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Sample records for app transgenic drosophila

  1. Neurologic and motor dysfunctions in APP transgenic mice

    PubMed Central

    Lalonde, Robert; Fukuchi, Ken-ichiro; Strazielle, Catherine

    2012-01-01

    The discovery of gene mutations underlying autosomal dominant Alzheimer’s disease has enabled researchers to reproduce several hallmarks of this disorder in transgenic mice, notably the formation of Aβ plaques in brain and cognitive deficits. APP transgenic mutants have also been investigated with respect to survival rates, neurologic functions, and motor coordination, which are all susceptible to alteration in Alzheimer dementia. Several transgenic lines expressing human mutated or wild-type APP had higher mortality rates than non-transgenic controls with or without the presence of Aβ plaques. Mortality rates were also elevated in APP transgenic mice with vascular amyloid accumulation, thereby implicating cerebrovascular factors in the precocious death observed in all APP transgenic models. In addition, myoclonic jumping has been described in APP mutants, together with seizure activity, abnormal limb-flexion and paw-clasping reflexes, and motor coordination deficits. The neurologic signs resemble the myoclonic movements, epileptic seizures, pathological reflexes, and gait problems observed in late-stage Alzheimer’s disease. PMID:23089603

  2. [Research progress of transgenic Drosophila model of Alzheimer disease].

    PubMed

    Tan, Yan; Ji, Yu-Bin; Zhao, Jian

    2013-03-01

    Alzheimer disease (AD) is a common neurodegenerative disease. Drosophila has been regard as one of the ideal models for Alzheimer because of its unique advantage on genetic manipulation. AD transgenic drosophila models not only help to elucidate the pathogenesis of Alzheimer disease, but also provide potential screening models for drugs to treat the disease. In this review, we summarize the recent research progress using AD transgenic drosophila.

  3. [Investigation of neuroprotective activity of apolipoprotein E peptide mimetic Cog1410 in transgenic lines of Drosophila melanogaster].

    PubMed

    Latypova, E M; Timoshenko, S I; Kislik, G A; Vitek, M; Shvartsman, A L; Sarantseva, S V

    2014-01-01

    The neuroprotective activity of apolipoprotein E (apoE) peptide mimetic Cog1410, containing amino acid sequence of the receptor-binding domain apoE, has been investigated in transgenic lines of Drosophila melanogaster expressing human APP and beta-secretase. Expression of two transgenes caused neuropathological processes attributed to Alzheimer's disease: neurodegeneration, cognitive abnormality and amyloid deposits formation in brain. It was shown that Cog 1410 reduces neurodegeneration in brain of transgenic flies and improves cognitive functions (odor recognition). These data suggest that Cog1410 is a potential neuroprotector that can be used in AD treatment.

  4. Endogenous murine Aβ increases amyloid deposition in APP23 but not in APPPS1 transgenic mice.

    PubMed

    Mahler, Jasmin; Morales-Corraliza, Jose; Stolz, Julia; Skodras, Angelos; Radde, Rebecca; Duma, Carmen C; Eisele, Yvonne S; Mazzella, Matthew J; Wong, Harrison; Klunk, William E; Nilsson, K Peter R; Staufenbiel, Matthias; Mathews, Paul M; Jucker, Mathias; Wegenast-Braun, Bettina M

    2015-07-01

    Endogenous murine amyloid-β peptide (Aβ) is expressed in most Aβ precursor protein (APP) transgenic mouse models of Alzheimer's disease but its contribution to β-amyloidosis remains unclear. We demonstrate ∼ 35% increased cerebral Aβ load in APP23 transgenic mice compared with age-matched APP23 mice on an App-null background. No such difference was found for the much faster Aβ-depositing APPPS1 transgenic mouse model between animals with or without the murine App gene. Nevertheless, both APP23 and APPPS1 mice codeposited murine Aβ, and immunoelectron microscopy revealed a tight association of murine Aβ with human Aβ fibrils. Deposition of murine Aβ was considerably less efficient compared with the deposition of human Aβ indicating a lower amyloidogenic potential of murine Aβ in vivo. The amyloid dyes Pittsburgh Compound-B and pentamer formyl thiophene acetic acid did not differentiate between amyloid deposits consisting of human Aβ and deposits of mixed human-murine Aβ. Our data demonstrate a differential effect of murine Aβ on human Aβ deposition in different APP transgenic mice. The mechanistically complex interaction of human and mouse Aβ may affect pathogenesis of the models and should be considered when models are used for translational preclinical studies.

  5. Genetic suppression of transgenic APP rescues Hypersynchronous network activity in a mouse model of Alzeimer's disease.

    PubMed

    Born, Heather A; Kim, Ji-Yoen; Savjani, Ricky R; Das, Pritam; Dabaghian, Yuri A; Guo, Qinxi; Yoo, Jong W; Schuler, Dorothy R; Cirrito, John R; Zheng, Hui; Golde, Todd E; Noebels, Jeffrey L; Jankowsky, Joanna L

    2014-03-12

    Alzheimer's disease (AD) is associated with an elevated risk for seizures that may be fundamentally connected to cognitive dysfunction. Supporting this link, many mouse models for AD exhibit abnormal electroencephalogram (EEG) activity in addition to the expected neuropathology and cognitive deficits. Here, we used a controllable transgenic system to investigate how network changes develop and are maintained in a model characterized by amyloid β (Aβ) overproduction and progressive amyloid pathology. EEG recordings in tet-off mice overexpressing amyloid precursor protein (APP) from birth display frequent sharp wave discharges (SWDs). Unexpectedly, we found that withholding APP overexpression until adulthood substantially delayed the appearance of epileptiform activity. Together, these findings suggest that juvenile APP overexpression altered cortical development to favor synchronized firing. Regardless of the age at which EEG abnormalities appeared, the phenotype was dependent on continued APP overexpression and abated over several weeks once transgene expression was suppressed. Abnormal EEG discharges were independent of plaque load and could be extinguished without altering deposited amyloid. Selective reduction of Aβ with a γ-secretase inhibitor has no effect on the frequency of SWDs, indicating that another APP fragment or the full-length protein was likely responsible for maintaining EEG abnormalities. Moreover, transgene suppression normalized the ratio of excitatory to inhibitory innervation in the cortex, whereas secretase inhibition did not. Our results suggest that APP overexpression, and not Aβ overproduction, is responsible for EEG abnormalities in our transgenic mice and can be rescued independently of pathology.

  6. Time-Dependent Increase of Chitinase1 in APP/PS1 Double Transgenic Mice.

    PubMed

    Xiao, Qian; Shi, Rui; Yang, Wenxiu; Zou, Yan; Du, Yinshi; Zhang, Man; Yu, Weihua; Lü, Yang

    2016-07-01

    It is reported that chitinase1 increases in Alzheimer's disease (AD). However, the alteration of chitinase1 in the progress of AD is still unclear. Thus, we designed the present study to detect chitinase1 level in different stages of APP/PS1 double transgenic mice. Experimental models were APP/PS1 double transgenic mice with 4, 12 and 22 months. Cognitive function was detected by Morris water maze test in APP/PS1 mice as well as controls. ELISA and the quantitative RT-PCR were used to detect chitinase1 level in different groups. The study displayed that expression of chitinase1 gradually increased in a time-dependent manner in APP/PS1 mice, while there were no statistical differences among the wild-type mice in varies ages. Moreover, chitnase1 increased significantly in APP/PS1 mice aged 12 and 22 months compared with the age matched wild-type group, respectively. However, no difference of chitnase1 was found between 4 months-old APP/PS1 mice and wild-type mice. Comparing with the age matched wild type group, the consequences of mRNA on the increase in chitnase1 is in accordance with protein in APP/PS1 mice. Furthermore, Morris water maze showed that 4 months-old APP/PS1 mice have normal spatial learning and impaired spatial memory; both spatial learning and spatial memory in 12 and 22 months-old APP/PS1 mice were declined. Time-dependent increase of chitnase1 in APP/PS1 double transgenic mice indicates that the level of chitinase1 is associated with decline of cognition. Therefore, chitinase1 might be a biomarker of disease progression in AD.

  7. Loss of Polo ameliorates APP-induced Alzheimer's disease-like symptoms in Drosophila.

    PubMed

    Peng, Fei; Zhao, Yu; Huang, Xirui; Chen, Changyan; Sun, Lili; Zhuang, Luming; Xue, Lei

    2015-11-24

    The amyloid precursor protein (APP) has been implicated in the pathogenesis of Alzheimer's disease (AD). Despite extensive studies, little is known about the regulation of APP's functions in vivo. Here we report that expression of human APP in Drosophila, in the same temporal-spatial pattern as its homolog APPL, induced morphological defects in wings and larval NMJ, larva and adult locomotion dysfunctions, male choice disorder and lifespan shortening. To identify additional genes that modulate APP functions, we performed a genetic screen and found that loss of Polo, a key regulator of cell cycle, partially suppressed APP-induced morphological and behavioral defects in larval and adult stages. Finally, we showed that eye-specific expression of APP induced retina degeneration and cell cycle re-entry, both phenotypes were mildly ameliorated by loss of Polo. These results suggest Polo is an important in vivo regulator of the pathological functions of APP, and provide insight into the role of cell cycle re-entry in AD pathogenesis.

  8. Curcumin improves bone microarchitecture and enhances mineral density in APP/PS1 transgenic mice.

    PubMed

    Yang, Mao-Wei; Wang, Tong-Hao; Yan, Pei-Pei; Chu, Li-Wei; Yu, Jiang; Gao, Zhi-Da; Li, Yuan-Zhou; Guo, Bao-Lei

    2011-01-15

    Alzheimer's disease and osteoporosis are often observed to co-occur in clinical practice. The present study aimed to evaluate the bone microarchitecture and bone mineral density (BMD) of the proximal tibia in APP/PS1 transgenic mice by micro-computed tomography (micro-CT), and to search for evidence that curcumin can be used to reduce bone mineral losses and treat osteoporosis after senile dementia in these transgenic mice. Three-month-old female mice were divided into the following groups (n=9 per group): wild-type mice (WT group); APP/PS1 transgenic mice (APP group); and APP/PS1 transgenic mice with curcumin treatment (APP+Cur group). Between 9 and 12 months of age, the APP+Cur group were administered curcumin orally (600ppm). CT scans of the proximal tibia were taken at 6, 9 and 12 months. At 6 months, there were little differences in the structural parameters. At 9 months, the APP groups displayed loss of bone volume ratio (BV/TV), trabecular thickness (Tb.Th), trabecular number (Tb.N) and connectivity density (Conn.D) and increases in trabecular separation (Tb.Sp) and geometric degree of anisotropy (DA) (P<0.05 or P<0.01), with significant changes in the BMD parameters. At 12 months, curcumin treatment led to constant increases in the trabecular bone mass of the metaphysis and clearly improved the BMD. By the same time, we measured the TNF-α and IL-6 in the serum among the different groups at 6, 9 and 12 months by enzyme-linked immunoassay(ELISA). These results suggest that APP/PS1 transgenic mice are susceptible to osteoporosis, and that curcumin can prevent further deterioration of the bone structure and produce beneficial changes in bone turnover. The change of inflammation cytokine, including TNF-α and IL-6, may play an important role in the mechanisms of action of curcumin, but the detail mechanism remains unknown.

  9. In vivo MRI and histological evaluation of brain atrophy in APP/PS1 transgenic mice.

    PubMed

    Delatour, Benoît; Guégan, Maryvonne; Volk, Andreas; Dhenain, Marc

    2006-06-01

    Regional cerebral atrophy was evaluated in APP/PS1 mice harboring mutated transgenes linked to familial Alzheimer's disease, using complementary methods. In vivo high resolution MRI was selected for measurements of brain atrophy and associated cerebrospinal fluid dilation; histological analysis was performed to reveal localized atrophies and to evaluate amyloid burden. Young APP/PS1 mice examined at a pre-amyloid stage (10 weeks) showed disruption in development (reduced intracranial and brain volumes). Comparison of young and old (24 months) mice, indicated that both APP/PS1 and control brains endure growth during adulthood. Aged APP/PS1 animals showed a moderate although significant global brain atrophy and a dilation of CSF space in posterior brain regions. The locus of this atrophy was identified in the midbrain area and not, as expected, at isocortical/hippocampal levels. Atrophy was also detected in fiber tracts. The severity of brain atrophy in old APP/PS1 mice was not correlated with the extent of cerebral amyloidosis. The relevance of current transgenic mouse models for the study of brain atrophy related to Alzheimer's disease is discussed.

  10. Loss of Polo ameliorates APP-induced Alzheimer’s disease-like symptoms in Drosophila

    PubMed Central

    Peng, Fei; Zhao, Yu; Huang, Xirui; Chen, Changyan; Sun, Lili; Zhuang, Luming; Xue, Lei

    2015-01-01

    The amyloid precursor protein (APP) has been implicated in the pathogenesis of Alzheimer’s disease (AD). Despite extensive studies, little is known about the regulation of APP’s functions in vivo. Here we report that expression of human APP in Drosophila, in the same temporal-spatial pattern as its homolog APPL, induced morphological defects in wings and larval NMJ, larva and adult locomotion dysfunctions, male choice disorder and lifespan shortening. To identify additional genes that modulate APP functions, we performed a genetic screen and found that loss of Polo, a key regulator of cell cycle, partially suppressed APP-induced morphological and behavioral defects in larval and adult stages. Finally, we showed that eye-specific expression of APP induced retina degeneration and cell cycle re-entry, both phenotypes were mildly ameliorated by loss of Polo. These results suggest Polo is an important in vivo regulator of the pathological functions of APP, and provide insight into the role of cell cycle re-entry in AD pathogenesis. PMID:26597721

  11. Transgenic Drosophila models of Alzheimer's disease and tauopathies

    PubMed Central

    2010-01-01

    Alzheimer's disease (AD) is the most common form of senile dementia. Aggregation of the amyloid- β42 peptide (Aβ42) and tau proteins are pathological hallmarks in AD brains. Accumulating evidence suggests that Aβ42 plays a central role in the pathogenesis of AD, and tau acts downstream of Aβ42 as a modulator of the disease progression. Tau pathology is also observed in frontotemporal dementia with Parkinsonism linked to chromosome 17 (FTDP-17) and other related diseases, so called tauopathies. Although most cases are sporadic, genes associated with familial AD and FTDP-17 have been identified, which led to the development of transgenic animal models. Drosophila has been a powerful genetic model system used in many fields of biology, and recently emerges as a model for human neurodegenerative diseases. In this review, we will summarize key features of transgenic Drosophila models of AD and tauopathies and a number of insights into disease mechanisms as well as therapeutic implications gained from these models. PMID:19967412

  12. Longitudinal behavioral changes in the APP/PS1 transgenic Alzheimer's disease model.

    PubMed

    Ferguson, Sherry A; Sarkar, Sumit; Schmued, Larry C

    2013-04-01

    The APP/PS1 double transgenic mouse is an Alzheimer's Disease-like model. However, cognitive deficits measured at one age do not necessarily indicate age-related progressions. Further, results of the most widely used behavioral assessment, water maze performance, are generally limited to 1-2 endpoints. Here, male APP/PS1 and noncarrier wildtypes (n=11/group) were assessed at 7-15 months of age for water maze, open field, and motor coordination performance. Body weights and motor coordination were comparable for both groups throughout. Beginning at approximately 9 months of age, the transgenic group exhibited hypoactivity in the open field which continued throughout. Latency to locate the platform and swim path length were longer in the transgenic group; however, these appeared to be more related to increased floating and thigmotactic behavior and only partially related to a cognitive impairment. Age-related decrements in performance were not substantial; however, substantial plaque numbers were measured in six representative 16-month-old transgenic mice. The stability of water maze performance may be related to the longitudinal testing and repetitive experience, which previous research has demonstrated can confer beneficial effects on behavior and plaque deposition in transgenic Alzheimer's Disease models [1]. These results emphasize the importance of measuring multiple water maze endpoints and demonstrate the feasibility of longitudinal assessments in this model.

  13. Bioassay of prion-infected blood plasma in PrP transgenic Drosophila.

    PubMed

    Thackray, Alana M; Andreoletti, Olivier; Bujdoso, Raymond

    2016-12-01

    In pursuit of a tractable bioassay to assess blood prion infectivity, we have generated prion protein (PrP) transgenic Drosophila, which show a neurotoxic phenotype in adulthood after exposure to exogenous prions at the larval stage. Here, we determined the sensitivity of ovine PrP transgenic Drosophila to ovine prion infectivity by exposure of these flies to a dilution series of scrapie-infected sheep brain homogenate. Ovine PrP transgenic Drosophila showed a significant neurotoxic response to dilutions of 10(-2) to 10(-10) of the original scrapie-infected sheep brain homogenate. Significantly, we determined that this prion-induced neurotoxic response in ovine PrP transgenic Drosophila was transmissible to ovine PrP transgenic mice, which is indicative of authentic mammalian prion detection by these flies. As a consequence, we considered that PrP transgenic Drosophila were sufficiently sensitive to exogenous mammalian prions to be capable of detecting prion infectivity in the blood of scrapie-infected sheep. To test this hypothesis, we exposed ovine PrP transgenic Drosophila to scrapie-infected plasma, a blood fraction notoriously difficult to assess by conventional prion bioassays. Notably, pre-clinical plasma from scrapie-infected sheep induced neurotoxicity in PrP transgenic Drosophila and this effect was more pronounced after exposure to samples collected at the clinical phase of disease. The neurotoxic phenotype in ovine PrP transgenic Drosophila induced by plasma from scrapie-infected sheep was transmissible since head homogenate from these flies caused neurotoxicity in recipient flies during fly-to-fly transmission. Our data show that PrP transgenic Drosophila can be used successfully to bioassay prion infectivity in blood from a prion-diseased mammalian host.

  14. Generation of a transgenic ORFeome library in Drosophila

    PubMed Central

    Bischof, Johannes; Sheils, Emma M.; Björklund, Mikael; Basler, Konrad

    2014-01-01

    Overexpression screens can be used to explore gene function in Drosophila melanogaster, but to demonstrate their full potential comprehensive and systematic collections of fly strains are required. Here we provide a protocol for high-throughput cloning of Drosophila open reading frames (ORFs) regulated by Upstream Activation Sequences (UAS sites); the resulting Gal4-inducible UAS-ORF plasmid library is then used to generate Drosophila strains by ΦC31 integrase-mediated site-specific integration. We also provide details for FLP/FRT-mediated in vivo exchange of epitope tags (or regulatory regions) in the ORF library strains, which further extends their potential applications. These transgenic UAS-ORF strains are a useful resource to complement and validate genetic experiments performed with loss-of-function mutants and RNAi lines. The duration of the complete protocol strongly depends on the number of ORFs required, but the procedure of injection and establishing balanced fly stocks can be completed within approx. 6-7 weeks for a few genes. PMID:24922270

  15. Osthole Upregulates BDNF to Enhance Adult Hippocampal Neurogenesis in APP/PS1 Transgenic Mice.

    PubMed

    Liu, Hong; Xue, Xinhong; Shi, Huijian; Qi, Lifeng; Gong, Dianrong

    2015-01-01

    Adult hippocampal neurogenesis occurs in the dentate gyrus (DG) of the mouse hippocampus, and plays roles in learning and memory progresses. In amyloid precursor protein (APP)/presenilin 1 (PS1) transgenic mice, a rodent model of Alzheimer's disease (AD), severe impairment of neurogenesis in the dentate subgranular zone (SGZ) of the DG has been reported. Osthole, an active constituent of Cnidium monnieri (L.) CUSSON, has been reported to exert neuroprotective effects and may promote neural stem cell proliferation. However, whether osthole ameliorates spatial memory deficits and improves hippocampal neurogenesis in APP/PS1 mice remains unknown. In this study we found that osthole (30 mg/kg intraperitoneally (i.p.) once daily) treatment dramatically ameliorated the cognitive impairments by Morris Water Maze test and passive avoidance test, and augmented neurogenesis in the DG of hippocampus in APP/PS1 mice. Furthermore, osthole treatment upregulated expression of brain-derived neurotrophic factor (BDNF) and enhanced activation of the BDNF receptor tyrosine receptor kinase B (TrkB) following increased phosphorylation of cyclic AMP response element-binding protein (CREB), indicating that osthole improves neurogenesis via stimulating BDNF/TrkB/CREB signaling in APP/PS1 transgenic mice.

  16. Deposition of BACE-1 Protein in the Brains of APP/PS1 Double Transgenic Mice

    PubMed Central

    Luo, Gang; Xu, Hongxia; Huang, Yinuo; Mo, Dapeng; Song, Ligang; Jia, Baixue; Wang, Bo; Jin, Zhanqiang; Miao, Zhongrong

    2016-01-01

    The main causes of Alzheimer's disease remain elusive. Previous data have implicated the BACE-1 protein as a central player in the pathogenesis of Alzheimer's disease. However, many inhibitors of BACE-1 have failed during preclinical and clinical trials for AD treatment. Therefore, uncovering the exact role of BACE-1 in AD may have significant impact on the future development of therapeutic agents. Three- and six-month-old female APP/PS1 double transgenic mice were used to study abnormal accumulation of BACE-1 protein in brains of mice here. Immunofluorescence, immunohistochemistry, and western blot were performed to measure the distributing pattern and expression level of BACE-1. We found obvious BACE-1 protein accumulation in 3-month-old APP/PS1 mice, which had increased by the time of 6 months. Coimmunostaining results showed BACE-1 surrounded amyloid plaques in brain sections. The abnormal protein expression might not be attributable to the upregulation of BACE-1 protein, as no significant difference of protein expression was observed between wild-type and APP/PS1 mice. With antibodies against BACE-1 and CD31, we found a high immunoreactive density of BACE-1 protein on the outer layer of brain blood vessels. The aberrant distribution of BACE-1 in APP/PS1 mice suggests BACE-1 may be involved in the microvascular abnormality of AD. PMID:27294139

  17. Progressive neuropathology and cognitive decline in a single Arctic APP transgenic mouse model.

    PubMed

    Rönnbäck, Annica; Zhu, Shunwei; Dillner, Karin; Aoki, Mikio; Lilius, Lena; Näslund, Jan; Winblad, Bengt; Graff, Caroline

    2011-02-01

    The Arctic APP mutation (E693G) leads to dementia with clinical features similar to Alzheimer disease (AD), but little is known about the pathogenic mechanism of this mutation. To address this question, we have generated a transgenic mouse model, TgAPParc, with neuron-specific expression of human APP with the Arctic mutation (hAPParc). Heterozygous mice from two separate founder lines with different levels of expression of hAPParc were analyzed with respect to brain morphology and behavior every 3 months until the age of 18 months. Standard histological stainings and immunohistochemistry using a panel of Aβ antibodies showed an age- and dose-dependant progression of amyloid deposition in the brain, starting in the subiculum and spreading to the thalamus. Cognitive behavioral testing revealed deficits in hippocampus-dependent spatial learning and memory in the Barnes maze test. This study demonstrates that the Arctic APP mutation is sufficient to cause amyloid deposition and cognitive dysfunction, and thus the TgAPParc mouse model provides a valuable tool to study the effect of the Arctic mutation in vivo without possible confounding effect of other APP mutations.

  18. APP transgenic modeling of Alzheimer's disease: mechanisms of neurodegeneration and aberrant neurogenesis.

    PubMed

    Crews, Leslie; Rockenstein, Edward; Masliah, Eliezer

    2010-03-01

    Neurodegenerative disorders of the aging population affect over 5 million people in the US and Europe alone. The common feature is the progressive accumulation of misfolded proteins with the formation of toxic oligomers. Alzheimer's disease (AD) is characterized by cognitive impairment, progressive degeneration of neuronal populations in the neocortex and limbic system, and formation of amyloid plaques and neurofibrillary tangles. Amyloid-beta (Abeta) is the product of proteolysis of amyloid precursor protein (APP) by beta and gamma-secretase enzymes. The neurodegenerative process in AD initiates with axonal and synaptic damage and is associated with progressive accumulation of toxic Abeta oligomers in the intracellular and extracellular space. In addition, neurodegeneration in AD is associated with alterations in neurogenesis. Abeta accumulation is the consequence of an altered balance between protein synthesis, aggregation rate, and clearance. Identification of genetic mutations in APP associated with familial forms of AD and gene polymorphisms associated with the more common sporadic variants of AD has led to the development of transgenic (tg) and knock out rodents as well as viral vector driven models of AD. While APP tg murine models with mutations in the N- and C-terminal flanking regions of Abeta are characterized by increased Abeta production with plaque formation, mutations in the mid-segment of Abeta result in increased formation of oligomers, and mutations toward the C-terminus (E22Q) segment results in amyloid angiopathy. Similar to AD, in APP tg models bearing familial mutations, formation of Abeta oligomers results in defective plasticity in the perforant pathway, selective neuronal degeneration, and alterations in neurogenesis. Promising results have been obtained utilizing APP tg models of AD to develop therapies including the use of beta- and gamma-secretase inhibitors, immunization, and stimulating neurogenesis.

  19. Differential proteomic and behavioral effects of long-term voluntary exercise in wild-type and APP-overexpressing transgenics.

    PubMed

    Rao, Shailaja Kishan; Ross, Jordan M; Harrison, Fiona E; Bernardo, Alexandra; Reiserer, Randall S; Reiserer, Ronald S; Mobley, James A; McDonald, Michael P

    2015-06-01

    Physical exercise may provide protection against the cognitive decline and neuropathology associated with Alzheimer's disease, although the mechanisms are not clear. In the present study, APP/PSEN1 double-transgenic and wild-type mice were allowed unlimited voluntary exercise for 7months. Consistent with previous reports, wheel-running improved cognition in the double-transgenic mice. Interestingly, the average daily distance run was strongly correlated with spatial memory in the water maze in wild-type mice (r(2)=.959), but uncorrelated in transgenics (r(2)=.013). Proteomics analysis showed that sedentary transgenic mice differed significantly from sedentary wild-types with respect to proteins involved in synaptic transmission, cytoskeletal regulation, and neurogenesis. When given an opportunity to exercise, the transgenics' deficiencies in cytoskeletal regulation and neurogenesis largely normalized, but abnormal synaptic proteins did not change. In contrast, exercise enhanced proteins associated with cytoskeletal regulation, oxidative phosphorylation, and synaptic transmission in wild-type mice. Soluble and insoluble Aβ40 and Aβ42 levels were significantly decreased in both cortex and hippocampus of active transgenics, suggesting that this may have played a role in the cognitive improvement in APP/PSEN1 mice. β-secretase was significantly reduced in active APP/PSEN1 mice compared to sedentary controls, suggesting a mechanism for reduced Aβ. Taken together, these data illustrate that exercise improves memory in wild-type and APP-overexpressing mice in fundamentally different ways.

  20. Intraneuronal APP and extracellular Aβ independently cause dendritic spine pathology in transgenic mouse models of Alzheimer's disease.

    PubMed

    Zou, Chengyu; Montagna, Elena; Shi, Yuan; Peters, Finn; Blazquez-Llorca, Lidia; Shi, Song; Filser, Severin; Dorostkar, Mario M; Herms, Jochen

    2015-06-01

    Alzheimer's disease (AD) is thought to be caused by accumulation of amyloid-β protein (Aβ), which is a cleavage product of amyloid precursor protein (APP). Transgenic mice overexpressing APP have been used to recapitulate amyloid-β pathology. Among them, APP23 and APPswe/PS1deltaE9 (deltaE9) mice are extensively studied. APP23 mice express APP with Swedish mutation and develop amyloid plaques late in their life, while cognitive deficits are observed in young age. In contrast, deltaE9 mice with mutant APP and mutant presenilin-1 develop amyloid plaques early but show typical cognitive deficits in old age. To unveil the reasons for different progressions of cognitive decline in these commonly used mouse models, we analyzed the number and turnover of dendritic spines as important structural correlates for learning and memory. Chronic in vivo two-photon imaging in apical tufts of layer V pyramidal neurons revealed a decreased spine density in 4-5-month-old APP23 mice. In age-matched deltaE9 mice, in contrast, spine loss was only observed on cortical dendrites that were in close proximity to amyloid plaques. In both cases, the reduced spine density was caused by decreased spine formation. Interestingly, the patterns of alterations in spine morphology differed between these two transgenic mouse models. Moreover, in APP23 mice, APP was found to accumulate intracellularly and its content was inversely correlated with the absolute spine density and the relative number of mushroom spines. Collectively, our results suggest that different pathological mechanisms, namely an intracellular accumulation of APP or extracellular amyloid plaques, may lead to spine abnormalities in young adult APP23 and deltaE9 mice, respectively. These distinct features, which may represent very different mechanisms of synaptic failure in AD, have to be taken into consideration when translating results from animal studies to the human disease.

  1. Life Extension Factor Klotho Prevents Mortality and Enhances Cognition in hAPP Transgenic Mice

    PubMed Central

    Zhu, Lei; Sanchez, Pascal E.; Worden, Kurtresha; Broestl, Lauren; Johnson, Erik; Ho, Kaitlyn; Yu, Gui-Qiu; Kim, Daniel; Betourne, Alexander; Kuro-o, Makoto; Masliah, Eliezer; Abraham, Carmela R.

    2015-01-01

    Aging is the principal demographic risk factor for Alzheimer disease (AD), the most common neurodegenerative disorder. Klotho is a key modulator of the aging process and, when overexpressed, extends mammalian lifespan, increases synaptic plasticity, and enhances cognition. Whether klotho can counteract deficits related to neurodegenerative diseases, such as AD, is unknown. Here we show that elevating klotho expression decreases premature mortality and network dysfunction in human amyloid precursor protein (hAPP) transgenic mice, which simulate key aspects of AD. Increasing klotho levels prevented depletion of NMDA receptor (NMDAR) subunits in the hippocampus and enhanced spatial learning and memory in hAPP mice. Klotho elevation in hAPP mice increased the abundance of the GluN2B subunit of NMDAR in postsynaptic densities and NMDAR-dependent long-term potentiation, which is critical for learning and memory. Thus, increasing wild-type klotho levels or activities improves synaptic and cognitive functions, and may be of therapeutic benefit in AD and other cognitive disorders. PMID:25673831

  2. Mitochondrial dysfunction in a transgenic mouse model expressing human amyloid precursor protein (APP) with the Arctic mutation.

    PubMed

    Rönnbäck, Annica; Pavlov, Pavel F; Mansory, Mansorah; Gonze, Prisca; Marlière, Nicolas; Winblad, Bengt; Graff, Caroline; Behbahani, Homira

    2016-02-01

    Accumulation of amyloid β-peptide (Aβ) in the brain is an important event in the pathogenesis of Alzheimer disease. We have used a transgenic mouse model expressing human amyloid precursor protein (APP) with the Arctic mutation to investigate whether Aβ deposition is correlated with mitochondrial functions in these animals. We found evidence of mitochondrial dysfunction (i.e., decreased mitochondrial membrane potential, increased production of reactive oxygen species and oxidative DNA damage) at 6 months of age, when the mice showed very mild Aβ deposition. More pronounced mitochondrial abnormalities were present in 24-month-old TgAPParc mice with more extensive Aβ pathology. This study demonstrates for the first time mitochondrial dysfunction in transgenic mice with a mutation within the Aβ peptide (the Arctic APP mutation), and confirms previous studies suggesting that mitochondrial dysfunction and oxidative stress is an early event in the pathogenesis of Alzheimer disease. This study demonstrates mitochondrial dysfunction in transgenic mice with a mutation within the amyloid beta (Aβ) peptide (the Arctic amyloid precursor protein (APP) mutation). We found evidence of mitochondrial dysfunction (i.e. decreased mitochondrial membrane potential (MMP), increased production of reactive oxygen species (ROS) and oxidative DNA damage) at 6 months of age, when very mild Aβ deposition is present in the mice. Also, the cytochrome c (COX) activity was significantly decreased in mitochondria from transgenic mice at 24 months of age.

  3. APP processing enzymes (secretases) as therapeutic targets: insights from the use of transgenics (Tgs) and transfected cells.

    PubMed

    Marks, Neville; Berg, Martin J

    2003-07-01

    Secretases degrade amyloid precursor protein (APP) releasing fragments (beta-peptides A beta, A beta x) that assemble to form hallmark extracellular deposits in Alzheimer's disease (AD) correlating with disease severity. As such, secretases supply targets for therapeutic intervention and form the focus of this overview. Progress in elucidating secretases and their modes of catalysis come from exploiting the use of transgenics or transfected cells. In addition to A beta x, secretases also release C-terminal fragments with putative signaling properties (amyloid intracellular domain, AICD) similar in concept to those available for conversion of the Notch-r to release the nuclear transactivator NICD. The review considers lingering questions on APP fragmentation by secretase action, ancillary proteins such as presenilins (PS1/2), nicastrin, XII, or proteases (caspases), and the influence of familial mutations (mAPP, mPS) in terms of fibrillogenesis.

  4. Therapeutic potential of human amniotic membrane-derived mesenchymal stem cells in APP transgenic mice

    PubMed Central

    Jiao, Hongliang; Shi, Ke; Zhang, Weijie; Yang, Liang; Yang, Lu; Guan, Fangxia; Yang, Bo

    2016-01-01

    Growing evidence indicates that the presence of extensive oxidative stress plays an essential role in the initiation and progression of Alzheimer's disease (AD). Amyloid-β (Aβ) aggregation is involved in the elevation of oxidative stress, contributing to mitochondrial dysfunction and lipid peroxidation. In the present study, human placenta amniotic membrane-derived mesenchymal stem cells (hAMMSCs) were intravenously injected into C57BL/6J-APP transgenic mice. hAMMSCs significantly ameliorated spatial learning and memory function, and were associated with a decreased amount of amyloid plaques of the brain. The correlation of oxidative stress with Aβ levels was lower in the hAMMSCs-injected group than in the phosphate-buffered saline (PBS)-injected group, as indicated by the increased level of antioxidative enzymes and the decreased level of lipid peroxidation product. The glutathione (GSH) level and ratio of GSH to glutathione disulfide were higher in the hAMMSC group than in the PBS group. The superoxide dismutase activity and malonaldehyde level were improved significantly as the level of Aβ decreased, but there was no such trend in the PBS group. As a result, our findings represent evidence that hAMMSC treatment might improve the pathology of AD and memory function through the regulation of oxidative stress. PMID:27588134

  5. Mushroom body miscellanea: transgenic Drosophila strains expressing anatomical and physiological sensor proteins in Kenyon cells

    PubMed Central

    Pech, Ulrike; Dipt, Shubham; Barth, Jonas; Singh, Priyanka; Jauch, Mandy; Thum, Andreas S.; Fiala, André; Riemensperger, Thomas

    2013-01-01

    The fruit fly Drosophila melanogaster represents a key model organism for analyzing how neuronal circuits regulate behavior. The mushroom body in the central brain is a particularly prominent brain region that has been intensely studied in several insect species and been implicated in a variety of behaviors, e.g., associative learning, locomotor activity, and sleep. Drosophila melanogaster offers the advantage that transgenes can be easily expressed in neuronal subpopulations, e.g., in intrinsic mushroom body neurons (Kenyon cells). A number of transgenes has been described and engineered to visualize the anatomy of neurons, to monitor physiological parameters of neuronal activity, and to manipulate neuronal function artificially. To target the expression of these transgenes selectively to specific neurons several sophisticated bi- or even multipartite transcription systems have been invented. However, the number of transgenes that can be combined in the genome of an individual fly is limited in practice. To facilitate the analysis of the mushroom body we provide a compilation of transgenic fruit flies that express transgenes under direct control of the Kenyon-cell specific promoter, mb247. The transgenes expressed are fluorescence reporters to analyze neuroanatomical aspects of the mushroom body, proteins to restrict ectopic gene expression to mushroom bodies, or fluorescent sensors to monitor physiological parameters of neuronal activity of Kenyon cells. Some of the transgenic animals compiled here have been published already, whereas others are novel and characterized here for the first time. Overall, the collection of transgenic flies expressing sensor and reporter genes in Kenyon cells facilitates combinations with binary transcription systems and might, ultimately, advance the physiological analysis of mushroom body function. PMID:24065891

  6. Thamnolia vermicularis extract improves learning ability in APP/PS1 transgenic mice by ameliorating both Aβ and Tau pathologies

    PubMed Central

    Li, Cong; Guo, Xiao-dan; Lei, Min; Wu, Jia-yi; Jin, Jia-zhen; Shi, Xiao-fan; Zhu, Zhi-yuan; Rukachaisirikul, Vatcharin; Hu, Li-hong; Wen, Tie-qiao; Shen, Xu

    2017-01-01

    Considering the complicated pathogenesis of Alzheimer's disease (AD), multi-targets have become a focus in the discovery of drugs for treatment of this disease. In the current work, we established a multi-target strategy for discovering active reagents capable of suppressing both Aβ level and Tau hyperphosphorylation from natural products, and found that the ethanol extract of Thamnolia vermicularis (THA) was able to improve learning ability in APP/PS1 transgenic mice by inhibiting both Aβ levels and Tau hyperphosphorylation. SH-SY5Y and CHO-APP/BACE1 cells and primary astrocytes were used in cell-based assays. APP/PS1 transgenic mice [B6C3-Tg(APPswe, PS1dE9)] were administered THA (300 mg·kg−1·d−1, ig) for 100 d. After the administration was completed, the learning ability of the mice was detected using a Morris water maze (MWM) assay; immunofluorescence staining, Congo red staining and Thioflavine S staining were used to detect the senile plaques in the brains of the mice. ELISA was used to evaluate Aβ and sAPPβ contents, and Western blotting and RT-PCR were used to investigate the relevant signaling pathway regulation in response to THA treatment. In SH-SY5Y cells, THΑ (1, 10, 20 μg/mL) significantly stimulated PI3K/AKT/mTOR and AMPK/raptor/mTOR signaling-mediated autophagy in the promotion of Aβ clearance as both a PI3K inhibitor and an AMPK indirect activator, and restrained Aβ production as a suppressor against PERK/eIF2α-mediated BACE1 expression. Additionally, THA functioned as a GSK3β inhibitor with an IC50 of 1.32±0.85 μg/mL, repressing Tau hyperphosphorylation. Similar effects on Aβ accumulation and Tau hyperphosphorylation were observed in APP/PS1 transgenic mice treated with THA. Furthermore, administration of THA effectively improved the learning ability of APP/PS1 transgenic mice, and markedly reduced the number of senile plaques in their hippocampus and cortex. The results highlight the potential of the natural product THA for the

  7. Global Analysis of S-nitrosylation Sites in the Wild Type (APP) Transgenic Mouse Brain-Clues for Synaptic Pathology *

    PubMed Central

    Zaręba-Kozioł, Monika; Szwajda, Agnieszka; Dadlez, Michał; Wysłouch-Cieszyńska, Aleksandra; Lalowski, Maciej

    2014-01-01

    Alzheimer's disease (AD) is characterized by an early synaptic loss, which strongly correlates with the severity of dementia. The pathogenesis and causes of characteristic AD symptoms are not fully understood. Defects in various cellular cascades were suggested, including the imbalance in production of reactive oxygen and nitrogen species. Alterations in S-nitrosylation of several proteins were previously demonstrated in various AD animal models and patients. In this work, using combined biotin-switch affinity/nano-LC-MS/MS and bioinformatic approaches we profiled endogenous S-nitrosylation of brain synaptosomal proteins from wild type and transgenic mice overexpressing mutated human Amyloid Precursor Protein (hAPP). Our data suggest involvement of S-nitrosylation in the regulation of 138 synaptic proteins, including MAGUK, CamkII, or synaptotagmins. Thirty-eight proteins were differentially S-nitrosylated in hAPP mice only. Ninety-five S-nitrosylated peptides were identified for the first time (40% of total, including 33 peptides exclusively in hAPP synaptosomes). We verified differential S-nitrosylation of 10 (26% of all identified) synaptosomal proteins from hAPP mice, by Western blotting with specific antibodies. Functional enrichment analysis linked S-nitrosylated proteins to various cellular pathways, including: glycolysis, gluconeogenesis, calcium homeostasis, ion, and vesicle transport, suggesting a basic role of this post-translational modification in the regulation of synapses. The linkage of SNO-proteins to axonal guidance and other processes related to APP metabolism exclusively in the hAPP brain, implicates S-nitrosylation in the pathogenesis of Alzheimer's disease. PMID:24895380

  8. Atorvastatin ameliorates cognitive impairment, Aβ1-42 production and Tau hyperphosphorylation in APP/PS1 transgenic mice.

    PubMed

    Zhou, Dongsheng; Liu, Huaxia; Li, Chenli; Wang, Fangyan; Shi, Yaosheng; Liu, Lingjiang; Zhao, Xin; Liu, Aiming; Zhang, Junfang; Wang, Chuang; Chen, Zhongming

    2016-06-01

    Amyloid-beta (Aβ) interacts with the serine/threonine protein kinase AKT (also known as protein kinase B)/glycogen synthase kinase 3β (GSK3β) pathway and deactivates GSK3β signaling, which result in microtubule protein tau phosphorylation. Atorvastatin, a HMG-CoA reductase inhibitor, has been proven to improve learning and memory performance, reduce Aβ and phosphorylated tau levels in mouse model of Alzheimer's disease (AD). However, it still remains unclear whether atorvastatin is responsible for regulation of AKT/GSK3β signaling and contributes to subsequent down-regulation of Aβ1-42 and phosphorylated tau in APP/PS1 transgenic (Tg APP/PS1) mice. Herein, we aimed to investigate the possible impacts of atorvastatin (10 mg/kg, p.o.) on the memory deficit by behavioral tests and changes of AKT/GSK3β signaling in hippocampus and prefrontal cortex by western blot test in Tg APP/PS1 mice. The results showed that treatment with atorvastatin significantly reversed the memory deficit in the Tg APP/PS1 mice in a novel object recognition and the Morris water maze tests. Moreover, atorvastatin significantly attenuated Aβ1-42 accumulation and phosphorylation of tau (Ser396) in the hippocampus and prefrontal cortex of Tg APP/PS1 mice. In addition, atorvastatin treatment also increased phosphorylation of AKT, inhibited GSK3β activity by increasing phosphorylation of GSK3β (Ser9) and decreasing the beta-site APP cleaving enzyme 1 (BACE1) expression. These results indicated that the memory ameliorating effect of atorvastatin may be, in part, by regulation the AKT/GSK3β signaling which may contribute to down-regulation of Aβ1-42 and tau hyperphosphorylation.

  9. Modulation of human neural stem cell differentiation in Alzheimer (APP23) transgenic mice by phenserine.

    PubMed

    Marutle, Amelia; Ohmitsu, Masao; Nilbratt, Mats; Greig, Nigel H; Nordberg, Agneta; Sugaya, Kiminobu

    2007-07-24

    In a previous study, we found that human neural stem cells (HNSCs) exposed to high concentrations of secreted amyloid-precursor protein (sAPP) in vitro differentiated into mainly astrocytes, suggesting that pathological alterations in APP processing during neurodegenerative conditions such as Alzheimer's disease (AD) may prevent neuronal differentiation of HNSCs. Thus, successful neuroplacement therapy for AD may require regulating APP expression to favorable levels to enhance neuronal differentiation of HNSCs. Phenserine, a recently developed cholinesterase inhibitor (ChEI), has been reported to reduce APP levels in vitro and in vivo. In this study, we found reductions of APP and glial fibrillary acidic protein (GFAP) levels in the hippocampus of APP23 mice after 14 days treatment with (+)-phenserine (25 mg/kg) lacking ChEI activity. No significant change in APP gene expression was detected, suggesting that (+)-phenserine decreases APP levels and reactive astrocytes by posttranscription regulation. HNSCs transplanted into (+)-phenserine-treated APP23 mice followed by an additional 7 days of treatment with (+)-phenserine migrated and differentiated into neurons in the hippocampus and cortex after 6 weeks. Moreover, (+)-phenserine significantly increased neuronal differentiation of implanted HNSCs in hippocampal and cortical regions of APP23 mice and in the CA1 region of control mice. These results indicate that (+)-phenserine reduces APP protein in vivo and increases neuronal differentiation of HNSCs. Combination use of HNSC transplantation and treatment with drugs such as (+)-phenserine that modulate APP levels in the brain may be a useful tool for understanding mechanisms regulating stem cell migration and differentiation during neurodegenerative conditions in AD.

  10. Vitamin C deficiency increases basal exploratory activity but decreases scopolamine-induced activity in APP/PSEN1 transgenic mice

    PubMed Central

    Harrison, F. E.; May, J. M.; McDonald, M. P.

    2010-01-01

    Vitamin C is a powerful antioxidant and its levels are decreased in Alzheimer's patients. Even sub-clinical vitamin C deficiency could impact disease development. To investigate this principle we crossed APP/PSEN1 transgenic mice with Gulo knockout mice unable to synthesize their own vitamin C. Experimental mice were maintained from 6 weeks of age on standard (0.33 g/L) or reduced (0.099 g/L) levels of vitamin C and then assessed for changes in behavior and neuropathology. APP/PSEN1 mice showed impaired spatial learning in the Barnes maze and water maze that was not further impacted by vitamin C level. However, long-term decreased vitamin C levels led to hyperactivity in transgenic mice, with altered locomotor habituation and increased omission errors in the Barnes maze. Decreased vitamin C also led to increased oxidative stress. Transgenic mice were more susceptible to the activity-enhancing effects of scopolamine and low vitamin C attenuated these effects in both genotypes. These data indicate an interaction between the cholinergic system and vitamin C that could be important given the cholinergic degeneration associated with Alzheimer's disease. PMID:19941887

  11. Memantine Lowers Amyloid-beta Peptide Levels in Neuronal Cultures and in APP/PS1 Transgenic Mice

    PubMed Central

    Alley, George M.; Bailey, Jason A; Chen, DeMao; Ray, Balmiki; Puli, Lakshman K.; Tanila, Heikki; Banerjee, Pradeep K; Lahiri, Debomoy K.

    2009-01-01

    Memantine is a moderate-affinity, uncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist that stabilizes cognitive, functional, and behavioral decline in patients with moderate to severe Alzheimer’s disease (AD). In AD, the extracellular deposition of fibrillogenic amyloid-beta peptides (Aβ) occurs due to aberrant processing of the full-length Aβ precursor protein (APP). Memantine protects neurons from the neurotoxic effects of Aβ and improves cognition in transgenic mice with high brain levels of Aβ. However, it is unknown how memantine protects cells against neurodegeneration and affects APP processing and Aβ production. We report the effects of memantine in three different systems. In human neuroblastoma cells, memantine, at therapeutically relevant concentrations (1-4 μM), decreased levels of secreted APP and Aβ1-40. Levels of the potentially amylodogenic Aβ1-42 were undetectable in these cells. In primary rat cortical neuronal cultures, memantine treatment lowered Aβ1-42 secretion. At the concentrations used, memantine treatment was not toxic to neuroblastoma or primary cultures and increased cell viability and/or metabolic activity under certain conditions. In APP/presenilin-1 (PS1) transgenic mice exhibiting high brain levels of Aβ1-42, oral dosing of memantine (20 mg/kg/day for 8 days) produced plasma drug concentration of 0.96 μM and significantly reduced the cortical levels of soluble Aβ1-42. The ratio of Aβ1-40/Aβ1-42 increased in treated mice, suggesting effects on the γ-secretase complex. Thus, memantine reduces the levels of Aβ peptides at therapeutic concentrations and may inhibit the accumulation of fibrillogenic Aβ in mammalian brains. Memantine’s ability to preserve neuronal cells against neurodegeneration, increase metabolic activity, and lower Aβ level has therapeutic implications for neurodegenerative disorders. PMID:19642202

  12. Increased BMP6 levels in the brains of Alzheimer's disease patients and APP transgenic mice are accompanied by impaired neurogenesis.

    PubMed

    Crews, Leslie; Adame, Anthony; Patrick, Christina; Delaney, Alexandra; Pham, Emiley; Rockenstein, Edward; Hansen, Lawrence; Masliah, Eliezer

    2010-09-15

    During aging and in the progression of Alzheimer's disease (AD), synaptic plasticity and neuronal integrity are disturbed. In addition to the alterations in plasticity in mature neurons, the neurodegenerative process in AD has been shown to be accompanied by alterations in neurogenesis. Members of the bone morphogenetic protein (BMP) family of growth factors have been implicated as important regulators of neurogenesis and neuronal cell fate determination during development; however, their role in adult neurogenesis and in AD is less clear. We show here by qRT-PCR analysis that BMP6 mRNA levels were significantly increased in the hippocampus of human patients with AD and in APP transgenic mice compared to controls. Immunoblot and immunohistochemical analyses confirmed that BMP6 protein levels were increased in human AD brains and APP transgenic mouse brains compared to controls and accumulated around hippocampal plaques. The increased levels of BMP6 were accompanied by defects in hippocampal neurogenesis in AD patients and APP transgenic mice. In support of a role for BMP6 in defective neurogenesis in AD, we show in an in vitro model of adult neurogenesis that treatment with amyloid-β(1-42) protein (Aβ) resulted in increased expression of BMP6, and that exposure to recombinant BMP6 resulted in reduced proliferation with no toxic effects. Together, these results suggest that Aβ-associated increases in BMP6 expression in AD may have deleterious effects on neurogenesis in the hippocampus, and therapeutic approaches could focus on normalization of BMP6 levels to protect against AD-related neurogenic deficits.

  13. Humulus japonicus inhibits the progression of Alzheimer's disease in a APP/PS1 transgenic mouse model

    PubMed Central

    Park, Tae-Shin; Ryu, Young-Kyoung; Park, Hye-Yeon; Kim, Jae Yun; Go, Jun; Noh, Jung-Ran; Kim, Yong-Hoon; Hwang, Jung Hwan; Choi, Dong-Hee; Oh, Won-Keun; Lee, Chul-Ho; Kim, Kyoung-Shim

    2017-01-01

    Humulus japonicus Siebold & Zucc. (HJ) has traditionally been administered to patients with pulmonary disease, skin disease and hypertension in Korea, and it is considered to exert anti-inflammatory, antioxidant, antimicrobial and anti-mycobacterial effects. However, its effects against Alzheimer's disease (AD) have yet to be explored. Thus, this study was carried out to investigate whether HJ has a beneficial effect on the progression of AD in an animal model. A methanolic extract of HJ (500 mg/kg/day) was intragastrically administered to 5-month-old APP/PS1 transgenic (Tg-APP/PS1) mice for 2.5 months. Novel object recognition and Y-maze alteration tests were used to assess cognitive function, and an immunohistochemical assay was performed to assess amyloid β (Aβ) deposition, tau phosphorylation and gliosis. An in vitro assay using a microglial cell line was also performed to investigate the anti-inflammatory effects of HJ. Our results revealed that HJ significantly decreased the mRNA and protein expression levels of tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, IL-6 and inducible nitric oxide synthase (iNOS) induced by lipopolysaccharide in the microglial cell line. The administration of HJ for 2 months improved the cognitive function of Tg-APP/PS1 mice. HJ notably reduced the area occupied by Aβ and neurofibrillary tangles, and the number of activated astrocytes and microglia in the cortex of Tg-APP/PS1 mice. The findings of our study suggest that HJ has the therapeutic potential to inhibit the progression of AD and to improve cognitive deterioration in Tg-APP/PS1 mice. PMID:28004107

  14. Transgenic inhibitors identify two roles for protein kinase A in Drosophila development.

    PubMed Central

    Kiger, J A; Eklund, J L; Younger, S H; O'Kane, C J

    1999-01-01

    We have initiated an analysis of protein kinase A (PKA) in Drosophila using transgenic techniques to modulate PKA activity in specific tissues during development. We have constructed GAL4/UAS-regulated transgenes in active and mutant forms that encode PKAc, the catalytic subunit of PKA, and PKI(1-31), a competitive inhibitor of PKAc. We present evidence that the wild-type transgenes are active and summarize the phenotypes produced by a number of GAL4 enhancer-detector strains. We compare the effects of transgenes encoding PKI(1-31) with those encoding PKAr*, a mutant regulatory subunit that constitutively inhibits PKAc because of its inability to bind cyclic AMP. Both inhibitors block larval growth, but only PKAr* alters pattern formation by activating the Hedgehog signaling pathway. Therefore, transgenic PKI(1-31) should provide a tool to investigate the role of PKAc in larval growth regulation without concomitant changes in pattern formation. The different effects of PKI(1-31) and PKAr* suggest two distinct roles, cytoplasmic and nuclear, for PKAc in Hedgehog signal transduction. Alternatively, PKAr* may target proteins other than PKAc, suggesting a role for free PKAr in signal transduction, a role inhibited by PKAc in reversal of the classical relationship of these subunits. PMID:10224260

  15. Amniotic Mesenchymal Stem Cells Decrease Aβ Deposition and Improve Memory in APP/PS1 Transgenic Mice.

    PubMed

    Zheng, Xiao-Yu; Wan, Qian-Quan; Zheng, Chuan-Yi; Zhou, Hong-Long; Dong, Xing-Yu; Deng, Qing-Shan; Yao, Hui; Fu, Qiang; Gao, Mou; Yan, Zhong-Jie; Wang, Shan-Shan; You, Yu; Lv, Jun; Wang, Xiang-Yu; Chen, Ke-En; Zhang, Mao-Ying; Xu, Ru-Xiang

    2017-04-10

    Transplantation of human amniotic mesenchymal stem cells (hAM-MSCs) seems to be a promising strategy for the treatment of neurodegenerative disorders, including Alzheimer's disease (AD). However, the clinical therapeutic effects of hAM-MSCs and their mechanisms of action in AD remain to be determined. Here, we used amyloid precursor protein (APP) and presenilin1 (PS1) double-transgenic mice to evaluate the effects of hAM-MSC transplantation on AD-related neuropathology and cognitive dysfunction. We found that hAM-MSC transplantation into the hippocampus dramatically reduced amyloid-β peptide (Aβ) deposition and rescued spatial learning and memory deficits in APP/PS1 mice. Interestingly, these effects were associated with increasing in Aβ-degrading factors, elevations in activated microglia, and the modulation of neuroinflammation. Furthermore, enhanced hippocampal neurogenesis in the subgranular zone (SGZ) of the dentate gyrus (DG) and enhanced synaptic plasticity following hAM-MSC treatment could be another important factor in reversing the cognitive decline in APP/PS1 mice. Instead, the mechanism underlying the improved cognition apparently involves a robust increase in hippocampal synaptic density and neurogenesis that is mediated by brain-derived neurotrophic factor (BDNF). In conclusion, our data suggest that hAM-MSCs may be a new and effective therapy for the treatment of AD.

  16. Long-term treadmill exercise inhibits the progression of Alzheimer's disease-like neuropathology in the hippocampus of APP/PS1 transgenic mice.

    PubMed

    Liu, Hui-li; Zhao, Gang; Zhang, He; Shi, Li-de

    2013-11-01

    Previously our study has demonstrated that long-term treadmill exercise improved cognitive deficit in APP/PS1 transgenic mice of Alzheimer's disease (AD) paralleled by enhanced long-term potentiation (LTP). The present study was undertaken to further investigate whether the treadmill running could inhibit the progression of Alzheimer's disease (AD)-like neuropathology in hippocampus of the APP/PS1 mouse models of AD, and to define a potential molecular mechanism underlying the exercise-induced reduction in AD-like neuropathology. Five months of treadmill exercise resulted in a robust reduction in β-amyloid (Aβ) deposition and tau phosphorylation in the hippocampus of APP/PS1 mice. This was accompanied by a significant decrease in APP phosphorylation and PS1 expression. We also observed GSK3, rather than CDK5, was inhibited by treadmill exercise. These results indicate that treadmill exercise is sufficient to inhibit the progression of AD-like neuropathology in the hippocampus of APP/PS1 transgenic mouse model, and may mediate APP processing in favor of reduced Aβ deposition. In addition, we demonstrate that treadmill exercise attenuates AD-like neuropathology in AD transgenic mice via a GSK3 dependent signaling pathway.

  17. Efficient gene knock-out and knock-in with transgenic Cas9 in Drosophila.

    PubMed

    Xue, Zhaoyu; Ren, Mengda; Wu, Menghua; Dai, Junbiao; Rong, Yikang S; Gao, Guanjun

    2014-03-21

    Bacterial Cas9 nuclease induces site-specific DNA breaks using small gRNA as guides. Cas9 has been successfully introduced into Drosophila for genome editing. Here, we improve the versatility of this method by developing a transgenic system that expresses Cas9 in the Drosophila germline. Using this system, we induced inheritable knock-out mutations by injecting only the gRNA into embryos, achieved highly efficient mutagenesis by expressing gRNA from the promoter of a novel non-coding RNA gene, and recovered homologous recombination-based knock-in of a fluorescent marker at a rate of 4.5% by co-injecting gRNA with a circular DNA donor.

  18. C. elegans RNA-dependent RNA polymerases rrf-1 and ego-1 silence Drosophila transgenes by differing mechanisms.

    PubMed

    Duan, Guowen; Saint, Robert B; Helliwell, Chris A; Behm, Carolyn A; Wang, Ming-Bo; Waterhouse, Peter M; Gordon, Karl H J

    2013-04-01

    Drosophila possesses the core gene silencing machinery but, like all insects, lacks the canonical RNA-dependent RNA polymerases (RdRps) that in C. elegans either trigger or enhance two major small RNA-dependent gene silencing pathways. Introduction of two different nematode RdRps into Drosophila showed them to be functional, resulting in differing silencing activities. While RRF-1 enhanced transitive dsRNA-dependent silencing, EGO-1 triggered dsRNA-independent silencing, specifically of transgenes. The strain w; da-Gal4; UAST-ego-1, constitutively expressing ego-1, is capable of silencing transgene including dsRNA hairpin upon a single cross, which created a powerful tool for research in Drosophila. In C. elegans, EGO-1 is involved in transcriptional gene silencing (TGS) of chromosome regions that are unpaired during meiosis. There was no opportunity for meiotic interactions involving EGO-1 in Drosophila that would explain the observed transgene silencing. Transgene DNA is, however, unpaired during the pairing of chromosomes in embryonic mitosis that is an unusual characteristic of Diptera, suggesting that in Drosophila, EGO-1 triggers transcriptional silencing of unpaired DNA during embryonic mitosis.

  19. Three-dimensional analysis of abnormal ultrastructural alteration in mitochondria of hippocampus of APP/PSEN1 transgenic mouse.

    PubMed

    Choi, Ki Ju; Kim, Mi Jeong; Je, A Reum; Jun, Sangmi; Lee, Chulhyun; Lee, Eunji; Jo, Mijung; Huh, Yang Hoon; Kweon, Hee-Seok

    2014-03-01

    Alzheimer's disease (AD) is a progressive neurodegenerative disorder. The deterioration of subcellular organelles, including the mitochondria, is another major ultrastructural characteristic of AD pathogenesis, in addition to amyloid plaque deposition. However, the three-dimensional (3-D) study of mitochondrial structural alteration in AD remains poorly understood. Therefore, ultrastructural analysis, 3-D electron tomography, and immunogold electron microscopy were performed in the present study to clarify the abnormal structural alterations in mitochondria caused by the progression of AD in APP/PSEN1 transgenic mice, expressing human amyloid precursor protein, as a model for AD. Amyloid beta (A beta) plaques accumulated and dystrophic neurites (DN) developed in the hippocampus of transgenic AD mouse brains. We also identified the loss of peroxiredoxin 3, an endogenous cytoprotective antioxidant enzyme and the accumulation of A beta in the hippocampal mitochondria of transgenic mice, which differs from those in age-matched wild-type mice. The mitochondria in A beta plaque-detected regions were severely disrupted, and the patterns of ultrastructural abnormalities were classified into three groups: disappearance of cristae, swelling of cristae, and bulging of the outer membrane. These results demonstrated that morpho-functional alterations of mitochondria and AD progression are closely associated and may be beneficial in investigating the function of mitochondria in AD pathogenesis.

  20. Interferon-gamma and tumor necrosis factor-alpha regulate amyloid-beta plaque deposition and beta-secretase expression in Swedish mutant APP transgenic mice.

    PubMed

    Yamamoto, Masaru; Kiyota, Tomomi; Horiba, Masahide; Buescher, James L; Walsh, Shannon M; Gendelman, Howard E; Ikezu, Tsuneya

    2007-02-01

    Reactive astrocytes and microglia in Alzheimer's disease surround amyloid plaques and secrete proinflammatory cytokines that affect neuronal function. Relationship between cytokine signaling and amyloid-beta peptide (Abeta) accumulation is poorly understood. Thus, we generated a novel Swedish beta-amyloid precursor protein mutant (APP) transgenic mouse in which the interferon (IFN)-gamma receptor type I was knocked out (APP/GRKO). IFN-gamma signaling loss in the APP/GRKO mice reduced gliosis and amyloid plaques at 14 months of age. Aggregated Abeta induced IFN-gamma production from co-culture of astrocytes and microglia, and IFN-gamma elicited tumor necrosis factor (TNF)-alpha secretion in wild type (WT) but not GRKO microglia co-cultured with astrocytes. Both IFN-gamma and TNF-alpha enhanced Abeta production from APP-expressing astrocytes and cortical neurons. TNF-alpha directly stimulated beta-site APP-cleaving enzyme (BACE1) expression and enhanced beta-processing of APP in astrocytes. The numbers of reactive astrocytes expressing BACE1 were increased in APP compared with APP/GRKO mice in both cortex and hippocampus. IFN-gamma and TNF-alpha activation of WT microglia suppressed Abeta degradation, whereas GRKO microglia had no changes. These results support the idea that glial IFN-gamma and TNF-alpha enhance Abeta deposition through BACE1 expression and suppression of Abeta clearance. Taken together, these observations suggest that proinflammatory cytokines are directly linked to Alzheimer's disease pathogenesis.

  1. Culex tarsalis Vitellogenin Gene Promoters Investigated In Silico and In Vivo Using Transgenic Drosophila melanogaster

    PubMed Central

    Chen, Song; Rasgon, Jason L.

    2014-01-01

    Introduction Genetic modification, or transgenesis, is a powerful technique to investigate the molecular interactions between vector-borne pathogens and their arthropod hosts, as well as a potential novel approach for vector-borne disease control. Transgenesis requires the use of specific regulatory regions, or promoters, to drive expression of genes of interest in desired target tissues. In mosquitoes, the vast majority of described promoters are from Anopheles and Aedes mosquitoes. Results Culex tarsalis is one of the most important vectors of arboviruses (including West Nile virus) in North America, yet it has not been the subject of molecular genetic study. In order to facilitate molecular genetic work in this important vector species, we isolated four fat body-specific promoter sequences located upstream of the Cx. tarsalis vitellogenin genes (Vg1a, Vg1b, Vg2a and Vg2b). Sequences were analyzed in silico to identify requisite cis-acting elements. The ability for promoter sequences to drive expression of green fluorescent protein (GFP) in vivo was investigated using transgenic Drosophila melanogaster. All four promoters were able to drive GFP expression but there was dramatic variation between promoters and between individual Drosophila lines, indicating significant position effects. The highest expression was observed in line Vg2bL3, which was >300-fold higher than the lowest line Vg1aL2. Conclusions These new promoters will be useful for driving expression of genes of interest in transgenic Cx. tarsalis and perhaps other insects. PMID:24586476

  2. Terminal retrotransposons activate a subtelomeric white transgene at the 2L telomere in Drosophila.

    PubMed Central

    Golubovsky, M D; Konev, A Y; Walter, M F; Biessmann, H; Mason, J M

    2001-01-01

    Genetically marked P elements inserted into the subtelomeric satellites of Drosophila show repression and variegation of the reporter gene. One such white+ reporter, inserted between the subtelomeric satellite and the terminal HeT-A array in the left arm of chromosome 2 (2L), is sensitive to its context; changes in the structure of the telomere region can be identified by changes in eye color. Addition of HeT-A or TART elements to the 2L terminus increases w+ expression, and loss of sequence from the end decreases expression. This indicates that the telomeric retrotransposons in Drosophila have an activating influence on the repressed subterminal reporter gene. Changes in eye color due to altered expression of the transgene also allow the detection of interactions between homologous telomeres. The 2L arms that terminate in long HeT-A/TART arrays showed increased expression of the subterminal w+ transgene when the terminal repeats on the homologue are absent or markedly shorter. We propose that the chromatin structure of the terminal HeT-A/TART array and the activity of a putative promoter/enhancer element on HeT-A are affected by telomeric interactions. Such trans-activation may reflect control over HeT-A transcription and, thus, transposition activity. PMID:11454760

  3. Curcumin promotes A-beta fibrillation and reduces neurotoxicity in transgenic Drosophila.

    PubMed

    Caesar, Ina; Jonson, Maria; Nilsson, K Peter R; Thor, Stefan; Hammarström, Per

    2012-01-01

    The pathology of Alzheimer's disease (AD) is characterized by the presence of extracellular deposits of misfolded and aggregated amyloid-β (Aβ) peptide and intraneuronal accumulation of tangles comprised of hyperphosphorylated Tau protein. For several years, the natural compound curcumin has been proposed to be a candidate for enhanced clearance of toxic Aβ amyloid. In this study we have studied the potency of feeding curcumin as a drug candidate to alleviate Aβ toxicity in transgenic Drosophila. The longevity as well as the locomotor activity of five different AD model genotypes, measured relative to a control line, showed up to 75% improved lifespan and activity for curcumin fed flies. In contrast to the majority of studies of curcumin effects on amyloid we did not observe any decrease in the amount of Aβ deposition following curcumin treatment. Conformation-dependent spectra from p-FTAA, a luminescent conjugated oligothiophene bound to Aβ deposits in different Drosophila genotypes over time, indicated accelerated pre-fibrillar to fibril conversion of Aβ(1-42) in curcumin treated flies. This finding was supported by in vitro fibrillation assays of recombinant Aβ(1-42). Our study shows that curcumin promotes amyloid fibril conversion by reducing the pre-fibrillar/oligomeric species of Aβ, resulting in a reduced neurotoxicity in Drosophila.

  4. Metabolomics reveals significant impairments in the immune system of the APP/PS1 transgenic mice of Alzheimer's disease.

    PubMed

    González-Domínguez, Raúl; García-Barrera, Tamara; Vitorica, Javier; Gómez-Ariza, José Luis

    2015-02-01

    Inflammatory processes and other failures related to the immune system are common features associated with Alzheimer's disease (AD), in both brain and the peripheral system. Thus, the study of the main organs of the immune system may have a great potential for the elucidation of pathological mechanisms underlying these abnormalities. This is the first metabolomic investigation performed in spleen and thymus from transgenic mice of AD. Tissues were fingerprinted using a metabolomic platform comprising GC-MS and ultra-HPLC-MS. Multivariate statistics demonstrated significant differences in numerous metabolites between the APP/PS1 mice and wild-type controls, and it was proven that multiple biochemical pathways are disturbed in these organs including abnormal metabolism of phospholipids, energy deficiencies, altered homeostasis of amino acids, oxidative stress, and others. Therefore, these findings highlight the importance of the proper metabolic functioning of peripheral immune system in the development of neurodegenerative disorders such as AD.

  5. Protective effects of intranasal losartan in the APP/PS1 transgenic mouse model of Alzheimer disease.

    PubMed

    Danielyan, Lusine; Klein, Roman; Hanson, Leah R; Buadze, Marine; Schwab, Matthias; Gleiter, Christoph H; Frey, William H

    2010-01-01

    The local renin-angiotensin system (RAS) in the brain is a multitasking system controlling a plethora of essential functions such as neurogenic hypertension, baroreflexes, and sympathetic activity. Aside from its vasoactive actions, brain angiotensin II (AT-II) has also been implicated in the pathogenesis of cognitive decline, and beneficial effects of angiotensin receptor blockers (ARBs) in Alzheimer (AD) and Parkinson diseases (PD) are suggested. However, the use of ARBs at antihypertensive dosages would lead to unwanted hypotensive reactions in AD patients. Here we treated the APP/PS1 transgenic mouse model of AD with the ARB losartan (10 mg/kg body weight) to determine whether blockade of the AT-II receptor subtype 1 (AT1-R) with intranasal losartan, using at a dosage far below its systemic antihypertensive dose, could maintain its neuroprotective effects independent of its systemic vasoactive action. Intranasal losartan treatment (10 mg/kg every other day for 2 months) of APP/PS1 mice decreased amyloid beta (Abeta) plaques 3.7-fold. Blood serum levels of interleukin-12 (IL-12)p40/p70, IL-1beta, and granulocyte-macrophage colony-stimulating factor (GM-CSF) were increased in the vehicle-treated APP/PS1 mice. Intranasal losartan not only decreased IL-12p40/p70, IL-1beta, and GM-CSF, but also increased IL-10, which suppresses inflammation. Furthermore, losartan markedly increased tyrosine hydroxylase expression in the striatum and locus coeruleus. In conclusion, losartan exerts direct neuroprotective effects via its Abeta-reducing and antiinflammatory effects in the central nervous system (CNS). Therefore, intranasal losartan and potentially other ARBs, at concentrations below their threshold for altering systemic blood pressure, offer a new approach for the treatment of AD.

  6. Synaptic Changes in the Dentate Gyrus of APP/PS1 Transgenic Mice Revealed by Electron Microscopy

    PubMed Central

    Merino-Serrais, Paula; Gonzalez, Santiago; DeFelipe, Javier

    2013-01-01

    Abstract Numerous studies have reported widespread synaptic dysfunction or loss in early stages of both Alzheimer disease (AD) patients and animal models; it is widely accepted that synapse loss is the major structural correlate of cognitive dysfunction. Elucidation of the changes that may affect synapses is crucial for understanding the pathogenic mechanisms underlying AD, but ultrastructural preservation of human postmortem brain tissue is often poor, and classical methods for quantification of synapses have significant technical limitations. We previously observed changes in dendritic spines in plaque-free regions of the neuropil of the dentate gyrus of double-transgenic APP/PS1 (amyloid precursor protein/presenilin 1) model mice by light microscopy. Here, we used electron microscopy to examine possible synaptic alterations in this region. We used standard stereologic techniques to determine numbers of synapses per volume. We were able to reconstruct and analyze thousands of synapses and their 3-dimensional characteristics using a focused ion beam/scanning electron microscope and 3-dimensional reconstruction software (EspINA), which performs semiautomated segmentation of synapses. Our results show that both numbers of synapses per volume and synaptic morphology are affected in plaque-free regions of APP/PS1 mice. Therefore, changes in the number and morphology of synapses seem to be widespread alterations in this animal model. PMID:23584198

  7. Intranasal BMP9 Ameliorates Alzheimer Disease-Like Pathology and Cognitive Deficits in APP/PS1 Transgenic Mice

    PubMed Central

    Wang, Zigao; Xiong, Lu; Wan, Wenbin; Duan, Lijie; Bai, Xiaojing; Zu, Hengbing

    2017-01-01

    Alzheimer’s disease (AD) is the most common type of dementia and has no effective therapies. Previous studies showed that bone morphogenetic protein 9 (BMP9), an important factor in the differentiation and phenotype maintenance of cholinergic neurons, ameliorated the cholinergic defects resulting from amyloid deposition. These findings suggest that BMP9 has potential as a therapeutic agent for AD. However, the effects of BMP9 on cognitive function in AD and its underlying mechanisms remain elusive. In the present study, BMP9 was delivered intranasally to 7-month-old APP/PS1 mice for 4 weeks. Our data showed that intranasal BMP9 administration significantly improved the spatial and associative learning and memory of APP/PS1 mice. We also found that intranasal BMP9 administration significantly reduced the amyloid β (Aβ) plaques overall, inhibited tau hyperphosphorylation, and suppressed neuroinflammation in the transgenic mouse brain. Furthermore, intranasal BMP9 administration significantly promoted the expression of low-density lipoprotein receptor-related protein 1 (LRP1), an important membrane receptor involved in the clearance of amyloid β via the blood-brain barrier (BBB), and elevated the phosphorylation levels of glycogen synthase kinase-3β (Ser9), which is considered the main kinase involved in tau hyperphosphorylation. Our results suggest that BMP9 may be a promising candidate for treating AD by targeting multiple key pathways in the disease pathogenesis. PMID:28228716

  8. Genetic and Transgenic Reagents for Drosophila simulans, D. mauritiana, D. yakuba, D. santomea, and D. virilis.

    PubMed

    Stern, David L; Crocker, Justin; Ding, Yun; Frankel, Nicolas; Kappes, Gretchen; Kim, Elizabeth; Kuzmickas, Ryan; Lemire, Andrew; Mast, Joshua D; Picard, Serge

    2017-04-03

    Species of the Drosophila melanogaster species subgroup, including the species D. simulans, D. mauritiana, D. yakuba, and D. santomea, have long served as model systems for studying evolution. However, studies in these species have been limited by a paucity of genetic and transgenic reagents. Here, we describe a collection of transgenic and genetic strains generated to facilitate genetic studies within and between these species. We have generated many strains of each species containing mapped piggyBac transposons including an enhanced yellow fluorescent protein (EYFP) gene expressed in the eyes and a ϕC31 attP site-specific integration site. We have tested a subset of these lines for integration efficiency and reporter gene expression levels. We have also generated a smaller collection of other lines expressing other genetically encoded fluorescent molecules in the eyes and a number of other transgenic reagents that will be useful for functional studies in these species. In addition, we have mapped the insertion locations of 58 transposable elements in D. virilis that will be useful for genetic mapping studies.

  9. Genetic and Transgenic Reagents for Drosophila simulans, D. mauritiana, D. yakuba, D. santomea, and D. virilis

    PubMed Central

    Stern, David L.; Crocker, Justin; Ding, Yun; Frankel, Nicolas; Kappes, Gretchen; Kim, Elizabeth; Kuzmickas, Ryan; Lemire, Andrew; Mast, Joshua D.; Picard, Serge

    2017-01-01

    Species of the Drosophila melanogaster species subgroup, including the species D. simulans, D. mauritiana, D. yakuba, and D. santomea, have long served as model systems for studying evolution. However, studies in these species have been limited by a paucity of genetic and transgenic reagents. Here, we describe a collection of transgenic and genetic strains generated to facilitate genetic studies within and between these species. We have generated many strains of each species containing mapped piggyBac transposons including an enhanced yellow fluorescent protein (EYFP) gene expressed in the eyes and a ϕC31 attP site-specific integration site. We have tested a subset of these lines for integration efficiency and reporter gene expression levels. We have also generated a smaller collection of other lines expressing other genetically encoded fluorescent molecules in the eyes and a number of other transgenic reagents that will be useful for functional studies in these species. In addition, we have mapped the insertion locations of 58 transposable elements in D. virilis that will be useful for genetic mapping studies. PMID:28280212

  10. A Mutant dec-1 Transgene Induces Dominant Female Sterility in Drosophila melanogaster

    PubMed Central

    Spangenberg, Daniel K.; Waring, Gail L.

    2007-01-01

    The Drosophila dec-1 gene produces three proproteins required for female fertility and eggshell assembly. The three proproteins are distinguished by their C termini. Fc106, the most abundant proprotein, is cleaved within the vitelline membrane to three mature derivatives in a developmentally regulated manner. To define sequences within fc106 that are critical for its function, we created wild-type and mutant versions of an fc106 cDNA transgene. The functional consequences of the mutations were assessed in dec-14, a female-sterile splicing mutant that does not produce the fc106 isoform. The fertility of dec-14 females was restored by the introduction of either a wild-type transgene or a transgene bearing a C-terminal deletion that included fc106-specific sequences. Surprisingly, the removal of internal coding sequences created an aberrant DEC-1 proprotein that induced female sterility when introduced into wild-type flies. Dominant female sterility was not associated with larger deletions that included the fc106 N terminus, suggesting that abnormal juxtaposition of N- and C-terminal sequences in the aberrant proprotein interfered with endogenous DEC-1 proteins. Changes in the fractionation behavior of the endogenous fc106 C-terminal derivative, s60, and morphological changes in the endochorion in response to expression of the aberrant proprotein support this interpretation. PMID:18039879

  11. Chemical mutagens, transposons, and transgenes to interrogate gene function in Drosophila melanogaster.

    PubMed

    Venken, Koen J T; Bellen, Hugo J

    2014-06-15

    The study of genetics, genes, and chromosomal inheritance was initiated by Thomas Morgan in 1910, when the first visible mutations were identified in fruit flies. The field expanded upon the work initiated by Herman Muller in 1926 when he used X-rays to develop the first balancer chromosomes. Today, balancers are still invaluable to maintain mutations and transgenes but the arsenal of tools has expanded vastly and numerous new methods have been developed, many relying on the availability of the genome sequence and transposable elements. Forward genetic screens based on chemical mutagenesis or transposable elements have resulted in the unbiased identification of many novel players involved in processes probed by specific phenotypic assays. Reverse genetic approaches have relied on the availability of a carefully selected set of transposon insertions spread throughout the genome to allow the manipulation of the region in the vicinity of each insertion. Lastly, the ability to transform Drosophila with single copy transgenes using transposons or site-specific integration using the ΦC31 integrase has allowed numerous manipulations, including the ability to create and integrate genomic rescue constructs, generate duplications, RNAi knock-out technology, binary expression systems like the GAL4/UAS system as well as other methods. Here, we will discuss the most useful methodologies to interrogate the fruit fly genome in vivo focusing on chemical mutagenesis, transposons and transgenes. Genome engineering approaches based on nucleases and RNAi technology are discussed in following chapters.

  12. Chemical Mutagens, Transposons, and Transgenes to Interrogate Gene Function in Drosophila melanogaster

    PubMed Central

    Venken, Koen J.T.; Bellen, Hugo J.

    2014-01-01

    The study of genetics, genes, and chromosomal inheritance was initiated by Thomas Morgan in when the first visible mutations were identified in fruit flies. The field expanded upon the work initiated by Herman Muller in 1926 when he used X-rays to develop the first balancer chromosomes. Today, balancers are still invaluable to maintain mutations and transgenes but the arsenal of tools has expanded vastly and numerous new methods have been developed, many relying on the availability of the genome sequence and transposable elements. Forward genetic screens based on chemical mutagenesis or transposable elements have resulted in the unbiased identification of many novel players involved in processes probed by specific phenotypic assays. Reverse genetic approaches have relied on the availability of a carefully selected set of transposon insertions spread throughout the genome to allow the manipulation of the region in the vicinity of each insertion. Lastly, the ability to transform Drosophila with single copy transgenes using transposons or site-specific integration using the ΦC31 integrase has allowed numerous manipulations, including the ability to create and integrate genomic rescue constructs, generate duplications, RNAi knock-out technology, binary expression systems like the GAL4/UAS system as well as other methods. Here, we will discuss the most useful methodologies to interrogate the fruit fly genome in vivo focusing on chemical mutagenesis, transposons and transgenes. Genome engineering approaches based on nucleases and RNAi technology are discussed in following chapters. PMID:24583113

  13. In vivo effects of APP are not exacerbated by BACE2 co-overexpression: behavioural characterization of a double transgenic mouse model.

    PubMed

    Azkona, Garikoitz; Levannon, Ditsa; Groner, Yoram; Dierssen, Mara

    2010-11-01

    Down syndrome, the most common genetic disorder leading to mental retardation, is caused by the presence of all or part of an extra copy of chromosome 21. At relatively early ages, Down syndrome patients develop progressive formation and extracellular aggregation of amyloid-β peptide, considered as one of the causal factors for the pathogenesis of Alzheimer's disease. This neuropathological hallmark has been attributed to the overexpression of APP but could also be contributed by other HSA21 genes. BACE2 maps to HSA21 and is homologous to BACE1, a β-secretase involved in the amyloidogenic pathway of APP proteolysis, and thus it has been hypothesized that the co-overexpression of both genes could contribute to Alzheimer's like neuropathology present in Down syndrome. The aim of the present study has been to analyse the impact of the co-overexpression of BACE2 and APP, using a double transgenic mouse model. Double transgenic mice did not present any neurological or sensorimotor alterations, nor genotype-dependent anxiety-like behaviour or age-associated cognitive dysfunction. Interestingly, TgBACE2-APP mice showed deregulation of BACE2 expression levels that were significantly increased with respect to single TgBACE2 mice. Co-overexpression of BACE2 and APP did not increase amyloid-β peptide concentration in brain. Our results suggest that the in vivo effects of APP are not exacerbated by BACE2 co-overexpression but may have some protective effects in specific behavioural and cognitive domains in transgenic mice.

  14. Focal glial activation coincides with increased BACE1 activation and precedes amyloid plaque deposition in APP[V717I] transgenic mice

    PubMed Central

    Heneka, Michael T; Sastre, Magdalena; Dumitrescu-Ozimek, Lucia; Dewachter, Ilse; Walter, Jochen; Klockgether, Thomas; Van Leuven, Fred

    2005-01-01

    Background Inflammation is suspected to contribute to the progression and severity of neurodegeneration in Alzheimer's disease (AD). Transgenic mice overexpressing the london mutant of amyloid precursor protein, APP [V717I], robustly recapitulate the amyloid pathology of AD. Methods Early and late, temporal and spatial characteristics of inflammation were studied in APP [V717I] mice at 3 and 16 month of age. Glial activation and expression of inflammatory markers were determined by immunohistochemistry and RT-PCR. Amyloid deposition was assessed by immunohistochemistry, thioflavine S staining and western blot experiments. BACE1 activity was detected in brain lysates and in situ using the BACE1 activity kit from R&D Systems, Wiesbaden, Germany. Results Foci of activated micro- and astroglia were already detected at age 3 months, before any amyloid deposition. Inflammation parameters comprised increased mRNA levels coding for interleukin-1β, interleukin-6, major histocompatibility complex II and macrophage-colony-stimulating-factor-receptor. Foci of CD11b-positive microglia expressed these cytokines and were neighbored by activated astrocytes. Remarkably, β-secretase (BACE1) mRNA, neuronal BACE1 protein at sites of focal inflammation and total BACE1 enzyme activity were increased in 3 month old APP transgenic mice, relative to age-matched non-transgenic mice. In aged APP transgenic mice, the mRNA of all inflammatory markers analysed was increased, accompanied by astroglial iNOS expression and NO-dependent peroxynitrite release, and with glial activation near almost all diffuse and senile Aβ deposits. Conclusion The early and focal glial activation, in conjunction with upregulated BACE1 mRNA, protein and activity in the presence of its substrate APP, is proposed to represent the earliest sites of amyloid deposition, likely evolving into amyloid plaques. PMID:16212664

  15. Search Strategies Used by "APP" Transgenic Mice during Navigation in the Morris Water Maze

    ERIC Educational Resources Information Center

    Janus, Christopher

    2004-01-01

    TgCRND8 mice represent a transgenic mouse model of Alzheimer's disease, with onset of cognitive impairment and increasing amyloid-[beta] plaques in their brains at 12 weeks of age. In this study, the spatial memory in 25- to 30-week-old TgCRND8 mice was analyzed in two reference and one working memory Morris water maze (MWM) tests. In reference…

  16. In vivo analysis of a fluorescent SUMO fusion in transgenic Drosophila

    PubMed Central

    Bocksberger, Marion; Karch, François; Gibert, Jean-Michel

    2014-01-01

    Sumoylation, the covalent attachment of SUMO, a 90 amino acid peptide related to ubiquitin, is a major modulator of protein functions. Fluorescent SUMO protein fusions have been used in cell cultures to visualize SUMO in vivo but not in multicellular organisms. We generated a transgenic line of Drosophila expressing an mCherry-SUMO fusion. We analyzed its pattern in vivo in salivary gland nuclei expressing Venus-HP1 to recognize the different chromatin components (Chromocenter, chromosome IV). We compared it to SUMO immunostaining on squashed polytene chromosomes and observed similar patterns. In addition to the previously reported SUMO localizations (chromosome arms and chromocenter), we identify 2 intense binding sites: the fourth chromosome telomere and the DAPI-bright band in the region 81F. PMID:25483255

  17. Splice form variant and amino acid changes in MDR49 confers DDT resistance in transgenic Drosophila

    PubMed Central

    Seong, Keon Mook; Sun, Weilin; Clark, John M.; Pittendrigh, Barry R.

    2016-01-01

    The ATP-binding cassette (ABC) transporters represent a superfamily of proteins that have important physiological roles in both prokaryotes and eukaryotes. In insects, ABC transporters have previously been implicated in insecticide resistance. The 91-R strain of Drosophila melanogaster has been intensely selected with DDT over six decades. A recent selective sweeps analysis of 91-R implicated the potential role of MDR49, an ABC transporter, in DDT resistance, however, to date the details of how MDR49 may play a role in resistance have not been elucidated. In this study, we investigated the impact of structural changes and an alternative splicing event in MDR49 on DDT-resistance in 91-R, as compared to the DDT susceptible strain 91-C. We observed three amino acid differences in MDR49 when 91-R was compared with 91-C, and only one isoform (MDR49B) was implicated in DDT resistance. A transgenic Drosophila strain containing the 91-R-MDR49B isoform had a significantly higher LD50 value as compared to the 91-C-MDR49B isoform at the early time points (6 h to 12 h) during DDT exposure. Our data support the hypothesis that the MDR49B isoform, with three amino acid mutations, plays a role in the early aspects of DDT resistance in 91-R. PMID:27003579

  18. Human Cryptochrome-1 Confers Light Independent Biological Activity in Transgenic Drosophila Correlated with Flavin Radical Stability

    PubMed Central

    Vieira, Jacqueline; Jones, Alex R.; Danon, Antoine; Sakuma, Michiyo; Hoang, Nathalie; Robles, David; Tait, Shirley; Heyes, Derren J.; Picot, Marie; Yoshii, Taishi; Helfrich-Förster, Charlotte; Soubigou, Guillaume; Coppee, Jean-Yves; Klarsfeld, André; Rouyer, Francois; Scrutton, Nigel S.; Ahmad, Margaret

    2012-01-01

    Cryptochromes are conserved flavoprotein receptors found throughout the biological kingdom with diversified roles in plant development and entrainment of the circadian clock in animals. Light perception is proposed to occur through flavin radical formation that correlates with biological activity in vivo in both plants and Drosophila. By contrast, mammalian (Type II) cryptochromes regulate the circadian clock independently of light, raising the fundamental question of whether mammalian cryptochromes have evolved entirely distinct signaling mechanisms. Here we show by developmental and transcriptome analysis that Homo sapiens cryptochrome - 1 (HsCRY1) confers biological activity in transgenic expressing Drosophila in darkness, that can in some cases be further stimulated by light. In contrast to all other cryptochromes, purified recombinant HsCRY1 protein was stably isolated in the anionic radical flavin state, containing only a small proportion of oxidized flavin which could be reduced by illumination. We conclude that animal Type I and Type II cryptochromes may both have signaling mechanisms involving formation of a flavin radical signaling state, and that light independent activity of Type II cryptochromes is a consequence of dark accumulation of this redox form in vivo rather than of a fundamental difference in signaling mechanism. PMID:22427812

  19. Splice form variant and amino acid changes in MDR49 confers DDT resistance in transgenic Drosophila.

    PubMed

    Seong, Keon Mook; Sun, Weilin; Clark, John M; Pittendrigh, Barry R

    2016-03-22

    The ATP-binding cassette (ABC) transporters represent a superfamily of proteins that have important physiological roles in both prokaryotes and eukaryotes. In insects, ABC transporters have previously been implicated in insecticide resistance. The 91-R strain of Drosophila melanogaster has been intensely selected with DDT over six decades. A recent selective sweeps analysis of 91-R implicated the potential role of MDR49, an ABC transporter, in DDT resistance, however, to date the details of how MDR49 may play a role in resistance have not been elucidated. In this study, we investigated the impact of structural changes and an alternative splicing event in MDR49 on DDT-resistance in 91-R, as compared to the DDT susceptible strain 91-C. We observed three amino acid differences in MDR49 when 91-R was compared with 91-C, and only one isoform (MDR49B) was implicated in DDT resistance. A transgenic Drosophila strain containing the 91-R-MDR49B isoform had a significantly higher LD50 value as compared to the 91-C-MDR49B isoform at the early time points (6 h to 12 h) during DDT exposure. Our data support the hypothesis that the MDR49B isoform, with three amino acid mutations, plays a role in the early aspects of DDT resistance in 91-R.

  20. Ectopic mitotic recombination in Drosophila probed with bacterial beta-galactosidase gene-based reporter transgenes.

    PubMed Central

    Bärtsch, S; Dücker, K; Würgler, F E; Sengstag, C

    1997-01-01

    Plasmids were constructed to investigate homologous mitotic recombination in Drosophila cells. Heteroalleles containing truncated but overlapping segments of the bacterial beta-galactosidase gene (lacZ) were positioned either on separate plasmids or as direct repeats on the same chromosome. Recombination reconstituted a functional lacZgene leading to expression of LacZ+activity detectable by histochemical staining. High extrachromosomal recombination (ECR) frequencies between unlinked heteroalleles were observed upon transient co-transfection into Drosophila melanogaster Schneider line 2 (S2) cells. Stably transfected cells containing the lacZ heteroalleles linked on a chromosome exhibited intrachromosomal recombination (ICR) frequencies two orders of magnitude lower than ECR frequencies. Recombination was inducible by exposing the cells to ethyl methanesulphonate or mitomycin C. Recombination products were characterized by multiplex PCR analysis and unequal sister chromatid recombination was found as the predominant mechanism reconstituting the lacZ gene. To investigate recombination in vivo imaginal disc cells from transgenic larvae carrying the reporter gene on the X chromosome were isolated and stained for LacZ+ activity. The presence of a few LacZ+ clones indicated that mitotic recombination events occurred at frequencies two orders of magnitude lower than the corresponding event in cultured cells and late during larval development. PMID:9380517

  1. Neuroinflammatory signals in Alzheimer disease and APP/PS1 transgenic mice: correlations with plaques, tangles, and oligomeric species.

    PubMed

    López-González, Irene; Schlüter, Agatha; Aso, Ester; Garcia-Esparcia, Paula; Ansoleaga, Belen; LLorens, Franc; Carmona, Margarita; Moreno, Jesús; Fuso, Andrea; Portero-Otin, Manuel; Pamplona, Reinald; Pujol, Aurora; Ferrer, Isidre

    2015-04-01

    To understand neuroinflammation-related gene regulation during normal aging and in sporadic Alzheimer disease (sAD), we performed functional genomics analysis and analyzed messenger RNA (mRNA) expression by quantitative reverse transcription-polymerase chain reaction of 22 genes involved in neuroinflammation-like responses in the cerebral cortex of wild-type and APP/PS1 transgenic mice. For direct comparisons, mRNA expression of 18 of the same genes was then analyzed in the entorhinal cortex, orbitofrontal cortex, and frontal cortex area 8 of middle-aged human subjects lacking Alzheimer disease-related pathology and in older subjects with sAD pathology covering Stages I-II/0(A), III-IV/A-B, and V-VI/C of Braak and Braak classification. Modifications of cytokine and immune mediator mRNA expression were found with normal aging in wild-type mice and in middle-aged individuals and patients with early stages of sAD-related pathology; these were accompanied by increased protein expression of certain mediators in ramified microglia. In APP/PS1 mice, inflammatory changes coincided with β-amyloid (Aβ) deposition; increased levels of soluble oligomers paralleled the modified mRNA expression of cytokines and mediators in wild-type mice. In patients with sAD, regulation was stage- and region-dependent and not merely acceleration and exacerbation of mRNA regulation with aging. Gene regulation at first stages of AD was not related to hyperphosphorylated tau deposition in neurofibrillary tangles, Aβ plaque burden, concentration of Aβ1-40 (Aβ40) and Aβ1-42 (Aβ42), or fibrillar Aβ linked to membranes but rather to increased levels of soluble oligomers. Thus, species differences and region- and stage-dependent inflammatory responses in sAD, particularly at the initial stages, indicate the need to identify new anti-inflammatory compounds with specific molecular therapeutic targets.

  2. Ablation of Prion Protein in Wild Type Human Amyloid Precursor Protein (APP) Transgenic Mice Does Not Alter The Proteolysis of APP, Levels of Amyloid-β or Pathologic Phenotype

    PubMed Central

    Baybutt, Herbert; Diack, Abigail B.; Kellett, Katherine A. B.; Piccardo, Pedro; Manson, Jean C.

    2016-01-01

    The cellular prion protein (PrPC) has been proposed to play an important role in the pathogenesis of Alzheimer’s disease. In cellular models PrPC inhibited the action of the β-secretase BACE1 on wild type amyloid precursor protein resulting in a reduction in amyloid-β (Aβ) peptides. Here we have assessed the effect of genetic ablation of PrPC in transgenic mice expressing human wild type amyloid precursor protein (line I5). Deletion of PrPC had no effect on the α- and β-secretase proteolysis of the amyloid precursor protein (APP) nor on the amount of Aβ38, Aβ40 or Aβ42 in the brains of the mice. In addition, ablation of PrPC did not alter Aβ deposition or histopathology phenotype in this transgenic model. Thus using this transgenic model we could not provide evidence to support the hypothesis that PrPC regulates Aβ production. PMID:27447728

  3. Focally Elevated Creatine Detected in Amyloid Precursor Protein (APP) Transgenic Mice and Alzheimer Disease Brain Tissue

    SciTech Connect

    Gallant,M.; Rak, M.; Szeghalmi, A.; Del Bigio, M.; Westaway, D.; Yang, J.; Julian, R.; Gough, K.

    2006-01-01

    The creatine/phosphocreatine system, regulated by creatine kinase, plays an important role in maintaining energy balance in the brain. Energy metabolism and the function of creatine kinase are known to be affected in Alzheimer diseased brain and in cells exposed to the {beta}-amyloid peptide. We used infrared microspectroscopy to examine hippocampal, cortical, and caudal tissue from 21-89-week-old transgenic mice expressing doubly mutant (K670N/M671L and V717F) amyloid precursor protein and displaying robust pathology from an early age. Microcrystalline deposits of creatine, suggestive of perturbed energetic status, were detected by infrared microspectroscopy in all animals with advanced plaque pathology. Relatively large creatine deposits were also found in hippocampal sections from post-mortem Alzheimer diseased human brain, compared with hippocampus from non-demented brain. We therefore speculate that this molecule is a marker of the disease process.

  4. Accelerated amyloid deposition, neurofibrillary degeneration and neuronal loss in double mutant APP/tau transgenic mice.

    PubMed

    Ribé, Elena M; Pérez, Mar; Puig, Berta; Gich, Ignasi; Lim, Filip; Cuadrado, Mar; Sesma, Teresa; Catena, Silvia; Sánchez, Belén; Nieto, María; Gómez-Ramos, Pilar; Morán, M Asunción; Cabodevilla, Felipe; Samaranch, Lluis; Ortiz, Lourdes; Pérez, Alberto; Ferrer, Isidro; Avila, Jesús; Gómez-Isla, Teresa

    2005-12-01

    Even though the idea that amyloid beta peptide accumulation is the primary event in the pathogenesis of Alzheimer's disease has become the leading hypothesis, the causal link between aberrant amyloid precursor protein processing and tau alterations in this type of dementia remains controversial. We further investigated the role of beta-amyloid production/deposition in tau pathology and neuronal cell death in the mouse brain by crossing Tg2576 and VLW lines expressing human mutant amyloid precursor protein and human mutant tau, respectively. The resulting double transgenic mice showed enhanced amyloid deposition accompanied by neurofibrillary degeneration and overt neuronal loss in selectively vulnerable brain limbic areas. These findings challenge the idea that tau pathology in Alzheimer's disease is merely a downstream effect of amyloid production/deposition and suggest that reciprocal interactions between beta-amyloid and tau alterations may take place in vivo.

  5. Human Matrix Attachment Regions Are Necessary for the Establishment but Not the Maintenance of Transgene Insulation in Drosophila melanogaster

    PubMed Central

    Namciu, Stephanie J.; Fournier, R. E. K.

    2004-01-01

    Human matrix attachment regions (MARs) can insulate transgene expression from chromosomal position effects in Drosophila melanogaster. To gain insight into the mechanism(s) by which chromosomal insulation occurs, we studied the expression phenotypes of Drosophila transformants expressing mini-white transgenes in which MAR sequences from the human apoB gene were arranged in a variety of ways. In agreement with previous reports, we found that a single copy of the insulating element was not sufficient for position-independent transgene expression; rather, two copies were required. However, the arrangement of the two elements within the transgene was unimportant, since chromosomal insulation was equally apparent when both copies of the insulator were upstream of the mini-white reporter as when the transcription unit was flanked by insulator elements. Moreover, experiments in which apoB 3′ MAR sequences were removed from integrated transgenes in vivo by site-specific recombination demonstrated that MAR sequences were required for the establishment but not for the maintenance of chromosomal insulation. These observations are not compatible with the chromosomal loop model in its simplest form. Alternate mechanisms for MAR function in this system are proposed. PMID:15542833

  6. Rapid and sustained cognitive recovery in APP/PS1 transgenic mice by co-administration of EPPS and donepezil

    PubMed Central

    Kim, Hye Yun; Kim, Hyunjin Vincent; Lee, Dongkeun K.; Yang, Seung-Hoon; Kim, YoungSoo

    2016-01-01

    Alzheimer’s disease (AD) is a neurodegenerative disease characterized by sequential progression of pathological events, such as aggregation of amyloid-β proteins, followed by outward symptoms of cognitive impairments. Given that a combination of different therapeutic strategies often provides more rapid and effective outcomes in diverse areas of clinical treatment, we hypothesized that administration of anti-amyloid drugs with cognitive enhancers would result in synergistic effects in AD treatment. Here, we co-administered 4-(2-hydroxyethyl)-1-piperazinepropane-sulphonic acid (EPPS), an amyloid-clearing chemical, and donepezil, an acetylcholinesterase inhibitor, to determine whether they could serve complementary roles for each other in regards to AD treatment. We found that oral administration of these two molecules led to a rapid and consistent cognitive improvement in APP/PS1 transgenic mice. Although there was no evidence for synergistic effects, our results indicated that EPPS and donepezil function complementary to each other without altering their individual effects. Thus, the combined use of disease-modifying and symptomatic relief drugs may be a promising approach in the treatment of AD. PMID:27796293

  7. Metabolomic investigation of systemic manifestations associated with Alzheimer's disease in the APP/PS1 transgenic mouse model.

    PubMed

    González-Domínguez, Raúl; García-Barrera, Tamara; Vitorica, Javier; Gómez-Ariza, José Luis

    2015-09-01

    There is growing evidence that Alzheimer's disease may be a widespread systemic disorder, so peripheral organs could be affected by pathological mechanisms occurring in this neurodegenerative disease. For this reason, a double metabolomic platform based on the combination of gas chromatography-mass spectrometry and ultra-high performance liquid chromatography-mass spectrometry was used for the first time to investigate metabolic changes in liver and kidney from the transgenic mice APP/PS1 against wild-type controls. Multivariate statistics showed significant differences in levels of numerous metabolites including phospholipids, sphingolipids, acylcarnitines, steroids, amino acids and other compounds, which denotes that multiple pathways might be associated with systemic pathogenesis of Alzheimer's in this mouse model, such as bioenergetic failures, oxidative stress, altered metabolism of membrane lipids, hyperammonemia or impaired homeostasis of steroids. Furthermore, it is noteworthy that some novel pathological mechanisms were found, such as impaired gluconeogenesis, polyol pathway or metabolism of branched chain amino acids, not previously described for Alzheimer's disease. Therefore, these findings clearly support the hypothesis that Alzheimer's disease may be considered as a systemic disorder.

  8. Prazosin, an α(1)-adrenoceptor antagonist, prevents memory deterioration in the APP23 transgenic mouse model of Alzheimer's disease.

    PubMed

    Katsouri, Loukia; Vizcaychipi, Marcela P; McArthur, Simon; Harrison, Ian; Suárez-Calvet, Marc; Lleo, Alberto; Lloyd, Dafydd G; Ma, Daqing; Sastre, Magdalena

    2013-04-01

    Noradrenergic deficits have been described in the hippocampus and the frontal cortex of Alzheimer's disease brains, which are secondary to locus coeruleus degeneration. Locus coeruleus is the brain stem nucleus responsible for synthesis of noradrenaline and from where all noradrenergic neurons project. In addition, it has been suggested that noradrenaline might play a role in modulating inflammatory responses in Alzheimer's disease. In this study we aimed to investigate the effect of various agonists and antagonists for adrenergic receptors on amyloid precursor protein processing. Among them, we found that prazosin, an α(1)-adrenoceptor antagonist, was able to reduce the generation of amyloid β in N2a cells. Treatment of transgenic APP23 mice with prazosin prevented memory deficits over time. Although prazosin did not influence amyloid plaque load, it induced astrocytic proliferation and increased the release of apolipoprotein E and anti-inflammatory cytokines. These findings suggest that chronic treatment with prazosin leads to an anti-inflammatory response with potential beneficial effects on cognitive performance.

  9. Effects of triptolide on hippocampal microglial cells and astrocytes in the APP/PS1 double transgenic mouse model of Alzheimer's disease

    PubMed Central

    Li, Jian-ming; Zhang, Yan; Tang, Liang; Chen, Yong-heng; Gao, Qian; Bao, Mei-hua; Xiang, Ju; Lei, De-liang

    2016-01-01

    The principal pathology of Alzheimer's disease includes neuronal extracellular deposition of amyloid-beta peptides and formation of senile plaques, which in turn induce neuroinflammation in the brain. Triptolide, a natural extract from the vine-like herb Tripterygium wilfordii Hook F, has potent anti-inflammatory and immunosuppressive efficacy. Therefore, we determined if triptolide can inhibit activation and proliferation of microglial cells and astrocytes in the APP/PS1 double transgenic mouse model of Alzheimer's disease. We used 1 or 5 μg/kg/d triptolide to treat APP/PS1 double transgenic mice (aged 4–4.5 months) for 45 days. Unbiased stereology analysis found that triptolide dose-dependently reduced the total number of microglial cells, and transformed microglial cells into the resting state. Further, triptolide (5 μg/kg/d) also reduced the total number of hippocampal astrocytes. Our in vivo test results indicate that triptolide suppresses activation and proliferation of microglial cells and astrocytes in the hippocampus of APP/PS1 double transgenic mice with Alzheimer's disease. PMID:27857756

  10. A novel phosphodiesterase-5 Inhibitor: Yonkenafil modulates neurogenesis, gliosis to improve cognitive function and ameliorates amyloid burden in an APP/PS1 transgenic mice model.

    PubMed

    Zhu, Lei; Yang, Jing-yu; Xue, Xue; Dong, Ying-xu; Liu, Yang; Miao, Feng-rong; Wang, Yong-feng; Xue, Hong; Wu, Chun-fu

    2015-09-01

    In Alzheimer's disease (AD), activated microglia invade and surround β-amyloid plaques, possibly contributing to the aggregation of amyloid β (Aβ), which affect the survival of neurons and lead to memory loss. Phosphodiesterase-5 (PDE-5) inhibitors have recently been shown a potential therapeutic effect on AD. In this study, the effects of yonkenafil (yonk), a novel PDE-5 inhibitor, on cognitive behaviors as well as the pathological features in transgenic AD mice were investigated. Seven-month-old APP/PS1 transgenic mice were treated with yonk (2, 6, or 18 mg/kg, intraperitoneal injection (i.p.)) or sildenafil (sild) (6 mg/kg, i.p.) daily for 3 months and then behavioral tests were performed. The results demonstrated that yonk improved nesting-building ability, ameliorated working memory deficits in the Y-maze tasks, and significantly improved learning and memory function in the Morris water maze (MWM) tasks. In addition, yonk reduced the area of Aβ plaques, and inhibited over-activation of microglia and astrocytes. Furthermore, yonk increased neurogenesis in the dentate granule brain region of APP/PS1 mice, indicated by increased BrdU(+)/NeuN(+) and BrdU(+)/DCX(+) cells compared to vehicle-treated transgenic mice. These results suggest that yonk could rescue cognitive deficits by ameliorated amyloid burden through regulating APP processing, inhibited the over-activation of microglia and astrocytes as well as restored neurogenesis.

  11. The evolution of A beta peptide burden in the APP23 transgenic mice: implications for A beta deposition in Alzheimer disease.

    PubMed Central

    Kuo, Y. M.; Beach, T. G.; Sue, L. I.; Scott, S.; Layne, K. J.; Kokjohn, T. A.; Kalback, W. M.; Luehrs, D. C.; Vishnivetskaya, T. A.; Abramowski, D.; Sturchler-Pierrat, C.; Staufenbiel, M.; Weller, R. O.; Roher, A. E.

    2001-01-01

    BACKGROUND: High levels of A beta in the cerebral cortex distinguish demented Alzheimer's disease (AD) from nondemented elderly individuals, suggesting that decreased amyloid-beta (A beta) peptide clearance from the brain is a key precipitating factor in AD. MATERIALS AND METHODS: The levels of A beta in brain and plasma as well as apolipoprotein E (ApoE) in brain were investigated by enzyme-linked immunosorbent assay (ELISA) and Western blotting at various times during the life span of the APP23 transgenic (Tg) and control mice. Histochemistry and immunocytochemistry were used to assess the morphologic characteristics of the brain parenchymal and cerebrovascular amyloid deposits and the intracellular amyloid precursor protein (APP) deposits in the APP23 Tg mice. RESULTS: No significant differences were found in the plasma levels of A beta between the APP23 Tg and control mice from 2-20 months of age. In contrast, soluble A beta levels in the brain were continually elevated, increasing 4-fold at 2 months and 33-fold in the APP23 Tg mice at 20 months of age when compared to the control mice. Soluble A beta42 was about 60% higher than A beta40. In the APP23 Tg mice, insoluble A beta40 remained at basal levels in the brain until 9 months and then rose to 680 microg/g cortex by 20 months. Insoluble A beta40 was negligible in non-Tg mice at all ages. Insoluble A beta42 in APP23 Tg mice rose to 60 microg/g cortex at 20 months, representing 24 times the control A beta42 levels. Elevated levels of ApoE in the brain were observed in the APP23 Tg mice at 2 months of age, becoming substantially higher by 20 months. ApoE colocalized with A beta in the plaques. Beta-amyloid precursor protein (betaAPP) deposits were detected within the neuronal cytoplasm from 4 months of age onward. Amyloid angiopathy in the APP23 Tg mice increased markedly with age, being by far more severe than in the Tg2576 mice. CONCLUSIONS: We suggest that the APP23 Tg mouse may develop an earlier blockage

  12. Phenotypic rescue by a bovine transgene in a Cu/Zn superoxide dismutase-null mutant of Drosophila melanogaster

    SciTech Connect

    Reveillaud, I.; Kongpachith, A.; Fleming, J.E.

    1994-02-01

    Null mutants for Cu/Zn superoxide dismutase (CuZnSOD) in Drosophila melanogaster are male sterile, have a greatly reduced adult life span, and are hypersensitive to paraquat. We have introduced a synthetic bovine CuZnSOD transgene under the transcriptional control of the D. melanogaster 5C actin promoter into a CuZnSOD-null mutant of D. melanogaster. This was carried out by P-element-mediated transformation of the Drosophila-bovine CuZnSOD transgene into a CuZnSOD{sup +} recipient strain followed by genetic crossing of the transgene into a strain carrying the CuZnSOD-null mutation, cSOD{sup n108}. The resulting transformants express bovine CuZnSOD exclusively to about 30% of normal Drosophila CuZnSOD levels. Expression of the Drosophila-bovine CuZnSOD transgene in the CuZnSOD-null mutant rescues male fertility and resistance to paraquat to apparently normal levels. However, adult life span is restored to only 30% of normal, and resistance to hyperoxia is 90% of that found in control flies. This striking differential restoration of pleiotropic phenotypes could be the result of a threshold of CuZnSOD expression necessary for normal male fertility and resistance to the toxicity of paraquat or hyperoxia which is lower than the threshold required to sustain a normal adult life span. Alternatively, the differential rescue of fertility, resistance to active oxygen, and life span might indicate different cell-specific transcriptional requirements for these functions which are normally provided by the control elements of the native CuZnSOD gene but are only partly compensated for by the transcriptional control elements of the actin 5C promoter. 29 refs., 5 figs., 1 tab.

  13. Hydrogen Sulfide Selectively Inhibits γ-Secretase Activity and Decreases Mitochondrial Aβ Production in Neurons from APP/PS1 Transgenic Mice.

    PubMed

    Zhao, Feng-Li; Qiao, Pei-Feng; Yan, Ning; Gao, Dan; Liu, Meng-Jie; Yan, Yong

    2016-05-01

    Hydrogen sulfide (H2S) is now considered to be a gasotransmitter and may be involved in the pathological process of Alzheimer's disease (AD). A majority of APP is associated with mitochondria and is a substrate for the mitochondrial γ-secretase. The mitochondria-associated APP metabolism where APP intracellular domains (AICD) and Aβ are generated locally and may contribute to mitochondrial dysfunction in AD. Here, we aimed to investigate the ability of H2S to mediate APP processing in mitochondria and assessed the possible mechanisms underlying H2S-mediated AD development. We treated neurons from APP/PS1 transgenic mice with a range of sodium hydrosulfide (NaHS) concentrations. NaHS attenuated APP processing and decreased Aβ production in mitochondria. Meanwhile, NaHS did not changed BACE-1 and ADAM10 (a disintegrin and metalloprotease 10) protein levels, but NaHS (30 μM) significantly increased the levels of presenilin 1(PS1), PEN-2, and NCT, as well as improved the γ-secretase activity, while NaHS (50 μM) exhibits the opposing effects. Furthermore, the intracellular ATP and the COX IV activity of APP/PS1 neurons were increased after 30 μM NaHS treatment, while the ROS level was decreased and the MMP was stabilized. The effect of NaHS differs from DAPT (a non-selective γ-secretase inhibitor), and it selectively inhibited γ-secretase in vitro, without interacting with Notch and modulating its cleavage. The results indicated that NaHS decreases Aβ accumulation in mitochondria by selectively inhibiting γ-secretase. Thus, we provide a mechanistic view of NaHS is a potential anti-AD drug candidate and it may decrease Aβ deposition in mitochondria by selectively inhibiting γ-secretase activity and therefore protecting the mitochondrial function during AD conditions.

  14. Running exercise delays neurodegeneration in amygdala and hippocampus of Alzheimer's disease (APP/PS1) transgenic mice.

    PubMed

    Lin, Tzu-Wei; Shih, Yao-Hsiang; Chen, Shean-Jen; Lien, Chi-Hsiang; Chang, Chia-Yuan; Huang, Tung-Yi; Chen, Shun-Hua; Jen, Chauying J; Kuo, Yu-Min

    2015-02-01

    Alzheimer's disease (AD) is an age-related neurodegenerative disease. Post-mortem examination and brain imaging studies indicate that neurodegeneration is evident in the hippocampus and amygdala of very early stage AD patients. Exercise training is known to enhance hippocampus- and amygdala-associated neuronal function. Here, we investigated the effects of exercise (running) on the neuronal structure and function of the hippocampus and amygdala in APP/PS1 transgenic (Tg) mice. At 4-months-old, an age before amyloid deposition, the amygdala-associated, but not the hippocampus-associated, long-term memory was impaired in the Tg mice. The dendritic complexities of the amygdalar basolateral neurons, but not those in the hippocampal CA1 and CA3 neurons, were reduced. Furthermore, the levels of BDNF/TrkB signaling molecules (i.e. p-TrkB, p-Akt and p-PKC) were reduced in the amygdala, but not in the hippocampus of the 4-month-old Tg mice. The concentrations of Aβ40 and Aβ42 in the amygdala were higher than those in the hippocampus. Ten weeks of treadmill training (from 1.5- to 4-month-old) increased the hippocampus-associated memory and dendritic arbor of the CA1 and CA3 neurons, and also restored the amygdala-associated memory and the dendritic arbor of amygdalar basolateral neurons in the Tg mice. Similarly, exercise training also increased the levels of p-TrkB, p-AKT and p-PKC in the hippocampus and amygdala. Furthermore, exercise training reduced the levels of soluble Aβ in the amygdala and hippocampus. Exercise training did not change the levels of APP or RAGE, but significantly increased the levels of LRP-1 in both brain regions of the Tg mice. In conclusion, our results suggest that tests of amygdala function should be incorporated into subject selection for early prevention trials. Long-term exercise protects neurons in the amygdala and hippocampus against AD-related degeneration, probably via enhancements of BDNF signaling pathways and Aβ clearance. Physical

  15. Effects of growth hormone-releasing hormone on sleep and brain interstitial fluid amyloid-β in an APP transgenic mouse model.

    PubMed

    Liao, Fan; Zhang, Tony J; Mahan, Thomas E; Jiang, Hong; Holtzman, David M

    2015-07-01

    Alzheimer's disease (AD) is a neurodegenerative disorder characterized by impairment of cognitive function, extracellular amyloid plaques, intracellular neurofibrillary tangles, and synaptic and neuronal loss. There is substantial evidence that the aggregation of amyloid β (Aβ) in the brain plays a key role in the pathogenesis of AD and that Aβ aggregation is a concentration dependent process. Recently, it was found that Aβ levels in the brain interstitial fluid (ISF) are regulated by the sleep-wake cycle in both humans and mice; ISF Aβ is higher during wakefulness and lower during sleep. Intracerebroventricular infusion of orexin increased wakefulness and ISF Aβ levels, and chronic sleep deprivation significantly increased Aβ plaque formation in amyloid precursor protein transgenic (APP) mice. Growth hormone-releasing hormone (GHRH) is a well-documented sleep regulatory substance which promotes non-rapid eye movement sleep. GHRHR(lit/lit) mice that lack functional GHRH receptor have shorter sleep duration and longer wakefulness during light periods. The current study was undertaken to determine whether manipulating sleep by interfering with GHRH signaling affects brain ISF Aβ levels in APPswe/PS1ΔE9 (PS1APP) transgenic mice that overexpress mutant forms of APP and PSEN1 that cause autosomal dominant AD. We found that intraperitoneal injection of GHRH at dark onset increased sleep and decreased ISF Aβ and that delivery of a GHRH antagonist via reverse-microdialysis suppressed sleep and increased ISF Aβ. The diurnal fluctuation of ISF Aβ in PS1APP/GHRHR(lit/lit) mice was significantly smaller than that in PS1APP/GHRHR(lit/+) mice. However despite decreased sleep in GHRHR deficient mice, this was not associated with an increase in Aβ accumulation later in life. One of several possibilities for the finding is the fact that GHRHR deficient mice have GHRH-dependent but sleep-independent factors which protect against Aβ deposition.

  16. Evaluation of the toxic potential of cefotaxime in the third instar larvae of transgenic Drosophila melanogaster.

    PubMed

    Rahul; Jyoti, Smita; Naz, Falaq; Siddique, Yasir Hasan

    2015-05-25

    The present study was carried out to evaluate the toxic potential of cefotaxime in the third instar larvae of transgenic Drosophila melanogaster (hsp70-lacZ)Bg(9). Cefotaxime at final concentration of 10, 20, 40, 60 and 80 μg/ml was mixed in the diet and the larvae were exposed to the selected doses for 6, 12, 24, 48 h. The hsp70 expression, trypan blue exclusion test, in situ histochemical β-galactosidase activity, lipid peroxidation, total protein content, glutathione (GSH) content, glutathione-S-transferase (GST) activity, protein carbonyl content, caspase 3 and 9 activity, apoptotic index and comet assay were taken as parameters for the study. The larvae exposed to 40, 60 and 80 μg/ml for 12, 24 and 48 h showed a dose and duration dependent significant increase in the activity of β-galactosidase and lipid peroxidation but decrease in the total GSH content as compared to unexposed larvae. The decrease in protein content was observed in the larvae exposed to 40, 60 and 80 μg/ml of cefotaxime for 24 and 48 h. The larvae exposed to 40, 60 and 80 μg/ml of cefotaxime for 24 and 48 h showed a dose and duration dependent increase in the tissue damage, GST, caspase 3 and 9 activity, PC content, apoptosis and the DNA tail length (comet assay). The result suggests that the cefotaxime is toxic at 40, 60 and 80 μg/ml of doses for the third instar larvae of transgenic D. melanogaster (hsp70-lacZ)Bg(9). Cefotaxime at 10 and 20 μg/ml was not toxic for any duration of exposure.

  17. Development of Cerebral Microbleeds in the APP23-Transgenic Mouse Model of Cerebral Amyloid Angiopathy—A 9.4 Tesla MRI Study

    PubMed Central

    Reuter, Björn; Venus, Alexander; Heiler, Patrick; Schad, Lothar; Ebert, Anne; Hennerici, Michael G.; Grudzenski, Saskia; Fatar, Marc

    2016-01-01

    Background: Cerebral amyloid angiopathy (CAA) is characterized by extracellular deposition of amyloid β (Aβ) around cerebral arteries and capillaries and leads to an increased risk for vascular dementia, spontaneous lobar hemorrhage, convexal subarachnoid hemorrhage, and transient focal neurological episodes, which might be an indicator of imminent spontaneous intracerebral hemorrhage. In CAA cerebral microbleeds (cMBs) with a cortical/juxtacortical distribution are frequently observed in standard magnetic resonance imaging (MRI). In vivo MRI of transgenic mouse models of CAA may serve as a useful tool to investigate translational aspects of the disease. Materials and Methods: APP23-transgenic mice demonstrate cerebrovascular Aβ deposition with subsequent neuropathological changes characteristic for CAA. We performed a 9.4 Tesla high field MRI study using T2, T2* and time of flight-magnetic resonance angiograpy (TOF-MRA) sequences in APP23-transgenic mice and wildtype (wt) littermates at the age of 8, 12, 16, 20 and 24 months, respectively. Numbers, size, and location of cMBs are reported. Results: T2* imaging demonstrated cMBs (diameter 50–300 μm) located in the neocortex and, to a lesser degree, in the thalamus. cMBs were detected at the earliest at 16 months of age. Numbers increased exponentially with age, with 2.5 ± 2 (median ± interquartilrange) at 16 months, 15 ± 6 at 20 months, and 31.5 ± 17 at 24 months of age, respectively. Conclusion: We report the temporal and spatial development of cMBs in the aging APP23-transgenic mouse model which develops characteristic pathological patterns known from human CAA. We expect this mouse model to serve as a useful tool to non-invasively monitor mid- and longterm translational aspects of CAA and to investigate experimental therapeutic strategies in longitudinal studies. PMID:27458375

  18. Hippocampal neurogenesis in the APP/PS1/nestin-GFP triple transgenic mouse model of Alzheimer's disease.

    PubMed

    Zeng, Q; Zheng, M; Zhang, T; He, G

    2016-02-09

    Alzheimer's disease (AD) is one of the most common causes of dementia. Although the exact mechanisms of AD are not entirely clear, the impairment in adult hippocampal neurogenesis has been reported to play a role in AD. To assess the relationship between AD and neurogenesis, we studied APP/PS1/nestin-green fluorescent protein (GFP) triple transgenic mice, a well-characterized mouse model of AD, which express GFP under the control of the nestin promoter. Different ages of AD mice and their wild-type littermates (WT) were used in our study. Immunofluorescent staining showed that neurogenesis occurred mainly in the subgranular zone (SGZ) of the dentate gyrus (DG) and subventricular zone (SVZ) of the lateral ventricles (LVs). The expression of neural stem cells (NSCs) (nestin) and neural precursors such as doublecortin (DCX) and GFAP in AD mice were decreased with age, as well as there being a reduction in 5-bromo-2-deoxyuridine (BrdU)-positive cells, when compared to WT. However, the number of maturate neurons (NeuN) was not significantly different between AD mice and wild-type controls, and NeuN changed only slightly with age. By Golgi-Cox staining, the morphologies of dendrites were observed, and significant differences existed between AD mice and wild-type controls. These results suggest that AD has a far-reaching influence on the regulation of adult hippocampal neurogenesis, leading to a gradual decrease in the generation of neural progenitors (NPCs), and inhibition of the differentiation and maturation of neurons.

  19. Genome-Wide Analysis of Self-Renewal in Drosophila Neural Stem Cells by Transgenic RNAi

    PubMed Central

    Neumüller, Ralph A.; Richter, Constance; Fischer, Anja; Novatchkova, Maria; Neumüller, Klaus G.; Knoblich, Juergen A.

    2011-01-01

    Summary The balance between stem cell self-renewal and differentiation is precisely controlled to ensure tissue homeostasis and prevent tumorigenesis. Here we use genome-wide transgenic RNAi to identify 620 genes potentially involved in controlling this balance in Drosophila neuroblasts. We quantify all phenotypes and derive measurements for proliferation, lineage, cell size, and cell shape. We identify a set of transcriptional regulators essential for self-renewal and use hierarchical clustering and integration with interaction data to create functional networks for the control of neuroblast self-renewal and differentiation. Our data identify key roles for the chromatin remodeling Brm complex, the spliceosome, and the TRiC/CCT-complex and show that the alternatively spliced transcription factor Lola and the transcriptional elongation factors Ssrp and Barc control self-renewal in neuroblast lineages. As our data are strongly enriched for genes highly expressed in murine neural stem cells, they are likely to provide valuable insights into mammalian stem cell biology as well. PMID:21549331

  20. A Drosophila Toolkit for the Visualization and Quantification of Viral Replication Launched from Transgenic Genomes

    PubMed Central

    Wernet, Mathias F.; Klovstad, Martha; Clandinin, Thomas R.

    2014-01-01

    Arthropod RNA viruses pose a serious threat to human health, yet many aspects of their replication cycle remain incompletely understood. Here we describe a versatile Drosophila toolkit of transgenic, self-replicating genomes (‘replicons’) from Sindbis virus that allow rapid visualization and quantification of viral replication in vivo. We generated replicons expressing Luciferase for the quantification of viral replication, serving as useful new tools for large-scale genetic screens for identifying cellular pathways that influence viral replication. We also present a new binary system in which replication-deficient viral genomes can be activated ‘in trans’, through co-expression of an intact replicon contributing an RNA-dependent RNA polymerase. The utility of this toolkit for studying virus biology is demonstrated by the observation of stochastic exclusion between replicons expressing different fluorescent proteins, when co-expressed under control of the same cellular promoter. This process is analogous to ‘superinfection exclusion’ between virus particles in cell culture, a process that is incompletely understood. We show that viral polymerases strongly prefer to replicate the genome that encoded them, and that almost invariably only a single virus genome is stochastically chosen for replication in each cell. Our in vivo system now makes this process amenable to detailed genetic dissection. Thus, this toolkit allows the cell-type specific, quantitative study of viral replication in a genetic model organism, opening new avenues for molecular, genetic and pharmacological dissection of virus biology and tool development. PMID:25386852

  1. Transgene expression of Drosophila melanogaster nucleoside kinase reverses mitochondrial thymidine kinase 2 deficiency.

    PubMed

    Krishnan, Shuba; Zhou, Xiaoshan; Paredes, João A; Kuiper, Raoul V; Curbo, Sophie; Karlsson, Anna

    2013-02-15

    A strategy to reverse the symptoms of thymidine kinase 2 (TK2) deficiency in a mouse model was investigated. The nucleoside kinase from Drosophila melanogaster (Dm-dNK) was expressed in TK2-deficient mice that have been shown to present with a severe phenotype caused by mitochondrial DNA depletion. The Dm-dNK(+/-) transgenic mice were shown to be able to rescue the TK2-deficient mice. The Dm-dNK(+/-)TK2(-/-) mice were normal as judged by growth and behavior during the observation time of 6 months. The Dm-dNK-expressing mice showed a substantial increase in thymidine-phosphorylating activity in investigated tissues. The Dm-dNK expression also resulted in highly elevated dTTP pools. The dTTP pool alterations did not cause specific mitochondrial DNA mutations or deletions when 6-month-old mice were analyzed. The mitochondrial DNA was also detected at normal levels. In conclusion, the Dm-dNK(+/-)TK2(-/-) mouse model illustrates how dTMP synthesized in the cell nucleus can compensate for loss of intramitochondrial dTMP synthesis in differentiated tissue. The data presented open new possibilities to treat the severe symptoms of TK2 deficiency.

  2. Immunocytochemical characterization of Alzheimer disease hallmarks in APP/PS1 transgenic mice treated with a new anti-amyloid-β vaccine.

    PubMed

    Carrera, Iván; Etcheverría, Ignacio; Li, Yi; Fernández-Novoa, Lucía; Lombardi, Valter; Vigo, Carmen; Palacios, Hector H; Benberin, Valery V; Cacabelos, Ramón; Aliev, Gjumrakch

    2013-01-01

    APP/PS1 double-transgenic mouse models of Alzheimer's disease (AD), which overexpress mutated forms of the gene for human amyloid precursor protein (APP) and presenilin 1 (PS1), have provided robust neuropathological hallmarks of AD-like pattern at early ages. This study characterizes immunocytochemical patterns of AD mouse brain as a model for human AD treated with the EB101 vaccine. In this novel vaccine, a new approach has been taken to circumvent past failures by judiciously selecting an adjuvant consisting of a physiological matrix embedded in liposomes, composed of naturally occurring phospholipids (phosphatidylcholine, phosphatidylglycerol, and cholesterol). Our findings showed that administration of amyloid-β₁₋₄₂ (Aβ) and sphingosine-1-phosphate emulsified in liposome complex (EB101) to APP/PS1 mice before onset of Aβ deposition (7 weeks of age) and/or at an older age (35 weeks of age) is effective in halting the progression and clearing the AD-like neuropathological hallmarks. Passive immunization with EB101 did not activate inflammatory responses from the immune system and astrocytes. Consistent with a decreased inflammatory background, the basal immunological interaction between the T cells and the affected areas (hippocampus) in the brain of treated mice was notably reduced. These results demonstrate that immunization with EB101 vaccine prevents and attenuates AD neuropathology in this type of double-transgenic mice.

  3. SUBFIELD AND LAYER-SPECIFIC DEPLETION IN CALBINDIN-D28K, CALRETININ AND PARVALBUMIN IMMUNOREACTIVITY IN THE DENTATE GYRUS OF APP/PS1 TRANSGENIC MICE

    PubMed Central

    Popovi, Miroljub; Caballero-Bleda, María; Kadish, Inga; van Groen, Thomas

    2008-01-01

    The depletion of neuronal calcium binding proteins deprives neurons of the capacity to buffer high levels of intracellular Ca2+ and this leaves them vulnerable to pathological processes, such as those present in Alzheimer’s disease (AD). The aim of the present study was to investigate the expression of the calcium binding proteins, calbindin-D28K, calretinin and parvalbumin in the dentate gyrus (DG) of APP/PS1 transgenic mice and their non-Tg littermates, as well as the relation with the deposition of human Aβ. We measured the expression of these three proteins at seven different rostro-caudal levels, and in the molecular, granular and polymorphic layers of the DG. We found that, except in the most caudal part of the DG, there is a substantial loss of calbindin-D28K immunoreactivity in all three layers of the DG in APP/PS1 mice compared to the non-Tg mice. Significant loss of calretinin immunoreactivity is present in most of the polymorphic layer of the DG of APP/PS1 mice compared to the non-Tg mice, as well as in the rostral and intermediate part of the inner molecular layer. Compared to the non-Tg mice parvalbumin immunoreactivity is significantly reduced throughout the whole polymorphic layer as well as in the rostral and intermediate part of the granular layer of DG in APP/PS1 mice. The relatively preservation of calbindin immunoreactivity in the caudal part of molecular and granular layers as well as calretinin immunoreactivity in the caudal part of polymorphic layer of the DG is likely related to the lower Aβ expression in those parts of DG. The present data suggest an involvement of calcium-dependent pathways in the pathogenesis of AD and indicate that there exists a subfield and layer-specific decrease in immunoreactivity which is related to the type of calcium-binding protein in APP/PS1 mice. Moreover, it seems that APP expression affects more the calbindin expression then parvalbumin and calretinin expression in the DG of APP/PS1 transgenic mice. PMID

  4. Neuro-peptide treatment with Cerebrolysin improves the survival of neural stem cell grafts in an APP transgenic model of Alzheimer disease.

    PubMed

    Rockenstein, Edward; Desplats, Paula; Ubhi, Kiren; Mante, Michael; Florio, Jazmin; Adame, Anthony; Winter, Stefan; Brandstaetter, Hemma; Meier, Dieter; Masliah, Eliezer

    2015-07-01

    Neural stem cells (NSCs) have been considered as potential therapy in Alzheimer's disease (AD) but their use is hampered by the poor survival of grafted cells. Supply of neurotrophic factors to the grafted cells has been proposed as a way to augment survival of the stem cells. In this context, we investigated the utility of Cerebrolysin (CBL), a peptidergic mixture with neurotrophic-like properties, as an adjunct to stem cell therapy in an APP transgenic (tg) model of AD. We grafted murine NSCs into the hippocampus of non-tg and APP tg that were treated systemically with CBL and analyzed after 1, 3, 6 and 9months post grafting. Compared to vehicle-treated non-tg mice, in the vehicle-treated APP tg mice there was considerable reduction in the survival of the grafted NSCs. Whereas, CBL treatment enhanced the survival of NSCs in both non-tg and APP tg with the majority of the surviving NSCs remaining as neuroblasts. The NSCs of the CBL treated mice displayed reduced numbers of caspase-3 and TUNEL positive cells and increased brain derived neurotrophic factor (BDNF) and furin immunoreactivity. These results suggest that CBL might protect grafted NSCs and as such be a potential adjuvant therapy when combined with grafting.

  5. 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.

  6. Noggin and BMP4 co-modulate adult hippocampal neurogenesis in the APP(swe)/PS1(DeltaE9) transgenic mouse model of Alzheimer's disease.

    PubMed

    Tang, Jun; Song, Min; Wang, Yanyan; Fan, Xiaotang; Xu, Haiwei; Bai, Yun

    2009-07-31

    In addition to the subventricular zone, the dentate gyrus of the hippocampus is one of the few brain regions in which neurogenesis continues into adulthood. Perturbation of neurogenesis can alter hippocampal function, and previous studies have shown that neurogenesis is dysregulated in Alzheimer disease (AD) brain. Bone morphogenetic protein-4 (BMP4) and its antagonist Noggin have been shown to play important roles both in embryonic development and in the adult nervous system, and may regulate hippocampal neurogenesis. Previous data indicated that increased expression of BMP4 mRNA within the dentate gyrus might contribute to decreased hippocampal cell proliferation in the APP(swe)/PS1(DeltaE9) mouse AD model. However, it is not known whether the BMP antagonist Noggin contributes to the regulation of neurogenesis. We therefore studied the relative expression levels and localization of BMP4 and its antagonist Noggin in the dentate gyrus and whether these correlated with changes in neurogenesis in 6-12 mo old APP(swe)/PS1(DeltaE9) transgenic mice. Bromodeoxyuridine (BrdU) was used to label proliferative cells. We report that decreased neurogenesis in the APP/PS1 transgenic mice was accompanied by increased expression of BMP4 and decreased expression of Noggin at both the mRNA and protein levels; statistical analysis showed that the number of proliferative cells at different ages correlated positively with Noggin expression and negatively with BMP4 expression. Intraventricular administration of a chimeric Noggin/Fc protein was used to block the action of endogenous BMP4; this resulted in a significant increase in the number of BrdU-labeled cells in dentate gyrus subgranular zone and hilus in APP/PS1 mice. These results suggest that BMP4 and Noggin co-modulate neurogenesis.

  7. De novo piRNA cluster formation in the Drosophila germ line triggered by transgenes containing a transcribed transposon fragment

    PubMed Central

    Olovnikov, Ivan; Ryazansky, Sergei; Shpiz, Sergey; Lavrov, Sergey; Abramov, Yuri; Vaury, Chantal; Jensen, Silke; Kalmykova, Alla

    2013-01-01

    PIWI-interacting RNAs (piRNAs) provide defence against transposable element (TE) expansion in the germ line of metazoans. piRNAs are processed from the transcripts encoded by specialized heterochromatic clusters enriched in damaged copies of transposons. How these regions are recognized as a source of piRNAs is still elusive. The aim of this study is to determine how transgenes that contain a fragment of the Long Interspersed Nuclear Elements (LINE)-like I transposon lead to an acquired TE resistance in Drosophila. We show that such transgenes, being inserted in unique euchromatic regions that normally do not produce small RNAs, become de novo bidirectional piRNA clusters that silence I-element activity in the germ line. Strikingly, small RNAs of both polarities are generated from the entire transgene and flanking genomic sequences—not only from the transposon fragment. Chromatin immunoprecipitation analysis shows that in ovaries, the trimethylated histone 3 lysine 9 (H3K9me3) mark associates with transgenes producing piRNAs. We show that transgene-derived hsp70 piRNAs stimulate in trans cleavage of cognate endogenous transcripts with subsequent processing of the non-homologous parts of these transcripts into piRNAs. PMID:23620285

  8. De novo piRNA cluster formation in the Drosophila germ line triggered by transgenes containing a transcribed transposon fragment.

    PubMed

    Olovnikov, Ivan; Ryazansky, Sergei; Shpiz, Sergey; Lavrov, Sergey; Abramov, Yuri; Vaury, Chantal; Jensen, Silke; Kalmykova, Alla

    2013-06-01

    PIWI-interacting RNAs (piRNAs) provide defence against transposable element (TE) expansion in the germ line of metazoans. piRNAs are processed from the transcripts encoded by specialized heterochromatic clusters enriched in damaged copies of transposons. How these regions are recognized as a source of piRNAs is still elusive. The aim of this study is to determine how transgenes that contain a fragment of the Long Interspersed Nuclear Elements (LINE)-like I transposon lead to an acquired TE resistance in Drosophila. We show that such transgenes, being inserted in unique euchromatic regions that normally do not produce small RNAs, become de novo bidirectional piRNA clusters that silence I-element activity in the germ line. Strikingly, small RNAs of both polarities are generated from the entire transgene and flanking genomic sequences--not only from the transposon fragment. Chromatin immunoprecipitation analysis shows that in ovaries, the trimethylated histone 3 lysine 9 (H3K9me3) mark associates with transgenes producing piRNAs. We show that transgene-derived hsp70 piRNAs stimulate in trans cleavage of cognate endogenous transcripts with subsequent processing of the non-homologous parts of these transcripts into piRNAs.

  9. Increased BMP6 levels in the brains of Alzheimer’s disease patients and APP transgenic mice are accompanied by impaired neurogenesis

    PubMed Central

    Crews, Leslie; Adame, Anthony; Patrick, Christina; DeLaney, Alexandra; Pham, Emiley; Rockenstein, Edward; Hansen, Lawrence; Masliah, Eliezer

    2010-01-01

    During aging and in the progression of Alzheimer’s disease (AD), synaptic plasticity and neuronal integrity are disturbed. In addition to the alterations in plasticity in mature neurons, the neurodegenerative process in AD has been shown to be accompanied by alterations in neurogenesis. Members of the bone morphogenetic protein (BMP) family of growth factors have been implicated as important regulators of neurogenesis and neuronal cell fate determination during development, however their role in adult neurogenesis and in AD is less clear. We show here by qRT-PCR analysis that BMP6 mRNA levels were significantly increased in the hippocampus of human patients with AD and in APP transgenic mice compared to controls. Immunoblot and immunohistochemical analyses confirmed that BMP6 protein levels were increased in human AD brains and APP transgenic mouse brains compared to controls and accumulated around hippocampal plaques. The increased levels of BMP6 were accompanied by defects in hippocampal neurogenesis in AD patients and APP transgenic mice. In support of a role for BMP6 in defective neurogenesis in AD, we show in an in vitro model of adult neurogenesis that treatment with amyloid-β1–42 protein (Aβ) resulted in increased expression of BMP6, and that exposure to recombinant BMP6 resulted in reduced proliferation with no toxic effects. Taken together, these results suggest that Aβ-associated increases in BMP6 expression in AD may have deleterious effects on neurogenesis in the hippocampus, and therapeutic approaches could focus on normalization of BMP6 levels to protect against AD-related neurogenic deficits. PMID:20844121

  10. Effects of proton radiation on evoked and spontaneous neuronal activity in the hippocampus of APP/PSEN1 transgenic mice

    PubMed Central

    Rudobeck, Emil; Szucs, Attila; Vlkolinsky, Roman

    2014-01-01

    Ground-based studies on space radiation indicate that exposure to charged particle radiation at relatively low doses may impair neuronal functions. Decrements in excitatory synaptic transmission and plasticity in the hippocampus have been previously reported in mouse brains irradiated with iron nuclei, but relatively little is known about the effects of protons on the synaptic activity in the hippocampus. Behavioral and neurophysiological decrements in irradiated subjects are also commonly observed in Alzheimer's disease (AD), and we hypothesized that irradiation with protons may exacerbate AD-like neurodegenerative pathology. We used transgenic (TG) mice with AD-like neurodegeneration to test whether whole-body irradiation with protons (150 MeV; 0.1, 0.5, 1 Gy) accelerates the onset of AD and/or exacerbates synaptic impairments. We measured evoked excitatory synaptic potentials, synaptic plasticity and spontaneous oscillations in hippocampal slices prepared from APP/PSEN1 double TG mice (males only) at 6 and 9 months post-irradiation. Our electrophysiological recordings indicate that most of the radiation-induced synaptic decrements can be observed at 9 months rather than 6 months post-irradiation and they are differently expressed in TG and wild-type (WT) mice. Presynaptic excitability evaluated by the amplitude of fiber volleys was significantly increased in non-irradiated TG mice when compared with non-irradiated WT mice, and irradiation did not cause further alterations. The post-synaptic, dendritic excitability, evaluated by the initial slope of the excitatory post-synaptic potentials (EPSPs), was reduced in TG mice exposed to 0.5 Gy, but increased relative to WT mice at the same dose. Interestingly, the suppressive effect on EPSP in TG mice was not observed at 1 Gy. Post-synaptic firing of action potentials, evaluated by the amplitude of population spikes (PS), was increased in non-irradiated TG mice when compared with WT controls. However, these increases

  11. Protective effect of tangeritin in transgenic Drosophila model of Parkinson's disease.

    PubMed

    Fatima, Ambreen; Khanam, Saba; Rahul, Rahul; Jyoti, Smita; Naz, Falaq; Ali, Fahad; Siddique, Yasir Hasan

    2017-01-01

    Parkinson's disease (PD) is a neurodegenerative disorder caused due to the loss of dopaminergic neurons in substantia nigra region of midbrain. The disease is characterized by the accumulation of alpha-synuclein into depositions known as lewy bodies. Till date there is no cure for PD but the limited number of medications may provide temporary relief from the PD symptoms. Flavonoids are a group of polyphenols found in plants. The health benefits of flavonoids have been universally accepted. Tangeritin is a pentamethoxy flavone found in the peels of Mandarin oranges (Citrus reticulata). The present study was conducted to study the effect of tangeritin on the symptoms of PD exhibited by the PD model transgenic flies (Drosophila melanogaster). Tangeritin at a final concentration of 5, 10 and 20 microM was added to the diet and the flies were allowed to feed on it for 24 days. At the same time other set of PD flies were allowed to feed on a diet having 10-3 M of L-Dopa. The effect of tangeritin was studied on the activity pattern, climbing ability, dopamine content, oxidative stress markers (lipid peroxidation, reduced glutathione, glutathione-S-transferase, protein carbonyl content and monoamine oxidase activity) and on the histopathology of the brain of PD model flies. The study showed that the exposure of PD flies to different doses of tangeritin showed a marked delay in the loss of climbing ability and increase in the dopamine content. Tangeritin also showed a reduction in various oxidative stress markers. Hence it is concluded that tangeritin showed a marked reduction in the PD symptoms and thus could be of great importance for further research in treating PD.

  12. A Transgenic Drosophila melanogaster Model To Study Human T-Lymphotropic Virus Oncoprotein Tax-1-Driven Transformation In Vivo.

    PubMed

    Shirinian, Margret; Kambris, Zakaria; Hamadeh, Lama; Grabbe, Caroline; Journo, Chloé; Mahieux, Renaud; Bazarbachi, Ali

    2015-08-01

    Human T-cell lymphotropic virus type 1 (HTLV-1)-induced adult T-cell leukemia/lymphoma is an aggressive malignancy. HTLV-2 is genetically related to HTLV-1 but does not cause any malignant disease. HTLV-1 Tax transactivator (Tax-1) contributes to leukemogenesis via NF-κB. We describe transgenic Drosophila models expressing Tax in the compound eye and plasmatocytes. We demonstrate that Tax-1 but not Tax-2 induces ommatidial perturbation and increased plasmatocyte proliferation and that the eye phenotype is dependent on Kenny (IKKγ/NEMO), thus validating this new in vivo model.

  13. Tip60 HAT activity mediates APP induced lethality and apoptotic cell death in the CNS of a Drosophila Alzheimer's disease model.

    PubMed

    Pirooznia, Sheila K; Sarthi, Jessica; Johnson, Ashley A; Toth, Meridith S; Chiu, Kellie; Koduri, Sravanthi; Elefant, Felice

    2012-01-01

    Histone acetylation of chromatin promotes dynamic transcriptional responses in neurons that influence neuroplasticity critical for cognitive ability. It has been demonstrated that Tip60 histone acetyltransferase (HAT) activity is involved in the transcriptional regulation of genes enriched for neuronal function as well as the control of synaptic plasticity. Accordingly, Tip60 has been implicated in the neurodegenerative disorder Alzheimer's disease (AD) via transcriptional regulatory complex formation with the AD linked amyloid precursor protein (APP) intracellular domain (AICD). As such, inappropriate complex formation may contribute to AD-linked neurodegeneration by misregulation of target genes involved in neurogenesis; however, a direct and causative epigenetic based role for Tip60 HAT activity in this process during neuronal development in vivo remains unclear. Here, we demonstrate that nervous system specific loss of Tip60 HAT activity enhances APP mediated lethality and neuronal apoptotic cell death in the central nervous system (CNS) of a transgenic AD fly model while remarkably, overexpression of Tip60 diminishes these defects. Notably, all of these effects are dependent upon the C-terminus of APP that is required for transcriptional regulatory complex formation with Tip60. Importantly, we show that the expression of certain AD linked Tip60 gene targets critical for regulating apoptotic pathways are modified in the presence of APP. Our results are the first to demonstrate a functional interaction between Tip60 and APP in mediating nervous system development and apoptotic neuronal cell death in the CNS of an AD fly model in vivo, and support a novel neuroprotective role for Tip60 HAT activity in AD neurodegenerative pathology.

  14. Antagonist of peroxisome proliferator-activated receptor {gamma} induces cerebellar amyloid-{beta} levels and motor dysfunction in APP/PS1 transgenic mice

    SciTech Connect

    Du, Jing; Sun, Bing; Chen, Kui; Fan, Li; Wang, Zhao

    2009-07-03

    Recent evidences show that peroxisome proliferator-activated receptor {gamma} (PPAR{gamma}) is involved in the modulation of the amyloid-{beta} (A{beta}) cascade causing Alzheimer's disease (AD) and treatment with PPAR{gamma} agonists protects against AD pathology. However, the function of PPAR{gamma} steady-state activity in A{beta} cascade and AD pathology remains unclear. In this study, an antagonist of PPAR{gamma}, GW9662, was injected into the fourth ventricle of APP/PS1 transgenic mice to inhibit PPAR{gamma} activity in cerebellum. The results show that inhibition of PPAR{gamma} significantly induced A{beta} levels in cerebellum and caused cerebellar motor dysfunction in APP/PS1 transgenic mice. Moreover, GW9662 treatment markedly decreased the cerebellar levels of insulin-degrading enzyme (IDE), which is responsible for the cellular degradation of A{beta}. Since cerebellum is spared from significant A{beta} accumulation and neurotoxicity in AD patients and animal models, these findings suggest a crucial role of PPAR{gamma} steady-state activity in protection of cerebellum against AD pathology.

  15. Neural stem cell transplants improve cognitive function without altering amyloid pathology in an APP/PS1 double transgenic model of Alzheimer's disease.

    PubMed

    Zhang, Wei; Wang, Pei-Jun; Sha, Hong-ying; Ni, Jiong; Li, Ming-hua; Gu, Guo-jun

    2014-10-01

    Neural stem cells (NSCs) are capable of self-renewal and are multipotent. Transplantation of NSCs may represent a promising approach for treating neurodegenerative disorders associated with cognitive decline, such as Alzheimer disease (AD) characterized by extensive loss of neurons. In this study, we investigated the effect of NSC transplantation on cognitive function in the amyloid precursor protein/presenilin-1 (APP/PS1) transgenic mouse, an AD mouse model with age-dependent cognitive deficits. We found that NSCs bilaterally transplanted into hippocampal regions improved spatial learning and memory function in these mice, but did not alter Aβ pathology. Immunohistochemical analyses determined that NSCs proliferated, migrated, and differentiated into three neuronal cell types. The improvement in cognitive function was correlated with enhanced long-term potentiation (LTP) and an increase in the neuron expression of proteins related to cognitive function: N-methyl-D-aspartate (NMDA) 2B unit, synaptophysin (SYP), protein kinase C ζ subtypes (PKCζ), tyrosine receptor kinase B (TrkB), and brain-derived neurotrophic factor (BDNF). Taken together, our data indicated that injected NSCs can rescue cognitive deficits in APP/PS1 transgenic mice by replacing neuronal cell types expressing multiple cognition-related proteins that enhance LTP.

  16. Downregulation of PI3K/Akt/mTOR signaling pathway in curcumin-induced autophagy in APP/PS1 double transgenic mice.

    PubMed

    Wang, Chen; Zhang, Xiong; Teng, Zhipeng; Zhang, Tong; Li, Yu

    2014-10-05

    Autophagy is a lysosomal degradation pathway, which is essential for cell survival, proliferation, differentiation and homeostasis. It is well known that beta-amyloid (Aβ) aggregation is one of key characteristics for Alzheimer's disease (AD), which triggers a complex pathological cascade, leading to neurodegeneration. Recent studies have shown that Aβ peptide is generated from amyloid β precursor protein (APP) during autophagic turnover of APP-rich organelles by autophagy. Aβ generation during normal autophagy is subsequently degraded by lysosomes. Curcumin, a nature plant extraction, has been reported to inhibit the generation and deposition of Aβ; however, the underlying mechanisms are not fully understood yet. In the present study, we reported that curcumin treatment not only attenuated cognitive impairment detected by Morris water maze test, but also inhibited the generation of Aβ investigated by immunohistochemistry in APP/PS1 double transgenic AD mice. Moreover, curcumin induced autophagy in the mice, evidenced by LC3 immunofluorescence analysis and western blot assays on LC3. Furthermore, we found that curcumin significantly decreased the expression of Phosphatidylinositol 3-Kinase (PI3K), phosphorylated Akt and rapamycin (mTOR) at protein levels, respectively. Taken together, our data suggests that curcumin inhibits Aβ generation and induces of autophagy by downregulating PI3K/Akt/mTOR signaling pathway, and further shows a neuroprotective effect. Meanwhile curcumin might be a candidate neuroprotective agent for AD patients treatment by inducing autophagy.

  17. Treadmill exercise enhances synaptic plasticity, but does not alter β-amyloid deposition in hippocampi of aged APP/PS1 transgenic mice.

    PubMed

    Zhao, G; Liu, H L; Zhang, H; Tong, X J

    2015-07-09

    Several studies reveal that the beneficial effects of exercise interventions are dependent on the progression of Alzheimer's disease (AD). We have previously shown that long-term treadmill exercise begun before the onset of β-amyloid (Aβ) pathology prevents the deficits of cognition and long-term potentiation (LTP) in amyloid precursor protein (APP)/presenilin 1 (PS1) transgenic mice (8 months of age) paralleled by the reduction of soluble Aβ levels and Aβ deposition in the hippocampus. In the present study, treadmill exercise was initiated at a developed Aβ deposition stage in order to further investigate whether or not treadmill exercise in this phase can delay the progression of AD in aged APP/PS1 mice (17 months of age). Our results show that 5-month treadmill exercise ameliorates the impairment of spatial learning and memory with age paralleled by synaptic plasticity enhancement in aged APP/PS1 mice. In addition, exercise-induced enhancement of synaptic plasticity was accompanied by a significant reduction of soluble Aβ levels rather than Aβ plaque deposition. Therefore, the investigation demonstrates that long-term treadmill exercise has beneficial effects on cognition and synaptic plasticity even when the brain has developed Aβ deposition, and changes in soluble Aβ levels rather than Aβ plaque deposition may contribute to exercise-induced benefits.

  18. Genetic deletion of TNFRII gene enhances the Alzheimer-like pathology in an APP transgenic mouse model via reduction of phosphorylated IκBα.

    PubMed

    Jiang, Hong; He, Ping; Xie, Junxia; Staufenbiel, Matthias; Li, Rena; Shen, Yong

    2014-09-15

    Tumor necrosis factor receptor II (TNFRII) is one of the TNF receptor superfamily members and our recent pathological studies show that TNFRII is deficient in the brains of Alzheimer's disease (AD). However, the mechanisms of TNFRII in AD pathogenesis remain unclear. In the present study, by using the gene-targeting approach to delete TNFRII in AD transgenic mouse model, we found that, in the brain of APP23 mice with TNFRII deletion (APP23/TNFRII(-/-)), AD-like pathology, i.e. plaque formation and microglial activation, occurs as early as 6 months of age. To test whether the increased levels of Aβ plaques was due to elevated Aβ, we measured Aβ and found that Aβ levels indeed were significantly increased at this age. Because β-secretase, BACE1, is critical enzyme for Aβ production, we have examined BACE1 and found that BACE1 is increased in both protein levels and enzymatic activity as early as 6 months of age; Having shown that BACE1 promoter region contains NF-κB binding sites, we found that cytoplasmic NF-κB was elevated and SUMO1 binding to IκBα was decreased. To further verify these findings, we have overexpressed TNFRII and identified that overexpressing TNFRII can reverse the findings from APP23/TNFRII(-/-) mice. Altogether, our results demonstrate novel roles of TNFRII in the regulation of Aβ production, suggesting a potential therapeutic strategy for AD by up-regulating TNFRII levels and elevating phosphorylated IκBα by SUMOylation.

  19. β-asarone improves learning and memory and reduces Acetyl Cholinesterase and Beta-amyloid 42 levels in APP/PS1 transgenic mice by regulating Beclin-1-dependent autophagy.

    PubMed

    Deng, Minzhen; Huang, Liping; Ning, Baile; Wang, Nanbu; Zhang, Qinxin; Zhu, Caixia; Fang, Yongqi

    2016-12-01

    Alzheimer's disease (AD) is the most common neurodegenerative disorder in the elderly, and studies have suggested that β-asarone has pharmacological effects on beta-amyloid (Aβ) injected in the rat hippocampus. However, the effect of β-asarone on autophagy in the APP/PS1 transgenic mouse is unreported. APP/PS1 transgenic mice were randomly divided into six groups (n=10/group): an untreated group, an Aricept-treated group, a 3-MA-treated group, a rapamycin-treated group, an LY294002-treated group, a β-asarone-treated group. The control group consisted of wild-type C57BL/6 mice. All treatments were administered to the mice for 30 days. Spatial learning and memory were assessed by water maze, passive avoidance, and step-down tests. AChE and Aβ42 levels in the hippocampus were determined by ELISA. p-Akt, p-mTOR, and LC3B expression were detected by flow cytometry. The expression of p-Akt, p-mTOR, Beclin-1, and p62 proteins was assessed by western blot. Changes in autophagy were viewed using a transmission electron microscope. APP and Beclin-1 mRNA levels were measured by Real-Time PCR. The learning and memory of APP/PS1 transgenic mice were improved significantly after β-asarone treatment compared with the untreated group. In addition, β-asarone treatment reduced AChE and Aβ42 levels, increased p-mTOR and p62 expression, decreased p-Akt, Beclin-1, and LC3B expression, decreased the number of autophagosomes and reduced APP mRNA and Beclin-1 mRNA levels compared with the untreated group. That is, β-asarone treatment can improve the learning and memory abilities of APP/PS1 transgenic mouse by inhibiting Beclin-1-dependent autophagy via the PI3K/Akt/mTOR pathway.

  20. L-theanine protects the APP (Swedish mutation) transgenic SH-SY5Y cell against glutamate-induced excitotoxicity via inhibition of the NMDA receptor pathway.

    PubMed

    Di, X; Yan, J; Zhao, Y; Zhang, J; Shi, Z; Chang, Y; Zhao, B

    2010-07-14

    As a natural analogue of glutamate, l-theanine is the unique amino acid derivative in green tea. Although its underlining mechanisms are not yet clear, it has been suggested that l-theanine treatment may prove beneficial to patients with neurodegenerative diseases. In this study, we investigated the neuroprotective effect and its mechanism of l-theanine in an in vitro model of Alzheimer's disease by using the human APP (Swedish mutation) transgenic SH-SY5Y cell. Amyloid beta (Abeta) neurotoxicity was triggered by l-glutamate in this cell line. Additionally, l-theanine significantly attenuated l-glutamate-induced apoptosis at similar levels to those seen with the NMDA receptor inhibitor MK-801 in the stably expressing APP Swedish mutation SH-SY5Y cells which over-generated Abeta. Meanwhile, the activation of c-Jun N-terminal kinase and caspase-3 induced by l-glutamate was suppressed by l-theanine. We also found that cells treated with l-theanine showed decreased production of nitric oxide resulting from the down-regulated protein levels of inducible nitric oxide synthase (iNOS) and neuronal nitric oxide synthase (nNOS). These results indicate that the inhibition of the NMDA subtype of glutamate receptors and its related pathways is the crucial point of the neuroprotective effect of l-theanine in the cell model. Thus, our present study supports the notion that l-theanine may provide effective prophylaxis and treatment for Alzheimer's disease.

  1. Neurofilament light gene deletion exacerbates amyloid, dystrophic neurite, and synaptic pathology in the APP/PS1 transgenic model of Alzheimer's disease.

    PubMed

    Fernandez-Martos, Carmen M; King, Anna E; Atkinson, Rachel A K; Woodhouse, Adele; Vickers, James C

    2015-10-01

    Alzheimer's disease (AD) is a progressive neurodegenerative disease associated with the loss of cognitive function. Neurofilament (NF) triplet proteins, the major structural (intermediate filament) proteins of neurons, are expressed in a subset of pyramidal cells that show a high degree of vulnerability to degeneration in AD. Alterations in the NF triplet proteins in amyloid-beta (Aβ) plaque-associated dystrophic neurites (DNs) represent the first cytoskeletal aberration to occur in the neocortex in the earliest stages of AD. We generated transgenic APP/PS1 (APPswe/PSEN1dE9) mice on the neurofilament light knockout (NFL KO) background to explore the role of NFL deletion in the context of DN formation, synaptic changes, and other neuropathologic features. Our analysis demonstrated that NFL deficiency significantly increased neocortical DN pathology, Aβ deposition, synapse vulnerability, and microgliosis in APP/PS1 mice. Thus, NFs may have a role in protecting neurites from dystrophy and in regulating cellular pathways related to the generation of Aβ plaques.

  2. Cis- and trans-acting influences on telomeric position effect in Drosophila melanogaster detected with a subterminal transgene.

    PubMed Central

    Mason, James M; Konev, Alexander Y; Golubovsky, Mikhail D; Biessmann, Harald

    2003-01-01

    One model of telomeric position effect (TPE) in Drosophila melanogaster proposes that reporter genes in the vicinity of telomeres are repressed by subterminal telomere-associated sequences (TAS) and that variegation of these genes is the result of competition between the repressive effects of TAS and the stimulating effects of promoters in the terminal HeT-A transposon array. The data presented here support this model, but also suggest that TPE is more complex. Activity of a telomeric white reporter gene increases in response to deletion of some or all of the TAS on the homolog. Only transgenes next to fairly long HeT-A arrays respond to this trans-interaction. HeT-A arrays of 6-18 kb respond by increasing the number of dark spots on the eye, while longer arrays increase the background eye color or increase the number of spots sufficiently to cause them to merge. Thus, expression of a subtelomeric reporter gene is influenced by the telomere structure in cis and trans. We propose that the forces involved in telomere length regulation in Drosophila are the underlying forces that manifest themselves as TPE. In the wild-type telomere TAS may play an important role in controlling telomere elongation by repressing HeT-A promoter activity. Modulation of this repression by the homolog may thus regulate telomere elongation. PMID:12663532

  3. Variation in meiotic recombination frequencies between allelic transgenes inserted at different sites in the Drosophila melanogaster genome.

    PubMed

    McMahan, Susan; Kohl, Kathryn P; Sekelsky, Jeff

    2013-08-07

    Meiotic crossovers are distributed nonrandomly across the genome. Classic studies in Drosophila suggest that the position of a gene along a chromosome arm can affect the outcome of the recombination process, with proximity to the centromere being associated with lower crossing over. To examine this phenomenon molecularly, we developed an assay that measures meiotic crossovers and noncrossover gene conversions between allelic transgenes inserted into different genomic positions. To facilitate collecting a large number of virgin females, we developed a useful genetic system that kills males and undesired classes of females. We found that the recombination frequency at a site in the middle of the X chromosome, where crossovers are normally frequent, was similar to the frequency at the centromere-proximal end of the euchromatin, where crossovers are normally infrequent. In contrast, we recovered no recombinants--crossovers or noncrossovers--at a site on chromosome 4 and at a site toward the distal end of the X chromosome. These results suggest that local sequence or chromatin features have a stronger impact on recombination rates in this transgene assay than position along the chromosome arm.

  4. Non-Mendelian Dominant Maternal Effects Caused by CRISPR/Cas9 Transgenic Components in Drosophila melanogaster

    PubMed Central

    Lin, Chun-Chieh; Potter, Christopher J.

    2016-01-01

    The CRISPR/Cas9 system has revolutionized genomic editing. The Cas9 endonuclease targets DNA via an experimentally determined guide RNA (gRNA). This results in a double-strand break at the target site . We generated transgenic Drosophila melanogaster in which the CRISPR/Cas9 system was used to target a GAL4 transgene in vivo. To our surprise, progeny whose genomes did not contain CRISPR/Cas9 components were still capable of mutating GAL4 sequences. We demonstrate this effect was caused by maternal deposition of Cas9 and gRNAs into the embryo, leading to extensive GAL4 mutations in both somatic and germline tissues. This serves as a cautionary observation on the effects of maternal contributions when conducting experiments using genomically encoded CRISPR/Cas9 components. These results also highlight a mode of artificial inheritance in which maternal contributions of DNA editing components lead to transmissible mutant defects even in animals whose genomes lack the editing components. We suggest calling this a dominant maternal effect to reflect it is caused by the gain of maternally contributed products. Models of CRISPR-mediated gene drive will need to incorporate dominant maternal effects in order to accurately predict the efficiency and dynamics of gene drive in a population. PMID:27638686

  5. Effects of harmine, an acetylcholinesterase inhibitor, on spatial learning and memory of APP/PS1 transgenic mice and scopolamine-induced memory impairment mice.

    PubMed

    He, Dandan; Wu, Hui; Wei, Yue; Liu, Wei; Huang, Fei; Shi, Hailian; Zhang, Beibei; Wu, Xiaojun; Wang, Changhong

    2015-12-05

    Harmine, a β-carboline alkaloid present in Peganum harmala with a wide spectrum of pharmacological activities, has been shown to exert strong inhibition against acetylcholinesterase in vitro. However, whether it can rescue the impaired cognition has not been elucidated yet. In current study, we examined its effects on scopolamine-induced memory impairment mice and APP/PS1 transgenic mice, one of the models for Alzheimer's disease, using Morris Water Maze test. In addition, whether harmine could penetrate blood brain barrier, interact with and inhibit acetylcholinesterase, and activate downstream signaling network was also investigated. Our results showed that harmine (20mg/kg) administered by oral gavage for 2 weeks could effectively enhance the spatial cognition of C57BL/6 mice impaired by intraperitoneal injection of scopolamine (1mg/kg). Meanwhile, long-term consumption of harmine (20mg/kg) for 10 weeks also slightly benefited the impaired memory of APP/PS1 mice. Furthermore, harmine could pass through blood brain barrier, penetrate into the brain parenchyma shortly after oral administration, and modulate the expression of Egr-1, c-Jun and c-Fos. Molecular docking assay disclosed that harmine molecule could directly dock into the catalytic active site of acetylcholinesterase, which was partially confirmed by its in vivo inhibitory activity on acetylcholinesterase. Taken together, all these results suggested that harmine could ameliorate impaired memory by enhancement of cholinergic neurotransmission via inhibiting the activity of acetylcholinesterase, which may contribute to its clinical use in the therapy of neurological diseases characterized with acetylcholinesterase deficiency.

  6. Complex interplay between brain function and structure during cerebral amyloidosis in APP transgenic mouse strains revealed by multi-parametric MRI comparison.

    PubMed

    Grandjean, Joanes; Derungs, Rebecca; Kulic, Luka; Welt, Tobias; Henkelman, Mark; Nitsch, Roger M; Rudin, Markus

    2016-07-01

    Alzheimer's disease is a fatal neurodegenerative disorder affecting the aging population. Neuroimaging methods, in particular magnetic resonance imaging (MRI), have helped reveal alterations in the brain structure, metabolism, and function of patients and in groups at risk of developing AD, yet the nature of these alterations is poorly understood. Neuroimaging in mice is attractive for investigating mechanisms underlying functional and structural changes associated with AD pathology. Several preclinical murine models of AD have been generated based on transgenic insertion of human mutated APP genes. Depending on the specific mutations, mouse strains express different aspects of amyloid pathology, e.g. intracellular amyloid-β (Aβ) aggregates, parenchymal plaques, or cerebral amyloid angiopathy. We have applied multi-parametric MRI in three transgenic mouse lines to compare changes in brain function with resting-state fMRI and structure with diffusion tensor imaging and high resolution anatomical imaging. E22ΔAβ developing intracellular Aβ aggregates did not present functional or structural alterations compared to their wild-type littermates. PSAPP mice displaying parenchymal amyloid plaques displayed mild functional changes within the supplementary and barrel field cortices, and increased isocortical volume relative to controls. Extensive reduction in functional connectivity in the sensory-motor cortices and within the default mode network, as well as local volume increase in the midbrain relative to wild-type have been observed in ArcAβ mice bearing intracellular Aβ aggregates as well as parenchymal and vascular amyloid deposits. Patterns of functional and structural changes appear to be strain-specific and not directly related to amyloid deposition.

  7. Transgenic Drosophila for Investigating DUX4 and FRG1, Two Genes Associated with Facioscapulohumeral Muscular Dystrophy (FSHD)

    PubMed Central

    Jones, Takako I.; Parilla, Megan; Jones, Peter L.

    2016-01-01

    Facioscapulohumeral muscular dystrophy (FSHD) is typically an adult onset dominant myopathy. Epigenetic changes in the chromosome 4q35 region linked to both forms of FSHD lead to a relaxation of repression and increased somatic expression of DUX4-fl (DUX4-full length), the pathogenic alternative splicing isoform of the DUX4 gene. DUX4-fl encodes a transcription factor expressed in healthy testis and pluripotent stem cells; however, in FSHD, increased levels of DUX4-fl in myogenic cells lead to aberrant regulation of target genes. DUX4-fl has proven difficult to study in vivo; thus, little is known about its normal and pathogenic roles. The endogenous expression of DUX4-fl in FSHD-derived human muscle and myogenic cells is extremely low, exogenous expression of DUX4-fl in somatic cells rapidly induces cytotoxicity, and, due in part to the lack of conservation beyond primate lineages, viable animal models based on DUX4-fl have been difficult to generate. By contrast, the FRG1 (FSHD region gene 1), which is linked to FSHD, is evolutionarily conserved from invertebrates to humans, and has been studied in several model organisms. FRG1 expression is critical for the development of musculature and vasculature, and overexpression of FRG1 produces a myopathic phenotype, yet the normal and pathological functions of FRG1 are not well understood. Interestingly, DUX4 and FRG1 were recently linked when the latter was identified as a direct transcriptional target of DUX4-FL. To better understand the pathways affected in FSHD by DUX4-fl and FRG1, we generated transgenic lines of Drosophila expressing either gene under control of the UAS/GAL4 binary system. Utilizing these lines, we generated screenable phenotypes recapitulating certain known consequences of DUX4-fl or FRG1 overexpression. These transgenic Drosophila lines provide resources to dissect the pathways affected by DUX4-fl or FRG1 in a genetically tractable organism and may provide insight into both muscle development

  8. Transgenic Drosophila for Investigating DUX4 and FRG1, Two Genes Associated with Facioscapulohumeral Muscular Dystrophy (FSHD).

    PubMed

    Jones, Takako I; Parilla, Megan; Jones, Peter L

    2016-01-01

    Facioscapulohumeral muscular dystrophy (FSHD) is typically an adult onset dominant myopathy. Epigenetic changes in the chromosome 4q35 region linked to both forms of FSHD lead to a relaxation of repression and increased somatic expression of DUX4-fl (DUX4-full length), the pathogenic alternative splicing isoform of the DUX4 gene. DUX4-fl encodes a transcription factor expressed in healthy testis and pluripotent stem cells; however, in FSHD, increased levels of DUX4-fl in myogenic cells lead to aberrant regulation of target genes. DUX4-fl has proven difficult to study in vivo; thus, little is known about its normal and pathogenic roles. The endogenous expression of DUX4-fl in FSHD-derived human muscle and myogenic cells is extremely low, exogenous expression of DUX4-fl in somatic cells rapidly induces cytotoxicity, and, due in part to the lack of conservation beyond primate lineages, viable animal models based on DUX4-fl have been difficult to generate. By contrast, the FRG1 (FSHD region gene 1), which is linked to FSHD, is evolutionarily conserved from invertebrates to humans, and has been studied in several model organisms. FRG1 expression is critical for the development of musculature and vasculature, and overexpression of FRG1 produces a myopathic phenotype, yet the normal and pathological functions of FRG1 are not well understood. Interestingly, DUX4 and FRG1 were recently linked when the latter was identified as a direct transcriptional target of DUX4-FL. To better understand the pathways affected in FSHD by DUX4-fl and FRG1, we generated transgenic lines of Drosophila expressing either gene under control of the UAS/GAL4 binary system. Utilizing these lines, we generated screenable phenotypes recapitulating certain known consequences of DUX4-fl or FRG1 overexpression. These transgenic Drosophila lines provide resources to dissect the pathways affected by DUX4-fl or FRG1 in a genetically tractable organism and may provide insight into both muscle development

  9. Region-specific metabolic alterations in the brain of the APP/PS1 transgenic mice of Alzheimer's disease.

    PubMed

    González-Domínguez, Raúl; García-Barrera, Tamara; Vitorica, Javier; Gómez-Ariza, José Luis

    2014-12-01

    Alzheimer's disease (AD) is the most common neurodegenerative disorder worldwide, but its etiology is still not completely understood. The identification of underlying pathological mechanisms is becoming increasingly important for the discovery of biomarkers and therapies, for which metabolomics presents a great potential. In this work, we studied metabolic alterations in different brain regions of the APP/PS1 mice by using a high-throughput metabolomic approach based on the combination of gas chromatography-mass spectrometry and ultra-high performance liquid chromatography-mass spectrometry. Multivariate statistics showed that metabolomic perturbations are widespread, affecting mainly the hippocampus and the cortex, but are also present in regions not primarily associated with AD such as the striatum, cerebellum and olfactory bulbs. Multiple metabolic pathways could be linked to the development of AD-type disorders in this mouse model, including abnormal purine metabolism, bioenergetic failures, dyshomeostasis of amino acids and disturbances in membrane lipids, among others. Interestingly, region-specific alterations were observed for some of the potential markers identified, associated with abnormal fatty acid composition of phospholipids and sphingomyelins, or differential regulation of neurotransmitter amino acids (e.g. glutamate, glycine, serine, N-acetyl-aspartate), not previously described to our knowledge. Therefore, these findings could provide a new insight into brain pathology in Alzheimer's disease.

  10. Noninvasive magnetic resonance imaging detection of cerebral amyloid angiopathy-related microvascular alterations using superparamagnetic iron oxide particles in APP transgenic mouse models of Alzheimer's disease: application to passive Abeta immunotherapy.

    PubMed

    Beckmann, Nicolau; Gérard, Christelle; Abramowski, Dorothée; Cannet, Catherine; Staufenbiel, Matthias

    2011-01-19

    Cerebral amyloid angiopathy (CAA) is a common feature of Alzheimer's disease (AD). More advanced stages are accompanied by microhemorrhages and vasculitis. Peripheral blood-borne macrophages are intimately linked to cerebrovascular pathology coincident with AD. Magnetic resonance imaging (MRI) was used to noninvasively study microvascular lesions in amyloid precursor protein transgenic mouse AD models. Foci of signal attenuation were detected in cortical and thalamic brain regions of aged APP23 mice. Their strength and number was considerably enhanced by intravenous administration of iron oxide nanoparticles, which are taken up by macrophages through absorptive endocytosis, 24 h before image acquisition. The number of cortical sites displaying signal attenuation increased with age. Histology at these sites demonstrated the presence of iron-containing macrophages in the vicinity of CAA-affected blood vessels. A fraction of the sites additionally showed thickened vessel walls and vasculitis. Consistent with the visualization of CAA-associated lesions, MRI detected a much smaller number of attenuated signal sites in APP23xPS45 mice, for which a strong presenilin mutation caused a shift toward amyloid β(42), thus reducing vascular amyloid. Similar results were obtained with APP24 and APP51 mice, which develop significantly less CAA and microvascular pathology than APP23. In a longitudinal study, we noninvasively demonstrated the reinforced formation of microvascular pathology during passive amyloid β immunotherapy of APP23 mice. Histology confirmed that foci of signal attenuation reflected an increase in CAA-related lesions. Our data demonstrate that MRI has the sensitivity to noninvasively monitor the development of vascular pathology and its possible enhancement by amyloid β immunotherapy in transgenic mice modeling AD.

  11. The Differences Between Cis- and Trans-Gene Inactivation Caused by Heterochromatin in Drosophila.

    PubMed

    Abramov, Yuriy A; Shatskikh, Aleksei S; Maksimenko, Oksana G; Bonaccorsi, Silvia; Gvozdev, Vladimir A; Lavrov, Sergey A

    2016-01-01

    Position-effect variegation (PEV) is the epigenetic disruption of gene expression near the de novo-formed euchromatin-heterochromatin border. Heterochromatic cis-inactivation may be accompanied by the trans-inactivation of genes on a normal homologous chromosome in trans-heterozygous combination with a PEV-inducing rearrangement. We characterize a new genetic system, inversion In(2)A4, demonstrating cis-acting PEV as well as trans-inactivation of the reporter transgenes on the homologous nonrearranged chromosome. The cis-effect of heterochromatin in the inversion results not only in repression but also in activation of genes, and it varies at different developmental stages. While cis-actions affect only a few juxtaposed genes, trans-inactivation is observed in a 500-kb region and demonstrates а nonuniform pattern of repression with intermingled regions where no transgene repression occurs. There is no repression around the histone gene cluster and in some other euchromatic sites. trans-Inactivation is accompanied by dragging of euchromatic regions into the heterochromatic compartment, but the histone gene cluster, located in the middle of the trans-inactivated region, was shown to be evicted from the heterochromatin. We demonstrate that trans-inactivation is followed by de novo HP1a accumulation in the affected transgene; trans-inactivation is specifically favored by the chromatin remodeler SAYP and prevented by Argonaute AGO2.

  12. The Differences Between Cis- and Trans-Gene Inactivation Caused by Heterochromatin in Drosophila

    PubMed Central

    Abramov, Yuriy A.; Shatskikh, Aleksei S.; Maksimenko, Oksana G.; Bonaccorsi, Silvia; Gvozdev, Vladimir A.; Lavrov, Sergey A.

    2016-01-01

    Position-effect variegation (PEV) is the epigenetic disruption of gene expression near the de novo–formed euchromatin-heterochromatin border. Heterochromatic cis-inactivation may be accompanied by the trans-inactivation of genes on a normal homologous chromosome in trans-heterozygous combination with a PEV-inducing rearrangement. We characterize a new genetic system, inversion In(2)A4, demonstrating cis-acting PEV as well as trans-inactivation of the reporter transgenes on the homologous nonrearranged chromosome. The cis-effect of heterochromatin in the inversion results not only in repression but also in activation of genes, and it varies at different developmental stages. While cis-actions affect only a few juxtaposed genes, trans-inactivation is observed in a 500-kb region and demonstrates а nonuniform pattern of repression with intermingled regions where no transgene repression occurs. There is no repression around the histone gene cluster and in some other euchromatic sites. trans-Inactivation is accompanied by dragging of euchromatic regions into the heterochromatic compartment, but the histone gene cluster, located in the middle of the trans-inactivated region, was shown to be evicted from the heterochromatin. We demonstrate that trans-inactivation is followed by de novo HP1a accumulation in the affected transgene; trans-inactivation is specifically favored by the chromatin remodeler SAYP and prevented by Argonaute AGO2. PMID:26500261

  13. Liraglutide Improves Water Maze Learning and Memory Performance While Reduces Hyperphosphorylation of Tau and Neurofilaments in APP/PS1/Tau Triple Transgenic Mice.

    PubMed

    Chen, Shuyi; Sun, Jie; Zhao, Gang; Guo, Ai; Chen, Yanlin; Fu, Rongxia; Deng, Yanqiu

    2017-04-06

    The purpose of this study was to explore how liraglutide affects AD-like pathology and cognitive function in APP/PS1/Tau triple transgenic (3 × Tg) Alzheimer disease (AD) model mice. Male 3 × Tg mice and C57BL/6 J mice were treated for 8 weeks with liraglutide (300 μg/kg/day, subcutaneous injection) or saline. Levels of phosphorylated tau, neurofilaments (NFs), extracellular signal-regulated kinase (ERK), and c-Jun N-terminal kinase (JNK) in brain tissues were assessed with western blots. Fluoro-Jade-B labeling were applied to detect pathological changes. The Morris water maze (MWM) was used to assess the spatial learning and memory. Liraglutide decreased levels of hyperphosphorylated tau and NFs in 3 × Tg liraglutide-treated (Tg + LIR) mice, increased ERK phosphorylation, and decreased JNK phosphorylation. Liraglutide also decreased the number of degenerative neurons in the hippocampus and cortex of Tg + LIR mice, and shortened their escape latencies and increased their hidden platform crossings in the MWM task. Liraglutide did not significantly affect the animals' body weight (BW) or fasting blood glucose. Liraglutide can reduce hyperphosphorylation of tau and NFs and reduce neuronal degeneration, apparently through alterations in JNK and ERK signaling, which may be related to its positive effects on AD-like learning and memory impairment.

  14. Intranasal deferoxamine attenuates synapse loss via up-regulating the P38/HIF-1α pathway on the brain of APP/PS1 transgenic mice

    PubMed Central

    Guo, Chuang; Zhang, Yu-Xin; Wang, Tao; Zhong, Man-Li; Yang, Zhao-Hui; Hao, Li-Juan; Chai, Rui; Zhang, Shuai

    2015-01-01

    The widely recognized neuroprotective effect of iron chelators is contributed by their ability to prevent reactive oxygen species (ROS) generation via the Fenton reaction, which sequesters redox-active Fe. An additional neuroprotective mechanism of iron-chelating compounds is to regulate the transcriptional activator hypoxia-inducible factor 1α (HIF-1α). In the present study, we observed that intranasal administration of deferoxamine decreased beta-amyloid (Aβ) deposition and rescued synapse loss in the brain of Aβ precursor protein and presenilin-1 (APP/PS1) double transgenic mice. We found that deferoxamine (DFO) up-regulated HIF-1α mRNA expression and its protein level, and further induced the proteins that are encoded from HIF-1-adaptive genes, including transferrin receptor (TFR), divalent metal transporter 1 (DMT1), and brain-derived neurotrophic factor (BDNF). The effects of DFO on the induction and stabilization of HIF-1α were further confirmed in vitro. This was accompanied by a decrease of Fe in the CA3 region of the hippocampus. Western blotting studies revealed that DFO differentially enhanced the phosphorylation of mitogen-activated protein kinase (MAPK)/P38 kinase in vitro and in vivo. The results suggest that the DFO may up-regulate several HIF-1-dependent neuroprotective-adaptive genes in AD via activating P38/HIF-1α pathway, which may serve as important therapeutic targets to the disease. PMID:26082716

  15. Impaired APP activity and altered Tau splicing in embryonic stem cell-derived astrocytes obtained from an APPsw transgenic minipig

    PubMed Central

    Hall, Vanessa J.; Lindblad, Maiken M.; Jakobsen, Jannik E.; Gunnarsson, Anders; Schmidt, Mette; Rasmussen, Mikkel A.; Volke, Daniela; Zuchner, Thole; Hyttel, Poul

    2015-01-01

    ABSTRACT Animal models of familial juvenile onset of Alzheimer's disease (AD) often fail to produce diverse pathological features of the disease by modification of single gene mutations that are responsible for the disease. They can hence be poor models for testing and development of novel drugs. Here, we analyze in vitro-produced stem cells and their derivatives from a large mammalian model of the disease created by overexpression of a single mutant human gene (APPsw). We produced hemizygous and homozygous radial glial-like cells following culture and differentiation of embryonic stem cells (ESCs) isolated from embryos obtained from mated hemizygous minipigs. These cells were confirmed to co-express varying neural markers, including NES, GFAP and BLBP, typical of type one radial glial cells (RGs) from the subgranular zone. These cells had altered expression of CCND1 and NOTCH1 and decreased expression of several ribosomal RNA genes. We found that these cells were able to differentiate into astrocytes upon directed differentiation. The astrocytes produced had decreased α- and β-secretase activity, increased γ-secretase activity and altered splicing of tau. This indicates novel aspects of early onset mechanisms related to cell renewal and function in familial AD astrocytes. These outcomes also highlight that radial glia could be a potentially useful population of cells for drug discovery, and that altered APP expression and altered tau phosphorylation can be detected in an in vitro model of the disease. Finally, it might be possible to use large mammal models to model familial AD by insertion of only a single mutation. PMID:26398935

  16. DNMT3L enables accumulation and inheritance of epimutations in transgenic Drosophila

    PubMed Central

    Basu, Amitava; Tomar, Archana; Dasari, Vasanthi; Mishra, Rakesh Kumar; Khosla, Sanjeev

    2016-01-01

    DNMT3L is an important epigenetic regulator in mammals, integrating DNA methylation and histone modification based epigenetic circuits. Here we show DNMT3L to be a part of the machinery that enables inheritance of epigenetic modifications from one generation to the next. Ectopic expression of DNMT3L in Drosophila, which lacks DNMT3L and its normal interacting partners DNMT3A and DNMT3B, lead to nuclear reprogramming that was gradual and progressive, resulting in melanotic tumors that were observed only when these flies were maintained for five generations. This global gene expression misregulation was accompanied by aberrations in the levels of H3K4me3 and H3K36me3, globally as well as at specific gene promoters. The levels of these epigenetic aberrations (epimutations) also increased progressively across successive generations. The accumulation and inheritance of epimutations across multiple generations recapitulates the important role of DNMT3L in intergenerational epigenetic inheritance in mammals. PMID:26795243

  17. DNMT3L enables accumulation and inheritance of epimutations in transgenic Drosophila.

    PubMed

    Basu, Amitava; Tomar, Archana; Dasari, Vasanthi; Mishra, Rakesh Kumar; Khosla, Sanjeev

    2016-01-22

    DNMT3L is an important epigenetic regulator in mammals, integrating DNA methylation and histone modification based epigenetic circuits. Here we show DNMT3L to be a part of the machinery that enables inheritance of epigenetic modifications from one generation to the next. Ectopic expression of DNMT3L in Drosophila, which lacks DNMT3L and its normal interacting partners DNMT3A and DNMT3B, lead to nuclear reprogramming that was gradual and progressive, resulting in melanotic tumors that were observed only when these flies were maintained for five generations. This global gene expression misregulation was accompanied by aberrations in the levels of H3K4me3 and H3K36me3, globally as well as at specific gene promoters. The levels of these epigenetic aberrations (epimutations) also increased progressively across successive generations. The accumulation and inheritance of epimutations across multiple generations recapitulates the important role of DNMT3L in intergenerational epigenetic inheritance in mammals.

  18. Expression of hsrω-RNAi transgene prior to heat shock specifically compromises accumulation of heat shock-induced Hsp70 in Drosophila melanogaster.

    PubMed

    Singh, Anand K; Lakhotia, Subhash C

    2016-01-01

    A delayed organismic lethality was reported in Drosophila following heat shock when developmentally active and stress-inducible noncoding hsrω-n transcripts were down-regulated during heat shock through hs-GAL4-driven expression of the hsrω-RNAi transgene, despite the characteristic elevation of all heat shock proteins (Hsp), including Hsp70. Here, we show that hsrω-RNAi transgene expression prior to heat shock singularly prevents accumulation of Hsp70 in all larval tissues without affecting transcriptional induction of hsp70 genes and stability of their transcripts. Absence of the stress-induced Hsp70 accumulation was not due to higher levels of Hsc70 in hsrω-RNAi transgene-expressing tissues. Inhibition of proteasomal activity during heat shock restored high levels of the induced Hsp70, suggesting very rapid degradation of the Hsp70 even during the stress when hsrω-RNAi transgene was expressed ahead of heat shock. Unexpectedly, while complete absence of hsrω transcripts in hsrω (66) homozygotes (hsrω-null) did not prevent high accumulation of heat shock-induced Hsp70, hsrω-RNAi transgene expression in hsrω-null background blocked Hsp70 accumulation. Nonspecific RNAi transgene expression did not affect Hsp70 induction. These observations reveal that, under certain conditions, the stress-induced Hsp70 can be selectively and rapidly targeted for proteasomal degradation even during heat shock. In the present case, the selective degradation of Hsp70 does not appear to be due to down-regulation of the hsrω-n transcripts per se; rather, this may be an indirect effect of the expression of hsrω-RNAi transgene whose RNA products may titrate away some RNA-binding proteins which may also be essential for stability of the induced Hsp70.

  19. Behavior of the hobo transposable element with regard to TPE repeats in transgenic lines of Drosophila melanogaster.

    PubMed

    Souames, Sémi; Bazin, Claude; Bonnivard, Eric; Higuet, Dominique

    2003-12-01

    The hobo transposable element of Drosophila melanogaster is known to induce a hybrid dysgenesis syndrome. Moreover it displays a polymorphism of a microsatellite in its coding region: TPE repeats. In European populations, surveys of the distribution of hobo elements with regard to TPE repeats revealed that the 5TPE element is distributed along a frequency gradient, and it is even more frequent than the 3TPE element in Western populations. This suggests that the invasive ability of the hobo elements could be related to the number of TPE repeats they contain. To test this hypothesis we monitored the evolution of 16 lines derived from five initial independent transgenic lines bearing the 3TPE element and/or the 5TPE element. Four lines bearing 5TPE elements and four bearing 3TPE elements were used as a noncompetitive genetic background to compare the evolution of the 5TPE element to that of the 3TPE element. Eight lines bearing both elements provided a competitive genetic context to study potential interactions between these two elements. We studied genetic and molecular aspects of the first 20 generations. At the molecular level, we showed that the 5TPE element is able to spread within the genome at least as efficiently as the 3TPE element. Surprisingly, at the genetic level we found that the 5TPE element is less active than the 3TPE element, and moreover may be able to regulate the activity of the 3TPE element. Our findings suggest that the invasive potential of the 5TPE element could be due not only to its intrinsic transposition capacity but also to a regulatory potential.

  20. Long-Term Treatment with Liraglutide, a Glucagon-Like Peptide-1 (GLP-1) Receptor Agonist, Has No Effect on β-Amyloid Plaque Load in Two Transgenic APP/PS1 Mouse Models of Alzheimer's Disease.

    PubMed

    Hansen, Henrik H; Fabricius, Katrine; Barkholt, Pernille; Kongsbak-Wismann, Pernille; Schlumberger, Chantal; Jelsing, Jacob; Terwel, Dick; Termont, Annelies; Pyke, Charles; Knudsen, Lotte Bjerre; Vrang, Niels

    2016-01-01

    One of the major histopathological hallmarks of Alzheimer's disease (AD) is cerebral deposits of extracellular β-amyloid peptides. Preclinical studies have pointed to glucagon-like peptide 1 (GLP-1) receptors as a potential novel target in the treatment of AD. GLP-1 receptor agonists, including exendin-4 and liraglutide, have been shown to promote plaque-lowering and mnemonic effects of in a number of experimental models of AD. Transgenic mouse models carrying genetic mutations of amyloid protein precursor (APP) and presenilin-1 (PS1) are commonly used to assess the pharmacodynamics of potential amyloidosis-lowering and pro-cognitive compounds. In this study, effects of long-term liraglutide treatment were therefore determined in two double APP/PS1 transgenic mouse models of Alzheimer's disease carrying different clinical APP/PS1 mutations, i.e. the 'London' (hAPPLon/PS1A246E) and 'Swedish' mutation variant (hAPPSwe/PS1ΔE9) of APP, with co-expression of distinct PS1 variants. Liraglutide was administered in 5 month-old hAPPLon/PS1A246E mice for 3 months (100 or 500 ng/kg/day, s.c.), or 7 month-old hAPPSwe/PS1ΔE9 mice for 5 months (500 ng/kg/day, s.c.). In both models, regional plaque load was quantified throughout the brain using stereological methods. Vehicle-dosed hAPPSwe/PS1ΔE9 mice exhibited considerably higher cerebral plaque load than hAPPLon/PS1A246E control mice. Compared to vehicle-dosed transgenic controls, liraglutide treatment had no effect on the plaque levels in hAPPLon/PS1A246E and hAPPSwe/PS1ΔE9 mice. In conclusion, long-term liraglutide treatment exhibited no effect on cerebral plaque load in two transgenic mouse models of low- and high-grade amyloidosis, which suggests differential sensitivity to long-term liraglutide treatment in various transgenic mouse models mimicking distinct pathological hallmarks of AD.

  1. Long-Term Treatment with Liraglutide, a Glucagon-Like Peptide-1 (GLP-1) Receptor Agonist, Has No Effect on β-Amyloid Plaque Load in Two Transgenic APP/PS1 Mouse Models of Alzheimer’s Disease

    PubMed Central

    Barkholt, Pernille; Kongsbak-Wismann, Pernille; Schlumberger, Chantal; Jelsing, Jacob; Terwel, Dick; Termont, Annelies; Pyke, Charles; Knudsen, Lotte Bjerre; Vrang, Niels

    2016-01-01

    One of the major histopathological hallmarks of Alzheimer’s disease (AD) is cerebral deposits of extracellular β-amyloid peptides. Preclinical studies have pointed to glucagon-like peptide 1 (GLP-1) receptors as a potential novel target in the treatment of AD. GLP-1 receptor agonists, including exendin-4 and liraglutide, have been shown to promote plaque-lowering and mnemonic effects of in a number of experimental models of AD. Transgenic mouse models carrying genetic mutations of amyloid protein precursor (APP) and presenilin-1 (PS1) are commonly used to assess the pharmacodynamics of potential amyloidosis-lowering and pro-cognitive compounds. In this study, effects of long-term liraglutide treatment were therefore determined in two double APP/PS1 transgenic mouse models of Alzheimer’s disease carrying different clinical APP/PS1 mutations, i.e. the ‘London’ (hAPPLon/PS1A246E) and ‘Swedish’ mutation variant (hAPPSwe/PS1ΔE9) of APP, with co-expression of distinct PS1 variants. Liraglutide was administered in 5 month-old hAPPLon/PS1A246E mice for 3 months (100 or 500 ng/kg/day, s.c.), or 7 month-old hAPPSwe/PS1ΔE9 mice for 5 months (500 ng/kg/day, s.c.). In both models, regional plaque load was quantified throughout the brain using stereological methods. Vehicle-dosed hAPPSwe/PS1ΔE9 mice exhibited considerably higher cerebral plaque load than hAPPLon/PS1A246E control mice. Compared to vehicle-dosed transgenic controls, liraglutide treatment had no effect on the plaque levels in hAPPLon/PS1A246E and hAPPSwe/PS1ΔE9 mice. In conclusion, long-term liraglutide treatment exhibited no effect on cerebral plaque load in two transgenic mouse models of low- and high-grade amyloidosis, which suggests differential sensitivity to long-term liraglutide treatment in various transgenic mouse models mimicking distinct pathological hallmarks of AD. PMID:27421117

  2. Noggin and BMP4 co-modulate adult hippocampal neurogenesis in the APP{sub swe}/PS1{sub {Delta}E9} transgenic mouse model of Alzheimer's disease

    SciTech Connect

    Tang, Jun; Song, Min; Wang, Yanyan; Fan, Xiaotang; Xu, Haiwei; Bai, Yun

    2009-07-31

    In addition to the subventricular zone, the dentate gyrus of the hippocampus is one of the few brain regions in which neurogenesis continues into adulthood. Perturbation of neurogenesis can alter hippocampal function, and previous studies have shown that neurogenesis is dysregulated in Alzheimer disease (AD) brain. Bone morphogenetic protein-4 (BMP4) and its antagonist Noggin have been shown to play important roles both in embryonic development and in the adult nervous system, and may regulate hippocampal neurogenesis. Previous data indicated that increased expression of BMP4 mRNA within the dentate gyrus might contribute to decreased hippocampal cell proliferation in the APP{sub swe}/PS1{sub {Delta}E9} mouse AD model. However, it is not known whether the BMP antagonist Noggin contributes to the regulation of neurogenesis. We therefore studied the relative expression levels and localization of BMP4 and its antagonist Noggin in the dentate gyrus and whether these correlated with changes in neurogenesis in 6-12 mo old APP{sub swe}/PS1{sub {Delta}E9} transgenic mice. Bromodeoxyuridine (BrdU) was used to label proliferative cells. We report that decreased neurogenesis in the APP/PS1 transgenic mice was accompanied by increased expression of BMP4 and decreased expression of Noggin at both the mRNA and protein levels; statistical analysis showed that the number of proliferative cells at different ages correlated positively with Noggin expression and negatively with BMP4 expression. Intraventricular administration of a chimeric Noggin/Fc protein was used to block the action of endogenous BMP4; this resulted in a significant increase in the number of BrdU-labeled cells in dentate gyrus subgranular zone and hilus in APP/PS1 mice. These results suggest that BMP4 and Noggin co-modulate neurogenesis.

  3. Overexpression of a Rrp1 transgene reduces the somatic mutation and recombination frequency induced by oxidative DNA damage in Drosophila melanogaster.

    PubMed

    Szakmary, A; Huang, S M; Chang, D T; Beachy, P A; Sander, M

    1996-02-20

    Recombination repair protein 1 (Rrp1) includes a C-terminal region homologous to several DNA repair proteins, including Escherichia coli exonuclease III and human APE, that repair oxidative and alkylation damage to DNA. The nuclease activities of Rrp1 include apurinic/apyrimidinic endonuclease, 3'-phosphodiesterase, 3'-phosphatase, and 3'-exonuclease. As shown previously, the C-terminal nuclease region of Rrp1 is sufficient to repair oxidative- and alkylation-induced DNA damage in repair-deficient E. coli mutants. DNA strand-transfer and single-stranded DNA renaturation activities are associated with the unique N-terminal region of Rrp1, which suggests possible additional functions that include recombinational repair or homologous recombination. By using the Drosophila w/w+ mosaic eye system, which detects loss of heterozygosity as changes in eye pigmentation, somatic mutation and recombination frequencies were determined in transgenic flies overexpressing wild-type Rrp1 protein from a heat-shock-inducible transgene. A large decrease in mosaic clone frequency is observed when Rrp1 overexpression precedes treatment with gamma-rays, bleomycin, or paraquat. In contrast, Rrp1 overexpression does not alter the spot frequency after treatment with the alkylating agents methyl methanesulfonate or methyl nitrosourea. A reduction in mosaic clone frequency depends on the expression of the Rrp1 transgene and on the nature of the induced DNA damage. These data suggest a lesion-specific involvement of Rrp1 in the repair of oxidative DNA damage.

  4. Early-Onset Network Hyperexcitability in Presymptomatic Alzheimer’s Disease Transgenic Mice Is Suppressed by Passive Immunization with Anti-Human APP/Aβ Antibody and by mGluR5 Blockade

    PubMed Central

    Kazim, Syed F.; Chuang, Shih-Chieh; Zhao, Wangfa; Wong, Robert K. S.; Bianchi, Riccardo; Iqbal, Khalid

    2017-01-01

    Cortical and hippocampal network hyperexcitability appears to be an early event in Alzheimer’s disease (AD) pathogenesis, and may contribute to memory impairment. It remains unclear if network hyperexcitability precedes memory impairment in mouse models of AD and what are the underlying cellular mechanisms. We thus evaluated seizure susceptibility and hippocampal network hyperexcitability at ~3 weeks of age [prior to amyloid beta (Aβ) plaque deposition, neurofibrillary pathology, and cognitive impairment] in a triple transgenic mouse model of familial AD (3xTg-AD mouse) that harbors mutated human Aβ precursor protein (APP), tau and presenilin 1 (PS1) genes. Audiogenic seizures were elicited in a higher proportion of 3xTg-AD mice compared with wild type (WT) controls. Seizure susceptibility in 3xTg-AD mice was attenuated either by passive immunization with anti-human APP/Aβ antibody (6E10) or by blockade of metabotropic glutamate receptor 5 (mGluR5) with the selective antagonist, 2-methyl-6-(phenylethynyl)pyridine hydrochloride (MPEP). In in vitro hippocampal slices, suppression of synaptic inhibition with the GABAA receptor antagonist, bicuculline, induced prolonged epileptiform (>1.5 s in duration) ictal-like discharges in the CA3 neuronal network in the majority of the slices from 3xTg-AD mice. In contrast, only short epileptiform (<1.5 s in duration) interictal-like discharges were observed following bicuculline application in the CA3 region of WT slices. The ictal-like activity in CA3 region of the hippocampus was significantly reduced in the 6E10-immunized compared to the saline-treated 3xTg-AD mice. MPEP acutely suppressed the ictal-like discharges in 3xTg-AD slices. Remarkably, epileptiform discharge duration positively correlated with intraneuronal human (transgenic) APP/Aβ expression in the CA3 region of the hippocampus. Our data suggest that in a mouse model of familial AD, hypersynchronous network activity underlying seizure susceptibility precedes

  5. Early-Onset Network Hyperexcitability in Presymptomatic Alzheimer's Disease Transgenic Mice Is Suppressed by Passive Immunization with Anti-Human APP/Aβ Antibody and by mGluR5 Blockade.

    PubMed

    Kazim, Syed F; Chuang, Shih-Chieh; Zhao, Wangfa; Wong, Robert K S; Bianchi, Riccardo; Iqbal, Khalid

    2017-01-01

    Cortical and hippocampal network hyperexcitability appears to be an early event in Alzheimer's disease (AD) pathogenesis, and may contribute to memory impairment. It remains unclear if network hyperexcitability precedes memory impairment in mouse models of AD and what are the underlying cellular mechanisms. We thus evaluated seizure susceptibility and hippocampal network hyperexcitability at ~3 weeks of age [prior to amyloid beta (Aβ) plaque deposition, neurofibrillary pathology, and cognitive impairment] in a triple transgenic mouse model of familial AD (3xTg-AD mouse) that harbors mutated human Aβ precursor protein (APP), tau and presenilin 1 (PS1) genes. Audiogenic seizures were elicited in a higher proportion of 3xTg-AD mice compared with wild type (WT) controls. Seizure susceptibility in 3xTg-AD mice was attenuated either by passive immunization with anti-human APP/Aβ antibody (6E10) or by blockade of metabotropic glutamate receptor 5 (mGluR5) with the selective antagonist, 2-methyl-6-(phenylethynyl)pyridine hydrochloride (MPEP). In in vitro hippocampal slices, suppression of synaptic inhibition with the GABAA receptor antagonist, bicuculline, induced prolonged epileptiform (>1.5 s in duration) ictal-like discharges in the CA3 neuronal network in the majority of the slices from 3xTg-AD mice. In contrast, only short epileptiform (<1.5 s in duration) interictal-like discharges were observed following bicuculline application in the CA3 region of WT slices. The ictal-like activity in CA3 region of the hippocampus was significantly reduced in the 6E10-immunized compared to the saline-treated 3xTg-AD mice. MPEP acutely suppressed the ictal-like discharges in 3xTg-AD slices. Remarkably, epileptiform discharge duration positively correlated with intraneuronal human (transgenic) APP/Aβ expression in the CA3 region of the hippocampus. Our data suggest that in a mouse model of familial AD, hypersynchronous network activity underlying seizure susceptibility precedes

  6. Drosophila mini-white model system: new insights into positive position effects and the role of transcriptional terminators and gypsy insulator in transgene shielding

    PubMed Central

    Silicheva, Margarita; Golovnin, Anton; Pomerantseva, Ekaterina; Parshikov, Aleksander; Georgiev, Pavel; Maksimenko, Oksana

    2010-01-01

    The white gene, which is responsible for eye pigmentation, is widely used to study position effects in Drosophila. As a result of insertion of P-element vectors containing mini-white without enhancers into random chromosomal sites, flies with different eye color phenotypes appear, which is usually explained by the influence of positive/negative regulatory elements located around the insertion site. We found that, in more than 70% of cases when mini-white expression was subject to positive position effects, deletion of the white promoter had no effect on eye pigmentation; in these cases, the transposon was inserted into the transcribed regions of genes. Therefore, transcription through the mini-white gene could be responsible for high levels of its expression in most of chromosomal sites. Consistently with this conclusion, transcriptional terminators proved to be efficient in protecting mini-white expression from positive position effects. On the other hand, the best characterized Drosophila gypsy insulator was poorly effective in terminating transcription and, as a consequence, only partially protected mini-white expression from these effects. Thus, to ensure maximum protection of a transgene from position effects, a perfect boundary/insulator element should combine three activities: to block enhancers, to provide a barrier between active and repressed chromatin, and to terminate transcription. PMID:19854952

  7. Ubiquitous overexpression of a transgene encoding the extracellular portion of the Drosophila roughest-irregular chiasm C protein induces early embryonic lethality.

    PubMed

    Moda, L; Machado, R C; Ramos, R G

    2000-09-01

    The cell adhesion molecule Rst-irreC is a transmembrane glycoprotein of the immunoglobulin superfamily involved in several important developmental processes in Drosophila, including axonal pathfinding in the optic lobe and programmed cell death and pigment cell differentiation in the pupal retina. As an initial step towards the "in vivo" functional analysis of this protein we have generated transgenic fly stocks carrying a truncated cDNA construct encoding only the extracellular domain of Rst-IrreC under the transcriptional control of the heat shock inducible promoter hsp70. We show that heat-shocking embryos bearing the transgene during the first 8hs of development lead to a 3-4 fold reduction in their viability compared to wild type controls. The embryonic lethality can already be produced by applying the heat pulse in the first 3hs of embryonic development, does not seem to be suppressed in the absence of wildtype product and is progressively reduced as the heat treatment is applied later in embryogenesis. These results are compatible with the hypothesis of the lethal phenotype being primarily due to heterophilic interactions between Rst-IrreC extracellular domain and an yet unknown ligand.

  8. Effects and possible mechanisms of action of acacetin on the behavior and eye morphology of Drosophila models of Alzheimer’s disease

    PubMed Central

    Wang, Xue; Perumalsamy, Haribalan; Kwon, Hyung Wook; Na, Young-Eun; Ahn, Young-Joon

    2015-01-01

    The human β-amyloid (Aβ) cleaving enzyme (BACE-1) is a target for Alzheimer’s disease (AD) treatments. This study was conducted to determine if acacetin extracted from the whole Agastache rugosa plant had anti-BACE-1 and behavioral activities in Drosophila melanogaster AD models and to determine acacetin’s mechanism of action. Acacetin (100, 300, and 500 μM) rescued amyloid precursor protein (APP)/BACE1-expressing flies and kept them from developing both eye morphology (dark deposits, ommatidial collapse and fusion, and the absence of ommatidial bristles) and behavioral (motor abnormalities) defects. The reverse transcription polymerase chain reaction analysis revealed that acacetin reduced both the human APP and BACE-1 mRNA levels in the transgenic flies, suggesting that it plays an important role in the transcriptional regulation of human BACE-1 and APP. Western blot analysis revealed that acacetin reduced Aβ production by interfering with BACE-1 activity and APP synthesis, resulting in a decrease in the levels of the APP carboxy-terminal fragments and the APP intracellular domain. Therefore, the protective effect of acacetin on Aβ production is mediated by transcriptional regulation of BACE-1 and APP, resulting in decreased APP protein expression and BACE-1 activity. Acacetin also inhibited APP synthesis, resulting in a decrease in the number of amyloid plaques. PMID:26530776

  9. Application of metabolomics based on direct mass spectrometry analysis for the elucidation of altered metabolic pathways in serum from the APP/PS1 transgenic model of Alzheimer's disease.

    PubMed

    González-Domínguez, Raúl; García-Barrera, Tamara; Vitorica, Javier; Gómez-Ariza, José Luis

    2015-03-25

    Metabolomic analysis of brain tissue from transgenic mouse models of Alzheimer's disease has demonstrated a great potential for the study of pathological mechanisms and the development of new therapies and biomarkers for diagnosis. However, in order to translate these investigations to the clinical practice it is necessary to corroborate these findings in peripheral samples. To this end, this work considers the application of a novel metabolomic platform based on the combination of a two-steps extraction procedure with complementary analysis by direct infusion electrospray mass spectrometry and flow infusion atmospheric pressure photoionization mass spectrometry for a holistic investigation of metabolic abnormalities in serum samples from APP/PS1 mice. A number of metabolites were found to be perturbed in this mouse model, including increased levels of di- and tri-acylglycerols, eicosanoids, inosine, choline and glycerophosphoethanolamine; reduced content of cholesteryl esters, free fatty acids, lysophosphocholines, amino acids, energy-related metabolites, phosphoethanolamine and urea, as well as abnormal distribution of phosphocholines depending on the fatty acid linked to the molecular moiety. This allowed the elucidation of possible pathways disturbed underlying to disease (abnormal homeostasis of phospholipids leading to membrane breakdown, energy-related failures, hyperammonemia and hyperlipidemia, among others), thus demonstrating the utility of peripheral samples to investigate pathology in the APP/PS1 model.

  10. APP physiological and pathophysiological functions: insights from animal models.

    PubMed

    Guo, Qinxi; Wang, Zilai; Li, Hongmei; Wiese, Mary; Zheng, Hui

    2012-01-01

    The amyloid precursor protein (APP) has been under intensive study in recent years, mainly due to its critical role in the pathogenesis of Alzheimer's disease (AD). β-Amyloid (Aβ) peptides generated from APP proteolytic cleavage can aggregate, leading to plaque formation in human AD brains. Point mutations of APP affecting Aβ production are found to be causal for hereditary early onset familial AD. It is very likely that elucidating the physiological properties of APP will greatly facilitate the understanding of its role in AD pathogenesis. A number of APP loss- and gain-of-function models have been established in model organisms including Caenorhabditis elegans, Drosophila, zebrafish and mouse. These in vivo models provide us valuable insights into APP physiological functions. In addition, several knock-in mouse models expressing mutant APP at a physiological level are available to allow us to study AD pathogenesis without APP overexpression. This article will review the current physiological and pathophysiological animal models of APP.

  11. Autophagy is involved in oral rAAV/Aβ vaccine-induced Aβ clearance in APP/PS1 transgenic mice.

    PubMed

    Wang, He-Cheng; Zhang, Tao; Kuerban, Bolati; Jin, Ying-Lan; Le, Weidong; Hara, Hideo; Fan, Dong-Sheng; Wang, Yan-Jiang; Tabira, Takeshi; Chui, De-Hua

    2015-08-01

    The imbalance between ß-amyloid (Aß) generation and clearance plays a fundamental role in the pathogenesis of Alzheimer's disease (AD). The sporadic form of AD is characterized by an overall impairment in Aß clearance. Immunotherapy targeting Aß clearance is believed to be a promising approach and is under active clinical investigation. Autophagy is a conserved pathway for degrading abnormal protein aggregates and is crucial for Aß clearance. We previously reported that oral vaccination with a recombinant AAV/Aß vaccine increased the clearance of Aß from the brain and improved cognitive ability in AD animal models, while the underlying mechanisms were not well understood. In this study, we first demonstrated that oral vaccination with rAAV/Aß decreased the p62 level and up-regulated the LC3B-II/LC3B-I ratio in APP/PS1 mouse brain, suggesting enhanced autophagy. Further, inhibition of the Akt/mTOR pathway may account for autophagy enhancement. We also found increased anti-Aß antibodies in the sera of APP/PS1 mice with oral vaccination, accompanied by elevation of complement factors C1q and C3 levels in the brain. Our results indicate that autophagy is closely involved in oral vaccination-induced Aß clearance, and modulating the autophagy pathway may be an important strategy for AD prevention and intervention.

  12. Age- and Brain Region-Specific Changes of Glucose Metabolic Disorder, Learning, and Memory Dysfunction in Early Alzheimer’s Disease Assessed in APP/PS1 Transgenic Mice Using 18F-FDG-PET

    PubMed Central

    Li, Xue-Yuan; Men, Wei-Wei; Zhu, Hua; Lei, Jian-Feng; Zuo, Fu-Xing; Wang, Zhan-Jing; Zhu, Zhao-Hui; Bao, Xin-Jie; Wang, Ren-Zhi

    2016-01-01

    Alzheimer’s disease (AD) is a leading cause of dementia worldwide, associated with cognitive deficits and brain glucose metabolic alteration. However, the associations of glucose metabolic changes with cognitive dysfunction are less detailed. Here, we examined the brains of APP/presenilin 1 (PS1) transgenic (Tg) mice aged 2, 3.5, 5 and 8 months using 18F-labed fluorodeoxyglucose (18F-FDG) microPET to assess age- and brain region-specific changes of glucose metabolism. FDG uptake was calculated as a relative standardized uptake value (SUVr). Morris water maze (MWM) was used to evaluate learning and memory dysfunction. We showed a glucose utilization increase in multiple brain regions of Tg mice at 2 and 3.5 months but not at 5 and 8 months. Comparisons of SUVrs within brains showed higher glucose utilization than controls in the entorhinal cortex, hippocampus, and frontal cortex of Tg mice at 2 and 3.5 months but in the thalamus and striatum at 3.5, 5 and 8 months. By comparing SUVrs in the entorhinal cortex and hippocampus, Tg mice were distinguished from controls at 2 and 3.5 months. In MWM, Tg mice aged 2 months shared a similar performance to the controls (prodromal-AD). By contrast, Tg mice failed training tests at 3.5 months but failed all MWM tests at 5 and 8 months, suggestive of partial or complete cognitive deficits (symptomatic-AD). Correlation analyses showed that hippocampal SUVrs were significantly correlated with MWM parameters in the symptomatic-AD stage. These data suggest that glucose metabolic disorder occurs before onset of AD signs in APP/PS1 mice with the entorhinal cortex and hippocampus affected first, and that regional FDG uptake increase can be an early biomarker for AD. Furthermore, hippocampal FDG uptake is a possible indicator for progression of Alzheimer’s cognition after cognitive decline, at least in animals. PMID:27763550

  13. Age- and Brain Region-Specific Changes of Glucose Metabolic Disorder, Learning, and Memory Dysfunction in Early Alzheimer's Disease Assessed in APP/PS1 Transgenic Mice Using (18)F-FDG-PET.

    PubMed

    Li, Xue-Yuan; Men, Wei-Wei; Zhu, Hua; Lei, Jian-Feng; Zuo, Fu-Xing; Wang, Zhan-Jing; Zhu, Zhao-Hui; Bao, Xin-Jie; Wang, Ren-Zhi

    2016-10-18

    Alzheimer's disease (AD) is a leading cause of dementia worldwide, associated with cognitive deficits and brain glucose metabolic alteration. However, the associations of glucose metabolic changes with cognitive dysfunction are less detailed. Here, we examined the brains of APP/presenilin 1 (PS1) transgenic (Tg) mice aged 2, 3.5, 5 and 8 months using (18)F-labed fluorodeoxyglucose ((18)F-FDG) microPET to assess age- and brain region-specific changes of glucose metabolism. FDG uptake was calculated as a relative standardized uptake value (SUVr). Morris water maze (MWM) was used to evaluate learning and memory dysfunction. We showed a glucose utilization increase in multiple brain regions of Tg mice at 2 and 3.5 months but not at 5 and 8 months. Comparisons of SUVrs within brains showed higher glucose utilization than controls in the entorhinal cortex, hippocampus, and frontal cortex of Tg mice at 2 and 3.5 months but in the thalamus and striatum at 3.5, 5 and 8 months. By comparing SUVrs in the entorhinal cortex and hippocampus, Tg mice were distinguished from controls at 2 and 3.5 months. In MWM, Tg mice aged 2 months shared a similar performance to the controls (prodromal-AD). By contrast, Tg mice failed training tests at 3.5 months but failed all MWM tests at 5 and 8 months, suggestive of partial or complete cognitive deficits (symptomatic-AD). Correlation analyses showed that hippocampal SUVrs were significantly correlated with MWM parameters in the symptomatic-AD stage. These data suggest that glucose metabolic disorder occurs before onset of AD signs in APP/PS1 mice with the entorhinal cortex and hippocampus affected first, and that regional FDG uptake increase can be an early biomarker for AD. Furthermore, hippocampal FDG uptake is a possible indicator for progression of Alzheimer's cognition after cognitive decline, at least in animals.

  14. Evaluation of the toxic potential of calcium carbide in the third instar larvae of transgenic Drosophila melanogaster (hsp70-lacZ)Bg(9).

    PubMed

    Danish, Mohd; Fatima, Ambreen; Khanam, Saba; Jyoti, Smita; Rahul; Ali, Fahad; Naz, Falaq; Siddique, Yasir Hasan

    2015-11-01

    In the present study the toxic potential of calcium carbide (CaC2) was studied on the third instar larvae of transgenic Drosophila melanogaster (hsp70-lacZ)Bg(9). The third instar larvae were exposed to 2, 4, 8, 16 and 32×10(-3)g/ml of CaC2 in diet for 24h. The results reveal that the dose 2×10(-3)g/ml was not toxic but the remaining doses showed a dose dependent significant increase in the hsp70 expression, β-galactosidase activity, tissue damage, oxidative stress markers (lipid peroxidation and protein carbonyl content), glutathione-S-transferase activity, expression of Caspase 3 and 9, apoptotic index and DNA damage (midgut cells). A significant reduction as compared to control group in total protein, glutathione content and acetylcholinesterase activity was also observed. The Inductively Coupled Plasma Atomic Emission Spectroscopy analysis (ICPAES) reveals the presence of copper, iron, sodium, aluminium, manganese, calcium, nickel and mercury. The toxic effects of CaC2 in the present study may be attributed to the impurities present in it.

  15. Analysis of a DNase I-hypersensitive site in transgenic Drosophila reveals a key regulatory element of Sgs3.

    PubMed Central

    Ramain, P; Giangrande, A; Richards, G; Bellard, M

    1988-01-01

    We have undertaken chromatin studies on transformed Drosophila strains carrying DNA sequences modified in the region of the DNase I (EC 3.1.4.5)-hypersensitive sites -750 and -600 base pairs upstream from the Sgs3 start site. Although both sites are developmentally specific, modifications in the -750 site have little or no effect on Sgs3-encoded transcript levels, whereas either deletion or replacement of sequences at the -600 site causes an important reduction in transcript levels. The element associated with the -600 site enhances Sgs3 transcription when displaced with respect to the start site. This combined approach has defined sequence elements necessary both for normal transcript levels as well as the chromatin structure characteristic of Sgs3 activity in vivo. Images PMID:3128796

  16. Bioinformatics and co-expression network analysis of differentially expressed lncRNAs and mRNAs in hippocampus of APP/PS1 transgenic mice with Alzheimer disease

    PubMed Central

    Fang, Min; Zhang, Pei; Zhao, Yanxin; Liu, Xueyuan

    2017-01-01

    APP/PS1 transgenic mice with Alzheimer disease (AD) are widely used as a reliable animal model in studies about behaviors, physiology, biochemistry and histomorphology of AD, but few studies have been conducted to investigate the role of lncRNAs in this model. In this study, lncRNA microarray was employed to detect the gene expression profile and lncRNA expression profile in the mouse brain. Then, bioinformatics was used to predict the differentially expressed genes related to AD (n=20). Among different lncRNAs (n=249), 99 were downregulated and 150 upregulated. Co-expression network was applied to analyze the co-expression of differential lncRNAs and different genes. In network, lncRNA Gm13498 and lncRNA 1700030L20Rik correlated with the most genes and their degrees were 6 and 5, respectively. Then, the function and signal transduction pathways related to the differentially co-expressed lncRNAs were analyzed with bioinformatics, and results showed that these lncRNAs were involved in the systemic development of neurons, intercellular communication, regulation of action potential of neurons, development and differentiation of oligodendrocytes, neurotransmitters transmission, and neuronal regeneration. Realtime PCR was employed to detect the expression of relevant lncRNAs and differentially expressed RNAs in 10 samples, and results were consistent with above findings from microarray. PMID:28386363

  17. Behavioral Changes and Hippocampus Glucose Metabolism in APP/PS1 Transgenic Mice via Electro-acupuncture at Governor Vessel Acupoints

    PubMed Central

    Cao, Jin; Tang, Yinshan; Li, Yujie; Gao, Kai; Shi, Xudong; Li, Zhigang

    2017-01-01

    Objective: Investigating the effects of electro-acupuncture (EA) treatment on mice with Alzheimer’s disease (AD), using Morris water maze (MWM) for spatial learning and memory behavior tests combined with micro-positron emission tomography (micro-PET) imaging for glucose metabolism in hippocampus. Methods: Thirty seven-month-old APP/PS1 mice were randomly divided into AD Model group (AD group), medicine group (M group) and EA group, C57BL/6 mice were used for Normal control group (N group), n = 10 in each group. Mice in M group received donepezil intervention by gavage with dose at 0.92 mg/kg. EA was applied at Baihui (GV20) and Yintang (GV29) acupoints for 20 min then pricked at Shuigou (GV26) acupoint, while mice in N, M and AD groups were received restriction for 20 min, with all treatment administrated once a day for 15 consecutive days. After the treatment, MWM was performed to observe behavioral changes in mice, then hippocampus glucose metabolism level was tested by micro-PET imaging. Results: Compared with that of AD group, the escape latency of M and EA groups declined significantly (P < 0.01), while the proportion of the platform quadrant swimming distance in total swimming distance showed an obvious increase (P < 0.01), and EA group occupied a higher percentage than that in M group. The micro-PET imaging showed that mice in AD group performed a lower glucose metabolic rate in hippocampus compared with N group (P < 0.01). Both M and EA groups presented a significant higher injected dose compared with AD group (P < 0.01), and the uptake rate of EA group was higher than M group. Conclusion: Both donepezil and EA have therapeutic effects on AD mice. To a certain extent, EA shows a better efficacy in treatment of AD by improving the spatial learning and memory ability, while also enhancing glucose metabolism in hippocampus. PMID:28174534

  18. Hazardous effect of organophosphate compound, dichlorvos in transgenic Drosophila melanogaster (hsp70-lacZ): induction of hsp70, anti-oxidant enzymes and inhibition of acetylcholinesterase.

    PubMed

    Gupta, Subash Chandra; Siddique, Hifzur Rahman; Saxena, Daya Krishna; Chowdhuri, Debapratim Kar

    2005-08-30

    We tested a working hypothesis that stress genes and anti-oxidant enzyme machinery are induced by the organophosphate compound dichlorvos in a non-target organism. Third instar larvae of Drosophila melanogaster transgenic for hsp70 were exposed to 0.1 to 100.0 ppb dichlorvos and 5.0 mM CuSO(4) (an inducer of oxidative stress and stress genes) and hsp70, and activities of acetylcholinesterase (AchE), superoxide dismutase (SOD), catalase (CAT) and lipid peroxidation (LPO) product were measured. The study was further extended to examine tissue damage, if any, under such conditions. A concentration- and time-dependent increase in hsp70 and anti-oxidant enzymes was observed in the exposed organism as compared to control. A comparison of stress gene expression with SOD, CAT activities and LPO product under similar experimental conditions revealed that induction of hsp70 precedes the anti-oxidant enzyme activities in the exposed organism. Further, concomitant with a significant inhibition of AChE activity, significant induction of hsp70 was observed following chemical exposure. Mild tissue damage was observed in the larvae exposed to 10.0 ppb dichlorvos for 48 h when hsp70 expression reaches plateau. Dichlorvos at 0.1 ppb dietary concentration did not evoke significant hsp70 expression, anti-oxidant enzymes and LPO and AchE inhibition in the exposed organism, and thereby, was found to be non-hazardous to D. melanogaster. Conversely, 1.0 ppb of the test chemical stimulated a significant induction of hsp70 and anti-oxidant enzymes and significant inhibition of AchE; hence this concentration of test chemical was hazardous to the organism. The present study suggests that (a) both stress genes and anti-oxidant enzymes are stimulated as indices of cellular defense against xenobiotic hazard in D. melanogaster with hsp70 being proposed as first-tier bio-indicator of cellular hazard, (b) 0.1 ppb of the test chemical may be regarded as No Observed Adverse Effect Level (NOAEL), and

  19. Hazardous effects of effluent from the chrome plating industry: 70 kDa heat shock protein expression as a marker of cellular damage in transgenic Drosophila melanogaster (hsp70-lacZ).

    PubMed

    Mukhopadhyay, Indranil; Saxena, Daya Krishna; Chowdhuri, Debapratim Kar

    2003-12-01

    Hazardous effects of an effluent from the chrome plating industry were examined by exposing transgenic Drosophila melanogaster (hsp70-lacZ) to various concentrations (0.05, 0.1, 1.0, 10.0, and 100.0 micro L/mL) of the effluent through diet. The emergence pattern of adult flies was affected, along with impaired reproductive performance at the higher dietary concentrations of the effluent. Interestingly, the effect of the effluent was more pronounced in male than in female flies. The effect of the effluent on development of adult flies was concurrent with the expression pattern of the heat shock protein 70 gene (hsp70), both in larval tissues and in the reproductive organs of adult flies. We observed a dose- and time-dependent expression of hsp70 in third instar larvae exposed for different time intervals. Absence of hsp70 expression in larvae exposed to 0.1 micro L/mL of the effluent indicated that this is the highest nontoxic concentration for Drosophila. The stress gene assay in the reproductive organs of adult flies revealed hsp70 expression in the testis of male flies only. However, trypan blue dye exclusion tests in these tissues indicate tissue damage in the male accessory gland of adult flies, which was further confirmed by ultrastructural observations. In the present study we demonstrate the utility of transgenic Drosophila as an alternative animal model for evaluating hazardous effects of the effluent from the chrome plating industry and further reveal the cytoprotective role of hsp70 and its expression as an early marker in environmental risk assessment.

  20. Apps Developed by Academics

    ERIC Educational Resources Information Center

    Shing, Sophia; Yuan, Benjamin

    2016-01-01

    In the days of the digital Wild West, developers from all backgrounds have joined in the gold rush trying to profit from the almost unbridled spending of well-to-do parents on educational products. In 2016, the Apple App Store had over 80,000 educational apps. The proliferation of educational apps has happened at a furious pace and more apps are…

  1. Smartphone apps for urolithiasis.

    PubMed

    Stevens, D J; McKenzie, K; Cui, H W; Noble, J G; Turney, B W

    2015-02-01

    There are an increasing number of healthcare smartphone applications ('apps') available. Urolithiasis presents a major healthcare burden. Patients are increasingly keen to educate themselves regarding the diagnosis and management of their condition. There is no formal regulation of healthcare apps, including a large number of apps relating to urolithiasis. This review aims to examine the range of apps available, and the prevalence of healthcare professional input. Four international smartphone app stores were searched: Apple's App Store, Google Play (Android), BlackBerry App World and the Windows Phone App store. A total of 42 unique apps were downloaded and analysed. Recorded data included the cost (£/$), publisher information, number of ratings, average rating and any documentation of medical professional involvement. Twenty-one (50%) apps required payment for download. The mean cost was £3.58 ($6.04) with range £0.61-£34.90 ($1.03-$58.87). Thirty-three (79%) of the 42 apps were designed to be used by patients. Fifteen (36%) of the 42 apps had clear input from health professionals. Twenty-two apps offered patient information, including dietary advice on lowering calcium intake, which is contrary to current evidence-based practice. We conclude that urolithiasis apps have future potential to inform both patients and healthcare professionals on stone management. However, inaccuracies in the recommendations made by some apps can be misleading or even harmful due to a lack of specialist involvement. We recommend improving the usefulness of these apps by seeking a 'quality stamp' from recognised urological organisations and greater clinician involvement in future app development.

  2. Characterization of a Drosophila Alzheimer's Disease Model: Pharmacological Rescue of Cognitive Defects

    PubMed Central

    Mhatre, Siddhita D.; Paddock, Brie E.; Miller, Sean; Michelson, Sarah J.; Delvadia, Radha; Desai, Arkit; Vinokur, Marianna; Melicharek, David J.; Utreja, Suruchi; Khandelwal, Preeti; Ansaloni, Sara; Goldstein, Lee E.; Moir, Robert D.; Lee, Jeremy C.; Tabb, Loni P.; Saunders, Aleister J.; Marenda, Daniel R.

    2011-01-01

    Transgenic models of Alzheimer's disease (AD) have made significant contributions to our understanding of AD pathogenesis, and are useful tools in the development of potential therapeutics. The fruit fly, Drosophila melanogaster, provides a genetically tractable, powerful system to study the biochemical, genetic, environmental, and behavioral aspects of complex human diseases, including AD. In an effort to model AD, we over-expressed human APP and BACE genes in the Drosophila central nervous system. Biochemical, neuroanatomical, and behavioral analyses indicate that these flies exhibit aspects of clinical AD neuropathology and symptomology. These include the generation of Aβ40 and Aβ42, the presence of amyloid aggregates, dramatic neuroanatomical changes, defects in motor reflex behavior, and defects in memory. In addition, these flies exhibit external morphological abnormalities. Treatment with a γ-secretase inhibitor suppressed these phenotypes. Further, all of these phenotypes are present within the first few days of adult fly life. Taken together these data demonstrate that this transgenic AD model can serve as a powerful tool for the identification of AD therapeutic interventions. PMID:21673973

  3. Apps for Ancient Civilizations

    ERIC Educational Resources Information Center

    Thompson, Stephanie

    2011-01-01

    This project incorporates technology and a historical emphasis on science drawn from ancient civilizations to promote a greater understanding of conceptual science. In the Apps for Ancient Civilizations project, students investigate an ancient culture to discover how people might have used science and math smartphone apps to make their lives…

  4. Mobile Apps for Librarians

    ERIC Educational Resources Information Center

    Power, June L.

    2013-01-01

    In an increasing mobile environment, library and reading-related activities often take place on a phone or tablet device. Not only does this mean that library Web sites must keep mobile navigability in mind, but also develop and utilize apps that allow patrons to interact with information and with libraries. While apps do not serve every purpose,…

  5. Adverse effect of tannery waste leachates in transgenic Drosophila melanogaster: role of ROS in modulation of Hsp70, oxidative stress and apoptosis.

    PubMed

    Siddique, Hifzur R; Gupta, Subash C; Mitra, Kalyan; Bajpai, Virendra K; Mathur, Neeraj; Murthy, Ramesh C; Saxena, Daya K; Chowdhuri, Debapratim K

    2008-08-01

    Leachate is a complex chemical mixture of chemicals produced as a result of leaching of solid wastes. The potential toxicity of leachates is a major environmental health concern. The present study evaluated the role of ROS in tannery leachates induced Hsp70 expression, antioxidant enzymes and apoptosis in Drosophila. Different concentrations (0.05-2.0%) of leachates prepared from tannery waste at different pH (7.00, 4.93 and 2.88) were mixed with Drosophila food and fed to the larvae for 2-48 h to examine the different stress and apoptotic markers. A concentration- and time-dependent significant increase in Hsp70 expression, ROS generation, antioxidant enzymes activities and MDA content were observed in the exposed larvae. Activities of antioxidant enzymes were delayed compared with Hsp70 expression and MDA level in the exposed organisms. Apoptotic cell death was observed in the exposed larvae at higher concentrations concurrent with a significant regression in Hsp70 along with a higher level of ROS generation. A positive correlation drawn between ROS generation and apoptotic markers and a negative correlation between apoptotic markers and Hsp70 expression at these concentrations indicated the important role of ROS in the induction of cellular damage in the exposed organisms. There was a significant generation of ROS in the larvae exposed to 0.5% of leachates which did not interfere with the protection of their cells by Hsp70 and antioxidant enzymes. However, generation of significantly higher levels of ROS in the larvae exposed to 1.0% and 2.0% leachates may decrease Hsp70 expression thus leading to mitochondria-mediated caspase-dependent apoptotic cell death.

  6. 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

  7. white+ transgene insertions presenting a dorsal/ventral pattern define a single cluster of homeobox genes that is silenced by the polycomb-group proteins in Drosophila melanogaster.

    PubMed Central

    Netter, S; Fauvarque, M O; Diez del Corral, R; Dura, J M; Coen, D

    1998-01-01

    We used the white gene as an enhancer trap and reporter of chromatin structure. We collected white+ transgene insertions presenting a peculiar pigmentation pattern in the eye: white expression is restricted to the dorsal half of the eye, with a clear-cut dorsal/ventral (D/V) border. This D/V pattern is stable and heritable, indicating that phenotypic expression of the white reporter reflects positional information in the developing eye. Localization of these transgenes led us to identify a unique genomic region encompassing 140 kb in 69D1-3 subject to this D/V effect. This region contains at least three closely related homeobox-containing genes that are constituents of the iroquois complex (IRO-C). IRO-C genes are coordinately regulated and implicated in similar developmental processes. Expression of these genes in the eye is regulated by the products of the Polycomb-group (Pc-G) and trithorax-group (trx-G) genes but is not modified by classical modifiers of position-effect variegation. Our results, together with the report of a Pc-G binding site in 69D, suggest that we have identified a novel cluster of target genes for the Pc-G and trx-G products. We thus propose that ventral silencing of the whole IRO-C in the eye occurs at the level of chromatin structure in a manner similar to that of the homeotic gene complexes, perhaps by local compaction of the region into a heterochromatin-like structure involving the Pc-G products. PMID:9584101

  8. International Space Apps Challenge

    NASA Video Gallery

    During the 2013 Space Apps Challenge, space enthusiasts with diverse backgrounds gathered April 20-21 for a collaborative, global problem-solving effort. Held at Kennedy Space Center Visitor Comple...

  9. Apps I Have Loved

    ERIC Educational Resources Information Center

    Schaffhauser, Dian

    2011-01-01

    According to a March estimate from Distimo, there were 653,614 apps in the iPhone, Android, iPad, BlackBerry, and Windows Mobile stores alone. So, is it any wonder that these busy people have found a few that come in handy on the job? Mobile apps are as indispensable to district IT executives as they are becoming in the classroom--for professional…

  10. Diet and Physical Activity Apps: Perceived Effectiveness by App Users

    PubMed Central

    Egelandsdal, Bjørg; Amdam, Gro V; Almli, Valerie L; Oostindjer, Marije

    2016-01-01

    Background Diet and physical activity apps are two types of health apps that aim to promote healthy eating and energy expenditure through monitoring of dietary intake and physical activity. No clear evidence showing the effectiveness of using these apps to promote healthy eating and physical activity has been previously reported. Objective This study aimed to identify how diet and physical activity (PA) apps affected their users. It also investigated if using apps was associated with changes in diet and PA. Methods First, 3 semi-structured focus group discussions concerning app usability were conducted (15 app users and 8 nonusers; mean age 24.2 years, SD 6.4), including outcome measures such as motivations, experiences, opinions, and adherence. Results from the discussions were used to develop a questionnaire. The questionnaire, which contained questions about behavior changes, app usage, perceived effectiveness, and opinions of app usability, was answered by 500 Norwegians, with a mean age of 25.8 years (SD 5.1). Results App users found diet and PA apps effective in promoting healthy eating and exercising. These apps affected their actions, health consciousness, and self-education about nutrition and PA; and were also a part of their social lives. Over half of the users perceived that apps were effective in assisting them to eat healthily and to exercise more. Diet apps were more effective when they were frequently used and over a long period of time, compared to infrequent or short-term use (P=.01 and P=.02, respectively). Users who used diet and PA apps, perceived apps as more effective than users who only used one type of app (all P<.05). App users were better at maintaining diet and PA behaviors than nonusers (all P<.05). Young adults found apps fun to use, but sometimes time consuming. They wanted apps to be designed to meet their personal expectations. Conclusions App usage influenced action, consciousness, self-education about nutrition and PA, and social

  11. Quantifying App Store Dynamics: Longitudinal Tracking of Mental Health Apps

    PubMed Central

    Nicholas, Jennifer; Christensen, Helen

    2016-01-01

    Background For many mental health conditions, mobile health apps offer the ability to deliver information, support, and intervention outside the clinical setting. However, there are difficulties with the use of a commercial app store to distribute health care resources, including turnover of apps, irrelevance of apps, and discordance with evidence-based practice. Objective The primary aim of this study was to quantify the longevity and rate of turnover of mental health apps within the official Android and iOS app stores. The secondary aim was to quantify the proportion of apps that were clinically relevant and assess whether the longevity of these apps differed from clinically nonrelevant apps. The tertiary aim was to establish the proportion of clinically relevant apps that included claims of clinical effectiveness. We performed additional subgroup analyses using additional data from the app stores, including search result ranking, user ratings, and number of downloads. Methods We searched iTunes (iOS) and the Google Play (Android) app stores each day over a 9-month period for apps related to depression, bipolar disorder, and suicide. We performed additional app-specific searches if an app no longer appeared within the main search Results On the Android platform, 50% of the search results changed after 130 days (depression), 195 days (bipolar disorder), and 115 days (suicide). Search results were more stable on the iOS platform, with 50% of the search results remaining at the end of the study period. Approximately 75% of Android and 90% of iOS apps were still available to download at the end of the study. We identified only 35.3% (347/982) of apps as being clinically relevant for depression, of which 9 (2.6%) claimed clinical effectiveness. Only 3 included a full citation to a published study. Conclusions The mental health app environment is volatile, with a clinically relevant app for depression becoming unavailable to download every 2.9 days. This poses

  12. There's an App for that!

    ERIC Educational Resources Information Center

    Dutton, Gail

    2011-01-01

    Important as training the sales force is, mobile training apps are being used for much more. Visual Eyes Inc., for example, has developed training apps for the U.S. military's combat medical teams that detail specific medical procedures, such as controlling hemorrhaging. Other apps, developed for corporations and government agencies, pass along…

  13. Efficiently, Effectively Detecting Mobile App Bugs with AppDoctor

    DTIC Science & Technology

    2014-04-01

    leading to the failure. Once AppDoctor collects a set of bug reports, it runs automated diagnosis to classify reports into bugs and FPs by replaying...convenience the apps bring. A key reason for buggy apps is that they must handle a vast variety of system and user actions such as being randomly killed by...the OS to save resources, but app developers, facing tough competitions, lack time to thor- oughly test these actions. AppDoctor is a system for effi

  14. Oyster Fisheries App

    NASA Technical Reports Server (NTRS)

    Perez Guerrero, Geraldo A.; Armstrong, Duane; Underwood, Lauren

    2015-01-01

    This project is creating a cloud-enabled, HTML 5 web application to help oyster fishermen and state agencies apply Earth science to improve the management of this important natural and economic resource. The Oyster Fisheries app gathers and analyzes environmental and water quality information, and alerts fishermen and resources managers about problems in oyster fishing waters. An intuitive interface based on Google Maps displays the geospatial information and provides familiar interactive controls to the users. Alerts can be tailored to notify users when conditions in specific leases or public fishing areas require attention. The app is hosted on the Amazon Web Services cloud. It is being developed and tested using some of the latest web development tools such as web components and Polymer.

  15. Mobile Apps in Cardiology: Review

    PubMed Central

    2013-01-01

    Background Cardiovascular diseases are the deadliest diseases worldwide, with 17.3 million deaths in 2008 alone. Among them, heart-related deaths are of the utmost relevance; a fact easily proven by the 7.25 million deaths caused by ischemic heart disease alone in that year. The latest advances in smartphones and mHealth have been used in the creation of thousands of medical apps related to cardiology, which can help to reduce these mortality rates. Objective The aim of this paper is to study the literature on mobile systems and applications currently available, as well as the existing apps related to cardiology from the leading app stores and to then classify the results to see what is available and what is missing, focusing particularly on commercial apps. Methods Two reviews have been developed. One is a literature review of mobile systems and applications, retrieved from several databases and systems such as Scopus, PubMed, IEEE Xplore, and Web of Knowledge. The other is a review of mobile apps in the leading app stores, Google play for Android and Apple’s App Store for iOS. Results Search queries up to May 2013 located 406 papers and 710 apps related to cardiology and heart disease. The most researched section in the literature associated with cardiology is related to mobile heart (and vital signs) monitoring systems and the methods involved in the classification of heart signs in order to detect abnormal functions. Other systems with a significant number of papers are mobile cardiac rehabilitation systems, blood pressure measurement, and systems for the detection of heart failure. The majority of apps for cardiology are heart monitors and medical calculators. Other categories with a high number of apps are those for ECG education and interpretation, cardiology news and journals, blood pressure tracking, heart rate monitoring using an external device, and CPR instruction. There are very few guides on cardiac rehabilitation and apps for the management of the

  16. Spatial Navigation in Complex and Radial Mazes in APP23 Animals and Neurotrophin Signaling as a Biological Marker of Early Impairment

    ERIC Educational Resources Information Center

    Hellweg, Rainer; Huber, Roman; Kuhl, Alexander; Riepe, Matthias W.; Lohmann, Peter

    2006-01-01

    Impairment of hippocampal function precedes frontal and parietal cortex impairment in human Alzheimer's disease(AD). Neurotrophins are critical for behavioral performance and neuronal survival in AD. We used complex and radial mazes to assess spatial orientation and learning in wild-type and B6-Tg(ThylAPP)23Sdz (APP23) animals, a transgenic mouse…

  17. Mobile Videoconferencing Apps for Telemedicine

    PubMed Central

    Liu, Wei-Li; Locatis, Craig; Ackerman, Michael

    2016-01-01

    Abstract Introduction: The quality and performance of several videoconferencing applications (apps) tested on iOS (Apple, Cupertino, CA) and Android™ (Google, Mountain View, CA) mobile platforms using Wi-Fi (802.11), third-generation (3G), and fourth-generation (4G) cellular networks are described. Materials and Methods: The tests were done to determine how well apps perform compared with videoconferencing software installed on computers or with more traditional videoconferencing using dedicated hardware. The rationale for app assessment and the testing methodology are described. Results: Findings are discussed in relation to operating system platform (iOS or Android) for which the apps were designed and the type of network (Wi-Fi, 3G, or 4G) used. The platform, network, and apps interact, and it is impossible to discuss videoconferencing experienced on mobile devices in relation to one of these factors without referencing the others. Conclusions: Apps for mobile devices can vary significantly from other videoconferencing software or hardware. App performance increased over the testing period due to improvements in network infrastructure and how apps manage bandwidth. PMID:26204322

  18. A Year with Google Apps

    ERIC Educational Resources Information Center

    Hastings, Robin

    2010-01-01

    In August 2008, the Missouri River Regional Library (MRRL), where the author serves as information technology coordinator, switched over from an internally hosted Microsoft Exchange email server to the Google Apps product. As the person who led the charge to use Google Apps and the person who actually flipped the switch, he was responsible for…

  19. 31 Flavors of Drosophila Rab proteins

    SciTech Connect

    Zhang, Jun; Schulze, Karen L.; Hiesinger, P. Robin; Suyama, Kaye; Wang, Stream; Fish, Matthew; Acar, Melih; Hoskins, Roger A.; Bellen, HugoJ.; Scott, Matthew P.

    2007-04-03

    Rab proteins are small GTPases that play important roles intransport of vesicle cargo and recruitment, association of motor andother proteins with vesicles, and docking and fusion of vesicles atdefined locations. In vertebrates, more than 75 Rab genes have beenidentified, some of which have been intensively studied for their rolesin endosome and synaptic vesicle trafficking. Recent studies of thefunctions of certain Rab proteins have revealed specific roles inmediating developmental signal transduction. We have begun a systematicgenetic study of the 33 Rab genes in Drosophila. Most of the fly proteinsare clearly related to specific vertebrate proteins. We report here thecreation of a set of transgenic fly lines that allow spatially andtemporally regulated expression of Drosophila Rab proteins. We generatedfluorescent protein-tagged wild-type, dominant-negative, andconstitutively active forms of 31 Drosophila Rab proteins. We describeDrosophila Rab expression patterns during embryogenesis, the subcellularlocalization of some Rab proteins, and comparisons of the localization ofwild-type, dominant-negative, and constitutively active forms of selectedRab proteins. The high evolutionary conservation and low redundancy ofDrosophila Rab proteins make these transgenic lines a useful toolkit forinvestigating Rab functions in vivo.

  20. Age-dependent cognitive decline in the APP23 model precedes amyloid deposition.

    PubMed

    Van Dam, Debby; D'Hooge, Rudi; Staufenbiel, Matthias; Van Ginneken, Chris; Van Meir, Frans; De Deyn, Peter P

    2003-01-01

    Heterozygous APP23 mice, expressing human amyloid-precursor protein with the Swedish double mutation and control littermates, were subjected to behavioral and neuromotor tasks at the age of 6-8 weeks, 3 and 6 months. A hidden-platform Morris-type water maze showed an age-dependent decline of spatial memory capacities in the APP23 model. From the age of 3 months onwards, the APP23 mice displayed major learning and memory deficits as demonstrated by severely impaired learning curves during acquisition and impaired probe trial performance. In addition to the cognitive deficit, APP23 mice displayed disturbed activity patterns. Overnight cage-activity recording showed hyperactivity in the transgenics for the three age groups tested. However, a short 2-h recording during dusk phase demonstrated lower activity levels in 6-month-old APP23 mice as compared to controls. Moreover, at this age, APP23 mice differed from control littermates in exploration and activity levels in the open-field paradigm. These findings are reminiscent of disturbances in circadian rhythms and activity observed in Alzheimer patients. Determination of plaque-associated human amyloid-beta 1-42 peptides in brain revealed a fivefold increase in heterozygous APP23 mice at 6 months as compared to younger transgenics. This increase coincided with the first appearance of plaques in hippocampus and neocortex. Spatial memory deficits preceded plaque formation and increase in plaque-associated amyloid-beta 1-42 peptides, but probe trial performance did correlate negatively with soluble amyloid-beta brain concentration in 3-month-old APP23 mutants. Detectable plaque formation is not the (only) causal factor contributing to memory defects in the APP23 model.

  1. Role of Drosophila Amyloid Precursor Protein in Memory Formation

    PubMed Central

    Preat, Thomas; Goguel, Valérie

    2016-01-01

    The amyloid precursor protein (APP) is a membrane protein engaged in complex proteolytic pathways. APP and its derivatives have been shown to play a central role in Alzheimer’s disease (AD), a progressive neurodegenerative disease characterized by memory decline. Despite a huge effort from the research community, the primary cause of AD remains unclear, making it crucial to better understand the physiological role of the APP pathway in brain plasticity and memory. Drosophila melanogaster is a model system well-suited to address this issue. Although relatively simple, the fly brain is highly organized, sustains several forms of learning and memory, and drives numerous complex behaviors. Importantly, molecules and mechanisms underlying memory processes are conserved from flies to mammals. The fly encodes a single non-essential APP homolog named APP-Like (APPL). Using in vivo inducible RNA interference strategies, it was shown that APPL knockdown in the mushroom bodies (MB)—the central integrative brain structure for olfactory memory—results in loss of memory. Several APPL derivatives, such as secreted and full-length membrane APPL, may play different roles in distinct types of memory phases. Furthermore, overexpression of Drosophila amyloid peptide exacerbates the memory deficit caused by APPL knockdown, thus potentiating memory decline. Data obtained in the fly support the hypothesis that APP acts as a transmembrane receptor, and that disruption of its normal function may contribute to cognitive impairment during early AD. PMID:28008309

  2. Selecting "App"ealing and "App"ropriate Book Apps for Beginning Readers

    ERIC Educational Resources Information Center

    Cahill, Maria; McGill-Franzen, Anne

    2013-01-01

    Beginning with a brief rationale for selecting quality digital picture book apps for beginning readers, the authors describe the elements of digital picture books and provide a brief review of the instructional benefits of digital picture book use for beginning readers. They then present a detailed taxonomy for selecting quality picture book apps.…

  3. Transgenic Animals.

    ERIC Educational Resources Information Center

    Jaenisch, Rudolf

    1988-01-01

    Describes three methods and their advantages and disadvantages for introducing genes into animals. Discusses the predictability and tissue-specificity of the injected genes. Outlines the applications of transgenic technology for studying gene expression, the early stages of mammalian development, mutations, and the molecular nature of chromosomes.…

  4. Visualization of Actin Cytoskeletal Dynamics in Fixed and Live Drosophila Egg Chambers.

    PubMed

    Groen, Christopher M; Tootle, Tina L

    2015-01-01

    Visualization of actin cytoskeletal dynamics is critical for understanding the spatial and temporal regulation of actin remodeling. Drosophila oogenesis provides an excellent model system for visualizing the actin cytoskeleton. Here, we present methods for imaging the actin cytoskeleton in Drosophila egg chambers in both fixed samples by phalloidin staining and in live egg chambers using transgenic actin labeling tools.

  5. Creating Innovative Student Projects with App Smashing

    ERIC Educational Resources Information Center

    Young, Donna

    2014-01-01

    The potential for using various apps to improve student learning is tremendous. Yet, despite the iPad's possibilities, apps are often limited in their functionality. No one has created that magical, one-size-fits-all app that accomplishes all of the tasks that you had in mind. Luckily, there is an answer to this common problem: app smashing.…

  6. The Ames dwarf mutation attenuates Alzheimer's disease phenotype of APP/PS1 mice.

    PubMed

    Puig, Kendra L; Kulas, Joshua A; Franklin, Whitney; Rakoczy, Sharlene G; Taglialatela, Giulio; Brown-Borg, Holly M; Combs, Colin K

    2016-04-01

    APP/PS1 double transgenic mice expressing human mutant amyloid precursor protein (APP) and presenilin-1 (PS1) demonstrate robust brain amyloid beta (Aβ) peptide containing plaque deposition, increased markers of oxidative stress, behavioral dysfunction, and proinflammatory gliosis. On the other hand, lack of growth hormone, prolactin, and thyroid-stimulating hormone due to a recessive mutation in the Prop 1 gene (Prop1df) in Ames dwarf mice results in a phenotype characterized by potentiated antioxidant mechanisms, improved learning and memory, and significantly increased longevity in homozygous mice. Based on this, we hypothesized that a similar hormone deficiency might attenuate disease changes in the brains of APP/PS1 mice. To test this idea, APP/PS1 mice were crossed to the Ames dwarf mouse line. APP/PS1, wild-type, df/+, df/df, df/+/APP/PS1, and df/df/APP/PS1 mice were compared at 6 months of age through behavioral testing and assessing amyloid burden, reactive gliosis, and brain cytokine levels. df/df mice demonstrated lower brain growth hormone and insulin-like growth factor 1 concentrations. This correlated with decreased astrogliosis and microgliosis in the df/df/APP/PS1 mice and, surprisingly, reduced Aβ plaque deposition and Aβ 1-40 and Aβ 1-42 concentrations. The df/df/APP/PS1 mice also demonstrated significantly elevated brain levels of multiple cytokines in spite of the attenuated gliosis. These data indicate that the df/df/APP/PS1 line is a unique resource in which to study aging and resistance to disease and suggest that the affected pituitary hormones may have a role in regulating disease progression.

  7. Urologists' usage and perceptions of urological apps.

    PubMed

    Dempster, Niall J; Risk, Rachel; Clark, Ross; Meddings, Robert N

    2014-12-01

    We conducted a survey of urologists to document their patterns of app usage and perceptions of app quality, and to assess their interest in future app usage. The survey was sent to all urologists on the mailing list of the British Association of Urological Surgeons (BAUS) (n=1613). A total of 115 responses were received (a response rate of 7%). Most respondents (89%) owned mobile devices capable of downloading apps. Most respondents (79%) used apps and about half (49%) used urological apps; the latter accessed a mean of 2.4 urological apps per month. Significantly more younger (defined as <45 years old) than older urologists used urological apps (P<0.001). Respondents' perception of the overall quality of apps produced for both urologists and patients was relatively low. The respondents' interest in future app usage was strong. There was greatest interest in apps such as logbooks or revalidation ones (87%), reference apps (86%) and ones which aided decision-making (85%). There was considerable support for the implementation of measures to provide urological app quality assurance; most respondents believed app peer review (78%) and validation (78%) would be beneficial and 48% supported regulatory oversight. There appears to be a need for high quality urological apps and opportunities therefore exist for national urological associations and academic units to lead developments.

  8. Drosophila spermiogenesis

    PubMed Central

    Fabian, Lacramioara; Brill, Julie A.

    2012-01-01

    Drosophila melanogaster spermatids undergo dramatic morphological changes as they differentiate from small round cells approximately 12 μm in diameter into highly polarized, 1.8 mm long, motile sperm capable of participating in fertilization. During spermiogenesis, syncytial cysts of 64 haploid spermatids undergo synchronous differentiation. Numerous changes occur at a subcellular level, including remodeling of existing organelles (mitochondria, nuclei), formation of new organelles (flagellar axonemes, acrosomes), polarization of elongating cysts and plasma membrane addition. At the end of spermatid morphogenesis, organelles, mitochondrial DNA and cytoplasmic components not needed in mature sperm are stripped away in a caspase-dependent process called individualization that results in formation of individual sperm. Here, we review the stages of Drosophila spermiogenesis and examine our current understanding of the cellular and molecular mechanisms involved in shaping male germ cell-specific organelles and forming mature, fertile sperm. PMID:23087837

  9. Developmental Toxicity Assays Using the Drosophila Model

    PubMed Central

    Rand, Matthew D.; Montgomery, Sara L.; Prince, Lisa; Vorojeikina, Daria

    2014-01-01

    The fruit fly (Drosophila melanogaster) has long been a premier model for developmental biologists and geneticists. The utility of Drosophila for toxicology studies has only recently gained broader recognition as a tool to elaborate molecular genetic mechanisms of toxic substances. In this article two practical applications of Drosophila for developmental toxicity assays are described. The first assay takes advantage of newly developed methods to render the fly embryo accessible to small molecules, toxicants and drugs. The second assay engages straightforward exposures to developing larvae and easy to score outcomes of adult development. With the extensive collections of flies that are publicly available and the ease with which to create transgenic flies, these two assays have a unique power for identifying and characterizing molecular mechanisms and cellular pathways specific to the mode of action of a number of toxicants and drugs. PMID:24789363

  10. Arsenic affects expression and processing of amyloid precursor protein (APP) in primary neuronal cells overexpressing the Swedish mutation of human APP.

    PubMed

    Zarazúa, Sergio; Bürger, Susanne; Delgado, Juan M; Jiménez-Capdeville, Maria E; Schliebs, Reinhard

    2011-06-01

    Arsenic poisoning due to contaminated water and soil, mining waste, glass manufacture, select agrochemicals, as well as sea food, affects millions of people world wide. Recently, an involvement of arsenic in Alzheimer's disease (AD) has been hypothesized (Gong and O'Bryant, 2010). The present study stresses the hypothesis whether sodium arsenite, and its main metabolite, dimethylarsinic acid (DMA), may affect expression and processing of the amyloid precursor protein (APP), using the cholinergic cell line SN56.B5.G4 and primary neuronal cells overexpressing the Swedish mutation of APP, as experimental approaches. Exposure of cholinergic SN56.B5.G4 cells with either sodium arsenite or DMA decreased cell viability in a concentration- and exposure-time dependent manner, and affected the activities of the cholinergic enzymes acetylcholinesterase and choline acetyltransferase. Both sodium arsenite and DMA exposure of SN56.B5.G4 cells resulted in enhanced level of APP, and sAPP in the membrane and cytosolic fractions, respectively. To reveal any effect of arsenic on APP processing, the amounts of APP cleavage products, sAPPβ, and β-amyloid (Aβ) peptides, released into the culture medium of primary neuronal cells derived from transgenic Tg2576 mice, were assessed by ELISA. Following exposure of neuronal cells by sodium arsenite for 12h, the membrane-bound APP level was enhanced, the amount of sAPPβ released into the culture medium was slightly higher, while the levels of Aβ peptides in the culture medium were considerably lower as compared to that assayed in the absence of any drug. The sodium arsenite-induced reduction of Aβ formation suggests an inhibition of the APP γ-cleavage step by arsenite. In contrast, DMA exposure of neuronal cells considerably increased formation of Aβ and sAPPβ, accompanied by enhanced membrane APP level. The DMA-induced changes in APP processing may be the result of the enhanced APP expression. Alternatively, increased Aβ production

  11. Psych-related iPhone apps.

    PubMed

    Harrison, Anthony Mark; Goozee, Rhianna

    2014-02-01

    iPhone apps are a widely utilised technology that have recently been identified as a useful medium for health research, clinical interventions and education. While some researchers have discussed advances in app technology, others promote specific apps that are not free to access. To our knowledge, no study has conducted a review of current, free iPhone apps related to psychology, psychiatry and mental health. Therefore, we conducted a pilot, web-based review exploring free iPhone apps using a replicable search strategy within the iTunes Store search function. A selection of apps were selected and subjectively assessed in terms of their usability, utility, graphics, and associated costs for the consumer. We concluded that the apps reviewed, though novel, are limited in their scope and utility. We also note a significant gap in more scientific, evidence-based app technology, and pose some pertinent ethical questions when developing future psych-related apps.

  12. Optogenetic pacing in Drosophila melanogaster

    PubMed Central

    Alex, Aneesh; Li, Airong; Tanzi, Rudolph E.; Zhou, Chao

    2015-01-01

    Electrical stimulation is currently the gold standard for cardiac pacing. However, it is invasive and nonspecific for cardiac tissues. We recently developed a noninvasive cardiac pacing technique using optogenetic tools, which are widely used in neuroscience. Optogenetic pacing of the heart provides high spatial and temporal precisions, is specific for cardiac tissues, avoids artifacts associated with electrical stimulation, and therefore promises to be a powerful tool in basic cardiac research. We demonstrated optogenetic control of heart rhythm in a well-established model organism, Drosophila melanogaster. We developed transgenic flies expressing a light-gated cation channel, channelrhodopsin-2 (ChR2), specifically in their hearts and demonstrated successful optogenetic pacing of ChR2-expressing Drosophila at different developmental stages, including the larva, pupa, and adult stages. A high-speed and ultrahigh-resolution optical coherence microscopy imaging system that is capable of providing images at a rate of 130 frames/s with axial and transverse resolutions of 1.5 and 3.9 μm, respectively, was used to noninvasively monitor Drosophila cardiac function and its response to pacing stimulation. The development of a noninvasive integrated optical pacing and imaging system provides a novel platform for performing research studies in developmental cardiology. PMID:26601299

  13. APP Regulates Microglial Phenotype in a Mouse Model of Alzheimer's Disease

    PubMed Central

    Manocha, Gunjan D.; Floden, Angela M.; Rausch, Keiko; Kulas, Joshua A.; McGregor, Brett A.; Rojanathammanee, Lalida; Puig, Kelley R.; Puig, Kendra L.; Karki, Sanjib; Nichols, Michael R.; Darland, Diane C.; Porter, James E.

    2016-01-01

    Prior work suggests that amyloid precursor protein (APP) can function as a proinflammatory receptor on immune cells, such as monocytes and microglia. Therefore, we hypothesized that APP serves this function in microglia during Alzheimer's disease. Although fibrillar amyloid β (Aβ)-stimulated cytokine secretion from both wild-type and APP knock-out (mAPP−/−) microglial cultures, oligomeric Aβ was unable to stimulate increased secretion from mAPP−/− cells. This was consistent with an ability of oligomeric Aβ to bind APP. Similarly, intracerebroventricular infusions of oligomeric Aβ produced less microgliosis in mAPP−/− mice compared with wild-type mice. The mAPP−/− mice crossed to an APP/PS1 transgenic mouse line demonstrated reduced microgliosis and cytokine levels and improved memory compared with wild-type mice despite robust fibrillar Aβ plaque deposition. These data define a novel function for microglial APP in regulating their ability to acquire a proinflammatory phenotype during disease. SIGNIFICANCE STATEMENT A hallmark of Alzheimer's disease (AD) brains is the accumulation of amyloid β (Aβ) peptide within plaques robustly invested with reactive microglia. This supports the notion that Aβ stimulation of microglial activation is one source of brain inflammatory changes during disease. Aβ is a cleavage product of the ubiquitously expressed amyloid precursor protein (APP) and is able to self-associate into a wide variety of differently sized and structurally distinct multimers. In this study, we demonstrate both in vitro and in vivo that nonfibrillar, oligomeric forms of Aβ are able to interact with the parent APP protein to stimulate microglial activation. This provides a mechanism by which metabolism of APP results in possible autocrine or paracrine Aβ production to drive the microgliosis associated with AD brains. PMID:27511018

  14. Analysis of Amyloid Precursor Protein Function in Drosophila melanogaster

    PubMed Central

    Cassar, Marlène; Kretzschmar, Doris

    2016-01-01

    The Amyloid precursor protein (APP) has mainly been investigated in connection with its role in Alzheimer’s Disease (AD) due to its cleavage resulting in the production of the Aβ peptides that accumulate in the plaques characteristic for this disease. However, APP is an evolutionary conserved protein that is not only found in humans but also in many other species, including Drosophila, suggesting an important physiological function. Besides Aβ, several other fragments are produced by the cleavage of APP; large secreted fragments derived from the N-terminus and a small intracellular C-terminal fragment. Although these fragments have received much less attention than Aβ, a picture about their function is finally emerging. In contrast to mammals, which express three APP family members, Drosophila expresses only one APP protein called APP-like or APPL. Therefore APPL functions can be studied in flies without the complication that other APP family members may have redundant functions. Flies lacking APPL are viable but show defects in neuronal outgrowth in the central and peripheral nervous system (PNS) in addition to synaptic changes. Furthermore, APPL has been connected with axonal transport functions. In the adult nervous system, APPL, and more specifically its secreted fragments, can protect neurons from degeneration. APPL cleavage also prevents glial death. Lastly, APPL was found to be involved in behavioral deficits and in regulating sleep/activity patterns. This review, will describe the role of APPL in neuronal development and maintenance and briefly touch on its emerging function in circadian rhythms while an accompanying review will focus on its role in learning and memory formation. PMID:27507933

  15. Cannabis Mobile Apps: A Content Analysis

    PubMed Central

    Popova, Lucy; Grana, Rachel; Zhao, Shirley; Chavez, Kathryn

    2015-01-01

    Background Mobile technology is pervasive and widely used to obtain information about drugs such as cannabis, especially in a climate of rapidly changing cannabis policy; yet the content of available cannabis apps is largely unknown. Understanding the resources available to those searching for cannabis apps will clarify how this technology is being used to reflect and influence cannabis use behavior. Objective We investigated the content of 59 cannabis-related mobile apps for Apple and Android devices as of November 26, 2014. Methods The Apple and Google Play app stores were searched using the terms “cannabis” and “marijuana.” Three trained coders classified the top 20 apps for each term and each store, using a coding guide. Apps were examined for the presence of 20 content codes derived by the researchers. Results Total apps available for each search term were 124 for cannabis and 218 for marijuana in the Apple App Store, and 250 each for cannabis and marijuana on Google Play. The top 20 apps in each category in each store were coded for 59 independent apps (30 Apple, 29 Google Play). The three most common content areas were cannabis strain classification (33.9%), facts about cannabis (20.3%), and games (20.3%). In the Apple App Store, most apps were free (77%), all were rated “17+” years, and the average user rating was 3.9/5 stars. The most popular apps provided cannabis strain classifications (50%), dispensary information (27%), or general facts about cannabis (27%). Only one app (3%) provided information or resources related to cannabis abuse, addiction, or treatment. On Google Play, most apps were free (93%), rated “high maturity” (79%), and the average user rating was 4.1/5. The most popular app types offered games (28%), phone utilities (eg, wallpaper, clock; 21%) and cannabis food recipes (21%); no apps addressed abuse, addiction, or treatment. Conclusions Cannabis apps are generally free and highly rated. Apps were most often informational

  16. Smartphone use in neurosurgery? APP-solutely!

    PubMed Central

    Zaki, Michael; Drazin, Doniel

    2014-01-01

    Background: A number of smartphone medical apps have recently emerged that may be helpful for the neurosurgical patient, practitioner, and trainee. This study aims to review the current neurosurgery-focused apps available for the iPhone, iPad, and Android platforms as of December 2013. Methods: Two of the most popular smartphone app stores (Apple Store and Android Google Play Store) were surveyed for neurosurgery-focused apps in December 2013. Search results were categorized based on their description page. Data were collected on price, rating, app release date, target audience, and medical professional involvement in app design. A review of the top apps in each category was performed. Results: The search resulted in 111 unique apps, divided into these 7 categories: 16 (14%) clinical tools, 17 (15%) conference adjunct, 27 (24%) education, 18 (16%) literature, 15 (14%) marketing, 10 (9%) patient information, and 8 (7%) reference. The average cost of paid apps was $23.06 (range: $0.99-89.99). Out of the 111 apps, 71 (64%) were free, 48 (43%) had reviews, and 14 (13%) had more than 10 reviews. Seventy-three (66%) apps showed evidence of medical professional involvement. The number of apps being released every year has been increasing since 2009. Conclusions: There are a number of neurosurgery-themed apps available to all audiences. There was a lack of patient information apps for nonspinal procedures. Most apps did not have enough reviews to evaluate their quality. There was also a lack of oversight to validate the accuracy of medical information provided in these apps. PMID:25101208

  17. Color Addition and Subtraction Apps

    ERIC Educational Resources Information Center

    Ruiz, Frances; Ruiz, Michael J.

    2015-01-01

    Color addition and subtraction apps in HTML5 have been developed for students as an online hands-on experience so that they can more easily master principles introduced through traditional classroom demonstrations. The evolution of the additive RGB color model is traced through the early IBM color adapters so that students can proceed step by step…

  18. Illuminating Apps for Fourth Grade

    ERIC Educational Resources Information Center

    Lennex, Lesia; Bodenlos, Emily

    2014-01-01

    Elementary science is chock-full of wonderful experiences for students. Do children see iPads as a tool for learning about science? Using Prensky (2010) as a guide, the researchers decided to see if "assessing students with their own" tools (p.178) using iPad apps would support learning discrete knowledge for electricity and light…

  19. A Drosophila gene encoding a protein resembling the human. beta. -amyloid protein precursor

    SciTech Connect

    Rosen, D.R.; Martin-Morris, L.; Luo, L.; White, K. )

    1989-04-01

    The authors have isolated genomic and cDNA clones for a Drosophila gene resembling the human {beta}-amyloid precursor protein (APP). This gene produces a nervous system-enriched 6.5-kilobase transcript. Sequencing of cDNAs derived from the 6.5-kilobase transcript predicts an 886-amino acid polypeptide. This polypeptide contains a putative transmembrane domain and exhibits strong sequence similarity to cytoplasmic and extracellular regions of the human {beta}-amyloid precursor protein. There is a high probability that this Drosophila gene corresponds to the essential Drosophila locus vnd, a gene required for embryonic nervous system development.

  20. A Drosophila gene encoding a protein resembling the human beta-amyloid protein precursor.

    PubMed Central

    Rosen, D R; Martin-Morris, L; Luo, L Q; White, K

    1989-01-01

    We have isolated genomic and cDNA clones for a Drosophila gene resembling the human beta-amyloid precursor protein (APP). This gene produces a nervous system-enriched 6.5-kilobase transcript. Sequencing of cDNAs derived from the 6.5-kilobase transcript predicts an 886-amino acid polypeptide. This polypeptide contains a putative transmembrane domain and exhibits strong sequence similarity to cytoplasmic and extracellular regions of the human beta-amyloid precursor protein. There is a high probability that this Drosophila gene corresponds to the essential Drosophila locus vnd, a gene required for embryonic nervous system development. Images PMID:2494667

  1. 15 CFR 740.7 - Computers (APP).

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 15 Commerce and Foreign Trade 2 2011-01-01 2011-01-01 false Computers (APP). 740.7 Section 740.7... Computers (APP). (a) Scope—(1) Commodities. License Exception APP authorizes exports and reexports of computers, including “electronic assemblies” and specially designed components therefor controlled by...

  2. 15 CFR 740.7 - Computers (APP).

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 15 Commerce and Foreign Trade 2 2010-01-01 2010-01-01 false Computers (APP). 740.7 Section 740.7... Computers (APP). (a) Scope—(1) Commodities. License Exception APP authorizes exports and reexports of computers, including “electronic assemblies” and specially designed components therefor controlled by...

  3. 15 CFR 740.7 - Computers (APP).

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... 15 Commerce and Foreign Trade 2 2012-01-01 2012-01-01 false Computers (APP). 740.7 Section 740.7... Computers (APP). (a) Scope—(1) Commodities. License Exception APP authorizes exports and reexports of computers, including “electronic assemblies” and specially designed components therefor controlled by...

  4. 15 CFR 740.7 - Computers (APP).

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 15 Commerce and Foreign Trade 2 2013-01-01 2013-01-01 false Computers (APP). 740.7 Section 740.7... Computers (APP). (a) Scope—(1) Commodities. License Exception APP authorizes exports and reexports of computers, including “electronic assemblies” and specially designed components therefor controlled by...

  5. Capitalizing on App Development Tools and Technologies

    ERIC Educational Resources Information Center

    Luterbach, Kenneth J.; Hubbell, Kenneth R.

    2015-01-01

    Instructional developers and others creating apps must choose from a wide variety of app development tools and technologies. Some app development tools have incorporated visual programming features, which enable some drag and drop coding and contextual programming. While those features help novices begin programming with greater ease, questions…

  6. APP Causes Hyperexcitability in Fragile X Mice.

    PubMed

    Westmark, Cara J; Chuang, Shih-Chieh; Hays, Seth A; Filon, Mikolaj J; Ray, Brian C; Westmark, Pamela R; Gibson, Jay R; Huber, Kimberly M; Wong, Robert K S

    2016-01-01

    Amyloid-beta protein precursor (APP) and metabolite levels are altered in fragile X syndrome (FXS) patients and in the mouse model of the disorder, Fmr1(KO) mice. Normalization of APP levels in Fmr1(KO) mice (Fmr1(KO) /APP(HET) mice) rescues many disease phenotypes. Thus, APP is a potential biomarker as well as therapeutic target for FXS. Hyperexcitability is a key phenotype of FXS. Herein, we determine the effects of APP levels on hyperexcitability in Fmr1(KO) brain slices. Fmr1(KO) /APP(HET) slices exhibit complete rescue of UP states in a neocortical hyperexcitability model and reduced duration of ictal discharges in a CA3 hippocampal model. These data demonstrate that APP plays a pivotal role in maintaining an appropriate balance of excitation and inhibition (E/I) in neural circuits. A model is proposed whereby APP acts as a rheostat in a molecular circuit that modulates hyperexcitability through mGluR5 and FMRP. Both over- and under-expression of APP in the context of the Fmr1(KO) increases seizure propensity suggesting that an APP rheostat maintains appropriate E/I levels but is overloaded by mGluR5-mediated excitation in the absence of FMRP. These findings are discussed in relation to novel treatment approaches to restore APP homeostasis in FXS.

  7. Apps of Steel: Are Exercise Apps Providing Consumers with Realistic Expectations?: A Content Analysis of Exercise Apps for Presence of Behavior Change Theory

    ERIC Educational Resources Information Center

    Cowan, Logan T.; Van Wagenen, Sarah A.; Brown, Brittany A.; Hedin, Riley J.; Seino-Stephan, Yukiko; Hall, P. Cougar; West, Joshua H.

    2013-01-01

    Objective. To quantify the presence of health behavior theory constructs in iPhone apps targeting physical activity. Methods. This study used a content analysis of 127 apps from Apple's (App Store) "Health & Fitness" category. Coders downloaded the apps and then used an established theory-based instrument to rate each app's inclusion of…

  8. Reduction of Abeta amyloid pathology in APPPS1 transgenic mice in the absence of gut microbiota.

    PubMed

    Harach, T; Marungruang, N; Duthilleul, N; Cheatham, V; Mc Coy, K D; Frisoni, G; Neher, J J; Fåk, F; Jucker, M; Lasser, T; Bolmont, T

    2017-02-08

    Alzheimer's disease is the most common form of dementia in the western world, however there is no cure available for this devastating neurodegenerative disorder. Despite clinical and experimental evidence implicating the intestinal microbiota in a number of brain disorders, its impact on Alzheimer's disease is not known. To this end we sequenced bacterial 16S rRNA from fecal samples of Aβ precursor protein (APP) transgenic mouse model and found a remarkable shift in the gut microbiota as compared to non-transgenic wild-type mice. Subsequently we generated germ-free APP transgenic mice and found a drastic reduction of cerebral Aβ amyloid pathology when compared to control mice with intestinal microbiota. Importantly, colonization of germ-free APP transgenic mice with microbiota from conventionally-raised APP transgenic mice increased cerebral Aβ pathology, while colonization with microbiota from wild-type mice was less effective in increasing cerebral Aβ levels. Our results indicate a microbial involvement in the development of Abeta amyloid pathology, and suggest that microbiota may contribute to the development of neurodegenerative diseases.

  9. Reduction of Abeta amyloid pathology in APPPS1 transgenic mice in the absence of gut microbiota

    PubMed Central

    Harach, T.; Marungruang, N.; Duthilleul, N.; Cheatham, V.; Mc Coy, K. D.; Frisoni, G.; Neher, J. J.; Fåk, F.; Jucker, M.; Lasser, T.; Bolmont, T.

    2017-01-01

    Alzheimer’s disease is the most common form of dementia in the western world, however there is no cure available for this devastating neurodegenerative disorder. Despite clinical and experimental evidence implicating the intestinal microbiota in a number of brain disorders, its impact on Alzheimer’s disease is not known. To this end we sequenced bacterial 16S rRNA from fecal samples of Aβ precursor protein (APP) transgenic mouse model and found a remarkable shift in the gut microbiota as compared to non-transgenic wild-type mice. Subsequently we generated germ-free APP transgenic mice and found a drastic reduction of cerebral Aβ amyloid pathology when compared to control mice with intestinal microbiota. Importantly, colonization of germ-free APP transgenic mice with microbiota from conventionally-raised APP transgenic mice increased cerebral Aβ pathology, while colonization with microbiota from wild-type mice was less effective in increasing cerebral Aβ levels. Our results indicate a microbial involvement in the development of Abeta amyloid pathology, and suggest that microbiota may contribute to the development of neurodegenerative diseases. PMID:28176819

  10. An over expression APP model for anti-Alzheimer disease drug screening created by zinc finger nuclease technology.

    PubMed

    Zhang, Xiaojing; Li, Hui; Mao, Yiqing; Li, Zhixin; Wang, Rong; Guo, Tingting; Jin, Ling; Song, Rongjing; Xu, Wei; Zhou, Na; Zhang, Yizhuang; Hu, Ruobi; Wang, Xi; Huang, Huakang; Lei, Zhen; Niu, Gang; Irwin, David M; Tan, Huanran

    2013-01-01

    Zinc Finger Nucleases (ZFNs), famous for their ability to precisely and efficiently modify specific genomic loci, have been employed in numerous transgenic model organism and cell constructions. Here we employ the ZFNs technology, with homologous recombination (HR), to construct sequence-specific Amyloid Precursor Protein (APP) knock-in cells. With the use of ZFNs, we established APP knock in cell lines with gene-modification efficiencies of about 7%. We electroporated DNA fragment containing the promoter and the protein coding regions of the zinc finger nucleases into cells, instead of the plasmids, to avoid problems associated with off target homologous recombination, and adopted a pair of mutated FokI cleavage domains to reduce the toxic effects of the ZFNs on cell growth. Since over-expression of APP, or a subdomain of it, might lead to an immediately lethal effect, we used the Cre-LoxP System to regulate APP expression. Our genetically transformed cell lines, w5c1 and s12c8, showed detectable APP and Amyloid β (Aβ) production. The Swedish double mutation in the APP coding sequence enhanced APP and Aβ abundance. What is more, the activity of the three key secretases in Aβ formation could be modulated, indicating that these transgenic cells have potential for drug screening to modify amyloid metabolism in cells. Our transformed cells could readily be propagated in culture and should provide an excellent experimental medium for elucidating aspects of the molecular pathogenesis of Alzheimer's disease, especially those concerning the amyloidogenic pathways involving mutations in the APP coding sequence. The cellular models may also serve as a tool for deriving potentially useful therapeutic agents.

  11. APP intracellular domain derived from amyloidogenic β- and γ-secretase cleavage regulates neprilysin expression

    PubMed Central

    Grimm, Marcus O. W.; Mett, Janine; Stahlmann, Christoph P.; Grösgen, Sven; Haupenthal, Viola J.; Blümel, Tamara; Hundsdörfer, Benjamin; Zimmer, Valerie C.; Mylonas, Nadine T.; Tanila, Heikki; Müller, Ulrike; Grimm, Heike S.; Hartmann, Tobias

    2015-01-01

    Alzheimer's disease (AD) is characterized by an accumulation of Amyloid-β (Aβ), released by sequential proteolytic processing of the amyloid precursor protein (APP) by β - and γ-secretase. Aβ peptides can aggregate, leading to toxic Aβ oligomers and amyloid plaque formation. Aβ accumulation is not only dependent on de novo synthesis but also on Aβ degradation. Neprilysin (NEP) is one of the major enzymes involved in Aβ degradation. Here we investigate the molecular mechanism of NEP regulation, which is up to now controversially discussed to be affected by APP processing itself. We found that NEP expression is highly dependent on the APP intracellular domain (AICD), released by APP processing. Mouse embryonic fibroblasts devoid of APP processing, either by the lack of the catalytically active subunit of the γ-secretase complex [presenilin (PS) 1/2] or by the lack of APP and the APP-like protein 2 (APLP2), showed a decreased NEP expression, activity and protein level. Similar results were obtained by utilizing cells lacking a functional AICD domain (APPΔCT15) or expressing mutations in the genes encoding for PS1. AICD supplementation or retransfection with an AICD encoding plasmid could rescue the down-regulation of NEP further strengthening the link between AICD and transcriptional NEP regulation, in which Fe65 acts as an important adaptor protein. Especially AICD generated by the amyloidogenic pathway seems to be more involved in the regulation of NEP expression. In line, analysis of NEP gene expression in vivo in six transgenic AD mouse models (APP and APLP2 single knock-outs, APP/APLP2 double knock-out, APP-swedish, APP-swedish/PS1Δexon9, and APPΔCT15) confirmed the results obtained in cell culture. In summary, in the present study we clearly demonstrate an AICD-dependent regulation of the Aβ-degrading enzyme NEP in vitro and in vivo and elucidate the underlying mechanisms that might be beneficial to develop new therapeutic strategies for the

  12. APP intracellular domain derived from amyloidogenic β- and γ-secretase cleavage regulates neprilysin expression.

    PubMed

    Grimm, Marcus O W; Mett, Janine; Stahlmann, Christoph P; Grösgen, Sven; Haupenthal, Viola J; Blümel, Tamara; Hundsdörfer, Benjamin; Zimmer, Valerie C; Mylonas, Nadine T; Tanila, Heikki; Müller, Ulrike; Grimm, Heike S; Hartmann, Tobias

    2015-01-01

    Alzheimer's disease (AD) is characterized by an accumulation of Amyloid-β (Aβ), released by sequential proteolytic processing of the amyloid precursor protein (APP) by β - and γ-secretase. Aβ peptides can aggregate, leading to toxic Aβ oligomers and amyloid plaque formation. Aβ accumulation is not only dependent on de novo synthesis but also on Aβ degradation. Neprilysin (NEP) is one of the major enzymes involved in Aβ degradation. Here we investigate the molecular mechanism of NEP regulation, which is up to now controversially discussed to be affected by APP processing itself. We found that NEP expression is highly dependent on the APP intracellular domain (AICD), released by APP processing. Mouse embryonic fibroblasts devoid of APP processing, either by the lack of the catalytically active subunit of the γ-secretase complex [presenilin (PS) 1/2] or by the lack of APP and the APP-like protein 2 (APLP2), showed a decreased NEP expression, activity and protein level. Similar results were obtained by utilizing cells lacking a functional AICD domain (APPΔCT15) or expressing mutations in the genes encoding for PS1. AICD supplementation or retransfection with an AICD encoding plasmid could rescue the down-regulation of NEP further strengthening the link between AICD and transcriptional NEP regulation, in which Fe65 acts as an important adaptor protein. Especially AICD generated by the amyloidogenic pathway seems to be more involved in the regulation of NEP expression. In line, analysis of NEP gene expression in vivo in six transgenic AD mouse models (APP and APLP2 single knock-outs, APP/APLP2 double knock-out, APP-swedish, APP-swedish/PS1Δexon9, and APPΔCT15) confirmed the results obtained in cell culture. In summary, in the present study we clearly demonstrate an AICD-dependent regulation of the Aβ-degrading enzyme NEP in vitro and in vivo and elucidate the underlying mechanisms that might be beneficial to develop new therapeutic strategies for the

  13. Diabetes mHealth Apps: Designing for Greater Uptake.

    PubMed

    Brahmbhatt, Ronak; Niakan, Shadi; Saha, Nishita; Tewari, Anukriti; Pirani, Ashfiya; Keshavjee, Natasha; Mugambi, Dora; Alavi, Nasrin; Keshavjee, Karim

    2017-01-01

    mHealth apps are not being used. Over 45,000 mhealth apps are languishing in mobile app stores. We evaluated over 200 diabetes mobile apps found in the Apple and Google app stores using a framework that we recently published. None of the apps met all 15 criteria identified by our framework. The largest number of apps fell into the category of Type 1 diabetes blood sugar and medication trackers. Other types of apps included educational apps such as recipe apps, guideline dissemination apps, simple diabetes education apps, etc. There is a need for more Type 2 apps and for all types of apps that are better integrated into EMRs for more holistic care that can be prescribed by clinicians and monitored and supported by the health care team.

  14. An Android Communication App Forensic Taxonomy.

    PubMed

    Azfar, Abdullah; Choo, Kim-Kwang Raymond; Liu, Lin

    2016-09-01

    Due to the popularity of Android devices and applications (apps), Android forensics is one of the most studied topics within mobile forensics. Communication apps, such as instant messaging and Voice over IP (VoIP), are one popular app category used by mobile device users, including criminals. Therefore, a taxonomy outlining artifacts of forensic interest involving the use of Android communication apps will facilitate the timely collection and analysis of evidentiary materials from such apps. In this paper, 30 popular Android communication apps were examined, where a logical extraction of the Android phone images was collected using XRY, a widely used mobile forensic tool. Various information of forensic interest, such as contact lists and chronology of messages, was recovered. Based on the findings, a two-dimensional taxonomy of the forensic artifacts of the communication apps is proposed, with the app categories in one dimension and the classes of artifacts in the other dimension. Finally, the artifacts identified in the study of the 30 communication apps are summarized using the taxonomy. It is expected that the proposed taxonomy and the forensic findings in this paper will assist forensic investigations involving Android communication apps.

  15. Transcriptional Memory in the Drosophila Embryo.

    PubMed

    Ferraro, Teresa; Esposito, Emilia; Mancini, Laure; Ng, Sam; Lucas, Tanguy; Coppey, Mathieu; Dostatni, Nathalie; Walczak, Aleksandra M; Levine, Michael; Lagha, Mounia

    2016-01-25

    Transmission of active transcriptional states from mother to daughter cells has the potential to foster precision in the gene expression programs underlying development. Such transcriptional memory has been specifically proposed to promote rapid reactivation of complex gene expression profiles after successive mitoses in Drosophila development [1]. By monitoring transcription in living Drosophila embryos, we provide the first evidence for transcriptional memory in animal development. We specifically monitored the activities of stochastically expressed transgenes in order to distinguish active and inactive mother cells and the behaviors of their daughter nuclei after mitosis. Quantitative analyses reveal that there is a 4-fold higher probability for rapid reactivation after mitosis when the mother experienced transcription. Moreover, memory nuclei activate transcription twice as fast as neighboring inactive mothers, thus leading to augmented levels of gene expression. We propose that transcriptional memory is a mechanism of precision, which helps coordinate gene activity during embryogenesis.

  16. IL-10 Alters Immunoproteostasis in APP mice, Increasing Plaque Burden and Worsening Cognitive Behavior

    PubMed Central

    Chakrabarty, Paramita; Li, Andrew; Ceballos-Diaz, Carolina; Eddy, James A.; Funk, Cory C; Moore, Brenda; DiNunno, Nadia; Rosario, Awilda M; Cruz, Pedro E; Verbeeck, Christophe; Sacino, Amanda; Nix, Sarah; Janus, Christopher; Price, Nathan D; Das, Pritam; Golde, Todd E

    2014-01-01

    Summary Anti-inflammatory strategies are proposed to have beneficial effects in Alzheimer's disease. To explore how anti-inflammatory cytokine signaling affects Aβ pathology, we investigated the effects of adeno-associated virus (AAV2/1) mediated expression of Interleukin (IL)-10 in the brains of APP transgenic mouse models. IL-10 expression resulted in increased Aβ accumulation and impaired memory in APP mice. A focused transcriptome analysis revealed changes consistent with enhanced IL-10 signaling and increased ApoE expression in IL-10 expressing APP mice. ApoE protein was selectively increased in the plaque-associated insoluble cellular fraction, likely due to direct interaction with aggregated Aβ in the IL-10 expressing APP mice. Ex vivo studies also show that IL-10 and ApoE can individually impair glial Aβ phagocytosis. Our observations that IL-10 has an unexpected negative effect on Aβ proteostasis and cognition in APP mouse models demonstrate the complex interplay between innate immunity and proteostasis in neurodegenerative diseases, an interaction we call immunoproteostasis. PMID:25619653

  17. Palmitoylated APP Forms Dimers, Cleaved by BACE1.

    PubMed

    Bhattacharyya, Raja; Fenn, Rebecca H; Barren, Cory; Tanzi, Rudolph E; Kovacs, Dora M

    2016-01-01

    A major rate-limiting step for Aβ generation and deposition in Alzheimer's disease brains is BACE1-mediated cleavage (β-cleavage) of the amyloid precursor protein (APP). We previously reported that APP undergoes palmitoylation at two cysteine residues (Cys186 and Cys187) in the E1-ectodomain. 8-10% of total APP is palmitoylated in vitro and in vivo. Palmitoylated APP (palAPP) shows greater preference for β-cleavage than total APP in detergent resistant lipid rafts. Protein palmitoylation is known to promote protein dimerization. Since dimerization of APP at its E1-ectodomain results in elevated BACE1-mediated cleavage of APP, we have now investigated whether palmitoylation of APP affects its dimerization and whether this leads to elevated β-cleavage of the protein. Here we report that over 90% of palAPP is dimerized while only ~20% of total APP forms dimers. PalAPP-dimers are predominantly cis-oriented while total APP dimerizes in both cis- and trans-orientation. PalAPP forms dimers 4.5-times more efficiently than total APP. Overexpression of the palmitoylating enzymes DHHC7 and DHHC21 that increase palAPP levels and Aβ release, also increased APP dimerization in cells. Conversely, inhibition of APP palmitoylation by pharmacological inhibitors reduced APP-dimerization in coimmunoprecipitation and FLIM/FRET assays. Finally, in vitro BACE1-activity assays demonstrate that palmitoylation-dependent dimerization of APP promotes β-cleavage of APP in lipid-rich detergent resistant cell membranes (DRMs), when compared to total APP. Most importantly, generation of sAPPβ-sAPPβ dimers is dependent on APP-palmitoylation while total sAPPβ generation is not. Since BACE1 shows preference for palAPP dimers over total APP, palAPP dimers may serve as novel targets for effective β-cleavage inhibitors of APP as opposed to BACE1 inhibitors.

  18. Palmitoylated APP Forms Dimers, Cleaved by BACE1

    PubMed Central

    Fenn, Rebecca H.; Barren, Cory; Tanzi, Rudolph E.; Kovacs, Dora M.

    2016-01-01

    A major rate-limiting step for Aβ generation and deposition in Alzheimer’s disease brains is BACE1-mediated cleavage (β-cleavage) of the amyloid precursor protein (APP). We previously reported that APP undergoes palmitoylation at two cysteine residues (Cys186 and Cys187) in the E1-ectodomain. 8–10% of total APP is palmitoylated in vitro and in vivo. Palmitoylated APP (palAPP) shows greater preference for β-cleavage than total APP in detergent resistant lipid rafts. Protein palmitoylation is known to promote protein dimerization. Since dimerization of APP at its E1-ectodomain results in elevated BACE1-mediated cleavage of APP, we have now investigated whether palmitoylation of APP affects its dimerization and whether this leads to elevated β-cleavage of the protein. Here we report that over 90% of palAPP is dimerized while only ~20% of total APP forms dimers. PalAPP-dimers are predominantly cis-oriented while total APP dimerizes in both cis- and trans-orientation. PalAPP forms dimers 4.5-times more efficiently than total APP. Overexpression of the palmitoylating enzymes DHHC7 and DHHC21 that increase palAPP levels and Aβ release, also increased APP dimerization in cells. Conversely, inhibition of APP palmitoylation by pharmacological inhibitors reduced APP-dimerization in coimmunoprecipitation and FLIM/FRET assays. Finally, in vitro BACE1-activity assays demonstrate that palmitoylation-dependent dimerization of APP promotes β-cleavage of APP in lipid-rich detergent resistant cell membranes (DRMs), when compared to total APP. Most importantly, generation of sAPPβ-sAPPβ dimers is dependent on APP-palmitoylation while total sAPPβ generation is not. Since BACE1 shows preference for palAPP dimers over total APP, palAPP dimers may serve as novel targets for effective β-cleavage inhibitors of APP as opposed to BACE1 inhibitors. PMID:27875558

  19. Neuroanatomy and transgenic technologies

    Technology Transfer Automated Retrieval System (TEKTRAN)

    This is a short review that introduces recent advances of neuroanatomy and transgenic technologies. The anatomical complexity of the nervous system remains a subject of tremendous fascination among neuroscientists. In order to tackle this extraordinary complexity, powerful transgenic technologies a...

  20. Hypnosis--there's an app for that: a systematic review of hypnosis apps.

    PubMed

    Sucala, Madalina; Schnur, Julie B; Glazier, Kimberly; Miller, Sarah J; Green, Joseph P; Montgomery, Guy H

    2013-01-01

    This study systematically reviews the hypnosis apps available via iTunes that were compatible with iPhone or iPad. Of 1455 apps identified on iTunes, 407 met inclusion criteria and were further reviewed. Most common hypnosis app targets were weight loss (23%), boosting self-esteem (20%), and relaxation/stress reduction (19%); 83% of apps delivered hypnosis via audio track, and 37% allowed tailoring. Less than 14% of apps reported disclaimers. None of the apps reported having been tested for efficacy, and none reported being evidence based. Although apps have the potential to enhance hypnosis delivery, it seems as though technology has raced ahead of the supporting science. Recommendations from clinical researchers and policy makers are needed to inform responsible hypnosis app development and use.

  1. Redefining Cheminformatics with Intuitive Collaborative Mobile Apps

    PubMed Central

    Clark, Alex M; Ekins, Sean; Williams, Antony J

    2012-01-01

    Abstract The proliferation of mobile devices such as smartphones and tablet computers has recently been extended to include a growing ecosystem of increasingly sophisticated chemistry software packages, commonly known as apps. The capabilities that these apps can offer to the practicing chemist are approaching those of conventional desktop-based software, but apps tend to be focused on a relatively small range of tasks. To overcome this, chemistry apps must be able to seamlessly transfer data to other apps, and through the network to other devices, as well as to other platforms, such as desktops and servers, using documented file formats and protocols whenever possible. This article describes the development and state of the art with regard to chemistry-aware apps that make use of facile data interchange, and some of the scenarios in which these apps can be inserted into a chemical information workflow to increase productivity. A selection of contemporary apps is used to demonstrate their relevance to pharmaceutical research. Mobile apps represent a novel approach for delivery of cheminformatics tools to chemists and other scientists, and indications suggest that mobile devices represent a disruptive technology for drug discovery, as they have been to many other industries. PMID:23198002

  2. APP Causes Hyperexcitability in Fragile X Mice

    PubMed Central

    Westmark, Cara J.; Chuang, Shih-Chieh; Hays, Seth A.; Filon, Mikolaj J.; Ray, Brian C.; Westmark, Pamela R.; Gibson, Jay R.; Huber, Kimberly M.; Wong, Robert K. S.

    2016-01-01

    Amyloid-beta protein precursor (APP) and metabolite levels are altered in fragile X syndrome (FXS) patients and in the mouse model of the disorder, Fmr1KO mice. Normalization of APP levels in Fmr1KO mice (Fmr1KO/APPHET mice) rescues many disease phenotypes. Thus, APP is a potential biomarker as well as therapeutic target for FXS. Hyperexcitability is a key phenotype of FXS. Herein, we determine the effects of APP levels on hyperexcitability in Fmr1KO brain slices. Fmr1KO/APPHET slices exhibit complete rescue of UP states in a neocortical hyperexcitability model and reduced duration of ictal discharges in a CA3 hippocampal model. These data demonstrate that APP plays a pivotal role in maintaining an appropriate balance of excitation and inhibition (E/I) in neural circuits. A model is proposed whereby APP acts as a rheostat in a molecular circuit that modulates hyperexcitability through mGluR5 and FMRP. Both over- and under-expression of APP in the context of the Fmr1KO increases seizure propensity suggesting that an APP rheostat maintains appropriate E/I levels but is overloaded by mGluR5-mediated excitation in the absence of FMRP. These findings are discussed in relation to novel treatment approaches to restore APP homeostasis in FXS. PMID:28018172

  3. Color Addition and Subtraction Apps

    NASA Astrophysics Data System (ADS)

    Ruiz, Frances; Ruiz, Michael J.

    2015-10-01

    Color addition and subtraction apps in HTML5 have been developed for students as an online hands-on experience so that they can more easily master principles introduced through traditional classroom demonstrations. The evolution of the additive RGB color model is traced through the early IBM color adapters so that students can proceed step by step in understanding mathematical representations of RGB color. Finally, color addition and subtraction are presented for the X11 colors from web design to illustrate yet another real-life application of color mixing.

  4. Assessing senescence in Drosophila using video tracking.

    PubMed

    Ardekani, Reza; Tavaré, Simon; Tower, John

    2013-01-01

    Senescence is associated with changes in gene expression, including the upregulation of stress response- and innate immune response-related genes. In addition, aging animals exhibit characteristic changes in movement behaviors including decreased gait speed and a deterioration in sleep/wake rhythms. Here, we describe methods for tracking Drosophila melanogaster movements in 3D with simultaneous quantification of fluorescent transgenic reporters. This approach allows for the assessment of correlations between behavior, aging, and gene expression as well as for the quantification of biomarkers of aging.

  5. A Guide to Help Consumers Choose Apps and Avoid App Overload

    ERIC Educational Resources Information Center

    Schuster, Ellen; Zimmerman, Lynda

    2014-01-01

    Mobile technology has transformed the way consumers access and use information. The exponential growth of mobile apps makes finding suitable, easy-to-use nutrition and health-related apps challenging. A guide for consumers helps them ask important questions before downloading apps. The guide can be adapted for other Extension disciplines.

  6. Expert Involvement Predicts mHealth App Downloads: Multivariate Regression Analysis of Urology Apps

    PubMed Central

    Osório, Luís; Cavadas, Vitor; Fraga, Avelino; Carrasquinho, Eduardo; Cardoso de Oliveira, Eduardo; Castelo-Branco, Miguel; Roobol, Monique J

    2016-01-01

    Background Urological mobile medical (mHealth) apps are gaining popularity with both clinicians and patients. mHealth is a rapidly evolving and heterogeneous field, with some urology apps being downloaded over 10,000 times and others not at all. The factors that contribute to medical app downloads have yet to be identified, including the hypothetical influence of expert involvement in app development. Objective The objective of our study was to identify predictors of the number of urology app downloads. Methods We reviewed urology apps available in the Google Play Store and collected publicly available data. Multivariate ordinal logistic regression evaluated the effect of publicly available app variables on the number of apps being downloaded. Results Of 129 urology apps eligible for study, only 2 (1.6%) had >10,000 downloads, with half having ≤100 downloads and 4 (3.1%) having none at all. Apps developed with expert urologist involvement (P=.003), optional in-app purchases (P=.01), higher user rating (P<.001), and more user reviews (P<.001) were more likely to be installed. App cost was inversely related to the number of downloads (P<.001). Only data from the Google Play Store and the developers’ websites, but not other platforms, were publicly available for analysis, and the level and nature of expert involvement was not documented. Conclusions The explicit participation of urologists in app development is likely to enhance its chances to have a higher number of downloads. This finding should help in the design of better apps and further promote urologist involvement in mHealth. Official certification processes are required to ensure app quality and user safety. PMID:27421338

  7. Toward new Drosophila paradigms.

    PubMed

    Andrioli, Luiz Paulo

    2012-08-01

    The fruit fly Drosophila melanogaster is a great model system in developmental biology studies and related disciplines. In a historical perspective, I focus on the formation of the Drosophila segmental body plan using a comparative approach. I highlight the evolutionary trend of increasing complexity of the molecular segmentation network in arthropods that resulted in an incredible degree of complexity at the gap gene level in derived Diptera. There is growing evidence that Drosophila is a highly derived insect, and we are still far from fully understanding the underlying evolutionary mechanisms that led to its complexity. In addition, recent data have altered how we view the transcriptional regulatory mechanisms that control segmentation in Drosophila. However, these observations are not all bad news for the field. Instead, they stimulate further study of segmentation in Drosophila and in other species as well. To me, these seemingly new Drosophila paradigms are very challenging ones.

  8. Optogenetic pacing in Drosophila melanogaster (Conference Presentation)

    NASA Astrophysics Data System (ADS)

    Alex, Aneesh; Li, Airong; Men, Jing; Jerwick, Jason; Tanzi, Rudolph E.; Zhou, Chao

    2016-03-01

    A non-invasive, contact-less cardiac pacing technology can be a powerful tool in basic cardiac research and in clinics. Currently, electrical pacing is the gold standard for cardiac pacing. Although highly effective in controlling the cardiac function, the invasive nature, non-specificity to cardiac tissues and possible tissue damage limits its capabilities. Optical pacing of heart is a promising alternative, which is non-invasive and more specific, has high spatial and temporal precision, and avoids shortcomings in electrical stimulation. Optical coherence tomography has been proved to be an effective technique in non-invasive imaging in vivo with ultrahigh resolution and imaging speed. In the last several years, non-invasive specific optical pacing in animal hearts has been reported in quail, zebrafish, and rabbit models. However, Drosophila Melanogaster, which is a significant model with orthologs of 75% of human disease genes, has rarely been studied concerning their optical pacing in heart. Here, we combined optogenetic control of Drosophila heartbeat with optical coherence microscopy (OCM) technique for the first time. The light-gated cation channel, channelrhodopsin-2 (ChR2) was specifically expressed by transgene as a pacemaker in drosophila heart. By stimulating the pacemaker with 472 nm pulsed laser light at different frequencies, we achieved non-invasive and more specific optical control of the Drosophila heart rhythm, which demonstrates the wide potential of optical pacing for studying cardiac dynamics and development. Imaging capability of our customized OCM system was also involved to observe the pacing effect visually. No tissue damage was found after long exposure to laser pulses, which proved the safety of optogenetic control of Drosophila heart.

  9. App Development Paradigms for Instructional Developers

    ERIC Educational Resources Information Center

    Luterbach, Kenneth J.; Hubbell, Kenneth R.

    2015-01-01

    To create instructional apps for desktop, laptop and mobile devices, developers must select a development tool. Tool selection is critical and complicated by the large number and variety of app development tools. One important criterion to consider is the type of development environment, which may primarily be visual or symbolic. Those distinct…

  10. Cool Apps: Productivity at Your Fingertips

    ERIC Educational Resources Information Center

    Flaherty, Bill

    2013-01-01

    In addition to listing apps and their value, this article focuses on ways people can be more productive by adopting certain workflows in several ways. Apps listed herein include those useful in calendaring, printing, photo-editing, image-recognition, image scanning, electronic signatures, and making and sharing lists and notes.

  11. Will HTML5 Kill the Native App?

    ERIC Educational Resources Information Center

    Fredette, Michelle

    2013-01-01

    For colleges and universities today, the question is no longer whether to develop a campus app or not. Instead, the debate has shifted to the best--and most cost-efficient--way to make campus applications accessible to the myriad devices and operating systems out there. Schools have a few options: They can develop multiple native app versions;…

  12. Is There an App for that?

    ERIC Educational Resources Information Center

    Douglas, Karen H.; Wojcik, Brian W.; Thompson, James R.

    2012-01-01

    Everyday technologies (e.g., iPods, iPads, and Smart Phones) other applications (apps) that can serve as supports to students with intellectual and related developmental disabilities. The extent to which apps that are currently on the market are aligned with the support needs of children was evaluated using the subscale framework of the…

  13. Smart apps for the smart plastic surgeon.

    PubMed

    Venkataram, Aniketh; Ellur, Sunderraj; Kujur, Abha Rani; Joseph, Vijay

    2015-01-01

    Smartphones have the ability to benefit plastic surgeons in all aspects of patient care and education. With the sheer number of applications available and more being created everyday, it is easy to miss out on apps which could be of great relevance. Moreover, the range of android applications available has not been extensively discussed in the literature. To this end, we have compiled an exhaustive list of android smartphone applications, which we feel can help our day to day functioning. The apps have been extensively reviewed and neatly described along with all their potential uses. In addition, we have made an effort to highlight 'non-medical' or efficiency apps which can improve departmental functioning. These apps have not been described in prior articles, and their functionality might not be known to all. We believe that the technology savvy plastic surgeon can make maximum use of these apps to his benefit.

  14. Smart apps for the smart plastic surgeon

    PubMed Central

    Venkataram, Aniketh; Ellur, Sunderraj; Kujur, Abha Rani; Joseph, Vijay

    2015-01-01

    Smartphones have the ability to benefit plastic surgeons in all aspects of patient care and education. With the sheer number of applications available and more being created everyday, it is easy to miss out on apps which could be of great relevance. Moreover, the range of android applications available has not been extensively discussed in the literature. To this end, we have compiled an exhaustive list of android smartphone applications, which we feel can help our day to day functioning. The apps have been extensively reviewed and neatly described along with all their potential uses. In addition, we have made an effort to highlight ‘non-medical’ or efficiency apps which can improve departmental functioning. These apps have not been described in prior articles, and their functionality might not be known to all. We believe that the technology savvy plastic surgeon can make maximum use of these apps to his benefit. PMID:25991890

  15. Cell Biology Apps for Apple Devices

    PubMed Central

    Stark, Louisa A.

    2012-01-01

    Apps for touch-pad devices hold promise for guiding and supporting learning. Students may use them in the classroom or on their own for didactic instruction, just-in-time learning, or review. Since Apple touch-pad devices (i.e., iPad and iPhone) have a substantial share of the touch-pad device market (Campbell, 2012), this Feature will explore cell biology apps available from the App Store. My review includes iPad and iPhone apps available in June 2012, but does not include courses, lectures, podcasts, audiobooks, texts, or other books. I rated each app on a five-point scale (1 star = lowest; 5 stars = highest) for educational and production values; I also provide an overall score. PMID:22949420

  16. Forensic Taxonomy of Android Social Apps.

    PubMed

    Azfar, Abdullah; Choo, Kim-Kwang Raymond; Liu, Lin

    2017-03-01

    An Android social app taxonomy incorporating artifacts that are of forensic interest will enable users and forensic investigators to identify the personally identifiable information (PII) stored by the apps. In this study, 30 popular Android social apps were examined. Artifacts of forensic interest (e.g., contacts lists, chronology of messages, and timestamp of an added contact) were recovered. In addition, images were located, and Facebook token strings used to tie account identities and gain access to information entered into Facebook by a user were identified. Based on the findings, a two-dimensional taxonomy of the forensic artifacts of the social apps is proposed. A comparative summary of existing forensic taxonomies of different categories of Android apps, designed to facilitate timely collection and analysis of evidentiary materials from Android devices, is presented.

  17. Cell biology apps for Apple devices.

    PubMed

    Stark, Louisa A

    2012-01-01

    Apps for touch-pad devices hold promise for guiding and supporting learning. Students may use them in the classroom or on their own for didactic instruction, just-in-time learning, or review. Since Apple touch-pad devices (i.e., iPad and iPhone) have a substantial share of the touch-pad device market (Campbell, 2012), this Feature will explore cell biology apps available from the App Store. My review includes iPad and iPhone apps available in June 2012, but does not include courses, lectures, podcasts, audiobooks, texts, or other books. I rated each app on a five-point scale (1 star = lowest; 5 stars = highest) for educational and production values; I also provide an overall score.

  18. Methylene Blue Modulates β-Secretase, Reverses Cerebral Amyloidosis, and Improves Cognition in Transgenic Mice*

    PubMed Central

    Mori, Takashi; Koyama, Naoki; Segawa, Tatsuya; Maeda, Masahiro; Maruyama, Nobuhiro; Kinoshita, Noriaki; Hou, Huayan; Tan, Jun; Town, Terrence

    2014-01-01

    Amyloid precursor protein (APP) proteolysis is required for production of amyloid-β (Aβ) peptides that comprise β-amyloid plaques in the brains of patients with Alzheimer disease (AD). Here, we tested whether the experimental agent methylene blue (MB), used for treatment of methemoglobinemia, might improve AD-like pathology and behavioral deficits. We orally administered MB to the aged transgenic PSAPP mouse model of cerebral amyloidosis and evaluated cognitive function and cerebral amyloid pathology. Beginning at 15 months of age, animals were gavaged with MB (3 mg/kg) or vehicle once daily for 3 months. MB treatment significantly prevented transgene-associated behavioral impairment, including hyperactivity, decreased object recognition, and defective spatial working and reference memory, but it did not alter nontransgenic mouse behavior. Moreover, brain parenchymal and cerebral vascular β-amyloid deposits as well as levels of various Aβ species, including oligomers, were mitigated in MB-treated PSAPP mice. These effects occurred with inhibition of amyloidogenic APP proteolysis. Specifically, β-carboxyl-terminal APP fragment and β-site APP cleaving enzyme 1 protein expression and activity were attenuated. Additionally, treatment of Chinese hamster ovary cells overexpressing human wild-type APP with MB significantly decreased Aβ production and amyloidogenic APP proteolysis. These results underscore the potential for oral MB treatment against AD-related cerebral amyloidosis by modulating the amyloidogenic pathway. PMID:25157105

  19. The Drosophila melanogaster cinnabar gene is a cell autonomous genetic marker in Aedes aegypti (Diptera: Culicidae).

    PubMed

    Sethuraman, Nagaraja; O'Brochta, David A

    2005-07-01

    The cinnabar gene of Drosophila melanogaster (Meigen) encodes for kynurenine hydroxylase, an enzyme involved in ommochrome biosynthesis. This gene is commonly included as a visible genetic marker in gene vectors used to create transgenic Aedes aegypti (L.) that are homozygous for the khw allele, the mosquito homolog of cinnabar. Unexpectedly, the phenotype of cells expressing kynurenine hydroxylase in transgenic Ae. aegypti is cell autonomous as demonstrated by the recovery of insects heterozygous for the kynurenine hydroxylase transgene with mosaic eye color patterns. In addition, a transgenic gynandromorph was recovered in which one-half of the insect was expressing the kynurenine hydroxylase transgene, including one eye with red pigmentation, whereas the other half of the insect was homozygous khw and included a white eye. The cell autonomous behavior of cinnabar in transgenic Ae. aegypti is unexpected and increases the utility of this genetic marker.

  20. App Chronic Disease Checklist: Protocol to Evaluate Mobile Apps for Chronic Disease Self-Management

    PubMed Central

    Anderson, Kevin; Burford, Oksana

    2016-01-01

    Background The availability of mobile health apps for self-care continues to increase. While little evidence of their clinical impact has been published, there is general agreement among health authorities and authors that consumers’ use of health apps assist in self-management and potentially clinical decision making. A consumer’s sustained engagement with a health app is dependent on the usability and functionality of the app. While numerous studies have attempted to evaluate health apps, there is a paucity of published methods that adequately recognize client experiences in the academic evaluation of apps for chronic conditions. Objective This paper reports (1) a protocol to shortlist health apps for academic evaluation, (2) synthesis of a checklist to screen health apps for quality and reliability, and (3) a proposed method to theoretically evaluate usability of health apps, with a view towards identifying one or more apps suitable for clinical assessment. Methods A Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow diagram was developed to guide the selection of the apps to be assessed. The screening checklist was thematically synthesized with reference to recurring constructs in published checklists and related materials for the assessment of health apps. The checklist was evaluated by the authors for face and construct validity. The proposed method for evaluation of health apps required the design of procedures for raters of apps, dummy data entry to test the apps, and analysis of raters’ scores. Results The PRISMA flow diagram comprises 5 steps: filtering of duplicate apps; eliminating non-English apps; removing apps requiring purchase, filtering apps not updated within the past year; and separation of apps into their core functionality. The screening checklist to evaluate the selected apps was named the App Chronic Disease Checklist, and comprises 4 sections with 6 questions in each section. The validity check verified

  1. Nebula/DSCR1 upregulation delays neurodegeneration and protects against APP-induced axonal transport defects by restoring calcineurin and GSK-3β signaling.

    PubMed

    Shaw, Jillian L; Chang, Karen T

    2013-01-01

    Post-mortem brains from Down syndrome (DS) and Alzheimer's disease (AD) patients show an upregulation of the Down syndrome critical region 1 protein (DSCR1), but its contribution to AD is not known. To gain insights into the role of DSCR1 in AD, we explored the functional interaction between DSCR1 and the amyloid precursor protein (APP), which is known to cause AD when duplicated or upregulated in DS. We find that the Drosophila homolog of DSCR1, Nebula, delays neurodegeneration and ameliorates axonal transport defects caused by APP overexpression. Live-imaging reveals that Nebula facilitates the transport of synaptic proteins and mitochondria affected by APP upregulation. Furthermore, we show that Nebula upregulation protects against axonal transport defects by restoring calcineurin and GSK-3β signaling altered by APP overexpression, thereby preserving cargo-motor interactions. As impaired transport of essential organelles caused by APP perturbation is thought to be an underlying cause of synaptic failure and neurodegeneration in AD, our findings imply that correcting calcineurin and GSK-3β signaling can prevent APP-induced pathologies. Our data further suggest that upregulation of Nebula/DSCR1 is neuroprotective in the presence of APP upregulation and provides evidence for calcineurin inhibition as a novel target for therapeutic intervention in preventing axonal transport impairments associated with AD.

  2. Motor impulsivity in APP-SWE mice: a model of Alzheimer's disease.

    PubMed

    Adriani, Walter; Ognibene, Elisa; Heuland, Emilie; Ghirardi, Orlando; Caprioli, Antonio; Laviola, Giovanni

    2006-09-01

    Among transgenic mouse models of Alzheimer's disease, APP-SWE mice have been shown to develop beta-amyloid plaques and to exhibit progressive impairment of cognitive function. Human Alzheimer's disease, however, also includes secondary clinical manifestations, spanning from hyperactivity to agitation. The aim of this study was a better characterization of motor impulsivity in APP-SWE mice, observed at 12 months of age, when levels of soluble beta-amyloid are elevated and beta-amyloid neuritic plaques start to appear. Mice were tested for spatial learning abilities in the Morris water maze (seven daily sessions, four trials per day). The distance traveled to reach the hidden platform showed a learning curve in both groups. This profile, however, was somewhat delayed in APP-SWE mice, thus confirming slightly impaired spatial capacities. To evaluate motor impulsivity, animals were trained to nose-poke for a food reward, which was delivered after a waiting interval that increased over days (15-60 s). Further nose-poking during this signaled waiting interval resulted in food-reward loss and electric-shock punishment. APP-SWE mice received an increased quantity of punishment and were able to earn fewer food rewards, suggesting inability to wait already at the lowest delay. After the animals were killed, prefrontal cortex samples were assessed for neurochemical parameters. Serotonin turnover was elevated in the prefrontal cortex of APP-SWE mice compared with controls. The results clearly confirm cognitive deficits, and are consistent with the hypothesis of reduced behavioral-inhibition abilities. Together with recent findings, APP-SWE mice emerge as a suitable animal model, characterized by a number of specific behavioral alterations, resembling primary and secondary symptoms of human Alzheimer's disease.

  3. Overview of an Algorithm Plugin Package (APP)

    NASA Astrophysics Data System (ADS)

    Linda, M.; Tilmes, C.; Fleig, A. J.

    2004-12-01

    Science software that runs operationally is fundamentally different than software that runs on a scientist's desktop. There are complexities in hosting software for automated production that are necessary and significant. Identifying common aspects of these complexities can simplify algorithm integration. We use NASA's MODIS and OMI data production systems as examples. An Algorithm Plugin Package (APP) is science software that is combined with algorithm-unique elements that permit the algorithm to interface with, and function within, the framework of a data processing system. The framework runs algorithms operationally against large quantities of data. The extra algorithm-unique items are constrained by the design of the data processing system. APPs often include infrastructure that is vastly similar. When the common elements in APPs are identified and abstracted, the cost of APP development, testing, and maintenance will be reduced. This paper is an overview of the extra algorithm-unique pieces that are shared between MODAPS and OMIDAPS APPs. Our exploration of APP structure will help builders of other production systems identify their common elements and reduce algorithm integration costs. Our goal is to complete the development of a library of functions and a menu of implementation choices that reflect common needs of APPs. The library and menu will reduce the time and energy required for science developers to integrate algorithms into production systems.

  4. There’s an App for That: Content Analysis of Paid Health and Fitness Apps

    PubMed Central

    Hall, P. Cougar; Hanson, Carl L; Barnes, Michael D; Giraud-Carrier, Christophe; Barrett, James

    2012-01-01

    Background The introduction of Apple’s iPhone provided a platform for developers to design third-party apps, which greatly expanded the functionality and utility of mobile devices for public health. Objective This study provides an overview of the developers’ written descriptions of health and fitness apps and appraises each app’s potential for influencing behavior change. Methods Data for this study came from a content analysis of health and fitness app descriptions available on iTunes during February 2011. The Health Education Curriculum Analysis Tool (HECAT) and the Precede-Proceed Model (PPM) were used as frameworks to guide the coding of 3336 paid apps. Results Compared to apps with a cost less than US $0.99, apps exceeding US $0.99 were more likely to be scored as intending to promote health or prevent disease (92.55%, 1925/3336 vs 83.59%, 1411/3336; P<.001), to be credible or trustworthy (91.11%, 1895/3336 vs 86.14%, 1454/3349; P<.001), and more likely to be used personally or recommended to a health care client (72.93%, 1517/2644 vs 66.77%, 1127/2644; P<.001). Apps related to healthy eating, physical activity, and personal health and wellness were more common than apps for substance abuse, mental and emotional health, violence prevention and safety, and sexual and reproductive health. Reinforcing apps were less common than predisposing and enabling apps. Only 1.86% (62/3336) of apps included all 3 factors (ie, predisposing, enabling, and reinforcing). Conclusions Development efforts could target public health behaviors for which few apps currently exist. Furthermore, practitioners should be cautious when promoting the use of apps as it appears most provide health-related information (predisposing) or make attempts at enabling behavior, with almost none including all theoretical factors recommended for behavior change. PMID:22584372

  5. Tannic acid is a natural β-secretase inhibitor that prevents cognitive impairment and mitigates Alzheimer-like pathology in transgenic mice.

    PubMed

    Mori, Takashi; Rezai-Zadeh, Kavon; Koyama, Naoki; Arendash, Gary W; Yamaguchi, Haruyasu; Kakuda, Nobuto; Horikoshi-Sakuraba, Yuko; Tan, Jun; Town, Terrence

    2012-02-24

    Amyloid precursor protein (APP) proteolysis is essential for production of amyloid-β (Aβ) peptides that form β-amyloid plaques in brains of Alzheimer disease (AD) patients. Recent focus has been directed toward a group of naturally occurring anti-amyloidogenic polyphenols known as flavonoids. We orally administered the flavonoid tannic acid (TA) to the transgenic PSAPP mouse model of cerebral amyloidosis (bearing mutant human APP and presenilin-1 transgenes) and evaluated cognitive function and AD-like pathology. Consumption of TA for 6 months prevented transgene-associated behavioral impairment including hyperactivity, decreased object recognition, and defective spatial reference memory, but did not alter nontransgenic mouse behavior. Accordingly, brain parenchymal and cerebral vascular β-amyloid deposits and abundance of various Aβ species including oligomers were mitigated in TA-treated PSAPP mice. These effects occurred with decreased cleavage of the β-carboxyl-terminal APP fragment, lowered soluble APP-β production, reduced β-site APP cleaving enzyme 1 protein stability and activity, and attenuated neuroinflammation. As in vitro validation, we treated well characterized mutant human APP-overexpressing murine neuron-like cells with TA and found significantly reduced Aβ production associated with less amyloidogenic APP proteolysis. Taken together, these results raise the possibility that dietary supplementation with TA may be prophylactic for AD by inhibiting β-secretase activity and neuroinflammation and thereby mitigating AD pathology.

  6. Presymptomatic alterations in energy metabolism and oxidative stress in the APP23 mouse model of Alzheimer disease.

    PubMed

    Hartl, Daniela; Schuldt, Victoria; Forler, Stephanie; Zabel, Claus; Klose, Joachim; Rohe, Michael

    2012-06-01

    Glucose hypometabolism is the earliest symptom observed in the brains of Alzheimer disease (AD) patients. In a former study, we analyzed the cortical proteome of the APP23 mouse model of AD at presymptomatic age (1 month) using a 2-D electrophoresis-based approach. Interestingly, long before amyloidosis can be observed in APP23 mice, proteins associated with energy metabolism were predominantly altered in transgenic as compared to wild-type mice indicating presymptomatic changes in energy metabolism. In the study presented here, we analyzed whether the observed changes were associated with oxidative stress and confirmed our previous findings in primary cortical neurons, which exhibited altered ADP/ATP levels if transgenic APP was expressed. Reactive oxygen species produced during energy metabolism have important roles in cell signaling and homeostasis as they modify proteins. We observed an overall up-regulation of protein oxidation status as shown by increased protein carbonylation in the cortex of presymptomatic APP23 mice. Interestingly, many carbonylated proteins, such as Vilip1 and Syntaxin were associated to synaptic plasticity. This demonstrates an important link between energy metabolism and synaptic function, which is altered in AD. In summary, we demonstrate that changes in cortical energy metabolism and increased protein oxidation precede the amyloidogenic phenotype in a mouse model for AD. These changes might contribute to synaptic failure observed in later disease stages, as synaptic transmission is particularly dependent on energy metabolism.

  7. NGF controls APP cleavage by downregulating APP phosphorylation at Thr668: relevance for Alzheimer's disease.

    PubMed

    Triaca, Viviana; Sposato, Valentina; Bolasco, Giulia; Ciotti, Maria Teresa; Pelicci, Piergiuseppe; Bruni, Amalia C; Cupidi, Chiara; Maletta, Raffaele; Feligioni, Marco; Nisticò, Robert; Canu, Nadia; Calissano, Pietro

    2016-08-01

    NGF has been implicated in forebrain neuroprotection from amyloidogenesis and Alzheimer's disease (AD). However, the underlying molecular mechanisms are still poorly understood. Here, we investigated the role of NGF signalling in the metabolism of amyloid precursor protein (APP) in forebrain neurons using primary cultures of septal neurons and acute septo-hippocampal brain slices. In this study, we show that NGF controls the basal level of APP phosphorylation at Thr668 (T668) by downregulating the activity of the Ser/Thr kinase JNK(p54) through the Tyr kinase signalling adaptor SH2-containing sequence C (ShcC). We also found that the specific NGF receptor, Tyr kinase A (TrkA), which is known to bind to APP, fails to interact with the fraction of APP molecules phosphorylated at T668 (APP(pT668) ). Accordingly, the amount of TrkA bound to APP is significantly reduced in the hippocampus of ShcC KO mice and of patients with AD in which elevated APP(pT668) levels are detected. NGF promotes TrkA binding to APP and APP trafficking to the Golgi, where APP-BACE interaction is hindered, finally resulting in reduced generation of sAPPβ, CTFβ and amyloid-beta (1-42). These results demonstrate that NGF signalling directly controls basal APP phosphorylation, subcellular localization and BACE cleavage, and pave the way for novel approaches specifically targeting ShcC signalling and/or the APP-TrkA interaction in AD therapy.

  8. A Behavior-Based Circuit Model of How Outcome Expectations Organize Learned Behavior in Larval "Drosophila"

    ERIC Educational Resources Information Center

    Schleyer, Michael; Saumweber, Timo; Nahrendorf, Wiebke; Fischer, Benjamin; von Alpen, Desiree; Pauls, Dennis; Thum, Andreas; Gerber, Bertram

    2011-01-01

    Drosophila larvae combine a numerically simple brain, a correspondingly moderate behavioral complexity, and the availability of a rich toolbox for transgenic manipulation. This makes them attractive as a study case when trying to achieve a circuit-level understanding of behavior organization. From a series of behavioral experiments, we suggest a…

  9. From analogue to apps--developing an app to prepare children for medical imaging procedures.

    PubMed

    Williams, Gigi; Greene, Siobhan

    2015-01-01

    The Royal Children's Hospital (RCH) in Melbourne has launched a world-first app for children that will help reduce anxiety and the need for anesthesia during medical imaging procedures. The free, game-based app, "Okee in Medical Imaging", helps children aged from four to eight years to prepare for all medical imaging procedures--X-ray, CT, MRI, ultrasound, nuclear medicine, and fluoroscopy. The app is designed to reduce anticipatory fear of imaging procedures, while helping to ensure that children attend imaging appointments equipped with the skills required for efficient and effective scans to be performed. This paper describes how the app was developed.

  10. Drosophila Blastorderm Analysis Software

    SciTech Connect

    2006-10-25

    PointCloudMake analyzes 3D fluorescent images of whole Drosophila embryo and produces a table-style "PointCloud" file which contains the coordinates and volumes of all the nuclei, cells, their associated relative gene expression levels along with morphological features of the embryo. See: Luengo Hendrix et at 2006 3D Morphology and Gene Expression in the Drosophila Blastoderm at Cellular Resolution manuscript submitted LBNL # LBNL-60178 Knowles DW, Keranen SVE, Biggin M. Sudar S (2002) Mapping organism expression levels at cellular resolution in developing Drosophila. In: Conchello JA, Cogswell CJ, Wilson T, editors. Three-Dimensional and Multidimensional Microscopy: Image Acquisition and Processing IX. pp. 57-64

  11. BACE2, as a novel APP theta-secretase, is not responsible for the pathogenesis of Alzheimer's disease in Down syndrome.

    PubMed

    Sun, Xiulian; He, Guiqiong; Song, Weihong

    2006-07-01

    Amyloid beta protein (Abeta), the major component of neuritic plaques in Alzheimer's disease (AD), is derived from APP by sequential cleavages of beta- and gamma-secretases. Beta-site APP cleaving enzyme 1 (BACE1) is the major beta-secretase in vivo. Beta-site APP cleaving enzyme 2 (BACE2) is the homologue of BACE1. The majority of people with Down syndrome (DS), also called Trisomy 21 syndrome, will develop AD neuropathology after middle age. We and others have shown that APP C99, the major beta-secretase product, and Abeta are markedly increased in DS. Since BACE2 is located on chromosome 21, it is speculated that BACE2 may play a role in AD pathogenesis in DS. In this report we found that BACE2 cleaves APP at a novel theta site downstream of the alpha site, abolishing Abeta production. Overexpression of BACE2 by lentivirus markedly reduced Abeta production in primary neurons derived from Swedish mutant APP transgenic mice. Despite an extra copy of the BACE2 gene in DS and the increase of its transcription, BACE2 protein levels are unchanged. Our data clearly demonstrate that BACE2, as a novel theta-secretase to cleave APP within the Abeta domain, is not involved in the AD pathogenesis of DS patients; instead, therapeutic interventions that potentiate BACE2 may prevent AD pathogenesis.

  12. The Top Chinese Mobile Health Apps: A Systematic Investigation

    PubMed Central

    Hsu, Jeffrey; Liu, Di; Yu, Ya Min; Zhao, Hui Tong; Chen, Zhi Rou; Li, Jiao

    2016-01-01

    Background China’s mHealth market is on track to become a global leader by industry size. The Chinese mobile app market and health care system have peculiarities that distinguish them from other app markets. To date, Chinese mHealth apps have not been systematically investigated. Objective The objective of this study was to provide an overview of Chinese mHealth apps as of December 2015. Methods We identified and investigated the most downloaded apps from the iOS and Android platforms. For each app, we analyzed and recorded its main service offered, mHealth initiative, disease and specialty focus, app cost, target user, Web app availability, and emphasis on information security. Standard descriptive statistics were used. Results A total of 234 apps met the inclusion criteria and were investigated. The apps targeting nonhealth care professionals focused on providing telemedicine and appointment-making services. The apps targeting health care professionals focused on education and peer reviewed articles. The most common disease-specific apps focused primarily on diabetes, hypertension, and hepatitis management. Most apps were free and available on both iOS and Android platforms. Conclusions The primary mHealth initiatives targeted by the apps reflect Chinese patients’ demand for access to medical care. Disease-specific apps are also representative of disease prevalence in China. Government press releases suggest that new policies on the horizon may shift the industry. PMID:27573724

  13. Finding a Depression App: A Review and Content Analysis of the Depression App Marketplace

    PubMed Central

    Shen, Nelson; Levitan, Michael-Jane; Johnson, Andrew; Bender, Jacqueline Lorene; Hamilton-Page, Michelle; Jadad, Alejandro (Alex) R

    2015-01-01

    Background Depression is highly prevalent and causes considerable suffering and disease burden despite the existence of wide-ranging treatment options. Mobile phone apps offer the potential to help close this treatment gap by confronting key barriers to accessing support for depression. Objectives Our goal was to identify and characterize the different types of mobile phone depression apps available in the marketplace. Methods A search for depression apps was conducted on the app stores of the five major mobile phone platforms: Android, iPhone, BlackBerry, Nokia, and Windows. Apps were included if they focused on depression and were available to people who self-identify as having depression. Data were extracted from the app descriptions found in the app stores. Results Of the 1054 apps identified by the search strategy, nearly one-quarter (23.0%, 243/1054) unique depression apps met the inclusion criteria. Over one-quarter (27.7%, 210/758) of the excluded apps failed to mention depression in the title or description. Two-thirds of the apps had as their main purpose providing therapeutic treatment (33.7%, 82/243) or psychoeducation (32.1%, 78/243). The other main purpose categories were medical assessment (16.9%, 41/243), symptom management (8.2%, 20/243), and supportive resources (1.6%, 4/243). A majority of the apps failed to sufficiently describe their organizational affiliation (65.0%, 158/243) and content source (61.7%, 150/243). There was a significant relationship (χ 2 5=50.5, P<.001) between the main purpose of the app and the reporting of content source, with most medical assessment apps reporting their content source (80.5%, 33/41). A fifth of the apps featured an e-book (20.6%, 50/243), audio therapy (16.9%, 41/243), or screening (16.9%, 41/243) function. Most apps had a dynamic user interface (72.4%, 176/243) and used text as the main type of media (51.9%, 126/243), and over a third (14.4%, 35/243) incorporated more than one form of media. Conclusion

  14. Meiosis in male Drosophila

    PubMed Central

    McKee, Bruce D.; Yan, Rihui; Tsai, Jui-He

    2012-01-01

    Meiosis entails sorting and separating both homologous and sister chromatids. The mechanisms for connecting sister chromatids and homologs during meiosis are highly conserved and include specialized forms of the cohesin complex and a tightly regulated homolog synapsis/recombination pathway designed to yield regular crossovers between homologous chromatids. Drosophila male meiosis is of special interest because it dispenses with large segments of the standard meiotic script, particularly recombination, synapsis and the associated structures. Instead, Drosophila relies on a unique protein complex composed of at least two novel proteins, SNM and MNM, to provide stable connections between homologs during meiosis I. Sister chromatid cohesion in Drosophila is mediated by cohesins, ring-shaped complexes that entrap sister chromatids. However, unlike other eukaryotes Drosophila does not rely on the highly conserved Rec8 cohesin in meiosis, but instead utilizes two novel cohesion proteins, ORD and SOLO, which interact with the SMC1/3 cohesin components in providing meiotic cohesion. PMID:23087836

  15. Efficient CRISPR/Cas9 plasmids for rapid and versatile genome editing in Drosophila.

    PubMed

    Gokcezade, Joseph; Sienski, Grzegorz; Duchek, Peter

    2014-09-17

    The CRISPR-associated RNA-guided nuclease Cas9 has emerged as a powerful tool for genome engineering in a variety of organisms. To achieve efficient gene targeting rates in Drosophila, current approaches require either injection of in vitro transcribed RNAs or injection into transgenic Cas9-expressing embryos. We report a simple and versatile alternative method for CRISPR-mediated genome editing in Drosophila using bicistronic Cas9/sgRNA expression vectors. Gene targeting with this single-plasmid injection approach is as efficient as in transgenic nanos-Cas9 embryos and allows the isolation of targeted knock-out and knock-in alleles by molecular screening within 2 months. Our strategy is independent of genetic background and does not require prior establishment of transgenic flies.

  16. Efficient CRISPR/Cas9 Plasmids for Rapid and Versatile Genome Editing in Drosophila

    PubMed Central

    Gokcezade, Joseph; Sienski, Grzegorz; Duchek, Peter

    2014-01-01

    The CRISPR-associated RNA-guided nuclease Cas9 has emerged as a powerful tool for genome engineering in a variety of organisms. To achieve efficient gene targeting rates in Drosophila, current approaches require either injection of in vitro transcribed RNAs or injection into transgenic Cas9-expressing embryos. We report a simple and versatile alternative method for CRISPR-mediated genome editing in Drosophila using bicistronic Cas9/sgRNA expression vectors. Gene targeting with this single-plasmid injection approach is as efficient as in transgenic nanos-Cas9 embryos and allows the isolation of targeted knock-out and knock-in alleles by molecular screening within 2 months. Our strategy is independent of genetic background and does not require prior establishment of transgenic flies. PMID:25236734

  17. Planet App: Kids' Book Apps Are Everywhere. But Are They Any Good?

    ERIC Educational Resources Information Center

    Bird, Elizabeth

    2011-01-01

    A proper picture book app lets a parent and child read, listen to, or explore a book in a fun and interactive manner. Typical options offered in these apps include turning off the sound (so that a parent or child can read on their own), changing from one language to another, and small interactive features, such as making the characters move. To…

  18. APP Function and Lipids: A Bidirectional Link

    PubMed Central

    Grimm, Marcus O. W.; Mett, Janine; Grimm, Heike S.; Hartmann, Tobias

    2017-01-01

    Extracellular neuritic plaques, composed of aggregated amyloid-β (Aβ) peptides, are one of the major histopathological hallmarks of Alzheimer’s disease (AD), a progressive, irreversible neurodegenerative disorder and the most common cause of dementia in the elderly. One of the most prominent risk factor for sporadic AD, carrying one or two aberrant copies of the apolipoprotein E (ApoE) ε4 alleles, closely links AD to lipids. Further, several lipid classes and fatty acids have been reported to be changed in the brain of AD-affected individuals. Interestingly, the observed lipid changes in the brain seem not only to be a consequence of the disease but also modulate Aβ generation. In line with these observations, protective lipids being able to decrease Aβ generation and also potential negative lipids in respect to AD were identified. Mechanistically, Aβ peptides are generated by sequential proteolytic processing of the amyloid precursor protein (APP) by β- and γ-secretase. The α-secretase appears to compete with β-secretase for the initial cleavage of APP, preventing Aβ production. All APP-cleaving secretases as well as APP are transmembrane proteins, further illustrating the impact of lipids on Aβ generation. Beside the pathological impact of Aβ, accumulating evidence suggests that Aβ and the APP intracellular domain (AICD) play an important role in regulating lipid homeostasis, either by direct effects or by affecting gene expression or protein stability of enzymes involved in the de novo synthesis of different lipid classes. This review summarizes the current literature addressing the complex bidirectional link between lipids and AD and APP processing including lipid alterations found in AD post mortem brains, lipids that alter APP processing and the physiological functions of Aβ and AICD in the regulation of several lipid metabolism pathways. PMID:28344547

  19. In focus: spotted wing drosophila, Drosophila suzukii, across perspectives

    Technology Transfer Automated Retrieval System (TEKTRAN)

    An effective response to the invasion of spotted wing Drosophila (SWD), Drosophila suzukii, requires proper taxonomic identification at the initial phase, understanding its basic biology and phenology, developing management tools, transferring information and technology quickly to user groups, and e...

  20. APP processing and the APP-KPI domain involvement in the amyloid cascade.

    PubMed

    Menéndez-González, M; Pérez-Pinera, P; Martínez-Rivera, M; Calatayud, M T; Blázquez Menes, B

    2005-01-01

    Alternative APP mRNA splicing can generate isoforms of APP containing a Kunitz protease inhibitor (KPI) domain. KPI is one of the main serine protease inhibitors. Protein and mRNA KPI(+)APP levels are elevated in Alzheimer's disease (AD) brain and are associated with increased amyloid beta deposition. In the last years increasing evidence on multiple points in the amyloid cascade where KPI(+)APP is involved has been accumulated, admitting an outstanding position in the pathogenesis of AD to the KPI domain. This review focuses on the APP processing, the molecular activity of KPI and its physiological and pathological roles and the KPI involvement in the amyloid cascade through the nerve growth factor, the lipoprotein receptor-related protein, the tumor necrosis factor-alpha converting enzyme and the Notch1 protein.

  1. Human umbilical cord blood cells ameliorate Alzheimer's disease in transgenic mice.

    PubMed

    Ende, N; Chen, R; Ende-Harris, D

    2001-01-01

    Having had success in extending the life of mice with a transgene for amyotropic lateral sclerosis (SOD1) mice and Huntington's disease (Hdexon1), we administered megadoses of human umbilical cord blood mononuclear cells to mice with Alzheimer's disease. These mice have an over-expression of human Alzheimer amyloid precursor protein (APP), die early and develop a CNS disorder that includes neophobia. When given 110 x 10(6) human umbilical cord blood mononuclear cells, these mice (HuAPP 695.SWE) had considerable extension of life with a p value of 0.001 when compared to control animals.

  2. Mobile App Rating Scale: A New Tool for Assessing the Quality of Health Mobile Apps

    PubMed Central

    Kavanagh, David J; Zelenko, Oksana; Tjondronegoro, Dian; Mani, Madhavan

    2015-01-01

    Background The use of mobile apps for health and well being promotion has grown exponentially in recent years. Yet, there is currently no app-quality assessment tool beyond “star”-ratings. Objective The objective of this study was to develop a reliable, multidimensional measure for trialling, classifying, and rating the quality of mobile health apps. Methods A literature search was conducted to identify articles containing explicit Web or app quality rating criteria published between January 2000 and January 2013. Existing criteria for the assessment of app quality were categorized by an expert panel to develop the new Mobile App Rating Scale (MARS) subscales, items, descriptors, and anchors. There were sixty well being apps that were randomly selected using an iTunes search for MARS rating. There were ten that were used to pilot the rating procedure, and the remaining 50 provided data on interrater reliability. Results There were 372 explicit criteria for assessing Web or app quality that were extracted from 25 published papers, conference proceedings, and Internet resources. There were five broad categories of criteria that were identified including four objective quality scales: engagement, functionality, aesthetics, and information quality; and one subjective quality scale; which were refined into the 23-item MARS. The MARS demonstrated excellent internal consistency (alpha = .90) and interrater reliability intraclass correlation coefficient (ICC = .79). Conclusions The MARS is a simple, objective, and reliable tool for classifying and assessing the quality of mobile health apps. It can also be used to provide a checklist for the design and development of new high quality health apps. PMID:25760773

  3. Smartphone app use among medical providers in ACGME training programs.

    PubMed

    Franko, Orrin I; Tirrell, Timothy F

    2012-10-01

    The past decade has witnessed the advent of the smartphone, a device armed with computing power, mobility and downloadable "apps," that has become commonplace within the medical field as both a personal and professional tool. The popularity of medically-related apps suggests that physicians use mobile technology to assist with clinical decision making, yet usage patterns have never been quantified. A digital survey examining smartphone and associated app usage was administered via email to all ACGME training programs. Data regarding respondent specialty, level of training, use of smartphones, use of smartphone apps, desired apps, and commonly used apps were collected and analyzed. Greater than 85% of respondents used a smartphone, of which the iPhone was the most popular (56%). Over half of the respondents reported using apps in their clinical practice; the most commonly used app types were drug guides (79%), medical calculators (18%), coding and billing apps (4%) and pregnancy wheels (4%). The most frequently requested app types were textbook/reference materials (average response: 55%), classification/treatment algorithms (46%) and general medical knowledge (43%). The clinical use of smartphones and apps will likely continue to increase, and we have demonstrated an absence of high-quality and popular apps despite a strong desire among physicians and trainees. This information should be used to guide the development of future healthcare delivery systems; expanded app functionality is almost certain but reliability and ease of use will likely remain major factors in determining the successful integration of apps into clinical practice.

  4. Commercially Available Mobile Phone Headache Diary Apps: A Systematic Review

    PubMed Central

    Huguet, Anna; McGrath, Patrick J; Stinson, Jennifer N; Wheaton, Mike

    2014-01-01

    Background Headache diaries are often used by headache sufferers to self-monitor headaches. With advances in mobile technology, mobile electronic diary apps are becoming increasingly common. Objective This review aims to identify and evaluate all commercially available mobile headache diary apps for the two most popular mobile phone platforms, iOS and Android. Methods The authors developed a priori a set of 7 criteria that define an ideal headache diary app intended to help headache sufferers better understand and manage their headaches, while providing relevant data to health professionals. The app criteria were intended as minimum requirements for an acceptable headache diary app that could be prescribed by health care professionals. Each app was evaluated and scored against each criterion. Results Of the 38 apps identified, none of the apps met all 7 app criteria. The 3 highest scoring apps, meeting 5 of the app criteria, were iHeadache (developed by Better QOL), ecoHeadache (developed by ecoTouchMedia), and Headache Diary Pro (developed by Froggyware). Only 18% of the apps were created with scientific or clinical headache expertise and none of the apps reported on psychometric properties. Conclusions Despite the growing market and demand, there is a concerning lack of scientific expertise and evidence base associated with headache diary apps. PMID:25138438

  5. CCK Response Deficiency in Synphilin-1 Transgenic Mice.

    PubMed

    Smith, Wanli W; Smith, Megan; Yang, Dejun; Choi, Pique P; Moghadam, Alexander; Li, Tianxia; Moran, Timothy H

    2015-01-01

    Previously, we have identified a novel role for the cytoplasmic protein, synphilin-1(SP1), in the controls of food intake and body weight in both mice and Drosophila. Ubiquitous overexpression of human SP1 in brain neurons in transgenic mice results in hyperphagia expressed as an increase in meal size. However, the mechanisms underlying this action of SP1 remain to be determined. Here we investigate a potential role for altered gut feedback signaling in the effects of SP1 on food intake. We examined responses to peripheral administration of cholecytokinin (CCK), amylin, and the glucagon like peptide-1 (GLP-1) receptor agonist, exendin-4. Intraperitoneal administration of CCK at doses ranging from 1-10 nmol/kg significantly reduced glucose intake in wild type (WT) mice, but failed to affect intake in SP1 transgenic mice. Moreover, there was a significant attenuation of CCK-induced c-Fos expression in the dorsal vagal complex in SP1 transgenic mice. In contrast, WT and SP1 transgenic mice were similarly responsive to both amylin and exendin-4 treatment. These studies demonstrate that SP1 results in a CCK response deficiency that may contribute to the increased meal size and overall hyperphagia in synphillin-1 transgenic mice.

  6. Beebook: light field mapping app

    NASA Astrophysics Data System (ADS)

    De Donatis, Mauro; Di Pietro, Gianfranco; Rinnone, Fabio

    2014-05-01

    In the last decade the mobile systems for field digital mapping were developed (see Wikipedia for "Digital geologic mapping"), also against many skeptic traditional geologists. Until now, hardware was often heavy (tablet PC) and software sometime difficult also for expert GIS users. At present, the advent of light tablet and applications makes things easier, but we are far to find a whole solution for a complex survey like the geological one where you have to manage complexities such information, hypothesis, data, interpretation. Beebook is a new app for Android devices, has been developed for fast ad easy mapping work in the field trying to try to solve this problem. The main features are: • off-line raster management, GeoTIFF ed other raster format using; • on-line map visualisation (Google Maps, OSM, WMS, WFS); • SR management and conversion using PROJ.4; • vector file mash-up (KML and SQLite format); • editing of vector data on the map (lines, points, polygons); • augmented reality using "Mixare" platform; • export of vector data in KML, CSV, SQLite (Spatialite) format; • note: GPS or manual point inserting linked to other application files (pictures, spreadsheet, etc.); • form: creation, edition and filling of customized form; • GPS: status control, tracker and positioning on map; • sharing: synchronization and sharing of data, forms, positioning and other information can be done among users. The input methods are different from digital keyboard to fingers touch, from voice recording to stylus. In particular the most efficient way of inserting information is the stylus (or pen): field geologists are familiar with annotation and sketches. Therefore we suggest the use of devices with stylus. The main point is that Beebook is the first "transparent" mobile GIS for tablet and smartphone deriving from previous experience as traditional mapping and different previous digital mapping software ideation and development (MapIT, BeeGIS, Geopaparazzi

  7. Oxidative stress accelerates amyloid deposition and memory impairment in a double-transgenic mouse model of Alzheimer's disease.

    PubMed

    Kanamaru, Takuya; Kamimura, Naomi; Yokota, Takashi; Iuchi, Katsuya; Nishimaki, Kiyomi; Takami, Shinya; Akashiba, Hiroki; Shitaka, Yoshitsugu; Katsura, Ken-Ichiro; Kimura, Kazumi; Ohta, Shigeo

    2015-02-05

    Oxidative stress is known to play a prominent role in the onset and early stage progression of Alzheimer's disease (AD). For example, protein oxidation and lipid peroxidation levels are increased in patients with mild cognitive impairment. Here, we created a double-transgenic mouse model of AD to explore the pathological and behavioral effects of oxidative stress. Double transgenic (APP/DAL) mice were constructed by crossing Tg2576 (APP) mice, which express a mutant form of human amyloid precursor protein (APP), with DAL mice expressing a dominant-negative mutant of mitochondrial aldehyde dehydrogenase 2 (ALDH2), in which oxidative stress is enhanced. Y-maze and object recognition tests were performed at 3 and 6 months of age to evaluate learning and memory. The accumulation of amyloid plaques, deposition of phosphorylated-tau protein, and number of astrocytes in the brain were assessed histopathologically at 3, 6, 9, and 12-15 months of age. The life span of APP/DAL mice was significantly shorter than that of APP or DAL mice. In addition, they showed accelerated amyloid deposition, tau phosphorylation, and gliosis. Furthermore, these mice showed impaired performance on Y-maze and object recognition tests at 3 months of age. These data suggest that oxidative stress accelerates cognitive dysfunction and pathological insults in the brain. APP/DAL mice could be a useful model for exploring new approaches to AD treatment.

  8. Impaired behavior of female tg-ArcSwe APP mice in the IntelliCage: A longitudinal study.

    PubMed

    Codita, Alina; Gumucio, Astrid; Lannfelt, Lars; Gellerfors, Pär; Winblad, Bengt; Mohammed, Abdul H; Nilsson, Lars N G

    2010-12-20

    Transgenic animals expressing mutant human amyloid precursor protein (APP) are used as models for Alzheimer disease (AD). Ideally, behavioral tests improve the predictive validity of studies on animals by mirroring the functional impact of AD-like neuropathology. Learning and memory studies in APP transgenic models have been difficult to replicate. Standardization of procedures, automatization or improved protocol design can improve reproducibility. Here the IntelliCage, an automated system, was used for behavioral testing of APP female transgenic mice with both the Arctic and Swedish mutations, the tg-ArcSwe model. Protocols covering exploration, operant learning, place learning and extinction of place preference as well as passive avoidance tests were used for longitudinal characterization of behavior. Differences in exploratory activity were significant at four months of age, when plaque-free tg-ArcSwe mice visited less frequently the IntelliCage corners and initially performed fewer visits with licks compared to non-tg animals, inside the new environment. Fourteen months old tg-ArcSwe mice required a longer time to re-habituate to the IntelliCages than non-tg mice. At both ages tg-ArcSwe mice perseverated in place preference extinction test. Fourteen months old tg-ArcSwe mice were impaired in hippocampus-dependent spatial passive avoidance learning. This deficit was found to inversely correlate to calbindin-D28k immunoreactivity in the polymorphic layer of the dentate gyrus. Reduced water intake and body weight were observed in 4 months old tg-ArcSwe animals. The body weight difference increased with age. Thus behavioral and metabolic changes in the tg-ArcSwe APP model were detected using the IntelliCage, a system which provides the opportunity for standardized automated longitudinal behavioral phenotyping.

  9. The Alzheimer Amyloid Precursor Protein (APP) and Fe65, an APP-Binding Protein, Regulate Cell Movement

    PubMed Central

    Sabo, Shasta L.; Ikin, Annat F.; Buxbaum, Joseph D.; Greengard, Paul

    2001-01-01

    FE65 binds to the Alzheimer amyloid precursor protein (APP), but the function of this interaction has not been identified. Here, we report that APP and FE65 are involved in regulation of cell movement. APP and FE65 colocalize with actin and Mena, an Abl-associated signaling protein thought to regulate actin dynamics, in lamellipodia. APP and FE65 specifically concentrate with β1-integrin in dynamic adhesion sites known as focal complexes, but not in more static adhesion sites known as focal adhesions. Overexpression of APP accelerates cell migration in an MDCK cell wound–healing assay. Coexpression of APP and FE65 dramatically enhances the effect of APP on cell movement, probably by regulating the amount of APP at the cell surface. These data are consistent with a role for FE65 and APP, possibly in a Mena-containing macromolecular complex, in regulation of actin-based motility. PMID:11425871

  10. Smartphone apps in microbiology--is better regulation required?

    PubMed

    Visvanathan, A; Hamilton, A; Brady, R R W

    2012-07-01

    Increasing diversity of available medical applications (apps) has led to their widespread use in healthcare delivery. However, app involvement in diagnosis and patient management has raised concerns, specifically regarding accuracy and reliability of content. Here, we report on the contemporary range of microbiology-themed apps and prevalence of medical professional involvement in app development. Of 94 microbiology-themed apps identified, only 34% had stated medical professional involvement. The lack of such involvement in app design is concerning and undermines consumers' ability to be informed regarding quality of content. We propose that increased regulatory measures are introduced to safeguard patient welfare.

  11. Weeding with transgenes.

    PubMed

    Duke, Stephen O

    2003-05-01

    Transgenes promise to reduce insecticide and fungicide use but relatively little has been done to significantly reduce herbicide use through genetic engineering. Recently, three strategies for transgene utilization have been developed that have the potential to change this. These are the improvement of weed-specific biocontrol agents, enhancement of crop competition or allelopathic traits, and production of cover crops that will self-destruct near the time of planting. Failsafe risk mitigation technologies are needed for most of these strategies.

  12. New insights into Drosophila vision.

    PubMed

    Dolph, Patrick

    2008-01-10

    Studies of the Drosophila visual system have provided valuable insights into the function and regulation of phototransduction signaling pathways. Much of this work has stemmed from or relied upon the genetic tools offered by the Drosophila system. In this issue of Neuron, Wang and colleagues and Acharya and colleagues have further exploited the Drosophila genetic system to characterize two new phototransduction players.

  13. [Inheritance and expression stability of transgene in transgenic animals].

    PubMed

    Kong, Qing-Ran; Liu, Zhong-Hua

    2011-05-01

    Transgenic technology is one of the most hotspots in biology. In the past decade, the progress in animal cloning has provided an alternative method to improve transgenic efficiency. Many kinds of transgenic animals have been successfully produced via the combination of transfection and nuclear transfer. However, the ultimate aim of transgenesis is not to produce several transgenic animals, but to service for the needs of human. In animal production, transgenic technology has been used to breed new livestock, which has received a lot of attention in China. It has been evidenced that inheritance and expression instability of transgene in transgenic animals is still the major limitation, which is attributed to position effect, epigenetic modification, and hereditary efficiency of transgene. In this review, we discussed the three points for promoting the industrialization of animal transgenic breeding.

  14. Compliance of blood donation apps with mobile OS usability guidelines.

    PubMed

    Ouhbi, Sofia; Fernández-Alemán, José Luis; Pozo, José Rivera; Bajta, Manal El; Toval, Ambrosio; Idri, Ali

    2015-06-01

    The aim of this paper is to employ the guidelines of Android, iOS, Blackberry and Windows Phone to analyze the usability compliance of free blood donation (BD) apps. An analysis process based on a systematic review protocol is used to select free BD apps. An assessment is conducted using a questionnaire composed of 13 questions concerning the compliance of free BD apps with Android, Blackberry, iOS and Windows Phone usability guidelines. A total of 133 free BD apps have been selected from the 188 BD apps identified. Around 63% of the free BD apps selected have a good compliance with mobile OS usability recommendations. Around 72% of Android, 57% of Windows Phone, 33% of iOS and 33% of Blackberry BD apps have a high usability score. The aspect of BD app behavior should be improved along with some style components: the use of pictures to explain ideas and the adaptation of the app to both horizontal and vertical orientations. Structure patterns should also be used to improve the structure aspect of a BD app. Usability is a quality aspect that should be improved in current BD apps. Our study provides smartphone users with a list of usable free BD apps and BD app developers with recommendations.

  15. easyHealthApps: e-Health Apps dynamic generation for smartphones & tablets.

    PubMed

    Paschou, Mersini; Sakkopoulos, Evangelos; Tsakalidis, Athanasios

    2013-06-01

    Mobile phones and especially smartphones have been embraced by a rapidly increasing number of people worldwide and this trend is expected to evolve even more in the years to come. There are numerous smartphone Apps that record critical medical data in an effort to solve a particular health issue each time. We studied such applications and not surprisingly, we have found that development and design effort is often repeated. Software patterns have been detected to exist, however re-usability has not been enforced. This leads to lost programming manpower and to increased probability of repeating bugs in Apps. Moreover, at the moment smartphone e-Health Apps demand time, effort and costs for development. Unfortunately even simple data recording Apps are practically impossible to be produced by multiple health domain users who are not developers. In this work, we propose, design and implement a simple and integrated solution which gives healthcare professionals and researchers the ability to create their own data intensive smartphone applications, independent of the desired healthcare domain. The proposed approach applies efficient software techniques that hide development from the users and enable App creation through a simple Web User Interface. The Apps produced are in native format and it is possible to dynamically receive m-Health business logic and the chosen UI. Evaluation of the proposed solution has shown that the generated Apps are functionally and UI equivalent to human-coded Apps according to a number of comparison parameters. Furthermore, e-Health professionals show particular interest in developing Apps on their own for a particular domain they focus on.

  16. The Fundamentals of Flying: Simple and Inexpensive Strategies for Employing Drosophila Genetics in Neuroscience Teaching Laboratories

    PubMed Central

    Pulver, Stefan R.; Berni, Jimena

    2012-01-01

    Drosophila researchers have developed a powerful suite of genetic techniques for studying the neural basis of animal behavior. Many of these tools can be exported to neuroscience teaching laboratories (Berni et al., 2010; Pulver et al., 2011a,b), but often neuroscience educators lack the basic knowledge and resources to obtain, generate and rear transgenic fruit flies on their own. Fly researchers in turn may take for granted resources that are readily available in research laboratories, but out of reach for educators. Our goal is to provide a primer for neuroscience educators who want to incorporate Drosophila genetics into their teaching, but have limited knowledge of fruit fly genetics, and/or small budgets. First we review the available methods for manipulating gene expression in Drosophila. Then we provide educators with blueprints for obtaining transgenic animals tailored for specific types of teaching modules. We outline simple techniques for rearing transgenic Drosophila, performing genetic crosses, and preparing a teaching laboratory without the use of expensive animal-care facilities. Overall, we try to break down the practical barriers educators may face when integrating modern neurogenetic experiments into teaching laboratories. PMID:23493248

  17. The heat shock response restricts virus infection in Drosophila

    PubMed Central

    Merkling, Sarah H.; Overheul, Gijs J.; van Mierlo, Joël T.; Arends, Daan; Gilissen, Christian; van Rij, Ronald P.

    2015-01-01

    Innate immunity is the first line of defence against pathogens and is essential for survival of the infected host. The fruit fly Drosophila melanogaster is an emerging model to study viral pathogenesis, yet antiviral defence responses remain poorly understood. Here, we describe the heat shock response, a cellular mechanism that prevents proteotoxicity, as a component of the antiviral immune response in Drosophila. Transcriptome analyses of Drosophila S2 cells and adult flies revealed strong induction of the heat shock response upon RNA virus infection. Dynamic induction patterns of heat shock pathway components were characterized in vitro and in vivo following infection with different classes of viruses. The heat shock transcription factor (Hsf), as well as active viral replication, were necessary for the induction of the response. Hsf-deficient adult flies were hypersensitive to virus infection, indicating a role of the heat shock response in antiviral defence. In accordance, transgenic activation of the heat shock response prolonged survival time after infection and enabled long-term control of virus replication to undetectable levels. Together, our results establish the heat shock response as an important constituent of innate antiviral immunity in Drosophila. PMID:26234525

  18. Enhancing undergraduate teaching and research with a Drosophila virginizing system.

    PubMed

    Venema, Dennis R

    2006-01-01

    Laboratory exercises using Drosophila crosses are an effective pedagogical method to complement traditional lecture and textbook presentations of genetics. Undergraduate thesis research is another common setting for using Drosophila. A significant barrier to using Drosophila for undergraduate teaching or research is the time and skill required to accurately collect virgins for use in controlled crosses. Erroneously collecting males or nonvirgin females contaminates crosses with unintended genotypes and confounds the results. Collecting adequate numbers of virgins requires large amounts of time, even for those skilled in virgin collection. I have adapted an effective method for virgin collection that eliminates these concerns and is straightforward to use in undergraduate settings. Using a heat-shock-induced, conditional lethal transgene specifically in males, male larvae can be eliminated from a culture before adults eclose. Females thus eclose in the absence of males and remain virgin, eliminating the need to laboriously score and segregate freshly eclosed females. This method is reliable, easily adaptable to any desired phenotypic marker, and readily scaleable to provide sufficient virgins for large laboratory classes or undergraduate research projects. In addition, it allows instructors lacking Drosophila expertise to use this organism as a pedagogical tool.

  19. Enhancing Undergraduate Teaching and Research with a Drosophila Virginizing System

    PubMed Central

    2006-01-01

    Laboratory exercises using Drosophila crosses are an effective pedagogical method to complement traditional lecture and textbook presentations of genetics. Undergraduate thesis research is another common setting for using Drosophila. A significant barrier to using Drosophila for undergraduate teaching or research is the time and skill required to accurately collect virgins for use in controlled crosses. Erroneously collecting males or nonvirgin females contaminates crosses with unintended genotypes and confounds the results. Collecting adequate numbers of virgins requires large amounts of time, even for those skilled in virgin collection. I have adapted an effective method for virgin collection that eliminates these concerns and is straightforward to use in undergraduate settings. Using a heat-shock–induced, conditional lethal transgene specifically in males, male larvae can be eliminated from a culture before adults eclose. Females thus eclose in the absence of males and remain virgin, eliminating the need to laboriously score and segregate freshly eclosed females. This method is reliable, easily adaptable to any desired phenotypic marker, and readily scaleable to provide sufficient virgins for large laboratory classes or undergraduate research projects. In addition, it allows instructors lacking Drosophila expertise to use this organism as a pedagogical tool. PMID:17146043

  20. Past1 Modulates Drosophila Eye Development

    PubMed Central

    Dorot, Orly; Steller, Hermann; Segal, Daniel; Horowitz, Mia

    2017-01-01

    Endocytosis is a multi-step process involving a large number of proteins, both general factors, such as clathrin and adaptor protein complexes, and unique proteins, which modulate specialized endocytic processes, like the EHD proteins. EHDs are a family of Eps15 Homology Domain containing proteins that consists of four mammalian homologs, one C. elegans, one Drosophila melanogaster and two plants orthologs. These membrane-associated proteins are involved in different steps of endocytic trafficking pathways. We have previously shown that the Drosophila EHD ortholog, PAST1, associates predominantly with the plasma membrane. Mutations in Past1 result in defects in endocytosis, male sterility, temperature sensitivity and premature death of the flies. Also, Past1 genetically interacts with Notch. In the present study, we investigated the role of PAST1 in the developing fly eye. In mutant flies lacking PAST1, abnormal differentiation of photoreceptors R1, R6 and R7 was evident, with partial penetrance. Likewise, five cone cells were present instead of four. Expression of transgenic PAST1 resulted in a dominant negative effect, with a phenotype similar to that of the deletion mutant, and appearance of additional inter-ommatidial pigment cells. Our results strongly suggest a role for PAST1 in differentiation of photoreceptors R1/R6/R7 and cone cells of the fly ommatidia. PMID:28060904

  1. Understanding and Capturing People’s Mobile App Privacy Preferences

    DTIC Science & Technology

    2013-10-28

    they collect might also include personal information such as users’ location, phone number, etc. Similar to targeted advertising libraries, mobile ...The percentage of users surprised about popular mobile apps using users’ location, phone ID and contact list. This figure shows the top 10 apps with...surprised by these popular mobile apps access users’ location, unique phone ID and contact list. Figure 17 shows the data related to the top 10 apps

  2. Hearing regulates Drosophila aggression.

    PubMed

    Versteven, Marijke; Vanden Broeck, Lies; Geurten, Bart; Zwarts, Liesbeth; Decraecker, Lisse; Beelen, Melissa; Göpfert, Martin C; Heinrich, Ralf; Callaerts, Patrick

    2017-02-21

    Aggression is a universal social behavior important for the acquisition of food, mates, territory, and social status. Aggression in Drosophila is context-dependent and can thus be expected to involve inputs from multiple sensory modalities. Here, we use mechanical disruption and genetic approaches in Drosophila melanogaster to identify hearing as an important sensory modality in the context of intermale aggressive behavior. We demonstrate that neuronal silencing and targeted knockdown of hearing genes in the fly's auditory organ elicit abnormal aggression. Further, we show that exposure to courtship or aggression song has opposite effects on aggression. Our data define the importance of hearing in the control of Drosophila intermale aggression and open perspectives to decipher how hearing and other sensory modalities are integrated at the neural circuit level.

  3. Appetitive associative olfactory learning in Drosophila larvae.

    PubMed

    Apostolopoulou, Anthi A; Widmann, Annekathrin; Rohwedder, Astrid; Pfitzenmaier, Johanna E; Thum, Andreas S

    2013-02-18

    In the following we describe the methodological details of appetitive associative olfactory learning in Drosophila larvae. The setup, in combination with genetic interference, provides a handle to analyze the neuronal and molecular fundamentals of specifically associative learning in a simple larval brain. Organisms can use past experience to adjust present behavior. Such acquisition of behavioral potential can be defined as learning, and the physical bases of these potentials as memory traces. Neuroscientists try to understand how these processes are organized in terms of molecular and neuronal changes in the brain by using a variety of methods in model organisms ranging from insects to vertebrates. For such endeavors it is helpful to use model systems that are simple and experimentally accessible. The Drosophila larva has turned out to satisfy these demands based on the availability of robust behavioral assays, the existence of a variety of transgenic techniques and the elementary organization of the nervous system comprising only about 10,000 neurons (albeit with some concessions: cognitive limitations, few behavioral options, and richness of experience questionable). Drosophila larvae can form associations between odors and appetitive gustatory reinforcement like sugar. In a standard assay, established in the lab of B. Gerber, animals receive a two-odor reciprocal training: A first group of larvae is exposed to an odor A together with a gustatory reinforcer (sugar reward) and is subsequently exposed to an odor B without reinforcement. Meanwhile a second group of larvae receives reciprocal training while experiencing odor A without reinforcement and subsequently being exposed to odor B with reinforcement (sugar reward). In the following both groups are tested for their preference between the two odors. Relatively higher preferences for the rewarded odor reflect associative learning--presented as a performance index (PI). The conclusion regarding the associative

  4. Techtalk: Mobile Apps and College Mathematics

    ERIC Educational Resources Information Center

    Hoang, Theresa V.; Caverly, David C.

    2013-01-01

    In this column, the authors discuss apps useful in developing mathematical reasoning. They place these into a theoretical framework, suggesting how they could be used in an instructional model such as the Algorithmic Instructional Technique (AIT) developed by Vasquez (2003). This model includes four stages: modeling, practice, transition, and…

  5. Ebola - What You Need to Know app.

    PubMed

    Evans, Roger

    2015-02-03

    This app is the pocket companion to the Ebola in Africa section of the International SOS website. With headquarters in London and Singapore, International SOS is a company that provides medical, clinical and security services in 81 countries for organisations with international operations.

  6. Motivating Instruction? There's an App for That!

    ERIC Educational Resources Information Center

    Bruhn, Allison; Hirsch, Shanna; Vogelgesang, Kari

    2017-01-01

    Keeping students engaged in the curriculum is extremely important when attempting to close the achievement gap for students with and at risk for disabilities. This is particularly important for students with learning disabilities or behavior disorders. This article discusses the use of applications (apps) for mobile technologies that may be used…

  7. North Tyneside Perspective on Primary Science APP

    ERIC Educational Resources Information Center

    Keilty, Ged

    2010-01-01

    The status of primary science as a core subject has been gradually corroded in recent years, with the abolition of targets for science and the focus of the primary national strategy on literacy and numeracy. The NAIGS Committee were very well positioned within local authorities to pilot APP, but first had to write the criteria. Towards the end of…

  8. Behavioral responses to odorants in drosophila require nervous system expression of the beta integrin gene myospheroid.

    PubMed

    Bhandari, Poonam; Gargano, Julia Warner; Goddeeris, Matthew M; Grotewiel, Michael S

    2006-09-01

    Integrins are cell adhesion molecules that mediate numerous developmental processes in addition to a variety of acute physiological events. Two reports implicate a Drosophila beta integrin, betaPS, in olfactory behavior. To further investigate the role of integrins in Drosophila olfaction, we used Gal4-driven expression of RNA interference (RNAi) transgenes to knock down expression of myospheroid (mys), the gene that encodes betaPS. Expression of mys-RNAi transgenes in the wing reduced betaPS immunostaining and produced morphological defects associated with loss-of-function mutations in mys, demonstrating that this strategy knocked down mys function. Expression of mys-RNAi transgenes in the antennae, antennal lobes, and mushroom bodies via two Gal4 lines, H24 and MT14, disrupted olfactory behavior but did not alter locomotor abilities or central nervous system structure. Olfactory behavior was normal in flies that expressed mys-RNAi transgenes via other Gal4 lines that specifically targeted the antennae, the projection neurons, the mushroom bodies, bitter and sweet gustatory neurons, or Pox neuro neurons. Our studies confirm that mys is important for the development or function of the Drosophila olfactory system. Additionally, our studies demonstrate that mys is required for normal behavioral responses to both aversive and attractive odorants. Our results are consistent with a model in which betaPS mediates events within the antennal lobes that influence odorant sensitivity.

  9. Taurine in drinking water recovers learning and memory in the adult APP/PS1 mouse model of Alzheimer's disease.

    PubMed

    Kim, Hye Yun; Kim, Hyunjin V; Yoon, Jin H; Kang, Bo Ram; Cho, Soo Min; Lee, Sejin; Kim, Ji Yoon; Kim, Joo Won; Cho, Yakdol; Woo, Jiwan; Kim, YoungSoo

    2014-12-12

    Alzheimer's disease (AD) is a lethal progressive neurological disorder affecting the memory. Recently, US Food and Drug Administration mitigated the standard for drug approval, allowing symptomatic drugs that only improve cognitive deficits to be allowed to accelerate on to clinical trials. Our study focuses on taurine, an endogenous amino acid found in high concentrations in humans. It has demonstrated neuroprotective properties against many forms of dementia. In this study, we assessed cognitively enhancing property of taurine in transgenic mouse model of AD. We orally administered taurine via drinking water to adult APP/PS1 transgenic mouse model for 6 weeks. Taurine treatment rescued cognitive deficits in APP/PS1 mice up to the age-matching wild-type mice in Y-maze and passive avoidance tests without modifying the behaviours of cognitively normal mice. In the cortex of APP/PS1 mice, taurine slightly decreased insoluble fraction of Aβ. While the exact mechanism of taurine in AD has not yet been ascertained, our results suggest that taurine can aid cognitive impairment and may inhibit Aβ-related damages.

  10. Taurine in drinking water recovers learning and memory in the adult APP/PS1 mouse model of Alzheimer's disease

    PubMed Central

    Kim, Hye Yun; Kim, Hyunjin V.; Yoon, Jin H.; Kang, Bo Ram; Cho, Soo Min; Lee, Sejin; Kim, Ji Yoon; Kim, Joo Won; Cho, Yakdol; Woo, Jiwan; Kim, YoungSoo

    2014-01-01

    Alzheimer's disease (AD) is a lethal progressive neurological disorder affecting the memory. Recently, US Food and Drug Administration mitigated the standard for drug approval, allowing symptomatic drugs that only improve cognitive deficits to be allowed to accelerate on to clinical trials. Our study focuses on taurine, an endogenous amino acid found in high concentrations in humans. It has demonstrated neuroprotective properties against many forms of dementia. In this study, we assessed cognitively enhancing property of taurine in transgenic mouse model of AD. We orally administered taurine via drinking water to adult APP/PS1 transgenic mouse model for 6 weeks. Taurine treatment rescued cognitive deficits in APP/PS1 mice up to the age-matching wild-type mice in Y-maze and passive avoidance tests without modifying the behaviours of cognitively normal mice. In the cortex of APP/PS1 mice, taurine slightly decreased insoluble fraction of Aβ. While the exact mechanism of taurine in AD has not yet been ascertained, our results suggest that taurine can aid cognitive impairment and may inhibit Aβ-related damages. PMID:25502280

  11. The App Squad: SLJ's Advisors Weigh in on Kids' Book Apps

    ERIC Educational Resources Information Center

    Ishizuka, Kathy

    2011-01-01

    In this article, "School Library Journal's" ("SLJ") advisors talk about book apps for kids. They discuss what they like, what one should look for in discerning the best for kids and teens, and where this all might be headed.

  12. Using transgenic reporter assays to functionally characterize enhancers in animals.

    PubMed

    Kvon, Evgeny Z

    2015-09-01

    Enhancers or cis-regulatory modules play an instructive role in regulating gene expression during animal development and in response to the environment. Despite their importance, we only have an incomplete map of enhancers in the genome and our understanding of the mechanisms governing their function is still limited. Recent advances in genomics provided powerful tools to generate genome-wide maps of potential enhancers. However, most of these methods are based on indirect measures of enhancer activity and have to be followed by functional testing. Animal transgenesis has been a valuable method to functionally test and characterize enhancers in vivo. In this review I discuss how different transgenic strategies are utilized to characterize enhancers in model organisms focusing on studies in Drosophila and mouse. I will further discuss recent large-scale transgenic efforts to systematically identify and catalog enhancers as well as highlight the challenges and future directions in the field.

  13. Low-Budget Apps for Students of All Abilities

    ERIC Educational Resources Information Center

    VanWeelden, Kimberly; Heath, Julia

    2013-01-01

    With more than 850,000 apps currently on the market, there are multiple apps that can be used to help all students in music education, particularly those with special needs. This article lists low-budget apps useful for the elementary or secondary general music classroom.

  14. Using Apps to Support Disciplinary Literacy and Science Learning

    ERIC Educational Resources Information Center

    Castek, Jill; Beach, Richard

    2013-01-01

    Apps, specialized programs used on mobile computers, can be used in innovative ways to enhance science and literacy learning. With the skilled guidance of their teachers, students can exploit app affordances for learning and acquire disciplinary literacies unique to science. This article showcases apps that help students to access information,…

  15. English Language Teaching Apps: Positioning Parents and Young Learners

    ERIC Educational Resources Information Center

    Chik, Alice

    2014-01-01

    Since the introduction of iPads in 2010, the sales of tablet computers and mobile applications (apps) have grown exponentially. iPads and other tablets are marketed as learning tools, and many apps target learners as young as six months old. This article reports on a research project examining the unique features of English learning apps based on…

  16. Educational Behavior Apps and Wearable Devices: Current Research and Prospects

    ERIC Educational Resources Information Center

    Lowe, Heather

    2016-01-01

    Dartmouth and MIT have developed educational behavior apps and wearable devices that collect contiguous streams of data from student users. Given the consent of the user, the app collects information about a student's physical activity, sleep patterns, and location to form conjectures about social and academic behavior. These apps have the…

  17. Using the Modern Technology That Is the "App"

    ERIC Educational Resources Information Center

    Bernardelli, Alessio

    2013-01-01

    A few years ago, the sight of the letters APP would have made teachers in England think of the Assessing Pupils' Progress assessment approach introduced by the government. Now, when they see those same letters they mostly think about smartphone and tablet applications, shortened to "apps." With the thousands of apps available in the…

  18. Cleaning up That Mess: A Framework for Classifying Educational Apps

    ERIC Educational Resources Information Center

    Cherner, Todd; Dix , Judy; Lee, Corey

    2014-01-01

    As tablet technologies continue to evolve, the emergence of educational applications (apps) is impacting the work of teacher educators. Beyond online lists of best apps for education and recommendations from colleagues, teacher educators have few resources available to support their teaching of how to select educational apps. In response, this…

  19. Athletic Training Education: There's an App for That

    ERIC Educational Resources Information Center

    Keeley, Kim; Potteiger, Kelly; Brown, Christopher D.

    2015-01-01

    Context: Mobile applications (apps) are growing in popularity due to the increased use of smartphones. Many available apps are educational in nature and may provide both students and educators freedom for learning to occur outside of the typical classroom environment. Objective: To provide a description of relevant apps along with a brief synopsis…

  20. Car App's Persuasive Design Principles and Behavior Change

    ERIC Educational Resources Information Center

    Zhang, Chao; Wan, Lili; Min, Daihwan

    2016-01-01

    The emphasis of this study lies in behavior change after using car apps that assist users in using their vehicles and establishing a process for examining the interrelationship between car app's persuasive characteristics and behavior change. A categorizing method was developed and 697 car apps were investigated and classified into eight…

  1. Mobile Phone Apps to Improve Medication Adherence: A Systematic Stepwise Process to Identify High-Quality Apps

    PubMed Central

    Richtering, Sarah S; Chalmers, John; Thiagalingam, Aravinda; Chow, Clara K; Redfern, Julie

    2016-01-01

    Background There are a growing number of mobile phone apps available to support people in taking their medications and to improve medication adherence. However, little is known about how these apps differ in terms of features, quality, and effectiveness. Objective We aimed to systematically review the medication reminder apps available in the Australian iTunes store and Google Play to assess their features and their quality in order to identify high-quality apps. Methods This review was conducted in a similar manner to a systematic review by using a stepwise approach that included (1) a search strategy; (2) eligibility assessment; (3) app selection process through an initial screening of all retrieved apps and full app review of the included apps; (4) data extraction using a predefined set of features considered important or desirable in medication reminder apps; (5) analysis by classifying the apps as basic and advanced medication reminder apps and scoring and ranking them; and (6) a quality assessment by using the Mobile App Rating Scale (MARS), a reliable tool to assess mobile health apps. Results We identified 272 medication reminder apps, of which 152 were found only in Google Play, 87 only in iTunes, and 33 in both app stores. Apps found in Google Play had more customer reviews, higher star ratings, and lower cost compared with apps in iTunes. Only 109 apps were available for free and 124 were recently updated in 2015 or 2016. Overall, the median number of features per app was 3.0 (interquartile range 4.0) and only 18 apps had ≥9 of the 17 desirable features. The most common features were flexible scheduling that was present in 56.3% (153/272) of the included apps, medication tracking history in 54.8% (149/272), snooze option in 34.9% (95/272), and visual aids in 32.4% (88/272). We classified 54.8% (149/272) of the included apps as advanced medication reminder apps and 45.2% (123/272) as basic medication reminder apps. The advanced apps had a higher number

  2. Chemical sensing in Drosophila.

    PubMed

    Benton, Richard

    2008-08-01

    Chemical sensing begins when peripheral receptor proteins recognise specific environmental stimuli and translate them into spatial and temporal patterns of sensory neuron activity. The chemosensory system of the fruit fly, Drosophila melanogaster, has become a dominant model to understand this process, through its accessibility to a powerful combination of molecular, genetic and electrophysiological analysis. Recent results have revealed many surprises in the biology of peripheral chemosensation in Drosophila, including novel structural and signalling properties of the insect odorant receptors (ORs), combinatorial mechanisms of chemical recognition by the gustatory receptors (GRs), and the implication of Transient Receptor Potential (TRP) ion channels as a novel class of chemosensory receptors.

  3. Studying aging in Drosophila.

    PubMed

    He, Ying; Jasper, Heinrich

    2014-06-15

    Drosophila melanogaster represents one of the most important genetically accessible model organisms for aging research. Studies in flies have identified single gene mutations that influence lifespan and have characterized endocrine signaling interactions that control homeostasis systemically. Recent studies have focused on the effects of aging on specific tissues and physiological processes, providing a comprehensive picture of age-related tissue dysfunction and the loss of systemic homeostasis. Here we review methodological aspects of this work and highlight technical considerations when using Drosophila to study aging and age-related diseases.

  4. Targeting BACE1 with siRNAs ameliorates Alzheimer disease neuropathology in a transgenic model.

    PubMed

    Singer, Oded; Marr, Robert A; Rockenstein, Edward; Crews, Leslie; Coufal, Nicole G; Gage, Fred H; Verma, Inder M; Masliah, Eliezer

    2005-10-01

    In Alzheimer disease, increased beta-secretase (BACE1) activity has been associated with neurodegeneration and accumulation of amyloid precursor protein (APP) products. Thus, inactivation of BACE1 could be important in the treatment of Alzheimer disease. In this study, we found that lowering BACE1 levels using lentiviral vectors expressing siRNAs targeting BACE1 reduced amyloid production and the neurodegenerative and behavioral deficits in APP transgenic mice, a model of Alzheimer disease. Our results suggest that lentiviral vector delivery of BACE1 siRNA can specifically reduce the cleavage of APP and neurodegeneration in vivo and indicate that this approach could have potential therapeutic value for treatment of Alzheimer disease.

  5. Smartphone Apps for Schizophrenia: A Systematic Review

    PubMed Central

    2015-01-01

    Background There is increasing interest in using mobile technologies such as smartphones for improving the care of patients with schizophrenia. However, less is known about the current clinical evidence for the feasibility and effectiveness of smartphone apps in this population. Objective To review the published literature of smartphone apps applied for the care of patients with schizophrenia and other psychotic disorders. Methods An electronic database search of Ovid MEDLINE, the Cochrane Central Register of Controlled Trials, Health Technology Assessment Database, Allied and Complementary Medicine, Health and Psychosocial Instruments, PsycINFO, and Embase was conducted on May 24, 2015. All eligible studies were systematically reviewed, and proportional meta-analyses were applied to pooled data on recruitment, retention, and adherence to examine the overall feasibility of smartphone interventions for schizophrenia. Results Our search produced 226 results from which 7 eligible articles were identified, reporting on 5 studies of smartphone apps for patients with schizophrenia. All examined feasibility, and one assessed the preliminary efficacy of a smartphone intervention for schizophrenia. Study lengths varied between 6 and 130 days. Overall retention was 92% (95% CI 82-98%). Participants consistently used the smartphone apps on more than 85% of days during the study period, averaging 3.95 interactions per person per day. Furthermore, participants responded to 71.9% of automated prompts (95% CI 65.7-77.8%). Participants reported a range of potential benefits from the various interventions, and user experience was largely positive. Conclusions Although small, the current published literature demonstrates strong evidence for the feasibility of using smartphones to enhance the care of people with schizophrenia. High rates of engagement and satisfaction with a broad range of apps suggest the nascent potential of this mobile technology. However, there remains limited

  6. The use of cultured Drosophila cells for studying the microtubule cytoskeleton.

    PubMed

    Nye, Jonathan; Buster, Daniel W; Rogers, Gregory C

    2014-01-01

    Cultured Drosophila cell lines have been developed into a powerful tool for studying a wide variety of cellular processes. Their ability to be easily and cheaply cultured as well as their susceptibility to protein knockdown via double-stranded RNA-mediated interference (RNAi) has made them the model system of choice for many researchers in the fields of cell biology and functional genomics. Here we describe basic techniques for gene knockdown, transgene expression, preparation for fluorescence microscopy, and centrosome enrichment using cultured Drosophila cells with an emphasis on studying the microtubule cytoskeleton.

  7. Protein synthesis elongation factor EF-1 alpha expression and longevity in Drosophila melanogaster.

    PubMed Central

    Shikama, N; Ackermann, R; Brack, C

    1994-01-01

    It has been proposed that the decline in protein synthesis observed in aging organisms may result from a decrease in elongation factor EF-1 alpha. Transgenic Drosophila melanogaster flies carrying an additional copy of the EF-1 alpha gene under control of a heat-inducible promoter have an extended lifespan, further indicating that the EF-1 alpha gene may play an important role in determining longevity. To test this hypothesis, we have quantitated EF-1 alpha mRNA, EF-1 alpha protein, and the EF-1 alpha complex-formation activity in these transgenic flies. Furthermore, we have tested whether the transgene construct is functional--i.e., whether transgenic mRNA is induced when flies are grown at higher temperature. The results show that although there is a clear difference in mean lifespan between the EF-1 alpha transgenic (E) flies and the control transgenic (C) flies, E flies do not express more EF-1 alpha protein or mRNA than C flies kept at the same experimental conditions. Although the transgene can be induced when E flies are heat-shocked at 37 degrees C, transgenic mRNA is not detectable in E flies aged at 29 degrees C. In both lines, the loss in catalytic activity with age is the same. We conclude that the E flies examined here do not live longer because of overexpressing the EF-1 alpha gene. Images PMID:8183891

  8. Sigma-2 receptor binding is decreased in female, but not male, APP/PS1 mice.

    PubMed

    Sahlholm, Kristoffer; Liao, Fan; Holtzman, David M; Xu, Jinbin; Mach, Robert H

    2015-05-01

    The sigma-2 receptor is a steroid-binding membrane-associated receptor which has been implicated in cell survival. Sigma-2 has recently been shown to bind amyloid-β (Aβ) oligomers in Alzheimer's disease (AD) brain. Furthermore, blocking this interaction was shown to prevent or reverse the effects of Aβ to cause cognitive impairment in mouse models and synaptic loss in neuronal cultures. In the present work, the density of sigma-2 receptors was measured in a double transgenic mouse model of amyloid-β deposition (APP/PS1). Comparisons were made between males and females and between transgenic and wt animals. Sigma-2 receptor density was assessed by quantitative autoradiography performed on coronal brain slices using [(3)H]N-[4-(3,4-dihydro-6,7-dimethoxyisoquinolin-2(1H)-yl)butyl]-2-methoxy-5-methyl-benzamide ([(3)H]RHM-1), which has a 300-fold selectivity for the sigma-2 receptor over the sigma-1 receptor. The translocator protein of 18 kDa (TSPO) is expressed on activated microglia and is a marker for neuroinflammation. TSPO has been found to be upregulated in neurodegenerative disorders, including AD. Therefore, in parallel with the sigma-2 autoradiography experiments, we measured TSPO expression using the selective radioligand, [(3)H]PBR28. We also quantified Aβ plaque burden in the same animals using a monoclonal antibody raised against aggregated Aβ. Sigma-2 receptor density was significantly decreased in piriform and motor cortices as well as striata of 16-month old female, but not male, APP/PS1 mice as compared to their wt counterparts. [(3)H]PBR28 binding and immunostaining for Aβ plaques were significantly increased in piriform and motor cortices of both male and female transgenic mice. In striatum however, significant increases were observed only in females.

  9. Apps and eating disorders: A systematic clinical appraisal

    PubMed Central

    Rothwell, Emily R.

    2015-01-01

    ABSTRACT Objective Smartphone applications (apps) are proliferating and health‐related apps are particularly popular. The aim of this study was to identify, characterize, and evaluate the clinical utility of apps designed either for people with eating disorders or for eating disorder professionals. Method A search of the major app stores identified 805 potentially relevant apps, of which 39 were primarily designed for people with eating disorders and five for professionals. Results The apps for people with eating disorders had four main functions. Most common was the provision of advice, the quality of which ranged from sound to potentially harmful. Five apps included self‐assessment tools but only two used methods that would generally be viewed as reliable. Four apps had the self‐monitoring of eating habits as a major feature. Entering information into these apps could be accomplished with varying degrees of ease, but viewing it was more difficult. One app allowed the transfer of information between patients and clinicians. Discussion The enthusiasm for apps outstrips the evidence supporting their use. Given their popularity, it is suggested that clinicians evaluate app use as part of routine assessment. The clinical utility of the existing apps is not clear. Some are capable of tracking key features over time, but none has the functions required for analytic self‐monitoring as in cognitive behavioral treatments. The full potential of apps has yet to be realized. Specialized apps could be designed to augment various forms of treatment, and there is the possibility that they could deliver an entire personalized intervention. © 2015 The Authors. International Journal of Eating Disorders published by Wiley Periodicals, Inc. (Int J Eat Disord 2015; 48:1038–1046) PMID:25728705

  10. Signaling by Drosophila capa neuropeptides.

    PubMed

    Davies, Shireen-A; Cabrero, Pablo; Povsic, Manca; Johnston, Natalie R; Terhzaz, Selim; Dow, Julian A T

    2013-07-01

    The capa peptide family, originally identified in the tobacco hawk moth, Manduca sexta, is now known to be present in many insect families, with increasing publications on capa neuropeptides each year. The physiological actions of capa peptides vary depending on the insect species but capa peptides have key myomodulatory and osmoregulatory functions, depending on insect lifestyle, and life stage. Capa peptide signaling is thus critical for fluid homeostasis and survival, making study of this neuropeptide family attractive for novel routes for insect control. In Dipteran species, including the genetically tractable Drosophila melanogaster, capa peptide action is diuretic; via elevation of nitric oxide, cGMP and calcium in the principal cells of the Malpighian tubules. The identification of the capa receptor (capaR) in several insect species has shown this to be a canonical GPCR. In D. melanogaster, ligand-activated capaR activity occurs in a dose-dependent manner between 10(-6) and 10(-12)M. Lower concentrations of capa peptide do not activate capaR, either in adult or larval Malpighian tubules. Use of transgenic flies in which capaR is knocked-down in only Malpighian tubule principal cells demonstrates that capaR modulates tubule fluid secretion rates and in doing so, sets the organismal response to desiccation. Thus, capa regulates a desiccation-responsive pathway in D. melanogaster, linking its role in osmoregulation and fluid homeostasis to environmental response and survival. The conservation of capa action between some Dipteran species suggests that capa's role in desiccation tolerance may not be confined to D. melanogaster.

  11. Ferritin Assembly in Enterocytes of Drosophila melanogaster

    PubMed Central

    Rosas-Arellano, Abraham; Vásquez-Procopio, Johana; Gambis, Alexis; Blowes, Liisa M.; Steller, Hermann; Mollereau, Bertrand; Missirlis, Fanis

    2016-01-01

    Ferritins are protein nanocages that accumulate inside their cavity thousands of oxidized iron atoms bound to oxygen and phosphates. Both characteristic types of eukaryotic ferritin subunits are present in secreted ferritins from insects, but here dimers between Ferritin 1 Heavy Chain Homolog (Fer1HCH) and Ferritin 2 Light Chain Homolog (Fer2LCH) are further stabilized by disulfide-bridge in the 24-subunit complex. We addressed ferritin assembly and iron loading in vivo using novel transgenic strains of Drosophila melanogaster. We concentrated on the intestine, where the ferritin induction process can be controlled experimentally by dietary iron manipulation. We showed that the expression pattern of Fer2LCH-Gal4 lines recapitulated iron-dependent endogenous expression of the ferritin subunits and used these lines to drive expression from UAS-mCherry-Fer2LCH transgenes. We found that the Gal4-mediated induction of mCherry-Fer2LCH subunits was too slow to effectively introduce them into newly formed ferritin complexes. Endogenous Fer2LCH and Fer1HCH assembled and stored excess dietary iron, instead. In contrast, when flies were genetically manipulated to co-express Fer2LCH and mCherry-Fer2LCH simultaneously, both subunits were incorporated with Fer1HCH in iron-loaded ferritin complexes. Our study provides fresh evidence that, in insects, ferritin assembly and iron loading in vivo are tightly regulated. PMID:26861293

  12. Antioxidants and cognitive training interact to affect oxidative stress and memory in APP/PSEN1 mice.

    PubMed

    Harrison, F E; Allard, J; Bixler, R; Usoh, C; Li, L; May, J M; McDonald, M P

    2009-10-01

    The present study investigated the relationships among oxidative stress, beta-amyloid and cognitive abilities in the APP/PSEN1 double-transgenic mouse model of Alzheimer's disease. In two experiments, long-term dietary supplements were given to aged APP/PSEN1 mice containing vitamin C alone (1 g/kg diet; Experiment 1) or in combination with a high (750 IU/kg diet, Experiments 1 and 2) or lower (400 IU/kg diet, Experiment 2) dose of vitamin E. Oxidative stress, measured by F(4)-neuroprostanes or malondialdehyde, was elevated in cortex of control-fed APP/PSEN1 mice and reduced to wild-type levels by vitamin supplementation. High-dose vitamin E with C was less effective at reducing oxidative stress than vitamin C alone or the low vitamin E+C diet combination. The high-dose combination also impaired water maze performance in mice of both genotypes. In Experiment 2, the lower vitamin E+C treatment attenuated spatial memory deficits in APP/PSEN1 mice and improved performance in wild-type mice in the water maze. Amyloid deposition was not reduced by antioxidant supplementation in either experiment.

  13. Heritable Endosymbionts of Drosophila

    PubMed Central

    Mateos, Mariana; Castrezana, Sergio J.; Nankivell, Becky J.; Estes, Anne M.; Markow, Therese A.; Moran, Nancy A.

    2006-01-01

    Although heritable microorganisms are increasingly recognized as widespread in insects, no systematic screens for such symbionts have been conducted in Drosophila species (the primary insect genetic models for studies of evolution, development, and innate immunity). Previous efforts screened relatively few Drosophila lineages, mainly for Wolbachia. We conducted an extensive survey of potentially heritable endosymbionts from any bacterial lineage via PCR screens of mature ovaries in 181 recently collected fly strains representing 35 species from 11 species groups. Due to our fly sampling methods, however, we are likely to have missed fly strains infected with sex ratio-distorting endosymbionts. Only Wolbachia and Spiroplasma, both widespread in insects, were confirmed as symbionts. These findings indicate that in contrast to some other insect groups, other heritable symbionts are uncommon in Drosophila species, possibly reflecting a robust innate immune response that eliminates many bacteria. A more extensive survey targeted these two symbiont types through diagnostic PCR in 1225 strains representing 225 species from 32 species groups. Of these, 19 species were infected by Wolbachia while only 3 species had Spiroplasma. Several new strains of Wolbachia and Spiroplasma were discovered, including ones divergent from any reported to date. The phylogenetic distribution of Wolbachia and Spiroplasma in Drosophila is discussed. PMID:16783009

  14. Transgenic Crops for Herbicide Resistance

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Since their introduction in 1995, crops made resistant to the broad-spectrum herbicides glyphosate and glufosinate with transgenes are widely available and used in much of the world. As of 2008, over 80% of the transgenic crops grown world-wide have this transgenic trait. This technology has had m...

  15. Surface Trafficking of APP and BACE in Live Cells.

    PubMed

    Bauereiss, Anna; Welzel, Oliver; Jung, Jasmin; Grosse-Holz, Simon; Lelental, Natalia; Lewczuk, Piotr; Wenzel, Eva M; Kornhuber, Johannes; Groemer, Teja W

    2015-06-01

    Amyloid-β (Aβ)-peptide, the major constituent of the plaques that develop during Alzheimer's disease, is generated via the cleavage of Aβ precursor protein (APP) by β-site APP-cleaving enzyme (BACE). Using live-cell imaging of APP and BACE labeled with pH-sensitive proteins, we could detect the release events of APP and BACE and their distinct kinetics. We provide kinetic evidence for the cleavage of APP by α-secretase on the cellular surface after exocytosis. Furthermore, simultaneous dual-color evanescent field illumination revealed that the two proteins are trafficked to the surface in separate compartments. Perturbing the membrane lipid composition resulted in a reduced frequency of exocytosis and affected BACE more strongly than APP. We propose that surface fusion frequency is a key factor regulating the aggregation of APP and BACE in the same membrane compartment and that this process can be modulated via pharmacological intervention.

  16. Transgenic mammals and biotechnology.

    PubMed

    Westphal, H

    1989-02-01

    Biotechnology has begun to realize the enormous potential of transgenic technology: mice with human genes that produce human proteins of therapeutic value in their milk, pigs that express bovine genes that help them gain weight and lose backfat, animals with engineered gene defects that mimic human genetic diseases.

  17. [Progress on transgenic mosquitoes].

    PubMed

    Yang, Pin

    2011-04-30

    The genetically modified mosquitoes have been developed aiming to control mosquito-borne diseases by either reducing population sizes or replacing existing populations with vectors unable to transmit the disease. introduces some progress on the generation of transgenic mosquitoes and their fitness in wild population. This paper

  18. Transgenic Farm Animals

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The development of recombinant DNA technology has enabled scientists to isolate single genes, analyze and modify their nucleotide structure(s), make copies of these isolated genes, and insert copies of these genes into the genome of plants and animals. The transgenic technology of adding genes to li...

  19. Apps for People With Rheumatoid Arthritis to Monitor Their Disease Activity: A Review of Apps for Best Practice and Quality

    PubMed Central

    Townsley, Hermaleigh; White, Bonnie; Langlotz, Tobias; Taylor, William J

    2017-01-01

    Background Rheumatoid arthritis (RA) is a chronic inflammatory arthritis requiring long-term treatment with regular monitoring by a rheumatologist to achieve good health outcomes. Since people with RA may wish to monitor their own disease activity with a smartphone app, it is important to understand the functions and quality of apps for this purpose. Objective The aim of our study was to assess the features and quality of apps to assist people to monitor their RA disease activity by (1) summarizing the available apps, particularly the instruments used for measurement of RA disease activity; (2) comparing the app features with American College of Rheumatology and European League against Rheumatism (ACR and EULAR) guidelines for monitoring of RA disease activity; and (3) rating app quality with the Mobile App Rating Scale (MARS). Methods Systematic searches of the New Zealand iTunes and Google Play app stores were used to identify all apps for monitoring of RA disease activity that could be used by people with RA. The apps were described by both key metadata and app functionality. App adherence with recommendations for monitoring of RA disease activity in clinical practice was evaluated by identifying whether apps included calculation of a validated composite disease activity measure and recorded results for future retrieval. App quality was assessed by 2 independent reviewers using the MARS. Results The search identified 721 apps in the Google Play store and 216 in the iTunes store, of which 19 unique apps met criteria for inclusion (8 from both app stores, 8 iTunes, and 3 Google Play). In total, 14 apps included at least one validated instrument measuring RA disease activity; 7 of 11 apps that allowed users to enter a joint count used the standard 28 swollen and tender joint count; 8 apps included at least one ACR and EULAR-recommended RA composite disease activity (CDA) measure; and 10 apps included data storage and retrieval. Only 1 app, Arthritis Power, included

  20. Vascular Dysfunction in a Transgenic Model of Alzheimer's Disease: Effects of CB1R and CB2R Cannabinoid Agonists

    PubMed Central

    Navarro-Dorado, Jorge; Villalba, Nuria; Prieto, Dolores; Brera, Begoña; Martín-Moreno, Ana M.; Tejerina, Teresa; de Ceballos, María L.

    2016-01-01

    There is evidence of altered vascular function, including cerebrovascular, in Alzheimer's disease (AD) and transgenic models of the disease. Indeed vasoconstrictor responses are increased, while vasodilation is reduced in both conditions. β-Amyloid (Aβ) appears to be responsible, at least in part, of alterations in vascular function. Cannabinoids, neuroprotective and anti-inflammatory agents, induce vasodilation both in vivo and in vitro. We have demonstrated a beneficial effect of cannabinoids in models of AD by preventing glial activation. In this work we have studied the effects of these compounds on vessel density in amyloid precursor protein (APP) transgenic mice, line 2576, and on altered vascular responses in aortae isolated ring. First we showed increased collagen IV positive vessels in AD brain compared to control subjects, with a similar increase in TgAPP mice, which was normalized by prolonged oral treatment with the CB1/CB2 mixed agonist WIN 55,212-2 (WIN) and the CB2 selective agonist JWH-133 (JWH). In Tg APP mice the vasoconstriction induced by phenylephrine and the thromboxane agonist U46619 was significantly increased, and no change in the vasodilation to acetylcholine (ACh) was observed. Tg APP displayed decreased vasodilation to both cannabinoid agonists, which were able to prevent decreased ACh relaxation in the presence of Aβ. In summary, we have confirmed and extended the existence of altered vascular responses in Tg APP mice. Moreover, our results suggest that treatment with cannabinoids may ameliorate the vascular responses in AD-type pathology. PMID:27695396

  1. Transgenic animal bioreactors.

    PubMed

    Houdebine, L M

    2000-01-01

    The production of recombinant proteins is one of the major successes of biotechnology. Animal cells are required to synthesize proteins with the appropriate post-translational modifications. Transgenic animals are being used for this purpose. Milk, egg white, blood, urine, seminal plasma and silk worm cocoon from transgenic animals are candidates to be the source of recombinant proteins at an industrial scale. Although the first recombinant protein produced by transgenic animals is expected to be in the market in 2000, a certain number of technical problems remain to be solved before the various systems are optimized. Although the generation of transgenic farm animals has become recently easier mainly with the technique of animal cloning using transfected somatic cells as nuclear donor, this point remains a limitation as far as cost is concerned. Numerous experiments carried out for the last 15 years have shown that the expression of the transgene is predictable only to a limited extent. This is clearly due to the fact that the expression vectors are not constructed in an appropriate manner. This undoubtedly comes from the fact that all the signals contained in genes have not yet been identified. Gene constructions thus result sometime in poorly functional expression vectors. One possibility consists in using long genomic DNA fragments contained in YAC or BAC vectors. The other relies on the identification of the major important elements required to obtain a satisfactory transgene expression. These elements include essentially gene insulators, chromatin openers, matrix attached regions, enhancers and introns. A certain number of proteins having complex structures (formed by several subunits, being glycosylated, cleaved, carboxylated...) have been obtained at levels sufficient for an industrial exploitation. In other cases, the mammary cellular machinery seems insufficient to promote all the post-translational modifications. The addition of genes coding for enzymes

  2. Hypergravity-induced altered behavior in Drosophila

    NASA Astrophysics Data System (ADS)

    Hosamani, Ravikumar; Wan, Judy; Marcu, Oana; Bhattacharya, Sharmila

    2012-07-01

    Microgravity and mechanical stress are important factors of the spaceflight environment, and affect astronaut health and behavior. Structural, functional, and behavioral mechanisms of all cells and organisms are adapted to Earth's gravitational force, 1G, while altered gravity can pose challenges to their adaptability to this new environment. On ground, hypergravity paradigms have been used to predict and complement studies on microgravity. Even small changes that take place at a molecular and genetic level during altered gravity may result in changes in phenotypic behavior. Drosophila provides a robust and simple, yet very reliable model system to understand the complexity of hypergravity-induced altered behavior, due to availability of a plethora of genetic tools. Locomotor behavior is a sensitive parameter that reflects the array of molecular adaptive mechanisms recruited during exposure to altered gravity. Thus, understanding the genetic basis of this behavior in a hypergravity environment could potentially extend our understanding of mechanisms of adaptation in microgravity. In our laboratory we are trying to dissect out the cellular and molecular mechanisms underlying hypergravity-induced oxidative stress, and its potential consequences on behavioral alterations by using Drosophila as a model system. In the present study, we employed pan-neuronal and mushroom body specific knock-down adult flies by using Gal4/UAS system to express inverted repeat transgenes (RNAi) to monitor and quantify the hypergravity-induced behavior in Drosophila. We established that acute hypergravity (3G for 60 min) causes a significant and robust decrease in the locomotor behavior in adult Drosophila, and that this change is dependent on genes related to Parkinson's disease, such as DJ-1α , DJ-1β , and parkin. In addition, we also showed that anatomically the control of this behavior is significantly processed in the mushroom body region of the fly brain. This work links a molecular

  3. Mobile app-based quantitative scanometric analysis.

    PubMed

    Wong, Jessica X H; Liu, Frank S F; Yu, Hua-Zhong

    2014-12-16

    The feasibility of using smartphones and other mobile devices as the detection platform for quantitative scanometric assays is demonstrated. The different scanning modes (color, grayscale, black/white) and grayscale converting protocols (average, weighted average/luminosity, and software specific) have been compared in determining the optical darkness ratio (ODR) values, a conventional quantitation measure for scanometric assays. A mobile app was developed to image and analyze scanometric assays, as demonstrated by paper-printed tests and a biotin-streptavidin assay on a plastic substrate. Primarily for ODR analysis, the app has been shown to perform as well as a traditional desktop scanner, augmenting that smartphones (and other mobile devices) promise to be a practical platform for accurate, quantitative chemical analysis and medical diagnostics.

  4. A Flippase-Mediated GAL80/GAL4 Intersectional Resource for Dissecting Appendage Development in Drosophila.

    PubMed

    Smith, Brittany N; Ghazanfari, Arash M; Bohm, Rudolf A; Welch, William P; Zhang, Bing; Masly, John P

    2015-08-13

    Drosophila imaginal discs provide an ideal model to study processes important for cell signaling and cell specification, tissue differentiation, and cell competition during development. One challenge to understanding genetic control of cellular processes and cell interactions is the difficulty in effectively targeting a defined subset of cells in developing tissues in gene manipulation experiments. A recently developed Flippase-induced intersectional GAL80/GAL4 repression method incorporates several gene manipulation technologies in Drosophila to enable such fine-scale dissection in neural tissues. In particular, this approach brings together existing GAL4 transgenes, newly developed enhancer-trap flippase transgenes, and GAL80 transgenes flanked by Flippase recognition target sites. The combination of these tools enables gene activation/repression in particular subsets of cells within a GAL4 expression pattern. Here, we expand the utility of a large collection of these enhancer-trap flippase transgenic insertion lines by characterizing their expression patterns in third larval instar imaginal discs. We screened 521 different enhancer-trap flippase lines and identified 28 that are expressed in imaginal tissues, including two transgenes that show sex-specific expression patterns. Using a line that expresses Flippase in the wing imaginal disc, we demonstrate the utility of this intersectional approach for studying development by knocking down gene expression of a key member of the planar cell polarity pathway. The results of our experiments show that these enhancer-trap flippase lines enable fine-scale manipulation in imaginal discs.

  5. A genetic mosaic approach for neural circuit mapping in Drosophila

    PubMed Central

    Bohm, Rudolf A.; Welch, William P.; Goodnight, Lindsey K.; Cox, Logan W.; Henry, Leah G.; Gunter, Tyler C.; Bao, Hong; Zhang, Bing

    2010-01-01

    Transgenic manipulation of subsets of brain cells is increasingly used for studying behaviors and their underlying neural circuits. In Drosophila, the GAL4–upstream activating sequence (UAS) binary system is powerful for gene manipulation, but GAL4 expression is often too broad for fine mapping of neural circuits. Here, we describe the development of unique molecular genetic tools to restrict GAL4 expression patterns. Building on the GAL4-UAS system, our method adds two components: a collection of enhancer-trap recombinase, Flippase (ET-FLP), transgenic lines that provide inheritable, reproducible, and tissue-specific FLP and an FRT-dependent GAL80 “flip-in” construct that converts FLP expression into tissue-specific repression of GAL4 by GAL80. By including a UAS-encoded fluorescent protein, circuit morphology can be simultaneously marked while the circuit function is assessed using another UAS transgene. In a proof-of-principle analysis, we applied this ET-FLP-induced intersectional GAL80/GAL4 repression (FINGR) method to map the neural circuitry underlying fly wing inflation. The FINGR system is versatile and powerful in combination with the vast collection of GAL4 lines for neural circuit mapping as well as for clonal analysis based on the infusion of the yeast-derived FRT/FLP system of mitotic recombination into Drosophila. The strategies and tactics underlying our FINGR system are also applicable to other genetically amenable organisms in which transgenes including the GAL4, UAS, GAL80, and FLP factors can be applied. PMID:20810922

  6. Audio App Brings a Better Nights Sleep

    NASA Technical Reports Server (NTRS)

    2015-01-01

    Neuroscientist Seth Horowitz was part of a NASA-funded team at State University of New York Stony Brook demonstrating that low-amplitude vestibular stimulation could induce sleep. After recognizing the same stimulation could be applied through sound, Horowitz founded Sleep Genius, located in Park City, Utah, and released a mobile app of the same name that helps people to get a more restful sleep.

  7. Combinatorial Gene Regulatory Functions Underlie Ultraconserved Elements in Drosophila.

    PubMed

    Warnefors, Maria; Hartmann, Britta; Thomsen, Stefan; Alonso, Claudio R

    2016-09-01

    Ultraconserved elements (UCEs) are discrete genomic elements conserved across large evolutionary distances. Although UCEs have been linked to multiple facets of mammalian gene regulation their extreme evolutionary conservation remains largely unexplained. Here, we apply a computational approach to investigate this question in Drosophila, exploring the molecular functions of more than 1,500 UCEs shared across the genomes of 12 Drosophila species. Our data indicate that Drosophila UCEs are hubs for gene regulatory functions and suggest that UCE sequence invariance originates from their combinatorial roles in gene control. We also note that the gene regulatory roles of intronic and intergenic UCEs (iUCEs) are distinct from those found in exonic UCEs (eUCEs). In iUCEs, transcription factor (TF) and epigenetic factor binding data strongly support iUCE roles in transcriptional and epigenetic regulation. In contrast, analyses of eUCEs indicate that they are two orders of magnitude more likely than the expected to simultaneously include protein-coding sequence, TF-binding sites, splice sites, and RNA editing sites but have reduced roles in transcriptional or epigenetic regulation. Furthermore, we use a Drosophila cell culture system and transgenic Drosophila embryos to validate the notion of UCE combinatorial regulatory roles using an eUCE within the Hox gene Ultrabithorax and show that its protein-coding region also contains alternative splicing regulatory information. Taken together our experiments indicate that UCEs emerge as a result of combinatorial gene regulatory roles and highlight common features in mammalian and insect UCEs implying that similar processes might underlie ultraconservation in diverse animal taxa.

  8. Combinatorial Gene Regulatory Functions Underlie Ultraconserved Elements in Drosophila

    PubMed Central

    Warnefors, Maria; Hartmann, Britta; Thomsen, Stefan; Alonso, Claudio R.

    2016-01-01

    Ultraconserved elements (UCEs) are discrete genomic elements conserved across large evolutionary distances. Although UCEs have been linked to multiple facets of mammalian gene regulation their extreme evolutionary conservation remains largely unexplained. Here, we apply a computational approach to investigate this question in Drosophila, exploring the molecular functions of more than 1,500 UCEs shared across the genomes of 12 Drosophila species. Our data indicate that Drosophila UCEs are hubs for gene regulatory functions and suggest that UCE sequence invariance originates from their combinatorial roles in gene control. We also note that the gene regulatory roles of intronic and intergenic UCEs (iUCEs) are distinct from those found in exonic UCEs (eUCEs). In iUCEs, transcription factor (TF) and epigenetic factor binding data strongly support iUCE roles in transcriptional and epigenetic regulation. In contrast, analyses of eUCEs indicate that they are two orders of magnitude more likely than the expected to simultaneously include protein-coding sequence, TF-binding sites, splice sites, and RNA editing sites but have reduced roles in transcriptional or epigenetic regulation. Furthermore, we use a Drosophila cell culture system and transgenic Drosophila embryos to validate the notion of UCE combinatorial regulatory roles using an eUCE within the Hox gene Ultrabithorax and show that its protein-coding region also contains alternative splicing regulatory information. Taken together our experiments indicate that UCEs emerge as a result of combinatorial gene regulatory roles and highlight common features in mammalian and insect UCEs implying that similar processes might underlie ultraconservation in diverse animal taxa. PMID:27247329

  9. An interactive app for color deficient viewers

    NASA Astrophysics Data System (ADS)

    Lau, Cheryl; Perdu, Nicolas; Rodríguez-Pardo, Carlos E.; Süsstrunk, Sabine; Sharma, Gaurav

    2015-01-01

    Color deficient individuals have trouble seeing color contrasts that could be very apparent to individuals with normal color vision. For example, for some color deficient individuals, red and green apples do not have the striking contrast they have for those with normal color vision, or the abundance of red cherries in a tree is not immediately clear due to a lack of perceived contrast. We present a smartphone app that enables color deficient users to visualize such problematic color contrasts in order to help them with daily tasks. The user interacts with the app through the touchscreen. As the user traces a path around the touchscreen, the colors in the image change continuously via a transform that enhances contrasts that are weak or imperceptible for the user under native viewing conditions. Specifically, we propose a transform that shears the data along lines parallel to the dimension corresponding to the affected cone sensitivity of the user. The amount and direction of shear are controlled by the user's finger movement over the touchscreen allowing them to visualize these contrasts. Using the GPU, this simple transformation, consisting of a linear shear and translation, is performed efficiently on each pixel and in real-time with the changing position of the user's finger. The user can use the app to aid daily tasks such as distinguishing between red and green apples or picking out ripe bananas.

  10. Aging studies in Drosophila melanogaster.

    PubMed

    Sun, Yaning; Yolitz, Jason; Wang, Cecilia; Spangler, Edward; Zhan, Ming; Zou, Sige

    2013-01-01

    Drosophila is a genetically tractable system ideal for investigating the mechanisms of aging and developing interventions for promoting healthy aging. Here we describe methods commonly used in Drosophila aging research. These include basic approaches for preparation of diets and measurements of lifespan, food intake, and reproductive output. We also describe some commonly used assays to measure changes in physiological and behavioral functions of Drosophila in aging, such as stress resistance and locomotor activity.

  11. Aging Studies in Drosophila melanogaster

    PubMed Central

    Sun, Yaning; Yolitz, Jason; Wang, Cecilia; Spangler, Edward; Zhan, Ming; Zou, Sige

    2015-01-01

    Summary Drosophila is a genetically tractable system ideal for investigating the mechanisms of aging and developing interventions for promoting healthy aging. Here we describe methods commonly used in Drosophila aging research. These include basic approaches for preparation of diets and measurements of lifespan, food intake and reproductive output. We also describe some commonly used assays to measure changes in physiological and behavioral functions of Drosophila in aging, such as stress resistance and locomotor activity. PMID:23929099

  12. Interrater Reliability of mHealth App Rating Measures: Analysis of Top Depression and Smoking Cessation Apps

    PubMed Central

    Chan, Steven; Raynor, Geoffrey Stephen; Shwarts, Erik; Shanahan, Meghan; Landman, Adam B

    2016-01-01

    Background There are over 165,000 mHealth apps currently available to patients, but few have undergone an external quality review. Furthermore, no standardized review method exists, and little has been done to examine the consistency of the evaluation systems themselves. Objective We sought to determine which measures for evaluating the quality of mHealth apps have the greatest interrater reliability. Methods We identified 22 measures for evaluating the quality of apps from the literature. A panel of 6 reviewers reviewed the top 10 depression apps and 10 smoking cessation apps from the Apple iTunes App Store on these measures. Krippendorff’s alpha was calculated for each of the measures and reported by app category and in aggregate. Results The measure for interactiveness and feedback was found to have the greatest overall interrater reliability (alpha=.69). Presence of password protection (alpha=.65), whether the app was uploaded by a health care agency (alpha=.63), the number of consumer ratings (alpha=.59), and several other measures had moderate interrater reliability (alphas>.5). There was the least agreement over whether apps had errors or performance issues (alpha=.15), stated advertising policies (alpha=.16), and were easy to use (alpha=.18). There were substantial differences in the interrater reliabilities of a number of measures when they were applied to depression versus smoking apps. Conclusions We found wide variation in the interrater reliability of measures used to evaluate apps, and some measures are more robust across categories of apps than others. The measures with the highest degree of interrater reliability tended to be those that involved the least rater discretion. Clinical quality measures such as effectiveness, ease of use, and performance had relatively poor interrater reliability. Subsequent research is needed to determine consistent means for evaluating the performance of apps. Patients and clinicians should consider conducting their

  13. Expanded ATXN3 frameshifting events are toxic in Drosophila and mammalian neuron models.

    PubMed

    Stochmanski, Shawn J; Therrien, Martine; Laganière, Janet; Rochefort, Daniel; Laurent, Sandra; Karemera, Liliane; Gaudet, Rebecca; Vyboh, Kishanda; Van Meyel, Don J; Di Cristo, Graziella; Dion, Patrick A; Gaspar, Claudia; Rouleau, Guy A

    2012-05-15

    Spinocerebellar ataxia type 3 is caused by the expansion of the coding CAG repeat in the ATXN3 gene. Interestingly, a -1 bp frameshift occurring within an (exp)CAG repeat would henceforth lead to translation from a GCA frame, generating polyalanine stretches instead of polyglutamine. Our results show that transgenic expression of (exp)CAG ATXN3 led to -1 frameshifting events, which have deleterious effects in Drosophila and mammalian neurons. Conversely, transgenic expression of polyglutamine-encoding (exp)CAA ATXN3 was not toxic. Furthermore, (exp)CAG ATXN3 mRNA does not contribute per se to the toxicity observed in our models. Our observations indicate that expanded polyglutamine tracts in Drosophila and mouse neurons are insufficient for the development of a phenotype. Hence, we propose that -1 ribosomal frameshifting contributes to the toxicity associated with (exp)CAG repeats.

  14. Misexpression of the white (w) gene triggers male-male courtship in Drosophila.

    PubMed Central

    Zhang, S D; Odenwald, W F

    1995-01-01

    We report here that the general ectopic expression of a tryptophan/guanine transmembrane transporter gene, white (w), induces male-male courtship in Drosophila. Activation of a hsp-70/miniwhite (mini-w) transgene in mature males results in a marked change in their sexual behavior such that they begin to vigorously court other mature males. In transformant populations containing equal numbers of both sexes, most males participate, thus forming male-male courtship chains, circles, and lariats. Mutations that ablate the w transgene function also abolish this inducible behavior. Female sexual behavior does not appear to be altered by ectopic w expression. By contrast, when exposed to an active homosexual courtship environment, non-transformant males alter their behavior and actively participate in the male-male chaining. These findings demonstrate that, in Drosophila, both genetic and environmental factors play a role in male sexual behavior. Images Fig. 1 Fig. 2 Fig. 3 Fig. 4 PMID:7777542

  15. APP as a Protective Factor in Acute Neuronal Insults

    PubMed Central

    Hefter, Dimitri; Draguhn, Andreas

    2017-01-01

    Despite its key role in the molecular pathology of Alzheimer’s disease (AD), the physiological function of amyloid precursor protein (APP) is unknown. Increasing evidence, however, points towards a neuroprotective role of this membrane protein in situations of metabolic stress. A key observation is the up-regulation of APP following acute (stroke, cardiac arrest) or chronic (cerebrovascular disease) hypoxic-ischemic conditions. While this mechanism may increase the risk or severity of AD, APP by itself or its soluble extracellular fragment APPsα can promote neuronal survival. Indeed, different animal models of acute hypoxia-ischemia, traumatic brain injury (TBI) and excitotoxicity have revealed protective effects of APP or APPsα. The underlying mechanisms involve APP-mediated regulation of calcium homeostasis via NMDA receptors (NMDAR), voltage-gated calcium channels (VGCC) or internal calcium stores. In addition, APP affects the expression of survival- or apoptosis-related genes as well as neurotrophic factors. In this review, we summarize the current understanding of the neuroprotective role of APP and APPsα and possible implications for future research and new therapeutic strategies. PMID:28210211

  16. Endogenous APP accumulates in synapses after BACE1 inhibition.

    PubMed

    Nigam, Saket Milind; Xu, Shaohua; Ackermann, Frauke; Gregory, Joshua A; Lundkvist, Johan; Lendahl, Urban; Brodin, Lennart

    2016-08-01

    BACE1-mediated cleavage of APP is a pivotal step in the production of the Alzheimer related Aβ peptide and inhibitors of BACE1 are currently in clinical development for the treatment of Alzheimer disease (AD). While processing and trafficking of APP has been extensively studied in non-neuronal cells, the fate of APP at neuronal synapses and in response to reduced BACE1 activity has not been fully elucidated. Here we examined the consequence of reduced BACE1 activity on endogenous synaptic APP by monitoring N- and C-terminal APP epitopes by immunocytochemistry. In control rodent primary hippocampal neuron cultures, labeling with antibodies directed to N-terminal APP epitopes showed a significant overlap with synaptic vesicle markers (SV2 or synaptotagmin). In contrast, labeling with antibodies directed to C-terminal epitopes of APP showed only a limited overlap with these proteins. In neurons derived from BACE1-deficient mice, and in control neurons treated with a BACE1 inhibitor, both the N-terminal and the C-terminal APP labeling overlapped significantly with synaptic vesicle markers. Moreover, BACE1 inhibition increased the proximity between the APP C-terminus and SV2 as shown by a proximity ligation assay. These results, together with biochemical observations, indicate that BACE1 can regulate the levels of full-length APP at neuronal synapses.

  17. Development of a Reporter System for In Vivo Monitoring of γ-Secretase Activity in Drosophila

    PubMed Central

    Hong, Young Gi; Roh, Seyun; Paik, Donggi; Jeong, Sangyun

    2017-01-01

    The γ-secretase complex represents an evolutionarily conserved family of transmembrane aspartyl proteases that cleave numerous type-I membrane proteins, including the β-amyloid precursor protein (APP) and the receptor Notch. All known rare mutations in APP and the γ-secretase catalytic component, presenilin, which lead to increased amyloid βpeptide production, are responsible for early-onset familial Alzheimer’s disease. β-amyloid protein precursor-like (APPL) is the Drosophila ortholog of human APP. Here, we created Notch- and APPL-based Drosophila reporter systems for in vivo monitoring of γ-secretase activity. Ectopic expression of the Notch- and APPL-based chimeric reporters in wings results in vein truncation phenotypes. Reporter-mediated vein truncation phenotypes are enhanced by the Notch gain-of-function allele and suppressed by RNAi-mediated knockdown of presenilin. Furthermore, we find that apoptosis partly contributes to the vein truncation phenotypes of the APPL-based reporter, but not to the vein truncation phenotypes of the Notch-based reporter. Taken together, these results suggest that both in vivo reporter systems provide a powerful genetic tool to identify genes that modulate γ-secretase activity and/or APPL metabolism. PMID:28152299

  18. Relative transgene expression frequencies in homozygous versus hemizygous transgenic mice.

    PubMed

    Chang, Su-Ping; Opsahl, Margaret L; Whitelaw, C Bruce A; Morley, Steven D; West, John D

    2013-12-01

    We have used a simple binomial model of stochastic transgene inactivation at the level of the chromosome or transgene, rather than the cellular level, for the analysis of two mouse transgenic lines that show variegated patterns of expression. This predicts the percentages of cells that express one, both or neither alleles of the transgene in homozygotes from the observed percentages of cells, which express the transgene in hemizygotes. It adequately explained the relationship between the numbers of cells expressing the transgene in hemizygous and homozygous mosaic 21OH/LacZ mouse adrenals and mosaic BLG/7 mouse mammary glands. The binomial model also predicted that a small proportion of cells in mosaic mammary glands of BLG/7 homozygotes would express both BLG/7 alleles but published data indicated that all cells expressing the transgene showed monoallelic expression. Although it didn't fit all of the BLG/7 data as precisely as a more complex model, which used several ad hoc assumptions to explain these results, the simple binomial model was able to explain the relationship in observed transgene expression frequencies between hemizygous and homozygous mosaic tissues for both 21OH/LacZ and BLG/7 mice. It may prove to be a useful general model for analysing other transgenic animals showing mosaic transgene expression.

  19. The Drosophila Auditory System

    PubMed Central

    Boekhoff-Falk, Grace; Eberl, Daniel F.

    2013-01-01

    Development of a functional auditory system in Drosophila requires specification and differentiation of the chordotonal sensilla of Johnston’s organ (JO) in the antenna, correct axonal targeting to the antennal mechanosensory and motor center (AMMC) in the brain, and synaptic connections to neurons in the downstream circuit. Chordotonal development in JO is functionally complicated by structural, molecular and functional diversity that is not yet fully understood, and construction of the auditory neural circuitry is only beginning to unfold. Here we describe our current understanding of developmental and molecular mechanisms that generate the exquisite functions of the Drosophila auditory system, emphasizing recent progress and highlighting important new questions arising from research on this remarkable sensory system. PMID:24719289

  20. Drosophila by the dozen

    SciTech Connect

    Celniker, Susan E.; Hoskins, Roger A.

    2007-07-13

    This year's conference on Drosophila research illustratedwell the current focus of Drosophila genomics on the comprehensiveidentification of functional elements in the genome sequence, includingmRNA transcripts arising from multiple alternative start sites and splicesites, a multiplicity of noncoding transcripts and small RNAs,identification of binding sites for transcription factors, sequenceconservation in related species and sequence variation within species.Resources and technologies for genetics and functional genomics aresteadily being improved, including the building of collections oftransposon insertion mutants and hairpin constructs for RNA interference(RNAi). The conference also highlighted progress in the use of genomicinformation by many laboratories to study diverse aspects of biology andmodels of human disease. Here we will review a few highlights of especialinterest to readers of Genome Biology.

  1. Fluorescence behavioral imaging (FBI) tracks identity in heterogeneous groups of Drosophila.

    PubMed

    Ramdya, Pavan; Schaffter, Thomas; Floreano, Dario; Benton, Richard

    2012-01-01

    Distinguishing subpopulations in group behavioral experiments can reveal the impact of differences in genetic, pharmacological and life-histories on social interactions and decision-making. Here we describe Fluorescence Behavioral Imaging (FBI), a toolkit that uses transgenic fluorescence to discriminate subpopulations, imaging hardware that simultaneously records behavior and fluorescence expression, and open-source software for automated, high-accuracy determination of genetic identity. Using FBI, we measure courtship partner choice in genetically mixed groups of Drosophila.

  2. p120 Catenin Is Required for the Stress Response in Drosophila

    PubMed Central

    Stefanatos, Rhoda K.; Bauer, Christin; Vidal, Marcos

    2013-01-01

    p120ctn is a ubiquitously expressed core component of cadherin junctions and essential for vertebrate development. Surprisingly, Drosophila p120ctn (dp120ctn) is dispensable for adherens junctions and development, which has discouraged Drosophila researchers from further pursuing the biological role of dp120ctn. Here we demonstrate that dp120ctn loss results in increased heat shock sensitivity and reduced animal lifespan, which are completely rescued by ectopic expression of a dp120ctn-GFP transgene. Transcriptomic analysis revealed multiple relish/NF-κB target genes differentially expressed upon loss of dp120ctn. Importantly, this aberrant gene expression was rescued by overexpression of dp120ctn-GFP or heterozygosity for relish. Our results uncover a novel role for dp120ctn in the regulation of animal stress response and immune signalling. This may represent an ancient role of p120ctn and can influence further studies in Drosophila and mammals. PMID:24349561

  3. Noncoding RNAs of trithorax response elements recruit Drosophila Ash1 to Ultrabithorax.

    PubMed

    Sanchez-Elsner, Tilman; Gou, Dawei; Kremmer, Elisabeth; Sauer, Frank

    2006-02-24

    Homeotic genes contain cis-regulatory trithorax response elements (TREs) that are targeted by epigenetic activators and transcribed in a tissue-specific manner. We show that the transcripts of three TREs located in the Drosophila homeotic gene Ultrabithorax (Ubx) mediate transcription activation by recruiting the epigenetic regulator Ash1 to the template TREs. TRE transcription coincides with Ubx transcription and recruitment of Ash1 to TREs in Drosophila. The SET domain of Ash1 binds all three TRE transcripts, with each TRE transcript hybridizing with and recruiting Ash1 only to the corresponding TRE in chromatin. Transgenic transcription of TRE transcripts restores recruitment of Ash1 to Ubx TREs and restores Ubx expression in Drosophila cells and tissues that lack endogenous TRE transcripts. Small interfering RNA-induced degradation of TRE transcripts attenuates Ash1 recruitment to TREs and Ubx expression, which suggests that noncoding TRE transcripts play an important role in epigenetic activation of gene expression.

  4. Transgenes for tea?

    PubMed

    Heritage, John

    2005-01-01

    So far, no compelling scientific evidence has been found to suggest that the consumption of transgenic or genetically modified (GM) plants by animals or humans is more likely to cause harm than is the consumption of their conventional counterparts. Despite this lack of scientific evidence, the economic prospects for GM plants are probably limited in the short term and there is public opposition to the technology. Now is a good time to address several issues concerning GM plants, including the potential for transgenes to migrate from GM plants to gut microbes or to animal or human tissues, the consequences of consuming GM crops, either as fresh plants or as silage, and the problems caused by current legislation on GM labelling and beyond.

  5. Apps Seeking Theories: Results of a Study on the Use of Health Behavior Change Theories in Cancer Survivorship Mobile Apps

    PubMed Central

    Fair, Kayla; Hong, Y Alicia; Beaudoin, Christopher E; Pulczinski, Jairus; Ory, Marcia G

    2015-01-01

    Background Thousands of mobile health apps are now available for use on mobile phones for a variety of uses and conditions, including cancer survivorship. Many of these apps appear to deliver health behavior interventions but may fail to consider design considerations based in human computer interface and health behavior change theories. Objective This study is designed to assess the presence of and manner in which health behavior change and health communication theories are applied in mobile phone cancer survivorship apps. Methods The research team selected a set of criteria-based health apps for mobile phones and assessed each app using qualitative coding methods to assess the application of health behavior change and communication theories. Each app was assessed using a coding derived from the taxonomy of 26 health behavior change techniques by Abraham and Michie with a few important changes based on the characteristics of mHealth apps that are specific to information processing and human computer interaction such as control theory and feedback systems. Results A total of 68 mobile phone apps and games built on the iOS and Android platforms were coded, with 65 being unique. Using a Cohen’s kappa analysis statistic, the inter-rater reliability for the iOS apps was 86.1 (P<.001) and for the Android apps, 77.4 (P<.001). For the most part, the scores for inclusion of theory-based health behavior change characteristics in the iOS platform cancer survivorship apps were consistently higher than those of the Android platform apps. For personalization and tailoring, 67% of the iOS apps (24/36) had these elements as compared to 38% of the Android apps (12/32). In the area of prompting for intention formation, 67% of the iOS apps (34/36) indicated these elements as compared to 16% (5/32) of the Android apps. Conclusions Mobile apps are rapidly emerging as a way to deliver health behavior change interventions that can be tailored or personalized for individuals. As these

  6. Sexual circuitry in Drosophila.

    PubMed

    Auer, Thomas O; Benton, Richard

    2016-06-01

    The sexual behavior of Drosophila melanogaster is an outstanding paradigm to understand the molecular and neuronal basis of sophisticated animal actions. We discuss recent advances in our knowledge of the genetic hardwiring of the underlying neuronal circuitry, and how pertinent sensory cues are differentially detected and integrated in the male and female brain. We also consider how experience influences these circuits over short timescales, and the evolution of these pathways over longer timescales to endow species-specific sexual displays and responses.

  7. Transgenics in crops

    NASA Technical Reports Server (NTRS)

    Li, Y.; Wu, Y. H.; McAvoy, R.; Duan, H.

    2001-01-01

    With rapid world population growth and declining availability of fresh water and arable land, a new technology is urgently needed to enhance agricultural productivity. Recent discoveries in the field of crop transgenics clearly demonstrate the great potential of this technology for increasing food production and improving food quality while preserving the environment for future generations. In this review, we briefly discuss some of the recent achievements in crop improvement that have been made using gene transfer technology.

  8. Just a Fad? Gamification in Health and Fitness Apps

    PubMed Central

    2014-01-01

    Background Gamification has been a predominant focus of the health app industry in recent years. However, to our knowledge, there has yet to be a review of gamification elements in relation to health behavior constructs, or insight into the true proliferation of gamification in health apps. Objective The objective of this study was to identify the extent to which gamification is used in health apps, and analyze gamification of health and fitness apps as a potential component of influence on a consumer’s health behavior. Methods An analysis of health and fitness apps related to physical activity and diet was conducted among apps in the Apple App Store in the winter of 2014. This analysis reviewed a sample of 132 apps for the 10 effective game elements, the 6 core components of health gamification, and 13 core health behavior constructs. A regression analysis was conducted in order to measure the correlation between health behavior constructs, gamification components, and effective game elements. Results This review of the most popular apps showed widespread use of gamification principles, but low adherence to any professional guidelines or industry standard. Regression analysis showed that game elements were associated with gamification (P<.001). Behavioral theory was associated with gamification (P<.05), but not game elements, and upon further analysis gamification was only associated with composite motivational behavior scores (P<.001), and not capacity or opportunity/trigger. Conclusions This research, to our knowledge, represents the first comprehensive review of gamification use in health and fitness apps, and the potential to impact health behavior. The results show that use of gamification in health and fitness apps has become immensely popular, as evidenced by the number of apps found in the Apple App Store containing at least some components of gamification. This shows a lack of integrating important elements of behavioral theory from the app industry

  9. Protection of Radial Glial-Like Cells in the Hippocampus of APP/PS1 Mice: a Novel Mechanism of Memantine in the Treatment of Alzheimer's Disease.

    PubMed

    Sun, Dayu; Chen, Junhua; Bao, Xiaohang; Cai, Yulong; Zhao, Jinghui; Huang, Jing; Huang, Wei; Fan, Xiaotang; Xu, Haiwei

    2015-08-01

    The failure of adult neurogenesis in the hippocampal dentate gyrus (DG) is closely correlated with memory decline in Alzheimer's disease (AD). Radial glial-like cells (RGLs) localized to the adult DG generate intermediate progenitor cells and immature neurons and thus contribute to adult hippocampus neurogenesis. Memantine (MEM) has been indicated to dramatically increase hippocampal neurogenesis by promoting the proliferation of RGLs. In this study, we examined the effect of MEM on the capacity for hippocampal cell proliferation and the amount of RGLs in APPswe/PS1∆E9 transgenic (APP/PS1) mice between 9 and 13 months of age. MEM could enhance hippocampal neurogenesis and increase the number of RGLs in the DG subgranular zone (DG-SGZ) of APP/PS1 mice of both ages. Moreover, MEM decreased amyloidogenesis in 13-month-old APP/PS1 mice and protected cultured radial glia cells (RGCs, L2.3 cells) from apoptosis induced by the β amyloid peptide (Aβ). Additionally, MEM inhibited microglial activation in a vertical process in DG-SGZ of APP/PS1 mice and decreased interacting with RGL processes. Reelin is involved in the proliferation of RGLs in the hippocampus, which was typically upregulated in the hippocampus of APP/PS1 mice by MEM and thought to be an active signaling pathway associated with the MEM-induced increase in RGLs. Our data suggest a previously uncharacterized role for MEM in treating AD.

  10. ALTERED EXPRESSION AND DISTRIBUTION OF ZINC TRANSPORTERS IN APP/PS1 TRANSGENIC MOUSE BRAIN

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Pathological accumulation of b-amyloid peptide (Ab) is an early and common feature of Alzheimer’s disease (AD). Previous studies have revealed that an elevation of zinc concentration can initiate the deposition of A' that leads to the formation of senile plaques (SP) and cerebral amyloid angiopathy ...

  11. Ensifer meliloti overexpressing Escherichia coli phytase gene ( appA) improves phosphorus (P) acquisition in maize plants

    NASA Astrophysics Data System (ADS)

    Sharma, Vikas; Kumar, Ajit; Archana, G.; Kumar, G. Naresh

    2016-10-01

    The Escherichia coli phytase gene appA encoding enzyme AppA was cloned in a broad host range plasmid pBBR1MCS2 ( lac promoter), termed pVA1, and transformed into the Ensifer meliloti 1020. Transformation of pVA1 in Ensifer meliloti { E. m (pVA1)} increased its phosphatase and phytase activity by ˜9- and ˜50-fold, respectively, compared to the transformants containing empty plasmid as control { E. m (pBBR1MCS2)}. The western blot experiments using rabbit anti-AppA antibody showed that AppA is translocated into the periplasm of the host after its expression. Ensifer meliloti harboring AppA protein { E. m (pVA1)} and { E. m (pBBR1MCS2)} could acidify the unbuffered phytate minimal media (pH 8.0) containing Ca-phytate or Na-phytate as sole organic P (Po) source to below pH 5.0 and released P. However, both { E. m (pVA1)} and { E. m (pBBR1MCS2)} neither dropped pH of the medium nor released P when the medium was buffered at pH 8.0 using Tris-Cl, indicating that acidification of medium was important for the enzymatic hydrolysis of phytate. Further experiments proved that maize plants inoculated with { E. m. (pVA1)} showed increase in growth under sterile semi solid agar (SSA) medium containing Na-phytate as sole P source. The present study could be helpful in generating better transgenic bioinoculants harboring phosphate mineralization properties that ultimately promote plant growth.

  12. Ensifer meliloti overexpressing Escherichia coli phytase gene (appA) improves phosphorus (P) acquisition in maize plants.

    PubMed

    Sharma, Vikas; Kumar, Ajit; Archana, G; Kumar, G Naresh

    2016-10-01

    The Escherichia coli phytase gene appA encoding enzyme AppA was cloned in a broad host range plasmid pBBR1MCS2 (lac promoter), termed pVA1, and transformed into the Ensifer meliloti 1020. Transformation of pVA1 in Ensifer meliloti {E. m (pVA1)} increased its phosphatase and phytase activity by ∼9- and ∼50-fold, respectively, compared to the transformants containing empty plasmid as control {E. m (pBBR1MCS2)}. The western blot experiments using rabbit anti-AppA antibody showed that AppA is translocated into the periplasm of the host after its expression. Ensifer meliloti harboring AppA protein {E. m (pVA1)} and {E. m (pBBR1MCS2)} could acidify the unbuffered phytate minimal media (pH 8.0) containing Ca-phytate or Na-phytate as sole organic P (Po) source to below pH 5.0 and released P. However, both {E. m (pVA1)} and {E. m (pBBR1MCS2)} neither dropped pH of the medium nor released P when the medium was buffered at pH 8.0 using Tris-Cl, indicating that acidification of medium was important for the enzymatic hydrolysis of phytate. Further experiments proved that maize plants inoculated with {E. m. (pVA1)} showed increase in growth under sterile semi solid agar (SSA) medium containing Na-phytate as sole P source. The present study could be helpful in generating better transgenic bioinoculants harboring phosphate mineralization properties that ultimately promote plant growth.

  13. NIP/DuoxA is essential for Drosophila embryonic development and regulates oxidative stress response.

    PubMed

    Xie, Xiaojun; Hu, Jack; Liu, Xiping; Qin, Hanjuan; Percival-Smith, Anthony; Rao, Yong; Li, Shawn S C

    2010-05-11

    NIP/DuoxA, originally cloned as a protein capable of binding to the cell fate determinant Numb in Drosophila, was recently identified as a modulator of reactive oxygen species (ROS) production in mammalian systems. Despite biochemical and cellular studies that link NIP/DuoxA to the generation of ROS through the dual oxidase (Duox) enzyme, the in vivo function of NIP/DuoxA has not been characterized to date. Here we report a genetic and functional characterization of nip in Drosophila melanogaster. We show that nip is essential for Drosophila development as nip null mutants die at the 1(st) larval instar. Expression of UAS-nip, but not UAS-Duox, rescued the lethality. To understand the function of nip beyond the early larval stage, we generated GAL4 inducible UAS-RNAi transgenes. da(G32)-GAL4 driven, ubiquitous RNAi-mediated silencing of nip led to profound abnormality in pre-adult development, crinkled wing and markedly reduced lifespan at 29 degrees C. Compared to wild type flies, da-GAL4 induced nip-RNAi transgenic flies exhibited significantly reduced ability to survive under oxidative stress and displayed impaired mitochondrial aconitase function. Our work provides in vivo evidence for a critical role for nip in the development and oxidative stress response in Drosophila.

  14. Arm-Gal4 inheritance influences development and lifespan in Drosophila melanogaster.

    PubMed

    Slade, F A; Staveley, B E

    2015-10-19

    The UAS-Gal4 ectopic expression system is a widely used and highly valued tool that allows specific gene expression in Drosophila melanogaster. Yeast transcription factor Gal4 can be directed using D. melanogaster transcriptional control elements, and is often assumed to have little effect on the organism. By evaluation of the consequences of maternal and paternal inheritance of a Gal4 transgene under the transcriptional regulation of armadillo control elements (arm-Gal4), we demonstrated that Gal4 expression could be detrimental to development and longevity. Male progeny expressing arm-Gal4 in the presence of UAS-lacZ transgene had reduced numbers and size of ommatidia, compared to flies expressing UAS-lacZ transgene under the control of other Gal4 transgenes. Aged at 25°C, the median life span of male flies with maternally inherited elav-Gal4 was 70 days, without a responding transgene or with UAS-lacZ. The median life span of maternally inherited arm-Gal4 male flies without a responding transgene was 48 days, and 40 days with the UAS-lacZ transgene. A partial rescue of this phenotype was observed with the expression of UAS-lacZ under paternal arm-Gal4 control, having an average median lifespan of 60 days. This data suggests that arm-Gal4 has detrimental effects on Drosophila development and lifespan that are directly dependent upon parental inheritance, and that the benign responder and reporter gene UAS-lacZ may influence D. melanogaster development. These findings should be taken into consideration during the design and execution of UAS-Gal4 expression experiments.

  15. Appy Hour: Health Sciences Professionals Learn About Apps.

    PubMed

    Casucci, Tallie; Gregory, Joan M; Shipman, Jean P

    2016-01-01

    Appy Hour is a recurring event hosted by an academic health sciences library featuring apps that are informally presented and demonstrated by invited speakers. The audience is encouraged to ask questions during the presentation of the featured app(s). This event provides learning and networking opportunities for health sciences faculty, staff, students, and health care professionals. This article illustrates the process for hosting the event, shares lessons learned, and discusses possible future directions to gain a wider audience.

  16. Specialized Binary Analysis for Vetting Android APPS Using GUI Logic

    DTIC Science & Technology

    2016-04-01

    the presence or rule out the absence of malice. The definition of malice of interest is an inconsistency between the action taken by the app and the...rule out the absence of malice. The definition of malice of interest is an inconsistency between the action taken by the app and the user expectation...techniques enable security analysts to quickly vet any given Android app even if the source code is unavailable. The definition of malice of interest is

  17. The Hydra FGFR, Kringelchen, partially replaces the Drosophila Heartless FGFR.

    PubMed

    Rudolf, Anja; Hübinger, Christine; Hüsken, Katrin; Vogt, Angelika; Rebscher, Nicole; Onel, Susanne-Filiz; Renkawitz-Pohl, Renate; Hassel, Monika

    2013-05-01

    Fibroblast growth factor receptors (FGFR) are highly conserved receptor tyrosine kinases, and evolved early in metazoan evolution. In order to investigate their functional conservation, we asked whether the Kringelchen FGFR in the freshwater polyp Hydra vulgaris, is able to functionally replace FGFR in fly embryos. In Drosophila, two endogenous FGFR, Breathless (Btl) and Heartless (Htl), ensure formation of the tracheal system and mesodermal cell migration as well as formation of the heart. Using UAS-kringelchen-5xmyc transgenic flies and targeted expression, we show that Kringelchen is integrated correctly into the cell membrane of mesodermal and tracheal cells in Drosophila. Nevertheless, Kringelchen expression driven in tracheal cells failed to rescue the btl (LG19) mutant. The Hydra FGFR was able to substitute for Heartless in the htl (AB42) null mutant; however, this occurred only during early mesodermal cell migration. Our data provide evidence for functional conservation of this early-diverged FGFR across these distantly related phyla, but also selectivity for the Htl FGFR in the Drosophila system.

  18. Human Intellectual Disability Genes Form Conserved Functional Modules in Drosophila

    PubMed Central

    Oortveld, Merel A. W.; Keerthikumar, Shivakumar; Oti, Martin; Nijhof, Bonnie; Fernandes, Ana Clara; Kochinke, Korinna; Castells-Nobau, Anna; van Engelen, Eva; Ellenkamp, Thijs; Eshuis, Lilian; Galy, Anne; van Bokhoven, Hans; Habermann, Bianca; Brunner, Han G.; Zweier, Christiane; Verstreken, Patrik; Huynen, Martijn A.; Schenck, Annette

    2013-01-01

    Intellectual Disability (ID) disorders, defined by an IQ below 70, are genetically and phenotypically highly heterogeneous. Identification of common molecular pathways underlying these disorders is crucial for understanding the molecular basis of cognition and for the development of therapeutic intervention strategies. To systematically establish their functional connectivity, we used transgenic RNAi to target 270 ID gene orthologs in the Drosophila eye. Assessment of neuronal function in behavioral and electrophysiological assays and multiparametric morphological analysis identified phenotypes associated with knockdown of 180 ID gene orthologs. Most of these genotype-phenotype associations were novel. For example, we uncovered 16 genes that are required for basal neurotransmission and have not previously been implicated in this process in any system or organism. ID gene orthologs with morphological eye phenotypes, in contrast to genes without phenotypes, are relatively highly expressed in the human nervous system and are enriched for neuronal functions, suggesting that eye phenotyping can distinguish different classes of ID genes. Indeed, grouping genes by Drosophila phenotype uncovered 26 connected functional modules. Novel links between ID genes successfully predicted that MYCN, PIGV and UPF3B regulate synapse development. Drosophila phenotype groups show, in addition to ID, significant phenotypic similarity also in humans, indicating that functional modules are conserved. The combined data indicate that ID disorders, despite their extreme genetic diversity, are caused by disruption of a limited number of highly connected functional modules. PMID:24204314

  19. Drosophila Ryanodine Receptors Mediate General Anesthesia by Halothane

    PubMed Central

    Gao, Shuying; Sandstrom, David J.; Smith, Harold E.; High, Brigit; Marsh, Jon W.; Nash, Howard A.

    2012-01-01

    Background Although in vitro studies have identified numerous possible targets, the molecules that mediate the in vivo effects of volatile anesthetics remain largely unknown. The mammalian ryanodine receptor (Ryr) is a known halothane target, and we hypothesized that it has a central role in anesthesia. Methods Gene function of the Drosophila Ryr (dRyr) was manipulated in the whole body or in specific tissues using a collection of mutants and transgenes, and responses to halothane were measured with a reactive climbing assay. Cellular responses to halothane were studied using Ca2+ imaging and patch clamp electrophysiology. Results Halothane potency strongly correlates with dRyr gene copy number, and missense mutations in regions known to be functionally important in mammalian Ryrs gene cause dominant hypersensitivity. Tissue-specific manipulation of dRyr shows that expression in neurons and glia, but not muscle, mediates halothane sensitivity. In cultured cells, halothane-induced Ca2+ efflux is strictly dRyr-dependent, suggesting a close interaction between halothane and dRyr. Ca2+ imaging and electrophysiology of Drosophila central neurons reveal halothane-induced Ca2+ flux that is altered in dRyr mutants and correlates with strong hyperpolarization. Conclusions In Drosophila, neurally-expressed dRyr mediates a substantial proportion of halothane's anesthetic effects in vivo, is potently activated by halothane in vitro, and activates an inhibitory conductance. Our results provide support for Ryr as an important mediator of immobilization by volatile anesthetics. PMID:23254148

  20. Regulation of cytochrome P450 expression in Drosophila: Genomic insights

    PubMed Central

    Giraudo, Maeva; Unnithan, G. Chandran; Le Goff, Gaëlle; Feyereisen, René

    2009-01-01

    Genomic tools such as the availability of the Drosophila genome sequence, the relative ease of stable transformation, and DNA microarrays have made the fruit fly a powerful model in insecticide toxicology research. We have used transgenic promoter-GFP constructs to document the detailed pattern of induced Cyp6a2 gene expression in larval and adult Drosophila tissues. We also compared various insecticides and xenobiotics for their ability to induce this cytochrome P450 gene, and show that the pattern of Cyp6a2 inducibility is comparable to that of vertebrate CYP2B genes, and different from that of vertebrate CYP1A genes, suggesting a degree of evolutionary conservation for the “phenobarbital-type” induction mechanism. Our results are compared to the increasingly diverse reports on P450 induction that can be gleaned from whole genome or from “detox” microarray experiments in Drosophila. These suggest that only a third of the genomic repertoire of CYP genes is inducible by xenobiotics, and that there are distinct subsets of inducers / induced genes, suggesting multiple xenobiotic transduction mechanisms. A relationship between induction and resistance is not supported by expression data from the literature. The relative abundance of expression data now available is in contrast to the paucity of studies on functional expression of P450 enzymes, and this remains a challenge for our understanding of the toxicokinetic aspects of insecticide action. PMID:20582327

  1. Quality of Smartphone Apps Related to Panic Disorder.

    PubMed

    Van Singer, Mathias; Chatton, Anne; Khazaal, Yasser

    2015-01-01

    Quality of smartphone apps related to panic: smartphone apps have a growing role in health care. This study assessed the quality of English-language apps for panic disorder (PD) and compared paid and free apps. Keywords related to PD were entered into the Google Play Store search engine. Apps were assessed using the following quality indicators: accountability, interactivity, self-help score (the potential of smartphone apps to help users in daily life), and evidence-based content quality. The Brief DISCERN score and the criteria of the "Health on the Net" label were also used as content quality indicators as well as the number of downloads. Of 247 apps identified, 52 met all inclusion criteria. The content quality and self-help scores of these PD apps were poor. None of the assessed indicators were associated with payment status or number of downloads. Multiple linear regressions showed that the Brief DISCERN score significantly predicted the content quality and self-help scores. Poor content quality and self-help scores of PD smartphone apps highlight the gap between their technological potential and the overall quality of available products.

  2. Quality of Smartphone Apps Related to Panic Disorder

    PubMed Central

    Van Singer, Mathias; Chatton, Anne; Khazaal, Yasser

    2015-01-01

    Quality of smartphone apps related to panic: smartphone apps have a growing role in health care. This study assessed the quality of English-language apps for panic disorder (PD) and compared paid and free apps. Keywords related to PD were entered into the Google Play Store search engine. Apps were assessed using the following quality indicators: accountability, interactivity, self-help score (the potential of smartphone apps to help users in daily life), and evidence-based content quality. The Brief DISCERN score and the criteria of the “Health on the Net” label were also used as content quality indicators as well as the number of downloads. Of 247 apps identified, 52 met all inclusion criteria. The content quality and self-help scores of these PD apps were poor. None of the assessed indicators were associated with payment status or number of downloads. Multiple linear regressions showed that the Brief DISCERN score significantly predicted the content quality and self-help scores. Poor content quality and self-help scores of PD smartphone apps highlight the gap between their technological potential and the overall quality of available products. PMID:26236242

  3. Regulation of global gene expression and cell proliferation by APP

    PubMed Central

    Wu, Yili; Zhang, Si; Xu, Qin; Zou, Haiyan; Zhou, Weihui; Cai, Fang; Li, Tingyu; Song, Weihong

    2016-01-01

    Down syndrome (DS), caused by trisomy of chromosome 21, is one of the most common genetic disorders. Patients with DS display growth retardation and inevitably develop characteristic Alzheimer’s disease (AD) neuropathology, including neurofibrillary tangles and neuritic plaques. The expression of amyloid precursor protein (APP) is increased in both DS and AD patients. To reveal the function of APP and elucidate the pathogenic role of increased APP expression in DS and AD, we performed gene expression profiling using microarray method in human cells overexpressing APP. A set of genes are significantly altered, which are involved in cell cycle, cell proliferation and p53 signaling. We found that overexpression of APP inhibits cell proliferation. Furthermore, we confirmed that the downregulation of two validated genes, PSMA5 and PSMB7, inhibits cell proliferation, suggesting that the downregulation of PSMA5 and PSMB7 is involved in APP-induced cell proliferation impairment. Taken together, this study suggests that APP regulates global gene expression and increased APP expression inhibits cell proliferation. Our study provides a novel insight that APP overexpression may contribute to the growth impairment in DS patients and promote AD pathogenesis by inhibiting cell proliferation including neural stem cell proliferation and neurogenesis. PMID:26936520

  4. Impaired theta-gamma coupling in APP-deficient mice

    PubMed Central

    Zhang, Xiaomin; Zhong, Wewei; Brankačk, Jurij; Weyer, Sascha W.; Müller, Ulrike C.; Tort, Adriano B. L.; Draguhn, Andreas

    2016-01-01

    Amyloid precursor protein (APP) is critically involved in the pathophysiology of Alzheimer’s disease, but its physiological functions remain elusive. Importantly, APP knockout (APP-KO) mice exhibit cognitive deficits, suggesting that APP plays a role at the neuronal network level. To investigate this possibility, we recorded local field potentials (LFPs) from the posterior parietal cortex, dorsal hippocampus and lateral prefrontal cortex of freely moving APP-KO mice. Spectral analyses showed that network oscillations within the theta- and gamma-frequency bands were not different between APP-KO and wild-type mice. Surprisingly, however, while gamma amplitude coupled to theta phase in all recorded regions of wild-type animals, in APP-KO mice theta-gamma coupling was strongly diminished in recordings from the parietal cortex and hippocampus, but not in LFPs recorded from the prefrontal cortex. Thus, lack of APP reduces oscillatory coupling in LFP recordings from specific brain regions, despite not affecting the amplitude of the oscillations. Together, our findings reveal reduced cross-frequency coupling as a functional marker of APP deficiency at the network level. PMID:26905287

  5. Regulation of global gene expression and cell proliferation by APP.

    PubMed

    Wu, Yili; Zhang, Si; Xu, Qin; Zou, Haiyan; Zhou, Weihui; Cai, Fang; Li, Tingyu; Song, Weihong

    2016-03-03

    Down syndrome (DS), caused by trisomy of chromosome 21, is one of the most common genetic disorders. Patients with DS display growth retardation and inevitably develop characteristic Alzheimer's disease (AD) neuropathology, including neurofibrillary tangles and neuritic plaques. The expression of amyloid precursor protein (APP) is increased in both DS and AD patients. To reveal the function of APP and elucidate the pathogenic role of increased APP expression in DS and AD, we performed gene expression profiling using microarray method in human cells overexpressing APP. A set of genes are significantly altered, which are involved in cell cycle, cell proliferation and p53 signaling. We found that overexpression of APP inhibits cell proliferation. Furthermore, we confirmed that the downregulation of two validated genes, PSMA5 and PSMB7, inhibits cell proliferation, suggesting that the downregulation of PSMA5 and PSMB7 is involved in APP-induced cell proliferation impairment. Taken together, this study suggests that APP regulates global gene expression and increased APP expression inhibits cell proliferation. Our study provides a novel insight that APP overexpression may contribute to the growth impairment in DS patients and promote AD pathogenesis by inhibiting cell proliferation including neural stem cell proliferation and neurogenesis.

  6. Pros and cons of using apps in clinical practice.

    PubMed

    Moore, Sally; Anderson, John; Cox, Susanne

    2012-10-01

    There is a lack of research on the use of smartphone apps among nurses in the UK, but the number of healthcare-related apps is increasing and it is likely that nurses will want to include them in practice. It will, therefore, be necessary to assess their effectiveness, appropriateness and efficacy to ensure they enhance patient care. This article looks at the literature on the subject and suggests some issues managers should consider before allowing the use of apps in their clinical areas. It also invites readers to take part in a survey on the use of apps in nursing.

  7. Alternative splicing regulation of APP exon 7 by RBFox proteins.

    PubMed

    Alam, Shafiul; Suzuki, Hitoshi; Tsukahara, Toshifumi

    2014-12-01

    RBFox proteins are well-known alternative splicing regulators. We have shown previously that during neuronal differentiation of P19 cells induced by all-trans retinoic acid and cell aggregation, RBFox1 shows markedly increased temporal expression. To find its key splicing regulation, we examined the effect of RBFox1 on 33 previously reported and validated neuronal splicing events of P19 cells. We observed that alternative splicing of three genes, specifically, amyloid precursor protein (APP), disks large homolog 3 (DLG3), and G protein, alpha activating activity polypeptide O (GNAO1), was altered by transient RBFox1 expression in HEK293 and HeLa cells. Moreover, an RBFox1 mutant (RBFox1FA) that was unable to bind the target RNA sequence ((U)GCAUG) did not induce these splicing events. APP generates amyloid beta peptides that are involved in the pathology of Alzheimer's disease, and therefore we examined APP alternative splicing regulation by RBFox1 and other splicing regulators. Our results indicated that RBFox proteins promote the skipping of APP exon 7, but not the inclusion of exon 8. We made APP6789 minigenes and observed that two (U)GCAUG sequences, located upstream of exon 7 and in exon 7, functioned to induce skipping of exon 7 by RBFox proteins. Overall, RBFox proteins may shift APP from exon 7 containing isoforms, APP770 and APP751, toward the exon 7 lacking isoform, APP695, which is predominant in neural tissues.

  8. smartApps Package v 4.8

    SciTech Connect

    Anderson, Robert

    2009-12-04

    The smartApps package provides high-speed communication links between multiple Umbra sessions and/or SMART sessions. Modules within Packages/smartApps: Packages/smartApps/smartBlackboard: The original Broadcast module connected Umbra connectors to the SMART (Sandia's Modular Architecture for Robotics and Teleoperation) blackboard using UDP and TCP connections. Connectors are added to the module for each connection. Originally written by Scott Gladwell and maintained and updated by Robert J. Anderson. Packages/smartApps/smartBroadcast: A highly efficient version of packet based communication for connecting distributed SMART and Umbra systems together using UDP broadcasts.

  9. Production of two highly active bacterial phytases with broad pH optima in germinated transgenic rice seeds.

    PubMed

    Hong, Chwan-Yang; Cheng, Kuo-Joan; Tseng, Tung-Hai; Wang, Chang-Sheng; Liu, Li-Fei; Yu, Su-May

    2004-02-01

    Phytate is the main storage form of phosphorus in many plant seeds, but phosphate bound in this form is not available to monogastric animals. Phytase, an enzyme that hydrolyzes phosphate from phytate, has the potential to enhance phosphorus availability in animal diets when engineered in rice seeds as a feed additive. Two genes, derived from a ruminal bacterium Selenomonas ruminantium (SrPf6) and Escherichia coli (appA), encoding highly active phytases were expressed in germinated transgenic rice seeds. Phytase expression was controlled by a germination inducible alpha-amylase gene (alphaAmy8) promoter, and extracellular phytase secretion directed by an betaAmy8 signal peptide sequence. The two phytases were expressed in germinated transgenic rice seeds transiently and in a temporally controlled and tissue-specific manner. No adverse effect on plant development or seed formation was observed. Up to 0.6 and 1.4 U of phytase activity per mg of total extracted cellular proteins were obtained in germinated transgenic rice seeds expressing appA and SrPf6 phytases, respectively, which represent 46-60 times of phytase activities compared to the non-transformant. The appA and SrPf6 phytases produced in germinated transgenic rice seeds had high activity over broad pH ranges of 3.0-5.5 and 2.0-6.0, respectively. Phytase levels and inheritance of transgenes in one highly expressing plant were stable over four generations. Germinated transgenic rice seeds, which produce a highly active recombinant phytase and are rich in hydrolytic enzymes, nutrients and minerals, could potentially be an ideal feed additive for improving the phytate-phosphorus digestibility in monogastric animals.

  10. The Drosophila melanogaster host model

    PubMed Central

    Igboin, Christina O.; Griffen, Ann L.; Leys, Eugene J.

    2012-01-01

    The deleterious and sometimes fatal outcomes of bacterial infectious diseases are the net result of the interactions between the pathogen and the host, and the genetically tractable fruit fly, Drosophila melanogaster, has emerged as a valuable tool for modeling the pathogen–host interactions of a wide variety of bacteria. These studies have revealed that there is a remarkable conservation of bacterial pathogenesis and host defence mechanisms between higher host organisms and Drosophila. This review presents an in-depth discussion of the Drosophila immune response, the Drosophila killing model, and the use of the model to examine bacterial–host interactions. The recent introduction of the Drosophila model into the oral microbiology field is discussed, specifically the use of the model to examine Porphyromonas gingivalis–host interactions, and finally the potential uses of this powerful model system to further elucidate oral bacterial-host interactions are addressed. PMID:22368770

  11. The App Map: A Tool for Systematic Evaluation of Apps for Early Literacy Learning

    ERIC Educational Resources Information Center

    Israelson, Madeleine Heins

    2015-01-01

    As portable devices become increasingly available in elementary classrooms teachers are expected to use these new technologies to engage students in both traditional print-based literacy learning and digital literacies practices, such as multimodal composing. Teachers face the daunting task of integrating apps into their current research-based…

  12. Transgenic algae engineered for higher performance

    DOEpatents

    Unkefer, Pat J; Anderson, Penelope S; Knight, Thomas J

    2014-10-21

    The present disclosure relates to transgenic algae having increased growth characteristics, and methods of increasing growth characteristics of algae. In particular, the disclosure relates to transgenic algae comprising a glutamine phenylpyruvate transaminase transgene and to transgenic algae comprising a glutamine phenylpyruvate transaminase transgene and a glutamine synthetase.

  13. Sex chromosome-specific regulation in the Drosophila male germline but little evidence for chromosomal dosage compensation or meiotic inactivation.

    PubMed

    Meiklejohn, Colin D; Landeen, Emily L; Cook, Jodi M; Kingan, Sarah B; Presgraves, Daven C

    2011-08-01

    The evolution of heteromorphic sex chromosomes (e.g., XY in males or ZW in females) has repeatedly elicited the evolution of two kinds of chromosome-specific regulation: dosage compensation--the equalization of X chromosome gene expression in males and females--and meiotic sex chromosome inactivation (MSCI)--the transcriptional silencing and heterochromatinization of the X during meiosis in the male (or Z in the female) germline. How the X chromosome is regulated in the Drosophila melanogaster male germline is unclear. Here we report three new findings concerning gene expression from the X in Drosophila testes. First, X chromosome-wide dosage compensation appears to be absent from most of the Drosophila male germline. Second, microarray analysis provides no evidence for X chromosome-specific inactivation during meiosis. Third, we confirm the previous discovery that the expression of transgene reporters driven by autosomal spermatogenesis-specific promoters is strongly reduced when inserted on the X chromosome versus the autosomes; but we show that this chromosomal difference in expression is established in premeiotic cells and persists in meiotic cells. The magnitude of the X-autosome difference in transgene expression cannot be explained by the absence of dosage compensation, suggesting that a previously unrecognized mechanism limits expression from the X during spermatogenesis in Drosophila. These findings help to resolve several previously conflicting reports and have implications for patterns of genome evolution and speciation in Drosophila.

  14. Environmental enrichment lessens cognitive decline in APP23 mice without affecting brain sirtuin expression.

    PubMed

    Polito, Letizia; Chierchia, Armando; Tunesi, Marta; Bouybayoune, Ihssane; Kehoe, Patrick Gavin; Albani, Diego; Forloni, Gianluigi

    2014-01-01

    Environmental enrichment (EE) is a non-pharmacological intervention reported to counteract pathological signs in models of Alzheimer's disease (AD). We developed EE protocols in APP23 mice and evaluated how they influenced cognitive decline and brain amyloid-β (Aβ) burden. We also investigated the involvement of sirtuins (SIRTs) as a possible molecular mediator of EE, by assessing hippocampal and cortical mRNA and protein levels of the SIRT family members (SIRT1 to SIRT7). APP23 transgenic mice were moved to EE cages (TG-EEs) starting from 3 months of age. TG-EEs were compared to transgenic mice housed in standard cages (TG-SHs) and to wild-type littermates in the two housing conditions (WT-EEs and WT-SHs). At 7 months of age, all mice were tested for behavioral performance with Morris Water Maze (MWM) and visual novel Object Recognition Test (vORT). After a month, a group underwent biochemical analyses, while another group continued in the EE environment till 18 months of age, when Aβ plaque load was assessed. At 7 months, TG-SHs had impaired behavioral performance in MWM and vORT. In contrast, TG-EE mice had restored behavioral performance. At 8 months, EE did not affect AβPP expression or processing, Aβ40/42, pGlu-Aβ3-40/3-42, or Aβ oligomer level. The expression of two Aβ degrading enzymes (insulin degrading enzyme and neprilysin) was not modulated by EE. Brain sirtuin mRNA and protein levels were unchanged, while brain-derived neurotrophic factor expression increased after EE. Aβ deposition was attenuated in 18-month-old TG-EE mice, without apparent reduction of neuroinflammatory signs. We suggest that EE had a beneficial effect on cognitive performance and lessened long-term Aβ accumulation, but brain sirtuin expression was not modulated when cognitive impairment was restored.

  15. Detection of age-dependent working memory deterioration in APP751SL mice.

    PubMed

    Blanchard, Julie; Martel, Guillaume; Brayda-Bruno, Laurent; Noguès, Xavier; Micheau, Jacques

    2011-03-17

    Despite huge advances on Alzheimer's disease (AD) etiology, the clinical diagnosis remains the unique commonly used tool to detect the onset of the disease. For instance, epidemiological studies report that the combination of episodic and working memory disorders represents the most consistent sign of progression from mild cognitive impairment to AD. However, such working memory disorders failed to be observed early in transgenic mouse models of AD because the behavioral procedures used do not tackle properly crucial components of working memory. The aim of the present work was to assess early occurrence of working memory impairments in APP(751SL) mice. Therefore, we designed a new behavioral task in the water-maze, based on the principle of a delayed matching to place task, where spatial recognition was assessed for four different platform locations within a single session. First, we showed that dorsal hippocampal but not medial prefrontal cortex lesions in C57Bl6 mice induced a time-dependent impairment of spatial recognition. Then, the hippocampal-like memory alterations were reproduced in 7-8-month-old APP(751SL) mice but not in younger animals (5-6-month-old). We also demonstrated that these working memory deficits are related to progressive Aβ accumulation in the hippocampus, but not in the other selected brain structures.

  16. Amyloid precursor protein in Drosophila glia regulates sleep and genes involved in glutamate recycling.

    PubMed

    Farca Luna, Abud Jose; Perier, Magali; Seugnet, Laurent

    2017-03-17

    The Amyloid Precursor Protein (App) plays a crucial role in Alzheimer disease (AD) via the production and deposition of toxic β-amyloid peptides. App is heavily expressed in neurons where the vast majority of studies investigating its function have been carried out, while almost nothing is known about its function in glia, where it is also expressed, and can potentially participate in the regulation of neuronal physiology. In this report, we investigated whether Appl, the Drosophila homolog of App, could influence sleep-wake regulation when its function is manipulated in glial cells. Appl inhibition in astrocyte-like and cortex glia resulted in higher sleep amounts and longer sleep bout duration during the night, while overexpression had the opposite effect. These sleep phenotypes were not the result of developmental defects, and were correlated with changes in expression in Glutamine Synthetase (GS) in astrocyte-like glia, and in changes in the gap-junction component innexin2 in cortex glia. Downregulating both GS and innexin2, but not either one individually, resulted in higher sleep amounts, similarly to Appl inhibition. Consistent with these results the expression of GS and innexin2 are increased following sleep deprivation indicating that these two genes are dynamically linked to vigilance states. Interestingly, the reduction of GS expression and the sleep phenotype observed upon Appl inhibition could be rescued by increasing the expression of the glutamate transporter dEaat1. In contrast, reducing dEaat1 expression severely disrupted sleep. These results associate glutamate recycling, sleep and a glial function for the App family proteins.StatementThe Amyloid Precursor Protein (App) has been intensively studied for its implication in Alzheimer Disease (AD). The attributed functions of App are linked to the physiology and cellular biology of neurons where the protein is predominantly expressed. Consequences on glia in AD are generally thought to be secondary

  17. Smartphone Apps for Measuring Human Health and Climate Change Co-Benefits: A Comparison and Quality Rating of Available Apps

    PubMed Central

    Sullivan, Rachel K; Marsh, Samantha; Halvarsson, Jakob; Holdsworth, Michelle; Waterlander, Wilma; Poelman, Maartje P; Salmond, Jennifer Ann; Christian, Hayley; Koh, Lenny SC; Cade, Janet E; Spence, John C; Woodward, Alistair

    2016-01-01

    Background Climate change and the burden of noncommunicable diseases are major global challenges. Opportunities exist to investigate health and climate change co-benefits through a shift from motorized to active transport (walking and cycling) and a shift in dietary patterns away from a globalized diet to reduced consumption of meat and energy dense foods. Given the ubiquitous use and proliferation of smartphone apps, an opportunity exists to use this technology to capture individual travel and dietary behavior and the associated impact on the environment and health. Objective The objective of the study is to identify, describe the features, and rate the quality of existing smartphone apps which capture personal travel and dietary behavior and simultaneously estimate the carbon cost and potential health consequences of these actions. Methods The Google Play and Apple App Stores were searched between October 19 and November 6, 2015, and a secondary Google search using the apps filter was conducted between August 8 and September 18, 2016. Eligible apps were required to estimate the carbon cost of personal behaviors with the potential to include features to maximize health outcomes. The quality of included apps was assessed by 2 researchers using the Mobile Application Rating Scale (MARS). Results Out of 7213 results, 40 apps were identified and rated. Multiple travel-related apps were identified, however no apps solely focused on the carbon impact or health consequences of dietary behavior. None of the rated apps provided sufficient information on the health consequences of travel and dietary behavior. Some apps included features to maximize participant engagement and encourage behavior change towards reduced greenhouse gas emissions. Most apps were rated as acceptable quality as determined by the MARS; 1 was of poor quality and 10 apps were of good quality. Interrater reliability of the 2 evaluators was excellent (ICC=0.94, 95% CI 0.87-0.97). Conclusions Existing

  18. Public Health Guidelines for Physical Activity: Is There an App for That? A Review of Android and Apple App Stores

    PubMed Central

    2015-01-01

    Background Physical activity participation is an important behavior for modifying lifestyle-related disease risk. Mobile health apps for chronic disease management and prevention are being developed at a rapid rate. However, it is unclear whether these apps are evidence-based. Current public health recommendations for physical activity participation for adults highlight the importance of engaging in 150 minutes weekly of purposeful exercise, and muscle strengthening activities on at least 2 days of the week. Objective The aims of the present review were to (1) identify available evidence-based physical activity apps, and (2) identify technological features that could be leveraged to improve health outcomes. Methods iTunes and Google Play mobile app stores were searched using keyword and category searching during a single day (February 18, 2014) for physical activity apps available in English. The description pages of eligible apps were reviewed by 4 independent reviewers for evidence-based content, technological, and descriptive features. An a priori subset of apps was downloaded for further review (n=6 affiliated with a non-commercial agency; n=10 top rated; n=10 random selection), and developers were contacted for information regarding evidence-informed content. Results The initial search yielded 2400 apps, of which 379 apps (n=206 iTunes; n=173 Google Play) were eligible. Primary results demonstrated no apps (n=0) adhering to evidence-based guidelines for aerobic physical activity, and 7 out of 379 implementing evidence-based guidelines for resistance training physical activity. Technological features of apps included social networking (n=207), pairing with a peripheral health device (n=61), and measuring additional health parameters (n=139). Secondary results revealed 1 app that referenced physical activity guidelines (150 minutes/weekly of exercise), and demonstrated that apps were based on various physical activity reports (n=4) or personal expertise (n=2

  19. App-assisted external ventricular drain insertion.

    PubMed

    Eftekhar, Behzad

    2016-09-01

    The freehand technique for insertion of an external ventricular drain (EVD) is based on fixed anatomical landmarks and does not take individual variations into consideration. A patient-tailored approach based on augmented-reality techniques using devices such as smartphones can address this shortcoming. The Sina neurosurgical assist (Sina) is an Android mobile device application (app) that was designed and developed to be used as a simple intraoperative neurosurgical planning aid. It overlaps the patient's images from previously performed CT or MRI studies on the image seen through the device camera. The device is held by an assistant who aligns the images and provides information about the relative position of the target and EVD to the surgeon who is performing EVD insertion. This app can be used to provide guidance and continuous monitoring during EVD placement. The author describes the technique of Sina-assisted EVD insertion into the frontal horn of the lateral ventricle and reports on its clinical application in 5 cases as well as the results of ex vivo studies of ease of use and precision. The technique has potential for further development and use with other augmented-reality devices.

  20. Medical apps in endocrine diseases – hide and seek

    PubMed Central

    von Jan, Ute

    2014-01-01

    Objectives: Quantitative review and categorization of available endocrinology related mobile apps for the iOS platform (Apple®) and outline of search strategies to identify appropriate mobile apps for this field. Methods: A total of 80 endocrinology related search terms were collected and grouped into 8 main categories covering different areas of endocrinology. These terms were then used to perform comprehensive searches in three categories of Apple’s app store, namely ‘Medicine’, ‘Health and Fitness’, and ‘Reference’. Results: Altogether, matches were found for only 33 of the 80 collected endocrinology related search terms; the majority of matches were found in the medical category, followed by matches for the health and fitness (27/33), and reference (16/33) categories. Restricting the search to these categories significantly helped in discriminating between health related apps and those having another purpose. The distribution of apps per category roughly matches what one can expect considering available data for incidence and prevalence of corresponding endocrinological conditions. Apps matching terms belonging to the spectrum of glucose homeostasis disorders are the most common. For conditions where patients do not have to constantly monitor their condition, apps tend to have a reference or educational character, while for conditions that require a high level of involvement from patients, there are proportionally more apps for self-management. With a single exception, the identified apps had not undergone regulation, and information about the data sources, professional backgrounds, and reliability of the content and integrated information sources was rare. Conclusions: While applying a good search strategy is important for finding apps for endocrinology related problems, users also need to consider whether the app they have found respects all necessary criteria regarding reliability, privacy and data protection before they place their trust in

  1. Plant biotechnology: transgenic crops.

    PubMed

    Shewry, Peter R; Jones, Huw D; Halford, Nigel G

    2008-01-01

    Transgenesis is an important adjunct to classical plant breeding, in that it allows the targeted manipulation of specific characters using genes from a range of sources. The current status of crop transformation is reviewed, including methods of gene transfer, the selection of transformed plants and control of transgene expression. The application of genetic modification technology to specific traits is then discussed, including input traits relating to crop production (herbicide tolerance and resistance to insects, pathogens and abiotic stresses) and output traits relating to the composition and quality of the harvested organs. The latter include improving the nutritional quality for consumers as well as the improvement of functional properties for food processing.

  2. Pantothenate kinase-associated neurodegeneration: insights from a Drosophila model.

    PubMed

    Wu, Zhihao; Li, Chenghua; Lv, Shan; Zhou, Bing

    2009-10-01

    Pantothenate-Kinase-Associated-Neurodegeneration (PKAN) is a devastating disease, resulting from mutations in pantothenate kinase 2 (PANK2), one of the four human pantothenate kinase genes (PANK1-4). Interestingly, PanK2 appears to be the only mitochondria-targeted human PanK. It is unknown whether the mitochondria-targeted PanK is associated with any unique function, nor whether PKAN is due solely to the loss of pantothenate kinase activity. Drosophila PANK [fumble (fbl)] encodes several isoforms of pantothenate kinase products, one of which localizes to mitochondria and the others cytosol. fbl flies exhibit many characteristic features reminiscent of PKAN patients. Various forms of Drosophila fbl and human PANK2 were introduced into fbl flies to study their in vivo functions. Only mitochondria-targeted Fbl or human PanK2 was able to rescue fbl mutation, with the rescuing ability sensitive to the expression level of the transgene. Transgenic lines with low expression of normal Fbl or PanK2 displayed similar phenotypes as PANK2 mutant transgenic flies. These PanK2 mutants all showed reduced and phenotype severity-correlated in vitro pantothenate kinase activities. Amazingly, cytosolic PanK3 and PanK4 could mostly, but not fully, rescue fbl defects except the male sterility. Therefore, fbl appears to be the orthologue of human PANK2, and PanK2 is functionally more potent than PanK3 and PanK4 in vivo. We suggest that mitochondria-located pantothenate kinase is required to achieve the maximal enzymatic activity to fulfill the most challenging task such as maintaining male fertility and optimal neuronal functions, and PKAN features are mainly due to the reduction of the total cellular pantothenate kinase activity in the most susceptible regions.

  3. Cloning and functional analysis of TipE, a novel membrane protein that enhances Drosophila para sodium channel function.

    PubMed

    Feng, G; Deák, P; Chopra, M; Hall, L M

    1995-09-22

    Voltage-dependent sodium channels are involved in the initiation and propagation of action potentials in many excitable cells. Here we report that tipE, a gene defined by a temperature-sensitive paralytic mutation in Drosophila, encodes a novel integral membrane protein that dramatically stimulates functional expression in Xenopus oocytes of the Drosophila sodium channel alpha subunit encoded by the paralytic (para) locus. Using a heat shock promoter to control tipE+ gene expression in transgenic flies, we demonstrate that tipE+ gene expression is required during pupal development to rescue adult paralysis. In addition, we demonstrate a role for the tipE gene product in adults.

  4. Myc Function in Drosophila

    PubMed Central

    Gallant, Peter

    2013-01-01

    Drosophila contains a single MYC gene. Like its vertebrate homologs, it encodes a transcription factor that activates many targets, including prominently genes involved in ribosome biogenesis and translation. This activity makes Myc a central regulator of growth and/or proliferation of many cell types, such as imaginal disc cells, polyploid cells, stem cells, and blood cells. Importantly, not only does Myc act cell autonomously but it also affects the fate of adjacent cells and tissues. This potential of Myc is harnessed by many different signaling pathways, involving, among others, Wg, Dpp, Hpo, ecdysone, insulin, and mTOR. PMID:24086064

  5. Feeding regulation in Drosophila

    PubMed Central

    Pool, Allan-Hermann; Scott, Kristin

    2014-01-01

    Neuromodulators play a key role in adjusting animal behavior based on environmental cues and internal needs. Here, we review the regulation of Drosophila feeding behavior to illustrate how neuromodulators achieve behavioral plasticity. Recent studies have made rapid progress in determining molecular and cellular mechanisms that translate the metabolic needs of the fly into changes in neuroendocrine and neuromodulatory states. These neuromodulators in turn promote or inhibit discrete feeding behavioral subprograms. This review highlights the links between physiological needs, neuromodulatory states, and feeding decisions. PMID:24937262

  6. The fitness of apps: a theory-based examination of mobile fitness app usage over 5 months

    PubMed Central

    Kim, Jinsook

    2017-01-01

    Background There are thousands of fitness-related smartphone applications (“apps”) available for free and purchase, but there is uncertainty if these apps help individuals achieve and maintain personal fitness. Technology usage attrition is also a concern among research studies on health technologies. Methods Usage of three fitness apps was examined over 5 months to assess adherence and effectiveness. Initially, 64 participants downloaded three free apps available on Android and iOS and 47 remained in the study until posttest. With a one group pre-posttest design and checkpoints at months 1, 3, and 5, exercise and exercise with fitness apps were examined in the framework of the Theory of Planned Behavior (TPB) using a validated survey. Apps were selected based on their function from the Functional Triad. Perceived fitness was also measured. T-tests, sign tests, Fisher’s exact tests, and linear and logistic regression were used to compare pre to posttests and users to non-users of the apps. Results Forty-seven participants completed both pre and posttests. Individual item scores indicated no significant change pre to posttest except for decreases observed in usefulness of using apps for exercise (attitude) (−0.78, P<0.01), peer influence on exercise (subjective norm) (−0.51, P<0.05), peer influence on exercise with apps (subjective norm) (−1.02, P<0.01), perceived difficulties in exercising with apps (perceived behavioral control) (−1.29, P<0.001), and the expected frequency of exercise with apps over the next 2 weeks (behavioral intention) (P<0.0001 in a sign test). Subscale total scores indicated significant decreases in subjective norm regarding exercise (−0.72, P<0.05), subjective norm regarding exercise with apps (−1.72, P<0.01), and perceived behavioral control over exercising with apps (−2.56, P<0.01) between pre and posttest. When comparing app users (n=32) to non-users (n=15), there was only a significant difference in subscale total

  7. Genome Engineering: Drosophila melanogaster and beyond

    PubMed Central

    Venken, Koen J.T.; Sarrion-Perdigones, Alejandro; Vandeventer, Paul J.; Abel, Nicholas S.; Christiansen, Audrey E.; Hoffman, Kristi L.

    2015-01-01

    A central challenge to investigating biological phenomena is the development of techniques to modify genomic DNA with nucleotide precision that can be transmitted through the germ line. Recent years have brought a boon in these technologies, now collectively known as genome engineering. Defined genomic manipulations at the nucleotide level enable a variety of reverse engineering paradigms, providing new opportunities to interrogate diverse biological functions. These genetic modifications include controlled removal, insertion, and substitution of genetic fragments, both small and large. Small fragments up to a few kilobases (e.g., single nucleotide mutations, small deletions, or gene tagging at single or multiple gene loci) to large fragments up to megabase resolution can be manipulated at single loci to create deletions, duplications, inversions, or translocations of substantial sections of whole chromosome arms. A specialized substitution of chromosomal portions that presumably are functionally orthologous between different organisms through syntenic replacement, can provide proof of evolutionary conservation between regulatory sequences. Large transgenes containing endogenous or synthetic DNA can be integrated at defined genomic locations, permitting an alternative proof of evolutionary conservation, and sophisticated transgenes can be used to interrogate biological phenomena. Precision engineering can additionally be used to manipulate the genomes of organelles (e.g., mitochondria). Novel genome engineering paradigms are often accelerated in existing, easily genetically tractable model organisms, primarily because these paradigms can be integrated in a rigorous, existing technology foundation. The Drosophila melanogaster fly model is ideal for these types of studies. Due to its small genome size, having just four chromosomes, the vast amount of cutting-edge genetic technologies, and its short life-cycle and inexpensive maintenance requirements, the fly is

  8. Therapeutic Potential of Secreted Amyloid Precursor Protein APPsα

    PubMed Central

    Mockett, Bruce G.; Richter, Max; Abraham, Wickliffe C.; Müller, Ulrike C.

    2017-01-01

    Cleavage of the amyloid precursor protein (APP) by α-secretase generates an extracellularly released fragment termed secreted APP-alpha (APPsα). Not only is this process of interest due to the cleavage of APP within the amyloid-beta sequence, but APPsα itself has many physiological properties that suggest its great potential as a therapeutic target. For example, APPsα is neurotrophic, neuroprotective, neurogenic, a stimulator of protein synthesis and gene expression, and enhances long-term potentiation (LTP) and memory. While most early studies have been conducted in vitro, effectiveness in animal models is now being confirmed. These studies have revealed that either upregulating α-secretase activity, acutely administering APPsα or chronic delivery of APPsα via a gene therapy approach can effectively treat mouse models of Alzheimer’s disease (AD) and other disorders such as traumatic head injury. Together these findings suggest the need for intensifying research efforts to harness the therapeutic potential of this multifunctional protein. PMID:28223920

  9. Mobile Apps to Support and Assess Foreign Language Learning

    ERIC Educational Resources Information Center

    Berns, Anke; Palomo-Duarte, Manuel; Dodero, Juan Manuel; Ruiz-Ladrón, Juan Miguel; Márquez, Andrea Calderón

    2015-01-01

    In the last two decades there have been many attempts to integrate all kinds of mobile devices and apps to support formal as well as informal learning processes. However, most of the available apps still support mainly individual learning, using mobile devices to deliver content rather than providing learners with the opportunity to interact with…

  10. "Apps"--An Innovative Way to Share Extension Knowledge

    ERIC Educational Resources Information Center

    Dvorak, Joseph S.; Franke-Dvorak, Tanya C.; Price, Randy R.

    2012-01-01

    Extension professionals across the country are continuously seeking innovative ways to reach clientele and to disseminate timely, educational information. A new avenue to reach clientele includes the use of smartphone "apps." The "Machinery Sizing" app, which was developed to ease the estimation of tractor horsepower to…

  11. WhatsApp in Clinical Practice: A Literature Review.

    PubMed

    Mars, Maurice; Scott, Richard E

    2016-01-01

    Several spontaneous telemedicine services using WhatsApp Messenger have started in South Africa raising issues of confidentiality, data security and storage, record keeping and reporting. This study reviewed the literature on WhatsApp in clinical practice, to determine how it is used, and users' satisfaction.

  12. BookMeUp: Creating a Book Suggestion App

    ERIC Educational Resources Information Center

    Clark, Jason

    2012-01-01

    The rise of apps and mobile devices has opened the door to small, dedicated software programs that are focused on singular tasks. From the author's perspective as head of digital access and web service manager at Montana State University, these apps offered an opportunity to build a focused digital service aimed at allowing someone to enter a…

  13. Availability and quality of mobile health app privacy policies.

    PubMed

    Sunyaev, Ali; Dehling, Tobias; Taylor, Patrick L; Mandl, Kenneth D

    2015-04-01

    Mobile health (mHealth) customers shopping for applications (apps) should be aware of app privacy practices so they can make informed decisions about purchase and use. We sought to assess the availability, scope, and transparency of mHealth app privacy policies on iOS and Android. Over 35,000 mHealth apps are available for iOS and Android. Of the 600 most commonly used apps, only 183 (30.5%) had privacy policies. Average policy length was 1755 (SD 1301) words with a reading grade level of 16 (SD 2.9). Two thirds (66.1%) of privacy policies did not specifically address the app itself. Our findings show that currently mHealth developers often fail to provide app privacy policies. The privacy policies that are available do not make information privacy practices transparent to users, require college-level literacy, and are often not focused on the app itself. Further research is warranted to address why privacy policies are often absent, opaque, or irrelevant, and to find a remedy.

  14. Using a Mobile Gaming App to Enhance Accounting Education

    ERIC Educational Resources Information Center

    Seow, Poh-Sun; Wong, Suay-Peng

    2016-01-01

    The authors describe the first mobile gaming app for learning accounting, Accounting Challenge (ACE). On September 30, 2016, ACE had been downloaded 23,230 times, spanning 90 countries, and had won three international teaching awards. The app was motivated by the aim to empower students to learn accounting in a fun way, outside of the classroom.…

  15. Examining Preservice Teachers' Criteria for Evaluating Educational Mobile Apps

    ERIC Educational Resources Information Center

    Baran, Evrim; Uygun, Erdem; Altan, Tugba

    2017-01-01

    Recent interest in integrating mobile apps into teaching will continue growing. There remains, however, a pressing need to develop methods and resources to support and educate preservice teachers about the use of these technologies. This case study aimed to examine preservice teachers' criteria for evaluating educational mobile apps. Nineteen…

  16. A Comprehensive Evaluation Rubric for Assessing Instructional Apps

    ERIC Educational Resources Information Center

    Lee, Cheng-Yuan; Cherner, Todd Sloan

    2015-01-01

    There is a pressing need for an evaluation rubric that examines all aspects of educational apps designed for instructional purposes. In past decades, many rubrics have been developed for evaluating educational computer-based programs; however, rubrics designed for evaluating the instructional implications of educational apps are scarce. When an…

  17. Free Play or Tight Spaces? Mapping Participatory Literacies in Apps

    ERIC Educational Resources Information Center

    Rowsell, Jennifer; Wohlwend, Karen

    2016-01-01

    Building on existing research applying app maps (Israelson, 2015), the authors take an ideological orientation to broaden app evaluations and consider participatory literacies, social and communicational practices relevant to children's everyday digitally mediated lives. Drawing from their North American elementary classroom studies on children's…

  18. Smartphone Technology and Apps: Rapidly Changing Health Promotion

    ERIC Educational Resources Information Center

    Kratzke, Cynthia; Cox, Carolyn

    2012-01-01

    Despite the increased availability of smartphones and health applications (apps), little is known about smartphone technology and apps for implementation in health promotion practice. Smartphones are mobile devices with capabilities for e-mail, text messaging, video viewing, and wireless Internet access. It is essential for health promotion…

  19. Mobile Distance Learning with Smartphones and Apps in Higher Education

    ERIC Educational Resources Information Center

    Vázquez-Cano, Esteban

    2014-01-01

    In this paper, the results of researcher' ongoing activities regarding the use of smartphones and a specific subject-app used at the Spanish National University of Distance Education (UNED) have been reported. The purpose of this trial is to assess the app's didactic use and potential to enhance student learning in university subjects in…

  20. Validation of a Tool Evaluating Educational Apps for Smart Education

    ERIC Educational Resources Information Center

    Lee, Jeong-Sook; Kim, Sung-Wan

    2015-01-01

    The purpose of this study is to develop and validate an evaluation tool of educational apps for smart education. Based on literature reviews, a potential model for evaluating educational apps was suggested. An evaluation tool consisting of 57 survey items was delivered to 156 students in middle and high schools. An exploratory factor analysis was…

  1. Environmental enrichment fails to rescue working memory deficits, neuron loss, and neurogenesis in APP/PS1KI mice.

    PubMed

    Cotel, Marie-Caroline; Jawhar, Sadim; Christensen, Ditte Z; Bayer, Thomas A; Wirths, Oliver

    2012-01-01

    Environmental enrichment has been used in a variety of transgenic mouse models of Alzheimer's disease (AD), however, with conflicting results. Here we studied the influence of environmental enrichment in a severely affected AD mouse model, showing a multiplicity of pathological alterations including hippocampal neuron loss. APP/PS1KI and wild type (WT) control mice were housed under standard conditions or in enriched cages equipped with various objects and running wheels. Amyloid plaque load, motor and working memory performance, axonopathy, as well as CA1 neuron number and hippocampal neurogenesis were assessed. Although a partial improvement in motor performance was observed, 4 months of enriched housing showed no beneficial effects in terms of working memory, Aβ plaque pathology, or neuron loss in APP/PS1KI mice. In addition, no changes in hippocampal neurogenesis and even an aggravation of the axonal phenotype were detected with a tendency toward a premature death. The APP/PS1KI model represents a model for mild to severe AD showing early behavioral deficits starting at 2 months of age with fast deterioration. Therefore our data might suggest that physical activity and enriched environment might be more beneficial in patients with mild cognitive impairment than in patients with incipient AD.

  2. GeoMapApp: A Cross-Platform app for Geophysical Data Exploration and Visualisation

    NASA Astrophysics Data System (ADS)

    Goodwillie, A. M.

    2015-12-01

    Apps that provide convenient, integrated access to a range of geophysical data have wide applicability in both research and teaching. GeoMapApp (http://www.geomapapp.org), a free, map-based data discovery and visualisation tool developed with NSF funding at Lamont-Doherty Earth Observatory provides casual and specialist users alike with intuitive access to hundreds of built-in geoscience data sets covering geophysics, geochemistry, geology, oceanography, and cryospherics. Users can also import their own data tables, spreadsheets, shapefiles, grids, and images. Simple manipulation and analysis tools combined with layering capabilities and engaging visualisations provide a powerful app with which to explore and interrogate geoscience data in its proper geospatial context thus helping users to more easily gain deeper insight and understanding from real-world data. The backbone of GeoMapApp is a regularly-updated multi-resolution elevation base map covering the oceans and continents and includes measurements ranging from Space Shuttle terrestrial data to ultra-high-resolution surveys of coral reefs and seafloor hydrothermal vent fields. Examples of built-in geophysical data sets include interactive earthquake locations and focal mechanism (CMT) solutions; underway cruise track profiles; plate tectonic velocities, seafloor crustal age and heat flow; multi-channel seismic reflection profiles; gravity, magnetic, and geoid anomalies; sidescan; subduction zone interface depths; and, EarthScope station locations. Dynamic links point to data sources and additional information. There are dedicated menus for GeoPRISMS, MARGINS, and Ridge2000 data sets. A versatile profiling tool provides instant access to data cross-sections, and contouring and 3-D views are also offered. Tabular data - both imported and built-in - can be displayed in a variety of ways and users can quickly select data points directly from the map. Layer opacity and on/off toggles allow easy data set

  3. Transgenic horticultural crops in Asia

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Modern biotechnology applications, including genetic engineering, are a powerful tool to complement the conventional methods of crop improvement. Asia currently has three countries cultivating biotech/transgenic crops – China, India, and the Philippines, but only China commercially grows a transgen...

  4. Enhancing Pharmacy Student Learning and Perceptions of Medical Apps

    PubMed Central

    Aungst, Timothy Dy; Brown, Nicole V; Cui, Yan; Tam, Leonard

    2016-01-01

    Background The use of mobile apps in health care is growing. Current and future practitioners must be equipped with the skills to navigate and utilize apps in patient care, yet few strategies exist for training health care professional students on the usage of apps. Objective To characterize first-year pharmacy student use of medical apps, evaluate first-year pharmacy student's perception of skills in finding, evaluating, and using medical apps before and after a focused learning experience, and assess student satisfaction and areas for improvement regarding the learning experience. Methods Students listened to a recorded, Web-based lecture on finding, evaluating, and using mobile apps in patient care. A 2-hour, interactive workshop was conducted during which students were led by an instructor through a discussion on strategies for finding and using apps in health care. The students practiced evaluating 6 different health care–related apps. Surveys were conducted before and after the focused learning experience to assess students' perceptions of medical apps and current use and perspectives on satisfaction with the learning experience and role of technology in health care. Results This educational intervention is the first described formal, interactive method to educate student pharmacists on medical apps. With a 99% response rate, surveys conducted before and after the learning experience displayed perceived improvement in student skills related to finding (52/119, 44% before vs 114/120, 95% after), evaluating (18/119, 15% before vs 112/120, 93% after), and using medical apps in patient care (31/119, 26% before vs 108/120, 90% after) and the health sciences classroom (38/119, 32% before vs 104/120, 87% after). Students described satisfaction with the educational experience and agreed that it should be repeated in subsequent years (89/120, 74% agreed or strongly agreed). Most students surveyed possessed portable electronic devices (107/119, 90% mobile phone) and

  5. All in the Family: How the APPs Regulate Neurogenesis

    PubMed Central

    Lazarov, Orly; Demars, Michael P.

    2012-01-01

    Recent intriguing evidence suggests that metabolites of amyloid precursor protein (APP), mutated in familial forms of Alzheimer’s disease (AD), play critical roles in developmental and postnatal neurogenesis. Of note is soluble APPα (sAPPα) that regulates neural progenitor cell proliferation. The APP family encompasses a group of ubiquitously expressed and evolutionarily conserved, type I transmembrane glycoproteins, whose functions have yet to be fully elucidated. APP can undergo proteolytic cleavage by mutually exclusive pathways. The subtle structural differences between metabolites generated in the different pathways, as well as their equilibrium, may be crucial for neuronal function. The implications of this new body of evidence are significant. Miscleavage of APP would readily impact developmental and postnatal neurogenesis, which might contribute to cognitive deficits characterizing Alzheimer’s disease. This review will discuss the implications of the role of the APP family in neurogenesis for neuronal development, cognitive function, and brain disorders that compromise learning and memory, such as AD. PMID:22675290

  6. Security Concerns in Android mHealth Apps

    PubMed Central

    He, Dongjing; Naveed, Muhammad; Gunter, Carl A.; Nahrstedt, Klara

    2014-01-01

    Mobile Health (mHealth) applications lie outside of regulatory protection such as HIPAA, which requires a baseline of privacy and security protections appropriate to sensitive medical data. However, mHealth apps, particularly those in the app stores for iOS and Android, are increasingly handling sensitive data for both professionals and patients. This paper presents a series of three studies of the mHealth apps in Google Play that show that mHealth apps make widespread use of unsecured Internet communications and third party servers. Both of these practices would be considered problematic under HIPAA, suggesting that increased use of mHealth apps could lead to less secure treatment of health data unless mHealth vendors make improvements in the way they communicate and store data. PMID:25954370

  7. Security Concerns in Android mHealth Apps.

    PubMed

    He, Dongjing; Naveed, Muhammad; Gunter, Carl A; Nahrstedt, Klara

    2014-01-01

    Mobile Health (mHealth) applications lie outside of regulatory protection such as HIPAA, which requires a baseline of privacy and security protections appropriate to sensitive medical data. However, mHealth apps, particularly those in the app stores for iOS and Android, are increasingly handling sensitive data for both professionals and patients. This paper presents a series of three studies of the mHealth apps in Google Play that show that mHealth apps make widespread use of unsecured Internet communications and third party servers. Both of these practices would be considered problematic under HIPAA, suggesting that increased use of mHealth apps could lead to less secure treatment of health data unless mHealth vendors make improvements in the way they communicate and store data.

  8. Myoblast fusion in Drosophila

    SciTech Connect

    Haralalka, Shruti; Abmayr, Susan M.

    2010-11-01

    The body wall musculature of a Drosophila larva is composed of an intricate pattern of 30 segmentally repeated muscle fibers in each abdominal hemisegment. Each muscle fiber has unique spatial and behavioral characteristics that include its location, orientation, epidermal attachment, size and pattern of innervation. Many, if not all, of these properties are dictated by founder cells, which determine the muscle pattern and seed the fusion process. Myofibers are then derived from fusion between a specific founder cell and several fusion competent myoblasts (FCMs) fusing with as few as 3-5 FCMs in the small muscles on the most ventral side of the embryo and as many as 30 FCMs in the larger muscles on the dorsal side of the embryo. The focus of the present review is the formation of the larval muscles in the developing embryo, summarizing the major issues and players in this process. We have attempted to emphasize experimentally-validated details of the mechanism of myoblast fusion and distinguish these from the theoretically possible details that have not yet been confirmed experimentally. We also direct the interested reader to other recent reviews that discuss myoblast fusion in Drosophila, each with their own perspective on the process . With apologies, we use gene nomenclature as specified by Flybase (http://flybase.org) but provide Table 1 with alternative names and references.

  9. Deconstructing Memory in Drosophila

    PubMed Central

    Margulies, Carla; Tully, Tim; Dubnau, Josh

    2011-01-01

    Unlike most organ systems, which have evolved to maintain homeostasis, the brain has been selected to sense and adapt to environmental stimuli by constantly altering interactions in a gene network that functions within a larger neural network. This unique feature of the central nervous system provides a remarkable plasticity of behavior, but also makes experimental investigations challenging. Each experimental intervention ramifies through both gene and neural networks, resulting in unpredicted and sometimes confusing phenotypic adaptations. Experimental dissection of mechanisms underlying behavioral plasticity ultimately must accomplish an integration across many levels of biological organization, including genetic pathways acting within individual neurons, neural network interactions which feed back to gene function, and phenotypic observations at the behavioral level. This dissection will be more easily accomplished for model systems such as Drosophila, which, compared with mammals, have relatively simple and manipulable nervous systems and genomes. The evolutionary conservation of behavioral phenotype and the underlying gene function ensures that much of what we learn in such model systems will be relevant to human cognition. In this essay, we have not attempted to review the entire Drosophila memory field. Instead, we have tried to discuss particular findings that provide some level of intellectual synthesis across three levels of biological organization: behavior, neural circuitry and biochemical pathways. We have attempted to use this integrative approach to evaluate distinct mechanistic hypotheses, and to propose critical experiments that will advance this field. PMID:16139203

  10. Epigenetic regulation in Drosophila.

    PubMed

    Lyko, F; Beisel, C; Marhold, J; Paro, R

    2006-01-01

    Epigenetic regulation of gene transcription relies on molecular marks like DNA methylation or histone modifications. Here we review recent advances in our understanding of epigenetic regulation in the fruit fly Drosophila melanogaster. In the past, DNA methylation research has primarily utilized mammalian model systems. However, several recent landmark discoveries have been made in other organisms. For example, the interaction between DNA methylation and histone methylation was first described in the filamentous fungus Neurospora crassa. Another example is provided by the interaction between epigenetic modifications and the RNA interference (RNAi) machinery that was first reported in the fission yeast Schizosaccharomyces pombe. Another organism with great experimental power is the fruit fly Drosophila. Epigenetic regulation by chromatin has been extensively analyzed in the fly and several of the key components have been discovered in this organism. In this chapter, we will focus on three aspects that represent the complexity of epigenetic gene regulation. (1) We will discuss the available data about the DNA methylation system, (2) we will illuminate the interaction between DNA methylation and chromatin regulation, and (3) we will provide an overview over the Polycomb system of epigenetic chromatin modifiers that has proved to be an important paradigm for a chromatin system regulating epigenetic programming.

  11. Using Mobile App Development Tools to Build a GIS Application

    NASA Astrophysics Data System (ADS)

    Mital, A.; Catchen, M.; Mital, K.

    2014-12-01

    Our group designed and built working web, android, and IOS applications using different mapping libraries as bases on which to overlay fire data from NASA. The group originally planned to make app versions for Google Maps, Leaflet, and OpenLayers. However, because the Leaflet library did not properly load on Android, the group focused efforts on the other two mapping libraries. For Google Maps, the group first designed a UI for the web app and made a working version of the app. After updating the source of fire data to one which also provided historical fire data, the design had to be modified to include the extra data. After completing a working version of the web app, the group used webview in android, a built in resource which allowed porting the web app to android without rewriting the code for android. Upon completing this, the group found Apple IOS devices had a similar capability, and so decided to add an IOS app to the project using a function similar to webview. Alongside this effort, the group began implementing an OpenLayers fire map using a simpler UI. This web app was completed fairly quickly relative to Google Maps; however, it did not include functionality such as satellite imagery or searchable locations. The group finished the project with a working android version of the Google Maps based app supporting API levels 14-19 and an OpenLayers based app supporting API levels 8-19, as well as a Google Maps based IOS app supporting both old and new screen formats. This project was implemented by high school and college students under an SGT Inc. STEM internship program

  12. Apps and EFL: A Case Study on the Use of Smartphone Apps to Learn English by Four Japanese University Students

    ERIC Educational Resources Information Center

    Mindog, Emily

    2016-01-01

    This study explores, describes and analyzes the utilization of smartphone apps by four Japanese university students to support learning English as a Foreign Language (EFL). Findings indicate that intermediate language learners use apps to access content and communicate on SNS and are not keen on studying discrete language parts. Participants…

  13. Mobile app versus Web app: a comparison using 2008-2012 "PubMed for Handhelds" server data.

    PubMed

    Fontelo, Paul; Liu, Fang

    2013-01-01

    Recent surveys show that mobile apps are more popular than Web apps. Apple's iTunes Store, now has about 800,000 apps and reported to have about 40 billion downloads. Android apps, although fewer, is available to the most number of smartphones today. About 40,000 apps are medical or health related. We developed a PubMed4Hh mobile app for iPhone/iPad users to search MEDLINE/PubMed with same features as our Web-based search tools, in use since 2002. Five-year (2008-2012) server data for PubMed4Hh and Web app were analyzed. Searches using the mobile app significantly increased compared to the same five-year time period. Month-by-month comparison showed a 3 to 5-fold increase in queries. The six-month total accesses comparison increased 280% from the previous four-year average. A review of 500 randomly selected queries revealed that the majority of queries were clinical questions ((97.8%) and 61% of these queries are searches related to therapy.

  14. Radiology: "killer app" for next generation networks?

    PubMed

    McNeill, Kevin M

    2004-03-01

    The core principles of digital radiology were well developed by the end of the 1980 s. During the following decade tremendous improvements in computer technology enabled realization of those principles at an affordable cost. In this decade work can focus on highly distributed radiology in the context of the integrated health care enterprise. Over the same period computer networking has evolved from a relatively obscure field used by a small number of researchers across low-speed serial links to a pervasive technology that affects nearly all facets of society. Development directions in network technology will ultimately provide end-to-end data paths with speeds that match or exceed the speeds of data paths within the local network and even within workstations. This article describes key developments in Next Generation Networks, potential obstacles, and scenarios in which digital radiology can become a "killer app" that helps to drive deployment of new network infrastructure.

  15. [Future trend medical apps. From the apps store directly into medical practice?].

    PubMed

    Gehring, H; Pramann, O; Imhoff, M; Albrecht, U-V

    2014-12-01

    In day to day medical care, patients, nursing staff and doctors currently face a bewildering and rapidly growing number of health-related apps running on various "smart" devices and there are also uncountable possibilities for the use of such technology. Concerning regulation, a risk-based approach is applied for development and use (including safety and security considerations) of medical and health-related apps. Considering safety-related issues as well as organizational matters, this is a sensible approach but requires honest self-assessment as well as a high degree of responsibility, networking and good quality management by all those involved. This cannot be taken for granted. Apart from regulatory aspects it is important to not only consider what is reasonable, helpful or profitable. Quality aspects, safety matters, data protection and privacy as well as liability issues must also be considered but are often not adequately respected. If software quality is compromised, this endangers patient safety as well as data protection, privacy and data integrity. This can for example result in unwanted advertising or unauthorized access to the stored data by third parties; therefore, local, regional and international regulatory measures need to be applied in order to ensure safe use of medical apps in all possible areas, including the operating room (OR) with its highly specialized demands. Lawmakers need to include impulses from all stakeholders in their considerations and this should include input from existing private initiatives that already deal with the use and evaluation of apps in a medical context. Of course, this process needs to respect pre-existing national, European as well as international (harmonized) standards.

  16. Pathology associated memory deficits in Swedish mutant genome-based amyloid precursor protein transgenic mice.

    PubMed

    Hock, Brian J; Lattal, K Matthew; Kulnane, Laura Shapiro; Abel, Ted; Lamb, Bruce T

    2009-12-01

    To gain insight into the relationship between pathological alterations and memory deficits observed in Alzheimer's disease (AD), a number of amyloid precursor protein (APP) transgenic animal models have been generated containing familial AD mutations. The most commonly utilized method involves a cDNA-based approach, utilizing heterologous promoters to drive expression of specific APP isoforms. As a result of the assumptions inherent in the design of each model, the different cDNA-based transgenic mouse models have revealed different relationships between the biochemical, pathological and behavioral alterations observed in these models. Here we provide further characterization of a genomic-based, amyloid precursor protein yeast artificial chromosome transgenic mouse model of AD, R1.40, that makes few assumptions regarding disease pathogenesis to study the relationship between brain pathology and altered behavior. Aged R1.40 transgenic and control mice were tested for learning and memory in the Morris water maze and for working memory in the Y maze. Results from the water maze demonstrated intact learning in the both control and R1.40 mice, but impairments in the long-term retention of this information in the transgenic mice, but not controls. Interestingly, however, long-term memory deficits did not correlate with the presence of Abeta deposits within the group of animals examined. By contrast, age-related working memory impairments were also observed in the Y maze in the R1.40 mice, and these deficits correlated with the presence of Abeta deposits. Our results demonstrate unique behavioral alterations in the R1.40 mouse model of AD that are likely both dependent and independent of Abeta deposition.

  17. Tools for neuroanatomy and neurogenetics in Drosophila

    SciTech Connect

    Pfeiffer, Barret D.; Jenett, Arnim; Hammonds, Ann S.; Ngo, Teri-T B.; Misra, Sima; Murphy, Christine; Scully, Audra; Carlson, Joseph W.; Wan, Kenneth H.; Laverty, Todd R.; Mungall, Chris; Svirskas, Rob; Kadonaga, James T.; Doe, Chris Q.; Eisen, Michael B.; Celniker, Susan E.; Rubin, Gerald M.

    2008-08-11

    We demonstrate the feasibility of generating thousands of transgenic Drosophila melanogaster lines in which the expression of an exogenous gene is reproducibly directed to distinct small subsets of cells in the adult brain. We expect the expression patterns produced by the collection of 5,000 lines that we are currently generating to encompass all neurons in the brain in a variety of intersecting patterns. Overlapping 3-kb DNA fragments from the flanking noncoding and intronic regions of genes thought to have patterned expression in the adult brain were inserted into a defined genomic location by site-specific recombination. These fragments were then assayed for their ability to function as transcriptional enhancers in conjunction with a synthetic core promoter designed to work with a wide variety of enhancer types. An analysis of 44 fragments from four genes found that >80% drive expression patterns in the brain; the observed patterns were, on average, comprised of <100 cells. Our results suggest that the D. melanogaster genome contains >50,000 enhancers and that multiple enhancers drive distinct subsets of expression of a gene in each tissue and developmental stage. We expect that these lines will be valuable tools for neuroanatomy as well as for the elucidation of neuronal circuits and information flow in the fly brain.

  18. Neuronal control of locomotor handedness in Drosophila.

    PubMed

    Buchanan, Sean M; Kain, Jamey S; de Bivort, Benjamin L

    2015-05-26

    Genetically identical individuals display variability in their physiology, morphology, and behaviors, even when reared in essentially identical environments, but there is little mechanistic understanding of the basis of such variation. Here, we investigated whether Drosophila melanogaster displays individual-to-individual variation in locomotor behaviors. We developed a new high-throughout platform capable of measuring the exploratory behavior of hundreds of individual flies simultaneously. With this approach, we find that, during exploratory walking, individual flies exhibit significant bias in their left vs. right locomotor choices, with some flies being strongly left biased or right biased. This idiosyncrasy was present in all genotypes examined, including wild-derived populations and inbred isogenic laboratory strains. The biases of individual flies persist for their lifetime and are nonheritable: i.e., mating two left-biased individuals does not yield left-biased progeny. This locomotor handedness is uncorrelated with other asymmetries, such as the handedness of gut twisting, leg-length asymmetry, and wing-folding preference. Using transgenics and mutants, we find that the magnitude of locomotor handedness is under the control of columnar neurons within the central complex, a brain region implicated in motor planning and execution. When these neurons are silenced, exploratory laterality increases, with more extreme leftiness and rightiness. This observation intriguingly implies that the brain may be able to dynamically regulate behavioral individuality.

  19. Farnesol-Detecting Olfactory Neurons in Drosophila

    PubMed Central

    Ronderos, David S.; Lin, Chun-Chieh; Potter, Christopher J.

    2014-01-01

    We set out to deorphanize a subset of putative Drosophila odorant receptors expressed in trichoid sensilla using a transgenic in vivo misexpression approach. We identified farnesol as a potent and specific activator for the orphan odorant receptor Or83c. Farnesol is an intermediate in juvenile hormone biosynthesis, but is also produced by ripe citrus fruit peels. Here, we show that farnesol stimulates robust activation of Or83c-expressing olfactory neurons, even at high dilutions. The CD36 homolog Snmp1 is required for normal farnesol response kinetics. The neurons expressing Or83c are found in a subset of poorly characterized intermediate sensilla. We show that these neurons mediate attraction behavior to low concentrations of farnesol and that Or83c receptor mutants are defective for this behavior. Or83c neurons innervate the DC3 glomerulus in the antennal lobe and projection neurons relaying information from this glomerulus to higher brain centers target a region of the lateral horn previously implicated in pheromone perception. Our findings identify a sensitive, narrowly tuned receptor that mediates attraction behavior to farnesol and demonstrates an effective approach to deorphanizing odorant receptors expressed in neurons located in intermediate and trichoid sensilla that may not function in the classical “empty basiconic neuron” system. PMID:24623773

  20. Effects of Spaceflight on Drosophila Neural Development

    NASA Technical Reports Server (NTRS)

    Keshishian, Haig S.

    1997-01-01

    The major goal from the animal side, however, has been achieved, namely to develop Drosophila lines where we can assay individual neuromuscular endings directly without dissection. This was achieved by means of using the GAL4-UAS system, where we have succeeded in establishing stocks of flies where the key neuromuscular connections can be assayed directly in undissected larvae by means of the expression of endogenously fluorescent reporters in the specific motor endings. The green fluorescent protein (GFP) as a reporter allows scoring of neural anatomy en-masse in whole mount using fluorescent microscopy without the need for either dissection or specific labeling. Two stocks have been developed. The first, which we developed first, uses the S65T mutant form, which has a dramatically brighter expression than the native protein. This animal will use GAL4 drivers with expression under the control of the elav gene, and which will ensure expression in all neurons of the embryo and larva. The second transgenic animal we have developed is of a novel kind, and makes use of dicistronic design, so that two copies of the protein will be expressed per insert. We have also developed a tricistronic form, but this has not yet been transformed into flies, and we do not imagine that this third line will be ready in time for the flight.

  1. Meiotic sex chromosome inactivation in Drosophila.

    PubMed

    Vibranovski, Maria D

    2014-01-01

    In several different taxa, there is indubitable evidence of transcriptional silencing of the X and Y chromosomes in male meiotic cells of spermatogenesis. However, the so called meiotic sex chromosome inactivation (MSCI) has been recently a hot bed for debate in Drosophila melanogaster. This review covers cytological and genetic observations, data from transgenic constructs with testis-specific promoters, global expression profiles obtained from mutant, wild-type, larvae and adult testes as well as from cells of different stages of spermatogenesis. There is no dispute on that D. melanogaster spermatogenesis presents a down-regulation of X chromosome that does not result from the lack of dosage compensation. However, the issue is currently focused on the level of reduction of X-linked expression, the precise time it occurs and how many genes are affected. The deep examination of data and experiments in this review exposes the limitations intrinsic to the methods of studying MSCI in D. melanogaster. The current methods do not allow us to affirm anything else than the X chromosome down-regulation in meiosis (MSCI). Therefore, conclusion about level, degree or precise timing is inadequate until new approaches are implemented to know the details of MSCI or other processes involved for D. melanogaster model.

  2. Meiotic Sex Chromosome Inactivation in Drosophila

    PubMed Central

    Vibranovski, Maria D.

    2014-01-01

    In several different taxa, there is indubitable evidence of transcriptional silencing of the X and Y chromosomes in male meiotic cells of spermatogenesis. However, the so called meiotic sex chromosome inactivation (MSCI) has been recently a hot bed for debate in Drosophila melanogaster. This review covers cytological and genetic observations, data from transgenic constructs with testis-specific promoters, global expression profiles obtained from mutant, wild-type, larvae and adult testes as well as from cells of different stages of spermatogenesis. There is no dispute on that D. melanogaster spermatogenesis presents a down-regulation of X chromosome that does not result from the lack of dosage compensation. However, the issue is currently focused on the level of reduction of X-linked expression, the precise time it occurs and how many genes are affected. The deep examination of data and experiments in this review exposes the limitations intrinsic to the methods of studying MSCI in D. melanogaster. The current methods do not allow us to affirm anything else than the X chromosome down-regulation in meiosis (MSCI). Therefore, conclusion about level, degree or precise timing is inadequate until new approaches are implemented to know the details of MSCI or other processes involved for D. melanogaster model. PMID:25057326

  3. Neuronal control of locomotor handedness in Drosophila

    PubMed Central

    Buchanan, Sean M.; Kain, Jamey S.; de Bivort, Benjamin L.

    2015-01-01

    Genetically identical individuals display variability in their physiology, morphology, and behaviors, even when reared in essentially identical environments, but there is little mechanistic understanding of the basis of such variation. Here, we investigated whether Drosophila melanogaster displays individual-to-individual variation in locomotor behaviors. We developed a new high-throughout platform capable of measuring the exploratory behavior of hundreds of individual flies simultaneously. With this approach, we find that, during exploratory walking, individual flies exhibit significant bias in their left vs. right locomotor choices, with some flies being strongly left biased or right biased. This idiosyncrasy was present in all genotypes examined, including wild-derived populations and inbred isogenic laboratory strains. The biases of individual flies persist for their lifetime and are nonheritable: i.e., mating two left-biased individuals does not yield left-biased progeny. This locomotor handedness is uncorrelated with other asymmetries, such as the handedness of gut twisting, leg-length asymmetry, and wing-folding preference. Using transgenics and mutants, we find that the magnitude of locomotor handedness is under the control of columnar neurons within the central complex, a brain region implicated in motor planning and execution. When these neurons are silenced, exploratory laterality increases, with more extreme leftiness and rightiness. This observation intriguingly implies that the brain may be able to dynamically regulate behavioral individuality. PMID:25953337

  4. Magnetic resonance imaging of amyloid plaques using hollow manganese oxide nanoparticles conjugated with antibody aβ1-40 in a transgenic mouse model.

    PubMed

    Kim, Jae-Hun; Ha, Tae Lin; Im, Geun Ho; Yang, Jehoon; Seo, Sang Won; Lee, In Su; Lee, Jung Hee

    2013-01-09

    In this study, we have shown the feasibility of hollow manganese oxide nanoparticles (HMON) conjugated with an antibody of Aβ1-40 peptide (abAβ40) (HMON-abAβ40) for MRI of amyloid plaques in APP/PS1 transgenic mice. MR brain images in APP/PS1 transgenic mice and their nontransgenic littermates were acquired using a 7.0 T MRI system before, and 24 and 72 h after an injection of HMON-abAβ40. After the injection of HMON-abAβ40, we found hyperenhanced spots in the frontal cortex area on T1-weighted MR images for transgenic mice, which corresponded qualitatively to amyloid plaques detected by thioflavin-S staining. For quantitative analysis, percent MR signal changes in six brain regions (olfactory cortex, frontal cortex, cerebral cortex, thalamus, hippocampus, and cerebellar cortex) were compared between transgenic and wild-type mice. We found significant increases in the percent MR signal changes in the olfactory cortex, frontal cortex, cerebral cortex, and hippocampus, but there were no significant differences in the thalamus and cerebellar cortex for transgenic mice compared with wild-type mice. This unique strategy allowed us to detect brain regions subjected to amyloid plaque deposition in Alzheimer's disease transgenic mouse models and has a potential to be developed for human applications, which has a current utility in preclinical research, particularly in monitoring therapeutic response for drug development in Alzheimer's disease.

  5. APP717, APP693, and PRIP gene mutations are rare in Alzheimer disease

    PubMed Central

    Schellenberg, Gerard D.; Anderson, Leojean; O'dahl, Sheldon; Wisjman, Ellen M.; Sadovnick, Adele D.; Ball, Melvyn J.; Larson, Eric B.; Kukull, Walter A.; Martin, George M.; Roses, Allen D.; Bird, Thomas D.

    1991-01-01

    The amyloid precursor protein (APP) gene codes for the precursor to the β-protein found in the amyloid deposits of Alzheimer disease (AD). Recently Goate et al. identified in codon 717 of this gene a missense mutation which segregates with AD in a familial AD (FAD) kindred. The same mutation was also found in affected subjects from a second FAD family but not in other FAD families or in normal controls. The following work was undertaken to determine the frequency of the codon 717 mutation in FAD and nonfamilial AD cases and in normal controls. We tested 76 FAD families, 127 “sporadic” AD subjects, 16 Down syndrome cases, and 256 normal controls for this mutation, and none were positive. We also tested for the APP codon 693 mutation associated with hereditary cerebral hemorrhage with amyloidosis–Dutch type, for PRIP gene missense mutations at codons 102, 117, and 200, and for the PRIP insertion mutations which are associated with Creutzfeld-Jakob disease and Gerstmann-Straussler Scheinker syndrome. No examples of these mutations were found in our population. Thus these APP and PRIP mutations are rare in both FAD and nonfamilial AD. ImagesFigure 1 PMID:1679288

  6. Mobile Apps for Weight Management: A Scoping Review

    PubMed Central

    2016-01-01

    Background Obesity remains a major public health concern. Mobile apps for weight loss/management are found to be effective for improving health outcomes in adults and adolescents, and are pursued as a cost-effective and scalable intervention for combating overweight and obesity. In recent years, the commercial market for ‘weight loss apps’ has expanded at rapid pace, yet little is known regarding the evidence-based quality of these tools for weight control. Objective To characterize the inclusion of evidence-based strategies, health care expert involvement, and scientific evaluation of commercial mobile apps for weight loss/management. Methods An electronic search was conducted between July 2014 and July 2015 of the official app stores for four major mobile operating systems. Three raters independently identified apps with a stated goal of weight loss/management, as well as weight loss/management apps targeted to pediatric users. All discrepancies regarding selection were resolved through discussion with a fourth rater. Metadata from all included apps were abstracted into a standard assessment criteria form and the evidence-based strategies, health care expert involvement, and scientific evaluation of included apps was assessed. Evidence-based strategies included: self-monitoring, goal-setting, physical activity support, healthy eating support, weight and/or health assessment, personalized feedback, motivational strategies, and social support. Results A total of 393 apps were included in this review. Self-monitoring was most common (139/393, 35.3%), followed by physical activity support (108/393, 27.5%), weight assessment (100/393, 25.4%), healthy eating support (91/393, 23.2%), goal-setting (84/393, 21.4%), motivational strategies (28/393, 7.1%), social support (21/393, 5.3%), and personalized feedback (7/393, 1.8%). Of apps, 0.8% (3/393) underwent scientific evaluation and 0.3% (1/393) reported health care expert involvement. No apps were comprehensive in the

  7. Absence of effects of Sir2 over-expression on lifespan in C. elegans and Drosophila

    PubMed Central

    Burnett, Camilla; Valentini, Sara; Cabreiro, Filipe; Goss, Martin; Somogyvári, Milán; Piper, Matthew D.; Hoddinott, Matthew; Sutphin, George L.; Leko, Vid; McElwee, Joshua J.; Vazquez, Rafael; Orfila, Anne-Marie; Ackerman, Daniel; Au, Catherine; Vinti, Giovanna; Riesen, Michèle; Howard, Ken; Neri, Christian; Bedalov, Antonio; Kaeberlein, Matt; Söti, Csaba; Partridge, Linda; Gems, David

    2011-01-01

    Over-expression of sirtuins (NAD+-dependent protein deacetylases) has been reported to increase lifespan in budding yeast, Caenorhabditis elegans and Drosophila melanogaster1-3. Studies of gene effects on ageing are vulnerable to confounding effects of genetic background4. We re-examined the reported effects of sirtuin over-expression on ageing and found that standardisation of genetic background and use of appropriate controls abolished the apparent effects in both C. elegans and Drosophila. In C. elegans, outcrossing of a line with high level sir-2.1 over-expression1 abrogated the longevity increase, but not sir-2.1 over-expression. Instead, longevity co-segregated with a second-site mutation affecting sensory neurons. Outcrossing of a line with low copy number sir-2.1 over-expression2 also abrogated longevity. A Drosophila strain with ubiquitous over-expression of dSir2 using the UAS-GAL4 system was long-lived relative to wild-type controls, as previously reported3, but not relative to the appropriate transgenic controls, and nor was a new line with stronger over-expression of dSir2. These findings underscore the importance of controlling for genetic background and the mutagenic effects of transgene insertions in studies of genetic effects on lifespan. The life extending effect of dietary restriction (DR) on ageing in Drosophila has also been reported to be dSir2 dependent3. We found that DR increased fly lifespan independently of dSir2. Our findings do not rule out a role for sirtuins in determination of metazoan lifespan, but they do cast doubt on the robustness of the previously reported effects on lifespan in C. elegans and Drosophila. PMID:21938067

  8. Expression of bovine superoxide dismutase in Drosophila melanogaster augments resistance of oxidative stress.

    PubMed Central

    Reveillaud, I; Niedzwiecki, A; Bensch, K G; Fleming, J E

    1991-01-01

    Superoxide dismutases (SOD) play a major role in the intracellular defense against oxygen radical damage to aerobic cells. In eucaryotes, the cytoplasmic form of the enzyme is a 32-kDa dimer containing two copper and two zinc atoms (CuZn SOD) that catalyzes the dismutation of the superoxide anion (O2-) to H2O2 and O2. Superoxide-mediated damage has been implicated in a number of biological processes, including aging and cancer; however, it is not certain whether endogenously elevated levels of SOD will reduce the pathological events resulting from such damage. To understand the in vivo relationship between an efficient dismutation of O2- and oxidative injury to biological structures, we generated transgenic strains of Drosophila melanogaster overproducing CuZn SOD. This was achieved by microinjecting Drosophila embryos with P-elements containing bovine CuZn SOD cDNA under the control of the Drosophila actin 5c gene promoter. Adult flies of the resulting transformed lines which expressed both mammalian and Drosophila CuZn SOD were then used as a novel model for evaluating the role of oxygen radicals in aging. Our data show that expression of enzymatically active bovine SOD in Drosophila flies confers resistance to paraquat, an O2(-)-generating compound. This is consistent with data on adult mortality, because there was a slight but significant increase in the mean lifespan of several of the transgenic lines. The highest level of expression of the active enzyme in adults was 1.60 times the normal value. Higher levels may have led to the formation of toxic levels of H2O2 during development, since flies that died during the process of eclosion showed an unusual accumulation of lipofuscin (age pigment) in some of their cells. In conclusion, our data show that free-radical detoxification has a minor by positive effect on mean longevity for several strains. Images PMID:1899285

  9. [Transgenics without Manichaeism].

    PubMed

    Valle, S

    2000-01-01

    We live in an era characterized by the hegemony of science and technology, an era fraught with questions awaiting answers which would enable a safe and sustainable future for humankind. The development of agro-industrial processes - food products in particular - through recombinant DNA technology has enhanced the profit prospects of the few big biotechnology companies and of large-scale farmers who have access to the latest technological developments. We thus oppose a moratorium on recombinant DNA technology. Moreover, hasty statements about risk-free transgenics may be misleading in the absence of extensive safety tests. There is a pressing need for the establishment of biosafety policy in this country involving the organized civil society and every government agency responsible for monitoring such matters. There is also the need to put in place a bio-surveillance and a code of ethics regarding genetic manipulation.

  10. Cytoplasmic myosin from Drosophila melanogaster

    PubMed Central

    1986-01-01

    Myosin is identified and purified from three different established Drosophila melanogaster cell lines (Schneider's lines 2 and 3 and Kc). Purification entails lysis in a low salt, sucrose buffer that contains ATP, chromatography on DEAE-cellulose, precipitation with actin in the absence of ATP, gel filtration in a discontinuous KI-KCl buffer system, and hydroxylapatite chromatography. Yield of pure cytoplasmic myosin is 5-10%. This protein is identified as myosin by its cross-reactivity with two monoclonal antibodies against human platelet myosin, the molecular weight of its heavy chain, its two light chains, its behavior on gel filtration, its ATP-dependent affinity for actin, its characteristic ATPase activity, its molecular morphology as demonstrated by platinum shadowing, and its ability to form bipolar filaments. The molecular weight of the cytoplasmic myosin's light chains and peptide mapping and immunochemical analysis of its heavy chains demonstrate that this myosin, purified from Drosophila cell lines, is distinct from Drosophila muscle myosin. Two-dimensional thin layer maps of complete proteolytic digests of iodinated muscle and cytoplasmic myosin heavy chains demonstrate that, while the two myosins have some tryptic and alpha-chymotryptic peptides in common, most peptides migrate with unique mobility. One-dimensional peptide maps of SDS PAGE purified myosin heavy chain confirm these structural data. Polyclonal antiserum raised and reacted against Drosophila myosin isolated from cell lines cross-reacts only weakly with Drosophila muscle myosin isolated from the thoraces of adult Drosophila. Polyclonal antiserum raised against Drosophila muscle myosin behaves in a reciprocal fashion. Taken together our data suggest that the myosin purified from Drosophila cell lines is a bona fide cytoplasmic myosin and is very likely the product of a different myosin gene than the muscle myosin heavy chain gene that has been previously identified and characterized. PMID

  11. Review: Thermal preference in Drosophila

    PubMed Central

    Dillon, Michael E.; Wang, George; Garrity, Paul A.; Huey, Raymond B.

    2009-01-01

    Environmental temperature strongly affects physiology of ectotherms. Small ectotherms, like Drosophila, cannot endogenously regulate body temperature so must rely on behavior to maintain body temperature within a physiologically permissive range. Here we review what is known about Drosophila thermal preference. Work on thermal behavior in this group is particularly exciting because it provides the opportunity to connect genes to neuromolecular mechanisms to behavior to fitness in the wild. PMID:20161211

  12. Safeguarding genetic information in Drosophila.

    PubMed

    Su, Tin Tin

    2011-12-01

    Eukaryotic cells employ a plethora of conserved proteins and mechanisms to ensure genome integrity. In metazoa, these mechanisms must operate in the context of organism development. This mini-review highlights two emerging features of DNA damage responses in Drosophila: a crosstalk between DNA damage responses and components of the spindle assembly checkpoint, and increasing evidence for the effect of DNA damage on the developmental program at multiple points during the Drosophila life cycle.

  13. Prolonged oral cannabinoid administration prevents neuroinflammation, lowers β-amyloid levels and improves cognitive performance in Tg APP 2576 mice

    PubMed Central

    2012-01-01

    Background Alzheimer's disease (AD) brain shows an ongoing inflammatory condition and non-steroidal anti-inflammatories diminish the risk of suffering the neurologic disease. Cannabinoids are neuroprotective and anti-inflammatory agents with therapeutic potential. Methods We have studied the effects of prolonged oral administration of transgenic amyloid precursor protein (APP) mice with two pharmacologically different cannabinoids (WIN 55,212-2 and JWH-133, 0.2 mg/kg/day in the drinking water during 4 months) on inflammatory and cognitive parameters, and on 18F-fluoro-deoxyglucose (18FDG) uptake by positron emission tomography (PET). Results Novel object recognition was significantly reduced in 11 month old Tg APP mice and 4 month administration of JWH was able to normalize this cognitive deficit, although WIN was ineffective. Wild type mice cognitive performance was unaltered by cannabinoid administration. Tg APP mice showed decreased 18FDG uptake in hippocampus and cortical regions, which was counteracted by oral JWH treatment. Hippocampal GFAP immunoreactivity and cortical protein expression was unaffected by genotype or treatment. In contrast, the density of Iba1 positive microglia was increased in Tg APP mice, and normalized following JWH chronic treatment. Both cannabinoids were effective at reducing the enhancement of COX-2 protein levels and TNF-α mRNA expression found in the AD model. Increased cortical β-amyloid (Aβ) levels were significantly reduced in the mouse model by both cannabinoids. Noteworthy both cannabinoids enhanced Aβ transport across choroid plexus cells in vitro. Conclusions In summary we have shown that chronically administered cannabinoid showed marked beneficial effects concomitant with inflammation reduction and increased Aβ clearance. PMID:22248049

  14. Health Behavior Theory in Popular Calorie Counting Apps: A Content Analysis

    PubMed Central

    Davis, Siena F; Ellsworth, Marisa A; Payne, Hannah E; Hall, Shelby M; Nordhagen, Amber L

    2016-01-01

    Background Although the Health & Fitness category of the Apple App Store features hundreds of calorie counting apps, the extent to which popular calorie counting apps include health behavior theory is unknown. Objective This study evaluates the presence of health behavior theory in calorie counting apps. Methods Data for this study came from an extensive content analysis of the 10 most popular calorie counting apps in the Health & Fitness category of the Apple App Store. Results Each app was given a theory score to reflect the extent to which health behavior theory was integrated into the app. The highest possible score was 60. Out of the 10 apps evaluated, My Diet Coach obtained the highest theory score of 15. MapMyFitness and Yumget received the lowest scores of 0. The average theory score among the apps was 5.6. Conclusions Most of the calorie counting apps in the sample contained minimal health behavior theory. PMID:26935898

  15. Chronic Apocynin Treatment Attenuates Beta Amyloid Plaque Size and Microglial Number in hAPP(751)SL Mice

    PubMed Central

    Lull, Melinda E.; Levesque, Shannon; Surace, Michael J.; Block, Michelle L.

    2011-01-01

    Background NADPH oxidase is implicated in neurotoxic microglial activation and the progressive nature of Alzheimer's Disease (AD). Here, we test the ability of two NADPH oxidase inhibitors, apocynin and dextromethorphan (DM), to reduce learning deficits and neuropathology in transgenic mice overexpressing human amyloid precursor protein with the Swedish and London mutations (hAPP(751)SL). Methods Four month old hAPP(751)SL mice were treated daily with saline, 15 mg/kg DM, 7.5 mg/kg DM, or 10 mg/kg apocynin by gavage for four months. Results Only hAPP(751)SL mice treated with apocynin showed reduced plaque size and a reduction in the number of cortical microglia, when compared to the saline treated group. Analysis of whole brain homogenates from all treatments tested (saline, DM, and apocynin) demonstrated low levels of TNFα, protein nitration, lipid peroxidation, and NADPH oxidase activation, indicating a low level of neuroinflammation and oxidative stress in hAPP(751)SL mice at 8 months of age that was not significantly affected by any drug treatment. Despite in vitro analyses demonstrating that apocynin and DM ameliorate Aβ-induced extracellular superoxide production and neurotoxicity, both DM and apocynin failed to significantly affect learning and memory tasks or synaptic density in hAPP(751)SL mice. To discern how apocynin was affecting plaque levels (plaque load) and microglial number in vivo, in vitro analysis of microglia was performed, revealing no apocynin effects on beta-amyloid (Aβ) phagocytosis, microglial proliferation, or microglial survival. Conclusions Together, this study suggests that while hAPP(751)SL mice show increases in microglial number and plaque load, they fail to exhibit elevated markers of neuroinflammation consistent with AD at 8 months of age, which may be a limitation of this animal model. Despite absence of clear neuroinflammation, apocynin was still able to reduce both plaque size and microglial number, suggesting that apocynin

  16. Cytokines in Drosophila immunity.

    PubMed

    Vanha-Aho, Leena-Maija; Valanne, Susanna; Rämet, Mika

    2016-02-01

    Cytokines are a large and diverse group of small proteins that can affect many biological processes, but most commonly cytokines are known as mediators of the immune response. In the event of an infection, cytokines are produced in response to an immune stimulus, and they function as key regulators of the immune response. Cytokines come in many shapes and sizes, and although they vary greatly in structure, their functions have been well conserved in evolution. The immune signaling pathways that respond to cytokines are remarkably conserved from fly to man. Therefore, Drosophila melanogaster, provides an excellent platform for studying the biology and function of cytokines. In this review, we will describe the cytokines and cytokine-like molecules found in the fly and discuss their roles in host immunity.

  17. Optogenetics in Drosophila Neuroscience.

    PubMed

    Riemensperger, Thomas; Kittel, Robert J; Fiala, André

    2016-01-01

    Optogenetic techniques enable one to target specific neurons with light-sensitive proteins, e.g., ion channels, ion pumps, or enzymes, and to manipulate their physiological state through illumination. Such artificial interference with selected elements of complex neuronal circuits can help to determine causal relationships between neuronal activity and the effect on the functioning of neuronal circuits controlling animal behavior. The advantages of optogenetics can best be exploited in genetically tractable animals whose nervous systems are, on the one hand, small enough in terms of cell numbers and to a certain degree stereotypically organized, such that distinct and identifiable neurons can be targeted reproducibly. On the other hand, the neuronal circuitry and the behavioral repertoire should be complex enough to enable one to address interesting questions. The fruit fly Drosophila melanogaster is a favorable model organism in this regard. However, the application of optogenetic tools to depolarize or hyperpolarize neurons through light-induced ionic currents has been difficult in adult flies. Only recently, several variants of Channelrhodopsin-2 (ChR2) have been introduced that provide sufficient light sensitivity, expression, and stability to depolarize central brain neurons efficiently in adult Drosophila. Here, we focus on the version currently providing highest photostimulation efficiency, ChR2-XXL. We exemplify the use of this optogenetic tool by applying it to a widely used aversive olfactory learning paradigm. Optogenetic activation of a population of dopamine-releasing neurons mimics the reinforcing properties of a punitive electric shock typically used as an unconditioned stimulus. In temporal coincidence with an odor stimulus this artificially induced neuronal activity causes learning of the odor signal, thereby creating a light-induced memory.

  18. Intracellular Aß triggers neuron loss in the cholinergic system of the APP/PS1KI mouse model of Alzheimer's disease.

    PubMed

    Christensen, Ditte Z; Bayer, Thomas A; Wirths, Oliver

    2010-07-01

    Loss of cholinergic neurons in the Nucleus Basalis of Meynert in Alzheimer's disease (AD) patients was one of the first discoveries of neuron loss in AD. Despite an intense focus on the cholinergic system in AD, the reason for this cholinergic neuron loss is yet unknown. In the present study we examined Abeta-induced pathology and neuron loss in the cholinergic system of the bigenic APP/PS1KI mouse model. Expression of the APP transgene was found in ChAT-positive neurons of motor nuclei accompanied by robust intracellular Abeta accumulation, whereas no APP expressing neurons and thus no intracellular Abeta accumulation were found in neither the forebrain or pons complexes, nor in the caudate putamen. This expression pattern was used as a model system to study the effect of intra- and extracellular Abeta accumulation on neuron loss in the cholinergic system. Stereological quantification revealed a loss of ChAT-positive neurons in APP/PS1KI mice only in the motor nuclei Mo5 and 7N accumulating intracellular Abeta. This study supports the hypothesis of intracellular Abeta accumulation as an early pathological alteration contributing to cell death in AD.

  19. Overexpression of phyA and appA genes improves soil organic phosphorus utilisation and seed phytase activity in Brassica napus.

    PubMed

    Wang, Yi; Ye, Xiangsheng; Ding, Guangda; Xu, Fangsen

    2013-01-01

    Phytate is the major storage form of organic phosphorus in soils and plant seeds, and phosphorus (P) in this form is unavailable to plants or monogastric animals. In the present study, the phytase genes phyA and appA were introduced into Brassica napus cv Westar with a signal peptide sequence and CaMV 35S promoter, respectively. Three independent transgenic lines, P3 and P11 from phyA and a18 from appA, were selected. The three transgenic lines exhibited significantly higher exuded phytase activity when compared to wild-type (WT) controls. A quartz sand culture experiment demonstrated that transgenic Brassica napus had significantly improved P uptake and plant biomass. A soil culture experiment revealed that seed yields of transgenic lines P11 and a18 increased by 20.9% and 59.9%, respectively, when compared to WT. When phytate was used as the sole P source, P accumulation in seeds increased by 20.6% and 46.9% with respect to WT in P11 and a18, respectively. The P3 line accumulated markedly more P in seeds than WT, while no significant difference was observed in seed yields when phytate was used as the sole P source. Phytase activities in transgenic canola seeds ranged from 1,138 to 1,605 U kg(-1) seeds, while no phytase activity was detected in WT seeds. Moreover, phytic acid content in P11 and a18 seeds was significantly lower than in WT. These results introduce an opportunity for improvement of soil and seed phytate-P bioavailability through genetic manipulation of oilseed rape, thereby increasing plant production and P nutrition for monogastric animals.

  20. FLZ Alleviates the Memory Deficits in Transgenic Mouse Model of Alzheimer’s Disease via Decreasing Beta-Amyloid Production and Tau Hyperphosphorylation

    PubMed Central

    Wang, Tao; Kong, Xiang-Chen; Tai, Wen-Jiao; Sun, Hua; Zhang, Dan

    2013-01-01

    Alzheimer’s disease (AD) is the most common cause of dementia worldwide and mainly characterized by the aggregated β-amyloid (Aβ) and hyperphosphorylated tau. FLZ is a novel synthetic derivative of natural squamosamide and has been proved to improve memory deficits in dementia animal models. In this study, we aimed to investigate the mechanisms of FLZ’s neuroprotective effect in APP/PS1 double transgenic mice and SH-SY5Y (APPwt/swe) cells. The results showed that treatment with FLZ significantly improved the memory deficits of APP/PS1 transgenic mice and decreased apoptosis of SH-SY5Y (APPwt/swe) cells. FLZ markedly attenuated Aβ accumulation and tau phosphorylation both in vivo and in vitro. Mechanistic study showed that FLZ interfered APP processing, i.e., FLZ decreased β-amyloid precursor protein (APP) phosphorylation, APP-carboxy-terminal fragment (APP-CTF) production and β-amyloid precursor protein cleaving enzyme 1 (BACE1) expression. These results indicated that FLZ reduced Aβ production through inhibiting amyloidogenic pathway. The mechanistic study about FLZ’s inhibitory effect on tau phosphorylation revealed t the involvement of Akt/glycogen synthase kinase 3β (GSK3β) pathway. FLZ treatment increased Akt activity and inhibited GSK3β activity both in vivo and in vitro. The inhibitory effect of FLZ on GSK3β activity and tau phosphorylation was suppressed by inhibiting Akt activity, indicating that Akt/GSK3β pathway might be the possible mechanism involved in the inhibitory effect of FLZ on tau hyperphosphorylation. These results suggested FLZ might be a potential anti-AD drug as it not only reduced Aβ production via inhibition amyloidogenic APP processing pathway, but also attenuated tau hyperphosphoylation mediated by Akt/GSK3β. PMID:24223757

  1. Phenylbutyric acid reduces amyloid plaques and rescues cognitive behavior in AD transgenic mice.

    PubMed

    Wiley, Jesse C; Pettan-Brewer, Christina; Ladiges, Warren C

    2011-06-01

    Trafficking through the secretory pathway is known to regulate the maturation of the APP-cleaving secretases and APP proteolysis. The coupling of stress signaling and pathological deterioration of the brain in Alzheimer's disease (AD) supports a mechanistic connection between endoplasmic reticulum (ER) stress and neurodegeneration. Consequently, small molecular chaperones, which promote protein folding and minimize ER stress, might be effective in delaying or attenuating the deleterious progression of AD. We tested this hypothesis by treating APPswePS1delta9 AD transgenic mice with the molecular chaperone phenylbutyric acid (PBA) for 14 months at a dose of 1 mg PBA g(-1) of body weight in the drinking water. Phenylbutyric acid treatment increased secretase-mediated APP cleavage, but was not associated with any increase in amyloid biosynthesis. The PBA-treated AD transgenic mice had significantly decreased incidence and size of amyloid plaques throughout the cortex and hippocampus. There was no change in total amyloid levels suggesting that PBA modifies amyloid aggregation or pathogenesis independently of biogenesis. The decrease in amyloid plaques was paralleled by increased memory retention, as PBA treatment facilitated cognitive performance in a spatial memory task in both wild-type and AD transgenic mice. The molecular mechanism underlying the cognitive facilitation of PBA is not clear; however, increased levels of both metabotropic and ionotropic glutamate receptors, as well as ADAM10 and TACE, were observed in the cortex and hippocampus of PBA-treated mice. The data suggest that PBA ameliorates the cognitive and pathological features of AD and supports the investigation of PBA as a therapeutic for AD.

  2. Evaluation of COTS Rad Detection Apps

    SciTech Connect

    Wagner, Eric

    2014-02-01

    Mobile applications are currently under distribution to smart phones utilizing the built-in charge coupled-device (CCD) camera as a radiation detector. The CCD detector has a very low but measurable gamma interaction cross section so the mechanism is feasible, especially for higher dose rate environments. Given that in a large release of radioactive material these ‘crowd sourced’ measurements will be put forth for consideration, a testing and evaluation of the accuracy and uncertainty of the Apps is a critical endeavor. Not only is the accuracy of the reported measurement of concern to the immediate user’s safety, a quantitative uncertainty is required for a government response such as the Federal Radiological Monitoring and Assessment Center (FRMAC) to accept the values for consideration in the determination of regions exceeding protective action guidelines. Already, prompted by the Fukushima nuclear material releases, several repositories of this crowd-sourced data have been created (http://japan.failedrobot.com, http://www.stubbytour.com/nuc/index_en.asp, and http://www.rdtn.org) although the question remains as to the reliability of measurements incorporated into these repositories. In cases of conflict between the real-time published crowd-sourced data and governmental protective actions prepared literature should be on-hand documenting why the difference, if any, exists. Four applications for iOS devices were obtained along with hardware to benchmark their performance. Gamma/X-Ray Detector by Stephan Hotto, Geiger Camera by Senscare, and RadioactivityCounter App by Hotray LTD are all the applications available for distribution within the US that utilize the CCD camera sensor for detection of radiation levels. The CellRad app under development by Idaho National Laboratory for the Android platform was evaluated. In addition, iRad Geiger with the associated hardware accessory was also benchmarked. Radiation fields were generated in a Cs-137 JL Shepherd

  3. The Med AppJam: a model for an interprofessional student-centered mHealth app competition.

    PubMed

    Youm, Julie; Wiechmann, Warren

    2015-03-01

    The Med AppJam is a 2-week long competition where students from the University of California, Irvine School of Medicine are partnered with students from the University of California, Irvine School of Information and Computer Sciences in interprofessional teams to develop mobile health applications for use by clinicians and patients. The success of the Med AppJam comes from the unique opportunity for students to mutually contribute their content expertise to improve the clinical landscape while expanding their technology literacy and savvy. Since 2012, about 285 computer science students and over 90 medical students have collaborated to design and develop 53 iOS mHealth apps during the event. The Med AppJam model has been replicated in an Autism AppJam, a competition focused on the needs of a specific population, and with high school students in a mini Pre-Med AppJam using a paper prototyping approach. It is proposed that other medical schools consider implementation of a local Med AppJam as a viable model for engaging students in technology for healthcare.

  4. Human BMP sequences can confer normal dorsal-ventral patterning in the Drosophila embryo.

    PubMed

    Padgett, R W; Wozney, J M; Gelbart, W M

    1993-04-01

    The type beta transforming growth factor family is composed of a series of processed, secreted growth factors, several of which have been implicated in important regulatory roles in cell determination, inductive interactions, and tissue differentiation. Among these factors, the sequence of the DPP protein from Drosophila is most similar to two of the vertebrate bone morphogenetic proteins, BMP2 and BMP4. Here we report that the human BMP4 ligand sequences can function in lieu of DPP in Drosophila embryos. We introduced the ligand region from human BMP4 into a genomic fragment of the dpp gene in place of the Drosophila ligand sequences and recovered transgenic flies by P-element transformation. We find that this chimeric dpp-BMP4 transgene can completely rescue the embryonic dorsal-ventral patterning defect of null dpp mutant genotypes. We infer that the chimeric DPP-BMP4 protein can be processed properly and, by analogy with the action of other family members, can activate the endogenous DPP receptor to carry out the events necessary for dorsal-ventral patterning. Our evidence suggests that the DPP-BMP4 signal transduction pathway has been functionally conserved for at least 600 million years.

  5. A new paramutation-like example at the Delta gene of Drosophila

    PubMed Central

    Capovilla, Maria; Robichon, Alain; Rassoulzadegan, Minoo

    2017-01-01

    The hereditary transmission of a phenotype independent from DNA sequence implies epigenetic effects. Paramutation is a heritable epigenetic phenomenon observed in plants and animals. To investigate paramutation in Drosophila, we used the P{ry+t7.2 = PZ}Dl05151 P-element insertion in the Drosophila melanogaster genome that causes a dominant visible phenotype: the presence of characteristic extra-veins in the fly wings. This extra-vein phenotype presents variable expressivity and incomplete penetrance. The insert is a PZ element located 680 bp upstream from the ATG of the Delta (Dl) gene, encoding the Notch ligand involved in wing vein development, and acts as a null allele. In the G2 offspring from a cross between the heterozygous transgenic stock and wild-type flies, we observed the transmission of the extra-vein phenotype to wild-type flies without the transgene, independently of gender and across many generations. This is a “paramutation-like” example in the fly: the heritable transmission of a phenotypic change not linked to a classical genetic mutation. A “paramutagenic” allele in heterozygotes transmits the phenotype of the heterozygotes to the wild-type allele (“paramutant”) in a stable manner through generations. Distinct from paramutation events so far described in Drosophila, here we deal with a dominant effect on a single gene involving variable hereditary signals. PMID:28355214

  6. UDP-galactose 4' epimerase (GALE) is essential for development of Drosophila melanogaster.

    PubMed

    Sanders, Rebecca D; Sefton, Jennifer M I; Moberg, Kenneth H; Fridovich-Keil, Judith L

    2010-01-01

    UDP-galactose 4' epimerase (GALE) catalyzes the interconversion of UDP-galactose and UDP-glucose in the final step of the Leloir pathway; human GALE (hGALE) also interconverts UDP-N-acetylgalactosamine and UDP-N-acetylglucosamine. GALE therefore plays key roles in the metabolism of dietary galactose, in the production of endogenous galactose, and in maintaining the ratios of key substrates for glycoprotein and glycolipid biosynthesis. Partial impairment of hGALE results in the potentially lethal disorder epimerase-deficiency galactosemia. We report here the generation and initial characterization of a first whole-animal model of GALE deficiency using the fruit fly Drosophila melanogaster. Our results confirm that GALE function is essential in developing animals; Drosophila lacking GALE die as embryos but are rescued by the expression of a human GALE transgene. Larvae in which GALE has been conditionally knocked down die within days of GALE loss. Conditional knockdown and transgene expression studies further demonstrate that GALE expression in the gut primordium and Malpighian tubules is both necessary and sufficient for survival. Finally, like patients with generalized epimerase deficiency galactosemia, Drosophila with partial GALE loss survive in the absence of galactose but succumb in development if exposed to dietary galactose. These data establish the utility of the fly model of GALE deficiency and set the stage for future studies to define the mechanism(s) and modifiers of outcome in epimerase deficiency galactosemia.

  7. Transgenic mice in developmental toxicology

    SciTech Connect

    Woychik, R.P.

    1992-01-01

    Advances in molecular biology and embryology are being utilized for the generation of transgenic mice, animals that contain specific additions, deletions, or modifications of genes or sequences in their DNA. Mouse embryonic stem cells and homologous recombination procedures have made it possible to target specific DNA structural alterations to highly localized region in the host chromosomes. The majority of the DNA structural rearrangements in transgenic mice can be passed through the germ line and used to establish new genetic traits in the carrier animals. Since the use of transgenic mice is having such an enormous impact on so many areas of mammalian biological research, including developmental toxicology, the objective of this review is to briefly describe the fundamental methodologies for generating transgenic mice and to describe one particular application that has direct relevance to the field of genetic toxicology.

  8. Transgenic mice in developmental toxicology

    SciTech Connect

    Woychik, R.P.

    1992-12-31

    Advances in molecular biology and embryology are being utilized for the generation of transgenic mice, animals that contain specific additions, deletions, or modifications of genes or sequences in their DNA. Mouse embryonic stem cells and homologous recombination procedures have made it possible to target specific DNA structural alterations to highly localized region in the host chromosomes. The majority of the DNA structural rearrangements in transgenic mice can be passed through the germ line and used to establish new genetic traits in the carrier animals. Since the use of transgenic mice is having such an enormous impact on so many areas of mammalian biological research, including developmental toxicology, the objective of this review is to briefly describe the fundamental methodologies for generating transgenic mice and to describe one particular application that has direct relevance to the field of genetic toxicology.

  9. Characterization of a mouse model overexpressing beta-site APP-cleaving enzyme 2 reveals a new role for BACE2.

    PubMed

    Azkona, G; Amador-Arjona, A; Obradors-Tarragó, C; Varea, E; Arqué, G; Pinacho, R; Fillat, C; de la Luna, S; Estivill, X; Dierssen, M

    2010-03-01

    BACE2 is homologous to BACE1, a beta-secretase that is involved in the amyloidogenic pathway of amyloid precursor protein (APP), and maps to the Down syndrome critical region of chromosome 21. Alzheimer disease neuropathology is common in Down syndrome patients at relatively early ages, and it has thus been speculated that BACE2 co-overexpression with APP would promote the early neurodegenerative phenotype. However, the in vivo function of BACE2 has not yet been elucidated. The aim of the present work has been to analyse the impact of in vivo BACE2 overexpression using a transgenic mouse model. Our results suggest that BACE2 is not involved in the amyloidogenic pathway, cognitive dysfunction or cholinergic degeneration. However, TgBACE2 animals showed increased anxiety-like behaviour along with increased numbers of noradrenergic neurones in locus coeruleus, thus suggesting an unexpected role of BACE2 overexpression.

  10. The Transgenic RNAi Project at Harvard Medical School: Resources and Validation.

    PubMed

    Perkins, Lizabeth A; Holderbaum, Laura; Tao, Rong; Hu, Yanhui; Sopko, Richelle; McCall, Kim; Yang-Zhou, Donghui; Flockhart, Ian; Binari, Richard; Shim, Hye-Seok; Miller, Audrey; Housden, Amy; Foos, Marianna; Randkelv, Sakara; Kelley, Colleen; Namgyal, Pema; Villalta, Christians; Liu, Lu-Ping; Jiang, Xia; Huan-Huan, Qiao; Wang, Xia; Fujiyama, Asao; Toyoda, Atsushi; Ayers, Kathleen; Blum, Allison; Czech, Benjamin; Neumuller, Ralph; Yan, Dong; Cavallaro, Amanda; Hibbard, Karen; Hall, Don; Cooley, Lynn; Hannon, Gregory J; Lehmann, Ruth; Parks, Annette; Mohr, Stephanie E; Ueda, Ryu; Kondo, Shu; Ni, Jian-Quan; Perrimon, Norbert

    2015-11-01

    To facilitate large-scale functional studies in Drosophila, the Drosophila Transgenic RNAi Project (TRiP) at Harvard Medical School (HMS) was established along with several goals: developing efficient vectors for RNAi that work in all tissues, generating a genome-scale collection of RNAi stocks with input from the community, distributing the lines as they are generated through existing stock centers, validating as many lines as possible using RT-qPCR and phenotypic analyses, and developing tools and web resources for identifying RNAi lines and retrieving existing information on their quality. With these goals in mind, here we describe in detail the various tools we developed and the status of the collection, which is currently composed of 11,491 lines and covering 71% of Drosophila genes. Data on the characterization of the lines either by RT-qPCR or phenotype is available on a dedicated website, the RNAi Stock Validation and Phenotypes Project (RSVP, http://www.flyrnai.org/RSVP.html), and stocks are available from three stock centers, the Bloomington Drosophila Stock Center (United States), National Institute of Genetics (Japan), and TsingHua Fly Center (China).

  11. The Transgenic RNAi Project at Harvard Medical School: Resources and Validation

    PubMed Central

    Perkins, Lizabeth A.; Holderbaum, Laura; Tao, Rong; Hu, Yanhui; Sopko, Richelle; McCall, Kim; Yang-Zhou, Donghui; Flockhart, Ian; Binari, Richard; Shim, Hye-Seok; Miller, Audrey; Housden, Amy; Foos, Marianna; Randkelv, Sakara; Kelley, Colleen; Namgyal, Pema; Villalta, Christians; Liu, Lu-Ping; Jiang, Xia; Huan-Huan, Qiao; Wang, Xia; Fujiyama, Asao; Toyoda, Atsushi; Ayers, Kathleen; Blum, Allison; Czech, Benjamin; Neumuller, Ralph; Yan, Dong; Cavallaro, Amanda; Hibbard, Karen; Hall, Don; Cooley, Lynn; Hannon, Gregory J.; Lehmann, Ruth; Parks, Annette; Mohr, Stephanie E.; Ueda, Ryu; Kondo, Shu; Ni, Jian-Quan; Perrimon, Norbert

    2015-01-01

    To facilitate large-scale functional studies in Drosophila, the Drosophila Transgenic RNAi Project (TRiP) at Harvard Medical School (HMS) was established along with several goals: developing efficient vectors for RNAi that work in all tissues, generating a genome-scale collection of RNAi stocks with input from the community, distributing the lines as they are generated through existing stock centers, validating as many lines as possible using RT–qPCR and phenotypic analyses, and developing tools and web resources for identifying RNAi lines and retrieving existing information on their quality. With these goals in mind, here we describe in detail the various tools we developed and the status of the collection, which is currently composed of 11,491 lines and covering 71% of Drosophila genes. Data on the characterization of the lines either by RT–qPCR or phenotype is available on a dedicated website, the RNAi Stock Validation and Phenotypes Project (RSVP, http://www.flyrnai.org/RSVP.html), and stocks are available from three stock centers, the Bloomington Drosophila Stock Center (United States), National Institute of Genetics (Japan), and TsingHua Fly Center (China). PMID:26320097

  12. Presenilin-Based Genetic Screens in Drosophila melanogaster Identify Novel Notch Pathway Modifiers

    PubMed Central

    Mahoney, Matt B.; Parks, Annette L.; Ruddy, David A.; Tiong, Stanley Y. K.; Esengil, Hanife; Phan, Alexander C.; Philandrinos, Panos; Winter, Christopher G.; Chatterjee, Runa; Huppert, Kari; Fisher, William W.; L'Archeveque, Lynn; Mapa, Felipa A.; Woo, Wendy; Ellis, Michael C.; Curtis, Daniel

    2006-01-01

    Presenilin is the enzymatic component of γ-secretase, a multisubunit intramembrane protease that processes several transmembrane receptors, such as the amyloid precursor protein (APP). Mutations in human Presenilins lead to altered APP cleavage and early-onset Alzheimer's disease. Presenilins also play an essential role in Notch receptor cleavage and signaling. The Notch pathway is a highly conserved signaling pathway that functions during the development of multicellular organisms, including vertebrates, Drosophila, and C. elegans. Recent studies have shown that Notch signaling is sensitive to perturbations in subcellular trafficking, although the specific mechanisms are largely unknown. To identify genes that regulate Notch pathway function, we have performed two genetic screens in Drosophila for modifiers of Presenilin-dependent Notch phenotypes. We describe here the cloning and identification of 19 modifiers, including nicastrin and several genes with previously undescribed involvement in Notch biology. The predicted functions of these newly identified genes are consistent with extracellular matrix and vesicular trafficking mechanisms in Presenilin and Notch pathway regulation and suggest a novel role for γ-tubulin in the pathway. PMID:16415372

  13. Presenilin-based genetic screens in Drosophila melanogaster identify novel notch pathway modifiers.

    PubMed

    Mahoney, Matt B; Parks, Annette L; Ruddy, David A; Tiong, Stanley Y K; Esengil, Hanife; Phan, Alexander C; Philandrinos, Panos; Winter, Christopher G; Chatterjee, Runa; Huppert, Kari; Fisher, William W; L'Archeveque, Lynn; Mapa, Felipa A; Woo, Wendy; Ellis, Michael C; Curtis, Daniel

    2006-04-01

    Presenilin is the enzymatic component of gamma-secretase, a multisubunit intramembrane protease that processes several transmembrane receptors, such as the amyloid precursor protein (APP). Mutations in human Presenilins lead to altered APP cleavage and early-onset Alzheimer's disease. Presenilins also play an essential role in Notch receptor cleavage and signaling. The Notch pathway is a highly conserved signaling pathway that functions during the development of multicellular organisms, including vertebrates, Drosophila, and C. elegans. Recent studies have shown that Notch signaling is sensitive to perturbations in subcellular trafficking, although the specific mechanisms are largely unknown. To identify genes that regulate Notch pathway function, we have performed two genetic screens in Drosophila for modifiers of Presenilin-dependent Notch phenotypes. We describe here the cloning and identification of 19 modifiers, including nicastrin and several genes with previously undescribed involvement in Notch biology. The predicted functions of these newly identified genes are consistent with extracellular matrix and vesicular trafficking mechanisms in Presenilin and Notch pathway regulation and suggest a novel role for gamma-tubulin in the pathway.

  14. Structural features of the KPI domain control APP dimerization, trafficking, and processing.

    PubMed

    Ben Khalifa, Naouel; Tyteca, Donatienne; Marinangeli, Claudia; Depuydt, Mathieu; Collet, Jean-François; Courtoy, Pierre J; Renauld, Jean-Christophe; Constantinescu, Stefan; Octave, Jean-Noël; Kienlen-Campard, Pascal

    2012-02-01

    The two major isoforms of human APP, APP695 and APP751, differ by the presence of a Kunitz-type protease inhibitor (KPI) domain in the extracellular region. APP processing and function is thought to be regulated by homodimerization. We used bimolecular fluorescence complementation (BiFC) to study dimerization of different APP isoforms and mutants. APP751 was found to form significantly more homodimers than APP695. Mutation of dimerization motifs in the TM domain did not affect fluorescence complementation, but native folding of KPI is critical for APP751 homodimerization. APP751 and APP695 dimers were mostly localized at steady state in the Golgi region, suggesting that most of the APP751 and 695 dimers are in the secretory pathway. Mutation of the KPI led to the retention of the APP homodimers in the endoplasmic reticulum. We finally showed that APP751 is more efficiently processed through the nonamyloidogenic pathway than APP695. These findings provide new insight on the particular role of KPI domain in APP dimerization. The correlation observed between dimerization, subcellular localization, and processing suggests that dimerization acts as an efficient regulator of APP trafficking in the secretory compartments that has major consequences on its processing.

  15. iPad Apps That Promote Mathematical Knowledge? "Yes, They Exist!"

    ERIC Educational Resources Information Center

    Larkin, Kevin

    2014-01-01

    Having trouble finding the right app? In this article, Kevin Larkin discusses the difficulties teachers encounter when searching the App Store for high quality, appropriate apps that support students' mathematical learning. Kevin provides a useful link to a collection of over 100 app reviews.

  16. The Quality and Accuracy of Mobile Apps to Prevent Driving After Drinking Alcohol

    PubMed Central

    Stoyanov, Stoyan R; Gandabhai, Shailen; Baldwin, Alexander

    2016-01-01

    Background Driving after the consumption of alcohol represents a significant problem globally. Individual prevention countermeasures such as personalized mobile apps aimed at preventing such behavior are widespread, but there is little research on their accuracy and evidence base. There has been no known assessment investigating the quality of such apps. Objective This study aimed to determine the quality and accuracy of apps for drink driving prevention by conducting a review and evaluation of relevant mobile apps. Methods A systematic app search was conducted following PRISMA guidelines. App quality was assessed using the Mobile App Rating Scale (MARS). Apps providing blood alcohol calculators (hereafter “calculators”) were reviewed against current alcohol advice for accuracy. Results A total of 58 apps (30 iOS and 28 Android) met inclusion criteria and were included in the final analysis. Drink driving prevention apps had significantly lower engagement and overall quality scores than alcohol management apps. Most calculators provided conservative blood alcohol content (BAC) time until sober calculations. None of the apps had been evaluated to determine their efficacy in changing either drinking or driving behaviors. Conclusions This novel study demonstrates that most drink driving prevention apps are not engaging and lack accuracy. They could be improved by increasing engagement features, such as gamification. Further research should examine the context and motivations for using apps to prevent driving after drinking in at-risk populations. Development of drink driving prevention apps should incorporate evidence-based information and guidance, lacking in current apps. PMID:27502956

  17. Apps for Highlights: our new column for your health management needs

    PubMed Central

    2016-01-01

    Millions of health and fitness apps are available in online App stores but people are confused about which ones to use and what are the possible benefits of using them. To broaden your understanding about uses and advantages of these mobile apps, every month in this issue, we will focus on a particular health issue and review related mobile apps. PMID:28293593

  18. Bootstrapping Security Policies for Wearable Apps Using Attributed Structural Graphs

    PubMed Central

    González-Tablas, Ana I.; Tapiador, Juan E.

    2016-01-01

    We address the problem of bootstrapping security and privacy policies for newly-deployed apps in wireless body area networks (WBAN) composed of smartphones, sensors and other wearable devices. We introduce a framework to model such a WBAN as an undirected graph whose vertices correspond to devices, apps and app resources, while edges model structural relationships among them. This graph is then augmented with attributes capturing the features of each entity together with user-defined tags. We then adapt available graph-based similarity metrics to find the closest app to a new one to be deployed, with the aim of reusing, and possibly adapting, its security policy. We illustrate our approach through a detailed smartphone ecosystem case study. Our results suggest that the scheme can provide users with a reasonably good policy that is consistent with the user’s security preferences implicitly captured by policies already in place. PMID:27187385

  19. NASA Viz iPad App Expands Coverage Across Universe

    NASA Video Gallery

    The NASA Visualization Explorer app has broadened its scope to includemore awe-inspiring discoveries beamed back to Earth from the agency'sentire fleet of satellites, spacecraft and space tele...

  20. Bootstrapping Security Policies for Wearable Apps Using Attributed Structural Graphs.

    PubMed

    González-Tablas, Ana I; Tapiador, Juan E

    2016-05-11

    We address the problem of bootstrapping security and privacy policies for newly-deployed apps in wireless body area networks (WBAN) composed of smartphones, sensors and other wearable devices. We introduce a framework to model such a WBAN as an undirected graph whose vertices correspond to devices, apps and app resources, while edges model structural relationships among them. This graph is then augmented with attributes capturing the features of each entity together with user-defined tags. We then adapt available graph-based similarity metrics to find the closest app to a new one to be deployed, with the aim of reusing, and possibly adapting, its security policy. We illustrate our approach through a detailed smartphone ecosystem case study. Our results suggest that the scheme can provide users with a reasonably good policy that is consistent with the user's security preferences implicitly captured by policies already in place.

  1. Transgenic plants for phytoremediation.

    PubMed

    Maestri, Elena; Marmiroli, Nelson

    2011-01-01

    Phytoremediation is a green, sustainable and promising solution to problems of environmental contamination. It entails the use of plants for uptake, sequestration, detoxification or volatilization of inorganic and organic pollutants from soils, water, sediments and possibly air. Phytoremediation was born from the observation that plants possessed physiological properties useful for environmental remediation. This was shortly followed by the application of breeding techniques and artificial selection to genetically improve some of the more promising and interesting species. Now, after nearly 20 years of research, transgenic plants for phytoremediation have been produced, but none have reached commercial existence. Three main approaches have been developed: (1) transformation with genes from other organisms (mammals, bacteria, etc.); (2) transformation with genes from other plant species; and (3) overexpression of genes from the same plant species. Many encouraging results have been reported, even though in some instances results have been contrary to expectations. This review will illustrate the main examples with a critical discussion of what we have learnt from them.

  2. Melanoma detection using a mobile phone app

    NASA Astrophysics Data System (ADS)

    Diniz, Luciano E.; Ennser, K.

    2016-03-01

    Mobile phones have had their processing power greatly increased since their invention a few decades ago. As a direct result of Moore's Law, this improvement has made available several applications that were impossible before. The aim of this project is to develop a mobile phone app, integrated with its camera coupled to an amplifying lens, to help distinguish melanoma. The proposed device has the capability of processing skin mole images and suggesting, using a score system, if it is a case of melanoma or not. This score system is based on the ABCDE signs of melanoma, and takes into account the area, the perimeter and the colors present in the nevus. It was calibrated and tested using images from the PH2 Dermoscopic Image Database from Pedro Hispano Hospital. The results show that the system created can be useful, with an accuracy of up to 100% for malign cases and 80% for benign cases (including common and atypical moles), when used in the test group.

  3. A Comparative Study of Drosophila and Human A-Type Lamins

    PubMed Central

    Schulze, Sandra R.; Curio-Penny, Beatrice; Speese, Sean; Dialynas, George; Cryderman, Diane E.; McDonough, Caitrin W.; Nalbant, Demet; Petersen, Melissa; Budnik, Vivian; Geyer, Pamela K.; Wallrath, Lori L.

    2009-01-01

    Nuclear intermediate filament proteins, called lamins, form a meshwork that lines the inner surface of the nuclear envelope. Lamins contain three domains: an N-terminal head, a central rod and a C-terminal tail domain possessing an Ig-fold structural motif. Lamins are classified as either A- or B-type based on structure and expression pattern. The Drosophila genome possesses two genes encoding lamins, Lamin C and lamin Dm0, which have been designated A- and B-type, respectively, based on their expression profile and structural features. In humans, mutations in the gene encoding A-type lamins are associated with a spectrum of predominantly tissue-specific diseases known as laminopathies. Linking the disease phenotypes to cellular functions of lamins has been a major challenge. Drosophila is being used as a model system to identify the roles of lamins in development. Towards this end, we performed a comparative study of Drosophila and human A-type lamins. Analysis of transgenic flies showed that human lamins localize predictably within the Drosophila nucleus. Consistent with this finding, yeast two-hybrid data demonstrated conservation of partner-protein interactions. Drosophila lacking A-type lamin show nuclear envelope defects similar to those observed with human laminopathies. Expression of mutant forms of the A-type Drosophila lamin modeled after human disease-causing amino acid substitutions revealed an essential role for the N-terminal head and the Ig-fold in larval muscle tissue. This tissue-restricted sensitivity suggests a conserved role for lamins in muscle biology. In conclusion, we show that (1) localization of A-type lamins and protein-partner interactions are conserved between Drosophila and humans, (2) loss of the Drosophila A-type lamin causes nuclear defects and (3) muscle tissue is sensitive to the expression of mutant forms of A-type lamin modeled after those causing disease in humans. These studies provide new insights on the role of lamins in

  4. Genetic control of cadmium tolerance in Drosophila melanogaster

    SciTech Connect

    Maroni, G.; Ann-Shu Ho; Theodore, L.

    1995-12-01

    Flies from a transgenic line of Drosophila melanogaster with two copies of the metallothionein allele Mtn{sup 3} were more tolerant to cadmium than strains with only one copy of the gene. However, flies with the Mtn{sup 3} allele were as tolerant as flies with the Mtn{sup 1} allele, despite the level of expression of Mtn{sup {minus}3} allele were as tolerant as flies with the Mtn{sup 1} allele, despite the level of expression of Mtn{sup 1} being three times higher than that of Mtn{sup {minus}3}. We propose that the substitution of Lys-40 (in Mtn{sup 3}) for Glu-40 (in Mtn{sup 1}) accounts for a reduction in binding affinity of Mtn{sup 1}, which offsets the increased expression levels. 6 refs., 3 figs., 2 tabs.

  5. Epigenetic stability increases extensively during Drosophila follicle stem cell differentiation.

    PubMed

    Skora, Andrew D; Spradling, Allan C

    2010-04-20

    Stem and embryonic cells facilitate programming toward multiple daughter cell fates, whereas differentiated cells resist reprogramming and oncogenic transformation. How alterations in the chromatin-based machinery of epigenetic inheritance contribute to these differences remains poorly known. We observed random, heritable changes in GAL4/UAS transgene programming during Drosophila ovarian follicle stem cell differentiation and used them to measure the stage-specific epigenetic stability of gene programming. The frequency of GAL4/UAS reprogramming declines more than 100-fold over the nine divisions comprising this stem cell lineage. Stabilization acts in cis, suggesting that it is chromatin-based, and correlates with increased S phase length. Our results suggest that stem/early progenitor cells cannot accurately transmit nongenetic information to their progeny; full epigenetic competence is acquired only gradually during early differentiation. Modulating epigenetic inheritance may be a critical process controlling transitions between the pleuripotent and differentiated states.

  6. Scientific Apps are here (and more will be coming).

    PubMed

    Young, Howard A

    2012-07-01

    The world of Apps is now well upon us although the application of this tool was a bit slow in coming to the scientific community. In this column I will briefly take a look at some of the Apps now available that are applicable to biomedical research. I will restrict my coverage to the Apple format, not because I am totally an Apple user (my PC is a Dell) but only because I do not have an Android device.

  7. Predictors of Utilization of a Novel Smoking Cessation Smartphone App

    PubMed Central

    Zeng, Emily Y.; Vilardaga, Roger; Heffner, Jaimee L.; Mull, Kristin E.

    2015-01-01

    Abstract Background: Understanding the characteristics of high and low utilizers of smartphone applications (apps) for smoking cessation would inform development of more engaging and effective apps, yet no studies to date have addressed this critical question. Informed by prior research on predictors of cessation Web site utilization, this study examines the degree to which baseline demographic factors (gender, age, and education), smoking-related factors (smoking level and friends' smoking), and psychological factors (depression and anxiety) are predictive of utilization of a smartphone app for smoking cessation called SmartQuit. Materials and Methods: Data came from 98 participants randomized to SmartQuit as part of a pilot trial from March to May 2013. We used negative binomial count regressions to examine the relationship between user characteristics and utilization of the app over an 8-week treatment period. Results: Lower education (risk ratio [RR]=0.492; p=0.021), heavier smoking (RR=0.613; p=0.033), and depression (RR=0.958; p=0.017) prospectively predicted lower app utilization. Women (RR=0.320; p=0.022), those with lower education (RR=0.491; p=0.013), and heavier smokers (RR=0.418; p=0.039) had lower utilization of app features known to predict smoking cessation. Conclusions: Many of the predictors of utilization of smoking cessation apps are the same as those of cessation Web sites. App-delivered smoking cessation treatment effectiveness could be enhanced by focusing on increasing engagement of women, those with lower education, heavy smokers, and those with current depressive symptoms. PMID:26171733

  8. A review of smartphone apps for smoking cessation available in Portuguese.

    PubMed

    Formagini, Taynara Dutra Batista; Ervilha, Rafaela Russi; Machado, Nathália Munck; Andrade, Bárbara Any Bianchi Bottaro de; Gomide, Henrique Pinto; Ronzani, Telmo Mota

    2017-03-09

    Smartphone apps are being developed as a complement to smoking cessation treatment. The current study aimed to analyze the content of available apps in Portuguese in two operational systems, Android and iOS. Fifty-one apps were found in iTunes and 600 in Google Play. Content evaluation included apps that focused on smoking cessation, with a total of 12 apps in iOS and 3 in Android. Each app was categorized according to its approach to smoking cessation and scored according to level of adherence to the Treating Tobacco Use and Dependence smoking cessation treatment guideline. Nine apps were classified as calendars, 8 as information tools, 6 as calculators, 3 as cigarette trackers, and 1 as hypnosis. The apps showed low level of adherence to the guideline, with a mean score of 12.8. We recommend that the available apps be revised and that future apps be developed using evidence-based practices for smoking cessation.

  9. The effect of focal brain injury on beta-amyloid plaque deposition, inflammation and synapses in the APP/PS1 mouse model of Alzheimer's disease.

    PubMed

    Collins, Jessica M; King, Anna E; Woodhouse, Adele; Kirkcaldie, Matthew T K; Vickers, James C

    2015-05-01

    Traumatic brain injury is a risk factor for Alzheimer's disease (AD), however the effect of such neural damage on the onset and progression of beta-amyloid (Aβ) plaque pathology is not well understood. This study utilized an in vivo model of focal brain injury to examine how localized damage may acutely affect the onset and progression of Aβ plaque deposition as well as inflammatory and synaptic changes, in the APP/PS1 (APPSWE, PSEN1dE9) transgenic model of AD relative to wild-type (Wt) mice. Acute focal brain injury in 3- and 9-month-old APP/PS1 and Wt mice was induced by insertion of a needle into the somatosensory neocortex, as compared to sham surgery, and examined at 24h and 7d post-injury (PI). Focal brain injury did not induce thioflavine-S stained or (pan-Aβ antibody) MOAB-2-labeled plaques at either 24h or 7d PI in 3-month-old APP/PS1 mice or Wt mice. Nine-month-old APP/PS1 mice demonstrate cortical Aβ plaques but focal injury had no statistically significant (p>0.05) effect on thioflavine-S or MOAB-2 plaque load surrounding the injury site at 24h PI or 7d PI. There was a significant (p<0.001) increase in cross-sectional cortical area occupied by Iba-1 positive microglia in injured mice compared to sham animals, however this response did not differ between APP/PS1 and Wt mice (p>0.05). For both Wt and APP/PS1 mice alike, synaptophysin puncta near the injury site were significantly reduced 24h PI (compared to sites distant to the injury and the corresponding area in sham mice; p<0.01), but not after 7d PI (p>0.05). There was no significant effect of genotype on this response (p>0.05). These results indicate that focal brain injury and the associated microglial response do not acutely alter Aβ plaque deposition in the APP/PS1 mouse model. Furthermore the current study demonstrated that the brains of both Wt and APP/PS1 mice are capable of recovering lost synaptophysin immunoreactivity post-injury, the latter in the presence of Aβ plaque pathology that

  10. User characteristics of a smartphone app to reduce alcohol consumption.

    PubMed

    Garnett, Claire; Crane, David; West, Robert; Michie, Susan; Brown, Jamie; Winstock, Adam

    2017-03-17

    Digital interventions are available to help people reduce their alcohol consumption, but it is not known who uses these interventions and how this treatment-seeking group compares with the general population of drinkers. The study objective was to compare the socio-demographic and drinking characteristics of users of the 'Drinks Meter' smartphone app with the general population of drinkers in England and website users of the same intervention. Data were used from the Drinks Meter app and website, and a nationally representative cross-sectional survey in England (Alcohol Toolkit Study). Participants were drinkers aged 16+ in England. Data were collected on participants' age, gender, region, sexual orientation, social grade and AUDIT score. Regression analyses were conducted to assess differences in socio-demographic and drinking characteristics between samples. Drinks Meter app users, compared with drinkers of the general population, were younger, more likely to be from the South, not heterosexual, less likely to be of a lower social grade and had a higher mean AUDIT score. Drinks Meter app users were younger than website users and reported greater alcohol consumption and related harms. Drinkers using the Drinks Meter app are more likely to be younger and report greater alcohol consumption and related harms compared with the general population of drinkers in England and website users of the same intervention. Apps that provide feedback on drinking appear to be reaching those who report greater alcohol consumption and related harms.

  11. ReadyVax: A new mobile vaccine information app.

    PubMed

    Bednarczyk, Robert A; Frew, Paula M; Salmon, Daniel A; Whitney, Ellen; Omer, Saad B

    2017-01-06

    Vaccine information of varying quality is available through many different sources. We describe the creation, release and utilization of ReadyVax, a new mobile smartphone app providing access to trustworthy, evidence-based vaccine information for a target audience of healthcare providers, pharmacists, and patients (including parents of children). We describe the information content and technical development of ReadyVax. Between the hard launch of the app on February 12, 2015 and October 8, 2016, the app has been downloaded by 5,142 unique users, with 6,841 total app sessions initiated, comprising a total of 15,491 screen views (2.3 screens/session on average). ReadyVax has been downloaded by users in 102 different countries; most users (52%) are from the United States. We are continuing outreach efforts to increase app use, and planning for development of an Android-compatible version of ReadyVax, to increase the available market for the app.

  12. The Analysis Of Smartphone Apps In Geomatics Education

    NASA Astrophysics Data System (ADS)

    Teo, T.-A.; Wu, H.-M.; Shih, T.-Y.; Tsai, F.

    2014-04-01

    Geomatics is a discipline of collecting, processing and analysing geospatial data. Data collection is a core process of geomatics which usually adopt precise equipment to measure geospatial data. With the development of technology, a smartphone in this present era is not simply for communication; several low cost measurement devices such as Global Positioning System (GPS), gyro and camera are assembled in a smartphone. Although the devices assembled in a smartphone could not meet the needs of accuracy requirement for many geomatics applications, millions of mobile applications (Apps) can be downloaded and installed from Google Play and Apple Store freely, and a variety of sensors can be chosen for user. Considering that the popularity and convenience of a smartphone, and assuming that the accuracy of those collected data is acceptable for learning purposes, it is expected that a smartphone can be employed in geomatics for hand-on education. For example, Vespucci OSM Editor is an App to edit the OpenStreetMap on Android. The user may have the hand-on experience on GPS positioning, web services and mapping via Vespucci OSM Editor. The aim of this paper is to collect and analyze different Apps for geomatics education. The Apps are classified into four categories, namely, surveying, remote sensing, GPS and Geographic Information System (GIS). In this paper, more than 20 free Apps are collected and analysed for different hand-on studies in geomatics education. Finally, all the related Apps are listed on a website for updating.

  13. Genome of Drosophila suzukii, the Spotted Wing Drosophila

    PubMed Central

    Chiu, Joanna C.; Jiang, Xuanting; Zhao, Li; Hamm, Christopher A.; Cridland, Julie M.; Saelao, Perot; Hamby, Kelly A.; Lee, Ernest K.; Kwok, Rosanna S.; Zhang, Guojie; Zalom, Frank G.; Walton, Vaughn M.; Begun, David J.

    2013-01-01

    Drosophila suzukii Matsumura (spotted wing drosophila) has recently become a serious pest of a wide variety of fruit crops in the United States as well as in Europe, leading to substantial yearly crop losses. To enable basic and applied research of this important pest, we sequenced the D. suzukii genome to obtain a high-quality reference sequence. Here, we discuss the basic properties of the genome and transcriptome and describe patterns of genome evolution in D. suzukii and its close relatives. Our analyses and genome annotations are presented in a web portal, SpottedWingFlyBase, to facilitate public access. PMID:24142924

  14. Nursing Central app Nursing Central app One-year subscription $169.95/£104 [Formula: see text].

    PubMed

    2013-12-04

    Nursing Central is a comprehensive mobile and web-aligned American app providing detailed information on diseases, tests, procedures, medicines and access to a range of evidence-based nursing journals and resources.

  15. The LH/CG receptor activates canonical signaling pathway when expressed in Drosophila.

    PubMed

    Graves, Justin; Markman, Svetlana; Alegranti, Yair; Gechtler, Jenia; Johnson, Ruth I; Cagan, Ross; Ben-Menahem, David

    2015-09-15

    G-protein coupled receptors (GPCRs) and their ligands provide precise tissue regulation and are therefore often restricted to specific animal phyla. For example, the gonadotropins and their receptors are crucial for vertebrate reproduction but absent from invertebrates. In mammals, LHR mainly couples to the PKA signaling pathway, and CREB is the major transcription factor of this pathway. Here we present the results of expressing elements of the human gonadotropin system in Drosophila. Specifically, we generated transgenic Drosophila expressing the human LH/CG receptor (denoted as LHR), a constitutively active form of LHR, and an hCG analog. We demonstrate activation-dependent signaling by LHR to direct Drosophila phenotypes including lethality and specific midline defects; these phenotypes were due to LHR activation of PKA/CREB pathway activity. That the LHR can act in an invertebrate demonstrates the conservation of factors required for GPCR function among phylogenetically distant organisms. This novel gonadotropin model may assist the identification of new modulators of mammalian fertility by exploiting the powerful genetic and pharmacological tools available in Drosophila.

  16. Organelle Transport in Cultured Drosophila Cells: S2 Cell Line and Primary Neurons.

    PubMed Central

    Gelfand, Vladimir I.

    2013-01-01

    Drosophila S2 cells plated on a coverslip in the presence of any actin-depolymerizing drug form long unbranched processes filled with uniformly polarized microtubules. Organelles move along these processes by microtubule motors. Easy maintenance, high sensitivity to RNAi-mediated protein knock-down and efficient procedure for creating stable cell lines make Drosophila S2 cells an ideal model system to study cargo transport by live imaging. The results obtained with S2 cells can be further applied to a more physiologically relevant system: axonal transport in primary neurons cultured from dissociated Drosophila embryos. Cultured neurons grow long neurites filled with bundled microtubules, very similar to S2 processes. Like in S2 cells, organelles in cultured neurons can be visualized by either organelle-specific fluorescent dyes or by using fluorescent organelle markers encoded by DNA injected into early embryos or expressed in transgenic flies. Therefore, organelle transport can be easily recorded in neurons cultured on glass coverslips using living imaging. Here we describe procedures for culturing and visualizing cargo transport in Drosophila S2 cells and primary neurons. We believe that these protocols make both systems accessible for labs studying cargo transport. PMID:24300413

  17. A Systematic Analysis of Drosophila Regulatory Peptide Expression in Enteroendocrine Cells.

    PubMed

    Chen, Ji; Kim, Seol-Min; Kwon, Jae Young

    2016-04-30

    The digestive system is gaining interest as a major regulator of various functions including immune defense, nutrient accumulation, and regulation of feeding behavior, aside from its conventional function as a digestive organ. The Drosophila midgut epithelium is completely renewed every 1-2 weeks due to differentiation of pluripotent intestinal stem cells in the midgut. Intestinal stem cells constantly divide and differentiate into enterocytes that secrete digestive enzymes and absorb nutrients, or enteroendocrine cells that secrete regulatory peptides. Regulatory peptides have important roles in development and metabolism, but study has mainly focused on expression and functions in the nervous system, and not much is known about the roles in endocrine functions of enteroendocrine cells. We systemically examined the expression of 45 regulatory peptide genes in the Drosophila midgut, and verified that at least 10 genes are expressed in the midgut enteroendocrine cells through RT-PCR, in situ hybridization, antisera, and 25 regulatory peptide-GAL transgenes. The Drosophila midgut is highly compartmentalized, and individual peptides in enteroendocrine cells were observed to express in specific regions of the midgut. We also confirmed that some peptides expressed in the same region of the midgut are expressed in mutually exclusive enteroendocrine cells. These results indicate that the midgut enteroendocrine cells are functionally differentiated into different subgroups. Through this study, we have established a basis to study regulatory peptide functions in enteroendocrine cells as well as the complex organization of enteroendocrine cells in the Drosophila midgut.

  18. Production of polyclonal anti-dUCH (Drosophila ubiquitin carboxyl-terminal hydrolase) antibodies.

    PubMed

    Tram, Nguyen Thi Quynh; Trang, Nguyen Thi Thu; Thao, Dang Thi Phuong; Thuoc, Tran Linh

    2013-04-01

    Ubiquitin carboxyl-terminal hydrolase L1 (UCH-L1), which is a member of the ubiquitin carboxyl-terminal hydrolase (UCH) family, is highly expressed in neurons. In vitro, UCH- L1 exhibits both ubiquitin hydrolase and ligase activity. Many studies have suggested that UCH-L1 is involved in the pathogenesis of Parkinson's disease and some different human cancer diseases, but its role in a living system is still unclear. Recently, Drosophila melanogaster has been shown to be a compatible model for studying human diseases. To investigate the role of UCH-L1 in a living system, the UCH-L1 homologous protein in Drosophila melanogaster (dUCH) is used for analyzing the role of the protein's function in transgenic Drosophila. Here, we used DNA molecular techniques to clone, express, and purify dUCH protein from Escherichia coli. The purified dUCH protein was injected into a rabbit to produce an anti-dUCH antibody, which was shown to have high specificity and sensitivity to the dUCH protein. The affinity of the antibody is 1:320,000 at 7.81 ng/μL antigen concentration. The 1:40,000 dilution-produced antibodies can detect antigen at a low concentration of 0.98 ng/μL. Success in producing this antibody provides good material for further experiments in the study of the role of UCH-L1 by a Drosophila model.

  19. The genetic basis of pigmentation differences within and between Drosophila species

    PubMed Central

    Massey, Jonathan; Wittkopp, Patricia J.

    2016-01-01

    In Drosophila, as well as in many other plants and animals, pigmentation is highly variable both within and between species. This variability, combined with powerful genetic and transgenic tools as well as knowledge of how pigment patterns are formed biochemically and developmentally, have made Drosophila pigmentation a premier system for investigating the genetic and molecular mechanisms responsible for phenotypic evolution. In this chapter, we review and synthesize findings from a rapidly growing body of case studies examining the genetic basis of pigmentation differences in the abdomen, thorax, wings, and pupal cases within and between Drosophila species. A core set of genes, including genes required for pigment synthesis (e.g., yellow, ebony, tan, Dat) as well as developmental regulators of these genes (e.g., bab1, bab2, omb, Dll, and wg) emerge as the primary sources of this variation, with most genes having been shown to contribute to pigmentation differences both within and between species. In cases where specific genetic changes contributing to pigmentation divergence were identified in these genes, the changes were always located in noncoding sequences and affected cis-regulatory activity. We conclude this chapter by discussing these and other lessons learned from evolutionary genetic studies of Drosophila pigmentation and identify topics we think should be the focus of future work with this model system. PMID:27282023

  20. Mobile Apps in Oncology: A Survey on Health Care Professionals’ Attitude Toward Telemedicine, mHealth, and Oncological Apps

    PubMed Central

    Schmidt-Graf, Friederike; Combs, Stephanie E

    2016-01-01

    Background Mobile apps are an evolving trend in the medical field. To date, few apps in an oncological context exist. Objective The aim was to analyze the attitude of health care professionals (HCPs) toward telemedicine, mHealth, and mobile apps in the field of oncology. Methods We developed and conducted an online survey with 24 questions evaluating HCPs’ general attitude toward telemedicine and patients using medical mobile apps. Specific questions on the possible functionality for patients and the resulting advantages and disadvantages for both the patients’ and HCPs’ daily clinical routine were evaluated. Results A total of 108 HCPs completed the survey. In all, 88.9% (96/108) considered telemedicine useful and 84.3% (91/108) supported the idea of an oncological app complementing classical treatment. Automatic reminders, timetables, and assessment of side effects and quality of life during therapy were rated as the most important functions. In contrast, uncertainty regarding medical responsibility and data privacy were reasons mostly named by critics. Most (64.8%, 70/108) were in favor of an alert function due to data input needing further clarification, and 94% (66/70) were willing to contact the patient after a critical alert. In all, 93.5% (101/108) supported the idea of using the collected data for scientific research. Moreover, 75.0% (81/108) believed establishing a mobile app could be beneficial for the providing hospital. Conclusions A majority of HCPs are in favor of telemedicine and the use of oncological apps by patients. Assessing side effects can lead to quicker response and thus lower inconvenience for patients. Clinical data, such as life quality and treatment satisfaction, could be used to evaluate and improve the therapy workflow. Eventually, a mobile app would enhance the patients’ relationship to their treating department because they are in permanent contact. PMID:27884810

  1. The Drosophila Helicase MLE Targets Hairpin Structures in Genomic Transcripts

    PubMed Central

    Cugusi, Simona; Li, Yujing; Jin, Peng; Lucchesi, John C.

    2016-01-01

    RNA hairpins are a common type of secondary structures that play a role in every aspect of RNA biochemistry including RNA editing, mRNA stability, localization and translation of transcripts, and in the activation of the RNA interference (RNAi) and microRNA (miRNA) pathways. Participation in these functions often requires restructuring the RNA molecules by the association of single-strand (ss) RNA-binding proteins or by the action of helicases. The Drosophila MLE helicase has long been identified as a member of the MSL complex responsible for dosage compensation. The complex includes one of two long non-coding RNAs and MLE was shown to remodel the roX RNA hairpin structures in order to initiate assembly of the complex. Here we report that this function of MLE may apply to the hairpins present in the primary RNA transcripts that generate the small molecules responsible for RNA interference. Using stocks from the Transgenic RNAi Project and the Vienna Drosophila Research Center, we show that MLE specifically targets hairpin RNAs at their site of transcription. The association of MLE at these sites is independent of sequence and chromosome location. We use two functional assays to test the biological relevance of this association and determine that MLE participates in the RNAi pathway. PMID:26752049

  2. Critical roles of long noncoding RNAs in Drosophila spermatogenesis

    PubMed Central

    Wen, Kejia; Yang, Lijuan; Xiong, Tuanlin; Di, Chao; Ma, Danhui; Wu, Menghua; Xue, Zhaoyu; Zhang, Xuedi; Long, Li; Zhang, Weimin; Zhang, Jiaying; Bi, Xiaolin; Dai, Junbiao; Zhang, Qiangfeng; Lu, Zhi John; Gao, Guanjun

    2016-01-01

    Long noncoding RNAs (lncRNAs), a recently discovered class of cellular RNAs, play important roles in the regulation of many cellular developmental processes. Although lncRNAs have been systematically identified in various systems, most of them have not been functionally characterized in vivo in animal models. In this study, we identified 128 testis-specific Drosophila lncRNAs and knocked out 105 of them using an optimized three-component CRISPR/Cas9 system. Among the lncRNA knockouts, 33 (31%) exhibited a partial or complete loss of male fertility, accompanied by visual developmental defects in late spermatogenesis. In addition, six knockouts were fully or partially rescued by transgenes in a trans configuration, indicating that those lncRNAs primarily work in trans. Furthermore, gene expression profiles for five lncRNA mutants revealed that testis-specific lncRNAs regulate global gene expression, orchestrating late male germ cell differentiation. Compared with coding genes, the testis-specific lncRNAs evolved much faster. Moreover, lncRNAs of greater functional importance exhibited higher sequence conservation, suggesting that they are under constant evolutionary selection. Collectively, our results reveal critical functions of rapidly evolving testis-specific lncRNAs in late Drosophila spermatogenesis. PMID:27516619

  3. Systems neuroscience in Drosophila: Conceptual and technical advantages.

    PubMed

    Kazama, H

    2015-06-18

    The fruit fly Drosophila melanogaster is ideally suited for investigating the neural circuit basis of behavior. Due to the simplicity and genetic tractability of the fly brain, neurons and circuits are identifiable across animals. Additionally, a large set of transgenic lines has been developed with the aim of specifically labeling small subsets of neurons and manipulating them in sophisticated ways. Electrophysiology and imaging can be applied in behaving individuals to examine the computations performed by each neuron, and even the entire population of relevant neurons in a particular region, because of the small size of the brain. Moreover, a rich repertoire of behaviors that can be studied is expanding to include those requiring cognitive abilities. Thus, the fly brain is an attractive system in which to explore both computations and mechanisms underlying behavior at levels spanning from genes through neurons to circuits. This review summarizes the advantages Drosophila offers in achieving this objective. A recent neurophysiology study on olfactory behavior is also introduced to demonstrate the effectiveness of these advantages.

  4. Taste and pheromone perception in the fruit fly Drosophila melanogaster.

    PubMed

    Ebbs, Michelle L; Amrein, Hubert

    2007-08-01

    Taste is an essential sense for detection of nutrient-rich food and avoidance of toxic substances. The Drosophila melanogaster gustatory system provides an excellent model to study taste perception and taste-elicited behaviors. "The fly" is unique in the animal kingdom with regard to available experimental tools, which include a wide repertoire of molecular-genetic analyses (i.e., efficient production of transgenics and gene knockouts), elegant behavioral assays, and the possibility to conduct electrophysiological investigations. In addition, fruit flies, like humans, recognize sugars as a food source, but avoid bitter tasting substances that are often toxic to insects and mammals alike. This paper will present recent research progress in the field of taste and contact pheromone perception in the fruit fly. First, we shall describe the anatomical properties of the Drosophila gustatory system and survey the family of taste receptors to provide an appropriate background. We shall then review taste and pheromone perception mainly from a molecular genetic perspective that includes behavioral, electrophysiological and imaging analyses of wild type flies and flies with genetically manipulated taste cells. Finally, we shall provide an outlook of taste research in this elegant model system for the next few years.

  5. Analysis of chromatin boundary activity in Drosophila cells

    PubMed Central

    Li, Mo; Belozerov, Vladimir E; Cai, Haini N

    2008-01-01

    Background Chromatin boundaries, also known as insulators, regulate gene activity by organizing active and repressive chromatin domains and modulate enhancer-promoter interactions. However, the mechanisms of boundary action are poorly understood, in part due to our limited knowledge about insulator proteins, and a shortage of standard assays by which diverse boundaries could be compared. Results We report here the development of an enhancer-blocking assay for studying insulator activity in Drosophila cultured cells. We show that the activities of diverse Drosophila insulators including suHw, SF1, SF1b, Fab7 and Fab8 are supported in these cells. We further show that double stranded RNA (dsRNA)-mediated knockdown of SuHw and dCTCF factors disrupts the enhancer-blocking function of suHw and Fab8, respectively, thereby establishing the effectiveness of using RNA interference in our cell-based assay for probing insulator function. Conclusion The novel boundary assay provides a quantitative and efficient method for analyzing insulator mechanism and can be further exploited in genome-wide RNAi screens for insulator components. It provides a useful tool that complements the transgenic and genetic approaches for studying this important class of regulatory elements. PMID:19077248

  6. Jupiter, a new Drosophila protein associated with microtubules.

    PubMed

    Karpova, Nina; Bobinnec, Yves; Fouix, Sylvaine; Huitorel, Philippe; Debec, Alain

    2006-05-01

    In this study we describe a novel Drosophila protein Jupiter, which shares properties with several structural microtubule-associated proteins (MAPs) including TAU, MAP2, MAP4. Jupiter is a soluble unfolded molecule with the high net positive charge, rich in Glycine. It possesses two degenerated repeats around the sequence PPGG, separated by a Serine-rich region. Jupiter associates with microtubules in vitro and, fused with the green fluorescent protein (GFP), is an excellent marker to follow microtubule dynamics in vivo. In a jupiter transgenic Drosophila strain generated by the "protein-trap" technique, Jupiter:GFP fusion protein localizes to the microtubule network through the cell cycle at the different stages of development. We found particularly high Jupiter:GFP concentrations in the young embryo, larval nervous system, precursors of eye photoreceptors and adult ovary. Moreover, from jupiter:gfp embryos we have established two permanent cell lines presenting strongly fluorescent microtubules during the whole cell cycle. In these cells, the distribution of the Jupiter:GFP fusion protein reproduces microtubule behavior upon treatment by the drugs colchicine and taxol. The jupiter cell lines and fly strain should be of wide interest for biologists interested in in vivo analysis of microtubule dynamics.

  7. Cooperativity, specificity, and evolutionary stability of Polycomb targeting in Drosophila.

    PubMed

    Schuettengruber, Bernd; Oded Elkayam, Noa; Sexton, Tom; Entrevan, Marianne; Stern, Shani; Thomas, Aubin; Yaffe, Eitan; Parrinello, Hugues; Tanay, Amos; Cavalli, Giacomo

    2014-10-09

    Metazoan genomes are partitioned into modular chromosomal domains containing active or repressive chromatin. In flies, Polycomb group (PcG) response elements (PREs) recruit PHO and other DNA-binding factors and act as nucleation sites for the formation of Polycomb repressive domains. The sequence specificity of PREs is not well understood. Here, we use comparative epigenomics and transgenic assays to show that Drosophila domain organization and PRE specification are evolutionarily conserved despite significant cis-element divergence within Polycomb domains, whereas cis-element evolution is strongly correlated with transcription factor binding divergence outside of Polycomb domains. Cooperative interactions of PcG complexes and their recruiting factor PHO stabilize PHO recruitment to low-specificity sequences. Consistently, PHO recruitment to sites within Polycomb domains is stabilized by PRC1. These data suggest that cooperative rather than hierarchical interactions among low-affinity sequences, DNA-binding factors, and the Polycomb machinery are giving rise to specific and strongly conserved 3D structures in Drosophila.

  8. Why Drosophila to Study Phototransduction?

    PubMed Central

    Pak, William L.

    2010-01-01

    This review recounts the early history of Drosophila phototransduction genetics, covering the period between approximately 1966 to 1979. Early in this period, the author felt that there was an urgent need for a new approach in phototransduction research. Through inputs from a number of colleagues, he was led to consider isolating Drosophila mutants that are defective in the electroretinogram. Thanks to the efforts of dedicated associates and technical staff, by the end of this period, he was able to accumulate a large number of such mutants. Particularly important in this effort was the use of the mutant assay protocol based on the “prolonged depolarizing afterpotential.” This collection of mutants formed the basis of the subsequent intensive investigations of the Drosophila phototransduction cascade by many investigators. PMID:20536286

  9. Genetic Modifiers of MeCP2 Function in Drosophila

    PubMed Central

    Cukier, Holly N.; Perez, Alma M.; Collins, Ann L.; Zhou, Zhaolan; Zoghbi, Huda Y.; Botas, Juan

    2008-01-01

    The levels of methyl-CpG–binding protein 2 (MeCP2) are critical for normal post-natal development and function of the nervous system. Loss of function of MeCP2, a transcriptional regulator involved in chromatin remodeling, causes classic Rett syndrome (RTT) as well as other related conditions characterized by autism, learning disabilities, or mental retardation. Increased dosage of MeCP2 also leads to clinically similar neurological disorders and mental retardation. To identify molecular mechanisms capable of compensating for altered MeCP2 levels, we generated transgenic Drosophila overexpressing human MeCP2. We find that MeCP2 associates with chromatin and is phosphorylated at serine 423 in Drosophila, as is found in mammals. MeCP2 overexpression leads to anatomical (i.e., disorganized eyes, ectopic wing veins) and behavioral (i.e., motor dysfunction) abnormalities. We used a candidate gene approach to identify genes that are able to compensate for abnormal phenotypes caused by MeCP2 increased activity. These genetic modifiers include other chromatin remodeling genes (Additional sex combs, corto, osa, Sex combs on midleg, and trithorax), the kinase tricornered, the UBE3A target pebble, and Drosophila homologues of the MeCP2 physical interactors Sin3a, REST, and N-CoR. These findings demonstrate that anatomical and behavioral phenotypes caused by MeCP2 activity can be ameliorated by altering other factors that might be more amenable to manipulation than MeCP2 itself. PMID:18773074

  10. Modelling the Drosophila embryo.

    PubMed

    Jaeger, Johannes

    2009-12-01

    I provide a historical overview on the use of mathematical models to gain insight into pattern formation during early development of the fruit fly Drosophila melanogaster. It is my intention to illustrate how the aims and methodology of modelling have changed from the early beginnings of a theoretical developmental biology in the 1960s to modern-day systems biology. I show that even early modelling attempts addressed interesting and relevant questions, which were not tractable by experimental approaches. Unfortunately, their validation was severely hampered by a lack of specificity and appropriate experimental evidence. There is a simple lesson to be learned from this: we cannot deduce general rules for pattern formation from first principles or spurious reproduction of developmental phenomena. Instead, we must infer such rules (if any) from detailed and accurate studies of specific developmental systems. To achieve this, mathematical modelling must be closely integrated with experimental approaches. I report on progress that has been made in this direction in the past few years and illustrate the kind of novel insights that can be gained from such combined approaches. These insights demonstrate the great potential (and some pitfalls) of an integrative, systems-level investigation of pattern formation.

  11. Micromechanics of Drosophila Audition

    NASA Astrophysics Data System (ADS)

    Göpfert, M. C.; Robert, D.

    2003-02-01

    An analysis is presented of the auditory micromechanics of the fruit fly Drosophila melanogaster. In this animal, the distal part of the antenna constitutes a resonantly tuned sound receiver, the vibrations of which are transduced by a chordotonal sense organ in the antenna's base. Analyzing the mechanical behavior of the antennal receiver by means of microscanning laser Doppler vibrometry, we show that the auditory system of wild-type flies exhibits a hardening stiffness nonlinearity and spontaneously generates oscillations in the absence of external stimuli. According to the deprivation of these mechanical properties in mechanosensory mutants, the receiver's nonlinearity and oscillation activity are introduced by chordotonal auditory neurons. Requiring the mechanoreceptor-specific extracellular linker protein No-mechanoreceptor-potential-A (NompA), NompC mechanosensory transduction channels, Beethoven (Btv), and Touch-insensitive-larva-B (TilB), nonlinearity and oscillation activity of the fly's antennal receiver depend on prominent components of the auditory transduction machinery and seem to originate from motility of auditory receptor cilia.

  12. APP-BP1 inhibits Aβ42 levels by interacting with Presenilin-1

    PubMed Central

    Chen, Yuzhi; Bodles, Angela M; McPhie, Donna L; Neve, Rachael L; Mrak, Robert E; Griffin, W Sue T

    2007-01-01

    Background The β-amyloid precursor protein (APP) is sequentially cleaved by the β- and then γ-secretase to generate the amyloid β-peptides Aβ40 and Aβ42. Increased Aβ42/Aβ40 ratios trigger amyloid plaque formations in Alzheimer's disease (AD). APP binds to APP-BP1, but the biological consequence is not well understood. Results We report that when the endogenous APP-BP1 was suppressed by small interfering RNAs (siRNAs), cell-associated Aβ42 was dramatically increased in APP695 expressing primary neurons. The accumulation of Aβ42 was accompanied by significant increases in APP and APP-CTF in APP-BP1 siRNA expressing neurons. In contrast, APP-BP1 overexpression in primary neurons significantly decreased the levels of Aβ and endogenous APP but not APLPs. We also investigated the potential mechanism of APP-BP1-mediated APP processing. APP-BP1 co-precipitated with Presenilin-1 (PS1) in native rat brain extracts, co-migrated with the γ-secretase components in brain membrane extracts in glycerol gradient centrifugation, and colocalized in primary neurons. Further, the endogenous PS1-CTF was significantly downregulated by APP-BP1 expression. Conclusion Our data suggest that APP-BP1 may inhibit Aβ42 production by interacting with PS1 under physiological conditions. PMID:17286867

  13. Impaired autophagy and APP processing in Alzheimer's disease: The potential role of Beclin 1 interactome.

    PubMed

    Salminen, Antero; Kaarniranta, Kai; Kauppinen, Anu; Ojala, Johanna; Haapasalo, Annakaisa; Soininen, Hilkka; Hiltunen, Mikko

    2013-01-01

    The accumulation of amyloid-β-containing neuritic plaques and intracellular tau protein tangles are key histopathological hallmarks of Alzheimer's disease (AD). This type of pathology clearly indicates that the mechanisms of neuronal housekeeping and protein quality control are compromised in AD. There is mounting evidence that the autophagosome-lysosomal degradation is impaired, which could disturb the processing of APP and provoke AD pathology. Beclin 1 is a molecular platform assembling an interactome with stimulating and suppressive components which regulate the initiation of the autophagosome formation. Recent studies have indicated that the expression Beclin 1 is reduced in AD brain. Moreover, the deficiency of Beclin 1 in cultured neurons and transgenic mice provokes the deposition of amyloid-β peptides whereas its overexpression reduces the accumulation of amyloid-β. There are several potential mechanisms, which could inhibit the function of Beclin 1 interactome and thus impair autophagy and promote AD pathology. The mechanisms include (i) reduction of Beclin 1 expression or its increased proteolytic cleavage by caspases, (ii) sequestration of Beclin 1 to non-functional locations, such as tau tangles, (iii) formation of inhibitory complexes between Beclin 1 and antiapoptotic Bcl-2 proteins or inflammasomes, (iv) interaction of Beclin 1 with inhibitory neurovirulent proteins, e.g. herpex simplex ICP34.5, or (v) inhibition of the Beclin 1/Vps34 complex through the activation of CDK1 and CDK5. We will shortly introduce the function of Beclin 1 interactome in autophagy and phagocytosis, review the recent evidence indicating that Beclin 1 regulates autophagy and APP processing in AD, and finally examine the potential mechanisms through which Beclin 1 dysfunction could be involved in the pathogenesis of AD.

  14. The MapApp Virtual Seabed Explorer

    NASA Astrophysics Data System (ADS)

    Haxby, W. F.; Ryan, W. B.; Carbotte, S. M.

    2003-12-01

    MapApp is a downloadable, open source, prototype client application running in a desktop personal computing environment with the capability to explore two hundred million years of global ocean floor geology and geochemistry. It accomplishes the exploration and discovery in an integrated data environment of bathymetry, gravity, magnetic anomalies, reflection profiles, crustal ages, sediment composition, bedrock petrology and chemistry. Exploration is undertaken in a single visual interface with spawned windowpanes that communicate with each other. These panes provide the viewport for charting subsea landscapes, the spreadsheet for examination and manipulation of data discovered either by direct encounter or by query, the notebook for recording and downloading either original data or derived products, and dialog boxes to set parameters for models. All data are real measurements and their metadata reside in relational databases. The data come from decades of marine geological and geophysical surveys, coring, dredging, deep-sea drilling, and submersible dives. The lessons learned include the importance of rigorous data management, the need for quality-control of data accuracy, the discipline to keep the interface simple and intuitive, and the requirement to be functional over large scales of variable spatial and temporal resolution. A technical challenge is the programming difficulties presented by continuously changing versions of the PC client operating systems. The greatest scientific challenge is cost-effective mining of published textural data and convincing competitive researchers to contribute their data that is often already many years old. To retain and expand the user community of students, educators and researchers, we are discovering that it is equally as important to grow content as to add functionality.

  15. Optogenetic Manipulation of Selective Neural Activity in Free-Moving Drosophila Adults.

    PubMed

    Hsiao, Po-Yen; Wu, Ming-Chin; Lin, Yen-Yin; Fu, Chein-Chung; Chiang, Ann-Shyn

    2016-01-01

    Activating selected neurons elicits specific behaviors in Drosophila adults. By combining optogenetics and laser-tracking techniques, we have recently developed an automated laser-tracking and optogenetic manipulation system (ALTOMS) for studying how brain circuits orchestrate complex behaviors. The established ALTOMS can independently target three lasers (473-nm blue laser, 593.5-nm yellow laser, and 1064-nm infrared laser) on any specified body part of two freely moving flies. Triggering light-sensitive proteins in real time, the blue laser and yellow laser can respectively activate and inhibit target neurons in artificial transgenic flies. Since infrared light is invisible to flies, we use the 1064-nm laser as an aversive stimulus in operant learning without perturbing visual inputs. Herein, we provide a detailed protocol for the construction of ALTOMS and optogenetic manipulation of target neurons in Drosophila adults during social interactions.

  16. Free flight odor tracking in Drosophila: Effect of wing chemosensors, sex and pheromonal gene regulation

    PubMed Central

    Houot, Benjamin; Gigot, Vincent; Robichon, Alain; Ferveur, Jean-François

    2017-01-01

    The evolution of powered flight in insects had major consequences for global biodiversity and involved the acquisition of adaptive processes allowing individuals to disperse to new ecological niches. Flies use both vision and olfactory input from their antennae to guide their flight; chemosensors on fly wings have been described, but their function remains mysterious. We studied Drosophila flight in a wind tunnel. By genetically manipulating wing chemosensors, we show that these structures play an essential role in flight performance with a sex-specific effect. Pheromonal systems are also involved in Drosophila flight guidance: transgenic expression of the pheromone production and detection gene, desat1, produced low, rapid flight that was absent in control flies. Our study suggests that the sex-specific modulation of free-flight odor tracking depends on gene expression in various fly tissues including wings and pheromonal-related tissues. PMID:28067325

  17. Protein kinase A inhibits a consolidated form of memory in Drosophila.

    PubMed

    Horiuchi, Junjiro; Yamazaki, Daisuke; Naganos, Shintaro; Aigaki, Toshiro; Saitoe, Minoru

    2008-12-30

    Increasing activity of the cAMP/protein kinase A (PKA) pathway has often been proposed as an approach to improve memory in various organisms. However, here we demonstrate that single-point mutations, which decrease PKA activity, dramatically improve aversive olfactory memory in Drosophila. These mutations do not affect formation of early memory phases or of protein synthesis-dependent long-term memory but do cause a significant increase in a specific consolidated form of memory, anesthesia-resistant memory. Significantly, heterozygotes of null mutations in PKA are sufficient to cause this memory increase. Expressing a PKA transgene in the mushroom bodies, brain structures critical for memory formation in Drosophila, reduces memory back to wild-type levels. These results indicate that although PKA is critical for formation of several memory phases, it also functions to inhibit at least one memory phase.

  18. A Drosophila RNAi library modulates Hippo pathway-dependent tissue growth.

    PubMed

    Vissers, Joseph H A; Manning, Samuel A; Kulkarni, Aishwarya; Harvey, Kieran F

    2016-01-13

    Libraries of transgenic Drosophila melanogaster carrying RNA interference (RNAi) constructs have been used extensively to perform large-scale functional genetic screens in vivo. For example, RNAi screens have facilitated the discovery of multiple components of the Hippo pathway, an evolutionarily conserved growth-regulatory network. Here we investigate an important technical limitation with the widely used VDRC KK RNAi collection. We find that approximately 25% of VDRC KK RNAi lines cause false-positive enhancement of the Hippo pathway, owing to ectopic expression of the Tiptop transcription factor. Of relevance to the broader Drosophila community, ectopic tiptop (tio) expression can also cause organ malformations and mask phenotypes such as organ overgrowth. To enhance the use of the VDRC KK RNAi library, we have generated a D. melanogaster strain that will allow researchers to test, in a single cross, whether their genetic screen of interest will be affected by ectopic tio expression.

  19. Role of P2X7 and P2Y2 receptors on α-secretase-dependent APP processing: Control of amyloid plaques formation “in vivo” by P2X7 receptor

    PubMed Central

    Miras-Portugal, M. Teresa; Diaz-Hernandez, Juan I.; Gomez-Villafuertes, Rosa; Diaz-Hernandez, Miguel; Artalejo, Antonio R.; Gualix, Javier

    2015-01-01

    Amyloid precursor protein (APP) is expressed in a large variety of neural and non-neural cells. The balance between non-pathogenic and pathologic forms of APP processing, mediated by α-secretase and β-secretase respectively, remains a crucial step to understand β-amyloid, Aβ42 peptide, formation and aggregation that are at the origin of the senile plaques in the brain, a characteristic hallmark of Alzheimer's disease (AD). In Neuro-2a, a neuroblastoma cell line that constitutively expresses APP, activation of the P2X7 receptor leads to reduction of α-secretase activity, the opposite effect being obtained by P2Y2 receptor activation. The in vivo approach was made possible by the use of J20 mice, a transgenic mouse model of familial Alzheimer's disease (FAD) expressing human APP mutant protein. This animal exhibits prominent amyloid plaques by six months of age. In vivo inhibition of the P2X7 receptor induced a significant decrease in the number and size of hippocampal amyloid plaques. This reduction is mediated by an increase in the proteolytic processing of APP through α-secretase activity, which correlates with an increase in the phosphorylated form of GSK-3, a less active form of this enzyme. The in vivo findings corroborate the therapeutic potential of P2X7 antagonists in the treatment of FAD. PMID:25848496

  20. Metabolite fingerprinting in transgenic lettuce.

    PubMed

    Garratt, Lee C; Linforth, Robert; Taylor, Andrew J; Lowe, Kenneth C; Power, J Brian; Davey, Michael R

    2005-03-01

    Metabolite fingerprinting has been achieved using direct atmospheric pressure chemical ionization-mass spectrometry (APCI-MS) and linked gas chromatography (GC-APCI/EI-MS) for transgenic lettuce (Lactuca sativa L. cv. Evola) plants expressing an IPT gene under the control of the senescence-specific SAG12 promoter from Arabidopsis thaliana (P(SAG12)-IPT). Mature heads of transgenic lettuce and their azygous controls were maintained under defined conditions to assess their shelf life. Transgenic lettuce plants exhibited delayed senescence and significant increases (up to a maximum of threefold) in the concentrations of three volatile organic compounds (VOCs), corresponding to molecular masses of 45, 47 and 63, when compared with heads from azygous plants. These VOCs were identified as acetaldehyde (45), ethanol (47) and dimethyl sulphide (63). The increase in dimethyl sulphide was paralleled by an accumulation of reactive oxygen species (ROS) in the heads of transgenic plants. These results demonstrate the applicability of metabolic fingerprinting techniques to elucidate the underlying pleiotropic responses of plants to transgene expression.

  1. Genome engineering: Drosophila melanogaster and beyond.

    PubMed

    Venken, Koen J T; Sarrion-Perdigones, Alejandro; Vandeventer, Paul J; Abel, Nicholas S; Christiansen, Audrey E; Hoffman, Kristi L

    2016-01-01

    A central challenge in investigating biological phenomena is the development of techniques to modify genomic DNA with nucleotide precision that can be transmitted through the germ line. Recent years have brought a boon in these technologies, now collectively known as genome engineering. Defined genomic manipulations at the nucleotide level enable a variety of reverse engineering paradigms, providing new opportunities to interrogate diverse biological functions. These genetic modifications include controlled removal, insertion, and substitution of genetic fragments, both small and large. Small fragments up to a few kilobases (e.g., single nucleotide mutations, small deletions, or gene tagging at single or multiple gene loci) to large fragments up to megabase resolution can be manipulated at single loci to create deletions, duplications, inversions, or translocations of substantial sections of whole chromosome arms. A specialized substitution of chromosomal portions that presumably are functionally orthologous between different organisms through syntenic replacement, can provide proof of evolutionary conservation between regulatory sequences. Large transgenes containing endogenous or synthetic DNA can be integrated at defined genomic locations, permitting an alternative proof of evolutionary conservation, and sophisticated transgenes can be used to interrogate biological phenomena. Precision engineering can additionally be used to manipulate the genomes of organelles (e.g., mitochondria). Novel genome engineering paradigms are often accelerated in existing, easily genetically tractable model organisms, primarily because these paradigms can be integrated in a rigorous, existing technology foundation. The Drosophila melanogaster fly model is ideal for these types of studies. Due to its small genome size, having just four chromosomes, the vast amount of cutting-edge genetic technologies, and its short life-cycle and inexpensive maintenance requirements, the fly is

  2. Ecdysone-inducible gene expression in mammalian cells and transgenic mice.

    PubMed Central

    No, D; Yao, T P; Evans, R M

    1996-01-01

    During metamorphosis of Drosophila melanogaster, a cascade of morphological changes is triggered by the steroid hormone 20-OH ecdysone via the ecdysone receptor, a member of the nuclear receptor superfamily. In this report, we have transferred insect hormone responsiveness to mammalian cells by the stable expression of a modified ecdysone receptor that regulates an optimized ecdysone responsive promoter. Inductions reaching 4 orders of magnitude have been achieved upon treatment with hormone. Transgenic mice expressing the modified ecdysone receptor can activate an integrated ecdysone responsive promoter upon administration of hormone. A comparison of tetracycline-based and ecdysone-based inducible systems reveals the ecdysone regulatory system exhibits lower basal activity and higher inducibility. Since ecdysone administration has no apparent effect on mammals, its use for regulating genes should be excellent for transient inducible expression of any gene in transgenic mice and for gene therapy. Images Fig. 1 Fig. 2 Fig. 3 Fig. 4 Fig. 5 Fig. 6 PMID:8622939

  3. Safe Sex Messages Within Dating and Entertainment Smartphone Apps: A Review

    PubMed Central

    Williams, Henrietta; Hocking, Jane S; Lim, Megan SC

    2016-01-01

    Background Smartphone apps provide a new platform for entertainment, information distribution, and health promotion activities, as well as for dating and casual sexual encounters. Previous research has shown high acceptability of sexual health interventions via smartphone apps; however, sexual health promotion apps were infrequently downloaded and underused. Integrating sexual health promotion into established apps might be a more effective method. Objective The objective of our study was to critically review popular sex-related apps and dating apps, in order to ascertain whether they contain any sexual health content. Methods Part 1: In January 2015, we used the term “sexual” to search for free apps in the Apple iTunes store and Android Google Play store, and categorized the sexual health content of the 137 apps identified. Part 2: We used the term “dating” to search for free geosocial-networking apps in the Apple iTunes and Android Google Play stores. The apps were downloaded to test functionality and to determine whether they included sexual health content. Results Part 1: Of the 137 apps identified, 15 (11.0%) had sexual health content and 15 (11.0%) contained messages about sexual assault or violence. The majority of the apps did not contain any sexual health content. Part 2: We reviewed 60 dating apps: 44 (73%) targeting heterosexual users, 9 (15%) targeting men who have sex with men (MSM), 3 (5%) targeting lesbian women, and 4 (7%) for group dating. Only 9 dating apps contained sexual health content, of which 7 targeted MSM. Conclusions The majority of sex-related apps and dating apps contained no sexual health content that could educate users about and remind them of their sexual risks. Sexual health practitioners and public health departments will need to work with app developers to promote sexual health within existing popular apps. For those apps that already contain sexual health messages, further study to investigate the effectiveness of the

  4. mHealth in Urology: A Review of Experts’ Involvement in App Development

    PubMed Central

    Pereira-Azevedo, Nuno; Carrasquinho, Eduardo; Cardoso de Oliveira, Eduardo; Cavadas, Vitor; Osório, Luís; Fraga, Avelino; Castelo-Branco, Miguel; Roobol, Monique J.

    2015-01-01

    Introduction Smartphones are increasingly playing a role in healthcare and previous studies assessing medical applications (apps) have raised concerns about lack of expert involvement and low content accuracy. However, there are no such studies in Urology. We reviewed Urology apps with the aim of assessing the level of participation of healthcare professionals (HCP) and scientific Urology associations in their development. Material and Methods A systematic search was performed on PubMed, Apple's App Store and Google's Play Store, for Urology apps, available in English. Apps were reviewed by three graders to determine the app’s platform, target customer, developer, app type, app category, price and the participation of a HCP or a scientific Urology association in the development. Results The search yielded 372 apps, of which 150 were specific for Urology. A fifth of all apps had no HCP involvement (20.7%) and only a third had been developed with a scientific Urology association (34.7%). The lowest percentage of HCP (13.4%) and urological association (1.9%) involvement was in apps designed for the general population. Furthermore, there was no contribution from an Urology society in "Electronic Medical Record" nor in "Patient Information" apps. A limitation of the study is that only Android and iOS apps were reviewed. Conclusions Despite the increasing Mobile Health (mHealth) market, this is the first study that demonstrates the lack of expert participation in the design of Urology apps, particularly in apps designed for the general public. Until clear regulation is enforced, the urological community should help regulate app development. Maintaining a register of certified apps or issuing an official scientific seal of approval could improve overall app quality. We propose that urologists become stakeholders in mHealth, shaping future app design and promoting peer-review app validation. PMID:25984916

  5. Smartphone apps to support hospital prescribing and pharmacology education: a review of current provision

    PubMed Central

    Haffey, Faye; Brady, Richard R W; Maxwell, Simon

    2014-01-01

    Junior doctors write the majority of hospital prescriptions but many indicate they feel underprepared to assume this responsibility and around 10% of prescriptions contain errors. Medical smartphone apps are now widely used in clinical practice and present an opportunity to provide support to inexperienced prescribers. This study assesses the contemporary range of smartphone apps with prescribing or related content. Six smartphone app stores were searched for apps aimed at the healthcare professional with drug, pharmacology or prescribing content. Three hundred and six apps were identified. 34% appeared to be for use within the clinical environment in order to aid prescribing, 14% out with the clinical setting and 51% of apps were deemed appropriate for both clinical and non-clinical use. Apps with drug reference material, such as textbooks, manuals or medical apps with drug information were the commonest apps found (51%), followed by apps offering drug or infusion rate dose calculation (26%). 68% of apps charged for download, with a mean price of £14.25 per app and a range of £0.62–101.90. A diverse range of pharmacology-themed apps are available and there is further potential for the development of contemporary apps to improve prescribing performance. Personalized app stores may help universities/healthcare organizations offer high quality apps to students to aid in pharmacology education. Users of prescribing apps must be aware of the lack of information regarding the medical expertise of app developers. This will enable them to make informed choices about the use of such apps in their clinical practice. PMID:23488599

  6. Smartphone apps to support hospital prescribing and pharmacology education: a review of current provision.

    PubMed

    Haffey, Faye; Brady, Richard R W; Maxwell, Simon

    2014-01-01

    Junior doctors write the majority of hospital prescriptions but many indicate they feel underprepared to assume this responsibility and around 10% of prescriptions contain errors. Medical smartphone apps are now widely used in clinical practice and present an opportunity to provide support to inexperienced prescribers. This study assesses the contemporary range of smartphone apps with prescribing or related content. Six smartphone app stores were searched for apps aimed at the healthcare professional with drug, pharmacology or prescribing content. Three hundred and six apps were identified. 34% appeared to be for use within the clinical environment in order to aid prescribing, 14% out with the clinical setting and 51% of apps were deemed appropriate for both clinical and non-clinical use. Apps with drug reference material, such as textbooks, manuals or medical apps with drug information were the commonest apps found (51%), followed by apps offering drug or infusion rate dose calculation (26%). 68% of apps charged for download, with a mean price of £14.25 per app and a range of £0.62-101.90. A diverse range of pharmacology-themed apps are available and there is further potential for the development of contemporary apps to improve prescribing performance. Personalized app stores may help universities/healthcare organizations offer high quality apps to students to aid in pharmacology education. Users of prescribing apps must be aware of the lack of information regarding the medical expertise of app developers. This will enable them to make informed choices about the use of such apps in their clinical practice.

  7. IDEAS and App Development Internship in Hardware and Software Design

    NASA Technical Reports Server (NTRS)

    Alrayes, Rabab D.

    2016-01-01

    In this report, I will discuss the tasks and projects I have completed while working as an electrical engineering intern during the spring semester of 2016 at NASA Kennedy Space Center. In the field of software development, I completed tasks for the G-O Caching Mobile App and the Asbestos Management Information System (AMIS) Web App. The G-O Caching Mobile App was written in HTML, CSS, and JavaScript on the Cordova framework, while the AMIS Web App is written in HTML, CSS, JavaScript, and C# on the AngularJS framework. My goals and objectives on these two projects were to produce an app with an eye-catching and intuitive User Interface (UI), which will attract more employees to participate; to produce a fully-tested, fully functional app which supports workforce engagement and exploration; to produce a fully-tested, fully functional web app that assists technicians working in asbestos management. I also worked in hardware development on the Integrated Display and Environmental Awareness System (IDEAS) wearable technology project. My tasks on this project were focused in PCB design and camera integration. My goals and objectives for this project were to successfully integrate fully functioning custom hardware extenders on the wearable technology headset to minimize the size of hardware on the smart glasses headset for maximum user comfort; to successfully integrate fully functioning camera onto the headset. By the end of this semester, I was able to successfully develop four extender boards to minimize hardware on the headset, and assisted in integrating a fully-functioning camera into the system.

  8. 'Selecting, appraising, recommending and using mobile applications (apps) in nursing'.

    PubMed

    Ferguson, Caleb; Jackson, Debra

    2017-03-31

    It's more than likely that a patient, their family member or a colleague may have recently asked you "Is there an app for that?" Mobile technology is inescapable. It is pervasive in almost every aspect of daily life. Wherever we look, people are often hunched over and fully immersed by a small 6 x 3 inch screen, whether it be walking on the street, travelling on the bus, at the coffee shop or in the clinic waiting room. Mobile devices have infiltrated most aspects of our lives and offer quick, adaptive tech-based solutions to many previously administrative, repetitive or otherwise time-consuming tasks. Everyday tasks such as banking, planning a trip on public transport, maintaining a diary or reviewing the weather all easily accomplished for most, via their mobile device. At the beginning of 2017 more than 2.2 million apps were available to download to various iOS devices such as iPads, iPhones and iPods, and more than 2.6 million apps were available in the Google Play store, formerly known as the Android Market (Statista 2017a, b). Mobile applications in the 'Health' category are now prolific and wide ranging including popular apps such as the 'Nursing Drug Handbook', 'Lark', 'Medscape' and BUPA's 'FoodSwitch' App. It's likely you already make use of a few nursing-related mobile apps, and possibly have even made recommendations to patients about health-related apps in the past. Yet, what informed your decision to download or recommend to patients? This article is protected by copyright. All rights reserved.

  9. Affecting Rhomboid-3 Function Causes a Dilated Heart in Adult Drosophila

    PubMed Central

    Yu, Lin; Lee, Teresa; Lin, Na; Wolf, Matthew J.

    2010-01-01

    Drosophila is a well recognized model of several human diseases, and recent investigations have demonstrated that Drosophila can be used as a model of human heart failure. Previously, we described that optical coherence tomography (OCT) can be used to rapidly examine the cardiac function in adult, awake flies. This technique provides images that are similar to echocardiography in humans, and therefore we postulated that this approach could be combined with the vast resources that are available in the fly community to identify new mutants that have abnormal heart function, a hallmark of certain cardiovascular diseases. Using OCT to examine the cardiac function in adult Drosophila from a set of molecularly-defined genomic deficiencies from the DrosDel and Exelixis collections, we identified an abnormally enlarged cardiac chamber in a series of deficiency mutants spanning the rhomboid 3 locus. Rhomboid 3 is a member of a highly conserved family of intramembrane serine proteases and processes Spitz, an epidermal growth factor (EGF)–like ligand. Using multiple approaches based on the examination of deficiency stocks, a series of mutants in the rhomboid-Spitz–EGF receptor pathway, and cardiac-specific transgenic rescue or dominant-negative repression of EGFR, we demonstrate that rhomboid 3 mediated activation of the EGF receptor pathway is necessary for proper adult cardiac function. The importance of EGF receptor signaling in the adult Drosophila heart underscores the concept that evolutionarily conserved signaling mechanisms are required to maintain normal myocardial function. Interestingly, prior work showing the inhibition of ErbB2, a member of the EGF receptor family, in transgenic knock-out mice or individuals that received herceptin chemotherapy is associated with the development of dilated cardiomyopathy. Our results, in conjunction with the demonstration that altered ErbB2 signaling underlies certain forms of mammalian cardiomyopathy, suggest that an

  10. An alternative domain near the nucleotide-binding site of Drosophila muscle myosin affects ATPase kinetics.

    PubMed

    Miller, Becky M; Zhang, Shuxing; Suggs, Jennifer A; Swank, Douglas M; Littlefield, Kimberly P; Knowles, Aileen F; Bernstein, Sanford I

    2005-10-14

    In Drosophila melanogaster expression of muscle myosin heavy chain isoforms occurs by alternative splicing of transcripts from a single gene. The exon 7 domain is one of four variable regions in the catalytic head and is located near the nucleotide-binding site. To ascribe a functional role to this domain, we created two chimeric myosin isoforms (indirect flight isoform-exon 7a and embryonic-exon 7d) that differ from the native indirect flight muscle and embryonic body-wall muscle isoforms only in the exon 7 region. Germline transformation and subsequent expression of the chimeric myosins in the indirect flight muscle of myosin-null Drosophila allowed us to purify the myosin for in vitro studies and to assess in vivo structure and function of transgenic muscles. Intriguingly, in vitro experiments show the exon 7 domain modulates myosin ATPase activity but has no effect on actin filament velocity, a novel result compared to similar studies with other Drosophila variable exons. Transgenic flies expressing the indirect flight isoform-exon 7a have normal indirect flight muscle structure, and flight and jump ability. However, expression of the embryonic-exon 7d chimeric isoform yields flightless flies that show improvements in both the structural stability of the indirect flight muscle and in locomotor abilities as compared to flies expressing the embryonic isoform. Overall, our results suggest the exon 7 domain participates in the regulation of the attachment of myosin to actin in order to fine-tune the physiological properties of Drosophila myosin isoforms.

  11. An integrated optical coherence microscopy imaging and optical stimulation system for optogenetic pacing in Drosophila melanogaster (Conference Presentation)

    NASA Astrophysics Data System (ADS)

    Alex, Aneesh; Li, Airong; Men, Jing; Jerwick, Jason; Tanzi, Rudolph E.; Zhou, Chao

    2016-03-01

    Electrical stimulation is the clinical standard for cardiac pacing. Although highly effective in controlling cardiac rhythm, the invasive nature, non-specificity to cardiac tissues and possible tissue damage limits its applications. Optogenetic pacing of the heart is a promising alternative, which is non-invasive and more specific, has high spatial and temporal precision, and avoids the shortcomings in electrical stimulation. Drosophila melanogaster, which is a powerful model organism with orthologs of nearly 75% of human disease genes, has not been studied for optogenetic pacing in the heart. Here, we developed a non-invasive integrated optical pacing and optical coherence microscopy (OCM) imaging system to control the heart rhythm of Drosophila at different developmental stages using light. The OCM system is capable of providing high imaging speed (130 frames/s) and ultrahigh imaging resolutions (1.5 μm and 3.9 μm for axial and transverse resolutions, respectively). A light-sensitive pacemaker was developed in Drosophila by specifically expressing the light-gated cation channel, channelrhodopsin-2 (ChR2) in transgenic Drosophila heart. We achieved non-invasive and specific optical control of the Drosophila heart rhythm throughout the fly's life cycle (larva, pupa, and adult) by stimulating the heart with 475 nm pulsed laser light. Heart response to stimulation pulses was monitored non-invasively with OCM. This integrated non-invasive optogenetic control and in vivo imaging technique provides a novel platform for performing research studies in developmental cardiology.

  12. Evaluation of Ligand-Inducible Expression Systems for Conditional Neuronal Manipulations of Sleep in Drosophila

    PubMed Central

    Li, Qiuling; Stavropoulos, Nicholas

    2016-01-01

    Drosophila melanogaster is a powerful model organism for dissecting the molecular mechanisms that regulate sleep, and numerous studies in the fly have identified genes that impact sleep–wake cycles. Conditional genetic analysis is essential to distinguish the mechanisms by which these genes impact sleep: some genes might exert their effects developmentally, for instance by directing the assembly of neuronal circuits that regulate sleep; other genes may regulate sleep in adulthood; and yet other genes might influence sleep by both developmental and adult mechanisms. Here we have assessed two ligand-inducible expression systems, Geneswitch and the Q-system, for conditional and neuronally restricted manipulations of sleep in Drosophila. While adult-specific induction of a neuronally expressed Geneswitch transgene (elav-GS) is compatible with studies of sleep as shown previously, developmental induction of elav-GS strongly and nonspecifically perturbs sleep in adults. The alterations of sleep in elav-GS animals occur at low doses of Geneswitch agonist and in the presence of transgenes unrelated to sleep, such as UAS-CD8-GFP. Furthermore, developmental elav-GS induction is toxic and reduces brood size, indicating multiple adverse effects of neuronal Geneswitch activation. In contrast, the transgenes and ligand of the Q-system do not significantly impact sleep–wake cycles when used for constitutive, developmental, or adult-specific neuronal induction. The nonspecific effects of developmental elav-GS activation on sleep indicate that such manipulations require cautious interpretation, and suggest that the Q-system or other strategies may be more suitable for conditional genetic analysis of sleep and other behaviors in Drosophila. PMID:27558667

  13. Valuable Features in Mobile Health Apps for Patients and Consumers: Content Analysis of Apps and User Ratings

    PubMed Central

    2015-01-01

    Background The explosion of mobile phones with app capabilities coupled with increased expectations of the patient-consumers’ role in managing their care presents a unique opportunity to use mobile health (mHealth) apps. Objectives The aim of this paper is to identify the features and characteristics most-valued by patient-consumers (“users”) that contribute positively to the rating of an app. Methods A collection of 234 apps associated with reputable health organizations found in the medical, health, and fitness categories of the Apple iTunes store and Google Play marketplace was assessed manually for the presence of 12 app features and characteristics. Regression analysis was used to determine which, if any, contributed positively to a user’s rating of the app. Results Analysis of these 12 features explained 9.3% (R 2=.093 n=234, P<.001) of the variation in an app’s rating, with only 5 reaching statistical significance. Of the 5 reaching statistical significance, plan or orders, export of data, usability, and cost contributed positively to a user’s rating, while the tracker feature detracted from it. Conclusions These findings suggest that users appreciate features that save time over current methods and identify an app as valuable when it is simple and intuitive to use, provides specific instructions to better manage a condition, and shares data with designated individuals. Although tracking is a core function of most health apps, this feature may detract from a user’s experience when not executed properly. Further investigation into mHealth app features is worthwhile given the inability of the most common features to explain a large portion of an app’s rating. In the future, studies should focus on one category in the app store, specific diseases, or desired behavior change, and methods should include measuring the quality of each feature, both through manual assessment and evaluation of user reviews. Additional investigations into understanding

  14. Expression specificity of GFAP transgenes.

    PubMed

    Su, Mu; Hu, Huimin; Lee, Youngjin; d'Azzo, Alessandra; Messing, Albee; Brenner, Michael

    2004-11-01

    Glial fibrillary acidic protein (GFAP) is an intermediate filament protein found predominantly in astrocytes. This specificity has recommended the GFAP gene promoter for targeting transgene expression to astrocytes. Although both we [Brenner et al. J. Neurosci. 14:1030-1037, (1994)] and others [Mucke et al. New Biol. 3:465-474, (1991)] have reported astrocyte specificity for GFAP promoters, we demonstrate here that these DNA sequences can also direct activity in neurons. The pattern of neuronal activity varied with both the nature of the expressed sequence and the transgene insertion site. Specifically, neuronal expression was very high for a protective protein/cathepsin A minigene, moderate for lacZ and undetectable for GFP. These findings, coupled with a survey of the literature, recommend that investigators using GFAP-driven transgenes verify specificity for each line studied, using a detection system whose sensitivity is sufficient to detect a compromising level of misexpression.

  15. Huperzine A activates Wnt/β-catenin signaling and enhances the nonamyloidogenic pathway in an Alzheimer transgenic mouse model.

    PubMed

    Wang, Chun-Yan; Zheng, Wei; Wang, Tao; Xie, Jing-Wei; Wang, Si-Ling; Zhao, Bao-Lu; Teng, Wei-Ping; Wang, Zhan-You

    2011-04-01

    Huperzine A (HupA) is a reversible and selective inhibitor of acetylcholinesterase (AChE), and it has multiple targets when used for Alzheimer's disease (AD) therapy. In this study, we searched for new mechanisms by which HupA could activate Wnt signaling and reduce amyloidosis in AD brain. A nasal gel containing HupA was prepared. No obvious toxicity of intranasal administration of HupA was found in mice. HupA was administered intranasally to β-amyloid (Aβ) precursor protein and presenilin-1 double-transgenic mice for 4 months. We observed an increase in ADAM10 and a decrease in BACE1 and APP695 protein levels and, subsequently, a reduction in Aβ levels and Aβ burden were present in HupA-treated mouse brain, suggesting that HupA enhances the nonamyloidogenic APP cleavage pathway. Importantly, our results further showed that HupA inhibited GSK3α/β activity, and enhanced the β-catenin level in the transgenic mouse brain and in SH-SY5Y cells overexpressing Swedish mutation APP, suggesting that the neuroprotective effect of HupA is not related simply to its AChE inhibition and antioxidation, but also involves other mechanisms, including targeting of the Wnt/β-catenin signaling pathway in AD brain.

  16. Evaluating and selecting mobile health apps: strategies for healthcare providers and healthcare organizations.

    PubMed

    Boudreaux, Edwin D; Waring, Molly E; Hayes, Rashelle B; Sadasivam, Rajani S; Mullen, Sean; Pagoto, Sherry

    2014-12-01

    Mobile applications (apps) to improve health are proliferating, but before healthcare providers or organizations can recommend an app to the patients they serve, they need to be confident the app will be user-friendly and helpful for the target disease or behavior. This paper summarizes seven strategies for evaluating and selecting health-related apps: (1) Review the scientific literature, (2) Search app clearinghouse websites, (3) Search app stores, (4) Review app descriptions, user ratings, and reviews, (5) Conduct a social media query within professional and, if available, patient networks, (6) Pilot the apps, and (7) Elicit feedback from patients. The paper concludes with an illustrative case example. Because of the enormous range of quality among apps, strategies for evaluating them will be necessary for adoption to occur in a way that aligns with core values in healthcare, such as the Hippocratic principles of nonmaleficence and beneficence.

  17. Popular Nutrition-Related Mobile Apps: A Feature Assessment

    PubMed Central

    Fallaize, Rosalind; Lovegrove, Julie A; Hwang, Faustina

    2016-01-01

    Background A key challenge in human nutrition is the assessment of usual food intake. This is of particular interest given recent proposals of eHealth personalized interventions. The adoption of mobile phones has created an opportunity for assessing and improving nutrient intake as they can be used for digitalizing dietary assessments and providing feedback. In the last few years, hundreds of nutrition-related mobile apps have been launched and installed by millions of users. Objective This study aims to analyze the main features of the most popular nutrition apps and to compare their strategies and technologies for dietary assessment and user feedback. Methods Apps were selected from the two largest online stores of the most popular mobile operating systems—the Google Play Store for Android and the iTunes App Store for iOS—based on popularity as measured by the number of installs and reviews. The keywords used in the search were as follows: calorie(s), diet, diet tracker, dietician, dietitian, eating, fit, fitness, food, food diary, food tracker, health, lose weight, nutrition, nutritionist, weight, weight loss, weight management, weight watcher, and ww calculator. The inclusion criteria were as follows: English language, minimum number of installs (1 million for Google Play Store) or reviews (7500 for iTunes App Store), relation to nutrition (ie, diet monitoring or recommendation), and independence from any device (eg, wearable) or subscription. Results A total of 13 apps were classified as popular for inclusion in the analysis. Nine apps offered prospective recording of food intake using a food diary feature. Food selection was available via text search or barcode scanner technologies. Portion size selection was only textual (ie, without images or icons). All nine of these apps were also capable of collecting physical activity (PA) information using self-report, the global positioning system (GPS), or wearable integrations. Their outputs focused

  18. APP independent and dependent effects on neurite outgrowth are modulated by the receptor associated protein (RAP).

    PubMed

    Billnitzer, Andrew J; Barskaya, Irina; Yin, Cailing; Perez, Ruth G

    2013-01-01

    Amyloid precursor protein (APP) and its secreted form, sAPP, contribute to the development of neurons in hippocampus, a brain region critical for learning and memory. Full-length APP binds the low-density lipoprotein receptor-related protein (LRP), which stimulates APP endocytosis. LRP also contributes to neurite growth. Furthermore, the receptor associated protein (RAP) binds LRP in a manner that blocks APP-LRP interactions. To elucidate APP contributions to neurite growth for full-length APP and sAPP, we cultured wild type (WT) and APP knockout (KO) neurons in sAPPα and/or RAP and measured neurite outgrowth at 1 day in vitro. Our data reveal that WT neurons had less axonal outgrowth including less axon branching. RAP treatment potentiated the inhibitory effects of APP. KO neurons had significantly more outgrowth and branching, especially in response to RAP, effects which were also associated with ERK2 activation. Our results affirm a major inhibitory role by full-length APP on all aspects of axonal and dendritic outgr