that past societies reconfigured their landscapes in response to shifting social and ecological factors. Understanding the connections between those factors and monument construction is critical, especially when multiple types of monuments were constructed across the same landscape. Geospatial technologies enable past cultural activities and environmental variables to be examined together at large scales. Many geospatial modeling approaches, however, are not designed for presence-only (occurrence) data, which can be limiting given that many archaeological site records are presence only. We use maximum entropy modeling (MaxEnt), which works with presence-only data, to predict the distribution of monuments across large landscapes, and we analyze MaxEnt output to quantify the contributions of spatioenvironmental variables to predicted distributions. We apply our approach to co-occurring Late Precontact (ca. A.D. 1000-1600) monuments in Michigan: (i) mounds and (ii) earthwork enclosures. Many of these features have been destroyed by modern development, and therefore, we conducted archival research to develop our monument occurrence database. We modeled each monument type separately using the same input variables. Analyzing variable contribution to MaxEnt output, we show that mound and enclosure landscape suitability was driven by contrasting variables. Proximity to inland lakes was key to mound placement, and proximity to rivers was key to sacred enclosures. This juxtaposition suggests that mounds met local needs for resource procurement success, whereas enclosures filled broader regional needs for intergroup exchange and shared ritual. Our study shows how MaxEnt can be used to develop sophisticated models of past cultural processes, including monument building, with imperfect, limited, presence-only data. PMID:27330115

  12. Of Mice and Melanoma: PDX System for Modeling Personalized Medicine.

    PubMed

    Hartsough, Edward J; Aplin, Andrew E

    2016-04-01

    Targeted therapies have advanced the treatment options for cutaneous melanoma, but many patients will progress on drug. Patient-derived xenografts (PDX) can be used to recapitulate therapy-resistant tumors. Furthermore, PDX modeling can be utilized in combination with targeted sequencing and phosphoproteomic platforms, providing preclinical basis for second-line targeted inhibitor strategies. See related article by Krepler et al., p. 1592.

  13. Antidepressant-like effect of mitragynine isolated from Mitragyna speciosa Korth in mice model of depression.

    PubMed

    Idayu, N Farah; Hidayat, M Taufik; Moklas, M A M; Sharida, F; Raudzah, A R Nurul; Shamima, A R; Apryani, Evhy

    2011-03-15

    Mitragyna speciosa Korth. leaves have been used for decades as a traditional medicine to treat diarrhea, diabetes and to improve blood circulation by natives of Malaysia, Thailand and other regions of Southeast Asia. Mitragynine is the major active alkaloid in the plant. To date, the role of mitragynine in psychological disorders such as depression is not scientifically evaluated. Hence, the present investigation evaluates the antidepressant effect of mitragynine in the mouse forced swim test (FST) and tail suspension test (TST), two models predictive of antidepressant activity and the effect of mitragynine towards neuroendocrine system of hypothalamic-pituitary-adrenal (HPA) axis by measuring the corticosterone concentration of mice exposed to FST and TST. An open-field test (OFT) was used to detect any association of immobility in the FST and TST with changes in motor activity of mice treated with mitragynine. In the present study, mitragynine at dose of 10 mg/kg and 30 mg/kg i.p. injected significantly reduced the immobility time of mice in both FST and TST without any significant effect on locomotor activity in OFT. Moreover, mitragynine significantly reduced the released of corticosterone in mice exposed to FST and TST at dose of 10 mg/kg and 30 mg/kg. Overall, the present study clearly demonstrated that mitragynine exerts an antidepressant effect in animal behavioral model of depression (FST and TST) and the effect appears to be mediated by an interaction with neuroendocrine HPA axis systems. PMID:20869223

  14. Neuropathology of mice with targeted disruption of Hexa gene, a model of Tay-Sachs disease.

    PubMed

    Taniike, M; Yamanaka, S; Proia, R L; Langaman, C; Bone-Turrentine, T; Suzuki, K

    1995-01-01

    A murine model of Tay-Sachs disease, the prototype of the GM2 gangliosidoses, was produced through the targeted disruption of the Hexa gene encoding the subunit of alpha-hexosaminidase A. The mice were completely devoid of beta-hexosaminidase A activity and accumulated GM2 ganglioside in the CNS in an age-dependent manner. Neurons with membranous cytoplasmic bodies (MCBs), identical to those described in Tay-Sachs disease, were identified in the brain of these mice. The neurons with MCBs were periodic acid-Schiff-positive on frozen sections and immunostained with anti-GM2 ganglioside antibody. However, unlike Tay-Sachs disease in which neurons throughout the brain are affected, the localization of storage neurons in these mice appeared to be limited to certain regions, i.e., cerebral cortex, the hippocampus, amygdala, hypothalamus, mammillary nucleus, etc. Storage neurons were absent in the olfactory bulb, cerebellar cortex and spinal anterior horns. The difference in the distribution of storage neurons suggests a difference of ganglioside metabolism between humans and mice. This model is useful for the study of the pathogenic mechanisms of neuronal storage in Tay-Sachs disease and for the evaluation of therapeutic strategies.

  15. Investigation of the influence of vanadium compounds treatment in NZO mice model--preliminary study.

    PubMed

    Krośniak, Mirosław; Francik, Renata; Kołodziejczyk, Katarzyna; Wojtanowska-Krośniak, Agnieszka; Tedeschi, Cinzia; Petrone, Veronica; Gryboś, Ryszard

    2014-01-01

    Abstract: New Zealand obese mice (NZO) are characterized by symptoms similar to human metabolic syndrome. Vanadium in different investigations showed anti-diabetic activity but until now an NZO mice model has not been tested with this element. The aim of this study was to investigate anti-diabetic activity of three vanadium compounds (VOSO4, VO(mal)2 and Na(VO(O2)2bpy) x 8H2O) in the NZO model. Metabolic syndrome was induced by special diet (1.5% of cholesterol and 15% of saturated fatty acids) during 8 weeks. In the next 5 weeks, the tested vanadium compounds were administered once daily, in a dose of 0.063 mmol/kg of body mass. At the end of the experiment, glucose, cholesterol, triglycerides and alanine transaminase were measured in the serum. The obtained results showed that the glucose level was decreased nearly to the healthy NZO mice in comparison to the NZO mice with metabolic syndrome. In all groups on the diet with cholesterol, the level of this parameter was statistically higher in comparison to the group without cholesterol addition. Vanadium treatment in a dose 0.063 mmol/kg of body mass does not influence cholesterol, triglycerides and alanine transaminase activity.

  16. Antidepressant-like effect of mitragynine isolated from Mitragyna speciosa Korth in mice model of depression.

    PubMed

    Idayu, N Farah; Hidayat, M Taufik; Moklas, M A M; Sharida, F; Raudzah, A R Nurul; Shamima, A R; Apryani, Evhy

    2011-03-15

    Mitragyna speciosa Korth. leaves have been used for decades as a traditional medicine to treat diarrhea, diabetes and to improve blood circulation by natives of Malaysia, Thailand and other regions of Southeast Asia. Mitragynine is the major active alkaloid in the plant. To date, the role of mitragynine in psychological disorders such as depression is not scientifically evaluated. Hence, the present investigation evaluates the antidepressant effect of mitragynine in the mouse forced swim test (FST) and tail suspension test (TST), two models predictive of antidepressant activity and the effect of mitragynine towards neuroendocrine system of hypothalamic-pituitary-adrenal (HPA) axis by measuring the corticosterone concentration of mice exposed to FST and TST. An open-field test (OFT) was used to detect any association of immobility in the FST and TST with changes in motor activity of mice treated with mitragynine. In the present study, mitragynine at dose of 10 mg/kg and 30 mg/kg i.p. injected significantly reduced the immobility time of mice in both FST and TST without any significant effect on locomotor activity in OFT. Moreover, mitragynine significantly reduced the released of corticosterone in mice exposed to FST and TST at dose of 10 mg/kg and 30 mg/kg. Overall, the present study clearly demonstrated that mitragynine exerts an antidepressant effect in animal behavioral model of depression (FST and TST) and the effect appears to be mediated by an interaction with neuroendocrine HPA axis systems.

  17. Spaced training rescues memory and ERK1/2 signaling in fragile X syndrome model mice.

    PubMed

    Seese, Ronald R; Wang, Kathleen; Yao, Yue Qin; Lynch, Gary; Gall, Christine M

    2014-11-25

    Recent studies have shown that short, spaced trains of afferent stimulation produce much greater long-term potentiation (LTP) than that obtained with a single, prolonged stimulation episode. The present studies demonstrate that spaced training regimens, based on these LTP timing rules, facilitate learning in wild-type (WT) mice and can offset learning and synaptic signaling impairments in the fragile X mental retardation 1 (Fmr1) knockout (KO) model of fragile X syndrome. We determined that 5 min of continuous training supports object location memory (OLM) in WT but not Fmr1 KO mice. However, the same amount of training distributed across three short trials, spaced by one hour, produced robust long-term memory in the KOs. At least three training trials were needed to realize the benefit of spacing, and intertrial intervals shorter or longer than 60 min were ineffective. Multiple short training trials also rescued novel object recognition in Fmr1 KOs. The spacing effect was surprisingly potent: just 1 min of OLM training, distributed across three trials, supported robust memory in both genotypes. Spacing also rescued training-induced activation of synaptic ERK1/2 in dorsal hippocampus of Fmr1 KO mice. These results show that a spaced training regimen designed to maximize synaptic potentiation facilitates recognition memory in WT mice and can offset synaptic signaling and memory impairments in a model of congenital intellectual disability.

  18. Mice deficient in biglycan and fibromodulin as a model for temporomandibular joint osteoarthritis.

    PubMed

    Wadhwa, Sunil; Embree, Mildred; Ameye, Laurent; Young, Marian F

    2005-01-01

    The temporomandibular joint (TMJ) within the craniofacial complex is unique. In humans, the TMJ can become diseased resulting in severe and disabling pain. There are no cures for TMJ disease at this time. Animal models of TMJ disease are scarce, but some exist, and they are described in this paper. We present in greater detail one animal model that is deficient in two extracellular matrix (ECM) proteoglycans, biglycan (BGN) and fibromodulin (FMOD). Doubly deficient BGN/FMOD mice develop premature TMJ osteoarthritis (OA). In order to explore the mechanistic basis of TMJ-OA, tissues from the condyle of mutant mice were examined for their relative capacity to differentiate and undergo apoptosis. Our data show that there is a redistribution of the critical ECM protein, type II collagen, in mutant mice compared with controls. Mutant mice also have increased apoptosis of the chondrocytes embedded in the articular cartilage. We speculate that the overall imbalance in apoptosis may be the cellular basis for the abnormal production of structural ECM proteins. The abnormal production of the ECM could, in turn, lead to premature erosion and degradation of the articular surface resulting in TMJ-OA. These data underscore the importance of the ECM in controlling the structural integrity of the TMJ. PMID:16612079

  19. B cell deficient mice are protected from biliary obstruction in the rotavirus-induced mouse model of biliary atresia.

    PubMed

    Feldman, Amy G; Tucker, Rebecca M; Fenner, Erika K; Pelanda, Roberta; Mack, Cara L

    2013-01-01

    A leading theory regarding the pathogenesis of biliary atresia (BA) is that bile duct injury is initiated by a virus infection, followed by an autoimmune response targeting bile ducts. In experimental models of autoimmune diseases, B cells have been shown to play an important role. The aim of this study was to determine the role of B cells in the development of biliary obstruction in the Rhesus rotavirus (RRV)-induced mouse model of BA. Wild-type (WT) and B cell-deficient (Ig-α(-/-)) mice received RRV shortly after birth. Ig-α(-/-) RRV-infected mice had significantly increased disease-free survival rate compared to WT RRV-infected BA mice (76.8% vs. 17.5%). In stark contrast to the RRV-infected BA mice, the RRV-infected Ig-α(-/-) mice did not have hyperbilirubinemia or bile duct obstruction. The RRV-infected Ig-α(-/-) mice had significantly less liver inflammation and Th1 cytokine production compared to RRV-infected WT mice. In addition, Ig-α(-/-) mice had significantly increased numbers of regulatory T cells (Tregs) at baseline and after RRV infection compared to WT mice. However, depletion of Tregs in Ig-α(-/-) mice did not induce biliary obstruction, indicating that the expanded Tregs in the Ig-α(-/-) mice were not the sole reason for protection from disease. Conclusion : B cell deficient Ig-α(-/-) mice are protected from biliary obstruction in the RRV-induced mouse model of BA, indicating a primary role of B cells in mediating disease pathology. The mechanism of protection may involve lack of B cell antigen presentation, which impairs T-cell activation and Th1 inflammation. Immune modulators that inhibit B cell function may be a new strategy for treatment of BA.

  20. Mathematical modeling of left ventricular dimensional changes in mice during aging.

    PubMed

    Yang, Tianyi; Chiao, Ying Ann; Wang, Yunji; Voorhees, Andrew; Han, Hai-Chao; Lindsey, Merry L; Jin, Yu-Fang

    2012-01-01

    Cardiac aging is characterized by diastolic dysfunction of the left ventricle (LV), which is due in part to increased LV wall stiffness. In the diastolic phase, myocytes are relaxed and extracellular matrix (ECM) is a critical determinant to the changes of LV wall stiffness. To evaluate the effects of ECM composition on cardiac aging, we developed a mathematical model to predict LV dimension and wall stiffness changes in aging mice by integrating mechanical laws and our experimental results. We measured LV dimension, wall thickness, LV mass, and collagen content for wild type (WT) C57/BL6J mice of ages ranging from 7.3 months to those of 34.0 months. The model was established using the thick wall theory and stretch-induced tissue growth to an isotropic and homogeneous elastic composite with mixed constituents. The initial conditions of the simulation were set based on the data from the young mice. Matlab simulations of this mathematical model demonstrated that the model captured the major features of LV remodeling with age and closely approximated experimental results. Specifically, the temporal progression of the LV interior and exterior dimensions demonstrated the same trend and order-of-magnitude change as our experimental results. In conclusion, we present here a validated mathematical model of cardiac aging that applies the thick-wall theory and stretch-induced tissue growth to LV remodeling with age. PMID:23281647

  1. Alisertib added to rituximab and vincristine is synthetic lethal and potentially curative in mice with aggressive DLBCL co-overexpressing MYC and BCL2.

    PubMed

    Mahadevan, Daruka; Morales, Carla; Cooke, Laurence S; Manziello, Ann; Mount, David W; Persky, Daniel O; Fisher, Richard I; Miller, Thomas P; Qi, Wenqing

    2014-01-01

    Pearson correlation coefficient for expression analysis of the Lymphoma/Leukemia Molecular Profiling Project (LLMPP) demonstrated Aurora A and B are highly correlated with MYC in DLBCL and mantle cell lymphoma (MCL), while both Auroras correlate with BCL2 only in DLBCL. Auroras are up-regulated by MYC dysregulation with associated aneuploidy and resistance to microtubule targeted agents such as vincristine. Myc and Bcl2 are differentially expressed in U-2932, TMD-8, OCI-Ly10 and Granta-519, but only U-2932 cells over-express mutated p53. Alisertib [MLN8237 or M], a highly selective small molecule inhibitor of Aurora A kinase, was synergistic with vincristine [VCR] and rituximab [R] for inhibition of cell proliferation, abrogation of cell cycle checkpoints and enhanced apoptosis versus single agent or doublet therapy. A DLBCL (U-2932) mouse model showed tumor growth inhibition (TGI) of ∼ 10-20% (p = 0.001) for M, VCR and M-VCR respectively, while R alone showed ∼ 50% TGI (p = 0.001). M-R and VCR-R led to tumor regression [TR], but relapsed 10 days after discontinuing therapy. In contrast, M-VCR-R demonstrated TR with no relapse >40 days after stopping therapy with a Kaplan-Meier survival of 100%. Genes that are modulated by M-VCR-R (CENP-C, Auroras) play a role in centromere-kinetochore function in an attempt to maintain mitosis in the presence of synthetic lethality. Together, our data suggest that the interaction between alisertib plus VCR plus rituximab is synergistic and synthetic lethal in Myc and Bcl-2 co-expressing DLBCL. Alisertib plus vincristine plus rituximab [M-VCR-R] may represent a new strategy for DLBCL therapy. PMID:24893165

  2. Alisertib Added to Rituximab and Vincristine Is Synthetic Lethal and Potentially Curative in Mice with Aggressive DLBCL Co-Overexpressing MYC and BCL2

    PubMed Central

    Mahadevan, Daruka; Morales, Carla; Cooke, Laurence S.; Manziello, Ann; Mount, David W.; Persky, Daniel O.; Fisher, Richard I.; Miller, Thomas P.; Qi, Wenqing

    2014-01-01

    Pearson correlation coefficient for expression analysis of the Lymphoma/Leukemia Molecular Profiling Project (LLMPP) demonstrated Aurora A and B are highly correlated with MYC in DLBCL and mantle cell lymphoma (MCL), while both Auroras correlate with BCL2 only in DLBCL. Auroras are up-regulated by MYC dysregulation with associated aneuploidy and resistance to microtubule targeted agents such as vincristine. Myc and Bcl2 are differentially expressed in U-2932, TMD-8, OCI-Ly10 and Granta-519, but only U-2932 cells over-express mutated p53. Alisertib [MLN8237 or M], a highly selective small molecule inhibitor of Aurora A kinase, was synergistic with vincristine [VCR] and rituximab [R] for inhibition of cell proliferation, abrogation of cell cycle checkpoints and enhanced apoptosis versus single agent or doublet therapy. A DLBCL (U-2932) mouse model showed tumor growth inhibition (TGI) of ∼10–20% (p = 0.001) for M, VCR and M-VCR respectively, while R alone showed ∼50% TGI (p = 0.001). M-R and VCR-R led to tumor regression [TR], but relapsed 10 days after discontinuing therapy. In contrast, M-VCR-R demonstrated TR with no relapse >40 days after stopping therapy with a Kaplan-Meier survival of 100%. Genes that are modulated by M-VCR-R (CENP-C, Auroras) play a role in centromere-kinetochore function in an attempt to maintain mitosis in the presence of synthetic lethality. Together, our data suggest that the interaction between alisertib plus VCR plus rituximab is synergistic and synthetic lethal in Myc and Bcl-2 co-expressing DLBCL. Alisertib plus vincristine plus rituximab [M-VCR-R] may represent a new strategy for DLBCL therapy. PMID:24893165

  3. Alisertib added to rituximab and vincristine is synthetic lethal and potentially curative in mice with aggressive DLBCL co-overexpressing MYC and BCL2.

    PubMed

    Mahadevan, Daruka; Morales, Carla; Cooke, Laurence S; Manziello, Ann; Mount, David W; Persky, Daniel O; Fisher, Richard I; Miller, Thomas P; Qi, Wenqing

    2014-01-01

    Pearson correlation coefficient for expression analysis of the Lymphoma/Leukemia Molecular Profiling Project (LLMPP) demonstrated Aurora A and B are highly correlated with MYC in DLBCL and mantle cell lymphoma (MCL), while both Auroras correlate with BCL2 only in DLBCL. Auroras are up-regulated by MYC dysregulation with associated aneuploidy and resistance to microtubule targeted agents such as vincristine. Myc and Bcl2 are differentially expressed in U-2932, TMD-8, OCI-Ly10 and Granta-519, but only U-2932 cells over-express mutated p53. Alisertib [MLN8237 or M], a highly selective small molecule inhibitor of Aurora A kinase, was synergistic with vincristine [VCR] and rituximab [R] for inhibition of cell proliferation, abrogation of cell cycle checkpoints and enhanced apoptosis versus single agent or doublet therapy. A DLBCL (U-2932) mouse model showed tumor growth inhibition (TGI) of ∼ 10-20% (p = 0.001) for M, VCR and M-VCR respectively, while R alone showed ∼ 50% TGI (p = 0.001). M-R and VCR-R led to tumor regression [TR], but relapsed 10 days after discontinuing therapy. In contrast, M-VCR-R demonstrated TR with no relapse >40 days after stopping therapy with a Kaplan-Meier survival of 100%. Genes that are modulated by M-VCR-R (CENP-C, Auroras) play a role in centromere-kinetochore function in an attempt to maintain mitosis in the presence of synthetic lethality. Together, our data suggest that the interaction between alisertib plus VCR plus rituximab is synergistic and synthetic lethal in Myc and Bcl-2 co-expressing DLBCL. Alisertib plus vincristine plus rituximab [M-VCR-R] may represent a new strategy for DLBCL therapy.

  4. A physiological model for simulation of benzene metabolism by rats and mice.

    PubMed

    Medinsky, M A; Sabourin, P J; Lucier, G; Birnbaum, L S; Henderson, R F

    1989-06-15

    Studies conducted by the National Toxicology Program on the chronic toxicity of benzene indicated that B6C3F1 mice are more sensitive to the toxic effects of benzene than are F344 rats. A physiological model was developed to describe the uptake and metabolism of benzene in rats and mice and to determine if the observed differences in toxic effects could be explained by differences in the pathways for metabolism of benzene or by differences in uptake of benzene. Major pathways for elimination of benzene included metabolism to hydroquinone glucuronide or hydroquinone sulfate, phenyl glucuronide or phenyl sulfate, muconic acid, and prephenyl mercapturic acid or phenyl mercapturic acid. Model simulations for total benzene metabolized and for profiles of benzene metabolites were conducted for oral or inhalation exposure and compared to data for urinary excretion of benzene metabolites after exposure of rats and mice to [14C]- or [3H]-benzene by inhalation or gavage. Results for total amount of benzene metabolized, expressed per kilogram body weight, indicated that for inhalation exposure concentrations up to 1000 ppm, mice metabolized at least two to three times as much benzene as did rats. Simulations of oral exposure to benzene resulted in more benzene metabolized per kilogram body weight by rats at oral exposures of greater than 50 mg/kg. Patterns of metabolites formed after either route of exposure were very different for F344/N rats and B6C3F1 mice. Rats primarily formed the detoxification metabolite, phenyl sulfate. Mice formed hydroquinone glucuronide and muconic acid in addition to phenyl sulfate. Hydroquinone and muconic acid are associated with pathways leading to the formation of the putative toxic metabolites of benzene. Metabolic rate parameters, Vmax and Km, were very different for hydroquinone conjugate and muconic acid formation compared to formation of phenyl conjugates and phenyl mercapturic acids. Putative toxication pathways could be characterized as

  5. Olfactory delayed matching to sample performance in mice: sex differences in the 5XFAD mouse model of Alzheimer's disease.

    PubMed

    Roddick, Kyle M; Schellinck, Heather M; Brown, Richard E

    2014-08-15

    While olfactory delayed matching-to-sample tasks have been used to assess working memory in rats, no such tasks have been tested in mice. Olfactory delayed matching-to-sample learning was assessed in male and female 5XFAD mice, a model of Alzheimer's disease, and their wildtype (B6SJL F1) littermates at 6-7 months of age using an operant olfactometer. All 5XFAD and wildtype mice were able to learn the delayed olfactory matching-to-sample task at 2 and 5s delays. Fewer mice learned with a 10s delay and only one mouse learned with a 30s delay. Female mice showed higher levels of performance on the delayed matching-to-sample task than males, indicative of better working memory. These results demonstrate for the first time that mice are able to learn an olfactory delayed matching to sample task.

  6. Of mice and men: modelling post-stroke depression experimentally

    PubMed Central

    Kronenberg, G; Gertz, K; Heinz, A; Endres, M

    2014-01-01

    At least one-third of stroke survivors suffer from depression. The development of comorbid depression after stroke is clinically highly significant because post-stroke depression is associated with increased mortality, slows recovery and leads to worse functional outcomes. Here, we review the evidence that post-stroke depression can be effectively modelled in experimental rodents via a variety of approaches. This opens an exciting new window onto the neurobiology of depression and permits probing potential underlying mechanisms such as disturbed cellular plasticity, neuroendocrine dysregulation, neuroinflammation, and neurodegeneration in a novel context. From the point of view of translational stroke research, extending the scope of experimental investigations beyond the study of short-term end points and, in particular, acute lesion size, may help improve the relevance of preclinical results to human disease. Furthermore, accumulating evidence from both clinical and experimental studies offers the tantalizing prospect of 5-hydroxytryptaminergic antidepressants as the first pharmacological therapy for stroke that would be available during the subacute and chronic phases of recovery. Interdisciplinary neuropsychiatric research will be called on to dissect the mechanisms underpinning the beneficial effects of antidepressants on stroke recovery. Linked Articles This article is part of a themed section on Animal Models in Psychiatry Research. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2014.171.issue-20 PMID:24838087

  7. Modeling mitochondrial dysfunctions in the brain: from mice to men.

    PubMed

    Breuer, Megan E; Willems, Peter H G M; Russel, Frans G M; Koopman, Werner J H; Smeitink, Jan A M

    2012-03-01

    The biologist Lewis Thomas once wrote: "my mitochondria comprise a very large proportion of me. I cannot do the calculation, but I suppose there is almost as much of them in sheer dry bulk as there is the rest of me". As humans, or indeed as any mammal, bird, or insect, we contain a specific molecular makeup that is driven by vast numbers of these miniscule powerhouses residing in most of our cells (mature red blood cells notwithstanding), quietly replicating, living independent lives and containing their own DNA. Everything we do, from running a marathon to breathing, is driven by these small batteries, and yet there is evidence that these molecular energy sources were originally bacteria, possibly parasitic, incorporated into our cells through symbiosis. Dysfunctions in these organelles can lead to debilitating, and sometimes fatal, diseases of almost all the bodies' major organs. Mitochondrial dysfunction has been implicated in a wide variety of human disorders either as a primary cause or as a secondary consequence. To better understand the role of mitochondrial dysfunction in human disease, a multitude of pharmacologically induced and genetically manipulated animal models have been developed showing to a greater or lesser extent the clinical symptoms observed in patients with known and unknown causes of the disease. This review will focus on diseases of the brain and spinal cord in which mitochondrial dysfunction has been proven or is suspected and on animal models that are currently used to study the etiology, pathogenesis and treatment of these diseases. PMID:21755361

  8. An alternant method to the traditional NASA hindlimb unloading model in mice.

    PubMed

    Ferreira, J Andries; Crissey, Jacqueline M; Brown, Marybeth

    2011-03-10

    The Morey-Holton hindlimb unloading (HU) method is a widely accepted National Aeronautics and Space Administration (NASA) ground-based model for studying disuse-atrophy in rodents. Our study evaluated an alternant method to the gold-standard Morey-Holton HU tail-traction technique in mice. Fifty-four female mice (4-8 mo.) were HU for 14 days (n=34) or 28 days (n=20). Recovery from HU was assessed after 3 days of normal cage ambulation following HU (n=22). Aged matched mice (n=76) served as weight-bearing controls. Prior to HU a tail ring was formed with a 2-0 sterile surgical steel wire that was passed through the 5(th), 6(th), or 7(th) inter-vertebral disc space and shaped into a ring from which the mice were suspended. Vertebral location for the tail-ring was selected to appropriately balance animal body weight without interfering with defecation. We determined the success of this novel HU technique by assessing body weight before and after HU, degree of soleus atrophy, and adrenal mass following HU. Body weight of the mice prior to HU (24.3 ± 2.9g) did not significantly decline immediately after 14d of HU (22.7 ± 1.9g), 28d of HU (21.3 + 2.1g) or after 3 days recovery (24.0 ± 1.8g). Soleus muscle mass significantly declined (-39.1%, and -46.6%) following HU for 14 days and 28 days respectively (p<0.001). Following 3 days of recovery soleus mass significantly increased to 74% of control values. Adrenal weights of HU mice were not different compared to control mice. The success of our novel HU method is evidenced by the maintenance of animal body weight, comparable adrenal gland weights, and soleus atrophy following HU, corresponding to expected literature values. The primary advantages of this HU method include: 1) ease of tail examination during suspension; 2) decreased likelihood of cyanotic, inflamed, and/or necrotic tails frequently observed with tail-taping and HU; 3) no possibility of mice chewing the traction tape and coming out of the suspension

  9. Linear and Nonlinear Growth Models for Value-Added Assessment: An Application to Spanish Primary and Secondary Schools' Progress in Reading Comprehension

    ERIC Educational Resources Information Center

    Lopez-Martin, Esther; Kuosmanen, Timo; Gaviria, Jose Luis

    2014-01-01

    Value-added models are considered one of the best alternatives not only for accountability purposes but also to improve the school system itself. The estimates provided by these models measure the contribution of schools to students' academic progress, once the effect of other factors outside school control are eliminated. The functional form…

  10. Impaired Maternal Behavior in Usp46 Mutant Mice: A Model for Trans-Generational Transmission of Maternal Care.

    PubMed

    Umemura, Shoya; Imai, Saki; Mimura, Ayumi; Fujiwara, Mari; Ebihara, Shizufumi

    2015-01-01

    Usp46 mutant mice (congenic strain on a B6 genetic background; MT mice) have a low weaning rate and display poor maternal behavior compared to C57BL/6J mice (B6 mice). Based on these observations, we examined how maternal behavior is shaped by cross-fostering and in-fostering MT and B6 mice. The experiments consisted of six groups: B6 mice fostered by their biological mother (B6-CO); MT mice fostered by their biological mother (MT-CO); B6 mice fostered by a different B6 mother (B6-IF); MT mice fostered by a different MT mother (MT-IF); B6 mice fostered by an MT mother (B6-CF); and MT mice fostered by a B6 mother (MT-CF). Maternal behavior was assessed using the pup-retrieval test in adult female offspring, and four parameters, time nursing pups in the nest, time sniffing or licking pups, rearing behavior, and latency to retrieve pups, were measured. Cross-fostering significantly reduced time spent nursing and sniffing/licking pup, and increased the number of instances of rearing in the B6-CF group, and improved three parameters of maternal behaviors (nursing, rearing and latency) in the MT-CF group. These results indicate that the level of maternal care is transmitted to their pups and proper maternal behaviors can be shaped if adequate postpartum maternal care is given, even in genetically vulnerable mice. However, the offspring's genotype may also influence the development of maternal behaviors in adulthood. Thus, MT mice may prove useful as a model for trans-generational transmission of maternal care, and these findings may provide insight into the mechanisms of maltreating behaviors in human child abuse.

  11. Transcriptional profiling reveals progeroid Ercc1-/Δ mice as a model system for glomerular aging

    PubMed Central

    2013-01-01

    Background Aging-related kidney diseases are a major health concern. Currently, models to study renal aging are lacking. Due to a reduced life-span progeroid models hold the promise to facilitate aging studies and allow examination of tissue-specific changes. Defects in genome maintenance in the Ercc1-/Δ progeroid mouse model result in premature aging and typical age-related pathologies. Here, we compared the glomerular transcriptome of young and aged Ercc1-deficient mice to young and aged WT mice in order to establish a novel model for research of aging-related kidney disease. Results In a principal component analysis, age and genotype emerged as first and second principal components. Hierarchical clustering of all 521 genes differentially regulated between young and old WT and young and old Ercc1-/Δ mice showed cluster formation between young WT and Ercc1-/Δ as well as old WT and Ercc1-/Δ samples. An unexpectedly high number of 77 genes were differentially regulated in both WT and Ercc1-/Δ mice (p < 0.0001). GO term enrichment analysis revealed these genes to be involved in immune and inflammatory response, cell death, and chemotaxis. In a network analysis, these genes were part of insulin signaling, chemokine and cytokine signaling and extracellular matrix pathways. Conclusion Beyond insulin signaling, we find chemokine and cytokine signaling as well as modifiers of extracellular matrix composition to be subject to major changes in the aging glomerulus. At the level of the transcriptome, the pattern of gene activities is similar in the progeroid Ercc1-/Δ mouse model constituting a valuable tool for future studies of aging-associated glomerular pathologies. PMID:23947592

  12. Behavioral models in mice. Implication of the alpha noradrenergic system.

    PubMed

    Hascoët, M; Bourin, M; Bradwejn, J

    1991-01-01

    1. The mechanism of action of drugs might change according to the test used. Several noradrenergic drugs were tested in order to understand their implication in the mobility tests. 2. It was found that clonidine, an Alpha 2 agonist, acted differently according to the test used. It provoked sedation in spontaneous activity test, and anti-immobility effects in the other tests. 3. Tail suspension test is able to show the double acting of clonidine. 4. Idazoxan might act either as an alpha 2 antagonist or as partial alpha 2 agonist. TST shown the unexpected partial alpha agonist effect of the molecule. 5. Forced swimming test is more specific for predicting antidepressant activity than tail suspension test which is close to a spontaneous activity model. PMID:1684874

  13. Behavioral models in mice. Implication of the alpha noradrenergic system.

    PubMed

    Hascoët, M; Bourin, M; Bradwejn, J

    1991-01-01

    1. The mechanism of action of drugs might change according to the test used. Several noradrenergic drugs were tested in order to understand their implication in the mobility tests. 2. It was found that clonidine, an Alpha 2 agonist, acted differently according to the test used. It provoked sedation in spontaneous activity test, and anti-immobility effects in the other tests. 3. Tail suspension test is able to show the double acting of clonidine. 4. Idazoxan might act either as an alpha 2 antagonist or as partial alpha 2 agonist. TST shown the unexpected partial alpha agonist effect of the molecule. 5. Forced swimming test is more specific for predicting antidepressant activity than tail suspension test which is close to a spontaneous activity model.

  14. [Establishment of a keloid model by transplanting human keloid onto the backs of nude mice].

    PubMed

    Philandrianos, C; Gonnelli, D; Andrac-Meyer, L; Bruno, M; Magalon, G; Mordon, S

    2014-08-01

    Keloid scar is a proliferative healing dysfunction formed by an excessive build-up of collagen fibers on the dermis. It is responsible of aesthetic and functional disabilities. There is no ideal treatment and recurrence occurs very often. Keloid scars occur only to human, that's why animal model needs to be made to study this pathology and new treatments. Few models have been described using human keloid scars implanted into subcutaneous tissue of nude mice or rat. To allow study of topical and laser treatment we have developed a new animal model using human keloid scar fragment with epidermal and dermal tissue implanted into back of nude mice like a full thickness skin graft. Keloid fragments from five donors have been grafted onto 40 nudes mice. Macroscopic and microscopic studies have been made at day 28, 56, 84 and 112. We observed integration of the fragments in all cases. Hyalinized collagen bundles were observed in all implant biopsies confirming the stability of the keloid architecture within 112 days. This model is easily reproducible and allows the study of topical treatment and laser due to the accessibility of the keloid.

  15. Histidine decarboxylase knockout mice, a genetic model of Tourette syndrome, show repetitive grooming after induced fear.

    PubMed

    Xu, Meiyu; Li, Lina; Ohtsu, Hiroshi; Pittenger, Christopher

    2015-05-19

    Tics, such as are seen in Tourette syndrome (TS), are common and can cause profound morbidity, but they are poorly understood. Tics are potentiated by psychostimulants, stress, and sleep deprivation. Mutations in the gene histidine decarboxylase (Hdc) have been implicated as a rare genetic cause of TS, and Hdc knockout mice have been validated as a genetic model that recapitulates phenomenological and pathophysiological aspects of the disorder. Tic-like stereotypies in this model have not been observed at baseline but emerge after acute challenge with the psychostimulant d-amphetamine. We tested the ability of an acute stressor to stimulate stereotypies in this model, using tone fear conditioning. Hdc knockout mice acquired conditioned fear normally, as manifested by freezing during the presentation of a tone 48h after it had been paired with a shock. During the 30min following tone presentation, knockout mice showed increased grooming. Heterozygotes exhibited normal freezing and intermediate grooming. These data validate a new paradigm for the examination of tic-like stereotypies in animals without pharmacological challenge and enhance the face validity of the Hdc knockout mouse as a pathophysiologically grounded model of tic disorders.

  16. Stress-Induced Executive Dysfunction in GDNF-Deficient Mice, A Mouse Model of Parkinsonism

    PubMed Central

    Buhusi, Mona; Olsen, Kaitlin; Yang, Benjamin Z.; Buhusi, Catalin V.

    2016-01-01

    Maladaptive reactivity to stress is linked to improper decision making, impulsivity, and discounting of delayed rewards. Chronic unpredictable stress (CUS) alters dopaminergic function, re-shapes dopaminergic circuits in key areas involved in decision making, and impairs prefrontal-cortex dependent response inhibition and working memory. Glial-derived neurotrophic factor (GDNF) is essential for regulating dopamine (DA) release in the basal ganglia and for the survival of dopaminergic neurons; GDNF-deficient mice are considered an animal model for aging-related Parkinsonism. Recently, GDNF expression in the striatum has been linked to resilience to stress. Here we investigated the effects of CUS on decision making in GDNF-heterozygous (HET) mice and their wild-type littermate controls (WT). Before CUS no differences in temporal discounting (TD) were found between genotypes. However, following CUS GDNF HET mice, having a partial reduction of GDNF levels, showed increased impulsive choice indexed by a reduction in percent Larger-Later (LL) choices in the TD paradigm, and a reduction in area under the TD curve. Moreover, stressed GDNF HET mice, but not their WT controls, showed decreased neuronal activation (number of cFos positive neurons) in the orbitofrontal cortex (OFC), nucleus accumbens (NA) core, and NA shell, suggestive of a maladaptive response to stress. Interestingly, area under the TD curve positively correlated with cFos activation in the NA core, and NA shell, but not with orbitofrontal activity. These results provide further evidence of the differential involvement of the OFC, NA core, and NA shell in impulsive choice, and identify GDNF-deficient mice as a double-hit (gene × environment) model of stress-related executive dysfunction, particularly relevant to substance abuse and Parkinson’s disease (PD). PMID:27445722

  17. Stress-Induced Executive Dysfunction in GDNF-Deficient Mice, A Mouse Model of Parkinsonism.

    PubMed

    Buhusi, Mona; Olsen, Kaitlin; Yang, Benjamin Z; Buhusi, Catalin V

    2016-01-01

    Maladaptive reactivity to stress is linked to improper decision making, impulsivity, and discounting of delayed rewards. Chronic unpredictable stress (CUS) alters dopaminergic function, re-shapes dopaminergic circuits in key areas involved in decision making, and impairs prefrontal-cortex dependent response inhibition and working memory. Glial-derived neurotrophic factor (GDNF) is essential for regulating dopamine (DA) release in the basal ganglia and for the survival of dopaminergic neurons; GDNF-deficient mice are considered an animal model for aging-related Parkinsonism. Recently, GDNF expression in the striatum has been linked to resilience to stress. Here we investigated the effects of CUS on decision making in GDNF-heterozygous (HET) mice and their wild-type littermate controls (WT). Before CUS no differences in temporal discounting (TD) were found between genotypes. However, following CUS GDNF HET mice, having a partial reduction of GDNF levels, showed increased impulsive choice indexed by a reduction in percent Larger-Later (LL) choices in the TD paradigm, and a reduction in area under the TD curve. Moreover, stressed GDNF HET mice, but not their WT controls, showed decreased neuronal activation (number of cFos positive neurons) in the orbitofrontal cortex (OFC), nucleus accumbens (NA) core, and NA shell, suggestive of a maladaptive response to stress. Interestingly, area under the TD curve positively correlated with cFos activation in the NA core, and NA shell, but not with orbitofrontal activity. These results provide further evidence of the differential involvement of the OFC, NA core, and NA shell in impulsive choice, and identify GDNF-deficient mice as a double-hit (gene × environment) model of stress-related executive dysfunction, particularly relevant to substance abuse and Parkinson's disease (PD). PMID:27445722

  18. Initiation-promotion model of tumor prevalence in mice from space radiation exposures.

    PubMed

    Cucinotta, F A; Wilson, J W

    1995-08-01

    Exposures in space consist of low-level background components from galactic cosmic rays (GCR), occasional intense-energetic solar-particle events, periodic passes through geomagnetic-trapped radiation, and exposure from possible onboard nuclear-propulsion engines. Risk models for astronaut exposure from such diverse components and modalities must be developed to assure adequate protection in future NASA missions. The low-level background exposures (GCR), including relativistic heavy ions (HZE), will be the ultimate limiting factor for astronaut career exposure. We consider herein a two-mutation, initiation-promotion, radiation-carcinogenesis model in mice in which the initiation stage is represented by a linear kinetics model of cellular repair/misrepair, including the track-structure model for heavy ion action cross-sections. The model is validated by comparison with the harderian gland tumor experiments of Alpen et al. for various ion beams. We apply the initiation-promotion model to exposures from galactic cosmic rays, using models of the cosmic-ray environment and heavy ion transport, and consider the effects of the age of the mice prior to and after the exposure and of the length of time in space on predictions of relative risk. Our results indicate that biophysical models of age-dependent radiation hazard will provide a better understanding of GCR risk than models that rely strictly on estimates of the initial slopes of these radiations.

  19. Initiation-promotion model of tumor prevalence in mice from space radiation exposures

    NASA Technical Reports Server (NTRS)

    Cucinotta, F. A.; Wilson, J. W.

    1995-01-01

    Exposures in space consist of low-level background components from galactic cosmic rays (GCR), occasional intense-energetic solar-particle events, periodic passes through geomagnetic-trapped radiation, and exposure from possible onboard nuclear-propulsion engines. Risk models for astronaut exposure from such diverse components and modalities must be developed to assure adequate protection in future NASA missions. The low-level background exposures (GCR), including relativistic heavy ions (HZE), will be the ultimate limiting factor for astronaut career exposure. We consider herein a two-mutation, initiation-promotion, radiation-carcinogenesis model in mice in which the initiation stage is represented by a linear kinetics model of cellular repair/misrepair, including the track-structure model for heavy ion action cross-sections. The model is validated by comparison with the harderian gland tumor experiments of Alpen et al. for various ion beams. We apply the initiation-promotion model to exposures from galactic cosmic rays, using models of the cosmic-ray environment and heavy ion transport, and consider the effects of the age of the mice prior to and after the exposure and of the length of time in space on predictions of relative risk. Our results indicate that biophysical models of age-dependent radiation hazard will provide a better understanding of GCR risk than models that rely strictly on estimates of the initial slopes of these radiations.

  20. Initiation-promotion model of tumor prevalence in mice from space radiation exposures.

    PubMed

    Cucinotta, F A; Wilson, J W

    1995-08-01

    Exposures in space consist of low-level background components from galactic cosmic rays (GCR), occasional intense-energetic solar-particle events, periodic passes through geomagnetic-trapped radiation, and exposure from possible onboard nuclear-propulsion engines. Risk models for astronaut exposure from such diverse components and modalities must be developed to assure adequate protection in future NASA missions. The low-level background exposures (GCR), including relativistic heavy ions (HZE), will be the ultimate limiting factor for astronaut career exposure. We consider herein a two-mutation, initiation-promotion, radiation-carcinogenesis model in mice in which the initiation stage is represented by a linear kinetics model of cellular repair/misrepair, including the track-structure model for heavy ion action cross-sections. The model is validated by comparison with the harderian gland tumor experiments of Alpen et al. for various ion beams. We apply the initiation-promotion model to exposures from galactic cosmic rays, using models of the cosmic-ray environment and heavy ion transport, and consider the effects of the age of the mice prior to and after the exposure and of the length of time in space on predictions of relative risk. Our results indicate that biophysical models of age-dependent radiation hazard will provide a better understanding of GCR risk than models that rely strictly on estimates of the initial slopes of these radiations. PMID:7480628

  1. Physiologically based Pharmacokinetic Modeling of 1,4-Dioxane in Rats, Mice, and Humans

    SciTech Connect

    Sweeney, Lisa M.; Thrall, Karla D.; Poet, Torka S.; Corley, Rick; Weber, Thomas J.; Locey, B. J.; Clarkson, Jacquelyn; Sager, S.; Gargas, M. L.

    2008-01-01

    ABSTRACT 1,4-Dioxane (CAS No. 123-91-1) is used primarily as a solvent or as a solvent stabilizer. It can cause lung, liver and kidney damage at sufficiently high exposure levels. Two physiologically-based pharmacokinetic (PBPK) models of 1,4-dioxane and its major metabolite, hydroxyethoxyacetic acid (HEAA), were published in 1990. These models have uncertainties and deficiencies that could be addressed and the model strengthened for use in a contemporary cancer risk assessment for 1,4-dioxane. Studies were performed to fill data gaps and reduce uncertainties pertaining to the pharmacokinetics of 1,4-dioxane and HEAA in rats, mice, and humans. Three types of studies were performed:partition coefficient measurements, blood time course in mice, and in vitro pharmacokinetics using rat, mouse, and human hepatocytes. Updated PBPK models were developed based on these new data and previously available data. The optimized rate of metabolism for the mouse was significantly higher than the value previously estimated. The optimized rat kinetic parameters were similar to those in the 1990 models. Only two human studies were identified. Model predictions were consistent with one study, but did not fit the second as well. In addition, a rat nasal exposure was completed. The results confirmed water directly contacts rat nasal tissues during drinking water under bioassays. Consistent with previous PBPK models, nasal tissues were not specifically included in the model. Use of these models will reduce the uncertainty in future 1,4-dioxane risk assessments.

  2. Towards the modelling of ageing and atherosclerosis effects in ApoE(-/-) mice aortic tissue.

    PubMed

    Waffenschmidt, Tobias; Cilla, Myriam; Sáez, Pablo; Pérez, Marta M; Martínez, Miguel A; Menzel, Andreas; Peña, Estefanía

    2016-08-16

    The goal of this work consists in a quantitative analysis and constitutive modelling of ageing processes associated to plaque formation in mice arteries. Reliable information on the characteristic evolution of pressure-stretch curves due to the ageing effects is extracted from previous inflation test experiments. Furthermore, characteristic age-dependent material parameters are identified on the basis of a continuum-mechanics-based parameter optimisation technique. The results indicate that the aorta-stiffness of the healthy control mice remains basically constant irrespective of the diet-time and age. In contrast, significant differences exist within the material response and in consequence within the material parameters between the ApoE(-/-) and the control mice as well as for the different locations over the aorta which is underlined by our experimental observations. With regard to the temporal evolution of the material parameters, we observe that the material parameters for the ApoE(-/-) mice aortas exhibit a saturation-type increase with respect to age. PMID:26924660

  3. Dynamics of behavioral disorders in transgenic mice with modeled Alzheimer's disease.

    PubMed

    Semina, I I; Baichurina, A Z; Makarova, E A; Leushina, A V; Kazakevich, Zh V; Gabdrakhmanova, M R; Mukhamed'yarov, M A; Zefirov, A L

    2015-03-01

    Age-related development of behavioral disorders in transgenic mice with modeled Alzheimer's disease carrying V6S3-Tg(APP695)85Dbo Tg(PSENI)85Dbo) genotype was assessed at the age of 7.5, 10 and 20 months in the following tests: open-field, plus maze, T-maze, conditioned passive avoidance response, rotarod, conflict situation with water deprivation, behavioral despair, and arecoline tremor. The main behavioral disorder in transgenic mice at all observation terms was memory impairment in conditioning with positive (but not negative) reinforcement. At the age of 7.5 and 10 months, transgenic mice also showed signs of nonspecific excitement and anxiety, depression-like state, and symptoms of cholinergic deficit. Our results suggest that appropriate age for behavioral tests in studies of effects of potential anti-Alzheimer drugs in transgenic V6S3-Tg(APP695)85Dbo Tg(PSENI)85Dbo) mice is 7.5-10 months.

  4. Towards the modelling of ageing and atherosclerosis effects in ApoE(-/-) mice aortic tissue.

    PubMed

    Waffenschmidt, Tobias; Cilla, Myriam; Sáez, Pablo; Pérez, Marta M; Martínez, Miguel A; Menzel, Andreas; Peña, Estefanía

    2016-08-16

    The goal of this work consists in a quantitative analysis and constitutive modelling of ageing processes associated to plaque formation in mice arteries. Reliable information on the characteristic evolution of pressure-stretch curves due to the ageing effects is extracted from previous inflation test experiments. Furthermore, characteristic age-dependent material parameters are identified on the basis of a continuum-mechanics-based parameter optimisation technique. The results indicate that the aorta-stiffness of the healthy control mice remains basically constant irrespective of the diet-time and age. In contrast, significant differences exist within the material response and in consequence within the material parameters between the ApoE(-/-) and the control mice as well as for the different locations over the aorta which is underlined by our experimental observations. With regard to the temporal evolution of the material parameters, we observe that the material parameters for the ApoE(-/-) mice aortas exhibit a saturation-type increase with respect to age.

  5. Effects of the essential oil from Citrus aurantium L. in experimental anxiety models in mice.

    PubMed

    Pultrini, Aline de Moraes; Galindo, Luciane Almeida; Costa, Mirtes

    2006-03-01

    Citrus aurantium L. is popularly used to treat anxiety, among other indications suggesting central nervous system action. Previous studies showed anxiolytic effect in the essential oil from peel in mice evaluated on the elevated plus maze [Carvalho-Freitas, M.I.R., Costa, M., 2002. Anxiolytic and sedative effects of extracts and essential oil from Citrus aurantium L. Biological and Pharmaceutical Bulletin 25, 1629-1633.]. In order to better characterize the activity of the essential oil, it was evaluated in two other experimental models: the light-dark box and the marble-burying test, respectively related to generalized anxiety disorder and to obsessive compulsive disorder. Mice were treated acutely by oral route 30 min (single dose) or once a day for 15 days (repeated doses) before experimental procedures. In light-dark box test, single treatment with essential oil augmented the time spent by mice in the light chamber and the number of transitions between the two compartments. There were no observed alterations in the parameters evaluated in light-dark box after repeated treatment. Otherwise, single and repeated treatments with essential oil were able to suppress marble-burying behavior. At effective doses in the behavioral tests, mice showed no impairment on rotarod procedure after both single and repeated treatments with essential oil, denoting absence of motor deficit. Results observed in marble-burying test, related to obsessive compulsive disorder, appear more consistent than those observed in light-dark box.

  6. Methanol Extract of Euchelus asper Prevents Bone Resorption in Ovariectomised Mice Model

    PubMed Central

    Balakrishnan, Babita; Chiplunkar, Shubhada Vivek; Indap, Madhavi Manohar

    2014-01-01

    Marine molluscs are widely distributed throughout the world and many bioactive compounds exhibiting antiviral, antitumor, antileukemic, and antibacterial activity have been reported worldwide. The present study was designed to investigate the beneficial effect of methanol extract of Euchelus asper (EAME) on estrogen deficiency induced osteoporosis in ovariectomised mice model. Forty-two female Swiss albino mice were randomly assigned into Sham operated (Sham) group and six ovariectomised (OVX) subgroups such as OVX with vehicle (OVX); OVX with estradiol (2 mg/kg/day); OVX with EAME of graded doses (25, 50, 100, and 200 mg/kg/day). Bone turnover markers like serum alkaline phosphatase (ALP), serum acid phosphatase (ACP), serum calcium, and histological investigations of tibia and uterus were analysed. Metaphyseal DNA content of the femur bone was also studied. Antiosteoclastogenic activity of EAME was examined. Administration of EAME was able to reduce the increased bone turnover markers in the ovariectomised mice. Histomorphometric analysis revealed an increase in bone trabeculation and restoration of trabecular separation by EAME treatment. Metaphyseal DNA content of the femur of the OVX mice was increased by EAME administration. EAME also showed a potent antiosteoclastogenic behaviour. Thus, the present study reveals that EAME was able to successfully reduce the estrogen deficiency induced bone loss. PMID:24995144

  7. CRISPR-Cas9 Knockin Mice for Genome Editing and Cancer Modeling

    PubMed Central

    Platt, Randall J.; Chen, Sidi; Zhou, Yang; Yim, Michael J.; Swiech, Lukasz; Kempton, Hannah R.; Dahlman, James E.; Parnas, Oren; Eisenhaure, Thomas M.; Jovanovic, Marko; Graham, Daniel B.; Jhunjhunwala, Siddharth; Xavier, Ramnik J.; Langer, Robert; Anderson, Daniel G.; Hacohen, Nir; Regev, Aviv; Feng, Guoping; Sharp, Phillip A.; Zhang, Feng

    2014-01-01

    SUMMARY CRISPR-Cas9 is a versatile genome editing technology for studying the function of genetic elements. To broadly enable the application of Cas9 in vivo, we established a Cre-dependent Cas9 knockin mouse. We demonstrated in vivo as well as ex vivo genome editing using adeno-associated virus (AAV)-, lenti-virus-, or particle-mediated delivery of guide RNA in neurons, immune cells, and endothelial cells. Using these mice, we simultaneously modeled the dynamics of KRAS, p53, and LKB1, the top three significantly mutated genes in lung adenocarcinoma. Delivery of a single AAV vector in the lung generated loss-of-function mutations in p53 and LKB1, as well as homology-directed repair-mediated KRASG12D mutations, leading to macroscopic tumors of adeno-carcinoma pathology. Together, these results suggest that Cas9 mice empower a wide range of biological and disease modeling applications. PMID:25263330

  8. Different attentional abilities among inbred mice strains using virtual object recognition task (VORT): SNAP25⁺/⁻ mice as a model of attentional deficit.

    PubMed

    Braida, Daniela; Ponzoni, Luisa; Matteoli, Michela; Sala M, Mariaelvina

    2016-01-01

    Autism spectrum disorder (ASD), attention-deficit hyperactivity disorder (ADHD), schizophrenia, Alzheimer's and Parkinson's disease are characterized by attentional deficits. In the present study we first applied the virtual object recognition test (VORT), where 3D objects were replaced with highly discriminated geometrical shapes and presented on two 3.5-inch widescreen displays, in different inbred mice strains (C57BL/6N, DBA/2J, BALB/cJ), in comparison with the standard object recognition test (NOR). In both NOR and VORT, there was a progressive decay of performance in terms of reduced discrimination index from 5 min to 72 h of inter-trial delay in all strains. However, BALB/cJ inbred mice showed a better long lasting performance than C57BL/6N and DBA/2J, when tested in NOR. In VORT, BALB/cJ showed the best performance. Total exploration time was always higher in BALB/cJ than C57BL/6N and DBA/2J mice. C57BL/6N were less explorative strain than DBA/2J and BALB/cJ mice. When VORT was applied to SNAP-25(+/-) mice, an impairment in both NOR and VORT was shown. However, when moving shapes were applied, these heterozygous mice improved their performance, suggesting that the introduction of motion is a strong cue that makes the task more valuable to study attention deficits. Taken together, these data indicate that VORT provides a useful and rapid tool to identify the attentional deficit in different inbred strains and genetically modified mice, enhancing the value of psychiatric mouse models.

  9. Cerebrolysin reverses hippocampal neural atrophy in a mice model of diabetes mellitus type 1.

    PubMed

    Sanchez-Vega, Lizzette; Juárez, Ismael; Gomez-Villalobos, Maria De Jesus; Flores, Gonzalo

    2015-06-01

    The animal model of streptozotocin-induced diabetes mellitus type 1 (DM1) is used to study neuronal and behavioral changes produced by an increase in blood-glucose levels. Our previous report showed that chronic streptozotocin administration induced atrophy of dendritic morphology of pyramidal neurons of the CA1 dorsal hippocampus. In addition, we showed that Cerebrolysin (Cbl), a neurotrophic peptide mixture, reduces the dendritic atrophy in animal models of aging. This study aimed to determine whether Cbl was capable of reducing behavioral and neuronal alterations, after 6 weeks of hyperglycemia in mice (streptozotocin-induced DM1). The levels of glucose in the blood were evaluated before and after streptozotocin administration and only animals with more than 240 mg/dL of blood-levels of glucose were used. After streptozotocin treatment, the mice received 6 weeks of Cbl, locomotor activity was measured and dendritic morphological changes were evaluated using Golgi-Cox stain procedure, and analyzed by the Sholl method. In mice treated with streptozotocin there was a clear reduction in the dendritic length of pyramidal neurons of the CA1 and granular cells of the dental gyrus of the dorsal hippocampus. Interestingly, Cbl reversed the morphological changes induced by streptozotocin. Our results extend the list of abnormal morphological changes detected in this model of DM, and support the possibility that Cbl may have beneficial effects in the management of brain alterations induced by DM.

  10. Social overcrowding as a chronic stress model that increases adiposity in mice

    PubMed Central

    Lin, En-Ju D; Sun, Meng; Choi, Eugene; Magee, Daniel; Stets, Colin; During, Matthew J

    2014-01-01

    Summary Stress is a widely recognized risk factor for psychiatric and metabolic disorders. A number of animal models utilizing various stressors have been developed to facilitate our understanding in the pathophysiology of stress-related dysfunctions. The most commonly used chronic stress paradigms include the unpredictable chronic mild stress paradigm, the social defeat paradigm and the social deprivation paradigm. Here we assess the potential of social crowding as an alternative chronic stress model to study the effects on affective behaviors and metabolic disturbances. Ten-week-old male C57BL/6 mice were housed in groups of four (control) or eight (social crowding; SC) in standard cage for 9 weeks. Exploration, anxiety- and depressive-like behaviors were assessed in the open field test, the elevated T-maze, the novelty-suppressed test, and the forced swim test. SC mice exhibited a modest anxiety-like phenotype without change in depressive-like behaviors. Nine weeks of social crowding did not affect the body weight, but robustly increased adiposity as determined by increased mass of fat depots. Consistent with the increased fat content, serum leptin was markedly elevated in the SC mice. Specific changes in gene expression were also observed in the hypothalamus and the white adipose tissue following SC housing. Our study demonstrates the potential of social crowding as an alternative model for the study of stress-related metabolic and behavioral dysfunctions. PMID:25462904

  11. ModObs: Atmospheric modelling for wind energy, climate and environment applications : exploring added value from new observation technique

    NASA Astrophysics Data System (ADS)

    Sempreviva, A. M.

    2009-04-01

    The EC FP6 Marie Curie Training Network "ModObs" http://www.modobs.windeng.net addresses the improvement of atmospheric boundary layer (ABL) models to investigate the interplay of processes at different temporal and spatial scales, and to explore the added value from new observation techniques. The overall goal is to bring young scientists to work together with experienced researchers in developing a better interaction amongst scientific communities of modelers and experimentalists, using a comprehensive approach to "Climate Change", "Clean Energy assessment" and "Environmental Policies", issues. This poster describes the work in progress of ten students, funded by the network, under the supervision of a team of scientists within atmospheric physics, engineering and satellite remote sensing and end-users such as companies in the private sector, all with the appropriate expertise to integrate the most advanced research methods and techniques in the following topics. MODELING: GLOBAL-TO-MESO SCALE: Analytical and process oriented numerical models will be used to study the interaction between the atmosphere and the ocean on a regional scale. Initial results indicate an interaction between the intensity of polar lows and the subsurface warm core often present in the Nordic Seas (11). The presence of waves, mainly swell, influence the MABL fluxes and turbulence structure. The regional and global wave effect on the atmosphere will be also studied and quantified (7) MESO-SCALE: Applicability of the planetary boundary layer (PBL) parametrizations in the meso-scale WRF model to marine atmospheric boundary layer (MABL) over the North Sea is investigated. The most suitable existing PBL parametrization will be additionally improved and used for downscaling North Sea past and future climates (2). Application of the meso-scale model (MM5 and WRF) for the wind energy in off-shore and coastal area. Set-up of the meso-scale model, post-processing and verification of the data from

  12. GLAST Deficiency in Mice Exacerbates Gap Detection Deficits in a Model of Salicylate-Induced Tinnitus

    PubMed Central

    Yu, Hong; Vikhe Patil, Kim; Han, Chul; Fabella, Brian; Canlon, Barbara; Someya, Shinichi; Cederroth, Christopher R.

    2016-01-01

    Gap detection or gap pre-pulse inhibition of the acoustic startle (GPIAS) has been successfully used in rat and guinea pig models of tinnitus, yet this system has been proven to have low efficacy in CBA mice, with low basal GPIAS and subtle tinnitus-like effects. Here, we tested five mouse strains (CBA, BalbC, CD-1, C57BL/6 and 129sv) for pre-pulse inhibition (PPI) and gap detection with varying interstimulus intervals (ISI) and found that mice from a CBA genetic background had the poorest capacities of suppressing the startle response in the presence of a pre-pulse or a gap. CD-1 mice displayed variable responses throughout all ISI. Interestingly, C57BL/6, 129sv and BalbC showed efficient suppression with either pre-pulses or gaps with shorter ISI. The glutamate aspartate transporter (GLAST) is expressed in support cells from the cochlea and buffers the excess of glutamate. We hypothesized that loss of GLAST function could sensitize the ear to tinnitus-inducing agents, such as salicylate. Using shorter ISI to obtain a greater dynamic range to assess tinnitus-like effects, we found that disruption of gap detection by salicylate was exacerbated across various intensities of a 32-kHz narrow band noise gap carrier in GLAST knockout (KO) mice when compared to their wild-type (WT) littermates. Auditory brainstem responses (ABR) and distortion-product otoacoustic emission (DPOAE) were performed to evaluate the effects on hearing functions. Salicylate caused greater auditory threshold shifts (near 15 dB) in GLAST KO mice than in WT mice across all tested frequencies, despite similarly reduced DPOAE. Despite these changes, inhibition using broad-band gap carriers and 32 kHz pre-pulses were not affected. Our study suggests that GLAST deficiency could become a useful experimental model to decipher the mechanisms underlying drug-induced tinnitus. Future studies addressing the neurological correlates of tinnitus in this model could provide additional insights into the

  13. GLAST Deficiency in Mice Exacerbates Gap Detection Deficits in a Model of Salicylate-Induced Tinnitus.

    PubMed

    Yu, Hong; Vikhe Patil, Kim; Han, Chul; Fabella, Brian; Canlon, Barbara; Someya, Shinichi; Cederroth, Christopher R

    2016-01-01

    Gap detection or gap pre-pulse inhibition of the acoustic startle (GPIAS) has been successfully used in rat and guinea pig models of tinnitus, yet this system has been proven to have low efficacy in CBA mice, with low basal GPIAS and subtle tinnitus-like effects. Here, we tested five mouse strains (CBA, BalbC, CD-1, C57BL/6 and 129sv) for pre-pulse inhibition (PPI) and gap detection with varying interstimulus intervals (ISI) and found that mice from a CBA genetic background had the poorest capacities of suppressing the startle response in the presence of a pre-pulse or a gap. CD-1 mice displayed variable responses throughout all ISI. Interestingly, C57BL/6, 129sv and BalbC showed efficient suppression with either pre-pulses or gaps with shorter ISI. The glutamate aspartate transporter (GLAST) is expressed in support cells from the cochlea and buffers the excess of glutamate. We hypothesized that loss of GLAST function could sensitize the ear to tinnitus-inducing agents, such as salicylate. Using shorter ISI to obtain a greater dynamic range to assess tinnitus-like effects, we found that disruption of gap detection by salicylate was exacerbated across various intensities of a 32-kHz narrow band noise gap carrier in GLAST knockout (KO) mice when compared to their wild-type (WT) littermates. Auditory brainstem responses (ABR) and distortion-product otoacoustic emission (DPOAE) were performed to evaluate the effects on hearing functions. Salicylate caused greater auditory threshold shifts (near 15 dB) in GLAST KO mice than in WT mice across all tested frequencies, despite similarly reduced DPOAE. Despite these changes, inhibition using broad-band gap carriers and 32 kHz pre-pulses were not affected. Our study suggests that GLAST deficiency could become a useful experimental model to decipher the mechanisms underlying drug-induced tinnitus. Future studies addressing the neurological correlates of tinnitus in this model could provide additional insights into the

  14. Cholestasis induced by model organic anions protects from acetaminophen hepatotoxicity in male CD-1 mice.

    PubMed

    Silva, Vanessa M; Hennig, Gayle E; Manautou, José E

    2006-01-25

    Administration of the non-metabolizable organic anion indocyanine green (ICG) prior to a toxic dose of acetaminophen (4-acetamidophenol; APAP) reduces liver injury 24h after dosing. ICG also produces a dose-dependent decrease in bile flow in mice and rats. Studies in bile duct-cannulated rats suggest that cholestasis can play a role in this protection. This study was conducted to determine if the ability of model organic anions to produce cholestasis is relevant to the protection against APAP hepatotoxicity afforded by ICG. In these studies, overnight fasted male CD-1 mice were dosed (i.v.) with the cholestatic dyes bromcresol green (BCG, 30 micromol/kg) and rose bengal (RB, 60 micromol/kg) immediately prior APAP administration (500 mg/kg, i.p.). Other groups of mice received the non-cholestatic dyes dibromosulphthalein (DBSP, 150 micromol/kg) and amaranth (AM, 300 micromol/kg) prior to APAP. Controls were given vehicle only. Hepatocellular necrosis was evident at 24 h in control mice receiving APAP. Pretreatment with the cholestatic dyes BCG and RB decreased the severity of hepatocellular necrosis induced by APAP. However, administration of the non-cholestatic dyes DBSP and AM did not alter APAP-induced liver damage. Glutathione replenishment was not altered by pretreatment with any of these dyes. Furthermore, ICG protected mice against carbon tetrachloride (CCl4) hepatotoxicity. Since CCl4 undergoes minimal biliary excretion and does not compete for biliary transport function, this finding supports the notion that cholestasis itself rather than competition for canalicular transporters is central to the hepatoprotection by ICG and other cholephilic dyes.

  15. Dietary DHA supplementation causes selective changes in phospholipids from different brain regions in both wild type mice and the Tg2576 mouse model of Alzheimer's disease

    PubMed Central

    Bascoul-Colombo, Cécile; Guschina, Irina A.; Maskrey, Benjamin H.; Good, Mark; O'Donnell, Valerie B.; Harwood, John L.

    2016-01-01

    Alzheimer's disease (AD) is of major concern in ageing populations and we have used the Tg2576 mouse model to understand connections between brain lipids and amyloid pathology. Because dietary docosahexaenoic acid (DHA) has been identified as beneficial, we compared mice fed with a DHA-supplemented diet to those on a nutritionally-sufficient diet. Major phospholipids from cortex, hippocampus and cerebellum were separated and analysed. Each phosphoglyceride had a characteristic fatty acid composition which was similar in cortex and hippocampus but different in the cerebellum. The biggest changes on DHA-supplementation were within ethanolamine phospholipids which, together with phosphatidylserine, had the highest proportions of DHA. Reciprocal alterations in DHA and arachidonate were found. The main diet-induced alterations were found in ethanolamine phospholipids, (and included their ether derivatives), as were the changes observed due to genotype. Tg mice appeared more sensitive to diet with generally lower DHA percentages when on the standard diet and higher relative proportions of DHA when the diet was supplemented. All four major phosphoglycerides analysed showed age-dependent decreases in polyunsaturated fatty acid contents. These data provide, for the first time, a detailed evaluation of phospholipids in different brain areas previously shown to be relevant to behaviour in the Tg2576 mouse model for AD. The lipid changes observed with genotype are consistent with the subtle alterations found in AD patients, especially for the ethanolamine phospholipid molecular species. They also emphasise the contrasting changes in fatty acid content induced by DHA supplementation within individual phospholipid classes. PMID:26968097

  16. Nobiletin treatment improves motor and cognitive deficits seen in MPTP-induced Parkinson model mice.

    PubMed

    Yabuki, Y; Ohizumi, Y; Yokosuka, A; Mimaki, Y; Fukunaga, K

    2014-02-14

    Nobiletin, a polymethoxylated flavonoid found in citrus fruit peel, reportedly improves memory impairment in rodent models. Here we report its effect on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced motor and cognitive deficits. Nobiletin administration (50mg/kg i.p.) for 2 consecutive weeks improved motor deficits seen in MPTP-induced Parkinson model mice by 2weeks, an effect that continued until 2weeks after drug withdrawal. Drug treatment promoted similar rescue of MPTP-induced cognitive impairment at equivalent time points. Nonetheless, nobiletin treatment did not block loss of dopaminergic neurons seen in the MPTP-treated mouse midbrain, nor did it rescue decreased tyrosine hydroxylase (TH) protein levels seen in the striatum or hippocampal CA1 region of these mice. Interestingly, nobiletin administration (50mg/kg i.p.) rescued reduced levels of Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) autophosphorylation and phosphorylation at Thr-34 of dopamine- and cAMP-regulated phosphoprotein-32 (DARPP-32) in striatum and hippocampal CA1 to levels seen in sham-operated mice. Likewise, CaMKII- and cAMP kinase-dependent TH phosphorylation was significantly restored by nobiletin treatment. MPTP-induced reduction of dopamine contents in the striatum and hippocampal CA1 region was improved by nobiletin administration (50mg/kg i.p.). Acute intraperitoneal administration of nobiletin also enhanced dopamine release in striatum and hippocampal CA1, an effect partially inhibited by treatment with nifedipine (a L-type Ca(2+) channel inhibitor) or NNC 55-0396 (a T-type Ca(2+) channel inhibitor) and completely abolished by combined treatment with both. Overall, our study describes a novel nobiletin activity in brain and suggests that nobiletin rescues motor and cognitive dysfunction in MPTP-induced Parkinson model mice, in part by enhancing dopamine release.

  17. INDUCTION OF CYP1A1 AD CYP1B1 AND FORMATION OF DNA ADDUCTS IN C57BL/6, BALB/C, AND F1 MICE FOLLOWING IN UTERO EXPOSURE TO 3-METHYLCHOLANTHRENE

    EPA Science Inventory

    Fetal mice are more sensitive to chemical carcinogens than are adults. Previous studies from our laboratory demonstrated differences in the mutational spectrum induced in the Ki-ras gene from lung tumors isolated from [D2 x B6D2F1]F2 mice and Balb/c mice treated in utero with 3�m...

  18. Glucose Transport into Everted Sacks of Intestine of Mice: A Model for the Study of Active Transport.

    ERIC Educational Resources Information Center

    Deyrup-Olsen, Ingrith; Linder, Alison R.

    1979-01-01

    Described is a laboratory procedure which uses the small intestines of mice as models for the transport of glucose and other solutes. Demonstrations are suitable for either introductory or advanced physiology courses. (RE)

  19. Expression of APP, BACE1, AChE and ChAT in an AD model in rats and the effect of donepezil hydrochloride treatment.

    PubMed

    Li, Qiang; Chen, Min; Liu, Hongmin; Yang, Liqun; Yang, Guiying

    2012-12-01

    The aim of this study was to investigate the pathological changes in a rat model of Alzheimer's disease (AD) and the effect of donepezil hydrochloride (HCl) treatment. The rat model of AD was established by the bilateral injection of amyloid β₁₋₄₀ (Aβ₁₋₄₀) into the hippocampus. Changes in spatial learning and memory functions were examined using the Morris water maze test and changes in catalase (CAT) and glutathione peroxidase (GSH-Px) activities were determined using chemical colorimetry. Moreover, the changes in acetylcholinesterase (AChE) and choline acetyltransferase (ChAT) expression were analyzed using immunohistochemical staining. The mRNA expression levels of the amyloid precursor protein (APP) and β-secreted enzyme 1 (BACE1) were evaluated using RT-PCR. The effects of donepezil HCl on the aforementioned indices were also observed. The rat memories of the platform quadrants in the blank, sham and donepezil HCl groups were improved compared with those of the rats in the model group. The ratio of swim distance in the fourth platform quadrant (l₄) to the total swim distance (l total) for the model group rats (l₄/l total) was significantly decreased compared with that for the blank and sham group rats. Following donepezil HCl treatment, the ratio of l₄/l total significantly increased. AD modeling caused a significant decrease in the CAT and GSH-Px activities in the brain tissues of the rats. The CAT and GSH-Px activities in the AD model rats significantly increased following donepezil HCl treatment. Moreover, donepezil HCl treatment significantly decreased the AChE, APP and BACE1 mRNA expression levels and increased the ChAT expression levels. Therefore, donepezil HCl was able to significantly decrease learning and memory damage in a rat model of AD.

  20. Preventive effects of Chlorella on cognitive decline in age-dependent dementia model mice.

    PubMed

    Nakashima, Yuya; Ohsawa, Ikuroh; Konishi, Fumiko; Hasegawa, Takashi; Kumamoto, Shoichiro; Suzuki, Yoshihiko; Ohta, Shigeo

    2009-10-30

    Oxidative stress is one of the major causes of age-dependent memory loss and cognitive decline. Cytotoxic aldehydes are derived from lipid peroxides and their accumulation may be responsible for age-dependent neurodegeneration, including Alzheimer's disease. Since aldehyde dehydrogenases detoxify such aldehydes, we constructed transgenic mice with mitochondrial aldehyde dehydrogenase 2 (ALDH2) activity deficiency (DAL101 mice) as an age-dependent dementia model. This model animal is age-dependently progressed by persistent oxidative stress, and thus enables us to investigate foods that prevent dementia. Since Chlorella, a kind of alga, exhibits various anti-oxidative effects, we investigated whether Chlorella has the potential to prevent age-dependent cognitive impairment. We fed Chlorella to DAL101 mice and investigated its effects on oxidative stress and the progression of cognitive decline using the Morris water-maze and object recognition tests. The diet with Chlorella tended to reduce oxidative stress and significantly prevented the decline of cognitive ability, as shown by both methods. Moreover, consumption of Chlorella decreased the number of activated astrocytes in the DAL101 brain. These findings suggest that the prolonged consumption of Chlorella has the potential to prevent the progression of cognitive impairment.

  1. Salivary Gland Dysplasia in Fgf10 Heterozygous Mice: A New Mouse Model of Xerostomia

    PubMed Central

    May, A.J.; Chatzeli, L.; Proctor, G.B.; Tucker, A.S.

    2016-01-01

    Xerostomia, or chronic dry mouth, is a common syndrome caused by a lack of saliva that can lead to severe eating difficulties, dental caries and oral candida infections. The prevalence of xerostomia increases with age and affects approximately 30% of people aged 65 or older. Given the large numbers of sufferers, and the potential increase in incidence given our aging population, it is important to understand the complex mechanisms that drive hyposalivation and the consequences for the dentition and oral mucosa. From this study we propose the Fgf10 +/- mouse as a model to investigate xerostomia. By following embryonic salivary gland development, in vivo and in vitro, we show that a reduction in Fgf10 causes a delay in branching of salivary glands. This leads to hypoplasia of the glands, a phenotype that is not rescued postnatally or by adulthood in both male and female Fgf10 +/- mice. Histological analysis of the glands showed no obvious defect in cellular differentiation or acini/ductal arrangements, however there was a significant reduction in their size and weight. Analysis of saliva secretion showed that hypoplasia of the glands led to a significant reduction in saliva production in Fgf10 +/- adults, giving rise to a reduced saliva pellicle in the oral cavity of these mice. Mature mice were shown to drink more and in many cases had severe tooth wear. The Fgf10 +/- mouse is therefore a useful model to explore the causes and effects of xerostomia.

  2. Salivary Gland Dysplasia in Fgf10 Heterozygous Mice: A New Mouse Model of Xerostomia.

    PubMed

    May, A J; Chatzeli, L; Proctor, G B; Tucker, A S

    2015-01-01

    Xerostomia, or chronic dry mouth, is a common syndrome caused by a lack of saliva that can lead to severe eating difficulties, dental caries and oral candida infections. The prevalence of xerostomia increases with age and affects approximately 30% of people aged 65 or older. Given the large numbers of sufferers, and the potential increase in incidence given our aging population, it is important to understand the complex mechanisms that drive hyposalivation and the consequences for the dentition and oral mucosa. From this study we propose the Fgf10 +/- mouse as a model to investigate xerostomia. By following embryonic salivary gland development, in vivo and in vitro, we show that a reduction in Fgf10 causes a delay in branching of salivary glands. This leads to hypoplasia of the glands, a phenotype that is not rescued postnatally or by adulthood in both male and female Fgf10 +/- mice. Histological analysis of the glands showed no obvious defect in cellular differentiation or acini/ductal arrangements, however there was a significant reduction in their size and weight. Analysis of saliva secretion showed that hypoplasia of the glands led to a significant reduction in saliva production in Fgf10 +/- adults, giving rise to a reduced saliva pellicle in the oral cavity of these mice. Mature mice were shown to drink more and in many cases had severe tooth wear. The Fgf10 +/- mouse is therefore a useful model to explore the causes and effects of xerostomia. PMID:26321752

  3. Modeling early-onset post-ischemic seizures in aging mice

    PubMed Central

    Wu, Chiping; Wang, Justin; Peng, Jessie; Patel, Nisarg; Huang, Yayi; Gao, Xiaoxing; Aljarallah, Salman; Eubanks, James H; McDonald, Robert; Zhang, Liang

    2016-01-01

    Stroke is the leading cause of seizures and epilepsy in the aged population, with post-stroke seizures being a poor prognostic factor. The pathological processes underlying post-stroke seizures are not well understood and studies of these seizures in aging/aged animals remain scarce. Therefore, our primary objective was to model post-stroke seizures in aging mice (C57 black strain, 16–20 month-old), with a focus on early-onset, convulsive seizures that occur within 24-hours of brain ischemia. We utilized a middle cerebral artery occlusion model and examined seizure activity and brain injury using combined behavioral and electroencephalographic monitoring and histological assessments. Aging mice exhibited vigorous convulsive seizures within hours of the middle cerebral artery occlusion. These seizures manifested with jumping, rapid running, barrel-rolling and/or falling all in the absence of hippocampal-cortical electrographic discharges. Seizure development was closely associated with severe brain injury and acute mortality. Anticonvulsive treatments after seizure occurrence offered temporary seizure control but failed to improve animal survival. A separate cohort of adult mice (6–8 months-old) exhibited analogous early-onset convulsive seizures following the middle cerebral artery occlusion but had better survival outcomes following anticonvulsive treatment. Collectively, our data suggest that early-onset convulsive seizures are a result of severe brain ischemia in aging animals. PMID:25943585

  4. Modeling early-onset post-ischemic seizures in aging mice.

    PubMed

    Wu, Chiping; Wang, Justin; Peng, Jessie; Patel, Nisarg; Huang, Yayi; Gao, Xiaoxing; Aljarallah, Salman; Eubanks, James H; McDonald, Robert; Zhang, Liang

    2015-09-01

    Stroke is the leading cause of seizures and epilepsy in the aged population, with post-stroke seizures being a poor prognostic factor. The pathological processes underlying post-stroke seizures are not well understood and studies of these seizures in aging/aged animals remain scarce. Therefore, our primary objective was to model post-stroke seizures in aging mice (C57 black strain, 16-20 months-old), with a focus on early-onset, convulsive seizures that occur within 24-hours of brain ischemia. We utilized a middle cerebral artery occlusion model and examined seizure activity and brain injury using combined behavioral and electroencephalographic monitoring and histological assessments. Aging mice exhibited vigorous convulsive seizures within hours of the middle cerebral artery occlusion. These seizures manifested with jumping, rapid running, barrel-rolling and/or falling all in the absence of hippocampal-cortical electrographic discharges. Seizure development was closely associated with severe brain injury and acute mortality. Anticonvulsive treatments after seizure occurrence offered temporary seizure control but failed to improve animal survival. A separate cohort of adult mice (6-8 months-old) exhibited analogous early-onset convulsive seizures following the middle cerebral artery occlusion but had better survival outcomes following anticonvulsive treatment. Collectively, our data suggest that early-onset convulsive seizures are a result of severe brain ischemia in aging animals.

  5. Geraniol produces antidepressant-like effects in a chronic unpredictable mild stress mice model.

    PubMed

    Deng, Xue-Yang; Xue, Jin-Song; Li, Hong-Yan; Ma, Zhan-Qiang; Fu, Qiang; Qu, Rong; Ma, Shi-Ping

    2015-12-01

    Geraniol (GE), which has neuroprotection and anti-inflammation activities, is mostly abundant in the essential oils of rose, ginger, lemon, orange, lavender etc. However, its antidepressant-like effect has not been reported before. The present study was designed to investigate whether GE confers an antidepressant effect in mice exposed to a chronic unpredictable mild stress (CUMS) model of depression and to explore its possible mechanisms. The results showed that GE treatments for 3 weeks significantly alleviated the depression-related behaviors of CUMS-exposed mice, as indicated by restored decreased sucrose preference and shortened immobile time in both the forced swimming tests (FST) and tail suspension tests (TST). And these ameliorative effects of GE treatment were involved with regulating CUMS-induced pro-inflammatory cytokine interleukin-1 beta (IL-1β) related neuro-inflammation. We further found that GE treatment reversed CUMS-induced IL-1β elevation, possibly by inhibiting nuclear factor kappa B (NF-κB) pathway activation and regulating nucleotide binding and oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome expression. Taken together, our findings suggested that GE exerted a potential antidepressant-like effect in CUMS mice model of depression, which may provide an insight into the potential of GE in therapeutic implications for depression. PMID:26454213

  6. Models Of Lower Extremity Damage In Mice: Time Course of Organ Damage & Immune Response

    PubMed Central

    Menzel, Christoph L; Pfeifer, Roman; Darwiche, Sophie S; Kobbe, Philipp; Gill, Roop; Shapiro, Richard A; Loughran, Patricia; Vodovotz, Yoram; Scott, Melanie J; Zenati, Mazen S; Billiar, Timothy R; Pape, Hans-Christoph

    2011-01-01

    Background Posttraumatic inflammatory changes have been identified as major causes of altered organ function and failure. Both hemorrhage and soft tissue damage induce these inflammatory changes. Exposure to heterologous bone in animal models has recently been shown to mimic this inflammatory response in a stable and reproducible fashion. This follow-up study tests the hypothesis that inflammatory responses are comparable between a novel trauma model (“pseudofracture”, PFx) and a bilateral femur fracture (BFF) model. Materials and Methods In C57BL/6 mice, markers for remote organ dysfunction and inflammatory responses were compared in 4 groups (control/sham/BFF/PFx) at the time points 2, 4, and 6 hours. Results Hepatocellular damage in BFF and PFx was highly comparable in extent and evolution, as shown by similar levels of NFκB activation and plasma ALT. Pulmonary inflammatory responses were also comparably elevated in both trauma models as early as 2h after trauma as measured by myeloperoxidase activity (MPO). Muscle damage was provoked in both BFF and PFx mice over the time course, although BFF induced significantly higher AST and CK levels. IL-6 levels were also similar with early and sustained increases over time in both trauma models. Conclusions Both BFF and PFx create similar reproducible inflammatory and remote organ responses. PFx will be a useful model to study longer term inflammatory effects that cannot be studied using BFF. PMID:21276982

  7. A cryoinjury model in neonatal mice for cardiac translational and regeneration research.

    PubMed

    Polizzotti, Brian D; Ganapathy, Balakrishnan; Haubner, Bernhard J; Penninger, Josef M; Kühn, Bernhard

    2016-03-01

    The introduction of injury models for neonatal mouse hearts has accelerated research on the mechanisms of cardiac regeneration in mammals. However, some existing models, such as apical resection and ligation of the left anterior descending artery, produce variable results, which may be due to technical difficulties associated with these methods. Here we present an alternative model for the study of cardiac regeneration in neonatal mice in which cryoinjury is used to induce heart injury. This model yields a reproducible injury size, does not induce known mechanisms of cardiac regeneration and leads to a sustained reduction of cardiac function. This protocol uses reusable cryoprobes that can be assembled in 5 min, with the entire procedure taking 15 min per pup. The subsequent heart collection and fixation takes 2 d to complete. Cryoinjury results in a myocardial scar, and the size of injury can be scaled by the use of different cryoprobes (0.5 and 1.5 mm). Cryoinjury models are medically relevant to diseases in human infants with heart disease. In summary, the myocardial cryoinjury model in neonatal mice described here is a useful tool for cardiac translational and regeneration research.

  8. Highly stabilized curcumin nanoparticles tested in an in vitro blood-brain barrier model and in Alzheimer's disease Tg2576 mice.

    PubMed

    Cheng, Kwok Kin; Yeung, Chin Fung; Ho, Shuk Wai; Chow, Shing Fung; Chow, Albert H L; Baum, Larry

    2013-04-01

    The therapeutic effects of curcumin in treating Alzheimer's disease (AD) depend on the ability to penetrate the blood-brain barrier. The latest nanoparticle technology can help to improve the bioavailability of curcumin, which is affected by the final particle size and stability. We developed a stable curcumin nanoparticle formulation to test in vitro and in AD model Tg2576 mice. Flash nanoprecipitation of curcumin, polyethylene glycol-polylactic acid co-block polymer, and polyvinylpyrrolidone in a multi-inlet vortex mixer, followed by freeze drying with β-cyclodextrin, produced dry nanocurcumin with mean particle size <80 nm. Nanocurcumin powder, unformulated curcumin, or placebo was orally administered to Tg2576 mice for 3 months. Before and after treatment, memory was measured by radial arm maze and contextual fear conditioning tests. Nanocurcumin produced significantly (p=0.04) better cue memory in the contextual fear conditioning test than placebo and tendencies toward better working memory in the radial arm maze test than ordinary curcumin (p=0.14) or placebo (p=0.12). Amyloid plaque density, pharmacokinetics, and Madin-Darby canine kidney cell monolayer penetration were measured to further understand in vivo and in vitro mechanisms. Nanocurcumin produced significantly higher curcumin concentration in plasma and six times higher area under the curve and mean residence time in brain than ordinary curcumin. The P(app) of curcumin and tetrahydrocurcumin were 1.8×10(-6) and 1.6×10(-5)cm/s, respectively, for nanocurcumin. Our novel nanocurcumin formulation produced highly stabilized nanoparticles with positive treatment effects in Tg2576 mice. PMID:23229335

  9. Effective Biology Teaching: A Value-Added Instructional Improvement Analysis Model. Research Watch. E&R Report No. 05.28

    ERIC Educational Resources Information Center

    Haynie, Glenda

    2006-01-01

    This research study developed a value-added instructional improvement analysis model. North Carolina state testing results were used in regression and residual analyses of student achievement. This analysis allowed for identification of the "most effective" and "least effective" biology teachers in Wake County Public Schools…

  10. Lessons learned from mice and man: mimicking human allergy through mouse models.

    PubMed

    Graham, Michelle T; Nadeau, Kari C

    2014-11-01

    The relevance of using mouse models to represent human allergic pathologies is still unclear. Recent studies suggest the limitations of using models as a standard for assessing immune response and tolerance mechanisms, as mouse models often do not sufficiently depict human atopic conditions. Allergy is a combination of aberrant responses to innocuous environmental agents and the subsequent TH2-mediated inflammatory responses. In this review, we will discuss current paradigms of allergy - specifically, TH2-mediated and IgE-associated immune responses - and current mouse models used to recreate these TH2-mediated pathologies. Our overall goal is to highlight discrepancies that exist between mice and men by examining the advantages and disadvantages of allergic mouse models with respect to the human allergic condition.

  11. Predator-elicited flight responses in Swiss-Webster mice: an experimental model of panic attacks.

    PubMed

    Griebel, G; Blanchard, D C; Blanchard, R J

    1996-02-01

    1. The nosological status of panic disorder is still a matter of debate. Nevertheless, evidence is emerging that panic attacks have a different pattern of drug responsiveness from other forms of anxiety. 2. Several experimental animal models of panic attacks have been developed. These vary in the extent to which they meet criteria for face validity, predictive validity and construct validity, normally applied to such models. 3. In the present review, the authors examine the possibility that predator-elicited flight responses in Swiss-Webster mice might serve as an experimental model for the screening of panic-modulating drugs. 4. Drug effects on flight responses clearly indicate that this model has good predictive validity as panic-promoting agents increase flight reactions, while panicolytic drug challenge induces opposite effects. In addition, drugs devoid of any effect on panic attack, also do not alter flight behavior. 5. These findings strongly suggest that the model of predator-elicited flight responses in Swiss-Webster mice is useful for the investigation of panic-modulating drugs.

  12. Physiologically-based pharmacokinetic modeling of target-mediated drug disposition of bortezomib in mice.

    PubMed

    Zhang, Li; Mager, Donald E

    2015-10-01

    Bortezomib is a reversible proteasome inhibitor with potent antineoplastic activity that exhibits dose- and time-dependent pharmacokinetics (PK). Proteasome-mediated bortezomib disposition is proposed as the primary source of its nonlinear and apparent nonstationary PK behavior. Single intravenous (IV) doses of bortezomib (0.25 and 1 mg/kg) were administrated to BALB/c mice, with blood and tissue samples obtained over 144 h, which were analyzed by LC/MS/MS. A physiologically based pharmacokinetic (PBPK) model incorporating tissue drug-target binding was developed to test the hypothesis of proteasome-mediated bortezomib disposition. The final model reasonably captured bortezomib plasma and tissue PK profiles, and parameters were estimated with good precision. The rank-order of model estimated tissue target density correlated well with experimentally measured proteasome concentrations reported in the literature, supporting the hypothesis that binding to proteasome influences bortezomib disposition. The PBPK model was further scaled-up to humans to assess the similarity of bortezomib disposition among species. Human plasma bortezomib PK profiles following multiple IV dosing (1.3 mg/m(2)) on days 1, 4, 8, and 11 were simulated by appropriately scaling estimated mouse parameters. Simulated and observed bortezomib concentrations after multiple dosing were in good agreement, suggesting target-mediated bortezomib disposition is likely for both mice and humans. Furthermore, the model predicts that renal impairment should exert minimal influence on bortezomib exposure in humans, confirming that bortezomib dose adjustment is not necessary for patients with renal impairment.

  13. Superstring theory in AdS(3) and plane waves

    NASA Astrophysics Data System (ADS)

    Son, John Sang Won

    This thesis is devoted to the study of string theory in AdS 3 and its applications to recent developments in string theory. The difficulties associated with formulating a consistent string theory in AdS3 and its underlying SL(2, R) WZW model are explained. We describe how these difficulties can be overcome by assuming that the SL(2, R) WZW model contains spectral flow symmetry. The existence of spectral flow symmetry in the fully quantum treatment is proved by a calculation of the one-loop string partition function. We consider Euclidean AdS 3 with the time direction periodically identified, and compute the torus partition function in this background. The string spectrum can be reproduced by viewing the one-loop calculation as the free energy of a gas of strings, thus providing a rigorous proof of the results based on spectral flow arguments. Next, we turn to spacetimes that are quotients of AdS 3, which include the BTZ black hole and conical spaces. Strings propagating in the conical space are described by taking an orbifold of strings in AdS3. We show that the twisted states of these orbifolds can be obtained by fractional spectral flow. We show that the shift in the ground state energy usually associated with orbifold twists is absent in this case, and offer a unified framework in which to view spectral flow. Lastly, we consider the RNS superstrings in AdS 3 x S3 x M , where M may be K3 or T 4, based on supersymmetric extensions of SL(2, R) and SU(2) WZW models. We construct the physical states and calculate the spectrum. A subsector of this theory describes strings propagating in the six dimensional plane wave obtained by the Penrose limit of AdS3 x S3 x M . We reproduce the plane wave spectrum by taking J and the radius to infinity. We show that the plane wave spectrum actually coincides with the large J spectrum at fixed radius, i.e. in AdS3 x S3. Relation to some recent topics of interest such as the Frolov-Tseytlin string and strings with critical tension

  14. Acute Phase Response and Neutrophils : Lymphocyte Ratio in Response to Astaxanthin in Staphylococcal Mice Mastitis Model

    PubMed Central

    Dolma, Tshering; Mukherjee, Reena; Pati, B. K.; De, U. K.

    2014-01-01

    The purpose of the study was to determine the immunotherapeutic effect of astaxanthin (AX) on total clinical score (TCS), C-reactive protein (CRP), and neutrophil : lymphocyte ratio in mice mastitis model challenged with pathogenic Staphylococcus aureus. Twenty-four lactating mice were divided in 4 equal groups: group I mice served as normal healthy control, group II, positive control, were challenged with pathogenic S. aureus, group III mice were challenged and treated with AX, and group IV were treated with amoxicillin plus sulbactum. The TCS was higher in postchallenged mice; however it was significantly higher in group II untreated mice as compared to group III and group IV mice. The neutrophil was higher and lymphocyte count was lower in group II mice at 120 hrs post challenge (PC). The CRP was positive in all the challenged group at 24 hrs PC, but it remained positive till 120 hrs PC in group II. The parameters are related to enhancement of the mammary defense and reduction of inflammation. Hence AX may be used alone or as an adjunct therapy with antibiotic for amelioration of mastitis. Development of such therapy may be useful to reduce the antibiotic burden in management of intramammary infection. PMID:26464919

  15. Impaired neuronal migration and endochondral ossification in Pex7 knockout mice: a model for rhizomelic chondrodysplasia punctata.

    PubMed

    Brites, Pedro; Motley, Alison M; Gressens, Pierre; Mooyer, Petra A W; Ploegaert, Ingrid; Everts, Vincent; Evrard, Philippe; Carmeliet, Peter; Dewerchin, Mieke; Schoonjans, Luc; Duran, Marinus; Waterham, Hans R; Wanders, Ronald J A; Baes, Myriam

    2003-09-15

    Rhizomelic chondrodysplasia punctata is a human autosomal recessive disorder characterized by skeletal, eye and brain abnormalities. The disorder is caused by mutations in the PEX7 gene, which encodes the receptor for a class of peroxisomal matrix enzymes. We describe the generation and characterization of a Pex7 mouse knockout (Pex7(-/-)). Pex7(-/-) mice are born severely hypotonic and have a growth impairment. Mortality in Pex7(-/-) mice is highest in the perinatal period although some Pex7(-/-) mice survived beyond 18 months. Biochemically Pex7(-/-) mice display the abnormalities related to a Pex7 deficiency, i.e. a severe depletion of plasmalogens, impaired alpha-oxidation of phytanic acid and impaired beta-oxidation of very-long-chain fatty acids. In the intermediate zone of the developing cerebral cortex Pex7(-/-) mice have an increase in neuronal density. In vivo neuronal birthdating revealed that Pex7(-/-) mice have a delay in neuronal migration. Analysis of bone ossification in newborn Pex7(-/-) mice revealed a defect in ossification of distal bone elements of the limbs as well as parts of the skull and vertebrae. These findings demonstrate that Pex7 knockout mice provide an important model to study the role of peroxisomal functioning in the pathogenesis of the human disorder.

  16. Proposed mechanistic description of dose-dependent BDE-47 urinary elimination in mice using a physiologically based pharmacokinetic model

    SciTech Connect

    Emond, Claude; Sanders, J. Michael; Wikoff, Daniele; Birnbaum, Linda S.

    2013-12-01

    Polybrominated diphenyl ethers (PBDEs) have been used in a wide variety of consumer applications as additive flame retardants. In North America, scientists have noted continuing increases in the levels of PBDE congeners measured in human serum. Some recent studies have found that PBDEs are associated with adverse health effects in humans, in experimental animals, and wildlife. This laboratory previously demonstrated that urinary elimination of 2,2′,4,4′-tetrabromodiphenyl ether (BDE-47) is saturable at high doses in mice; however, this dose-dependent urinary elimination has not been observed in adult rats or immature mice. Thus, the primary objective of this study was to examine the mechanism of urinary elimination of BDE-47 in adult mice using a physiologically based pharmacokinetic (PBPK) model. To support this objective, additional laboratory data were collected to evaluate the predictions of the PBPK model using novel information from adult multi-drug resistance 1a/b knockout mice. Using the PBPK model, the roles of mouse major urinary protein (a blood protein carrier) and P-glycoprotein (an apical membrane transporter in proximal tubule cells in the kidneys, brain, intestines, and liver) were investigated in BDE-47 elimination. The resulting model and new data supported the major role of m-MUP in excretion of BDE-47 in the urine of adult mice, and a lesser role of P-gp as a transporter of BDE-47 in mice. This work expands the knowledge of BDE-47 kinetics between species and provides information for determining the relevancy of these data for human risk assessment purposes. - Highlights: • We report the first study on PBPK model on flame retardant in mice for BDE-47. • We examine mechanism of urinary elimination of BDE-47 in mice using a PBPK model. • We investigated roles of m-MUP and P-gp as transporters in urinary elimination.

  17. Evidence for the Need to More Closely Examine School Effects in Value-Added Modeling and Related Accountability Policies

    ERIC Educational Resources Information Center

    Franco, M. Suzanne; Seidel, Kent

    2014-01-01

    Value-added approaches for attributing student growth to teachers often use weighted estimates of building-level factors based on "typical" schools to represent a range of community, school, and other variables related to teacher and student work that are not easily measured directly. This study examines whether such estimates are likely…

  18. An inducible hepatocellular carcinoma model for preclinical evaluation of antiangiogenic therapy in adult mice.

    PubMed

    Runge, Anja; Hu, Junhao; Wieland, Matthias; Bergeest, Jan-Philip; Mogler, Carolin; Neumann, André; Géraud, Cyrill; Arnold, Bernd; Rohr, Karl; Komljenovic, Dorde; Schirmacher, Peter; Goerdt, Sergij; Augustin, Hellmut G

    2014-08-01

    The limited availability of experimental tumor models that faithfully mimic the progression of human tumors and their response to therapy remains a major bottleneck to the clinical translation and application of novel therapeutic principles. To address this challenge in hepatocellular carcinoma (HCC), one of the deadliest and most common cancers in the world, we developed and validated an inducible model of hepatocarcinogenesis in adult mice. Tumorigenesis was triggered by intravenous adenoviral delivery of Cre recombinase in transgenic mice expressing the hepatocyte-specific albumin promoter, a loxP-flanked stop cassette, and the SV40 large T-antigen (iAST). Cre recombinase-mediated excision of the stop cassette led to a transient viral hepatitis and resulted in multinodular tumorigenesis within 5 to 8 weeks. Tumor nodules with histologic characteristics of human HCC established a functional vasculature by cooption, remodeling, and angiogenic expansion of the preexisting sinusoidal liver vasculature with increasing signs of vascular immaturity during tumor progression. Treatment of mice with sorafenib rapidly resulted in the induction of vascular regression, inhibition of tumor growth, and enhanced overall survival. Vascular regression was characterized by loss of endothelial cells leaving behind avascular type IV collagen-positive empty sleeves with remaining pericytes. Sorafenib treatment led to transcriptional changes of Igf1, Id1, and cMet over time, which may reflect the emergence of potential escape mechanisms. Taken together, our results established the iAST model of inducible hepatocarcinogenesis as a robust and versatile preclinical model to study HCC progression and validate novel therapies. PMID:24906623

  19. Antinociceptive effect of matrine on vincristine-induced neuropathic pain model in mice.

    PubMed

    Linglu, Dun; Yuxiang, Li; Yaqiong, Xu; Ru, Zhou; Lin, Ma; Shaoju, Jin; Juan, Du; Tao, Sun; Jianqiang, Yu

    2014-06-01

    Chemotherapy drugs treatment causes neuropathic pain, hyperalgesia and allodynia are common components of neuropathic pain, so effectively therapeutic strategy is required. In this study, we evaluated the antinociceptive effects of matrine on vincristine-induced neuropathic pain in mice. Vincristine (100 μg/kg i.p.) was administered once per day for 7 days (day 0-6) in mice. Matrine (15, 30, 60 mg/kg, i.p.) was repeated administration in early phase (day 0-6) or late phase (day 7-13). Hyperalgesia and allodynia were evaluated by withdrawal response using von Frey filaments, plantar and cold-plate on 7, 14 and 21 day. Injection of vincristine produced mechanical hyperalgesia and cold allodynia. Matrine was found to produce a protective role in both von Frey filaments and cold-plate test. The analysis of the effect supports the hypothesis that matrine is useful in therapy of vincristine-induced neuropathic pain. In conclusion, this study demonstrates that administration of matrine is associated with antinociceptive effect on mechanical and cold stimuli in a mice model of vincristine-induced neuropathy pain.

  20. Erythropoietin and the use of a transgenic model of erythropoietin-deficient mice

    PubMed Central

    Pichon, Aurélien; Jeton, Florine; El Hasnaoui-Saadani, Raja; Hagström, Luciana; Launay, Thierry; Beaudry, Michèle; Marchant, Dominique; Quidu, Patricia; Macarlupu, Jose-Luis; Favret, Fabrice; Richalet, Jean-Paul; Voituron, Nicolas

    2016-01-01

    Despite its well-known role in red blood cell production, it is now accepted that erythropoietin (Epo) has other physiological functions. Epo and its receptors are expressed in many tissues, such as the brain and heart. The presence of Epo/Epo receptors in these organs suggests other roles than those usually assigned to this protein. Thus, the aim of this review is to describe the effects of Epo deficiency on adaptation to normoxic and hypoxic environments and to suggest a key role of Epo on main physiological adaptive functions. Our original model of Epo-deficient (Epo-TAgh) mice allowed us to improve our knowledge of the possible role of Epo in O2 homeostasis. The use of anemic transgenic mice revealed Epo as a crucial component of adaptation to hypoxia. Epo-TAgh mice survive well in hypoxic conditions despite low hematocrit. Furthermore, Epo plays a key role in neural control of ventilatory acclimatization and response to hypoxia, in deformability of red blood cells, in cerebral and cardiac angiogenesis, and in neuro- and cardioprotection. PMID:27800506

  1. Preliminary investigation of a mice model of Klebsiella pneumoniae subsp. ozaenae induced pneumonia.

    PubMed

    Renois, Fanny; Jacques, Jérôme; Guillard, Thomas; Moret, Hélène; Pluot, Michel; Andreoletti, Laurent; de Champs, Christophe

    2011-11-01

    In the present study, we comparatively assessed the pathophysiological mechanisms developed during lung infection of BALB/C female mice infected by an original wild type Klebsiella pneumoniae subsp. ozaenae strain (CH137) or by a referent subspecies K. pneumoniae. subsp. pneumoniae strain (ATCC10031). The mice infected with 2.10⁶ CFU K. p. subsp. pneumoniae (n = 10) showed transient signs of infection and all of them recovered. All of those infected with 1.10⁶ CFU K. p. subsp. ozaenae (n = 10) developed pneumonia within 24 h and died between 48 and 72 h. Few macrophages, numerous polymorphonuclear cells and lymphocytes were observed in their lungs in opposite to K. p. subsp. pneumoniae. In bronchoalveolar lavage, a significant increase in MIP-2, IL-6, KC and MCP-1 levels was only observed in K. p. subsp. ozaenae infected mice whereas high levels of TNF-α were evidenced with the two subspecies. Our findings indicated a lethal effect of a wild type K. p. subsp. ozaenae strain by acute pneumonia reflecting an insufficient alveolar macrophage response. This model might be of a major interest to comparatively explore the pathogenicity of K. p. subsp ozaenae strains and to further explore the physiopathological mechanisms of gram-negative bacteria induced human pneumonia.

  2. Mutant Enpp1asj mice as a model for generalized arterial calcification of infancy.

    PubMed

    Li, Qiaoli; Guo, Haitao; Chou, David W; Berndt, Annerose; Sundberg, John P; Uitto, Jouni

    2013-09-01

    Generalized arterial calcification of infancy (GACI), an autosomal recessive disorder, is characterized by early mineralization of blood vessels, often diagnosed by prenatal ultrasound and usually resulting in demise during the first year of life. It is caused in most cases by mutations in the ENPP1 gene, encoding an enzyme that hydrolyzes ATP to AMP and inorganic pyrophosphate, the latter being a powerful anti-mineralization factor. Recently, a novel mouse phenotype was recognized as a result of ENU mutagenesis - those mice developed stiffening of the joints, hence the mutant mouse was named 'ages with stiffened joints' (asj). These mice harbor a missense mutation, p.V246D, in the Enpp1 gene. Here we demonstrate that the mutant ENPP1 protein is largely absent in the liver of asj mice, and the lack of enzymatic activity results in reduced inorganic pyrophosphate (PPi) levels in the plasma, accompanied by extensive mineralization of a number of tissues, including arterial blood vessels. The progress of mineralization is highly dependent on the mineral composition of the diet, with significant shortening of the lifespan on a diet enriched in phosphorus and low in magnesium. These results suggest that the asj mouse can serve as an animal model for GACI.

  3. Role of cinnarizine and nifedipine on anticonvulsant effect of sodium valproate and carbamazepine in maximal electroshock and pentylenetetrazole model of seizures in mice

    PubMed Central

    Brahmane, Ranjana I.; Wanmali, Vikrant V.; Pathak, Swanand S.; Salwe, Kartik J.

    2010-01-01

    Objective: To study the effect of calcium channel blockers (CCBs) cinnarizine and nifedipine on maximal electroshock (MES)-induced and pentylenetetrazole (PTZ)-induced convulsions and also their effect in combination with conventional antiepileptic drugs (CAED). Materials and Methods: For this study, Swiss albino mice were used. Effects of cinnarizine (30 mg/kg), nifedipine (5 mg/kg), sodium valproate (300 mg/kg) and carbamazepine (8 mg/kg) alone and in combination were studied in MES and PTZ seizure models. Abolition of hind limb tonic extension was an index of anticonvulsant activity in MES, while for PTZ seizures, failure to observe even a single episode of tonic spasm for 5 s duration for 1 h was the index. With this, percentage protection was calculated and statistical analysis was carried out using Fisher’s exact test (Ovvind Langsrud software, German version). Results: In MES seizures, augmented effects were obtained when cinnarizine was combined with sodium valproate, i.e. 100%. In PTZ-induced seizures, augmented effects were obtained when nifedipine was combined with sodium valproate, i.e. 100%. Thus, cinnarizine added to sodium valproate therapy produces significant protection against MES seizures while nifedipine added to sodium valproate therapy produces significant protection against PTZ seizures. Conclusion: The results provide a lead for potential benefit of adding CCBs to sodium valproate in the treatment of epilepsy, which needs to be explored further. PMID:21350614

  4. Genetically inbred Balb/c mice differ from outbred Swiss Webster mice on discrete measures of sociability: relevance to a genetic mouse model of autism spectrum disorders.

    PubMed

    Jacome, Luis F; Burket, Jessica A; Herndon, Amy L; Deutsch, Stephen I

    2011-12-01

    The Balb/c mouse is proposed as a model of human disorders with prominent deficits of sociability, such as autism spectrum disorders (ASDs) that may involve pathophysiological disruption of NMDA receptor-mediated neurotransmission. A standard procedure was used to measure sociability in 8-week-old male genetically inbred Balb/c and outbred Swiss Webster mice. Moreover, because impaired sociability may influence the social behavior of stimulus mice, we also measured the proportion of total episodes of social approach made by the stimulus mouse while test and stimulus mice were allowed to interact freely. Three raters with good inter-rater agreement evaluated operationally defined measures of sociability chosen because of their descriptive similarity to deficits of social behavior reported in persons with ASDs. The data support previous reports that the Balb/c mouse is a genetic mouse model of impaired sociability. The data also show that the behavior of the social stimulus mouse is influenced by the impaired sociability of the Balb/c strain. Interestingly, operationally defined measures of sociability did not necessarily correlate with each other within mouse strain and the profile of correlated measures differed between strains. Finally, "stereotypic" behaviors (i.e. rearing, grooming and wall climbing) recorded during the session of free interaction between the test and social stimulus mice were more intensely displayed by Swiss Webster than Balb/c mice, suggesting that the domains of sociability and "restricted repetitive and stereotyped patterns of behavior" are independent of each other in the Balb/c strain.

  5. A Biomathematical Model of Pneumococcal Lung Infection and Antibiotic Treatment in Mice

    PubMed Central

    Schirm, Sibylle; Ahnert, Peter; Wienhold, Sandra; Mueller-Redetzky, Holger; Nouailles-Kursar, Geraldine; Loeffler, Markus; Witzenrath, Martin; Scholz, Markus

    2016-01-01

    Pneumonia is considered to be one of the leading causes of death worldwide. The outcome depends on both, proper antibiotic treatment and the effectivity of the immune response of the host. However, due to the complexity of the immunologic cascade initiated during infection, the latter cannot be predicted easily. We construct a biomathematical model of the murine immune response during infection with pneumococcus aiming at predicting the outcome of antibiotic treatment. The model consists of a number of non-linear ordinary differential equations describing dynamics of pneumococcal population, the inflammatory cytokine IL-6, neutrophils and macrophages fighting the infection and destruction of alveolar tissue due to pneumococcus. Equations were derived by translating known biological mechanisms and assuming certain response kinetics. Antibiotic therapy is modelled by a transient depletion of bacteria. Unknown model parameters were determined by fitting the predictions of the model to data sets derived from mice experiments of pneumococcal lung infection with and without antibiotic treatment. Time series of pneumococcal population, debris, neutrophils, activated epithelial cells, macrophages, monocytes and IL-6 serum concentrations were available for this purpose. The antibiotics Ampicillin and Moxifloxacin were considered. Parameter fittings resulted in a good agreement of model and data for all experimental scenarios. Identifiability of parameters is also estimated. The model can be used to predict the performance of alternative schedules of antibiotic treatment. We conclude that we established a biomathematical model of pneumococcal lung infection in mice allowing predictions regarding the outcome of different schedules of antibiotic treatment. We aim at translating the model to the human situation in the near future. PMID:27196107

  6. Added value of high-resolution regional climate model over the Bohai Sea and Yellow Sea areas

    NASA Astrophysics Data System (ADS)

    Li, Delei; von Storch, Hans; Geyer, Beate

    2016-04-01

    Added value from dynamical downscaling has long been a crucial and debatable issue in regional climate studies. A 34 year (1979-2012) high-resolution (7 km grid) atmospheric hindcast over the Bohai Sea and the Yellow Sea (BYS) has been performed using COSMO-CLM (CCLM) forced by ERA-Interim reanalysis data (ERA-I). The accuracy of CCLM in surface wind reproduction and the added value of dynamical downscaling to ERA-I have been investigated through comparisons with the satellite data (including QuikSCAT Level2B 12.5 km version 3 (L2B12v3) swath data and MODIS images) and in situ observations, with adoption of quantitative metrics and qualitative assessment methods. The results revealed that CCLM has a reliable ability to reproduce the regional wind characteristics over the BYS areas. Over marine areas, added value to ERA-I has been detected in the coastal areas with complex coastlines and orography. CCLM was better able to represent light and moderate winds but has even more added value for strong winds relative to ERA-I. Over land areas, the high-resolution CCLM hindcast can add value to ERA-I in reproducing wind intensities and direction, wind probability distribution and extreme winds mainly at mountain areas. With respect to atmospheric processes, CCLM outperforms ERA-I in resolving detailed temporal and spatial structures for phenomena of a typhoon and of a coastal atmospheric front; CCLM generates some orography related phenomena such as a vortex street which is not captured by ERA-I. These added values demonstrate the utility of the 7-km-resolution CCLM for regional and local climate studies and applications. The simulation was constrained with adoption of spectral nudging method. The results may be different when simulations are considered, which are not constrained by spectral nudging.

  7. Effects of meclofenamic acid on limbic epileptogenesis in mice kindling models.

    PubMed

    Jin, Miaomiao; Dai, Yunjian; Xu, Cenglin; Wang, Yi; Wang, Shuang; Chen, Zhong

    2013-05-24

    The most avid goal for antiepileptic drugs (AEDs) development today is to discover potential agents to prevent epilepsy or slow the process of epileptogenesis. Accumulating evidence reveals that gap junctions in the brain may be involved in epileptogenesis. Meclofenamic acid (MFA), a gap junction blocker, has not yet been applied in epileptogenic models to test whether it has antiepileptogenic or disease-modifying properties or not. In this study, we investigated the effects of MFA on limbic epileptogenesis in amygdaloid kindling and hippocampus rapid kindling models in mice. We found that intracerebroventricular (i.c.v., 2 μl) administration of either dose of MFA (100 μM, 1mM or 100mM) 15 min prior daily kindling stimulus decreased seizure stage, shortened the after-discharge duration (ADD) and increased the number of stimulations required to elicit stage 5 seizure. MFA also prevented the establishment of post-kindling enhanced amygdala excitability, evident as the increase of afterdischarge threshold (ADT) compared with pre-kindling values. Furthermore, MFA retarded kindling acquisition in mice hippocampus rapid kindling model as well, which demonstrated that the antiepileptogenic effects of MFA were not specific to the amygdala but also occur in other limbic structures such as the hippocampus. Our results confirm that MFA can slow the limbic epileptogenesis in both amygdaloid kindling and hippocampus rapid kindling models, and indicate that MFA may be a potential drug that has antiepileptogenic or disease-modifying properties.

  8. Histidine decarboxylase knockout mice, a genetic model of Tourette syndrome, show repetitive grooming after induced fear

    PubMed Central

    Xu, Meiyu; Li, Lina; Ohtsu, Hiroshi; Pittenger, Christopher

    2015-01-01

    Tics, such as are seen in Tourette syndrome (TS), are common and can cause profound morbidity, but they are poorly understood. Tics are potentiated by psychostimulants, stress, and sleep deprivation. Mutations in the gene histidine decarboxylase (Hdc) have been implicated as a rare genetic cause of TS, and Hdc knockout mice have been validated as a genetic model that recapitulates phenomenological and pathophysiological aspects of the disorder. Tic-like stereotypies in this model have not been observed at baseline but emerge after acute challenge with the psychostimulant D-amphetamine. We tested the ability of an acute stressor to stimulate stereotypies in this model, using tone fear conditioning. Hdc knockout mice acquired conditioned fear normally, as manifest by freezing during the presentation of a tone 48 hours after it had been paired with a shock. During the 30 minutes following tone presentation they showed increased grooming. Heterozygotes exhibited normal freezing and intermediate grooming. These data validate a new paradigm for the examination of tic-like stereotypies in animals without pharmacological challenge and enhance the face validity of the Hdc knockout mouse as a pathophysiologically grounded model of tic disorders. PMID:25841792

  9. Soleus muscles of SAMP8 mice provide an accelerated model of skeletal muscle senescence.

    PubMed

    Derave, Wim; Eijnde, Bert O; Ramaekers, Monique; Hespel, Peter

    2005-07-01

    Animal models are valuable research tools towards effective prevention of sarcopenia and towards a better understanding of the mechanisms underlying skeletal muscle aging. We investigated whether senescence-accelerated mouse (SAM) strains provide valid models for skeletal muscle aging studies. Male senescence-prone mice SAMP6 and SAMP8 were studied at age 10, 25 and 60 weeks and compared with senescence-resistant strain, SAMR1. Soleus and EDL muscles were tested for in vitro contractile properties, phosphocreatine content, muscle mass and fiber-type distribution. Declined muscle mass and contractility were observed at 60 weeks, the differences being more pronounced in SAMP8 than SAMP6 and more pronounced in soleus than EDL. Likewise, age-related decreases in muscle phosphocreatine content and type-II fiber size were most pronounced in SAMP8 soleus. In conclusion, typical features of muscular senescence occur at relatively young age in SAMP8 and nearly twice as fast as compared with other models. We suggest that soleus muscles of SAMP8 mice provide a cost-effective model for muscular aging studies. PMID:16023814

  10. Immunomodulatory activity of mefenamic acid in mice models of cell-mediated and humoral immunity

    PubMed Central

    Shabbir, Arham; Arshad, Hafiza Maida; Shahzad, Muhammad; Shamsi, Sadia; Ashraf, Muhammad Imran

    2016-01-01

    Objectives: Previously, different nonsteroidal anti-inflammatory drugs (NSAIDs) have been evaluated for their potential immunomodulatory activities. Mefenamic acid is a well-known NSAID and is used in the treatment of musculoskeletal disorders, inflammation, fever, and pain. To the best of our knowledge, promising data regarding the immunomodulatory activity of mefenamic acid is scarce. Current study investigates the immunomodulatory activity of mefenamic acid in different models of cell-mediated and humoral immunity. Materials and Methods: Immunomodulatory effects on cell-mediated immunity were evaluated using dinitrochlorobenzene-induced delayed type hypersensitivity (DTH) and cyclophosphamide-induce myelosuppression assays. While effects on humoral immunity were evaluated using hemagglutination assay and mice lethality test. Results: Hematological analysis showed that mefenamic acid significantly reduced white blood cell count, red blood cell (RBC) count, hemoglobin content, lymphocytes levels, and neutrophils levels in healthy mice as compared with control, suggesting the immunosuppressive activity of mefenamic acid. Treatment with mefenamic acid also significantly reduced all the hematological parameters in cyclophosphamide-induced neutropenic mice, as compared with positive control group. We found that treatment with mefenamic acid significantly suppressed DTH after 24 h, 48 h, and 72 h, as compared with positive control group. Mefenamic acid treated groups showed a significant reduction in antibody titer against sheep RBCs as compared to control group, similar to the effect of cyclophosphamide. We also found increased mice lethality rate in mefenamic acid treated groups, as compared with positive control group. Conclusions: The results provided basic information of immunosuppression of mefenamic acid on both cell-mediated and humoral immunity. PMID:27127320

  11. Changes in phagocytosis and expression of microglial cells in craniocerebral injury mice models.

    PubMed

    Guo, F Y; Liu, T; Chen, J J; Gao, W; Yang, F; Zhou, X Y; Liao, Y L

    2016-01-01

    The objective of this study was to investigate the changes in phagocytic function and expression quantities of CD11b and tumor necrosis factor-α (TNF-α) among microglia cells of craniocerebral injury mice. Modified Feeney method was used to establish the craniocerebral injury mice models. Twenty-one male SPF mice were divided into a control group and a trauma group. The scalp was incised and a bone window was opened in the control group without cerebral injury. In the trauma group, the mice were sacrificed after the craniocerebral injury at 1, 3, 6, 12, 24 and 48 h to make frozen sections of cerebral tissues. The phagocytic rate of microglia cells was observed by using fluorescent microsphere. The changes in the expression quantities of CD11b and TNF-α were detected by enzyme-linked immuno sorbent assay (ELISA). The phagocytic ability of the microglia cells after the craniocerebral injury increased at 1 h after injury compared with that of the control group (P less than 0.01). The expression of surface antigen CD11b of the microglia cells and the expression of TNF-α increased at 1, 3, 6, 12, 24 and 48 h after the injury compared with those of the control group (P less than 0.01). The phagocytic ability of the microglia cells increased. The expressions of CD11b and TNF-α were also gradually enhanced in the acute phase after craniocerebral injury, and then gradually decreased to the normal level. The expressions of CD11b and TNF-α indicated a high consistency with the changing trend of the phagocytic ability, suggesting that the microglia cells may participate in the regulation of the inflammatory process of the central nervous system through absorbing apoptotic cells and increasing and secreting inflammatory and anti-inflammatory factors.

  12. Animal models of physiologic markers of male reproduction: genetically defined infertile mice

    SciTech Connect

    Chubb, C.

    1987-10-01

    The present report focuses on novel animal models of male infertility: genetically defined mice bearing single-gene mutations that induce infertility. The primary goal of the investigations was to identify the reproductive defects in these mutant mice. The phenotypic effects of the gene mutations were deciphered by comparing the mutant mice to their normal siblings. Initially testicular steroidogenesis and spermatogenesis were investigated. The physiologic markers for testicular steroidogenesis were steroid secretion by testes perifused in vitro, seminal vesicle weight, and Leydig cell histology. Spermatogenesis was evaluated by the enumeration of homogenization-resistant sperm/spermatids in testes and by morphometric analyses of germ cells in the seminiferous epithelium. If testicular function appeared normal, the authors investigated the sexual behavior of the mice. The parameters of male sexual behavior that were quantified included mount patency, mount frequency, intromission latency, thrusts per intromission, ejaculation latency, and ejaculation duration. Females of pairs breeding under normal circumstances were monitored for the presence of vaginal plugs and pregnancies. The patency of the ejaculatory process was determined by quantifying sperm in the female reproductive tract after sexual behavior tests. Sperm function was studied by quantitatively determining sperm motility during videomicroscopic observation. Also, the ability of epididymal sperm to function within the uterine environment was analyzed by determining sperm capacity to initiate pregnancy after artificial insemination. Together, the experimental results permitted the grouping of the gene mutations into three general categories. They propose that the same biological markers used in the reported studies can be implemented in the assessment of the impact that environmental toxins may have on male reproduction.

  13. Human brain tumor xenografts in nude mice as a chemotherapy model.

    PubMed

    Houchens, D P; Ovejera, A A; Riblet, S M; Slagel, D E

    1983-06-01

    Two human brain tumors which were previously established in nude mice were used to determine antitumor efficacy of various therapeutic agents. These tumors were a medulloblastoma (TE-671) and a glioma (U-251) with mass doubling times of 3.5 and 5.5 days respectively as subcutaneous implants in nude mice. Intracranial (i.c.) tumor challenge was accomplished by inoculating tissue culture-grown cells of either tumor into the right cerebral hemisphere to a depth of 3 mm. Median survival time (MST) in untreated mice with 10(5) i.c. injected TE-671 cells was approximately 30 days and 53 days in the U-251 tumor. With 2 X 10(5) U-251 tumor cells the MST was 27-31 days. Groups of mice which had been inoculated with tumor were treated with various doses and schedules of antineoplastic compounds by the i.p. route. The TE-671 tumor responded to AZQ treatment with an increase in life span (ILS) of 37% compared to untreated controls and an ILS of 30% with CCNU treatment. BCNU and PCNU were ineffective. With the U-251 tumor BCNU produced an ILS of greater than 60%, with 75% cures, greater than 112% ILS with PCNU and 49% ILS with CCNU. Neither tumor responded to procarbazine, PALA, dianhydrogalactitol, D-O-norleucine or dibromodulcitol. The U-251 tumor was treated on various schedules and doses with BCNU and found to respond well on late as well as early treatment. A new drug (rapamycin) being investigated by the NCI was found to be very effective against the U-251 tumor. This model system should prove valuable in assessing the effects of various chemotherapeutic modalities against brain tumors.

  14. Changes in phagocytosis and expression of microglial cells in craniocerebral injury mice models.

    PubMed

    Guo, F Y; Liu, T; Chen, J J; Gao, W; Yang, F; Zhou, X Y; Liao, Y L

    2016-01-01

    The objective of this study was to investigate the changes in phagocytic function and expression quantities of CD11b and tumor necrosis factor-α (TNF-α) among microglia cells of craniocerebral injury mice. Modified Feeney method was used to establish the craniocerebral injury mice models. Twenty-one male SPF mice were divided into a control group and a trauma group. The scalp was incised and a bone window was opened in the control group without cerebral injury. In the trauma group, the mice were sacrificed after the craniocerebral injury at 1, 3, 6, 12, 24 and 48 h to make frozen sections of cerebral tissues. The phagocytic rate of microglia cells was observed by using fluorescent microsphere. The changes in the expression quantities of CD11b and TNF-α were detected by enzyme-linked immuno sorbent assay (ELISA). The phagocytic ability of the microglia cells after the craniocerebral injury increased at 1 h after injury compared with that of the control group (P less than 0.01). The expression of surface antigen CD11b of the microglia cells and the expression of TNF-α increased at 1, 3, 6, 12, 24 and 48 h after the injury compared with those of the control group (P less than 0.01). The phagocytic ability of the microglia cells increased. The expressions of CD11b and TNF-α were also gradually enhanced in the acute phase after craniocerebral injury, and then gradually decreased to the normal level. The expressions of CD11b and TNF-α indicated a high consistency with the changing trend of the phagocytic ability, suggesting that the microglia cells may participate in the regulation of the inflammatory process of the central nervous system through absorbing apoptotic cells and increasing and secreting inflammatory and anti-inflammatory factors. PMID:27358141

  15. Biphasic effects of Morus alba leaves green tea extract on mice in chronic forced swimming model.

    PubMed

    Sattayasai, Jintana; Tiamkao, Siriporn; Puapairoj, Prapawadee

    2008-04-01

    In this study, the effects of an aqueous extract of Morus alba leaves green tea (ME) on mouse behaviors (depression, anxiety, climbing activity and thermal response), muscle coordination and muscle strength were studied. Male IRC mice received a single intraperitoneal injection of either the ME, desipramine or diazepam. Thirty minutes after injection, the mice were tested in all experimental models. A significant antidepressant-like effect could be detected in the animals receiving either 100 or 200 mg/kg ME. The effect of 200 mg/kg ME in decreasing the immobility time was comparable to 10 mg/kg desipramine. With higher dose (1000 mg/kg), a significant increase in immobility time could be observed. In the elevated plus maze, no increase in time in the open arm could be observed in mice treated with ME at either 100 or 200 mg/kg. However, high doses of ME (500 or 1000 mg/kg) decreased both time in the open arm and the number of entries in the maze. No change in thermal response could be seen in mice treated with ME at doses up to 500 mg/kg, however, at 1000 mg/kg, the response time to heat was increased significantly. The ME at either 500 or 1000 mg/kg also decreased muscle coordination, strength and climbing activity significantly when compared with the control. This study suggests that ME possesses an antidepressant- without an anxiolytic-like effect, however, at high doses, the extract might show the sedative effect and alter other functions such as muscle strength, animal activity in the maze and pain response.

  16. Effect of leptin infusion on insulin sensitivity and lipid metabolism in diet-induced lipodystrophy model mice

    PubMed Central

    Nagao, Koji; Inoue, Nao; Ujino, Yoko; Higa, Kouki; Shirouchi, Bungo; Wang, Yu-Ming; Yanagita, Teruyoshi

    2008-01-01

    Background Lipodystrophies are rare acquired and genetic disorders characterized by the complete or partial absence of body fat with a line of metabolic disorders. Previous studies demonstrated that dietary conjugated linoleic acid (CLA) induces hepatic steatosis and hyperinsulinemia through the drastic reduction of adipocytokine levels due to a paucity of adipose tissue in mice and the pathogenesis of these metabolic abnormalities in CLA-fed mice is similar to that in human lipodystrophy. The present study explores the effect of leptin infusion on the pathogenesis of diet-induced lipodystrophy in mice. C57BL/6N mice were assigned to three groups: (1) mice were fed a semisynthetic diet supplemented with 6% corn oil and infused PBS intraperitoneally (normal group), (2) mice were fed a semisynthetic diet supplemented with 4% corn oil plus 2% CLA and infused PBS intraperitoneally (lipodystrophy-control group), and (3) mice were fed a semisynthetic diet supplemented with 4% corn oil plus 2% CLA and infused recombinant murine leptin intraperitoneally (lipodystrophy-leptin group). All mice were fed normal or lipodystrophy model diets for 4 weeks and were infused intrapeneally 0 or 5 μg of leptin per day from third week of the feeding period for 1 week. Results The results indicate that leptin infusion can attenuate hepatic steatosis and hyperinsulinemia through the reduction of hepatic triglyceride synthesis and the improvement of insulin sensitivity in diet-induced lipodystrophy model mice. Conclusion We expect the use of this model for clarifying the pathophysiology of lipodystrophy-induced metabolic abnormalities and evaluating the efficacy and safety of drug and dietary treatment. PMID:18348717

  17. Liraglutide can reverse memory impairment, synaptic loss and reduce plaque load in aged APP/PS1 mice, a model of Alzheimer's disease.

    PubMed

    McClean, Paula L; Hölscher, Christian

    2014-01-01

    Type 2 diabetes is a risk factor in the development of Alzheimer's disease (AD). It has been shown that insulin signalling is desensitised in the brains of AD patients. The incretin hormone Glucagon-like peptide-1 (GLP-1) facilitates insulin signalling, and long-lasting analogues such as liraglutide (Victoza(®)) are on the market as type 2 diabetes treatments. We have previously shown that liraglutide improved cognitive function, reduced amyloid plaque deposition, inflammation, overall APP and oligomer levels and enhanced LTP when injected peripherally for two months in 7 month old APPswe/PS1ΔE9 (APP/PS1) mice. This showed that liraglutide has preventive effects at the early stage of AD development. The current study investigated whether Liraglutide would have restorative effects in late-stage Alzheimer's disease in mice. Accordingly, 14-month-old APP/PS1 and littermate control mice were injected with Liraglutide (25 nmol/kg bw) ip. for 2 months. Spatial memory was improved by Liraglutide-treatment in APP/PS1 mice compared with APP/PS1 saline-treated mice. Overall plaque load was reduced by 33%, and inflammation reduced by 30%, while neuronal progenitor cell count in the dentate gyrus was increased by 50%. LTP was significantly enhanced in APP/PS1 liraglutide-treated mice compared with APP/PS1 saline mice, corroborated with increased synapse numbers in hippocampus and cortex. Total brain APP and beta-amyloid oligomer levels were reduced in Liraglutide-treated APP/PS1 mice while IDE levels were increased. These results demonstrate that Liraglutide not only has preventive properties, but also can reverse some of the key pathological hallmarks of AD. Liraglutide is now being tested in clinical trials in AD patients. This article is part of the Special Issue entitled 'The Synaptic Basis of Neurodegenerative Disorders'.

  18. Investigation into the optimal surgical conditions for coronary artery ligation for establishing a myocardial infarction model in mice

    PubMed Central

    YUE, XIA; YU, HONGSHENG; LIN, XIALU; LIU, KUI; WANG, XIN; ZHOU, FEI; ZHAO, JINSHUN; ZOU, BAOBO

    2013-01-01

    In the present study, the left anterior descending coronary arteries of mice under anesthesia were ligated, and the optimal surgical conditions for coronary artery ligation (CAL) in the establishment of a myocardial infarction (MI) mouse model were investigated. All mice that survived were sacrificed seven days subsequent to the successful surgery. Body weight, blood serum and heart tissues were obtained for further analysis or biochemical and histopathological examinations. The survival rate of the mice following the CAL procedure was 70%. The aspartate aminotransferase (AST), creatine kinase (CK) and lactate dehydrogenase (LDH) concentrations in the serum of the experimental mice were significantly increased compared with those of the control mice, which reflected the enzyme release from the infarcted myocardial cells. Histopathological examination showed different degrees of MI in the heart