ApoE4 expression accelerates hippocampus-dependent cognitive deficits by enhancing Aβ impairment of insulin signaling in an Alzheimer’s disease mouse model

PubMed Central

Chan, Elizabeth S.; Shetty, Mahesh Shivarama; Sajikumar, Sreedharan; Chen, Christopher; Soong, Tuck Wah; Wong, Boon-Seng

2016-01-01

The apolipoprotein E4 (ApoE4) is the strongest genetic risk factor for Alzheimer’s disease (AD). The AD brain was shown to be insulin resistant at end stage, but the interplay between insulin signaling, ApoE4 and Aβ across time, and their involvement in memory decline is unclear. To investigate insulin response in the ageing mouse hippocampus, we crossed the human ApoE-targeted replacement mice with the mutant human amyloid precursor protein (APP) mice (ApoExAPP). While hippocampal Aβ levels were comparable between ApoE3xAPP and ApoE4xAPP mice at 26 weeks, insulin response was impaired in the ApoE4xAPP hippocampus. Insulin treatment was only able to stimulate insulin signaling and increased AMPA-GluR1 phosphorylation in forskolin pre-treated hippocampal slices from ApoE3xAPP mice. In ApoE4xAPP mice, insulin dysfunction was also associated with poorer spatial memory performance. Using dissociated hippocampal neuron in vitro, we showed that insulin response in ApoE3 and ApoE4 neurons increased AMPA receptor-mediated miniature excitatory postsynaptic current (mEPSC) amplitudes and GluR1-subunit insertion. Pre-treatment of ApoE3 neurons with Aβ42 did not affect insulin-mediated GluR1 subunit insertion. However, impaired insulin sensitivity observed only in the presence of ApoE4 and Aβ42, attenuated GluR1-subunit insertion. Taken together, our results suggest that ApoE4 enhances Aβ inhibition of insulin-stimulated AMPA receptor function, which accelerates memory impairment in ApoE4xAPP mice. PMID:27189808

Cerebral amyloid angiopathy increases susceptibility to infarction after focal cerebral ischemia in Tg2576 mice.

PubMed

Milner, Eric; Zhou, Meng-Liang; Johnson, Andrew W; Vellimana, Ananth K; Greenberg, Jacob K; Holtzman, David M; Han, Byung Hee; Zipfel, Gregory J

2014-10-01

We and others have shown that soluble amyloid β-peptide (Aβ) and cerebral amyloid angiopathy (CAA) cause significant cerebrovascular dysfunction in mutant amyloid precursor protein (APP) mice, and that these deficits are greater in aged APP mice having CAA compared with young APP mice lacking CAA. Amyloid β-peptide in young APP mice also increases infarction after focal cerebral ischemia, but the impact of CAA on ischemic brain injury is unknown. To determine this, we assessed cerebrovascular reactivity, cerebral blood flow (CBF), and extent of infarction and neurological deficits after transient middle cerebral artery occlusion in aged APP mice having extensive CAA versus young APP mice lacking CAA (and aged-matched littermate controls). We found that aged APP mice have more severe cerebrovascular dysfunction that is CAA dependent, have greater CBF compromise during and immediately after middle cerebral artery occlusion, and develop larger infarctions after middle cerebral artery occlusion. These data indicate CAA induces a more severe form of cerebrovascular dysfunction than amyloid β-peptide alone, leading to intra- and postischemic CBF deficits that ultimately exacerbate cerebral infarction. Our results shed mechanistic light on human studies identifying CAA as an independent risk factor for ischemic brain injury. © 2014 American Heart Association, Inc.

Amyloid-β Precursor Protein Modulates the Sorting of Testican-1 and Contributes to Its Accumulation in Brain Tissue and Cerebrospinal Fluid from Patients with Alzheimer Disease.

PubMed

Barrera-Ocampo, Alvaro; Arlt, Sönke; Matschke, Jakob; Hartmann, Ursula; Puig, Berta; Ferrer, Isidre; Zürbig, Petra; Glatzel, Markus; Sepulveda-Falla, Diego; Jahn, Holger

2016-09-01

The mechanisms leading to amyloid-β (Aβ) accumulation in sporadic Alzheimer disease (AD) are unknown but both increased production or impaired clearance likely contribute to aggregation. To understand the potential roles of the extracellular matrix proteoglycan Testican-1 in the pathophysiology of AD, we used samples from AD patients and controls and an in vitro approach. Protein expression analysis showed increased levels of Testican-1 in frontal and temporal cortex of AD patients; histological analysis showed that Testican-1 accumulates and co-aggregates with Aβ plaques in the frontal, temporal and entorhinal cortices of AD patients. Proteomic analysis identified 10 fragments of Testican-1 in cerebrospinal fluid (CSF) from AD patients. HEK293T cells expressing human wild type or mutant Aβ precursor protein (APP) were transfected with Testican-1. The co-expression of both proteins modified the sorting of Testican-1 into the endocytic pathway leading to its transient accumulation in Golgi, which seemed to affect APP processing, as indicated by reduced Aβ40 and Aβ42 levels in APP mutant cells. In conclusion, patient data reflect a clearance impairment that may favor Aβ accumulation in AD brains and our in vitro model supports the notion that the interaction between APP and Testican-1 may be a key step in the production and aggregation of Aβ species. © 2016 Oxford University Press OR American Association of Neuropathologists.

Learning Discloses Abnormal Structural and Functional Plasticity at Hippocampal Synapses in the APP23 Mouse Model of Alzheimer's Disease

ERIC Educational Resources Information Center

Middei, Silvia; Roberto, Anna; Berretta, Nicola; Panico, Maria Beatrice; Lista, Simone; Bernardi, Giorgio; Mercuri, Nicola B.; Ammassari-Teule, Martine; Nistico, Robert

2010-01-01

B6-Tg/Thy1APP23Sdz (APP23) mutant mice exhibit neurohistological hallmarks of Alzheimer's disease but show intact basal hippocampal neurotransmission and synaptic plasticity. Here, we examine whether spatial learning differently modifies the structural and electrophysiological properties of hippocampal synapses in APP23 and wild-type mice. While…

Studies on the control of development: isolation of Bacillus subtilis mutants blocked early in sporulation and defective in synthesis of highly phosphorylated nucleotides.

PubMed

Rhaese, H J; Hoch, J A; Groscurth, R

1977-03-01

To test our model on the mechanism of initiation of differentiation in Bacillus subtilis, we tested early blocked (stage 0) sporulation mutants for their ability to synthesize highly phosphorylated nucleotides. We also isolated early blocked asporogenous mutants with the aid of the intercalating drug tilorone. Among all mutants tested we found that the spo0F-bearing strain was unable to synthesize adenosine 3'(2')-triphosphate 5'-triphosphate, pppAppp. A revertant of this mutant regained the ability to both sporulate and synthesize pppAppp. Ribosomes of the asporogenous mutant isolated at T2 (2 hr after the end of logarithmic growth) of sporulation, in contrast to the wild type, do not synthesize adenosine 3'(2')-diphosphate 5'-diphosphate, ppApp, or adenosine 3'(2')-diphosphate 5'-triphosphate, pppApp, but synthesize guanosine 3'(2')-diphosphate 5'-diphosphate, ppGpp, and guanosine 3'(2')-diphosphate 5'-triphosphate, pppGpp. This behavior is characteristic of ribosomes from vegetative, not sporulating, cells. Ribosomes from the sporogenous revertant behave like those of the wild type. The results suggest that the spo0F mutation may be a mutation in the structural gene for pppAppp synthetase. The inability to synthesize pppAppp in this strain also prevents the formation of "sporulation-specific ribosomes," i.e., ribosomes that synthetize ppApp and pppApp. The present experiments suggest that the nucleotide pppAppp participates in the initiation of sporulation by triggering a sequencies of events required for the production of heat-resistant spores.

The Alzheimer Disease Protective Mutation A2T Modulates Kinetic and Thermodynamic Properties of Amyloid-β (Aβ) Aggregation*

PubMed Central

Benilova, Iryna; Gallardo, Rodrigo; Ungureanu, Andreea-Alexandra; Castillo Cano, Virginia; Snellinx, An; Ramakers, Meine; Bartic, Carmen; Rousseau, Frederic; Schymkowitz, Joost; De Strooper, Bart

2014-01-01

Missense mutations in alanine 673 of the amyloid precursor protein (APP), which corresponds to the second alanine of the amyloid β (Aβ) sequence, have dramatic impact on the risk for Alzheimer disease; A2V is causative, and A2T is protective. Assuming a crucial role of amyloid-Aβ in neurodegeneration, we hypothesized that both A2V and A2T mutations cause distinct changes in Aβ properties that may at least partially explain these completely different phenotypes. Using human APP-overexpressing primary neurons, we observed significantly decreased Aβ production in the A2T mutant along with an enhanced Aβ generation in the A2V mutant confirming earlier data from non-neuronal cell lines. More importantly, thioflavin T fluorescence assays revealed that the mutations, while having little effect on Aβ42 peptide aggregation, dramatically change the properties of the Aβ40 pool with A2V accelerating and A2T delaying aggregation of the Aβ peptides. In line with the kinetic data, Aβ A2T demonstrated an increase in the solubility at equilibrium, an effect that was also observed in all mixtures of the A2T mutant with the wild type Aβ40. We propose that in addition to the reduced β-secretase cleavage of APP, the impaired propensity to aggregate may be part of the protective effect conferred by A2T substitution. The interpretation of the protective effect of this mutation is thus much more complicated than proposed previously. PMID:25253695

Replacement of Val3 in human thymidylate synthase affects its kinetic properties and intracellular stability .

PubMed

Huang, Xiao; Gibson, Lydia M; Bell, Brittnaie J; Lovelace, Leslie L; Peña, Maria Marjorette O; Berger, Franklin G; Berger, Sondra H; Lebioda, Lukasz

2010-03-23

Human and other mammalian thymidylate synthase (TS) enzymes have an N-terminal extension of approximately 27 amino acids that is not present in bacterial TSs. The extension, which is disordered in all reported crystal structures of TSs, has been considered to play a primary role in protein turnover but not in catalytic activity. In mammalian cells, the variant V3A has a half-life similar to that of wild-type human TS (wt hTS) while V3T is much more stable; V3L, V3F, and V3Y have half-lives approximately half of that for wt hTS. Catalytic turnover rates for most Val3 mutants are only slightly diminished, as expected. However, two mutants, V3L and V3F, have strongly compromised dUMP binding, with K(m,app) values increased by factors of 47 and 58, respectively. For V3L, this observation can be explained by stabilization of the inactive conformation of the loop of residues 181-197, which prevents substrate binding. In the crystal structure of V3L, electron density corresponding to a leucine residue is present in a position that stabilizes the loop of residues 181-197 in the inactive conformation. Since this density is not observed in other mutants and all other leucine residues are ordered in this structure, it is likely that this density represents Leu3. In the crystal structure of a V3F.FdUMP binary complex, the nucleotide is bound in an alternative mode to that proposed for the catalytic complex, indicating that the high K(m,app) value is caused not by stabilization of the inactive conformer but by substrate binding in a nonproductive, inhibitory site. These observations show that the N-terminal extension affects the conformational state of the hTS catalytic region. Each of the mechanisms leading to the high K(m,app) values can be exploited to facilitate design of compounds acting as allosteric inhibitors of hTS.

Tyr115, gln165 and trp209 contribute to the 1, 2-epoxy-3-(p-nitrophenoxy)propane-conjugating activity of glutathione S-transferase cGSTM1-1.

PubMed

Chern, M K; Wu, T C; Hsieh, C H; Chou, C C; Liu, L F; Kuan, I C; Yeh, Y H; Hsiao, C D; Tam, M F

2000-07-28

We investigated the epoxidase activity of a class mu glutathione S-transferase (cGSTM1-1), using 1,2-epoxy-3-(p-nitrophenoxy)propane (EPNP) as substrate. Trp209 on the C-terminal tail, Arg107 on the alpha4 helix, Asp161 and Gln165 on the alpha6 helix of cGSTM1-1 were selected for mutagenesis and kinetic studies. A hydrophobic side-chain at residue 209 is needed for the epoxidase activity of cGSTM1-1. Replacing Trp209 with histidine, isoleucine or proline resulted in a fivefold to 28-fold decrease in the k(cat)(app) of the enzyme, while a modest 25 % decrease in the k(cat)(app) was observed for the W209F mutant. The rGSTM1-1 enzyme has serine at the correponding position. The k(cat)(app) of the S209W mutant is 2. 5-fold higher than that of the wild-type rGSTM1-1. A charged residue is needed at position 107 of cGSTM1-1. The K(m)(app)(GSH) of the R107L mutant is 38-fold lower than that of the wild-type enzyme. On the contrary, the R107E mutant has a K(m)(app)(GSH) and a k(cat)(app) that are 11-fold and 35 % lower than those of the wild-type cGSTM1-1. The substitutions of Gln165 with Glu or Leu have minimal effect on the affinity of the mutants towards GSH or EPNP. However, a discernible reduction in k(cat)(app) was observed. Asp161 is involved in maintaining the structural integrity of the enzyme. The K(m)(app)(GSH) of the D161L mutant is 616-fold higher than that of the wild-type enzyme. In the hydrogen/deuterium exchange experiments, this mutant has the highest level of deuteration among all the proteins tested. We also elucidated the structure of cGSTM1-1 co-crystallized with the glutathionyl-conjugated 1, 2-epoxy-3-(p-nitrophenoxy)propane (EPNP) at 2.8 A resolution. The product found in the active site was 1-hydroxy-2-(S-glutathionyl)-3-(p-nitrophenoxy)propane, instead of the conventional 2-hydroxy isomer. The EPNP moiety orients towards Arg107 and Gln165 in dimer AB, and protrudes into a hydrophobic region formed by the loop connecting beta1 and alpha1 and part of the C-terminal tail in dimer CD. The phenoxyl ring forms strong ring stacking with the Trp209 side-chain in dimer CD. We hypothesize that these two conformations represent the EPNP moiety close to the initial and final stages of the reaction mechanism, respectively. Copyright 2000 Academic Press.

Opposite Dysregulation of Fragile-X Mental Retardation Protein and Heteronuclear Ribonucleoprotein C Protein Associates with Enhanced APP Translation in Alzheimer Disease.

PubMed

Borreca, Antonella; Gironi, Katia; Amadoro, Giusy; Ammassari-Teule, Martine

2016-07-01

Amyloid precursor protein (APP) is overexpressed in familiar and sporadic Alzheimer Disease (AD) patients suggesting that, in addition to abnormalities in APP cleavage, enhanced levels of APP full length might contribute to the pathology. Based on data showing that the two RNA binding proteins (RBPs), Fragile-X Mental Retardation Protein (FMRP) and heteronuclear Ribonucleoprotein C (hnRNP C), exert an opposite control on APP translation, we have analyzed whether expression and translation of these two RBPs vary in relation to changes in APP protein and mRNA levels in the AD brain at 1, 3, and 6 months of age. Here, we show that, as expected, human APP is overexpressed in hippocampal total extract from Tg2576 mice at all age points. APP overexpression, however, is not stable over time but reaches its maximal level in 1-month-old mutants in association with the stronger (i) reduction of FMRP and (ii) augmentation of hnRNP C. APP levels then decrease progressively as a function of age in close relationship with the gradual normalization of FMRP and hnRNP C levels. Consistent with the mouse data, expression of FMRP and hnRNP C are, respectively, decreased and increased in hippocampal synaptosomes from sporadic AD patients. Our findings identify two RBP targets that might be manipulated for reducing abnormally elevated levels of APP in the AD brain, with the hypothesis that acting upstream of amyloidogenic processing might contribute to attenuate the amyloid burden.

X11/Mint Genes Control Polarized Localization of Axonal Membrane Proteins in Vivo

PubMed Central

Gross, Garrett G.; Lone, G. Mohiddin; Leung, Lok Kwan; Hartenstein, Volker

2013-01-01

Mislocalization of axonal proteins can result in misassembly and/or miswiring of neural circuits, causing disease. To date, only a handful of genes that control polarized localization of axonal membrane proteins have been identified. Here we report that Drosophila X11/Mint proteins are required for targeting several proteins, including human amyloid precursor protein (APP) and Drosophila APP-like protein (APPL), to axonal membranes and for their exclusion from dendrites of the mushroom body in Drosophila, a brain structure involved in learning and memory. Axonal localization of APP is mediated by an endocytic motif, and loss of X11/Mint results in a dramatic increase in cell-surface levels of APPL, especially on dendrites. Mutations in genes required for endocytosis show similar mislocalization of these proteins to dendrites, and strongly enhance defects seen in X11/Mint mutants. These results suggest that X11/Mint-dependent endocytosis in dendrites may serve to promote the axonal localization of membrane proteins. Since X11/Mint binds to APP, and abnormal trafficking of APP contributes to Alzheimer's disease, deregulation of X11/Mint may be important for Alzheimer's disease pathogenesis. PMID:23658195

Differential regulation of amyloid precursor protein sorting with pathological mutations results in a distinct effect on amyloid-β production.

PubMed

Lin, Yen-Chen; Wang, Jia-Yi; Wang, Kai-Chen; Liao, Jhih-Ying; Cheng, Irene H

2014-11-01

The deposition of amyloid-β (Aβ) peptide, which is generated from amyloid precursor protein (APP), is the pathological hallmark of Alzheimer's disease (AD). Three APP familial AD mutations (D678H, D678N, and H677R) located at the sixth and seventh amino acid of Aβ have distinct effect on Aβ aggregation, but their influence on the physiological and pathological roles of APP remain unclear. We found that the D678H mutation strongly enhances amyloidogenic cleavage of APP, thus increasing the production of Aβ. This enhancement of amyloidogenic cleavage is likely because of the acceleration of APPD678H sorting into the endosomal-lysosomal pathway. In contrast, the APPD678N and APPH677R mutants do not cause the same effects. Therefore, this study indicates a regulatory role of D678H in APP sorting and processing, and provides genetic evidence for the importance of APP sorting in AD pathogenesis. The internalization of amyloid precursor protein (APP) increases its opportunity to be processed by β-secretase and to produce Amyloid-β (Aβ) that causes Alzheimer's disease (AD). We report a pathogenic APPD678H mutant that enhances APP internalization into the endosomal-lysosomal pathway and thus promotes the β-secretase cleavage and Aβ production. This study provides genetic evidence for the importance of APP sorting in AD pathogenesis. © 2014 International Society for Neurochemistry.

Secreted Amyloid β-Proteins in a Cell Culture Model Include N-Terminally Extended Peptides That Impair Synaptic Plasticity

PubMed Central

2014-01-01

Evidence for a central role of amyloid β-protein (Aβ) in the genesis of Alzheimer’s disease (AD) has led to advanced human trials of Aβ-lowering agents. The “amyloid hypothesis” of AD postulates deleterious effects of small, soluble forms of Aβ on synaptic form and function. Because selectively targeting synaptotoxic forms of soluble Aβ could be therapeutically advantageous, it is important to understand the full range of soluble Aβ derivatives. We previously described a Chinese hamster ovary (CHO) cell line (7PA2 cells) that stably expresses mutant human amyloid precursor protein (APP). Here, we extend this work by purifying an sodium dodecyl sulfate (SDS)-stable, ∼8 kDa Aβ species from the 7PA2 medium. Mass spectrometry confirmed its identity as a noncovalently bonded Aβ40 homodimer that impaired hippocampal long-term potentiation (LTP) in vivo. We further report the detection of Aβ-containing fragments of APP in the 7PA2 medium that extend N-terminal from Asp1 of Aβ. These N-terminally extended Aβ-containing monomeric fragments are distinct from soluble Aβ oligomers formed from Aβ1-40/42 monomers and are bioactive synaptotoxins secreted by 7PA2 cells. Importantly, decreasing β-secretase processing of APP elevated these alternative synaptotoxic APP fragments. We conclude that certain synaptotoxic Aβ-containing species can arise from APP processing events N-terminal to the classical β-secretase cleavage site. PMID:24840308

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. Copyright © 2016 Elsevier Inc. All rights reserved.

Interferon-γ and Tumor Necrosis Factor-α Regulate Amyloid-β Plaque Deposition and β-Secretase Expression in Swedish Mutant APP Transgenic Mice

PubMed Central

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

2007-01-01

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-β peptide (Aβ) accumulation is poorly understood. Thus, we generated a novel Swedish β-amyloid precursor protein mutant (APP) transgenic mouse in which the interferon (IFN)-γ receptor type I was knocked out (APP/GRKO). IFN-γ signaling loss in the APP/GRKO mice reduced gliosis and amyloid plaques at 14 months of age. Aggregated Aβ induced IFN-γ production from co-culture of astrocytes and microglia, and IFN-γ elicited tumor necrosis factor (TNF)-α secretion in wild type (WT) but not GRKO microglia co-cultured with astrocytes. Both IFN-γ and TNF-α enhanced Aβ production from APP-expressing astrocytes and cortical neurons. TNF-α directly stimulated β-site APP-cleaving enzyme (BACE1) expression and enhanced β-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-γ and TNF-α activation of WT microglia suppressed Aβ degradation, whereas GRKO microglia had no changes. These results support the idea that glial IFN-γ and TNF-α enhance Aβ deposition through BACE1 expression and suppression of Aβ clearance. Taken together, these observations suggest that proinflammatory cytokines are directly linked to Alzheimer’s disease pathogenesis. PMID:17255335

Amyloid Precursor Protein Translation Is Regulated by a 3’UTR Guanine Quadruplex

PubMed Central

Sharoni, Michal; Olson, Kalee; Sebastian, Neeraj P.; Ansaloni, Sara; Schweitzer-Stenner, Reinhard; Akins, Michael R.; Bevilacqua, Philip C.; Saunders, Aleister J.

2015-01-01

A central event in Alzheimer’s disease is the accumulation of amyloid β (Aβ) peptides generated by the proteolytic cleavage of the amyloid precursor protein (APP). APP overexpression leads to increased Aβ generation and Alzheimer’s disease in humans and altered neuronal migration and increased long term depression in mice. Conversely, reduction of APP expression results in decreased Aβ levels in mice as well as impaired learning and memory and decreased numbers of dendritic spines. Together these findings indicate that therapeutic interventions that aim to restore APP and Aβ levels must do so within an ideal range. To better understand the effects of modulating APP levels, we explored the mechanisms regulating APP expression focusing on post-transcriptional regulation. Such regulation can be mediated by RNA regulatory elements such as guanine quadruplexes (G-quadruplexes), non-canonical structured RNA motifs that affect RNA stability and translation. Via a bioinformatics approach, we identified a candidate G-quadruplex within the APP mRNA in its 3’UTR (untranslated region) at residues 3008–3027 (NM_201414.2). This sequence exhibited characteristics of a parallel G-quadruplex structure as revealed by circular dichroism spectrophotometry. Further, as with other G-quadruplexes, the formation of this structure was dependent on the presence of potassium ions. This G-quadruplex has no apparent role in regulating transcription or mRNA stability as wild type and mutant constructs exhibited equivalent mRNA levels as determined by real time PCR. Instead, we demonstrate that this G-quadruplex negatively regulates APP protein expression using dual luciferase reporter and Western blot analysis. Taken together, our studies reveal post-transcriptional regulation by a 3’UTR G-quadruplex as a novel mechanism regulating APP expression. PMID:26618502

Deficits in working memory and motor performance in the APP/PS1ki mouse model for Alzheimer's disease.

PubMed

Wirths, Oliver; Breyhan, Henning; Schäfer, Stephanie; Roth, Christian; Bayer, Thomas A

2008-06-01

The APP/PS1ki mouse model for Alzheimer's disease (AD) exhibits robust brain and spinal cord axonal degeneration and hippocampal CA1 neuron loss starting at 6 months of age. It expresses human mutant APP751 with the Swedish and London mutations together with two FAD-linked knocked-in mutations (PS1 M233T and PS1 L235P) in the murine PS1 gene. The present report covers a phenotypical analysis of this model using either behavioral tests for working memory and motor performance, as well as an analysis of weight development and body shape. At the age of 6 months, a dramatic, age-dependent change in all of these properties and characteristics was observed, accompanied by a significantly reduced ability to perform working memory and motor tasks. The APP/PS1ki mice were smaller and showed development of a thoracolumbar kyphosis, together with an incremental loss of body weight. While 2-month-old APP/PS1ki mice were inconspicuous in all of these tasks and properties, there is a massive age-related impairment in all tested behavioral paradigms. We have previously reported robust axonal degeneration in brain and spinal cord, as well as abundant hippocampal CA1 neuron loss starting at 6 months of age in the APP/PS1ki mouse model, which coincides with the onset of motor and memory deficits described in the present report.

Attenuating astrocyte activation accelerates plaque pathogenesis in APP/PS1 mice

PubMed Central

Kraft, Andrew W.; Hu, Xiaoyan; Yoon, Hyejin; Yan, Ping; Xiao, Qingli; Wang, Yan; Gil, So Chon; Brown, Jennifer; Wilhelmsson, Ulrika; Restivo, Jessica L.; Cirrito, John R.; Holtzman, David M.; Kim, Jungsu; Pekny, Milos; Lee, Jin-Moo

2013-01-01

The accumulation of aggregated amyloid-β (Aβ) in amyloid plaques is a neuropathological hallmark of Alzheimer's disease (AD). Reactive astrocytes are intimately associated with amyloid plaques; however, their role in AD pathogenesis is unclear. We deleted the genes encoding two intermediate filament proteins required for astrocyte activation—glial fibrillary acid protein (Gfap) and vimentin (Vim)—in transgenic mice expressing mutant human amyloid precursor protein and presenilin-1 (APP/PS1). The gene deletions increased amyloid plaque load: APP/PS1 Gfap−/−Vim−/− mice had twice the plaque load of APP/PS1 Gfap+/+Vim+/+ mice at 8 and 12 mo of age. APP expression and soluble and interstitial fluid Aβ levels were unchanged, suggesting that the deletions had no effect on APP processing or Aβ generation. Astrocyte morphology was markedly altered by the deletions: wild-type astrocytes had hypertrophied processes that surrounded and infiltrated plaques, whereas Gfap−/−Vim−/− astrocytes had little process hypertrophy and lacked contact with adjacent plaques. Moreover, Gfap and Vim gene deletion resulted in a marked increase in dystrophic neurites (2- to 3-fold higher than APP/PS1 Gfap+/+Vim+/+ mice), even after normalization for amyloid load. These results suggest that astrocyte activation limits plaque growth and attenuates plaque-related dystrophic neurites. These activities may require intimate contact between astrocyte and plaque.—Kraft, A. W., Hu, X., Yoon, H., Yan, P., Xiao, Q., Wang, Y., Gil, S. C., Brown, J., Wilhelmsson, U., Restivo, J. L., Cirrito, J. R., Holtzman, D. M., Kim, J., Pekny, M., Lee, J.-M. Attenuating astrocyte activation accelerates plaque pathogenesis in APP/PS1 mice. PMID:23038755

GPR3 Stimulates Aβ Production via Interactions with APP and β-Arrestin2

PubMed Central

Nelson, Christopher D.; Sheng, Morgan

2013-01-01

The orphan G protein-coupled receptor (GPCR) GPR3 enhances the processing of Amyloid Precursor Protein (APP) to the neurotoxic beta-amyloid (Aβ) peptide via incompletely understood mechanisms. Through overexpression and shRNA knockdown experiments in HEK293 cells, we show that β-arrestin2 (βarr2), a GPCR-interacting scaffold protein reported to bind γ-secretase, is an essential factor for GPR3-stimulated Aβ production. For a panel of GPR3 receptor mutants, the degree of stimulation of Aβ production correlates with receptor-β-arrestin binding and receptor trafficking to endocytic vesicles. However, GPR3’s recruitment of βarr2 cannot be the sole explanation, because interaction with βarr2 is common to most GPCRs, whereas GPR3 is relatively unique among GPCRs in enhancing Aβ production. In addition to β-arrestin, APP is present in a complex with GPR3 and stimulation of Aβ production by GPR3 mutants correlates with their level of APP binding. Importantly, among a broader selection of GPCRs, only GPR3 and prostaglandin E receptor 2 subtype EP2 (PTGER2; another GPCR that increases Aβ production) interact with APP, and PTGER2 does so in an agonist-stimulated manner. These data indicate that a subset of GPCRs, including GPR3 and PTGER2, can associate with APP when internalized via βarr2, and thereby promote the cleavage of APP to generate Aβ. PMID:24069330

Delta-Secretase Phosphorylation by SRPK2 Enhances Its Enzymatic Activity, Provoking Pathogenesis in Alzheimer's Disease.

PubMed

Wang, Zhi-Hao; Liu, Pai; Liu, Xia; Manfredsson, Fredric P; Sandoval, Ivette M; Yu, Shan Ping; Wang, Jian-Zhi; Ye, Keqiang

2017-09-07

Delta-secretase, a lysosomal asparagine endopeptidase (AEP), simultaneously cleaves both APP and tau, controlling the onset of pathogenesis of Alzheimer's disease (AD). However, how this protease is post-translationally regulated remains unclear. Here we report that serine-arginine protein kinase 2 (SRPK2) phosphorylates delta-secretase and enhances its enzymatic activity. SRPK2 phosphorylates serine 226 on delta-secretase and accelerates its autocatalytic cleavage, leading to its cytoplasmic translocation and escalated enzymatic activities. Delta-secretase is highly phosphorylated in human AD brains, tightly correlated with SRPK2 activity. Overexpression of a phosphorylation mimetic (S226D) in young 3xTg mice strongly promotes APP and tau fragmentation and facilitates amyloid plaque deposits and neurofibrillary tangle (NFT) formation, resulting in cognitive impairment. Conversely, viral injection of the non-phosphorylatable mutant (S226A) into 5XFAD mice decreases APP and tau proteolytic cleavage, attenuates AD pathologies, and reverses cognitive defects. Our findings support that delta-secretase phosphorylation by SRPK2 plays a critical role in aggravating AD pathogenesis. Copyright © 2017 Elsevier Inc. All rights reserved.

The metabolic enhancer piracetam ameliorates the impairment of mitochondrial function and neurite outgrowth induced by beta-amyloid peptide.

PubMed

Kurz, C; Ungerer, I; Lipka, U; Kirr, S; Schütt, T; Eckert, A; Leuner, K; Müller, W E

2010-05-01

beta-Amyloid peptide (Abeta) is implicated in the pathogenesis of Alzheimer's disease by initiating a cascade of events from mitochondrial dysfunction to neuronal death. The metabolic enhancer piracetam has been shown to improve mitochondrial dysfunction following brain aging and experimentally induced oxidative stress. We used cell lines (PC12 and HEK cells) and murine dissociated brain cells. The protective effects of piracetam in vitro and ex vivo on Abeta-induced impairment of mitochondrial function (as mitochondrial membrane potential and ATP production), on secretion of soluble Abeta and on neurite outgrowth in PC12 cells were investigated. Piracetam improves mitochondrial function of PC12 cells and acutely dissociated brain cells from young NMRI mice following exposure to extracellular Abeta(1-42). Similar protective effects against Abeta(1-42) were observed in dissociated brain cells from aged NMRI mice, or mice transgenic for mutant human amyloid precursor protein (APP) treated with piracetam for 14 days. Soluble Abeta load was markedly diminished in the brain of those animals after treatment with piracetam. Abeta production by HEK cells stably transfected with mutant human APP was elevated by oxidative stress and this was reduced by piracetam. Impairment of neuritogenesis is an important consequence of Abeta-induced mitochondrial dysfunction and Abeta-induced reduction of neurite growth in PC12 cells was substantially improved by piracetam. Our findings strongly support the concept of improving mitochondrial function as an approach to ameliorate the detrimental effects of Abeta on brain function.

Neuroprotective Effect of Osthole on Neuron Synapses in an Alzheimer's Disease Cell Model via Upregulation of MicroRNA-9.

PubMed

Li, Shaoheng; Yan, Yuhui; Jiao, Yanan; Gao, Zhong; Xia, Yang; Kong, Liang; Yao, Yingjia; Tao, Zhenyu; Song, Jie; Yan, Yaping; Zhang, Guangxian; Yang, Jingxian

2016-09-01

Accumulation of β-amyloid peptide (Aβ) in the brain plays an important role in the pathogenesis of Alzheimer's disease (AD). It has been reported that osthole exerts its neuroprotective effect on neuronal synapses, but its exact mechanism is obscure. Recently, microRNAs have been demonstrated to play a crucial role in inducing synaptotoxicity by Aβ, implying that targeting microRNAs could be a therapeutic approach of AD. In the present study, we investigated the neuroprotective effects of osthole on a cell model of AD by transducing APP695 Swedish mutant (APP695swe, APP) into mouse cortical neurons and human SH-SY5Y cells. In this study, the cell counting kit CCK-8, apoptosis assay, immunofluorescence analysis, enzyme-linked immunosorbent assay (ELISA), quantitative real-time polymerase chain reaction, and Western blot assay were used. We found that osthole could enhance cell viability, prevent cell death, and reverse the reduction of synaptic proteins (synapsin-1, synaptophysin, and postsynaptic density-95) in APP-overexpressed cells, which was attributed to increases in microRNA-9 (miR-9) expression and subsequent decreases in CAMKK2 and p-AMPKα expressions. These results demonstrated that osthole plays a neuroprotective activity role in part through upregulating miR-9 in AD.

Mechanisms of AD neurodegeneration may be independent of Aβ and its derivatives.

PubMed

Robakis, Nikolaos K

2011-03-01

Alzheimer's disease (AD) is the most common cause of dementia in the aged population. Most cases are sporadic although a small percent are familial (FAD) linked to genetic mutations. AD is caused by severe neurodegeneration in the hippocampus and neocortical regions of the brain but the cause of this neuronal loss is unclear. A widely discussed theory posits that amyloid depositions of Aβ peptides or their soluble forms are the causative agents of AD. Extensive research in the last 20 years however, failed to produce convincing evidence that brain amyloid is the main cause of AD neurodegeneration. Moreover, a number of observations, including absence of correlations between amyloid deposits and cognition, detection in normal individuals of amyloid loads similar to AD, and animal models with behavioral abnormalities independent of amyloid, are inconsistent with this theory. Other theories propose soluble Aβ peptides or their oligomers as agents that promote AD. These peptides, however, are normal components of human CSF and serum and there is little evidence of disease-associated increases in soluble Aβ and oligomers. That mutants of amyloid precursor protein (APP) and presenilin (PS) promote FAD suggests these proteins play crucial roles in neuronal function and survival. Accordingly, PS regulates production of signaling peptides and cell survival pathways while APP functions in cell death and may promote endosomal abnormalities. Evidence that FAD mutations inhibit the biological functions of PS combined with absence of haploinsufficiency mutants, support a model of allelic interference where inactive FAD mutant alleles promote autosomal dominant neurodegeneration by also inhibiting the functions of wild type alleles. Copyright © 2011 Elsevier Inc. All rights reserved.

Molecular determinants and thermodynamics of the amyloid precursor protein transmembrane domain implicated in Alzheimer's disease

PubMed Central

Wang, Hao; Barreyro, Laura; Provasi, Davide; Djemil, Imane; Torres-Arancivia, Celia; Filizola, Marta; Ubarretxena-Belandia, Iban

2011-01-01

The deposition of toxic amyloid-β peptide (Aβ) aggregates in the brain is a hallmark of Alzheimer's disease. The intramembrane proteolysis by γ-secretase of the amyloid precursor protein carboxy-terminal fragment (APP-βCTF) constitutes the final step in the production of Aβs. Mounting evidence suggests that APP-βCTF is a transmembrane domain (TMD) dimer, and that dimerization might modulate the production of Aβ species that are prone to aggregation, and therefore most toxic. We combined experimental and computational approaches to study the molecular determinants and thermodynamics of APP-βCTF dimerization, and produced a unifying structural model that reconciles much of the published data. Using a cell assay, which exploits a dimerization-dependent activator of transcription, we identified specific dimerization-disrupting mutations located mostly at the N-terminus of the TMD of APP-βCTF. The ability of selected mutants to disrupt the dimerization of full length APP-βCTF was confirmed by fluorescence resonance energy transfer experiments. Free-energy estimates of wild-type (WT) and mutants of the TMD of APP-βCTF derived from enhanced molecular dynamics simulations showed that the dimeric state is comprised of different arrangements, in which either 709GXXXA713 or 700GXXXG704GXXXG708 interaction motifs can engage in symmetric or asymmetric associations. Mutations along the TMD of APP-βCTF were found to modulate the relative free energy of the dimeric configurations, and to differently affect the distribution of interfaces within the dimeric state. This observation might have important biological implications, since dimers with a different arrangement of the transmembrane helices are likely to be recognized differently by γ-secretase and lead to a variation of Aβ levels. PMID:21440556

In vivo effects on photosynthesis gene expression of base pair exchanges in the gene encoding the light-responsive BLUF domain of AppA in Rhodobacter sphaeroides.

PubMed

Metz, Sebastian; Hendriks, Johnny; Jäger, Andreas; Hellingwerf, Klaas; Klug, Gabriele

2010-01-01

The Rhodobacter sphaeroides protein AppA has the unique quality of sensing and transmitting light and redox signals. By acting as antirepressor to the PpsR protein, it acts as a major regulator in photosynthesis gene expression. In this study, we show that by introducing amino acid exchanges into the AppA protein, the in vivo activity as an antirepressor can be greatly altered. The tryptophan 104 to phenylalanine (W104F) base exchange greatly diminished blue-light sensitivity of the BLUF domain. From the obtained in vivo data, the difference in thermal recovery rate of the signaling state of the BLUF domain between the wild type and mutated protein was calculated, predicting an about 10-fold faster recovery in the mutant, which is consistent with in vitro data. Introduction of a tyrosine 21 to phenylalanine (Y21F) or to cysteine (Y21C) mutation led to a complete loss of AppA antirepressor activity, while additionally leading to an increase of photosynthesis gene expression after illumination with high blue-light quantities. Interestingly, this effect is not visible in a W104F/Y21F double mutant that again shows a wild-type-like behavior of the BLUF domain after blue-light illumination, thus restoring the activity of AppA.

Fe65 is required for Tip60-directed histone H4 acetylation at DNA strand breaks

PubMed Central

Stante, Maria; Minopoli, Giuseppina; Passaro, Fabiana; Raia, Maddalena; Vecchio, Luigi Del; Russo, Tommaso

2009-01-01

Fe65 is a binding partner of the Alzheimer's β-amyloid precursor protein APP. The possible involvement of this protein in the cellular response to DNA damage was suggested by the observation that Fe65 null mice are more sensitive to genotoxic stress than WT counterpart. Fe65 associated with chromatin under basal conditions and its involvement in DNA damage repair requires this association. A known partner of Fe65 is the histone acetyltransferase Tip60. Considering the crucial role of Tip60 in DNA repair, we explored the hypothesis that the phenotype of Fe65 null cells depended on its interaction with Tip60. We demonstrated that Fe65 knockdown impaired recruitment of Tip60-TRRAP complex to DNA double strand breaks and decreased histone H4 acetylation. Accordingly, the efficiency of DNA repair was decreased upon Fe65 suppression. To explore whether APP has a role in this mechanism, we analyzed a Fe65 mutant unable to bind to APP. This mutant failed to rescue the phenotypes of Fe65 null cells; furthermore, APP/APLP2 suppression results in the impairment of recruitment of Tip60-TRRAP complex to DNA double strand breaks, decreased histone H4 acetylation and repair efficiency. On these bases, we propose that Fe65 and its interaction with APP play an important role in the response to DNA damage by assisting the recruitment of Tip60-TRRAP to DNA damage sites. PMID:19282473

Amyloid precursor protein interaction network in human testis: sentinel proteins for male reproduction.

PubMed

Silva, Joana Vieira; Yoon, Sooyeon; Domingues, Sara; Guimarães, Sofia; Goltsev, Alexander V; da Cruz E Silva, Edgar Figueiredo; Mendes, José Fernando F; da Cruz E Silva, Odete Abreu Beirão; Fardilha, Margarida

2015-01-16

Amyloid precursor protein (APP) is widely recognized for playing a central role in Alzheimer's disease pathogenesis. Although APP is expressed in several tissues outside the human central nervous system, the functions of APP and its family members in other tissues are still poorly understood. APP is involved in several biological functions which might be potentially important for male fertility, such as cell adhesion, cell motility, signaling, and apoptosis. Furthermore, APP superfamily members are known to be associated with fertility. Knowledge on the protein networks of APP in human testis and spermatozoa will shed light on the function of APP in the male reproductive system. We performed a Yeast Two-Hybrid screen and a database search to study the interaction network of APP in human testis and sperm. To gain insights into the role of APP superfamily members in fertility, the study was extended to APP-like protein 2 (APLP2). We analyzed several topological properties of the APP interaction network and the biological and physiological properties of the proteins in the APP interaction network were also specified by gene ontologyand pathways analyses. We classified significant features related to the human male reproduction for the APP interacting proteins and identified modules of proteins with similar functional roles which may show cooperative behavior for male fertility. The present work provides the first report on the APP interactome in human testis. Our approach allowed the identification of novel interactions and recognition of key APP interacting proteins for male reproduction, particularly in sperm-oocyte interaction.

Increased Vulnerability of the Hippocampus in Transgenic Mice Overexpressing APP and Triple Repeat Tau.

PubMed

Arner, Andrew; Rockenstein, Edward; Mante, Michael; Florio, Jazmin; Masliah, Deborah; Salehi, Bahar; Adame, Anthony; Overk, Cassia; Masliah, Eliezer; Rissman, Robert A

2018-01-01

 Alzheimer's disease (AD) is the most common tauopathy, characterized by progressive accumulation of amyloid-β (Aβ) and hyperphosphorylated tau. While pathology associated with the 4-repeat (4R) tau isoform is more abundant in corticobasal degeneration and progressive supranuclear palsy, both 3R and 4R tau isoforms accumulate in AD. Many studies have investigated interactions between Aβ and 4R tau in double transgenic mice, but few, if any, have examined the effects of Aβ with 3R tau. To examine this relationship, we crossed our APP751 mutant line with our recently characterized 3R tau mutant model to create a bigenic line (hAPP-3RTau) to model AD neuropathology. Mice were analyzed at 3 and 6 months of age for pathological and behavioral endpoints. While both the 3RTau and the hAPP-3RTau mice showed neuronal loss, increased tau aggregation, Aβ plaques and exhibited more behavioral deficits compared to the non-tg control, the bigenic mice often displaying relatively worsening levels. We found that even in young animals we found that the presence of APP/Aβ increased the accumulation of 3R tau in the neocortex and hippocampus. This observation was accompanied by activation of GSK3 and neurodegeneration in the neocortex and CA1 region. These results suggest that in addition to 4R tau, APP/Aβ may also enhance accumulation of 3R tau, a process which may be directly relevant to pathogenic pathways in AD. Our results demonstrate that this bigenic model closely parallels the pathological course of AD and may serve as a valuable model for testing new pharmacological interventions.

Full-length amyloid precursor protein regulates lipoprotein metabolism and amyloid-β clearance in human astrocytes.

PubMed

Fong, Lauren K; Yang, Max M; Dos Santos Chaves, Rodrigo; Reyna, Sol M; Langness, Vanessa F; Woodruff, Grace; Roberts, Elizabeth A; Young, Jessica E; Goldstein, Lawrence S B

2018-06-01

Mounting evidence suggests that alterations in cholesterol homeostasis are involved in Alzheimer's disease (AD) pathogenesis. Amyloid precursor protein (APP) or multiple fragments generated by proteolytic processing of APP have previously been implicated in the regulation of cholesterol metabolism. However, the physiological function of APP in regulating lipoprotein homeostasis in astrocytes, which are responsible for de novo cholesterol biosynthesis and regulation in the brain, remains unclear. To address this, here we used CRISPR/Cas9 genome editing to generate isogenic APP-knockout (KO) human induced pluripotent stem cells (hiPSCs) and differentiated them into human astrocytes. We found that APP-KO astrocytes have reduced cholesterol and elevated levels of sterol regulatory element-binding protein (SREBP) target gene transcripts and proteins, which were both downstream consequences of reduced lipoprotein endocytosis. To elucidate which APP fragments regulate cholesterol homeostasis and examine whether familial AD mutations in APP affect lipoprotein metabolism, we analyzed an isogenic allelic series harboring the APP Swedish and APP V717F variants. Only astrocytes homozygous for the APP Swedish (APP Swe/Swe ) mutation, which had reduced full-length APP (FL APP) due to increased β-secretase cleavage, recapitulated the APP-KO phenotypes. Astrocytic internalization of amyloid-β (Aβ), another ligand for low-density lipoprotein (LDL) receptors, was also impaired in APP-KO and APP Swe/Swe astrocytes. Finally, impairing cleavage of FL APP through β-secretase inhibition in APP Swe/Swe astrocytes reversed the LDL and Aβ endocytosis defects. In conclusion, FL APP is involved in the endocytosis of LDL receptor ligands and required for proper cholesterol homeostasis and Aβ clearance in human astrocytes. Published under license by The American Society for Biochemistry and Molecular Biology, Inc.

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. Copyright © 2014 Elsevier Inc. All rights reserved.

The Prenylflavonoid Xanthohumol Reduces Alzheimer-Like Changes and Modulates Multiple Pathogenic Molecular Pathways in the Neuro2a/APPswe Cell Model of AD.

PubMed

Huang, Xianfeng; Wang, Jing; Chen, Xiao; Liu, Pan; Wang, Shujin; Song, Fangchen; Zhang, Zaijun; Zhu, Feiqi; Huang, Xinfeng; Liu, Jianjun; Song, Guoqiang; Spencer, Peter S; Yang, Xifei

2018-01-01

Alzheimer's disease (AD) is a progressive neurodegenerative disorder that has proved refractory to drug treatment. Given evidence of neuroprotection in animal models of ischemic stroke, we assessed the prenylflavonoid xanthohumol from the Common Hop ( Humulus lupulus L.) for therapeutic potential in murine neuroblastoma N2a cells stably expressing human Swedish mutant amyloid precursor protein (N2a/APP), a well-characterized cellular model of AD. The ELISA and Western-blot analysis revealed that xanthohumol (Xn) inhibited Aβ accumulation and APP processing, and that Xn ameliorated tau hyperphosphorylation via PP2A, GSK3β pathways in N2a/APP cells. The amelioration of tau hyperphosphorylation by Xn was also validated on HEK293/Tau cells, another cell line with tau hyperphosphorylation. Proteomic analysis (2D-DIGE-coupled MS) revealed a total of 30 differentially expressed lysate proteins in N2a/APP vs. wild-type (WT) N2a cells (N2a/WT), and a total of 21 differentially expressed proteins in lysates of N2a/APP cells in the presence or absence of Xn. Generally, these 51 differential proteins could be classified into seven main categories according to their functions, including: endoplasmic reticulum (ER) stress-associated proteins; oxidative stress-associated proteins; proteasome-associated proteins; ATPase and metabolism-associated proteins; cytoskeleton-associated proteins; molecular chaperones-associated proteins, and others. We used Western-blot analysis to validate Xn-associated changes of some key proteins in several biological/pathogenic processes. Taken together, we show that Xn reduces AD-related changes in stably transfected N2a/APP cells. The underlying mechanisms involve modulation of multiple pathogenic pathways, including those involved in ER stress, oxidative stress, proteasome molecular systems, and the neuronal cytoskeleton. These results suggest Xn may have potential for the treatment of AD and/or neuropathologically related neurodegenerative diseases.

Protective effects of a dimeric derivative of ferulic acid in animal models of Alzheimer's disease.

PubMed

Jung, Jun-Sub; Yan, Ji-Jing; Li, Hong-Mei; Sultan, Md Tipu; Yu, Jaehoon; Lee, Hee-Sul; Shin, Kye-Jung; Song, Dong-Keun

2016-07-05

Ferulic acid is a compound with potent anti-oxidant and anti-inflammatory activities. We previously reported the protective effects of ferulic acid administration against two animal models of Alzheimer's disease (AD): intracerebroventricular (i.c.v.) injection of Aß1-42 in mice and APP/PS1 mutant transgenic mice. In this study using the same AD animal models, we examined the effect of KMS4001, one of dimeric derivatives of ferulic acid. Intragastric pretreatment of mice with KMS4001 (30mg/kg/day) for 5 days significantly attenuated the Aß1-42 (i.c.v.)-induced memory impairment both in passive avoidance test and in Y-maze test. APP/PS1 mutant transgenic mice at KMS4001 doses of 3 and 30mg/kg/day via drinking water showed the significantly enhanced novel-object recognition memory at both 1.5 and 3 months after the start of KMS4001 treatment. Treatment of APP/PS1 mutant transgenic mice with KMS4001 for 3 months at the doses of 3 and 30mg/kg/day markedly decreased Aβ1-40 and Aβ1-42 levels in the frontal cortex. The KMS4001 dose-response relationships for Aβ decrease and for improvement in novel-object recognition test corresponded to each other. Taken together, these results suggest that KMS4001 could be an effective drug candidate against AD. Copyright © 2016 Elsevier B.V. All rights reserved.

Arf6 controls beta-amyloid production by regulating macropinocytosis of the Amyloid Precursor Protein to lysosomes.

PubMed

Tang, Weihao; Tam, Joshua H K; Seah, Claudia; Chiu, Justin; Tyrer, Andrea; Cregan, Sean P; Meakin, Susan O; Pasternak, Stephen H

2015-07-14

Alzheimer's disease (AD) is characterized by the deposition of Beta-Amyloid (Aβ) peptides in the brain. Aβ peptides are generated by cleavage of the Amyloid Precursor Protein (APP) by the β - and γ - secretase enzymes. Although this process is tightly linked to the internalization of cell surface APP, the compartments responsible are not well defined. We have found that APP can be rapidly internalized from the cell surface to lysosomes, bypassing early and late endosomes. Here we show by confocal microscopy and electron microscopy that this pathway is mediated by macropinocytosis. APP internalization is enhanced by antibody binding/crosslinking of APP suggesting that APP may function as a receptor. Furthermore, a dominant negative mutant of Arf6 blocks direct transport of APP to lysosomes, but does not affect classical endocytosis to endosomes. Arf6 expression increases through the hippocampus with the development of Alzheimer's disease, being expressed mostly in the CA1 and CA2 regions in normal individuals but spreading through the CA3 and CA4 regions in individuals with pathologically diagnosed AD. Disruption of lysosomal transport of APP reduces both Aβ40 and Aβ42 production by more than 30 %. Our findings suggest that the lysosome is an important site for Aβ production and that altering APP trafficking represents a viable strategy to reduce Aβ production.

Amyloid protein-mediated differential DNA methylation status regulates gene expression in Alzheimer's disease model cell line

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sung, Hye Youn; Choi, Eun Nam; Ahn Jo, Sangmee

2011-11-04

Highlights: Black-Right-Pointing-Pointer Genome-wide DNA methylation pattern in Alzheimer's disease model cell line. Black-Right-Pointing-Pointer Integrated analysis of CpG methylation and mRNA expression profiles. Black-Right-Pointing-Pointer Identify three Swedish mutant target genes; CTIF, NXT2 and DDR2 gene. Black-Right-Pointing-Pointer The effect of Swedish mutation on alteration of DNA methylation and gene expression. -- Abstract: The Swedish mutation of amyloid precursor protein (APP-sw) has been reported to dramatically increase beta amyloid production through aberrant cleavage at the beta secretase site, causing early-onset Alzheimer's disease (AD). DNA methylation has been reported to be associated with AD pathogenesis, but the underlying molecular mechanism of APP-sw-mediated epigenetic alterationsmore » in AD pathogenesis remains largely unknown. We analyzed genome-wide interplay between promoter CpG DNA methylation and gene expression in an APP-sw-expressing AD model cell line. To identify genes whose expression was regulated by DNA methylation status, we performed integrated analysis of CpG methylation and mRNA expression profiles, and identified three target genes of the APP-sw mutant; hypomethylated CTIF (CBP80/CBP20-dependent translation initiation factor) and NXT2 (nuclear exporting factor 2), and hypermethylated DDR2 (discoidin domain receptor 2). Treatment with the demethylating agent 5-aza-2 Prime -deoxycytidine restored mRNA expression of these three genes, implying methylation-dependent transcriptional regulation. The profound alteration in the methylation status was detected at the -435, -295, and -271 CpG sites of CTIF, and at the -505 to -341 region in the promoter of DDR2. In the promoter region of NXT2, only one CpG site located at -432 was differentially unmethylated in APP-sw cells. Thus, we demonstrated the effect of the APP-sw mutation on alteration of DNA methylation and subsequent gene expression. This epigenetic regulatory mechanism may contribute to the pathogenesis of AD.« less

Trehalose Alters Subcellular Trafficking and the Metabolism of the Alzheimer-associated Amyloid Precursor Protein*

PubMed Central

Tien, Nguyen T.; Karaca, Ilker; Tamboli, Irfan Y.

2016-01-01

The disaccharide trehalose is commonly considered to stimulate autophagy. Cell treatment with trehalose could decrease cytosolic aggregates of potentially pathogenic proteins, including mutant huntingtin, α-synuclein, and phosphorylated tau that are associated with neurodegenerative diseases. Here, we demonstrate that trehalose also alters the metabolism of the Alzheimer disease-related amyloid precursor protein (APP). Cell treatment with trehalose decreased the degradation of full-length APP and its C-terminal fragments. Trehalose also reduced the secretion of the amyloid-β peptide. Biochemical and cell biological experiments revealed that trehalose alters the subcellular distribution and decreases the degradation of APP C-terminal fragments in endolysosomal compartments. Trehalose also led to strong accumulation of the autophagic marker proteins LC3-II and p62, and decreased the proteolytic activation of the lysosomal hydrolase cathepsin D. The combined data indicate that trehalose decreases the lysosomal metabolism of APP by altering its endocytic vesicular transport. PMID:26957541

Structural and functional characterization of cargo-binding sites on the μ4-subunit of adaptor protein complex 4.

PubMed

Ross, Breyan H; Lin, Yimo; Corales, Esteban A; Burgos, Patricia V; Mardones, Gonzalo A

2014-01-01

Adaptor protein (AP) complexes facilitate protein trafficking by playing key roles in the selection of cargo molecules to be sorted in post-Golgi compartments. Four AP complexes (AP-1 to AP-4) contain a medium-sized subunit (μ1-μ4) that recognizes YXXØ-sequences (Ø is a bulky hydrophobic residue), which are sorting signals in transmembrane proteins. A conserved, canonical region in μ subunits mediates recognition of YXXØ-signals by means of a critical aspartic acid. Recently we found that a non-canonical YXXØ-signal on the cytosolic tail of the Alzheimer's disease amyloid precursor protein (APP) binds to a distinct region of the μ4 subunit of the AP-4 complex. In this study we aimed to determine the functionality of both binding sites of μ4 on the recognition of the non-canonical YXXØ-signal of APP. We found that substitutions in either binding site abrogated the interaction with the APP-tail in yeast-two hybrid experiments. Further characterization by isothermal titration calorimetry showed instead loss of binding to the APP signal with only the substitution R283D at the non-canonical site, in contrast to a decrease in binding affinity with the substitution D190A at the canonical site. We solved the crystal structure of the C-terminal domain of the D190A mutant bound to this non-canonical YXXØ-signal. This structure showed no significant difference compared to that of wild-type μ4. Both differential scanning fluorimetry and limited proteolysis analyses demonstrated that the D190A substitution rendered μ4 less stable, suggesting an explanation for its lower binding affinity to the APP signal. Finally, in contrast to overexpression of the D190A mutant, and acting in a dominant-negative manner, overexpression of μ4 with either a F255A or a R283D substitution at the non-canonical site halted APP transport at the Golgi apparatus. Together, our analyses support that the functional recognition of the non-canonical YXXØ-signal of APP is limited to the non-canonical site of μ4.

Structural and Functional Characterization of Cargo-Binding Sites on the μ4-Subunit of Adaptor Protein Complex 4

PubMed Central

Ross, Breyan H.; Lin, Yimo; Corales, Esteban A.; Burgos, Patricia V.; Mardones, Gonzalo A.

2014-01-01

Adaptor protein (AP) complexes facilitate protein trafficking by playing key roles in the selection of cargo molecules to be sorted in post-Golgi compartments. Four AP complexes (AP-1 to AP-4) contain a medium-sized subunit (μ1-μ4) that recognizes YXXØ-sequences (Ø is a bulky hydrophobic residue), which are sorting signals in transmembrane proteins. A conserved, canonical region in μ subunits mediates recognition of YXXØ-signals by means of a critical aspartic acid. Recently we found that a non-canonical YXXØ-signal on the cytosolic tail of the Alzheimer's disease amyloid precursor protein (APP) binds to a distinct region of the μ4 subunit of the AP-4 complex. In this study we aimed to determine the functionality of both binding sites of μ4 on the recognition of the non-canonical YXXØ-signal of APP. We found that substitutions in either binding site abrogated the interaction with the APP-tail in yeast-two hybrid experiments. Further characterization by isothermal titration calorimetry showed instead loss of binding to the APP signal with only the substitution R283D at the non-canonical site, in contrast to a decrease in binding affinity with the substitution D190A at the canonical site. We solved the crystal structure of the C-terminal domain of the D190A mutant bound to this non-canonical YXXØ-signal. This structure showed no significant difference compared to that of wild-type μ4. Both differential scanning fluorimetry and limited proteolysis analyses demonstrated that the D190A substitution rendered μ4 less stable, suggesting an explanation for its lower binding affinity to the APP signal. Finally, in contrast to overexpression of the D190A mutant, and acting in a dominant-negative manner, overexpression of μ4 with either a F255A or a R283D substitution at the non-canonical site halted APP transport at the Golgi apparatus. Together, our analyses support that the functional recognition of the non-canonical YXXØ-signal of APP is limited to the non-canonical site of μ4. PMID:24498434

MicroRNA-153 Physiologically Inhibits Expression of Amyloid-β Precursor Protein in Cultured Human Fetal Brain Cells and Is Dysregulated in a Subset of Alzheimer Disease Patients*

PubMed Central

Long, Justin M.; Ray, Balmiki; Lahiri, Debomoy K.

2012-01-01

Regulation of amyloid-β (Aβ) precursor protein (APP) expression is complex. MicroRNAs (miRNAs) are expected to participate in the molecular network that controls this process. The composition of this network is, however, still undefined. Elucidating the complement of miRNAs that regulate APP expression should reveal novel drug targets capable of modulating Aβ production in AD. Here, we investigated the contribution of miR-153 to this regulatory network. A miR-153 target site within the APP 3′-untranslated region (3′-UTR) was predicted by several bioinformatic algorithms. We found that miR-153 significantly reduced reporter expression when co-transfected with an APP 3′-UTR reporter construct. Mutation of the predicted miR-153 target site eliminated this reporter response. miR-153 delivery in both HeLa cells and primary human fetal brain cultures significantly reduced APP expression. Delivery of a miR-153 antisense inhibitor to human fetal brain cultures significantly elevated APP expression. miR-153 delivery also reduced expression of the APP paralog APLP2. High functional redundancy between APP and APLP2 suggests that miR-153 may target biological pathways in which they both function. Interestingly, in a subset of human AD brain specimens with moderate AD pathology, miR-153 levels were reduced. This same subset also exhibited elevated APP levels relative to control specimens. Therefore, endogenous miR-153 inhibits expression of APP in human neurons by specifically interacting with the APP 3′-UTR. This regulatory interaction may have relevance to AD etiology, where low miR-153 levels may drive increased APP expression in a subset of AD patients. PMID:22733824

Behavioural inflexibility in a comorbid rat model of striatal ischemic injury and mutant hAPP overexpression.

PubMed

Levit, Alexander; Regis, Aaron M; Garabon, Jessica R; Oh, Seung-Hun; Desai, Sagar J; Rajakumar, Nagalingam; Hachinski, Vladimir; Agca, Yuksel; Agca, Cansu; Whitehead, Shawn N; Allman, Brian L

2017-08-30

Alzheimer disease (AD) and stroke coexist and interact; yet how they interact is not sufficiently understood. Both AD and basal ganglia stroke can impair behavioural flexibility, which can be reliably modeled in rats using an established operant based set-shifting test. Transgenic Fischer 344-APP21 rats (TgF344) overexpress pathogenic human amyloid precursor protein (hAPP) but do not spontaneously develop overt pathology, hence TgF344 rats can be used to model the effect of vascular injury in the prodromal stages of Alzheimer disease. We demonstrate that the injection of endothelin-1 (ET1) into the dorsal striatum of TgF344 rats (Tg-ET1) produced an exacerbation of behavioural inflexibility with a behavioural phenotype that was distinct from saline-injected wildtype & TgF344 rats as well as ET1-injected wildtype rats (Wt-ET1). In addition to profiling the types of errors made, interpolative modeling using logistic exposure-response regression provided an informative analysis of the timing and efficiency of behavioural flexibility. During set-shifting, Tg-ET1 committed fewer perseverative errors than Wt-ET1. However, Tg-ET1 committed significantly more regressive errors and had a less efficient strategy change than all other groups. Thus, behavioural flexibility was more vulnerable to striatal ischemic injury in TgF344 rats. Copyright © 2017 Elsevier B.V. All rights reserved.

Ear2 deletion causes early memory and learning deficits in APP/PS1 mice.

PubMed

Kummer, Markus P; Hammerschmidt, Thea; Martinez, Ana; Terwel, Dick; Eichele, Gregor; Witten, Anika; Figura, Stefanie; Stoll, Monika; Schwartz, Stephanie; Pape, Hans-Christian; Schultze, Joachim L; Weinshenker, David; Heneka, Michael T; Urban, Inga

2014-06-25

To assess the consequences of locus ceruleus (LC) degeneration and subsequent noradrenaline (NA) deficiency in early Alzheimer's disease (AD), mice overexpressing mutant amyloid precursor protein and presenilin-1 (APP/PS1) were crossed with Ear2(-/-) mice that have a severe loss of LC neurons projecting to the hippocampus and neocortex. Testing spatial memory and hippocampal long-term potentiation revealed an impairment in APP/PS1 Ear2(-/-) mice, whereas APP/PS1 or Ear2(-/-) mice showed only minor changes. These deficits were associated with distinct synaptic changes including reduced expression of the NMDA 2A subunit and increased levels of NMDA receptor 2B in APP/PS1 Ear2(-/-) mice. Acute pharmacological replacement of NA by L-threo-DOPS partially restored phosphorylation of β-CaMKII and spatial memory performance in APP/PS1 Ear2(-/-) mice. These changes were not accompanied by altered APP processing or amyloid β peptide (Aβ) deposition. Thus, early LC degeneration and subsequent NA reduction may contribute to cognitive deficits via CaMKII and NMDA receptor dysfunction independent of Aβ and suggests that NA supplementation could be beneficial in treating AD. Copyright © 2014 the authors 0270-6474/14/348845-10$15.00/0.

Rapid endocytosis of the low density lipoprotein receptor-related protein modulates cell surface distribution and processing of the beta-amyloid precursor protein.

PubMed

Cam, Judy A; Zerbinatti, Celina V; Li, Yonghe; Bu, Guojun

2005-04-15

The low density lipoprotein receptor-related protein (LRP) is a approximately 600-kDa multifunctional endocytic receptor that is highly expressed in the brain. LRP and its ligands apolipoprotein E, alpha2-macroglobulin, and beta-amyloid precursor protein (APP), are genetically linked to Alzheimer disease and are found in characteristic plaque deposits in brains of patients with Alzheimer disease. To identify which extracellular domains of LRP interact with APP, we used minireceptors of each of the individual LRP ligand binding domains and assessed their ability to bind and degrade a soluble APP fragment. LRP minireceptors containing ligand binding domains II and IV, but not I or III, interacted with APP. To test whether APP trafficking is directly related to the rapid endocytosis of LRP, we generated stable Chinese hamster ovary cell lines expressing either a wild-type LRP minireceptor or its endocytosis mutants. Chinese hamster ovary cells stably expressing wild-type LRP minireceptor had less cell surface APP than pcDNA3 vector-transfected cells, whereas those stably expressing endocytosis-defective LRP minireceptors accumulated APP at the cell surface. We also found that the steady-state levels of the amyloid beta-peptides (Abeta) is dictated by the relative expression levels of APP and LRP, probably reflecting the dual roles of LRP in both Abeta production and clearance. Together, these data establish a relationship between LRP rapid endocytosis and APP trafficking and proteolytic processing to generate Abeta.

Developing smartphone apps for behavioural studies: The AlcoRisk app case study.

PubMed

Smith, Anthony; de Salas, Kristy; Lewis, Ian; Schüz, Benjamin

2017-08-01

Smartphone apps have emerged as valuable research tools to sample human behaviours at their time of occurrence within natural environments. Human behaviour sampling methods, such as Ecological Momentary Assessment (EMA), aim to facilitate research that is situated in ecologically valid real world environments rather than laboratory environments. Researchers have trialled a range of EMA smartphone apps to sample human behaviours such as dieting, physical activity and smoking. Software development processes for EMA smartphones apps, however, are not widely documented with little guidance provided for the integration of complex multidisciplinary behavioural and technical fields. In this paper, the AlcoRisk app for studying alcohol consumption and risk taking tendencies is presented alongside a software development process that integrates these multidisciplinary fields. The software development process consists of three stages including requirements analysis, feature and interface design followed by app implementation. Results from a preliminary feasibility study support the efficacy of the AlcoRisk app's software development process. Copyright © 2017 Elsevier Inc. All rights reserved.

Defects in Mitochondrial Dynamics and Metabolomic Signatures of Evolving Energetic Stress in Mouse Models of Familial Alzheimer's Disease

PubMed Central

Trushina, Eugenia; Nemutlu, Emirhan; Zhang, Song; Christensen, Trace; Camp, Jon; Mesa, Janny; Siddiqui, Ammar; Tamura, Yasushi; Sesaki, Hiromi; Wengenack, Thomas M.; Dzeja, Petras P.; Poduslo, Joseph F.

2012-01-01

Background The identification of early mechanisms underlying Alzheimer's Disease (AD) and associated biomarkers could advance development of new therapies and improve monitoring and predicting of AD progression. Mitochondrial dysfunction has been suggested to underlie AD pathophysiology, however, no comprehensive study exists that evaluates the effect of different familial AD (FAD) mutations on mitochondrial function, dynamics, and brain energetics. Methods and Findings We characterized early mitochondrial dysfunction and metabolomic signatures of energetic stress in three commonly used transgenic mouse models of FAD. Assessment of mitochondrial motility, distribution, dynamics, morphology, and metabolomic profiling revealed the specific effect of each FAD mutation on the development of mitochondrial stress and dysfunction. Inhibition of mitochondrial trafficking was characteristic for embryonic neurons from mice expressing mutant human presenilin 1, PS1(M146L) and the double mutation of human amyloid precursor protein APP(Tg2576) and PS1(M146L) contributing to the increased susceptibility of neurons to excitotoxic cell death. Significant changes in mitochondrial morphology were detected in APP and APP/PS1 mice. All three FAD models demonstrated a loss of the integrity of synaptic mitochondria and energy production. Metabolomic profiling revealed mutation-specific changes in the levels of metabolites reflecting altered energy metabolism and mitochondrial dysfunction in brains of FAD mice. Metabolic biomarkers adequately reflected gender differences similar to that reported for AD patients and correlated well with the biomarkers currently used for diagnosis in humans. Conclusions Mutation-specific alterations in mitochondrial dynamics, morphology and function in FAD mice occurred prior to the onset of memory and neurological phenotype and before the formation of amyloid deposits. Metabolomic signatures of mitochondrial stress and altered energy metabolism indicated alterations in nucleotide, Krebs cycle, energy transfer, carbohydrate, neurotransmitter, and amino acid metabolic pathways. Mitochondrial dysfunction, therefore, is an underlying event in AD progression, and FAD mouse models provide valuable tools to study early molecular mechanisms implicated in AD. PMID:22393443

The metabolic enhancer piracetam ameliorates the impairment of mitochondrial function and neurite outgrowth induced by ß-amyloid peptide

PubMed Central

Kurz, C; Ungerer, I; Lipka, U; Kirr, S; Schütt, T; Eckert, A; Leuner, K; Müller, WE

2010-01-01

Background and purpose: β-Amyloid peptide (Aβ) is implicated in the pathogenesis of Alzheimer's disease by initiating a cascade of events from mitochondrial dysfunction to neuronal death. The metabolic enhancer piracetam has been shown to improve mitochondrial dysfunction following brain aging and experimentally induced oxidative stress. Experimental approach: We used cell lines (PC12 and HEK cells) and murine dissociated brain cells. The protective effects of piracetam in vitro and ex vivo on Aβ-induced impairment of mitochondrial function (as mitochondrial membrane potential and ATP production), on secretion of soluble Aβ and on neurite outgrowth in PC12 cells were investigated. Key results: Piracetam improves mitochondrial function of PC12 cells and acutely dissociated brain cells from young NMRI mice following exposure to extracellular Aβ1-42. Similar protective effects against Aβ1-42 were observed in dissociated brain cells from aged NMRI mice, or mice transgenic for mutant human amyloid precursor protein (APP) treated with piracetam for 14 days. Soluble Aβ load was markedly diminished in the brain of those animals after treatment with piracetam. Aβ production by HEK cells stably transfected with mutant human APP was elevated by oxidative stress and this was reduced by piracetam. Impairment of neuritogenesis is an important consequence of Aβ-induced mitochondrial dysfunction and Aβ-induced reduction of neurite growth in PC12 cells was substantially improved by piracetam. Conclusion and implications: Our findings strongly support the concept of improving mitochondrial function as an approach to ameliorate the detrimental effects of Aβ on brain function. This article is commented on by Moncada, pp. 217–219 of this issue. To view this commentary visit http://dx.doi.org/10.1111/j.1476-5381.2010.00706.x and to view related papers by Pravdic et al. and Puerta et al. visit http://dx.doi.org/10.1111/j.1476-5381.2010.00698.x and http://dx.doi.org/10.1111/j.1476-5381.2010.00663.x PMID:20218980

Trehalose Alters Subcellular Trafficking and the Metabolism of the Alzheimer-associated Amyloid Precursor Protein.

PubMed

Tien, Nguyen T; Karaca, Ilker; Tamboli, Irfan Y; Walter, Jochen

2016-05-13

The disaccharide trehalose is commonly considered to stimulate autophagy. Cell treatment with trehalose could decrease cytosolic aggregates of potentially pathogenic proteins, including mutant huntingtin, α-synuclein, and phosphorylated tau that are associated with neurodegenerative diseases. Here, we demonstrate that trehalose also alters the metabolism of the Alzheimer disease-related amyloid precursor protein (APP). Cell treatment with trehalose decreased the degradation of full-length APP and its C-terminal fragments. Trehalose also reduced the secretion of the amyloid-β peptide. Biochemical and cell biological experiments revealed that trehalose alters the subcellular distribution and decreases the degradation of APP C-terminal fragments in endolysosomal compartments. Trehalose also led to strong accumulation of the autophagic marker proteins LC3-II and p62, and decreased the proteolytic activation of the lysosomal hydrolase cathepsin D. The combined data indicate that trehalose decreases the lysosomal metabolism of APP by altering its endocytic vesicular transport. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

The YeastGenome app: the Saccharomyces Genome Database at your fingertips.

PubMed

Wong, Edith D; Karra, Kalpana; Hitz, Benjamin C; Hong, Eurie L; Cherry, J Michael

2013-01-01

The Saccharomyces Genome Database (SGD) is a scientific database that provides researchers with high-quality curated data about the genes and gene products of Saccharomyces cerevisiae. To provide instant and easy access to this information on mobile devices, we have developed YeastGenome, a native application for the Apple iPhone and iPad. YeastGenome can be used to quickly find basic information about S. cerevisiae genes and chromosomal features regardless of internet connectivity. With or without network access, you can view basic information and Gene Ontology annotations about a gene of interest by searching gene names and gene descriptions or by browsing the database within the app to find the gene of interest. With internet access, the app provides more detailed information about the gene, including mutant phenotypes, references and protein and genetic interactions, as well as provides hyperlinks to retrieve detailed information by showing SGD pages and views of the genome browser. SGD provides online help describing basic ways to navigate the mobile version of SGD, highlights key features and answers frequently asked questions related to the app. The app is available from iTunes (http://itunes.com/apps/yeastgenome). The YeastGenome app is provided freely as a service to our community, as part of SGD's mission to provide free and open access to all its data and annotations.

Evidence against roles for phorbol binding protein Munc13-1, ADAM adaptor Eve-1, or vesicle trafficking phosphoproteins Munc18 or NSF as phospho-state-sensitive modulators of phorbol/PKC-activated Alzheimer APP ectodomain shedding

PubMed Central

Ikin, Annat F; Causevic, Mirsada; Pedrini, Steve; Benson, Lyndsey S; Buxbaum, Joseph D; Suzuki, Toshiharu; Lovestone, Simon; Higashiyama, Shigeki; Mustelin, Tomas; Burgoyne, Robert D; Gandy, Sam

2007-01-01

Background Shedding of the Alzheimer amyloid precursor protein (APP) ectodomain can be accelerated by phorbol esters, compounds that act via protein kinase C (PKC) or through unconventional phorbol-binding proteins such as Munc13-1. We have previously demonstrated that application of phorbol esters or purified PKC potentiates budding of APP-bearing secretory vesicles at the trans-Golgi network (TGN) and toward the plasma membrane where APP becomes a substrate for enzymes responsible for shedding, known collectively as α-secretase(s). However, molecular identification of the presumptive "phospho-state-sensitive modulators of ectodomain shedding" (PMES) responsible for regulated shedding has been challenging. Here, we examined the effects on APP ectodomain shedding of four phorbol-sensitive proteins involved in regulation of vesicular membrane trafficking of APP: Munc13-1, Munc18, NSF, and Eve-1. Results Overexpression of either phorbol-sensitive wildtype Munc13-1 or phorbol-insensitive Munc13-1 H567K resulted in increased basal APP ectodomain shedding. However, in contrast to the report of Roßner et al (2004), phorbol ester-dependent APP ectodomain shedding from cells overexpressing APP and Munc13-1 wildtype was indistinguishable from that observed following application of phorbol to cells overexpressing APP and Munc13-1 H567K mutant. This pattern of similar effects on basal and stimulated APP shedding was also observed for Munc18 and NSF. Eve-1, an ADAM adaptor protein reported to be essential for PKC-regulated shedding of pro-EGF, was found to play no obvious role in regulated shedding of sAPPα. Conclusion Our results indicate that, in the HEK293 system, Munc13-1, Munc18, NSF, and EVE-1 fail to meet essential criteria for identity as PMES for APP. PMID:18067682

Evidence against roles for phorbol binding protein Munc13-1, ADAM adaptor Eve-1, or vesicle trafficking phosphoproteins Munc18 or NSF as phospho-state-sensitive modulators of phorbol/PKC-activated Alzheimer APP ectodomain shedding.

PubMed

Ikin, Annat F; Causevic, Mirsada; Pedrini, Steve; Benson, Lyndsey S; Buxbaum, Joseph D; Suzuki, Toshiharu; Lovestone, Simon; Higashiyama, Shigeki; Mustelin, Tomas; Burgoyne, Robert D; Gandy, Sam

2007-12-09

Shedding of the Alzheimer amyloid precursor protein (APP) ectodomain can be accelerated by phorbol esters, compounds that act via protein kinase C (PKC) or through unconventional phorbol-binding proteins such as Munc13-1. We have previously demonstrated that application of phorbol esters or purified PKC potentiates budding of APP-bearing secretory vesicles at the trans-Golgi network (TGN) and toward the plasma membrane where APP becomes a substrate for enzymes responsible for shedding, known collectively as alpha-secretase(s). However, molecular identification of the presumptive "phospho-state-sensitive modulators of ectodomain shedding" (PMES) responsible for regulated shedding has been challenging. Here, we examined the effects on APP ectodomain shedding of four phorbol-sensitive proteins involved in regulation of vesicular membrane trafficking of APP: Munc13-1, Munc18, NSF, and Eve-1. Overexpression of either phorbol-sensitive wildtype Munc13-1 or phorbol-insensitive Munc13-1 H567K resulted in increased basal APP ectodomain shedding. However, in contrast to the report of Rossner et al (2004), phorbol ester-dependent APP ectodomain shedding from cells overexpressing APP and Munc13-1 wildtype was indistinguishable from that observed following application of phorbol to cells overexpressing APP and Munc13-1 H567K mutant. This pattern of similar effects on basal and stimulated APP shedding was also observed for Munc18 and NSF. Eve-1, an ADAM adaptor protein reported to be essential for PKC-regulated shedding of pro-EGF, was found to play no obvious role in regulated shedding of sAPPalpha. Our results indicate that, in the HEK293 system, Munc13-1, Munc18, NSF, and EVE-1 fail to meet essential criteria for identity as PMES for APP.

Amyloid precursor protein modulates ERK-1 and -2 signaling.

PubMed

Venezia, Valentina; Nizzari, Mario; Repetto, Emanuela; Violani, Elisabetta; Corsaro, Alessandro; Thellung, Stefano; Villa, Valentina; Carlo, Pia; Schettini, Gennaro; Florio, Tullio; Russo, Claudio

2006-12-01

The amyloid precursor protein (APP) is a transmembrane protein with a short cytoplasmic tail whose physiological function is unclear, although it is well documented that the proteolytic processing of APP could influence the development of Alzheimer's disease (AD) through the formation of membrane-bound C-terminal fragments (CTFs) and of beta-amyloid peptides (Abeta). We have recently shown that tyrosine-phosphorylated APP and CTFs may interact with Grb2 and ShcA adaptor proteins and that this coupling occurs at a higher extent in AD subjects only. To study the interaction between APP or CTFs and ShcA/Grb2 and to investigate their molecular target we have used as experimental model two different cell lines: H4 human neuroglioma cells and APP/APLP null mouse embryonic fibroblast cells (MEFs). Here we show that in H4 cells APP interacts with Grb2; conversely in APP/APLP-null MEF cells this interaction is possible only after the reintroduction of human APP by transfection. We have also shown that in MEF cells the transfection of a plasmid encoding for human APP wild-type enhances the phosphorylation of ERK-1 and -2 as revealed by Western blotting and immunofluorescence experiments. Finally, also in H4 cells the overexpression of APP upregulates the levels of phospho-ERK-1 and -2. In summary our data suggest that APP may influence phospho-ERK-1 and -2 signaling through its binding with Grb2 and ShcA adaptors. The meaning of this event is not clear, but APP interaction with these adaptors could be relevant to regulate mitogenic pathway.

Disruption of Axonal Transport Perturbs Bone Morphogenetic Protein (BMP) - Signaling and Contributes to Synaptic Abnormalities in Two Neurodegenerative Diseases

PubMed Central

Kang, Min Jung; Hansen, Timothy J.; Mickiewicz, Monique; Kaczynski, Tadeusz J.; Fye, Samantha; Gunawardena, Shermali

2014-01-01

Formation of new synapses or maintenance of existing synapses requires the delivery of synaptic components from the soma to the nerve termini via axonal transport. One pathway that is important in synapse formation, maintenance and function of the Drosophila neuromuscular junction (NMJ) is the bone morphogenetic protein (BMP)-signaling pathway. Here we show that perturbations in axonal transport directly disrupt BMP signaling, as measured by its downstream signal, phospho Mad (p-Mad). We found that components of the BMP pathway genetically interact with both kinesin-1 and dynein motor proteins. Thick vein (TKV) vesicle motility was also perturbed by reductions in kinesin-1 or dynein motors. Interestingly, dynein mutations severely disrupted p-Mad signaling while kinesin-1 mutants showed a mild reduction in p-Mad signal intensity. Similar to mutants in components of the BMP pathway, both kinesin-1 and dynein motor protein mutants also showed synaptic morphological defects. Strikingly TKV motility and p-Mad signaling were disrupted in larvae expressing two human disease proteins; expansions of glutamine repeats (polyQ77) and human amyloid precursor protein (APP) with a familial Alzheimer's disease (AD) mutation (APPswe). Consistent with axonal transport defects, larvae expressing these disease proteins showed accumulations of synaptic proteins along axons and synaptic abnormalities. Taken together our results suggest that similar to the NGF-TrkA signaling endosome, a BMP signaling endosome that directly interacts with molecular motors likely exist. Thus problems in axonal transport occurs early, perturbs BMP signaling, and likely contributes to the synaptic abnormalities observed in these two diseases. PMID:25127478

Influence of Human Factor Issues on Patient-Centered mHealth Apps' Impact; Where Do We Stand?

PubMed

Wildenbos, G A; Peute, L W; Jaspers, M W M

2016-01-01

This paper discusses the preliminary results of a literature review on studies published in 2014-2015 concerning patient-centered mHealth applications' (apps) impact. Abstracts were included when they described a mHealth app targeted at patients and reported on the effects of this app on patient care. From a total of 559 potentially relevant articles, 17 papers were finally included. Nine studies reported a positive impact of the patient-centered mHealth app on patient care; 4 of these studies were randomized controlled trials. Measured impacts in the 17 studies focused on improving patients' physical activity, self-efficacy and medication adherence. Human factors issues potentially mediating these effects were discussed in all studies. Transitions in the interaction between healthcare providers and their patients were most often discussed as influencing the impact of the mHealth app. More research is needed, focussing on human issues mediating the effect of patient-centered mHealth apps to precipitate knowledge on the effectiveness of mHealth. This research should preferably be guided by socio-technical models.

Human apoB overexpression and a high-cholesterol diet differently modify the brain APP metabolism in the transgenic mouse model of atherosclerosis.

PubMed

Bjelik, Annamária; Bereczki, Erika; Gonda, Szilvia; Juhász, Anna; Rimanóczy, Agnes; Zana, Marianna; Csont, Tamás; Pákáski, Magdolna; Boda, Krisztina; Ferdinandy, Péter; Dux, László; Janka, Zoltán; Sántha, Miklós; Kálmán, János

2006-09-01

Epidemiological and biochemical data suggest a link between the cholesterol metabolism, the amyloid precursor protein (APP) processing and the increased cerebral beta-amyloid (Abeta) deposition in Alzheimer's disease (AD). The individual and combined effects of a high-cholesterol (HC) diet and the overexpression of the human apoB-100 gene were therefore examined on the cerebral expression and processing of APP in homozygous apoB-100 transgenic mice [Tg (apoB(+/+))], a validated model of atherosclerosis. When fed with 2% cholesterol for 17 weeks, only the wild-type mice exhibited significantly increased APP695 (123%) and APP770 (138%) mRNA levels in the cortex. The HC diet-induced hypercholesterolemia significantly increased the APP isoform levels in the membrane-bound fraction, not only in the wild-type animals (114%), but also in the Tg apoB(+/+) group (171%). The overexpression of human apoB-100 gene by the liver alone reduced the brain APP isoform levels in the membrane-bound fraction (78%), whereas the levels were increased by the combined effect of HC and the overexpression of the human apoB-100 gene (134%). The protein kinase C and beta-secretase protein levels were not altered by the individual or combined effects of these two factors. Our data indicate that the two atherogenic factors, the HC diet and the overexpression of the human apoB-100 gene by the liver, could exert different effects on the processing and expression of APP in the mice brain.

Genetic mouse models of brain ageing and Alzheimer's disease.

PubMed

Bilkei-Gorzo, Andras

2014-05-01

Progression of brain ageing is influenced by a complex interaction of genetic and environmental factors. Analysis of genetically modified animals with uniform genetic backgrounds in a standardised, controlled environment enables the dissection of critical determinants of brain ageing on a molecular level. Human and animal studies suggest that increased load of damaged macromolecules, efficacy of DNA maintenance, mitochondrial activity, and cellular stress defences are critical determinants of brain ageing. Surprisingly, mouse lines with genetic impairment of anti-oxidative capacity generally did not show enhanced cognitive ageing but rather an increased sensitivity to oxidative challenge. Mouse lines with impaired mitochondrial activity had critically short life spans or severe and rapidly progressing neurodegeneration. Strains with impaired clearance in damaged macromolecules or defects in the regulation of cellular stress defences showed alterations in the onset and progression of cognitive decline. Importantly, reduced insulin/insulin-like growth factor signalling generally increased life span but impaired cognitive functions revealing a complex interaction between ageing of the brain and of the body. Brain ageing is accompanied by an increased risk of developing Alzheimer's disease. Transgenic mouse models expressing high levels of mutant human amyloid precursor protein showed a number of symptoms and pathophysiological processes typical for early phase of Alzheimer's disease. Generally, therapeutic strategies effective against Alzheimer's disease in humans were also active in the Tg2576, APP23, APP/PS1 and 5xFAD lines, but a large number of false positive findings were also reported. The 3xtg AD model likely has the highest face and construct validity but further studies are needed. Copyright © 2013 Elsevier Inc. All rights reserved.

The Exosome Secretory Pathway Transports Amyloid Precursor Protein Carboxyl-terminal Fragments from the Cell into the Brain Extracellular Space*

PubMed Central

Perez-Gonzalez, Rocio; Gauthier, Sebastien A.; Kumar, Asok; Levy, Efrat

2012-01-01

In vitro studies have shown that neuronal cell cultures secrete exosomes containing amyloid-β precursor protein (APP) and the APP-processing products, C-terminal fragments (CTFs) and amyloid-β (Aβ). We investigated the secretion of full-length APP (flAPP) and APP CTFs via the exosome secretory pathway in vivo. To this end, we developed a novel protocol designed to isolate exosomes secreted into mouse brain extracellular space. Exosomes with typical morphology were isolated from freshly removed mouse brains and from frozen mouse and human brain tissues, demonstrating that exosomes can be isolated from post-mortem tissue frozen for long periods of time. flAPP, APP CTFs, and enzymes that cleave both flAPP and APP CTFs were identified in brain exosomes. Although higher levels of both flAPP and APP CTFs were observed in exosomes isolated from the brains of transgenic mice overexpressing human APP (Tg2576) compared with wild-type control mice, there was no difference in the number of secreted brain exosomes. These data indicate that the levels of flAPP and APP CTFs associated with exosomes mirror the cellular levels of flAPP and APP CTFs. Interestingly, exosomes isolated from the brains of both Tg2576 and wild-type mice are enriched with APP CTFs relative to flAPP. Thus, we hypothesize that the exosome secretory pathway plays a pleiotropic role in the brain: exosome secretion is beneficial to the cell, acting as a specific releasing system of neurotoxic APP CTFs and Aβ, but the secretion of exosomes enriched with APP CTFs, neurotoxic proteins that are also a source of secreted Aβ, is harmful to the brain. PMID:23129776

Experimental assessment of the importance of amino acid positions identified by an entropy-based correlation analysis of multiple-sequence alignments.

PubMed

Dietrich, Susanne; Borst, Nadine; Schlee, Sandra; Schneider, Daniel; Janda, Jan-Oliver; Sterner, Reinhard; Merkl, Rainer

2012-07-17

The analysis of a multiple-sequence alignment (MSA) with correlation methods identifies pairs of residue positions whose occupation with amino acids changes in a concerted manner. It is plausible to assume that positions that are part of many such correlation pairs are important for protein function or stability. We have used the algorithm H2r to identify positions k in the MSAs of the enzymes anthranilate phosphoribosyl transferase (AnPRT) and indole-3-glycerol phosphate synthase (IGPS) that show a high conn(k) value, i.e., a large number of significant correlations in which k is involved. The importance of the identified residues was experimentally validated by performing mutagenesis studies with sAnPRT and sIGPS from the archaeon Sulfolobus solfataricus. For sAnPRT, five H2r mutant proteins were generated by replacing nonconserved residues with alanine or the prevalent residue of the MSA. As a control, five residues with conn(k) values of zero were chosen randomly and replaced with alanine. The catalytic activities and conformational stabilities of the H2r and control mutant proteins were analyzed by steady-state enzyme kinetics and thermal unfolding studies. Compared to wild-type sAnPRT, the catalytic efficiencies (k(cat)/K(M)) were largely unaltered. In contrast, the apparent thermal unfolding temperature (T(M)(app)) was lowered in most proteins. Remarkably, the strongest observed destabilization (ΔT(M)(app) = 14 °C) was caused by the V284A exchange, which pertains to the position with the highest correlation signal [conn(k) = 11]. For sIGPS, six H2r mutant and four control proteins with alanine exchanges were generated and characterized. The k(cat)/K(M) values of four H2r mutant proteins were reduced between 13- and 120-fold, and their T(M)(app) values were decreased by up to 5 °C. For the sIGPS control proteins, the observed activity and stability decreases were much less severe. Our findings demonstrate that positions with high conn(k) values have an increased probability of being important for enzyme function or stability.

Apps seeking theories: results of a study on the use of health behavior change theories in cancer survivorship mobile apps.

PubMed

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

2015-03-27

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. 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. 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. 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. Mobile apps are rapidly emerging as a way to deliver health behavior change interventions that can be tailored or personalized for individuals. As these apps and games continue to evolve and include interactive and adaptive sensors and other forms of dynamic feedback, their content and interventional elements need to be grounded in human computer interface design and health behavior and communication theory and practice.

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 apps and games continue to evolve and include interactive and adaptive sensors and other forms of dynamic feedback, their content and interventional elements need to be grounded in human computer interface design and health behavior and communication theory and practice. PMID:25830810

APP metabolism regulates tau proteostasis in human cerebral cortex neurons.

PubMed

Moore, Steven; Evans, Lewis D B; Andersson, Therese; Portelius, Erik; Smith, James; Dias, Tatyana B; Saurat, Nathalie; McGlade, Amelia; Kirwan, Peter; Blennow, Kaj; Hardy, John; Zetterberg, Henrik; Livesey, Frederick J

2015-05-05

Accumulation of Aβ peptide fragments of the APP protein and neurofibrillary tangles of the microtubule-associated protein tau are the cellular hallmarks of Alzheimer's disease (AD). To investigate the relationship between APP metabolism and tau protein levels and phosphorylation, we studied human-stem-cell-derived forebrain neurons with genetic forms of AD, all of which increase the release of pathogenic Aβ peptides. We identified marked increases in intracellular tau in genetic forms of AD that either mutated APP or increased its dosage, suggesting that APP metabolism is coupled to changes in tau proteostasis. Manipulating APP metabolism by β-secretase and γ-secretase inhibition, as well as γ-secretase modulation, results in specific increases and decreases in tau protein levels. These data demonstrate that APP metabolism regulates tau proteostasis and suggest that the relationship between APP processing and tau is not mediated solely through extracellular Aβ signaling to neurons. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

Amyloid precursor protein expression and processing are differentially regulated during cortical neuron differentiation.

PubMed

Bergström, Petra; Agholme, Lotta; Nazir, Faisal Hayat; Satir, Tugce Munise; Toombs, Jamie; Wellington, Henrietta; Strandberg, Joakim; Bontell, Thomas Olsson; Kvartsberg, Hlin; Holmström, Maria; Boreström, Cecilia; Simonsson, Stina; Kunath, Tilo; Lindahl, Anders; Blennow, Kaj; Hanse, Eric; Portelius, Erik; Wray, Selina; Zetterberg, Henrik

2016-07-07

Amyloid precursor protein (APP) and its cleavage product amyloid β (Aβ) have been thoroughly studied in Alzheimer's disease. However, APP also appears to be important for neuronal development. Differentiation of induced pluripotent stem cells (iPSCs) towards cortical neurons enables in vitro mechanistic studies on human neuronal development. Here, we investigated expression and proteolytic processing of APP during differentiation of human iPSCs towards cortical neurons over a 100-day period. APP expression remained stable during neuronal differentiation, whereas APP processing changed. α-Cleaved soluble APP (sAPPα) was secreted early during differentiation, from neuronal progenitors, while β-cleaved soluble APP (sAPPβ) was first secreted after deep-layer neurons had formed. Short Aβ peptides, including Aβ1-15/16, peaked during the progenitor stage, while processing shifted towards longer peptides, such as Aβ1-40/42, when post-mitotic neurons appeared. This indicates that APP processing is regulated throughout differentiation of cortical neurons and that amyloidogenic APP processing, as reflected by Aβ1-40/42, is associated with mature neuronal phenotypes.

Phosphorylation of amyloid precursor protein at threonine 668 is essential for its copper-responsive trafficking in SH-SY5Y neuroblastoma cells.

PubMed

Acevedo, Karla M; Opazo, Carlos M; Norrish, David; Challis, Leesa M; Li, Qiao-Xin; White, Anthony R; Bush, Ashley I; Camakaris, James

2014-04-18

Amyloid precursor protein (APP) undergoes post-translational modification, including O- and N-glycosylation, ubiquitination, and phosphorylation as it traffics through the secretory pathway. We have previously reported that copper promotes a change in the cellular localization of APP. We now report that copper increases the phosphorylation of endogenous APP at threonine 668 (Thr-668) in SH-SY5Y neuronal cells. The level of APPT668-p (detected using a phospho-site-specific antibody) exhibited a copper-dependent increase. Using confocal microscopy imaging we demonstrate that the phospho-deficient mutant, Thr-668 to alanine (T668A), does not exhibit detectable copper-responsive APP trafficking. In contrast, mutating a serine to an alanine at residue 655 does not affect copper-responsive trafficking. We further investigated the importance of the Thr-668 residue in copper-responsive trafficking by treating SH-SY5Y cells with inhibitors for glycogen synthase kinase 3-β (GSK3β) and cyclin-dependent kinases (Cdk), the main kinases that phosphorylate APP at Thr-668 in neurons. Our results show that the GSK3β kinase inhibitors LiCl, SB 216763, and SB 415286 prevent copper-responsive APP trafficking. In contrast, the Cdk inhibitors Purvalanol A and B had no significant effect on copper-responsive trafficking in SH-SY5Y cells. In cultured primary hippocampal neurons, copper promoted APP re-localization to the axon, and this effect was inhibited by the addition of LiCl, indicating that a lithium-sensitive kinase(s) is involved in copper-responsive trafficking in hippocampal neurons. This is consistent with APP axonal transport to the synapse, where APP is involved in a number of functions. We conclude that copper promotes APP trafficking by promoting a GSK3β-dependent phosphorylation in SH-SY5Y cells.

Phosphorylation of Amyloid Precursor Protein at Threonine 668 Is Essential for Its Copper-responsive Trafficking in SH-SY5Y Neuroblastoma Cells*

PubMed Central

Acevedo, Karla M.; Opazo, Carlos M.; Norrish, David; Challis, Leesa M.; Li, Qiao-Xin; White, Anthony R.; Bush, Ashley I.; Camakaris, James

2014-01-01

Amyloid precursor protein (APP) undergoes post-translational modification, including O- and N-glycosylation, ubiquitination, and phosphorylation as it traffics through the secretory pathway. We have previously reported that copper promotes a change in the cellular localization of APP. We now report that copper increases the phosphorylation of endogenous APP at threonine 668 (Thr-668) in SH-SY5Y neuronal cells. The level of APPT668-p (detected using a phospho-site-specific antibody) exhibited a copper-dependent increase. Using confocal microscopy imaging we demonstrate that the phospho-deficient mutant, Thr-668 to alanine (T668A), does not exhibit detectable copper-responsive APP trafficking. In contrast, mutating a serine to an alanine at residue 655 does not affect copper-responsive trafficking. We further investigated the importance of the Thr-668 residue in copper-responsive trafficking by treating SH-SY5Y cells with inhibitors for glycogen synthase kinase 3-β (GSK3β) and cyclin-dependent kinases (Cdk), the main kinases that phosphorylate APP at Thr-668 in neurons. Our results show that the GSK3β kinase inhibitors LiCl, SB 216763, and SB 415286 prevent copper-responsive APP trafficking. In contrast, the Cdk inhibitors Purvalanol A and B had no significant effect on copper-responsive trafficking in SH-SY5Y cells. In cultured primary hippocampal neurons, copper promoted APP re-localization to the axon, and this effect was inhibited by the addition of LiCl, indicating that a lithium-sensitive kinase(s) is involved in copper-responsive trafficking in hippocampal neurons. This is consistent with APP axonal transport to the synapse, where APP is involved in a number of functions. We conclude that copper promotes APP trafficking by promoting a GSK3β-dependent phosphorylation in SH-SY5Y cells. PMID:24610780

Dl-3-n-Butylphthalide Inhibits NLRP3 Inflammasome and Mitigates Alzheimer's-Like Pathology via Nrf2-TXNIP-TrX Axis.

PubMed

Wang, Chun-Yan; Xu, Ye; Wang, Xu; Guo, Chuang; Wang, Tao; Wang, Zhan-You

2018-04-25

Oxidative stress and neuroinflammation play important roles in the pathology of Alzheimer's disease (AD). Thioredoxin-interacting protein (TXNIP), an endogenous inhibitor of antioxidant thioredoxin, is suspected to be an important modulator of oxidative stress and inflammation. However, the underlying mechanism involved in the abnormal homeostasis of TXNIP-thioredoxin (TrX) in AD pathogenesis remains unclear. Using the Swedish mutant form of APP (APPswe)/PSEN1dE9 transgenic mouse (APP/PS1) and human-derived neuronal cells as model systems, we disclosed the impairment of the nuclear factor erythroid 2-related factor 2 (Nrf2)-TXNIP-TrX signaling in Alzheimer's-like pathology. We observed that the immune staining of TXNIP was increased in postmortem AD brain. The chronic accumulation of inflammatory mediator in neuronal cells facilitates interactions of TXNIP-nucleotide binding oligomerization domain-like receptor family, pyrin domain containing 3 (NLRP3) and NLRP3-ASC, which increases β-amyloid (Aβ) secretion. The antioxidant Dl-3-n-butylphthalide (Dl-NBP) is commonly used for cerebral ischemia treatment. In our study, we elucidated for new mechanisms by which Dl-NBP enhanced TrX activity, suppressed TXNIP, and ameliorated neuronal apoptosis in the APP/PS1 mouse brains. In human glioblastoma A172 cells and neuroblastoma SH-SY5Y cells, we delineated the Dl-NBP-mediated signaling pathways by which Dl-NBP-dependent upregulation of Nrf2 mediated the reciprocal regulation of reducing proinflammatory cytokine and inhibiting Aβ production in the glial and neuronal cells overexpressing APPswe. Our data provide a novel insight into the molecular mechanism that impairments of Nrf2-TXNIP-TrX system may be involved in the imbalance of cellular redox homeostasis and inflammatory damage in the AD brain. Dl-NBP treatment could suppress TXNIP-NLRP3 interaction and inhibit NLRP3 inflammasome activation via upregulating Nrf2. These findings may provide an instrumental therapeutic approach for AD. Antioxid. Redox Signal. 00, 000-000.

Pharmacological activation of LXRs decreases amyloid-β levels in Niemann-Pick type C model cells.

PubMed

Stefulj, Jasminka; Peric, Maja; Malnar, Martina; Kosicek, Marko; Schweinzer, Cornelia; Zivkovic, Jelena; Scholler, Monika; Panzenboeck, Ute; Hecimovic, Silva

2013-01-01

Niemann-Pick type C disease (NPC) is an inherited disorder mainly caused by loss-of-function mutations in the NPC1 gene, that lead to intracellular cholesterol accumulation and disturbed cholesterol homeostasis. Similarly to Alzheimer's disease (AD), NPC is associated with progressive neurodegeneration and altered metabolism of amyloid precursor protein (APP). Liver X receptors (LXRs), the key transcriptional regulators of cholesterol homeostasis, were reported to play neuroprotective roles in NPC mice. We investigated the impacts of LXRs on APP metabolism in mutant CHO cells lacking the NPC1 gene (-NPC1 cells). Pharmacological activation of LXRs in -NPC1 cells tended to reduce the ratio of total secreted APP (sAPP) to full length APP (flAPP) levels and sAPPβ levels as well as to increase the ratio of APP Cterminal fragments to flAPP levels, resulting in decreased levels of amyloid β (Aβ) peptides. -NPC1 cells treated with LXR agonist TO901317 (TO90) displayed a modest increase in cholesterol efflux to apolipoprotein A-I (apoA-I) but not to HDL3, or in the absence of extracellular cholesterol acceptors. The observed similar reduction of Aβ levels upon TO90 treatment in the presence or in the absence of extracellular apoA-I indicated a cholesterol-efflux independent effect of TO90 on Aβ levels. Furthermore, TO90 had no effect on the cholesterol synthesis rate in -NPC1 cells, while it reduced the rate of cholesterol esterification. The obtained results indicate that LXR activation may decrease Aβ levels in NPC1- deficient conditions. The underlying mechanism of this action does not appear to be related to effects on cholesterol efflux or synthesis rates.

Adaptor protein 2–mediated endocytosis of the β-secretase BACE1 is dispensable for amyloid precursor protein processing

PubMed Central

Prabhu, Yogikala; Burgos, Patricia V.; Schindler, Christina; Farías, Ginny G.; Magadár, Javier G.; Bonifacino, Juan S.

2012-01-01

The β-site amyloid precursor protein (APP)–cleaving enzyme 1 (BACE1) is a transmembrane aspartyl protease that catalyzes the proteolytic processing of APP and other plasma membrane protein precursors. BACE1 cycles between the trans-Golgi network (TGN), the plasma membrane, and endosomes by virtue of signals contained within its cytosolic C-terminal domain. One of these signals is the DXXLL-motif sequence DISLL, which controls transport between the TGN and endosomes via interaction with GGA proteins. Here we show that the DISLL sequence is embedded within a longer [DE]XXXL[LI]-motif sequence, DDISLL, which mediates internalization from the plasma membrane by interaction with the clathrin-associated, heterotetrameric adaptor protein 2 (AP-2) complex. Mutation of this signal or knockdown of either AP-2 or clathrin decreases endosomal localization and increases plasma membrane localization of BACE1. Remarkably, internalization-defective BACE1 is able to cleave an APP mutant that itself cannot be delivered to endosomes. The drug brefeldin A reversibly prevents BACE1-catalyzed APP cleavage, ruling out that this reaction occurs in the endoplasmic reticulum (ER) or ER–Golgi intermediate compartment. Taken together, these observations support the notion that BACE1 is capable of cleaving APP in late compartments of the secretory pathway. PMID:22553349

Memory deficiency, cerebral amyloid angiopathy, and amyloid-β plaques in APP+PS1 double transgenic rat model of Alzheimer's disease.

PubMed

Klakotskaia, Diana; Agca, Cansu; Richardson, Rachel A; Stopa, Edward G; Schachtman, Todd R; Agca, Yuksel

2018-01-01

Transgenic rat models of Alzheimer's disease were used to examine differences in memory and brain histology. Double transgenic female rats (APP+PS1) over-expressing human amyloid precursor protein (APP) and presenilin 1 (PS1) and single transgenic rats (APP21) over-expressing human APP were compared with wild type Fischer rats (WT). The Barnes maze assessed learning and memory and showed that both APP21 and APP+PS1 rats made significantly more errors than the WT rats during the acquisition phase, signifying slower learning. Additionally, the APP+PS1 rats made significantly more errors following a retention interval, indicating impaired memory compared to both the APP21 and WT rats. Immunohistochemistry using an antibody against amyloid-β (Aβ) showed extensive and mostly diffuse Aβ plaques in the hippocampus and dense plaques that contained tau in the cortex of the brains of the APP+PS1 rats. Furthermore, the APP+PS1 rats also showed vascular changes, including cerebral amyloid angiopathy with extensive Aβ deposits in cortical and leptomeningeal blood vessel walls and venous collagenosis. In addition to the Aβ accumulation observed in arterial, venous, and capillary walls, APP+PS1 rats also displayed enlarged blood vessels and perivascular space. Overall, the brain histopathology and behavioral assessment showed that the APP+PS1 rats demonstrated behavioral characteristics and vascular changes similar to those commonly observed in patients with Alzheimer's disease.

β- but not γ-secretase proteolysis of APP causes synaptic and memory deficits in a mouse model of dementia.

PubMed

Tamayev, Robert; Matsuda, Shuji; Arancio, Ottavio; D'Adamio, Luciano

2012-03-01

A mutation in the BRI2/ITM2b gene causes loss of BRI2 protein leading to familial Danish dementia (FDD). BRI2 deficiency of FDD provokes an increase in amyloid-β precursor protein (APP) processing since BRI2 is an inhibitor of APP proteolysis, and APP mediates the synaptic/memory deficits in FDD. APP processing is linked to Alzheimer disease (AD) pathogenesis, which is consistent with a common mechanism involving toxic APP metabolites in both dementias. We show that inhibition of APP cleavage by β-secretase rescues synaptic/memory deficits in a mouse model of FDD. β-cleavage of APP yields amino-terminal-soluble APPβ (sAPPβ) and β-carboxyl-terminal fragments (β-CTF). Processing of β-CTF by γ-secretase releases amyloid-β (Aβ), which is assumed to cause AD. However, inhibition of γ-secretase did not ameliorate synaptic/memory deficits of FDD mice. These results suggest that sAPPβ and/or β-CTF, rather than Aβ, are the toxic species causing dementia, and indicate that reducing β-cleavage of APP is an appropriate therapeutic approach to treating human dementias. Our data and the failures of anti-Aβ therapies in humans advise against targeting γ-secretase cleavage of APP and/or Aβ. Copyright © 2012 EMBO Molecular Medicine.

β- but not γ-secretase proteolysis of APP causes synaptic and memory deficits in a mouse model of dementia

PubMed Central

Tamayev, Robert; Matsuda, Shuji; Arancio, Ottavio; D'Adamio, Luciano

2012-01-01

A mutation in the BRI2/ITM2b gene causes loss of BRI2 protein leading to familial Danish dementia (FDD). BRI2 deficiency of FDD provokes an increase in amyloid-β precursor protein (APP) processing since BRI2 is an inhibitor of APP proteolysis, and APP mediates the synaptic/memory deficits in FDD. APP processing is linked to Alzheimer disease (AD) pathogenesis, which is consistent with a common mechanism involving toxic APP metabolites in both dementias. We show that inhibition of APP cleavage by β-secretase rescues synaptic/memory deficits in a mouse model of FDD. β-cleavage of APP yields amino-terminal-soluble APPβ (sAPPβ) and β-carboxyl-terminal fragments (β-CTF). Processing of β-CTF by γ-secretase releases amyloid-β (Aβ), which is assumed to cause AD. However, inhibition of γ-secretase did not ameliorate synaptic/memory deficits of FDD mice. These results suggest that sAPPβ and/or β-CTF, rather than Aβ, are the toxic species causing dementia, and indicate that reducing β-cleavage of APP is an appropriate therapeutic approach to treating human dementias. Our data and the failures of anti-Aβ therapies in humans advise against targeting γ-secretase cleavage of APP and/or Aβ. PMID:22170863

There's an app for that shirt! Evaluation of augmented reality tracking methods on deformable surfaces for fashion design

NASA Astrophysics Data System (ADS)

Ruzanka, Silvia; Chang, Ben; Behar, Katherine

2013-03-01

In this paper we present appARel, a creative research project at the intersection of augmented reality, fashion, and performance art. appARel is a mobile augmented reality application that transforms otherwise ordinary garments with 3D animations and modifications. With appARel, entire fashion collections can be uploaded in a smartphone application, and "new looks" can be downloaded in a software update. The project will culminate in a performance art fashion show, scheduled for March 2013. appARel includes textile designs incorporating fiducial markers, garment designs that incorporate multiple markers with the human body, and iOS and Android apps that apply different augments, or "looks", to a garment. We discuss our philosophy for combining computer-generated and physical objects; and share the challenges we encountered in applying fiduciary markers to the 3D curvatures of the human body.

Hierarchical regulation of photosynthesis gene expression by the oxygen-responsive PrrBA and AppA-PpsR systems of Rhodobacter sphaeroides.

PubMed

Gomelsky, Larissa; Moskvin, Oleg V; Stenzel, Rachel A; Jones, Denise F; Donohue, Timothy J; Gomelsky, Mark

2008-12-01

In the facultatively phototrophic proteobacterium Rhodobacter sphaeroides, formation of the photosynthetic apparatus is oxygen dependent. When oxygen tension decreases, the response regulator PrrA of the global two-component PrrBA system is believed to directly activate transcription of the puf, puh, and puc operons, encoding structural proteins of the photosynthetic complexes, and to indirectly upregulate the photopigment biosynthesis genes bch and crt. Decreased oxygen also results in inactivation of the photosynthesis-specific repressor PpsR, bringing about derepression of the puc, bch, and crt operons. We uncovered a hierarchical relationship between these two regulatory systems, earlier thought to function independently. We also more accurately assessed the spectrum of gene targets of the PrrBA system. First, expression of the appA gene, encoding the PpsR antirepressor, is PrrA dependent, which establishes one level of hierarchical dominance of the PrrBA system over AppA-PpsR. Second, restoration of the appA transcript to the wild-type level is insufficient for rescuing phototrophic growth impairment of the prrA mutant, whereas inactivation of ppsR is sufficient. This suggests that in addition to controlling appA transcription, PrrA affects the activity of the AppA-PpsR system via an as yet unidentified mechanism(s). Third, PrrA directly activates several bch and crt genes, traditionally considered to be the PpsR targets. Therefore, in R. sphaeroides, the global PrrBA system regulates photosynthesis gene expression (i) by rigorous control over the photosynthesis-specific AppA-PpsR regulatory system and (ii) by extensive direct transcription activation of genes encoding structural proteins of photosynthetic complexes as well as genes encoding photopigment biosynthesis enzymes.

Modelling APOE ɛ3/4 allele-associated sporadic Alzheimer's disease in an induced neuron.

PubMed

Kim, Hongwon; Yoo, Junsang; Shin, Jaein; Chang, Yujung; Jung, Junghyun; Jo, Dong-Gyu; Kim, Janghwan; Jang, Wonhee; Lengner, Christopher J; Kim, Byung-Soo; Kim, Jongpil

2017-08-01

The recent generation of induced neurons by direct lineage conversion holds promise for in vitro modelling of sporadic Alzheimer's disease. Here, we report the generation of induced neuron-based model of sporadic Alzheimer's disease in mice and humans, and used this system to explore the pathogenic mechanisms resulting from the sporadic Alzheimer's disease risk factor apolipoprotein E (APOE) ɛ3/4 allele. We show that mouse and human induced neurons overexpressing mutant amyloid precursor protein in the background of APOE ɛ3/4 allele exhibit altered amyloid precursor protein (APP) processing, abnormally increased production of amyloid-β42 and hyperphosphorylation of tau. Importantly, we demonstrate that APOE ɛ3/4 patient induced neuron culture models can faithfully recapitulate molecular signatures seen in APOE ɛ3/4-associated sporadic Alzheimer's disease patients. Moreover, analysis of the gene network derived from APOE ɛ3/4 patient induced neurons reveals a strong interaction between APOE ɛ3/4 and another Alzheimer's disease risk factor, desmoglein 2 (DSG2). Knockdown of DSG2 in APOE ɛ3/4 induced neurons effectively rescued defective APP processing, demonstrating the functional importance of this interaction. These data provide a direct connection between APOE ɛ3/4 and another Alzheimer's disease susceptibility gene and demonstrate in proof of principle the utility of induced neuron-based modelling of Alzheimer's disease for therapeutic discovery. © The Author (2017). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

APP Processing Induced by Herpes Simplex Virus Type 1 (HSV-1) Yields Several APP Fragments in Human and Rat Neuronal Cells

PubMed Central

Civitelli, Livia; Argnani, Rafaela; Piacentini, Roberto; Ripoli, Cristian; Manservigi, Roberto; Grassi, Claudio; Garaci, Enrico; Palamara, Anna Teresa

2010-01-01

Lifelong latent infections of the trigeminal ganglion by the neurotropic herpes simplex virus type 1 (HSV-1) are characterized by periodic reactivation. During these episodes, newly produced virions may also reach the central nervous system (CNS), causing productive but generally asymptomatic infections. Epidemiological and experimental findings suggest that HSV-1 might contribute to the pathogenesis of Alzheimer's disease (AD). This multifactorial neurodegenerative disorder is related to an overproduction of amyloid beta (Aβ) and other neurotoxic peptides, which occurs during amyloidogenic endoproteolytic processing of the transmembrane amyloid precursor protein (APP). The aim of our study was to identify the effects of productive HSV-1 infection on APP processing in neuronal cells. We found that infection of SH-SY5Y human neuroblastoma cells and rat cortical neurons is followed by multiple cleavages of APP, which result in the intra- and/or extra-cellular accumulation of various neurotoxic species. These include: i) APP fragments (APP-Fs) of 35 and 45 kDa (APP-F35 and APP-F45) that comprise portions of Aβ; ii) N-terminal APP-Fs that are secreted; iii) intracellular C-terminal APP-Fs; and iv) Aβ1-40 and Aβ1-42. Western blot analysis of infected-cell lysates treated with formic acid suggests that APP-F35 may be an Aβ oligomer. The multiple cleavages of APP that occur in infected cells are produced in part by known components of the amyloidogenic APP processing pathway, i.e., host-cell β-secretase, γ-secretase, and caspase-3-like enzymes. These findings demonstrate that HSV-1 infection of neuronal cells can generate multiple APP fragments with well-documented neurotoxic potentials. It is tempting to speculate that intra- and extracellular accumulation of these species in the CNS resulting from repeated HSV-1 reactivation could, in the presence of other risk factors, play a co-factorial role in the development of AD. PMID:21085580

76 FR 50481 - Announcement of Requirements and Registration for “Lifeline Facebook App Challenge”; Correction

Federal Register 2010, 2011, 2012, 2013, 2014

2011-08-15

... DEPARTMENT OF HEALTH AND HUMAN SERVICES Announcement of Requirements and Registration for ``Lifeline Facebook App Challenge''; Correction AGENCY: Office of the Assistant Secretary for Preparedness... Requirements and Registration for ``Lifeline Facebook App Challenge''. DATES: This correction is effective...

Familial Alzheimer’s mutations within APPTM increase Aβ42 production by enhancing accessibility of ɛ-cleavage site

NASA Astrophysics Data System (ADS)

Chen, Wen; Gamache, Eric; Rosenman, David J.; Xie, Jian; Lopez, Maria M.; Li, Yue-Ming; Wang, Chunyu

2014-01-01

The high Aβ42/Aβ40 production ratio is a hallmark of familial Alzheimer’s disease, which can be caused by mutations in the amyloid precursor protein (APP). The C-terminus of Aβ is generated by γ-secretase cleavage within the transmembrane domain of APP (APPTM), a process that is primed by an initial ɛ-cleavage at either T48 or L49, resulting in subsequent production of Aβ42 or Aβ40, respectively. Here we solve the dimer structures of wild-type APPTM (AAPTM WT) and mutant APPTM (FAD mutants V44M) with solution NMR. The right-handed APPTM helical dimer is mediated by GXXXA motif. From the NMR structural and dynamic data, we show that the V44M and V44A mutations can selectively expose the T48 site by weakening helical hydrogen bonds and increasing hydrogen-deuterium exchange rate (kex). We propose a structural model in which FAD mutations (V44M and V44A) can open the T48 site γ-secretase for the initial ɛ-cleavage, and consequently shift cleavage preference towards Aβ42.

Screening for Small Molecule Inhibitors of Statin-Induced APP C-terminal Toxic Fragment Production

PubMed Central

Poksay, Karen S.; Sheffler, Douglas J.; Spilman, Patricia; Campagna, Jesus; Jagodzinska, Barbara; Descamps, Olivier; Gorostiza, Olivia; Matalis, Alex; Mullenix, Michael; Bredesen, Dale E.; Cosford, Nicholas D. P.; John, Varghese

2017-01-01

Alzheimer’s disease (AD) is characterized by neuronal and synaptic loss. One process that could contribute to this loss is the intracellular caspase cleavage of the amyloid precursor protein (APP) resulting in release of the toxic C-terminal 31-amino acid peptide APP-C31 along with the production of APPΔC31, full-length APP minus the C-terminal 31 amino acids. We previously found that a mutation in APP that prevents this caspase cleavage ameliorated synaptic loss and cognitive impairment in a murine AD model. Thus, inhibition of this cleavage is a reasonable target for new therapeutic development. In order to identify small molecules that inhibit the generation of APP-C31, we first used an APPΔC31 cleavage site-specific antibody to develop an AlphaLISA to screen several chemical compound libraries for the level of N-terminal fragment production. This antibody was also used to develop an ELISA for validation studies. In both high throughput screening (HTS) and validation testing, the ability of compounds to inhibit simvastatin- (HTS) or cerivastatin- (validation studies) induced caspase cleavage at the APP-D720 cleavage site was determined in Chinese hamster ovary (CHO) cells stably transfected with wildtype (wt) human APP (CHO-7W). Several compounds, as well as control pan-caspase inhibitor Q-VD-OPh, inhibited APPΔC31 production (measured fragment) and rescued cell death in a dose-dependent manner. The effective compounds fell into several classes including SERCA inhibitors, inhibitors of Wnt signaling, and calcium channel antagonists. Further studies are underway to evaluate the efficacy of lead compounds – identified here using cells and tissues expressing wt human APP – in mouse models of AD expressing mutated human APP, as well as to identify additional compounds and determine the mechanisms by which they exert their effects. PMID:28261092

Fine ambient particles induce oxidative stress and metal binding genes in human alveolar machrophages

EPA Science Inventory

Exposure to ambient pollutant particles (APP) increased respiratory morbidity and mortality. The alveolar macrophages (AMs) are one cell type in the lung directly exposed to APP. Upon contact with APP, AMs are activated and produce reactive oxygen species, but the scope ofthis ox...

Bulkiness or aromatic nature of tyrosine-143 of actin is important for the weak binding between F-actin and myosin-ADP-phosphate

DOE Office of Scientific and Technical Information (OSTI.GOV)

Gomibuchi, Yuki; Uyeda, Taro Q.P.; Wakabayashi, Takeyuki, E-mail: tw007@nasu.bio.teikyo-u.ac.jp

2013-11-29

Highlights: •The effect of mutation of Tyr143 that becomes more exposed on assembly was examined. •Mutation of tyrosine-143 of Dictyostelium actin changed actin polymerizability. •The bulkiness or aromatic nature of Tyr143 is important for the weak binding. •The weak interaction between myosin and actin strengthened by Tyr143Trp mutation. -- Abstract: Actin filaments (F-actin) interact with myosin and activate its ATPase to support force generation. By comparing crystal structures of G-actin and the quasi-atomic model of F-actin based on high-resolution cryo-electron microscopy, the tyrosine-143 was found to be exposed more than 60 Å{sup 2} to the solvent in F-actin. Because tyrosine-143more » flanks the hydrophobic cleft near the hydrophobic helix that binds to myosin, the mutant actins, of which the tyrosine-143 was replaced with tryptophan, phenylalanine, or isoleucine, were generated using the Dictyostelium expression system. It polymerized significantly poorly when induced by NaCl, but almost normally by KCl. In the presence of phalloidin and KCl, the extents of the polymerization of all the mutant actins were comparable to that of the wild-type actin so that the actin-activated myosin ATPase activity could be reliably compared. The affinity of skeletal heavy meromyosin to F-actin and the maximum ATPase activity (V{sub max}) were estimated by a double reciprocal plot. The Tyr143Trp-actin showed the higher affinity (smaller K{sub app}) than that of the wild-type actin, with the V{sub max} being almost unchanged. The K{sub app} and V{sub max} of the Tyr143Phe-actin were similar to those of the wild-type actin. However, the activation by Tyr143Ile-actin was much smaller than the wild-type actin and the accurate determination of K{sub app} was difficult. Comparison of the myosin ATPase activated by the various mutant actins at the same concentration of F-actin showed that the extent of activation correlates well with the solvent-accessible surface areas (ASA) of the replaced amino acid molecule. Because 1/K{sub app} reflects the affinity of F-actin for the myosin–ADP-phosphate intermediate (M.ADP.Pi) through the weak binding, these data suggest that the bulkiness or the aromatic nature of the tyrosin-143 is important for the initial binding of the M.ADP.Pi intermediate with F-actin but not for later processes such as the phosphate release.« less

Preserved Fronto-Striatal Plasticity and Enhanced Procedural Learning in a Transgenic Mouse Model of Alzheimer's Disease Overexpressing Mutant "hAPPswe"

ERIC Educational Resources Information Center

Middei, Silvia; Geracitano, Raffaella; Caprioli, Antonio; Mercuri, Nicola; Ammassari-Teule, Martine

2004-01-01

Mutations in the amyloid precursor protein (APP) gene inducing abnormal processing and deposition of [beta]-amyloid protein in the brain have been implicated in the pathogenesis of Alzheimer's disease (AD). Although Tg2576 mice with the Swedish mutation ("hAPPswe") exhibit age-related [Alpha][beta]-plaque formation in brain regions like the…

Amyloid Precursor Protein (APP) Mediated Regulation of Ganglioside Homeostasis Linking Alzheimer's Disease Pathology with Ganglioside Metabolism

PubMed Central

Grimm, Marcus O. W.; Zinser, Eva G.; Grösgen, Sven; Hundsdörfer, Benjamin; Rothhaar, Tatjana L.; Burg, Verena K.; Kaestner, Lars; Bayer, Thomas A.; Lipp, Peter; Müller, Ulrike; Grimm, Heike S.; Hartmann, Tobias

2012-01-01

Gangliosides are important players for controlling neuronal function and are directly involved in AD pathology. They are among the most potent stimulators of Aβ production, are enriched in amyloid plaques and bind amyloid beta (Aβ). However, the molecular mechanisms linking gangliosides with AD are unknown. Here we identified the previously unknown function of the amyloid precursor protein (APP), specifically its cleavage products Aβ and the APP intracellular domain (AICD), of regulating GD3-synthase (GD3S). Since GD3S is the key enzyme converting a- to b-series gangliosides, it therefore plays a major role in controlling the levels of major brain gangliosides. This regulation occurs by two separate and additive mechanisms. The first mechanism directly targets the enzymatic activity of GD3S: Upon binding of Aβ to the ganglioside GM3, the immediate substrate of the GD3S, enzymatic turnover of GM3 by GD3S was strongly reduced. The second mechanism targets GD3S expression. APP cleavage results, in addition to Aβ release, in the release of AICD, a known candidate for gene transcriptional regulation. AICD strongly down regulated GD3S transcription and knock-in of an AICD deletion mutant of APP in vivo, or knock-down of Fe65 in neuroblastoma cells, was sufficient to abrogate normal GD3S functionality. Equally, knock-out of the presenilin genes, presenilin 1 and presenilin 2, essential for Aβ and AICD production, or of APP itself, increased GD3S activity and expression and consequently resulted in a major shift of a- to b-series gangliosides. In addition to GD3S regulation by APP processing, gangliosides in turn altered APP cleavage. GM3 decreased, whereas the ganglioside GD3, the GD3S product, increased Aβ production, resulting in a regulatory feedback cycle, directly linking ganglioside metabolism with APP processing and Aβ generation. A central aspect of this homeostatic control is the reduction of GD3S activity via an Aβ-GM3 complex and AICD-mediated repression of GD3S transcription. PMID:22470521

Overexpression of amyloid precursor protein increases copper content in HEK293 cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Suazo, Miriam; Hodar, Christian; Morgan, Carlos

2009-05-15

Amyloid precursor protein (APP) is a transmembrane glycoprotein widely expressed in mammalian tissues and plays a central role in Alzheimer's disease. However, its physiological function remains elusive. Cu{sup 2+} binding and reduction activities have been described in the extracellular APP135-156 region, which might be relevant for cellular copper uptake and homeostasis. Here, we assessed Cu{sup 2+} reduction and {sup 64}Cu uptake in two human HEK293 cell lines overexpressing APP. Our results indicate that Cu{sup 2+} reduction increased and cells accumulated larger levels of copper, maintaining cell viability at supra-physiological levels of Cu{sup 2+} ions. Moreover, wild-type cells exposed to bothmore » Cu{sup 2+} ions and APP135-155 synthetic peptides increased copper reduction and uptake. Complementation of function studies in human APP751 transformed Fre1 defective Saccharomyces cerevisiae cells rescued low Cu{sup 2+} reductase activity and increased {sup 64}Cu uptake. We conclude that Cu{sup 2+} reduction activity of APP facilitates copper uptake and may represent an early step in cellular copper homeostasis.« less

RNAi-mediated knock-down of Dab and Numb attenuate Aβ levels via γ-secretase mediated APP processing.

PubMed

Xie, Zhongcong; Dong, Yuanlin; Maeda, Uta; Xia, Weiming; Tanzi, Rudolph E

2012-03-22

Amyloid-β-protein (Aβ), the key component of senile plaques in Alzheimer's disease (AD) brain, is produced from amyloid precursor protein (APP) by cleavage of β-secretase and then γ-secretase. APP adaptor proteins with phosphotyrosine-binding (PTB) domains, including Dab (gene: DAB) and Numb (gene: NUMB), can bind to and interact with the conserved YENPTY-motif in the APP C-terminus. Here we describe, for the first time, the effects of RNAi knock-down of Dab and Numb expression on APP processing and Aβ production. RNAi knock-down of Dab and Numb in H4 human neuroglioma cells stably transfected to express either FL-APP (H4-FL-APP cells) or APP-C99 (H4-APP-C99 cells) increased levels of APP-C-terminal fragments (APP-CTFs) and lowered Aβ levels in both cell lines by inhibiting γ-secretase cleavage of APP. Finally, RNAi knock-down of APP also reduced levels of Numb in H4-APP cells. These findings suggest that pharmacologically blocking interaction of APP with Dab and Numb may provide novel therapeutic strategies of AD. The notion of attenuating γ-secretase cleavage of APP via the APP adaptor proteins, Dab and Numb, is particularly attractive with regard to therapeutic potential, given that side effects of γ-secretase inhibition owing to impaired proteolysis of other γ-secretase substrates, e.g. Notch, might be avoided.

Contribution of Kunitz protease inhibitor and transmembrane domains to amyloid precursor protein homodimerization.

PubMed

Ben Khalifa, N; Tyteca, D; Courtoy, P J; Renauld, J C; Constantinescu, S N; Octave, J N; Kienlen-Campard, P

2012-01-01

The two major isoforms of the human amyloid precursor protein (APP) are APP695 and APP751. They differ by the insertion of a Kunitz-type protease inhibitor (KPI) sequence in the extracellular domain of APP751. APP-KPI isoforms are increased in Alzheimer's disease brains, and they could be associated with disease progression. Recent studies have shown that APP processing to Aβ is regulated by homodimerization, which involves both extracellular and juxtamembrane/transmembrane (JM/TM) regions. Our aim is to understand the mechanisms controlling APP dimerization and the contribution of the ectodomain and JM/TM regions to this process. We used bimolecular fluorescence complementation approaches coupled to fluorescence-activated cell sorting analysis to measure the dimerization level of different APP isoforms and APP C-terminal fragments (C99) mutated in their JM/TM region. APP751 was found to form significantly more homodimers than APP695. Mutation of dimerization motifs in the TM domain of APP or C99 did not significantly affect fluorescence complementation. These findings indicate that the KPI domain plays a major role in APP dimerization. They set the basis for further investigation of the relation between dimerization, metabolism and function of APP. Copyright © 2012 S. Karger AG, Basel.

Genetic dissection of Alzheimer disease, a heterogeneous disorder.

PubMed

Schellenberg, G D

1995-09-12

The genetics of Alzheimer disease (AD) are complex and not completely understood. Mutations in the amyloid precursor protein gene (APP) can cause early-onset autosomal dominant AD. In vitro studies indicate that cells expressing mutant APPs overproduce pathogenic forms of the A beta peptide, the major component of AD amyloid. However, mutations in the APP gene are responsible for 5% or less of all early-onset familial AD. A locus on chromosome 14 is responsible for AD in other early-onset AD families and represents the most severe form of the disease in terms of age of onset and rate of decline. Attempts to identify the AD3 gene by positional cloning methods are underway. At least one additional early-onset AD locus remains to be located. In late-onset AD, the apolipoprotein E gene allele epsilon 4 is a risk factor for AD. This allele appears to act as a dose-dependent age-of-onset modifier. The epsilon 2 allele of this gene may be protective. Other late-onset susceptibility factors remain to be identified.

Herpes simplex virus interferes with amyloid precursor protein processing.

PubMed

Shipley, Suzanne J; Parkin, Edward T; Itzhaki, Ruth F; Dobson, Curtis B

2005-08-18

The early events underlying Alzheimer's disease (AD) remain uncertain, although environmental factors may be involved. Work in this laboratory has shown that the combination of herpes simplex virus type 1 (HSV1) in brain and carriage of the APOE-epsilon4 allele of the APOE gene strongly increases the risk of developing AD. The development of AD is thought to involve abnormal aggregation or deposition of a 39-43 amino acid protein--beta amyloid (Abeta)--within the brain. This is cleaved from the much larger transmembranal protein 'amyloid precursor protein' (APP). Any agent able to interfere directly with Abeta or APP metabolism may therefore have the capacity to contribute towards AD. One recent report showed that certain HSV1 glycoprotein peptides may aggregate like Abeta; a second study described a role for APP in transport of virus in squid axons. However to date the effects of acute herpesvirus infection on metabolism of APP in human neuronal-type cells have not been investigated. In order to find if HSV1 directly affects APP and its degradation, we have examined this protein from human neuroblastoma cells (normal and transfected with APP 695) infected with the virus, using Western blotting. We have found that acute HSV1 (and also HSV2) infection rapidly reduces full length APP levels--as might be expected--yet surprisingly markedly increases levels of a novel C-terminal fragment of APP of about 55 kDa. This band was not increased in cells treated with the protein synthesis inhibitor cycloheximide Herpes virus infection leads to rapid loss of full length APP from cells, yet also causes increased levels of a novel 55 kDa C-terminal APP fragment. These data suggest that infection can directly alter the processing of a transmembranal protein intimately linked to the aetiology of AD.

Genetic cathepsin B deficiency reduces beta-amyloid in transgenic mice expressing human wild-type amyloid precursor protein.

PubMed

Hook, Vivian Y H; Kindy, Mark; Reinheckel, Thomas; Peters, Christoph; Hook, Gregory

2009-08-21

Neurotoxic beta-amyloid (Abeta) peptides participate in Alzheimer's disease (AD); therefore, reduction of Abeta generated from APP may provide a therapeutic approach for AD. Gene knockout studies in transgenic mice producing human Abeta may identify targets for reducing Abeta. This study shows that knockout of the cathepsin B gene in mice expressing human wild-type APP (hAPPwt) results in substantial decreases in brain Abeta40 and Abeta42 by 67% and decreases in levels of the C-terminal beta-secretase fragment (CTFbeta) derived from APP. In contrast, knockout of cathepsin B in mice expressing hAPP with the rare Swedish (Swe) and Indiana (Ind) mutations had no effect on Abeta. The difference in reduction of Abeta in hAPPwt mice, but not in hAPPSwe/Ind mice, shows that the transgenic model can affect cathepsin B gene knockout results. Since most AD patients express hAPPwt, these data validate cathepsin B as a target for development of inhibitors to lower Abeta in AD.

RNAi-mediated knock-down of Dab and Numb attenuate Aβ levels via γ-secretase mediated APP processing

PubMed Central

2012-01-01

Amyloid-β-protein (Aβ), the key component of senile plaques in Alzheimer's disease (AD) brain, is produced from amyloid precursor protein (APP) by cleavage of β-secretase and then γ-secretase. APP adaptor proteins with phosphotyrosine-binding (PTB) domains, including Dab (gene: DAB) and Numb (gene: NUMB), can bind to and interact with the conserved YENPTY-motif in the APP C-terminus. Here we describe, for the first time, the effects of RNAi knock-down of Dab and Numb expression on APP processing and Aβ production. RNAi knock-down of Dab and Numb in H4 human neuroglioma cells stably transfected to express either FL-APP (H4-FL-APP cells) or APP-C99 (H4-APP-C99 cells) increased levels of APP-C-terminal fragments (APP-CTFs) and lowered Aβ levels in both cell lines by inhibiting γ-secretase cleavage of APP. Finally, RNAi knock-down of APP also reduced levels of Numb in H4-APP cells. These findings suggest that pharmacologically blocking interaction of APP with Dab and Numb may provide novel therapeutic strategies of AD. The notion of attenuating γ-secretase cleavage of APP via the APP adaptor proteins, Dab and Numb, is particularly attractive with regard to therapeutic potential, given that side effects of γ-secretase inhibition owing to impaired proteolysis of other γ-secretase substrates, e.g. Notch, might be avoided. PMID:23211096

Integrated approach reveals diet, APOE genotype and sex affect immune response in APP mice.

PubMed

Nam, Kyong Nyon; Wolfe, Cody M; Fitz, Nicholas F; Letronne, Florent; Castranio, Emilie L; Mounier, Anais; Schug, Jonathan; Lefterov, Iliya; Koldamova, Radosveta

2018-01-01

Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder that is influenced by genetic and environmental risk factors, such as inheritance of ε4 allele of APOE (APOE4), sex and diet. Here, we examined the effect of high fat diet (HFD) on amyloid pathology and expression profile in brains of AD model mice expressing human APOE isoforms (APP/E3 and APP/E4 mice). APP/E3 and APP/E4 mice were fed HFD or Normal diet for 3months. We found that HFD significantly increased amyloid plaques in male and female APP/E4, but not in APP/E3 mice. To identify differentially expressed genes and gene-networks correlated to diet, APOE isoform and sex, we performed RNA sequencing and applied Weighted Gene Co-expression Network Analysis. We determined that the immune response network with major hubs Tyrobp/DAP12, Csf1r, Tlr2, C1qc and Laptm5 correlated significantly and positively to the phenotype of female APP/E4-HFD mice. Correspondingly, we found that in female APP/E4-HFD mice, microglia coverage around plaques, particularly of larger size, was significantly reduced. This suggests altered containment of the plaque growth and sex-dependent vulnerability in response to diet. The results of our study show concurrent impact of diet, APOE isoform and sex on the brain transcriptome and AD-like phenotype. Copyright © 2017 Elsevier B.V. All rights reserved.

Substance Abuse and Mental Health Services Administration (SAMHSA) Behavioral Health Disaster Response App.

PubMed

Seligman, Jamie; Felder, Stephanie S; Robinson, Maryann E

2015-10-01

The Substance Abuse and Mental Health Services Administration (SAMHSA) in the Department of Health and Human Services offers extensive disaster behavior health resources to assist disaster survivors in preparing for, responding to, and recovering from natural and manmade disasters. One of SAMHSA's most innovative resources is the SAMHSA Behavioral Health Disaster Response App (SAMHSA Disaster App). The SAMHSA Disaster App prepares behavioral health responders for any type of traumatic event by allowing them to access disaster-related materials and other key resources right on their phone, at the touch of a button. The SAMHSA Disaster App is available on iPhone, Android, and BlackBerry devices.

Suppression of angiogenesis by atmospheric pressure plasma in human aortic endothelial cells

NASA Astrophysics Data System (ADS)

Gweon, Bomi; Kim, Hyeonyu; Kim, Kijung; Kim, Mina; Shim, Eunyoung; Kim, Sunja; Choe, Wonho; Shin, Jennifer H.

2014-03-01

Atmospheric pressure plasma (APP) has been recognized as a promising tool for cancer therapy based on its ability to remove cancer cells by causing apoptosis and necrosis. However, the effect of APP on the neighboring tissues of tumors remains unknown. Moreover, the role of APP on the vessels near tumors could be very important, because once a tumor becomes vascularized, the potential for metastasis can increase dramatically. We show in the present study that APP can induce cell cycle arrest in endothelial cells and further suppress the angiogenesis process. These results strongly support the use of APP in cancer treatment.

Circadian and Brain State Modulation of Network Hyperexcitability in Alzheimer's Disease.

PubMed

Brown, Rosalind; Lam, Alice D; Gonzalez-Sulser, Alfredo; Ying, Andrew; Jones, Mary; Chou, Robert Chang-Chih; Tzioras, Makis; Jordan, Crispin Y; Jedrasiak-Cape, Izabela; Hemonnot, Anne-Laure; Abou Jaoude, Maurice; Cole, Andrew J; Cash, Sydney S; Saito, Takashi; Saido, Takaomi; Ribchester, Richard R; Hashemi, Kevan; Oren, Iris

2018-01-01

Network hyperexcitability is a feature of Alzheimer' disease (AD) as well as numerous transgenic mouse models of AD. While hyperexcitability in AD patients and AD animal models share certain features, the mechanistic overlap remains to be established. We aimed to identify features of network hyperexcitability in AD models that can be related to epileptiform activity signatures in AD patients. We studied network hyperexcitability in mice expressing amyloid precursor protein (APP) with mutations that cause familial AD, and compared a transgenic model that overexpresses human APP (hAPP) (J20), to a knock-in model expressing APP at physiological levels (APP NL/F ). We recorded continuous long-term electrocorticogram (ECoG) activity from mice, and studied modulation by circadian cycle, behavioral, and brain state. We report that while J20s exhibit frequent interictal spikes (IISs), APP NL/F mice do not. In J20 mice, IISs were most prevalent during daylight hours and the circadian modulation was associated with sleep. Further analysis of brain state revealed that IIS in J20s are associated with features of rapid eye movement (REM) sleep. We found no evidence of cholinergic changes that may contribute to IIS-circadian coupling in J20s. In contrast to J20s, intracranial recordings capturing IIS in AD patients demonstrated frequent IIS in non-REM (NREM) sleep. The salient differences in sleep-stage coupling of IIS in APP overexpressing mice and AD patients suggests that different mechanisms may underlie network hyperexcitability in mice and humans. We posit that sleep-stage coupling of IIS should be an important consideration in identifying mouse AD models that most closely recapitulate network hyperexcitability in human AD.

Expert Involvement and Adherence to Medical Evidence in Medical Mobile Phone Apps: A Systematic Review.

PubMed

Subhi, Yousif; Bube, Sarah Hjartbro; Rolskov Bojsen, Signe; Skou Thomsen, Ann Sofia; Konge, Lars

2015-07-27

Both clinicians and patients use medical mobile phone apps. Anyone can publish medical apps, which leads to contents with variable quality that may have a serious impact on human lives. We herein provide an overview of the prevalence of expert involvement in app development and whether or not app contents adhere to current medical evidence. To systematically review studies evaluating expert involvement or adherence of app content to medical evidence in medical mobile phone apps. We systematically searched 3 databases (PubMed, The Cochrane Library, and EMBASE), and included studies evaluating expert involvement or adherence of app content to medical evidence in medical mobile phone apps. Two authors performed data extraction independently. Qualitative analysis of the included studies was performed. Based on inclusion criteria, 52 studies were included in this review. These studies assessed a total of 6520 apps. Studies dealt with a variety of medical specialties and topics. As much as 28 studies assessed expert involvement, which was found in 9-67% of the assessed apps. Thirty studies (including 6 studies that also assessed expert involvement) assessed adherence of app content to current medical evidence. Thirteen studies found that 10-87% of the assessed apps adhered fully to the compared evidence (published studies, recommendations, and guidelines). Seventeen studies found that none of the assessed apps (n=2237) adhered fully to the compared evidence. Most medical mobile phone apps lack expert involvement and do not adhere to relevant medical evidence.

Should We Recommend Renal Diet-Related Apps to Our Patients? An Evaluation of the Quality and Health Literacy Demand of Renal Diet-Related Mobile Applications.

PubMed

Lambert, Kelly; Mullan, Judy; Mansfield, Kylie; Owen, Paris

2017-11-01

Mobile phone applications (apps) are increasingly being used by patients with chronic kidney disease (CKD). We sought to describe the main purpose of commonly available renal diet apps and to quantify the accuracy of information, technical quality, and health literacy demand of renal diet apps. The design was content analysis. All eligible renal diet apps in the Australian Apple App Store, Google Play, Windows Phone, and Blackberry App World were evaluated. Eligible apps were in English and were related to kidney disease in humans (of any type or stage). Exclusion criteria included apps which were prohibited because of password protection. Renal diet information in the apps was compared with evidence-based guidelines for the management of kidney disease to quantify information accuracy. App information was evaluated using the Silberg Scale. Technical quality and health literacy demand were evaluated using the Mobile Application Rating Scale. A total of 21 apps were eligible for evaluation. The main purpose of these apps was to provide food and nutrition information (57.1%) or for educative purposes for CKD patients (38.1%). Only 47.6% (10/21) of apps contained accurate evidence-based information. Overall, app technical quality was considered acceptable (mean Mobile Application Rating Scale score 3.19 ± 0.35 out of 5), with 80.9% of apps scoring acceptable or greater for app technical quality. Scores for health literacy demand also indicated that most apps (15/21, 71.4%) were acceptable. A range of apps currently exist that may provide individuals with CKD with useful food and nutrition information or increase their knowledge of the renal diet. These apps are also mainly of acceptable technical quality and health literacy demand. However, caution is required when using renal diet apps because more than half of the apps evaluated were not accurate and evidence based. Copyright © 2017 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.

GENETIC CATHEPSIN B DEFICIENCY REDUCES β-AMYLOID IN TRANSGENIC MICE EXPRESSING HUMAN WILD-TYPE AMYLOID PRECURSOR PROTEIN

PubMed Central

Hook, Vivian Y. H.; Kindy, Mark; Reinheckel, Thomas; Peters, Christoph; Hook, Gregory

2009-01-01

Neurotoxic β-amyloid (Aβ) peptides participate in Alzheimer’s disease (AD); therefore, reduction of Aβ generated from APP may provide a therapeutic approach for AD. Gene knockout studies in transgenic mice producing human Aβ may identify targets for reducing Aβ. This study shows that knockout of the cathepsin B gene in mice expressing human wild-type APP (hAPPwt) results in substantial decrease of Aβ40 and Aβ42 by 67% in brain, and decreases levels of the C-terminal β-secretase fragment (CTFβ) derived from APP. In contrast, knockout of cathepsin B in mice expressing hAPP with the rare Swedish (Swe) and Indiana (Ind) mutations had no effect on Aβ. The difference in reduction of Aβ in hAPPwt mice, but not in hAPPSwe/Ind mice, shows that the transgenic model can affect cathepsin B gene knockout results. Since most AD patients express hAPPwt, these data validate cathepsin B as a target for development of inhibitors to lower Aβ in AD. PMID:19501042

Expression of endogenous mouse APP modulates β-amyloid deposition in hAPP-transgenic mice.

PubMed

Steffen, Johannes; Krohn, Markus; Schwitlick, Christina; Brüning, Thomas; Paarmann, Kristin; Pietrzik, Claus U; Biverstål, Henrik; Jansone, Baiba; Langer, Oliver; Pahnke, Jens

2017-06-20

Amyloid-β (Aβ) deposition is one of the hallmarks of the amyloid hypothesis in Alzheimer's disease (AD). Mouse models using APP-transgene overexpression to generate amyloid plaques have shown to model only certain parts of the disease. The extent to which the data from mice can be transferred to man remains controversial. Several studies have shown convincing treatment results in reducing Aβ and enhancing cognition in mice but failed totally in human. One model-dependent factor has so far been almost completely neglected: the endogenous expression of mouse APP and its effects on the transgenic models and the readout for therapeutic approaches.Here, we report that hAPP-transgenic models of amyloidosis devoid of endogenous mouse APP expression (mAPP-knockout / mAPPko) show increased amounts and higher speed of Aβ deposition than controls with mAPP. The number of senile plaques and the level of aggregated hAβ were elevated in mAPPko mice, while the deposition in cortical blood vessels was delayed, indicating an alteration in the general aggregation propensity of hAβ together with endogenous mAβ. Furthermore, the cellular response to Aβ deposition was modulated: mAPPko mice developed a pronounced and age-dependent astrogliosis, while microglial association to amyloid plaques was diminished. The expression of human and murine aggregation-prone proteins with differing amino acid sequences within the same mouse model might not only alter the extent of deposition but also modulate the route of pathogenesis, and thus, decisively influence the study outcome, especially in translational research.

Identification of a novel amyloid precursor protein processing pathway that generates secreted N-terminal fragments.

PubMed

Vella, Laura J; Cappai, Roberto

2012-07-01

Alzheimer's disease (AD) is a neurodegenerative disorder of the central nervous system. The proteolytic processing of the amyloid precursor protein (APP) into the β-amyloid (Aβ) peptide is a central event in AD. While the pathway that generates Aβ is well described, many questions remain concerning general APP metabolism and its metabolites. It is becoming clear that the amino-terminal region of APP can be processed to release small N-terminal fragments (NTFs). The purpose of this study was to investigate the occurrence and generation of APP NTFs in vivo and in cell culture (SH-SY5Y) in order to delineate the cellular pathways implicated in their generation. We were able to detect 17- to 28-kDa APP NTFs in human and mouse brain tissue that are distinct from N-APP fragments previously reported. We show that the 17- to 28-kDa APP NTFs were highly expressed in mice from the age of 2 wk to adulthood. SH-SY5Y studies indicate the generation of APP NTFs involves a novel APP processing pathway, regulated by protein kinase C, but independent of α-secretase or β-secretase 1 (BACE) activity. These results identify a novel, developmentally regulated APP processing pathway that may play an important role in the physiological function of APP.

An Aberrant Phosphorylation of Amyloid Precursor Protein Tyrosine Regulates Its Trafficking and the Binding to the Clathrin Endocytic Complex in Neural Stem Cells of Alzheimer's Disease Patients

PubMed Central

Poulsen, Ebbe T.; Iannuzzi, Filomena; Rasmussen, Helle F.; Maier, Thorsten J.; Enghild, Jan J.; Jørgensen, Arne L.; Matrone, Carmela

2017-01-01

Alzheimer's disease (AD) is the most common cause of dementia and is likely caused by defective amyloid precursor protein (APP) trafficking and processing in neurons leading to amyloid plaques containing the amyloid-β (Aβ) APP peptide byproducts. Understanding how APP is targeted to selected destinations inside neurons and identifying the mechanisms responsible for the generation of Aβ are thus the keys for the advancement of new therapies. We previously developed a mouse model with a mutation at tyrosine (Tyr) 682 in the C-terminus of APP. This residue is needed for APP to bind to the coating protein Clathrin and to the Clathrin adaptor protein AP2 as well as for the correct APP trafficking and sorting in neurons. By extending these findings to humans, we found that APP binding to Clathrin is decreased in neural stem cells from AD sufferers. Increased APP Tyr phosphorylation alters APP trafficking in AD neurons and it is associated to Fyn Tyr kinase activation. We show that compounds affecting Tyr kinase activity and counteracting defects in AD neurons can control APP location and compartmentalization. APP Tyr phosphorylation is thus a potential therapeutic target for AD. PMID:28360834

Mobile phone applications for the care and prevention of HIV and other sexually transmitted diseases: a review.

PubMed

Muessig, Kathryn E; Pike, Emily C; Legrand, Sara; Hightow-Weidman, Lisa B

2013-01-04

Mobile phone applications (apps) provide a new platform for delivering tailored human immunodeficiency virus (HIV) and sexually transmitted disease (STD) prevention and care. To identify and evaluate currently available mobile phone apps related to the prevention and care of HIV and other STDs. We searched the Apple iTunes and Android Google Play stores for HIV/STD-related apps, excluding apps that exclusively targeted industry, providers, and researchers. Each eligible app was downloaded, tested, and assessed for user ratings and functionality as well as 6 broad content areas of HIV prevention and care: HIV/STD disease knowledge, risk reduction/safer sex, condom promotion, HIV/STD testing information, resources for HIV-positive persons, and focus on key populations. Search queries up to May 2012 identified 1937 apps. Of these, 55 unique apps met the inclusion criteria (12 for Android, 29 for iPhone, and 14 for both platforms). Among these apps, 71% provided disease information about HIV/STDs, 36% provided HIV/STD testing information or resources, 29% included information about condom use or assistance locating condoms, and 24% promoted safer sex. Only 6 apps (11%) covered all 4 of these prevention areas. Eight apps (15%) provided tools or resources specifically for HIV/STD positive persons. Ten apps included information for a range of sexual orientations, 9 apps appeared to be designed for racially/ethnically diverse audiences, and 15 apps featured interactive components. Apps were infrequently downloaded (median 100-500 downloads) and not highly rated (average customer rating 3.7 out of 5 stars). Most available HIV/STD apps have failed to attract user attention and positive reviews. Public health practitioners should work with app developers to incorporate elements of evidence-based interventions for risk reduction and improve app inclusiveness and interactivity.

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…

Carcinostatic effects of diverse ascorbate derivatives in comparison with aliphatic chain moiety structures: Promotion by combined hyperthermia and reduced cytotoxicity to normal cells.

PubMed

Asada, Ryoko; Kageyama, Katsuhiro; Tanaka, Hiroshi; Kimura, Masatugu; Saitoh, Yasukazu; Miwa, Nobuhiko

2012-05-01

In this study, using human tongue squamous carcinoma cells (HSC-4) carcinostatic activity was compared for diverse L-ascorbic acid (Asc) derivatives, including the 'straight-C(16)-chain types', 6-O-palmitoyl-Asc (A6-P) and Asc-2-phosphate-6-O-palmitate sodium salt (APPS), as well as the 'branched-C(16)-chain types', Asc-2-phosphate-6-O-(2'-hexyl)decanoate (APHD), an isomer of APPS, and Asc-2,3,5,6-O-tetra-(2'-hexyl)decanoate (VCIP). The order of magnitude of the carcinostatic effects at 37°C was: APPS>A6-P = APHD>VCIP and at 42°C was APPS = A6-P>APHD>VCIP. Therefore, the two straight-C(16)-chain derivatives, APPS and A6-P, had a greater effect compared to the two branched-C(16)-chain Asc derivatives, which are considered to have more difficulty with 'orientation along cell-membrane-glycerolipid direction'. APPS-treated HCS-4 cells were observed for a decrease in cell number, cell shrinkage, pycnosis indicative of apoptosis and cell deformation. The order of cytotoxicity for the normal human dermal fibroblasts (OUMS-36) at 37°C was: A6-P (50% inhibitory concentration: 150-300 μM)>APHD (450-600 μM)>Asc = APPS (800-1000 μM). Accordingly, APHD was more cytotoxic than APPS, since the straight-C(16)-chain type, which was eliminated after the enzymatic esterolysis of APPS, is metabolized via the 'fatty acid β-oxidation cycle' more efficiently in normal cells. Thus, APPS had a greater advantage over APHD, A6-P and VCIP in terms of carcinostatic effects at 37°C, carcinostasis promotion at 42°C and a decrease of cytotoxicity to normal cells. This observation suggests a marked potential for aliphatic chain-moiety structures as anticancer agents, due to their cancer-selective carcinostasis and combined efficacy with hyperthermia, without causing side effects.

Numb endocytic adapter proteins regulate the transport and processing of the amyloid precursor protein in an isoform-dependent manner: implications for Alzheimer disease pathogenesis.

PubMed

Kyriazis, George A; Wei, Zelan; Vandermey, Miriam; Jo, Dong-Gyu; Xin, Ouyang; Mattson, Mark P; Chan, Sic L

2008-09-12

Central to the pathogenesis of Alzheimer disease is the aberrant processing of the amyloid precursor protein (APP) to generate amyloid beta-peptide (Abeta), the principle component of amyloid plaques. The cell fate determinant Numb is a phosphotyrosine binding domain (PTB)-containing endocytic adapter protein that interacts with the carboxyl-terminal domain of APP. The physiological relevance of this interaction is unknown. Mammals produce four alternatively spliced variants of Numb that differ in the length of their PTB and proline-rich region. In the current study, we determined the influence of the four human Numb isoforms on the intracellular trafficking and processing of APP. Stable expression of Numb isoforms that differ in the PTB but not in the proline-rich region results in marked differences in the sorting of APP to the recycling and degradative pathways. Neural cells expressing Numb isoforms that lack the insert in the PTB (short PTB (SPTB)) exhibited marked accumulation of APP in Rab5A-labeled early endosomal and recycling compartments, whereas those expressing isoforms with the insertion in the PTB (long PTB (LPTB)) exhibited reduced amounts of cellular APP and its proteolytic derivatives relative to parental control cells. Neither the activities of the beta- and gamma-secretases nor the expression of APP mRNA were significantly different in the stably transfected cells, suggesting that the differential effects of the Numb proteins on APP metabolism is likely to be secondary to altered APP trafficking. In addition, the expression of SPTB-Numb increases at the expense of LPTB-Numb in neuronal cultures subjected to stress, suggesting a role for Numb in stress-induced Abeta production. Taken together, these results suggest distinct roles for the human Numb isoforms in APP metabolism and may provide a novel potential link between altered Numb isoform expression and increased Abeta generation.

Herpes simplex virus interferes with amyloid precursor protein processing

PubMed Central

Shipley, Suzanne J; Parkin, Edward T; Itzhaki, Ruth F; Dobson, Curtis B

2005-01-01

Background The early events underlying Alzheimer's disease (AD) remain uncertain, although environmental factors may be involved. Work in this laboratory has shown that the combination of herpes simplex virus type 1 (HSV1) in brain and carriage of the APOE-ε4 allele of the APOE gene strongly increases the risk of developing AD. The development of AD is thought to involve abnormal aggregation or deposition of a 39–43 amino acid protein – β amyloid (Aβ) – within the brain. This is cleaved from the much larger transmembranal protein 'amyloid precursor protein' (APP). Any agent able to interfere directly with Aβ or APP metabolism may therefore have the capacity to contribute towards AD. One recent report showed that certain HSV1 glycoprotein peptides may aggregate like Aβ; a second study described a role for APP in transport of virus in squid axons. However to date the effects of acute herpesvirus infection on metabolism of APP in human neuronal-type cells have not been investigated. In order to find if HSV1 directly affects APP and its degradation, we have examined this protein from human neuroblastoma cells (normal and transfected with APP 695) infected with the virus, using Western blotting. Results We have found that acute HSV1 (and also HSV2) infection rapidly reduces full length APP levels – as might be expected – yet surprisingly markedly increases levels of a novel C-terminal fragment of APP of about 55 kDa. This band was not increased in cells treated with the protein synthesis inhibitor cycloheximide Conclusion Herpes virus infection leads to rapid loss of full length APP from cells, yet also causes increased levels of a novel 55 kDa C-terminal APP fragment. These data suggest that infection can directly alter the processing of a transmembranal protein intimately linked to the aetiology of AD. PMID:16109164

Amyloid precursor protein regulates migration and metalloproteinase gene expression in prostate cancer cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Miyazaki, Toshiaki; Ikeda, Kazuhiro; Horie-Inoue, Kuniko

Highlights: • APP knockdown reduced proliferation and migration of prostate cancer cells. • APP knockdown reduced expression of metalloproteinase and EMT-related genes. • APP overexpression promoted LNCaP cell migration. • APP overexpression increased expression of metalloproteinase and EMT-related genes. - Abstract: Amyloid precursor protein (APP) is a type I transmembrane protein, and one of its processed forms, β-amyloid, is considered to play a central role in the development of Alzheimer’s disease. We previously showed that APP is a primary androgen-responsive gene in prostate cancer and that its increased expression is correlated with poor prognosis for patients with prostate cancer. APPmore » has also been implicated in several human malignancies. Nevertheless, the mechanism underlying the pro-proliferative effects of APP on cancers is still not well-understood. In the present study, we explored a pathophysiological role for APP in prostate cancer cells using siRNA targeting APP (siAPP). The proliferation and migration of LNCaP and DU145 prostate cancer cells were significantly suppressed by siAPP. Differentially expressed genes in siAPP-treated cells compared to control siRNA-treated cells were identified by microarray analysis. Notably, several metalloproteinase genes, such as ADAM10 and ADAM17, and epithelial–mesenchymal transition (EMT)-related genes, such as VIM, and SNAI2, were downregulated in siAPP-treated cells as compared to control cells. The expression of these genes was upregulated in LNCaP cells stably expressing APP when compared with control cells. APP-overexpressing LNCaP cells exhibited enhanced migration in comparison to control cells. These results suggest that APP may contribute to the proliferation and migration of prostate cancer cells by modulating the expression of metalloproteinase and EMT-related genes.« less

In-Situ Bioreduction and Removal of Ammonium Perchlorate

DTIC Science & Technology

2006-05-09

Ader, PhD. Max Coleman, PhD. Swades Chaudhuri, PhD. Susan O’Connor MSc, MSc Royce Bruce, MSc. Urania Michaelidou, MSc. Melissa Rice, MSc. Sarah...1993. SeqApp, 1.9a157 ed. Biocomputing Office, Biology Dept., Indiana University, Bloomington, IN. 44. Giordano , G., L. Saracino, and L. Grillet. 1985...Mutant of E. coli K-12. Biocimica et Biophysica Acta 839:181-190. 45. Guigliarelli, B., A. Magalon, M. Asso, P. Bertrand, C. Frixon, G. Giordano

Simplified Novel Application (SNApp) framework: a guide to developing and implementing second-generation mobile applications for behavioral health research.

PubMed

Fillo, Jennifer; Staplefoote-Boynton, B Lynette; Martinez, Angel; Sontag-Padilla, Lisa; Shadel, William G; Martino, Steven C; Setodji, Claude M; Meeker, Daniella; Scharf, Deborah

2016-12-01

Advances in mobile technology and mobile applications (apps) have opened up an exciting new frontier for behavioral health researchers, with a "second generation" of apps allowing for the simultaneous collection of multiple streams of data in real time. With this comes a host of technical decisions and ethical considerations unique to this evolving approach to research. Drawing on our experience developing a second-generation app for the simultaneous collection of text message, voice, and self-report data, we provide a framework for researchers interested in developing and using second-generation mobile apps to study health behaviors. Our Simplified Novel Application (SNApp) framework breaks the app development process into four phases: (1) information and resource gathering, (2) software and hardware decisions, (3) software development and testing, and (4) study start-up and implementation. At each phase, we address common challenges and ethical issues and make suggestions for effective and efficient app development. Our goal is to help researchers effectively balance priorities related to the function of the app with the realities of app development, human subjects issues, and project resource constraints.

The zinc ionophore clioquinol reverses autophagy arrest in chloroquine-treated ARPE-19 cells and in APP/mutant presenilin-1-transfected Chinese hamster ovary cells.

PubMed

Seo, Bo-Ra; Lee, Sook-Jeong; Cho, Kyung Sook; Yoon, Young Hee; Koh, Jae-Young

2015-12-01

Arrested autophagy may contribute to the pathogenesis of Alzheimer's disease. Because we found that chloroquine (CQ) causes arrested autophagy but clioquinol (ClioQ), a zinc ionophore, activates autophagic flux, in the present study, we examined whether ClioQ can overcome arrested autophagy induced by CQ or mutant presenilin-1 (mPS1). CQ induced vacuole formation and cell death in adult retinal pigment epithelial (ARPE-19) cells, but co-treatment with ClioQ attenuated CQ-associated toxicity in a zinc-dependent manner. Increases in lysosome dilation and blockage of autophagic flux by CQ were also markedly attenuated by ClioQ treatment. Interestingly, CQ increased lysosomal pH in amyloid precursor protein (APP)/mPS1-expressing Chinese hamster ovary 7WΔE9 (CHO-7WΔE9) cell line, and ClioQ partially re-acidified lysosomes. Furthermore, accumulation of amyloid-β (Aβ) oligomers in CHO-7WΔE9 cells was markedly attenuated by ClioQ. Moreover, intracellular accumulation of exogenously applied fluorescein isothiocyanate-conjugated Aβ(1-42) was also increased by CQ but was returned to control levels by ClioQ. These results suggest that modulation of lysosomal functions by manipulating lysosomal zinc levels may be a useful strategy for clearing intracellular Aβ oligomers. Copyright © 2015 Elsevier Inc. All rights reserved.

Identification and characterization of the sodium-binding site of activated protein C.

PubMed

He, X; Rezaie, A R

1999-02-19

Activated protein C (APC) requires both Ca2+ and Na+ for its optimal catalytic function. In contrast to the Ca2+-binding sites, the Na+-binding site(s) of APC has not been identified. Based on a recent study with thrombin, the 221-225 loop is predicted to be a potential Na+-binding site in APC. The sequence of this loop is not conserved in trypsin. We engineered a Gla domainless form of protein C (GDPC) in which the 221-225 loop was replaced with the corresponding loop of trypsin. We found that activated GDPC (aGDPC) required Na+ (or other alkali cations) for its amidolytic activity with dissociation constant (Kd(app)) = 44.1 +/- 8.6 mM. In the presence of Ca2+, however, the requirement for Na+ by aGDPC was eliminated, and Na+ stimulated the cleavage rate 5-6-fold with Kd(app) = 2.3 +/- 0.3 mM. Both cations were required for efficient factor Va inactivation by aGDPC. In the presence of Ca2+, the catalytic function of the mutant was independent of Na+. Unlike aGDPC, the mutant did not discriminate among monovalent cations. We conclude that the 221-225 loop is a Na+-binding site in APC and that an allosteric link between the Na+ and Ca2+ binding loops modulates the structure and function of this anticoagulant enzyme.

Amyloid precursor protein and Presenilin 1 interaction studied by FRET in human H4 cells.

PubMed

Nizzari, Mario; Venezia, Valentina; Bianchini, Paolo; Caorsi, Valentina; Diaspro, Alberto; Repetto, Emanuela; Thellung, Stefano; Corsaro, Alessandro; Carlo, Pia; Schettini, Gennaro; Florio, Tullio; Russo, Claudio

2007-01-01

The mayor pathologic hallmarks of Alzheimer's disease (AD) are senile plaque and neurofibrillary tangles. Senile plaque are primarily made up of deposits of amyloid-beta protein, a proteolytic product derived from the amyloid precursor protein (APP). APP is a transmembrane protein detected into the endoplasmic reticulum, in the Golgi apparatus, at the cell surface, recycled by endocytosis to endosomes, whose physiological function is unclear. Presenilins (PS), are a component of gamma-secretase complex that cleave alpha-CTFs (carboxy-terminal fragment), or beta-CTFs, leaving 40 or 42 amino acids amyloid-beta peptides and 58 or 56 amino acids intracellular domains (AICD). Where the amyloid-beta peptides is generated is not clear. The study of APP-PS interaction in specific cell compartments provides a good opportunity to light upon the molecular mechanisms regulating the activity of the "gamma-secretase complex," and where beta-amyloid is generated. In our study we used a biophysical assay of protein proximity: fluorescence resonance energy transfer (FRET), that can provide information about molecular interactions when two proteins are in the close proximity (<10 nm), to examine the subcellular localization and interaction between APP and PS1 in human neuroglioma cells (H4). Confocal microscopic analysis reveals extensive colocalization in different cells' compartment, and centrosomal or microtubule organizing center (MTOC) localization of APP and PS1, but not necessarily a close molecular interaction. We used FRET to determine if APP and PS1 interact at the cell centrosome. FRET data suggest a close interaction between APP and PS1 in subcellular compartments and at the centrosome of H4 cells. Using this approach we show that APP and PS1 are closely associated in the centrosomes of the H4 cell.

Amyloid precursor protein expression is enhanced in human platelets from subjects with Alzheimer's disease and frontotemporal lobar degeneration: a real-time PCR study.

PubMed

Vignini, Arianna; Morganti, Stefano; Salvolini, Eleonora; Sartini, Davide; Luzzi, Simona; Fiorini, Rosamaria; Provinciali, Leandro; Di Primio, Roberto; Mazzanti, Laura; Emanuelli, Monica

2013-12-01

Frontotemporal lobar degeneration (FTLD) and Alzheimer's disease (AD) represent the most frequent causes of early-onset and late-onset degenerative dementia, respectively. A correct diagnosis entails the choice of appropriate therapies. In this view the present study aimed to identify biomarkers that could improve the differential diagnosis. We recently found an overexpression of platelet amyloid precursor protein (APP) in AD; furthermore, recent studies have suggested the presence of changes in APP processing in FTLD. In this context, we analyzed the mRNA expression level of Total APP (TOT) and APP containing a Kunitz-type serine protease inhibitor domain (KPI) in platelets obtained from AD patients, subjects with FTLD, and healthy subjects. In addition, we evaluated the correlation between platelet APP mRNA expression levels and cognitive impairment.Differential gene expression measurements revealed a significant up-regulation of APP TOT and APP KPI in both AD and FTLD patients compared to the controls (being AD/Controls: 1.67 for APP TOT and 1.47 for APP KPI; FTLD/Controls: 1.62 for APP TOT and 1.51 for APP KPI; p < 0.05), although it is interesting to note that in FTLD patients this expression did not correlate with the severity of cognitive impairment.This could be related to a reduced beta-amyloid (Aβ) formation, caused by an alteration of secretase enzymatic activity, even though a post-transcriptional regulation of APP mRNAs in FTLD cannot be excluded.

Amyloid precursor protein expression is enhanced in human platelets from subjects with Alzheimer's disease and Frontotemporal lobar degeneration: A Real-time PCR study.

PubMed

Vignini, Arianna; Morganti, Stefano; Salvolini, Eleonora; Sartini, Davide; Luzzi, Simona; Fiorini, Rosamaria; Provinciali, Leandro; Di Primio, Roberto; Mazzanti, Laura; Emanuelli, Monica

2013-10-26

Frontotemporal lobar degeneration (FTLD) and Alzheimer's disease (AD) represent the most frequent causes of early-onset and late-onset degenerative dementia, respectively. A correct diagnosis entails the choice of appropriate therapies. In this view the present study aimed to identify biomarkers that could improve the differential diagnosis. We recently found an overexpression of platelet amyloid precursor protein (APP) in AD; furthermore, recent studies have suggested the presence of changes in APP processing in FTLD. In this context, we analyzed the mRNA expression level of Total APP (TOT) and APP containing a Kunitz-type serine protease inhibitor domain (KPI) in platelets obtained from AD patients, subjects with FTLD, and healthy subjects. In addition, we evaluated the correlation between platelet APP mRNA expression levels and cognitive impairment. Differential gene expression measurements revealed a significant up-regulation of APP TOT and APP KPI in both AD and FTLD patients compared to the controls (being AD/Controls: 1.67 for APP TOT and 1.47 for APP KPI; FTLD/Controls: 1.62 for APP TOT and 1.51 for APP KPI; p<0.05) , although it is interesting to note that in FTLD patients this expression did not correlate with the severity of cognitive impairment. This could be related to a reduced beta-amyloid (Aβ) formation, caused by an alteration of secretase enzymatic activity, even though a post-transcriptional regulation of APP mRNAs in FTLD cannot be excluded. © 2013.

beta. -Amyloid precursor protein of Alzheimer disease occurs as 110- to 135-kilodalton membrane-associated proteins in neural and nonneural tissues

DOE Office of Scientific and Technical Information (OSTI.GOV)

Selkoe, D.J.; Podlisny, M.B.; Joachim, C.L.

1988-10-01

Progressive cerebral deposition of extracellular filaments composed of the {beta}-amyloid protein ({beta}AP) is a constant feature of Alzheimer disease (AD). Since the gene on chromosome 21 encoding the {beta}AP precursor ({beta}APP) is not known to be altered in AD, transcriptional or posttranslational changes may underlie accelerated {beta}AP deposition. Using two antibodies to the predicted carboxyl terminus of {beta}APP, the authors have identified the native {beta}APP in brain and nonneural human tissues as a 110- to 135-kDa protein complex that is insoluble in buffer and found in various membrane-rich subcellular fractions. These proteins are relatively uniformly distributed in adult brain, abundantmore » in fetal brain, and detected in nonneural tissues that contain {beta}APP mRNA. Similarly sized proteins occur in rat, cow, and monkey brain and in cultured human HL-60 and HeLa cells; the precise patterns in the 110- to 135-kDa range are heterogeneous among various tissues and cell lines. They conclude that the highly conserved {beta}APP molecule occurs in mammalian tissues as a heterogeneous group of membrane-associated proteins of {approx} 120 kDa. Detection of the nonamyloidogenic carboxyl terminus within plaques suggests that proteolytic processing of the {beta}APP into insoluble filaments occurs locally in cortical regions that develop {beta}-amyloid deposits with age.« less

MEDication reminder APPs to improve medication adherence in Coronary Heart Disease (MedApp-CHD) Study: a randomised controlled trial protocol

PubMed Central

Chow, Clara K; Thiagalingam, Aravinda; Rogers, Kris; Chalmers, John; Redfern, Julie

2017-01-01

Introduction The growing number of smartphone health applications available in the app stores makes these apps a promising tool to help reduce the global problem of non-adherence to long-term medications. However, to date, there is limited evidence that available medication reminder apps are effective. This study aims to determine the impact of medication reminder apps on adherence to cardiovascular medication when compared with usual care for people with coronary heart disease (CHD) and to determine whether an advanced app compared with a basic app is associated with higher adherence. Methods and analysis Randomised controlled trial with follow-up at 3 months to evaluate the feasibility and effectiveness of medication reminder apps on medication adherence compared with usual care. An estimated sample size of 156 patients with CHD will be randomised to one of three groups (usual care group, basic medication reminder app group and advanced medication reminder app group). The usual care group will receive standard care for CHD with no access to a medication reminder app. The basic medication reminder app group will have access to a medication reminder app with a basic feature of providing simple daily reminders with no interactivity. The advanced medication reminder app group will have access to a medication reminder app with additional interactive and customisable features. The primary outcome is medication adherence measured by the eight-item Morisky Medication Adherence Scale at 3 months. Secondary outcomes include clinical measurements of blood pressure and cholesterol levels, and medication knowledge. A process evaluation will also be performed to assess the feasibility of the intervention by evaluating the acceptability, utility and engagement with the apps. Ethics and dissemination Ethical approval has been obtained from the Western Sydney Local Health Network Human Research Ethics Committee (AU/RED/HREC/1/WMEAD/3). Study findings will be disseminated via usual scientific forums. Trial registration number ACTRN12616000661471; Pre-results PMID:28993388

Mobile Phone Applications for the Care and Prevention of HIV and Other Sexually Transmitted Diseases: A Review

PubMed Central

Pike, Emily C; LeGrand, Sara; Hightow-Weidman, Lisa B

2013-01-01

Background Mobile phone applications (apps) provide a new platform for delivering tailored human immunodeficiency virus (HIV) and sexually transmitted disease (STD) prevention and care. Objective To identify and evaluate currently available mobile phone apps related to the prevention and care of HIV and other STDs. Methods We searched the Apple iTunes and Android Google Play stores for HIV/STD-related apps, excluding apps that exclusively targeted industry, providers, and researchers. Each eligible app was downloaded, tested, and assessed for user ratings and functionality as well as 6 broad content areas of HIV prevention and care: HIV/STD disease knowledge, risk reduction/safer sex, condom promotion, HIV/STD testing information, resources for HIV-positive persons, and focus on key populations. Results Search queries up to May 2012 identified 1937 apps. Of these, 55 unique apps met the inclusion criteria (12 for Android, 29 for iPhone, and 14 for both platforms). Among these apps, 71% provided disease information about HIV/STDs, 36% provided HIV/STD testing information or resources, 29% included information about condom use or assistance locating condoms, and 24% promoted safer sex. Only 6 apps (11%) covered all 4 of these prevention areas. Eight apps (15%) provided tools or resources specifically for HIV/STD positive persons. Ten apps included information for a range of sexual orientations, 9 apps appeared to be designed for racially/ethnically diverse audiences, and 15 apps featured interactive components. Apps were infrequently downloaded (median 100-500 downloads) and not highly rated (average customer rating 3.7 out of 5 stars). Conclusions Most available HIV/STD apps have failed to attract user attention and positive reviews. Public health practitioners should work with app developers to incorporate elements of evidence-based interventions for risk reduction and improve app inclusiveness and interactivity. PMID:23291245

Neurobehavioral characterization of APP23 transgenic mice with the SHIRPA primary screen.

PubMed

Lalonde, R; Dumont, M; Staufenbiel, M; Strazielle, C

2005-02-10

The SHIRPA primary screen comprises 40 measures covering various reflexes and basic sensorimotor functions. This multi-test battery was used to compare non-transgenic controls with APP23 transgenic mice, expressing the 751 isoform of human beta-amyloid precursor protein and characterized by amyloid deposits in parenchyma and vessel walls. The APP23 mice were distinguishable from controls by pathological limb reflexes, myoclonic jumping, seizure activity, and tail malformation. In addition, this mouse model of Alzheimer's disease was also marked by a crooked swimming trajectory. APP23 mice were also of lighter weight and were less inclined to stay immobile during a transfer arousal test. Despite the neurologic signs, APP23 transgenic mice were not deficient in stationary beam, coat-hanger, and rotorod tests, indicating intact motor coordination abilities.

Activation of Ras-ERK Signaling and GSK-3 by Amyloid Precursor Protein and Amyloid Beta Facilitates Neurodegeneration in Alzheimer's Disease.

PubMed

Kirouac, Lisa; Rajic, Alexander J; Cribbs, David H; Padmanabhan, Jaya

2017-01-01

It is widely accepted that amyloid β (Aβ) generated from amyloid precursor protein (APP) oligomerizes and fibrillizes to form neuritic plaques in Alzheimer's disease (AD), yet little is known about the contribution of APP to intracellular signaling events preceding AD pathogenesis. The data presented here demonstrate that APP expression and neuronal exposure to oligomeric Aβ42 enhance Ras/ERK signaling cascade and glycogen synthase kinase 3 (GSK-3) activation. We find that RNA interference (RNAi)-directed knockdown of APP in B103 rat neuroblastoma cells expressing APP inhibits Ras-ERK signaling and GSK-3 activation, indicating that APP acts upstream of these signal transduction events. Both ERK and GSK-3 are known to induce hyperphosphorylation of tau and APP at Thr668, and our findings suggest that aberrant signaling by APP facilitates these events. Supporting this notion, analysis of human AD brain samples showed increased expression of Ras, activation of GSK-3, and phosphorylation of APP and tau, which correlated with Aβ levels in the AD brains. Furthermore, treatment of primary rat neurons with Aβ recapitulated these events and showed enhanced Ras-ERK signaling, GSK-3 activation, upregulation of cyclin D1, and phosphorylation of APP and tau. The finding that Aβ induces Thr668 phosphorylation on APP, which enhances APP proteolysis and Aβ generation, denotes a vicious feedforward mechanism by which APP and Aβ promote tau hyperphosphorylation and neurodegeneration in AD. Based on these results, we hypothesize that aberrant proliferative signaling by APP plays a fundamental role in AD neurodegeneration and that inhibition of this would impede cell cycle deregulation and neurodegeneration observed in AD.

48 CFR 323.7100 - Policy.

Code of Federal Regulations, 2011 CFR

2011-10-01

... WORKPLACE Green Purchasing Requirements 323.7100 Policy. (a) The HHS guidelines and procedures for “green purchasing” may be found in the HHS Affirmative Procurement Plan (APP), “Purchasing Environmentally Preferable Products and Services at the U.S. Department of Health and Human Services.” The APP encompasses...

The Role of Hedonic Behavior in Reducing Perceived Risk

PubMed Central

Jia, Jayson S.; Jia, Jianmin; Hsee, Christopher K.; Shiv, Baba

2016-01-01

Understanding how human populations naturally respond to and cope with risk is important for fields ranging from psychology to public health. We used geophysical and individual-level mobile-phone data (mobile-apps, telecommunications, and Web usage) of 157,358 victims of the 2013 Ya’an earthquake to diagnose the effects of the disaster and investigate how experiencing real risk (at different levels of intensity) changes behavior. Rather than limiting human activity, higher earthquake intensity resulted in graded increases in usage of communications apps (e.g., social networking, messaging), functional apps (e.g., informational tools), and hedonic apps (e.g., music, videos, games). Combining mobile data with a field survey (N = 2,000) completed 1 week after the earthquake, we use an instrumental-variable approach to show that only increases in hedonic behavior reduced perceived risk. Thus, hedonic behavior could potentially serve as a population-scale coping and recovery strategy that is often missing in risk management and policy considerations. PMID:27881710

The Role of Hedonic Behavior in Reducing Perceived Risk.

PubMed

Jia, Jayson S; Jia, Jianmin; Hsee, Christopher K; Shiv, Baba

2017-01-01

Understanding how human populations naturally respond to and cope with risk is important for fields ranging from psychology to public health. We used geophysical and individual-level mobile-phone data (mobile-apps, telecommunications, and Web usage) of 157,358 victims of the 2013 Ya'an earthquake to diagnose the effects of the disaster and investigate how experiencing real risk (at different levels of intensity) changes behavior. Rather than limiting human activity, higher earthquake intensity resulted in graded increases in usage of communications apps (e.g., social networking, messaging), functional apps (e.g., informational tools), and hedonic apps (e.g., music, videos, games). Combining mobile data with a field survey ( N = 2,000) completed 1 week after the earthquake, we use an instrumental-variable approach to show that only increases in hedonic behavior reduced perceived risk. Thus, hedonic behavior could potentially serve as a population-scale coping and recovery strategy that is often missing in risk management and policy considerations.

Function of Protein Phosphatase 2A in Control of Proliferation: Isolation and Analysis of Dominant-Defective Mutants

DTIC Science & Technology

1999-06-01

subunits are expressed ubiquitously and appear to be encoded by small and quite homogeneous gene families. In plants , however, A and C subunit gene...1996). In both plants and animals, different B subunit isoforms are encoded by two or more unrelated gene families, some of which are expressed in a...PP2A functions in whole plants and in mammalian tissue culture cells. This genetic system may also prove useful for analyzing interactions between

Nicergoline stimulates protein kinase C mediated alpha-secretase processing of the amyloid precursor protein in cultured human neuroblastoma SH-SY5Y cells.

PubMed

Cedazo-Minguez, A; Bonecchi, L; Winblad, B; Post, C; Wong, E H; Cowburn, R F; Benatti, L

1999-10-01

We investigated the ability of the antidementia agents, nicergoline, aniracetam and hydergine to stimulate PKC mediated alpha-secretase amyloid precursor protein (APP) processing in cultured human neuroblastoma SH-SY5Y cells. Western immunoblotting of cell conditioned media using the Mabs 22C11 and 6E10 revealed the presence of 2 bands with molecular mass of 90 and 120 kDa, corresponding to possible alternatively glycosylated forms of secreted APP (APPs). Short-term (30 min and 2 h) treatment of cells with nicergoline gave an increased intensity of both bands, compared to non-treated cells. Maximal nicergoline effects, of the order of 150-200% over basal APPs release, were seen at concentrations between 1 and 10 microM. Under the same condition, 1 microM PdBu, used as a positive control, gave 500-1000% increases of basal APPs release. In contrast, aniracetam and hydergine, did not show any effect on APPs secretion. 2 h treatment with nicergoline had no effect on cellular full-length APP levels, as determined by immunoblotting of cell extracts with 22C11 and CT15 antibodies. Immunoblotting with PKC isoform specific antibodies of soluble and membrane fractions prepared from 2 h treated cells, showed that nicergoline (50 microM) and PdBu (1 microM) both induced translocation of PKC alpha, gamma and epsilon, but not PKC beta. The involvement of PKC in mediating nicergoline stimulated APPs release was also studied using specific inhibitors. 1 microM calphostin C, a broad range PKC inhibitor, significantly reduced both PdBu (1 microM) and nicergoline (10 microM) induced APPs release. In contrast, Go6976 (1 microM), a selective PKC alpha and beta1 inhibitor, as well as the cAMP-dependent protein kinase inhibitor, H89 (1 microM) were without effect. These results indicate that nicergoline can modulate alpha-secretase APP processing by a PKC dependent mechanism that is likely to involve the gamma and epsilon isoforms of this enzyme.

Periodontitis in humans and non-human primates: oral-systemic linkage inducing acute phase proteins.

PubMed

Ebersole, Jeffrey L; Cappelli, David; Mathys, Erik C; Steffen, Michelle J; Singer, Robert E; Montgomery, Michael; Mott, Glen E; Novak, M John

2002-12-01

The acute phase response (APR) represents a systemic counterpart to the localized inflammatory response. This report describes patient-oriented and non-human primate model studies to determine the effect of periodontal disease on systemic acute phase proteins (APP). Patient-oriented studies included comparison of the levels of APP, using enzyme-linked immunosorbent assay (ELISA), with the presence and severity of periodontitis in localized chronic periodontitis (LCP), generalized aggressive periodontitis (GAP), and Sjogren's syndrome (SS) patients. The non-human primate experiments evaluated the serum level of APPs under natural conditions, following mechanical hygiene, experimental gingivitis, and during ligature-induced periodontitis. Analysis of the LCP population showed what appeared to be a threshold of periodontal disease severity required for elevating the C-reactive protein (CRP) and haptoglobin (HG). The results demonstrated a significant elevation in CRP in the GAP versus the control groups, as well as lower levels of all mediators in healthy non-smokers (HNS) versus smokers (HS), suggesting that these systemic inflammatory markers were altered in response to challenge by noxious materials from smoking. Significantly different levels of CRP, HG, and alpha1-antiproteinase were noted in the SS patients suggesting that the autoimmune aspects of Sjögren's syndrome may impact upon oral health and systemic responses. Parallel evidence was also obtained from the primate studies. Providing mechanical oral hygiene, which significantly lowered clinical inflammation and bleeding of the gingiva, decreased the serum APP levels. Both CRP and fibrinogen were significantly elevated during progressing periodontitis, which also appeared to have an impact on serum lipids and lipoproteins. These findings supported results relating chronic oral infections and the inflammation of periodontitis as contributors to and/or triggers for systemic inflammatory responses. Finally, similarities in the clinical and microbiological parameters of gingival inflammation and periodontitis between humans and non-human primates was extended to identification of changes in serum APP in the non-human primates that appeared to be in direct response to the induction of progressing periodontitis. These systemic changes provide additional evidence for the biological plausibility of periodontal infections contributing to various systemic diseases.

Posttraumatic Stress Disorder and Mobile Health: App Investigation and Scoping Literature Review

PubMed Central

2017-01-01

Background Posttraumatic stress disorder (PTSD) is a prevalent mental health issue among veterans. Access to PTSD treatment is influenced by geographic (ie, travel distance to facilities), temporal (ie, time delay between services), financial (ie, eligibility and cost of services), and cultural (ie, social stigma) barriers. Objective The emergence of mobile health (mHealth) apps has the potential to bridge many of these access gaps by providing remote resources and monitoring that can offer discrete assistance to trauma survivors with PTSD and enhance patient-clinician relationships. In this study, we investigate the current mHealth capabilities relevant to PTSD. Methods This study consists of two parts: (1) a review of publicly available PTSD apps designed to determine the availability of PTSD apps, which includes more detailed information about three dominant apps and (2) a scoping literature review performed using a systematic method to determine app usage and efforts toward validation of such mHealth apps. App usage relates to how the end users (eg, clinicians and patients) are interacting with the app, whereas validation is testing performed to ensure the app’s purpose and specifications are met. Results The results suggest that though numerous apps have been developed to aid in the diagnosis and treatment of PTSD symptoms, few apps were designed to be integrated with clinical PTSD treatment, and minimal efforts have been made toward enhancing the usability and validation of PTSD apps. Conclusions These findings expose the need for studies relating to the human factors evaluation of such tools, with the ultimate goal of increasing access to treatment and widening the app adoption rate for patients with PTSD. PMID:29074470

Direct Reading of Bona Fide Barcode Assays for Diagnostics with Smartphone Apps.

PubMed

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

2015-06-30

The desire to develop new point-of-care (POC) diagnostic tools has led to the adaptation of smartphones to tackle limitations in state-of-the-art instrumentation and centralized laboratory facilities. Today's smartphones possess the computer-like ability to image and process data using mobile apps; barcode scanners are one such type of apps. We demonstrate herein that a diagnostic assay can be performed by patterning immunoassay strips in a bona fide barcode format such that after target binding and signal enhancement, the linear barcode can be read directly with a standard smartphone app. Quantitative analysis can then be performed based on the grayscale intensities with a customized mobile app. This novel diagnostic concept has been validated for a real-world application, i.e., the detection of human chorionic gonadotropin, a pregnancy hormone. With the possibility of multiplex detection, the barcode assay protocol promises to boost POC diagnosis research by the direct adaptation of mobile devices and apps.

Direct Reading of Bona Fide Barcode Assays for Diagnostics with Smartphone Apps

PubMed Central

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

2015-01-01

The desire to develop new point-of-care (POC) diagnostic tools has led to the adaptation of smartphones to tackle limitations in state-of-the-art instrumentation and centralized laboratory facilities. Today’s smartphones possess the computer-like ability to image and process data using mobile apps; barcode scanners are one such type of apps. We demonstrate herein that a diagnostic assay can be performed by patterning immunoassay strips in a bona fide barcode format such that after target binding and signal enhancement, the linear barcode can be read directly with a standard smartphone app. Quantitative analysis can then be performed based on the grayscale intensities with a customized mobile app. This novel diagnostic concept has been validated for a real-world application, i.e., the detection of human chorionic gonadotropin, a pregnancy hormone. With the possibility of multiplex detection, the barcode assay protocol promises to boost POC diagnosis research by the direct adaptation of mobile devices and apps. PMID:26122608

Direct Reading of Bona Fide Barcode Assays for Diagnostics with Smartphone Apps

NASA Astrophysics Data System (ADS)

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

2015-06-01

The desire to develop new point-of-care (POC) diagnostic tools has led to the adaptation of smartphones to tackle limitations in state-of-the-art instrumentation and centralized laboratory facilities. Today’s smartphones possess the computer-like ability to image and process data using mobile apps; barcode scanners are one such type of apps. We demonstrate herein that a diagnostic assay can be performed by patterning immunoassay strips in a bona fide barcode format such that after target binding and signal enhancement, the linear barcode can be read directly with a standard smartphone app. Quantitative analysis can then be performed based on the grayscale intensities with a customized mobile app. This novel diagnostic concept has been validated for a real-world application, i.e., the detection of human chorionic gonadotropin, a pregnancy hormone. With the possibility of multiplex detection, the barcode assay protocol promises to boost POC diagnosis research by the direct adaptation of mobile devices and apps.

Dentate gyrus volume is reduced before onset of plaque formation in PDAPP mice: A magnetic resonance microscopy and stereologic analysis

PubMed Central

Redwine, Jeffrey M.; Kosofsky, Barry; Jacobs, Russell E.; Games, Dora; Reilly, John F.; Morrison, John H.; Young, Warren G.; Bloom, Floyd E.

2003-01-01

High-resolution magnetic resonance microscopy (MRM) was used to determine regional brain volumetric changes in a mouse model of Alzheimer's disease. These transgenic (Tg) mice overexpress human mutant amyloid precursor protein (APP) V717F under control of platelet-derived growth factor promoter (PDAPP mice), and cortical and hippocampal β-amyloid (Aβ) deposits accumulate in heterozygotes after 8–10 mos. We used MRM to obtain 3D volumetric data on mouse brains imaged in their skulls to define genotype- and age-related changes. Hippocampal, cerebellar, and brain volumes and corpus callosum length were quantified in 40-, 100-, 365-, and 630-day-old mice. Measurements taken at age 100 days, before Aβ deposition, revealed a 12.3% reduction of hippocampus volume in Tg mice compared with WT controls. This reduction persisted without progression to age 21 mos. A significant 18% increase in hippocampal volume occurred between 40 and 630 days in WT mice, and no corresponding significant increase occurred in Tg mice. Cavalieri volume estimates of hippocampal subfields from 100-day-old Tg mice further localized a 28% volume deficit in the dentate gyrus. In addition, corpus callosum length was reduced by ≈25% in Tg mice at all ages analyzed. In summary, reduced hippocampal volume and corpus callosum length can be detected by MRM before Aβ deposition. We conclude that overexpression of APP and amyloid may initiate pathologic changes before the appearance of plaques, suggesting novel targets for the treatment of Alzheimer's disease and further reinforcing the need for early diagnosis and treatment. PMID:12552120

Leadership capabilities of physiotherapy leaders in Ireland: Part 2. Clinical specialists and advanced physiotherapy practitioners.

PubMed

McGowan, E; Elliott, N; Stokes, E

2018-05-07

Investigation of the leadership capabilities of physiotherapy managers found that they report predominantly demonstrating capabilities associated with the human resource and structural frames. However, little is known about the leadership capabilities of clinical specialists and advanced physiotherapy practitioners (APPs) who also are identified as having responsibility for leadership. To explore clinical specialists´ and APPs' perceptions of their leadership capabilities and compare them with the reported leadership capabilities of physiotherapy managers. Semi-structured interviews were conducted with a purposive sample of 17 physiotherapy clinical specialists and APPs from a range of practice settings across Ireland. The interviews were analyzed using template analysis and the coding template was based on the Bolman and Deal Leadership framework. The participants described demonstrating leadership capabilities associated with each of the four leadership frames. However, the language used by the clinical specialists/APPs suggested that they work predominantly through the human resource frame. Structural frame capabilities were reported by the clinical specialists/APPs and there were some differences to those reported by the managers. In keeping with the reported leadership capabilities of the physiotherapy managers, the employment of capabilities associated with the political frame varied between participants and symbolic frame capabilities were underused. There are many similarities in the self-reported leadership capabilities of managers and clinical specialists/APPs. However, differences were also noted. Both cohorts of physiotherapy leaders may benefit from specific development programs to develop leadership capabilities associated with the political and symbolic frames.

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.

MEDication reminder APPs to improve medication adherence in Coronary Heart Disease (MedApp-CHD) Study: a randomised controlled trial protocol.

PubMed

Santo, Karla; Chow, Clara K; Thiagalingam, Aravinda; Rogers, Kris; Chalmers, John; Redfern, Julie

2017-10-08

The growing number of smartphone health applications available in the app stores makes these apps a promising tool to help reduce the global problem of non-adherence to long-term medications. However, to date, there is limited evidence that available medication reminder apps are effective. This study aims to determine the impact of medication reminder apps on adherence to cardiovascular medication when compared with usual care for people with coronary heart disease (CHD) and to determine whether an advanced app compared with a basic app is associated with higher adherence. Randomised controlled trial with follow-up at 3 months to evaluate the feasibility and effectiveness of medication reminder apps on medication adherence compared with usual care. An estimated sample size of 156 patients with CHD will be randomised to one of three groups (usual care group, basic medication reminder app group and advanced medication reminder app group). The usual care group will receive standard care for CHD with no access to a medication reminder app. The basic medication reminder app group will have access to a medication reminder app with a basic feature of providing simple daily reminders with no interactivity. The advanced medication reminder app group will have access to a medication reminder app with additional interactive and customisable features. The primary outcome is medication adherence measured by the eight-item Morisky Medication Adherence Scale at 3 months. Secondary outcomes include clinical measurements of blood pressure and cholesterol levels, and medication knowledge. A process evaluation will also be performed to assess the feasibility of the intervention by evaluating the acceptability, utility and engagement with the apps. Ethical approval has been obtained from the Western Sydney Local Health Network Human Research Ethics Committee (AU/RED/HREC/1/WMEAD/3). Study findings will be disseminated via usual scientific forums. ACTRN12616000661471; Pre-results. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

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.

High quantity but limited quality in healthcare applications intended for HIV-infected patients.

PubMed

Robustillo Cortés, María de las Aguas; Cantudo Cuenca, María Rosa; Morillo Verdugo, Ramón; Calvo Cidoncha, Elena

2014-08-01

The aim of this study was to evaluate, through the creation of a specific questionnaire, the information quality in mobile applications (apps) aimed at human immunodeficiency virus (HIV)-infected patients. We also established a quality rating and identified the main strengths and weaknesses of this kind of health app. Smartphone apps specifically related to HIV/acquired immunodeficiency syndrome (AIDS) were searched. We conducted a key word search with the terms "HIV," "AIDS," and "acquired immune deficiency syndrome" in the Apple™ (Cupertino, CA) App Store and the Android™ Google™ (Mountain View, CA) Play Store. A questionnaire was developed based on the different quality recommendations for health apps up to December 2012. The recommendations consulted were as follows: the Happtique Health App Certification Program, the Food and Drug Administration (Mobile Medical Applications), and recommendations for the design, use, and evaluation of health apps of the Agency of Health Quality in Andalusia. A group of 17 experts assessed the importance of the different sections by using a Delphi method. In total, 41 health apps were analyzed. Only one app (2.4%), called in Practice HIV, approached class A. The remaining were classed as follows: 2 (4.9%) class B, 1 (2.4%) class C, 5 (12.2%) class D and E, and 27 (65.9%) class F (not exceeding minimum criteria). The design and the relevance were highlighted among the strengths. The main areas for improvement are provision of services and confidentiality in addition to privacy policies. The quality of the revised apps is limited. Only one app complied with the excellence criteria, and over 50% of the apps did not exceed minimum quality standards. The worst rated aspects were political advertising and logical security.

Mental Health Mobile Apps: From Infusion to Diffusion in the Mental Health Social System.

PubMed

East, Marlene Lynette; Havard, Byron C

2015-01-01

The roles of mental health educators and professionals in the diffusion of mental health mobile apps are addressed in this viewpoint article. Mental health mobile apps are emerging technologies that fit under the broad heading of mobile health (mHealth). mHealth, encompassed within electronic health (eHealth), reflects the use of mobile devices for the practice of public health. Well-designed mental health mobile apps that present content in interactive, engaging, and stimulating ways can promote cognitive learning, personal growth, and mental health enhancement. As key influencers in the mental health social system, counselor educators and professional associations may either help or hinder diffusion of beneficial mHealth technologies. As mental health mobile apps move towards ubiquity, research will continue to be conducted. The studies published thus far, combined with the potential of mental health mobile apps for learning and personal growth, offer enough evidence to compel mental health professionals to infuse these technologies into education and practice. Counselor educators and professional associations must use their influential leadership roles to train students and practitioners in how to research, evaluate, and integrate mental health mobile apps into practice. The objectives of this article are to (1) increase awareness of mHealth and mental health mobile apps, (2) demonstrate the potential for continued growth in mental health mobile apps based on technology use and acceptance theory, mHealth organizational initiatives, and evidence about how humans learn, (3) discuss evidence-based benefits of mental health mobile apps, (4) examine the current state of mHealth diffusion in the mental health profession, and (5) offer solutions for impelling innovation diffusion by infusing mental health mobile apps into education, training, and clinical settings. This discussion has implications for counselor educators, mental health practitioners, associations, continuing education providers, and app developers.

Epic Allies: Development of a Gaming App to Improve Antiretroviral Therapy Adherence Among Young HIV-Positive Men Who Have Sex With Men.

PubMed

LeGrand, Sara; Muessig, Kathryn Elizabeth; McNulty, Tobias; Soni, Karina; Knudtson, Kelly; Lemann, Alex; Nwoko, Nkechinyere; Hightow-Weidman, Lisa B

2016-05-13

In the United States, the human immunodeficiency virus (HIV) disproportionately affects young men who have sex with men (YMSM). For HIV-positive individuals, adherence to antiretroviral therapy (ART) is critical for achieving optimal health outcomes and reducing secondary transmission of HIV. However, YMSM often struggle with ART adherence. Novel mobile phone apps that incorporate game-based mechanics and social networking elements represent a promising intervention approach for improving ART adherence among YMSM. This study used a multiphase, iterative development process to create an ART adherence app for YMSM. The three-phase development process included: (1) theory-based concept development jointly by public health researchers and the technology team, (2) assessment of the target population's ART adherence needs and app preferences and development and testing of a clickable app prototype, and (3) development and usability testing of the final app prototype. The initial theory-based app concept developed in Phase One included medication reminders, daily ART adherence tracking and visualization, ART educational modules, limited virtual interactions with other app users, and gamification elements. In Phase Two, adherence needs, including those related to information, motivation, and behavioral skills, were identified. Participants expressed preferences for an ART adherence app that was informational, interactive, social, and customizable. Based on the findings from Phase Two, additional gaming features were added in Phase Three, including an interactive battle, superhero app theme, and app storyline. Other features were modified to increase interactivity and customization options and integrate the game theme. During usability testing of the final prototype, participants were able to understand and navigate the app successfully and rated the app favorably. An iterative development process was critical for the development of an ART adherence game app that was viewed as highly acceptable, relevant, and useful by YMSM.

Epic Allies: Development of a Gaming App to Improve Antiretroviral Therapy Adherence Among Young HIV-Positive Men Who Have Sex With Men

PubMed Central

Muessig, Kathryn Elizabeth; McNulty, Tobias; Soni, Karina; Knudtson, Kelly; Lemann, Alex; Nwoko, Nkechinyere; Hightow-Weidman, Lisa B

2016-01-01

Background In the United States, the human immunodeficiency virus (HIV) disproportionately affects young men who have sex with men (YMSM). For HIV-positive individuals, adherence to antiretroviral therapy (ART) is critical for achieving optimal health outcomes and reducing secondary transmission of HIV. However, YMSM often struggle with ART adherence. Novel mobile phone apps that incorporate game-based mechanics and social networking elements represent a promising intervention approach for improving ART adherence among YMSM. Objective This study used a multiphase, iterative development process to create an ART adherence app for YMSM. Methods The three-phase development process included: (1) theory-based concept development jointly by public health researchers and the technology team, (2) assessment of the target population’s ART adherence needs and app preferences and development and testing of a clickable app prototype, and (3) development and usability testing of the final app prototype. Results The initial theory-based app concept developed in Phase One included medication reminders, daily ART adherence tracking and visualization, ART educational modules, limited virtual interactions with other app users, and gamification elements. In Phase Two, adherence needs, including those related to information, motivation, and behavioral skills, were identified. Participants expressed preferences for an ART adherence app that was informational, interactive, social, and customizable. Based on the findings from Phase Two, additional gaming features were added in Phase Three, including an interactive battle, superhero app theme, and app storyline. Other features were modified to increase interactivity and customization options and integrate the game theme. During usability testing of the final prototype, participants were able to understand and navigate the app successfully and rated the app favorably. Conclusions An iterative development process was critical for the development of an ART adherence game app that was viewed as highly acceptable, relevant, and useful by YMSM. PMID:27178752

Effect of flavonols on wine astringency and their interaction with human saliva.

PubMed

Ferrer-Gallego, Raúl; Brás, Natércia F; García-Estévez, Ignacio; Mateus, Nuno; Rivas-Gonzalo, Julián C; de Freitas, Victor; Escribano-Bailón, M Teresa

2016-10-15

The addition of external phenolic compounds to wines in order to improve their sensory quality is an established winemaking practice. This study was aimed at evaluating the effect of the addition of quercetin 3-O-glucoside on the astringency and bitterness of wines. Sensory results showed that the addition of this flavonol to wines results in an increase in astringency and bitterness. Additionally, flavonol-human salivary protein interactions were studied using fluorescence spectroscopy, dynamic light scattering and molecular dynamic simulations (MD). The apparent Stern-Volmer (KsvApp) and the apparent bimolecular quenching constants (kqApp) were calculated from fluorescence spectra. The KsvApp was 12620±390M(-1), and the apparent biomolecular constant was 3.94×10(12)M(-1)s(-1), which suggests that a complex was formed between the human salivary proteins and quercetin 3-O-glucoside. MD simulations showed that the quercetin 3-O-glucoside molecules have the ability to bind to the IB937 model peptide. Copyright © 2016 Elsevier Ltd. All rights reserved.

Methods to uncover an antibody epitope in the KPI domain of Alzheimer's amyloid precursor protein for immunohistochemistry in human brain.

PubMed

Campbell, E; Pearson, R C; Parkinson, D

1999-11-15

A novel polyclonal antibody (Ab993), specific for a KPI domain epitope of APP, was characterised for use in immunoprecipitation, Western blotting and immunohistochemistry. Conditioned medium from NTera2/D1 cells was used for immunoprecipitation and Western blots. Paraffin-embedded human brain sections were used for immunohistochemistry. The antibody recognised KPI-containing APP on Western blots after standard solubilisation but immunoprecipitation of soluble APP required reduction with 2-mercaptoethanol followed by alkylation of reduced sulphydryl bonds with sodium iodoacetate. Immunohistochemical staining of human brain sections was significantly enhanced by this pre-treatment. Microwaving of sections also increased immunolabelling, by a mechanism that was additive to reduction and alkylation. Incubation in 80% formic acid did not confer any enhancement of immunoreactivity. Ab993, applied with the methods reported here, is expected to be valuable in investigations of the pathogenesis of Alzheimer's disease to determine the source of the beta-amyloid peptide.

Building quality mHealth for low resource settings.

PubMed

Ettinger, Kate Michi; Pharaoh, Hamilton; Buckman, Reymound Yaw; Conradie, Hoffie; Karlen, Walter

In low- and middle-income countries (LMIC), community health care workers (CHCW) are the primary point of care for millions of people. Mobile phone health applications (mHealth app) are the preferred technology platform to deliver clinical support to CHCW. In LMIC, limited regulatory oversight exists to guide quality and safety for medical devices, including mHealth. During the development of a mHealth app to assist CHCW with patient assessment and clinical diagnosis in rural South Africa, we applied human-centred design (HCD) and a bioethics consultation. The HCD approach enabled us to develop a mHealth app that responded to the needs and capacities of CHCW. The bioethics consultation prompted early consideration of safety concerns, social implications of our mHealth app and our technology's impact on the CHCW-patient relationship. In this study, we found that combining a HCD approach with bioethics consultation improved the design quality and reduced safety concerns for our mHealth app.

Development of Decision Support Formulas for the Prediction of Bladder Outlet Obstruction and Prostatic Surgery in Patients With Lower Urinary Tract Symptom/Benign Prostatic Hyperplasia: Part II, External Validation and Usability Testing of a Smartphone App.

PubMed

Choo, Min Soo; Jeong, Seong Jin; Cho, Sung Yong; Yoo, Changwon; Jeong, Chang Wook; Ku, Ja Hyeon; Oh, Seung-June

2017-04-01

We aimed to externally validate the prediction model we developed for having bladder outlet obstruction (BOO) and requiring prostatic surgery using 2 independent data sets from tertiary referral centers, and also aimed to validate a mobile app for using this model through usability testing. Formulas and nomograms predicting whether a subject has BOO and needs prostatic surgery were validated with an external validation cohort from Seoul National University Bundang Hospital and Seoul Metropolitan Government-Seoul National University Boramae Medical Center between January 2004 and April 2015. A smartphone-based app was developed, and 8 young urologists were enrolled for usability testing to identify any human factor issues of the app. A total of 642 patients were included in the external validation cohort. No significant differences were found in the baseline characteristics of major parameters between the original (n=1,179) and the external validation cohort, except for the maximal flow rate. Predictions of requiring prostatic surgery in the validation cohort showed a sensitivity of 80.6%, a specificity of 73.2%, a positive predictive value of 49.7%, and a negative predictive value of 92.0%, and area under receiver operating curve of 0.84. The calibration plot indicated that the predictions have good correspondence. The decision curve showed also a high net benefit. Similar evaluation results using the external validation cohort were seen in the predictions of having BOO. Overall results of the usability test demonstrated that the app was user-friendly with no major human factor issues. External validation of these newly developed a prediction model demonstrated a moderate level of discrimination, adequate calibration, and high net benefit gains for predicting both having BOO and requiring prostatic surgery. Also a smartphone app implementing the prediction model was user-friendly with no major human factor issue.

acn-1, a C. elegans homologue of ACE, genetically interacts with the let-7 microRNA and other heterochronic genes.

PubMed

Metheetrairut, Chanatip; Ahuja, Yuri; Slack, Frank J

2017-10-02

The heterochronic pathway in C. elegans controls the relative timing of cell fate decisions during post-embryonic development. It includes a network of microRNAs (miRNAs), such as let-7, and protein-coding genes, such as the stemness factors, LIN-28 and LIN-41. Here we identified the acn-1 gene, a homologue of mammalian angiotensin-converting enzyme (ACE), as a new suppressor of the stem cell developmental defects of let-7 mutants. Since acn-1 null mutants die during early larval development, we used RNAi to characterize the role of acn-1 in C. elegans seam cell development, and determined its interaction with heterochronic factors, including let-7 and its downstream interactors - lin-41, hbl-1, and apl-1. We demonstrate that although RNAi knockdown of acn-1 is insufficient to cause heterochronic defects on its own, loss of acn-1 suppresses the retarded phenotypes of let-7 mutants and enhances the precocious phenotypes of hbl-1, though not lin-41, mutants. Conversely, the pattern of acn-1 expression, which oscillates during larval development, is disrupted by lin-41 mutants but not by hbl-1 mutants. Finally, we show that acn-1(RNAi) enhances the let-7-suppressing phenotypes caused by loss of apl-1, a homologue of the Alzheimer's disease-causing amyloid precursor protein (APP), while significantly disrupting the expression of apl-1 during the L4 larval stage. In conclusion, acn-1 interacts with heterochronic genes and appears to function downstream of let-7 and its target genes, including lin-41 and apl-1.

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 apps capturing travel and dietary behavior and the associated health and environmental impact are of mixed quality. Most apps do not include all desirable features or provide sufficient health information. Further research is needed to determine the potential of smartphone apps to evoke behavior change resulting in climate change and health co-benefits. PMID:27993762

Human Brain-Derived Aβ Oligomers Bind to Synapses and Disrupt Synaptic Activity in a Manner That Requires APP.

PubMed

Wang, Zemin; Jackson, Rosemary J; Hong, Wei; Taylor, Walter M; Corbett, Grant T; Moreno, Arturo; Liu, Wen; Li, Shaomin; Frosch, Matthew P; Slutsky, Inna; Young-Pearse, Tracy L; Spires-Jones, Tara L; Walsh, Dominic M

2017-12-06

Compelling genetic evidence links the amyloid precursor protein (APP) to Alzheimer's disease (AD) and several theories have been advanced to explain the relationship. A leading hypothesis proposes that a small amphipathic fragment of APP, the amyloid β-protein (Aβ), self-associates to form soluble aggregates that impair synaptic and network activity. Here, we used the most disease-relevant form of Aβ, protein isolated from AD brain. Using this material, we show that the synaptotoxic effects of Aβ depend on expression of APP and that the Aβ-mediated impairment of synaptic plasticity is accompanied by presynaptic effects that disrupt the excitatory/inhibitory (E/I) balance. The net increase in the E/I ratio and inhibition of plasticity are associated with Aβ localizing to synapses and binding of soluble Aβ aggregates to synapses requires the expression of APP. Our findings indicate a role for APP in AD pathogenesis beyond the generation of Aβ and suggest modulation of APP expression as a therapy for AD. SIGNIFICANCE STATEMENT Here, we report on the plasticity-disrupting effects of amyloid β-protein (Aβ) isolated from Alzheimer's disease (AD) brain and the requirement of amyloid precursor protein (APP) for these effects. We show that Aβ-containing AD brain extracts block hippocampal LTP, augment glutamate release probability, and disrupt the excitatory/inhibitory balance. These effects are associated with Aβ localizing to synapses and genetic ablation of APP prevents both Aβ binding and Aβ-mediated synaptic dysfunctions. Our results emphasize the importance of APP in AD and should stimulate new studies to elucidate APP-related targets suitable for pharmacological manipulation. Copyright © 2017 the authors 0270-6474/17/3711947-20$15.00/0.

Lycopene attenuates Aβ1-42 secretion and its toxicity in human cell and Caenorhabditis elegans models of Alzheimer disease.

PubMed

Chen, Wei; Mao, Liuqun; Xing, Huanhuan; Xu, Lei; Fu, Xiang; Huang, Liyingzi; Huang, Dongling; Pu, Zhijun; Li, Qinghua

2015-11-03

Growing evidence suggests concentration of lycopene was reduced in plasma of patients with Alzheimer disease (AD). Lycopene, a member of the carotenoid family, has been identified as an antioxidant to attenuate oxidative damage and has neuroprotective role in several AD models. However, whether lycopene is involved in the pathogenesis of AD and molecular underpinnings are elusive. In this study, we found that lycopene can significantly delay paralysis in the Aβ1-42-transgenic Caenorhabditis elegans strain GMC101. Lycopene treatment reduced Aβ1-42 secretion in SH-SY5Y cells overexpressing the Swedish mutant form of human β-amyloid precursor protein (APPsw). Next, we found lycopene can down-regulate expression level of β-amyloid precursor protein(APP) in APPsw cells. Moreover, lycopene treatment can not change endogenous reactive oxygen species level and apoptosis in APPsw cells. However, lycopene treatment protected against H2O2-induced oxidative stress and copper-induced damage in APPsw cells. Collectively, our data support that elevated lycopene contributes to the lower pathogenesis of AD. Our findings suggest that increasing lycopene in neurons may be a novel approach to attenuate onset and development of AD. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

There comes a baby! What should I do? Smartphones' pregnancy-related applications: A web-based overview.

PubMed

Bert, Fabrizio; Passi, Stefano; Scaioli, Giacomo; Gualano, Maria R; Siliquini, Roberta

2016-09-01

Our article aims to give an overview of the most mentioned smartphones' pregnancy-related applications (Apps). A keywords string with selected keywords was entered both in a general search engine (Google(®)) and PubMed. While PubMed returned no pertinent results, a total of 370 web pages were found on Google(®), and 146 of them were selected. All the pregnancy-related Apps cited at least eight times were included. Information about App's producer, price, contents, privacy policy, and presence of a scientific board was collected. Finally, nine apps were considered. The majority of them were free and available in the two main online markets (Apple(®) App Store and Android(®) Google Play). Five apps presented a privacy policy statement, while a scientific board was mentioned in only three. Further studies are needed in order to deepen the knowledge regarding the main risks of these devices, such as privacy loss, contents control concerns, the digital divide and a potential humanization reduction. © The Author(s) 2015.

Influence of relief on permanent preservation areas.

PubMed

Dos Santos, Alexandre Rosa; Chimalli, Tessa; Peluzio, João Batista Esteves; da Silva, Aderbal Gomes; Dos Santos, Gleissy Mary Amaral Dino Alves; Lorenzon, Alexandre Simões; Teixeira, Thaisa Ribeiro; de Castro, Nero Lemos Martins; Soares Ribeiro, Carlos Antonio Alvares

2016-01-15

Many countries have environmental legislation to protecting natural resources on private property. In Brazil, the Brazilian Forestry Code determines specific areas to maintain with natural vegetation cover, known as areas of permanent preservation (APP). Currently, there are few studies that relate topographic variables on APP. In this context, we sought to evaluate the influence of relief on the conservation of areas of permanent preservation (APP) in the areas surrounding Caparaó National Park, Brazil. By using the chi-squared statistical test, we verified that the presence of forest cover is closely associated with altitude. The classes of APP in better conservation status are slopes in addition to hilltops and mountains, whereas APP streams and springs are among the areas most affected by human activities. The most deforested areas are located at altitudes below 1100.00 m and on slopes less than 45°. All orientations of the sides were significant for APP conservation status, with the southern, southeastern, and southwestern sides showing the lower degrees of impact. The methodology can be adjusted to environmental legislation to other countries.

UNDERSTANDING POLYSPECIFICITY WITHIN THE SUBSTRATE-BINDING CAVITY OF THE HUMAN MULTIDRUG RESISTANCE P-GLYCOPROTEIN

PubMed Central

Martinez, Lorena; Arnaud, Ophélie; Henin, Emilie; Tao, Houchao; Chaptal, Vincent; Doshi, Rupak; Andrieu, Thibaud; Dussurgey, Sébastien; Tod, Michel; Di Pietro, Attilio; Zhang, Qinghai; Chang, Geoffrey; Falson, Pierre

2015-01-01

Human P-glycoprotein (P-gp) controls drugs bioavailability by pumping out of the cells many structurally-unrelated drugs. The x-ray structure of the mouse P-gp ortholog was solved with two SSS- and one RRR-enantiomers of the selenohexapeptide inhibitor QZ59, found within the putative drug-binding pocket of the membrane domain outer leaflet. This offered the first opportunity to localize the well-known H- and R- drug-substrate sites in light of QZ59 inhibition mechanisms that were characterized here in cellulo and modelled towards Hoechst 33342 and daunorubicin transport. We found that QZ59-SSS competes efficiently with both substrates, displaying KI,app values of 0.15 and 0.3 μM, respectively 13 and 2 times lower than corresponding Km,app. In contrast, QZ59-RRR non-competitively inhibited daunorubicin transport with moderate efficacy (KI,app = 1.9 μM) and displayed a mixed-type inhibition towards Hoechst 33342 transport, resulting from a mainly non-competitive (Ki2,app = 1.6 μM) and a poor but significant competitive tendency (Ki1,app = 5 μM). These results suppose a positional overlap of QZ59 – drug-transport sites, total for the SSS enantiomer and partial for the RRR one. Crystal structures analysis suggests that the H site overlaps both QZ59-SSS locations while the R-site overlaps the most embedded one. PMID:24219411

Guidelines and Recommendations for Developing Interactive eHealth Apps for Complex Messaging in Health Promotion.

PubMed

Heffernan, Kayla Joanne; Chang, Shanton; Maclean, Skye Tamara; Callegari, Emma Teresa; Garland, Suzanne Marie; Reavley, Nicola Jane; Varigos, George Andrew; Wark, John Dennis

2016-02-09

The now ubiquitous catchphrase, "There's an app for that," rings true owing to the growing number of mobile phone apps. In excess of 97,000 eHealth apps are available in major app stores. Yet the effectiveness of these apps varies greatly. While a minority of apps are developed grounded in theory and in conjunction with health care experts, the vast majority are not. This is concerning given the Hippocratic notion of "do no harm." There is currently no unified formal theory for developing interactive eHealth apps, and development is especially difficult when complex messaging is required, such as in health promotion and prevention. This paper aims to provide insight into the creation of interactive eHealth apps for complex messaging, by leveraging the Safe-D case study, which involved complex messaging required to guide safe but sufficient UV exposure for vitamin D synthesis in users. We aim to create recommendations for developing interactive eHealth apps for complex messages based on the lessons learned during Safe-D app development. For this case study we developed an Apple and Android app, both named Safe-D, to safely improve vitamin D status in young women through encouraging safe ultraviolet radiation exposure. The app was developed through participatory action research involving medical and human computer interaction researchers, subject matter expert clinicians, external developers, and target users. The recommendations for development were created from analysis of the development process. By working with clinicians and implementing disparate design examples from the literature, we developed the Safe-D app. From this development process, recommendations for developing interactive eHealth apps for complex messaging were created: (1) involve a multidisciplinary team in the development process, (2) manage complex messages to engage users, and (3) design for interactivity (tailor recommendations, remove barriers to use, design for simplicity). This research has provided principles for developing interactive eHealth apps for complex messaging as guidelines by aggregating existing design concepts and expanding these concepts and new learnings from our development process. A set of guidelines to develop interactive eHealth apps generally, and specifically those for complex messaging, was previously missing from the literature; this research has contributed these principles. Safe-D delivers complex messaging simply, to aid education, and explicitly, considering user safety.

Guidelines and Recommendations for Developing Interactive eHealth Apps for Complex Messaging in Health Promotion

PubMed Central

Heffernan, Kayla Joanne; Maclean, Skye Tamara; Callegari, Emma Teresa; Garland, Suzanne Marie; Reavley, Nicola Jane; Varigos, George Andrew; Wark, John Dennis

2016-01-01

Background The now ubiquitous catchphrase, “There’s an app for that,” rings true owing to the growing number of mobile phone apps. In excess of 97,000 eHealth apps are available in major app stores. Yet the effectiveness of these apps varies greatly. While a minority of apps are developed grounded in theory and in conjunction with health care experts, the vast majority are not. This is concerning given the Hippocratic notion of “do no harm.” There is currently no unified formal theory for developing interactive eHealth apps, and development is especially difficult when complex messaging is required, such as in health promotion and prevention. Objective This paper aims to provide insight into the creation of interactive eHealth apps for complex messaging, by leveraging the Safe-D case study, which involved complex messaging required to guide safe but sufficient UV exposure for vitamin D synthesis in users. We aim to create recommendations for developing interactive eHealth apps for complex messages based on the lessons learned during Safe-D app development. Methods For this case study we developed an Apple and Android app, both named Safe-D, to safely improve vitamin D status in young women through encouraging safe ultraviolet radiation exposure. The app was developed through participatory action research involving medical and human computer interaction researchers, subject matter expert clinicians, external developers, and target users. The recommendations for development were created from analysis of the development process. Results By working with clinicians and implementing disparate design examples from the literature, we developed the Safe-D app. From this development process, recommendations for developing interactive eHealth apps for complex messaging were created: (1) involve a multidisciplinary team in the development process, (2) manage complex messages to engage users, and (3) design for interactivity (tailor recommendations, remove barriers to use, design for simplicity). Conclusions This research has provided principles for developing interactive eHealth apps for complex messaging as guidelines by aggregating existing design concepts and expanding these concepts and new learnings from our development process. A set of guidelines to develop interactive eHealth apps generally, and specifically those for complex messaging, was previously missing from the literature; this research has contributed these principles. Safe-D delivers complex messaging simply, to aid education, and explicitly, considering user safety. PMID:26860623

A Smartphone App (AfyaData) for Innovative One Health Disease Surveillance from Community to National Levels in Africa: Intervention in Disease Surveillance

PubMed Central

Sindato, Calvin; Mwabukusi, Mpoki; Teesdale, Scott; Olsen, Jennifer

2017-01-01

Background We describe the development and initial achievements of a participatory disease surveillance system that relies on mobile technology to promote Community Level One Health Security (CLOHS) in Africa. Objective The objective of this system, Enhancing Community-Based Disease Outbreak Detection and Response in East and Southern Africa (DODRES), is to empower community-based human and animal health reporters with training and information and communication technology (ICT)–based solutions to contribute to disease detection and response, thereby complementing strategies to improve the efficiency of infectious disease surveillance at national, regional, and global levels. In this study, we refer to techno-health as the application of ICT-based solutions to enhance early detection, timely reporting, and prompt response to health events in human and animal populations. Methods An EpiHack, involving human and animal health experts as well as ICT programmers, was held in Tanzania in 2014 to identify major challenges facing early detection, timely reporting, and prompt response to disease events. This was followed by a project inception workshop in 2015, which brought together key stakeholders, including policy makers and community representatives, to refine the objectives and implementation plan of the DODRES project. The digital ICT tools were developed and packaged together as the AfyaData app to support One Health disease surveillance. Community health reporters (CHRs) and officials from animal and human health sectors in Morogoro and Ngorongoro districts in Tanzania were trained to use the AfyaData app. The AfyaData supports near- to real-time data collection and submission at both community and health facility levels as well as the provision of feedback to reporters. The functionality of the One Health Knowledge Repository (OHKR) app has been integrated into the AfyaData app to provide health information on case definitions of diseases of humans and animals and to synthesize advice that can be transmitted to CHRs with next step response activities or interventions. Additionally, a WhatsApp social group was made to serve as a platform to sustain interactions between community members, local government officials, and DODRES team members. Results Within the first 5 months (August-December 2016) of AfyaData tool deployment, a total of 1915 clinical cases in livestock (1816) and humans (99) were reported in Morogoro (83) and Ngorongoro (1832) districts. Conclusions These initial results suggest that the DODRES community-level model creates an opportunity for One Health engagement of people in their own communities in the detection of infectious human and animal disease threats. Participatory approaches supported by digital and mobile technologies should be promoted for early disease detection, timely reporting, and prompt response at the community, national, regional, and global levels. PMID:29254916

Capacity Ratios to Assess the Solvency of a College’s Advanced Pharmacy Practice Experience Program

PubMed Central

McClellan, Nicole H.; Byrd, Debbie C.

2013-01-01

Objective. To use the capacity ratio to determine solvency in 10 advanced pharmacy practice experiences (APPEs) offered by a college of pharmacy. Methods. Availability in each APPE was determined based on preceptor responses, and student need was tabulated from 3 preference forms. Capacity ratios were calculated by dividing preceptor availability by the sum of student requests plus 20% of student requests; ratios ≥ 1 indicated solvency. For the 3 required APPEs, minimum capacity ratios were calculated by dividing availability by the sum of student number plus 20% of the student number. When possible, the capacity ratio for the APPE was calculated by geographic zone. Results. The 3 required APPEs had statewide minimum capacity ratios that were consistent with solvency: advanced community (2.8), advanced institutional (1.6), and ambulatory care (2.5). Only 3 of 7 elective APPEs demonstrated solvency. The elective APPEs for which requests exceeded availability were association management (0.8), emergency medicine (0.8), cardiology (0.6), and human immunodeficiency virus (HIV) ambulatory care clinic (0.4). Analysis by zone revealed additional insolvent practice experiences in some locations. Conclusions. The capacity ratio allowed for assessment of 10 APPEs and identification of practice experience areas that need expansion. While the capacity ratio is a proposed standardized assessment, it does have some limitations, such as an inability to account for practice experience quality, scheduling conflicts, and geographic zone issues. PMID:23519687

Circadian and Brain State Modulation of Network Hyperexcitability in Alzheimer’s Disease

PubMed Central

Ying, Andrew; Jones, Mary; Chou, Robert Chang-Chih; Jordan, Crispin Y.; Jedrasiak-Cape, Izabela; Abou Jaoude, Maurice; Hashemi, Kevan

2018-01-01

Abstract Network hyperexcitability is a feature of Alzheimer’ disease (AD) as well as numerous transgenic mouse models of AD. While hyperexcitability in AD patients and AD animal models share certain features, the mechanistic overlap remains to be established. We aimed to identify features of network hyperexcitability in AD models that can be related to epileptiform activity signatures in AD patients. We studied network hyperexcitability in mice expressing amyloid precursor protein (APP) with mutations that cause familial AD, and compared a transgenic model that overexpresses human APP (hAPP) (J20), to a knock-in model expressing APP at physiological levels (APPNL/F). We recorded continuous long-term electrocorticogram (ECoG) activity from mice, and studied modulation by circadian cycle, behavioral, and brain state. We report that while J20s exhibit frequent interictal spikes (IISs), APPNL/F mice do not. In J20 mice, IISs were most prevalent during daylight hours and the circadian modulation was associated with sleep. Further analysis of brain state revealed that IIS in J20s are associated with features of rapid eye movement (REM) sleep. We found no evidence of cholinergic changes that may contribute to IIS-circadian coupling in J20s. In contrast to J20s, intracranial recordings capturing IIS in AD patients demonstrated frequent IIS in non-REM (NREM) sleep. The salient differences in sleep-stage coupling of IIS in APP overexpressing mice and AD patients suggests that different mechanisms may underlie network hyperexcitability in mice and humans. We posit that sleep-stage coupling of IIS should be an important consideration in identifying mouse AD models that most closely recapitulate network hyperexcitability in human AD. PMID:29780880

Modeling Late-Onset Sporadic Alzheimer's Disease through BMI1 Deficiency.

PubMed

Flamier, Anthony; El Hajjar, Jida; Adjaye, James; Fernandes, Karl J; Abdouh, Mohamed; Bernier, Gilbert

2018-05-29

Late-onset sporadic Alzheimer's disease (AD) is the most prevalent form of dementia, but its origin remains poorly understood. The Bmi1/Ring1 protein complex maintains transcriptional repression of developmental genes through histone H2A mono-ubiquitination, and Bmi1 deficiency in mice results in growth retardation, progeria, and neurodegeneration. Here, we demonstrate that BMI1 is silenced in AD brains, but not in those with early-onset familial AD, frontotemporal dementia, or Lewy body dementia. BMI1 expression was also reduced in cortical neurons from AD patient-derived induced pluripotent stem cells but not in neurons overexpressing mutant APP and PSEN1. BMI1 knockout in human post-mitotic neurons resulted in amyloid beta peptide secretion and deposition, p-Tau accumulation, and neurodegeneration. Mechanistically, BMI1 was required to repress microtubule associated protein tau (MAPT) transcription and prevent GSK3beta and p53 stabilization, which otherwise resulted in neurodegeneration. Restoration of BMI1 activity through genetic or pharmaceutical approaches could represent a therapeutic strategy against AD. Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

Mental Health Mobile Apps: From Infusion to Diffusion in the Mental Health Social System

PubMed Central

2015-01-01

The roles of mental health educators and professionals in the diffusion of mental health mobile apps are addressed in this viewpoint article. Mental health mobile apps are emerging technologies that fit under the broad heading of mobile health (mHealth). mHealth, encompassed within electronic health (eHealth), reflects the use of mobile devices for the practice of public health. Well-designed mental health mobile apps that present content in interactive, engaging, and stimulating ways can promote cognitive learning, personal growth, and mental health enhancement. As key influencers in the mental health social system, counselor educators and professional associations may either help or hinder diffusion of beneficial mHealth technologies. As mental health mobile apps move towards ubiquity, research will continue to be conducted. The studies published thus far, combined with the potential of mental health mobile apps for learning and personal growth, offer enough evidence to compel mental health professionals to infuse these technologies into education and practice. Counselor educators and professional associations must use their influential leadership roles to train students and practitioners in how to research, evaluate, and integrate mental health mobile apps into practice. The objectives of this article are to (1) increase awareness of mHealth and mental health mobile apps, (2) demonstrate the potential for continued growth in mental health mobile apps based on technology use and acceptance theory, mHealth organizational initiatives, and evidence about how humans learn, (3) discuss evidence-based benefits of mental health mobile apps, (4) examine the current state of mHealth diffusion in the mental health profession, and (5) offer solutions for impelling innovation diffusion by infusing mental health mobile apps into education, training, and clinical settings. This discussion has implications for counselor educators, mental health practitioners, associations, continuing education providers, and app developers. PMID:26543907

Mitosis-specific phosphorylation of amyloid precursor protein at Threonine 668 leads to its altered processing and association with centrosomes

PubMed Central

2011-01-01

Background Atypical expression of cell cycle regulatory proteins has been implicated in Alzheimer's disease (AD), but the molecular mechanisms by which they induce neurodegeneration are not well understood. We examined transgenic mice expressing human amyloid precursor protein (APP) and presenilin 1 (PS1) for changes in cell cycle regulatory proteins to determine whether there is a correlation between cell cycle activation and pathology development in AD. Results Our studies in the AD transgenic mice show significantly higher levels of cyclin E, cyclin D1, E2F1, and P-cdc2 in the cells in the vicinity of the plaques where maximum levels of Threonine 668 (Thr668)-phosphorylated APP accumulation was observed. This suggests that the cell cycle regulatory proteins might be influencing plaque pathology by affecting APP phosphorylation. Using neuroglioma cells overexpressing APP we demonstrate that phosphorylation of APP at Thr668 is mitosis-specific. Cells undergoing mitosis show altered cellular distribution and localization of P-APP at the centrosomes. Also, Thr668 phosphorylation in mitosis correlates with increased processing of APP to generate Aβ and the C-terminal fragment of APP, which is prevented by pharmacological inhibitors of the G1/S transition. Conclusions The data presented here suggests that cell cycle-dependent phosphorylation of APP may affect its normal cellular function. For example, association of P-APP with the centrosome may affect spindle assembly and cell cycle progression, further contributing to the development of pathology in AD. The experiments with G1/S inhibitors suggest that cell cycle inhibition may impede the development of Alzheimer's pathology by suppressing modification of βAPP, and thus may represent a novel approach to AD treatment. Finally, the cell cycle regulated phosphorylation and processing of APP into Aβ and the C-terminal fragment suggest that these proteins may have a normal function during mitosis. PMID:22112898

Qualitative Assessment of the Feasibility, Usability, and Acceptability of a Mobile Client Data App for Community-Based Maternal, Neonatal, and Child Care in Rural Ghana.

PubMed

Rothstein, Jessica D; Jennings, Larissa; Moorthy, Anitha; Yang, Fan; Gee, Lisa; Romano, Karen; Hutchful, David; Labrique, Alain B; LeFevre, Amnesty E

2016-01-01

Mobile phone applications may enhance the delivery of critical health services and the accuracy of health service data. Yet, the opinions and experiences of frontline health workers on using mobile apps to track pregnant and recently delivered women are underreported. This evaluation qualitatively assessed the feasibility, usability, and acceptability of a mobile Client Data App for maternal, neonatal, and child client data management by community health nurses (CHNs) in rural Ghana. The mobile app enabled CHNs to enter, summarize, and query client data. It also sent visit reminders for clients and provided a mechanism to report level of care to district officers. Fourteen interviews and two focus groups with CHNs, midwives, and district health officers were conducted, coded, and thematically analyzed. Results indicated that the app was easily integrated into care, improved CHN productivity, and was acceptable due to its capacity to facilitate client follow-up, data reporting, and decision-making. However, the feasibility and usability of the app were hindered by high client volumes, staff shortages, and software and device challenges. Successful integration of mobile client data apps for frontline health workers in rural and resource-poor settings requires real-time monitoring, program investments, and targeted changes in human resources.

Qualitative Assessment of the Feasibility, Usability, and Acceptability of a Mobile Client Data App for Community-Based Maternal, Neonatal, and Child Care in Rural Ghana

PubMed Central

Jennings, Larissa; Moorthy, Anitha; Yang, Fan; Gee, Lisa; Romano, Karen; Hutchful, David; Labrique, Alain B.; LeFevre, Amnesty E.

2016-01-01

Mobile phone applications may enhance the delivery of critical health services and the accuracy of health service data. Yet, the opinions and experiences of frontline health workers on using mobile apps to track pregnant and recently delivered women are underreported. This evaluation qualitatively assessed the feasibility, usability, and acceptability of a mobile Client Data App for maternal, neonatal, and child client data management by community health nurses (CHNs) in rural Ghana. The mobile app enabled CHNs to enter, summarize, and query client data. It also sent visit reminders for clients and provided a mechanism to report level of care to district officers. Fourteen interviews and two focus groups with CHNs, midwives, and district health officers were conducted, coded, and thematically analyzed. Results indicated that the app was easily integrated into care, improved CHN productivity, and was acceptable due to its capacity to facilitate client follow-up, data reporting, and decision-making. However, the feasibility and usability of the app were hindered by high client volumes, staff shortages, and software and device challenges. Successful integration of mobile client data apps for frontline health workers in rural and resource-poor settings requires real-time monitoring, program investments, and targeted changes in human resources. PMID:28070186

A Presenilin-1 Mutation Identified in Familial Alzheimer Disease with Cotton Wool Plaques Causes a Nearly Complete Loss of γ-Secretase Activity*

PubMed Central

Heilig, Elizabeth A.; Xia, Weiming; Shen, Jie; Kelleher, Raymond J.

2010-01-01

Mutations in presenilin-1 and presenilin-2 (PS1 and PS2) are the most common cause of familial Alzheimer disease. PS1 and PS2 are the presumptive catalytic components of the multisubunit γ-secretase complex, which proteolyzes a number of type I transmembrane proteins, including the amyloid precursor protein (APP) and Notch. APP processing by γ-secretase produces β-amyloid peptides (Aβ40 and Aβ42) that accumulate in the Alzheimer disease brain. Here we identify a pathogenic L435F mutation in PS1 in two affected siblings with early-onset familial Alzheimer disease characterized by deposition of cerebral cotton wool plaques. The L435F mutation resides in a conserved C-terminal PAL sequence implicated in active site conformation and catalytic activity. The impact of PS1 mutations in and around the PAL motif on γ-secretase activity was assessed by expression of mutant PS1 in mouse embryo fibroblasts lacking endogenous PS1 and PS2. Surprisingly, the L435F mutation caused a nearly complete loss of γ-secretase activity, including >90% reductions in the generation of Aβ40, Aβ42, and the APP and Notch intracellular domains. Two nonpathogenic PS1 mutations, P433L and L435R, caused essentially complete loss of γ-secretase activity, whereas two previously identified pathogenic PS1 mutations, P436Q and P436S, caused partial loss of function with substantial reductions in production of Aβ40, Aβ42, and the APP and Notch intracellular domains. These results argue against overproduction of Aβ42 as an essential property of presenilin proteins bearing pathogenic mutations. Rather, our findings provide support for the hypothesis that pathogenic mutations cause a general loss of presenilin function. PMID:20460383

Mobile Phone Apps for Smoking Cessation: Quality and Usability Among Smokers With Psychosis.

PubMed

Ferron, Joelle C; Brunette, Mary F; Geiger, Pamela; Marsch, Lisa A; Adachi-Mejia, Anna M; Bartels, Stephen J

2017-03-03

Smoking is one of the top preventable causes of mortality in people with psychotic disorders such as schizophrenia. Cessation treatment improves abstinence outcomes, but access is a barrier. Mobile phone apps are one way to increase access to cessation treatment; however, whether they are usable by people with psychotic disorders, who often have special learning needs, is not known. Researchers reviewed 100 randomly selected apps for smoking cessation to rate them based on US guidelines for nicotine addiction treatment and to categorize them based on app functions. We aimed to test the usability and usefulness of the top-rated apps in 21 smokers with psychotic disorders. We identified 766 smoking cessation apps and randomly selected 100 for review. Two independent reviewers rated each app with the Adherence Index to US Clinical Practice Guideline for Treating Tobacco Use and Dependence. Then, smokers with psychotic disorders evaluated the top 9 apps within a usability testing protocol. We analyzed quantitative results using descriptive statistics and t tests. Qualitative data were open-coded and analyzed for themes. Regarding adherence to practice guidelines, most of the randomly sampled smoking cessation apps scored poorly-66% rated lower than 10 out of 100 on the Adherence Index (Mean 11.47, SD 11.8). Regarding usability, three common usability problems emerged: text-dense content, abstract symbols on the homepage, and subtle directions to edit features. In order for apps to be effective and usable for this population, developers should utilize a balance of text and simple design that facilitate ease of navigation and content comprehension that will help people learn quit smoking skills. ©Joelle C Ferron, Mary F Brunette, Pamela Geiger, Lisa A Marsch, Anna M Adachi-Mejia, Stephen J Bartels. Originally published in JMIR Human Factors (http://humanfactors.jmir.org), 03.03.2017.

Reducing expression of synapse-restricting protein Ephexin5 ameliorates Alzheimer’s-like impairment in mice

PubMed Central

Sell, Gabrielle L.; Schaffer, Thomas B.; Margolis, Seth S.

2017-01-01

Accumulation of amyloid-β (Aβ) protein may cause synapse degeneration and cognitive impairment in Alzheimer’s disease (AD) by reactivating expression of the developmental synapse repressor protein Ephexin5 (also known as ARHGEF15). Here, we have reported that Aβ is sufficient to acutely promote the production of Ephexin5 in mature hippocampal neurons and in mice expressing human amyloid precursor protein (hAPP mice), a model for familial AD that produces high brain levels of Aβ. Ephexin5 expression was highly elevated in the hippocampi of human AD patients, indicating its potential relevance to AD. We also observed elevated Ephexin5 expression in the hippocampi of hAPP mice. Removal of Ephexin5 expression eliminated hippocampal dendritic spine loss and rescued AD-associated behavioral deficits in the hAPP mice. Furthermore, selective reduction of Ephexin5 expression using shRNA in the dentate gyrus of presymptomatic adolescent hAPP mice was sufficient to protect these mice from developing cognitive impairment. Thus, pathological elevation of Ephexin5 expression critically drives Aβ-induced memory impairment, and strategies aimed at reducing Ephexin5 levels may represent an effective approach to treating AD. PMID:28346227

Transplantation of Human Menstrual Blood-Derived Mesenchymal Stem Cells Alleviates Alzheimer's Disease-Like Pathology in APP/PS1 Transgenic Mice.

PubMed

Zhao, Yongjia; Chen, Xin; Wu, Yichen; Wang, Yanling; Li, Yifei; Xiang, Charlie

2018-01-01

Extracellular β-amyloid (Aβ) plaques and neurofibrillary tangles (NFTs) are the pathological hallmarks of Alzheimer's disease (AD). Mesenchymal stem cells (MSCs) have shown therapeutic efficacy in many neurodegenerative diseases, including AD. Human menstrual blood-derived stem cells (MenSCs) are a novel source of MSCs advantageous for their higher proliferation rate and because they are easy to obtain without ethical concerns. Although MenSCs have exhibited therapeutic efficacy in some diseases, their effects on AD remain elusive. In the present study, we showed that intracerebral transplantation of MenSCs dramatically improved the spatial learning and memory of APP/PS1 mice. In addition, MenSCs significantly ameliorated amyloid plaques and reduced tau hyperphosphorylation in APP/PS1 mice. Remarkably, we also found that intracerebral transplantation of MenSCs markedly increased several Aβ degrading enzymes and modulated a panel of proinflammatory cytokines associated with an altered microglial phenotype, suggesting an Aβ degrading and anti-inflammatory impact of MenSCs in the brains of APP/PS1 mice. In conclusion, these findings suggest that MenSCs are a promising therapeutic candidate for AD.

Smartphone Apps for Measuring Human Health and Climate Change Co-Benefits: A Comparison and Quality Rating of Available Apps.

PubMed

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; Maddison, Ralph

2016-12-19

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. 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. 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). 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). Existing apps capturing travel and dietary behavior and the associated health and environmental impact are of mixed quality. Most apps do not include all desirable features or provide sufficient health information. Further research is needed to determine the potential of smartphone apps to evoke behavior change resulting in climate change and health co-benefits. ©Rachel K Sullivan, Samantha Marsh, Jakob Halvarsson, Michelle Holdsworth, Wilma Waterlander, Maartje P Poelman, Jennifer Ann Salmond, Hayley Christian, Lenny SC Koh, Janet E Cade, John C Spence, Alistair Woodward, Ralph Maddison. Originally published in JMIR Mhealth and Uhealth (http://mhealth.jmir.org), 19.12.2016.

GeneStoryTeller: a mobile app for quick and comprehensive information retrieval of human genes.

PubMed

Eleftheriou, Stergiani V; Bourdakou, Marilena M; Athanasiadis, Emmanouil I; Spyrou, George M

2015-01-01

In the last few years, mobile devices such as smartphones and tablets have become an integral part of everyday life, due to their software/hardware rapid development, as well as the increased portability they offer. Nevertheless, up to now, only few Apps have been developed in the field of bioinformatics, capable to perform fast and robust access to services. We have developed the GeneStoryTeller, a mobile application for Android platforms, where users are able to instantly retrieve information regarding any recorded human gene, derived from eight publicly available databases, as a summary story. Complementary information regarding gene-drugs interactions, functional annotation and disease associations for each selected gene is also provided in the gene story. The most challenging part during the development of the GeneStoryTeller was to keep balance between storing data locally within the app and obtaining the updated content dynamically via a network connection. This was accomplished with the implementation of an administrative site where data are curated and synchronized with the application requiring a minimum human intervention. © The Author(s) 2015. Published by Oxford University Press.

77 FR 38093 - Meeting of National Council on the Humanities

Federal Register 2010, 2011, 2012, 2013, 2014

2012-06-26

... NATIONAL FOUNDATION ON THE ARTS AND THE HUMANITIES Meeting of National Council on the Humanities AGENCY: National Endowment for the Humanities, National Foundation on the Arts and the Humanities. ACTION.... App.), notice is hereby given that the National Council on the Humanities will meet for the following...

By the People, for the People: the Crowdsourcing of "STREETBUMP": AN Automatic Pothole Mapping App

NASA Astrophysics Data System (ADS)

Carrera, F.; Guerin, S.; Thorp, J. B.

2013-05-01

This paper traces the genesis and development of StreetBump, a smartphone application to map the location of potholes in Boston, Massachusetts. StreetBump belongs to a special category of "subliminal" crowdsourcing mobile applications that turn humans into sensors. Once started, it automatically collects road condition information without any human intervention, using the accelerometers and GPS inside smartphones. The StreetBump app evolved from a hardware device designed and built by WPI's City Lab starting in 2003, which was originally intended to measure and map boat wakes in the city of Venice, Italy (Chiu, 2004). A second version of the custom hardware with onboard GPS and accelerometers was adapted to use in Boston, Massachusetts, to map road damage (potholes) in 2006 (Angelini, 2006). In 2009, Prof. Carrera proposed to the newly created office of New Urban Mechanics in the City of Boston to migrate the concept to Smartphones, based on the Android platform. The first prototype of the mobile app, called StreetBump, was released in 2010 by the authors (Harmon, 2010). In 2011, the app provided the basis for a worldwide Innocentive competition to develop the best postprocessing algorithms to identify the real potholes vs. other phone bumps (Moskowitz, 2011). Starting in 2012, the City of Boston has begun using a subsequent version of the app to operationally manage road repairs based on the data collected by StreetBump. The novelty of this app is not purely technological, but lies also in the top-to-bottom crowdsourcing of all its components. The app was designed to rely on the crowd to confirm the presence of damage though repeat hits (or lack thereof) as more users travel the same roads over time. Moreover, the non-trivial post-processing of the StreetBump data was itself the subject of a crowdsourced competition through an Innocentive challenge for the best algorithm. The release of the StreetBump code as open-source allowed the development of the final version of the app now used on a daily basis by the Department of Public Works in Boston, thus making it perhaps the first example of an app that was crowdsourced "from soup to nuts".

Identification of Small Peptides in Human Cerebrospinal Fluid upon Amyloid-β Degradation.

PubMed

Mizuta, Naoki; Yanagida, Kanta; Kodama, Takashi; Tomonaga, Takeshi; Takami, Mako; Oyama, Hiroshi; Kudo, Takashi; Ikeda, Manabu; Takeda, Masatoshi; Tagami, Shinji; Okochi, Masayasu

2017-01-01

Amyloid-β (Aβ) degradation in brains of Alzheimer disease patients is a crucial focus for the clarification of disease pathogenesis. Nevertheless, the mechanisms underlying Aβ degradation in the human brain remain unclear. This study aimed to quantify the levels of small C-terminal Aβ fragments generated upon Aβ degradation in human cerebrospinal fluid (CSF). A fraction containing small peptides was isolated and purified from human CSF by high-pressure liquid chromatography. Degradation products of Aβ C termini were identified and measured by liquid chromatography-tandem mass spectrometry. The C-terminal fragments of Aβ in the conditioned medium of cultured cells transfected with the Swedish variant of βAPP (sw βAPP) were analyzed. These fragments in brains of PS1 I213T knock-in transgenic mice, overexpressing sw βAPP, were also analyzed. The peptide fragments GGVV and GVV, produced by the cleavage of Aβ40, were identified in human CSF as well as in the brains of the transgenic mice and in the conditioned medium of the cultured cells. Relative to Aβ40 levels, GGVV and GVV levels were 7.6 ± 0.81 and 1.5 ± 0.18%, respectively, in human CSF. Levels of the GGVV fragment did not increase by the introduction of genes encoding neprilysin and insulin-degrading enzyme to the cultured cells. Our results indicate that a substantial amount of Aβ40 in human brains is degraded via a neprilysin- or insulin-degrading enzyme-independent pathway. © 2017 S. Karger AG, Basel.

Mobile app for human-interaction with sitter robots

NASA Astrophysics Data System (ADS)

Das, Sumit Kumar; Sahu, Ankita; Popa, Dan O.

2017-05-01

Human environments are often unstructured and unpredictable, thus making the autonomous operation of robots in such environments is very difficult. Despite many remaining challenges in perception, learning, and manipulation, more and more studies involving assistive robots have been carried out in recent years. In hospital environments, and in particular in patient rooms, there are well-established practices with respect to the type of furniture, patient services, and schedule of interventions. As a result, adding a robot into semi-structured hospital environments is an easier problem to tackle, with results that could have positive benefits to the quality of patient care and the help that robots can offer to nursing staff. When working in a healthcare facility, robots need to interact with patients and nurses through Human-Machine Interfaces (HMIs) that are intuitive to use, they should maintain awareness of surroundings, and offer safety guarantees for humans. While fully autonomous operation for robots is not yet technically feasible, direct teleoperation control of the robot would also be extremely cumbersome, as it requires expert user skills, and levels of concentration not available to many patients. Therefore, in our current study we present a traded control scheme, in which the robot and human both perform expert tasks. The human-robot communication and control scheme is realized through a mobile tablet app that can be customized for robot sitters in hospital environments. The role of the mobile app is to augment the verbal commands given to a robot through natural speech, camera and other native interfaces, while providing failure mode recovery options for users. Our app can access video feed and sensor data from robots, assist the user with decision making during pick and place operations, monitor the user health over time, and provides conversational dialogue during sitting sessions. In this paper, we present the software and hardware framework that enable a patient sitter HMI, and we include experimental results with a small number of users that demonstrate that the concept is sound and scalable.

A Self-Regulation Theory-Based Asthma Management Mobile App for Adolescents: A Usability Assessment.

PubMed

Sage, Adam; Roberts, Courtney; Geryk, Lorie; Sleath, Betsy; Tate, Deborah; Carpenter, Delesha

2017-02-01

Self-regulation theory suggests people learn to influence their own behavior through self-monitoring, goal-setting, feedback, self-reward, and self-instruction, all of which smartphones are now capable of facilitating. Several mobile apps exist to manage asthma; however, little evidence exists about whether these apps employ user-centered design processes that adhere to government usability guidelines for mobile apps. Building upon a previous study that documented adolescent preferences for an asthma self-management app, we employed a user-centered approach to assess the usability of a high-fidelity wireframe for an asthma self-management app intended for use by adolescents with persistent asthma. Individual interviews were conducted with adolescents (ages 11-18 years) with persistent asthma who owned a smartphone (N=8). Adolescents were asked to evaluate a PDF app wireframe consisting of 76 screen shots displaying app features, including log in and home screen, profile setup, settings and info, self-management features, and graphical displays for charting asthma control and medication. Preferences, comments, and suggestions for each set of screen shots were assessed using the audio-recorded interviews. Two coders reached consensus on adolescent evaluations of the following aspects of app features: (1) usability, (2) behavioral intentions to use, (3) confusing aspects, and (4) suggestions for improvement. The app wireframe was generally well received, and several suggestions for improvement were recorded. Suggestions included increased customization of charts and notifications, reminders, and alerts. Participants preferred longitudinal data about asthma control and medication use to be displayed using line graphs. All participants reported that they would find an asthma management app like the one depicted in the wireframe useful for managing their asthma. Early stage usability tests guided by government usability guidelines (usability.gov) revealed areas for improvement for an asthma self-management app for adolescents. Addressing these areas will be critical to developing an engaging and effective asthma self-management app that is capable of improving adolescent asthma outcomes. ©Adam Sage, Courtney Roberts, Lorie Geryk, Betsy Sleath, Deborah Tate, Delesha Carpenter. Originally published in JMIR Human Factors (http://humanfactors.jmir.org), 01.02.2017.

Spatial Distribution of Partner-Seeking Men Who Have Sex With Men Using Geosocial Networking Apps: Epidemiologic Study

PubMed Central

Algarin, Angel B; Ward, Patrick J; Christian, W Jay; Rudolph, Abby E; Holloway, Ian W

2018-01-01

Background Geosocial networking apps have made sexual partner-seeking easier for men who have sex with men, raising both challenges and opportunities for human immunodeficiency virus and sexually transmitted infection prevention and research. Most studies on men who have sex with men geosocial networking app use have been conducted in large urban areas, despite research indicating similar patterns of online- and app-based sex-seeking among men who have sex with men in rural and midsize cities. Objective The goal of our research was to examine the spatial distribution of geosocial networking app usage and characterize areas with increasing numbers of partner-seeking men who have sex with men in a midsize city in the South. Methods Data collection points (n=62) were spaced in 2-mile increments along 9 routes (112 miles) covering the county encompassing the city. At each point, staff logged into 3 different geosocial networking apps to record the number of geosocial networking app users within a 1-mile radius. Data were collected separately during weekday daytime (9:00 AM to 4:00 PM) and weekend nighttime (8:00 PM to 12:00 AM) hours. Empirical Bayesian kriging was used to create a raster estimating the number of app users throughout the county. Raster values were summarized for each of the county's 208 Census block groups and used as the outcome measure (ie, geosocial networking app usage). Negative binomial regression and Wilcoxon signed rank sum tests were used to examine Census block group variables (eg, median income, median age) associated with geosocial networking app usage and temporal differences in app usage, respectively. Results The number of geosocial networking app users within a 1-mile radius of the data collection points ranged from 0 to 36 during weekday daytime hours and 0 to 39 during weekend nighttime hours. In adjusted analyses, Census block group median income and percent Hispanic ethnicity were negatively associated with geosocial networking app usage for all 3 geosocial networking apps during weekday daytime and weekend nighttime hours. Population density and the presence of businesses were positively associated with geosocial networking app usage for all 3 geosocial networking apps during both times. Conclusions In this midsize city, geosocial networking app usage was highest in areas that were more population-dense, were lower income, and had more businesses. This research is an example of how geosocial networking apps’ geospatial capabilities can be used to better understand patterns of virtual partner-seeking among men who have sex with men. PMID:29853441

The circular RNA ciRS-7 promotes APP and BACE1 degradation in an NF-κB-dependent manner.

PubMed

Shi, Zhemin; Chen, Ting; Yao, Qingbin; Zheng, Lina; Zhang, Zhen; Wang, Jingzhao; Hu, Zhimei; Cui, Hongmei; Han, Yawei; Han, Xiaohui; Zhang, Kun; Hong, Wei

2017-04-01

The aberrant accumulation of β-amyloid peptide (Aβ) in the brain is a key feature of Alzheimer's disease (AD), and enhanced cleavage of β-amyloid precursor protein (APP) by β-site APP-cleaving enzyme 1 (BACE1) has a major causative role in AD. Despite their prominence in AD pathogenesis, the regulation of BACE1 and APP is incompletely understood. In this study, we report that the circular RNA circular RNA sponge for miR-7 (ciRS-7) has an important role in regulating BACE1 and APP protein levels. Previous studies have shown that ciRS-7, which is highly expressed in the human brain, is down-regulated in the brain of people with AD but the relevance of this finding was not clear. We have found that ciRS-7 is not involved in the regulation of APP and BACE1 gene expression, but instead reduces the protein levels of APP and BACE1 by promoting their degradation via the proteasome and lysosome. Consequently, overexpression of ciRS-7 reduces the generation of Aβ, indicating a potential neuroprotective role of ciRS-7. Our data also suggest that ciRS-7 modulates APP and BACE1 levels in a nuclear factor-κB (NF-κB)-dependent manner: ciRS-7 expression inhibits translation of NF-κB and induces its cytoplasmic localization, thus derepressing expression of UCHL1, which promotes APP and BACE1 degradation. Additionally, we demonstrated that APP reduces the level of ciRS-7, revealing a mutual regulation of ciRS-7 and APP. Taken together, our data provide a molecular mechanism implicating reduced ciRS-7 expression in AD, suggesting that ciRS-7 may represent a useful target in the development of therapeutic strategies for AD. © 2017 Federation of European Biochemical Societies.

Development and testing of an iOS waiting room "app" for contraceptive counseling in a Title X family planning clinic.

PubMed

Gilliam, Melissa L; Martins, Summer L; Bartlett, Emily; Mistretta, Stephanie Q; Holl, Jane L

2014-11-01

Long-acting reversible contraceptive (LARC) methods, such as the intrauterine device and implant, are highly effective but used by less than 10% of US women. The objective of our study was to improve LARC interest by enhancing clinic counseling. A quality improvement methodology was used to evaluate intrauterine device service delivery in 3 Chicago Title X clinics. To address identified barriers, we developed a theory-based iOS application (app) for patients to use in the clinic waiting room using human-centered design. The final prototype was tested in a randomized controlled trial in a Title X clinic with sexually active females (79% African American) under age 30 years. Our sample of 60 was chosen to detect an increase from 10% (baseline) to 45% (app intervention) in the proportion of patients expressing interest in discussing a LARC method during their clinic visit with 80% power and two-sided α = 0.05. After completing demographic and baseline knowledge questionnaires, participants were randomized 1:1 to intervention (app) or standard care arms. App users also completed a posttest. Our primary outcome was expressed interest in discussing a LARC method during the clinic visit. Secondary outcomes were contraceptive knowledge and LARC selection. App testers (n = 17) preferred interactive, visually appealing design and video testimonials. In the pilot randomized controlled trial (n = 52), app users had a significantly higher knowledge of contraceptive effectiveness (P = .0001) and increased interest in the implant (7.1-32.1%, P = .02) after the intervention. Users were highly satisfied with the app. Staff reported no problems using the app in the clinic. Use of a theory-based counseling app offers a novel method to optimize wait time while minimizing clinic flow disruption. Preliminary data demonstrate that app use was associated with improvements in patients' contraceptive knowledge and interest in the implant. Copyright © 2014 Elsevier Inc. All rights reserved.

Specific interactions between amyloid-β peptide and curcumin derivatives: Ab initio molecular simulations

NASA Astrophysics Data System (ADS)

Ishimura, Hiromi; Kadoya, Ryushi; Suzuki, Tomoya; Murakawa, Takeru; Shulga, Sergiy; Kurita, Noriyuki

2015-07-01

Alzheimer's disease is caused by accumulation of amyloid-β (Aβ) peptides in a brain. To suppress the production of Aβ peptides, it is effective to inhibit the cleavage of amyloid precursor protein (APP) by secretases. However, because the secretases also play important roles to produce vital proteins for human body, inhibitors for the secretases may have side effects. To propose new agents for protecting the cleavage site of APP from the attacking of the γ-secretase, we have investigated here the specific interactions between a short APP peptide and curcumin derivatives, using protein-ligand docking as well as ab initio molecular simulations.

Preferences for a Mobile HIV Prevention App for Men Who Have Sex With Men.

PubMed

Goldenberg, Tamar; McDougal, Sarah J; Sullivan, Patrick S; Stekler, Joanne D; Stephenson, Rob

2014-10-29

The Centers for Disease Control and Prevention recommends that sexually active men who have sex with men (MSM) in the United States test for human immunodeficiency virus (HIV) at least three times per year, but actual testing frequency is much less frequent. Though mHealth is a popular vehicle for delivering HIV interventions, there are currently no mobile phone apps that target MSM with the specific aim of building an HIV testing plan, and none that focuses on developing a comprehensive prevention plan and link MSM to additional HIV prevention and treatment resources. Previous research has suggested a need for more iterative feedback from the target population to ensure use of these interventions. The purpose of this study is to understand MSM's preferences for functionality, format, and design of a mobile phone-based HIV prevention app and to examine MSM's willingness to use an app for HIV prevention. We conducted focus group discussions with 38 gay and bisexual men, with two in-person groups in Atlanta, two in Seattle, and one online focus group discussion with gay and bisexual men in rural US regions. These discussions addressed MSM's general preferences for apps, HIV testing barriers and facilitators for MSM, and ways that an HIV prevention app could address these barriers and facilitators to increase the frequency of HIV testing and prevention among MSM. During focus group discussions, participants were shown screenshots and provided feedback on potential app functions. Participants provided preferences on functionality of the app, including the type and delivery of educational content, the value of interactive engagement, and the importance of social networking as an app component. Participants also discussed preferences on how the language should be framed for the delivery of information, identifying that an app needs to be simultaneously fun and professional. Privacy and altruistic motivation were considered to be important factors in men's willingness to use a mobile HIV prevention app. Finally, men described the potential impact that a mobile HIV prevention app could have, identifying individual, interpersonal, and community-based benefits. In summary, participants described a comprehensive app that should incorporate innovative ideas to educate and engage men so that they would be motivated to use the app. In order for an app to be useful, it needs to feel safe and trustworthy, which is essential when considering the app's language and privacy. Participants provided a range of preferences for using an HIV prevention app, including what they felt MSM need with regards to HIV prevention and what they want in order to engage with an app. Making an HIV prevention app enjoyable and usable for MSM is a difficult challenge. However, the usability of the app is vital because no matter how great the intervention, if MSM do not use the app, then it will not be useful.

A Smartphone App (AfyaData) for Innovative One Health Disease Surveillance from Community to National Levels in Africa: Intervention in Disease Surveillance.

PubMed

Karimuribo, Esron Daniel; Mutagahywa, Eric; Sindato, Calvin; Mboera, Leonard; Mwabukusi, Mpoki; Kariuki Njenga, M; Teesdale, Scott; Olsen, Jennifer; Rweyemamu, Mark

2017-12-18

We describe the development and initial achievements of a participatory disease surveillance system that relies on mobile technology to promote Community Level One Health Security (CLOHS) in Africa. The objective of this system, Enhancing Community-Based Disease Outbreak Detection and Response in East and Southern Africa (DODRES), is to empower community-based human and animal health reporters with training and information and communication technology (ICT)-based solutions to contribute to disease detection and response, thereby complementing strategies to improve the efficiency of infectious disease surveillance at national, regional, and global levels. In this study, we refer to techno-health as the application of ICT-based solutions to enhance early detection, timely reporting, and prompt response to health events in human and animal populations. An EpiHack, involving human and animal health experts as well as ICT programmers, was held in Tanzania in 2014 to identify major challenges facing early detection, timely reporting, and prompt response to disease events. This was followed by a project inception workshop in 2015, which brought together key stakeholders, including policy makers and community representatives, to refine the objectives and implementation plan of the DODRES project. The digital ICT tools were developed and packaged together as the AfyaData app to support One Health disease surveillance. Community health reporters (CHRs) and officials from animal and human health sectors in Morogoro and Ngorongoro districts in Tanzania were trained to use the AfyaData app. The AfyaData supports near- to real-time data collection and submission at both community and health facility levels as well as the provision of feedback to reporters. The functionality of the One Health Knowledge Repository (OHKR) app has been integrated into the AfyaData app to provide health information on case definitions of diseases of humans and animals and to synthesize advice that can be transmitted to CHRs with next step response activities or interventions. Additionally, a WhatsApp social group was made to serve as a platform to sustain interactions between community members, local government officials, and DODRES team members. Within the first 5 months (August-December 2016) of AfyaData tool deployment, a total of 1915 clinical cases in livestock (1816) and humans (99) were reported in Morogoro (83) and Ngorongoro (1832) districts. These initial results suggest that the DODRES community-level model creates an opportunity for One Health engagement of people in their own communities in the detection of infectious human and animal disease threats. Participatory approaches supported by digital and mobile technologies should be promoted for early disease detection, timely reporting, and prompt response at the community, national, regional, and global levels. ©Esron Daniel Karimuribo, Eric Mutagahywa, Calvin Sindato, Leonard Mboera, Mpoki Mwabukusi, M Kariuki Njenga, Scott Teesdale, Jennifer Olsen, Mark Rweyemamu. Originally published in JMIR Public Health and Surveillance (http://publichealth.jmir.org), 18.12.2017.

A canine model of Alzheimer's disease generated by overexpressing a mutated human amyloid precursor protein.

PubMed

Lee, Geun-Shik; Jeong, Yeon Woo; Kim, Joung Joo; Park, Sun Woo; Ko, Kyeong Hee; Kang, Mina; Kim, Yu Kyung; Jung, Eui-Man; Moon, Changjong; Hyun, Sang Hwan; Hwang, Kyu-Chan; Kim, Nam-Hyung; Shin, Taeyoung; Jeung, Eui-Bae; Hwang, Woo Suk

2014-04-01

Canines are considered the most authentic model for studying multifactorial human diseases, as these animals typically share a common environment with man. Somatic cell nuclear transfer (SCNT) technology along with genetic engineering of nuclear donor cells provides a unique opportunity for examining human diseases using transgenic canines. In the present study, we generated transgenic canines that overexpressed the human amyloid precursor protein (APP) gene containing well-characterized familial Alzheimer's disease (AD) mutations. We successfully obtained five out of six live puppies by SCNT. This was confirmed by observing the expression of green fluorescence protein in the body as a visual transgenic marker and the overexpression of the mutated APP gene in the brain. The transgenic canines developed AD-like symptoms, such as enlarged ventricles, an atrophied hippocampus, and β-amyloid plaques in the brain. Thus, the transgenic canines we created can serve as a novel animal model for studying human AD.

New Insights to Clathrin and Adaptor Protein 2 for the Design and Development of Therapeutic Strategies

PubMed Central

Poulsen, Ebbe Toftgaard; Larsen, Agnete; Zollo, Alen; Jørgensen, Arne L.; Sanggaard, Kristian W.; Enghild, Jan J.; Matrone, Carmela

2015-01-01

The Amyloid Precursor Protein (APP) has been extensively studied for its role as the precursor of the β-amyloid protein (Aβ) in Alzheimer’s disease (AD). However, our understanding of the normal function of APP is still patchy. Emerging evidence indicates that a dysfunction in APP trafficking and degradation can be responsible for neuronal deficits and progressive degeneration in humans. We recently reported that the Y682 mutation in the 682YENPTY687 domain of APP affects its binding to specific adaptor proteins and leads to its anomalous trafficking, to defects in the autophagy machinery and to neuronal degeneration. In order to identify adaptors that influence APP function, we performed pull-down experiments followed by quantitative mass spectrometry (MS) on hippocampal tissue extracts of three month-old mice incubated with either the 682YENPTY687 peptide, its mutated form, 682GENPTY687 or its phosphorylated form, 682pYENPTY687. Our experiments resulted in the identification of two proteins involved in APP internalization and trafficking: Clathrin heavy chain (hc) and its Adaptor Protein 2 (AP-2). Overall our results consolidate and refine the importance of Y682 in APP normal functions from an animal model of premature aging and dementia. Additionally, they open the perspective to consider Clathrin hc and AP-2 as potential targets for the design and development of new therapeutic strategies. PMID:26690411

Pred-Skin: A Fast and Reliable Web Application to Assess Skin Sensitization Effect of Chemicals.

PubMed

Braga, Rodolpho C; Alves, Vinicius M; Muratov, Eugene N; Strickland, Judy; Kleinstreuer, Nicole; Trospsha, Alexander; Andrade, Carolina Horta

2017-05-22

Chemically induced skin sensitization is a complex immunological disease with a profound impact on quality of life and working ability. Despite some progress in developing alternative methods for assessing the skin sensitization potential of chemical substances, there is no in vitro test that correlates well with human data. Computational QSAR models provide a rapid screening approach and contribute valuable information for the assessment of chemical toxicity. We describe the development of a freely accessible web-based and mobile application for the identification of potential skin sensitizers. The application is based on previously developed binary QSAR models of skin sensitization potential from human (109 compounds) and murine local lymph node assay (LLNA, 515 compounds) data with good external correct classification rate (0.70-0.81 and 0.72-0.84, respectively). We also included a multiclass skin sensitization potency model based on LLNA data (accuracy ranging between 0.73 and 0.76). When a user evaluates a compound in the web app, the outputs are (i) binary predictions of human and murine skin sensitization potential; (ii) multiclass prediction of murine skin sensitization; and (iii) probability maps illustrating the predicted contribution of chemical fragments. The app is the first tool available that incorporates quantitative structure-activity relationship (QSAR) models based on human data as well as multiclass models for LLNA. The Pred-Skin web app version 1.0 is freely available for the web, iOS, and Android (in development) at the LabMol web portal ( http://labmol.com.br/predskin/ ), in the Apple Store, and on Google Play, respectively. We will continuously update the app as new skin sensitization data and respective models become available.

Spatial Distribution of Partner-Seeking Men Who Have Sex With Men Using Geosocial Networking Apps: Epidemiologic Study.

PubMed

Algarin, Angel B; Ward, Patrick J; Christian, W Jay; Rudolph, Abby E; Holloway, Ian W; Young, April M

2018-05-31

Geosocial networking apps have made sexual partner-seeking easier for men who have sex with men, raising both challenges and opportunities for human immunodeficiency virus and sexually transmitted infection prevention and research. Most studies on men who have sex with men geosocial networking app use have been conducted in large urban areas, despite research indicating similar patterns of online- and app-based sex-seeking among men who have sex with men in rural and midsize cities. The goal of our research was to examine the spatial distribution of geosocial networking app usage and characterize areas with increasing numbers of partner-seeking men who have sex with men in a midsize city in the South. Data collection points (n=62) were spaced in 2-mile increments along 9 routes (112 miles) covering the county encompassing the city. At each point, staff logged into 3 different geosocial networking apps to record the number of geosocial networking app users within a 1-mile radius. Data were collected separately during weekday daytime (9:00 AM to 4:00 PM) and weekend nighttime (8:00 PM to 12:00 AM) hours. Empirical Bayesian kriging was used to create a raster estimating the number of app users throughout the county. Raster values were summarized for each of the county's 208 Census block groups and used as the outcome measure (ie, geosocial networking app usage). Negative binomial regression and Wilcoxon signed rank sum tests were used to examine Census block group variables (eg, median income, median age) associated with geosocial networking app usage and temporal differences in app usage, respectively. The number of geosocial networking app users within a 1-mile radius of the data collection points ranged from 0 to 36 during weekday daytime hours and 0 to 39 during weekend nighttime hours. In adjusted analyses, Census block group median income and percent Hispanic ethnicity were negatively associated with geosocial networking app usage for all 3 geosocial networking apps during weekday daytime and weekend nighttime hours. Population density and the presence of businesses were positively associated with geosocial networking app usage for all 3 geosocial networking apps during both times. In this midsize city, geosocial networking app usage was highest in areas that were more population-dense, were lower income, and had more businesses. This research is an example of how geosocial networking apps' geospatial capabilities can be used to better understand patterns of virtual partner-seeking among men who have sex with men. ©Angel B Algarin, Patrick J Ward, W Jay Christian, Abby E Rudolph, Ian W Holloway, April M Young. Originally published in the Journal of Medical Internet Research (http://www.jmir.org), 31.05.2018.

The low density lipoprotein receptor-related protein 1B retains beta-amyloid precursor protein at the cell surface and reduces amyloid-beta peptide production.

PubMed

Cam, Judy A; Zerbinatti, Celina V; Knisely, Jane M; Hecimovic, Silva; Li, Yonghe; Bu, Guojun

2004-07-09

The low density lipoprotein (LDL) receptor-related protein 1B (LRP1B) is a newly identified member of the LDL receptor family that shares high homology with the LDL receptor-related protein (LRP). LRP1B was originally described as a putative tumor suppressor in lung cancer cells; however, its expression profile in several regions of adult human brain suggests it may have additional functions in the central nervous system. Since LRP1B has overlapping ligand binding properties with LRP, we investigated whether LRP1B, like LRP, could interact with the beta-amyloid precursor protein (APP) and modulate its processing to amyloid-beta peptides (Abetas). Using an LRP1B minireceptor (mLRP1B4) generated to study the trafficking of LRP1B, we found that mLRP1B4 and APP form an immunoprecipitable complex. Furthermore mLRP1B4 bound and facilitated the degradation of a soluble isoform of APP containing a Kunitz proteinase inhibitor domain but not soluble APP lacking a Kunitz proteinase inhibitor domain. A functional consequence of mLRP1B4 expression was a significant accumulation of APP at the cell surface, which is likely related to the slow endocytosis rate of LRP1B. More importantly, mLRP1B4-expressing cells that accumulated cell surface APP produced less Abeta and secreted more soluble APP. These findings reveal that LRP1B is a novel binding partner of APP that functions to decrease APP processing to Abeta. Consequently LRP1B expression could function to protect against the pathogenesis of Alzheimer's disease.

Lessons from a Rare Familial Dementia: Amyloid and Beyond

PubMed Central

Cantlon, Adam; Frigerio, Carlo Sala; Walsh, Dominic M.

2015-01-01

Here we review the similarities between a rare inherited disorder, familial British dementia (FBD), and the most common of all late-life neurological conditions, Alzheimer's diseases (AD). We describe the symptoms, pathology and genetics of FBD, the biology of the BRI2 protein and mouse models of FBD and familial Danish dementia. In particular, we focus on the evolving recognition of the importance of protein oligomers and aberrant processing of the amyloid β-protein precursor (APP) - themes that are common to both FBD and AD. The initial discovery that FBD is phenotypically similar to AD, but associated with the deposition of an amyloid peptide (ABri) distinct from the amyloid β-protein (Aβ) led many to assume that amyloid production alone is sufficient to initiate disease and that ABri is the molecular equivalent of Aβ. Parallel with work on Aβ, studies of ABri producing animal models and in vitro ABri toxicity experiments caused a revision of the amyloid hypothesis and a focus on soluble oligomers of Aβ and ABri. Contemporaneous other studies suggested that loss of the ABri precursor protein (BRI2) may underlie the cognitive deficits in FBD. In this regard it is important to note that BRI2 has been shown to interact with and regulate the processing of APP, and that mutant BRI2 leads to altered cleavage of APP. A synthesis of these results suggests that a “two-hit mechanism” better explains FBD than earlier toxic gain of function and toxic loss of function models. The lessons learned from the study of FBD imply that the molecular pathology of AD is also likely to involve both aberrant aggregation (in AD, Aβ) and altered APP processing. With regard to FBD, we propose that the C-terminal 11 amino acid of FBD-BRI2 interfere with both the normal function of BRI2 and promotes the production of cystine cross-linked toxic ABri oligomers. In this scenario, loss of BRI2 function leads to altered APP processing in as yet underappreciated ways. Given the similarities between FBD and AD it seems likely that study of the structure of ABri oligomers and FBD-induced changes in APP metabolites will further our understanding of AD. PMID:26405694

Preferences for a Mobile HIV Prevention App for Men Who Have Sex With Men

PubMed Central

McDougal, Sarah J; Sullivan, Patrick S; Stekler, Joanne D; Stephenson, Rob

2014-01-01

Background The Centers for Disease Control and Prevention recommends that sexually active men who have sex with men (MSM) in the United States test for human immunodeficiency virus (HIV) at least three times per year, but actual testing frequency is much less frequent. Though mHealth is a popular vehicle for delivering HIV interventions, there are currently no mobile phone apps that target MSM with the specific aim of building an HIV testing plan, and none that focuses on developing a comprehensive prevention plan and link MSM to additional HIV prevention and treatment resources. Previous research has suggested a need for more iterative feedback from the target population to ensure use of these interventions. Objective The purpose of this study is to understand MSM’s preferences for functionality, format, and design of a mobile phone-based HIV prevention app and to examine MSM’s willingness to use an app for HIV prevention. Methods We conducted focus group discussions with 38 gay and bisexual men, with two in-person groups in Atlanta, two in Seattle, and one online focus group discussion with gay and bisexual men in rural US regions. These discussions addressed MSM’s general preferences for apps, HIV testing barriers and facilitators for MSM, and ways that an HIV prevention app could address these barriers and facilitators to increase the frequency of HIV testing and prevention among MSM. During focus group discussions, participants were shown screenshots and provided feedback on potential app functions. Results Participants provided preferences on functionality of the app, including the type and delivery of educational content, the value of interactive engagement, and the importance of social networking as an app component. Participants also discussed preferences on how the language should be framed for the delivery of information, identifying that an app needs to be simultaneously fun and professional. Privacy and altruistic motivation were considered to be important factors in men’s willingness to use a mobile HIV prevention app. Finally, men described the potential impact that a mobile HIV prevention app could have, identifying individual, interpersonal, and community-based benefits. Conclusions In summary, participants described a comprehensive app that should incorporate innovative ideas to educate and engage men so that they would be motivated to use the app. In order for an app to be useful, it needs to feel safe and trustworthy, which is essential when considering the app’s language and privacy. Participants provided a range of preferences for using an HIV prevention app, including what they felt MSM need with regards to HIV prevention and what they want in order to engage with an app. Making an HIV prevention app enjoyable and usable for MSM is a difficult challenge. However, the usability of the app is vital because no matter how great the intervention, if MSM do not use the app, then it will not be useful. PMID:25355249

The effect of mutations on the structure of insulin fibrils studied by Fourier transform infrared (FTIR) spectroscopy and electron microscopy.

PubMed

Garriques, Liza Nielsen; Frokjaer, Sven; Carpenter, John F; Brange, Jens

2002-12-01

Fibril formation (aggregation) of human and bovine insulin and six human insulin mutants in hydrochloric acid were investigated by visual inspection, Thioflavin T fluorescence spectroscopy, transmission electron microscopy (TEM), and Fourier transform infrared (FTIR) spectroscopy. The fibrillation tendencies of the wild-type insulins and the insulin mutants were (in order of decreasing fibrillation tendencies): Glu(B1) + Glu(B27) = bovine < human < des-(B1,B2)-insulin < Ser(B2) + Asp(B10) < Glu(A13) + Glu(B10) = Gln(B17) < Asp(B10). Transmission electron micrographs showed that the protofibrils of the mutants were similar to those of wild-type insulins and had a diameter of 5-10 nm and lengths varying from 50 nm to several microns. The fibrils of human insulin mutants exhibited varying degrees of lateral aggregation. The Asp(B10) mutant and human insulin had greater tendency to form laterally aggregated fibrils arranged in parallel bundles, whereas fibrils of the other mutants and bovine insulin were mainly arranged in helical filaments. FTIR spectroscopy showed that the native secondary structure of the wild-type insulins and the human insulin mutants in hydrochloric acid were identical, whereas the secondary structure of the fibrils formed by heating at 50 degrees C depended on the amino acid substitution. FTIR spectra of fibrils of the human insulin mutants exhibited different beta-sheet bands at 1,620-1,640 cm(-1), indicating that the beta-sheet interactions in the fibrils depended on variations in the primary structure of insulin. Copyright 2002 Wiley-Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 91:2473-2480, 2002

Tip60 HAT Action Mediates Environmental Enrichment Induced Cognitive Restoration

PubMed Central

Xu, Songjun; Panikker, Priyalakshmi; Iqbal, Sahira; Elefant, Felice

2016-01-01

Environmental enrichment (EE) conditions have beneficial effects for reinstating cognitive ability in neuropathological disorders like Alzheimer’s disease (AD). While EE benefits involve epigenetic gene control mechanisms that comprise histone acetylation, the histone acetyltransferases (HATs) involved remain largely unknown. Here, we examine a role for Tip60 HAT action in mediating activity- dependent beneficial neuroadaptations to EE using the Drosophila CNS mushroom body (MB) as a well-characterized cognition model. We show that flies raised under EE conditions display enhanced MB axonal outgrowth, synaptic marker protein production, histone acetylation induction and transcriptional activation of cognition linked genes when compared to their genotypically identical siblings raised under isolated conditions. Further, these beneficial changes are impaired in both Tip60 HAT mutant flies and APP neurodegenerative flies. While EE conditions provide some beneficial neuroadaptive changes in the APP neurodegenerative fly MB, such positive changes are significantly enhanced by increasing MB Tip60 HAT levels. Our results implicate Tip60 as a critical mediator of EE-induced benefits, and provide broad insights into synergistic behavioral and epigenetic based therapeutic approaches for treatment of cognitive disorder. PMID:27454757

Tip60 HAT Action Mediates Environmental Enrichment Induced Cognitive Restoration.

PubMed

Xu, Songjun; Panikker, Priyalakshmi; Iqbal, Sahira; Elefant, Felice

2016-01-01

Environmental enrichment (EE) conditions have beneficial effects for reinstating cognitive ability in neuropathological disorders like Alzheimer's disease (AD). While EE benefits involve epigenetic gene control mechanisms that comprise histone acetylation, the histone acetyltransferases (HATs) involved remain largely unknown. Here, we examine a role for Tip60 HAT action in mediating activity- dependent beneficial neuroadaptations to EE using the Drosophila CNS mushroom body (MB) as a well-characterized cognition model. We show that flies raised under EE conditions display enhanced MB axonal outgrowth, synaptic marker protein production, histone acetylation induction and transcriptional activation of cognition linked genes when compared to their genotypically identical siblings raised under isolated conditions. Further, these beneficial changes are impaired in both Tip60 HAT mutant flies and APP neurodegenerative flies. While EE conditions provide some beneficial neuroadaptive changes in the APP neurodegenerative fly MB, such positive changes are significantly enhanced by increasing MB Tip60 HAT levels. Our results implicate Tip60 as a critical mediator of EE-induced benefits, and provide broad insights into synergistic behavioral and epigenetic based therapeutic approaches for treatment of cognitive disorder.

Established amyloid-β pathology is unaffected by chronic treatment with the selective serotonin reuptake inhibitor paroxetine.

PubMed

Severino, Maurizio; Sivasaravanaparan, Mithula; Olesen, Louise Ø; von Linstow, Christian U; Metaxas, Athanasios; Bouzinova, Elena V; Khan, Asif Manzoor; Lambertsen, Kate L; Babcock, Alicia A; Gramsbergen, Jan Bert; Wiborg, Ove; Finsen, Bente

2018-01-01

Treatment with selective serotonin reuptake inhibitors has been suggested to mitigate amyloid-β (Aβ) pathology in Alzheimer's disease, in addition to an antidepressant mechanism of action. We investigated whether chronic treatment with paroxetine, a selective serotonin reuptake inhibitor, mitigates Aβ pathology in plaque-bearing double-transgenic amyloid precursor protein (APP) swe /presenilin 1 (PS1) ΔE9 mutants. In addition, we addressed whether serotonin depletion affects Aβ pathology. Treatments were assessed by measurement of serotonin transporter occupancy and high-performance liquid chromatography. The effect of paroxetine on Aβ pathology was evaluated by stereological plaque load estimation and Aβ 42 /Aβ 40 ratio by enzyme-linked immunosorbent assay. Contrary to our hypothesis, paroxetine therapy did not mitigate Aβ pathology, and depletion of brain serotonin did not exacerbate Aβ pathology. However, chronic paroxetine therapy increased mortality in APP swe /PS1 ΔE9 transgenic mice. Our results question the ability of selective serotonin reuptake inhibitor therapy to ameliorate established Aβ pathology. The severe adverse effect of paroxetine may discourage its use for disease-modifying purposes in Alzheimer's disease.

Impaired retrograde transport of axonal autophagosomes contributes to autophagic stress in Alzheimer’s disease neurons

PubMed Central

Tammineni, Prasad; Ye, Xuan; Feng, Tuancheng; Aikal, Daniyal; Cai, Qian

2017-01-01

Neurons face unique challenges of transporting nascent autophagic vacuoles (AVs) from distal axons toward the soma, where mature lysosomes are mainly located. Autophagy defects have been linked to Alzheimer’s disease (AD). However, the mechanisms underlying altered autophagy remain unknown. Here, we demonstrate that defective retrograde transport contributes to autophagic stress in AD axons. Amphisomes predominantly accumulate at axonal terminals of mutant hAPP mice and AD patient brains. Amyloid-β (Aβ) oligomers associate with AVs in AD axons and interact with dynein motors. This interaction impairs dynein recruitment to amphisomes through competitive interruption of dynein-Snapin motor-adaptor coupling, thus immobilizing them in distal axons. Consistently, deletion of Snapin in mice causes AD-like axonal autophagic stress, whereas overexpressing Snapin in hAPP neurons reduces autophagic accumulation at presynaptic terminals by enhancing AV retrograde transport. Altogether, our study provides new mechanistic insight into AD-associated autophagic stress, thus establishing a foundation for ameliorating axonal pathology in AD. DOI: http://dx.doi.org/10.7554/eLife.21776.001 PMID:28085665

Low-frequency magnetic fields do not aggravate disease in mouse models of Alzheimer's disease and amyotrophic lateral sclerosis

PubMed Central

Liebl, Martina P.; Windschmitt, Johannes; Besemer, Anna S.; Schäfer, Anne-Kathrin; Reber, Helmut; Behl, Christian; Clement, Albrecht M.

2015-01-01

Low-frequency magnetic fields (LF-MF) generated by power lines represent a potential environmental health risk and are classified as possibly carcinogenic by the World Health Organization. Epidemiological studies indicate that LF-MF might propagate neurodegenerative diseases like Alzheimer's disease (AD) or amyotrophic lateral sclerosis (ALS). We conducted a comprehensive analysis to determine whether long-term exposure to LF-MF (50 Hz, 1 mT) interferes with disease development in established mouse models for AD and ALS, namely APP23 mice and mice expressing mutant Cu/Zn-superoxide dismutase (SOD1), respectively. Exposure for 16 months did not aggravate learning deficit of APP23 mice. Likewise, disease onset and survival of SOD1G85R or SOD1G93A mice were not altered upon LF-MF exposure for ten or eight months, respectively. These results and an extended biochemical analysis of protein aggregation, glial activation and levels of toxic protein species suggests that LF-MF do not affect cellular processes involved in the pathogenesis of AD or ALS. PMID:25717019

Wearable Atmospheric Pressure Plasma Fabrics Produced by Knitting Flexible Wire Electrodes for the Decontamination of Chemical Warfare Agents

PubMed Central

Jung, Heesoo; Seo, Jin Ah; Choi, Seungki

2017-01-01

One of the key reasons for the limited use of atmospheric pressure plasma (APP) is its inability to treat non-flat, three-dimensional (3D) surface structures, such as electronic devices and the human body, because of the rigid electrode structure required. In this study, a new APP system design—wearable APP (WAPP)—that utilizes a knitting technique to assemble flexible co-axial wire electrodes into a large-area plasma fabric is presented. The WAPP device operates in ambient air with a fully enclosed power electrode and grounded outer electrode. The plasma fabric is flexible and lightweight, and it can be scaled up for larger areas, making it attractive for wearable APP applications. Here, we report the various plasma properties of the WAPP device and successful test results showing the decontamination of toxic chemical warfare agents, namely, mustard (HD), soman (GD), and nerve (VX) agents. PMID:28098192

Wearable Atmospheric Pressure Plasma Fabrics Produced by Knitting Flexible Wire Electrodes for the Decontamination of Chemical Warfare Agents

NASA Astrophysics Data System (ADS)

Jung, Heesoo; Seo, Jin Ah; Choi, Seungki

2017-01-01

One of the key reasons for the limited use of atmospheric pressure plasma (APP) is its inability to treat non-flat, three-dimensional (3D) surface structures, such as electronic devices and the human body, because of the rigid electrode structure required. In this study, a new APP system design—wearable APP (WAPP)—that utilizes a knitting technique to assemble flexible co-axial wire electrodes into a large-area plasma fabric is presented. The WAPP device operates in ambient air with a fully enclosed power electrode and grounded outer electrode. The plasma fabric is flexible and lightweight, and it can be scaled up for larger areas, making it attractive for wearable APP applications. Here, we report the various plasma properties of the WAPP device and successful test results showing the decontamination of toxic chemical warfare agents, namely, mustard (HD), soman (GD), and nerve (VX) agents.

Wearable Atmospheric Pressure Plasma Fabrics Produced by Knitting Flexible Wire Electrodes for the Decontamination of Chemical Warfare Agents.

PubMed

Jung, Heesoo; Seo, Jin Ah; Choi, Seungki

2017-01-18

One of the key reasons for the limited use of atmospheric pressure plasma (APP) is its inability to treat non-flat, three-dimensional (3D) surface structures, such as electronic devices and the human body, because of the rigid electrode structure required. In this study, a new APP system design-wearable APP (WAPP)-that utilizes a knitting technique to assemble flexible co-axial wire electrodes into a large-area plasma fabric is presented. The WAPP device operates in ambient air with a fully enclosed power electrode and grounded outer electrode. The plasma fabric is flexible and lightweight, and it can be scaled up for larger areas, making it attractive for wearable APP applications. Here, we report the various plasma properties of the WAPP device and successful test results showing the decontamination of toxic chemical warfare agents, namely, mustard (HD), soman (GD), and nerve (VX) agents.

78 FR 4878 - Arts and Artifacts Indemnity Panel Advisory Committee

Federal Register 2010, 2011, 2012, 2013, 2014

2013-01-23

... NATIONAL FOUNDATION ON THE ARTS AND THE HUMANITIES Arts and Artifacts Indemnity Panel Advisory Committee AGENCY: Federal Council on the Arts and the Humanities; National Endowment for the Humanities... U.S.C. App.), notice is hereby given that the Federal Council on the Arts and the Humanities will...

77 FR 64146 - Arts and Artifacts Indemnity Panel Advisory Committee

Federal Register 2010, 2011, 2012, 2013, 2014

2012-10-18

... NATIONAL FOUNDATION ON THE ARTS AND THE HUMANITIES Arts and Artifacts Indemnity Panel Advisory Committee AGENCY: Federal Council on the Arts and the Humanities, National Endowment for the Humanities... U.S.C. App.), notice is hereby given that the Federal Council on the Arts and the Humanities will...

78 FR 69455 - Meetings of Humanities Panel

Federal Register 2010, 2011, 2012, 2013, 2014

2013-11-19

... NATIONAL FOUNDATION ON THE ARTS AND THE HUMANITIES Meetings of Humanities Panel AGENCY: National Endowment for the Humanities. ACTION: Notice of meetings. SUMMARY: Pursuant to section 10(a)(2) of the Federal Advisory Committee Act (5 U.S.C. App.), notice is hereby given that twelve meetings of the...

Structural Characterization of the E2 Domain of APL-1, a C. Elegans Homolog of Human Amyloid Precursor Protein, and its Heparin Binding Site

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hoopes, J.; Liu, X; Xu, X

2010-01-01

The amyloid {beta}-peptide deposit found in the brain tissue of patients with Alzheimer disease is derived from a large heparin-binding protein precursor APP. The biological function of APP and its homologs is not precisely known. Here we report the x-ray structure of the E2 domain of APL-1, an APP homolog in Caenorhabditis elegans, and compare it to the human APP structure. We also describe the structure of APL-1 E2 in complex with sucrose octasulfate, a highly negatively charged disaccharide, which reveals an unexpected binding pocket between the two halves of E2. Based on the crystal structure, we are able tomore » map, using site-directed mutagenesis, a surface groove on E2 to which heparin may bind. Our biochemical data also indicate that the affinity of E2 for heparin is influenced by pH: at pH 5, the binding appears to be much stronger than that at neutral pH. This property is likely caused by histidine residues in the vicinity of the mapped heparin binding site and could be important for the proposed adhesive function of APL-1.« less

MyShake - A smartphone app to detect earthquake

NASA Astrophysics Data System (ADS)

Kong, Q.; Allen, R. M.; Schreier, L.; Kwon, Y. W.

2015-12-01

We designed an android app that harnesses the accelerometers in personal smartphones to record earthquake-shaking data for research, hazard information and warnings. The app has the function to distinguish earthquake shakings from daily human activities based on the different patterns behind the movements. It also can be triggered by the traditional earthquake early warning (EEW) system to record for a certain amount of time to collect earthquake data. When the app is triggered by the earthquake-like movements, it sends the trigger information back to our server which contains time and location of the trigger, at the same time, it stores the waveform data on local phone first, and upload to our server later. Trigger information from multiple phones will be processed in real time on the server to find the coherent signal to confirm the earthquakes. Therefore, the app provides the basis to form a smartphone seismic network that can detect earthquake and even provide warnings. A planned public roll-out of MyShake could collect millions of seismic recordings for large earthquakes in many regions around the world.

Modulation of beta-amyloid precursor protein trafficking and processing by the low density lipoprotein receptor family.

PubMed

Cam, Judy A; Bu, Guojun

2006-08-18

Amyloid-beta peptide (Abeta) accumulation in the brain is an early, toxic event in the pathogenesis of Alzheimer's disease (AD). Abeta is produced by proteolytic processing of a transmembrane protein, beta-amyloid precursor protein (APP), by beta- and gamma-secretases. Mounting evidence has demonstrated that alterations in APP cellular trafficking and localization directly impact its processing to Abeta. Recent studies have shown that members of the low-density lipoprotein receptor family, including LRP, LRP1B, SorLA/LR11, and apolipoprotein E (apoE) receptor 2, interact with APP and regulate its endocytic trafficking. Another common feature of these receptors is their ability to bind apoE, which exists in three isoforms in humans and the presence of the epsilon4 allele represents a genetic risk factor for AD. In this review, we summarize the current understanding of the function of these apoE receptors with a focus on their role in APP trafficking and processing. Knowledge of the interactions between these distinct low-density lipoprotein receptor family members and APP may ultimately influence future therapies for AD.

BIDS apps: Improving ease of use, accessibility, and reproducibility of neuroimaging data analysis methods

PubMed Central

Auer, Tibor; Churchill, Nathan W.; Flandin, Guillaume; Guntupalli, J. Swaroop; Raffelt, David; Quirion, Pierre-Olivier; Smith, Robert E.; Strother, Stephen C.; Varoquaux, Gaël

2017-01-01

The rate of progress in human neurosciences is limited by the inability to easily apply a wide range of analysis methods to the plethora of different datasets acquired in labs around the world. In this work, we introduce a framework for creating, testing, versioning and archiving portable applications for analyzing neuroimaging data organized and described in compliance with the Brain Imaging Data Structure (BIDS). The portability of these applications (BIDS Apps) is achieved by using container technologies that encapsulate all binary and other dependencies in one convenient package. BIDS Apps run on all three major operating systems with no need for complex setup and configuration and thanks to the comprehensiveness of the BIDS standard they require little manual user input. Previous containerized data processing solutions were limited to single user environments and not compatible with most multi-tenant High Performance Computing systems. BIDS Apps overcome this limitation by taking advantage of the Singularity container technology. As a proof of concept, this work is accompanied by 22 ready to use BIDS Apps, packaging a diverse set of commonly used neuroimaging algorithms. PMID:28278228

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

Developing an App by Exploiting Web-Based Mobile Technology to Inspect Controlled Substances in Patient Care Units

PubMed Central

2017-01-01

We selected iOS in this study as the App operation system, Objective-C as the programming language, and Oracle as the database to develop an App to inspect controlled substances in patient care units. Using a web-enabled smartphone, pharmacist inspection can be performed on site and the inspection result can be directly recorded into HIS through the Internet, so human error of data translation can be minimized and the work efficiency and data processing can be improved. This system not only is fast and convenient compared to the conventional paperwork, but also provides data security and accuracy. In addition, there are several features to increase inspecting quality: (1) accuracy of drug appearance, (2) foolproof mechanism to avoid input errors or miss, (3) automatic data conversion without human judgments, (4) online alarm of expiry date, and (5) instant inspection result to show not meted items. This study has successfully turned paper-based medication inspection into inspection using a web-based mobile device. PMID:28286761

Developing an App by Exploiting Web-Based Mobile Technology to Inspect Controlled Substances in Patient Care Units.

PubMed

Lu, Ying-Hao; Lee, Li-Yao; Chen, Ying-Lan; Cheng, Hsing-I; Tsai, Wen-Tsung; Kuo, Chen-Chun; Chen, Chung-Yu; Huang, Yaw-Bin

2017-01-01

We selected iOS in this study as the App operation system, Objective-C as the programming language, and Oracle as the database to develop an App to inspect controlled substances in patient care units. Using a web-enabled smartphone, pharmacist inspection can be performed on site and the inspection result can be directly recorded into HIS through the Internet, so human error of data translation can be minimized and the work efficiency and data processing can be improved. This system not only is fast and convenient compared to the conventional paperwork, but also provides data security and accuracy. In addition, there are several features to increase inspecting quality: (1) accuracy of drug appearance, (2) foolproof mechanism to avoid input errors or miss, (3) automatic data conversion without human judgments, (4) online alarm of expiry date, and (5) instant inspection result to show not meted items. This study has successfully turned paper-based medication inspection into inspection using a web-based mobile device.

Fe65 does not stabilize AICD during activation of transcription in a luciferase assay

DOE Office of Scientific and Technical Information (OSTI.GOV)

Huysseune, Sandra; Kienlen-Campard, Pascal; Octave, Jean-Noel

2007-09-21

The APP intracellular domain (AICD) could be involved in signaling via interaction with the adaptor protein Fe65, and with the histone acetyl transferase Tip60. However, the real function of AICD and Fe65 in regulation of transcription remains controversial. In this study, the human APPGal4 fusion protein was expressed in CHO cells and the transcriptional activity of AICDGal4 was measured in a luciferase-based reporter assay. AICDGal4 was stabilized by expression of Fe65 and levels of AICDGal4 controlled luciferase activity. On the contrary, when human APP was expressed in CHO cells, coexpression of Fe65 increased luciferase activity without affecting the amount ofmore » AICD fragment. AICD produced from APP was protected from degradation by orthophenanthroline, but not by lactacystine, indicating that AICD is not a substrate of the chymotryptic activity of the proteasome. It is concluded that Fe65 can control luciferase activity without stabilizing the labile AICD fragment.« less

Control of Aβ release from human neurons by differentiation status and RET signaling.

PubMed

Scholz, Diana; Chernyshova, Yana; Leist, Marcel

2013-01-01

Few studies have compared the processing of endogenous human amyloid precursor protein (APP) in younger and older neurons. Here, we characterized LUHMES cells as a human model to study Alzheimer's disease-related processes during neuronal maturation and aging. Differentiated LUHMES expressed and spontaneously processed APP via the secretase pathways, and they secreted amyloid β (Aβ) peptide. This was inhibited by cholesterol depletion or secretase inhibition, but not by block of tau phosphorylation. In vitro aged cells increased Aβ secretion without upregulation of APP or secretases. We identified the medium constituent glial cell line-derived neurotrophic factor (GDNF) as responsible for this effect. GDNF-triggered Aβ release was associated with rapid upregulation of the GDNF coreceptor "rearranged during transfection" (RET). Other direct (neurturin) or indirect (nerve growth factor) RET activators also increased Aβ, whereas different neurotrophins were ineffective. Downstream of RET, we found activation of protein kinase B (AKT) to be involved. Accordingly, inhibitors of the AKT regulator phosphatidylinositol-3-kinase completely blocked GDNF-triggered AKT phosphorylation and Aβ increase. This suggests that RET signaling affects Aβ release from aging neurons. Copyright © 2013 Elsevier Inc. All rights reserved.

New Type of BACE1 siRNA Delivery to Cells

PubMed Central

Jabłkowski, Maciej; Szemraj, Maciej; Oszajca, Katarzyna; Janiszewska, Grażyna; Bartkowiak, Jacek; Szemraj, Janusz

2014-01-01

Background Small interfering RNA (siRNA) gene therapy is a new molecular approach in the search for an efficient therapy for Alzheimer disease (AD), based on the principle of RNA interference. Reducing BACE activity can have great therapeutic potential for the treatment of AD. In this study, receptor-mediated delivery was used to deliver opioid peptide-conjugated BACE 1 to INR-32 human neuroblastoma cells. Material/Methods An INR-32 human neuroblastoma cell line was stably transfected to express the APP cDNA coding fragment containing the predicted sites for cleavage by α, β, or γ-secretase. This was then treated with BACE 1 siRNA to silence BACE gene expression. BACE gene transcription and translation was determined using BACE-1 siRNA cross-linked with opioid peptide, together with RT-PCR, Western blot analysis, and ELISA. Results Receptor-mediated delivery was used to introduce BACE1 siRNA to the APP – INR 32 human neuroblastoma cells. Decreased BACE mRNA and protein expression were observed after the cells were transfected with BACE1 siRNA. Conclusions Delivery of BACE1 siRNA appears to specifically reduce the cleavage of APP by inhibiting BACE1 activity. PMID:25491230

GeneStoryTeller: a mobile app for quick and comprehensive information retrieval of human genes

PubMed Central

Eleftheriou, Stergiani V.; Bourdakou, Marilena M.; Athanasiadis, Emmanouil I.; Spyrou, George M.

2015-01-01

In the last few years, mobile devices such as smartphones and tablets have become an integral part of everyday life, due to their software/hardware rapid development, as well as the increased portability they offer. Nevertheless, up to now, only few Apps have been developed in the field of bioinformatics, capable to perform fast and robust access to services. We have developed the GeneStoryTeller, a mobile application for Android platforms, where users are able to instantly retrieve information regarding any recorded human gene, derived from eight publicly available databases, as a summary story. Complementary information regarding gene–drugs interactions, functional annotation and disease associations for each selected gene is also provided in the gene story. The most challenging part during the development of the GeneStoryTeller was to keep balance between storing data locally within the app and obtaining the updated content dynamically via a network connection. This was accomplished with the implementation of an administrative site where data are curated and synchronized with the application requiring a minimum human intervention. Database URL: http://bioserver-3.bioacademy.gr/Bioserver/GeneStoryTeller/. PMID:26055097

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 Aβ plaque pathology and memory impairment. This early-onset network hyperexcitability can be suppressed by passive immunization with an anti-human APP/Aβ antibody and by mGluR5 blockade in 3xTg-AD mice. PMID:28392767

η-Secretase processing of APP inhibits neuronal activity in the hippocampus.

PubMed

Willem, Michael; Tahirovic, Sabina; Busche, Marc Aurel; Ovsepian, Saak V; Chafai, Magda; Kootar, Scherazad; Hornburg, Daniel; Evans, Lewis D B; Moore, Steven; Daria, Anna; Hampel, Heike; Müller, Veronika; Giudici, Camilla; Nuscher, Brigitte; Wenninger-Weinzierl, Andrea; Kremmer, Elisabeth; Heneka, Michael T; Thal, Dietmar R; Giedraitis, Vilmantas; Lannfelt, Lars; Müller, Ulrike; Livesey, Frederick J; Meissner, Felix; Herms, Jochen; Konnerth, Arthur; Marie, Hélène; Haass, Christian

2015-10-15

Alzheimer disease (AD) is characterized by the accumulation of amyloid plaques, which are predominantly composed of amyloid-β peptide. Two principal physiological pathways either prevent or promote amyloid-β generation from its precursor, β-amyloid precursor protein (APP), in a competitive manner. Although APP processing has been studied in great detail, unknown proteolytic events seem to hinder stoichiometric analyses of APP metabolism in vivo. Here we describe a new physiological APP processing pathway, which generates proteolytic fragments capable of inhibiting neuronal activity within the hippocampus. We identify higher molecular mass carboxy-terminal fragments (CTFs) of APP, termed CTF-η, in addition to the long-known CTF-α and CTF-β fragments generated by the α- and β-secretases ADAM10 (a disintegrin and metalloproteinase 10) and BACE1 (β-site APP cleaving enzyme 1), respectively. CTF-η generation is mediated in part by membrane-bound matrix metalloproteinases such as MT5-MMP, referred to as η-secretase activity. η-Secretase cleavage occurs primarily at amino acids 504-505 of APP695, releasing a truncated ectodomain. After shedding of this ectodomain, CTF-η is further processed by ADAM10 and BACE1 to release long and short Aη peptides (termed Aη-α and Aη-β). CTFs produced by η-secretase are enriched in dystrophic neurites in an AD mouse model and in human AD brains. Genetic and pharmacological inhibition of BACE1 activity results in robust accumulation of CTF-η and Aη-α. In mice treated with a potent BACE1 inhibitor, hippocampal long-term potentiation was reduced. Notably, when recombinant or synthetic Aη-α was applied on hippocampal slices ex vivo, long-term potentiation was lowered. Furthermore, in vivo single-cell two-photon calcium imaging showed that hippocampal neuronal activity was attenuated by Aη-α. These findings not only demonstrate a major functionally relevant APP processing pathway, but may also indicate potential translational relevance for therapeutic strategies targeting APP processing.

Topical Application of Trisodium Ascorbyl 6-Palmitate 2-Phosphate Actively Supplies Ascorbate to Skin Cells in an Ascorbate Transporter-Independent Manner

PubMed Central

Shibuya, Shuichi; Sakaguchi, Ikuyo; Ito, Shintaro; Kato, Eiko; Watanabe, Kenji; Izuo, Naotaka; Shimizu, Takahiko

2017-01-01

Ascorbic acid (AA) possesses multiple beneficial functions, such as regulating collagen biosynthesis and redox balance in the skin. AA derivatives have been developed to overcome this compound’s high fragility and to assist with AA supplementation to the skin. However, how AA derivatives are transferred into cells and converted to AA in the skin remains unclear. In the present study, we showed that AA treatment failed to increase the cellular AA level in the presence of AA transporter inhibitors, indicating an AA transporter-dependent action. In contrast, torisodium ascorbyl 6-palmitate 2-phosphate (APPS) treatment significantly enhanced the cellular AA level in skin cells despite the presence of inhibitors. In ex vivo experiments, APPS treatment also increased the AA content in a human epidermis model. Interestingly, APPS was readily metabolized and converted to AA in keratinocyte lysates via an intrinsic mechanism. Furthermore, APPS markedly repressed the intracellular superoxide generation and promoted viability associated with an enhanced AA level in Sod1-deficient skin cells. These findings indicate that APPS effectively restores the AA level and normalizes the redox balance in skin cells in an AA transporter-independent manner. Topical treatment of APPS is a beneficial strategy for supplying AA and improving the physiology of damaged skin. PMID:28640219

Formative Work to Develop a Tailored HIV Testing Smartphone App for Diverse, At-Risk, HIV-Negative Men Who Have Sex With Men: A Focus Group Study.

PubMed

Mitchell, Jason W; Torres, Maria Beatriz; Joe, Jennifer; Danh, Thu; Gass, Bobbi; Horvath, Keith J

2016-11-16

Although gay, bisexual, and other men who have sex with men (MSM) are disproportionately affected by human immunodeficiency virus (HIV) infection, few test for HIV at regular intervals. Smartphone apps may be an ideal tool to increase regular testing among MSM. However, the success of apps to encourage regular testing among MSM will depend on how frequently the apps are downloaded, whether they continue to be used over months or years, and the degree to which such apps are tailored to the needs of this population. The primary objectives of this study were to answer the following questions. (1) What features and functions of smartphone apps do MSM believe are associated with downloading apps to their mobile phones? (2) What features and functions of smartphone apps are most likely to influence MSM's sustained use of apps over time? (3) What features and functions do MSM prefer in an HIV testing smartphone app? We conducted focus groups (n=7, with a total of 34 participants) with a racially and ethnically diverse group of sexually active HIV-negative MSM (mean age 32 years; 11/34 men, 33%, tested for HIV ≥10 months ago) in the United States in Miami, Florida and Minneapolis, Minnesota. Focus groups were digitally recorded, transcribed verbatim, and deidentified for analysis. We used a constant comparison method (ie, grounded theory coding) to examine and reexamine the themes that emerged from the focus groups. Men reported cost, security, and efficiency as their primary reasons influencing whether they download an app. Usefulness and perceived necessity, as well as peer and posted reviews, affected whether they downloaded and used the app over time. Factors that influenced whether they keep and continue to use an app over time included reliability, ease of use, and frequency of updates. Poor performance and functionality and lack of use were the primary reasons why men would delete an app from their phone. Participants also shared their preferences for an app to encourage regular HIV testing by providing feedback on test reminders, tailored testing interval recommendations, HIV test locator, and monitoring of personal sexual behaviors. Mobile apps for HIV prevention have proliferated, despite relatively little formative research to understand best practices for their development and implementation. The findings of this study suggest key design characteristics that should be used to guide development of an HIV testing app to promote regular HIV testing for MSM. The features and functions identified in this and prior research, as well as existing theories of behavior change, should be used to guide mobile app development in this critical area. ©Jason W Mitchell, Maria Beatriz Torres, Jennifer Joe, Thu Danh, Bobbi Gass, Keith J Horvath. Originally published in JMIR Mhealth and Uhealth (http://mhealth.jmir.org), 16.11.2016.

Role of serotype-specific polysaccharide in the resistance of Streptococcus mutans to phagocytosis by human polymorphonuclear leukocytes.

PubMed

Tsuda, H; Yamashita, Y; Toyoshima, K; Yamaguchi, N; Oho, T; Nakano, Y; Nagata, K; Koga, T

2000-02-01

To clarify the role of cell surface components of Streptococcus mutans in resistance to phagocytosis by human polymorphonuclear leukocytes (PMNs), several isogenic mutants of S. mutans defective in cell surface components were studied with a luminol-enhanced chemiluminescence (CL) assay, a killing assay, and a transmission electron microscope. The CL responses of human PMNs to mutant Xc11 defective in a major cell surface antigen, PAc, and mutant Xc16 defective in two surface glucosyltransferases (GTF-I and GTF-SI) were the same as the response to the wild-type strain, Xc. In contrast, mutant Xc24R, which was defective in serotype c-specific polysaccharide, induced a markedly higher CL response than the other strains. The killing assay showed that human PMNs killed more Xc24R than the parent strain and the other mutants. The transmission electron microscopic observation indicated that Xc24R cells were more internalized by human PMNs than the parental strain Xc. These results may be reflected by the fact that strain Xc24R was more phagocytosed than strain Xc. The CL response of human PMNs to a mutant defective in polysaccharide serotype e or f was similar to the response to Xc24R. Furthermore, mutants defective in serotype-specific polysaccharide were markedly more hydrophobic than the wild-type strains and the other mutants, suggesting that the hydrophilic nature of polysaccharides may protect the bacterium from phagocytosis. We conclude that the serotype-specific polysaccharide, but not the cell surface proteins on the cell surface of S. mutans, may play an important role in the resistance to phagocytosis.

Role of Serotype-Specific Polysaccharide in the Resistance of Streptococcus mutans to Phagocytosis by Human Polymorphonuclear Leukocytes

PubMed Central

Tsuda, Hiromasa; Yamashita, Yoshihisa; Toyoshima, Kuniaki; Yamaguchi, Noboru; Oho, Takahiko; Nakano, Yoshio; Nagata, Kengo; Koga, Toshihiko

2000-01-01

To clarify the role of cell surface components of Streptococcus mutans in resistance to phagocytosis by human polymorphonuclear leukocytes (PMNs), several isogenic mutants of S. mutans defective in cell surface components were studied with a luminol-enhanced chemiluminescence (CL) assay, a killing assay, and a transmission electron microscope. The CL responses of human PMNs to mutant Xc11 defective in a major cell surface antigen, PAc, and mutant Xc16 defective in two surface glucosyltransferases (GTF-I and GTF-SI) were the same as the response to the wild-type strain, Xc. In contrast, mutant Xc24R, which was defective in serotype c-specific polysaccharide, induced a markedly higher CL response than the other strains. The killing assay showed that human PMNs killed more Xc24R than the parent strain and the other mutants. The transmission electron microscopic observation indicated that Xc24R cells were more internalized by human PMNs than the parental strain Xc. These results may be reflected by the fact that strain Xc24R was more phagocytosed than strain Xc. The CL response of human PMNs to a mutant defective in polysaccharide serotype e or f was similar to the response to Xc24R. Furthermore, mutants defective in serotype-specific polysaccharide were markedly more hydrophobic than the wild-type strains and the other mutants, suggesting that the hydrophilic nature of polysaccharides may protect the bacterium from phagocytosis. We conclude that the serotype-specific polysaccharide, but not the cell surface proteins on the cell surface of S. mutans, may play an important role in the resistance to phagocytosis. PMID:10639428

Lessons from the pilot of a mobile application to map assistive technology suppliers in Africa.

PubMed

Visagie, Surona J; Matter, Rebecca; Kayange, George M; Chiwaula, Mussa; Harniss, Mark; Mji, Gubela; Scheffler, Elsje

2018-01-01

A pilot project to develop and implement a mobile smartphone application (App) that tracks and maps assistive technology (AT) availability in southern Africa was launched in Botswana in 2016. The App was developed and tested through an iterative process. The concept of the App (AT-Info-Map) was well received by most stakeholders within the pilot country, and broader networks. Several technical and logistical obstacles were encountered. These included high data costs; difficulty in accessing AT information from the public healthcare sector, the largest supplier of AT; and the high human resource demand of collecting and keeping up-to-date device-level information within a complex and fragmented supply sector that spans private, public and civil society entities. The challenges were dealt with by keeping the data burden low and eliminating product-level tracking. The App design was expanded to include disability services, contextually specific AT categories and make navigation more intuitive. Long-term sustainability strategies like generating funding through advertisements on the App or supplier usage fees must be explored. Outreach and sensitisation programmes about both the App and AT in general must be intensified. The project team must continually strengthen partnerships with private and public stakeholders to ensure ongoing project engagement. The lessons learnt might be of value to others who wish to embark on initiatives in AT and/or implement Apps in health or disability in southern Africa and in low-resourced settings around the world.

Carbon storage regulator A contributes to the virulence of Haemophilus ducreyi in humans by multiple mechanisms.

PubMed

Gangaiah, Dharanesh; Li, Wei; Fortney, Kate R; Janowicz, Diane M; Ellinger, Sheila; Zwickl, Beth; Katz, Barry P; Spinola, Stanley M

2013-02-01

The carbon storage regulator A (CsrA) controls a wide variety of bacterial processes, including metabolism, adherence, stress responses, and virulence. Haemophilus ducreyi, the causative agent of chancroid, harbors a homolog of csrA. Here, we generated an unmarked, in-frame deletion mutant of csrA to assess its contribution to H. ducreyi pathogenesis. In human inoculation experiments, the csrA mutant was partially attenuated for pustule formation compared to its parent. Deletion of csrA resulted in decreased adherence of H. ducreyi to human foreskin fibroblasts (HFF); Flp1 and Flp2, the determinants of H. ducreyi adherence to HFF cells, were downregulated in the csrA mutant. Compared to its parent, the csrA mutant had a significantly reduced ability to tolerate oxidative stress and heat shock. The enhanced sensitivity of the mutant to oxidative stress was more pronounced in bacteria grown to stationary phase compared to that in bacteria grown to mid-log phase. The csrA mutant also had a significant survival defect within human macrophages when the bacteria were grown to stationary phase but not to mid-log phase. Complementation in trans partially or fully restored the mutant phenotypes. These data suggest that CsrA contributes to virulence by multiple mechanisms and that these contributions may be more profound in bacterial cell populations that are not rapidly dividing in the human host.

Creating Effective Mobile Phone Apps to Optimize Antiretroviral Therapy Adherence: Perspectives From Stimulant-Using HIV-Positive Men Who Have Sex With Men.

PubMed

Horvath, Keith J; Alemu, Dawit; Danh, Thu; Baker, Jason V; Carrico, Adam W

2016-04-15

The use of stimulant drugs among men who have sex with men (MSM) with human immunodeficiency virus (HIV) is associated with decreased odds of antiretroviral therapy (ART) adherence and elevated risk of forward HIV transmission. Advancing tailored and innovative mobile phone-based ART adherence app interventions for stimulant-using HIV-positive MSM requires greater understanding of their needs and preferences in this emerging area. The purpose of this study is to (1) assess reasons that stimulant-using HIV-positive MSM download and sustain their use of mobile phone apps in general, and (2) obtain feedback on features and functions that these men prefer in a mobile phone app to optimize their ART adherence. Focus groups were conducted with stimulant-using HIV-positive MSM (24-57 years of age; mostly non-Hispanic white; 42% once a week or more frequent stimulant drug use) in San Francisco and Minneapolis. Our aim was to explore the mobile phone app features and functions that they considered when deciding to download and sustain their use of general apps over time, as well as specific features and functions that they would like to see incorporated into an ART adherence mobile app. Focus groups were audiorecorded and transcribed verbatim. Thematic analysis was applied to transcripts using line-by-line open coding and organizing codes into meaningful themes. Men reported that they currently had a variety of health and wellness, social media and networking, gaming and entertainment, and utility apps on their mobile phones. Downloading apps to their mobile phones was influenced by the cost of the app, recommendations by a trusted source, and the time it takes to download. In addition, downloading and sustained use of apps was more likely to occur when men had control over most features of the app and apps were perceived to be useful, engaging, secure, and credible. Participants suggested that ART adherence mobile phone apps include social networking features, connections to local resources and their medical chart, and breaking HIV news and updates. Although some men expressed concerns about daily self-monitoring of HIV medication doses, many appreciated receiving a summary of their medication adherence over time and suggested that feedback about missed doses be delivered in an encouraging and humorous manner. In this study, we were able to recruit a relatively high proportion (42%) of HIV-positive MSM reporting weekly or more stimulant use. These results suggest critical design elements that may need to be considered during development of ART adherence-related mobile phone apps for this, and possibly other, high-risk groups. In particular, finding the optimal balance of security, engagement, usefulness, control capabilities, and credibility will be critical to sustained used of HIV treatment apps.

The polyketide synthase gene pks4 is essential for sexual development and regulates fruiting body morphology in Sordaria macrospora.

PubMed

Schindler, Daniel; Nowrousian, Minou

2014-07-01

Filamentous ascomycetes have long been known as producers of a variety of secondary metabolites, many of which have toxic effects on other organisms. However, the role of these metabolites in the biology of the fungi that produce them remains in most cases enigmatic. A major group of fungal secondary metabolites are polyketides. They are chemically diverse, but have in common that their chemical scaffolds are synthesized by polyketide synthases (PKSs). In a previous study, we analyzed development-dependent expression of pks genes in the filamentous ascomycete Sordaria macrospora. Here, we show that a deletion mutant of the pks4 gene is sterile, producing only protoperithecia but no mature perithecia, whereas overexpression of pks4 leads to enlarged, malformed fruiting bodies. Thus, correct expression levels of pks4 are essential for wild type-like perithecia formation. The predicted PKS4 protein has a domain structure that is similar to homologs in other fungi, but conserved residues of a methyl transferase domain present in other fungi are mutated in PKS4. Expression of several developmental genes is misregulated in the pks4 mutant. Surprisingly, the development-associated app gene is not downregulated in the mutant, in contrast to all other previously studied mutants with a block at the protoperithecial stage. Our data show that the polyketide synthase gene pks4 is essential for sexual development and plays a role in regulating fruiting body morphology. Copyright © 2014 Elsevier Inc. All rights reserved.

Evaluating the Usability and Usefulness of a Mobile App for Atrial Fibrillation Using Qualitative Methods: Exploratory Pilot Study.

PubMed

Hirschey, Jaclyn; Bane, Sunetra; Mansour, Moussa; Sperber, Jodi; Agboola, Stephen; Kvedar, Joseph; Jethwani, Kamal

2018-03-15

Atrial fibrillation (AFib) is the most common form of heart arrhythmia and a potent risk factor for stroke. Nonvitamin K antagonist oral anticoagulants (NOACs) are routinely prescribed to manage AFib stroke risk; however, nonadherence to treatment is a concern. Additional tools that support self-care and medication adherence may benefit patients with AFib. The aim of this study was to evaluate the perceived usability and usefulness of a mobile app designed to support self-care and treatment adherence for AFib patients who are prescribed NOACs. A mobile app to support AFib patients was previously developed based on early stage interview and usability test data from clinicians and patients. An exploratory pilot study consisting of naturalistic app use, surveys, and semistructured interviews was then conducted to examine patients' perceptions and everyday use of the app. A total of 12 individuals with an existing diagnosis of nonvalvular AFib completed the 4-week study. The average age of participants was 59 years. All participants somewhat or strongly agreed that the app was easy to use, and 92% (11/12) reported being satisfied or very satisfied with the app. Participant feedback identified changes that may improve app usability and usefulness for patients with AFib. Areas of usability improvement were organized by three themes: app navigation, clarity of app instructions and design intent, and software bugs. Perceptions of app usefulness were grouped by three key variables: core needs of the patient segment, patient workflow while managing AFib, and the app's ability to support the patient's evolving needs. The results of this study suggest that mobile tools that target self-care and treatment adherence may be helpful to AFib patients, particularly those who are newly diagnosed. Additionally, participant feedback provided insight into the varied needs and health experiences of AFib patients, which may improve the design and targeting of the intervention. Pilot studies that qualitatively examine patient perceptions of usability and usefulness are a valuable and often underutilized method for assessing the real-world acceptability of an intervention. Additional research evaluating the AFib Connect mobile app over a longer period, and including a larger, more diverse sample of AFib patients, will be helpful for understanding whether the app is perceived more broadly to be useful and effective in supporting patient self-care and medication adherence. ©Jaclyn Hirschey, Sunetra Bane, Moussa Mansour, Jodi Sperber, Stephen Agboola, Joseph Kvedar, Kamal Jethwani. Originally published in JMIR Human Factors (http://humanfactors.jmir.org), 15.03.2018.

Expression of CALR mutants causes mpl-dependent thrombocytosis in zebrafish.

PubMed

Lim, K-H; Chang, Y-C; Chiang, Y-H; Lin, H-C; Chang, C-Y; Lin, C-S; Huang, L; Wang, W-T; Gon-Shen Chen, C; Chou, W-C; Kuo, Y-Y

2016-10-07

CALR mutations are identified in about 30% of JAK2/MPL-unmutated myeloproliferative neoplasms (MPNs) including essential thrombocythemia (ET) and primary myelofibrosis. Although the molecular pathogenesis of CALR mutations leading to MPNs has been studied using in vitro cell lines models, how mutant CALR may affect developmental hematopoiesis remains unknown. Here we took advantage of the zebrafish model to examine the effects of mutant CALR on early hematopoiesis and model human CALR-mutated MPNs. We identified three zebrafish genes orthologous to human CALR, referred to as calr, calr3a and calr3b. The expression of CALR-del52 and CALR-ins5 mutants caused an increase in the hematopoietic stem/progenitor cells followed by thrombocytosis without affecting normal angiogenesis. The expression of CALR mutants also perturbed early developmental hematopoiesis in zebrafish. Importantly, morpholino knockdown of mpl but not epor or csf3r could significantly attenuate the effects of mutant CALR. Furthermore, the expression of mutant CALR caused jak-stat signaling activation in zebrafish that could be blocked by JAK inhibitors (ruxolitinib and fedratinib). These findings showed that mutant CALR activates jak-stat signaling through an mpl-dependent mechanism to mediate pathogenic thrombopoiesis in zebrafish, and illustrated that the signaling machinery related to mutant CALR tumorigenesis are conserved between human and zebrafish.

Octylphenol (OP) alters the expression of members of the amyloid protein family in the hypothalamus of the snapping turtle, Chelydra serpentina serpentina.

PubMed Central

Trudeau, Vance L; Chiu, Suzanne; Kennedy, Sean W; Brooks, Ronald J

2002-01-01

The gonadal estrogen estradiol-17beta (E(2)) is important for developing and regulating hypothalamic function and many aspects of reproduction in vertebrates. Pollutants such as octylphenol (OP) that mimic the actions of estrogens are therefore candidate endocrine-disrupting chemicals. We used a differential display strategy (RNA-arbitrarily primed polymerase chain reaction) to isolate partial cDNA sequences of neurotransmitter, developmental, and disease-related genes that may be regulated by OP or E(2) in the snapping turtle Chelydra serpentina serpentina hypothalamus. Hatchling and year-old male snapping turtles were exposed to a 10 ng/mL nominal concentration of waterborne OP or E(2) for 17 days. One transcript [421 base pairs (bp)] regulated by OP and E(2) was 93% identical to human APLP-2. APLP-2 and the amyloid precursor protein (APP) regulate neuronal differentiation and are also implicated in the genesis of Alzheimer disease in humans. Northern blot analysis determined that the turtle hypothalamus contains a single APLP-2 transcript of 3.75 kb in length. Exposure to OP upregulated hypothalamic APLP-2 mRNA levels 2-fold (p < 0.05) in month-old and yearling turtles. E(2) did not affect APLP-2 mRNA levels in hatchlings but stimulated a 2-fold increase (p < 0.05) in APLP-2 mRNA levels in yearling males. The protein beta-amyloid, a selectively processed peptide derived from APP, is also involved in neuronal differentiation, and accumulation of this neurotoxic peptide causes neuronal degeneration in the brains of patients with Alzheimer disease. Therefore, we also sought to determine the effects of estrogens on the expression of beta-amyloid. Using homology cloning based on known sequences, we isolated a cDNA fragment (474 bp) from turtle brain with 88% identity to human APP. Northern blot analysis determined that a single 3.5-kb transcript was expressed in the turtle hypothalamus. Waterborne OP also increased the expression of hypothalamic APP after 35 days of exposure. Our results indicate that low levels of OP are bioactive and can alter the expression of APLP-2 and APP. Because members of the APP gene family are involved in neuronal development, we hypothesize that OP exposure may disrupt hypothalamic development in young turtles. PMID:11882478

Octylphenol (OP) alters the expression of members of the amyloid protein family in the hypothalamus of the snapping turtle, Chelydra serpentina serpentina.

PubMed

Trudeau, Vance L; Chiu, Suzanne; Kennedy, Sean W; Brooks, Ronald J

2002-03-01

The gonadal estrogen estradiol-17beta (E(2)) is important for developing and regulating hypothalamic function and many aspects of reproduction in vertebrates. Pollutants such as octylphenol (OP) that mimic the actions of estrogens are therefore candidate endocrine-disrupting chemicals. We used a differential display strategy (RNA-arbitrarily primed polymerase chain reaction) to isolate partial cDNA sequences of neurotransmitter, developmental, and disease-related genes that may be regulated by OP or E(2) in the snapping turtle Chelydra serpentina serpentina hypothalamus. Hatchling and year-old male snapping turtles were exposed to a 10 ng/mL nominal concentration of waterborne OP or E(2) for 17 days. One transcript [421 base pairs (bp)] regulated by OP and E(2) was 93% identical to human APLP-2. APLP-2 and the amyloid precursor protein (APP) regulate neuronal differentiation and are also implicated in the genesis of Alzheimer disease in humans. Northern blot analysis determined that the turtle hypothalamus contains a single APLP-2 transcript of 3.75 kb in length. Exposure to OP upregulated hypothalamic APLP-2 mRNA levels 2-fold (p < 0.05) in month-old and yearling turtles. E(2) did not affect APLP-2 mRNA levels in hatchlings but stimulated a 2-fold increase (p < 0.05) in APLP-2 mRNA levels in yearling males. The protein beta-amyloid, a selectively processed peptide derived from APP, is also involved in neuronal differentiation, and accumulation of this neurotoxic peptide causes neuronal degeneration in the brains of patients with Alzheimer disease. Therefore, we also sought to determine the effects of estrogens on the expression of beta-amyloid. Using homology cloning based on known sequences, we isolated a cDNA fragment (474 bp) from turtle brain with 88% identity to human APP. Northern blot analysis determined that a single 3.5-kb transcript was expressed in the turtle hypothalamus. Waterborne OP also increased the expression of hypothalamic APP after 35 days of exposure. Our results indicate that low levels of OP are bioactive and can alter the expression of APLP-2 and APP. Because members of the APP gene family are involved in neuronal development, we hypothesize that OP exposure may disrupt hypothalamic development in young turtles.

Using Behavioral Intervention Technologies to Help Low-Income and Latino Smokers Quit: Protocol of a Randomized Controlled Trial

PubMed Central

Bunge, Eduardo L; Barrera, Alinne Z; Wickham, Robert E; Lee, Jessica

2016-01-01

Background The Institute for International Internet Interventions for Health at Palo Alto University proposes to develop digital tools specifically to help low-income English- and Spanish-speaking smokers to quit. Individuals from lower-income countries and those with lower social status quit at lower rates than those from high-income countries and those with higher social status. Objective We plan to launch a project designed to test whether a mobile-based digital intervention designed with systematic input from low-income English- and Spanish-speaking smokers from a public-sector health care system can significantly improve its acceptability, utilization, and effectiveness. Methods Using human-centered development methods, we will involve low-income patients in the design of a Web app/text messaging tool. We will also use their input to improve our recruitment and dissemination strategies. We will iteratively develop versions of the digital interventions informed by our human-centered approach. The project involves three specific aims: (1) human-centered development of an English/Spanish smoking cessation web app, (2) improvement of dissemination strategies, and (3) evaluation of resulting smoking cessation web app. We will develop iterative versions of a digital smoking cessation tool that is highly responsive to the needs and preferences of the users. Input from participants will identify effective ways of reaching and encouraging low-income English- and Spanish-speaking smokers to use the digital smoking cessation interventions to be developed. This information will support ongoing dissemination and implementation efforts beyond the grant period. We will evaluate the effectiveness of the successive versions of the resulting stop smoking Web app by an online randomized controlled trial. Increased effectiveness will be defined as increased utilization of the Web app and higher abstinence rates than those obtained by a baseline usual care Web app. Results Recruitment will begin January 2016, the study is intended to be completed by summer 2018, and the results should be available by fall 2019. Conclusions This study will provide useful knowledge in developing, testing, and disseminating mobile-based interventions for low-income smokers. ClinicalTrial ClinicalTrials.gov NCT02666482; https://clinicaltrials.gov/ct2/show/NCT02666482 (Archived by WebCite at http://www.webcitation.org/6gtcwaT28) PMID:27302623

Popular Nutrition-Related Mobile Apps: A Feature Assessment.

PubMed

Franco, Rodrigo Zenun; Fallaize, Rosalind; Lovegrove, Julie A; Hwang, Faustina

2016-08-01

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. 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. 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. 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 predominantly on energy balance between dietary intake and PA. None of these nine apps offered features directly related to diet plans and motivational coaching. In contrast, the remaining four of the 13 apps focused on these opportunities, but without food diaries. One app-FatSecret-also had an innovative feature for connecting users with health professionals, and another-S Health-provided a nutrient balance score. The high number of installs indicates that there is a clear interest and opportunity for diet monitoring and recommendation using mobile apps. All the apps collecting dietary intake used the same nutrition assessment method (ie, food diary record) and technologies for data input (ie, text search and barcode scanner). Emerging technologies, such as image recognition, natural language processing, and artificial intelligence, were not identified. None of the apps had a decision engine capable of providing personalized diet advice.

Mutations in Prickle Orthologs Cause Seizures in Flies, Mice, and Humans

PubMed Central

Tao, Hirotaka; Manak, J. Robert; Sowers, Levi; Mei, Xue; Kiyonari, Hiroshi; Abe, Takaya; Dahdaleh, Nader S.; Yang, Tian; Wu, Shu; Chen, Shan; Fox, Mark H.; Gurnett, Christina; Montine, Thomas; Bird, Thomas; Shaffer, Lisa G.; Rosenfeld, Jill A.; McConnell, Juliann; Madan-Khetarpal, Suneeta; Berry-Kravis, Elizabeth; Griesbach, Hilary; Saneto, Russell P.; Scott, Matthew P.; Antic, Dragana; Reed, Jordan; Boland, Riley; Ehaideb, Salleh N.; El-Shanti, Hatem; Mahajan, Vinit B.; Ferguson, Polly J.; Axelrod, Jeffrey D.; Lehesjoki, Anna-Elina; Fritzsch, Bernd; Slusarski, Diane C.; Wemmie, John; Ueno, Naoto; Bassuk, Alexander G.

2011-01-01

Epilepsy is heritable, yet few causative gene mutations have been identified, and thus far no human epilepsy gene mutations have been found to produce seizures in invertebrates. Here we show that mutations in prickle genes are associated with seizures in humans, mice, and flies. We identified human epilepsy patients with heterozygous mutations in either PRICKLE1 or PRICKLE2. In overexpression assays in zebrafish, prickle mutations resulted in aberrant prickle function. A seizure phenotype was present in the Prickle1-null mutant mouse, two Prickle1 point mutant (missense and nonsense) mice, and a Prickle2-null mutant mouse. Drosophila with prickle mutations displayed seizures that were responsive to anti-epileptic medication, and homozygous mutant embryos showed neuronal defects. These results suggest that prickle mutations have caused seizures throughout evolution. PMID:21276947

78 FR 63500 - Federal Council on the Arts and the Humanities; Arts and Artifacts Indemnity Panel Advisory...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-10-24

... NATIONAL FOUNDATION ON THE ARTS AND THE HUMANITIES Federal Council on the Arts and the Humanities... Humanities ACTION: Notice of meeting. SUMMARY: Pursuant to section 10(a)(2) of the Federal Advisory Committee Act (5 U.S.C. App.), notice is hereby given that the Federal Council on the Arts and the Humanities...

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

MotorBrain: A mobile app for the assessment of users' motor performance in neurology.

PubMed

Vianello, Andrea; Chittaro, Luca; Burigat, Stefano; Budai, Riccardo

2017-05-01

Human motor skills or impairments have been traditionally assessed by neurologists by means of paper-and-pencil tests or special hardware. More recently, technologies such as digitizing tablets and touchscreens have offered neurologists new assessment possibilities, but their use has been restricted to a specific medical condition, or to stylus-operated mobile devices. The objective of this paper is twofold. First, we propose a mobile app (MotorBrain) that offers six computerized versions of traditional motor tests, can be used directly by patients (with and without the supervision of a clinician), and aims at turning millions of smartphones and tablets available to the general public into data collection and assessment tools. Then, we carry out a study to determine whether the data collected by MotorBrain can be meaningful for describing aging in human motor performance. A sample of healthy participants (N= 133) carried out the motor tests using MotorBrain on a smartphone. Participants were split into two groups (Young, Old) based on their age (less than or equal to 30 years, greater than or equal to 50 years, respectively). The data collected by the app characterizes accuracy, reaction times, and speed of movement. It was analyzed to investigate differences between the two groups. The app does allow measuring differences in neuromotor performance. Data collected by the app allowed us to assess performance differences due to the aging of the neuromuscular system. Data collected through MotorBrain is suitable to make meaningful distinctions among different kinds of performance, and allowed us to highlight performance differences associated to aging. MotorBrain supports the building of a large database of neuromotor data, which can be used for normative purposes in clinical use. Copyright © 2017 Elsevier B.V. All rights reserved.

Developing an eBook-Integrated High-Fidelity Mobile App Prototype for Promoting Child Motor Skills and Taxonomically Assessing Children's Emotional Responses Using Face and Sound Topology.

PubMed

Brown, William; Liu, Connie; John, Rita Marie; Ford, Phoebe

2014-01-01

Developing gross and fine motor skills and expressing complex emotion is critical for child development. We introduce "StorySense", an eBook-integrated mobile app prototype that can sense face and sound topologies and identify movement and expression to promote children's motor skills and emotional developmental. Currently, most interactive eBooks on mobile devices only leverage "low-motor" interaction (i.e. tapping or swiping). Our app senses a greater breath of motion (e.g. clapping, snapping, and face tracking), and dynamically alters the storyline according to physical responses in ways that encourage the performance of predetermined motor skills ideal for a child's gross and fine motor development. In addition, our app can capture changes in facial topology, which can later be mapped using the Facial Action Coding System (FACS) for later interpretation of emotion. StorySense expands the human computer interaction vocabulary for mobile devices. Potential clinical applications include child development, physical therapy, and autism.

48 CFR 323.7100 - Policy.

Code of Federal Regulations, 2012 CFR

2012-10-01

... 323.7100 Federal Acquisition Regulations System HEALTH AND HUMAN SERVICES SOCIOECONOMIC PROGRAMS ENVIRONMENT, ENERGY AND WATER EFFICIENCY, RENEWABLE ENERGY TECHNOLOGIES, OCCUPATIONAL SAFETY, AND DRUG-FREE... Preferable Products and Services at the U.S. Department of Health and Human Services.” The APP encompasses...

48 CFR 323.7100 - Policy.

Code of Federal Regulations, 2013 CFR

2013-10-01

... 323.7100 Federal Acquisition Regulations System HEALTH AND HUMAN SERVICES SOCIOECONOMIC PROGRAMS ENVIRONMENT, ENERGY AND WATER EFFICIENCY, RENEWABLE ENERGY TECHNOLOGIES, OCCUPATIONAL SAFETY, AND DRUG-FREE... Preferable Products and Services at the U.S. Department of Health and Human Services.” The APP encompasses...

Lactose digestion by human jejunal biopsies: the relationship between hydrolysis and absorption.

PubMed Central

Dawson, D J; Lobley, R W; Burrows, P C; Miller, V; Holmes, R

1986-01-01

The relationship between lactose hydrolysis and absorption of released glucose was investigated by determining the kinetics of lactose digestion by jejunal biopsies incubated in vitro. Lactase activity in intact biopsies correlated with conventional assay of tissue homogenates (r = 0.85, p less than 0.001), and glucose uptake from 28 mM lactose was directly proportional to lactase activity (r = 0.95, p less than 0.001) in 21 subjects with normal lactase levels, six with hypolactasia (primary or secondary to coeliac disease) and two with lactose intolerance but normal lactase activity. Kinetic analysis at 0.56-56 mM lactose in five normal subjects showed saturable kinetics for hydrolysis (app Km = 33.9 +/- 2.2 mM; app Vmax = 26.5 +/- 1.1 nmol/min/mg dry weight) but glucose uptake could be fitted to a model either of saturable uptake (app Kt = 47.2 +/- 0.3 mM; app Jmax = 14.1 +/- 0.2 nmol/min/mg) or saturable uptake plus a linear component (app Kt = 21.3 +/- 1.15; app Jmax = 4.59 +/- 0.12; app Kd = 0.093 +/- 0.010 nmol/min/mg/mM). The proportion of glucose taken into the tissue did not significantly exceed 50% of the total released at any lactose concentration suggesting the lack of an efficient capture mechanism for the released glucose. The results suggest that lactose hydrolysis is the rate limiting step in the overall absorption of glucose from lactose in vitro, and that the relationship between hydrolysis and absorption is the same in normal subjects and in hypolactasic subjects. PMID:3084346

Improvement of Endurance Based on Muscle Fiber-Type Composition by Treatment with Dietary Apple Polyphenols in Rats.

PubMed

Mizunoya, Wataru; Miyahara, Hideo; Okamoto, Shinpei; Akahoshi, Mariko; Suzuki, Takahiro; Do, Mai-Khoi Q; Ohtsubo, Hideaki; Komiya, Yusuke; Lan, Mu; Waga, Toshiaki; Iwata, Akira; Nakazato, Koichi; Ikeuchi, Yoshihide; Anderson, Judy E; Tatsumi, Ryuichi

2015-01-01

A recent study demonstrated a positive effect of apple polyphenol (APP) intake on muscle endurance of young-adult animals. While an enhancement of lipid metabolism may be responsible, in part, for the improvement, the contributing mechanisms still need clarification. Here we show that an 8-week intake of 5% (w/w) APP in the diet, up-regulates two features related to fiber type: the ratio of myosin heavy chain (MyHC) type IIx/IIb and myoglobin protein expression in plantaris muscle of 9-week-old male Fischer F344 rats compared to pair-fed controls (P < 0.05). Results were demonstrated by our SDS-PAGE system specialized for MyHC isoform separation and western blotting of whole muscles. Animal-growth profiles (food intake, body-weight gain, and internal-organ weights) did not differ between the control and 5% APP-fed animals (n = 9/group). Findings may account for the increase in fatigue resistance of lower hind limb muscles, as evidenced by a slower decline in the maximum isometric planter-flexion torque generated by a 100-s train of electrical stimulation of the tibial nerve. Additionally, the fatigue resistance was lower after 8 weeks of a 0.5% APP diet than after 5% APP, supporting an APP-dose dependency of the shift in fiber-type composition. Therefore, the present study highlights a promising contribution of dietary APP intake to increasing endurance based on fiber-type composition in rat muscle. Results may help in developing a novel strategy for application in animal sciences, and human sports and age-related health sciences.

Creating Effective Mobile Phone Apps to Optimize Antiretroviral Therapy Adherence: Perspectives From Stimulant-Using HIV-Positive Men Who Have Sex With Men

PubMed Central

Alemu, Dawit; Danh, Thu; Baker, Jason V; Carrico, Adam W

2016-01-01

Background The use of stimulant drugs among men who have sex with men (MSM) with human immunodeficiency virus (HIV) is associated with decreased odds of antiretroviral therapy (ART) adherence and elevated risk of forward HIV transmission. Advancing tailored and innovative mobile phone–based ART adherence app interventions for stimulant-using HIV-positive MSM requires greater understanding of their needs and preferences in this emerging area. Objective The purpose of this study is to (1) assess reasons that stimulant-using HIV-positive MSM download and sustain their use of mobile phone apps in general, and (2) obtain feedback on features and functions that these men prefer in a mobile phone app to optimize their ART adherence. Methods Focus groups were conducted with stimulant-using HIV-positive MSM (24-57 years of age; mostly non-Hispanic white; 42% once a week or more frequent stimulant drug use) in San Francisco and Minneapolis. Our aim was to explore the mobile phone app features and functions that they considered when deciding to download and sustain their use of general apps over time, as well as specific features and functions that they would like to see incorporated into an ART adherence mobile app. Focus groups were audiorecorded and transcribed verbatim. Thematic analysis was applied to transcripts using line-by-line open coding and organizing codes into meaningful themes. Results Men reported that they currently had a variety of health and wellness, social media and networking, gaming and entertainment, and utility apps on their mobile phones. Downloading apps to their mobile phones was influenced by the cost of the app, recommendations by a trusted source, and the time it takes to download. In addition, downloading and sustained use of apps was more likely to occur when men had control over most features of the app and apps were perceived to be useful, engaging, secure, and credible. Participants suggested that ART adherence mobile phone apps include social networking features, connections to local resources and their medical chart, and breaking HIV news and updates. Although some men expressed concerns about daily self-monitoring of HIV medication doses, many appreciated receiving a summary of their medication adherence over time and suggested that feedback about missed doses be delivered in an encouraging and humorous manner. Conclusions In this study, we were able to recruit a relatively high proportion (42%) of HIV-positive MSM reporting weekly or more stimulant use. These results suggest critical design elements that may need to be considered during development of ART adherence-related mobile phone apps for this, and possibly other, high-risk groups. In particular, finding the optimal balance of security, engagement, usefulness, control capabilities, and credibility will be critical to sustained used of HIV treatment apps. PMID:27084049

Selection of Salmonella enterica Serovar Typhi Genes Involved during Interaction with Human Macrophages by Screening of a Transposon Mutant Library

PubMed Central

Sabbagh, Sébastien C.; Lepage, Christine; McClelland, Michael; Daigle, France

2012-01-01

The human-adapted Salmonella enterica serovar Typhi (S. Typhi) causes a systemic infection known as typhoid fever. This disease relies on the ability of the bacterium to survive within macrophages. In order to identify genes involved during interaction with macrophages, a pool of approximately 105 transposon mutants of S. Typhi was subjected to three serial passages of 24 hours through human macrophages. Mutants recovered from infected macrophages (output) were compared to the initial pool (input) and those significantly underrepresented resulted in the identification of 130 genes encoding for cell membrane components, fimbriae, flagella, regulatory processes, pathogenesis, and many genes of unknown function. Defined deletions in 28 genes or gene clusters were created and mutants were evaluated in competitive and individual infection assays for uptake and intracellular survival during interaction with human macrophages. Overall, 26 mutants had defects in the competitive assay and 14 mutants had defects in the individual assay. Twelve mutants had defects in both assays, including acrA, exbDB, flhCD, fliC, gppA, mlc, pgtE, typA, waaQGP, SPI-4, STY1867-68, and STY2346. The complementation of several mutants by expression of plasmid-borne wild-type genes or gene clusters reversed defects, confirming that the phenotypic impairments within macrophages were gene-specific. In this study, 35 novel phenotypes of either uptake or intracellular survival in macrophages were associated with Salmonella genes. Moreover, these results reveal several genes encoding molecular mechanisms not previously known to be involved in systemic infection by human-adapted typhoidal Salmonella that will need to be elucidated. PMID:22574205

Reduced Aβ secretion by human neurons under conditions of strongly increased BACE activity.

PubMed

Scholz, Diana; Chernyshova, Yana; Ückert, Anna-Katharina; Leist, Marcel

2018-05-27

The initial step in the amyloidogenic cascade of amyloid precursor protein (APP) processing is catalyzed by beta-site APP-cleaving enzyme (BACE), and this protease has increased activities in affected areas of Alzheimer's disease brains. We hypothesized that altered APP processing, due to augmented BACE activity, would affect the actions of direct and indirect BACE inhibitors. We therefore compared postmitotic human neurons (LUHMES) with their BACE-overexpressing counterparts (BLUHMES). Although β-cleavage of APP was strongly increased in BLUHMES, they produced less full-length and truncated amyloid beta (Aβ) than LUHMES. Moreover, low concentrations of BACE inhibitors decreased cellular BACE activity as expected, but increased Aβ 1-40 levels. Several other approaches to modulate BACE activity led to a similar, apparently paradoxical, behavior. For instance, reduction of intracellular acidification by bepridil increased Aβ production in parallel with decreased BACE activity. In contrast to BLUHMES, the respective control cells (LUHMES or BLUHMES with catalytically inactive BACE) showed conventional pharmacological responses. Other non-canonical neurochemical responses (so-called 'rebound effects') are well-documented for the Aβ pathway, especially for γ-secretase: a partial block of its activity leads to an increased Aβ secretion by some cell types. We therefore compared LUHMES and BLUHMES regarding rebound effects of γ-secretase inhibitors and found an Aβ rise in LUHMES but not in BLUHMES. Thus, different cellular factors are responsible for the γ-secretase- vs. BACE-related Aβ rebound. We conclude that increased BACE activity, possibly accompanied by an altered cellular localization pattern, can dramatically influence Aβ generation in human neurons and affect pharmacological responses to secretase inhibitors. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Mutagenesis in human cells with accelerated H and Fe ions

NASA Technical Reports Server (NTRS)

Kronenberg, Amy

1994-01-01

The overall goals of this research were to determine the risks of mutation induction and the spectra of mutations induced by energetic protons and iron ions at two loci in human lymphoid cells. During the three year grant period the research has focused in three major areas: (1) the acquisition of sufficient statistics for human TK6 cell mutation experiments using Fe ions (400 MeV/amu), Fe ions (600 MeV/amu) and protons (250 MeV/amu); (2) collection of thymidine kinase- deficient (tk) mutants or hypoxanthine phosphoribosyltransferase deficient (hprt) mutants induced by either Fe 400 MeV/amu, Fe 600 MeV/amu, or H 250 MeV/amu for subsequent molecular analysis; and (3) molecular characterization of mutants isolated after exposure to Fe ions (600 MeV/amu). As a result of the shutdown of the BEVALAC heavy ion accelerator in December 1992, efforts were rearranged somewhat in time to complete our dose-response studies and to complete mutant collections in particular for the Fe ion beams prior to the shutdown. These goals have been achieved. A major effort was placed on collection, re-screening, and archiving of 3 different series of mutants for the various particle beam exposures: tk-ng mutants, tk-sg mutants, and hprt-deficient mutants. Where possible, groups of mutants were isolated for several particle fluences. Comparative analysis of mutation spectra has occured with characterization of the mutation spectrum for hprt-deficient mutants obtained after exposure of TK6 cells to Fe ions (600 MeV/amu) and a series of spontaneous mutants.

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 predominantly on energy balance between dietary intake and PA. None of these nine apps offered features directly related to diet plans and motivational coaching. In contrast, the remaining four of the 13 apps focused on these opportunities, but without food diaries. One app—FatSecret—also had an innovative feature for connecting users with health professionals, and another—S Health—provided a nutrient balance score. Conclusions The high number of installs indicates that there is a clear interest and opportunity for diet monitoring and recommendation using mobile apps. All the apps collecting dietary intake used the same nutrition assessment method (ie, food diary record) and technologies for data input (ie, text search and barcode scanner). Emerging technologies, such as image recognition, natural language processing, and artificial intelligence, were not identified. None of the apps had a decision engine capable of providing personalized diet advice. PMID:27480144

Targeting of KRAS mutant tumors by HSP90 inhibitors involves degradation of STK33

PubMed Central

Azoitei, Ninel; Hoffmann, Christopher M.; Ellegast, Jana M.; Ball, Claudia R.; Obermayer, Kerstin; Gößele, Ulrike; Koch, Britta; Faber, Katrin; Genze, Felicitas; Schrader, Mark; Kestler, Hans A.; Döhner, Hartmut; Chiosis, Gabriela; Glimm, Hanno

2012-01-01

Previous efforts to develop drugs that directly inhibit the activity of mutant KRAS, the most commonly mutated human oncogene, have not been successful. Cancer cells driven by mutant KRAS require expression of the serine/threonine kinase STK33 for their viability and proliferation, identifying STK33 as a context-dependent therapeutic target. However, specific strategies for interfering with the critical functions of STK33 are not yet available. Here, using a mass spectrometry-based screen for STK33 protein interaction partners, we report that the HSP90/CDC37 chaperone complex binds to and stabilizes STK33 in human cancer cells. Pharmacologic inhibition of HSP90, using structurally divergent small molecules currently in clinical development, induced proteasome-mediated degradation of STK33 in human cancer cells of various tissue origin in vitro and in vivo, and triggered apoptosis preferentially in KRAS mutant cells in an STK33-dependent manner. Furthermore, HSP90 inhibitor treatment impaired sphere formation and viability of primary human colon tumor-initiating cells harboring mutant KRAS. These findings provide mechanistic insight into the activity of HSP90 inhibitors in KRAS mutant cancer cells, indicate that the enhanced requirement for STK33 can be exploited to target mutant KRAS-driven tumors, and identify STK33 depletion through HSP90 inhibition as a biomarker-guided therapeutic strategy with immediate translational potential. PMID:22451720

Targeted inactivation of the mouse locus encoding coagulation factor XIII-A: hemostatic abnormalities in mutant mice and characterization of the coagulation deficit.

PubMed

Lauer, Peter; Metzner, Hubert J; Zettlmeissl, Gerd; Li, Meng; Smith, Austin G; Lathe, Richard; Dickneite, Gerhard

2002-12-01

Blood coagulation factor XIII (FXIII) promotes cross-linking of fibrin during blood coagulation; impaired clot stabilization in human genetic deficiency is associated with marked pathologies of major clinical impact, including bleeding symptoms and deficient wound healing. To investigate the role of FXIII we employed homologous recombination to generate a targeted deletion of the inferred exon 7 of the FXIII-A gene. FXIII transglutaminase activity in plasma was reduced to about 50% in mice heterozygous for the mutant allele, and was abolished in homozygous null mice. Plasma fibrin gamma-dimerization was also indetectable in the homozygous deficient animals, confirming the absence of activatable FXIII. Homozygous mutant mice were fertile, although reproduction was impaired. Bleeding episodes, hematothorax, hematoperitoneum and subcutaneous hemorrhage in mutant mice were associated with reduced survival. Arrest of tail-tip bleeding in FXIII-A deficient mice was markedly and significantly delayed; replacement of mutant mice with human plasma FXIII (Fibrogammin P) restored bleeding time to within the normal range. Thrombelastography (TEG) experiments demonstrated impaired clot stabilization in FXIII-A mutant mice, replacement with human FXIII led to dose-dependent TEG normalization. The mutant mice thus reiterate some key features of the human genetic disorder: they will be valuable in assessing the role of FXIII in other associated pathologies and the development of new therapies.

Mutant protein of recombinant human granulocyte colony-stimulating factor for receptor binding assay.

PubMed

Watanabe, M; Fukamachi, H; Uzumaki, H; Kabaya, K; Tsumura, H; Ishikawa, M; Matsuki, S; Kusaka, M

1991-05-15

A new mutant protein of recombinant human granulocyte colony-stimulating factor (rhG-CSF) was produced for the studies on receptors for human G-CSF. The mutant protein [(Tyr1, Tyr3]rhG-CSF), the biological activity of which was almost equal to that of rhG-CSF, was prepared by the replacement of threonine-1 and leucine-3 of rhG-CSF with tyrosine. The radioiodinated preparation of the mutant protein showed high specific radioactivity and retained full biological activity for at least 3 weeks. The binding capacity of the radioiodinated ligand was compared with that of [35S]rhG-CSF. Both radiolabeled ligands showed specific binding to murine bone marrow cells. Unlabeled rhG-CSF and human G-CSF purified from the culture supernatant of the human bladder carcinoma cell line 5637 equally competed for the binding of labeled rhG-CSFs in a dose-dependent manner, demonstrating that the sugar moiety of human G-CSF made no contribution to the binding of human G-CSF to target cells. In contrast, all other colony-stimulating factors and lymphokines examined did not affect the binding. Scatchard analysis of the specific binding of both labeled ligands revealed a single class of binding site with an apparent dissociation constant (Kd) of 20-30 pM and 100-200 maximal binding sites per cell. These data indicate that the radioiodinated preparation of the mutant protein binds the same specific receptor with the same affinity as [35S]rhG-CSF. The labeled mutant protein also showed specific binding to human circulating neutrophils.(ABSTRACT TRUNCATED AT 250 WORDS)

Induction of diphtheria toxin-resistant mutants in human cells by ultraviolet light

DOE Office of Scientific and Technical Information (OSTI.GOV)

Rocchi, P.; Ferreri, A.M.; Capucci, A.

1981-01-01

Stable spontaneous mutants resistant to the protein synthesis inhibitor diphtheria toxin (DT) have been selected in human cell line EUE at a very low frequency (less than 8 x 10(-6)). U.v.-induced mutation has been quantitatively measured: treatment of cells with u.v. light increased the frequencies of diphtheria toxin resistant (DTr) mutants up to 1000-fold. The maximum recovery of DTr mutants was observed after a short expression period, for all u.v. doses tested, and was followed by a decrease in mutation frequency on subsequent passages.

Induction of diphtheria toxin-resistant mutants in human cells by ultraviolet light

DOE Office of Scientific and Technical Information (OSTI.GOV)

Rocchi, P.; Ferreri, A.M.; Capucci, A.

1981-01-01

Stable spontaneous mutants resistant to the protein synthesis inhibitor diphtheria toxin (DT) have been selected in human cell line EUE at a very low frequency (< 8 x 10/sup -6/). U.v.-induced mutation has been quantitatively measured: treatment of cells with u.v. light increased the frequencies of diphtheria toxin resistant (DTsup(r)) mutants up to 1000-fold. The maximum recovery of DTsup(r) mutants was observed after a short expression period, for all u.v. doses tested, and was followed by a decrease in mutation frequency on subsequent passages.

Quantifying multi-dimensional attributes of human activities at various geographic scales based on smartphone tracking.

PubMed

Zhou, Xiaolu; Li, Dongying

2018-05-09

Advancement in location-aware technologies, and information and communication technology in the past decades has furthered our knowledge of the interaction between human activities and the built environment. An increasing number of studies have collected data regarding individual activities to better understand how the environment shapes human behavior. Despite this growing interest, some challenges exist in collecting and processing individual's activity data, e.g., capturing people's precise environmental contexts and analyzing data at multiple spatial scales. In this study, we propose and implement an innovative system that integrates smartphone-based step tracking with an app and the sequential tile scan techniques to collect and process activity data. We apply the OpenStreetMap tile system to aggregate positioning points at various scales. We also propose duration, step and probability surfaces to quantify the multi-dimensional attributes of activities. Results show that, by running the app in the background, smartphones can measure multi-dimensional attributes of human activities, including space, duration, step, and location uncertainty at various spatial scales. By coordinating Global Positioning System (GPS) sensor with accelerometer sensor, this app can save battery which otherwise would be drained by GPS sensor quickly. Based on a test dataset, we were able to detect the recreational center and sports center as the space where the user was most active, among other places visited. The methods provide techniques to address key issues in analyzing human activity data. The system can support future studies on behavioral and health consequences related to individual's environmental exposure.

Mobile Applications for Patient-centered Care Coordination: A Review of Human Factors Methods Applied to their Design, Development, and Evaluation

PubMed Central

Westbrook, J. I.

2015-01-01

Summary Objectives To examine if human factors methods were applied in the design, development, and evaluation of mobile applications developed to facilitate aspects of patient-centered care coordination. Methods We searched MEDLINE and EMBASE (2013-2014) for studies describing the design or the evaluation of a mobile health application that aimed to support patients’ active involvement in the coordination of their care. Results 34 papers met the inclusion criteria. Applications ranged from tools that supported self-management of specific conditions (e.g. asthma) to tools that provided coaching or education. Twelve of the 15 papers describing the design or development of an app reported the use of a human factors approach. The most frequently used methods were interviews and surveys, which often included an exploration of participants’ current use of information technology. Sixteen papers described the evaluation of a patient application in practice. All of them adopted a human factors approach, typically an examination of the use of app features and/or surveys or interviews which enquired about patients’ views of the effects of using the app on their behaviors (e.g. medication adherence), knowledge, and relationships with healthcare providers. No study in our review assessed the impact of mobile applications on health outcomes. Conclusion The potential of mobile health applications to assist patients to more actively engage in the management of their care has resulted in a large number of applications being developed. Our review showed that human factors approaches are nearly always adopted to some extent in the design, development, and evaluation of mobile applications. PMID:26293851

Regulation of neuronal APL-1 expression by cholesterol starvation.

PubMed

Wiese, Mary; Antebi, Adam; Zheng, Hui

2012-01-01

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the deposition of β-amyloid plaques composed primarily of the amyloid-β peptide, a cleavage product of amyloid precursor protein (APP). While mutations in APP lead to the development of Familial Alzheimer's Disease (FAD), sporadic AD has only one clear genetic modifier: the ε4 allele of the apolipoprotein E (ApoE) gene. Cholesterol starvation in Caenorhabditis elegans leads to molting and arrest phenotypes similar to loss-of-function mutants of the APP ortholog, apl-1 (amyloid precursor-like protein 1), and lrp-1 (lipoprotein receptor-related protein 1), suggesting a potential interaction between apl-1 and cholesterol metabolism. Previously, we found that RNAi knock-down of apl-1 leads to aldicarb hypersensitivity, indicating a defect in synaptic function. Here we find the same defect is recapitulated during lrp-1 knock-down and by cholesterol starvation. A cholesterol-free diet or loss of lrp-1 directly affects APL-1 levels as both lead to loss of APL-1::GFP fluorescence in neurons. However, loss of cholesterol does not affect global transcription or protein levels as seen by qPCR and Western blot. Our results show that cholesterol and lrp-1 are involved in the regulation of synaptic transmission, similar to apl-1. Both are able to modulate APL-1 protein levels in neurons, however cholesterol changes do not affect global apl-1 transcription or APL-1 protein indicating the changes are specific to neurons. Thus, regulation of synaptic transmission and molting by LRP-1 and cholesterol may be mediated by their ability to control APL-1 neuronal protein expression.

Using the Habit App for Weight Loss Problem Solving: Development and Feasibility Study.

PubMed

Pagoto, Sherry; Tulu, Bengisu; Agu, Emmanuel; Waring, Molly E; Oleski, Jessica L; Jake-Schoffman, Danielle E

2018-06-20

Reviews of weight loss mobile apps have revealed they include very few evidence-based features, relying mostly on self-monitoring. Unfortunately, adherence to self-monitoring is often low, especially among patients with motivational challenges. One behavioral strategy that is leveraged in virtually every visit of behavioral weight loss interventions and is specifically used to deal with adherence and motivational issues is problem solving. Problem solving has been successfully implemented in depression mobile apps, but not yet in weight loss apps. This study describes the development and feasibility testing of the Habit app, which was designed to automate problem-solving therapy for weight loss. Two iterative single-arm pilot studies were conducted to evaluate the feasibility and acceptability of the Habit app. In each pilot study, adults who were overweight or obese were enrolled in an 8-week intervention that included the Habit app plus support via a private Facebook group. Feasibility outcomes included retention, app usage, usability, and acceptability. Changes in problem-solving skills and weight over 8 weeks are described, as well as app usage and weight change at 16 weeks. Results from both pilots show acceptable use of the Habit app over 8 weeks with on average two to three uses per week, the recommended rate of use. Acceptability ratings were mixed such that 54% (13/24) and 73% (11/15) of participants found the diet solutions helpful and 71% (17/24) and 80% (12/15) found setting reminders for habits helpful in pilots 1 and 2, respectively. In both pilots, participants lost significant weight (P=.005 and P=.03, respectively). In neither pilot was an effect on problem-solving skills observed (P=.62 and P=.27, respectively). Problem-solving therapy for weight loss is feasible to implement in a mobile app environment; however, automated delivery may not impact problem-solving skills as has been observed previously via human delivery. ClinicalTrials.gov NCT02192905; https://clinicaltrials.gov/ct2/show/NCT02192905 (Archived by WebCite at http://www.webcitation.org/6zPQmvOF2). ©Sherry Pagoto, Bengisu Tulu, Emmanuel Agu, Molly E Waring, Jessica L Oleski, Danielle E Jake-Schoffman. Originally published in JMIR Mhealth and Uhealth (http://mhealth.jmir.org), 20.06.2018.

Thiamine deficiency induces oxidative stress and exacerbates the plaque pathology in Alzheimer’s mouse model

PubMed Central

Karuppagounder, Saravanan S.; Xu, Hui; Shi, Qingli; Chen, Lian H.; Pedrini, Steve; Pechman, David; Baker, Harriet; Beal, M. Flint; Gandy, Sam E.; Gibson, Gary E.

2009-01-01

Mitochondrial dysfunction, oxidative stress and reductions in thiamine-dependent enzymes have been implicated in multiple neurological disorders including Alzheimer's disease (AD). Experimental thiamine deficiency (TD) is an established model for reducing the activities of thiamine-dependent enzymes in brain. TD diminishes thiamine dependent enzymes throughout the brain, but produces a time-dependent selective neuronal loss, glial activation, inflammation, abnormalities in oxidative metabolism and clusters of degenerating neurites in only specific thalamic regions. The present studies tested how TD alters brain pathology in Tg19959 transgenic mice over expressing a double mutant form of the amyloid precursor protein (APP). TD exacerbated amyloid plaque pathology in transgenic mice and enlarged the area occupied by plaques in cortex, hippocampus and thalamus by 50%, 200% and 200%, respectively. TD increased Aβ1–42 levels by about three-fold, β-CTF (C99) levels by 33% and β-secretase (BACE1) protein levels by 43%. TD induced inflammation in areas of plaque formation. Thus, the induction of mild impairment of oxidative metabolism, oxidative stress and inflammation induced by TD alters metabolism of APP and/or Aβ and promotes accumulation of plaques independent of neuron loss or neuritic clusters. PMID:18406011

ALS mutations in FUS cause neuronal dysfunction and death in Caenorhabditis elegans by a dominant gain-of-function mechanism

PubMed Central

Murakami, Tetsuro; Yang, Seung-Pil; Xie, Lin; Kawano, Taizo; Fu, Donald; Mukai, Asuka; Bohm, Christopher; Chen, Fusheng; Robertson, Janice; Suzuki, Hiroshi; Tartaglia, Gian Gaetano; Vendruscolo, Michele; Kaminski Schierle, Gabriele S.; Chan, Fiona T.S.; Moloney, Aileen; Crowther, Damian; Kaminski, Clemens F.; Zhen, Mei; St George-Hyslop, Peter

2012-01-01

It is unclear whether mutations in fused in sarcoma (FUS) cause familial amyotrophic lateral sclerosis via a loss-of-function effect due to titrating FUS from the nucleus or a gain-of-function effect from cytoplasmic overabundance. To investigate this question, we generated a series of independent Caenorhabditis elegans lines expressing mutant or wild-type (WT) human FUS. We show that mutant FUS, but not WT-FUS, causes cytoplasmic mislocalization associated with progressive motor dysfunction and reduced lifespan. The severity of the mutant phenotype in C. elegans was directly correlated with the severity of the illness caused by the same mutation in humans, arguing that this model closely replicates key features of the human illness. Importantly, the mutant phenotype could not be rescued by overexpression of WT-FUS, even though WT-FUS had physiological intracellular localization, and was not recruited to the cytoplasmic mutant FUS aggregates. Our data suggest that FUS mutants cause neuronal dysfunction by a dominant gain-of-function effect related either to neurotoxic aggregates of mutant FUS in the cytoplasm or to dysfunction in its RNA-binding functions. PMID:21949354

ALS mutations in FUS cause neuronal dysfunction and death in Caenorhabditis elegans by a dominant gain-of-function mechanism.

PubMed

Murakami, Tetsuro; Yang, Seung-Pil; Xie, Lin; Kawano, Taizo; Fu, Donald; Mukai, Asuka; Bohm, Christopher; Chen, Fusheng; Robertson, Janice; Suzuki, Hiroshi; Tartaglia, Gian Gaetano; Vendruscolo, Michele; Kaminski Schierle, Gabriele S; Chan, Fiona T S; Moloney, Aileen; Crowther, Damian; Kaminski, Clemens F; Zhen, Mei; St George-Hyslop, Peter

2012-01-01

It is unclear whether mutations in fused in sarcoma (FUS) cause familial amyotrophic lateral sclerosis via a loss-of-function effect due to titrating FUS from the nucleus or a gain-of-function effect from cytoplasmic overabundance. To investigate this question, we generated a series of independent Caenorhabditis elegans lines expressing mutant or wild-type (WT) human FUS. We show that mutant FUS, but not WT-FUS, causes cytoplasmic mislocalization associated with progressive motor dysfunction and reduced lifespan. The severity of the mutant phenotype in C. elegans was directly correlated with the severity of the illness caused by the same mutation in humans, arguing that this model closely replicates key features of the human illness. Importantly, the mutant phenotype could not be rescued by overexpression of WT-FUS, even though WT-FUS had physiological intracellular localization, and was not recruited to the cytoplasmic mutant FUS aggregates. Our data suggest that FUS mutants cause neuronal dysfunction by a dominant gain-of-function effect related either to neurotoxic aggregates of mutant FUS in the cytoplasm or to dysfunction in its RNA-binding functions.

The application of pH-sensitive fluorescent dyes in lactic acid bacteria reveals distinct extrusion systems for unmodified and conjugated dyes.

PubMed

Glaasker, E; Konings, W N; Poolman, B

1996-01-01

Intracellular pH in bacteria can be measured efficiently between internal pH values of 6.5 and 8.5 with the fluorescent pH indicator 2',7'-bis-(2-carboxyethyl)-5[and-6]-carboxyfluorescein (BCECF). A new fluorescent pH probe with a lower pKa(app) than BCECF was synthesized from fluorescein isothiocyanate and glutamate. The new probe, N-(fluorescein thio-ureanyl)-glutamate (FTUG), was much less sensitive to changes in concentrations of KCl than was BCECF. Similar to BCECF, an efflux of FTUG independent of the proton motive force, but dependent on ATP, was observed both in Lactobacillus plantarum and Lactococcus lactis. Corrections for probe efflux allowed accurate measurements of the pHin. Similar intracellular pH values were determined with FTUG and BCECF, in the range where both probes can be applied, and the pH values correlated well with those estimated from the distribution of radio-labelled benzoic acid. Since FITC can easily be coupled to substrates containing an amino group, it is possible to develop other FITC derivatives as well. The mechanisms of probe excretion and the nature of the excreted product(s) were studied in further detail for BCECF and FTUG. BCECF was excreted from wild-type L. lactis in an unmodified form as was determined by chromatographic and mass spectrometry analysis. In the case of FTUG, the excreted product was a conjugated derivative. Unmodified FTUG was not excreted, although it was present in cellular extracts from L. lactis. Exit of BCECF was completely inhibited in a BCECF efflux mutant (Bef-) of L. lactis, whereas FTUG-conjugate efflux in this mutant was similar to the wild-type. Addition of indomethacin, a known inhibitor of BCECF efflux in human epithelial cells, resulted in complete inhibition of BCECF efflux in wild-type L. lactis, whereas FTUG-conjugate exit was only slightly affected. The results of the mutant and inhibitor studies suggest that FTUG-conjugate and BCECF efflux in L. lactis are mediated by different ATP-driven extrusion systems for organic anions.

Survival of a bacterioferritin deletion mutant of Brucella melitensis 16M in human monocyte-derived macrophages.

PubMed Central

Denoel, P A; Crawford, R M; Zygmunt, M S; Tibor, A; Weynants, V E; Godfroid, F; Hoover, D L; Letesson, J J

1997-01-01

A bacterioferritin (BFR) deletion mutant of Brucella melitensis 16M was generated by gene replacement. The deletion was complemented with a broad-host-range vector carrying the wild-type bfr gene, pBBR-bfr. The survival and growth of the mutant, B. melitensis PAD 2-78, were similar to those of its parental strain in human monocyte-derived macrophages (MDM). These results suggest that BFR is not essential for the intracellular survival of B. melitensis in human MDM. PMID:9317046

Human COQ9 Rescues a coq9 Yeast Mutant by Enhancing Coenzyme Q Biosynthesis from 4-Hydroxybenzoic Acid and Stabilizing the CoQ-Synthome

PubMed Central

He, Cuiwen H.; Black, Dylan S.; Allan, Christopher M.; Meunier, Brigitte; Rahman, Shamima; Clarke, Catherine F.

2017-01-01

Coq9 is required for the stability of a mitochondrial multi-subunit complex, termed the CoQ-synthome, and the deamination step of Q intermediates that derive from para-aminobenzoic acid (pABA) in yeast. In human, mutations in the COQ9 gene cause neonatal-onset primary Q10 deficiency. In this study, we determined whether expression of human COQ9 could complement yeast coq9 point or null mutants. We found that expression of human COQ9 rescues the growth of the temperature-sensitive yeast mutant, coq9-ts19, on a non-fermentable carbon source and increases the content of Q6, by enhancing Q biosynthesis from 4-hydroxybenzoic acid (4HB). To study the mechanism for the rescue by human COQ9, we determined the steady-state levels of yeast Coq polypeptides in the mitochondria of the temperature-sensitive yeast coq9 mutant expressing human COQ9. We show that the expression of human COQ9 significantly increased steady-state levels of yeast Coq4, Coq6, Coq7, and Coq9 at permissive temperature. Human COQ9 polypeptide levels persisted at non-permissive temperature. A small amount of the human COQ9 co-purified with tagged Coq6, Coq6-CNAP, indicating that human COQ9 interacts with the yeast Q-biosynthetic complex. These findings suggest that human COQ9 rescues the yeast coq9 temperature-sensitive mutant by stabilizing the CoQ-synthome and increasing Q biosynthesis from 4HB. This finding provides a powerful approach to studying the function of human COQ9 using yeast as a model. PMID:28736527

Structural Basis for a Switch in Receptor Binding Specificity of Two H5N1 Hemagglutinin Mutants

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zhu, Xueyong; Viswanathan, Karthik; Raman, Rahul

Avian H5N1 influenza viruses continue to spread in wild birds and domestic poultry with sporadic infection in humans. Receptor binding specificity changes are a prerequisite for H5N1 viruses and other zoonotic viruses to be transmitted among humans. Previous reported hemagglutinin (HA) mutants from ferret-transmissible H5N1 viruses of A/Viet Nam/1203/04 and A/Indonesia/5/05 showed slightly increased, but still very weak, binding to human receptors. From mutagenesis and glycan array studies, we previously identified two H5N1 HA mutants that could more effectively switch receptor specificity to human-like α2-6 linked sialosides with avidity comparable to wild-type H5 HA binding to avian-like α2-3 linked sialosides.more » Here, crystal structures of these two H5 HA mutants free and in complex with human and avian glycan receptor analogues reveal the structural basis for their preferential binding to human receptors. These findings suggest continuous surveillance should be maintained to monitor and assess human-to-human transmission potential of H5N1 viruses.« less

Structural Basis for a Switch in Receptor Binding Specificity of Two H5N1 Hemagglutinin Mutants

DOE PAGES

Zhu, Xueyong; Viswanathan, Karthik; Raman, Rahul; ...

2015-11-01

Avian H5N1 influenza viruses continue to spread in wild birds and domestic poultry with sporadic infection in humans. Receptor binding specificity changes are a prerequisite for H5N1 viruses and other zoonotic viruses to be transmitted among humans. Previous reported hemagglutinin (HA) mutants from ferret-transmissible H5N1 viruses of A/Viet Nam/1203/04 and A/Indonesia/5/05 showed slightly increased, but still very weak, binding to human receptors. From mutagenesis and glycan array studies, we previously identified two H5N1 HA mutants that could more effectively switch receptor specificity to human-like α2-6 linked sialosides with avidity comparable to wild-type H5 HA binding to avian-like α2-3 linked sialosides.more » Here, crystal structures of these two H5 HA mutants free and in complex with human and avian glycan receptor analogues reveal the structural basis for their preferential binding to human receptors. These findings suggest continuous surveillance should be maintained to monitor and assess human-to-human transmission potential of H5N1 viruses.« less

A Novel Form of Compensation in the Tg2576 Amyloid Mouse Model of Alzheimer’s Disease

PubMed Central

Somogyi, Attila; Katonai, Zoltán; Alpár, Alán; Wolf, Ervin

2016-01-01

One century after its first description, pathology of Alzheimer’s disease (AD) is still poorly understood. Amyloid-related dendritic atrophy and membrane alterations of susceptible brain neurons in AD, and in animal models of AD are widely recognized. However, little effort has been made to study the potential effects of combined morphological and membrane alterations on signal transfer and synaptic integration in neurons that build up affected neural networks in AD. In this study spatial reconstructions and electrophysiological measurements of layer II/III pyramidal neurons of the somatosensory cortex from wild-type (WT) and transgenic (TG) human amyloid precursor protein (hAPP) overexpressing Tg2576 mice were used to build faithful segmental cable models of these neurons. Local synaptic activities were simulated in various points of the dendritic arbors and properties of subthreshold dendritic impulse propagation and predictors of synaptic input pattern recognition ability were quantified and compared in modeled WT and TG neurons. Despite the widespread dendritic degeneration and membrane alterations in mutant mouse neurons, surprisingly little, or no change was detected in steady-state and 50 Hz sinusoidal voltage transfers, current transfers, and local and propagation delays of PSPs traveling along dendrites of TG neurons. Synaptic input pattern recognition ability was also predicted to be unaltered in TG neurons in two different soma-dendritic membrane models investigated. Our simulations predict the way how subthreshold dendritic signaling and pattern recognition are preserved in TG neurons: amyloid-related membrane alterations compensate for the pathological effects that dendritic atrophy has on subthreshold dendritic signal transfer and integration in layer II/III somatosensory neurons of this hAPP mouse model for AD. Since neither propagation of single PSPs nor integration of multiple PSPs (pattern recognition) changes in TG neurons, we conclude that AD-related neuronal hyperexcitability cannot be accounted for by altered subthreshold dendritic signaling in these neurons but hyperexcitability is related to changes in active membrane properties and network connectivity. PMID:27378850

A Novel Form of Compensation in the Tg2576 Amyloid Mouse Model of Alzheimer's Disease.

PubMed

Somogyi, Attila; Katonai, Zoltán; Alpár, Alán; Wolf, Ervin

2016-01-01

One century after its first description, pathology of Alzheimer's disease (AD) is still poorly understood. Amyloid-related dendritic atrophy and membrane alterations of susceptible brain neurons in AD, and in animal models of AD are widely recognized. However, little effort has been made to study the potential effects of combined morphological and membrane alterations on signal transfer and synaptic integration in neurons that build up affected neural networks in AD. In this study spatial reconstructions and electrophysiological measurements of layer II/III pyramidal neurons of the somatosensory cortex from wild-type (WT) and transgenic (TG) human amyloid precursor protein (hAPP) overexpressing Tg2576 mice were used to build faithful segmental cable models of these neurons. Local synaptic activities were simulated in various points of the dendritic arbors and properties of subthreshold dendritic impulse propagation and predictors of synaptic input pattern recognition ability were quantified and compared in modeled WT and TG neurons. Despite the widespread dendritic degeneration and membrane alterations in mutant mouse neurons, surprisingly little, or no change was detected in steady-state and 50 Hz sinusoidal voltage transfers, current transfers, and local and propagation delays of PSPs traveling along dendrites of TG neurons. Synaptic input pattern recognition ability was also predicted to be unaltered in TG neurons in two different soma-dendritic membrane models investigated. Our simulations predict the way how subthreshold dendritic signaling and pattern recognition are preserved in TG neurons: amyloid-related membrane alterations compensate for the pathological effects that dendritic atrophy has on subthreshold dendritic signal transfer and integration in layer II/III somatosensory neurons of this hAPP mouse model for AD. Since neither propagation of single PSPs nor integration of multiple PSPs (pattern recognition) changes in TG neurons, we conclude that AD-related neuronal hyperexcitability cannot be accounted for by altered subthreshold dendritic signaling in these neurons but hyperexcitability is related to changes in active membrane properties and network connectivity.

STK33 kinase activity is nonessential in KRAS-dependent cancer cells.

PubMed

Babij, Carol; Zhang, Yihong; Kurzeja, Robert J; Munzli, Anke; Shehabeldin, Amro; Fernando, Manory; Quon, Kim; Kassner, Paul D; Ruefli-Brasse, Astrid A; Watson, Vivienne J; Fajardo, Flordeliza; Jackson, Angela; Zondlo, James; Sun, Yu; Ellison, Aaron R; Plewa, Cherylene A; San, Miguel Tisha; Robinson, John; McCarter, John; Schwandner, Ralf; Judd, Ted; Carnahan, Josette; Dussault, Isabelle

2011-09-01

Despite the prevalence of KRAS mutations in human cancers, there remain no targeted therapies for treatment. The serine-threonine kinase STK33 has been proposed to be required for the survival of mutant KRAS-dependent cell lines, suggesting that small molecule kinase inhibitors of STK33 may be useful to treat KRAS-dependent tumors. In this study, we investigated the role of STK33 in mutant KRAS human cancer cells using RNA interference, dominant mutant overexpression, and small molecule inhibitors. As expected, KRAS downregulation decreased the survival of KRAS-dependent cells. In contrast, STK33 downregulation or dominant mutant overexpression had no effect on KRAS signaling or survival of these cells. Similarly, a synthetic lethal siRNA screen conducted in a broad panel of KRAS wild-type or mutant cells identified KRAS but not STK33 as essential for survival. We also obtained similar negative results using small molecule inhibitors of the STK33 kinase identified by high-throughput screening. Taken together, our findings refute earlier proposals that STK33 inhibition may be a useful therapeutic approach to target human KRAS mutant tumors. ©2011 AACR.

Evaluation of an advanced-practice physiotherapist in triaging patients with lumbar spine pain: surgeon-physiotherapist level of agreement and patient satisfaction.

PubMed

Robarts, Susan; Stratford, Paul; Kennedy, Deborah; Malcolm, Barry; Finkelstein, Joel

2017-08-01

Surgery for lumbar spine pain is indicated for specific etiologies. Given the majority of individuals referred to spine surgeons are not surgical candidates, care delivery is inefficient, with consultations being of limited value for most. Using specially trained physiotherapists in triage is a human resource strategy that may optimize surgeons' time and the patient experience. An advanced-practice physiotherapist (APP) and a surgeon assessed consecutive patients with lumbar spine pain presenting at an academic health centre's spine surgery clinic. The second assessor was blinded to the outcome of the first. We used the κ statistic to evaluate surgeon-APP level of chance-corrected agreement concerning patients' need for a surgical consultation. To assess satisfaction with the APP, patients completed a modified version of the validated Visit-specific Questionnaire. The sample included 102 participants (54 women) with a mean age of 54.3 ± 14.3 years and a mean Oswestry Disability Index score of 35.4 ± 16.6. The assessors' overall agreement was 86%. The κ coefficient for the need for a surgical consultation was 0.69 (95% confidence interval 0.54-0.84). The APP identified that 77% of patients did not require a surgical consultation. Twenty-one patients underwent surgery. Satisfaction scores for the APP were very high (mean score 92 out of 100). In triaging patients with lumbar spine pain, the APP and surgeon had a high level of agreement. An APP performing triage at a surgical centre can effectively reduce wait lists by 70%, reserving surgical consultations for those patients in whom they are indicated.

The efficacy of smartphone‐based mental health interventions for depressive symptoms: a meta‐analysis of randomized controlled trials

PubMed Central

Firth, Joseph; Torous, John; Nicholas, Jennifer; Carney, Rebekah; Pratap, Abhishek; Rosenbaum, Simon; Sarris, Jerome

2017-01-01

The rapid advances and adoption of smartphone technology presents a novel opportunity for delivering mental health interventions on a population scale. Despite multi‐sector investment along with wide‐scale advertising and availability to the general population, the evidence supporting the use of smartphone apps in the treatment of depression has not been empirically evaluated. Thus, we conducted the first meta‐analysis of smartphone apps for depressive symptoms. An electronic database search in May 2017 identified 18 eligible randomized controlled trials of 22 smartphone apps, with outcome data from 3,414 participants. Depressive symptoms were reduced significantly more from smartphone apps than control conditions (g=0.38, 95% CI: 0.24‐0.52, p<0.001), with no evidence of publication bias. Smartphone interventions had a moderate positive effect in comparison to inactive controls (g=0.56, 95% CI: 0.38‐0.74), but only a small effect in comparison to active control conditions (g=0.22, 95% CI: 0.10‐0.33). Effects from smartphone‐only interventions were greater than from interventions which incorporated other human/computerized aspects along the smartphone component, although the difference was not statistically significant. The studies of cognitive training apps had a significantly smaller effect size on depression outcomes (p=0.004) than those of apps focusing on mental health. The use of mood monitoring softwares, or interventions based on cognitive behavioral therapy, or apps incorporating aspects of mindfulness training, did not affect significantly study effect sizes. Overall, these results indicate that smartphone devices are a promising self‐management tool for depression. Future research should aim to distil which aspects of these technologies produce beneficial effects, and for which populations. PMID:28941113

Caspase-9 mediates synaptic plasticity and memory deficits of Danish dementia knock-in mice: caspase-9 inhibition provides therapeutic protection.

PubMed

Tamayev, Robert; Akpan, Nsikan; Arancio, Ottavio; Troy, Carol M; D'Adamio, Luciano

2012-12-10

Mutations in either Aβ Precursor protein (APP) or genes that regulate APP processing, such as BRI2/ITM2B and PSEN1/PSEN2, cause familial dementias. Although dementias due to APP/PSEN1/PSEN2 mutations are classified as familial Alzheimer disease (FAD) and those due to mutations in BRI2/ITM2B as British and Danish dementias (FBD, FDD), data suggest that these diseases have a common pathogenesis involving toxic APP metabolites. It was previously shown that FAD mutations in APP and PSENs promote activation of caspases leading to the hypothesis that aberrant caspase activation could participate in AD pathogenesis. Here, we tested whether a similar mechanism applies to the Danish BRI2/ITM2B mutation. We have generated a genetically congruous mouse model of FDD, called FDD(KI), which presents memory and synaptic plasticity deficits. We found that caspase-9 is activated in hippocampal synaptic fractions of FDD(KI) mice and inhibition of caspase-9 activity rescues both synaptic plasticity and memory deficits. These data directly implicate caspase-9 in the pathogenesis of Danish dementia and suggest that reducing caspase-9 activity is a valid therapeutic approach to treating human dementias.

Caspase-9 mediates synaptic plasticity and memory deficits of Danish dementia knock-in mice: caspase-9 inhibition provides therapeutic protection

PubMed Central

2012-01-01

Background Mutations in either Aβ Precursor protein (APP) or genes that regulate APP processing, such as BRI2/ITM2B and PSEN1/PSEN2, cause familial dementias. Although dementias due to APP/PSEN1/PSEN2 mutations are classified as familial Alzheimer disease (FAD) and those due to mutations in BRI2/ITM2B as British and Danish dementias (FBD, FDD), data suggest that these diseases have a common pathogenesis involving toxic APP metabolites. It was previously shown that FAD mutations in APP and PSENs promote activation of caspases leading to the hypothesis that aberrant caspase activation could participate in AD pathogenesis. Results Here, we tested whether a similar mechanism applies to the Danish BRI2/ITM2B mutation. We have generated a genetically congruous mouse model of FDD, called FDDKI, which presents memory and synaptic plasticity deficits. We found that caspase-9 is activated in hippocampal synaptic fractions of FDDKI mice and inhibition of caspase-9 activity rescues both synaptic plasticity and memory deficits. Conclusion These data directly implicate caspase-9 in the pathogenesis of Danish dementia and suggest that reducing caspase-9 activity is a valid therapeutic approach to treating human dementias. PMID:23217200

75 FR 71444 - Renewal of Charter for the Advisory Committee on Blood Safety and Availability

Federal Register 2010, 2011, 2012, 2013, 2014

2010-11-23

... DEPARTMENT OF HEALTH AND HUMAN SERVICES Renewal of Charter for the Advisory Committee on Blood..., Department of Health and Human Services. ACTION: Notice. SUMMARY: As stipulated by the Federal Advisory Committee Act, as amended (5 U.S.C. App), the U.S. Department of Health and Human Services is hereby...

78 FR 42555 - Federal Council on the Arts and the Humanities, Arts and Artifacts Indemnity Panel Advisory...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-07-16

... NATIONAL FOUNDATION ON THE ARTS AND THE HUMANITIES Federal Council on the Arts and the Humanities, Arts and Artifacts Indemnity Panel Advisory Committee Meeting AGENCY: National Endowment for the... Committee Act (5 U.S.C. App.), notice is hereby given that the Federal Council on the Arts and the...

Canine Degenerative Myelopathy: Biochemical characterization of superoxide dismutase 1 in the first naturally occurring non-human amyotrophic lateral sclerosis model1

PubMed Central

Crisp, Matthew J.; Beckett, Jeffrey; Coates, Joan R.; Miller, Timothy M.

2013-01-01

Mutations in canine superoxide dismutase 1 (SOD1) have recently been shown to cause canine degenerative myelopathy, a disabling neurodegenerative disorder affecting specific breeds of dogs characterized by progressive motor neuron loss and paralysis until death, or more common, euthanasia. This discovery makes canine degenerative myelopathy the first and only naturally occurring non-human model of amyotrophic lateral sclerosis (ALS), closely paralleling the clinical, pathological, and genetic presentation of its human counterpart, SOD1-mediated familial ALS. To further understand the biochemical role that canine SOD1 plays in this disease and how it may be similar to human SOD1, we characterized the only two SOD1 mutations described in affected dogs to date, E40K and T18S. We show that a detergent-insoluble species of mutant SOD1 is present in spinal cords of affected dogs that increases with disease progression. Our in vitro results indicate that both canine SOD1 mutants form enzymatically active dimers, arguing against a loss of function in affected homozygous animals. Further studies show that these mutants, like most human SOD1 mutants, have an increased propensity to form aggregates in cell culture, with 10-20% of cells possessing visible aggregates. Creation of the E40K mutation in human SOD1 recapitulates the normal enzymatic activity but not the aggregation propensity seen with the canine mutant. Our findings lend strong biochemical support to the toxic role of SOD1 in canine degenerative myelopathy and establish close parallels for the role mutant SOD1 plays in both canine and human disorders. PMID:23707216

Canine degenerative myelopathy: biochemical characterization of superoxide dismutase 1 in the first naturally occurring non-human amyotrophic lateral sclerosis model.

PubMed

Crisp, Matthew J; Beckett, Jeffrey; Coates, Joan R; Miller, Timothy M

2013-10-01

Mutations in canine superoxide dismutase 1 (SOD1) have recently been shown to cause canine degenerative myelopathy, a disabling neurodegenerative disorder affecting specific breeds of dogs characterized by progressive motor neuron loss and paralysis until death, or more common, euthanasia. This discovery makes canine degenerative myelopathy the first and only naturally occurring non-human model of amyotrophic lateral sclerosis (ALS), closely paralleling the clinical, pathological, and genetic presentation of its human counterpart, SOD1-mediated familial ALS. To further understand the biochemical role that canine SOD1 plays in this disease and how it may be similar to human SOD1, we characterized the only two SOD1 mutations described in affected dogs to date, E40K and T18S. We show that a detergent-insoluble species of mutant SOD1 is present in spinal cords of affected dogs that increases with disease progression. Our in vitro results indicate that both canine SOD1 mutants form enzymatically active dimers, arguing against a loss of function in affected homozygous animals. Further studies show that these mutants, like most human SOD1 mutants, have an increased propensity to form aggregates in cell culture, with 10-20% of cells possessing visible aggregates. Creation of the E40K mutation in human SOD1 recapitulates the normal enzymatic activity but not the aggregation propensity seen with the canine mutant. Our findings lend strong biochemical support to the toxic role of SOD1 in canine degenerative myelopathy and establish close parallels for the role mutant SOD1 plays in both canine and human disorders. Copyright © 2013 Elsevier Inc. All rights reserved.

Interest in using mobile technology to help self-manage alcohol use among persons living with the human immunodeficiency virus: A Florida Cohort cross-sectional study.

PubMed

Sharpe, J Danielle; Zhou, Zhi; Escobar-Viera, César G; Morano, Jamie P; Lucero, Robert J; Ibañez, Gladys E; Hart, Mark; Cook, Christa L; Cook, Robert L

2018-01-02

Alcohol consumption at hazardous levels is more prevalent and associated with poor health outcomes among persons living with the human immunodeficiency virus (HIV; PLWH). Although PLWH are receptive to using technology to manage health issues, it is unknown whether a cell phone app to self-manage alcohol use would be acceptable among PLWH who drink. The objectives of this study were to determine factors associated with interest in an app to self-manage drinking and to identify differences in baseline mobile technology use among PLWH by drinking level. The study population included 757 PLWH recruited from 2014 to 2016 into the Florida Cohort, an ongoing cohort study investigating the utilization of health services and HIV care outcomes among PLWH. Participants completed a questionnaire examining demographics, substance use, mobile technology use, and other health behaviors. Multivariable logistic regression was used to identify factors significantly associated with interest in an app to self-manage drinking. We also determined whether mobile technology use varied by drinking level. Of the sample, 40% of persons who drink at hazardous levels, 34% of persons who drink at nonhazardous levels, and 19% of persons who do not drink were interested in a self-management app for alcohol use. Multivariable logistic regression analysis indicated that nonhazardous drinking (adjusted odds ratio [AOR] = 1.78; confidence interval [CI 95%]: 1.10-2.88) and hazardous drinking (AOR = 2.58; CI: 1.60-4.16) were associated with interest, controlling for age, gender, education, and drug use. Regarding mobile technology use, most of the sample reported smartphone ownership (56%), text messaging (89%), and at least one cell phone app (69%). Regardless of drinking level, overall mobile technology use among PLWH was moderate, whereas PLWH who consumed alcohol expressed greater interest in a cell phone app to self-manage alcohol use. This indicates that many PLWH who drink would be interested in and prepared for a mobile technology-based intervention to reduce alcohol consumption.

Spatial genetic and morphologic structure of wolves and coyotes in relation to environmental heterogeneity in a Canis hybrid zone.

PubMed

Benson, John F; Patterson, Brent R; Wheeldon, Tyler J

2012-12-01

Eastern wolves have hybridized extensively with coyotes and gray wolves and are listed as a 'species of special concern' in Canada. However, a distinct population of eastern wolves has been identified in Algonquin Provincial Park (APP) in Ontario. Previous studies of the diverse Canis hybrid zone adjacent to APP have not linked genetic analysis with field data to investigate genotype-specific morphology or determine how resident animals of different ancestry are distributed across the landscape in relation to heterogeneous environmental conditions. Accordingly, we studied resident wolves and coyotes in and adjacent to APP to identify distinct Canis types, clarify the extent of the APP eastern wolf population beyond the park boundaries and investigate fine-scale spatial genetic structure and landscape-genotype associations in the hybrid zone. We documented three genetically distinct Canis types within the APP region that also differed morphologically, corresponding to putative gray wolves, eastern wolves and coyotes. We also documented a substantial number of hybrid individuals (36%) that were admixed between 2 or 3 of the Canis types. Breeding eastern wolves were less common outside of APP, but occurred in some unprotected areas where they were sympatric with a diverse combination of coyotes, gray wolves and hybrids. We found significant spatial genetic structure and identified a steep cline extending west from APP where the dominant genotype shifted abruptly from eastern wolves to coyotes and hybrids. The genotypic pattern to the south and northwest was a more complex mosaic of alternating genotypes. We modelled genetic ancestry in response to prey availability and human disturbance and found that individuals with greater wolf ancestry occupied areas of higher moose density and fewer roads. Our results clarify the structure of the Canis hybrid zone adjacent to APP and provide unique insight into environmental conditions influencing hybridization dynamics between wolves and coyotes. © 2012 Blackwell Publishing Ltd.

Candidate genes for panhypopituitarism identified by gene expression profiling

PubMed Central

Mortensen, Amanda H.; MacDonald, James W.; Ghosh, Debashis

2011-01-01

Mutations in the transcription factors PROP1 and PIT1 (POU1F1) lead to pituitary hormone deficiency and hypopituitarism in mice and humans. The dysmorphology of developing Prop1 mutant pituitaries readily distinguishes them from those of Pit1 mutants and normal mice. This and other features suggest that Prop1 controls the expression of genes besides Pit1 that are important for pituitary cell migration, survival, and differentiation. To identify genes involved in these processes we used microarray analysis of gene expression to compare pituitary RNA from newborn Prop1 and Pit1 mutants and wild-type littermates. Significant differences in gene expression were noted between each mutant and their normal littermates, as well as between Prop1 and Pit1 mutants. Otx2, a gene critical for normal eye and pituitary development in humans and mice, exhibited elevated expression specifically in Prop1 mutant pituitaries. We report the spatial and temporal regulation of Otx2 in normal mice and Prop1 mutants, and the results suggest Otx2 could influence pituitary development by affecting signaling from the ventral diencephalon and regulation of gene expression in Rathke's pouch. The discovery that Otx2 expression is affected by Prop1 deficiency provides support for our hypothesis that identifying molecular differences in mutants will contribute to understanding the molecular mechanisms that control pituitary organogenesis and lead to human pituitary disease. PMID:21828248

Treatment with a Small Molecule Mutant IDH1 Inhibitor Suppresses Tumorigenic Activity and Decreases Production of the Oncometabolite 2-Hydroxyglutarate in Human Chondrosarcoma Cells

PubMed Central

Li, Luyuan; Paz, Ana C.; Wilky, Breelyn A.; Johnson, Britt; Galoian, Karina; Rosenberg, Andrew; Hu, Guozhi; Tinoco, Gabriel; Bodamer, Olaf; Trent, Jonathan C.

2015-01-01

Chondrosarcomas are malignant bone tumors that produce cartilaginous matrix. Mutations in isocitrate dehydrogenase enzymes (IDH1/2) were recently described in several cancers including chondrosarcomas. The IDH1 inhibitor AGI-5198 abrogates the ability of mutant IDH1 to produce the oncometabolite D-2 hydroxyglutarate (D-2HG) in gliomas. We sought to determine if treatment with AGI-5198 would similarly inhibit tumorigenic activity and D-2HG production in IDH1-mutant human chondrosarcoma cells. Two human chondrosarcoma cell lines, JJ012 and HT1080 with endogenous IDH1 mutations and a human chondrocyte cell line C28 with wild type IDH1 were employed in our study. Mutation analysis of IDH was performed by PCR-based DNA sequencing, and D-2HG was detected using tandem mass spectrometry. We confirmed that JJ012 and HT1080 harbor IDH1 R132G and R132C mutation, respectively, while C28 has no mutation. D-2HG was detectable in cell pellets and media of JJ012 and HT1080 cells, as well as plasma and urine from an IDH-mutant chondrosarcoma patient, which decreased after tumor resection. AGI-5198 treatment decreased D-2HG levels in JJ012 and HT1080 cells in a dose-dependent manner, and dramatically inhibited colony formation and migration, interrupted cell cycling, and induced apoptosis. In conclusion, our study demonstrates anti-tumor activity of a mutant IDH1 inhibitor in human chondrosarcoma cell lines, and suggests that D-2HG is a potential biomarker for IDH mutations in chondrosarcoma cells. Thus, clinical trials of mutant IDH inhibitors are warranted for patients with IDH-mutant chondrosarcomas. PMID:26368816

Developing an eBook-Integrated High-Fidelity Mobile App Prototype for Promoting Child Motor Skills and Taxonomically Assessing Children’s Emotional Responses Using Face and Sound Topology

PubMed Central

Brown, William; Liu, Connie; John, Rita Marie; Ford, Phoebe

2014-01-01

Developing gross and fine motor skills and expressing complex emotion is critical for child development. We introduce “StorySense”, an eBook-integrated mobile app prototype that can sense face and sound topologies and identify movement and expression to promote children’s motor skills and emotional developmental. Currently, most interactive eBooks on mobile devices only leverage “low-motor” interaction (i.e. tapping or swiping). Our app senses a greater breath of motion (e.g. clapping, snapping, and face tracking), and dynamically alters the storyline according to physical responses in ways that encourage the performance of predetermined motor skills ideal for a child’s gross and fine motor development. In addition, our app can capture changes in facial topology, which can later be mapped using the Facial Action Coding System (FACS) for later interpretation of emotion. StorySense expands the human computer interaction vocabulary for mobile devices. Potential clinical applications include child development, physical therapy, and autism. PMID:25954336

Fused pulmonary lobes is a rat model of human Fraser syndrome

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kiyozumi, Daiji; Nakano, Itsuko; Takahashi, Ken L.

Highlights: {yields} Fused pulmonary lobes (fpl) mutant rats exhibit similar phenotypes to Fraser syndrome. {yields} The fpl gene harbors a nonsense mutation in Fraser syndrome-associated gene Frem2. {yields} Fpl mutant is defined as a first model of human Fraser syndrome in rats. -- Abstract: Fused pulmonary lobes (fpl) is a mutant gene that is inherited in an autosomal recessive manner and causes various developmental defects, including fusion of pulmonary lobes, and eyelid and digit anomalies in rats. Since these developmental defects closely resemble those observed in patients with Fraser syndrome, a recessive multiorgan disorder, and its model animals, we investigatedmore » whether the abnormal phenotypes observed in fpl/fpl mutant rats are attributable to a genetic disorder similar to Fraser syndrome. At the epidermal basement membrane in fpl/fpl mutant neonates, the expression of QBRICK, a basement membrane protein whose expression is attenuated in Fraser syndrome model mice, was greatly diminished compared with control littermates. Quantitative RT-PCR analyses of Fraser syndrome-related genes revealed that Frem2 transcripts were markedly diminished in QBRICK-negative embryos. Genomic DNA sequencing of the fpl/fpl mutant identified a nonsense mutation that introduced a stop codon at serine 2005 in Frem2. These findings indicate that the fpl mutant is a rat model of human Fraser syndrome.« less

A low, adaptive dose of gamma-rays reduced the number and altered the spectrum of S1- mutants in human-hamster hybrid AL cells

NASA Technical Reports Server (NTRS)

Ueno, A. M.; Vannais, D. B.; Gustafson, D. L.; Wong, J. C.; Waldren, C. A.

1996-01-01

We examined the effects of a low, adaptive dose of 137Cs-gamma-irradiation (0.04 Gy) on the number and kinds of mutants induced in AL human-hamster hybrid cells by a later challenge dose of 4 Gy. The yield of S1- mutants was significantly less (by 53%) after exposure to both the adaptive and challenge doses compared to the challenge dose alone. The yield of hprt- mutants was similarly decreased. Incubation with cycloheximide (CX) or 3-aminobenzamide largely negated the decrease in mutant yield. The adaptive dose did not perturb the cell cycle, was not cytotoxic, and did not of itself increase the mutant yield above background. The adaptive dose did, however, alter the spectrum of S1- mutants from populations exposed only to the adaptive dose, as well as affecting the spectrum of S1- mutants generated by the challenge dose. The major change in both cases was a significant increase in the proportion of complex mutations compared to small mutations and simple deletions.

Targeting neuronal MAPK14/p38α activity to modulate autophagy in the Alzheimer disease brain.

PubMed

Alam, John; Scheper, Wiep

2016-12-01

Dysregulated autophagic-lysosomal degradation of proteins has been linked to the most common genetic defect in familial Alzheimer disease, and has been correlated with disease progression in both human disease and in animal models. Recently, it was demonstrated that the expression of MAPK14/p38α protein is upregulated in the brain of APP-PS1 transgenic Alzheimer mouse and further that genetic deficiency of Mapk14 in the APP-PS1 mouse stimulates macroautophagy/autophagy, which then leads to reduced amyloid pathology via increasing autophagic-lysosomal degradation of BACE1. The findings resolve at least in the context of the APP-PS1 mouse, prior conflicting in vitro observations that have implicated MAPK14 in autophagic processes, and indicate that inhibition of MAPK14 enzyme activity has potential as a therapeutic approach to mitigate a critical physiological defect within neurons of the Alzheimer disease brain. Moreover, the findings suggest that biomarkers of BACE1 activity could be utilized to evaluate the effects of MAPK14 inhibition and other autophagy-inducing therapeutic approaches in human clinical studies, thereby potentially facilitating the clinical development of such agents.

Regional acetylcholinesterase activity and its correlation with behavioral performances in 15-month old transgenic mice expressing the human C99 fragment of APP.

PubMed

Dumont, M; Lalonde, R; Ghersi-Egea, J-F; Fukuchi, K; Strazielle, C

2006-09-01

In addition to Abeta plaques and neurofibrillary tangles, Alzheimer's disease (AD) is characterized by increased brain levels of APP C-terminal fragments. In the present investigation, the cholinergic innervation in forebrain regions of transgenic mice (Tg13592) expressing the human betaAPP C99 fragment was compared to that of non-transgenic controls by measuring the activity of the non-specific catabolic enzyme, acetylcholinesterase (AChE). The AchE activity of Tg13592 mice was altered in several regions implicated in the functional loop of regulation between septum and hippocampus, vulnerable in Alzheimer pathology and critically involved in cognitive functions. In particular, AChE activity was upregulated in three basal forebrain regions containing cholinergic cell bodies, prelimbic cortex, anterior subiculum, and paraventricular thalamus, but downregulated in lateral septum and reticular thalamus. The increased activity in medial septum and anterior subiculum was linearly correlated with poor performances in a spatial learning task, possibly due to cell stress mechanisms. Because of some similarities in terms of neurochemistry and behavior, this mouse model may be of use for studying prodromal AD.

Targeting neuronal MAPK14/p38α activity to modulate autophagy in the Alzheimer disease brain

PubMed Central

Alam, John; Scheper, Wiep

2016-01-01

ABSTRACT Dysregulated autophagic-lysosomal degradation of proteins has been linked to the most common genetic defect in familial Alzheimer disease, and has been correlated with disease progression in both human disease and in animal models. Recently, it was demonstrated that the expression of MAPK14/p38α protein is upregulated in the brain of APP-PS1 transgenic Alzheimer mouse and further that genetic deficiency of Mapk14 in the APP-PS1 mouse stimulates macroautophagy/autophagy, which then leads to reduced amyloid pathology via increasing autophagic-lysosomal degradation of BACE1. The findings resolve at least in the context of the APP-PS1 mouse, prior conflicting in vitro observations that have implicated MAPK14 in autophagic processes, and indicate that inhibition of MAPK14 enzyme activity has potential as a therapeutic approach to mitigate a critical physiological defect within neurons of the Alzheimer disease brain. Moreover, the findings suggest that biomarkers of BACE1 activity could be utilized to evaluate the effects of MAPK14 inhibition and other autophagy-inducing therapeutic approaches in human clinical studies, thereby potentially facilitating the clinical development of such agents. PMID:27715387

78 FR 12063 - Announcement of Requirements and Registration for healthfinder.gov Mobile App Challenge; Correction

Federal Register 2010, 2011, 2012, 2013, 2014

2013-02-21

... DEPARTMENT OF HEALTH AND HUMAN SERVICES Announcement of Requirements and Registration for..., Office of the Assistant Secretary for Health, Office of the Secretary, Department of Health and Human... subsection of the terms and conditions. FOR FURTHER INFORMATION CONTACT: Silje Lier, MPH, Communication...

Human Cytomegalovirus UL99-Encoded pp28 Is Required for the Cytoplasmic Envelopment of Tegument-Associated Capsids

PubMed Central

Silva, Maria C.; Yu, Qian-Chun; Enquist, Lynn; Shenk, Thomas

2003-01-01

The human cytomegalovirus UL99-encoded pp28 is a myristylated phosphoprotein that is a constituent of the virion. The pp28 protein is positioned within the tegument of the virus particle, a protein structure that resides between the capsid and envelope. In the infected cell, pp28 is found in a cytoplasmic compartment derived from the Golgi apparatus, where the virus buds into vesicles to acquire its final membrane. We have constructed two mutants of human cytomegalovirus that fail to produce the pp28 protein, a substitution mutant (BADsubUL99) and a point mutant (BADpmUL99), and we have propagated them by complementation in pp28-expressing fibroblasts. Both mutant viruses are profoundly defective for growth in normal fibroblasts; no infectious virus could be detected after infection. Whereas normal levels of viral DNA and late proteins were observed in mutant virus-infected cells, large numbers of tegument-associated capsids accumulated in the cytoplasm that failed to acquire an envelope. We conclude that pp28 is required for the final envelopment of the human cytomegalovirus virion in the cytoplasm. PMID:12970444

Tumours with class 3 BRAF mutants are sensitive to the inhibition of activated RAS.

PubMed

Yao, Zhan; Yaeger, Rona; Rodrik-Outmezguine, Vanessa S; Tao, Anthony; Torres, Neilawattie M; Chang, Matthew T; Drosten, Matthias; Zhao, Huiyong; Cecchi, Fabiola; Hembrough, Todd; Michels, Judith; Baumert, Hervé; Miles, Linde; Campbell, Naomi M; de Stanchina, Elisa; Solit, David B; Barbacid, Mariano; Taylor, Barry S; Rosen, Neal

2017-08-10

Approximately 200 BRAF mutant alleles have been identified in human tumours. Activating BRAF mutants cause feedback inhibition of GTP-bound RAS, are RAS-independent and signal either as active monomers (class 1) or constitutively active dimers (class 2). Here we characterize a third class of BRAF mutants-those that have impaired kinase activity or are kinase-dead. These mutants are sensitive to ERK-mediated feedback and their activation of signalling is RAS-dependent. The mutants bind more tightly than wild-type BRAF to RAS-GTP, and their binding to and activation of wild-type CRAF is enhanced, leading to increased ERK signalling. The model suggests that dysregulation of signalling by these mutants in tumours requires coexistent mechanisms for maintaining RAS activation despite ERK-dependent feedback. Consistent with this hypothesis, melanomas with these class 3 BRAF mutations also harbour RAS mutations or NF1 deletions. By contrast, in lung and colorectal cancers with class 3 BRAF mutants, RAS is typically activated by receptor tyrosine kinase signalling. These tumours are sensitive to the inhibition of RAS activation by inhibitors of receptor tyrosine kinases. We have thus defined three distinct functional classes of BRAF mutants in human tumours. The mutants activate ERK signalling by different mechanisms that dictate their sensitivity to therapeutic inhibitors of the pathway.

Functional repair of p53 mutation in colorectal cancer cells using trans-splicing.

PubMed

He, Xingxing; Liao, Jiazhi; Liu, Fang; Yan, Junwei; Yan, Jingjun; Shang, Haitao; Dou, Qian; Chang, Ying; Lin, Jusheng; Song, Yuhu

2015-02-10

Mutation in the p53 gene is arguably the most frequent type of gene-specific alterations in human cancers. Current p53-based gene therapy contains the administration of wt-p53 or the suppression of mutant p53 expression in p53-defective cancer cells. . We hypothesized that trans-splicing could be exploited as a tool for the correction of mutant p53 transcripts in p53-mutated human colorectal cancer (CRC) cells. In this study, the plasmids encoding p53 pre-trans-splicing molecules (PTM) were transfected into human CRC cells carrying p53 mutation. The plasmids carrying p53-PTM repaired mutant p53 transcripts in p53-mutated CRC cells, which resulted in a reduction in mutant p53 transcripts and an induction of wt-p53 simultaneously. Intratumoral administration of adenovirus vectors carrying p53 trans-splicing cassettes suppressed the growth of tumor xenografts. Repair of mutant p53 transcripts by trans-splicing induced cell-cycle arrest and apoptosis in p53-defective colorectal cancer cells in vitro and in vivo. In conclusion, the present study demonstrated for the first time that trans-splicing was exploited as a strategy for the repair of mutant p53 transcripts, which revealed that trans-splicing would be developed as a new therapeutic approach for human colorectal cancers carrying p53 mutation.

Isolation and characterization of a pigmentless-conidium mutant of Aspergillus fumigatus with altered conidial surface and reduced virulence.

PubMed Central

Jahn, B; Koch, A; Schmidt, A; Wanner, G; Gehringer, H; Bhakdi, S; Brakhage, A A

1997-01-01

Aspergillus fumigatus is an important pathogen of immunocompromised hosts, causing pneumonia and invasive disseminated disease with high mortality. The factors contributing to the predominance of A. fumigatus as an opportunistic pathogen are largely unknown. Since the survival of conidia in the host is a prerequisite for establishing disease, we have been attempting to identify factors which are associated with conidia and, simultaneously, important for infection. Therefore, an A. fumigatus mutant strain (white [W]) lacking conidial pigmentation was isolated. Scanning electron microscopy revealed that conidia of the W mutant also differed in their surface morphology from those of the wild type (WT). Mutant (W) and WT conidia were compared with respect to their capacities to stimulate an oxidative response in human phagocytes, their intracellular survival in human monocytes, and virulence in a murine animal model. Luminol-dependent chemiluminescence was 10-fold higher when human neutrophils or monocytes were challenged with W conidia compared with WT conidia. Furthermore, mutant conidia were more susceptible to killing by oxidants in vitro and were more efficiently damaged by human monocytes in vitro than WT conidia. In a murine animal model, the W mutant strain showed reduced virulence compared with the WT. A reversion analysis of the W mutant demonstrated that all phenotypes associated with the W mutant, i.e., altered conidial surface, amount of reactive oxygen species release, susceptibility to hydrogen peroxide, and reduced virulence in an murine animal model, coreverted in revertants which had regained the ability to produce green spores. This finding strongly suggests that the A. fumigatus mutant described here carries a single mutation which caused all of the observed phenotypes. Our results suggest that the conidium pigment or a structural feature related to it contributes to fungal resistance against host defense mechanisms in A. fumigatus infections. PMID:9393803

The Na+/H+ exchanger NHE6 modulates endosomal pH to control processing of amyloid precursor protein in a cell culture model of Alzheimer disease.

PubMed

Prasad, Hari; Rao, Rajini

2015-02-27

Early intervention may be key to safe and effective therapies in patients with Alzheimer disease. Endosomal dysfunction is an early step in neurodegeneration. Endosomes are a major site of production of Aβ peptide from the processing of amyloid precursor protein (APP) by clipping enzymes (β- and γ-secretases). The β-secretase enzyme BACE1 requires acidic lumen pH for optimum function, and acid pH promotes Aβ aggregation. The Na(+)/H(+) exchanger NHE6 provides a leak pathway for protons, limiting luminal acidification by proton pumps. Like APP, NHE6 expression was induced upon differentiation of SH-SY5Y neuroblastoma cells and localized to an endosomal compartment. Therefore, we investigated whether NHE6 expression altered APP localization and processing in a stably transfected cell culture model of human APP expression. We show that co-expression with NHE6 or treatment with the Na(+)/H(+) ionophore monensin shifted APP away from the trans-Golgi network into early and recycling endosomes in HEK293 cells. NHE6 alkalinized the endosomal lumen, similar to monensin, and significantly attenuated APP processing and Aβ secretion. In contrast, Aβ production was elevated upon NHE6 knockdown. We show that NHE6 transcript and protein levels are lowered in Alzheimer brains relative to control. These findings, taken together with emerging genetic evidence linking endosomal Na(+)/H(+) exchangers with Alzheimer disease, suggest that proton leak pathways may regulate Aβ generation and contribute to disease etiology. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

The Na+/H+ Exchanger NHE6 Modulates Endosomal pH to Control Processing of Amyloid Precursor Protein in a Cell Culture Model of Alzheimer Disease*

PubMed Central

Prasad, Hari; Rao, Rajini

2015-01-01

Early intervention may be key to safe and effective therapies in patients with Alzheimer disease. Endosomal dysfunction is an early step in neurodegeneration. Endosomes are a major site of production of Aβ peptide from the processing of amyloid precursor protein (APP) by clipping enzymes (β- and γ-secretases). The β-secretase enzyme BACE1 requires acidic lumen pH for optimum function, and acid pH promotes Aβ aggregation. The Na+/H+ exchanger NHE6 provides a leak pathway for protons, limiting luminal acidification by proton pumps. Like APP, NHE6 expression was induced upon differentiation of SH-SY5Y neuroblastoma cells and localized to an endosomal compartment. Therefore, we investigated whether NHE6 expression altered APP localization and processing in a stably transfected cell culture model of human APP expression. We show that co-expression with NHE6 or treatment with the Na+/H+ ionophore monensin shifted APP away from the trans-Golgi network into early and recycling endosomes in HEK293 cells. NHE6 alkalinized the endosomal lumen, similar to monensin, and significantly attenuated APP processing and Aβ secretion. In contrast, Aβ production was elevated upon NHE6 knockdown. We show that NHE6 transcript and protein levels are lowered in Alzheimer brains relative to control. These findings, taken together with emerging genetic evidence linking endosomal Na+/H+ exchangers with Alzheimer disease, suggest that proton leak pathways may regulate Aβ generation and contribute to disease etiology. PMID:25561733

Cell Transformation by PTP1B Truncated Mutants Found in Human Colon and Thyroid Tumors.

PubMed

Mei, Wenhan; Wang, Kemin; Huang, Jian; Zheng, Xinmin

2016-01-01

Expression of wild-type protein tyrosine phosphatase (PTP) 1B may act either as a tumor suppressor by dysregulation of protein tyrosine kinases or a tumor promoter through Src dephosphorylation at Y527 in human breast cancer cells. To explore whether mutated PTP1B is involved in human carcinogenesis, we have sequenced PTP1B cDNAs from human tumors and found splice mutations in ~20% of colon and thyroid tumors. The PTP1BΔE6 mutant expressed in these two tumor types and another PTP1BΔE5 mutant expressed in colon tumor were studied in more detail. Although PTP1BΔE6 revealed no phosphatase activity compared with wild-type PTP1B and the PTP1BΔE5 mutant, its expression induced oncogenic transformation of rat fibroblasts without Src activation, indicating that it involved signaling pathways independent of Src. The transformed cells were tumourigenic in nude mice, suggesting that the PTP1BΔE6 affected other molecule(s) in the human tumors. These observations may provide a novel therapeutic target for colon and thyroid cancer.

An efficient deletion mutant packaging system for defective herpes simplex virus vectors: Potential applications to human gene therapy and neuronal physiology

DOE Office of Scientific and Technical Information (OSTI.GOV)

Geller, A.I.; Keyomarsi, K.; Bryan, J.

1990-11-01

The authors have previously described a defective herpes simplex virus (HSV-1) vector system that permits that introduction of virtually any gene into nonmitotic cells. pHSVlac, the prototype vector, stably expresses Escherichia coli {beta}-galactosidase from a constitutive promoter in many human cell lines, in cultured rat neurons from throughout the nervous system, and in cells in the adult rat brain. HSV-1 vectors expressing other genes may prove useful for studying neuronal physiology or performing human gene therapy for neurological diseases, such as Parkinson disease or brain tumors. A HSV-1 temperature-sensitive (ts) mutant, ts K, has been used as helper virus; tsmore » mutants revert to wild type. In contrast, HSV-1 deletion mutants essentially cannot revert to wild type; therefore, use of a deletion mutant as helper virus might permit human gene therapy with HSV-1 vectors. They now report an efficient packaging system for HSV-1 VECTORS USING A DELETION MUTANT, d30EBA, as helper virus; virus is grown on the complementing cell line M64A. pHSVlac virus prepared using the deletion mutant packaging system stably expresses {beta}-galactosidase in cultured rat sympathetic neurons and glia. Both D30EBA and ts K contain a mutation in the IE3 gene of HSV-1 strain 17 and have the same phenotype; therefore, changing the helper virus from ts K to D30EBA does not alter the host range or other properties of the HSV-1 vector system.« less

Trehalose protects from aggravation of amyloid pathology induced by isoflurane anesthesia in APP(swe) mutant mice.

PubMed

Perucho, Juan; Casarejos, Maria J; Gomez, Ana; Solano, Rosa M; de Yébenes, Justo Garcia; Mena, Maria A

2012-03-01

There is an open controversy about the role of surgery and anesthesia in the pathogenesis of Alzheimer's disease (AD). Clinical studies have shown a high prevalence of these procedures in subjects with AD but the interpretation of these studies is difficult because of the co-existence of multiple variables. Experimental studies in vitro and in vivo have shown that small molecular weight volatile anesthetics enhance amyloidogenesis in vitro and produce behavioral deficits and brain lesions similar to those found in patients with AD. We examined the effect of co-treatment with trehalose on isoflurane-induced amyloidogenesis in mice. WT and APP(swe) mice, of 11 months of age, were exposed to 1% isoflurane, 3 times, for 1.5 hours each time and sacrificed 24 hours after their last exposure to isoflurane. The right hemi-brain was used for histological analysis and the contra-lateral hemi-brain used for biochemical studies. In this study, we have shown that repetitive exposure to isoflurane in pre-symptomatic mature APP(swe) mice increases apoptosis in hippocampus and cerebral cortex, enhances astrogliosis and the expression of GFAP and that these effects are prevented by co-treatment with trehalose, a disaccharide with known effects as enhancer of autophagy. We have also confirmed that in our model the co-treatment with trehalose increases the expression of autophagic markers as well as the expression of chaperones. Cotreatment with trehalose reduces the levels of β amyloid peptide aggregates, tau plaques and levels of phospho-tau. Our study, therefore, provides new therapeutic avenues that could help to prevent the putative pro-amyloidogenic properties of small volatile anesthetics.

The full-length form of the Drosophila amyloid precursor protein is involved in memory formation.

PubMed

Bourdet, Isabelle; Preat, Thomas; Goguel, Valérie

2015-01-21

The APP plays a central role in AD, a pathology that first manifests as a memory decline. Understanding the role of APP in normal cognition is fundamental in understanding the progression of AD, and mammalian studies have pointed to a role of secreted APPα in memory. In Drosophila, we recently showed that APPL, the fly APP ortholog, is required for associative memory. In the present study, we aimed to characterize which form of APPL is involved in this process. We show that expression of a secreted-APPL form in the mushroom bodies, the center for olfactory memory, is able to rescue the memory deficit caused by APPL partial loss of function. We next assessed the impact on memory of the Drosophila α-secretase kuzbanian (KUZ), the enzyme initiating the nonamyloidogenic pathway that produces secreted APPLα. Strikingly, KUZ overexpression not only failed to rescue the memory deficit caused by APPL loss of function, it exacerbated this deficit. We further show that in addition to an increase in secreted-APPL forms, KUZ overexpression caused a decrease of membrane-bound full-length species that could explain the memory deficit. Indeed, we observed that transient expression of a constitutive membrane-bound mutant APPL form is sufficient to rescue the memory deficit caused by APPL reduction, revealing for the first time a role of full-length APPL in memory formation. Our data demonstrate that, in addition to secreted APPL, the noncleaved form is involved in memory, raising the possibility that secreted and full-length APPL act together in memory processes. Copyright © 2015 the authors 0270-6474/15/351043-09$15.00/0.

Differential effects on enzyme stability and kinetic parameters of mutants related to human triosephosphate isomerase deficiency.

PubMed

Cabrera, Nallely; Torres-Larios, Alfredo; García-Torres, Itzhel; Enríquez-Flores, Sergio; Perez-Montfort, Ruy

2018-06-01

Human triosephosphate isomerase (TIM) deficiency is a very rare disease, but there are several mutations reported to be causing the illness. In this work, we produced nine recombinant human triosephosphate isomerases which have the mutations reported to produce TIM deficiency. These enzymes were characterized biophysically and biochemically to determine their kinetic and stability parameters, and also to substitute TIM activity in supporting the growth of an Escherichia coli strain lacking the tim gene. Our results allowed us to rate the deleteriousness of the human TIM mutants based on the type and severity of the alterations observed, to classify four "unknown severity mutants" with altered residues in positions 62, 72, 122 and 154 and to explain in structural terms the mutation V231M, the most affected mutant from the kinetic point of view and the only homozygous mutation reported besides E104D. Copyright © 2018 Elsevier B.V. All rights reserved.

Acute γ-secretase Inhibition of Nonhuman Primate CNS Shifts Amyloid Precursor Protein (APP) Metabolism from Amyloid-β Production to Alternative APP Fragments without Amyloid-β Rebound

PubMed Central

Cook, Jacquelynn J.; Wildsmith, Kristin R.; Gilberto, David B.; Holahan, Marie A.; Kinney, Gene G.; Mathers, Parker D.; Michener, Maria S.; Price, Eric A.; Shearman, Mark S.; Simon, Adam J.; Wang, Jennifer X.; Wu, Guoxin; Yarasheski, Kevin E.; Bateman, Randall J.

2010-01-01

The accumulation of amyloid beta (Aβ) in Alzheimer’s disease is caused by an imbalance of production and clearance, which leads to increased soluble Aβ species and extracellular plaque formation in the brain. Multiple Aβ-lowering therapies are currently in development: an important goal is to characterize the molecular mechanisms of action and effects on physiological processing of Aβ, as well as other amyloid precursor protein (APP) metabolites, in models which approximate human Aβ physiology. To this end, we report the translation of the human in vivo stable-isotope-labeling kinetics (SILK) method to a rhesus monkey cisterna magna ported (CMP) nonhuman primate model, and use the model to test the mechanisms of action of a γ-secretase inhibitor (GSI). A major concern of inhibiting the enzymes which produce Aβ (β- and γ-secretase) is that precursors of Aβ may accumulate and cause a rapid increase in Aβ production when enzyme inhibition discontinues. In this study, the GSI MK-0752 was administered to conscious CMP rhesus monkeys in conjunction with in vivo stable isotope labeling, and dose-dependently reduced newly generated CNS Aβ. In contrast to systemic Aβ metabolism, CNS Aβ production was not increased after the GSI was cleared. These results indicate that most of the CNS APP was metabolized to products other than Aβ, including C-terminal truncated forms of Aβ: 1–14, 1–15 and 1–16; this demonstrates an alternative degradation pathway for CNS amyloid precursor protein during γ-secretase inhibition. PMID:20463236

Faster and Riskier? Online Context of Sex Seeking Among Men Who Have Sex With Men in China.

PubMed

Cao, Bolin; Liu, Chuncheng; Stein, Gabriella; Tang, Weiming; Best, John; Zhang, Ye; Yang, Bin; Huang, Shujie; Wei, Chongyi; Tucker, Joseph D

2017-04-01

Many men who have sex with men (MSM) seek sex partners online, creating barriers and opportunities for human immunodeficiency virus prevention. The purpose of this study was to examine the characteristics of MSM and the risks associated with seeking sex through websites, gay apps, and both platforms in China. Data were collected through a cross-sectional online survey from September through October 2014 from 3 large gay Web portals. Sociodemographic information, sexual behaviors, and online sex seeking behaviors were measured. Multinomial logistic regression was performed to compare sexual risk behaviors among website users, gay app users, and men who used both platforms. Of the 1201 participants, 377 (31.4%) were website-only users, 487 (40.5%) were gay app-only users, and 337 (28.0%) were men who used both platforms. These 3 MSM subgroups have distinct sociodemographic characteristics. Overall, 57.6% of participants reported having engaged in condomless anal sex with their last male partner in the past 6 months, but there was no significant difference in condomless sex between the 3 groups. Men who used both platforms viewed more sexually transmitted disease-related messages than website-only users (adjusted odds ratio, 2.19; 95% confidence interval, 1.57-3.05). Condom usage behaviors were unaffected by the medium through which sexual partners were found. However, the high frequency of condomless sex suggests that websites and gay apps are both risk environments. This study suggests using multiple platforms for human immunodeficiency virus/sexually transmitted disease social media interventions may be useful.

Amyloid β-induced impairments on mitochondrial dynamics, hippocampal neurogenesis, and memory are restored by phosphodiesterase 7 inhibition.

PubMed

Bartolome, Fernando; de la Cueva, Macarena; Pascual, Consuelo; Antequera, Desiree; Fernandez, Tamara; Gil, Carmen; Martinez, Ana; Carro, Eva

2018-02-20

The phosphodiesterase (PDE) 7 inhibitor S14 is a cell-permeable small heterocyclic molecule that is able to cross the blood-brain barrier. We previously found that intraperitoneal treatment with S14 exerted neuroprotection in an Alzheimer's disease (AD) model (in APP/PS1 mice). The objective of this study was to investigate the neurogenic and cellular effects of oral administration of S14 on amyloid β (Aβ) overload. We orally administered the PDE7 inhibitor S14 (15 mg/kg/day) or vehicle in 6-month-old APP/PS1 mice. After 5 weeks of S14 treatment, we evaluated cognitive functions and brain tissues. We also assessed the effects of S14 on the Aβ-treated human neuroblastome SH-SY5Y cell line. Targeting the cyclic adenosine monophosphate (cAMP)/cAMP-response element binding protein (CREB) pathway, S14 rescued cognitive decline by improving hippocampal neurogenesis in APP/PS1 transgenic mice. Additionally, S14 treatment reverted the Aβ-induced reduction in mitochondrial mass in APP/PS1 mice and in the human neuroblastoma SH-SY5Y cells co-exposed to Aβ. The restoration of the mitochondrial mass was found to be a dual effect of S14: a rescue of the mitochondrial biogenesis formerly slowed down by Aβ overload, and a reduction in the Aβ-increased mitochondrial clearance mechanism of mitophagy. Here, we show new therapeutic effects of the PDE7 inhibitor, confirming S14 as a potential therapeutic drug for AD.

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.

TB Mobile: a mobile app for anti-tuberculosis molecules with known targets

PubMed Central

2013-01-01

Background An increasing number of researchers are focused on strategies for developing inhibitors of Mycobacterium tuberculosis (Mtb) as tuberculosis (TB) drugs. Results In order to learn from prior work we have collated information on molecules screened versus Mtb and their targets which has been made available in the Collaborative Drug Discovery (CDD) database. This dataset contains published data on target, essentiality, links to PubMed, TBDB, TBCyc (which provides a pathway-based visualization of the entire cellular biochemical network) and human homolog information. The development of mobile cheminformatics apps could lower the barrier to drug discovery and promote collaboration. Therefore we have used this set of over 700 molecules screened versus Mtb and their targets to create a free mobile app (TB Mobile) that displays molecule structures and links to the bioinformatics data. By input of a molecular structures and performing a similarity search within the app we can infer potential targets or search by targets to retrieve compounds known to be active. Conclusions TB Mobile may assist researchers as part of their workflow in identifying potential targets for hits generated from phenotypic screening and in prioritizing them for further follow-up. The app is designed to lower the barriers to accessing this information, so that all researchers with an interest in combatting this deadly disease can use it freely to the benefit of their own efforts. PMID:23497706

GEnomes Management Application (GEM.app): a new software tool for large-scale collaborative genome analysis.

PubMed

Gonzalez, Michael A; Lebrigio, Rafael F Acosta; Van Booven, Derek; Ulloa, Rick H; Powell, Eric; Speziani, Fiorella; Tekin, Mustafa; Schüle, Rebecca; Züchner, Stephan

2013-06-01

Novel genes are now identified at a rapid pace for many Mendelian disorders, and increasingly, for genetically complex phenotypes. However, new challenges have also become evident: (1) effectively managing larger exome and/or genome datasets, especially for smaller labs; (2) direct hands-on analysis and contextual interpretation of variant data in large genomic datasets; and (3) many small and medium-sized clinical and research-based investigative teams around the world are generating data that, if combined and shared, will significantly increase the opportunities for the entire community to identify new genes. To address these challenges, we have developed GEnomes Management Application (GEM.app), a software tool to annotate, manage, visualize, and analyze large genomic datasets (https://genomics.med.miami.edu/). GEM.app currently contains ∼1,600 whole exomes from 50 different phenotypes studied by 40 principal investigators from 15 different countries. The focus of GEM.app is on user-friendly analysis for nonbioinformaticians to make next-generation sequencing data directly accessible. Yet, GEM.app provides powerful and flexible filter options, including single family filtering, across family/phenotype queries, nested filtering, and evaluation of segregation in families. In addition, the system is fast, obtaining results within 4 sec across ∼1,200 exomes. We believe that this system will further enhance identification of genetic causes of human disease. © 2013 Wiley Periodicals, Inc.

Effects of minimal exposures to atmospheric pressure plasma on the activity of Salmonella Typhimurium: Deactivation of bacterial motility and suppression of host-cell invasion.

PubMed

Park, Jin-Sung; Kim, Kijung; Han, Je-Hyun; Gweon, Bomi; Ko, Ung Hyun; Yoo, Suk Jae; Choe, Wonho; Shin, Jennifer H

2016-09-01

Atmospheric pressure plasma (APP) has been shown effective in sterilization by reducing the number of viable microbes during surface cleaning, food processing, or human tissue treatment. For safe conduct, the majority of previous research focused on complete abolition of microbes, which may require severe treatments. Our aim is to investigate the minimal treatment conditions necessary for effective inactivation of bacteria in such a manner that the APP treated bacteria would not be able to harm the host cells. For this, we ought to identify the objective criteria to make the bacteria dysfunctional. We choose the motile properties and the host-cell invasion capability as two measures to quantify the pathogenic state of bacteria. In this paper, we investigated how the APP treatment in a minimal dosage affects the activity of Salmonella Typhimurium. At 100 W and 15 kHz for 20 s, the APP treatment effectively suppressed active "run and tumble" type motility and induced formation of abnormally long structures. With 20 s exposure, the bacterial cells failed to cause pyroptosis in the host cells with >90% survival after 12 h of co-incubation. Our results suggest novel measures to evaluate the functional pathogenic state for identifying safe APP treatment conditions. Copyright © 2016 Elsevier Inc. All rights reserved.

Repeat propofol anesthesia does not exacerbate plaque deposition or synapse loss in APP/PS1 Alzheimer's disease mice.

PubMed

Woodhouse, Adele; Fernandez-Martos, Carmen Maria; Atkinson, Rachel Alice Kathryn; Hanson, Kelsey Anne; Collins, Jessica Marie; O'Mara, Aidan Ryan; Terblanche, Nico; Skinner, Marcus Welby; Vickers, James Clement; King, Anna Elizabeth

2018-04-25

There is increasing interest in whether anesthetic agents affect the risk or progression of Alzheimer's disease (AD). To mitigate many of the methodological issues encountered in human retrospective cohort studies we have used a transgenic model of AD to investigate the effect of propofol on AD pathology. Six month-old amyloid precursor protein/presenilin 1 (APP/PS1) transgenic AD mice and control mice were exposed to 3 doses of propofol (200 mg/kg) or vehicle, delivered at monthly intervals. There was no difference in the extent of β-amyloid (Aβ) immunolabeled plaque deposition in APP/PS1 mice in vehicle versus propofol treatment groups. We also detected no difference in plaque-associated synapse loss in APP/PS1 mice following repeat propofol exposure relative to vehicle. Western blotting indicated that there was no difference in post-synaptic density protein 95, synaptophysin or glutamic acid decarboxylase 65/67 expression in control or APP/PS1 mice subjected to repeat propofol treatment relative to vehicle. These data suggest that repeat propofol anesthesia may not exacerbate plaque deposition or associated synapse loss in AD. Interestingly, this data also provides some of the first evidence suggesting that repeat propofol exposure in adult wild-type mice does not result in robust long-term alterations in the levels of key excitatory and inhibitory synaptic markers.

Fast-to-slow shift of muscle fiber-type composition by dietary apple polyphenols in rats: Impact of the low-dose supplementation.

PubMed

Mizunoya, Wataru; Okamoto, Shinpei; Miyahara, Hideo; Akahoshi, Mariko; Suzuki, Takahiro; Do, Mai-Khoi Q; Ohtsubo, Hideaki; Komiya, Yusuke; Qahar, Mulan; Waga, Toshiaki; Nakazato, Koichi; Ikeuchi, Yoshihide; Anderson, Judy E; Tatsumi, Ryuichi

2017-03-01

Our previous studies demonstrated that an 8-week intake of 5% (w/w) apple polyphenol (APP) in the diet improves muscle endurance of young-adult rats. In order to identify a lower limit of the dietary contribution of APP to the effect, the experiments were designed for lower-dose supplementation (8-week feeding of 0.5% APP in AIN-93G diet) to 12-week-old male Sprague-Dawley rats. Results clearly showed that the 0.5% APP diet significantly up-regulates slower myosin-heavy-chain (MyHC) isoform ratios (IIx and IIa relative to total MyHC) and myoglobin expression in lower hind-limb muscles examined (P < 0.05). There was a trend to increased fatigue resistance detected from measurements of relative isometric plantar-flexion force torque generated by a stimulus train delivered to the tibial nerve (F(98, 1372) = 1.246, P = 0.0574). Importantly, there was no significant difference in the animal body-phenotypes or locomotor activity shown as total moving distance in light and dark periods. Therefore, the present study encourages the notion that even low APP-intake may increase the proportions of fatigue-resistant myofibers, and has promise as a strategy for modifying performance in human sports and improving function in age-related muscle atrophy. © 2016 Japanese Society of Animal Science.

A Neisseria meningitidis fbpABC mutant is incapable of using nonheme iron for growth.

PubMed

Khun, H H; Kirby, S D; Lee, B C

1998-05-01

The neisserial fbpABC locus has been proposed to act as an iron-specific ABC transporter system. To confirm this assigned function, we constructed an fbpABC mutant in Neisseria meningitidis by insertional inactivation of fbpABC with a selectable antibiotic marker. The mutant was unable to use iron supplied from human transferrin, human lactoferrin, or iron chelates. However, the use of iron from heme and human hemoglobin was unimpaired. These results support the obligatory participation of fbpABC in neisserial periplasmic iron transport and do not indicate a role for this genetic locus in the heme iron pathway.

A Neisseria meningitidis fbpABC Mutant Is Incapable of Using Nonheme Iron for Growth

PubMed Central

Khun, Heng H.; Kirby, Shane D.; Lee, B. Craig

1998-01-01

The neisserial fbpABC locus has been proposed to act as an iron-specific ABC transporter system. To confirm this assigned function, we constructed an fbpABC mutant in Neisseria meningitidis by insertional inactivation of fbpABC with a selectable antibiotic marker. The mutant was unable to use iron supplied from human transferrin, human lactoferrin, or iron chelates. However, the use of iron from heme and human hemoglobin was unimpaired. These results support the obligatory participation of fbpABC in neisserial periplasmic iron transport and do not indicate a role for this genetic locus in the heme iron pathway. PMID:9573125

The Caenorhabditis elegans mucolipin-like gene cup-5 is essential for viability and regulates lysosomes in multiple cell types.

PubMed

Hersh, Bradley M; Hartwieg, Erika; Horvitz, H Robert

2002-04-02

The misregulation of programmed cell death, or apoptosis, contributes to the pathogenesis of many diseases. We used Nomarski microscopy to screen for mutants containing refractile cell corpses in a C. elegans strain in which all programmed cell death is blocked and such corpses are absent. We isolated a mutant strain that accumulates refractile bodies resembling irregular cell corpses. We rescued this mutant phenotype with the C. elegans mucolipidosis type IV (ML-IV) homolog, the recently identified cup-5 (coelomocyte-uptake defective) gene. ML-IV is a human autosomal recessive lysosomal storage disease characterized by psychomotor retardation and ophthalmological abnormalities. Our null mutations in cup-5 cause maternal-effect lethality. In addition, cup-5 mutants contain excess lysosomes in many and possibly all cell types and contain lamellar structures similar to those observed in ML-IV cell lines. The human ML-IV gene is capable of rescuing both the maternal-effect lethality and the lysosome-accumulation abnormality of cup-5 mutants. cup-5 mutants seem to contain excess apoptotic cells as detected by staining with terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling. We suggest that the increased apoptosis seen in cup-5 mutants is a secondary consequence of the lysosomal defect, and that abnormalities in apoptosis may be associated with human lysosomal storage disorders.

Transient Go: A Mobile App for Transient Astronomy Outreach

NASA Astrophysics Data System (ADS)

Crichton, D.; Mahabal, A.; Djorgovski, S. G.; Drake, A.; Early, J.; Ivezic, Z.; Jacoby, S.; Kanbur, S.

2016-12-01

Augmented Reality (AR) is set to revolutionize human interaction with the real world as demonstrated by the phenomenal success of `Pokemon Go'. That very technology can be used to rekindle the interest in science at the school level. We are in the process of developing a prototype app based on sky maps that will use AR to introduce different classes of astronomical transients to students as they are discovered i.e. in real-time. This will involve transient streams from surveys such as the Catalina Real-time Transient Survey (CRTS) today and the Large Synoptic Survey Telescope (LSST) in the near future. The transient streams will be combined with archival and latest image cut-outs and other auxiliary data as well as historical and statistical perspectives on each of the transient types being served. Such an app could easily be adapted to work with various NASA missions and NSF projects to enrich the student experience.

Nature apps: Waiting for the revolution.

PubMed

Jepson, Paul; Ladle, Richard J

2015-12-01

Apps are small task-orientated programs with the potential to integrate the computational and sensing capacities of smartphones with the power of cloud computing, social networking, and crowdsourcing. They have the potential to transform how humans interact with nature, cause a step change in the quantity and resolution of biodiversity data, democratize access to environmental knowledge, and reinvigorate ways of enjoying nature. To assess the extent to which this potential is being exploited in relation to nature, we conducted an automated search of the Google Play Store using 96 nature-related terms. This returned data on ~36 304 apps, of which ~6301 were nature-themed. We found that few of these fully exploit the full range of capabilities inherent in the technology and/or have successfully captured the public imagination. Such breakthroughs will only be achieved by increasing the frequency and quality of collaboration between environmental scientists, information engineers, computer scientists, and interested publics.

orco mutant mosquitoes lose strong preference for humans and are not repelled by volatile DEET.

PubMed

DeGennaro, Matthew; McBride, Carolyn S; Seeholzer, Laura; Nakagawa, Takao; Dennis, Emily J; Goldman, Chloe; Jasinskiene, Nijole; James, Anthony A; Vosshall, Leslie B

2013-06-27

Female mosquitoes of some species are generalists and will blood-feed on a variety of vertebrate hosts, whereas others display marked host preference. Anopheles gambiae and Aedes aegypti have evolved a strong preference for humans, making them dangerously efficient vectors of malaria and Dengue haemorrhagic fever. Specific host odours probably drive this strong preference because other attractive cues, including body heat and exhaled carbon dioxide (CO2), are common to all warm-blooded hosts. Insects sense odours via several chemosensory receptor families, including the odorant receptors (ORs), membrane proteins that form heteromeric odour-gated ion channels comprising a variable ligand-selective subunit and an obligate co-receptor called Orco (ref. 6). Here we use zinc-finger nucleases to generate targeted mutations in the orco gene of A. aegypti to examine the contribution of Orco and the odorant receptor pathway to mosquito host selection and sensitivity to the insect repellent DEET (N,N-diethyl-meta-toluamide). orco mutant olfactory sensory neurons have greatly reduced spontaneous activity and lack odour-evoked responses. Behaviourally, orco mutant mosquitoes have severely reduced attraction to honey, an odour cue related to floral nectar, and do not respond to human scent in the absence of CO2. However, in the presence of CO2, female orco mutant mosquitoes retain strong attraction to both human and animal hosts, but no longer strongly prefer humans. orco mutant females are attracted to human hosts even in the presence of DEET, but are repelled upon contact, indicating that olfactory- and contact-mediated effects of DEET are mechanistically distinct. We conclude that the odorant receptor pathway is crucial for an anthropophilic vector mosquito to discriminate human from non-human hosts and to be effectively repelled by volatile DEET.

78 FR 70311 - Eunice Kennedy Shriver National Institute of Child Health & Human Development; Notice of Closed...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-11-25

... DEPARTMENT OF HEALTH AND HUMAN SERVICES National Institutes of Health Eunice Kennedy Shriver National Institute of Child Health & Human Development; Notice of Closed Meeting Pursuant to section 10(d) of the Federal Advisory Committee Act, as amended (5 U.S.C. App.), notice is hereby given of the following meeting. The meeting will be closed to...

77 FR 12600 - Eunice Kennedy Shriver National Institute of Child Health and Human Development; Notice of Closed...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-03-01

... DEPARTMENT OF HEALTH AND HUMAN SERVICES National Institutes of Health Eunice Kennedy Shriver National Institute of Child Health and Human Development; Notice of Closed Meeting Pursuant to section 10(d) of the Federal Advisory Committee Act, as amended (5 U.S.C. App.), notice is hereby given of the following meeting. The meeting will be closed to...

Induction of mutations by bismuth-212 alpha particles at two genetic loci in human B-lymphoblasts.

PubMed

Metting, N F; Palayoor, S T; Macklis, R M; Atcher, R W; Liber, H L; Little, J B

1992-12-01

The human lymphoblast cell line TK6 was exposed to the alpha-particle-emitting radon daughter 212Bi by adding DTPA-chelated 212Bi directly to the cell suspension. Cytotoxicity and mutagenicity at two genetic loci were measured, and the molecular nature of mutant clones was studied by Southern blot analysis. Induced mutant fractions were 2.5 x 10(-5)/Gy at the hprt locus and 3.75 x 10(-5)/Gy at the tk locus. Molecular analysis of HPRT- mutant DNAs showed a high frequency (69%) of clones with partial or full deletions of the hprt gene among radiation-induced mutants compared with spontaneous mutants (31%). Chi-squared analyses of mutational spectra show a significant difference (P < or = 0.005) between spontaneous mutants and alpha-particle-induced mutants. Comparison with published studies of accelerator-produced heavy-ion exposures of TK6 cells indicates that the induction of mutations at the hprt locus, and perhaps a subset of mutations at the tk locus, is a simple linear function of particle fluence regardless of the ion species or its LET.

Immunization with a Recombinant, Pseudomonas fluorescens-Expressed, Mutant Form of Bacillus anthracis-Derived Protective Antigen Protects Rabbits from Anthrax Infection.

PubMed

Reed, Matthew D; Wilder, Julie A; Mega, William M; Hutt, Julie A; Kuehl, Philip J; Valderas, Michelle W; Chew, Lawrence L; Liang, Bertrand C; Squires, Charles H

2015-01-01

Protective antigen (PA), one of the components of the anthrax toxin, is the major component of human anthrax vaccine (Biothrax). Human anthrax vaccines approved in the United States and Europe consist of an alum-adsorbed or precipitated (respectively) supernatant material derived from cultures of toxigenic, non-encapsulated strains of Bacillus anthracis. Approved vaccination schedules in humans with either of these vaccines requires several booster shots and occasionally causes adverse injection site reactions. Mutant derivatives of the protective antigen that will not form the anthrax toxins have been described. We have cloned and expressed both mutant (PA SNKE167-ΔFF-315-E308D) and native PA molecules recombinantly and purified them. In this study, both the mutant and native PA molecules, formulated with alum (Alhydrogel), elicited high titers of anthrax toxin neutralizing anti-PA antibodies in New Zealand White rabbits. Both mutant and native PA vaccine preparations protected rabbits from lethal, aerosolized, B. anthracis spore challenge subsequent to two immunizations at doses of less than 1 μg.

Alzheimer's Disease: APP, Gamma Secretase, APOE, CLU, CR1, PICALM, ABCA7, BIN1, CD2AP, CD33, EPHA1, and MS4A2, and Their Relationships with Herpes Simplex, C. Pneumoniae, Other Suspect Pathogens, and the Immune System

PubMed Central

Carter, Chris

2011-01-01

Alzheimer's disease susceptibility genes, APP and gamma-secretase, are involved in the herpes simplex life cycle, and that of other suspect pathogens (C. pneumoniae, H. pylori, C. neoformans, B. burgdorferri, P. gingivalis) or immune defence. Such pathogens promote beta-amyloid deposition and tau phosphorylation and may thus be causative agents, whose effects are conditioned by genes. The antimicrobial effects of beta-amyloid, the localisation of APP/gamma-secretase in immunocompetent dendritic cells, and gamma secretase cleavage of numerous pathogen receptors suggest that this network is concerned with pathogen disposal, effects which may be abrogated by the presence of beta-amyloid autoantibodies in the elderly. These autoantibodies, as well as those to nerve growth factor and tau, also observed in Alzheimer's disease, may well be antibodies to pathogens, due to homology between human autoantigens and pathogen proteins. NGF or tau antibodies promote beta-amyloid deposition, neurofibrillary tangles, or cholinergic neuronal loss, and, with other autoantibodies, such as anti-ATPase, are potential agents of destruction, whose formation is dictated by sequence homology between pathogen and human proteins, and thus by pathogen strain and human genes. Pathogen elimination in the ageing population and removal of culpable autoantibodies might reduce the incidence and offer hope for a cure in this affliction. PMID:22254144

Suppression of amyloid beta A11 antibody immunoreactivity by vitamin C: possible role of heparan sulfate oligosaccharides derived from glypican-1 by ascorbate-induced, nitric oxide (NO)-catalyzed degradation.

PubMed

Cheng, Fang; Cappai, Roberto; Ciccotosto, Giuseppe D; Svensson, Gabriel; Multhaup, Gerd; Fransson, Lars-Åke; Mani, Katrin

2011-08-05

Amyloid β (Aβ) is generated from the copper- and heparan sulfate (HS)-binding amyloid precursor protein (APP) by proteolytic processing. APP supports S-nitrosylation of the HS proteoglycan glypican-1 (Gpc-1). In the presence of ascorbate, there is NO-catalyzed release of anhydromannose (anMan)-containing oligosaccharides from Gpc-1-nitrosothiol. We investigated whether these oligosaccharides interact with Aβ during APP processing and plaque formation. anMan immunoreactivity was detected in amyloid plaques of Alzheimer (AD) and APP transgenic (Tg2576) mouse brains by immunofluorescence microscopy. APP/APP degradation products detected by antibodies to the C terminus of APP, but not Aβ oligomers detected by the anti-Aβ A11 antibody, colocalized with anMan immunoreactivity in Tg2576 fibroblasts. A 50-55-kDa anionic, sodium dodecyl sulfate-stable, anMan- and Aβ-immunoreactive species was obtained from Tg2576 fibroblasts using immunoprecipitation with anti-APP (C terminus). anMan-containing HS oligo- and disaccharide preparations modulated or suppressed A11 immunoreactivity and oligomerization of Aβ42 peptide in an in vitro assay. A11 immunoreactivity increased in Tg2576 fibroblasts when Gpc-1 autoprocessing was inhibited by 3-β[2(diethylamino)ethoxy]androst-5-en-17-one (U18666A) and decreased when Gpc-1 autoprocessing was stimulated by ascorbate. Neither overexpression of Gpc-1 in Tg2576 fibroblasts nor addition of copper ion and NO donor to hippocampal slices from 3xTg-AD mice affected A11 immunoreactivity levels. However, A11 immunoreactivity was greatly suppressed by the subsequent addition of ascorbate. We speculate that temporary interaction between the Aβ domain and small, anMan-containing oligosaccharides may preclude formation of toxic Aβ oligomers. A portion of the oligosaccharides are co-secreted with the Aβ peptides and deposited in plaques. These results support the notion that an inadequate supply of vitamin C could contribute to late onset AD in humans.

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:18583063

The UX of amila pregnancy on mobile device

NASA Astrophysics Data System (ADS)

Hussain, Azham; Mkpojiogu, Emmanuel O. C.; Fadzil, Najdawati Mohd; Hassan, Norhasizasuriati Mohd

2017-10-01

The increased use of mobile devices has led to an upsurge in the number of mobile applications. This makes the usability of these applications a very crucial and critical issue. The Amila Pregnancy mobile app is revolutionizing the delivery of healthcare services to pregnancy woman across the globe and is increasingly becoming beneficial in their daily life. Only a few digital interventions have been developed for pregnant woman, and little is known about the acceptability and usability of such mobile apps that provide assistance to pregnant women. Usability comprises everything that is connected with the intuitive and efficient handling of user interaction with human-made devices. This paper reports the result of a usability evaluation for Amila Pregnancy mobile application. In the study five attributes of perceived usability was measured following Jakob Nielsen principles, namely: effectiveness, efficiency, learnability, memorability and satisfaction. In addition, performance metrics were also captured. The results reveal the difficulty users had in interpreting displayed icon, locating the information provided, re-finding it and in navigating through the mobile app. The study suggests that the main menu of the app need to be further improved upon to enhance its usability.

The Relationship Between Individual Characteristics and Interest in Using a Mobile Phone App for HIV Self-Management: Observational Cohort Study of People Living With HIV.

PubMed

Lucero, Robert James; Frimpong, Jemima A; Fehlberg, Elizabeth A; Bjarnadottir, Ragnhildur I; Weaver, Michael T; Cook, Christa; Modave, Francois; Rathore, Mobeen H; Morano, Jamie P; Ibanez, Gladys; Cook, Robert L

2017-07-27

The human immunodeficiency virus (HIV) continues to be a major health issue in the United States, and an estimated 1.2 million people in the United States are living with HIV. As part of Healthy People 2020, the Office of Disease Prevention and Health Promotion has targeted the persistent demographic and geographic disparities in HIV prevalence and management. Preliminary evidence suggests that mobile health technology (smartphone apps) may be a promising way to support HIV self-management among vulnerable populations of people living with HIV (PLWH) who lack access to appropriate health care services. This study examines the association between individual characteristics of PLWH and level of interest in using a free mobile phone app for HIV self-management. This study was conducted using cross-sectional survey data collected in the Florida Cohort Study between 2014 and 2016 (N=766). Associations between individual characteristics of PLWH and level of interest in using a free mobile phone app for HIV self-management were examined using bivariate analysis and logistic regression. Overall, 85.5% (655/766) of respondents were interested in using a free mobile phone app that supports HIV self-management. Participants expressed the highest interest in app functions that facilitate communication with health care providers (568/740, 76.8%) or help to identify relevant health care services (556/745 74.6%). Age (OR 0.959, 95% CI 0.936-0.982), education (OR 1.281, 95% CI 1.027-1.598) and disability or inability to work (OR 0.296, 95% CI 0.145-0.606) were all significantly associated with being interested in using a free mobile phone app for HIV self-management. This study indicates that a majority of PLWH are interested in using a free mobile phone app to self-manage their condition. The findings can inform the development of mobile phone apps that support effective HIV self-management. ©Robert James Lucero, Jemima A Frimpong, Elizabeth A Fehlberg, Ragnhildur I Bjarnadottir, Michael T Weaver, Christa Cook, Francois Modave, Mobeen H Rathore, Jamie P Morano, Gladys Ibanez, Robert L Cook. Originally published in JMIR Mhealth and Uhealth (http://mhealth.jmir.org), 27.07.2017.

Translation, Cross-Cultural Adaptation, and Validation of the Malay Version of the System Usability Scale Questionnaire for the Assessment of Mobile Apps.

PubMed

Mohamad Marzuki, Muhamad Fadhil; Yaacob, Nor Azwany; Yaacob, Najib Majdi

2018-05-14

A mobile app is a programmed system designed to be used by a target user on a mobile device. The usability of such a system refers not only to the extent to which product can be used to achieve the task that it was designed for, but also its effectiveness and efficiency, as well as user satisfaction. The System Usability Scale is one of the most commonly used questionnaires used to assess the usability of a system. The original 10-item version of System Usability Scale was developed in English and thus needs to be adapted into local languages to assess the usability of a mobile apps developed in other languages. The aim of this study is to translate and validate (with cross-cultural adaptation) the English System Usability Scale questionnaire into Malay, the main language spoken in Malaysia. The development of a translated version will allow the usability of mobile apps to be assessed in Malay. Forward and backward translation of the questionnaire was conducted by groups of Malay native speakers who spoke English as their second language. The final version was obtained after reconciliation and cross-cultural adaptation. The content of the Malay System Usability Scale questionnaire for mobile apps was validated by 10 experts in mobile app development. The efficacy of the questionnaire was further probed by testing the face validity on 10 mobile phone users, followed by reliability testing involving 54 mobile phone users. The content validity index was determined to be 0.91, indicating good relevancy of the 10 items used to assess the usability of a mobile app. Calculation of the face validity index resulted in a value of 0.94, therefore indicating that the questionnaire was easily understood by the users. Reliability testing showed a Cronbach alpha value of .85 (95% CI 0.79-0.91) indicating that the translated System Usability Scale questionnaire is a reliable tool for the assessment of usability of a mobile app. The Malay System Usability Scale questionnaire is a valid and reliable tool to assess the usability of mobile app in Malaysia. ©Muhamad Fadhil Mohamad Marzuki, Nor Azwany Yaacob, Najib Majdi Yaacob. Originally published in JMIR Human Factors (http://humanfactors.jmir.org), 14.05.2018.

Decreasing the expression of PICALM reduces endocytosis and the activity of β-secretase: implications for Alzheimer's disease.

PubMed

Thomas, Rhian S; Henson, Alex; Gerrish, Amy; Jones, Lesley; Williams, Julie; Kidd, Emma J

2016-07-18

Polymorphisms in the gene for phosphatidylinositol binding clathrin assembly protein (PICALM), an endocytic-related protein, are associated with a small, increased risk of developing Alzheimer's disease (AD), strongly suggesting that changes in endocytosis are involved in the aetiology of the disease. We have investigated the involvement of PICALM in the processing of amyloid precursor protein (APP) to understand how PICALM could be linked to the development of AD. We used siRNA to deplete levels of PICALM, its isoforms and clathrin heavy chain in the human brain-derived H4 neuroglioma cell line that expresses endogenous levels of APP. We then used Western blotting, ELISA and immunohistochemistry to detect intra- and extracellular protein levels of endocytic-related proteins, APP and APP metabolites including β-amyloid (Aβ). Levels of functional endocytosis were quantified using ALEXA 488-conjugated transferrin and flow cytometry as a marker of clathrin-mediated endocytosis (CME). Following depletion of all the isoforms of PICALM by siRNA in H4 cells, levels of intracellular APP, intracellular β-C-terminal fragment (β-CTF) and secreted sAPPβ (APP fragments produced by β-secretase cleavage) were significantly reduced but Aβ40 was not affected. Functional endocytosis was significantly reduced after both PICALM and clathrin depletion, highlighting the importance of PICALM in this process. However, depletion of clathrin did not affect APP but did reduce β-CTF levels. PICALM depletion altered the intracellular distribution of clathrin while clathrin reduction affected the subcellular pattern of PICALM labelling. Both PICALM and clathrin depletion reduced the expression of BACE1 mRNA and PICALM siRNA reduced protein levels. Individual depletion of PICALM isoforms 1 and 2 did not affect APP levels while clathrin depletion had a differential effect on the isoforms, increasing isoform 1 while decreasing isoform 2 expression. The depletion of PICALM in brain-derived cells has significant effects on the processing of APP, probably by reducing CME. In particular, it affects the production of β-CTF which is increasingly considered to be an important mediator in AD independent of Aβ. Thus a decrease in PICALM expression in the brain could be beneficial to slow or prevent the development of AD.

Assessing the Quality of Mobile Exercise Apps Based on the American College of Sports Medicine Guidelines: A Reliable and Valid Scoring Instrument.

PubMed

Guo, Yi; Bian, Jiang; Leavitt, Trevor; Vincent, Heather K; Vander Zalm, Lindsey; Teurlings, Tyler L; Smith, Megan D; Modave, François

2017-03-07

Regular physical activity can not only help with weight management, but also lower cardiovascular risks, cancer rates, and chronic disease burden. Yet, only approximately 20% of Americans currently meet the physical activity guidelines recommended by the US Department of Health and Human Services. With the rapid development of mobile technologies, mobile apps have the potential to improve participation rates in exercise programs, particularly if they are evidence-based and are of sufficient content quality. The goal of this study was to develop and test an instrument, which was designed to score the content quality of exercise program apps with respect to the exercise guidelines set forth by the American College of Sports Medicine (ACSM). We conducted two focus groups (N=14) to elicit input for developing a preliminary 27-item scoring instruments based on the ACSM exercise prescription guidelines. Three reviewers who were no sports medicine experts independently scored 28 exercise program apps using the instrument. Inter- and intra-rater reliability was assessed among the 3 reviewers. An expert reviewer, a Fellow of the ACSM, also scored the 28 apps to create criterion scores. Criterion validity was assessed by comparing nonexpert reviewers' scores to the criterion scores. Overall, inter- and intra-rater reliability was high with most coefficients being greater than .7. Inter-rater reliability coefficients ranged from .59 to .99, and intra-rater reliability coefficients ranged from .47 to 1.00. All reliability coefficients were statistically significant. Criterion validity was found to be excellent, with the weighted kappa statistics ranging from .67 to .99, indicating a substantial agreement between the scores of expert and nonexpert reviewers. Finally, all apps scored poorly against the ACSM exercise prescription guidelines. None of the apps received a score greater than 35, out of a possible maximal score of 70. We have developed and presented valid and reliable scoring instruments for exercise program apps. Our instrument may be useful for consumers and health care providers who are looking for apps that provide safe, progressive general exercise programs for health and fitness. ©Yi Guo, Jiang Bian, Trevor Leavitt, Heather K Vincent, Lindsey Vander Zalm, Tyler L Teurlings, Megan D Smith, François Modave. Originally published in the Journal of Medical Internet Research (http://www.jmir.org), 07.03.2017.

COPS5 (Jab1) protein increases β site processing of amyloid precursor protein and amyloid β peptide generation by stabilizing RanBP9 protein levels.

PubMed

Wang, Hongjie; Dey, Debleena; Carrera, Ivan; Minond, Dmitriy; Bianchi, Elisabetta; Xu, Shaohua; Lakshmana, Madepalli K

2013-09-13

Increased processing of amyloid precursor protein (APP) and accumulation of neurotoxic amyloid β peptide (Aβ) in the brain is central to the pathogenesis of Alzheimer's disease (AD). Therefore, the identification of molecules that regulate Aβ generation is crucial for future therapeutic approaches for AD. We demonstrated previously that RanBP9 regulates Aβ generation in a number of cell lines and primary neuronal cultures by forming tripartite protein complexes with APP, low-density lipoprotein-related protein, and BACE1, consequently leading to increased amyloid plaque burden in the brain. RanBP9 is a scaffold protein that exists and functions in multiprotein complexes. To identify other proteins that may bind RanBP9 and regulate Aβ levels, we used a two-hybrid analysis against a human brain cDNA library and identified COPS5 as a novel RanBP9-interacting protein. This interaction was confirmed by coimmunoprecipitation experiments in both neuronal and non-neuronal cells and mouse brain. Colocalization of COPS5 and RanBP9 in the same subcellular compartments further supported the interaction of both proteins. Furthermore, like RanBP9, COPS5 robustly increased Aβ generation, followed by increased soluble APP-β (sAPP-β) and decreased soluble-APP-α (sAPP-α) levels. Most importantly, down-regulation of COPS5 by siRNAs reduced Aβ generation, implying that endogenous COPS5 regulates Aβ generation. Finally, COPS5 levels were increased significantly in AD brains and APΔE9 transgenic mice, and overexpression of COPS5 strongly increased RanBP9 protein levels by increasing its half-life. Taken together, these results suggest that COPS5 increases Aβ generation by increasing RanBP9 levels. Thus, COPS5 is a novel RanBP9-binding protein that increases APP processing and Aβ generation by stabilizing RanBP9 protein levels.

Cerebrolysin modulates pronerve growth factor/nerve growth factor ratio and ameliorates the cholinergic deficit in a transgenic model of Alzheimer's disease.

PubMed

Ubhi, Kiren; Rockenstein, Edward; Vazquez-Roque, Ruben; Mante, Michael; Inglis, Chandra; Patrick, Christina; Adame, Anthony; Fahnestock, Margaret; Doppler, Edith; Novak, Philip; Moessler, Herbert; Masliah, Eliezer

2013-02-01

Alzheimer's disease (AD) is characterized by degeneration of neocortex, limbic system, and basal forebrain, accompanied by accumulation of amyloid-β and tangle formation. Cerebrolysin (CBL), a peptide mixture with neurotrophic-like effects, is reported to improve cognition and activities of daily living in patients with AD. Likewise, CBL reduces synaptic and behavioral deficits in transgenic (tg) mice overexpressing the human amyloid precursor protein (hAPP). The neuroprotective effects of CBL may involve multiple mechanisms, including signaling regulation, control of APP metabolism, and expression of neurotrophic factors. We investigate the effects of CBL in the hAPP tg model of AD on levels of neurotrophic factors, including pro-nerve growth factor (NGF), NGF, brain-derived neurotrophic factor (BDNF), neurotropin (NT)-3, NT4, and ciliary neurotrophic factor (CNTF). Immunoblot analysis demonstrated that levels of pro-NGF were increased in saline-treated hAPP tg mice. In contrast, CBL-treated hAPP tg mice showed levels of pro-NGF comparable to control and increased levels of mature NGF. Consistently with these results, immunohistochemical analysis demonstrated increased NGF immunoreactivity in the hippocampus of CBL-treated hAPP tg mice. Protein levels of other neurotrophic factors, including BDNF, NT3, NT4, and CNTF, were unchanged. mRNA levels of NGF and other neurotrophins were also unchanged. Analysis of neurotrophin receptors showed preservation of the levels of TrKA and p75(NTR) immunoreactivity per cell in the nucleus basalis. Cholinergic cells in the nucleus basalis were reduced in the saline-treated hAPP tg mice, and treatment with CBL reduced these cholinergic deficits. These results suggest that the neurotrophic effects of CBL might involve modulation of the pro-NGF/NGF balance and a concomitant protection of cholinergic neurons. Copyright © 2012 Wiley Periodicals, Inc.

Zebrafish cdc6 hypomorphic mutation causes Meier-Gorlin syndrome-like phenotype.

PubMed

Yao, Likun; Chen, Jing; Wu, Xiaotong; Jia, Shunji; Meng, Anming

2017-11-01

Cell Division Cycle 6 (Cdc6) is a component of pre-replicative complex (preRC) forming on DNA replication origins in eukaryotes. Recessive mutations in ORC1, ORC4, ORC6, CDT1 or CDC6 of the preRC in human cause Meier-Gorlin syndrome (MGS) that is characterized by impaired post-natal growth, short stature and microcephaly. However, vertebrate models of MGS have not been reported. Through N-ethyl-N-nitrosourea mutagenesis and Cas9 knockout, we generate several cdc6 mutant lines in zebrafish. Loss-of-function mutations of cdc6, as manifested by cdc6tsu4305 and cdc6tsu7cd mutants, lead to embryonic lethality due to cell cycle arrest at the S phase and extensive apoptosis. Embryos homozygous for a cdc6 hypomorphic mutation, cdc6tsu21cd, develop normally during embryogenesis. Later on, compared with their wild-type (WT) siblings, cdc6tsu21cd mutant fish show growth retardation, and their body weight and length in adulthood are greatly reduced, which resemble human MGS. Surprisingly, cdc6tsu21cd mutant fish become males with a short life and fail to mate with WT females, suggesting defective reproduction. Overexpression of Cdc6 mutant forms, which mimic human CDC6(T323R) mutation found in a MGS patient, in zebrafish cdc6tsu4305 mutant embryos partially represses cell death phenotype, suggesting that the human CDC6(T323R) mutation is a hypomorph. cdc6tsu21cd mutant fish will be useful to detect more tissue defects and develop medical treatment strategies for MGS patients. © The Author 2017. Published by Oxford University Press.

Zebrafish cdc6 hypomorphic mutation causes Meier-Gorlin syndrome-like phenotype

PubMed Central

Yao, Likun; Chen, Jing; Wu, Xiaotong; Jia, Shunji; Meng, Anming

2017-01-01

Abstract Cell Division Cycle 6 (Cdc6) is a component of pre-replicative complex (preRC) forming on DNA replication origins in eukaryotes. Recessive mutations in ORC1, ORC4, ORC6, CDT1 or CDC6 of the preRC in human cause Meier-Gorlin syndrome (MGS) that is characterized by impaired post-natal growth, short stature and microcephaly. However, vertebrate models of MGS have not been reported. Through N-ethyl-N-nitrosourea mutagenesis and Cas9 knockout, we generate several cdc6 mutant lines in zebrafish. Loss-of-function mutations of cdc6, as manifested by cdc6tsu4305 and cdc6tsu7cd mutants, lead to embryonic lethality due to cell cycle arrest at the S phase and extensive apoptosis. Embryos homozygous for a cdc6 hypomorphic mutation, cdc6tsu21cd, develop normally during embryogenesis. Later on, compared with their wild-type (WT) siblings, cdc6tsu21cd mutant fish show growth retardation, and their body weight and length in adulthood are greatly reduced, which resemble human MGS. Surprisingly, cdc6tsu21cd mutant fish become males with a short life and fail to mate with WT females, suggesting defective reproduction. Overexpression of Cdc6 mutant forms, which mimic human CDC6(T323R) mutation found in a MGS patient, in zebrafish cdc6tsu4305 mutant embryos partially represses cell death phenotype, suggesting that the human CDC6(T323R) mutation is a hypomorph. cdc6tsu21cd mutant fish will be useful to detect more tissue defects and develop medical treatment strategies for MGS patients. PMID:28985365

Dihydrofolate-Reductase Mutations in Plasmodium knowlesi Appear Unrelated to Selective Drug Pressure from Putative Human-To-Human Transmission in Sabah, Malaysia.

PubMed

Grigg, Matthew J; Barber, Bridget E; Marfurt, Jutta; Imwong, Mallika; William, Timothy; Bird, Elspeth; Piera, Kim A; Aziz, Ammar; Boonyuen, Usa; Drakeley, Christopher J; Cox, Jonathan; White, Nicholas J; Cheng, Qin; Yeo, Tsin W; Auburn, Sarah; Anstey, Nicholas M

2016-01-01

Malaria caused by zoonotic Plasmodium knowlesi is an emerging threat in Eastern Malaysia. Despite demonstrated vector competency, it is unknown whether human-to-human (H-H) transmission is occurring naturally. We sought evidence of drug selection pressure from the antimalarial sulfadoxine-pyrimethamine (SP) as a potential marker of H-H transmission. The P. knowlesi dihdyrofolate-reductase (pkdhfr) gene was sequenced from 449 P. knowlesi malaria cases from Sabah (Malaysian Borneo) and genotypes evaluated for association with clinical and epidemiological factors. Homology modelling using the pvdhfr template was used to assess the effect of pkdhfr mutations on the pyrimethamine binding pocket. Fourteen non-synonymous mutations were detected, with the most common being at codon T91P (10.2%) and R34L (10.0%), resulting in 21 different genotypes, including the wild-type, 14 single mutants, and six double mutants. One third of the P. knowlesi infections were with pkdhfr mutants; 145 (32%) patients had single mutants and 14 (3%) had double-mutants. In contrast, among the 47 P. falciparum isolates sequenced, three pfdhfr genotypes were found, with the double mutant 108N+59R being fixed and the triple mutants 108N+59R+51I and 108N+59R+164L occurring with frequencies of 4% and 8%, respectively. Two non-random spatio-temporal clusters were identified with pkdhfr genotypes. There was no association between pkdhfr mutations and hyperparasitaemia or malaria severity, both hypothesized to be indicators of H-H transmission. The orthologous loci associated with resistance in P. falciparum were not mutated in pkdhfr. Subsequent homology modelling of pkdhfr revealed gene loci 13, 53, 120, and 173 as being critical for pyrimethamine binding, however, there were no mutations at these sites among the 449 P. knowlesi isolates. Although moderate diversity was observed in pkdhfr in Sabah, there was no evidence this reflected selective antifolate drug pressure in humans.

Expression of the Flp proteins by Haemophilus ducreyi is necessary for virulence in human volunteers.

PubMed

Janowicz, Diane M; Cooney, Sean A; Walsh, Jessica; Baker, Beth; Katz, Barry P; Fortney, Kate R; Zwickl, Beth W; Ellinger, Sheila; Munson, Robert S

2011-09-22

Haemophilus ducreyi, the causative agent of the sexually transmitted disease chancroid, contains a flp (fimbria like protein) operon that encodes proteins predicted to contribute to adherence and pathogenesis. H. ducreyi mutants that lack expression of Flp1 and Flp2 or TadA, which has homology to NTPases of type IV secretion systems, have decreased abilities to attach to and form microcolonies on human foreskin fibroblasts (HFF). A tadA mutant is attenuated in its ability to cause disease in human volunteers and in the temperature dependent rabbit model, but a flp1flp2 mutant is virulent in rabbits. Whether a flp deletion mutant would cause disease in humans is not clear. We constructed 35000HPΔflp1-3, a deletion mutant that lacks expression of all three Flp proteins but has an intact tad secretion system. 35000HPΔflp1-3 was impaired in its ability to form microcolonies and to attach to HFF in vitro when compared to its parent (35000HP). Complementation of the mutant with flp1-3 in trans restored the parental phenotype. To test whether expression of Flp1-3 was necessary for virulence in humans, ten healthy adult volunteers were experimentally infected with a fixed dose of 35000HP (ranging from 54 to 67 CFU) on one arm and three doses of 35000HPΔflp1-3 (ranging from 63 to 961 CFU) on the other arm. The overall papule formation rate for the parent was 80% (95% confidence interval, CI, 55.2%-99.9%) and for the mutant was 70.0% (95% CI, 50.5%-89.5%) (P = 0.52). Mutant papules were significantly smaller (mean, 11.2 mm2) than were parent papules (21.8 mm2) 24 h after inoculation (P = 0.018). The overall pustule formation rates were 46.7% (95% CI 23.7-69.7%) at 30 parent sites and 6.7% (95% CI, 0.1-19.1%) at 30 mutant sites (P = 0.001). These data suggest that production and secretion of the Flp proteins contributes to microcolony formation and attachment to HFF cells in vitro. Expression of flp1-3 is also necessary for H. ducreyi to initiate disease and progress to pustule formation in humans. Future studies will focus on how Flp proteins contribute to microcolony formation and attachment in vivo. © 2011 Janowicz et al; licensee BioMed Central Ltd.

Novel Genes Required for the Fitness of Streptococcus pyogenes in Human Saliva

PubMed Central

Zhu, Luchang; Charbonneau, Amelia R. L.; Waller, Andrew S.; Olsen, Randall J.; Beres, Stephen B.

2017-01-01

ABSTRACT Streptococcus pyogenes (group A streptococcus [GAS]) causes 600 million cases of pharyngitis each year. Despite this considerable disease burden, the molecular mechanisms used by GAS to infect, cause clinical pharyngitis, and persist in the human oropharynx are poorly understood. Saliva is ubiquitous in the human oropharynx and is the first material GAS encounters in the upper respiratory tract. Thus, a fuller understanding of how GAS survives and proliferates in saliva may provide valuable insights into the molecular mechanisms at work in the human oropharynx. We generated a highly saturated transposon insertion mutant library in serotype M1 strain MGAS2221, a strain genetically representative of a pandemic clone that arose in the 1980s and spread globally. The transposon mutant library was exposed to human saliva to screen for GAS genes required for wild-type fitness in this clinically relevant fluid. Using transposon-directed insertion site sequencing (TraDIS), we identified 92 genes required for GAS fitness in saliva. The more prevalent categories represented were genes involved in carbohydrate transport/metabolism, amino acid transport/metabolism, and inorganic ion transport/metabolism. Using six isogenic mutant strains, we confirmed that each of the mutants was significantly impaired for growth or persistence in human saliva ex vivo. Mutants with an inactivated Spy0644 (sptA) or Spy0646 (sptC) gene had especially severe persistence defects. This study is the first to use of TraDIS to study bacterial fitness in human saliva. The new information we obtained will be valuable for future translational maneuvers designed to prevent or treat human GAS infections. IMPORTANCE The human bacterial pathogen Streptococcus pyogenes (group A streptococcus [GAS]) causes more than 600 million cases of pharyngitis annually worldwide, 15 million of which occur in the United States. The human oropharynx is the primary anatomic site for GAS colonization and infection, and saliva is the first material encountered. Using a genome-wide transposon mutant screen, we identified 92 GAS genes required for wild-type fitness in human saliva. Many of the identified genes are involved in carbohydrate transport/metabolism, amino acid transport/metabolism, and inorganic ion transport/metabolism. The new information is potentially valuable for developing novel GAS therapeutics and vaccine research. PMID:29104937

Development of an affinity-matured humanized anti-epidermal growth factor receptor antibody for cancer immunotherapy.

PubMed

Nakanishi, Takeshi; Maru, Takamitsu; Tahara, Kazuhiro; Sanada, Hideaki; Umetsu, Mitsuo; Asano, Ryutaro; Kumagai, Izumi

2013-02-01

We showed previously that humanization of 528, a murine anti-epidermal growth factor receptor (EGFR) antibody, causes reduced affinity for its target. Here, to improve the affinity of the humanized antibody for use in cancer immunotherapy, we constructed phage display libraries focused on the complementarity-determining regions (CDRs) of the antibody and carried out affinity selection. Two-step selections using libraries constructed in a stepwise manner enabled a 32-fold affinity enhancement of humanized 528 (h528). Thermodynamic analysis of the interactions between the variable domain fragment of h528 (h528Fv) mutants and the soluble extracellular domain of EGFR indicated that the h528Fv mutants obtained from the first selection showed a large increase in negative enthalpy change due to binding, resulting in affinity enhancement. Furthermore, mutants from the second selection showed a decrease in entropy loss, which led to further affinity maturation. These results suggest that a single mutation in the heavy chain variable domain (i.e. Tyr(52) to Trp) enthalpically contributed for overcoming the energetic barrier to the antigen-antibody interaction, which was a major hurdle for the in vitro affinity maturation of h528. We reported previously that the humanized bispecific diabody hEx3 Db, which targets EGFR and CD3, shows strong anti-tumor activity. hEx3 Db mutants, in which the variable domains of h528 were replaced with those of the affinity-enhanced mutants, were prepared and characterized. In a growth inhibition assay of tumor cells, the hEx3 Db mutants showed stronger anti-tumor activity than that of hEx3 Db, suggesting that affinity enhancement of h528Fv enhances the anti-tumor activity of the bispecific diabody.

Huperzine A alleviates synaptic deficits and modulates amyloidogenic and nonamyloidogenic pathways in APPswe/PS1dE9 transgenic mice.

PubMed

Wang, Ying; Tang, Xi Can; Zhang, Hai Yan

2012-02-01

Huperzine A (HupA) is a potent acetylcholinesterase inhibitor (AChEI) used in the treatment of Alzheimer's disease (AD). Recently, HupA was shown to be active in modulating the nonamyloidogenic metabolism of β-amyloid precursor protein (APP) in APP-transfected human embryonic kidney cell line (HEK293swe). However, in vivo research concerning the mechanism of HupA in APP transgenic mice has not yet been fully elucidated. The present study indicates that the loss of dendritic spine density and synaptotagmin levels in the brain of APPswe/presenilin-1 (PS1) transgenic mice was significantly ameliorated by chronic HupA treatment and provides evidence that this neuroprotection was associated with reduced amyloid plaque burden and oligomeric β-amyloid (Aβ) levels in the cortex and hippocampus of APPswe/PS1dE9 transgenic mice. Our findings further demonstrate that the amelioration effect of HupA on Aβ deposits may be mediated, at least in part, by regulation of the compromised expression of a disintegrin and metalloprotease 10 (ADAM10) and excessive membrane trafficking of β-site APP cleavage enzyme 1 (BACE1) in these transgenic mice. In addition, extracellular signal-regulated kinases 1/2 (Erk1/2) phosphorylation may also be partially involved in the effect of HupA on APP processing. In conclusion, our work for the first time demonstrates the neuroprotective effect of HupA on synaptic deficits in APPswe/PS1dE9 transgenic mice and further clarifies the potential pharmacological targets for this protective effect, in which modulation of nonamyloidogenic and amyloidogenic APP processing pathways may be both involved. These findings may provide adequate evidence for the clinical and experimental benefits gained from HupA treatment. Copyright © 2011 Wiley Periodicals, Inc.

Chimeric proteins combining phosphatase and cellulose-binding activities: proof-of-concept and application in the hydrolysis of paraoxon.

PubMed

Gonçalves, Larissa M; Chaimovich, Hernan; Cuccovia, Iolanda M; Marana, Sandro R

2014-05-01

Phosphatases for organophosphate degradation and carbohydrate-binding domains (CBMs) have potential biotechnological applications. As a proof-of-concept, a soluble chimeric protein that combines acid phosphatase (AppA) from Escherichia coli and a CBM from Xanthomonas axonopodis pv. citri (AppA-CBM) was produced in E.coli. AppACBM adsorbed in microcrystalline cellulose Avicel PH101 catalyzed the hydrolysis of p-nitrophenyl phosphate (PNPP). The binding to microcrystalline cellulose displayed saturation behavior with an apparent binding constant (Kb) of 22 ± 5 mg and a maximum binding (Bmax) of 1.500 ± 0.001 enzyme units. Binding was highest at pH 2.5 and decreased above pH 6.5, as previously observed for family 2 CBMs. The Km values for PNPP of AppA-CBM and native AppA were identical (2.7 mM). To demonstrate that this strategy for protein engineering has practical applications and is largely functional, even for phosphatases exhibiting diverse folds, a chimeric protein combining human paraoxonase 1 (hPON1) and the CBM was produced. Both PON1-CBM and hPON1 had identical K_m values for paraoxon (1.3 mM). Additionally, hPON1 bound to microcrystalline cellulose with a Kb of 27 ± 3 mg, the same as that observed for AppA-CBM. These data show that the phosphatase domains are as functional in both of the chimeric proteins as they are in the native enzymes and that the CBM domain maintains the same cellulose affinity. Therefore, the engineering of chimeric proteins combining domains of phosphatases and CBMs is fully feasible, resulting in chimeric enzymes that exhibit potential for OP detoxification.

PPARγ agonist pioglitazone improves cerebellar dysfunction at pre-Aβ deposition stage in APPswe/PS1dE9 Alzheimer's disease model mice

DOE Office of Scientific and Technical Information (OSTI.GOV)

Toba, Junya; Nikkuni, Miyu; Ishizeki, Masato

Alzheimer's disease (AD) is one of the best known neurodegenerative diseases; it causes dementia and its pathological features include accumulation of amyloid β (Aβ) and neurofibrillary tangles (NFTs) in the brain. Elevated Cdk5 activity and CRMP2 phosphorylation have been reported in the brains of AD model mice at the early stage of the disease, but the significance thereof in human AD remains unelucidated. We have recently reported that Aβ accumulation in the cerebellum of AD model APPswe/PS1dE9 (APP/PS1) mice, and cerebellar dysfunctions, such as impairment of motor coordination ability and long-term depression (LTD) induction, at the pre-Aβ accumulation stage. Inmore » the present study, we found increased phosphorylation levels of CRMP2 as well as increased p35 protein levels in the cerebellum of APP/PS1 mice. Interestingly, we show that pioglitazone, an agonist of peroxisome proliferator-activated receptor γ, normalized the p35 protein and CRMP2 phosphorylation levels in the cerebellum. Impaired motor coordination ability and LTD in APP/PS1 mice were ameliorated by pioglitazone treatment at the pre-Aβ accumulation stage. These results suggest a correlation between CRMP2 phosphorylation and AD pathophysiology, and indicate the effectiveness of pioglitazone treatment at the pre-Aβ accumulation stage in AD model mice. -- Highlights: •Phosphorylation level of CRMP2 increased in the cerebellum of APP/PS1 mice. •p35 protein levels increased in the cerebellum of APP/PS1 mice. •Pioglitazone treatment improved cerebellar dysfunction of APP/PS1 mice.« less

VA FitHeart, a Mobile App for Cardiac Rehabilitation: Usability Study.

PubMed

Beatty, Alexis L; Magnusson, Sara L; Fortney, John C; Sayre, George G; Whooley, Mary A

2018-01-15

Cardiac rehabilitation (CR) improves outcomes for patients with ischemic heart disease or heart failure but is underused. New strategies to improve access to and engagement in CR are needed. There is considerable interest in technology-facilitated home CR. However, little is known about patient acceptance and use of mobile technology for CR. The aim of this study was to develop a mobile app for technology-facilitated home CR and seek to determine its usability. We recruited patients eligible for CR who had access to a mobile phone, tablet, or computer with Internet access. The mobile app includes physical activity goal setting, logs for tracking physical activity and health metrics (eg, weight, blood pressure, and mood), health education, reminders, and feedback. Study staff demonstrated the mobile app to participants in person and then observed participants completing prespecified tasks with the mobile app. Participants completed the System Usability Scale (SUS, 0-100), rated likelihood to use the mobile app (0-100), questionnaires on mobile app use, and participated in a semistructured interview. The Unified Theory of Acceptance and Use of Technology and the Theory of Planned Behavior informed the analysis. On the basis of participant feedback, we made iterative revisions to the mobile app between users. We conducted usability testing in 13 participants. The first version of the mobile app was used by the first 5 participants, and revised versions were used by the final 8 participants. From the first version to revised versions, task completion success rate improved from 44% (11/25 tasks) to 78% (31/40 tasks; P=.05), SUS improved from 54 to 76 (P=.04; scale 0-100, with 100 being the best usability), and self-reported likelihood of use remained high at 76 and 87 (P=.30; scale 0-100, with 100 being the highest likelihood). In interviews, patients expressed interest in tracking health measures ("I think it'll be good to track my exercise and to see what I'm doing"), a desire for introductory training ("Initially, training with a technical person, instead of me relying on myself"), and an expectation for sharing data with providers ("It would also be helpful to share with my doctor, it just being a matter of clicking a button and sharing it with my doctor"). With participant feedback and iterative revisions, we significantly improved the usability of a mobile app for CR. Patient expectations for using a mobile app for CR include tracking health metrics, introductory training, and sharing data with providers. Iterative mixed-method evaluation may be useful for improving the usability of health technology. ©Alexis L Beatty, Sara L Magnusson, John C Fortney, George G Sayre, Mary A Whooley. Originally published in JMIR Human Factors (http://humanfactors.jmir.org), 15.01.2018.

GGA1 regulates signal-dependent sorting of BACE1 to recycling endosomes, which moderates Aβ production

PubMed Central

Toh, Wei Hong; Chia, Pei Zhi Cheryl; Hossain, Mohammed Iqbal; Gleeson, Paul A.

2018-01-01

The diversion of the membrane-bound β-site amyloid precursor protein–(APP) cleaving enzyme (BACE1) from the endolysosomal pathway to recycling endosomes represents an important transport step in the regulation of amyloid beta (Aβ) production. However, the mechanisms that regulate endosome sorting of BACE1 are poorly understood. Here we assessed the transport of BACE1 from early to recycling endosomes and have identified essential roles for the sorting nexin 4 (SNX4)-mediated, signal-independent pathway and for a novel signal-mediated pathway. The signal-mediated pathway is regulated by the phosphorylation of the DXXLL-motif sequence DISLL in the cytoplasmic tail of BACE1. The phosphomimetic S498D BACE1 mutant was trafficked to recycling endosomes at a faster rate compared with wild-type BACE1 or the nonphosphorylatable S498A mutant. The rapid transit of BACE1 S498D from early endosomes was coupled with reduced levels of amyloid precursor protein processing and Aβ production, compared with the S498A mutant. We show that the adaptor, GGA1, and retromer are essential to mediate rapid trafficking of phosphorylated BACE1 to recycling endosomes. In addition, the BACE1 DISLL motif is phosphorylated and regulates endosomal trafficking, in primary neurons. Therefore, post-translational phosphorylation of DISLL enhances the exit of BACE1 from early endosomes, a pathway mediated by GGA1 and retromer, which is important in regulating Aβ production. PMID:29142073

A novel aminoacid determinant of HIV-1 restriction in the TRIM5α variable 1 region isolated in a random mutagenic screen.

PubMed

Pham, Quang Toan; Veillette, Maxime; Brandariz-Nuñez, Alberto; Pawlica, Paulina; Thibert-Lefebvre, Caroline; Chandonnet, Nadia; Diaz-Griffero, Felipe; Berthoux, Lionel

2013-05-01

Human-derived antiretroviral transgenes are of great biomedical interest and are actively pursued. HIV-1 is efficiently inhibited at post-entry, pre-integration replication stages by point mutations in the variable region 1 (v1) of the human restriction factor TRIM5α. Here we use a mutated megaprimer approach to create a mutant library of TRIM5αHu v1 and to isolate a mutation at Gly330 (G330E) that inhibits transduction of an HIV-1 vector as efficiently as the previously described mutants at positions Arg332 and Arg335. As was the case for these other mutations, modification of the local v1 charge toward increased acidity was key to inhibiting HIV-1. G330E TRIM5αHu also disrupted replication-competent HIV-1 propagation in a human T cell line. Interestingly, G330E did not enhance restriction of HIV-1 when combined with mutations at Arg332 or Arg335. Accordingly, the triple mutant G330E-R332G-R335G bound purified recombinant HIV-1 capsid tubes less efficiently than the double mutant R332G-R335G did. In a structural model of the TRIM5αHu PRYSPRY domain, the addition of G330E to the double mutant R332G-R335G caused extensive changes to the capsid-binding surface, which may explain why the triple mutant was no more restrictive than the double mutant. The HIV-1 inhibitory potential of Gly330 mutants was not predicted by examination of natural TRIM5α orthologs that are known to strongly inhibit HIV-1. This work underlines the potential of random mutagenesis to isolate novel variants of human proteins with antiviral properties. Copyright © 2013 Elsevier B.V. All rights reserved.

Dominant-negative mutants of platelet-derived growth factor revert the transformed phenotype of human astrocytoma cells.

PubMed Central

Shamah, S M; Stiles, C D; Guha, A

1993-01-01

Malignant astrocytoma is the most common primary human brain tumor. Most astrocytomas express a combination of platelet-derived growth factor (PDGF) and PDGF receptor which could close an autocrine loop. It is not known whether these autocrine loops contribute to the transformed phenotype of astrocytoma cells or are incidental to that phenotype. Here we show that dominant-negative mutants of the PDGF ligand break the autocrine loop and revert the phenotype of BALB/c 3T3 cells transformed by the PDGF-A or PDGF-B (c-sis) gene. Then, we show that these mutants are selective in that they do not alter the phenotype of 3T3 cells transformed by an activated Ha-ras or v-src gene or by simian virus 40. Finally, we show that these mutants revert the transformed phenotype of two independent human astrocytoma cell lines. They have no effect on the growth of human medulloblastoma, bladder carcinoma, or colon carcinoma cell lines. These observations are consistent with the view that PDGF autocrine loops contribute to the transformed phenotype of at least some human astrocytomas. Images PMID:8246942

Ionomic screening of field-grown soybeans identifies mutants with altered seed elemental composition

USDA-ARS?s Scientific Manuscript database

Soybean seeds contain high levels of mineral nutrients essential for human and animal nutrition. High throughput elemental profiling (ionomics) has identified mutants in model plant species grown in controlled environments. Here, we describe a method for identifying potential soybean ionomics mutant...

γ-secretase binding sites in aged and Alzheimer's disease human cerebrum: the choroid plexus as a putative origin of CSF Aβ.

PubMed

Liu, Fei; Xue, Zhi-Qin; Deng, Si-Hao; Kun, Xiong; Luo, Xue-Gang; Patrylo, Peter R; Rose, Gregory M; Cai, Huaibin; Struble, Robert G; Cai, Yan; Yan, Xiao-Xin

2013-05-01

Deposition of β -amyloid (Aβ) peptides, cleavage products of β-amyloid precursor protein (APP) by β-secretase-1 (BACE1) and γ-secretase, is a neuropathological hallmark of Alzheimer's disease (AD). γ-Secretase inhibition is a therapeutical anti-Aβ approach, although changes in the enzyme's activity in AD brain are unclear. Cerebrospinal fluid (CSF) Aβ peptides are thought to derive from brain parenchyma and thus may serve as biomarkers for assessing cerebral amyloidosis and anti-Aβ efficacy. The present study compared active γ-secretase binding sites with Aβ deposition in aged and AD human cerebrum, and explored the possibility of Aβ production and secretion by the choroid plexus (CP). The specific binding density of [(3) H]-L-685,458, a radiolabeled high-affinity γ-secretase inhibitor, in the temporal neocortex and hippocampal formation was similar for AD and control cases with similar ages and post-mortem delays. The CP in post-mortem samples exhibited exceptionally high [(3) H]-L-685,458 binding density, with the estimated maximal binding sites (Bmax) reduced in the AD relative to control groups. Surgically resected human CP exhibited APP, BACE1 and presenilin-1 immunoreactivity, and β-site APP cleavage enzymatic activity. In primary culture, human CP cells also expressed these amyloidogenic proteins and released Aβ40 and Aβ42 into the medium. Overall, our results suggest that γ-secretase activity appears unaltered in the cerebrum in AD and is not correlated with regional amyloid plaque pathology. The CP appears to be a previously unrecognised non-neuronal contributor to CSF Aβ, probably at reduced levels in AD. © 2013 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

γ-Secretase binding sites in aged and Alzheimer’s disease human cerebrum: The choroid plexus as a putative origin of CSF Aβ

PubMed Central

Liu, Fei; Xue, Zhi-Qin; Deng, Si-Hao; Kun, Xiong; Luo, Xue-Gang; Patrylo, Peter R.; Rose, Gregory M.; Cai, Huaibin; Struble, Robert G.; Cai, Yan; Yan, Xiao-Xin

2013-01-01

Deposition of β-amyloid (Aβ) peptides, cleavage products of β-amyloid precursor protein (APP) by β-secretase-1 (BACE1) and γ-secretase, is a neuropathological hallmark of Alzheimer’s disease (AD). γ-Secretase inhibition is a therapeutical anti-Aβ approach, although less is clear about the change of the enzyme’s activity in AD brain. Cerebrospinal fluid (CSF) Aβ peptides are considered to derive from brain parenchyma, thus may serve as biomarkers for assessing cerebral amyloidosis and anti-Aβ efficacy. The present study compared active γ-secretase binding sites with Aβ deposition in aged and AD human cerebrum, and explored a possibility of Aβ production and secretion by the choroid plexus (CP). Specific binding density of [3H]-L-685,458, a radiolabeled high affinity γ-secretase inhibitor, in the temporal neocortex and hippocampal formation was similar for AD and control cases with comparable ages and postmortem delays. The CP in postmortem samples exhibited exceptionally high [3H]-L-685,458 binding density, with the estimated maximal binding sites (Bmax) reduced in the AD relative to control groups. Surgically resected human CP exhibited APP, BACE1 and presenilin-1 immunoreactivity, and β-site APP cleavage enzymatic activity. In primary culture, human CP cells also expressed these amyloidogenic proteins but released Aβ40 and Aβ42 into the medium. These results suggest that γ-secretase activity appears not altered in the cerebrum in AD related to aged control, nor correlated with regional amyloid plaque pathology. The choroid plexus appears to represent a novel non-neuronal source in the brain that may contribute Aβ into cerebrospinal fluid, probably at reduced levels in AD. PMID:23432732

Usability and Acceptability of a Mobile Comprehensive HIV Prevention App for Men Who Have Sex With Men: A Pilot Study

PubMed Central

Driggers, Robert; Stekler, Joanne D; Siegler, Aaron; Goldenberg, Tamar; McDougal, Sarah J; Caucutt, Jason; Jones, Jeb; Stephenson, Rob

2017-01-01

Background Men who have sex with men (MSM) are the group most impacted by the human immunodeficiency virus (HIV) epidemic and the only subgroup in the United States among which new HIV diagnoses are not decreasing. To achieve the US National HIV/AIDS (acquired immunodeficiency syndrome) Strategy goals of reducing new diagnoses by 25%, high (eg, 30-50%) coverage of multiple HIV prevention interventions is needed in both urban and rural areas. Mobile phone “apps” are an important channel through which prevention services could be provided at scale and at low marginal cost. Objective The aim of this study was to evaluate the usability and acceptability of a theory-based Android mobile phone app for HIV prevention. Methods The app included self-assessment tools; prevention recommendations; commodity (condoms, HIV self-tests) ordering; reminders to MSM for basic HIV prevention services, HIV testing, condom use, screening for preexposure prophylaxis (PrEP) and nonoccupational postexposure prophylaxis (nPEP); and prevention and treatment provider locators. The study recruited HIV-negative, Android-using MSM in Atlanta and Seattle who were asked to use the app for 4 months and complete a post-use survey. We measured the use of the app and its features, ordering of commodities, self-report of establishing an HIV testing plan, being HIV tested in the community, and starting PrEP or using nPEP. Usability was assessed using the system usability scale (SUS). Results A total of 121 MSM were enrolled (59.5%, 72/121 from Atlanta; 40.5%, 49/121 from Seattle). Median age was 28. Nearly half (48.8%, 59/121) were nonwhite, and most (85.9%, 104/121) were gay-identified. Most had tested for HIV in the past (85.1%, 103/121), and 52 (43.0%, 52/121) had a plan to test for HIV regularly. Men used the app for an average of 17.7 minutes over the first 4 months. Over the 4-month period, over half ordered condoms (63.6%, 77/121) and HIV test kits (52.8%, 64/121) on the app. Eight of 86 (9%) PrEP-eligible MSM started PrEP during the 4-month period; of those, 6 of the 8 reported that the app influenced their decision to start PrEP. The mean SUS was 73 (above average). Conclusions A theory-based mobile phone app was acceptable to MSM and was rated as having above-average usability. Most men used the commodity-ordering features of the app during the 4-month evaluation period, and nearly 1 in 10 PrEP-eligible men started PrEP, with most attributing their decision to start PrEP in part to the app. A broader, randomized controlled study of the impact of the app on uptake of prevention behaviors for MSM is warranted. PMID:28279949

Evaluating the Dietary and Nutritional Apps in the Google Play Store.

PubMed

Schumer, Harleigh; Amadi, Chioma; Joshi, Ashish

2018-01-01

The objective of this study was to evaluate the features of diet and nutrition apps available in the Google Play Store. A search was conducted in August 2017 using the Google Play Store database to identify apps related to diet and nutrition. Terms entered into the app search engine included 'diet apps' and 'nutrition apps'. The first 50 apps resulting from each search term was assessed. Duplicates were removed, and a comparative analysis was performed on the remaining diet and nutrition apps. A total of 86 diet and nutrition apps were identified. One hundred percent (n = 86) of the apps retrieved were freely available. More than half of the apps were applicable to a target user group of all ages (94%, n = 81). Stratified analysis across unique diet and nutrition apps (total, n = 72) showed a higher average rating for the diet apps (4.4) in comparison to that for the nutrition apps (4.3). Diet apps were more likely to be recently updated than the nutrition apps (72% vs. 66%), and diet apps were more likely to feature app purchase than nutrition apps (36% vs. 19%). The average rating was slightly higher for diet apps not featuring in-app purchases, but ratings were similar for the nutrition apps. A centralized resource is needed that can provide information on health-related apps to allow for systematic evaluation of their effectiveness. Further research needs to examine improved methods of designing app-store platforms and presenting the available apps to properly guide users in app selection.

21 CFR Appendix D to Part 101 - Nutrition Facts for Cooked Fish

Code of Federal Regulations, 2013 CFR

2013-04-01

... 21 Food and Drugs 2 2013-04-01 2013-04-01 false Nutrition Facts for Cooked Fish D Appendix D to Part 101 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) FOOD FOR HUMAN CONSUMPTION FOOD LABELING Pt. 101, App. D Appendix D to Part 101—Nutrition Facts...

21 CFR Appendix D to Part 101 - Nutrition Facts for Cooked Fish

Code of Federal Regulations, 2014 CFR

2014-04-01

... 21 Food and Drugs 2 2014-04-01 2014-04-01 false Nutrition Facts for Cooked Fish D Appendix D to Part 101 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) FOOD FOR HUMAN CONSUMPTION FOOD LABELING Pt. 101, App. D Appendix D to Part 101—Nutrition Facts...

21 CFR Appendix D to Part 101 - Nutrition Facts for Cooked Fish

Code of Federal Regulations, 2012 CFR

2012-04-01

... 21 Food and Drugs 2 2012-04-01 2012-04-01 false Nutrition Facts for Cooked Fish D Appendix D to Part 101 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) FOOD FOR HUMAN CONSUMPTION FOOD LABELING Pt. 101, App. D Appendix D to Part 101—Nutrition Facts...

21 CFR Appendix D to Part 101 - Nutrition Facts for Cooked Fish

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 2 2010-04-01 2010-04-01 false Nutrition Facts for Cooked Fish D Appendix D to Part 101 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) FOOD FOR HUMAN CONSUMPTION FOOD LABELING Pt. 101, App. D Appendix D to Part 101—Nutrition Facts...

21 CFR Appendix D to Part 101 - Nutrition Facts for Cooked Fish

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 2 2011-04-01 2011-04-01 false Nutrition Facts for Cooked Fish D Appendix D to Part 101 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) FOOD FOR HUMAN CONSUMPTION FOOD LABELING Pt. 101, App. D Appendix D to Part 101—Nutrition Facts...

Static Analysis of Mobile Programs

DTIC Science & Technology

2017-02-01

information flow analysis has the potential to significantly aid human auditors , but it is handicapped by high false positive rates. Instead, auditors ...presents these specifications to a human auditor for validation. We have implemented this framework for a taint analysis of An- droid apps that relies on...of queries to a human auditor . 6.4 Inferring Library Information Flow Specifications Using Dynamic Anal- ysis In [15], we present a technique to mine

Lysosome and calcium dysregulation in Alzheimer's disease: partners in crime.

PubMed

McBrayer, MaryKate; Nixon, Ralph A

2013-12-01

Early-onset FAD (familial Alzheimer's disease) is caused by mutations of PS1 (presenilin 1), PS2 (presenilin 2) and APP (amyloid precursor protein). Beyond the effects of PS1 mutations on proteolytic functions of the γ-secretase complex, mutant or deficient PS1 disrupts lysosomal function and Ca2+ homoeostasis, both of which are considered strong pathogenic factors in FAD. Loss of PS1 function compromises assembly and proton-pumping activity of the vacuolar-ATPase on lysosomes, leading to defective lysosomal acidification and marked impairment of autophagy. Additional dysregulation of cellular Ca2+ by mutant PS1 in FAD has been ascribed to altered ion channels in the endoplasmic reticulum; however, rich stores of Ca2+ in lysosomes are also abnormally released in PS1-deficient cells secondary to the lysosomal acidification defect. The resultant rise in cytosolic Ca2+ activates Ca2+-dependent enzymes, contributing substantially to calpain overactivation that is a final common pathway leading to neurofibrillary degeneration in all forms of AD (Alzheimer's disease). In the present review, we discuss the close inter-relationships among deficits of lysosomal function, autophagy and Ca2+ homoeostasis as a pathogenic process in PS1-related FAD and their relevance to sporadic AD.

PHO4 transcription factor regulates triacylglycerol metabolism under low-phosphate conditions in Saccharomyces cerevisiae.

PubMed

Yadav, Kamlesh Kumar; Singh, Neelima; Rajasekharan, Ram

2015-10-01

In Saccharomyces cerevisiae, PHM8 encodes a phosphatase that catalyses the dephosphorylation of lysophosphatidic acids to monoacylglycerol and nucleotide monophosphate to nucleoside and releases free phosphate. In this report, we investigated the role of PHM8 in triacylglycerol metabolism and its transcriptional regulation by a phosphate responsive transcription factor Pho4p under low-phosphate conditions. We found that the wild-type (BY4741) cells accumulate triacylglycerol and the expression of PHM8 was high under low-phosphate conditions. Overexpression of PHM8 in the wild-type, phm8Δ and quadruple phosphatase mutant (pah1Δdpp1Δlpp1Δapp1Δ) caused an increase in the triacylglycerol levels. However, the introduction of the PHM8 deletion into the quadruple phosphatase mutant resulted in a reduction in triacylglycerol levels and LPA phosphatase activity. The transcriptional activator Pho4p binds to the PHM8 promoter under low-phosphate conditions, activating PHM8 expression, which leads to the formation of monoacylglycerol from LPA. The synthesized monoacylglycerol is acylated to diacylglycerol by Dga1p, which is further acylated to triacylglycerol by the same enzyme. © 2015 The Authors. Molecular Microbiology published by John Wiley & Sons Ltd.

Usability and Acceptability of a Mobile Comprehensive HIV Prevention App for Men Who Have Sex With Men: A Pilot Study.

PubMed

Sullivan, Patrick S; Driggers, Robert; Stekler, Joanne D; Siegler, Aaron; Goldenberg, Tamar; McDougal, Sarah J; Caucutt, Jason; Jones, Jeb; Stephenson, Rob

2017-03-09

Men who have sex with men (MSM) are the group most impacted by the human immunodeficiency virus (HIV) epidemic and the only subgroup in the United States among which new HIV diagnoses are not decreasing. To achieve the US National HIV/AIDS (acquired immunodeficiency syndrome) Strategy goals of reducing new diagnoses by 25%, high (eg, 30-50%) coverage of multiple HIV prevention interventions is needed in both urban and rural areas. Mobile phone "apps" are an important channel through which prevention services could be provided at scale and at low marginal cost. The aim of this study was to evaluate the usability and acceptability of a theory-based Android mobile phone app for HIV prevention. The app included self-assessment tools; prevention recommendations; commodity (condoms, HIV self-tests) ordering; reminders to MSM for basic HIV prevention services, HIV testing, condom use, screening for preexposure prophylaxis (PrEP) and nonoccupational postexposure prophylaxis (nPEP); and prevention and treatment provider locators. The study recruited HIV-negative, Android-using MSM in Atlanta and Seattle who were asked to use the app for 4 months and complete a post-use survey. We measured the use of the app and its features, ordering of commodities, self-report of establishing an HIV testing plan, being HIV tested in the community, and starting PrEP or using nPEP. Usability was assessed using the system usability scale (SUS). A total of 121 MSM were enrolled (59.5%, 72/121 from Atlanta; 40.5%, 49/121 from Seattle). Median age was 28. Nearly half (48.8%, 59/121) were nonwhite, and most (85.9%, 104/121) were gay-identified. Most had tested for HIV in the past (85.1%, 103/121), and 52 (43.0%, 52/121) had a plan to test for HIV regularly. Men used the app for an average of 17.7 minutes over the first 4 months. Over the 4-month period, over half ordered condoms (63.6%, 77/121) and HIV test kits (52.8%, 64/121) on the app. Eight of 86 (9%) PrEP-eligible MSM started PrEP during the 4-month period; of those, 6 of the 8 reported that the app influenced their decision to start PrEP. The mean SUS was 73 (above average). A theory-based mobile phone app was acceptable to MSM and was rated as having above-average usability. Most men used the commodity-ordering features of the app during the 4-month evaluation period, and nearly 1 in 10 PrEP-eligible men started PrEP, with most attributing their decision to start PrEP in part to the app. A broader, randomized controlled study of the impact of the app on uptake of prevention behaviors for MSM is warranted. ©Patrick S Sullivan, Robert Driggers, Joanne D Stekler, Aaron J Siegler, Tamar Goldenberg, Sarah J McDougal, Jason Caucutt, Jeb Jones, Rob Stephenson. Originally published in JMIR Mhealth and Uhealth (http://mhealth.jmir.org), 09.03.2017.

Isoflurane-Induced Caspase-3 Activation Is Dependent on Cytosolic Calcium and Can Be Attenuated by Memantine

PubMed Central

Zhang, Guohua; Dong, Yuanlin; Zhang, Bin; Ichinose, Fumito; Wu, Xu; Culley, Deborah J.; Crosby, Gregory

2008-01-01

Increasing evidence indicates that caspase activation and apoptosis are associated with a variety of neurodegenerative disorders, including Alzheimer's disease. We reported that anesthetic isoflurane can induce apoptosis, alter processing of the amyloid precursor protein (APP), and increase amyloid-β protein (Aβ) generation. However, the mechanism by which isoflurane induces apoptosis is primarily unknown. We therefore set out to assess effects of extracellular calcium concentration on isoflurane-induced caspase-3 activation in H4 human neuroglioma cells stably transfected to express human full-length APP (H4-APP cells). In addition, we tested effects of RNA interference (RNAi) silencing of IP3 receptor, NMDA receptor, and endoplasmic reticulum (ER) calcium pump, sacro-/ER calcium ATPase (SERCA1). Finally, we examined the effects of the NMDA receptor partial antagonist, memantine, in H4-APP cells and brain tissue of naive mice. EDTA (10 mm), BAPTA (10 μm), and RNAi silencing of IP3 receptor, NMDA receptor, or SERCA1 attenuated capase-3 activation. Memantine (4 μm) inhibited isoflurane-induced elevations in cytosolic calcium levels and attenuated isoflurane-induced caspase-3 activation, apoptosis, and cell viability. Memantine (20 mg/kg, i.p.) reduced isoflurane-induced caspase-3 activation in brain tissue of naive mice. These results suggest that disruption of calcium homeostasis underlies isoflurane-induced caspase activation and apoptosis. We also show for the first time that the NMDA receptor partial antagonist, memantine, can prevent isoflurane-induced caspase-3 activation and apoptosis in vivo and in vitro. These findings, indicating that isoflurane-induced caspase activation and apoptosis are dependent on cytosolic calcium levels, should facilitate the provision of safer anesthesia care, especially for Alzheimer's disease and elderly patients. PMID:18434534

Mobile based Appliances switching using Bluetooth

NASA Astrophysics Data System (ADS)

Gupta, Sureshchandra J., Dr; Desai, Kalp; Gaikawad, Deepak; Pawar, Vijay N.; Gangal, Devendranath R.

2008-04-01

How many times do you have to get up from your desk to switch on your Air conditioner or fan when you are completely into your table work? How many times do you feel lazy to get off your comfort to switch on/off your home appliances in different rooms? How much energy do you lose in a day for operating your appliances? The solution is either a large amount of manual work—or the idea that is presented over here: APP-CON (APP-CON stands for appliances control). Here the ordinary cell phone with bluetooth capability acts as remote designed in such a manner that it acts as a helping hand to human by reducing its manual work and therefore saving human energy. The cell phone control of APP-CON units lets you access many of your home appliances situated in different rooms by using just a single remote from distance. Electronics hobbyists would love to make such a remote control themselves. But they find it difficult due to complex circuitry rather than the high cost because of using a number of frequency counting techniques and decade counters. The APP-CON system given here overcomes the aforesaid problems by using a single microcontroller and moreover a simple program or software for bluetooth enabled cell phone and employing simple coding and decoding of remote signals. Here the mobile based remote control is used to operate a number of home appliances basically consists of Bluetooth technology. The unit consists of a transmitter and a receiver consisting of a microcontroller. The importance of bluetooth technology is that the signal to be transmitted from transmitter to the receiver is done without requiring line of sight.

Exosomes: vehicles for the transfer of toxic proteins associated with neurodegenerative diseases?

PubMed

Bellingham, Shayne A; Guo, Belinda B; Coleman, Bradley M; Hill, Andrew F

2012-01-01

Exosomes are small membranous vesicles secreted by a number of cell types including neurons and can be isolated from conditioned cell media or bodily fluids such as urine and plasma. Exosome biogenesis involves the inward budding of endosomes to form multivesicular bodies (MVB). When fused with the plasma membrane, the MVB releases the vesicles into the extracellular environment as exosomes. Proposed functions of these vesicles include roles in cell-cell signaling, removal of unwanted proteins, and the transfer of pathogens between cells. One such pathogen which exploits this pathway is the prion, the infectious particle responsible for the transmissible neurodegenerative diseases such as Creutzfeldt-Jakob disease (CJD) of humans or bovine spongiform encephalopathy (BSE) of cattle. Similarly, exosomes are also involved in the processing of the amyloid precursor protein (APP) which is associated with Alzheimer's disease. Exosomes have been shown to contain full-length APP and several distinct proteolytically cleaved products of APP, including Aβ. In addition, these fragments can be modulated using inhibitors of the proteases involved in APP cleavage. These observations provide further evidence for a novel pathway in which PrP and APP fragments are released from cells. Other proteins such as superoxide dismutase I and alpha-synuclein (involved in amyotrophic lateral sclerosis and Parkinson's disease, respectively) are also found associated with exosomes. This review will focus on the role of exosomes in neurodegenerative disorders and discuss the potential of these vesicles for the spread of neurotoxicity, therapeutics, and diagnostics for these diseases.

Phenotypic characterization of adenovirus type 12 temperature-sensitive mutants in productive infection and transformation.

PubMed

Hama, S; Kimura, G

1980-01-01

Eleven temperature-sensitive mutants of adenovirus type 12, capable of forming plaques in human cells at 33 C but not at 39.5 C, were isolated from a stock of a wild-type strain after treatment with either nitrous acid or hydroxylamine. Complementation tests in doubly infected human cells permitted a tentative assignment of eight of these mutants to six complementation groups. Temperature-shift experiments revealed that one mutant is affected early and most of the other mutants are affected late. Only the early mutant, H12ts505, was temperature sensitive in viral DNA replication. Infectious virions of all the mutants except H12ts505 and two of the late mutants produced at 33 C, appeared to be more heat labile than those of the wild type. Only H12ts505 was temperature sensitive for the establishment of transformation of rat 3Y1 cells. One of the late mutants (H12ts504) had an increased transforming ability at the permissive temperature. Results of temperature-shift transformation experiments suggest that a viral function affected in H12ts505 is required for "initiation" of transformation. Some of the growth properties of H12ts505-transformed cells were also temperature dependent, suggesting that a functional expression of a gene mutation in H12ts505 is required to maintain at least some aspects of the transformed state.

Erratum: Erratum to: "Numerical simulation of the two-phase flow produced by spraying a liquid by a nozzle"

NASA Astrophysics Data System (ADS)

Simakov, N. N.

2018-04-01

Page 1010, left column, line 4 from bottom should read "radius R APP" instead of "diameter D APP" Page 1010, right column, before the formula (19) should read " R APP" instead of " D APP" Page 1010, in the caption to Fig. 5 should read "radius R APP" instead of "diameter D APP" Page 1011, in the caption to Fig. 6 should read "radius R APP" instead of "diameter D APP" Page 1011, left column, second paragraph after Fig. 6, line 4 from top should read "radius R APP" instead of "diameter D APP" Page 1011, the same paragraph, lines 1, 2 from bottom, in the expression for Qm and after it should read "radius R APP" instead of "diameter D APP" Page 1011, left column, paragraph 3 after Fig. 6, last two lines should read " R APP =" instead of " D APP =" Page 1011, Fig. 7, the notation on the abscissa axis should read " R APP" instead of " D APP" Page 1011, in the caption to Fig. 7 should read "radius R APP" instead of "diameter D APP" Page 1011, in caption to Fig. 8 should read "for both radii R APP" instead of "for both diameters D APP" Page 1012, in caption to Fig. 9 should read "for both radii R APP" instead of "for both diameters D APP"

Diaminopurine-Resistant Mutants of Cultured, Diploid Human Fibroblasts

PubMed Central

Rappaport, Harriet; DeMars, Robert

1973-01-01

Clones of cells resistant to 2,6-diaminopurine were detected in skin fibroblast cultures derived from 13 of 21 normal humans of both sexes from 17 unrelated families. Almost all of the cultures that yielded mutants were chosen for further study from among a total of 83 surveyed because they displayed a slight resistance to low concentrations of diaminopurine. The incidences of mutant colonies ranged between about 10-5 and 10-4 per cell surviving prior mutagenic treatment with MNNG. The incidences of spontaneous mutants were about 10-7 to 10-5 in three unrelated cultures. Most independent mutants had distinctly reduced activity of adenine phosphoribosyltransferase but some had apparently normal amounts of activity. Two mutants from unrelated boys had little or no detectable enzyme activity and were unable to effectively use exogenous adenine for growth when purine biosynthesis was blocked with azaserine. Most mutants could utilize exogenous adenine, just as most azaguanine-resistant fibroblast mutants can utilize exogenous hypoxanthine, even when their hypoxanthine-guanine phosphoribosyltransferase activity is reduced. Diverse genetic changes conferred diaminopurine resistance but their specific natures are still undefined. Gross numerical or structural chromosome abnormalities were not observed in the mutants examined so far. Since at least one gene responsible for adenine phosphoribosyltransferase activity is on autosome No. 16 our results suggest that at least some of the cultures yielding mutants were heterozygous and that alleles conferring diaminopurine resistance may be frequent enough to comprise a polymorphism. PMID:4358687

Evaluating the Dietary and Nutritional Apps in the Google Play Store

PubMed Central

Schumer, Harleigh; Amadi, Chioma

2018-01-01

Objectives The objective of this study was to evaluate the features of diet and nutrition apps available in the Google Play Store. Methods A search was conducted in August 2017 using the Google Play Store database to identify apps related to diet and nutrition. Terms entered into the app search engine included ‘diet apps’ and ‘nutrition apps’. The first 50 apps resulting from each search term was assessed. Duplicates were removed, and a comparative analysis was performed on the remaining diet and nutrition apps. Results A total of 86 diet and nutrition apps were identified. One hundred percent (n = 86) of the apps retrieved were freely available. More than half of the apps were applicable to a target user group of all ages (94%, n = 81). Stratified analysis across unique diet and nutrition apps (total, n = 72) showed a higher average rating for the diet apps (4.4) in comparison to that for the nutrition apps (4.3). Diet apps were more likely to be recently updated than the nutrition apps (72% vs. 66%), and diet apps were more likely to feature app purchase than nutrition apps (36% vs. 19%). The average rating was slightly higher for diet apps not featuring in-app purchases, but ratings were similar for the nutrition apps. Conclusions A centralized resource is needed that can provide information on health-related apps to allow for systematic evaluation of their effectiveness. Further research needs to examine improved methods of designing app-store platforms and presenting the available apps to properly guide users in app selection. PMID:29503751

Medical applications: a database and characterization of apps in Apple iOS and Android platforms.

PubMed

Seabrook, Heather J; Stromer, Julie N; Shevkenek, Cole; Bharwani, Aleem; de Grood, Jill; Ghali, William A

2014-08-27

Medical applications (apps) for smart phones and tablet computers are growing in number and are commonly used in healthcare. In this context, there is a need for a diverse community of app users, medical researchers, and app developers to better understand the app landscape. In mid-2012, we undertook an environmental scan and classification of the medical app landscape in the two dominant platforms by searching the medical category of the Apple iTunes and Google Play app download sites. We identified target audiences, functions, costs and content themes using app descriptions and captured these data in a database. We only included apps released or updated between October 1, 2011 and May 31, 2012, with a primary "medical" app store categorization, in English, that contained health or medical content. Our sample of Android apps was limited to the most popular apps in the medical category. Our final sample of Apple iOS (n = 4561) and Android (n = 293) apps illustrate a diverse medical app landscape. The proportion of Apple iOS apps for the public (35%) and for physicians (36%) is similar. Few Apple iOS apps specifically target nurses (3%). Within the Android apps, those targeting the public dominated in our sample (51%). The distribution of app functions is similar in both platforms with reference being the most common function. Most app functions and content themes vary considerably by target audience. Social media apps are more common for patients and the public, while conference apps target physicians. We characterized existing medical apps and illustrated their diversity in terms of target audience, main functions, cost and healthcare topic. The resulting app database is a resource for app users, app developers and health informatics researchers.

Structural characterization of V57D and V57P mutants of human cystatin C, an amyloidogenic protein

DOE Office of Scientific and Technical Information (OSTI.GOV)

Orlikowska, Marta; Szymańska, Aneta; Borek, Dominika

2013-04-01

Val57 point mutants of human cystatin C, which were designed to assess the influence of changes in the properties of the L1 loop on the dimerization propensity, were structurally characterized. Wild-type human cystatin C (hCC wt) is a low-molecular-mass protein (120 amino-acid residues, 13 343 Da) that is found in all nucleated cells. Physiologically, it functions as a potent regulator of cysteine protease activity. While the biologically active hCC wt is a monomeric protein, all crystallization efforts to date have resulted in a three-dimensional domain-swapped dimeric structure. In the recently published structure of a mutated hCC, the monomeric fold wasmore » preserved by a stabilization of the conformationally constrained loop L1 caused by a single amino-acid substitution: Val57Asn. Additional hCC mutants were obtained in order to elucidate the relationship between the stability of the L1 loop and the propensity of human cystatin C to dimerize. In one mutant Val57 was substituted by an aspartic acid residue, which is favoured in β-turns, and in the second mutant proline, a residue known for broadening turns, was substituted for the same Val57. Here, 2.26 and 3.0 Å resolution crystal structures of the V57D andV57P mutants of hCC are reported and their dimeric architecture is discussed in terms of the stabilization and destabilization effects of the introduced mutations.« less

Sensors and Apps for Community-Based Atmospheric Monitoring

EPA Science Inventory

Recent advances in both sensors and wireless communication provide opportunities for improved exposure assessment and increasing community involvement in reducing levels of human exposure to airborne contaminants. These new technologies can enhance data collection to answer scien...

Integrative proteomics, genomics, and translational immunology approaches reveal mutated forms of Proteolipid Protein 1 (PLP1) and mutant-specific immune response in multiple sclerosis.

PubMed

Qendro, Veneta; Bugos, Grace A; Lundgren, Debbie H; Glynn, John; Han, May H; Han, David K

2017-03-01

In order to gain mechanistic insights into multiple sclerosis (MS) pathogenesis, we utilized a multi-dimensional approach to test the hypothesis that mutations in myelin proteins lead to immune activation and central nervous system autoimmunity in MS. Mass spectrometry-based proteomic analysis of human MS brain lesions revealed seven unique mutations of PLP1; a key myelin protein that is known to be destroyed in MS. Surprisingly, in-depth genomic analysis of two MS patients at the genomic DNA and mRNA confirmed mutated PLP1 in RNA, but not in the genomic DNA. Quantification of wild type and mutant PLP RNA levels by qPCR further validated the presence of mutant PLP RNA in the MS patients. To seek evidence linking mutations in abundant myelin proteins and immune-mediated destruction of myelin, specific immune response against mutant PLP1 in MS patients was examined. Thus, we have designed paired, wild type and mutant peptide microarrays, and examined antibody response to multiple mutated PLP1 in sera from MS patients. Consistent with the idea of different patients exhibiting unique mutation profiles, we found that 13 out of 20 MS patients showed antibody responses against specific but not against all the mutant-PLP1 peptides. Interestingly, we found mutant PLP-directed antibody response against specific mutant peptides in the sera of pre-MS controls. The results from integrative proteomic, genomic, and immune analyses reveal a possible mechanism of mutation-driven pathogenesis in human MS. The study also highlights the need for integrative genomic and proteomic analyses for uncovering pathogenic mechanisms of human diseases. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Characterization of multilocus lesions in human cells exposed to X radiation and radon

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chaudhry, M.A.; Jiang, Q.; Ricanati, M.

Human TK6 lymphoblasts were exposed to X radiation or radon, and thymidine kinase negative (TK{sup -/-}) mutants were selected, isolated and harvested for analysis of structural changes in the TK gene. A large majority (82%) of the radon-induced mutants, 74% of the X-radiation-induced mutants and 45% of the spontaneous mutants lost the entire active TK allele. To analyze these mutants further we measured the loss of heterozygosity at several loci neighboring the TK locus on chromosome 17q. A greater proportion (61%) of the radon-induced mutants than X-radiation-induced or spontaneous mutants harbored the smaller lesions involving the TK allele alone ormore » extending from the TK locus to one or both of the closest neighboring sequences tested. Further, 21% of the X-radiation-induced mutants but only 5% of the radon-induced mutants lost heterozygosity at the col1A1 locus, 31 Mb from the TK gene. These results are in agreement with a recent analysis of radon- and X-radiation-induced lesions inactivating the HPRT gene of TK6 cells, in which we reported that a lower percentage of radon- than X-radiation-induced mutants showed lesions extending to markers 800 kb or more from the HPRT gene on the X chromosome. In the present study, we observed that the percentage of slowly growing and very slowly growing TK{sup -/-} mutants was greater after treatment with radon than after treatment with X radiation, regardless of the type of lesion present. It is possible, therefore, that the radon-induced lesions are complex and/or less easily repaired, leading to slow growth in a large proportion of the surviving mutant cells. 36 refs., 6 figs., 2 tabs.« less

Sequence-specific 1H-NMR assignments for the aromatic region of several biologically active, monomeric insulins including native human insulin.

PubMed

Roy, M; Lee, R W; Kaarsholm, N C; Thøgersen, H; Brange, J; Dunn, M F

1990-06-12

The aromatic region of the 1H-FT-NMR spectrum of the biologically fully-potent, monomeric human insulin mutant, B9 Ser----Asp, B27 Thr----Glu has been investigated in D2O. At 1 to 5 mM concentrations, this mutant insulin is monomeric above pH 7.5. Coupling and amino acid classification of all aromatic signals is established via a combination of homonuclear one- and two-dimensional methods, including COSY, multiple quantum filters, selective spin decoupling and pH titrations. By comparisons with other insulin mutants and with chemically modified native insulins, all resonances in the aromatic region are given sequence-specific assignments without any reliance on the various crystal structures reported for insulin. These comparisons also give the sequence-specific assignments of most of the aromatic resonances of the mutant insulins B16 Tyr----Glu, B27 Thr----Glu and B25 Phe----Asp and the chemically modified species des-(B23-B30) insulin and monoiodo-Tyr A14 insulin. Chemical dispersion of the assigned resonances, ring current perturbations and comparisons at high pH have made possible the assignment of the aromatic resonances of human insulin, and these studies indicate that the major structural features of the human insulin monomer (including those critical to biological function) are also present in the monomeric mutant.

MicroRNA-339-5p down-regulates protein expression of β-site amyloid precursor protein-cleaving enzyme 1 (BACE1) in human primary brain cultures and is reduced in brain tissue specimens of Alzheimer disease subjects.

PubMed

Long, Justin M; Ray, Balmiki; Lahiri, Debomoy K

2014-02-21

Alzheimer disease (AD) results, in part, from the excess accumulation of the amyloid-β (Aβ) peptide as neuritic plaques in the brain. The short Aβ peptide is derived from the large transmembrane Aβ precursor protein (APP). The rate-limiting step in the production of Aβ from APP is mediated by the β-site APP-cleaving enzyme 1 (BACE1). Dysregulation of BACE1 levels leading to excess Aβ deposition is implicated in sporadic AD. Thus, elucidating the full complement of regulatory pathways that control BACE1 expression is key to identifying novel drug targets central to the Aβ-generating process. MicroRNAs (miRNAs) are expected to participate in this molecular network. Here, we identified a known miRNA, miR-339-5p, as a key contributor to this regulatory network. Two distinct miR-339-5p target sites were predicted in the BACE1 3'-UTR by in silico analyses. Co-transfection of miR-339-5p with a BACE1 3'-UTR reporter construct resulted in significant reduction in reporter expression. Mutation of both target sites eliminated this effect. Delivery of the miR-339-5p mimic also significantly inhibited expression of BACE1 protein in human glioblastoma cells and human primary brain cultures. Delivery of target protectors designed against the miR-339-5p BACE1 3'-UTR target sites in primary human brain cultures significantly elevated BACE1 expression. Finally, miR-339-5p levels were found to be significantly reduced in brain specimens isolated from AD patients as compared with age-matched controls. Therefore, miR-339-5p regulates BACE1 expression in human brain cells and is most likely dysregulated in at least a subset of AD patients making this miRNA a novel drug target.

MicroRNA-339-5p Down-regulates Protein Expression of β-Site Amyloid Precursor Protein-Cleaving Enzyme 1 (BACE1) in Human Primary Brain Cultures and Is Reduced in Brain Tissue Specimens of Alzheimer Disease Subjects*

PubMed Central

Long, Justin M.; Ray, Balmiki; Lahiri, Debomoy K.

2014-01-01

Alzheimer disease (AD) results, in part, from the excess accumulation of the amyloid-β (Aβ) peptide as neuritic plaques in the brain. The short Aβ peptide is derived from the large transmembrane Aβ precursor protein (APP). The rate-limiting step in the production of Aβ from APP is mediated by the β-site APP-cleaving enzyme 1 (BACE1). Dysregulation of BACE1 levels leading to excess Aβ deposition is implicated in sporadic AD. Thus, elucidating the full complement of regulatory pathways that control BACE1 expression is key to identifying novel drug targets central to the Aβ-generating process. MicroRNAs (miRNAs) are expected to participate in this molecular network. Here, we identified a known miRNA, miR-339-5p, as a key contributor to this regulatory network. Two distinct miR-339-5p target sites were predicted in the BACE1 3′-UTR by in silico analyses. Co-transfection of miR-339-5p with a BACE1 3′-UTR reporter construct resulted in significant reduction in reporter expression. Mutation of both target sites eliminated this effect. Delivery of the miR-339-5p mimic also significantly inhibited expression of BACE1 protein in human glioblastoma cells and human primary brain cultures. Delivery of target protectors designed against the miR-339-5p BACE1 3′-UTR target sites in primary human brain cultures significantly elevated BACE1 expression. Finally, miR-339-5p levels were found to be significantly reduced in brain specimens isolated from AD patients as compared with age-matched controls. Therefore, miR-339-5p regulates BACE1 expression in human brain cells and is most likely dysregulated in at least a subset of AD patients making this miRNA a novel drug target. PMID:24352696

“Let’s get Wasted!” and Other Apps: Characteristics, Acceptability, and Use of Alcohol-Related Smartphone Applications

PubMed Central

Weaver, Emma R; Horyniak, Danielle R; Jenkinson, Rebecca; Dietze, Paul

2013-01-01

Background Smartphone applications (“apps”) offer a number of possibilities for health promotion activities. However, young people may also be exposed to apps with incorrect or poor quality information, since, like the Internet, apps are mostly unregulated. Little is known about the quality of alcohol-related apps or what influence they may have on young people’s behavior. Objective To critically review popular alcohol-related smartphone apps and to explore young people’s opinions of these apps, their acceptability, and use for alcohol-related health promotion. Methods First, a content analysis of 500 smartphone apps available via Apple iTunes and Android Google Play stores was conducted. Second, all available blood alcohol concentration (BAC) apps were tested against four individual case profiles of known BAC from a previous study. Third, two focus group discussions explored how young people use alcohol-related apps, particularly BAC apps. Results 384 apps were included; 50% (192) were entertainment apps, 39% (148) were BAC apps, and 11% (44) were health promotion and/or stop drinking–related apps. When testing the BAC apps, there was wide variation in results, with apps tending to overestimate BAC scores compared with recorded scores. Participants were skeptical of the accuracy of BAC apps, and there was an overall concern that these apps would be used as a form of entertainment, further encouraging young people to drink, rather than reduce their drinking and risk taking. Conclusions The majority of popular alcohol-related apps encouraged alcohol consumption. Apps estimating blood alcohol concentration were widely available but were highly unreliable. Health departments and prominent health organizations need to endorse alcohol smartphone apps that are accurate and evidence-based to give specific apps credibility in the ever-expanding market of unregulated apps. PMID:25100681

Immunogenicity of a meningococcal native outer membrane vesicle vaccine with attenuated endotoxin and over-expressed factor H binding protein in infant rhesus monkeys

PubMed Central

Koeberling, Oliver; Seubert, Anja; Santos, George; Colaprico, Annalisa; Ugozzoli, Mildred; Donnelly, John; Granoff, Dan M.

2011-01-01

We previously investigated immunogenicity of meningococcal native outer membrane vesicle (NOMV) vaccines prepared from recombinant strains with attenuated endotoxin (ΔLpxL1) and over-expressed factor H binding protein (fHbp) in a mouse model. The vaccines elicited broad serum bactericidal antibody responses. While human toll-like receptor 4 (TLR-4) is mainly stimulated by wildtype meningococcal endotoxin, mouse TLR-4 is stimulated by both the wildtype and mutant endotoxin. An adjuvant effect in mice of the mutant endotoxin would be expected to be much less in humans, and may have contributed to the broad mouse bactericidal responses. Here we show that as previously reported for humans, rhesus primate peripheral blood mononuclear cells incubated with a NOMV vaccine from ΔLpxL1 recombinant strains had lower proinflammatory cytokine responses than with a control wildtype NOMV vaccine. The cytokine responses to the mutant vaccine were similar to those elicited by a detergent-treated, wildtype outer membrane vesicle vaccine that had been safely administered to humans. Monkeys (N=4) were immunized beginning at ages 2 to 3 months with three doses of a NOMV vaccine prepared from ΔLpxL1 recombinant strains with over-expressed fHbp in the variant 1 and 2 groups. The mutant NOMV vaccine elicited serum bactericidal titers ≥1:4 against all 10 genetically diverse strains tested, including 9 with heterologous PorA to those in the vaccine. Negative-control animals had serum bactericidal titers <1:4. Thus, the mutant NOMV vaccine elicited broadly protective serum antibodies in a non-human infant primate model that is more relevant for predicting human antibody responses than mice. PMID:21571025

Sialylation of lipooligosaccharides is dispensable for the virulence of Haemophilus ducreyi in humans.

PubMed

Spinola, Stanley M; Li, Wei; Fortney, Kate R; Janowicz, Diane M; Zwickl, Beth; Katz, Barry P; Munson, Robert S

2012-02-01

Sialylated glycoconjugates on the surfaces of mammalian cells play important roles in intercellular communication and self-recognition. The sialic acid preferentially expressed in human tissues is N-acetylneuraminic acid (Neu5Ac). In a process called molecular mimicry, many bacterial pathogens decorate their cell surface glycolipids with Neu5Ac. Incorporation of Neu5Ac into bacterial glycolipids promotes bacterial interactions with host cell receptors called Siglecs. These interactions affect bacterial adherence, resistance to serum killing and phagocytosis, and innate immune responses. Haemophilus ducreyi, the etiologic agent of chancroid, expresses lipooligosaccharides (LOS) that are highly sialylated. However, an H. ducreyi sialyltransferase (lst) mutant, whose LOS contain reduced levels of Neu5Ac, is fully virulent in human volunteers. Recently, a second sialyltransferase gene (Hd0053) was discovered in H. ducreyi, raising the possibility that Hd0053 compensated for the loss of lst during human infection. CMP-Neu5Ac is the obligate nucleotide sugar donor for all bacterial sialyltransferases; LOS derived from an H. ducreyi CMP-Neu5Ac synthetase (neuA) mutant has no detectable Neu5Ac. Here, we compared an H. ducreyi neuA mutant to its wild-type parent in several models of pathogenesis. In human inoculation experiments, the neuA mutant formed papules and pustules at rates that were no different than those of its parent. When grown in media with and without Neu5Ac supplementation, the neuA mutant and its parent had similar phenotypes in bactericidal, macrophage uptake, and dendritic cell activation assays. Although we cannot preclude a contribution of LOS sialylation to ulcerative disease, these data strongly suggest that sialylation of LOS is dispensable for H. ducreyi pathogenesis in humans.

21 CFR Appendix C to Part 101 - Nutrition Facts for Raw Fruits and Vegetables

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 2 2011-04-01 2011-04-01 false Nutrition Facts for Raw Fruits and Vegetables C Appendix C to Part 101 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) FOOD FOR HUMAN CONSUMPTION FOOD LABELING Pt. 101, App. C Appendix C to Part 101—Nutrition Facts...

21 CFR Appendix C to Part 101 - Nutrition Facts for Raw Fruits and Vegetables

Code of Federal Regulations, 2012 CFR

2012-04-01

... 21 Food and Drugs 2 2012-04-01 2012-04-01 false Nutrition Facts for Raw Fruits and Vegetables C Appendix C to Part 101 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) FOOD FOR HUMAN CONSUMPTION FOOD LABELING Pt. 101, App. C Appendix C to Part 101—Nutrition Facts...

21 CFR Appendix C to Part 101 - Nutrition Facts for Raw Fruits and Vegetables

Code of Federal Regulations, 2013 CFR

2013-04-01

... 21 Food and Drugs 2 2013-04-01 2013-04-01 false Nutrition Facts for Raw Fruits and Vegetables C Appendix C to Part 101 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) FOOD FOR HUMAN CONSUMPTION FOOD LABELING Pt. 101, App. C Appendix C to Part 101—Nutrition Facts...

21 CFR Appendix C to Part 101 - Nutrition Facts for Raw Fruits and Vegetables

Code of Federal Regulations, 2014 CFR

2014-04-01

... 21 Food and Drugs 2 2014-04-01 2014-04-01 false Nutrition Facts for Raw Fruits and Vegetables C Appendix C to Part 101 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) FOOD FOR HUMAN CONSUMPTION FOOD LABELING Pt. 101, App. C Appendix C to Part 101—Nutrition Facts...

45 CFR Appendix B to Part 1168 - Disclosure Form To Report Lobbying

Code of Federal Regulations, 2012 CFR

2012-10-01

... 45 Public Welfare 3 2012-10-01 2012-10-01 false Disclosure Form To Report Lobbying B Appendix B to Part 1168 Public Welfare Regulations Relating to Public Welfare (Continued) NATIONAL FOUNDATION ON THE ARTS AND THE HUMANITIES NATIONAL ENDOWMENT FOR THE HUMANITIES NEW RESTRICTIONS ON LOBBYING Pt. 1168, App. B Appendix B to Part 1168—Disclosure...

21 CFR Appendix C to Part 101 - Nutrition Facts for Raw Fruits and Vegetables

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 2 2010-04-01 2010-04-01 false Nutrition Facts for Raw Fruits and Vegetables C Appendix C to Part 101 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) FOOD FOR HUMAN CONSUMPTION FOOD LABELING Pt. 101, App. C Appendix C to Part 101—Nutrition Facts...

Review of infectious diseases applications for iPhone/iPad and Android: from pocket to patient.

PubMed

Moodley, Amaran; Mangino, Julie E; Goff, Debra A

2013-10-01

The explosion of medical applications (apps) in the Apple and Google Play app stores has made it increasingly difficult to find relevant and reliable infectious diseases (ID) apps. Apple created a section called "Apps for Healthcare Professionals"; however, several ID apps are missing. Google Play's ID category has several non-ID apps. Many apps involve diagnosis and patient management, creating a need for regulations and oversight by the US Food and Drug Administration. There are no standards to guide accuracy or reliability of medical apps' content. We searched Apple and Google Play app stores to identify new ID apps. Over 1200 apps were identified. We applied several exclusion criteria to identify adult/pediatric apps with data from trustworthy sources that were not reviewed within the last year. Twelve new ID apps were identified with a comprehensive list of 24 ID apps to assist healthcare professionals at the point of care.

Defective transport of the obesity mutant PC1/3 N222D contributes to loss of function.

PubMed

Prabhu, Yogikala; Blanco, Elias H; Liu, Ming; Peinado, Juan R; Wheeler, Matthew C; Gekakis, Nicholas; Arvan, Peter; Lindberg, Iris

2014-07-01

Mutations in the PCSK1 gene encoding prohormone convertase 1/3 (PC1/3) are strongly associated with obesity in humans. The PC1/3(N222D) mutant mouse thus far represents the only mouse model that mimics the PC1/3 obesity phenotype in humans. The present investigation addresses the cell biology of the N222D mutation. Metabolic labeling experiments reveal a clear defect in the kinetics of insulin biosynthesis in islets from PC1/3(N222D) mutant mice, resulting in an increase in both proinsulin and its processing intermediates, predominantly lacking cleavage at the Arg-Arg site. Although the mutant PC1/3 zymogen is correctly processed to the 87-kDa form, pulse-chase immunoprecipitation experiments, labeling, and immunohistochemical experiments using uncleavable variants all demonstrate that the PC1/3-N222D protein is largely mislocalized compared with similar wild-type (WT) constructs, being predominantly retained in the endoplasmic reticulum. The PC1/3-N222D mutant also undergoes more efficient degradation via the ubiquitin-proteasome system than the WT enzyme. Lastly, the mutant PC1/3-N222D protein coimmunoprecipitates with WT PC1/3 and exerts a modest effect on intracellular retention of the WT enzyme. These profound alterations in the cell biology of PC1/3-N222D are likely to contribute to the defective insulin biosynthetic events observed in the mutant mice and may be relevant to the dramatic contributions of polymorphisms in this gene to human obesity.

Defective Transport of the Obesity Mutant PC1/3 N222D Contributes to Loss of Function

PubMed Central

Prabhu, Yogikala; Blanco, Elias H.; Liu, Ming; Peinado, Juan R.; Wheeler, Matthew C.; Gekakis, Nicholas; Arvan, Peter

2014-01-01

Mutations in the PCSK1 gene encoding prohormone convertase 1/3 (PC1/3) are strongly associated with obesity in humans. The PC1/3N222D mutant mouse thus far represents the only mouse model that mimics the PC1/3 obesity phenotype in humans. The present investigation addresses the cell biology of the N222D mutation. Metabolic labeling experiments reveal a clear defect in the kinetics of insulin biosynthesis in islets from PC1/3N222D mutant mice, resulting in an increase in both proinsulin and its processing intermediates, predominantly lacking cleavage at the Arg-Arg site. Although the mutant PC1/3 zymogen is correctly processed to the 87-kDa form, pulse-chase immunoprecipitation experiments, labeling, and immunohistochemical experiments using uncleavable variants all demonstrate that the PC1/3-N222D protein is largely mislocalized compared with similar wild-type (WT) constructs, being predominantly retained in the endoplasmic reticulum. The PC1/3-N222D mutant also undergoes more efficient degradation via the ubiquitin-proteasome system than the WT enzyme. Lastly, the mutant PC1/3-N222D protein coimmunoprecipitates with WT PC1/3 and exerts a modest effect on intracellular retention of the WT enzyme. These profound alterations in the cell biology of PC1/3-N222D are likely to contribute to the defective insulin biosynthetic events observed in the mutant mice and may be relevant to the dramatic contributions of polymorphisms in this gene to human obesity. PMID:24828610

Mobile Apps for the Dietary Approaches to Stop Hypertension (DASH): App Quality Evaluation.

PubMed

DiFilippo, Kristen Nicole; Huang, Wen-Hao David; Chapman-Novakofski, Karen M

2018-03-08

To identify the availability and quality of apps supporting Dietary Approaches to Stop Hypertension (DASH) education. The researchers identified DASH apps over 1 month in the Apple App Store. Five registered dietitians used the App Quality Evaluation (AQEL) to evaluate app quality on 7 domains. Interrater reliability was tested using intraclass correlations. One paid and 3 free DASH apps were evaluated. Interrater reliability (n = 5) was good for 3 apps and fair for 1 app. Only the paid app scored high (>8 of 10) on most AQEL quality domains. Based on lower quality found among the included free apps, further development of free apps is warranted. Whereas the paid app may be useful in supporting DASH education, future research should determine whether improvements in clinical outcomes are found and whether this app should be improved to address AQEL domains better. Copyright © 2018 Society for Nutrition Education and Behavior. Published by Elsevier Inc. All rights reserved.

AppVis: Enabling data-rich apps in app inventor

NASA Astrophysics Data System (ADS)

Harunani, Farzeen

MIT App Inventor has enabled middle school students to learn computing while creating their own apps--including apps that serve community needs. However, few resources exist for building apps that gather and share data. There is a need for new tools and an instructional materials for students to build data-enabled, community-focused apps. We developed an extension for App Inventor, called AppVis, which allows app-makers to publish and retrieve data from iSENSE, our existing web-based collaborative data visualization platform. We used AppVis and supporting instructional materials in two one-week summer camps attended by a total of 33 middle school students. Based on student interview data and analysis of their final apps, our approach was broadly accessible to a diverse population of students. Students were motivated to build apps that could be used by their own communities. This thesis presents the design of AppVis and results from students' work in summer camps.

mHealthApps: A Repository and Database of Mobile Health Apps.

PubMed

Xu, Wenlong; Liu, Yin

2015-03-18

The market of mobile health (mHealth) apps has rapidly evolved in the past decade. With more than 100,000 mHealth apps currently available, there is no centralized resource that collects information on these health-related apps for researchers in this field to effectively evaluate the strength and weakness of these apps. The objective of this study was to create a centralized mHealth app repository. We expect the analysis of information in this repository to provide insights for future mHealth research developments. We focused on apps from the two most established app stores, the Apple App Store and the Google Play Store. We extracted detailed information of each health-related app from these two app stores via our python crawling program, and then stored the information in both a user-friendly array format and a standard JavaScript Object Notation (JSON) format. We have developed a centralized resource that provides detailed information of more than 60,000 health-related apps from the Apple App Store and the Google Play Store. Using this information resource, we analyzed thousands of apps systematically and provide an overview of the trends for mHealth apps. This unique database allows the meta-analysis of health-related apps and provides guidance for research designs of future apps in the mHealth field.

Trans fatty acids enhance amyloidogenic processing of the Alzheimer amyloid precursor protein (APP).

PubMed

Grimm, Marcus O W; Rothhaar, Tatjana L; Grösgen, Sven; Burg, Verena K; Hundsdörfer, Benjamin; Haupenthal, Viola J; Friess, Petra; Kins, Stefan; Grimm, Heike S; Hartmann, Tobias

2012-10-01

Hydrogenation of oils and diary products of ruminant animals leads to an increasing amount of trans fatty acids in the human diet. Trans fatty acids are incorporated in several lipids and accumulate in the membrane of cells. Here we systematically investigate whether the regulated intramembrane proteolysis of the amyloid precursor protein (APP) is affected by trans fatty acids compared to the cis conformation. Our experiments clearly show that trans fatty acids compared to cis fatty acids increase amyloidogenic and decrease nonamyloidogenic processing of APP, resulting in an increased production of amyloid beta (Aβ) peptides, main components of senile plaques, which are a characteristic neuropathological hallmark for Alzheimer's disease (AD). Moreover, our results show that oligomerization and aggregation of Aβ are increased by trans fatty acids. The mechanisms identified by this in vitro study suggest that the intake of trans fatty acids potentially increases the AD risk or causes an earlier onset of the disease. Copyright © 2012 Elsevier Inc. All rights reserved.

sAPP modulates iron efflux from brain microvascular endothelial cells by stabilizing the ferrous iron exporter ferroportin

PubMed Central

McCarthy, Ryan C; Park, Yun-Hee; Kosman, Daniel J

2014-01-01

A sequence within the E2 domain of soluble amyloid precursor protein (sAPP) stimulates iron efflux. This activity has been attributed to a ferroxidase activity suggested for this motif. We demonstrate that the stimulation of efflux supported by this peptide and by sAPPα is due to their stabilization of the ferrous iron exporter, ferroportin (Fpn), in the plasma membrane of human brain microvascular endothelial cells (hBMVEC). The peptide does not bind ferric iron explaining why it does not and thermodynamically cannot promote ferrous iron autoxidation. This peptide specifically pulls Fpn down from the plasma membrane of hBMVEC; based on these results, FTP, for ferroportin-targeting peptide, correctly identifies the function of this peptide. The data suggest that in stabilizing Fpn via the targeting due to the FTP sequence, sAPP will increase the flux of iron into the cerebral interstitium. This inference correlates with the observation of significant iron deposition in the amyloid plaques characteristic of Alzheimer’s disease. PMID:24867889

Qualitative evaluation of mobile cancer apps with particular attention to the target group, content, and advertising.

PubMed

Böhme, Cathleen; von Osthoff, Marc Baron; Frey, Katrin; Hübner, Jutta

2018-01-01

Medical apps are gaining importance rapidly. Also in the field of cancer care, apps are offered. Yet, so far little is known with respect to their quality. In a pilot phase we developed a rating tool based on formal and content-related criteria for the assessment of cancer apps. We used this instrument on cancer apps available in the App Store (iOS) concerning breast, prostate and colorectal cancer. The results were stratified according to target group, content and advertising. We assessed 41 mobile cancer apps. Six apps (14.63%) scored very high, fifteen apps (36.59%) high, seventeen apps (41.46%) were deficient, and three apps (7.32%) were insufficient. The largest group of apps represents those apps with the "deficient" rating. The very good to good apps had reliable sources, a concrete intent/ purpose in their app description, and a strict distinction of scientific content and advertisement. Apps with the predicates "deficient" or "insufficient" had particularly poor ratings, e.g. in the subscales "information on sources" and "data protection". Almost half of the tested apps were deficient or insufficient. In order to improve safety of patients using apps, some regulation seems mandatory. Putting apps under the legislation for medical products might be one way to better regulate and control quality. Second, efforts should focus on the development of checklists that make it easier for patients to search for suitable cancer apps.

Aβ-Induced Inflammatory Processes in Microglia Cells of APP23 Transgenic Mice

PubMed Central

Bornemann, Klaus D.; Wiederhold, Karl-Heinz; Pauli, Chantal; Ermini, Florian; Stalder, Martina; Schnell, Lisa; Sommer, Bernd; Jucker, Mathias; Staufenbiel, Matthias

2001-01-01

A microglial response is part of the inflammatory processes in Alzheimer’s disease (AD). We have used APP23 transgenic mice overexpressing human amyloid precursor protein with the Swedish mutation to characterize this microglia response to amyloid deposits in aged mice. Analyses with MAC-1 and F4/80 antibodies as well as in vivo labeling with bromodeoxyuridine demonstrate that microglia in the plaque vicinity are in an activated state and that proliferation contributes to their accumulation at the plaque periphery. The amyloid-induced microglia activation may be mediated by scavenger receptor A, which is generally elevated, whereas the increased immunostaining of the receptor for advanced glycation end products is more restricted. Although components of the phagocytic machinery such as macrosialin and Fc receptors are increased in activated microglia, efficient clearance of amyloid is missing seemingly because of the lack of amyloid-bound autoantibodies. Similarly, although up-regulation of major histocompatibility complex class II (IA) points toward an intact antigen-presenting function of microglia, lack of T and B lymphocytes does not indicate a cell-mediated immune response in the brains of APP23 mice. The similar characteristics of microglia in the APP23 mice and in AD render the mouse model suitable to study the role of inflammatory processes during AD pathogenesis. PMID:11141480

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

PubMed

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

2016-12-02

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. 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. 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. 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 of features per app compared with the basic apps. Using the MARS instrument, we were able to identify high-quality apps that were rated as being very interesting and entertaining, highly interactive and customizable, intuitive, and easy to use and to navigate as well as having a high level of visual appeal and good-quality information. Many medication reminder apps are available in the app stores; however, the majority of them did not have many of the desirable features and were, therefore, considered low quality. Through a systematic stepwise process, we were able to identify high-quality apps to be tested in a future study that will provide evidence on the use of medication reminder apps to improve medication adherence. ©Karla Santo, Sarah S Richtering, John Chalmers, Aravinda Thiagalingam, Clara K Chow, Julie Redfern. Originally published in JMIR Mhealth and Uhealth (http://mhealth.jmir.org), 02.12.2016.

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 of features per app compared with the basic apps. Using the MARS instrument, we were able to identify high-quality apps that were rated as being very interesting and entertaining, highly interactive and customizable, intuitive, and easy to use and to navigate as well as having a high level of visual appeal and good-quality information. Conclusions Many medication reminder apps are available in the app stores; however, the majority of them did not have many of the desirable features and were, therefore, considered low quality. Through a systematic stepwise process, we were able to identify high-quality apps to be tested in a future study that will provide evidence on the use of medication reminder apps to improve medication adherence. PMID:27913373

phoP, SPI1, SPI2 and aroA mutants of Salmonella Enteritidis induce a different immune response in chickens.

PubMed

Elsheimer-Matulova, Marta; Varmuzova, Karolina; Kyrova, Kamila; Havlickova, Hana; Sisak, Frantisek; Rahman, Masudur; Rychlik, Ivan

2015-09-17

Poultry is the most frequent reservoir of non-typhoid Salmonella enterica for humans. Understanding the interactions between chickens and S. enterica is therefore important for vaccine design and subsequent decrease in the incidence of human salmonellosis. In this study we therefore characterized the interactions between chickens and phoP, aroA, SPI1 and SPI2 mutants of S. Enteritidis. First we tested the response of HD11 chicken macrophage-like cell line to S. Enteritidis infection monitoring the transcription of 36 genes related to immune response. All the mutants and the wild type strain induced inflammatory signaling in the HD11 cell line though the response to SPI1 mutant infection was different from the rest of the mutants. When newly hatched chickens were inoculated, the phoP as well as the SPI1 mutant did not induce an expression of any of the tested genes in the cecum. Despite this, such chickens were protected against challenge with wild-type S. Enteritidis. On the other hand, inoculation of chickens with the aroA or SPI2 mutant induced expression of 27 and 18 genes, respectively, including genes encoding immunoglobulins. Challenge of chickens inoculated with these two mutants resulted in repeated induction of 11 and 13 tested genes, respectively, including the genes encoding immunoglobulins. In conclusion, SPI1 and phoP mutants induced protective immunity without inducing an inflammatory response and antibody production. Inoculation of chickens with the SPI2 and aroA mutants also led to protective immunity but was associated with inflammation and antibody production. The differences in interaction between the mutants and chicken host can be used for a more detailed understanding of the chicken immune system.

Functions of transmembrane domain 3 of human melanocortin-4 receptor.

PubMed

Mo, Xiu-Lei; Yang, Rui; Tao, Ya-Xiong

2012-12-01

The melanocortin-4 receptor (MC4R) is a G protein-coupled receptor critical for maintaining energy homeostasis. Transmembrane domain 3 (TM3) of MC4R contains residues that were suggested to be essential in ligand binding and signaling. Several MC4R mutations in TM3 are associated with human obesity. To gain a better understanding of the functions of TM3, we analyzed the functions of 26 residues in TM3 using alanine-scanning mutagenesis. We showed that all mutants had normal cell-surface expression. Four mutants were defective in ligand binding and signaling and six mutants had normal ligand binding but impaired cAMP production. L140A had increased basal cAMP level. To further characterize the function of L140, we generated 17 additional L140 mutants. Fifteen L140 mutants had significantly decreased cell-surface expression, with L140R and L140V expressed normally. Ten L140 mutants had increased basal cAMP activities. Four L140 mutants were defective in ligand-stimulated cAMP generation. Interestingly, with the ERK1/2 pathway, we showed that nine constitutively active mutants had similar levels of basal pERK1/2 as that of WT, and two signaling defective mutants had similar levels of pERK1/2 as that of WT upon agonist stimulation, different from their cAMP signaling properties, suggesting biased signaling in these mutant receptors. In summary, we identified 13 residues in TM3 that were essential for ligand binding and/or signaling. Moreover, L140 was critical for locking MC4R in inactive conformation and several mutants showed biased signaling in cAMP and ERK1/2 signaling pathways.

Phenotypic outcomes in Mouse and Human Foxc1 dependent Dandy-Walker cerebellar malformation suggest shared mechanisms.

PubMed

Haldipur, Parthiv; Dang, Derek; Aldinger, Kimberly A; Janson, Olivia K; Guimiot, Fabien; Adle-Biasette, Homa; Dobyns, William B; Siebert, Joseph R; Russo, Rosa; Millen, Kathleen J

2017-01-16

FOXC1 loss contributes to Dandy-Walker malformation (DWM), a common human cerebellar malformation. Previously, we found that complete Foxc1 loss leads to aberrations in proliferation, neuronal differentiation and migration in the embryonic mouse cerebellum (Haldipur et al., 2014). We now demonstrate that hypomorphic Foxc1 mutant mice have granule and Purkinje cell abnormalities causing subsequent disruptions in postnatal cerebellar foliation and lamination. Particularly striking is the presence of a partially formed posterior lobule which echoes the posterior vermis DW 'tail sign' observed in human imaging studies. Lineage tracing experiments in Foxc1 mutant mouse cerebella indicate that aberrant migration of granule cell progenitors destined to form the posterior-most lobule causes this unique phenotype. Analyses of rare human del chr 6p25 fetal cerebella demonstrate extensive phenotypic overlap with our Foxc1 mutant mouse models, validating our DWM models and demonstrating that many key mechanisms controlling cerebellar development are likely conserved between mouse and human.

RAS signaling and anti-RAS therapy: lessons learned from genetically engineered mouse models, human cancer cells, and patient-related studies.

PubMed

Fang, Bingliang

2016-01-01

Activating mutations of oncogenic RAS genes are frequently detected in human cancers. The studies in genetically engineered mouse models (GEMMs) reveal that Kras-activating mutations predispose mice to early onset tumors in the lung, pancreas, and gastrointestinal tract. Nevertheless, most of these tumors do not have metastatic phenotypes. Metastasis occurs when tumors acquire additional genetic changes in other cancer driver genes. Studies on clinical specimens also demonstrated that KRAS mutations are present in premalignant tissues and that most of KRAS mutant human cancers have co-mutations in other cancer driver genes, including TP53, STK11, CDKN2A, and KMT2C in lung cancer; APC, TP53, and PIK3CA in colon cancer; and TP53, CDKN2A, SMAD4, and MED12 in pancreatic cancer. Extensive efforts have been devoted to develop therapeutic agents that target enzymes involved in RAS posttranslational modifications, that inhibit downstream effectors of RAS signaling pathways, and that kill RAS mutant cancer cells through synthetic lethality. Recent clinical studies have revealed that sorafenib, a pan-RAF and VEGFR inhibitor, has impressive benefits for KRAS mutant lung cancer patients. Combination therapy of MEK inhibitors with either docetaxel, AKT inhibitors, or PI3K inhibitors also led to improved clinical responses in some KRAS mutant cancer patients. This review discusses knowledge gained from GEMMs, human cancer cells, and patient-related studies on RAS-mediated tumorigenesis and anti-RAS therapy. Emerging evidence demonstrates that RAS mutant cancers are heterogeneous because of the presence of different mutant alleles and/or co-mutations in other cancer driver genes. Effective subclassifications of RAS mutant cancers may be necessary to improve patients' outcomes through personalized precision medicine. © The Author 2015. Published by ABBS Editorial Office in association with Oxford University Press on behalf of the Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences.

Users’ Adoption of Mental Health Apps: Examining the Impact of Information Cues

PubMed Central

Huang, Hsiao-Ying

2017-01-01

Background Numerous mental health apps have been developed and made available to users on the current app market. Users may find it difficult and overwhelming to select apps from the hundreds of choices that are available in the app marketplace. Clarifying what information cues may impact a user’s selection and adoption of mental health apps is now a critical and pressing issue. Objective The aim of this study was to investigate the impact of information cues on users’ adoption of anxiety apps using observational data from the Android app market. Methods A systematic search of anxiety apps was conducted on the Android app store by using keywords search. The title and metadata information of a total of 274 apps that met our criteria were collected and analyzed. Three trained researchers recorded the app rankings from the search results page on different dates and Web browsers. Results Our results show that ratings (r=.56, P<.001) and reviews (r=.39, P<.001) have significant positive correlations with the number of installs, and app prices have significant negative correlations with installs (r=−.36). The results also reveal that lower-priced apps have higher ratings (r=−.23, P<.001) and a greater number of app permission requests (r=.18, P=.002) from the device. For app titles, we found that apps with titles related to symptoms have significantly lower installs than apps with titles that are not related to symptoms (P<.001). Conclusions This study revealed a relationship between information cues and users’ adoption of mental health apps by analyzing observational data. As the first of its kind, we found impactful indicators for mental health app adoptions. We also discovered a labeling effect of app titles that could hinder mental health app adoptions and which may provide insight for future designs of mental health apps and their search mechanisms. PMID:28659256

mHealth in Urology: A Review of Experts' Involvement in App Development.

PubMed

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

2015-01-01

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. 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. 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. 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.

Pro-smoking apps: where, how and who are most at risk.

PubMed

BinDhim, Nasser F; Freeman, Becky; Trevena, Lyndal

2015-03-01

Pro-smoking applications (app) provide information about brands of tobacco products, where to buy them, and encourage their use. It is unclear in which countries these apps are being downloaded, or whether app stores play a role in promoting or regulating these apps, particularly those that appear to target children. The lifetime popularity of 107 pro-smoking apps was investigated, using a third-party app metrics service that aggregates data from app stores about app download popularity by country. Apps were deemed popular if at any time in their lifespan they achieved a top 25 ranking overall across all apps, or a top 25 ranking in any particular category of apps, such as 'educational games'. Fifty-eight pro-smoking apps reached 'popularity' status in Apple and Android stores in one or more of 49 countries, particularly Italy, Egypt, Germany, Belgium and the USA. The daily downloads in each country ranged from approximately 2000 to 80 000. The Apple store featured five of the pro-smoking apps in various categories, and two apps were featured by the Android market. Two pro-smoking apps in the Apple store were extremely popular in the 'Educational Games' and 'Kids' Games' categories. Pro-smoking apps were popular in many countries. Most apps were assigned to entertainment and games categories, with some apps specifically targeting children through placement in categories directed at children. App stores that feature pro-smoking apps may be in violation of tobacco control laws. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

Smartphone applications in burns.

PubMed

Wurzer, Paul; Parvizi, Daryousch; Lumenta, David B; Giretzlehner, Michael; Branski, Ludwik K; Finnerty, Celeste C; Herndon, David N; Tuca, Alexandru; Rappl, Thomas; Smolle, Christian; Kamolz, Lars P

2015-08-01

Since the introduction of applications (apps) for smartphones, the popularity of medical apps has been rising. The aim of this review was to demonstrate the current availability of apps related to burns on Google's Android and Apple's iOS store as well as to include a review of their developers, features, and costs. A systematic online review of Google Play Store and Apple's App Store was performed by using the following search terms: "burn," "burns," "thermal," and the German word "Verbrennung." All apps that were programmed for use as medical apps for burns were included. The review was performed from 25 February until 1 March 2014. A closer look at the free and paid calculation apps including a standardized patient was performed. Four types of apps were identified: calculators, information apps, book/journal apps, and games. In Google Play Store, 31 apps were related to burns, of which 20 were calculation apps (eight for estimating the total body surface area (TBSA) and nine for total fluid requirement (TFR)). In Apple's App Store, under the category of medicine, 39 apps were related to burns, of which 21 were calculation apps (19 for estimating the TBSA and 17 for calculating the TFR). In 19 out of 32 available calculation apps, our study showed a correlation of the calculated TFR compared to our standardized patient. The review demonstrated that many apps for medical burns are available in both common app stores. Even free available calculation apps may provide a more objective and reproducible procedure compared to manual/subjective estimations, although there is still a lack of data security especially in personal data entered in calculation apps. Further clinical studies including smartphone apps for burns should be performed. Copyright © 2014 Elsevier Ltd and ISBI. All rights reserved.

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

Smartphone apps for orthopaedic sports medicine - a smart move?

PubMed

Wong, Seng Juong; Robertson, Greg A; Connor, Katie L; Brady, Richard R; Wood, Alexander M

2015-01-01

With the advent of smartphones together with their downloadable applications (apps), there is increasing opportunities for doctors, including orthopaedic sports surgeons, to integrate such technology into clinical practice. However, the clinical reliability of these medical apps remains questionable. We reviewed available apps themed specifically towards Orthopaedic Sports Medicine and related conditions and assessed the level of medical professional involvement in their design and content, along with a review of these apps. The most popular smartphone app stores (Android, Apple, Blackberry, Windows, Samsung, Nokia) were searched for Orthopaedic Sports medicine themed apps, using the search terms; Orthopaedic Sports Medicine, Orthopaedics, Sports medicine, Knee Injury, Shoulder Injury, Anterior Cruciate Ligament Tear, Medial Collateral Ligament Tear, Rotator Cuff Tear, Meniscal Tear, Tennis Elbow. All English language apps related to orthopaedic sports medicine were included. A total of 76 individual Orthopaedic Sports Medicine themed apps were identified. According to app store classifications, there were 45 (59 %) medical themed apps, 28 (37 %) health and fitness themed apps, 1 (1 %) business app, 1 (1 %) reference app and 1 (1 %) sports app. Forty-nine (64 %) apps were available for download free of charge. For those that charged access, the prices ranged from £0.69 to £69.99. Only 51 % of sports medicine apps had customer satisfaction ratings and 39 % had named medical professional involvement in their development or content. We found the majority of Orthopaedic Sports Medicine apps had no named medical professional involvement, raising concerns over their content and evidence-base. We recommend increased regulation of such apps to improve the accountability of app content.

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. © 2013 The British Pharmacological Society.

Analysis of Mycobacterium avium subsp. paratuberculosis mutant libraries reveals loci-dependent transcription biases and strategies to novel mutant discovery

USDA-ARS?s Scientific Manuscript database

Mycobacterium avium subsp. paratuberculosis (MAP) is the etiologic agent of Johne’s disease in ruminants and it has been implicated as a cause of Crohn’s disease in humans. The generation of comprehensive random mutant banks by transposon mutagenesis is a fundamental wide genomic technology utilized...

Pro-smoking apps for smartphones: the latest vehicle for the tobacco industry?

PubMed

BinDhim, Nasser F; Freeman, Becky; Trevena, Lyndal

2014-01-01

Smartphone use is growing exponentially and will soon become the only mobile phone handset for about 6 billion users. Smartphones are ideal marketing targets as consumers can be reached anytime, anywhere. Smartphone application (app) stores are global shops that sell apps to users all around the world. Although smartphone stores have a wide collection of health-related apps they also have a wide set of harmful apps. In this study, the availability of 'pro-smoking' apps in two of the largest smartphone app stores (Apple App store and Android Market) was examined. In February 2012, we searched the Apple App Store and Android Market for pro-smoking apps, using the keywords Smoke, Cigarette, Cigar, Smoking and Tobacco. We excluded apps that were not tobacco-related and then assessed the tobacco-related apps against our inclusion criteria. 107 pro-smoking apps were identified and classified into six categories based on functionality.42 of these apps were from the Android Market and downloaded by over 6 million users. Some apps have explicit images of cigarette brands. Tobacco products are being promoted in the new 'smartphone app' medium which has global reach, a huge consumer base of various age groups and underdeveloped regulation. The paper also provides two examples of app store responses to country-specific laws and regulations that could be used to control the harmful contents in the app stores for individual countries.

Faster forgetting contributes to impaired spatial memory in the PDAPP mouse: Deficit in memory retrieval associated with increased sensitivity to interference?

PubMed Central

Daumas, Stephanie; Sandin, Johan; Chen, Karen S.; Kobayashi, Dione; Tulloch, Jane; Martin, Stephen J.; Games, Dora; Morris, Richard G.M.

2008-01-01

Two experiments were conducted to investigate the possibility of faster forgetting by PDAPP mice (a well-established model of Alzheimer’s disease as reported by Games and colleagues in an earlier paper). Experiment 1, using mice aged 13–16 mo, confirmed the presence of a deficit in a spatial reference memory task in the water maze by hemizygous PDAPP mice relative to littermate controls. However, after overtraining to a criterion of equivalent navigational performance, a series of memory retention tests revealed faster forgetting in the PDAPP group. Very limited retraining was sufficient to reinstate good memory in both groups, indicating that their faster forgetting may be due to retrieval failure rather than trace decay. In Experiment 2, 6-mo-old PDAPP and controls were required to learn each of a series of spatial locations to criterion with their memory assessed 10 min after learning each location. No memory deficit was apparent in the PDAPP mice initially, but a deficit built up through the series of locations suggestive of increased sensitivity to interference. Faster forgetting and increased interference may each reflect a difficulty in accessing memory traces. This interpretation of one aspect of the cognitive deficit in human mutant APP mice has parallels to deficits observed in patients with Alzheimer’s disease, further supporting the validity of transgenic models of the disease. PMID:18772249

Analysis of mutant quantity and quality in human-hamster hybrid AL and AL-179 cells exposed to 137Cs-gamma or HZE-Fe ions

NASA Technical Reports Server (NTRS)

Waldren, C.; Vannais, D.; Drabek, R.; Gustafson, D.; Kraemer, S.; Lenarczyk, M.; Kronenberg, A.; Hei, T.; Ueno, A.; Chatterjee, A. (Principal Investigator)

1998-01-01

We measured the number of mutants and the kinds of mutations induced by 137Cs-gamma and by HZE-Fe (56Fe [600 MeV/amu, LET = 190 KeV/micrometer) in standard AL human hamster hybrid cells and in a new variant hybrid, AL-179. We found that HZE-Fe was more mutagenic than 137Cs-gamma per unit dose (about 1.6 fold), but was slightly less mutagenic per mean lethal dose, DO, at both the S1 and hprt- loci of AL cells. On the other hand, HZE-Fe induced about nine fold more complex S1- mutants than 137Cs-gamma rays, 28% vs 3%. 137Cs-gamma rays induced about twice as many S1- mutants and hprt-mutants in AL-179 as in AL cells, and about nine times more of the former were complex, and potentially unstable kinds of mutations.

Free smoking cessation mobile apps available in Australia: a quality review and content analysis.

PubMed

Thornton, Louise; Quinn, Catherine; Birrell, Louise; Guillaumier, Ashleigh; Shaw, Brad; Forbes, Erin; Deady, Mark; Kay-Lambkin, Frances

2017-12-01

This review aimed to identify free, high-quality, smoking cessation mobile applications (apps) that adhere to Australian smoking cessation treatment guidelines. A systematic search of smoking cessation apps was conducted using Google. The technical quality of relevant apps was rated using the Mobile Application Rating Scale. The content of apps identified as high quality was assessed for adherence to smoking cessation treatment guidelines. 112 relevant apps were identified. The majority were of poor technical quality and only six 'high-quality' apps were identified. These apps adhered to Australian treatment guidelines in part. The efficacy of two apps had been previously evaluated. In lieu of more substantial research in this area, it is suggested that the high-quality apps identified in this review may be more likely than other available apps to encourage smoking cessation. Implications for public health: Smoking cessation apps have the potential to address many barriers that prevent smoking cessation support being provided; however few high-quality smoking cessation apps are currently available in Australia, very few have been evaluated and the app market is extremely volatile. More research to evaluate smoking cessation apps, and sustained funding for evidence-based apps, is needed. © 2017 The Authors.

Sod1 deficiency reduces incubation time in mouse models of prion disease.

PubMed

Akhtar, Shaheen; Grizenkova, Julia; Wenborn, Adam; Hummerich, Holger; Fernandez de Marco, Mar; Brandner, Sebastian; Collinge, John; Lloyd, Sarah E

2013-01-01

Prion infections, causing neurodegenerative conditions such as Creutzfeldt-Jakob disease and kuru in humans, scrapie in sheep and BSE in cattle are characterised by prolonged and variable incubation periods that are faithfully reproduced in mouse models. Incubation time is partly determined by genetic factors including polymorphisms in the prion protein gene. Quantitative trait loci studies in mice and human genome-wide association studies have confirmed that multiple genes are involved. Candidate gene approaches have also been used and identified App, Il1-r1 and Sod1 as affecting incubation times. In this study we looked for an association between App, Il1-r1 and Sod1 representative SNPs and prion disease incubation time in the Northport heterogeneous stock of mice inoculated with the Chandler/RML prion strain. No association was seen with App, however, significant associations were seen with Il1-r1 (P = 0.02) and Sod1 (P<0.0001) suggesting that polymorphisms at these loci contribute to the natural variation observed in incubation time. Furthermore, following challenge with Chandler/RML, ME7 and MRC2 prion strains, Sod1 deficient mice showed highly significant reductions in incubation time of 20, 13 and 24%, respectively. No differences were detected in Sod1 expression or activity. Our data confirm the protective role of endogenous Sod1 in prion disease.

Turnover of C99 is Controlled by a Crosstalk between ERAD and Ubiquitin-Independent Lysosomal Degradation in Human Neuroglioma Cells

PubMed Central

Bustamante, Hianara A.; Rivera-Dictter, Andrés; Cavieres, Viviana A.; Muñoz, Vanessa C.; González, Alexis; Lin, Yimo; Mardones, Gonzalo A.; Burgos, Patricia V.

2013-01-01

Alzheimer’s disease (AD) is characterized by the buildup of amyloid-β peptides (Aβ) aggregates derived from proteolytic processing of the β-amyloid precursor protein (APP). Amyloidogenic cleavage of APP by β-secretase/BACE1 generates the C-terminal fragment C99/CTFβ that can be subsequently cleaved by γ-secretase to produce Aβ. Growing evidence indicates that high levels of C99/CTFβ are determinant for AD. Although it has been postulated that γ-secretase-independent pathways must control C99/CTFβ levels, the contribution of organelles with degradative functions, such as the endoplasmic reticulum (ER) or lysosomes, is unclear. In this report, we investigated the turnover and amyloidogenic processing of C99/CTFβ in human H4 neuroglioma cells, and found that C99/CTFβ is localized at the Golgi apparatus in contrast to APP, which is mostly found in endosomes. Conditions that localized C99/CTFβ to the ER resulted in its degradation in a proteasome-dependent manner that first required polyubiquitination, consistent with an active role of the ER associated degradation (ERAD) in this process. Furthermore, when proteasomal activity was inhibited C99/CTFβ was degraded in a chloroquine (CQ)-sensitive compartment, implicating lysosomes as alternative sites for its degradation. Our results highlight a crosstalk between degradation pathways within the ER and lysosomes to avoid protein accumulation and toxicity. PMID:24376644

Turnover of C99 is controlled by a crosstalk between ERAD and ubiquitin-independent lysosomal degradation in human neuroglioma cells.

PubMed

Bustamante, Hianara A; Rivera-Dictter, Andrés; Cavieres, Viviana A; Muñoz, Vanessa C; González, Alexis; Lin, Yimo; Mardones, Gonzalo A; Burgos, Patricia V

2013-01-01

Alzheimer's disease (AD) is characterized by the buildup of amyloid-β peptides (Aβ) aggregates derived from proteolytic processing of the β-amyloid precursor protein (APP). Amyloidogenic cleavage of APP by β-secretase/BACE1 generates the C-terminal fragment C99/CTFβ that can be subsequently cleaved by γ-secretase to produce Aβ. Growing evidence indicates that high levels of C99/CTFβ are determinant for AD. Although it has been postulated that γ-secretase-independent pathways must control C99/CTFβ levels, the contribution of organelles with degradative functions, such as the endoplasmic reticulum (ER) or lysosomes, is unclear. In this report, we investigated the turnover and amyloidogenic processing of C99/CTFβ in human H4 neuroglioma cells, and found that C99/CTFβ is localized at the Golgi apparatus in contrast to APP, which is mostly found in endosomes. Conditions that localized C99/CTFβ to the ER resulted in its degradation in a proteasome-dependent manner that first required polyubiquitination, consistent with an active role of the ER associated degradation (ERAD) in this process. Furthermore, when proteasomal activity was inhibited C99/CTFβ was degraded in a chloroquine (CQ)-sensitive compartment, implicating lysosomes as alternative sites for its degradation. Our results highlight a crosstalk between degradation pathways within the ER and lysosomes to avoid protein accumulation and toxicity.

Loss of function of ATXN1 increases amyloid beta-protein levels by potentiating beta-secretase processing of beta-amyloid precursor protein.

PubMed

Zhang, Can; Browne, Andrew; Child, Daniel; Divito, Jason R; Stevenson, Jesse A; Tanzi, Rudolph E

2010-03-19

Alzheimer disease (AD) is a devastating neurodegenerative disease with complex and strong genetic inheritance. Four genes have been established to either cause familial early onset AD (APP, PSEN1, and PSEN2) or to increase susceptibility for late onset AD (APOE). To date approximately 80% of the late onset AD genetic variance remains elusive. Recently our genome-wide association screen identified four novel late onset AD candidate genes. Ataxin 1 (ATXN1) is one of these four AD candidate genes and has been indicated to be the disease gene for spinocerebellar ataxia type 1, which is also a neurodegenerative disease. Mounting evidence suggests that the excessive accumulation of Abeta, the proteolytic product of beta-amyloid precursor protein (APP), is the primary AD pathological event. In this study, we ask whether ATXN1 may lead to AD pathogenesis by affecting Abeta and APP processing utilizing RNA interference in a human neuronal cell model and mouse primary cortical neurons. We show that knock-down of ATXN1 significantly increases the levels of both Abeta40 and Abeta42. This effect could be rescued with concurrent overexpression of ATXN1. Moreover, overexpression of ATXN1 decreased Abeta levels. Regarding the underlying molecular mechanism, we show that the effect of ATXN1 expression on Abeta levels is modulated via beta-secretase cleavage of APP. Taken together, ATXN1 functions as a genetic risk modifier that contributes to AD pathogenesis through a loss-of-function mechanism by regulating beta-secretase cleavage of APP and Abeta levels.

Loss of Function of ATXN1 Increases Amyloid β-Protein Levels by Potentiating β-Secretase Processing of β-Amyloid Precursor Protein*

PubMed Central

Zhang, Can; Browne, Andrew; Child, Daniel; DiVito, Jason R.; Stevenson, Jesse A.; Tanzi, Rudolph E.

2010-01-01

Alzheimer disease (AD) is a devastating neurodegenerative disease with complex and strong genetic inheritance. Four genes have been established to either cause familial early onset AD (APP, PSEN1, and PSEN2) or to increase susceptibility for late onset AD (APOE). To date ∼80% of the late onset AD genetic variance remains elusive. Recently our genome-wide association screen identified four novel late onset AD candidate genes. Ataxin 1 (ATXN1) is one of these four AD candidate genes and has been indicated to be the disease gene for spinocerebellar ataxia type 1, which is also a neurodegenerative disease. Mounting evidence suggests that the excessive accumulation of Aβ, the proteolytic product of β-amyloid precursor protein (APP), is the primary AD pathological event. In this study, we ask whether ATXN1 may lead to AD pathogenesis by affecting Aβ and APP processing utilizing RNA interference in a human neuronal cell model and mouse primary cortical neurons. We show that knock-down of ATXN1 significantly increases the levels of both Aβ40 and Aβ42. This effect could be rescued with concurrent overexpression of ATXN1. Moreover, overexpression of ATXN1 decreased Aβ levels. Regarding the underlying molecular mechanism, we show that the effect of ATXN1 expression on Aβ levels is modulated via β-secretase cleavage of APP. Taken together, ATXN1 functions as a genetic risk modifier that contributes to AD pathogenesis through a loss-of-function mechanism by regulating β-secretase cleavage of APP and Aβ levels. PMID:20097758

77 FR 71198 - Environmental Assessment and Finding of No Significant Impact Related to Exemption From the...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-11-29

... Levels for Hostile Action (10 CFR Part 50, App. E, IV.B.1.) Emergency Response Organization Augmentation... proposed action will not significantly impact the quality of the human environment, and that the proposed...

A microfluidics-based mobility shift assay to identify new inhibitors of β-secretase for Alzheimer's disease.

PubMed

Liu, Rongfeng; Liu, Yu-Chih; Meng, Junwei; Zhu, Haiyan; Zhang, Xuehong

2017-11-01

The β-secretase (BACE1) initiates the generation of toxic amyloid-β peptide (Aβ) from amyloid-β precursor protein (APP), which was widely considered to play a key role in the pathogenesis of Alzheimer's disease (AD). Here, a novel microfluidics-based mobility shift assay (MMSA) was developed, validated, and applied for the screening of BACE1 inhibitors for AD. First, the BACE1 activity assay was established with a new fluorescent peptide substrate (FAM-EVNLDAEF) derived from the Swedish mutant APP, and high-quality ratiometric data were generated in both endpoint and kinetic modes by electrophoretic separation of peptide substrate from the BACE1 cleaved product (FAM-EVNL) before fluorescence quantification. To validate the assay, the inhibition and kinetic parameter values of two known inhibitors (AZD3839 and AZD3293) were evaluated, and the results were in good agreement with those reported by other methods. Finally, the assay was applied to screen for new inhibitors from a 900-compound library in a 384-well format, and one novel hit (IC 50 = 26.5 ± 1.5 μM) was identified. Compared with the common fluorescence-based assays, the primary advantage of the direct MMSA was to discover novel BACE1 inhibitors with lower auto-fluorescence interference, and its superb capability for kinetic study. Graphical abstract Microfluidics-based mobility shift assay for BACE1.

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…

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 life. It facilitated maintaining a healthy diet and exercising more. Diet and PA apps of the future can be further strengthened by being tailored to meet personal needs. PMID:27056639

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

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 both an RA CDA measure and tracked data, but this app did not include the standard 28 tender and swollen joint count. The median overall MARS score for apps was 3.41/5. Of the 6 apps that scored ≥4/5 on the overall MARS rating, only 1 included a CDA score endorsed by ACR and EULAR; however, this app did not have a data tracking function. Conclusions This review found a lack of high-quality apps for longitudinal assessment of RA disease activity. Current apps fall into two categories: simple calculators primarily for rheumatologists and data tracking tools for people with RA. The latter do not uniformly collect data using validated instruments or composite disease activity measures. There is a need for appropriate, high-quality apps for use by rheumatologists and patients together in co-management of RA. PMID:28223263

A systematic review of smartphone applications for smoking cessation.

PubMed

Haskins, Brianna L; Lesperance, Donna; Gibbons, Patric; Boudreaux, Edwin D

2017-06-01

Tobacco use is the leading cause of preventable disease and death in the USA. However, limited data exists regarding smoking cessation mobile app quality and intervention effectiveness. Innovative and scalable interventions are needed to further alleviate the public health implications of tobacco addiction. The proliferation of the smartphone and the advent of mobile phone health interventions have made treatment more accessible than ever. The purpose of this review was to examine the relation between published scientific literature and available commercial smartphone health apps for smoking cessation to identify the percentage of scientifically supported apps that were commercially available to consumers and to determine how many of the top commercially available apps for smoking cessation were supported by the published scientific literature. Adhering to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, apps were reviewed in four phases: (1) identified apps from the scientific literature, (2) searched app stores for apps identified in the literature, (3) identified top apps available in leading app stores, and (4) determined which top apps available in stores had scientific support. Seven articles identified six apps with some level of scientific support, three (50%) were available in at least one app store. Conversely, among the top 50 apps suggested by each of the leading app stores, only two (4%) had any scientific support. While half of the scientifically vetted apps remain available to consumers, they are difficult to find among the many apps that are identified through app store searches.

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 classification of, and ambiguity in, wording of questions within constructs. The proposed method to evaluate shortlisted and downloaded apps comprises instructions to attempt set-up of a dummy user profile, and dummy data entry to represent in-range and out-of-range clinical measures simulating a range of user behaviors. A minimum score of 80% by consensus (using the Intraclass Correlation Coefficient) between raters is proposed to identify apps suitable for clinical trials. Conclusions The flow diagram allows researchers to shortlist health apps that are potentially suitable for formal evaluation. The evaluation checklist enables quantitative comparison of shortlisted apps based on constructs reported in the literature. The use of multiple raters, and comparison of their scores, is proposed to manage inherent subjectivity in assessing user experiences. Initial trial of the combined protocol is planned for apps pertaining to the self-monitoring of asthma; these results will be reported elsewhere. PMID:27815233

The parkin Mutant Phenotype in the Fly Is Largely Rescued by Metal-Responsive Transcription Factor (MTF-1) ▿ †

PubMed Central

Saini, Nidhi; Georgiev, Oleg; Schaffner, Walter

2011-01-01

The gene for Parkin, an E3 ubiquitin ligase, is mutated in some familial forms of Parkinson's disease, a severe neurodegenerative disorder. A homozygous mutant of the Drosophila ortholog of human parkin is viable but results in severe motoric impairment including an inability to fly, female and male sterility, and a decreased life span. We show here that a double mutant of the genes for Parkin and the metal-responsive transcription factor 1 (MTF-1) is not viable. MTF-1, which is conserved from insects to mammals, is a key regulator of heavy metal homeostasis and detoxification and plays additional roles in other stress conditions, notably oxidative stress. In contrast to the synthetic lethality of the double mutant, elevated expression of MTF-1 dramatically ameliorates the parkin mutant phenotype, as evidenced by a prolonged life span, motoric improvement including short flight episodes, and female fertility. At the cellular level, muscle and mitochondrial structures are substantially improved. A beneficial effect is also seen with a transgene encoding human MTF-1. We propose that Parkin and MTF-1 provide complementary functions in metal homeostasis, oxidative stress and other cellular stress responses. Our findings also raise the possibility that MTF-1 gene polymorphisms in humans could affect the severity of Parkinson's disease. PMID:21383066

Gain and loss of function of ALS-related mutations of TARDBP (TDP-43) cause motor deficits in vivo.

PubMed

Kabashi, Edor; Lin, Li; Tradewell, Miranda L; Dion, Patrick A; Bercier, Valérie; Bourgouin, Patrick; Rochefort, Daniel; Bel Hadj, Samar; Durham, Heather D; Vande Velde, Christine; Rouleau, Guy A; Drapeau, Pierre

2010-02-15

TDP-43 has been found in inclusion bodies of multiple neurological disorders, including amyotrophic lateral sclerosis, frontotemporal dementia, Parkinson's disease and Alzheimer's disease. Mutations in the TDP-43 encoding gene, TARDBP, have been subsequently reported in sporadic and familial ALS patients. In order to investigate the pathogenic nature of these mutants, the effects of three consistently reported TARDBP mutations (A315T, G348C and A382T) were tested in cell lines, primary cultured motor neurons and living zebrafish embryos. Each of the three mutants and wild-type (WT) human TDP-43 localized to nuclei when expressed in COS1 and Neuro2A cells by transient transfection. However, when expressed in motor neurons from dissociated spinal cord cultures these mutant TARDBP alleles, but less so for WT TARDBP, were neurotoxic, concomitant with perinuclear localization and aggregation of TDP-43. Finally, overexpression of mutant, but less so of WT, human TARDBP caused a motor phenotype in zebrafish (Danio rerio) embryos consisting of shorter motor neuronal axons, premature and excessive branching as well as swimming deficits. Interestingly, knock-down of zebrafisfh tardbp led to a similar phenotype, which was rescued by co-expressing WT but not mutant human TARDBP. Together these approaches showed that TARDBP mutations cause motor neuron defects and toxicity, suggesting that both a toxic gain of function as well as a novel loss of function may be involved in the molecular mechanism by which mutant TDP-43 contributes to disease pathogenesis.

Development of a Rating Tool for Mobile Cancer Apps: Information Analysis and Formal and Content-Related Evaluation of Selected Cancer Apps.

PubMed

Böhme, Cathleen; von Osthoff, Marc Baron; Frey, Katrin; Hübner, Jutta

2017-08-17

Mobile apps are offered in large numbers and have different qualities. The aim of this article was to develop a rating tool based on formal and content-related criteria for the assessment of cancer apps and to test its applicability on apps. After a thorough analysis of the literature, we developed a specific rating tool for cancer apps based on the MARS (mobile app rating system) and a rating tool for cancer websites. This instrument was applied to apps freely available in stores and focusing on some cancer topic. Ten apps were rated on the basis of 22 criteria. Sixty percent of the apps (6/10) were rated poor and insufficient. The rating by different scientists was homogenous. The good apps had reliable sources were regularly updated and had a concrete intent/purpose in their app description. In contrast, the apps that were rated poor had no distinction of scientific content and advertisement. In some cases, there was no imprint to identify the provider. As apps of poor quality can give misinformation and lead to wrong treatment decisions, efforts have to be made to increase usage of high-quality apps. Certification would help cancer patients to identify reliable apps, yet acceptance of a certification system must be backed up.

The Top Chinese Mobile Health Apps: A Systematic Investigation.

PubMed

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

2016-08-29

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. The objective of this study was to provide an overview of Chinese mHealth apps as of December 2015. 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. 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. 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.

Smartphone apps for snoring.

PubMed

Camacho, M; Robertson, M; Abdullatif, J; Certal, V; Kram, Y A; Ruoff, C M; Brietzke, S E; Capasso, R

2015-10-01

To identify and systematically evaluate user-friendly smartphone snoring apps. The Apple iTunes app store was searched for snoring apps that allow recording and playback. Snoring apps were downloaded, evaluated and rated independently by four authors. Two patients underwent polysomnography, and the data were compared with simultaneous snoring app recordings, and one patient used the snoring app at home. Of 126 snoring apps, 13 met the inclusion and exclusion criteria. The most critical app feature was the ability to graphically display the snoring events. The Quit Snoring app received the highest overall rating. When this app's recordings were compared with in-laboratory polysomnography data, app snoring sensitivities ranged from 64 to 96 per cent, and snoring positive predictive values ranged from 93 to 96 per cent. A chronic snorer used the app nightly for one month and tracked medical interventions. Snoring decreased from 200 to 10 snores per hour, and bed partner snoring complaint scores decreased from 9 to 2 (on a 0-10 scale). Select smartphone apps are user-friendly for recording and playing back snoring sounds. Preliminary comparison of more than 1500 individual snores demonstrates the potential clinical utility of such apps; however, further validation testing is recommended.

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 challenges for consumers and clinicians seeking relevant and long-term apps, as well as for researchers seeking to evaluate the evidence base for publicly available apps. PMID:27507641

Emergency Preparedness and Disaster Response: There's An App for That.

PubMed

Bachmann, Daniel J; Jamison, Nathan K; Martin, Andrew; Delgado, Jose; Kman, Nicholas E

2015-10-01

Smartphone applications (or apps) are becoming increasingly popular with emergency responders and health care providers, as well as the public as a whole. There are thousands of medical apps available for Smartphones and tablet computers, with more added each day. These include apps to view textbooks, guidelines, medication databases, medical calculators, and radiology images. Hypothesis/Problem With an ever expanding catalog of apps that relate to disaster medicine, it is hard for both the lay public and responders to know where to turn for effective Smartphone apps. A systematic review of these apps was conducted. A search of the Apple iTunes store (Version 12; Apple Inc.; Cupertino, California USA) was performed using the following terms obtained from the PubMed Medical Subject Headings Database: Emergency Preparedness, Emergency Responders, Disaster, Disaster Planning, Disaster Medicine, Bioterrorism, Chemical Terrorism, Hazardous Materials (HazMat), and the Federal Emergency Management Agency (FEMA). After excluding any unrelated apps, a working list of apps was formed and categorized based on topics. Apps were grouped based on applicability to responders, the lay public, or regional preparedness, and were then ranked based on iTunes user reviews, value, relevance to audience, and user interface. This search revealed 683 applications and was narrowed to 219 based on relevance to the field. After grouping the apps as described above, and subsequently ranking them, the highest quality apps were determined from each group. The Community Emergency Response Teams and FEMA had the best apps for National Disaster Medical System responders. The Centers for Disease Control and Prevention (CDC) had high-quality apps for emergency responders in a variety of fields. The National Library of Medicine's Wireless Information System for Emergency Responders (WISER) app was an excellent app for HazMat responders. The American Red Cross had the most useful apps for natural disasters. Numerous valuable apps for public use, including alert apps, educational apps, and a well-made regional app, were also identified. Smartphone applications are fast becoming essential to emergency responders and the lay public. Many high-quality apps existing in various price ranges and serving different populations were identified. This field is changing rapidly and it deserves continued analysis as more apps are developed.

Mobile medical and health apps: state of the art, concerns, regulatory control and certification

PubMed Central

Boulos, Maged N. Kamel; Brewer, Ann C.; Karimkhani, Chante; Buller, David B.; Dellavalle, Robert P.

2014-01-01

This paper examines the state of the art in mobile clinical and health-related apps. A 2012 estimate puts the number of health-related apps at no fewer than 40,000, as healthcare professionals and consumers continue to express concerns about the quality of many apps, calling for some form of app regulatory control or certification to be put in place. We describe the range of apps on offer as of 2013, and then present a brief survey of evaluation studies of medical and health-related apps that have been conducted to date, covering a range of clinical disciplines and topics. Our survey includes studies that highlighted risks, negative issues and worrying deficiencies in existing apps. We discuss the concept of ‘apps as a medical device’ and the relevant regulatory controls that apply in USA and Europe, offering examples of apps that have been formally approved using these mechanisms. We describe the online Health Apps Library run by the National Health Service in England and the calls for a vetted medical and health app store. We discuss the ingredients for successful apps beyond the rather narrow definition of ‘apps as a medical device’. These ingredients cover app content quality, usability, the need to match apps to consumers’ general and health literacy levels, device connectivity standards (for apps that connect to glucometers, blood pressure monitors, etc.), as well as app security and user privacy. ‘Happtique Health App Certification Program’ (HACP), a voluntary app certification scheme, successfully captures most of these desiderata, but is solely focused on apps targeting the US market. HACP, while very welcome, is in ways reminiscent of the early days of the Web, when many “similar” quality benchmarking tools and codes of conduct for information publishers were proposed to appraise and rate online medical and health information. It is probably impossible to rate and police every app on offer today, much like in those early days of the Web, when people quickly realised the same regarding informational Web pages. The best first line of defence was, is, and will always be to educate consumers regarding the potentially harmful content of (some) apps. PMID:24683442

Adherence to evidence-based guidelines among diabetes self-management apps.

PubMed

Breland, Jessica Y; Yeh, Vivian M; Yu, Jessica

2013-09-01

Smartphone apps can provide real-time, interactive self-management aid to individuals with diabetes. It is currently unclear whether existing diabetes self-management apps follow evidence-based guidelines. The purpose of this study was to evaluate the extent to which existing diabetes self-management apps address the seven self-management behaviors recommended by the American Association of Diabetes Educators (the AADE7™). The term "diabetes" identified relevant self-management apps via the Apple App Store search engine in March 2012. Ratings were based on app descriptions and downloads. Chi-square analyses assessed differences in apps based on developer type. Apps promoted a median of two AADE7™ skills. Overall reliability between description and download ratings was good (kappa = .66). Reliability of individual skills was variable (kappa = .25 to .91). Most diabetes apps do not conform to evidence-based recommendations, and future app reviews would benefit from testing app performance. Future apps may also benefit from theory-based designs.

Quality Assessment of Medical Apps that Target Medication-Related Problems.

PubMed

Loy, John Shiguang; Ali, Eskinder Eshetu; Yap, Kevin Yi-Lwern

2016-10-01

The advent of smartphones has enabled a plethora of medical apps for disease management. As of 2012, there are 40,000 health care-related mobile apps available in the market. Since most of these medical apps do not go through any stringent quality assessment, there is a risk of consumers being misinformed or misled by unreliable information. In this regard, apps that target medication-related problems (MRPs) are not an exception. There is little information on what constitutes quality in apps that target MRPs and how good the existing apps are. To develop a quality assessment tool for evaluating apps that target MRPs and assess the quality of such apps available in the major mobile app stores (iTunes and Google Play). The top 100 free and paid apps in the medical categories of iTunes and Google Play stores (total of 400 apps) were screened for inclusion in the final analysis. English language apps that targeted MRPs were downloaded on test devices to evaluate their quality. Apps intended for clinicians, patients, or both were eligible for evaluation. The quality assessment tool consisted of 4 sections (appropriateness, reliability, usability, privacy), which determined the overall quality of the apps. Apps that fulfilled the inclusion criteria were classified based on the presence of any 1 or more of the 5 features considered important for apps targeting MRPs (monitoring, interaction checker, dose calculator, medication information, medication record). Descriptive statistics and Mann-Whitney tests were used for analysis. Final analysis was based on 59 apps that fulfilled the study inclusion criteria. Apps with interaction checker (66.9%) and monitoring features (54.8%) had the highest and lowest overall qualities. Paid apps generally scored higher for usability than free apps (P = 0.006) but lower for privacy (P = 0.003). Half of the interaction checker apps were unable to detect interactions with herbal medications. Blood pressure and heart rate monitoring apps had the highest overall quality scores (67.7%), while apps that monitored visual, hearing, and temperature changes scored the lowest (35.5%). A quality assessment tool for evaluating medical apps targeting MRPs has been developed. Clinicians can use this tool to guide their assessments of medical apps that are appropriate for use in the health care setting. Although potentially useful apps were identified, many apps were found to have deficiencies in quality, among which was poor reliability scores for most of the apps. Continued assessments of the quality of apps targeting MRPs are recommended to ensure their usefulness for clinicians and patients. No outside funding supported this study. The authors have no conflicts of interests directly related to this study. Study concept and design were contributed by Loy and Yap. Loy collected the data and took the lead in data interpretation, along with Ali and Yap. The manuscript was primarily written by Loy, along with Yap, and revised primarily by Ali, along with Yap.

Effectiveness of a Smartphone Application for the Management of Metabolic Syndrome Components Focusing on Weight Loss: A Preliminary Study.

PubMed

Toro-Ramos, Tatiana; Lee, Dong-Hwa; Kim, Youngin; Michaelides, Andreas; Oh, Tae Jung; Kim, Kyoung Min; Jang, Hak Chul; Lim, Soo

2017-11-01

There are inconsistent results for the effectiveness of using smartphone applications (apps) or websites on weight loss. We investigated the efficacy of a smartphone intervention using a designated app that utilizes a lifestyle intervention-focused approach, including a human coaching element, toward weight loss in overweight or obese Korean adults. One hundred four adults aged 20-60 years with a body mass index ≥23 kg/m 2 , who signed up for a smartphone program for weight loss (using the Noom app), were recruited. Participants received an in-person orientation about the study and app use, and a baseline blood sample was obtained. The in-app intervention with daily behavior and nutrition education content and coaching lasted 15 weeks. The primary endpoint of the study was a change in weight. The secondary endpoints were changes in metabolic risk factors such as blood pressure, waist circumference, and glucose and lipid profiles. Body composition changes were also assessed, and body weight at 52 weeks was measured to ascertain long-term effects. Participants showed a clinically significant weight loss effect of -7.5% at the end of the 15-week program (P < 0.001), and at a 52-week follow-up, a weight loss effect of -5.2% was maintained. At 15 weeks, percent body fat and visceral fat decreased by -6.0 ± 5.4% and -3.4 ± 2.7 kg, respectively (both P < 0.001). Fasting glucose level also decreased significantly by -5.7 ± 14.6 mg/dL at 15 weeks. Lipid parameters showed significant improvements, except for high-density lipoprotein cholesterol. The frequency of logging meals and exercise was associated with body fat loss. This advanced smartphone app was a useful tool to maintain weight loss in overweight or obese people.

Development of a methodology for the standardisation and improvement of 'Smartphone' photography of patterned bruises and other cutaneous injuries.

PubMed

Biggs, Paul R; Evans, Samuel T; Jones, Michael D; Theobald, Peter S

2013-09-01

Human bite-mark analyses can play a prominent role in forensic case investigations, including those involving sexual assault. High-quality photographs routinely secure a link between a bite-mark and an individual's dentition. Access to around the clock forensic photography, however, is often limited, resulting in delay and/or missed opportunities to record valuable evidence. The emergence of Smartphone high-quality photographic technology now provides a previously unimagined opportunity to gather timely forensic photographic evidence. Problems can arise, however, due to the relatively poor quality of the photographs, as a result of many of those taking photographs having received little or no forensic photography training. This study compares unassisted photography with assisted photography, by a specifically developed camera application (App), to provide a standardised method for taking forensic photographs. An App, written in Java, was hosted on the Google Android Operating System, on a Samsung Galaxy SII Smartphone. Twenty-four volunteers participated in a study to photograph a pseudo bite-mark using three methods, (1) unassisted (as a control), (2) assisted by an ABFO No.2 right-angled photographic reference scale and (3) assisted by the App. The App, method (3), was shown to consistently outperform methods (1) and (2), demonstrating greater standardisation and precision (p<0.001). Analysis of the data showed the extent to which acquiring an accurate photograph depends on the image being orthogonal to the camera. It appears likely that the relatively inaccurate photographs acquired by methods (1) and (2), were as a result of deviation from the plane, orthogonal to the bite-mark. Therefore, the App was successful in ensuring that the camera was both orthogonal and at an appropriate distance, relative to the bite-mark. Thus, the App enhanced the abilities of non-experts to acquire more accurate photographs and created the potential to significantly improve the quality of forensic photographs. Copyright © 2013. Published by Elsevier Ireland Ltd.

Therapeutic impact of rHuEPO on abnormal platelet APP, BACE 1, presenilin 1, ADAM 10 and Aβ expressions in chronic kidney disease patients with cognitive dysfunction like Alzheimer's disease: A pilot study.

PubMed

G, Vinothkumar; S, Krishnakumar; Sureshkumar; G, Shivashekar; S, Sreedhar; Preethikrishnan; S, Dinesh; A, Sundaram; D, Balakrishnan; Riya; P, Venkataraman

2018-08-01

Cognitive dysfunction is reported to be a major cause of morbidity in chronic kidney disease (CKD). The senile plaques (SPs) in the brain are one of the most pathophysiological characteristics of cognitive dysfunction and its major constituent amyloid β (Aβ) released from amyloid precursor protein (APP) by β (BACE1) and γ (presenilin 1) secretases . Platelets contain more than 95% of the circulating APP and implicate as a candidate biomarker for cognitive decline. Recombinant human erythropoietin (rHuEPO) is a standard therapy for anemia in CKD and also acts as a neuroprotective agent. The aim of the study is to determine the impact of rHuEPO therapy on platelet APP processing in CKD with Cognitive Dysfunction. A total of 60 subjects comprising of 30 CKD without cognitive dysfunction and 30 CKD with cognitive dysfunction based on neuropsychological assessment. APP, BACE1, Presenilin 1, ADAM 10 (α secretase) and Aβ expressions in platelets were determined by western blotting and lipid peroxidation (LPO) in platelet rich plasma (PRP) was done by spectrophotometrically. The parameters were statistically compared with Alzheimer's disease (AD), Normocytic normochromic anemic and healthy subjects. Significantly (p < 0.05) decreased APP, ADAM 10 while increased BACE1, Presenilin 1, Aβ and LPO were observed in CKD with cognitive dysfunction like AD subjects compared to other groups. The parameters were reassessed in CKD with cognitive dysfunction subjects after rHuEPO (100 IU/ kg, weekly twice, 6 months) therapy. All the parameters were retrieved significantly (p < 0.05) along with improved neuropsychological tests scoring after rHuEPO therapy. This study demonstrated that rHuEPO is an effective neuroprotective agent in the context of CKD associated cognitive dysfunction and proved its clinical usefulness. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

Insight into inhibition of the human amyloid beta protein precursor (APP: PDB ID ) using (E)-N-(pyridin-2-ylmethylene)arylamine (LR) models: structure elucidation of a family of ZnX2-LR complexes.

PubMed

Basu Baul, Tushar S; Kundu, Sajal; Singh, Palwinder; Shaveta; Guedes da Silva, M Fátima C

2015-02-07

The amyloid beta precursor protein (APP) and its neurotoxic cleavage product amyloid beta (Aβ) are a cause of Alzheimer's disease and appear essential for neuronal development and cell homeostasis. Proteolytic processing of APP is influenced by metal ions and protein ligands, however the structural and functional mechanism of APP regulation is not known so far. In this context, molecular modeling studies were performed to understand the molecular behavior of (E)-N-(pyridin-2-ylmethylene)arylamines (LR) with an E2 domain of the APP in its complex with zinc (APP; PDB ID: ). Docking results indeed confirmed that the LR interacts with Zn in the binding site of the protein between two α-helical chains. In view of these findings, LR was further investigated for complexation reactions with Zn(2+) in order to establish the structural models in solution and in the solid state. Five new Zn(2+) complexes of compositions viz. [Zn(Br)2(L2-Me)] (), [Zn(Br)2(L2-OMe)] (), [Zn(i)2(L2-OMe)] (), [Zn(NO3)2(L2-OMe)(H2O)] () and [Zn(L4-Me)2(H2O)2](NO3)2 () were synthesized and their structures were ascertained by microanalysis, IR and (1)H NMR spectroscopy, and single-crystal X-ray diffraction. The zinc atom in complex exhibits a distorted tetrahedral geometry while the crystal structures of complexes and show distorted square pyramidal geometries. The zinc cation in and has an octahedral coordination environment, but in the zinc coordination geometry is less distorted. The Zn(ii) cations take part in one ( and ) or two () 5-membered metallacycles imposed by the NN or NNO chelation modes of LR. The significant intermolecular ππ interactions are also discussed.

Cilostazol Upregulates Autophagy via SIRT1 Activation: Reducing Amyloid-β Peptide and APP-CTFβ Levels in Neuronal Cells.

PubMed

Lee, Hye Rin; Shin, Hwa Kyoung; Park, So Youn; Kim, Hye Young; Bae, Sun Sik; Lee, Won Suk; Rhim, Byung Yong; Hong, Ki Whan; Kim, Chi Dae

2015-01-01

Autophagy is a vital pathway for the removal of β-amyloid peptide (Aβ) and the aggregated proteins that cause Alzheimer's disease (AD). We previously found that cilostazol induced SIRT1 expression and its activity in neuronal cells, and thus, we hypothesized that cilostazol might stimulate clearances of Aβ and C-terminal APP fragment β subunit (APP-CTFβ) by up-regulating autophagy.When N2a cells were exposed to soluble Aβ1-42, protein levels of beclin-1, autophagy-related protein5 (Atg5), and SIRT1 decreased significantly. Pretreatment with cilostazol (10-30 μM) or resveratrol (20 μM) prevented these Aβ1-42 evoked suppressions. LC3-II (a marker of mammalian autophagy) levels were significantly increased by cilostazol, and this increase was reduced by 3-methyladenine. To evoke endogenous Aβ overproduction, N2aSwe cells (N2a cells stably expressing human APP containing the Swedish mutation) were cultured in medium with or without tetracycline (Tet+ for 48 h and then placed in Tet- condition). Aβ and APP-CTFβ expressions were increased after 12~24 h in Tet- condition, and these increased expressions were significantly reduced by pretreating cilostazol. Cilostazol-induced reductions in the expressions of Aβ and APP-CTFβ were blocked by bafilomycin A1 (a blocker of autophagosome to lysosome fusion). After knockdown of the SIRT1 gene (to ~40% in SIRT1 protein), cilostazol failed to elevate the expressions of beclin-1, Atg5, and LC3-II, indicating that cilostazol increases these expressions by up-regulating SIRT1. Further, decreased cell viability induced by Aβ was prevented by cilostazol, and this inhibition was reversed by 3-methyladenine, indicating that the protective effect of cilostazol against Aβ induced neurotoxicity is, in part, ascribable to the induction of autophagy. In conclusion, cilostazol modulates autophagy by increasing the activation of SIRT1, and thereby enhances Aβ clearance and increases cell viability.

In silico approach to explore the disruption in the molecular mechanism of human hyaluronidase 1 by mutant E268K that directs Natowicz syndrome.

PubMed

Meshach Paul, D; Rajasekaran, R

2017-03-01

Natowicz syndrome (mucopolysaccharidoses type 9) is a lysosomal storage disorder caused by deficient or defective human hyaluronidase 1. The disorder is not well studied at the molecular level. Therefore, a new in silico approach was proposed to study the molecular basis on which one clinically observed mutation, Glu268Lys, results in a defective enzyme. The native and mutant structures were subjected to comparative analyses using a conformational sampling approach for geometrical variables viz, RMSF, RMSD, and Ramachandran plot. In addition, the strength of a Cys207-Cys221 disulfide bond and electrostatic interaction between Arg265 and Asp206 were studied, as they are known to be involved in the catalytic activity of the enzyme. Native and mutant E268K showed statistically significant variations with p < 0.05 in RMSD, Ramachandran plot, strengths of disulfide bond, and electrostatic interactions. Further, single model analysis showed variations between native and mutant structures in terms of intra-protein interactions, hydrogen bond dilution, secondary structure, and dihedral angles. Docking analysis predicted the mutant to have a less favorable substrate binding energy compared to the native protein. Additionally, steered MD analysis indicated that the substrate should have more affinity to the native than mutant enzymes. The observed changes theoretically explain the less favorable binding energy of substrate towards mutant E268K, thereby providing a structural basis for its reduced catalytic activity. Hence, our study provides a basis for understanding the disruption in the molecular mechanism of human hyaluronidase 1 by mutation E268K, which may prove useful for the development of synthetic chaperones as a treatment option for Natowicz syndrome.

Native Mutant Huntingtin in Human Brain

PubMed Central

Sapp, Ellen; Valencia, Antonio; Li, Xueyi; Aronin, Neil; Kegel, Kimberly B.; Vonsattel, Jean-Paul; Young, Anne B.; Wexler, Nancy; DiFiglia, Marian

2012-01-01

Huntington disease (HD) is caused by polyglutamine expansion in the N terminus of huntingtin (htt). Analysis of human postmortem brain lysates by SDS-PAGE and Western blot reveals htt as full-length and fragmented. Here we used Blue Native PAGE (BNP) and Western blots to study native htt in human postmortem brain. Antisera against htt detected a single band broadly migrating at 575–850 kDa in control brain and at 650–885 kDa in heterozygous and Venezuelan homozygous HD brains. Anti-polyglutamine antisera detected full-length mutant htt in HD brain. There was little htt cleavage even if lysates were pretreated with trypsin, indicating a property of native htt to resist protease cleavage. A soluble mutant htt fragment of about 180 kDa was detected with anti-htt antibody Ab1 (htt-(1–17)) and increased when lysates were treated with denaturants (SDS, 8 m urea, DTT, or trypsin) before BNP. Wild-type htt was more resistant to denaturants. Based on migration of in vitro translated htt fragments, the 180-kDa segment terminated ≈htt 670–880 amino acids. If second dimension SDS-PAGE followed BNP, the 180-kDa mutant htt was absent, and 43–50 kDa htt fragments appeared. Brain lysates from two HD mouse models expressed native full-length htt; a mutant fragment formed if lysates were pretreated with 8 m urea + DTT. Native full-length mutant htt in embryonic HD140Q/140Q mouse primary neurons was intact during cell death and when cell lysates were exposed to denaturants before BNP. Thus, native mutant htt occurs in brain and primary neurons as a soluble full-length monomer. PMID:22375012

Combinational Deletion of Three Membrane Protein-Encoding Genes Highly Attenuates Yersinia pestis while Retaining Immunogenicity in a Mouse Model of Pneumonic Plague

PubMed Central

Tiner, Bethany L.; Kirtley, Michelle L.; Erova, Tatiana E.; Popov, Vsevolod L.; Baze, Wallace B.; van Lier, Christina J.; Ponnusamy, Duraisamy; Andersson, Jourdan A.; Motin, Vladimir L.; Chauhan, Sadhana

2015-01-01

Previously, we showed that deletion of genes encoding Braun lipoprotein (Lpp) and MsbB attenuated Yersinia pestis CO92 in mouse and rat models of bubonic and pneumonic plague. While Lpp activates Toll-like receptor 2, the MsbB acyltransferase modifies lipopolysaccharide. Here, we deleted the ail gene (encoding the attachment-invasion locus) from wild-type (WT) strain CO92 or its lpp single and Δlpp ΔmsbB double mutants. While the Δail single mutant was minimally attenuated compared to the WT bacterium in a mouse model of pneumonic plague, the Δlpp Δail double mutant and the Δlpp ΔmsbB Δail triple mutant were increasingly attenuated, with the latter being unable to kill mice at a 50% lethal dose (LD50) equivalent to 6,800 LD50s of WT CO92. The mutant-infected animals developed balanced TH1- and TH2-based immune responses based on antibody isotyping. The triple mutant was cleared from mouse organs rapidly, with concurrent decreases in the production of various cytokines and histopathological lesions. When surviving animals infected with increasing doses of the triple mutant were subsequently challenged on day 24 with the bioluminescent WT CO92 strain (20 to 28 LD50s), 40 to 70% of the mice survived, with efficient clearing of the invading pathogen, as visualized in real time by in vivo imaging. The rapid clearance of the triple mutant, compared to that of WT CO92, from animals was related to the decreased adherence and invasion of human-derived HeLa and A549 alveolar epithelial cells and to its inability to survive intracellularly in these cells as well as in MH-S murine alveolar and primary human macrophages. An early burst of cytokine production in macrophages elicited by the triple mutant compared to WT CO92 and the mutant's sensitivity to the bactericidal effect of human serum would further augment bacterial clearance. Together, deletion of the ail gene from the Δlpp ΔmsbB double mutant severely attenuated Y. pestis CO92 to evoke pneumonic plague in a mouse model while retaining the required immunogenicity needed for subsequent protection against infection. PMID:25605764

Combinational deletion of three membrane protein-encoding genes highly attenuates yersinia pestis while retaining immunogenicity in a mouse model of pneumonic plague.

PubMed

Tiner, Bethany L; Sha, Jian; Kirtley, Michelle L; Erova, Tatiana E; Popov, Vsevolod L; Baze, Wallace B; van Lier, Christina J; Ponnusamy, Duraisamy; Andersson, Jourdan A; Motin, Vladimir L; Chauhan, Sadhana; Chopra, Ashok K

2015-04-01

Previously, we showed that deletion of genes encoding Braun lipoprotein (Lpp) and MsbB attenuated Yersinia pestis CO92 in mouse and rat models of bubonic and pneumonic plague. While Lpp activates Toll-like receptor 2, the MsbB acyltransferase modifies lipopolysaccharide. Here, we deleted the ail gene (encoding the attachment-invasion locus) from wild-type (WT) strain CO92 or its lpp single and Δlpp ΔmsbB double mutants. While the Δail single mutant was minimally attenuated compared to the WT bacterium in a mouse model of pneumonic plague, the Δlpp Δail double mutant and the Δlpp ΔmsbB Δail triple mutant were increasingly attenuated, with the latter being unable to kill mice at a 50% lethal dose (LD50) equivalent to 6,800 LD50s of WT CO92. The mutant-infected animals developed balanced TH1- and TH2-based immune responses based on antibody isotyping. The triple mutant was cleared from mouse organs rapidly, with concurrent decreases in the production of various cytokines and histopathological lesions. When surviving animals infected with increasing doses of the triple mutant were subsequently challenged on day 24 with the bioluminescent WT CO92 strain (20 to 28 LD50s), 40 to 70% of the mice survived, with efficient clearing of the invading pathogen, as visualized in real time by in vivo imaging. The rapid clearance of the triple mutant, compared to that of WT CO92, from animals was related to the decreased adherence and invasion of human-derived HeLa and A549 alveolar epithelial cells and to its inability to survive intracellularly in these cells as well as in MH-S murine alveolar and primary human macrophages. An early burst of cytokine production in macrophages elicited by the triple mutant compared to WT CO92 and the mutant's sensitivity to the bactericidal effect of human serum would further augment bacterial clearance. Together, deletion of the ail gene from the Δlpp ΔmsbB double mutant severely attenuated Y. pestis CO92 to evoke pneumonic plague in a mouse model while retaining the required immunogenicity needed for subsequent protection against infection. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

76 FR 14035 - Notice of Establishment

Federal Register 2010, 2011, 2012, 2013, 2014

2011-03-15

... DEPARTMENT OF HEALTH AND HUMAN SERVICES National Institutes of Health Notice of Establishment Pursuant to the Federal Advisory Committee Act, as amended (5 U.S.C. app.), the Director, National... research in immunology and infectious diseases. Duration of this committee is continuing unless formally...

75 FR 28028 - National Cancer Institute; Notice of Meeting

Federal Register 2010, 2011, 2012, 2013, 2014

2010-05-19

... DEPARTMENT OF HEALTH AND HUMAN SERVICES National Institutes of Health National Cancer Institute.... App.), notice is hereby given of a meeting of the National Cancer Institute Clinical Trials and... the meeting. Name of Committee: National Cancer Institute Clinical Trials and Translational Research...

76 FR 7869 - National Cancer Institute; Notice of Meeting

Federal Register 2010, 2011, 2012, 2013, 2014

2011-02-11

... DEPARTMENT OF HEALTH AND HUMAN SERVICES National Institutes of Health National Cancer Institute.... App.), notice is hereby given of a meeting of the National Cancer Institute Director's Consumer... Committee: National Cancer Institute Director's Consumer Liaison Group; DCLG. Date: February 22-23, 2011...

76 FR 22407 - National Cancer Institute; Notice of Meeting

Federal Register 2010, 2011, 2012, 2013, 2014

2011-04-21

... DEPARTMENT OF HEALTH AND HUMAN SERVICES National Institutes of Health National Cancer Institute.... App.), notice is hereby given of a meeting of the National Cancer Institute Clinical Trials and... the meeting. Name of Committee: National Cancer Institute Clinical Trials and Translational Research...

76 FR 3148 - Fogarty International Center; Notice of Meeting

Federal Register 2010, 2011, 2012, 2013, 2014

2011-01-19

... DEPARTMENT OF HEALTH AND HUMAN SERVICES National Institutes of Health Fogarty International Center.... App.), notice is hereby given of a meeting of the Fogarty International Center Advisory Board. The... clearly unwarranted invasion of personal privacy. Name of Committee: Fogarty International Center Advisory...

Mobile Application Use Among Obstetrics and Gynecology Residents.

PubMed

Perry, Rachel; Burns, Roshan M; Simon, Rebecca; Youm, Julie

2017-10-01

Mobile applications (apps) are increasingly used in clinical settings, particularly among resident physicians. Apps available to patients and physicians are rapidly expanding. We aimed to describe obstetrics and gynecology (ob-gyn) residents' use of and attitudes toward ob-gyn-related mobile apps. We conducted a cross-sectional survey of residents at all 19 California ob-gyn programs using a web-based questionnaire. Responses were analyzed using descriptive and chi-square statistics. Of 386 residents contacted, 197 (51%) completed the survey. All respondents owned mobile devices (100% smartphone, 74% tablet), and 93% used apps in the clinical setting. Commonly used ob-gyn-related apps were pregnancy wheels (84%), cervical cancer screening algorithms (68%), and contraceptive eligibility guidelines (47%). Only 53% of respondents recommended apps to patients, with many reporting not being aware of appropriate apps. Sixty-two percent of respondents used apps for learning, but only 3 ob-gyn-specific apps were mentioned. Most chose apps based on recommendations from other residents. Residents viewed mobile technology as an important clinical tool (92%) that improves efficiency (89%). App use did not differ by gender, age, or postgraduate year. Mobile technology and ob-gyn-related app use are widely used among California ob-gyn residents, who feel that apps enhance their ability to care for patients. Context of app use varies, with most residents using apps during clinical care, but only half recommending apps to patients. Recommendations from other residents are the common resource for discovering new apps, suggesting a need for more formal guidance on finding and evaluating apps.

Smartphone apps for spinal surgery: is technology good or evil?

PubMed

Robertson, Greg A J; Wong, Seng Juong; Brady, Richard R; Subramanian, Ashok S

2016-05-01

The increased utilization of smartphones together with their downloadable applications (apps) provides opportunity for doctors, including spinal surgeons, to integrate such technology into clinical practice. However, the clinical reliability of the medical app sector remains questionable. We reviewed available apps themed specifically towards spinal surgery and related conditions and assessed the level of medical professional involvement in their design and content. The most popular smartphone app stores (Android, Apple, Blackberry, Windows, Samsung, Nokia) were searched for spinal surgery-themed apps, using the disease terms Spinal Surgery, Back Surgery, Spine, Disc Prolapse, Sciatica, Radiculopathy, Spinal Stenosis, Scoliosis, Spinal Fracture and Spondylolisthesis. A total of 78 individual spinal surgery themed apps were identified, of which there were six duplicates (N = 72). According to app store classifications, there were 57 (79 %) medical themed apps, 11 (15 %) health and fitness themed apps, 1 (1 %) business and 3 (4 %) education themed apps. Forty-five (63 %) apps were available for download free of charge. For those that charged access, the prices ranged from £0.62 to £47.99. Only 44 % of spinal surgery apps had customer satisfaction ratings and 56 % had named medical professional involvement in their development or content. This is the first study to specifically address the characteristics of apps related to spinal surgery. We found that nearly half of spinal surgery apps had no named medical professional involvement, raising concerns over app content and evidence base for their use. We recommend increased regulation of spinal surgical apps to improve the accountability of app content.

[AVIAN RECOMBINANT VIRUS H5N1 INFLUENZA (A/VIETNAM/1203/04) AND ITS ESCAPE-MUTANT m13(13) INDUCE EARLY SIGNALING REACTIONS OF THE IMMUNITY IN HUMAN LYMPHOCYTES].

PubMed

Sokolova, T M; Poloskov, V V; Shuvalov, A N; Rudneva, I A; Ershov, F I

2016-01-01

The innate immune receptors TLR4, TLR7, TLR8, and RIG1 recognized the structures of the influenza viruses in human lymphocytes and were activated by the recombinant avian influenza virus A/Vietnam/1203/04 and its escape-mutant m13(13) during early period of interaction. The stimulated levels are not connected with viral reproduction. Donor cells with the low constitutive immune receptors gene expression levels showed higher stimulation. Inflammation virus effects resulted in. increasing production of TNF-alpha and IFN-gamma by lymphocytes. Signaling gene reactions of the parent and mutant viruses endosomal as well as cytoplasmic receptors are very similar. The mutant virus A/Vietnam/1203/04 (HA S145F), stimulated an increase in the transcription level of the membrane receptor gene TLR4 and a decrease in the level of activation of TNF-alpha gene. Further studies of natural influenza virus isolates are necessary to estimate the role of HA antigenic changes on immune reactions in humans.

Minos-insertion mutant of the Drosophila GBA gene homologue showed abnormal phenotypes of climbing ability, sleep and life span with accumulation of hydroxy-glucocerebroside.

PubMed

Kawasaki, Haruhisa; Suzuki, Takahiro; Ito, Kumpei; Takahara, Tsubasa; Goto-Inoue, Naoko; Setou, Mitsutoshi; Sakata, Kazuki; Ishida, Norio

2017-05-30

Gaucher's disease in humans is considered a deficiency of glucocerebrosidase (GlcCerase) that result in the accumulation of its substrate, glucocerebroside (GlcCer). Although mouse models of Gaucher's disease have been reported from several laboratories, these models are limited due to the perinatal lethality of GlcCerase gene. Here, we examined phenotypes of Drosophila melanogaster homologues genes of the human Gaucher's disease gene by using Minos insertion. One of two Minos insertion mutants to unknown function gene (CG31414) accumulates the hydroxy-GlcCer in whole body of Drosophila melanogaster. This mutant showed abnormal phenotypes of climbing ability and sleep, and short lifespan. These abnormal phenotypes are very similar to that of Gaucher's disease in human. In contrast, another Minos insertion mutant (CG31148) and its RNAi line did not show such severe phenotype as observed in CG31414 gene mutation. The data suggests that Drosophila CG31414 gene mutation might be useful for unraveling the molecular mechanism of Gaucher's disease. Copyright © 2017 Elsevier B.V. All rights reserved.

Use of and Beliefs About Mobile Phone Apps for Diabetes Self-Management: Surveys of People in a Hospital Diabetes Clinic and Diabetes Health Professionals in New Zealand.

PubMed

Boyle, Leah; Grainger, Rebecca; Hall, Rosemary M; Krebs, Jeremy D

2017-06-30

People with diabetes mellitus (DM) are using mobile phone apps to support self-management. The numerous apps available to assist with diabetes management have a variety of functions. Some functions, like insulin dose calculators, have significant potential for harm. The study aimed to establish (1) whether people with DM in Wellington, New Zealand, use apps for DM self-management and evaluate desirable features of apps and (2) whether health professionals (HPs) in New Zealand treating people with DM recommend apps to patients, the features HPs regard as important, and their confidence with recommending apps. A survey of patients seen at a hospital diabetes clinic over 12 months (N=539) assessed current app use and desirable features. A second survey of HPs attending a diabetes conference (n=286) assessed their confidence with app recommendations and perceived usefulness. Of the 189 responders (35.0% response rate) to the patient survey, 19.6% (37/189) had used a diabetes app. App users were younger and in comparison to other forms of diabetes mellitus, users prominently had type 1 DM. The most favored feature of the app users was a glucose diary (87%, 32/37), and an insulin calculator was the most desirable function for a future app (46%, 17/37). In non-app users, the most desirable feature for a future app was a glucose diary (64.4%, 98/152). Of the 115 responders (40.2% response rate) to the HPs survey, 60.1% (68/113) had recommended a diabetes app. Diaries for blood glucose levels and carbohydrate counting were considered the most useful app features and the features HPs felt most confident to recommend. HPs were least confident in recommending insulin calculation apps. The use of apps to record blood glucose was the most favored function in apps used by people with diabetes, with interest in insulin dose calculating function. HPs do not feel confident in recommending insulin dose calculators. There is an urgent need for an app assessment process to give confidence in the quality and safety of diabetes management apps to people with diabetes (potential app users) and HPs (potential app prescribers). ©Leah Boyle, Rebecca Grainger, Rosemary M Hall, Jeremy D Krebs. Originally published in JMIR Mhealth and Uhealth (http://mhealth.jmir.org), 30.06.2017.

Smartphone use in neurosurgery? APP-solutely!

PubMed

Zaki, Michael; Drazin, Doniel

2014-01-01

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. 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. 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. 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.

The Quality and Accuracy of Mobile Apps to Prevent Driving After Drinking Alcohol.

PubMed

Wilson, Hollie; Stoyanov, Stoyan R; Gandabhai, Shailen; Baldwin, Alexander

2016-08-08

Driving after the consumption of alcohol represents a significant problem globally. Individual prevention countermeasures such as personalized mobile app 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. 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. 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. 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. 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.

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

Can the silkworm (Bombyx mori) be used as a human disease model?

PubMed

Tabunoki, Hiroko; Bono, Hidemasa; Ito, Katsuhiko; Yokoyama, Takeshi

2016-02-01

Bombyx mori (silkworm) is the most famous lepidopteran in Japan. B. mori has long been used in the silk industry and also as a model insect for agricultural research. In recent years, B. mori has attracted interest in its potential for use in pathological analysis of model animals. For example, the human macular carotenoid transporter was discovered using information of B. mori carotenoid transporter derived from yellow-cocoon strain. The B. mori carotenoid transport system is useful in human studies. To develop a human disease model, we characterized the human homologs of B. mori, and by constructing KAIKO functional annotation pipeline, and to analyze gene expression profile of a unique B. mori mutant strain using microarray analysis. As a result, we identified a novel molecular network involved in Parkinson's disease. Here we describe the potential use of a spontaneous mutant silkworm strain as a human disease model. We also summarize recent progress in the application of genomic information for annotation of human homologs in B. mori. The B. mori mutant will provide a clue to pathological mechanisms, and the findings will be helpful for the development of therapies and for medical drug discovery.

Chromosomal mutations and chromosome loss measured in a new human-hamster hybrid cell line, ALC: studies with colcemid, ultraviolet irradiation, and 137Cs gamma-rays

NASA Technical Reports Server (NTRS)

Kraemer, S. M.; Waldren, C. A.; Chatterjee, A. (Principal Investigator)

1997-01-01

Small mutations, megabase deletions, and aneuploidy are involved in carcinogenesis and genetic defects, so it is important to be able to quantify these mutations and understand mechanisms of their creation. We have previously quantified a spectrum of mutations, including megabase deletions, in human chromosome 11, the sole human chromosome in a hamster-human hybrid cell line AL. S1- mutants have lost expression of a human cell surface antigen, S1, which is encoded by the M1C1 gene at 11p13 so that mutants can be detected via a complement-mediated cytotoxicity assay in which S1+ cells are killed and S1- cells survive. But loss of genes located on the tip of the short arm of 11 (11p15.5) is lethal to the AL hybrid, so that mutants that have lost the entire chromosome 11 die and escape detection. To circumvent this, we fused AL with Chinese hamster ovary (CHO) cells to produce a new hybrid, ALC, in which the requirement for maintaining 11p15.5 is relieved, allowing us to detect mutations events involving loss of 11p15.5. We evaluated the usefulness of this hybrid by conducting mutagenesis studies with colcemid, 137Cs gamma-radiation and UV 254 nm light. Colcemid induced 1000 more S1- mutants per unit dose in ALC than in AL; the increase for UV 254 nm light was only two-fold; and the increase for 137Cs gamma-rays was 12-fold. The increase in S1- mutant fraction in ALC cells treated with colcemid and 137Cs gamma-rays were largely due to chromosome loss and 11p deletions often containing a breakpoint within the centromeric region.

Pharmacological NAD-Boosting Strategies Improve Mitochondrial Homeostasis in Human Complex I-Mutant Fibroblasts.

PubMed

Felici, Roberta; Lapucci, Andrea; Cavone, Leonardo; Pratesi, Sara; Berlinguer-Palmini, Rolando; Chiarugi, Alberto

2015-06-01

Mitochondrial disorders are devastating genetic diseases for which efficacious therapies are still an unmet need. Recent studies report that increased availability of intracellular NAD obtained by inhibition of the NAD-consuming enzyme poly(ADP-ribose) polymerase (PARP)-1 or supplementation with the NAD-precursor nicotinamide riboside (NR) ameliorates energetic derangement and symptoms in mouse models of mitochondrial disorders. Whether these pharmacological approaches also improve bioenergetics of human cells harboring mitochondrial defects is unknown. It is also unclear whether the same signaling cascade is prompted by PARP-1 inhibitors and NR supplementation to improve mitochondrial homeostasis. Here, we show that human fibroblasts mutant for the NADH dehydrogenase (ubiquinone) Fe-S protein 1 (NDUFS1) subunit of respiratory complex I have similar ATP, NAD, and mitochondrial content compared with control cells, but show reduced mitochondrial membrane potential. Interestingly, mutant cells also show increased transcript levels of mitochondrial DNA but not nuclear DNA respiratory complex subunits, suggesting activation of a compensatory response. At variance with prior work in mice, however, NR supplementation, but not PARP-1 inhibition, increased intracellular NAD content in NDUFS1 mutant human fibroblasts. Conversely, PARP-1 inhibitors, but not NR supplementation, increased transcription of mitochondrial transcription factor A and mitochondrial DNA-encoded respiratory complexes constitutively induced in mutant cells. Still, both NR and PARP-1 inhibitors restored mitochondrial membrane potential and increased organelle content as well as oxidative activity of NDUFS1-deficient fibroblasts. Overall, data provide the first evidence that in human cells harboring a mitochondrial respiratory defect exposure to NR or PARP-1, inhibitors activate different signaling pathways that are not invariantly prompted by NAD increases, but equally able to improve energetic derangement. Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics.

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

PubMed

Anderson, Kevin; Burford, Oksana; Emmerton, Lynne

2016-11-04

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. 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. 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. 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 classification of, and ambiguity in, wording of questions within constructs. The proposed method to evaluate shortlisted and downloaded apps comprises instructions to attempt set-up of a dummy user profile, and dummy data entry to represent in-range and out-of-range clinical measures simulating a range of user behaviors. A minimum score of 80% by consensus (using the Intraclass Correlation Coefficient) between raters is proposed to identify apps suitable for clinical trials. The flow diagram allows researchers to shortlist health apps that are potentially suitable for formal evaluation. The evaluation checklist enables quantitative comparison of shortlisted apps based on constructs reported in the literature. The use of multiple raters, and comparison of their scores, is proposed to manage inherent subjectivity in assessing user experiences. Initial trial of the combined protocol is planned for apps pertaining to the self-monitoring of asthma; these results will be reported elsewhere. ©Kevin Anderson, Oksana Burford, Lynne Emmerton. Originally published in JMIR Research Protocols (http://www.researchprotocols.org), 04.11.2016.

Overview of smartphone applications for sleep analysis.

PubMed

Ong, Adrian A; Gillespie, M Boyd

2016-03-01

To review and assess the current selection of sleep analysis smartphone applications (apps) available for download. The iOS and Google Play mobile app store were searched for sleep analysis apps targeted for consumer use. Alarm clock, sleep-aid, snoring and sleep-talking recorder, fitness tracker apps, and apps geared towards health professionals were excluded. App information and features were obtained from in-store descriptions, and the app developer website. A total of 51 unique sleep apps in both iOS and Google Play stores were included. The apps were rated 3.8/5 in both stores, and had an average price of $1.12 in the iOS store and $0.58 in the Google Play store. >65% of sleep apps report on sleep structure, including duration, time awake, and time in light/deep sleep, while reporting of REM was limited. The availability of extra features was variable, ranging from 4% to 73% of apps. There are a variety of sleep analysis apps with a range of functionality. The apps with the most reviews from the each store are featured. Many apps provide data on sleep structure; however the algorithms are not validated by scientific literature or studies. Since patients may inquire about their sleep habits from these apps, it is necessary for physicians to be aware of the most common apps and the features offered and their limitations in order to properly counsel patients.

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

Client-Focused Security Assessment of mHealth Apps and Recommended Practices to Prevent or Mitigate Transport Security Issues

PubMed Central

Müthing, Jannis; Jäschke, Thomas

2017-01-01

Background Mobile health (mHealth) apps show a growing importance for patients and health care professionals. Apps in this category are diverse. Some display important information (ie, drug interactions), whereas others help patients to keep track of their health. However, insufficient transport security can lead to confidentiality issues for patients and medical professionals, as well as safety issues regarding data integrity. mHealth apps should therefore deploy intensified vigilance to protect their data and integrity. This paper analyzes the state of security in mHealth apps. Objective The objectives of this study were as follows: (1) identification of relevant transport issues in mHealth apps, (2) development of a platform for test purposes, and (3) recommendation of practices to mitigate them. Methods Security characteristics relevant to the transport security of mHealth apps were assessed, presented, and discussed. These characteristics were used in the development of a prototypical platform facilitating streamlined tests of apps. For the tests, six lists of the 10 most downloaded free apps from three countries and two stores were selected. As some apps were part of these top 10 lists in more than one country, 53 unique apps were tested. Results Out of the 53 apps tested from three European App Stores for Android and iOS, 21/53 (40%) showed critical results. All 21 apps failed to guarantee the integrity of data displayed. A total of 18 apps leaked private data or were observable in a way that compromised confidentiality between apps and their servers; 17 apps used unprotected connections; and two apps failed to validate certificates correctly. None of the apps tested utilized certificate pinning. Many apps employed analytics or ad providers, undermining user privacy. Conclusions The tests show that many mHealth apps do not apply sufficient transport security measures. The most common security issue was the use of any kind of unprotected connection. Some apps used secure connections only for selected tasks, leaving all other traffic vulnerable. PMID:29046271

Client-Focused Security Assessment of mHealth Apps and Recommended Practices to Prevent or Mitigate Transport Security Issues.

PubMed

Müthing, Jannis; Jäschke, Thomas; Friedrich, Christoph M

2017-10-18

Mobile health (mHealth) apps show a growing importance for patients and health care professionals. Apps in this category are diverse. Some display important information (ie, drug interactions), whereas others help patients to keep track of their health. However, insufficient transport security can lead to confidentiality issues for patients and medical professionals, as well as safety issues regarding data integrity. mHealth apps should therefore deploy intensified vigilance to protect their data and integrity. This paper analyzes the state of security in mHealth apps. The objectives of this study were as follows: (1) identification of relevant transport issues in mHealth apps, (2) development of a platform for test purposes, and (3) recommendation of practices to mitigate them. Security characteristics relevant to the transport security of mHealth apps were assessed, presented, and discussed. These characteristics were used in the development of a prototypical platform facilitating streamlined tests of apps. For the tests, six lists of the 10 most downloaded free apps from three countries and two stores were selected. As some apps were part of these top 10 lists in more than one country, 53 unique apps were tested. Out of the 53 apps tested from three European App Stores for Android and iOS, 21/53 (40%) showed critical results. All 21 apps failed to guarantee the integrity of data displayed. A total of 18 apps leaked private data or were observable in a way that compromised confidentiality between apps and their servers; 17 apps used unprotected connections; and two apps failed to validate certificates correctly. None of the apps tested utilized certificate pinning. Many apps employed analytics or ad providers, undermining user privacy. The tests show that many mHealth apps do not apply sufficient transport security measures. The most common security issue was the use of any kind of unprotected connection. Some apps used secure connections only for selected tasks, leaving all other traffic vulnerable. ©Jannis Müthing, Thomas Jäschke, Christoph M Friedrich. Originally published in JMIR Mhealth and Uhealth (http://mhealth.jmir.org), 18.10.2017.

Commercially available mobile phone headache diary apps: a systematic review.

PubMed

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

2014-08-19

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. 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. 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. 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. Despite the growing market and demand, there is a concerning lack of scientific expertise and evidence base associated with headache diary apps.

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

Host range phenotype induced by mutations in the internal ribosomal entry site of poliovirus RNA.

PubMed Central

Shiroki, K; Ishii, T; Aoki, T; Ota, Y; Yang, W X; Komatsu, T; Ami, Y; Arita, M; Abe, S; Hashizume, S; Nomoto, A

1997-01-01

Most poliovirus strains infect only primates. The host range (HR) of poliovirus is thought to be primarily determined by a cell surface molecule that functions as poliovirus receptor (PVR), since it has been shown that transgenic mice are made poliovirus sensitive by introducing the human PVR gene into the genome. The relative levels of neurovirulence of polioviruses tested in these transgenic mice were shown to correlate well with the levels tested in monkeys (H. Horie et al., J. Virol. 68:681-688, 1994). Mutants of the virulent Mahoney strain of poliovirus have been generated by disruption of nucleotides 128 to 134, at stem-loop II within the 5' noncoding region, and four of these mutants multiplicated well in human HeLa cells but poorly in mouse TgSVA cells that had been established from the kidney of the poliovirus-sensitive transgenic mouse. Neurovirulence tests using the two animal models revealed that these mutants were strongly attenuated only in tests with the mouse model and were therefore HR mutants. The virus infection cycle in TgSVA cells was restricted by an internal ribosomal entry site (IRES)-dependent initiation process of translation. Viral protein synthesis and the associated block of cellular protein synthesis were not observed in TgSVA cells infected with three of four HR mutants and was evident at only a low level in the remaining mutant. The mutant RNAs were functional in a cell-free protein synthesis system from HeLa cells but not in those from TgSVA and mouse neuroblastoma NS20Y cells. These results suggest that host factor(s) affecting IRES-dependent translation of poliovirus differ between human and mouse cells and that the mutant IRES constructs detect species differences in such host factor(s). The IRES could potentially be a host range determinant for poliovirus infection. PMID:8985316

Application of a haematopoetic progenitor cell-targeted adeno-associated viral (AAV) vector established by selection of an AAV random peptide library on a leukaemia cell line

PubMed Central

Stiefelhagen, Marius; Sellner, Leopold; Kleinschmidt, Jürgen A; Jauch, Anna; Laufs, Stephanie; Wenz, Frederik; Zeller, W Jens; Fruehauf, Stefan; Veldwijk, Marlon R

2008-01-01

Background For many promising target cells (e.g.: haematopoeitic progenitors), the susceptibility to standard adeno-associated viral (AAV) vectors is low. Advancements in vector development now allows the generation of target cell-selected AAV capsid mutants. Methods To determine its suitability, the method was applied on a chronic myelogenous leukaemia (CML) cell line (K562) to obtain a CML-targeted vector and the resulting vectors tested on leukaemia, non-leukaemia, primary human CML and CD34+ peripheral blood progenitor cells (PBPC); standard AAV2 and a random capsid mutant vector served as controls. Results Transduction of CML (BV173, EM3, K562 and Lama84) and AML (HL60 and KG1a) cell lines with the capsid mutants resulted in an up to 36-fold increase in CML transduction efficiency (K562: 2-fold, 60% ± 2% green fluorescent protein (GFP)+ cells; BV173: 9-fold, 37% ± 2% GFP+ cells; Lama84: 36-fold, 29% ± 2% GFP+ cells) compared to controls. For AML (KG1a, HL60) and one CML cell line (EM3), no significant transduction (<1% GFP+ cells) was observed for any vector. Although the capsid mutant clone was established on a cell line, proof-of-principle experiments using primary human cells were performed. For CML (3.2-fold, mutant: 1.75% ± 0.45% GFP+ cells, p = 0.03) and PBPC (3.5-fold, mutant: 4.21% ± 3.40% GFP+ cells) a moderate increase in gene transfer of the capsid mutant compared to control vectors was observed. Conclusion Using an AAV random peptide library on a CML cell line, we were able to generate a capsid mutant, which transduced CML cell lines and primary human haematopoietic progenitor cells with higher efficiency than standard recombinant AAV vectors. PMID:18789140

The Rise and Need for Mobile Apps for Maternal and Child Health Care in China: Survey Based on App Markets.

PubMed

Zhang, Puhong; Dong, Le; Chen, Huan; Chai, Yanling; Liu, Jianbo

2018-06-08

Mobile health services are thriving in the field of maternal and child health in China due to expansions in the field of electronic health and the introduction of the two-child policy. There are numerous maternal and child health apps in computer stores, but the exact number of apps, number of downloads, and features of these apps is not known. This study aimed to explore the use of maternal and child health apps in Android and iOS app stores and to describe the key functional features of the most popular apps, with the purpose of providing insight into further research and development of maternal and child health mobile health products. The researchers conducted a search in the 3 most popular Android app stores (Tencent MyApp, Baidu Mobile Assistant, and 360 Mobile Assistant) and the iTunes App Store in China. All apps regarding family planning (contraception and preparing for pregnancy), pregnancy and perinatal care, neonatal care and health, and development for children under 6 years were included in the initial analysis. Maternal and child health mobile apps with predominant features of product marketing, children's songs, animation, or games were excluded from the study. The 50 most frequently used apps in each of the Android stores as well as the iTunes store (a total of 78 deduplicated apps) were selected and downloaded for an in-depth analysis. A total of 5276 Android apps and 877 iOS apps developed for maternal and child health care were identified. Of the 78 most frequently used apps, 43 (55%) apps focused on one stage of MCH care, mainly targeting child care (25 apps) and before pregnancy care (11 apps), whereas 35 (45%) of the apps covered 2 or more stages, most of which (32 apps) included both pregnancy and child care services. The app features that were commonly adopted by the popular apps were health education, communication, health status self-monitoring, a diary, reminders, and counseling. Within the app feature of "health status self-monitoring," the researchers found 47 specific tools supporting activities such as pregnancy preparation, fetal heart monitoring, blood glucose and blood pressure monitoring, and doctor visits. A few apps were equipped with external devices (n=3) or sensors. No app with intelligent decision-support features to support disease management for conditions such as gestational diabetes and pregnancy-induced hypertension was found. A small number of apps (n=5) had a Web connection with hospital information systems to support appointment making, payments, hospital service guidance, or checking of laboratory results. There are thousands of maternal and child health apps in the Chinese market. Child care, pregnancy, and before pregnancy were the mostly covered maternal and child health stages, in that order. Various app features and tools were adopted by maternal and child health apps, but the use of internal or external sensors, intelligent decision support, and tethering with existing hospital information systems was rare and these features need more research and development. ©Puhong Zhang, Le Dong, Huan Chen, Yanling Chai, Jianbo Liu. Originally published in JMIR Mhealth and Uhealth (http://mhealth.jmir.org), 08.06.2018.

Uptake and Usage of IntelliCare: A Publicly Available Suite of Mental Health and Well-Being Apps.

PubMed

Lattie, Emily G; Schueller, Stephen M; Sargent, Elizabeth; Stiles-Shields, Colleen; Tomasino, Kathryn Noth; Corden, Marya E; Begale, Mark; Karr, Chris J; Mohr, David C

2016-05-01

Treatments for depression and anxiety have several behavioral and psychological targets and rely on varied strategies. Digital mental health treatments often employ feature-rich approaches addressing several targets and strategies. These treatments, often optimized for desktop computer use, are at odds with the ways people use smartphone applications. Smartphone use tends to focus on singular functions with easy navigation to desired tools. The IntelliCare suite of apps was developed to address the discrepancy between need for diverse behavioral strategies and constraints imposed by typical app use. Each app focuses on one strategy for a limited subset of clinical aims all pertinent to depression and anxiety. This study presents the uptake and usage of apps from the IntelliCare suite following an open deployment on a large app marketplace. Thirteen lightweight apps, including 12 interactive apps and one Hub app that coordinates use across those interactive apps, were developed and made free to download on the Google Play store. De-identified app usage data from the first year of IntelliCare suite deployment were analyzed for this study. In the first year of public availability, 5,210 individuals downloaded one or more of the IntelliCare apps, for a total of 10,131 downloads. Nearly a third of these individuals (31.8%) downloaded more than one of these apps. The modal number of launches for each of the apps was 1, however the mean number of app launches per app ranged from 3.10 to 16.98, reflecting considerable variability in the use of each app. The use rate of the IntelliCare suite of apps is higher than public deployments of other comparable digital resources. Our findings suggest that people will use multiple apps and provides support for the concept of app suites as a useful strategy for providing diverse behavioral strategies.

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 content is needed. PMID:27826133

Assessment of medication adherence app features, functionality, and health literacy level and the creation of a searchable Web-based adherence app resource for health care professionals and patients.

PubMed

Heldenbrand, Seth; Martin, Bradley C; Gubbins, Paul O; Hadden, Kristie; Renna, Catherine; Shilling, Rebecca; Dayer, Lindsey

2016-01-01

To assess the features and level of health literacy (HL) of available medication adherence apps and to create a searchable website to assist health care providers (HCP) and patients identify quality adherence apps. Medication nonadherence continues to be a significant problem and leads to poor health outcomes and avoidable health care expense. The average adherence rate for chronic medications, regardless of disease state, is approximately 50% leaving significant room for improvement. Smartphone adherence apps are a novel resource to address medication nonadherence. With widespread smartphone use and the growing number of adherence apps, both HCP and patients should be able to identify quality adherence apps to maximize potential benefits. Assess the features, functionality and level of HL of available adherence apps and create a searchable website to help both HCP and patients identify quality adherence apps. Online marketplaces (iTunes, Google Play, Blackberry) were searched in June of 2014 to identify available adherence apps. Online descriptions were recorded and scored based on 28 author-identified features across 4 domains. The 100 highest-scoring apps were user-tested with a standardized regimen to evaluate their functionality and level of HL. 461 adherence apps were identified. 367 unique apps were evaluated after removing "Lite/Trial" versions. The median initial score based on descriptions was 15 (max of 68; range: 3 to 47). Only 77 apps of the top 100 highest-scoring apps completed user-testing and HL evaluations. The median overall user-testing score was 30 (max of 73; range: 16 to 55). App design, functionality, and level of HL varies widely among adherence apps. While no app is perfect, several apps scored highly across all domains. The website www.medappfinder.com is a searchable tool that helps HCP and patients identify quality apps in a crowded marketplace. Copyright © 2016 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

MedAd-AppQ: A quality assessment tool for medication adherence apps on iOS and android platforms.

PubMed

Ali, Eskinder Eshetu; Teo, Amanda Kai Sin; Goh, Sherlyn Xue Lin; Chew, Lita; Yap, Kevin Yi-Lwern

2018-02-02

With the recent proliferation of smartphone medication adherence applications (apps), it is increasingly more difficult for patients and clinicians to identify the most useful app. To develop a quality assessment tool for medication adherence apps, and evaluate the quality of such apps from the major app stores. In this study, a Medication Adherence App Quality assessment tool (MedAd-AppQ) was developed and two evaluators independently assessed apps that fulfilled the following criteria: availability in English, had at least a medication reminder feature, non-specific to certain disease conditions (generic apps), free of technical malfunctions and availability on both the iPhone Operating System (iOS) and Android platforms. Descriptive statistics, Mann-Whitney U test, Pearson product moment correlation and Spearman rank-order correlation were used for statistical analysis. MedAd-AppQ was designed to have 24 items (total 43 points) categorized under three sections: content reliability (11 points), feature usefulness (29 points) and feature convenience (3 points). The three sections of MedAd-AppQ were found to have inter-rater correlation coefficients of 0.801 (p-value < .001) or higher. Based on analysis of 52 apps (27 iOS and 25 Android), quality scores ranged between 7/43 (16.3%) and 28/43 (65.1%). There was no significant difference between the quality scores of the Android and iOS versions. None of the apps had features for self-management of side effects. Only two apps in each platform provided disease-related and/or medication information. MedAd-AppQ can be used to reliably assess the quality of adherence apps. Clinicians can use the tool in selecting apps for use by patients. Developers of adherence apps should consider features that provide therapy-related information and help patients in medications and side-effects management. Copyright © 2018 Elsevier Inc. All rights reserved.

Quality of Publicly Available Physical Activity Apps: Review and Content Analysis

PubMed Central

Alkhaldi, Ghadah; Slee, April; Hamilton, Fiona L; Murray, Elizabeth

2018-01-01

Background Within the new digital health landscape, the rise of health apps creates novel prospects for health promotion. The market is saturated with apps that aim to increase physical activity (PA). Despite the wide distribution and popularity of PA apps, there are limited data on their effectiveness, user experience, and safety of personal data. Objective The purpose of this review and content analysis was to evaluate the quality of the most popular PA apps on the market using health care quality indicators. Methods The top-ranked 400 free and paid apps from iTunes and Google Play stores were screened. Apps were included if the primary behavior targeted was PA, targeted users were adults, and the apps had stand-alone functionality. The apps were downloaded on mobile phones and assessed by 2 reviewers against the following quality assessment criteria: (1) users’ data privacy and security, (2) presence of behavior change techniques (BCTs) and quality of the development and evaluation processes, and (3) user ratings and usability. Results Out of 400 apps, 156 met the inclusion criteria, of which 65 apps were randomly selected to be downloaded and assessed. Almost 30% apps (19/65) did not have privacy policy. Every app contained at least one BCT, with an average number of 7 and a maximum of 13 BCTs. All but one app had commercial affiliation, 12 consulted an expert, and none reported involving users in the app development. Only 12 of 65 apps had a peer-reviewed study connected to the app. User ratings were high, with only a quarter of the ratings falling below 4 stars. The median usability score was excellent—86.3 out of 100. Conclusions Despite the popularity of PA apps available on the commercial market, there were substantial shortcomings in the areas of data safety and likelihood of effectiveness of the apps assessed. The limited quality of the apps may represent a missed opportunity for PA promotion. PMID:29563080

Enabling Psychiatrists to be Mobile Phone App Developers: Insights Into App Development Methodologies.

PubMed

Zhang, Melvyn Wb; Tsang, Tammy; Cheow, Enquan; Ho, Cyrus Sh; Yeong, Ng Beng; Ho, Roger Cm

2014-11-11

The use of mobile phones, and specifically smartphones, in the last decade has become more and more prevalent. The latest mobile phones are equipped with comprehensive features that can be used in health care, such as providing rapid access to up-to-date evidence-based information, provision of instant communications, and improvements in organization. The estimated number of health care apps for mobile phones is increasing tremendously, but previous research has highlighted the lack of critical appraisal of new apps. This lack of appraisal of apps has largely been due to the lack of clinicians with technical knowledge of how to create an evidence-based app. We discuss two freely available methodologies for developing Web-based mobile phone apps: a website builder and an app builder. With these, users can program not just a Web-based app, but also integrate multimedia features within their app, without needing to know any programming language. We present techniques for creating a mobile Web-based app using two well-established online mobile app websites. We illustrate how to integrate text-based content within the app, as well as integration of interactive videos and rich site summary (RSS) feed information. We will also briefly discuss how to integrate a simple questionnaire survey into the mobile-based app. A questionnaire survey was administered to students to collate their perceptions towards the app. These two methodologies for developing apps have been used to convert an online electronic psychiatry textbook into two Web-based mobile phone apps for medical students rotating through psychiatry in Singapore. Since the inception of our mobile Web-based app, a total of 21,991 unique users have used the mobile app and online portal provided by WordPress, and another 717 users have accessed the app via a Web-based link. The user perspective survey results (n=185) showed that a high proportion of students valued the textbook and objective structured clinical examination videos featured in the app. A high proportion of students concurred that a self-designed mobile phone app would be helpful for psychiatry education. These methodologies can enable busy clinicians to develop simple mobile Web-based apps for academic, educational, and research purposes, without any prior knowledge of programming. This will be beneficial for both clinicians and users at large, as there will then be more evidence-based mobile phone apps, or at least apps that have been appraised by a clinician.

Enabling Psychiatrists to be Mobile Phone App Developers: Insights Into App Development Methodologies

PubMed Central

Tsang, Tammy; Cheow, Enquan; Ho, Cyrus SH; Yeong, Ng Beng; Ho, Roger CM

2014-01-01

Background The use of mobile phones, and specifically smartphones, in the last decade has become more and more prevalent. The latest mobile phones are equipped with comprehensive features that can be used in health care, such as providing rapid access to up-to-date evidence-based information, provision of instant communications, and improvements in organization. The estimated number of health care apps for mobile phones is increasing tremendously, but previous research has highlighted the lack of critical appraisal of new apps. This lack of appraisal of apps has largely been due to the lack of clinicians with technical knowledge of how to create an evidence-based app. Objective We discuss two freely available methodologies for developing Web-based mobile phone apps: a website builder and an app builder. With these, users can program not just a Web-based app, but also integrate multimedia features within their app, without needing to know any programming language. Methods We present techniques for creating a mobile Web-based app using two well-established online mobile app websites. We illustrate how to integrate text-based content within the app, as well as integration of interactive videos and rich site summary (RSS) feed information. We will also briefly discuss how to integrate a simple questionnaire survey into the mobile-based app. A questionnaire survey was administered to students to collate their perceptions towards the app. Results These two methodologies for developing apps have been used to convert an online electronic psychiatry textbook into two Web-based mobile phone apps for medical students rotating through psychiatry in Singapore. Since the inception of our mobile Web-based app, a total of 21,991 unique users have used the mobile app and online portal provided by WordPress, and another 717 users have accessed the app via a Web-based link. The user perspective survey results (n=185) showed that a high proportion of students valued the textbook and objective structured clinical examination videos featured in the app. A high proportion of students concurred that a self-designed mobile phone app would be helpful for psychiatry education. Conclusions These methodologies can enable busy clinicians to develop simple mobile Web-based apps for academic, educational, and research purposes, without any prior knowledge of programming. This will be beneficial for both clinicians and users at large, as there will then be more evidence-based mobile phone apps, or at least apps that have been appraised by a clinician. PMID:25486985

RNA interference-mediated silencing of mutant superoxide dismutase rescues cyclosporin A-induced death in cultured neuroblastoma cells

PubMed Central

Maxwell, Michele M.; Pasinelli, Piera; Kazantsev, Aleksey G.; Brown, Robert H.

2004-01-01

Amyotrophic lateral sclerosis (ALS) is a progressive and fatal neurodegenerative disorder resulting from selective death of motor neurons in the brain and spinal cord. In ≈25% of familial ALS cases, the disease is caused by dominantly acting point mutations in the gene encoding cytosolic Cu,Zn superoxide dismutase (SOD1). In cell culture and in rodent models of ALS, mutant SOD1 proteins exhibit dose-dependent toxicity; thus, agents that reduce mutant protein expression would be powerful therapeutic tools. A wealth of recent evidence has demonstrated that the mechanism of RNA-mediated interference (RNAi) can be exploited to achieve potent and specific gene silencing in vitro and in vivo. We have evaluated the utility of RNAi for selective silencing of mutant SOD1 expression in cultured cells and have identified small interfering RNAs capable of specifically inhibiting expression of ALS-linked mutant, but not wild-type, SOD1. We have investigated the functional effects of RNAi-mediated silencing of mutant SOD1 in cultured murine neuroblastoma cells. In this model, stable expression of mutant, but not wild-type, human SOD1 sensitizes cells to cytotoxic stimuli. We find that silencing of mutant SOD1 protects these cells against cyclosporin A-induced cell death. These results demonstrate a positive physiological effect caused by RNAi-mediated silencing of a dominant disease allele. The present study further supports the therapeutic potential of RNAi-based methods for the treatment of inherited human diseases, including ALS. PMID:14981234

The pattern of trabecular bone microarchitecture in the distal femur of typically developing children and its effect on processing of magnetic resonance images.

PubMed

Modlesky, Christopher M; Whitney, Daniel G; Carter, Patrick T; Allerton, Brianne M; Kirby, Joshua T; Miller, Freeman

2014-03-01

Magnetic resonance imaging (MRI) is used to assess trabecular bone microarchitecture in humans; however, image processing can be labor intensive and time consuming. One aim of this study was to determine the pattern of trabecular bone microarchitecture in the distal femur of typically developing children. A second aim was to determine the proportion and location of magnetic resonance images that need to be processed to yield representative estimates of trabecular bone microarchitecture. Twenty-six high resolution magnetic resonance images were collected immediately above the growth plate in the distal femur of 6-12year-old typically developing children (n=40). Measures of trabecular bone microarchitecture [i.e., apparent trabecular bone volume to total volume (appBV/TV), trabecular number (appTb.N), trabecular thickness (appTb.Th) and trabecular separation (appTb.Sp)] in the lateral aspect of the distal femur were determined using the twenty most central images (20IM). The average values for appBV/TV, appTb.N, appTb.Th and appTb.Sp from 20IM were compared to the average values from 10 images (10IM), 5 images (5IM) and 3 images (3IM) equally dispersed throughout the total image set and one image (1IM) from the center of the total image set using linear regression analysis. The resulting mathematical models were cross-validated using the leave-one-out technique. Distance from the growth plate was strongly and inversely related to appBV/TV (r(2)=0.68, p<0.001) and appTb.N (r(2)=0.92, p<0.001) and was strongly and positively related to appTb.Sp (r(2)=0.86, p<0.001). The relationship between distance from the growth plate and appTb.Th was not linear (r(2)=0.06, p=0.28), but instead it was quadratic and statistically significant (r(2)=0.54, p<0.001). Trabecular bone microarchitecture estimates from 10IM, 5IM, 3IM and 1IM were not different from estimates from 20IM (p>0.05). However, there was a progressive decrease in the strength of the relationships as a smaller proportion of images were used to predict estimates from 20IM (r(2)=0.98 to 0.99 using 10IM, 0.94 to 0.96 using 5IM, 0.87 to 0.90 using 3IM and 0.66 to 0.72 using 1IM; all p<0.001). Using the resulting mathematical models and the leave-one-out cross-validation analysis, measures of trabecular bone microarchitecture estimated from the 10IM and 5IM partial image sets agreed extremely well with estimates from 20IM. The findings indicate that partial magnetic resonance image sets can be used to provide reasonable estimates of trabecular bone microarchitecture status in the distal femur of typically developing children. However, because the relative amount of trabecular bone in the distal femur decreases with distance from the growth plate due to a decrease in trabecular number, careful positioning of the region of interest and sampling from throughout the region of interest is necessary. Copyright © 2013 Elsevier Inc. All rights reserved.

The Cytoscape app article collection

PubMed Central

Pico, Alexander R; Bader, Gary D; Demchak, Barry; Guitart Pla, Oriol; Hull, Timothy; Longabaugh, William; Lopes, Christian; Lotia, Samad; Molenaar, Piet; Montojo, Jason; Morris, John H; Ono, Keiichiro; Schwikowski, Benno; Welker, David; Ideker, Trey

2014-01-01

As a network visualization and analysis platform, Cytoscape relies on apps to provide domain-specific features and functions. There are many resources available to support Cytoscape app development and distribution, including the Cytoscape App Store and an online “cookbook” for app developers. This article collection is another resource to help researchers find out more about relevant Cytoscape apps and to provide app developers with useful implementation tips. The collection will grow over time as new Cytoscape apps are developed and published. PMID:25580224

Practical Considerations for Use of Mobile Apps at the Tactical Edge

DTIC Science & Technology

2014-06-01

and logging The commercial app stores must scale to very large numbers of users (e.g., iTunes has over 800 million accounts, most with credit cards ...over a million Android apps and a million iOS apps are available for download from the Google Play and Apple iTunes app stores, respectively. Of these...apps and a million iOS apps are available for download from the Google Play and Apple iTunes app stores, respectively. Of these, most would not be

Incorporation of Mobile Application (App) Measures Into the Diagnosis of Smartphone Addiction.

PubMed

Lin, Yu-Hsuan; Lin, Po-Hsien; Chiang, Chih-Lin; Lee, Yang-Han; Yang, Cheryl C H; Kuo, Terry B J; Lin, Sheng-Hsuan

2017-07-01

Global smartphone expansion has brought about unprecedented addictive behaviors. The current diagnosis of smartphone addiction is based solely on information from clinical interview. This study aimed to incorporate application (app)-recorded data into psychiatric criteria for the diagnosis of smartphone addiction and to examine the predictive ability of the app-recorded data for the diagnosis of smartphone addiction. Smartphone use data of 79 college students were recorded by a newly developed app for 1 month between December 1, 2013, and May 31, 2014. For each participant, psychiatrists made a diagnosis for smartphone addiction based on 2 approaches: (1) only diagnostic interview (standard diagnosis) and (2) both diagnostic interview and app-recorded data (app-incorporated diagnosis). The app-incorporated diagnosis was further used to build app-incorporated diagnostic criteria. In addition, the app-recorded data were pooled as a score to predict smartphone addiction diagnosis. When app-incorporated diagnosis was used as a gold standard for 12 candidate criteria, 7 criteria showed significant accuracy (area under receiver operating characteristic curve [AUC] > 0.7) and were constructed as app-incorporated diagnostic criteria, which demonstrated remarkable accuracy (92.4%) for app-incorporated diagnosis. In addition, both frequency and duration of daily smartphone use significantly predicted app-incorporated diagnosis (AUC = 0.70 for frequency; AUC = 0.72 for duration). The combination of duration, frequency, and frequency trend for 1 month can accurately predict smartphone addiction diagnosis (AUC = 0.79 for app-incorporated diagnosis; AUC = 0.71 for standard diagnosis). The app-incorporated diagnosis, combining both psychiatric interview and app-recorded data, demonstrated substantial accuracy for smartphone addiction diagnosis. In addition, the app-recorded data performed as an accurate screening tool for app-incorporated diagnosis. © Copyright 2017 Physicians Postgraduate Press, Inc.

A biopsy of Breast Cancer mobile applications: state of the practice review.

PubMed

Giunti, G; Giunta, D H; Guisado-Fernandez, E; Bender, J L; Fernandez-Luque, L

2018-02-01

Breast cancer is the most common cancer in women. The use of mobile software applications for health and wellbeing promotion has grown exponentially in recent years. We systematically reviewed the breast cancer apps available in today's leading smartphone application stores and characterized them based on their features, evidence base and target audiences. A cross-sectional study was performed to characterize breast cancer apps from the two major smartphone app stores (iOS and Android). Apps that matched the keywords "breast cancer" were identified and data was extracted using a structured form. Reviewers independently evaluated the eligibility and independently classified the apps. A total of 1473 apps were a match. After removing duplicates and applying the selection criteria only 599 apps remained. Inter-rater reliability was determined using Fleiss-Cohen's Kappa. The majority of apps were free 471 (78.63%). The most common type of application was Disease and Treatment information apps (29.22%), Disease Management (19.03%) and Awareness Raising apps (15.03%). Close to 1 out of 10 apps dealt with alternative or homeopathic medicine. The majority of the apps were intended for patients (75.79%). Only one quarter of all apps (24.54%) had a disclaimer about usage and less than one fifth (19.70%) mentioned references or source material. Gamification specialists determined that 19.36% contained gamification elements. This study analyzed a large number of breast cancer-focused apps available to consumers. There has been a steady increase of breast cancer apps over the years. The breast cancer app ecosystem largely consists of start-ups and entrepreneurs. Evidence base seems to be lacking in these apps and it would seem essential that expert medical personnel be involved in the creation of medical apps. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

An evaluation of diabetes targeted apps for Android smartphone in relation to behaviour change techniques.

PubMed

Hoppe, C D; Cade, J E; Carter, M

2017-06-01

Mobile applications (apps) could support diabetes management through dietary, weight and blood glucose self-monitoring, as well as by promoting behaviour change. The present study aimed to evaluate diabetes apps for content, functions and behaviour change techniques (BCTs). Diabetes self-management apps for Android smartphones were searched for on the Google Play Store. Ten apps each from the following search terms were included; 'diabetes', 'diabetes type 1', 'diabetes type 2', 'gestational diabetes'. Apps were evaluated by being scored according to their number of functions and BCTs, price, and user rating. The mean (SD) number of functions was 8.9 (5.9) out of a possible maximum of 27. Furthermore, the mean (SD) number of BCTs was 4.4 (2.6) out of a possible maximum of 26. Apps with optimum BCT had significantly more functions [13.8; 95% confidence interval (CI) = 11.9-15.9] than apps that did not (4.7; 95% CI = 3.2-6.2; P < 0.01) and significantly more BCTs (5.8; 95% CI = 4.8-7.0) than apps without (3.1; 95% CI = 2.2-4.1; P < 0.01). Additionally, apps with optimum BCT also cost more than other apps. In the adjusted models, highly rated apps had an average of 4.8 (95% CI = 0.9-8.7; P = 0.02) more functions than lower rated apps. 'Diabetes apps' include few functions or BCTs compared to the maximum score possible. Apps with optimum BCTs could indicate higher quality. App developers should consider including both specific functions and BCTs in 'diabetes apps' to make them more helpful. More research is needed to understand the components of an effective app for people with diabetes. © 2016 The British Dietetic Association Ltd.

Cannabis Mobile Apps: A Content Analysis.

PubMed

Ramo, Danielle E; Popova, Lucy; Grana, Rachel; Zhao, Shirley; Chavez, Kathryn

2015-08-12

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. We investigated the content of 59 cannabis-related mobile apps for Apple and Android devices as of November 26, 2014. 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. 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. Cannabis apps are generally free and highly rated. Apps were most often informational (facts, strain classification), or recreational (games), likely reflecting and influencing the growing acceptance of cannabis for medical and recreational purposes. Apps addressing addiction or cessation were underrepresented in the most popular cannabis mobile apps. Differences among apps for Apple and Android platforms likely reflect differences in the population of users, developer choice, and platform regulations.

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 (facts, strain classification), or recreational (games), likely reflecting and influencing the growing acceptance of cannabis for medical and recreational purposes. Apps addressing addiction or cessation were underrepresented in the most popular cannabis mobile apps. Differences among apps for Apple and Android platforms likely reflect differences in the population of users, developer choice, and platform regulations. PMID:26268634

Human Granuloma In Vitro Model, for TB Dormancy and Resuscitation

PubMed Central

Kapoor, Nidhi; Pawar, Santosh; Sirakova, Tatiana D.; Deb, Chirajyoti; Warren, William L.; Kolattukudy, Pappachan E.

2013-01-01

Tuberculosis (TB) is responsible for death of nearly two million people in the world annually. Upon infection, Mycobacterium tuberculosis (Mtb) causes formation of granuloma where the pathogen goes into dormant state and can live for decades before resuscitation to develop active disease when the immune system of the host is weakened and/or suppressed. In an attempt to better understand host-pathogen interactions, several groups have been developing in vitro models of human tuberculosis granuloma. However, to date, an in vitro granuloma model in which Mtb goes into dormancy and can subsequently resuscitate under conditions that mimic weakening of the immune system has not been reported. We describe the development of a biomimetic in vitro model of human tuberculosis granuloma using human primary leukocytes, in which the Mtb exhibited characteristics of dormant mycobacteria as demonstrated by (1) loss of acid-fastness, (2) accumulation of lipid bodies (3) development of rifampicin-tolerance and (4) gene expression changes. Further, when these micro granulomas were treated with immunosuppressant anti-tumor necrosis factor-alpha monoclonal antibodies (anti-TNFα mAbs), resuscitation of Mtb was observed as has been found in humans. In this human in vitro granuloma model triacylglycerol synthase 1deletion mutant (Δtgs1) with impaired ability to accumulate triacylglycerides (TG), but not the complemented mutant, could not go into dormancy. Deletion mutant of lipY, with compromised ability to mobilize the stored TG, but not the complemented mutant, was unable to come out of dormancy upon treatment with anti-TNFα mAbs. In conclusion, we have developed an in vitro human tuberculosis granuloma model that largely exhibits functional features of dormancy and resuscitation observed in human tuberculosis. PMID:23308269

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

A review of mobile apps for epilepsy self-management.

PubMed

Escoffery, Cam; McGee, Robin; Bidwell, Jonathan; Sims, Christopher; Thropp, Eliana Kovitch; Frazier, Cherise; Mynatt, Elizabeth D

2018-04-01

Mobile health app developers increasingly are interested in supporting the daily self-care of people with chronic conditions. The purpose of this study was to review mobile applications (apps) to promote epilepsy self-management. It investigates the following: 1) the available mobile apps for epilepsy, 2) how these apps support patient education and self-management (SM), and 3) their usefulness in supporting management of epilepsy. We conducted the review in Fall 2017 and assessed apps on the Apple App Store that related to the terms "epilepsy" and "seizure". Inclusion criteria included apps (adult and pediatric) that, as follows, were: 1) developed for patients or the community; 2) made available in English, and 3) less than $5.00. Exclusion criteria included apps that were designed for dissemination of publications, focused on healthcare providers, or were available in other languages. The search resulted in 149 apps, of which 20 met the selection criteria. A team reviewed each app in terms of three sets of criteria: 1) epilepsy-specific descriptions and SM categories employed by the apps and 2) Mobile App Rating Scale (MARS) subdomain scores for reviewing engagement, functionality, esthetics, and information; and 3) behavioral change techniques. Most apps were for adults and free. Common SM domains for the apps were treatment, seizure tracking, response, and safety. A number of epilepsy apps existed, but many offered similar functionalities and incorporated few SM domains. The findings underline the need for mobile apps to cover broader domains of SM and behavioral change techniques and to be evaluated for outcomes. Copyright © 2017 Elsevier Inc. All rights reserved.

Identification and Evaluation of Medical Translator Mobile Applications Using an Adapted APPLICATIONS Scoring System.

PubMed

Khander, Amrin; Farag, Sara; Chen, Katherine T

2017-12-22

With an increasing number of patients requiring translator services, many providers are turning to mobile applications (apps) for assistance. However, there have been no published reviews of medical translator apps. To identify and evaluate medical translator mobile apps using an adapted APPLICATIONS scoring system. A list of apps was identified from the Apple iTunes and Google Play stores, using the search term, "medical translator." Apps not found on two different searches, not in an English-based platform, not used for translation, or not functional after purchase, were excluded. The remaining apps were evaluated using an adapted APPLICATIONS scoring system, which included both objective and subjective criteria. App comprehensiveness was a weighted score defined by the number of non-English languages included in each app relative to the proportion of non-English speakers in the United States. The Apple iTunes and Google Play stores. Medical translator apps identified using the search term "medical translator." Main Outcomes and Measures: Compilation of medical translator apps for provider usage. A total of 524 apps were initially found. After applying the exclusion criteria, 20 (8.2%) apps from the Google Play store and 26 (9.2%) apps from the Apple iTunes store remained for evaluation. The highest scoring apps, Canopy Medical Translator, Universal Doctor Speaker, and Vocre Translate, scored 13.5 out of 18.7 possible points. A large proportion of apps initially found did not function as medical translator apps. Using the APPLICATIONS scoring system, we have identified and evaluated medical translator apps for providers who care for non-English speaking patients.

Diabetes Applications for Arabic Speakers: A Critical Review of Available Apps for Android and iOS Operated Smartphones.

PubMed

Alhuwail, Dari

2016-01-01

Today, 415 million adults have diabetes; more than 35 million of diabetic adults live in the Middle East and North Africa region. Smartphone penetration in the region is high and applications, or apps, for diabetics have shown promising results in recent years. This study took place between September and December 2015 and reviewed all currently available smartphone diabetes apps for Arabic speakers in both the Apple App and Google Play stores. There were only few diabetes apps for Arabic speakers; only eighteen apps were discovered and considered for this study. Most apps were informational. Only three apps offered utilities such as glucose reading conversion. The apps had issues related to information quality and adherence to latest evidence-based medical advice. There is a need for more evidence-based Arabic diabetes apps with improved functionality. Future research of Arabic diabetes apps should also focus on the involvement and engagement of the patients in the design of these apps.

The Potential of Mobile Apps for Improving Asthma Self-Management: A Review of Publicly Available and Well-Adopted Asthma Apps.

PubMed

Tinschert, Peter; Jakob, Robert; Barata, Filipe; Kramer, Jan-Niklas; Kowatsch, Tobias

2017-08-02

Effective disease self-management lowers asthma's burden of disease for both individual patients and health care systems. In principle, mobile health (mHealth) apps could enable effective asthma self-management interventions that improve a patient's quality of life while simultaneously reducing the overall treatment costs for health care systems. However, prior reviews in this field have found that mHealth apps for asthma lack clinical evaluation and are often not based on medical guidelines. Yet, beyond the missing evidence for clinical efficacy, little is known about the potential apps might have for improving asthma self-management. The aim of this study was to assess the potential of publicly available and well-adopted mHealth apps for improving asthma self-management. The Apple App store and Google Play store were systematically searched for asthma apps. In total, 523 apps were identified, of which 38 apps matched the selection criteria to be included in the review. Four requirements of app potential were investigated: app functions, potential to change behavior (by means of a behavior change technique taxonomy), potential to promote app use (by means of a gamification components taxonomy), and app quality (by means of the Mobile Application Rating Scale [MARS]). The most commonly implemented functions in the 38 reviewed asthma apps were tracking (30/38, 79%) and information (26/38, 68%) functions, followed by assessment (20/38, 53%) and notification (18/38, 47%) functions. On average, the reviewed apps applied 7.12 of 26 available behavior change techniques (standard deviation [SD]=4.46) and 4.89 of 31 available gamification components (SD=4.21). Average app quality was acceptable (mean=3.17/5, SD=0.58), whereas subjective app quality lied between poor and acceptable (mean=2.65/5, SD=0.87). Additionally, the sum scores of all review frameworks were significantly correlated (lowest correlation: r 36 =.33, P=.04 between number of functions and gamification components; highest correlation: r 36 =.80, P<.001 between number of behavior change techniques and gamification components), which suggests that an app's potential tends to be consistent across review frameworks. Several apps were identified that performed consistently well across all applied review frameworks, thus indicating the potential mHealth apps offer for improving asthma self-management. However, many apps suffer from low quality. Therefore, app reviews should be considered as a decision support tool before deciding which app to integrate into a patient's asthma self-management. Furthermore, several research-practice gaps were identified that app developers should consider addressing in future asthma apps. ©Peter Tinschert, Robert Jakob, Filipe Barata, Jan-Niklas Kramer, Tobias Kowatsch. Originally published in JMIR Mhealth and Uhealth (http://mhealth.jmir.org), 02.08.2017.

Human mutant huntingtin disrupts vocal learning in transgenic songbirds.

PubMed

Liu, Wan-Chun; Kohn, Jessica; Szwed, Sarah K; Pariser, Eben; Sepe, Sharon; Haripal, Bhagwattie; Oshimori, Naoki; Marsala, Martin; Miyanohara, Atsushi; Lee, Ramee

2015-11-01

Speech and vocal impairments characterize many neurological disorders. However, the neurogenetic mechanisms of these disorders are not well understood, and current animal models do not have the necessary circuitry to recapitulate vocal learning deficits. We developed germline transgenic songbirds, zebra finches (Taneiopygia guttata) expressing human mutant huntingtin (mHTT), a protein responsible for the progressive deterioration of motor and cognitive function in Huntington's disease (HD). Although generally healthy, the mutant songbirds had severe vocal disorders, including poor vocal imitation, stuttering, and progressive syntax and syllable degradation. Their song abnormalities were associated with HD-related neuropathology and dysfunction of the cortical-basal ganglia (CBG) song circuit. These transgenics are, to the best of our knowledge, the first experimentally created, functional mutant songbirds. Their progressive and quantifiable vocal disorder, combined with circuit dysfunction in the CBG song system, offers a model for genetic manipulation and the development of therapeutic strategies for CBG-related vocal and motor disorders.

Viral Quasispecies Evolution

PubMed Central

Sheldon, Julie; Perales, Celia

2012-01-01

Summary: Evolution of RNA viruses occurs through disequilibria of collections of closely related mutant spectra or mutant clouds termed viral quasispecies. Here we review the origin of the quasispecies concept and some biological implications of quasispecies dynamics. Two main aspects are addressed: (i) mutant clouds as reservoirs of phenotypic variants for virus adaptability and (ii) the internal interactions that are established within mutant spectra that render a virus ensemble the unit of selection. The understanding of viruses as quasispecies has led to new antiviral designs, such as lethal mutagenesis, whose aim is to drive viruses toward low fitness values with limited chances of fitness recovery. The impact of quasispecies for three salient human pathogens, human immunodeficiency virus and the hepatitis B and C viruses, is reviewed, with emphasis on antiviral treatment strategies. Finally, extensions of quasispecies to nonviral systems are briefly mentioned to emphasize the broad applicability of quasispecies theory. PMID:22688811

Spatial constraints govern competition of mutant clones in human epidermis.

PubMed

Lynch, M D; Lynch, C N S; Craythorne, E; Liakath-Ali, K; Mallipeddi, R; Barker, J N; Watt, F M

2017-10-24

Deep sequencing can detect somatic DNA mutations in tissues permitting inference of clonal relationships. This has been applied to human epidermis, where sun exposure leads to the accumulation of mutations and an increased risk of skin cancer. However, previous studies have yielded conflicting conclusions about the relative importance of positive selection and neutral drift in clonal evolution. Here, we sequenced larger areas of skin than previously, focusing on cancer-prone skin spanning five decades of life. The mutant clones identified were too large to be accounted for solely by neutral drift. Rather, using mathematical modelling and computational lattice-based simulations, we show that observed clone size distributions can be explained by a combination of neutral drift and stochastic nucleation of mutations at the boundary of expanding mutant clones that have a competitive advantage. These findings demonstrate that spatial context and cell competition cooperate to determine the fate of a mutant stem cell.

75 FR 11894 - National Cancer Institute; Notice of Meeting

Federal Register 2010, 2011, 2012, 2013, 2014

2010-03-12

... DEPARTMENT OF HEALTH AND HUMAN SERVICES National Institutes of Health National Cancer Institute.... App.), notice is hereby given of a meeting of the National Cancer Institute Director's Consumer... Committee: National Cancer Institute Director's Consumer Liaison Group. Date: March 24-26, 2010. Time: March...

76 FR 574 - National Cancer Institute; Notice of Meeting

Federal Register 2010, 2011, 2012, 2013, 2014

2011-01-05

... DEPARTMENT OF HEALTH AND HUMAN SERVICES National Institutes of Health National Cancer Institute.... App.), notice is hereby given of a meeting of the National Cancer Institute Clinical Trials and... advance of the meeting. Name of Committee: National Cancer Institute Clinical Trials and Translational...

76 FR 51378 - National Cancer Institute; Notice of Meeting

Federal Register 2010, 2011, 2012, 2013, 2014

2011-08-18

... DEPARTMENT OF HEALTH AND HUMAN SERVICES National Institutes of Health National Cancer Institute.... App.), notice is hereby given of a meeting of the National Cancer Institute Board of Scientific... Committee: National Cancer Institute Board of Scientific Advisors, caBIG Oversight Ad hoc Subcommittee. Date...

75 FR 37451 - National Cancer Institute; Notice of Meeting

Federal Register 2010, 2011, 2012, 2013, 2014

2010-06-29

... Prevention Research; 93.394, Cancer Detection and Diagnosis Research; 93.395, Cancer Treatment Research; 93... DEPARTMENT OF HEALTH AND HUMAN SERVICES National Institutes of Health National Cancer Institute.... App.), notice is hereby given of a meeting of the National Cancer Institute Director's Consumer...

IRIS Toxicological Review of Bromobenzene (External Review Draft)

EPA Science Inventory

EPA has conducted a peer review of the scientific basis supporting the human health hazard and dose-response assessment of Bromobenzene that will appear on the Integrated Risk Information System (IRIS) database. Peer review is meant to ensure that science is used credibly and app...

76 FR 52960 - National Cancer Institute Notice of Meeting

Federal Register 2010, 2011, 2012, 2013, 2014

2011-08-24

... DEPARTMENT OF HEALTH AND HUMAN SERVICES National Institutes of Health National Cancer Institute.... App.), notice is hereby given of a meeting of the National Cancer Institute Clinical Trials and... interpretation or other reasonable accommodations, should notify the Contact Person listed below in advance of...

77 FR 58851 - National Cancer Institute; Notice of Meeting

Federal Register 2010, 2011, 2012, 2013, 2014

2012-09-24

... DEPARTMENT OF HEALTH AND HUMAN SERVICES National Institutes of Health National Cancer Institute.... App.), notice is hereby given of a meeting of the National Cancer Institute Director's Consumer... reasonable accommodations, should notify the Contact Person listed below in advance of the meeting. Name of...

76 FR 20693 - National Cancer Institute; Notice of Meeting

Federal Register 2010, 2011, 2012, 2013, 2014

2011-04-13

... DEPARTMENT OF HEALTH AND HUMAN SERVICES National Institutes of Health National Cancer Institute.... App.), notice is hereby given of a meeting of the National Cancer Institute Director's Consumer... reasonable accommodations, should notify the Contact Person listed below in advance of the meeting. Name of...

75 FR 2150 - National Cancer Institute; Notice of Meeting

Federal Register 2010, 2011, 2012, 2013, 2014

2010-01-14

... DEPARTMENT OF HEALTH AND HUMAN SERVICES National Institutes of Health National Cancer Institute.... App.), notice is hereby given of a meeting of the National Cancer Institute Clinical Trials and... interpretation or other reasonable accommodations, should notify the Contact Person listed below in advance of...

77 FR 35414 - National Cancer Institute; Notice of Meeting

Federal Register 2010, 2011, 2012, 2013, 2014

2012-06-13

... DEPARTMENT OF HEALTH AND HUMAN SERVICES National Institutes of Health National Cancer Institute.... App.), notice is hereby given of a meeting of the National Cancer Institute Clinical Trials and... interpretation or other reasonable accommodations, should notify the Contact Person listed below in advance of...