Effects of oil extraction methods on physical and chemical properties of red salmon oils (Oncorhynchus nerka)

USDA-ARS?s Scientific Manuscript database

Four different red salmon oil extraction processes were used to extract oil from red salmon heads: RS1 involved a mixture of ground red salmon heads and water, no heat treatment, and centrifugation; RS2 involved ground red salmon heads (no water added), heat treatment, and centrifugation; RS3 involv...

Determination of the transforming activities of adenovirus oncogenes.

PubMed

Nevels, Michael; Dobner, Thomas

2007-01-01

The last 50 yr of molecular biological investigations into human adenoviruses (Ads) have contributed enormously to our understanding of the basic principles of normal and malignant cell growth. Much of this knowledge stems from analyses of the Ad productive infection cycle in permissive host cells. Also, initial observations concerning the transforming potential of human Ads subsequently revealed decisive insights into the molecular mechanisms of the origins of cancer and established Ads as a model system for explaining virus-mediated transformation processes. Today it is well established that cell transformation by human Ads is a multistep process involving several gene products encoded in early transcription units 1A (E1A) and 1B (E1B). Moreover, a large body of evidence now indicates that alternative or additional mechanisms are engaged in Ad-mediated oncogenic transformation involving gene products encoded in early region 4 (E4) as well as epigenetic changes resulting from viral DNA integration. In particular, studies on the transforming potential of several E4 gene products have now revealed new pathways that point to novel general mechanisms of virus-mediated oncogenesis. In this chapter we describe in vitro and in vivo assays to determine the transforming and oncogenic activities of the E1A, E1B, and E4 oncoproteins in primary baby rat kidney cells and athymic nude mice.

Determination of the transforming activities of adenovirus oncogenes.

PubMed

Speiseder, Thomas; Nevels, Michael; Dobner, Thomas

2014-01-01

The last 50 years of molecular biological investigations into human adenoviruses (Ads) have contributed enormously to our understanding of the basic principles of normal and malignant cell growth. Much of this knowledge stems from analyses of the Ad productive infection cycle in permissive host cells. Also, initial observations concerning the transforming potential of human Ads subsequently revealed decisive insights into the molecular mechanisms of the origins of cancer and established Ads as a model system for explaining virus-mediated transformation processes. Today it is well established that cell transformation by human Ads is a multistep process involving several gene products encoded in early transcription units 1A (E1A) and 1B (E1B). Moreover, a large body of evidence now indicates that alternative or additional mechanisms are engaged in Ad-mediated oncogenic transformation involving gene products encoded in early region 4 (E4) as well as epigenetic changes resulting from viral DNA integration. In particular, studies on the transforming potential of several E4 gene products have now revealed new pathways that point to novel general mechanisms of virus-mediated oncogenesis. In this chapter we describe in vitro and in vivo assays to determine the transforming and oncogenic activities of the E1A, E1B, and E4 oncoproteins in primary baby rat kidney cells, human amniotic fluid cells and athymic nude mice.

Microbial trophic interactions and mcrA gene expression in monitoring of anaerobic digesters.

PubMed

Alvarado, Alejandra; Montañez-Hernández, Lilia E; Palacio-Molina, Sandra L; Oropeza-Navarro, Ricardo; Luévanos-Escareño, Miriam P; Balagurusamy, Nagamani

2014-01-01

Anaerobic digestion (AD) is a biological process where different trophic groups of microorganisms break down biodegradable organic materials in the absence of oxygen. A wide range of AD technologies is being used to convert livestock manure, municipal and industrial wastewaters, and solid organic wastes into biogas. AD gains importance not only because of its relevance in waste treatment but also because of the recovery of carbon in the form of methane, which is a renewable energy and is used to generate electricity and heat. Despite the advances on the engineering and design of new bioreactors for AD, the microbiology component always poses challenges. Microbiology of AD processes is complicated as the efficiency of the process depends on the interactions of various trophic groups involved. Due to the complex interdependence of microbial activities for the functionality of the anaerobic bioreactors, the genetic expression of mcrA, which encodes a key enzyme in methane formation, is proposed as a parameter to monitor the process performance in real time. This review evaluates the current knowledge on microbial groups, their interactions, and their relationship to the performance of anaerobic biodigesters with a focus on using mcrA gene expression as a tool to monitor the process.

Frontotemporal neural systems supporting semantic processing in Alzheimer's disease.

PubMed

Peelle, Jonathan E; Powers, John; Cook, Philip A; Smith, Edward E; Grossman, Murray

2014-03-01

We hypothesized that semantic memory for object concepts involves both representations of visual feature knowledge in modality-specific association cortex and heteromodal regions that are important for integrating and organizing this semantic knowledge so that it can be used in a flexible, contextually appropriate manner. We examined this hypothesis in an fMRI study of mild Alzheimer's disease (AD). Participants were presented with pairs of printed words and asked whether the words matched on a given visual-perceptual feature (e.g., guitar, violin: SHAPE). The stimuli probed natural kinds and manufactured objects, and the judgments involved shape or color. We found activation of bilateral ventral temporal cortex and left dorsolateral prefrontal cortex during semantic judgments, with AD patients showing less activation of these regions than healthy seniors. Moreover, AD patients showed less ventral temporal activation than did healthy seniors for manufactured objects, but not for natural kinds. We also used diffusion-weighted MRI of white matter to examine fractional anisotropy (FA). Patients with AD showed significantly reduced FA in the superior longitudinal fasciculus and inferior frontal-occipital fasciculus, which carry projections linking temporal and frontal regions of this semantic network. Our results are consistent with the hypothesis that semantic memory is supported in part by a large-scale neural network involving modality-specific association cortex, heteromodal association cortex, and projections between these regions. The semantic deficit in AD thus arises from gray matter disease that affects the representation of feature knowledge and processing its content, as well as white matter disease that interrupts the integrated functioning of this large-scale network.

Distributed Processing with a Mainframe-Based Hospital Information System: A Generalized Solution

PubMed Central

Kirby, J. David; Pickett, Michael P.; Boyarsky, M. William; Stead, William W.

1987-01-01

Over the last two years the Medical Center Information Systems Department at Duke University Medical Center has been developing a systematic approach to distributing the processing and data involved in computerized applications at DUMC. The resulting system has been named MAPS- the Micro-ADS Processing System. A key characteristic of MAPS is that it makes it easy to execute any existing mainframe ADS application with a request from a PC. This extends the functionality of the mainframe application set to the PC without compromising the maintainability of the PC or mainframe systems.

Oxidative stress, protein modification and Alzheimer disease.

PubMed

Tramutola, A; Lanzillotta, C; Perluigi, M; Butterfield, D Allan

2017-07-01

Alzheimer disease (AD) is a progressive neurodegenerative disease that affects the elderly population with complex etiology. Many hypotheses have been proposed to explain different causes of AD, but the exact mechanisms remain unclear. In this review, we focus attention on the oxidative-stress hypothesis of neurodegeneration and we discuss redox proteomics approaches to analyze post-mortem human brain from AD brain. Collectively, these studies have provided valuable insights into the molecular mechanisms involved both in the pathogenesis and progression of AD, demonstrating the impairment of numerous cellular processes such as energy production, cellular structure, signal transduction, synaptic function, mitochondrial function, cell cycle progression, and degradative systems. Each of these cellular functions normally contributes to maintain healthy neuronal homeostasis, so the deregulation of one or more of these functions could contribute to the pathology and clinical presentation of AD. In particular, we discuss the evidence demonstrating the oxidation/dysfunction of a number of enzymes specifically involved in energy metabolism that support the view that reduced glucose metabolism and loss of ATP are crucial events triggering neurodegeneration and progression of AD. Copyright © 2016 Elsevier Inc. All rights reserved.

Role of BRI2 in dementia.

PubMed

Del Campo, Marta; Teunissen, Charlotte E

2014-01-01

Alzheimer's disease (AD), the most common form of dementia, shares clinical and pathological similarities with familial British and Danish dementias (FBD and FDD). Whereas the etiology of sporadic AD remains unclear, familial AD is linked to mutations in amyloid-β protein precursor (AβPP), presenilin 1 (PS1), and presenilin 2 (PS2). Similarly, FBD and FDD originate from mutations in the BRI2 gene (or ITM2b), causing amyloid angiopathy and neurofibrillary tangles analogous to those observed in AD. Recent studies on the role of BRI2 in FBD and FDD have revealed that the three diseases may share pathophysiological pathways leading to dementia. Interestingly, BRI2 is a potential regulator of AβPP processing, and it can inhibit the production and fibrillation of Aβ. This suggests a role of BRI2 in the amyloid cascade, which is the prevailing hypothesis about AD pathogenesis. To understand a possible relationship of BRI2 with AD, we reviewed the relevant studies on this protein. The data included not only the protein's structure, expression pattern, function, and involvement in FBD and FDD, but also its relationship with memory deficits and the main pathological proteins involved in AD. Thus, we highlight and discuss the potential links between BRI2 and AD, leading to the formulation of a modified hypothesis about AD etiology.

Adding It Up: A Rationale for Mapping Public Resources for Children, Youth and Families

ERIC Educational Resources Information Center

Flynn-Khan, Margaret; Ferber, Thaddeus; Gaines, Elizabeth; Pittman, Karen

2006-01-01

This introduction, one of three parts of "Adding It Up: A Guide to Mapping Public Resources for Children, Youth and Families," explains the why, how and what behind creating a children, youth, and families (CYF) resource map. Setting the stage for what's involved in the process, this overview provides a good framework for understanding both the…

Anti-neuroinflammatory Potential of Natural Products in Attenuation of Alzheimer's Disease

PubMed Central

Shal, Bushra; Ding, Wei; Ali, Hussain; Kim, Yeong S.; Khan, Salman

2018-01-01

Alzheimer's disease (AD) is a chronic progressive neurodegenerative disorder associated with dementia and cognitive impairment most common in elderly population. Various pathophysiological mechanisms have been proposed by numerous researcher, although, exact mechanism is not yet elucidated. Several studies have been indicated that neuroinflammation associated with deposition of amyloid- beta (Aβ) in brain is a major hallmark toward the pathology of neurodegenerative diseases. So, there is a need to unravel the link of inflammatory process in neurodegeneration. Increased microglial activation, expression of cytokines, reactive oxygen species (ROS), and nuclear factor kappa B (NF-κB) participate in inflammatory process of AD. This review mainly concentrates on involvement of neuroinflammation and the molecular mechanisms adapted by various natural compounds, phytochemicals and herbal formulations in various signaling pathways involved in neuroprotection. Currently, pharmacologically active natural products, having anti-neuroinflammatory potential are being focused which makes them potential candidate to cure AD. A number of preclinical and clinical trials have been done on nutritional and botanical agents. Analysis of anti-inflammatory and neuroprotective phytochemicals such as terpenoids, phenolic derivatives, alkaloids, glycosides, and steroidal saponins displays therapeutic potential toward amelioration and prevention of devastating neurodegeneration observed in AD. PMID:29896105

Integrating Process Skills Instruction into the Traditional Science Curriculum.

ERIC Educational Resources Information Center

Radford, David L.

The study of science involves learning the processes of science as well as its content. The recent revival of interest in developing thinking skills has encouraged added emphasis on process skills instruction. A science teacher wanting to add instruction of process skills is faced with several problems: (1) texts and lab manuals are not likely to…

A high performance, ad-hoc, fuzzy query processing system for relational databases

NASA Technical Reports Server (NTRS)

Mansfield, William H., Jr.; Fleischman, Robert M.

1992-01-01

Database queries involving imprecise or fuzzy predicates are currently an evolving area of academic and industrial research. Such queries place severe stress on the indexing and I/O subsystems of conventional database environments since they involve the search of large numbers of records. The Datacycle architecture and research prototype is a database environment that uses filtering technology to perform an efficient, exhaustive search of an entire database. It has recently been modified to include fuzzy predicates in its query processing. The approach obviates the need for complex index structures, provides unlimited query throughput, permits the use of ad-hoc fuzzy membership functions, and provides a deterministic response time largely independent of query complexity and load. This paper describes the Datacycle prototype implementation of fuzzy queries and some recent performance results.

Targeting modulates audiences’ brain and behavioral responses to safe sex video ads

PubMed Central

Lowen, Steven B; Shi, Zhenhao; Bissey, Bryn; Metzger, David S.; Langleben, Daniel D.

2016-01-01

Video ads promoting condom use are a key component of media campaigns to stem the HIV epidemic. Recent neuroimaging studies in the context of smoking cessation, point to personal relevance as one of the key variables that determine the effectiveness of public health messages. While minority men who have sex with men (MSM) are at the highest risk of HIV infection, most safe-sex ads feature predominantly Caucasian actors in heterosexual scenarios. We compared brain respons of 45 African American MSM to safe sex ads that were matched (i.e. ‘Targeted’) to participants’ sexual orientation and race, and ‘Untargeted’ ads that were un matched for these characteristics. Ad recall, perceived ‘convincingness’ and attitudes towards condom use were also assessed. We found that Targeted ads were better remembered than the Untargeted ads but perceived as equally convincing. Targeted ads engaged brain regions involved in self-referential processing and memory, including the amygdala, hippocampus, temporal and medial prefrontal cortices (MPFC) and the precuneus. Connectivity between MPFC and precuneus and middle temporal gyrus was stronger when viewing Targeted ads. Our results suggest that targeting may increase cognitive processing of safe sex ads and justify further prospective studies linking brain response to media public health interventions and clinical outcomes. PMID:27217112

Microbial trophic interactions and mcrA gene expression in monitoring of anaerobic digesters

PubMed Central

Alvarado, Alejandra; Montañez-Hernández, Lilia E.; Palacio-Molina, Sandra L.; Oropeza-Navarro, Ricardo; Luévanos-Escareño, Miriam P.; Balagurusamy, Nagamani

2014-01-01

Anaerobic digestion (AD) is a biological process where different trophic groups of microorganisms break down biodegradable organic materials in the absence of oxygen. A wide range of AD technologies is being used to convert livestock manure, municipal and industrial wastewaters, and solid organic wastes into biogas. AD gains importance not only because of its relevance in waste treatment but also because of the recovery of carbon in the form of methane, which is a renewable energy and is used to generate electricity and heat. Despite the advances on the engineering and design of new bioreactors for AD, the microbiology component always poses challenges. Microbiology of AD processes is complicated as the efficiency of the process depends on the interactions of various trophic groups involved. Due to the complex interdependence of microbial activities for the functionality of the anaerobic bioreactors, the genetic expression of mcrA, which encodes a key enzyme in methane formation, is proposed as a parameter to monitor the process performance in real time. This review evaluates the current knowledge on microbial groups, their interactions, and their relationship to the performance of anaerobic biodigesters with a focus on using mcrA gene expression as a tool to monitor the process. PMID:25429286

Preserved and Impaired Emotional Memory in Alzheimer’s Disease

PubMed Central

Klein-Koerkamp, Yanica; Baciu, Monica; Hot, Pascal

2012-01-01

Patients with early atrophy of both limbic structures involved in memory and emotion processing in Alzheimer’s disease (AD) provide a unique clinical population for investigating how emotion is able to modulate retention processes. This review focuses on the emotional enhancement effect (EEE), defined as the improvement of memory for emotional events compared with neutral ones. The assessment of the EEE for different memory systems in AD suggests that the EEE could be preserved under specific retrieval instructions. The first part of this review examines these data in light of compelling evidence that the amygdala can modulate processes of hippocampus-dependent memory. We argue that the EEE could be a useful paradigm to reduce impairment in episodic memory tasks. In the second part, we discuss theoretical consequences of the findings in favor of an EEE, according to which a compensatory mechanism in patients with AD solicits greater amygdala functioning or additional networks, even when amygdala atrophy is present. These considerations emphasize the relevance of investigating patients with AD to understand the relationship between emotion and memory processes. PMID:23049516

Inserting Phase Change Lines into Microsoft Excel® Graphs.

PubMed

Dubuque, Erick M

2015-10-01

Microsoft Excel® is a popular graphing tool used by behavior analysts to visually display data. However, this program is not always friendly to the graphing conventions used by behavior analysts. For example, adding phase change lines has typically been a cumbersome process involving the insertion of line objects that do not move when new data is added to a graph. The purpose of this article is to describe a novel way to add phase change lines that move when new data is added and when graphs are resized.

Very Large Scale Integrated Circuits for Military Systems.

DTIC Science & Technology

1981-01-01

ABBREVIATIONS A/D Analog-to-digital C AGC Automatic Gain Control A A/J Anti-jam ASP Advanced Signal Processor AU Arithmetic Units C.AD Computer-Aided...ESM) equipments (Ref. 23); in lieu of an adequate automatic proces- sing capability, the function is now performed manually (Ref. 24), which involves...a human operator, displays, etc., and a sacrifice in performance (acquisition speed, saturation signal density). Various automatic processing

Impaired emotional memory enhancement on recognition of pictorial stimuli in Alzheimer's disease: no influence of the nature of encoding.

PubMed

Chainay, Hanna; Sava, Alexandra; Michael, George A; Landré, Lionel; Versace, Rémy; Krolak-Salmon, Pierre

2014-01-01

There is some discrepancy in the results regarding emotional enhancement of memory (EEM) in Alzheimer's disease (AD). Some studies report better retrieval of emotional information, especially positive, than neutral information. This observation is similar to the positivity effect reported in healthy older adults. It was suggested that this effect is due to privileged, deeper and more controlled processing of positive information. One way of testing this is to control both the intention to encode the information and the cognitive resources involved during encoding. Studies investigating EEM in AD patients did not systematically control the nature of encoding. Consequently, the purpose of our study was to examine EEM in AD while manipulating the nature of encoding. Two experiments were conducted. In Experiment 1 the intention to encode stimuli was manipulated by giving or not giving instructions to participants about the subsequent retrieval. In Experiment 2 cognitive resources involved during encoding were varied (low vs high). In both experiments participants performed immediate recognition task of negative, positive and neutral pictures. 41 mild AD patients and 44 older healthy adults participated in Exp. 1, and 17 mild AD patients and 20 older healthy adults participated in Exp. 2. AD patients did not present EEM. Positivity effect, better performance for positive than neutral and negative pictures was observed with older healthy adults. The data suggest that EEM is disturbed in mild AD patients, with respect to both negative and positive stimuli, at least concerning laboratory, not real-life material. They also suggest there is a positivity effect in healthy older adults and lend support to the idea that this effect is due to preferential cognitive processing of positive information in this population. Copyright © 2013 Elsevier Ltd. All rights reserved.

Targeting modulates audiences' brain and behavioral responses to safe sex video ads.

PubMed

Wang, An-Li; Lowen, Steven B; Shi, Zhenhao; Bissey, Bryn; Metzger, David S; Langleben, Daniel D

2016-10-01

Video ads promoting condom use are a key component of media campaigns to stem the HIV epidemic. Recent neuroimaging studies in the context of smoking cessation, point to personal relevance as one of the key variables that determine the effectiveness of public health messages. While minority men who have sex with men (MSM) are at the highest risk of HIV infection, most safe-sex ads feature predominantly Caucasian actors in heterosexual scenarios. We compared brain respons of 45 African American MSM to safe sex ads that were matched (i.e. 'Targeted') to participants' sexual orientation and race, and 'Untargeted' ads that were un matched for these characteristics. Ad recall, perceived 'convincingness' and attitudes towards condom use were also assessed. We found that Targeted ads were better remembered than the Untargeted ads but perceived as equally convincing. Targeted ads engaged brain regions involved in self-referential processing and memory, including the amygdala, hippocampus, temporal and medial prefrontal cortices (MPFC) and the precuneus. Connectivity between MPFC and precuneus and middle temporal gyrus was stronger when viewing Targeted ads. Our results suggest that targeting may increase cognitive processing of safe sex ads and justify further prospective studies linking brain response to media public health interventions and clinical outcomes. © The Author (2016). Published by Oxford University Press. For Permissions, please email: journals.permissions@oup.com.

The Innate Immunity in Alzheimer Disease- Relevance to Pathogenesis and Therapy.

PubMed

Blach-Olszewska, Zofia; Zaczynska, Ewa; Gustaw-Rothenberg, Kasia; Avila-Rodrigues, Marco; Barreto, George E; Leszek, Jerzy; Aliev, Gjumrakch

2015-01-01

The genetic, cellular, and molecular changes associated with Alzheimer disease provide evidence of immune and inflammatory processes involvement in its pathogenesis. These are supported by epidemiological studies, which show some benefit of long-term use of NSAID. The hypothesis that AD is in fact an immunologically mediated and even inflammatory pathological process may be in fact scientifically intriguing. There are several obstacles that suggest the need for more complex view, in the process of targeting inflammation and immunity in AD. In our previous studies we proposed a reliable methodology to assess innate immunity in Alzheimer patients and controls. The methodology is based on the phenomenon of human leukocytes being resistant to viral infection. The unspecific character of the resistance, dependent on interferons and tumor necrosis factor, and occurrence in cells ex vivo indicate that an in vivo mechanism of innate immunity may be involved. The above mentioned resistance could be estimated in a test based on peripheral blood leukocytes infection by vesicular stomachs virus.

TSPO ligand PK11195 improves Alzheimer-related outcomes in aged female 3xTg-AD mice.

PubMed

Christensen, Amy; Pike, Christian J

2018-06-17

Alzheimer's disease (AD) pathogenesis is a multifactorial process that involves numerous pathways within the central nervous system. Thus, interventions that interact with several disease-related pathways may offer an increased opportunity for successful prevention and treatment of AD. Translocator protein 18 kD (TSPO) is a mitochondrial protein that is associated with regulation of many cellular processes including inflammation, steroid synthesis, apoptosis, and mitochondrial respiration. Although TSPO ligands have been shown to be protective in several neurodegenerative paradigms, little work has been done to assess their potential as treatments for AD. Female 3xTg-AD mice were administered the TSPO ligand PK11195 once weekly for 5 weeks beginning at an age 16 months, an age characterized by extensive β-amyloid pathology and behavioral impairments. Animals treated with PK11195 showed improvements in behavior and modest reductions of in both soluble and deposited β-amyloid. The finding that short-term PK11195 treatment was effective in improving both behavioral and pathological outcomes in a model of late-stage AD supports further investigation of TSPO ligands as potential therapeutics for the treatment of AD. Copyright © 2018. Published by Elsevier B.V.

Process for tertiary oil recovery using tall oil pitch

DOEpatents

Radke, C.J.

1983-07-25

A process and compositions for enhancing the recovery of acid crudes are disclosed. The process involves injecting caustic solutions into the reservoir to maintain a pH of 11 to 13. The fluid contains an effective amount of multivalent cation for inhibiting alkaline silica dissolution with the reservoir. A tall oil pitch soap is added as a polymeric mobility control agent. (DMC)

URANIUM SEPARATION PROCESS

DOEpatents

McVey, W.H.; Reas, W.H.

1959-03-10

The separation of uranium from an aqueous solution containing a water soluble uranyl salt is described. The process involves adding an alkali thiocyanate to the aqueous solution, contacting the resulting solution with methyl isobutyl ketons and separating the resulting aqueous and organic phase. The uranium is extracted in the organic phase as UO/sub 2/(SCN)/sub/.

Enhancing the placebo response: fMRI Evidence of Memory and Semantic Processing in Placebo Analgesia

PubMed Central

Craggs, Jason G.; Price, Donald D.; Robinson, Michael E.

2014-01-01

Two groups of patients with irritable bowel syndrome (IBS) rated pain and underwent fMRI brain scanning during experimentally induced rectal distension (20 sec, 7 stimuli). Group #1 was tested under baseline (natural history) and a verbally induced placebo condition, whereas Group #2 was tested under baseline, and standard placebo (no verbal suggestion for pain reduction) and intrarectal lidocaine conditions. As hypothesized, intrarectal lidocaine reduced evoked pain and pain-related brain activity within Group #2Between-group comparisons showed that adding a verbal suggestion to a placebo condition increased neural activity involved in memory and semantic processing, areas that process the placebo suggestions. These areas, in turn, are likely to influence brain areas involved in emotions and analgesia and consequently the placebo effect. These placebo suggestions also added significant decreases in activity of brain areas that process pain. The test stimulus itself seems to cue these effects and is consistent with previous explanations that somatic focus and sensory feedback reinforce expectations and other factors that mediate placebo analgesic effects. PMID:24412799

Effect of vitamin E administration on the elevated oxygen stress and the telomeric and subtelomeric status in Alzheimer's disease.

PubMed

Guan, Jing-Zhi; Guan, Wei-Ping; Maeda, Toyoki; Makino, Naoki

2012-01-01

Oxidative stress (OS) may be involved in the neurodegenerative process in Alzheimer's disease (AD). Telomeres, the repeated sequences that cap chromosome ends, undergo shortening with each cell division, are sensitive to OS, and serve as markers of a cell's replicative history. Telomere length shortening has been reported to relate to OS with aging process and aging-associated diseases, but the telomeric changes were not always identical, especially in change of telomere length distribution and subtelomeric methylation. The involvement of an OS-associated telomere change in the pathogenesis of AD has been discussed for decades, and the telomere length and telomerase activity were analyzed. However, other telomeric factors, such as the telomere distribution and subtelomeric methylation status, have not yet been analyzed. The subtelomeric methylation status as well as the telomere length were studied in AD with an antioxidant vitamin in terms of OS. We measured urinary 8-iso-PGF2α, a lipid-peroxidation product as an OS marker, and methylated and non-methylated telomere lengths in the peripheral blood mononuclear cells by Southern blotting in AD patients before and after vitamin E treatment. The level of urinary 8-iso-PGF2α was found to have increased in AD. Middle-ranged telomeres (4.4-9.4 kb) increased and the shortest telomeres (<4.4 kb) decreased in AD patients. Telomeres were more methylated in both long telomeres and in short telomeres in AD compared with the control. The oral administration of the antioxidant vitamin E in 400 mg/day for 6 months in AD patients partly reversed AD-associated alterations in OS marker levels. AD patients showed an elevated OS marker level, and vitamin E lowered the OS level. In comparison with controls, AD patients showed shorter telomere lengths. Cells with short and long telomeres bore relatively hypermethylated subtelomeres in AD patients. Aging-associated accumulation of cells bearing short telomeres was not observed in AD. These results imply that long telomeres with hypomethylation tend to shorten faster, and cells bearing short telomeres with hypomethylation tend to more easily enter into a senescent state under elevated OS stress in AD. However, no significant effect on the altered telomeric profiles in AD patients could be detected after a 6-month administration of vitamin E. Copyright © 2011 S. Karger AG, Basel.

[From physiopathology to treatment of Alzheimer's disease].

PubMed

Delacourte, A

2006-10-01

The natural and molecular history of familial or sporadic Alzheimer's disease (AD) shows that APP (amyloid protein precursor) dysfunction is a consensual central etiological factor in Alzheimer's disease (AD). This is demonstrated by 1) genetic defects involving APP gene or APP dysfunction (such as PS1 or PS2), leading to the formation of neocortical amyloid plaques in familial AD; 2) transgenic mice with these mutated genes that develop plaques; 3) both sporadic and familial AD develop plaques. But two alternatives to explain the physiopathology can be proposed: a gain of toxic function of AB peptide (reflected by the amyloid cascade hypothesis) or a loss of function of APP, a ubiquitous and well conserved protein with numerous possible neurotrophic activities. On the other hand, AD is also characterized by another inescapable degenerating process: tauopathy, an intraneuronal aggregation of tau proteins into neurofibrillary tangles. Remarkably enough, progression of tauopathy in neocortical areas fully explains the progressive clinical deficits of AD, from memory loss to aphasia, apraxia, agnosia. Also one has to bare in mind that most demented patients and most dementing neurodegenerative disorders have a tauopathy. From that, it is concluded that APP an Tau are solid therapeutic targets. But if we know that APP and Tau dysfunctions interact to boost neurodegeneration in AD, we still do no know what are the intraneuronal signaling pathways to activate or to inhibit to stop the degenerating process. There are many hypotheses and many possible approaches: the inhibition of toxicity of plaque, of AB protofibrils, or of AB oligomers inside or outside the neuron, using vaccination or ligands (Alzhemed). On the other hand, modulation of secretases that cleave APP by inhibiting those involved in the amyloidogenic pathway or by stimulating those of the non-amyloidogenic pathway, is a major route of research. Also modulation of kinases or phosphatases possibly involved in the aggregation of tau is also investigated. Because animal models are not perfectly relevant, at the end of the long and costly pathway of drug discovery, therapeutic trials are the only way to test these different hypotheses.

On knowledge transfer management as a learning process for ad hoc teams

NASA Astrophysics Data System (ADS)

Iliescu, D.

2017-08-01

Knowledge management represents an emerging domain becoming more and more important. Concepts like knowledge codification and personalisation, knowledge life-cycle, social and technological dimensions, knowledge transfer and learning management are integral parts. Focus goes here in the process of knowledge transfer for the case of ad hoc teams. The social dimension of knowledge transfer plays an important role. No single individual actors involved in the process, but a collective one, representing the organisation. It is critically important for knowledge to be managed from the life-cycle point of view. A complex communication network needs to be in place to supports the process of knowledge transfer. Two particular concepts, the bridge tie and transactive memory, would eventually enhance the communication. The paper focuses on an informational communication platform supporting the collaborative work on knowledge transfer. The platform facilitates the creation of a topic language to be used in knowledge modelling, storage and reuse, by the ad hoc teams.

A quantum probability account of order effects in inference.

PubMed

Trueblood, Jennifer S; Busemeyer, Jerome R

2011-01-01

Order of information plays a crucial role in the process of updating beliefs across time. In fact, the presence of order effects makes a classical or Bayesian approach to inference difficult. As a result, the existing models of inference, such as the belief-adjustment model, merely provide an ad hoc explanation for these effects. We postulate a quantum inference model for order effects based on the axiomatic principles of quantum probability theory. The quantum inference model explains order effects by transforming a state vector with different sequences of operators for different orderings of information. We demonstrate this process by fitting the quantum model to data collected in a medical diagnostic task and a jury decision-making task. To further test the quantum inference model, a new jury decision-making experiment is developed. Using the results of this experiment, we compare the quantum inference model with two versions of the belief-adjustment model, the adding model and the averaging model. We show that both the quantum model and the adding model provide good fits to the data. To distinguish the quantum model from the adding model, we develop a new experiment involving extreme evidence. The results from this new experiment suggest that the adding model faces limitations when accounting for tasks involving extreme evidence, whereas the quantum inference model does not. Ultimately, we argue that the quantum model provides a more coherent account for order effects that was not possible before. Copyright © 2011 Cognitive Science Society, Inc.

Semiclassical Virasoro blocks from AdS 3 gravity

DOE PAGES

Hijano, Eliot; Kraus, Per; Perlmutter, Eric; ...

2015-12-14

We present a unified framework for the holographic computation of Virasoro conformal blocks at large central charge. In particular, we provide bulk constructions that correctly reproduce all semiclassical Virasoro blocks that are known explicitly from conformal field theory computations. The results revolve around the use of geodesic Witten diagrams, recently introduced in [1], evaluated in locally AdS 3 geometries generated by backreaction of heavy operators. We also provide an alternative computation of the heavy-light semiclassical block — in which two external operators become parametrically heavy — as a certain scattering process involving higher spin gauge fields in AdS 3; thismore » approach highlights the chiral nature of Virasoro blocks. Finally, these techniques may be systematically extended to compute corrections to these blocks and to interpolate amongst the different semiclassical regimes.« less

Authoritative parenting and issue involvement as indicators of ad recall: an empirical investigation of anti-drug ads for parents.

PubMed

Quick, Brian L; Stephenson, Michael T

2007-01-01

This investigation explores the role of authoritative parenting and issue involvement in regard to the recall of parental anti-drug ads encouraging child monitoring. In addition, the study tested whether issue involvement mediates the association between authoritative parenting and recall of parental anti-drug television ads among parents (N = 185) with adolescents in Grades 6, 7, and 8. The results indicate that (a) authoritative parenting is positively associated with favorable attitudes toward monitoring children and issue involvement regarding adolescent drug use, (b) issue involvement is associated with ad recall, (c) issue involvement mediates the relationship between authoritative parenting and ad recall, (d) ad recall is not associated with favorable attitudes toward parental monitoring, and (e) favorable attitudes regarding parental monitoring are positively associated with intentions to engage in monitoring within the next 6 months.

The effects of involvement and ad type on attitudes toward direct-to-consumer advertising of prescription drugs.

PubMed

Limbu, Yam; Torres, Ivonne M

2009-01-01

This article examines consumers' attitudes toward Direct-to-Consumer (DTC) advertising of prescription drugs that are influenced by the use different types of DTC ads and product involvement. Our findings suggest that product involvement and the type of DTC ad are significant predictors of consumers' attitudinal responses toward DTC advertising. High involvement consumers have more favorable attitudes toward the drug's price, DTC ad and brand name, and a higher intention to ask a doctor about the advertised drug than low involvement consumers. In contrast to Informational and Reminder DTC ads, Persuasive ads have more favorable effects on consumers' reactions to DTC prescription drug advertising.

Glycogen synthase kinase-3 (GSK-3) inhibitors for the treatment of Alzheimer's disease.

PubMed

Medina, Miguel; Avila, Jesús

2010-01-01

Originally discovered because of its role in the regulation of glucose metabolism, Glycogen Synthase Kinase-3 (GSK-3) it is now recognised as a crucial player in a diverse series of cellular processes involved in Alzheimer's disease (AD) pathology. Besides having been identified as the major tau protein kinase, GSK-3 mediates Aβ neurotoxicity, plays an essential role in synaptic plasticity and memory, might be involved in Aβ formation, and it has an important role in inflammation and neuronal survival, all key features of AD neuropathology. Moreover, AD was one of the earliest disorders linked to GSK-3 dysfunction. Thus, the discovery of small molecule GSK-3 inhibitors has attracted significant attention to the protein both as therapeutic target for the therapeutic intervention in neurodegenerative diseases as well as a means to understand the molecular basis of these disorders.

Pain in People With Alzheimer Disease: Potential Applications for Psychophysical and Neurophysiological Research

PubMed Central

Monroe, Todd B.; Gore, John C.; Chen, Li Min; Mion, Lorraine C.; Cowan, Ronald L.

2015-01-01

Pain management in people with dementia is a critical problem. Recently, psychophysical and neuroimaging techniques have been used to extend our understanding of pain processing in the brain as well as to identify structural and functional changes in Alzheimer disease (AD). But interpreting the complex relationship between AD pathology, brain activation, and pain reports is challenging. This review proposes a conceptual framework for designing and interpreting psychophysical and neuroimaging studies of pain processing in people with AD. Previous human studies describe the lateral (sensory) and medial (affective) pain networks. Although the majority of the literature on pain supports the lateral and medial networks, some evidence supports an additional rostral pain network, which is believed to function in the production of pain behaviors. The sensory perception of pain as assessed through verbal report and behavioral display may be altered in AD. In addition, neural circuits mediating pain perception and behavioral expression may be hyperactive or underactive, depending on the brain region involved, stage of the disease, and type of pain (acute experimental stimuli or chronic medical conditions). People with worsening AD may therefore experience pain but be unable to indicate pain through verbal or behavioral reports, leaving them at great risk of experiencing untreated pain. Psychophysical (verbal or behavioral) and neurophysiological (brain activation) approaches can potentially address gaps in our knowledge of pain processing in AD by revealing the relationship between neural processes and verbal and behavioral outcomes in the presence of acute or chronic pain. PMID:23277361

The Literacy Factor: Adding Value to Training. Investigation of the Inclusion of Literacy in Training Packages in the Food Processing Industry.

ERIC Educational Resources Information Center

Sanguinetti, Jill

The effects of the inclusion of literacy and numeracy competencies within Australia's food processing industry training package were examined in two case studies of training at two food processing facilities in Victoria. The first case study involved a large pasta factory that had approximately 270 employees and a contract with a registered…

Dyslipidemia and dementia: current epidemiology, genetic evidence and mechanisms behind the associations

PubMed Central

Reitz, Christiane

2013-01-01

The role of cholesterol in the etiology of Alzheimer’s disease (AD) is still controversial. Some studies aiming to explore the association between lipids and/or lipid lowering treatment and AD indicate a harmful effect of dyslipidemia and a beneficial effect of statin therapy on AD risk. The findings are supported by genetic linkage and association studies that have clearly identified several genes involved in cholesterol metabolism or transport as AD susceptibility genes, including Apolipoprotein E (APOE), Apolipoprotein J (APOJ, CLU) and the sortilin-related receptor (SORL1). Functional cell biology studies support a critical involvement of lipid raft cholesterol in the modulation of AbetaPP processing by β- and γ-secretase resulting in altered Aβ production. Contradictory evidence comes from epidemiological studies showing no or controversial association between dyslipidemia and AD risk, cell biology studies suggesting that there is little exchange between circulating and brain cholesterol, that increased membrane cholesterol is protective by inhibiting loss of membrane integrity through amyloid cytotoxicity, and that cellular cholesterol inhibits co-localization of BACE1 and AbetaPP in non-raft membrane domains and thereby increasing generation of plasmin, an Aβ-degrading enzyme. The aim of this review is to summarize the findings of epidemiologic and cell biologic studies aiming to elucidate the role of cholesterol in AD etiology. PMID:21965313

Archaeal community dynamics and abiotic characteristics in a mesophilic anaerobic co-digestion process treating fruit and vegetable processing waste sludge with chopped fresh artichoke waste.

PubMed

Ros, M; Franke-Whittle, I H; Morales, A B; Insam, H; Ayuso, M; Pascual, J A

2013-05-01

This study evaluated the feasibility of obtaining methane in anaerobic digestion (AD) from the waste products generated by the processing of fruit and vegetables. During the first phase (0-55 d) of the AD using sludge from fruit and vegetable processing, an average value of 244±88 L kg(-1) dry matter d(-1)of biogas production was obtained, and methane content reached 65% of the biogas. Co-digestion with chopped fresh artichoke wastes in a second phase (55-71 d) enhanced biogas production, and resulted in an average value of 354±68 L kg(-1) dry matter d(-1), with higher methane content (more than 70%). The archaeal community involved in methane production was studied using the ANAEROCHIP microarray and real-time PCR. Results indicated that species of Methanosaeta and Methanosarcina were important during the AD process. Methanosarcina numbers increased after the addition of chopped fresh artichoke, while Methanosaeta numbers decreased. Copyright © 2013 Elsevier Ltd. All rights reserved.

Nanotechnology-based drug delivery systems for Alzheimer's disease management: Technical, industrial, and clinical challenges.

PubMed

Wen, Ming Ming; El-Salamouni, Noha S; El-Refaie, Wessam M; Hazzah, Heba A; Ali, Mai M; Tosi, Giovanni; Farid, Ragwa M; Blanco-Prieto, Maria J; Billa, Nashiru; Hanafy, Amira S

2017-01-10

Alzheimer's disease (AD) is a neurodegenerative disease with high prevalence in the rapidly growing elderly population in the developing world. The currently FDA approved drugs for the management of symptomatology of AD are marketed mainly as conventional oral medications. Due to their gastrointestinal side effects and lack of brain targeting, these drugs and dosage regiments hinder patient compliance and lead to treatment discontinuation. Nanotechnology-based drug delivery systems (NTDDS) administered by different routes can be considered as promising tools to improve patient compliance and achieve better therapeutic outcomes. Despite extensive research, literature screening revealed that clinical activities involving NTDDS application in research for AD are lagging compared to NTDDS for other diseases such as cancers. The industrial perspectives, processability, and cost/benefit ratio of using NTDDS for AD treatment are usually overlooked. Moreover, active and passive immunization against AD are by far the mostly studied alternative AD therapies because conventional oral drug therapy is not yielding satisfactorily results. NTDDS of approved drugs appear promising to transform this research from 'paper to clinic' and raise hope for AD sufferers and their caretakers. This review summarizes the recent studies conducted on NTDDS for AD treatment, with a primary focus on the industrial perspectives and processability. Additionally, it highlights the ongoing clinical trials for AD management. Copyright © 2016 Elsevier B.V. All rights reserved.

Traffic jam hypothesis: Relationship between endocytic dysfunction and Alzheimer's disease.

PubMed

Kimura, Nobuyuki; Yanagisawa, Katsuhiko

2017-07-08

Membrane trafficking pathways, like the endocytic pathway, carry out fundamental cellular processes that are essential for normal functioning. One such process is regulation of cell surface receptor signaling. A growing body of evidence suggests that β-amyloid protein (Aβ) plays a key role in Alzheimer's disease (AD) pathogenesis. Cleavage of Aβ from its precursor, β-amyloid precursor protein (APP), occurs through the endocytic pathway in neuronal cells. In early-stage AD, intraneuronal accumulation of abnormally enlarged endosomes is common, indicating that endosome trafficking is disrupted. Strikingly, genome-wide association studies reveal that several endocytosis-related genes are associated with AD onset. Also, recent studies demonstrate that alteration in endocytosis induces not only Aβ pathology but also the propagation of tau protein pathology, another key pathological feature of AD. Endocytic dysfunction can disrupt neuronal physiological functions, such as synaptic vesicle transport and neurotransmitter release. Thus, "traffic jams" in the endocytic pathway may be involved in AD pathogenesis and may serve as a novel target for the development of new therapeutics. Copyright © 2017 Elsevier Ltd. All rights reserved.

Uncovering the Social Deficits in the Autistic Brain. A Source-Based Morphometric Study

PubMed Central

Grecucci, Alessandro; Rubicondo, Danilo; Siugzdaite, Roma; Surian, Luca; Job, Remo

2016-01-01

Autism is a neurodevelopmental disorder that mainly affects social interaction and communication. Evidence from behavioral and functional MRI studies supports the hypothesis that dysfunctional mechanisms involving social brain structures play a major role in autistic symptomatology. However, the investigation of anatomical abnormalities in the brain of people with autism has led to inconsistent results. We investigated whether specific brain regions, known to display functional abnormalities in autism, may exhibit mutual and peculiar patterns of covariance in their gray-matter concentrations. We analyzed structural MRI images of 32 young men affected by autistic disorder (AD) and 50 healthy controls. Controls were matched for sex, age, handedness. IQ scores were also monitored to avoid confounding. A multivariate Source-Based Morphometry (SBM) was applied for the first time on AD and controls to detect maximally independent networks of gray matter. Group comparison revealed a gray-matter source that showed differences in AD compared to controls. This network includes broad temporal regions involved in social cognition and high-level visual processing, but also motor and executive areas of the frontal lobe. Notably, we found that gray matter differences, as reflected by SBM, significantly correlated with social and behavioral deficits displayed by AD individuals and encoded via the Autism Diagnostic Observation Schedule scores. These findings provide support for current hypotheses about the neural basis of atypical social and mental states information processing in autism. PMID:27630538

Can foreign proteins imported into yeast mitochondria interfere with PIM1p protease and/or chaperone function?

PubMed

Saveliev, A S; Kovaleva, I E; Novikova, L A; Isaeva, L V; Luzikov, V N

1999-03-15

When studying the fate of mammalian apocytochrome P450scc (apo-P450scc) imported in small amounts into isolated yeast mitochondria, we found that it undergoes degradation, this process being retarded if recipient mitochondria are preloaded in vivo (to about 0.2% of total organelle protein) with a fusion protein composed of mammalian adrenodoxin reductase and adrenodoxin (AdR-Ad); in parallel we observed aggregation of apo-P450scc. These effects suggest some overload of Pim1p protease and/or mtHsp70 system by AdR-Ad, as both of them are involved in the degradation of apo-P450scc (see Savel'ev et al. J. Biol. Chem. 273, 20596-20602, 1998). However, under the same conditions AdR-Ad was not able to impede the import of proteins into mitochondria and the development of the mitochondrial respiratory machinery in yeast, the processes requiring the mtHsp70 system and Pim1p, respectively. These data imply that chaperones and Pim1p protease prefer their natural targets in mitochondria to imported foreign proteins. Copyright 1999 Academic Press.

Relative preservation of the recognition of positive facial expression "happiness" in Alzheimer disease.

PubMed

Maki, Yohko; Yoshida, Hiroshi; Yamaguchi, Tomoharu; Yamaguchi, Haruyasu

2013-01-01

Positivity recognition bias has been reported for facial expression as well as memory and visual stimuli in aged individuals, whereas emotional facial recognition in Alzheimer disease (AD) patients is controversial, with possible involvement of confounding factors such as deficits in spatial processing of non-emotional facial features and in verbal processing to express emotions. Thus, we examined whether recognition of positive facial expressions was preserved in AD patients, by adapting a new method that eliminated the influences of these confounding factors. Sensitivity of six basic facial expressions (happiness, sadness, surprise, anger, disgust, and fear) was evaluated in 12 outpatients with mild AD, 17 aged normal controls (ANC), and 25 young normal controls (YNC). To eliminate the factors related to non-emotional facial features, averaged faces were prepared as stimuli. To eliminate the factors related to verbal processing, the participants were required to match the images of stimulus and answer, avoiding the use of verbal labels. In recognition of happiness, there was no difference in sensitivity between YNC and ANC, and between ANC and AD patients. AD patients were less sensitive than ANC in recognition of sadness, surprise, and anger. ANC were less sensitive than YNC in recognition of surprise, anger, and disgust. Within the AD patient group, sensitivity of happiness was significantly higher than those of the other five expressions. In AD patient, recognition of happiness was relatively preserved; recognition of happiness was most sensitive and was preserved against the influences of age and disease.

Molecular analysis of meso- and thermophilic microbiota associated with anaerobic biowaste degradation

PubMed Central

2012-01-01

Background Microbial anaerobic digestion (AD) is used as a waste treatment process to degrade complex organic compounds into methane. The archaeal and bacterial taxa involved in AD are well known, whereas composition of the fungal community in the process has been less studied. The present study aimed to reveal the composition of archaeal, bacterial and fungal communities in response to increasing organic loading in mesophilic and thermophilic AD processes by applying 454 amplicon sequencing technology. Furthermore, a DNA microarray method was evaluated in order to develop a tool for monitoring the microbiological status of AD. Results The 454 sequencing showed that the diversity and number of bacterial taxa decreased with increasing organic load, while archaeal i.e. methanogenic taxa remained more constant. The number and diversity of fungal taxa increased during the process and varied less in composition with process temperature than bacterial and archaeal taxa, even though the fungal diversity increased with temperature as well. Evaluation of the microarray using AD sample DNA showed correlation of signal intensities with sequence read numbers of corresponding target groups. The sensitivity of the test was found to be about 1%. Conclusions The fungal community survives in anoxic conditions and grows with increasing organic loading, suggesting that Fungi may contribute to the digestion by metabolising organic nutrients for bacterial and methanogenic groups. The microarray proof of principle tests suggest that the method has the potential for semiquantitative detection of target microbial groups given that comprehensive sequence data is available for probe design. PMID:22727142

Nonbranded or branded direct-to-consumer prescription drug advertising-which is more effective?

PubMed

Rollins, Brent L; King, Karen; Zinkhan, George; Perri, Matthew

2011-01-01

Recently, pharmaceutical manufacturers have increased the amount of nonbranded, disease-education focused, direct-to-consumer advertisements. A comparison to branded, product-specific, ads was examined through a series of survey questions measuring consumer attitudes and the role of involvement. Nonbranded ads compared favorably to branded ads and should remain a viable part of the marketing mix. Consumers' level of disease state involvement was the strongest determinant of attitudes overall and within the two ad groupings, as highly involved consumers had significantly more positives attitudes regarding the nonbranded ads. Regardless of involvement level, however, nonbranded ads maintained positive attitude levels.

The Impact of Vitamin E and Other Fat-Soluble Vitamins on Alzheimer´s Disease.

PubMed

Grimm, Marcus O W; Mett, Janine; Hartmann, Tobias

2016-10-26

Alzheimer's disease (AD) is the most common cause of dementia in the elderly population, currently affecting 46 million people worldwide. Histopathologically, the disease is characterized by the occurrence of extracellular amyloid plaques composed of aggregated amyloid-β (Aβ) peptides and intracellular neurofibrillary tangles containing the microtubule-associated protein tau. Aβ peptides are derived from the sequential processing of the amyloid precursor protein (APP) by enzymes called secretases, which are strongly influenced by the lipid environment. Several vitamins have been reported to be reduced in the plasma/serum of AD-affected individuals indicating they have an impact on AD pathogenesis. In this review we focus on vitamin E and the other lipophilic vitamins A, D, and K, and summarize the current knowledge about their status in AD patients, their impact on cognitive functions and AD risk, as well as their influence on the molecular mechanisms of AD. The vitamins might affect the generation and clearance of Aβ both by direct effects and indirectly by altering the cellular lipid homeostasis. Additionally, vitamins A, D, E, and K are reported to influence further mechanisms discussed to be involved in AD pathogenesis, e.g., Aβ-aggregation, Aβ-induced neurotoxicity, oxidative stress, and inflammatory processes, as summarized in this article.

The Impact of Vitamin E and Other Fat-Soluble Vitamins on Alzheimer´s Disease

PubMed Central

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

2016-01-01

Alzheimer’s disease (AD) is the most common cause of dementia in the elderly population, currently affecting 46 million people worldwide. Histopathologically, the disease is characterized by the occurrence of extracellular amyloid plaques composed of aggregated amyloid-β (Aβ) peptides and intracellular neurofibrillary tangles containing the microtubule-associated protein tau. Aβ peptides are derived from the sequential processing of the amyloid precursor protein (APP) by enzymes called secretases, which are strongly influenced by the lipid environment. Several vitamins have been reported to be reduced in the plasma/serum of AD-affected individuals indicating they have an impact on AD pathogenesis. In this review we focus on vitamin E and the other lipophilic vitamins A, D, and K, and summarize the current knowledge about their status in AD patients, their impact on cognitive functions and AD risk, as well as their influence on the molecular mechanisms of AD. The vitamins might affect the generation and clearance of Aβ both by direct effects and indirectly by altering the cellular lipid homeostasis. Additionally, vitamins A, D, E, and K are reported to influence further mechanisms discussed to be involved in AD pathogenesis, e.g., Aβ-aggregation, Aβ-induced neurotoxicity, oxidative stress, and inflammatory processes, as summarized in this article. PMID:27792188

Long-Term Mangiferin Extract Treatment Improves Central Pathology and Cognitive Deficits in APP/PS1 Mice.

PubMed

Infante-Garcia, Carmen; Ramos-Rodriguez, Juan Jose; Delgado-Olmos, Irene; Gamero-Carrasco, Carlos; Fernandez-Ponce, Maria Teresa; Casas, Lourdes; Mantell, Casimiro; Garcia-Alloza, Monica

2017-08-01

Alzheimer's disease (AD) is the most common cause of dementia; however, available treatments have had limited success. Therefore AD patients are in tremendous need of new pharmacological approaches that may delay or slow the progression of the disease. In addition to the classical neuropathological features, immunological and inflammatory processes are also involved in AD pathogenesis. Naturally occurring compounds, such as Mangifera indica Linn (MGF) extracts have previously been shown to significantly reduce peripheral inflammatory processes. In order to explore the role of MGF in AD central pathology, we have orally treated APP/PS1 mice for 22 weeks. While MGF did not affect amyloid pathology, tau hyperphosphorylation was significantly reduced in the cortex and hippocampus. Also, inflammatory processes, measured by microglia and astrocyte burdens, were diminished in MGF-treated mice. Moreover, neuronal morphological alterations, such as abnormal neurite curvature and dystrophies, highly increased in APP/PS1 mice, were significantly ameliorated by long-term MGF treatment. Reduction of all these pathological features were accompanied by compelling improvements of episodic and spatial memory in APP/PS1 mice treated with MGF. Altogether our data suggest that MGF may provide a useful tool to target different aspects of AD pathology and could lead to more effective future therapeutic or preventive strategies.

Tolerogenic dendritic cells in autoimmune diseases: crucial players in induction and prevention of autoimmunity.

PubMed

Torres-Aguilar, Honorio; Blank, Miri; Jara, Luis J; Shoenfeld, Yehuda

2010-11-01

The immune system has evolved to coordinate responses against numerous invading pathogens and simultaneously remain silent facing self-antigens and those derived from commensal organisms. But, if both processes are not maintained in strict balance, a potential threat can emerge due to the risk of chronic inflammation and/or autoimmunity development. Therefore, there is a negative immune regulation where tolerogenic dendritic cells (tDCs) participate actively. Under steady-state conditions, tDC are notably involved in the elimination of autoreactive T cells at the thymus, and in the control of T cells specific to self and harmless antigens in the periphery. But in the presence of foreign antigens in an inflammatory milieu, dendritic cells (DCs) mature and induce T cells activation and their migration to B cell areas to assist in antibody production. Additionally, there are other factors such as infections, anti tumoral immune responses, trauma-mediated disruption, etc. that may induce alterations in the balance between tolerogenic and immunogenic functions of DCs and instigate the development of autoimmune diseases (ADs). Therefore, in recent years, DCs have emerged as therapeutic targets to control of ADs. Diverse strategies in vitro and/or in animal models of ADs have explored the tolerogenic functions of DCs and demonstrated their feasibility to prevent or control an autoimmune process, but still leaving a void in their application in clinical assays. The purpose of this paper is to give a general overview of the current literature on the significance of tDCs in tolerance maintenance to self and innocuous antigens, the most relevant alterations involved in the pathophysiology of ADs, the cellular and molecular mechanisms involved in their tolerogenic function and the current strategies used to exploit their tolerogenic potential. Published by Elsevier B.V.

Eye movement analysis and cognitive processing: detecting indicators of conversion to Alzheimer’s disease

PubMed Central

Pereira, Marta LG Freitas; Camargo, Marina von Zuben A; Aprahamian, Ivan; Forlenza, Orestes V

2014-01-01

A great amount of research has been developed around the early cognitive impairments that best predict the onset of Alzheimer’s disease (AD). Given that mild cognitive impairment (MCI) is no longer considered to be an intermediate state between normal aging and AD, new paths have been traced to acquire further knowledge about this condition and its subtypes, and to determine which of them have a higher risk of conversion to AD. It is now known that other deficits besides episodic and semantic memory impairments may be present in the early stages of AD, such as visuospatial and executive function deficits. Furthermore, recent investigations have proven that the hippocampus and the medial temporal lobe structures are not only involved in memory functioning, but also in visual processes. These early changes in memory, visual, and executive processes may also be detected with the study of eye movement patterns in pathological conditions like MCI and AD. In the present review, we attempt to explore the existing literature concerning these patterns of oculomotor changes and how these changes are related to the early signs of AD. In particular, we argue that deficits in visual short-term memory, specifically in iconic memory, attention processes, and inhibitory control, may be found through the analysis of eye movement patterns, and we discuss how they might help to predict the progression from MCI to AD. We add that the study of eye movement patterns in these conditions, in combination with neuroimaging techniques and appropriate neuropsychological tasks based on rigorous concepts derived from cognitive psychology, may highlight the early presence of cognitive impairments in the course of the disease. PMID:25031536

Abnormalities of peptide metabolism in Alzheimer disease.

PubMed

Panchal, Maï; Rholam, Mohamed; Brakch, Noureddine

2004-10-01

The steady-state level of peptide hormones represents a balance between their biosynthesis and proteolytic processing by convertases and their catabolism by proteolytic enzymes. Low levels of neuropeptide Y, somatostatin and corticotropin-releasing factor, described in Alzheimer disease (AD), were related to a defect in proteolytic processing of their protein precursors. In contrast the abundance of beta-amyloid peptides, the major protein constituents of senile plaques is likely related to inefficient catabolism. Therefore, attention is mainly focused on convertases that generate active peptides and counter-regulatory proteases that are involved in their catabolism. Some well-described proteases such as NEP are thought to be involved in beta-amyloid catabolism. The search of other possible candidates represents a primary effort in the field. A variety of vascular risk factors such as diabetes, hypertension and arteriosclerosis suggest that the functional vascular defect contributes to AD pathology. It has also been described that beta-amyloid peptides potentiate endothelin-1 induced vasoconstriction. In this review, we will critically evaluate evidence relating proteases implicated in amyloid protein precursor proteolytic processing and beta-amyloid catabolism.

Process for decomposing lignin in biomass

DOEpatents

Rector, Kirk Davin; Lucas, Marcel; Wagner, Gregory Lawrence; Kimball, David Bryan; Hanson, Susan Kloek

2014-10-28

A mild inexpensive process for treating lignocellulosic biomass involves oxidative delignification of wood using an aqueous solution prepared by dissolving a catalytic amount of manganese (III) acetate into water and adding hydrogen peroxide. Within 4 days and without agitation, the solution was used to convert poplar wood sections into a fine powder-like delignified, cellulose rich materials that included individual wood cells.

Glucose repression may involve processes with different sugar kinase requirements.

PubMed Central

Sanz, P; Nieto, A; Prieto, J A

1996-01-01

Adding glucose to Saccharomyces cerevisiae cells growing among nonfermentable carbon sources leads to glucose repression. This process may be resolved into several steps. An early repression response requires any one of the three glucose kinases present in S. cerevisiae (HXK1, HXK2, or GLK1). A late response is only achieved when Hxk2p is present. PMID:8755906

Building a scholar in writing (BSW): A model for developing students' critical writing skills.

PubMed

Bailey, Annette; Zanchetta, Margareth; Velasco, Divine; Pon, Gordon; Hassan, Aafreen

2015-11-01

Several authors have highlighted the importance of writing in developing reflective thinking skills, transforming knowledge, communicating expressions, and filling knowledge gaps. However, difficulties with higher order processing and critical analysis affect students' ability to write critical and thoughtful essays. The Building a Scholar in Writing (BSW) model is a 6-step process of increasing intricacies in critical writing development. Development of critical writing is proposed to occur in a processed manner that transitions from presenting simple ideas (just bones) in writing, to connecting ideas (connecting bones), to formulating a thesis and connecting key components (constructing a skeleton), to supporting ideas with evidence (adding muscle), to building creativity and originality (adding essential organs), and finally, developing strong, integrated, critical arguments (adding brain). This process symbolically represents the building of a scholar. The idea of building a scholar equates to progressively giving life and meaning to a piece of writing with unique scholarly characteristics. This progression involves a transformation in awareness, thinking, and understanding, as well as advancement in students' level of critical appraisal skills. Copyright © 2015 Elsevier Ltd. All rights reserved.

Expression of Somatostatin, cortistatin, and their receptors, as well as dopamine receptors, but not of neprilysin, are reduced in the temporal lobe of Alzheimer's disease patients.

PubMed

Gahete, Manuel D; Rubio, Alicia; Durán-Prado, Mario; Avila, Jesús; Luque, Raúl M; Castaño, Justo P

2010-01-01

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by severe cognitive deficit, wherein the impairment of episodic memory is the major hallmark. AD patients exhibit augmented accumulation of amyloid-beta (Abeta) and hyperphosphorylated tau protein in specific brain regions. In addition, several neuropeptides/neurotransmitter axes clearly associated with cognitive processes, Abeta turnover, and tau phosphorylation have also been found to be impaired in AD, such as somatostatin (SST)/cortistatin (CST) and dopamine (DA) systems. However, to date there is no precise quantitative data on the expression of these systems in the human brain of AD and normal patients. Here we measured by quantitative real-time PCR the mRNA levels of SST/CST, their receptors (sst1-5 and DA receptors (drd1-5) in addition to neprilysin (a SST-regulated enzyme involved in Abeta degradation) in three regions of the temporal lobe, one of the cortical regions most severely affected by AD. Our results reveal that some components of SST/CST- and DA-axes are divergently altered in the three areas of AD patients. Despite this region-specific regulation, an overall, common reduction of these systems was observed in the temporal lobe of AD patients. Conversely, neprilysin expression was not altered in AD, suggesting that Abeta accumulation observed in AD is due to a lack of neprilysin activation by SST rather than to a reduction of its expression. Collectively, our results define a comprehensive scenario wherein reduction of ssts, drds, and sst ligands SST and CST, could be involved, at least in part, in some of the more important defects observed in AD.

Functional correlates of preserved naming performance in amnestic Mild Cognitive Impairment.

PubMed

Catricalà, Eleonora; Della Rosa, Pasquale A; Parisi, Laura; Zippo, Antonio G; Borsa, Virginia M; Iadanza, Antonella; Castiglioni, Isabella; Falini, Andrea; Cappa, Stefano F

2015-09-01

Naming abilities are typically preserved in amnestic Mild Cognitive Impairment (aMCI), a condition associated with increased risk of progression to Alzheimer's disease (AD). We compared the functional correlates of covert picture naming and word reading between a group of aMCI subjects and matched controls. Unimpaired picture naming performance was associated with more extensive activations, in particular involving the parietal lobes, in the aMCI group. In addition, in the condition associated with higher processing demands (blocks of categorically homogeneous items, living items), increased activity was observed in the aMCI group, in particular in the left fusiform gyrus. Graph analysis provided further evidence of increased modularity and reduced integration for the homogenous sets in the aMCI group. The functional modifications associated with preserved performance may reflect, in the case of more demanding tasks, compensatory mechanisms for the subclinical involvement of semantic processing areas by AD pathology. Copyright © 2015 Elsevier Ltd. All rights reserved.

Technological advances and applications of hydrolytic enzymes for valorization of lignocellulosic biomass.

PubMed

Manisha; Yadav, Sudesh Kumar

2017-12-01

Hydrolytic enzymes are indispensable tools in the production of various foodstuffs, drugs, and consumables owing to their applications in almost every industrial process nowadays. One of the foremost areas of interest involving the use of hydrolytic enzymes is in the transformation of lignocellulosic biomass into value added products. However, limitations of the processes due to inadequate enzyme activity and stability with a narrow range of pH and temperature optima often limit their effective usage. The innovative technologies, involving manipulation of enzyme activity and stability through mutagenesis, genetic engineering and metagenomics lead to a major leap in all the fields using hydrolytic enzymes. This article provides recent advancement towards the isolation and use of microbes for lignocellulosic biomass utilisation, microbes producing the hydrolytic enzymes, the modern age technologies used to manipulate and enhance the hydrolytic enzyme activity and the applications of such enzymes in value added products development from lignocellulosic biomass. Copyright © 2017 Elsevier Ltd. All rights reserved.

Silencing of galectin-1 inhibits retinal neovascularization and ameliorates retinal hypoxia in a murine model of oxygen-induced ischemic retinopathy.

PubMed

Yang, Ning; Zhang, Wenxi; He, Tao; Xing, Yiqiao

2017-06-01

Aberrant neovascularization is a consequence of inappropriate angiogenic signaling and contributes to several diseases. Although many regulators of pathogenic angiogenesis have been identified, the understanding of this process remains incomplete. Galectin-1 (Gal-1), as a homodimeric protein with a single carbohydrate-recognition domain, is implicated in several pathologic processes, including angiogenesis; however, its involvement in retinal neovascularization (RNV) remains unknown. Here, we investigated the anti-angiogenic effect of silencing Gal-1 through intravitreal injection in a mouse model of oxygen-induced retinopathy (OIR). Our results revealed that Gal-1 was overexpressed and closely related to retinal neo-vessels in OIR retinas. After silencing Gal-1 via intravitreal injection of adenoviral-Gal-1-RNA interference (Ad-Gal-1-RNAi), RNV and retinal hypoxia were significantly attenuated, indicating the anti-angiogenic effect of Gal-1 inhibition. Western blot analysis and real-time polymerase chain reaction indicated that the expression of both neuropilin-1 (Nrp-1) and B cell lymphoma-2 (Bcl-2) decreased after intravitreal injection of Ad-Gal-1-RNAi, implying the possible involvement of Nrp-1 and Bcl-2 in Gal-1-related angiogenic processes. Additionally, whole-mount fluorescence and hematoxylin and eosin staining showed that intravitreal injection of Ad-Gal-1-RNAi did not significantly disrupt the retinal vasculature and neuronal structure of room air mice. Moreover, Ad-Gal-1-RNAi transfer promoted retinal vascular sprouting and increased retinal vascular perfusion, likely through decreased phosphorylation of myosin phosphatase target protein-1. Collectively, our results demonstrated that Gal-1 functions as an important regulator in RNV and offers a promising strategy for the treatment of RNV diseases, such as proliferative diabetic retinopathy and retinopathy of prematurity. Copyright © 2017 Elsevier Ltd. All rights reserved.

Treatment of corn ethanol distillery wastewater using two-stage anaerobic digestion.

PubMed

Ráduly, B; Gyenge, L; Szilveszter, Sz; Kedves, A; Crognale, S

In this study the mesophilic two-stage anaerobic digestion (AD) of corn bioethanol distillery wastewater is investigated in laboratory-scale reactors. Two-stage AD technology separates the different sub-processes of the AD in two distinct reactors, enabling the use of optimal conditions for the different microbial consortia involved in the different process phases, and thus allowing for higher applicable organic loading rates (OLRs), shorter hydraulic retention times (HRTs) and better conversion rates of the organic matter, as well as higher methane content of the produced biogas. In our experiments the reactors have been operated in semi-continuous phase-separated mode. A specific methane production of 1,092 mL/(L·d) has been reached at an OLR of 6.5 g TCOD/(L·d) (TCOD: total chemical oxygen demand) and a total HRT of 21 days (5.7 days in the first-stage, and 15.3 days in the second-stage reactor). Nonetheless the methane concentration in the second-stage reactor was very high (78.9%); the two-stage AD outperformed the reference single-stage AD (conducted at the same reactor loading rate and retention time) by only a small margin in terms of volumetric methane production rate. This makes questionable whether the higher methane content of the biogas counterbalances the added complexity of the two-stage digestion.

Identifying challenges in project consultants engagement practices

NASA Astrophysics Data System (ADS)

Shariffuddin, Nadia Alina Amir; Abidin, Nazirah Zainul

2017-10-01

Construction projects, green or conventional, involve multi-faceted disciplines engaged with the goal of delivering products i.e. building, infrastructure etc. at the best quality within stipulated budgets. For green projects, additional attention is added for environmental quality. Due to the various responsibilities and liabilities involved as well as the complexity of the construction process itself, formal engagement of multi-disciplinary professionals i.e. project consultants is required in any construction project. Poor selection of project consultants will lead to a multitude of complications resulting in delay, cost escalation, conflicts and poor quality. This paper explores the challenges that occur during the engagement of project consultants in a green project. As the engagement decision involves developers and architects, these two groups of respondents with green project backgrounds were approached qualitatively using interview technique. The challenges identified are limited experience and knowledge, consultants' fee vs. quality, green complexity, conflicts of interest, clients' extended expectation and less demand in green projects. The construction shifts to green project demands engagement of project consultants with added skills. It is expected that through the identification of challenges, better management and administration can be created which would give impact to the overall process of engagement in green projects.

Pathway-Based Analysis of Genome-Wide siRNA Screens Reveals the Regulatory Landscape of App Processing

PubMed Central

Camargo, Luiz Miguel; Zhang, Xiaohua Douglas; Loerch, Patrick; Caceres, Ramon Miguel; Marine, Shane D.; Uva, Paolo; Ferrer, Marc; de Rinaldis, Emanuele; Stone, David J.; Majercak, John; Ray, William J.; Yi-An, Chen; Shearman, Mark S.; Mizuguchi, Kenji

2015-01-01

The progressive aggregation of Amyloid-β (Aβ) in the brain is a major trait of Alzheimer's Disease (AD). Aβ is produced as a result of proteolytic processing of the β-amyloid precursor protein (APP). Processing of APP is mediated by multiple enzymes, resulting in the production of distinct peptide products: the non-amyloidogenic peptide sAPPα and the amyloidogenic peptides sAPPβ, Aβ40, and Aβ42. Using a pathway-based approach, we analyzed a large-scale siRNA screen that measured the production of different APP proteolytic products. Our analysis identified many of the biological processes/pathways that are known to regulate APP processing and have been implicated in AD pathogenesis, as well as revealing novel regulatory mechanisms. Furthermore, we also demonstrate that some of these processes differentially regulate APP processing, with some mechanisms favouring production of certain peptide species over others. For example, synaptic transmission having a bias towards regulating Aβ40 production over Aβ42 as well as processes involved in insulin and pancreatic biology having a bias for sAPPβ production over sAPPα. In addition, some of the pathways identified as regulators of APP processing contain genes (CLU, BIN1, CR1, PICALM, TREM2, SORL1, MEF2C, DSG2, EPH1A) recently implicated with AD through genome wide association studies (GWAS) and associated meta-analysis. In addition, we provide supporting evidence and a deeper mechanistic understanding of the role of diabetes in AD. The identification of these processes/pathways, their differential impact on APP processing, and their relationships to each other, provide a comprehensive systems biology view of the “regulatory landscape” of APP. PMID:25723573

Genome-wide association study of CSF levels of 59 alzheimer's disease candidate proteins: significant associations with proteins involved in amyloid processing and inflammation.

PubMed

Kauwe, John S K; Bailey, Matthew H; Ridge, Perry G; Perry, Rachel; Wadsworth, Mark E; Hoyt, Kaitlyn L; Staley, Lyndsay A; Karch, Celeste M; Harari, Oscar; Cruchaga, Carlos; Ainscough, Benjamin J; Bales, Kelly; Pickering, Eve H; Bertelsen, Sarah; Fagan, Anne M; Holtzman, David M; Morris, John C; Goate, Alison M

2014-10-01

Cerebrospinal fluid (CSF) 42 amino acid species of amyloid beta (Aβ42) and tau levels are strongly correlated with the presence of Alzheimer's disease (AD) neuropathology including amyloid plaques and neurodegeneration and have been successfully used as endophenotypes for genetic studies of AD. Additional CSF analytes may also serve as useful endophenotypes that capture other aspects of AD pathophysiology. Here we have conducted a genome-wide association study of CSF levels of 59 AD-related analytes. All analytes were measured using the Rules Based Medicine Human DiscoveryMAP Panel, which includes analytes relevant to several disease-related processes. Data from two independently collected and measured datasets, the Knight Alzheimer's Disease Research Center (ADRC) and Alzheimer's Disease Neuroimaging Initiative (ADNI), were analyzed separately, and combined results were obtained using meta-analysis. We identified genetic associations with CSF levels of 5 proteins (Angiotensin-converting enzyme (ACE), Chemokine (C-C motif) ligand 2 (CCL2), Chemokine (C-C motif) ligand 4 (CCL4), Interleukin 6 receptor (IL6R) and Matrix metalloproteinase-3 (MMP3)) with study-wide significant p-values (p<1.46×10-10) and significant, consistent evidence for association in both the Knight ADRC and the ADNI samples. These proteins are involved in amyloid processing and pro-inflammatory signaling. SNPs associated with ACE, IL6R and MMP3 protein levels are located within the coding regions of the corresponding structural gene. The SNPs associated with CSF levels of CCL4 and CCL2 are located in known chemokine binding proteins. The genetic associations reported here are novel and suggest mechanisms for genetic control of CSF and plasma levels of these disease-related proteins. Significant SNPs in ACE and MMP3 also showed association with AD risk. Our findings suggest that these proteins/pathways may be valuable therapeutic targets for AD. Robust associations in cognitively normal individuals suggest that these SNPs also influence regulation of these proteins more generally and may therefore be relevant to other diseases.

Angiotensins in Alzheimer's disease - friend or foe?

PubMed

Kehoe, Patrick G; Miners, Scott; Love, Seth

2009-12-01

The renin-angiotensin system (RAS) is an important regulator of blood pressure. Observational and experimental studies suggest that alterations in blood pressure and components of the brain RAS contribute to the development and progression of Alzheimer's disease (AD), resulting in changes that can lead or contribute to cognitive decline. The complexity of the RAS and diversity of its interactions with neurological processes have recently become apparent but large gaps in our understanding still remain. Modulation of activity of components of the brain RAS offers substantial opportunities for the treatment and prevention of dementia, including AD. This paper reviews molecular, genetic, experimental and clinical data as well as the therapeutic opportunities that relate to the involvement of the RAS in AD.

Complete genome sequence of 'Mycobacterium neoaurum' NRRL B-3805, an androstenedione (AD) producer for industrial biotransformation of sterols.

PubMed

Rodríguez-García, Antonio; Fernández-Alegre, Estela; Morales, Alejandro; Sola-Landa, Alberto; Lorraine, Jess; Macdonald, Sandy; Dovbnya, Dmitry; Smith, Margaret C M; Donova, Marina; Barreiro, Carlos

2016-04-20

Microbial bioconversion of sterols into high value steroid precursors, such as 4-androstene-3,17-dione (AD), is an industrial challenge. Genes and enzymes involved in sterol degradation have been proposed, although the complete pathway is not yet known. The genome sequencing of the AD producer strain 'Mycobacterium neoaurum' NRRL B-3805 (formerly Mycobacterium sp. NRRL B-3805) will serve to elucidate the critical steps for industrial processes and will provide the basis for further genetic engineering. The genome comprises a circular chromosome (5 421 338bp), is devoid of plasmids and contains 4844 protein-coding genes. Copyright © 2016 Elsevier B.V. All rights reserved.

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.

Food advertising on Argentinean television: are ultra-processed foods in the lead?

PubMed

Allemandi, Lorena; Castronuovo, Luciana; Tiscornia, M Victoria; Ponce, Miguel; Schoj, Veronica

2018-01-01

To describe the number of processed and ultra-processed food (PUPF) advertisements (ads) targeted to children on Argentinean television (TV), to analyse the advertising techniques used and the nutritional quality of the foods advertised, and to determine the potential exposure of children to unhealthy food advertising in our country. Five free-to-air channels and the three most popular children's cable networks were recorded from 07.00 to 22.00 hours for 6 weeks. Ads were classified by target audience, type of product, advertised food categories and advertising strategies used. The NOVA system was used to classify food products according to industrial food processing level. Nutritional quality was analysed using the Pan American Health Organization's nutrient profile model. Buenos Aires, Argentina. Results are considered applicable to most of the country. The study did not involve human subjects. Of the sample of food ads, PUPF products were more frequently advertised during children's programmes (98·9 %) v. programmes targeted to the general audience (93·7 %, χ 2=45·92, P<0·01). The top five food categories were desserts, dairy products, non-alcoholic sugary beverages, fast-food restaurants, and salty snacks. Special promotions and the appearance of cartoon characters were much more frequent in ads targeting children. Argentinean children are estimated to be exposed to sixty-one ads for unhealthy PUPF products per week. Our study showed that Argentinean children are exposed to a high number of unhealthy PUPF ads on TV. The Argentinean Government should build on this information to design and implement a comprehensive policy to reduce exposure to unhealthy food marketing that includes TV and other communication channels and places.

New Beginnings in Alzheimer's Disease: The Most Prevalent Tauopathy.

PubMed

Hernández, Félix; Llorens-Martín, María; Bolós, Marta; Pérez, Mar; Cuadros, Raquel; Pallas-Bazarra, Noemí; Zabala, Juan C; Avila, Jesús

2018-01-01

Alzheimer's disease (AD) is characterized by the presence of two aberrant structures: namely senile plaques, composed of amyloid-β peptide (Aβ), and neurofibrillary tangles, composed of tau protein. In this regard, Aβ and tau protein have been widely studied in research efforts aiming to find a therapy for AD. Aβ and tau pathologies do not always overlap. The precursor of Aβ is expressed in peripheral tissues and in the central nervous system (CNS), whereas tau is mainly a neuronal protein. Since AD is a disease of the CNS, it has been proposed that Aβ may initiate the disease process, with tau being the executor. In this review, we will focus on future studies of tau pathology, although we will comment on new beginnings for AD, as other molecules other than Aβ and tau may be involved in the onset of dementia.

Time distortions in Alzheimer’s disease: a systematic review and theoretical integration

PubMed Central

El Haj, Mohamad; Kapogiannis, Dimitrios

2016-01-01

Time perception is an essential function of the human brain, which is compromised in Alzheimer’s disease (AD). Here, we review empirical findings on time distortions in AD and provide a theoretical framework that integrates time and memory distortions in AD and explains their bidirectional modulation. The review was based on a literature survey performed on the PubMed and PsycInfo databases. According to our theoretical framework, time distortions may induce decline in the ability to mentally project oneself in time (i.e., mental time travel), and consequently may contribute to an episodic memory compromise in AD. Conversely, episodic memory compromise in AD may result in a loss of the ability to retrieve information about time and/or the ability to project oneself in subjective time. The relationship between time distortions and memory decline in AD can be jointly attributed to hippocampus involvement, as this brain area supports both time perception and memory and is preferentially targeted by the neuropathological processes of AD. Clinical implications of time distortions are discussed and directions for future research are suggested. PMID:28721270

Amyloid precursor protein and endosomal-lysosomal dysfunction in Alzheimer's disease: inseparable partners in a multifactorial disease.

PubMed

Nixon, Ralph A

2017-07-01

Abnormalities of the endosomal-lysosomal network (ELN) are a signature feature of Alzheimer's disease (AD). These include the earliest known cytopathology that is specific to AD and that affects endosomes and induces the progressive failure of lysosomes, each of which are directly linked by distinct mechanisms to neurodegeneration. The origins of ELN dysfunction and β-amyloidogenesis closely overlap, which reflects their common genetic basis, the established early involvement of endosomes and lysosomes in amyloid precursor protein (APP) processing and clearance, and the pathologic effect of certain APP metabolites on ELN functions. Genes that promote β-amyloidogenesis in AD (APP, PSEN1/2, and APOE4) have primary effects on ELN function. The importance of primary ELN dysfunction to pathogenesis is underscored by the mutations in more than 35 ELN-related genes that, thus far, are known to cause familial neurodegenerative diseases even though different pathogenic proteins may be involved. In this article, I discuss growing evidence that implicates AD gene-driven ELN disruptions as not only the antecedent pathobiology that underlies β-amyloidogenesis but also as the essential partner with APP and its metabolites that drive the development of AD, including tauopathy, synaptic dysfunction, and neurodegeneration. The striking amelioration of diverse deficits in animal AD models by remediating ELN dysfunction further supports a need to integrate APP and ELN relationships, including the role of amyloid-β, into a broader conceptual framework of how AD arises, progresses, and may be effectively therapeutically targeted.-Nixon, R. A. Amyloid precursor protein and endosomal-lysosomal dysfunction in Alzheimer's disease: inseparable partners in a multifactorial disease. © FASEB.

SLIP CASTING METHOD

DOEpatents

Allison, A.G.

1959-09-01

S>A process is described for preparing a magnesium oxide slip casting slurry which when used in conjunction with standard casting techniques results in a very strong "green" slip casting and a fired piece of very close dimensional tolerance. The process involves aging an aqueous magnestum oxide slurry, having a basic pH value, until it attains a specified critical viscosity at which time a deflocculating agent is added without upsetting the basic pH value.

Nanostructured Origami (Trademark) 3D Fabrication and Self Assembly Process for Soldier Combat Systems

DTIC Science & Technology

2004-12-01

the Japanese art of “ origami ”) involves patterning adjacent 2D membranes that can be lifted off (using methods we have developed) of a silicon...innovative process holds immense potential for the Army’s Objective Force Warrior. Nanostructured Origami enables many practical and promising...Nanostructured Origami allows such devices to be formed from a single, micro/nanofabricated layer. In addition, nanoarchitecture can be added

APP Function and Lipids: A Bidirectional Link

PubMed Central

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

2017-01-01

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

Protein Kinase Activity Decreases with Higher Braak Stages of Alzheimer’s Disease Pathology

PubMed Central

Rosenberger, Andrea F.N.; Hilhorst, Riet; Coart, Elisabeth; García Barrado, Leandro; Naji, Faris; Rozemuller, Annemieke J.M.; van der Flier, Wiesje M.; Scheltens, Philip; Hoozemans, Jeroen J.M.; van der Vies, Saskia M.

2015-01-01

Alzheimer’s disease (AD) is characterized by a long pre-clinical phase (20–30 years), during which significant brain pathology manifests itself. Disease mechanisms associated with pathological hallmarks remain elusive. Most processes associated with AD pathogenesis, such as inflammation, synaptic dysfunction, and hyper-phosphorylation of tau are dependent on protein kinase activity. The objective of this study was to determine the involvement of protein kinases in AD pathogenesis. Protein kinase activity was determined in postmortem hippocampal brain tissue of 60 patients at various stages of AD and 40 non-demented controls (Braak stages 0-VI) using a peptide-based microarray platform. We observed an overall decrease of protein kinase activity that correlated with disease progression. The phosphorylation of 96.7% of the serine/threonine peptides and 37.5% of the tyrosine peptides on the microarray decreased significantly with increased Braak stage (p-value <0.01). Decreased activity was evident at pre-clinical stages of AD pathology (Braak I-II). Increased phosphorylation was not observed for any peptide. STRING analysis in combination with pathway analysis and identification of kinases responsible for peptide phosphorylation showed the interactions between well-known proteins in AD pathology, including the Ephrin-receptor A1 (EphA1), a risk gene for AD, and sarcoma tyrosine kinase (Src), which is involved in memory formation. Additionally, kinases that have not previously been associated with AD were identified, e.g., protein tyrosine kinase 6 (PTK6/BRK), feline sarcoma oncogene kinase (FES), and fyn-associated tyrosine kinase (FRK). The identified protein kinases are new biomarkers and potential drug targets for early (pre-clinical) intervention. PMID:26519433

Mechanisms of mononuclear phagocyte recruitment in Alzheimer's disease.

PubMed

Hickman, Suzanne E; El Khoury, Joseph

2010-04-01

Alzheimer's disease (AD) is associated with a significant neuroinflammatory component. Mononuclear phagocytes including monocytes and microglia are the principal cells involved, and they accumulate at perivascular sites of beta-amyloid (Abeta) deposition and in senile plaques. Recent evidence suggests that mononuclear phagocyte accumulation in the AD brain is dependent on chemokines. CCL2, a major monocyte chemokine, is upregulated in the AD brain. Interaction of CCL2 with its receptor CCR2 regulates mononuclear phagocyte accumulation in a mouse model of AD. CCR2 deficiency leads to lower mononuclear phagocyte accumulation and is associated with higher brain Abeta levels, specifically around blood vessels, suggesting that monocytes accumulate at sites of Abeta deposition in an initial attempt to clear these deposits and stop or delay their neurotoxic effects. Indeed, enhancing mononuclear phagocyte accumulation delays progression of AD. Here we review the mechanisms of mononuclear phagocyte accumulation in AD and discuss the potential roles of additional chemokines and their receptors in this process. We also propose a multi-step model for recruitment of mononuclear phagocytes into the brain. The first step involves egress of monocyte/microglial precursors from the bone marrow into the blood. The second step is crossing the blood-brain barrier to the perivascular areas and into the brain parenchyma. The final step includes movement of monocytes/microglia from areas of the brain that lack any amyloid deposition to senile plaques. Understanding the mechanism of recruitment of mononuclear phagocytes to the AD brain is necessary to further understand the role of these cells in the pathogenesis of AD and to identify any potential therapeutic use of these cells for the treatment of this disease.

[Benefit Assessment and Price Negotiation Under AMNOG: Calculable Process or Unfair Poker Game?

PubMed

Radic, D; Haugk, S; Radic, M

2016-09-16

Ever since the introduction of the Market Restructuring Act, the evaluation and price negotiations of drugs have been controversial. While the Federal Joint Committee considers that the process is transparent and in accordance with clear evidence-based criteria, representatives of pharmaceutical companies are particularly critical of the fact that the central association of statutory health insurance is involved in both the determination of added therapeutic benefit of drugs as well as in the subsequent price negotiation. In this study, we investigate these 2 contradictory assessments empirically. For this purpose, we model the benefit assessment and price negotiation processes under AMNOG and analyze their relationship. We show that the number of patients in the target population, and the annual cost of therapy for the appropriate comparator therapy have a negative influence on the determination of the added benefit of the new therapy. The added value itself has a positive (negative) effect on the mark-up for the appropriate comparator therapy (price discount), while the annual treatment costs of the new therapy (which appropriate comparator therapy) have a positive (negative) influence. We find clues, but no significant evidence for the hypothesis that the decisions on the added value of new medicines and the subsequent price negotiations are interdependent. © Georg Thieme Verlag KG Stuttgart · New York.

Humor and Comparatives in Ads for High- and Low-Involvement Products.

ERIC Educational Resources Information Center

Wu, Bob T. W.; And Others

1989-01-01

Investigates the effectiveness of humor in advertising, comparative advertising, and consumer involvement with the product. Finds that humorous ads are more eye catching but less impressive and less sufficient in information than nonhumorous ads. Finds the performance of comparative ads is generally negative and especially so in the high…

How emotional pictures influence visuospatial binding in short-term memory in ageing and Alzheimer's disease?

PubMed

Borg, Céline; Leroy, Nicolas; Favre, Emilie; Laurent, Bernard; Thomas-Antérion, Catherine

2011-06-01

The present study examines the prediction that emotion can facilitate short-term memory. Nevertheless, emotion also recruits attention to process information, thereby disrupting short-term memory when tasks involve high attentional resources. In this way, we aimed to determine whether there is a differential influence of emotional information on short-term memory in ageing and Alzheimer's disease (AD). Fourteen patients with mild AD, 14 healthy older participants (NC), and 14 younger adults (YA) performed two tasks. In the first task, involving visual short-term memory, participants were asked to remember a picture among four different pictures (negative or neutral) following a brief delay. The second task, a binding memory task, required the recognition by participants of a picture according to its spatial location. The attentional cost involved was higher than for the first task. The pattern of results showed that visual memory performance was better for negative stimuli than for neutral ones, irrespective of the group. In contrast, binding memory performance was essentially poorer for the location of negative pictures in the NC group, and for the location of both negative and neutral stimuli in the AD group, in comparison to the YA group. Taken together, these results show that emotion has beneficial effects on visual short-term memory in ageing and AD. In contrast, emotion does not improve their performances in the binding condition. Copyright © 2011 Elsevier Inc. All rights reserved.

Decrease in Adult Neurogenesis and Neuroinflammation Are Involved in Spatial Memory Impairment in the Streptozotocin-Induced Model of Sporadic Alzheimer's Disease in Rats.

PubMed

Bassani, Taysa Bervian; Bonato, Jéssica M; Machado, Meira M F; Cóppola-Segovia, Valentín; Moura, Eric L R; Zanata, Silvio M; Oliveira, Rúbia M M W; Vital, Maria A B F

2018-05-01

Early impairments in cerebral glucose metabolism and insulin signaling pathways may participate in the pathogenesis of the sporadic form of Alzheimer's disease (sAD). Intracerebroventricular (ICV) injections of low doses of streptozotocin (STZ) are used to mimic sAD and study these alterations in rodents. Streptozotocin causes impairments in insulin signaling and has been reported to trigger several alterations in the brain, such as oxidative stress, neuroinflammation, and dysfunctions in adult neurogenesis, which may be involved in cognitive decline and are features of human AD. The aim of the present study was to assess the influence of neuroinflammation on the process of adult neurogenesis and consequent cognitive deficits in the STZ-ICV model of sAD in Wistar rats. Streptozotocin caused an acute and persistent neuroinflammatory response, reflected by reactive microgliosis and astrogliosis in periventricular areas and the dorsal hippocampus, accompanied by a marked reduction of the proliferation of neural stem cells in the dentate gyrus of the hippocampus and subventricular zone. Streptozotocin also reduced the survival, differentiation, and maturation of newborn neurons, resulting in impairments in short-term and long-term spatial memory. These results support the hypothesis that neuroinflammation has a detrimental effect on neurogenesis, and both neuroinflammation and impairments in neurogenesis contribute to cognitive deficits in the STZ-ICV model of sAD.

Changes in connectivity of the posterior default network node during visual processing in mild cognitive impairment: staged decline between normal aging and Alzheimer's disease.

PubMed

Krajcovicova, Lenka; Barton, Marek; Elfmarkova-Nemcova, Nela; Mikl, Michal; Marecek, Radek; Rektorova, Irena

2017-12-01

Visual processing difficulties are often present in Alzheimer's disease (AD), even in its pre-dementia phase (i.e. in mild cognitive impairment, MCI). The default mode network (DMN) modulates the brain connectivity depending on the specific cognitive demand, including visual processes. The aim of the present study was to analyze specific changes in connectivity of the posterior DMN node (i.e. the posterior cingulate cortex and precuneus, PCC/P) associated with visual processing in 17 MCI patients and 15 AD patients as compared to 18 healthy controls (HC) using functional magnetic resonance imaging. We used psychophysiological interaction (PPI) analysis to detect specific alterations in PCC connectivity associated with visual processing while controlling for brain atrophy. In the HC group, we observed physiological changes in PCC connectivity in ventral visual stream areas and with PCC/P during the visual task, reflecting the successful involvement of these regions in visual processing. In the MCI group, the PCC connectivity changes were disturbed and remained significant only with the anterior precuneus. In between-group comparison, we observed significant PPI effects in the right superior temporal gyrus in both MCI and AD as compared to HC. This change in connectivity may reflect ineffective "compensatory" mechanism present in the early pre-dementia stages of AD or abnormal modulation of brain connectivity due to the disease pathology. With the disease progression, these changes become more evident but less efficient in terms of compensation. This approach can separate the MCI from HC with 77% sensitivity and 89% specificity.

Neuropsychological mechanisms of Digit Symbol Substitution Test impairment in Asperger Disorder.

PubMed

Yoran-Hegesh, Roni; Kertzman, Semion; Vishne, Tali; Weizman, Abraham; Kotler, Moshe

2009-03-31

Our aim was to investigate the neurocognitive mechanisms recruited by adolescents with Asperger Disorder (AD), in comparison to controls, and to detect the underlying mechanisms during the complex information processing required for the performance of the Digit Symbol Substitution Test (DSST). Male adolescents (n=23; mean age 15.1+/-3.6 years) with a DSM-IV diagnosis of AD were compared with a normal male control group with similar demographic characteristics (n=43; mean age: 15.1+/-3.6 years). A computerized neurocognitive battery was administered and included: Inspection Time (IT), Finger Tapping Test (FTT), Simple Reaction Time (SRT), Choice Reaction Time (CRT), Digit Running task (DRT), Stroop test and Digit Symbol Substitution Test (DSST). Adolescents with AD performed significantly worse than controls on the DSST. This impaired DSST performance was related to cognitive mechanisms different from those employed by normal controls. Motor slowness and inability to deal with increased amounts of information affected the performance of the AD group, while shifting of attention was the limiting factor in the controls. Both groups were similarly dependent on response selection. This study demonstrated differences in performance in complex cognitive tasks between adolescents with AD and normal controls that may be related to differences in neurocognitive mechanisms underlying information processing. Future neuroimaging studies are needed to clarify the neural network involved in the differences in cognitive performance between AD subjects and normal controls.

Nicotinamide Forestalls Pathology and Cognitive Decline in Alzheimer Mice: Evidence for Improved Neuronal Bioenergetics and Autophagy Procession

PubMed Central

Liu, Dong; Pitta, Michael; Jiang, Haiyang; Lee, Jong-Hwan; Zhang, Guofeng; Chen, Xinzhi; Kawamoto, Elisa M.; Mattson, Mark P.

2012-01-01

Impaired brain energy metabolism and oxidative stress are implicated in cognitive decline and the pathological accumulations of amyloid β-peptide (Aβ) and hyperphosphorylated Tau (p-Tau) in Alzheimer's disease (AD). To determine whether improving brain energy metabolism will forestall disease progress in AD, the impact of the NAD+ precursor nicotinamide on brain cell mitochondrial function and macroautophagy, bioenergetics-related signaling and cognitive performance were studied in cultured neurons and in a mouse model of AD. Oxidative stress resulted in decreased mitochondrial mass, mitochondrial degeneration and autophagosome accumulation in neurons. Nicotinamide preserved mitochondrial integrity and autophagy function, and reduced neuronal vulnerability to oxidative/metabolic insults and Aβ toxicity. NAD+ biosynthesis, autophagy and PI3K signaling were required for the neuroprotective action of nicotinamide. Treatment of 3xTgAD mice with nicotinamide for 8 months resulted in improved cognitive performance, and reduced Aβ and p-Tau pathologies in hippocampus and cerebral cortex. Nicotinamide treatment preserved mitochondrial integrity, and improved autophagy-lysosome procession by enhancing lysosome/autolysosome acidification to reduce autophagosome accumulation. Treatment of 3xTgAD mice with nicotinamide resulted in elevated levels of activated neuroplasticity-related kinases (Akt and ERKs) and the transcription factor cyclic AMP response element-binding protein in the hippocampus and cerebral cortex. Thus, nicotinamide suppresses AD pathology and cognitive decline in a mouse model of AD by a mechanism involving improved brain bioenergetics with preserved functionality of mitochondria and the autophagy system. PMID:23273573

Erotic and disgust-inducing pictures--differences in the hemodynamic responses of the brain.

PubMed

Stark, Rudolf; Schienle, Anne; Girod, Cornelia; Walter, Bertram; Kirsch, Peter; Blecker, Carlo; Ott, Ulrich; Schäfer, Axel; Sammer, Gebhard; Zimmermann, Mark; Vaitl, Dieter

2005-09-01

The aim of this fMRI study was to explore brain structures that are involved in the processing of erotic and disgust-inducing pictures. The stimuli were chosen to trigger approach and withdrawal tendencies, respectively. By adding sadomasochistic (SM) scenes to the design and examining 12 subjects with and 12 subjects without sadomasochistic preferences, we introduced a picture category that induced erotic pleasure in one sample and disgust in the other sample. Since we also presented neutral pictures, all subjects viewed pictures of four different categories: neutral, disgust-inducing, erotic, and SM erotic pictures. The analysis indicated that several brain structures are commonly involved in the processing of disgust-inducing and erotic pictures (occipital cortex, hippocampus, thalamus, and the amygdala). The ventral striatum was specifically activated when subjects saw highly sexually arousing pictures. This indicates the involvement of the human reward system during the processing of visual erotica.

A survey of automated methods for sensemaking support

NASA Astrophysics Data System (ADS)

Llinas, James

2014-05-01

Complex, dynamic problems in general present a challenge for the design of analysis support systems and tools largely because there is limited reliable a priori procedural knowledge descriptive of the dynamic processes in the environment. Problem domains that are non-cooperative or adversarial impute added difficulties involving suboptimal observational data and/or data containing the effects of deception or covertness. The fundamental nature of analysis in these environments is based on composite approaches involving mining or foraging over the evidence, discovery and learning processes, and the synthesis of fragmented hypotheses; together, these can be labeled as sensemaking procedures. This paper reviews and analyzes the features, benefits, and limitations of a variety of automated techniques that offer possible support to sensemaking processes in these problem domains.

One size does not fit all: face emotion processing impairments in semantic dementia, behavioural-variant frontotemporal dementia and Alzheimer's disease are mediated by distinct cognitive deficits.

PubMed

Miller, Laurie A; Hsieh, Sharpley; Lah, Suncica; Savage, Sharon; Hodges, John R; Piguet, Olivier

2012-01-01

Patients with frontotemporal dementia (both behavioural variant [bvFTD] and semantic dementia [SD]) as well as those with Alzheimer's disease (AD) show deficits on tests of face emotion processing, yet the mechanisms underlying these deficits have rarely been explored. We compared groups of patients with bvFTD (n = 17), SD (n = 12) or AD (n = 20) to an age- and education-matched group of healthy control subjects (n = 36) on three face emotion processing tasks (Ekman 60, Emotion Matching and Emotion Selection) and found that all three patient groups were similarly impaired. Analyses of covariance employed to partial out the influences of language and perceptual impairments, which frequently co-occur in these patients, provided evidence of different underlying cognitive mechanisms. These analyses revealed that language impairments explained the original poor scores obtained by the SD patients on the Ekman 60 and Emotion Selection tasks, which involve verbal labels. Perceptual deficits contributed to Emotion Matching performance in the bvFTD and AD patients. Importantly, all groups remained impaired on one task or more following these analyses, denoting a primary emotion processing disturbance in these dementia syndromes. These findings highlight the multifactorial nature of emotion processing deficits in patients with dementia.

Into the Fourth Dimension: Dysregulation of Genome Architecture in Aging and Alzheimer's Disease.

PubMed

Winick-Ng, Warren; Rylett, R Jane

2018-01-01

Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by synapse dysfunction and cognitive impairment. Understanding the development and progression of AD is challenging, as the disease is highly complex and multifactorial. Both environmental and genetic factors play a role in AD pathogenesis, highlighted by observations of complex DNA modifications at the single gene level, and by new evidence that also implicates changes in genome architecture in AD patients. The four-dimensional structure of chromatin in space and time is essential for context-dependent regulation of gene expression in post-mitotic neurons. Dysregulation of epigenetic processes have been observed in the aging brain and in patients with AD, though there is not yet agreement on the impact of these changes on transcription. New evidence shows that proteins involved in genome organization have altered expression and localization in the AD brain, suggesting that the genomic landscape may play a critical role in the development of AD. This review discusses the role of the chromatin organizers and epigenetic modifiers in post-mitotic cells, the aging brain, and in the development and progression of AD. How these new insights can be used to help determine disease risk and inform treatment strategies will also be discussed.

Disruption of Semantic Network in Mild Alzheimer’s Disease Revealed by Resting-State fMRI

PubMed Central

Mascali, Daniele; DiNuzzo, Mauro; Serra, Laura; Mangia, Silvia; Maraviglia, Bruno; Bozzali, Marco; Giove, Federico

2018-01-01

Subtle semantic deficits can be observed in Alzheimer’s disease (AD) patients even in the early stages of the illness. In this work, we tested the hypothesis that the semantic control network is deregulated in mild AD patients. We assessed the integrity of the semantic control system using resting-state functional magnetic resonance imaging in a cohort of patients with mild AD (n = 38; mean mini-mental state examination = 20.5) and in a group of age-matched healthy controls (n = 19). Voxel-wise analysis spatially constrained in the left fronto-temporal semantic control network identified two regions with altered functional connectivity (FC) in AD patients, specifically in the pars opercularis (POp, BA44) and in the posterior middle temporal gyrus (pMTG, BA21). Using whole-brain seed-based analysis, we demonstrated that these two regions have altered FC even beyond the semantic control network. In particular, the pMTG displayed a wide-distributed pattern of lower connectivity to several brain regions involved in language-semantic processing, along with a possibly compensatory higher connectivity to the Wernicke’s area. We conclude that in mild AD brain regions belonging to the semantic control network are abnormally connected not only within the network, but also to other areas known to be critical for language processing. PMID:29197559

Updating working memory in aircraft noise and speech noise causes different fMRI activations

PubMed Central

Sætrevik, Bjørn; Sörqvist, Patrik

2015-01-01

The present study used fMRI/BOLD neuroimaging to investigate how visual-verbal working memory is updated when exposed to three different background-noise conditions: speech noise, aircraft noise and silence. The number-updating task that was used can distinguish between “substitution processes,” which involve adding new items to the working memory representation and suppressing old items, and “exclusion processes,” which involve rejecting new items and maintaining an intact memory set. The current findings supported the findings of a previous study by showing that substitution activated the dorsolateral prefrontal cortex, the posterior medial frontal cortex and the parietal lobes, whereas exclusion activated the anterior medial frontal cortex. Moreover, the prefrontal cortex was activated more by substitution processes when exposed to background speech than when exposed to aircraft noise. These results indicate that (a) the prefrontal cortex plays a special role when task-irrelevant materials should be denied access to working memory and (b) that, when compensating for different types of noise, either different cognitive mechanisms are involved or those cognitive mechanisms that are involved are involved to different degrees. PMID:25352319

Sterile products: advances and challenges in formulation, manufacturing and regulatory aspects--a regulatory review perspective.

PubMed

Hussong, David

2010-09-01

For several decades, the FDA has undertaken many initiatives to improve the quality and safety of sterile drug products. In recent years, efforts have also been undertaken to accelerate the rate for application approval by adding earlier involvement of microbiology reviewers in drug development. Product and manufacturing process development, as well as safe use and product design, are among the elements of enhanced technical involvement. An overview of the product quality microbiology aspects for sterile drugs is provided.

Chemical Blistering: Cellular and Macromolecular Components

DTIC Science & Technology

1985-12-15

minutes of exposure. Warthin and Weller (2) and Sinclslr (3) noted that the process initially involves dostrurtion of the bezel and lower spinous...Clark, W. H., Jr., Risen, A. Z., Van Scott, R. J., and Vaughan, J. H., ads) McGraw-Hill, New York, pp.589-598. 2. Warthin , A. S., and Weller, C. V

77 FR 58584 - Stream Global Services, Inc., AdCenter, Beaverton, OR; Notice of a Revised Determination on...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-09-21

... supply of services like or directly competitive with the customer relationship management and business... subject worker group includes workers involved in employment related to the supply of customer relationship management and business process outsourcing services. The subject worker group does not include on...

Informing Hospital Change Processes through Visualization and Simulation: A Case Study at a Children's Emergency Clinic.

PubMed

Persson, Johanna; Dalholm, Elisabeth Hornyánszky; Johansson, Gerd

2014-01-01

To demonstrate the use of visualization and simulation tools in order to involve stakeholders and inform the process in hospital change processes, illustrated by an empirical study from a children's emergency clinic. Reorganization and redevelopment of a hospital is a complex activity that involves many stakeholders and demands. Visualization and simulation tools have proven useful for involving practitioners and eliciting relevant knowledge. More knowledge is desired about how these tools can be implemented in practice for hospital planning processes. A participatory planning process including practitioners and researchers was executed over a 3-year period to evaluate a combination of visualization and simulation tools to involve stakeholders in the planning process and to elicit knowledge about needs and requirements. The initial clinic proposal from the architect was discarded as a result of the empirical study. Much general knowledge about the needs of the organization was extracted by means of the adopted tools. Some of the tools proved to be more accessible than others for the practitioners participating in the study. The combination of tools added value to the process by presenting information in alternative ways and eliciting questions from different angles. Visualization and simulation tools inform a planning process (or other types of change processes) by providing the means to see beyond present demands and current work structures. Long-term involvement in combination with accessible tools is central for creating a participatory setting where the practitioners' knowledge guides the process. © 2014 Vendome Group, LLC.

Musical cognition in Alzheimer's disease: application of the Montreal Battery of Evaluation of Amusia.

PubMed

Campanelli, Alessandra; Rendace, Lidia; Parisi, Francesco; D'Antonio, Fabrizia; Imbriano, Letizia; de Lena, Carlo; Trebbastoni, Alessandro

2016-07-01

The aim of this study was to assess certain musical abilities in 30 patients with Alzheimer's disease (AD) and 30 healthy controls by using the complete version of the Montreal Battery of Evaluation of Amusia (MBEA). This battery evaluates melodic (scale, contour, and interval) and temporal (rhythm and meter) perception of music and musical memory. We found that altered musical processing is a common feature in AD. Despite that, AD subjects show partially spared abilities for temporal organization of music, though not for melodic perception and musical memory. This peculiar dysfunctional pattern could depend on the neurodegenerative involvement of some specific areas for music perception and memory in the brains of AD patients. Further studies are needed to investigate the usefulness of additional musical tests like the MBEA on larger samples to confirm our preliminary data. © 2016 New York Academy of Sciences.

Visual Perceptual Organization Ability in Autopsy-Verified Dementia with Lewy Bodies and Alzheimer’s Disease

PubMed Central

Mitolo, Micaela; Hamilton, Joanne M.; Landy, Kelly M.; Hansen, Lawrence A.; Galasko, Douglas; Pazzaglia, Francesca; Salmon, David P.

2018-01-01

Objectives Prominent impairment of visuospatial processing is a feature of dementia with Lewy bodies (DLB), and diagnosis of this impairment may help clinically distinguish DLB from Alzheimer’s disease (AD). The current study compared autopsy-confirmed DLB and AD patients on the Hooper Visual Organization Test (VOT), a test that requires perceptual and mental reorganization of parts of an object into an identifiable whole. The VOT may be particularly sensitive to DLB since it involves integration of visual information processed in separate dorsal and ventral visual “streams”. Methods Demographically similar DLB (n = 28), AD (n = 115), and normal control (NC; n = 85) participants were compared on the VOT and additional neuropsychological tests. Patient groups did not differ in dementia severity at time of VOT testing. High and Low AD-Braak stage DLB subgroups were compared to examine the influence of concomitant AD pathology on VOT performance. Results Both patient groups were impaired compared to NC participants. VOT scores of DLB patients were significantly lower than those of AD patients. The diagnostic sensitivity and specificity of the VOT for patients versus controls was good, but marginal for DLB versus AD. High-Braak and low-Braak DLB patients did not differ on the VOT, but High-Braak DLB performed worse than Low-Braak DLB on tests of episodic memory and language. Conclusions Visual perceptual organization ability is more impaired in DLB than AD but not strongly diagnostic. The disproportionate severity of this visual perceptual deficit in DLB is not related to degree of concomitant AD pathology, which suggests that it might primarily reflect Lewy body pathology. PMID:27221597

Promoting competition in Swedish primary care.

PubMed

Norén, Lars; Ranerup, Agneta

2015-01-01

The purpose of this paper is to examine the role of accreditation documents (ADs) in the competition based on provider quality in a quasi-market for primary healthcare. The paper uses a mixed-method research methodology to analyse two primary healthcare ADs in two Swedish regions. In total, 19 interviews were conducted with actors involved in the creation and use of such documents. This paper points to the crucial role of ADs in the identification of quality differences that influence the competition in primary healthcare. This finding contrasts with the commonly held laissez-faire idea that competition causes providers to develop their own service concepts and where the invisible hand creates quality differences. The paper adds to the discussion with its detailed description of how ADs create competition among primary healthcare providers through selection processes, quality differentiation, and ranking. The paper does not explore quality differences in the medical treatment of patients in primary healthcare centres. The paper provides insights for politicians on how to use ADs to control competition and regulate choice. The paper takes an innovative approach to the examination of how ADs increase the competition in primary healthcare choice.

Polyhexamethyl biguanide can eliminate contaminant yeasts from fuel-ethanol fermentation process.

PubMed

Elsztein, Carolina; de Menezes, João Assis Scavuzzi; de Morais, Marcos Antonio

2008-09-01

Industrial ethanol fermentation is a non-sterile process and contaminant microorganisms can lead to a decrease in industrial productivity and significant economic loss. Nowadays, some distilleries in Northeastern Brazil deal with bacterial contamination by decreasing must pH and adding bactericides. Alternatively, contamination can be challenged by adding a pure batch of Saccharomyces cerevisiae-a time-consuming and costly process. A better strategy might involve the development of a fungicide that kills contaminant yeasts while preserving S. cerevisiae cells. Here, we show that polyhexamethyl biguanide (PHMB) inhibits and kills the most important contaminant yeasts detected in the distilleries of Northeastern Brazil without affecting the cell viability and fermentation capacity of S. cerevisiae. Moreover, some physiological data suggest that PHMB acts through interaction with the yeast membrane. These results support the development of a new strategy for controlling contaminant yeast population whilst keeping industrial yields high.

Monophasic demyelination reduces brain growth in children

PubMed Central

Weier, Katrin; Longoni, Giulia; Fonov, Vladimir S.; Bar-Or, Amit; Marrie, Ruth Ann; Yeh, E. Ann; Narayanan, Sridar; Arnold, Douglas L.; Verhey, Leonard H.; Banwell, Brenda; Collins, D. Louis

2017-01-01

Objective: To investigate how monophasic acquired demyelinating syndromes (ADS) affect age-expected brain growth over time. Methods: We analyzed 83 pediatric patients imaged serially from initial demyelinating attack: 18 with acute disseminated encephalomyelitis (ADEM) and 65 with other monophasic ADS presentations (monoADS). We further subdivided the monoADS group by the presence (n = 33; monoADSlesion) or absence (n = 32; monoADSnolesion) of T2 lesions involving the brain at onset. We used normative data to compare brain volumes and calculate age- and sex-specific z scores, and used mixed-effect models to investigate their relationship with time from demyelinating illness. Results: Children with monophasic demyelination (ADEM, non-ADEM with brain lesions, and those without brain involvement) demonstrated reduced age-expected brain growth on serial images, driven by reduced age-expected white matter growth. Cortical gray matter volumes were not reduced at onset but demonstrated reduced age-expected growth afterwards in all groups. Brain volumes differed from age- and sex-expected values to the greatest extent in children with ADEM. All patient groups failed to recover age-expected brain growth trajectories. Conclusions: Brain volume, and more importantly age-expected brain growth, is negatively affected by acquired demyelination, even in the absence of chronicity, implicating factors other than active inflammation as operative in this process. PMID:28381515

Monophasic demyelination reduces brain growth in children.

PubMed

Aubert-Broche, Bérengère; Weier, Katrin; Longoni, Giulia; Fonov, Vladimir S; Bar-Or, Amit; Marrie, Ruth Ann; Yeh, E Ann; Narayanan, Sridar; Arnold, Douglas L; Verhey, Leonard H; Banwell, Brenda; Collins, D Louis

2017-05-02

To investigate how monophasic acquired demyelinating syndromes (ADS) affect age-expected brain growth over time. We analyzed 83 pediatric patients imaged serially from initial demyelinating attack: 18 with acute disseminated encephalomyelitis (ADEM) and 65 with other monophasic ADS presentations (monoADS). We further subdivided the monoADS group by the presence (n = 33; monoADSlesion) or absence (n = 32; monoADSnolesion) of T2 lesions involving the brain at onset. We used normative data to compare brain volumes and calculate age- and sex-specific z scores, and used mixed-effect models to investigate their relationship with time from demyelinating illness. Children with monophasic demyelination (ADEM, non-ADEM with brain lesions, and those without brain involvement) demonstrated reduced age-expected brain growth on serial images, driven by reduced age-expected white matter growth. Cortical gray matter volumes were not reduced at onset but demonstrated reduced age-expected growth afterwards in all groups. Brain volumes differed from age- and sex-expected values to the greatest extent in children with ADEM. All patient groups failed to recover age-expected brain growth trajectories. Brain volume, and more importantly age-expected brain growth, is negatively affected by acquired demyelination, even in the absence of chronicity, implicating factors other than active inflammation as operative in this process. © 2017 American Academy of Neurology.

Incomplete KLK7 Secretion and Upregulated LEKTI Expression Underlie Hyperkeratotic Stratum Corneum in Atopic Dermatitis.

PubMed

Igawa, Satomi; Kishibe, Mari; Minami-Hori, Masako; Honma, Masaru; Tsujimura, Hisashi; Ishikawa, Junko; Fujimura, Tsutomu; Murakami, Masamoto; Ishida-Yamamoto, Akemi

2017-02-01

Atopic dermatitis (AD) is a common inflammatory skin disorder. Chronic AD lesions present hyperkeratosis, indicating a disturbed desquamation process. KLK7 is a serine protease involved in the proteolysis of extracellular corneodesmosome components, including desmocollin 1 and corneodesmosin, which leads to desquamation. KLK7 is secreted by lamellar granules and upregulated in AD lesional skin. However, despite increased KLK7 protein levels, immunostaining and electron microscopy indicated numerous corneodesmosomes remaining in the uppermost layer of the stratum corneum from AD lesions. We aimed to clarify the discrepancy between KLK7 overexpression and retention of corneodesmosomes on AD corneocytes. Western blot analysis indicated abnormal corneodesmosin degradation patterns in stratum corneum from AD lesions. The KLK activity of tape-stripped corneocytes from AD lesions was not significantly elevated in in situ zymography, which was our new attempt to detect the protease activity more precisely than conventional assays. This ineffective KLK activation was associated with impaired KLK7 secretion from lamellar granules and increased expression of LEKTI in AD. Such imbalances in protease-protease inhibitor interactions could lead to abnormal proteolysis of corneodesmosomes and compact hyperkeratosis. Upregulated expression of LEKTI might be a compensatory mechanism to prevent further barrier dysfunction in AD. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Is elevated norepinephrine an etiological factor in some cases of Alzheimer's disease?

PubMed

Fitzgerald, Paul J

2010-09-01

Loss of norepinephrine (NE) releasing neurons, in the locus coeruleus of the brainstem, is well documented to occur in Alzheimer's disease (AD). However, this process does not necessarily result in decreased release of NE, since compensatory mechanisms may produce increased release of this neurotransmitter. Independent of potential loss of locus coeruleus cells, brain NE levels may be elevated in some persons with AD, both before and during disease progression. Here I examine evidence that elevated, endogenous brain NE is an etiological factor in some cases of AD, and not merely an epiphenomenon of the disease. To explore this etiological hypothesis in AD, I examine the following eight lines of evidence: 1) direct evidence of elevated NE or its metabolites in AD; 2) studies of tricyclic antidepressants, which may principally boost NE; 3) studies of clonidine and other alpha2 adrenergic agonist drugs, which may principally lower the concentration of NE; 4) studies of beta adrenoceptor blocking drugs, including propranolol; 5) comorbidity of AD and bipolar disorder, where both disorders may involve elevated NE; 6) comorbidity of AD and hypertension; 7) comorbidity of AD and obesity; and 8) potential interaction between AD and psychological stress, where stressors are known to release NE. These lines of evidence tend to support the elevated NE etiological hypothesis.

Mesenchymal Stromal Cells Engineered to Produce IGF-I by Recombinant Adenovirus Ameliorate Liver Fibrosis in Mice

PubMed Central

Fiore, Esteban J.; Bayo, Juan M.; Garcia, Mariana G.; Malvicini, Mariana; Lloyd, Rodrigo; Piccioni, Flavia; Rizzo, Manglio; Peixoto, Estanislao; Sola, M. Beatriz; Atorrasagasti, Catalina; Alaniz, Laura; Camilletti, María A.; Enguita, Mónica; Prieto, Jesús; Aquino, Jorge B.

2015-01-01

Liver cirrhosis involves chronic wound healing and fibrotic processes. Mesenchymal stromal cells (MSCs) are multipotent adult progenitor cells that are used as vehicles of therapeutic genes. Insulin growth factor like-I (IGF-I) was shown to counteract liver fibrosis. We aimed at analyzing the effect of applying IGF-I overexpressing mouse bone marrow-derived MSCs on hepatic fibrosis. Fibrosis was induced by chronic thioacetamide application or bile duct ligation. MSCs engineered to produce green fluorescent protein (GFP) (AdGFP-MSCs) or IGF-I (AdIGF-I-MSCs) were applied systemically, and changes in collagen deposition and in the expression of key pro-fibrogenic and pro-regenerative genes/proteins were assessed. In addition, immunogenicity of transduced cells was analyzed. Liver fibrosis was further ameliorated after a single-dose application of AdIGF-I-MSCs when compared with AdGFP-MSCs and/or recombinant IGF-I treatments. Interestingly, an early and transitory upregulation in IGF-I and hepatocyte growth factor (HGF) mRNA expression was found in the liver of MSC-treated animals, which was more pronounced in AdIGF-I-MSCs condition. A reduction in hepatic stellate cell activation status was found after incubation with MSCs conditioned media. In addition, the AdIGF-I-MSCs cell-free supernatant induced the expression of IGF-I and HGF in primary cultured hepatocytes. From day 1 after transplantation, the proliferation marker proliferating cell nuclear antigen was upregulated in the liver of AdIGF-I-MSCs group, mainly in hepatocytes. MSCs were in vivo traced till day 14 after injection. In addition, multiple doses of Ad-IGF-I-MSCs likely suppressed antiviral immune response and it further reduced collagen deposition. Our results uncover early events that are likely involved in the anti-fibrogenic effect of genetically modified MSCs and overall would support the use of AdIGF-I-MSCs in treatment of liver fibrosis. PMID:25315017

Aberrant proteolytic processing and therapeutic strategies in Alzheimer disease.

PubMed

Tomita, Taisuke

2017-05-01

Amyloid-β peptide (Aβ) and tau are major components of senile plaques and neurofibrillary tangles, respectively, deposited in the brains of Alzheimer disease (AD) patients. Aβ is derived from amyloid-β precursor protein that is sequentially cleaved by two aspartate proteases, β- and γ-secretases. Secreted Aβ is then catabolized by several proteases. Several lines of evidence suggest that accumulation of Aβ by increased production or decreased degradation induces the tau-mediated neuronal toxicity and symptomatic manifestations of AD. Thus, the dynamics of cerebral Aβ, called as "Aβ economy", would be the mechanistic basis of AD pathogenesis. Partial loss of γ-secretase activity leads to the increased generation of toxic Aβ isoforms, indicating that activation of γ-secretase would provide a beneficial effect for AD. After extensive discovery and development efforts, BACE1, which is a β-secretase enzyme, has emerged as a prime drug target for lowering brain Aβ levels. Recent studies revealed the decreased clearance of Aβ in sporadic AD patients, suggesting the importance of the catabolic mechanism in the pathogenesis of AD. I will discuss with these proteolytic mechanisms involved in the regulation of Aβ economy, and development of effective treatment and diagnostics for AD. Copyright © 2017 Elsevier Ltd. All rights reserved.

Adaptive trials for tuberculosis: early reflections on theory and practice.

PubMed

Montgomery, C M

2016-08-01

Adaptive designs (ADs) have been proposed for anti-tuberculosis treatment trials. This call for innovation occurs against the backdrop of fundamental changes in the acceptable evidence base in anti-tuberculosis treatment. To contextualise ADs for tuberculosis (TB) and explore early responses from those working in the field. In this qualitative study investigating processes of theoretical and practical change in randomised controlled trials, 24 interviews were conducted with professionals involved in AD trials, half of whom worked in the TB field. Clinical trialists working on AD trials in TB are positive about the efficiency these designs offer, but remain cautious about their suitability. In addition to technical concerns, informants discussed the challenges of implementing AD in developing countries, including limited regulatory capacity to evaluate proposals, investments needed in infrastructure and site capacity, and challenges regarding informed consent. Respondents identified funding, interdisciplinary communication and regulatory and policy responses as additional concerns potentially affecting the success of AD for TB. Empirical research is needed into patient experiences of AD, including informed consent. Further consideration of the contexts of innovation in trial design is needed. These are fundamental to the successful translation of theory into practice.

Alterations in protein phosphorylation in the amygdala of the 5XFamilial Alzheimer's disease animal model.

PubMed

Yang, Eun-Jeong; Mahmood, Usman; Kim, Hyunju; Choi, Moonseok; Choi, Yunjung; Lee, Jean-Pyo; Chang, Moon-Jeong; Kim, Hye-Sun

2017-04-01

Alzheimer's disease is the most common disease underlying dementia in humans. Two major neuropathological hallmarks of AD are neuritic plaques primarily composed of amyloid beta peptide and neurofibrillary tangles primarily composed of hyperphosphorylated tau. In addition to impaired memory function, AD patients often display neuropsychiatric symptoms and abnormal emotional states such as confusion, delusion, manic/depressive episodes and altered fear status. Brains from AD patients show atrophy of the amygdala which is involved in fear expression and emotional processing as well as hippocampal atrophy. However, which molecular changes are responsible for the altered emotional states observed in AD remains to be elucidated. Here, we observed that the fear response as assessed by evaluating fear memory via a cued fear conditioning test was impaired in 5XFamilial AD (5XFAD) mice, an animal model of AD. Compared to wild-type mice, 5XFAD mice showed changes in the phosphorylation of twelve proteins in the amygdala. Thus, our study provides twelve potential protein targets in the amygdala that may be responsible for the impairment in fear memory in AD. Copyright © 2017 The Authors. Production and hosting by Elsevier B.V. All rights reserved.

Pharmacotherapeutic targets in Alzheimer's disease

PubMed Central

Biran, Yif'at; Masters, Colin L; Barnham, Kevin J; Bush, Ashley I; Adlard, Paul A

2009-01-01

Abstract Alzheimer's disease (AD) is a progressive neurodegenerative disorder which is characterized by an increasing impairment in normal memory and cognitive processes that significantly diminishes a person's daily functioning. Despite decades of research and advances in our understanding of disease aetiology and pathogenesis, there are still no effective disease-modifying drugs available for the treatment of AD. However, numerous compounds are currently undergoing pre-clinical and clinical evaluations. These candidate pharma-cotherapeutics are aimed at various aspects of the disease, such as the microtubule-associated τ-protein, the amyloid-β (Aβ) peptide and metal ion dyshomeostasis – all of which are involved in the development and progression of AD. We will review the way these pharmacological strategies target the biochemical and clinical features of the disease and the investigational drugs for each category. PMID:19040415

GSK-3 mediates the okadaic acid-induced modification of collapsin response mediator protein-2 in human SK-N-SH neuroblastoma cells.

PubMed

Ni, Mei-Hui; Wu, Chih-Ching; Chan, Wen-Hsiung; Chien, Kun-Yi; Yu, Jau-Song

2008-04-15

Collapsin response mediator protein-2 (CRMP-2), a phosphoprotein involved in axonal outgrowth and microtubule dynamics, is aberrantly phosphorylated in Alzheimer's disease (AD) brain. Alteration of glycogen synthase kinase-3 (GSK-3) activity is associated with the pathogenesis of AD. Here, we show that CRMP-2 is one of the major substrates for GSK-3 in pig brain extracts. Both GSK-3alpha and 3beta phosphorylate purified pig brain CRMP-2 and significantly alter its mobility in SDS-gels, resembling the CRMP-2 modification observed in AD brain. Interestingly, this modification can be detected in SK-N-SH neuroblastoma cells treated with a phosphatase inhibitor, okadaic acid (OA), and GSK-3 inhibitors completely block this OA-induced event. Knockdown of both GSK-3alpha and 3beta, but not either kinase alone, impairs OA-induced modification of CRMP-2. Mutation of Ser-518 or Ser-522 of CRMP-2, which are highly phosphorylated in AD brain, to Ala blocks the OA-induced modification of CRMP-2 in SK-N-SH cells. Ser-522 prephosphorylated by Cdk5 is required for subsequent GSK-3alpha-mediated phosphorylation of CRMP-2 in vitro. Collectively, our results demonstrate for the first time that OA can induce phosphorylation of CRMP-2 in SK-N-SH cells at sites aberrantly phosphorylated in AD brain, and both GSK-3alpha and 3beta and Ser-522 kinase(s) are involved in this process.

Sol-gel processing with inorganic metal salt precursors

DOEpatents

Hu, Zhong-Cheng

2004-10-19

Methods for sol-gel processing that generally involve mixing together an inorganic metal salt, water, and a water miscible alcohol or other organic solvent, at room temperature with a macromolecular dispersant material, such as hydroxypropyl cellulose (HPC) added. The resulting homogenous solution is incubated at a desired temperature and time to result in a desired product. The methods enable production of high quality sols and gels at lower temperatures than standard methods. The methods enable production of nanosize sols from inorganic metal salts. The methods offer sol-gel processing from inorganic metal salts.

Multi-compartmental modeling of SORLA’s influence on amyloidogenic processing in Alzheimer’s disease

PubMed Central

2012-01-01

Background Proteolytic breakdown of the amyloid precursor protein (APP) by secretases is a complex cellular process that results in formation of neurotoxic Aβ peptides, causative of neurodegeneration in Alzheimer’s disease (AD). Processing involves monomeric and dimeric forms of APP that traffic through distinct cellular compartments where the various secretases reside. Amyloidogenic processing is also influenced by modifiers such as sorting receptor-related protein (SORLA), an inhibitor of APP breakdown and major AD risk factor. Results In this study, we developed a multi-compartment model to simulate the complexity of APP processing in neurons and to accurately describe the effects of SORLA on these processes. Based on dose–response data, our study concludes that SORLA specifically impairs processing of APP dimers, the preferred secretase substrate. In addition, SORLA alters the dynamic behavior of β-secretase, the enzyme responsible for the initial step in the amyloidogenic processing cascade. Conclusions Our multi-compartment model represents a major conceptual advance over single-compartment models previously used to simulate APP processing; and it identified APP dimers and β-secretase as the two distinct targets of the inhibitory action of SORLA in Alzheimer’s disease. PMID:22727043

The Motivational Factor of Erasmus Students at the University

ERIC Educational Resources Information Center

Fombona, Javier; Rodríguez, Celestino; Sevillano, Ángeles Pascual

2013-01-01

This study involved 377 ERASMUS students from the University of Oviedo in an academic year. An ad-hoc questionnaire was applied in on-line format to determine students' perceptions and opinions and to understand the motivations that impel them to participate in these activities and their degree of satisfaction. The study analyzes the process of…

Constraints on Enhanced Extinction Resulting from Extinction Treatment in the Presence of an Added Excitor

ERIC Educational Resources Information Center

Urcelay, Gonzalo P.; Lipatova, Olga; Miller, Ralph R.

2009-01-01

Three Pavlovian fear conditioning experiments with rats as subjects explored the effect of extinction in the presence of a concurrent excitor. Our aim was to explore this particular treatment, documented in previous studies to deepen extinction, with novel control groups to shed light on the processes involved in extinction. Relative to subjects…

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.

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

Zinc and Copper Differentially Modulate Amyloid Precursor Protein Processing by γ-Secretase and Amyloid-β Peptide Production.

PubMed

Gerber, Hermeto; Wu, Fang; Dimitrov, Mitko; Garcia Osuna, Guillermo M; Fraering, Patrick C

2017-03-03

Recent evidence suggests involvement of biometal homeostasis in the pathological mechanisms in Alzheimer's disease (AD). For example, increased intracellular copper or zinc has been linked to a reduction in secreted levels of the AD-causing amyloid-β peptide (Aβ). However, little is known about whether these biometals modulate the generation of Aβ. In the present study we demonstrate in both cell-free and cell-based assays that zinc and copper regulate Aβ production by distinct molecular mechanisms affecting the processing by γ-secretase of its Aβ precursor protein substrate APP-C99. We found that Zn 2+ induces APP-C99 dimerization, which prevents its cleavage by γ-secretase and Aβ production, with an IC 50 value of 15 μm Importantly, at this concentration, Zn 2+ also drastically raised the production of the aggregation-prone Aβ43 found in the senile plaques of AD brains and elevated the Aβ43:Aβ40 ratio, a promising biomarker for neurotoxicity and AD. We further demonstrate that the APP-C99 histidine residues His-6, His-13, and His-14 control the Zn 2+ -dependent APP-C99 dimerization and inhibition of Aβ production, whereas the increased Aβ43:Aβ40 ratio is substrate dimerization-independent and involves the known Zn 2+ binding lysine Lys-28 residue that orientates the APP-C99 transmembrane domain within the lipid bilayer. Unlike zinc, copper inhibited Aβ production by directly targeting the subunits presenilin and nicastrin in the γ-secretase complex. Altogether, our data demonstrate that zinc and copper differentially modulate Aβ production. They further suggest that dimerization of APP-C99 or the specific targeting of individual residues regulating the production of the long, toxic Aβ species, may offer two therapeutic strategies for preventing AD. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

Correlation functions in the D1-D5 orbifold CFT

NASA Astrophysics Data System (ADS)

i Tormo, Joan Garcia; Taylor, Marika

2018-06-01

The D1-D5 system has an orbifold point in its moduli space, at which it may be described by an N = (4,4) supersymmetric sigma model with target space M N /S( N) where M is T^4 or K3. In this paper we consider correlation functions involving chiral operators constructed from twist fields: we find explicit expressions for processes involving a twist n operator joining n twist operators of arbitrary twist. These expressions are universal, in that they are independent of the choice of M , and the final results can be expressed in a compact form. We explain how these results are relevant to the black hole microstate programme: one point functions of chiral operators can be used to reconstruct AdS3 near horizon regions of D1-D5 microstates and to match microstates constructed in supergravity with the CFT.

Altered enzymatic activity and allele frequency of OMI/HTRA2 in Alzheimer's disease

PubMed Central

Westerlund, Marie; Behbahani, Homira; Gellhaar, Sandra; Forsell, Charlotte; Belin, Andrea Carmine; Anvret, Anna; Zettergren, Anna; Nissbrandt, Hans; Lind, Charlotta; Sydow, Olof; Graff, Caroline; Olson, Lars; Ankarcrona, Maria; Galter, Dagmar

2011-01-01

The serine-protease OMI/HTRA2, required for several cellular processes, including mitochondrial function, autophagy, chaperone activity, and apoptosis, has been implicated in the pathogenesis of both Alzheimer's disease (AD) and Parkinson's disease (PD). Western blot quantification of OMI/HTRA2 in frontal cortex of patients with AD (n=10) and control subjects (n=10) in two separate materials indicated reduced processed (active, 35 kDa) OMI/HTRA2 levels, whereas unprocessed (50 kDa) enzyme levels were not significantly different between the groups. Interestingly, the specific protease activity of OMI/HTRA2 was found to be significantly increased in patients with AD (n=10) compared to matched control subjects (n=10) in frontal cortex in two separate materials. Comparison of OMI/HTRA2 mRNA levels in frontal cortex and hippocampus, two brain areas particularly affected by AD, indicated similar levels in patients with AD (n=10) and matched control subjects (n=10). In addition, we analyzed the occurrence of the OMI/HTRA2 variants A141S and G399S in Swedish case-control materials for AD and PD and found a weak association of A141S with AD, but not with PD. In conclusion, our genetic, histological, and biochemical findings give further support to an involvement of OMI/HTRA2 in the pathology of AD; however, further studies are needed to clarify the role of this gene in neurodegeneration.—Westerlund, M., Behbahani, H., Gellhaar, S., Forsell, C., Carmine Belin, A., Anvret, A., Zettergren, A., Nissbrandt, H., Lind, C., Sydow, O., Graff, C., Olson, L., Ankarcrona, M., Galter, D. Altered enzymatic activity and allele frequency of OMI/HTRA2 in Alzheimer's disease. PMID:21163861

Into the Fourth Dimension: Dysregulation of Genome Architecture in Aging and Alzheimer’s Disease

PubMed Central

Winick-Ng, Warren; Rylett, R. Jane

2018-01-01

Alzheimer’s disease (AD) is a progressive neurodegenerative disease characterized by synapse dysfunction and cognitive impairment. Understanding the development and progression of AD is challenging, as the disease is highly complex and multifactorial. Both environmental and genetic factors play a role in AD pathogenesis, highlighted by observations of complex DNA modifications at the single gene level, and by new evidence that also implicates changes in genome architecture in AD patients. The four-dimensional structure of chromatin in space and time is essential for context-dependent regulation of gene expression in post-mitotic neurons. Dysregulation of epigenetic processes have been observed in the aging brain and in patients with AD, though there is not yet agreement on the impact of these changes on transcription. New evidence shows that proteins involved in genome organization have altered expression and localization in the AD brain, suggesting that the genomic landscape may play a critical role in the development of AD. This review discusses the role of the chromatin organizers and epigenetic modifiers in post-mitotic cells, the aging brain, and in the development and progression of AD. How these new insights can be used to help determine disease risk and inform treatment strategies will also be discussed. PMID:29541020

Implicit and Explicit Self-Esteem in Current, Remitted, Recovered, and Comorbid Depression and Anxiety Disorders: The NESDA Study.

PubMed

van Tuijl, Lonneke A; Glashouwer, Klaske A; Bockting, Claudi L H; Tendeiro, Jorge N; Penninx, Brenda W J H; de Jong, Peter J

2016-01-01

Dual processing models of psychopathology emphasize the relevance of differentiating between deliberative self-evaluative processes (explicit self-esteem; ESE) and automatically-elicited affective self-associations (implicit self-esteem; ISE). It has been proposed that both low ESE and ISE would be involved in major depressive disorder (MDD) and anxiety disorders (AD). Further, it has been hypothesized that MDD and AD may result in a low ISE "scar" that may contribute to recurrence after remission. However, the available evidence provides no straightforward support for the relevance of low ISE in MDD/AD, and studies testing the relevance of discrepant SE even showed that especially high ISE combined with low ESE is predictive of the development of internalizing symptoms. However, these earlier findings have been limited by small sample sizes, poorly defined groups in terms of comorbidity and phase of the disorders, and by using inadequate indices of discrepant SE. Therefore, this study tested further the proposed role of ISE and discrepant SE in a large-scale study allowing for stricter differentiation between groups and phase of disorder. In the context of the Netherlands Study of Depression and Anxiety (NESDA), we selected participants with current MDD (n = 60), AD (n = 111), and comorbid MDD/AD (n = 71), remitted MDD (n = 41), AD (n = 29), and comorbid MDD/AD (n = 14), recovered MDD (n = 136) and AD (n = 98), and never MDD or AD controls (n = 382). The Implicit Association Test was used to index ISE and the Rosenberg Self-Esteem Scale indexed ESE. Controls reported higher ESE than all other groups, and current comorbid MDD/AD had lower ESE than all other clinical groups. ISE was only lower than controls in current comorbid AD/MDD. Discrepant self-esteem (difference between ISE and ESE) was not associated with disorder status once controlling for ESE. Cross-sectional design limits causal inferences. Findings suggest a prominent role for ESE in MDD and AD, while in comorbid MDD/AD negative self-evaluations are also present at the implicit level. There was no evidence to support the view that AD and MDD would result in a low ISE "scar".

Decellularized silk fibroin scaffold primed with adipose mesenchymal stromal cells improves wound healing in diabetic mice

PubMed Central

2014-01-01

Introduction Silk fibroin (SF) scaffolds have been shown to be a suitable substrate for tissue engineering and to improve tissue regeneration when cellularized with mesenchymal stromal cells (MSCs). We here demonstrate, for the first time, that electrospun nanofibrous SF patches cellularized with human adipose-derived MSCs (Ad-MSCs-SF), or decellularized (D-Ad-MSCs-SF), are effective in the treatment of skin wounds, improving skin regeneration in db/db diabetic mice. Methods The conformational and structural analyses of SF and D-Ad-MSCs-SF patches were performed by scanning electron microscopy, confocal microscopy, Fourier transform infrared spectroscopy and differential scanning calorimetry. Wounds were performed by a 5 mm punch biopsy tool on the mouse’s back. Ad-MSCs-SF and D-Ad-MSCs-SF patches were transplanted and the efficacy of treatments was assessed by measuring the wound closure area, by histological examination and by gene expression profile. We further investigated the in vitro angiogenic properties of Ad-MSCs-SF and D-Ad-MSCs-SF patches by affecting migration of human umbilical vein endothelial cells (HUVECs), keratinocytes (KCs) and dermal fibroblasts (DFs), through the aortic ring assay and, finally, by evaluating the release of angiogenic factors. Results We found that Ad-MSCs adhere and grow on SF, maintaining their phenotypic mesenchymal profile and differentiation capacity. Conformational and structural analyses on SF and D-Ad-MSCs-SF samples, showed that sterilization, decellularization, freezing and storing did not affect the SF structure. When grafted in wounds of diabetic mice, both Ad-MSCs-SF and D-Ad-MSCs-SF significantly improved tissue regeneration, reducing the wound area respectively by 40% and 35%, within three days, completing the process in around 10 days compared to 15–17 days of controls. RT2 gene profile analysis of the wounds treated with Ad-MSCs-SF and D-Ad-MSCs-SF showed an increment of genes involved in angiogenesis and matrix remodeling. Finally, Ad-MSCs-SF and D-Ad-MSCs-SF co-cultured with HUVECs, DFs and KCs, preferentially enhanced the HUVECs’ migration and the release of angiogenic factors stimulating microvessel outgrowth in the aortic ring assay. Conclusions Our results highlight for the first time that D-Ad-MSCs-SF patches are almost as effective as Ad-MSCs-SF patches in the treatment of diabetic wounds, acting through a complex mechanism that involves stimulation of angiogenesis. Our data suggest a potential use of D-Ad-MSCs-SF patches in chronic diabetic ulcers in humans. PMID:24423450

Decellularized silk fibroin scaffold primed with adipose mesenchymal stromal cells improves wound healing in diabetic mice.

PubMed

Navone, Stefania Elena; Pascucci, Luisa; Dossena, Marta; Ferri, Anna; Invernici, Gloria; Acerbi, Francesco; Cristini, Silvia; Bedini, Gloria; Tosetti, Valentina; Ceserani, Valentina; Bonomi, Arianna; Pessina, Augusto; Freddi, Giuliano; Alessandrino, Antonio; Ceccarelli, Piero; Campanella, Rolando; Marfia, Giovanni; Alessandri, Giulio; Parati, Eugenio Agostino

2014-01-14

Silk fibroin (SF) scaffolds have been shown to be a suitable substrate for tissue engineering and to improve tissue regeneration when cellularized with mesenchymal stromal cells (MSCs). We here demonstrate, for the first time, that electrospun nanofibrous SF patches cellularized with human adipose-derived MSCs (Ad-MSCs-SF), or decellularized (D-Ad-MSCs-SF), are effective in the treatment of skin wounds, improving skin regeneration in db/db diabetic mice. The conformational and structural analyses of SF and D-Ad-MSCs-SF patches were performed by scanning electron microscopy, confocal microscopy, Fourier transform infrared spectroscopy and differential scanning calorimetry. Wounds were performed by a 5 mm punch biopsy tool on the mouse's back. Ad-MSCs-SF and D-Ad-MSCs-SF patches were transplanted and the efficacy of treatments was assessed by measuring the wound closure area, by histological examination and by gene expression profile. We further investigated the in vitro angiogenic properties of Ad-MSCs-SF and D-Ad-MSCs-SF patches by affecting migration of human umbilical vein endothelial cells (HUVECs), keratinocytes (KCs) and dermal fibroblasts (DFs), through the aortic ring assay and, finally, by evaluating the release of angiogenic factors. We found that Ad-MSCs adhere and grow on SF, maintaining their phenotypic mesenchymal profile and differentiation capacity. Conformational and structural analyses on SF and D-Ad-MSCs-SF samples, showed that sterilization, decellularization, freezing and storing did not affect the SF structure. When grafted in wounds of diabetic mice, both Ad-MSCs-SF and D-Ad-MSCs-SF significantly improved tissue regeneration, reducing the wound area respectively by 40% and 35%, within three days, completing the process in around 10 days compared to 15-17 days of controls. RT2 gene profile analysis of the wounds treated with Ad-MSCs-SF and D-Ad-MSCs-SF showed an increment of genes involved in angiogenesis and matrix remodeling. Finally, Ad-MSCs-SF and D-Ad-MSCs-SF co-cultured with HUVECs, DFs and KCs, preferentially enhanced the HUVECs' migration and the release of angiogenic factors stimulating microvessel outgrowth in the aortic ring assay. Our results highlight for the first time that D-Ad-MSCs-SF patches are almost as effective as Ad-MSCs-SF patches in the treatment of diabetic wounds, acting through a complex mechanism that involves stimulation of angiogenesis. Our data suggest a potential use of D-Ad-MSCs-SF patches in chronic diabetic ulcers in humans.

Disruption of Semantic Network in Mild Alzheimer's Disease Revealed by Resting-State fMRI.

PubMed

Mascali, Daniele; DiNuzzo, Mauro; Serra, Laura; Mangia, Silvia; Maraviglia, Bruno; Bozzali, Marco; Giove, Federico

2018-02-10

Subtle semantic deficits can be observed in Alzheimer's disease (AD) patients even in the early stages of the illness. In this work, we tested the hypothesis that the semantic control network is deregulated in mild AD patients. We assessed the integrity of the semantic control system using resting-state functional magnetic resonance imaging in a cohort of patients with mild AD (n = 38; mean mini-mental state examination = 20.5) and in a group of age-matched healthy controls (n = 19). Voxel-wise analysis spatially constrained in the left fronto-temporal semantic control network identified two regions with altered functional connectivity (FC) in AD patients, specifically in the pars opercularis (POp, BA44) and in the posterior middle temporal gyrus (pMTG, BA21). Using whole-brain seed-based analysis, we demonstrated that these two regions have altered FC even beyond the semantic control network. In particular, the pMTG displayed a wide-distributed pattern of lower connectivity to several brain regions involved in language-semantic processing, along with a possibly compensatory higher connectivity to the Wernicke's area. We conclude that in mild AD brain regions belonging to the semantic control network are abnormally connected not only within the network, but also to other areas known to be critical for language processing. Copyright © 2017 The Author(s). Published by Elsevier Ltd.. All rights reserved.

Impact of Animated Spokes-Characters in Print Direct-to-Consumer Prescription Drug Advertising: An Elaboration Likelihood Model Approach.

PubMed

Bhutada, Nilesh S; Rollins, Brent L; Perri, Matthew

2017-04-01

A randomized, posttest-only online survey study of adult U.S. consumers determined the advertising effectiveness (attitude toward ad, brand, company, spokes-characters, attention paid to the ad, drug inquiry intention, and perceived product risk) of animated spokes-characters in print direct-to-consumer (DTC) advertising of prescription drugs and the moderating effects of consumers' involvement. Consumers' responses (n = 490) were recorded for animated versus nonanimated (human) spokes-characters in a fictitious DTC ad. Guided by the elaboration likelihood model, data were analyzed using a 2 (spokes-character type: animated/human) × 2 (involvement: high/low) factorial multivariate analysis of covariance (MANCOVA). The MANCOVA indicated significant main effects of spokes-character type and involvement on the dependent variables after controlling for covariate effects. Of the several ad effectiveness variables, consumers only differed on their attitude toward the spokes-characters between the two spokes-character types (specifically, more favorable attitudes toward the human spokes-character). Apart from perceived product risk, high-involvement consumers reacted more favorably to the remaining ad effectiveness variables compared to the low-involvement consumers, and exhibited significantly stronger drug inquiry intentions during their next doctor visit. Further, the moderating effect of consumers' involvement was not observed (nonsignificant interaction effect between spokes-character type and involvement).

Age Drives Distortion of Brain Metabolic, Vascular and Cognitive Functions, and the Gut Microbiome

PubMed Central

Hoffman, Jared D.; Parikh, Ishita; Green, Stefan J.; Chlipala, George; Mohney, Robert P.; Keaton, Mignon; Bauer, Bjoern; Hartz, Anika M. S.; Lin, Ai-Ling

2017-01-01

Advancing age is the top risk factor for the development of neurodegenerative disorders, including Alzheimer’s disease (AD). However, the contribution of aging processes to AD etiology remains unclear. Emerging evidence shows that reduced brain metabolic and vascular functions occur decades before the onset of cognitive impairments, and these reductions are highly associated with low-grade, chronic inflammation developed in the brain over time. Interestingly, recent findings suggest that the gut microbiota may also play a critical role in modulating immune responses in the brain via the brain-gut axis. In this study, our goal was to identify associations between deleterious changes in brain metabolism, cerebral blood flow (CBF), gut microbiome and cognition in aging, and potential implications for AD development. We conducted our study with a group of young mice (5–6 months of age) and compared those to old mice (18–20 months of age) by utilizing metabolic profiling, neuroimaging, gut microbiome analysis, behavioral assessments and biochemical assays. We found that compared to young mice, old mice had significantly increased levels of numerous amino acids and fatty acids that are highly associated with inflammation and AD biomarkers. In the gut microbiome analyses, we found that old mice had increased Firmicutes/Bacteroidetes ratio and alpha diversity. We also found impaired blood-brain barrier (BBB) function and reduced CBF as well as compromised learning and memory and increased anxiety, clinical symptoms often seen in AD patients, in old mice. Our study suggests that the aging process involves deleterious changes in brain metabolic, vascular and cognitive functions, and gut microbiome structure and diversity, all which may lead to inflammation and thus increase the risk for AD. Future studies conducting comprehensive and integrative characterization of brain aging, including crosstalk with peripheral systems and factors, will be necessary to define the mechanisms underlying the shift from normal aging to pathological processes in the etiology of AD. PMID:28993728

Updating working memory in aircraft noise and speech noise causes different fMRI activations.

PubMed

Saetrevik, Bjørn; Sörqvist, Patrik

2015-02-01

The present study used fMRI/BOLD neuroimaging to investigate how visual-verbal working memory is updated when exposed to three different background-noise conditions: speech noise, aircraft noise and silence. The number-updating task that was used can distinguish between "substitution processes," which involve adding new items to the working memory representation and suppressing old items, and "exclusion processes," which involve rejecting new items and maintaining an intact memory set. The current findings supported the findings of a previous study by showing that substitution activated the dorsolateral prefrontal cortex, the posterior medial frontal cortex and the parietal lobes, whereas exclusion activated the anterior medial frontal cortex. Moreover, the prefrontal cortex was activated more by substitution processes when exposed to background speech than when exposed to aircraft noise. These results indicate that (a) the prefrontal cortex plays a special role when task-irrelevant materials should be denied access to working memory and (b) that, when compensating for different types of noise, either different cognitive mechanisms are involved or those cognitive mechanisms that are involved are involved to different degrees. © 2014 The Authors. Scandinavian Journal of Psychology published by Scandinavian Psychological Associations and John Wiley & Sons Ltd.

Two step novel hydrogen system using additives to enhance hydrogen release from the hydrolysis of alane and activated aluminum

DOEpatents

Zidan, Ragaiy; Teprovich, Joseph A.; Motyka, Theodore

2015-12-01

A system for the generation of hydrogen for use in portable power systems is set forth utilizing a two-step process that involves the thermal decomposition of AlH.sub.3 (10 wt % H.sub.2) followed by the hydrolysis of the activated aluminum (Al*) byproduct to release additional H.sub.2. Additionally, a process in which water is added directly without prior history to the AlH.sub.3:PA composite is also disclosed.

Loops in AdS from conformal field theory

DOE PAGES

Aharony, Ofer; Alday, Luis F.; Bissi, Agnese; ...

2017-07-10

We propose and demonstrate a new use for conformal field theory (CFT) crossing equations in the context of AdS/CFT: the computation of loop amplitudes in AdS, dual to non-planar correlators in holographic CFTs. Loops in AdS are largely unexplored, mostly due to technical difficulties in direct calculations. We revisit this problem, and the dual 1=N expansion of CFTs, in two independent ways. The first is to show how to explicitly solve the crossing equations to the first subleading order in 1=N 2, given a leading order solution. This is done as a systematic expansion in inverse powers of the spin, to all orders. These expansions can be resummed, leading to the CFT data for nite values of the spin. Our second approach involves Mellin space. We show how the polar part of the four-point, loop-level Mellin amplitudes can be fully reconstructed from the leading-order data. The anomalous dimensions computed with both methods agree. In the case ofmore » $$\\phi$$ 4 theory in AdS, our crossing solution reproduces a previous computation of the one-loop bubble diagram. We can go further, deriving the four-point scalar triangle diagram in AdS, which had never been computed. In the process, we show how to analytically derive anomalous dimensions from Mellin amplitudes with an in nite series of poles, and discuss applications to more complicated cases such as the N = 4 super-Yang-Mills theory.« less

Loops in AdS from conformal field theory

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

Aharony, Ofer; Alday, Luis F.; Bissi, Agnese

We propose and demonstrate a new use for conformal field theory (CFT) crossing equations in the context of AdS/CFT: the computation of loop amplitudes in AdS, dual to non-planar correlators in holographic CFTs. Loops in AdS are largely unexplored, mostly due to technical difficulties in direct calculations. We revisit this problem, and the dual 1=N expansion of CFTs, in two independent ways. The first is to show how to explicitly solve the crossing equations to the first subleading order in 1=N 2, given a leading order solution. This is done as a systematic expansion in inverse powers of the spin, to all orders. These expansions can be resummed, leading to the CFT data for nite values of the spin. Our second approach involves Mellin space. We show how the polar part of the four-point, loop-level Mellin amplitudes can be fully reconstructed from the leading-order data. The anomalous dimensions computed with both methods agree. In the case ofmore » $$\\phi$$ 4 theory in AdS, our crossing solution reproduces a previous computation of the one-loop bubble diagram. We can go further, deriving the four-point scalar triangle diagram in AdS, which had never been computed. In the process, we show how to analytically derive anomalous dimensions from Mellin amplitudes with an in nite series of poles, and discuss applications to more complicated cases such as the N = 4 super-Yang-Mills theory.« less

Loops in AdS from conformal field theory

NASA Astrophysics Data System (ADS)

Aharony, Ofer; Alday, Luis F.; Bissi, Agnese; Perlmutter, Eric

2017-07-01

We propose and demonstrate a new use for conformal field theory (CFT) crossing equations in the context of AdS/CFT: the computation of loop amplitudes in AdS, dual to non-planar correlators in holographic CFTs. Loops in AdS are largely unexplored, mostly due to technical difficulties in direct calculations. We revisit this problem, and the dual 1 /N expansion of CFTs, in two independent ways. The first is to show how to explicitly solve the crossing equations to the first subleading order in 1 /N 2, given a leading order solution. This is done as a systematic expansion in inverse powers of the spin, to all orders. These expansions can be resummed, leading to the CFT data for finite values of the spin. Our second approach involves Mellin space. We show how the polar part of the four-point, loop-level Mellin amplitudes can be fully reconstructed from the leading-order data. The anomalous dimensions computed with both methods agree. In the case of ϕ 4 theory in AdS, our crossing solution reproduces a previous computation of the one-loop bubble diagram. We can go further, deriving the four-point scalar triangle diagram in AdS, which had never been computed. In the process, we show how to analytically derive anomalous dimensions from Mellin amplitudes with an infinite series of poles, and discuss applications to more complicated cases such as the N = 4 super-Yang-Mills theory.

Analysing the mechanisms of sludge digestion enhanced by iron.

PubMed

Hao, Xiaodi; Wei, Jing; van Loosdrecht, Mark C M; Cao, Daqi

2017-06-15

Carbon-neutral operation of wastewater treatment plants (WWTPs) requires enhancing anaerobic digestion (AD) of excess sludge for a higher energy conversion efficiency. Among others, iron has been identified to function on enhancing methane production in AD. As an industrial residual, waste iron scraps (WISs) have been reported as potentially enhancing CH 4 production in AD. With this study, the mechanisms of AD enhanced by WISs are analysed in a two-phase process: acidogenic phase (AP) and methanogenic phase (MP). Semi-continuous tests substantially excluded ORP reduction and hydrogen-evolution corrosion induced by WISs in enhancing CH 4 production, although WISs (10 g Fe/L) could indeed increase CH 4 production by 10.1% and 21.4% when added in AP and MP respectively. Detection on both FISH and enzymatic activities of involved microorganisms revealed that the stimulating effects of WISs on anaerobes (both catabolism and anabolism) could play an important (96.3%) role in enhancing CH 4 production, which would facilitate hydrolysis of refractory organics and improvement of electron transport rate (ETR). Copyright © 2017 Elsevier Ltd. All rights reserved.

Globular adiponectin induces a pro-inflammatory response in human astrocytic cells

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

Wan, Zhongxiao; Mah, Dorrian; Simtchouk, Svetlana

Highlights: • Adiponectin receptors are expressed in human astrocytes. • Globular adiponectin induces secretion of IL-6 and MCP-1 from cultured astrocytes. • Adiponectin may play a pro-inflammatory role in astrocytes. - Abstract: Neuroinflammation, mediated in part by activated brain astrocytes, plays a critical role in the development of neurodegenerative disorders, including Alzheimer’s disease (AD). Adiponectin is the most abundant adipokine secreted from adipose tissue and has been reported to exert both anti- and pro-inflammatory effects in peripheral tissues; however, the effects of adiponectin on astrocytes remain unknown. Shifts in peripheral concentrations of adipokines, including adiponectin, could contribute to the observedmore » link between midlife adiposity and increased AD risk. The aim of the present study was to characterize the effects of globular adiponectin (gAd) on pro-inflammatory cytokine mRNA expression and secretion in human U373 MG astrocytic cells and to explore the potential involvement of nuclear factor (NF)-κB, p38 mitogen-activated protein kinase (MAPK), extracellular signal-regulated kinase (ERK)1/2, c-Jun N-terminal kinase (JNK) and phosphatidylinositide 3-kinases (PI3 K) signaling pathways in these processes. We demonstrated expression of adiponectin receptor 1 (adipoR1) and adipoR2 in U373 MG cells and primary human astrocytes. gAd induced secretion of interleukin (IL)-6 and monocyte chemoattractant protein (MCP)-1, and gene expression of IL-6, MCP-1, IL-1β and IL-8 in U373 MG cells. Using specific inhibitors, we found that NF-κB, p38MAPK and ERK1/2 pathways are involved in gAd-induced induction of cytokines with ERK1/2 contributing the most. These findings provide evidence that gAd may induce a pro-inflammatory phenotype in human astrocytes.« less

Phospho-Tau Accumulation and Structural Alterations of the Golgi Apparatus of Cortical Pyramidal Neurons in the P301S Tauopathy Mouse Model

PubMed Central

Antón-Fernández, Alejandro; Merchán-Rubira, Jesús; Avila, Jesús; Hernández, Félix; DeFelipe, Javier; Muñoz, Alberto

2017-01-01

The Golgi apparatus (GA) is a highly dynamic organelle involved in the processing and sorting of cellular proteins. In Alzheimer’s disease (AD), it has been shown to decrease in size and become fragmented in neocortical and hippocampal neuronal subpopulations. This fragmentation and decrease in size of the GA in AD has been related to the accumulation of hyperphosphorylated tau. However, the involvement of other pathological factors associated with the course of the disease, such as the extracellular accumulation of amyloid-β (Aβ) aggregates, cannot be ruled out, since both pathologies are present in AD patients. Here we use the P301S tauopathy mouse model to examine possible alterations of the GA in neurons that overexpress human tau (P301S mutated gene) in neocortical and hippocampal neurons, using double immunofluorescence techniques and confocal microscopy. Quantitative analysis revealed that neurofibrillary tangle (NFT)-bearing neurons had important morphological alterations and reductions in the surface area and volume of the GA compared with NFT-free neurons. Since in this mouse model there are no Aβ aggregates typical of AD, the present findings support the idea that the progressive accumulation of phospho-tau is associated with structural alterations of the GA, and that these changes may occur in the absence of Aβ pathology. PMID:28922155

Phospho-Tau Accumulation and Structural Alterations of the Golgi Apparatus of Cortical Pyramidal Neurons in the P301S Tauopathy Mouse Model.

PubMed

Antón-Fernández, Alejandro; Merchán-Rubira, Jesús; Avila, Jesús; Hernández, Félix; DeFelipe, Javier; Muñoz, Alberto

2017-01-01

The Golgi apparatus (GA) is a highly dynamic organelle involved in the processing and sorting of cellular proteins. In Alzheimer's disease (AD), it has been shown to decrease in size and become fragmented in neocortical and hippocampal neuronal subpopulations. This fragmentation and decrease in size of the GA in AD has been related to the accumulation of hyperphosphorylated tau. However, the involvement of other pathological factors associated with the course of the disease, such as the extracellular accumulation of amyloid-β (Aβ) aggregates, cannot be ruled out, since both pathologies are present in AD patients. Here we use the P301S tauopathy mouse model to examine possible alterations of the GA in neurons that overexpress human tau (P301S mutated gene) in neocortical and hippocampal neurons, using double immunofluorescence techniques and confocal microscopy. Quantitative analysis revealed that neurofibrillary tangle (NFT)-bearing neurons had important morphological alterations and reductions in the surface area and volume of the GA compared with NFT-free neurons. Since in this mouse model there are no Aβ aggregates typical of AD, the present findings support the idea that the progressive accumulation of phospho-tau is associated with structural alterations of the GA, and that these changes may occur in the absence of Aβ pathology.

New evidence about the relationship between water channel activity and calcium in salinity-stressed pepper plants.

PubMed

Cabañero, Francisco J; Martínez-Ballesta, M Carmen; Teruel, José A; Carvajal, Micaela

2006-02-01

This study, of how Ca2+ availability (intracellular, extracellular or linked to the membrane) influences the functionality of aquaporins of pepper (Capsicum annuum L.) plants grown under salinity stress, was carried out in plants treated with NaCl (50 mM), CaCl2 (10 mM), and CaCl2 (10 mM) + NaCl (50 mM). For this, water transport through the plasma membrane of isolated protoplasts, and the involvement of aquaporins and calcium (extracellular, intracellular and linked to the membrane) has been determined. After these treatments, it could be seen that the calcium concentration was reduced in the apoplast, in the cells and on the plasma membrane of roots of pepper plants grown under saline conditions; these concentrations were increased or restored when extra calcium was added to the nutrient solution. Protoplasts extracted from plants grown under Ca2+ starvation showed no aquaporin functionality. However, for the protoplasts to which calcium was added, an increase of aquaporin functionality of the plasma membrane was observed [osmotic water permeability (Pf) inhibition after Hg addition]. Interestingly, when verapamil (a Ca2+ channel blocker) was added, no functionality was observed, even when Ca2+ was added with verapamil. Therefore, calcium seems to be involved in plasma membrane aquaporin regulation via a chain of processes within the cell but not by alteration of the stability of the plasma membrane.

Asymmetric Distribution of GFAP in Glioma Multipotent Cells

PubMed Central

Guichet, Pierre-Olivier; Guelfi, Sophie; Ripoll, Chantal; Teigell, Marisa; Sabourin, Jean-Charles; Bauchet, Luc; Rigau, Valérie; Rothhut, Bernard; Hugnot, Jean-Philippe

2016-01-01

Asymmetric division (AD) is a fundamental mechanism whereby unequal inheritance of various cellular compounds during mitosis generates unequal fate in the two daughter cells. Unequal repartitions of transcription factors, receptors as well as mRNA have been abundantly described in AD. In contrast, the involvement of intermediate filaments in this process is still largely unknown. AD occurs in stem cells during development but was also recently observed in cancer stem cells. Here, we demonstrate the asymmetric distribution of the main astrocytic intermediate filament, namely the glial fibrillary acid protein (GFAP), in mitotic glioma multipotent cells isolated from glioblastoma (GBM), the most frequent type of brain tumor. Unequal mitotic repartition of GFAP was also observed in mice non-tumoral neural stem cells indicating that this process occurs across species and is not restricted to cancerous cells. Immunofluorescence and videomicroscopy were used to capture these rare and transient events. Considering the role of intermediate filaments in cytoplasm organization and cell signaling, we propose that asymmetric distribution of GFAP could possibly participate in the regulation of normal and cancerous neural stem cell fate. PMID:26953813

Abnormal functional connectivity of hippocampus during episodic memory retrieval processing network in amnestic mild cognitive impairment.

PubMed

Bai, Feng; Zhang, Zhijun; Watson, David R; Yu, Hui; Shi, Yongmei; Yuan, Yonggui; Zang, Yufeng; Zhu, Chaozhe; Qian, Yun

2009-06-01

Functional connectivity magnetic resonance imaging technique has revealed the importance of distributed network structures in higher cognitive processes in the human brain. The hippocampus has a key role in a distributed network supporting memory encoding and retrieval. Hippocampal dysfunction is a recurrent finding in memory disorders of aging such as amnestic mild cognitive impairment (aMCI) in which learning- and memory-related cognitive abilities are the predominant impairment. The functional connectivity method provides a novel approach in our attempts to better understand the changes occurring in this structure in aMCI patients. Functional connectivity analysis was used to examine episodic memory retrieval networks in vivo in twenty 28 aMCI patients and 23 well-matched control subjects, specifically between the hippocampal structures and other brain regions. Compared with control subjects, aMCI patients showed significantly lower hippocampus functional connectivity in a network involving prefrontal lobe, temporal lobe, parietal lobe, and cerebellum, and higher functional connectivity to more diffuse areas of the brain than normal aging control subjects. In addition, those regions associated with increased functional connectivity with the hippocampus demonstrated a significantly negative correlation to episodic memory performance. aMCI patients displayed altered patterns of functional connectivity during memory retrieval. The degree of this disturbance appears to be related to level of impairment of processes involved in memory function. Because aMCI is a putative prodromal syndrome to Alzheimer's disease (AD), these early changes in functional connectivity involving the hippocampus may yield important new data to predict whether a patient will eventually develop AD.

Intracellular APP Domain Regulates Serine-Palmitoyl-CoA Transferase Expression and Is Affected in Alzheimer's Disease

PubMed Central

Grimm, Marcus O. W.; Grösgen, Sven; Rothhaar, Tatjana L.; Burg, Verena K.; Hundsdörfer, Benjamin; Haupenthal, Viola J.; Friess, Petra; Müller, Ulrike; Fassbender, Klaus; Riemenschneider, Matthias; Grimm, Heike S.; Hartmann, Tobias

2011-01-01

Lipids play an important role as risk or protective factors in Alzheimer's disease (AD), a disease biochemically characterized by the accumulation of amyloid beta peptides (Aβ), released by proteolytic processing of the amyloid precursor protein (APP). Changes in sphingolipid metabolism have been associated to the development of AD. The key enzyme in sphingolipid de novo synthesis is serine-palmitoyl-CoA transferase (SPT). In the present study we identified a new physiological function of APP in sphingolipid synthesis. The APP intracellular domain (AICD) was found to decrease the expression of the SPT subunit SPTLC2, the catalytic subunit of the SPT heterodimer, resulting in that decreased SPT activity. AICD function was dependent on Fe65 and SPTLC2 levels are increased in APP knock-in mice missing a functional AICD domain. SPTLC2 levels are also increased in familial and sporadic AD postmortem brains, suggesting that SPT is involved in AD pathology. PMID:21660213

False Recognition in Behavioral Variant Frontotemporal Dementia and Alzheimer's Disease-Disinhibition or Amnesia?

PubMed

Flanagan, Emma C; Wong, Stephanie; Dutt, Aparna; Tu, Sicong; Bertoux, Maxime; Irish, Muireann; Piguet, Olivier; Rao, Sulakshana; Hodges, John R; Ghosh, Amitabha; Hornberger, Michael

2016-01-01

Episodic memory recall processes in Alzheimer's disease (AD) and behavioral variant frontotemporal dementia (bvFTD) can be similarly impaired, whereas recognition performance is more variable. A potential reason for this variability could be false-positive errors made on recognition trials and whether these errors are due to amnesia per se or a general over-endorsement of recognition items regardless of memory. The current study addressed this issue by analysing recognition performance on the Rey Auditory Verbal Learning Test (RAVLT) in 39 bvFTD, 77 AD and 61 control participants from two centers (India, Australia), as well as disinhibition assessed using the Hayling test. Whereas both AD and bvFTD patients were comparably impaired on delayed recall, bvFTD patients showed intact recognition performance in terms of the number of correct hits. However, both patient groups endorsed significantly more false-positives than controls, and bvFTD and AD patients scored equally poorly on a sensitivity index (correct hits-false-positives). Furthermore, measures of disinhibition were significantly associated with false positives in both groups, with a stronger relationship with false-positives in bvFTD. Voxel-based morphometry analyses revealed similar neural correlates of false positive endorsement across bvFTD and AD, with both patient groups showing involvement of prefrontal and Papez circuitry regions, such as medial temporal and thalamic regions, and a DTI analysis detected an emerging but non-significant trend between false positives and decreased fornix integrity in bvFTD only. These findings suggest that false-positive errors on recognition tests relate to similar mechanisms in bvFTD and AD, reflecting deficits in episodic memory processes and disinhibition. These findings highlight that current memory tests are not sufficient to accurately distinguish between bvFTD and AD patients.

Can zebrafish be used as animal model to study Alzheimer's disease?

PubMed Central

Santana, Soraya; Rico, Eduardo P; Burgos, Javier S

2012-01-01

Zebrafish is rapidly emerging as a promising model organism to study various central nervous system (CNS) disorders, including Alzheimer’s disease (AD). AD is the main cause of dementia in the human population and there is an urgency to understand the causes of this neurodegenerative disease. In this respect, the development of new animal models to study the underlying neurodegenerative mechanisms of AD is an urgent need. In this review we analyze the current situation in the use of zebrafish as a model for AD, discussing the reasons to use this experimental paradigm in CNS investigation and analyzing the several strategies adopted to induce an AD-like pathology in zebrafish. We discuss the strategies of performing interventions to cause damage in the zebrafish brain by altering the major neurotransmitter systems (such as cholinergic, glutamatergic or GABAergic circuits). We also analyze the several transgenic zebrafish constructed for the AD study, discussing both the familial-AD models based on APP processing pathway (APP and presenilins) and in the TAU hyperphosphorylation, together with the genes involved in sporadic-AD, as apolipoprotein E. We conclude that zebrafish is in a preliminary stage of development in the AD field, and that the transgenic animals must be improved to use this fish as an optimal model for AD research. Furthermore, a deeper knowledge of the zebrafish brain and a better characterization of the injury caused by alterations in the major neurotransmitter systems are needed. PMID:23383380

Association of Brain DNA methylation in SORL1, ABCA7, HLA-DRB5, SLC24A4, and BIN1 with pathological diagnosis of Alzheimer disease.

PubMed

Yu, Lei; Chibnik, Lori B; Srivastava, Gyan P; Pochet, Nathalie; Yang, Jingyun; Xu, Jishu; Kozubek, James; Obholzer, Nikolaus; Leurgans, Sue E; Schneider, Julie A; Meissner, Alexander; De Jager, Philip L; Bennett, David A

2015-01-01

Recent large-scale genome-wide association studies have discovered several genetic variants associated with Alzheimer disease (AD); however, the extent to which DNA methylation in these AD loci contributes to the disease susceptibility remains unknown. To examine the association of brain DNA methylation in 28 reported AD loci with AD pathologies. Ongoing community-based clinical pathological cohort studies of aging and dementia (the Religious Orders Study and the Rush Memory and Aging Project) among 740 autopsied participants 66.0 to 108.3 years old. DNA methylation levels at individual CpG sites generated from dorsolateral prefrontal cortex tissue using a bead assay. Pathological diagnosis of AD by National Institute on Aging-Reagan criteria following a standard postmortem examination. Overall, 447 participants (60.4%) met the criteria for pathological diagnosis of AD. Brain DNA methylation in SORL1, ABCA7, HLA-DRB5, SLC24A4, and BIN1 was associated with pathological AD. The association was robustly retained after replacing the binary trait of pathological AD with 2 quantitative and molecular specific hallmarks of AD, namely, Aβ load and paired helical filament tau tangle density. Furthermore, RNA expression of transcripts of SORL1 and ABCA7 was associated with paired helical filament tau tangle density, and the expression of BIN1 was associated with Aβ load. Brain DNA methylation in multiple AD loci is associated with AD pathologies. The results provide further evidence that disruption of DNA methylation is involved in the pathological process of AD.

Therapeutic approaches of leptin in Alzheimer's disease.

PubMed

Carro, Eva M

2009-11-01

Novel approaches in the understanding of the neurodegeneration observed in Alzheimer's disease (AD), involving neurochemical as well as biochemical techniques are being developed, opening up new possibilities in the direction of a metabolic degeneration. Indeed, brain lipids are closely involved in amyloid beta-related pathogenic pathways. An important modulator of lipid homeostasis is the pluripotent peptide leptin, which has been shown to reduce amyloid beta levels and tau-related pathological pathways, the major pathological hallmarks of AD. These data suggest that leptin holds promise as a novel therapeutic tool for AD. In this article, with some patent literature we will review here some of the most promising approaches involving leptin to cure and prevent, rather than to treat, AD symptoms.

The effect of types of banner ad, Web localization, and customer involvement on Internet users' attitudes.

PubMed

Chen, Jengchung Victor; Ross, William H; Yen, David C; Akhapon, Lerdsuwankij

2009-02-01

In this study, three characteristics of Web sites were varied: types of banner ad, Web localization, and involvement in purchasing a product. The dependent variable was attitude toward the site. In laboratory experiments conducted in Thailand and Taiwan, participants browsed versions of a Web site containing different types of banner ads and products. As a within-participants factor, each participant browsed both a standardized English-language Web site and a localized Web site. Results showed that animated (rather than static) banner ads, localized versions (rather than a standardized version) of Web sites, and high (rather than low) product involvement led to favorable attitudes toward the site.

Distinct patterns of brain activity evoked by histamine-induced itch reveal an association with itch intensity and disease severity in atopic dermatitis

PubMed Central

Ishiuji, Y.; Coghill, R.C.; Patel, T.S.; Oshiro, Y.; Kraft, R.A.; Yosipovitch, G.

2009-01-01

Summary Background Little is known about brain mechanisms supporting the experience of chronic puritus in disease states. Objectives To examine the difference in brain processing of histamine-induced itch in patients with active atopic dermatitis (AD) vs. healthy controls with the emerging technique of functional magnetic resonance imaging (fMRI) using arterial spin labelling (ASL). Methods Itch was induced with histamine iontophoresis in eight patients with AD and seven healthy subjects. Results We found significant differences in brain processing of histamine-induced itch between patients with AD and healthy subjects. Patients with AD exhibited bilateral activation of the anterior cingulate cortex (ACC), posterior cingulate cortex (PCC), retrosplenial cingulate cortex and dorsolateral prefrontal cortex (DLPFC) as well as contralateral activation of the caudate nucleus and putamen. In contrast, healthy subjects activated the primary motor cortex, primary somatosensory cortex and superior parietal lobe. The PCC and precuneus exhibited significantly greater activity in patients vs. healthy subjects. A significant correlation between percentage changes of brain activation was noted in the activation of the ACC and contralateral insula and histamine-induced itch intensity as well as disease severity in patients with AD. In addition, an association was noted between DLPFC activity and disease severity. Conclusions Our results demonstrate that ASL fMRI is a promising technique to assess brain activity in chronic itch. Brain activity of acute itch in AD seems to differ from that in healthy subjects. Moreover, the activity in cortical areas involved in affect and emotion correlated to measures of disease severity. PMID:19663870

Neuroinflammation in Alzheimer's Disease: The Preventive and Therapeutic Potential of Polyphenolic Nutraceuticals.

PubMed

Sawikr, Yousef; Yarla, Nagendra Sastry; Peluso, Ilaria; Kamal, Mohammad Amjad; Aliev, Gjumrakch; Bishayee, Anupam

2017-01-01

Brain inflammation, characterized by increased microglia and astrocyte activation, increases during aging and is a key feature of neurodegenerative diseases, such as Alzheimer's disease (AD). In AD, neuronal death and synaptic impairment, induced by amyloid-β (Aβ) peptide, are at least in part mediated by microglia and astrocyte activation. Glial activation results in the sustained production of proinflammatory cytokines and reactive oxygen species, giving rise to a chronic inflammatory process. Astrocytes are the most abundant glial cells in the central nervous system and are involved in the neuroinflammation. Astrocytes can be activated by numerous factors, including free saturated fatty acids, pathogens, lipopolysaccharide, and oxidative stress. Activation of astrocytes produces inflammatory cytokines and the enzyme cyclooxygenase-2, enhancing the production of Aβ. Furthermore, the role of the receptor for advanced glycation end products/nuclear factor-κB (NF-κB) axis in neuroinflammation is in line with the nonenzymatic glycosylation theory of aging, suggesting a central role of the advanced glycation end products in the age-related cognitive and a possible role of nutraceuticals in the prevention of neuroinflammation and AD. However, modulation of P-glycoprotein, rather than antioxidant and anti-inflammatory effects, could be the major mechanism of polyphenolic compounds, including flavonoids. Curcumin, resvertrol, piperine, and other polyphenols have been explored as novel therapeutic and preventive agents for AD. The aim of this review is to critically analyze and discuss the mechanisms involved in neuroinflammation and the possible role of nutraceuticals in the prevention and therapy of AD by targeting neuroinflammation. © 2017 Elsevier Inc. All rights reserved.

Development of a cleaning process for uranium chips machined with a glycol-water-borax coolant

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

Taylor, P.A.

1984-12-01

A chip-cleaning process has been developed to remove the new glycol-water-borax coolant from oralloy chips. The process involves storing the freshly cut chips in Freon-TDF until they are cleaned, washing with water, and displacing the water with Freon-TDF. The wash water can be reused many times and still yield clean chips and then be added to the coolant to make up for evaporative losses. The Freon-TDF will be cycled by evaporation. The cleaning facility is currently being designed and should be operational by April 1985.

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

PubMed Central

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

2015-01-01

Alzheimer's disease (AD) is characterized by an accumulation of Amyloid-β (Aβ), released by sequential proteolytic processing of the amyloid precursor protein (APP) by β - and γ-secretase. Aβ peptides can aggregate, leading to toxic Aβ oligomers and amyloid plaque formation. Aβ accumulation is not only dependent on de novo synthesis but also on Aβ degradation. Neprilysin (NEP) is one of the major enzymes involved in Aβ degradation. Here we investigate the molecular mechanism of NEP regulation, which is up to now controversially discussed to be affected by APP processing itself. We found that NEP expression is highly dependent on the APP intracellular domain (AICD), released by APP processing. Mouse embryonic fibroblasts devoid of APP processing, either by the lack of the catalytically active subunit of the γ-secretase complex [presenilin (PS) 1/2] or by the lack of APP and the APP-like protein 2 (APLP2), showed a decreased NEP expression, activity and protein level. Similar results were obtained by utilizing cells lacking a functional AICD domain (APPΔCT15) or expressing mutations in the genes encoding for PS1. AICD supplementation or retransfection with an AICD encoding plasmid could rescue the down-regulation of NEP further strengthening the link between AICD and transcriptional NEP regulation, in which Fe65 acts as an important adaptor protein. Especially AICD generated by the amyloidogenic pathway seems to be more involved in the regulation of NEP expression. In line, analysis of NEP gene expression in vivo in six transgenic AD mouse models (APP and APLP2 single knock-outs, APP/APLP2 double knock-out, APP-swedish, APP-swedish/PS1Δexon9, and APPΔCT15) confirmed the results obtained in cell culture. In summary, in the present study we clearly demonstrate an AICD-dependent regulation of the Aβ-degrading enzyme NEP in vitro and in vivo and elucidate the underlying mechanisms that might be beneficial to develop new therapeutic strategies for the treatment of AD. PMID:26074811

Relationship between chronic disturbance of 2,3-diphosphoglycerate metabolism in erythrocytes and Alzheimer disease.

PubMed

Kosenko, Elena A; Aliev, Gjumrakch; Kaminsky, Yury G

2016-01-01

Alzheimer disease (AD) is one of the most common neurodegenerative disorders widely occurring among the elderly. The pathogenic mechanisms involved in the development of this disease are still unknown. In AD, in addition to brain, a number of peripheral tissues and cells are affected, including erythrocytes. In this study, we analyzed glycolytic energy metabolism, antioxidant status, glutathione, adenylate and proteolytic systems in erythrocytes from patients with AD and compared with those from age-matched controls and young adult controls. Glycolytic enzymes hexokinase, phosphofructokinase, bisphosphoglycerate mutase and bisphosphoglycerate phosphatase displayed lower activities in agematched controls, and higher activities in AD patients, as compared to those in young adult control subjects. In both aging and AD, oxidative stress is increased in erythrocytes whereas elevated concentrations of hydrogen peroxide and organic hydroperoxides as well as decreased glutathione/glutathione disulfide ratio and glutathione transferase activity can be detected. These oxidative disturbances are also accompanied by reductions in ATP levels, adenine nucleotide pool size and adenylate energy charge. Caspase-3 and calpain activities in age-matched controls and AD patients were about three times those of young adult controls. 2,3-diphosphoglycerate levels were significantly decreased in AD patients. Taken together these data suggest that AD patients are associated with chronic disturbance of 2,3-diphosphoglycerate metabolism in erythrocytes. These defects may play a central role in pathophysiological processes predisposing elderly subjects to dementia.

The Pathway Coexpression Network: Revealing pathway relationships

PubMed Central

Tanzi, Rudolph E.

2018-01-01

A goal of genomics is to understand the relationships between biological processes. Pathways contribute to functional interplay within biological processes through complex but poorly understood interactions. However, limited functional references for global pathway relationships exist. Pathways from databases such as KEGG and Reactome provide discrete annotations of biological processes. Their relationships are currently either inferred from gene set enrichment within specific experiments, or by simple overlap, linking pathway annotations that have genes in common. Here, we provide a unifying interpretation of functional interaction between pathways by systematically quantifying coexpression between 1,330 canonical pathways from the Molecular Signatures Database (MSigDB) to establish the Pathway Coexpression Network (PCxN). We estimated the correlation between canonical pathways valid in a broad context using a curated collection of 3,207 microarrays from 72 normal human tissues. PCxN accounts for shared genes between annotations to estimate significant correlations between pathways with related functions rather than with similar annotations. We demonstrate that PCxN provides novel insight into mechanisms of complex diseases using an Alzheimer’s Disease (AD) case study. PCxN retrieved pathways significantly correlated with an expert curated AD gene list. These pathways have known associations with AD and were significantly enriched for genes independently associated with AD. As a further step, we show how PCxN complements the results of gene set enrichment methods by revealing relationships between enriched pathways, and by identifying additional highly correlated pathways. PCxN revealed that correlated pathways from an AD expression profiling study include functional clusters involved in cell adhesion and oxidative stress. PCxN provides expanded connections to pathways from the extracellular matrix. PCxN provides a powerful new framework for interrogation of global pathway relationships. Comprehensive exploration of PCxN can be performed at http://pcxn.org/. PMID:29554099

Recognition memory span in autopsy-confirmed Dementia with Lewy Bodies and Alzheimer's Disease.

PubMed

Salmon, David P; Heindel, William C; Hamilton, Joanne M; Vincent Filoteo, J; Cidambi, Varun; Hansen, Lawrence A; Masliah, Eliezer; Galasko, Douglas

2015-08-01

Evidence from patients with amnesia suggests that recognition memory span tasks engage both long-term memory (i.e., secondary memory) processes mediated by the diencephalic-medial temporal lobe memory system and working memory processes mediated by fronto-striatal systems. Thus, the recognition memory span task may be particularly effective for detecting memory deficits in disorders that disrupt both memory systems. The presence of unique pathology in fronto-striatal circuits in Dementia with Lewy Bodies (DLB) compared to AD suggests that performance on the recognition memory span task might be differentially affected in the two disorders even though they have quantitatively similar deficits in secondary memory. In the present study, patients with autopsy-confirmed DLB or AD, and Normal Control (NC) participants, were tested on separate recognition memory span tasks that required them to retain increasing amounts of verbal, spatial, or visual object (i.e., faces) information across trials. Results showed that recognition memory spans for verbal and spatial stimuli, but not face stimuli, were lower in patients with DLB than in those with AD, and more impaired relative to NC performance. This was despite similar deficits in the two patient groups on independent measures of secondary memory such as the total number of words recalled from long-term storage on the Buschke Selective Reminding Test. The disproportionate vulnerability of recognition memory span task performance in DLB compared to AD may be due to greater fronto-striatal involvement in DLB and a corresponding decrement in cooperative interaction between working memory and secondary memory processes. Assessment of recognition memory span may contribute to the ability to distinguish between DLB and AD relatively early in the course of disease. Copyright © 2015 Elsevier Ltd. All rights reserved.

Recognition Memory Span in Autopsy-Confirmed Dementia with Lewy Bodies and Alzheimer’s Disease

PubMed Central

Salmon, David P.; Heindel, William C.; Hamilton, Joanne M.; Filoteo, J. Vincent; Cidambi, Varun; Hansen, Lawrence A.; Masliah, Eliezer; Galasko, Douglas

2016-01-01

Evidence from patients with amnesia suggests that recognition memory span tasks engage both long-term memory (i.e., secondary memory) processes mediated by the diencephalic-medial temporal lobe memory system and working memory processes mediated by fronto-striatal systems. Thus, the recognition memory span task may be particularly effective for detecting memory deficits in disorders that disrupt both memory systems. The presence of unique pathology in fronto-striatal circuits in Dementia with Lewy Bodies (DLB) compared to AD suggests that performance on the recognition memory span task might be differentially affected in the two disorders even though they have quantitatively similar deficits in secondary memory. In the present study, patients with autopsy-confirmed DLB or AD, and normal control (NC) participants, were tested on separate recognition memory span tasks that required them to retain increasing amounts of verbal, spatial, or visual object (i.e., faces) information across trials. Results showed that recognition memory spans for verbal and spatial stimuli, but not face stimuli, were lower in patients with DLB than in those with AD, and more impaired relative to NC performance. This was despite similar deficits in the two patient groups on independent measures of secondary memory such as the total number of words recalled from Long-Term Storage on the Buschke Selective Reminding Test. The disproportionate vulnerability of recognition memory span task performance in DLB compared to AD may be due to greater fronto-striatal involvement in DLB and a corresponding decrement in cooperative interaction between working memory and secondary memory processes. Assessment of recognition memory span may contribute to the ability to distinguish between DLB and AD relatively early in the course of disease. PMID:26184443

Biochemicals from food waste and recalcitrant biomass via syngas fermentation: A review.

PubMed

Wainaina, Steven; Horváth, Ilona Sárvári; Taherzadeh, Mohammad J

2018-01-01

An effective method for the production of value-added chemicals from food waste and lignocellulosic materials is a hybrid thermal-biological process, which involves gasification of the solid materials to syngas (primarily CO and H 2 ) followed by fermentation. This paper reviews the recent advances in this process. The special focus is on the cultivation methods that involve the use of single strains, defined mixed cultures and undefined mixed cultures for production of carboxylic acids and higher alcohols. A rate limiting step in these processes is the low mass transfer between the gas and the liquid phases. Therefore, novel techniques that can enhance the gas-liquid mass transfer including membrane- and trickle-bed bioreactors were discussed. Such bioreactors have shown promising results in increasing the volumetric mass transfer coefficient (k L a). High gas pressure also influences the mass transfer in certain batch processes, although the presence of impurities in the gas would impede the process. Copyright © 2017 Elsevier Ltd. All rights reserved.

Timing in turn-taking and its implications for processing models of language

PubMed Central

Levinson, Stephen C.; Torreira, Francisco

2015-01-01

The core niche for language use is in verbal interaction, involving the rapid exchange of turns at talking. This paper reviews the extensive literature about this system, adding new statistical analyses of behavioral data where they have been missing, demonstrating that turn-taking has the systematic properties originally noted by Sacks et al. (1974; hereafter SSJ). This system poses some significant puzzles for current theories of language processing: the gaps between turns are short (of the order of 200 ms), but the latencies involved in language production are much longer (over 600 ms). This seems to imply that participants in conversation must predict (or ‘project’ as SSJ have it) the end of the current speaker’s turn in order to prepare their response in advance. This in turn implies some overlap between production and comprehension despite their use of common processing resources. Collecting together what is known behaviorally and experimentally about the system, the space for systematic explanations of language processing for conversation can be significantly narrowed, and we sketch some first model of the mental processes involved for the participant preparing to speak next. PMID:26124727

Integrating mRNA and miRNA Weighted Gene Co-Expression Networks with eQTLs in the Nucleus Accumbens of Subjects with Alcohol Dependence

PubMed Central

Blevins, Tana; Aliev, Fazil; Adkins, Amy; Hack, Laura; Bigdeli, Tim; D. van der Vaart, Andrew; Web, Bradley Todd; Bacanu, Silviu-Alin; Kalsi, Gursharan; Kendler, Kenneth S.; Miles, Michael F.; Dick, Danielle; Riley, Brien P.; Dumur, Catherine; Vladimirov, Vladimir I.

2015-01-01

Alcohol consumption is known to lead to gene expression changes in the brain. After performing weighted gene co-expression network analyses (WGCNA) on genome-wide mRNA and microRNA (miRNA) expression in Nucleus Accumbens (NAc) of subjects with alcohol dependence (AD; N = 18) and of matched controls (N = 18), six mRNA and three miRNA modules significantly correlated with AD were identified (Bonferoni-adj. p≤ 0.05). Cell-type-specific transcriptome analyses revealed two of the mRNA modules to be enriched for neuronal specific marker genes and downregulated in AD, whereas the remaining four mRNA modules were enriched for astrocyte and microglial specific marker genes and upregulated in AD. Gene set enrichment analysis demonstrated that neuronal specific modules were enriched for genes involved in oxidative phosphorylation, mitochondrial dysfunction and MAPK signaling. Glial-specific modules were predominantly enriched for genes involved in processes related to immune functions, i.e. cytokine signaling (all adj. p≤ 0.05). In mRNA and miRNA modules, 461 and 25 candidate hub genes were identified, respectively. In contrast to the expected biological functions of miRNAs, correlation analyses between mRNA and miRNA hub genes revealed a higher number of positive than negative correlations (χ2 test p≤ 0.0001). Integration of hub gene expression with genome-wide genotypic data resulted in 591 mRNA cis-eQTLs and 62 miRNA cis-eQTLs. mRNA cis-eQTLs were significantly enriched for AD diagnosis and AD symptom counts (adj. p = 0.014 and p = 0.024, respectively) in AD GWAS signals in a large, independent genetic sample from the Collaborative Study on Genetics of Alcohol (COGA). In conclusion, our study identified putative gene network hubs coordinating mRNA and miRNA co-expression changes in the NAc of AD subjects, and our genetic (cis-eQTL) analysis provides novel insights into the etiological mechanisms of AD. PMID:26381263

Combining high performance simulation, data acquisition, and graphics display computers

NASA Technical Reports Server (NTRS)

Hickman, Robert J.

1989-01-01

Issues involved in the continuing development of an advanced simulation complex are discussed. This approach provides the capability to perform the majority of tests on advanced systems, non-destructively. The controlled test environments can be replicated to examine the response of the systems under test to alternative treatments of the system control design, or test the function and qualification of specific hardware. Field tests verify that the elements simulated in the laboratories are sufficient. The digital computer is hosted by a Digital Equipment Corp. MicroVAX computer with an Aptec Computer Systems Model 24 I/O computer performing the communication function. An Applied Dynamics International AD100 performs the high speed simulation computing and an Evans and Sutherland PS350 performs on-line graphics display. A Scientific Computer Systems SCS40 acts as a high performance FORTRAN program processor to support the complex, by generating numerous large files from programs coded in FORTRAN that are required for the real time processing. Four programming languages are involved in the process, FORTRAN, ADSIM, ADRIO, and STAPLE. FORTRAN is employed on the MicroVAX host to initialize and terminate the simulation runs on the system. The generation of the data files on the SCS40 also is performed with FORTRAN programs. ADSIM and ADIRO are used to program the processing elements of the AD100 and its IOCP processor. STAPLE is used to program the Aptec DIP and DIA processors.

Functional neuroanatomy of sustained memory encoding performance in healthy aging and in Alzheimer's disease.

PubMed

Weis, Susanne; Leube, Dirk; Erb, Michael; Heun, Reinhard; Grodd, Wolfgang; Kircher, Tilo

2011-07-01

The aim of our study was to examine brain networks involved with sustaining memory encoding performance in healthy aging and in Alzheimer's disease (AD). Since different brain regions are affected by degradation in these two conditions, it might be conceivable that different compensation mechanisms occur to keep up memory performance in aging and in AD. Using an event-related functional magnetic resonance imaging (FMRI) design and a correlation analysis, 8 patients suffering from AD and 29 elderly control subjects were scanned while they studied a list of words for a subsequent memory test. Individual performance was assessed on the basis of a subsequent recognition test, and brain regions were identified where functional activations during study correlated with memory performance. In both groups, successful memory encoding performance was significantly correlated with the activation of the right frontal cortex. Furthermore, in healthy controls, there was a significant correlation of memory performance and the activation of the left medial and lateral temporal lobe. In contrast, in AD patients, increasing memory performance goes along with increasing activation of the hippocampus and a bilateral brain network including the frontal and temporal cortices. Our data show that in healthy aging and in AD, common and distinct compensatory mechanisms are employed to keep up a certain level of memory performance. Both in healthy aging and in patients with AD, an increased level of monitoring and control processes mediated by the (right) frontal lobe seems to be necessary to maintain a certain level of memory performance. In addition, memory performance in healthy older subjects seems to rely on an increased effort in encoding item-specific semantic and contextual information in lateral areas of the (left) temporal lobe. In AD patients, on the other hand, the maintenance of memory performance is related to an increase of activation of the (left) hippocampus in conjunction with a bilateral network of cortical areas that might be involved with phonological and visual rehearsal of the incoming information.

A safety review of the medications used to treat atopic dermatitis.

PubMed

Shukla, Shweta; Feldman, Steven R; Strowd, Lindsay C

2018-02-01

Atopic dermatitis (AD) is a common disease in children and adults which causes severe physical discomfort and psychosocial distress. Recently novel therapies for AD have been FDA approved for use which creates the need to review the safety surrounding current FDA approved AD medications. Areas covered: Published clinical studies involving topical and oral FDA approved medications for AD are included in this review. Authors used PubMed research database to search for clinical trials involving AD patients. Expert opinion: AD is a common disease which currently has limited FDA approved medications. Given the chronicity of this disease, medications are needed which control disease while minimizing side effects to allow for long term use. Newer approved medications show promise but safety data is limited given their relatively new utilization for AD.

Metagenome, metatranscriptome, and metaproteome approaches unraveled compositions and functional relationships of microbial communities residing in biogas plants.

PubMed

Hassa, Julia; Maus, Irena; Off, Sandra; Pühler, Alfred; Scherer, Paul; Klocke, Michael; Schlüter, Andreas

2018-06-01

The production of biogas by anaerobic digestion (AD) of agricultural residues, organic wastes, animal excrements, municipal sludge, and energy crops has a firm place in sustainable energy production and bio-economy strategies. Focusing on the microbial community involved in biomass conversion offers the opportunity to control and engineer the biogas process with the objective to optimize its efficiency. Taxonomic profiling of biogas producing communities by means of high-throughput 16S rRNA gene amplicon sequencing provided high-resolution insights into bacterial and archaeal structures of AD assemblages and their linkages to fed substrates and process parameters. Commonly, the bacterial phyla Firmicutes and Bacteroidetes appeared to dominate biogas communities in varying abundances depending on the apparent process conditions. Regarding the community of methanogenic Archaea, their diversity was mainly affected by the nature and composition of the substrates, availability of nutrients and ammonium/ammonia contents, but not by the temperature. It also appeared that a high proportion of 16S rRNA sequences can only be classified on higher taxonomic ranks indicating that many community members and their participation in AD within functional networks are still unknown. Although cultivation-based approaches to isolate microorganisms from biogas fermentation samples yielded hundreds of novel species and strains, this approach intrinsically is limited to the cultivable fraction of the community. To obtain genome sequence information of non-cultivable biogas community members, metagenome sequencing including assembly and binning strategies was highly valuable. Corresponding research has led to the compilation of hundreds of metagenome-assembled genomes (MAGs) frequently representing novel taxa whose metabolism and lifestyle could be reconstructed based on nucleotide sequence information. In contrast to metagenome analyses revealing the genetic potential of microbial communities, metatranscriptome sequencing provided insights into the metabolically active community. Taking advantage of genome sequence information, transcriptional activities were evaluated considering the microorganism's genetic background. Metaproteome studies uncovered enzyme profiles expressed by biogas community members. Enzymes involved in cellulose and hemicellulose decomposition and utilization of other complex biopolymers were identified. Future studies on biogas functional microbial networks will increasingly involve integrated multi-omics analyses evaluating metagenome, transcriptome, proteome, and metabolome datasets.

The Legal System and Alzheimer's Disease: Social Workers and Lawyers' Perceptions and Experiences.

PubMed

Werner, Perla; Doron, Israel Issi

2016-01-01

The expected increase in the number of people living with Alzheimer's disease (AD) worldwide will be accompanied by an increase in the number of cases involving persons with AD brought up to the courts. This study examined the perceptions and experiences of social workers and lawyers regarding these cases. Three focus groups including social workers and lawyers (n = 26) were conducted. Two main themes were raised by the participants: (a) the role of social workers and lawyers in court cases regarding AD, and (b) the need for improving legal encounters involving persons with AD. Similarities and differences were found in both professionals' interpretations of these shared themes. Results of this study emphasize the need for increasing the knowledge and interprofessional training provided to social workers and lawyers involved in legal cases dealing with issues involving persons with Alzheimer's disease.

Entertainment-education and recruitment of cornea donors: the role of emotion and issue involvement.

PubMed

Bae, Hyuhn-Suhck

2008-01-01

This study examined the role of emotional responses and viewer's level of issue involvement to an entertainment-education show about cornea donation in order to predict intention to register as cornea donors. Results confirmed that sympathy and empathy responses operated as a catalyst for issue involvement, which emerged as an important intermediary in the persuasion process. Issue involvement also was found to be a common causal antecedent of attitude, subjective norm, and perceived behavioral control, the last two of which predict intentions unlike attitude, which does not. The revised path model confirmed that involvement directly influences intention. The findings of this study suggest that adding emotion and involvement in the Theory of Planned Behavior (TPB) enhances the explanatory power of the theory in predicting intentions, which indicates the possibility of combining the Elaboration Likelihood Model (ELM) and the TPB in the prediction of human behaviors.

Using Surveillance of Mental Health to Increase Understanding of Youth Involvement in High-Risk Behaviors: A Value-Added Analysis

ERIC Educational Resources Information Center

Dowdy, Erin; Furlong, Michael J.; Sharkey, Jill D.

2013-01-01

This study examined the potential utility of adding items that assessed youths' emotional and behavioral disorders to a commonly used surveillance survey. The goal was to evaluate whether the added items could enhance understanding of youths' involvement in high-risk behaviors. A sample of 3,331 adolescents in Grades 8, 10, and 12 from four…

Implicit and Explicit Self-Esteem in Current, Remitted, Recovered, and Comorbid Depression and Anxiety Disorders: The NESDA Study

PubMed Central

van Tuijl, Lonneke A.; Glashouwer, Klaske A.; Bockting, Claudi L. H.; Tendeiro, Jorge N.; Penninx, Brenda W. J. H.; de Jong, Peter J.

2016-01-01

Background Dual processing models of psychopathology emphasize the relevance of differentiating between deliberative self-evaluative processes (explicit self-esteem; ESE) and automatically-elicited affective self-associations (implicit self-esteem; ISE). It has been proposed that both low ESE and ISE would be involved in major depressive disorder (MDD) and anxiety disorders (AD). Further, it has been hypothesized that MDD and AD may result in a low ISE “scar” that may contribute to recurrence after remission. However, the available evidence provides no straightforward support for the relevance of low ISE in MDD/AD, and studies testing the relevance of discrepant SE even showed that especially high ISE combined with low ESE is predictive of the development of internalizing symptoms. However, these earlier findings have been limited by small sample sizes, poorly defined groups in terms of comorbidity and phase of the disorders, and by using inadequate indices of discrepant SE. Therefore, this study tested further the proposed role of ISE and discrepant SE in a large-scale study allowing for stricter differentiation between groups and phase of disorder. Method In the context of the Netherlands Study of Depression and Anxiety (NESDA), we selected participants with current MDD (n = 60), AD (n = 111), and comorbid MDD/AD (n = 71), remitted MDD (n = 41), AD (n = 29), and comorbid MDD/AD (n = 14), recovered MDD (n = 136) and AD (n = 98), and never MDD or AD controls (n = 382). The Implicit Association Test was used to index ISE and the Rosenberg Self-Esteem Scale indexed ESE. Results Controls reported higher ESE than all other groups, and current comorbid MDD/AD had lower ESE than all other clinical groups. ISE was only lower than controls in current comorbid AD/MDD. Discrepant self-esteem (difference between ISE and ESE) was not associated with disorder status once controlling for ESE. Limitations Cross-sectional design limits causal inferences. Conclusion Findings suggest a prominent role for ESE in MDD and AD, while in comorbid MDD/AD negative self-evaluations are also present at the implicit level. There was no evidence to support the view that AD and MDD would result in a low ISE “scar”. PMID:27846292

Quantitative Balance and Gait Measurement in Patients with Frontotemporal Dementia and Alzheimer Diseases: A Pilot Study.

PubMed

Velayutham, Selva Ganapathy; Chandra, Sadanandavalli Retnaswami; Bharath, Srikala; Shankar, Ravi Girikamatha

2017-01-01

Alzhiemers disease and Frontotemporal dementia are common neurodegenerative dementias with a wide prevalence. Falls are a common cause of morbidity in these patients. Identifying subclinical involvement of these parameters might serve as a tool in differential analysis of these distinct parameters involved in these conditions and also help in planning preventive strategies to prevent falls. Eight patients in age and gender matched patients in each group were compared with normal controls. Standardizes methods of gait and balance aseesment were done in all persons. Results revealed subclinical involvement of gait and balancesin all groups specially during divided attention. The parameters were significantly more affected in patients. Patients with AD and FTD had involement of over all ambulation index balance more affected in AD patients FTD patients showed step cycle, stride length abnormalities. There is balance and gait involvement in normal ageing as well as patients with AD and FTD. The pattern of involvement in AD correlates with WHERE pathway involvement and FTD with frontal subcortical circuits involvement. Identification the differential patterns of involvement in subclinical stage might help to differentiate normal ageing and the different types of cortical dementias. This could serve as an additional biomarker and also assist in initiating appropriate training methods to prevent future falls.

Relating Anaerobic Digestion Microbial Community and Process Function.

PubMed

Venkiteshwaran, Kaushik; Bocher, Benjamin; Maki, James; Zitomer, Daniel

2015-01-01

Anaerobic digestion (AD) involves a consortium of microorganisms that convert substrates into biogas containing methane for renewable energy. The technology has suffered from the perception of being periodically unstable due to limited understanding of the relationship between microbial community structure and function. The emphasis of this review is to describe microbial communities in digesters and quantitative and qualitative relationships between community structure and digester function. Progress has been made in the past few decades to identify key microorganisms influencing AD. Yet, more work is required to realize robust, quantitative relationships between microbial community structure and functions such as methane production rate and resilience after perturbations. Other promising areas of research for improved AD may include methods to increase/control (1) hydrolysis rate, (2) direct interspecies electron transfer to methanogens, (3) community structure-function relationships of methanogens, (4) methanogenesis via acetate oxidation, and (5) bioaugmentation to study community-activity relationships or improve engineered bioprocesses.

Gelsolin Restores Aβ-Induced Alterations in Choroid Plexus Epithelium

PubMed Central

Vargas, Teo; Antequera, Desiree; Ugalde, Cristina; Spuch, Carlos; Carro, Eva

2010-01-01

Histologically, Alzheimer's disease (AD) is characterized by senile plaques and cerebrovascular amyloid deposits. In previous studies we demonstrated that in AD patients, amyloid-β (Aβ) peptide also accumulates in choroid plexus, and that this process is associated with mitochondrial dysfunction and epithelial cell death. However, the molecular mechanisms underlying Aβ accumulation at the choroid plexus epithelium remain unclear. Aβ clearance, from the brain to the blood, involves Aβ carrier proteins that bind to megalin, including gelsolin, a protein produced specifically by the choroid plexus epithelial cells. In this study, we show that treatment with gelsolin reduces Aβ-induced cytoskeletal disruption of blood-cerebrospinal fluid (CSF) barrier at the choroid plexus. Additionally, our results demonstrate that gelsolin plays an important role in decreasing Aβ-induced cytotoxicity by inhibiting nitric oxide production and apoptotic mitochondrial changes. Taken together, these findings make gelsolin an appealing tool for the prophylactic treatment of AD. PMID:20369065

Biological strategies for enhanced hydrolysis of lignocellulosic biomass during anaerobic digestion: Current status and future perspectives.

PubMed

Shrestha, Shilva; Fonoll, Xavier; Khanal, Samir Kumar; Raskin, Lutgarde

2017-12-01

Lignocellulosic biomass is the most abundant renewable bioresource on earth. In lignocellulosic biomass, the cellulose and hemicellulose are bound with lignin and other molecules to form a complex structure not easily accessible to microbial degradation. Anaerobic digestion (AD) of lignocellulosic biomass with a focus on improving hydrolysis, the rate limiting step in AD of lignocellulosic feedstocks, has received considerable attention. This review highlights challenges with AD of lignocellulosic biomass, factors contributing to its recalcitrance, and natural microbial ecosystems, such as the gastrointestinal tracts of herbivorous animals, capable of performing hydrolysis efficiently. Biological strategies that have been evaluated to enhance hydrolysis of lignocellulosic biomass include biological pretreatment, co-digestion, and inoculum selection. Strategies to further improve these approaches along with future research directions are outlined with a focus on linking studies of microbial communities involved in hydrolysis of lignocellulosics to process engineering. Copyright © 2017 Elsevier Ltd. All rights reserved.

Neprilysin and Aβ Clearance: Impact of the APP Intracellular Domain in NEP Regulation and Implications in Alzheimer’s Disease

PubMed Central

Grimm, Marcus O. W.; Mett, Janine; Stahlmann, Christoph P.; Haupenthal, Viola J.; Zimmer, Valerie C.; Hartmann, Tobias

2013-01-01

One of the characteristic hallmarks of Alzheimer’s disease (AD) is an accumulation of amyloid β (Aβ) leading to plaque formation and toxic oligomeric Aβ complexes. Besides the de novo synthesis of Aβ caused by amyloidogenic processing of the amyloid precursor protein (APP), Aβ levels are also highly dependent on Aβ degradation. Several enzymes are described to cleave Aβ. In this review we focus on one of the most prominent Aβ degrading enzymes, the zinc-metalloprotease Neprilysin (NEP). In the first part of the review we discuss beside the general role of NEP in Aβ degradation the alterations of the enzyme observed during normal aging and the progression of AD. In vivo and cell culture experiments reveal that a decreased NEP level results in an increased Aβ level and vice versa. In a pathological situation like AD, it has been reported that NEP levels and activity are decreased and it has been suggested that certain polymorphisms in the NEP gene result in an increased risk for AD. Conversely, increasing NEP activity in AD mouse models revealed an improvement in some behavioral tests. Therefore it has been suggested that increasing NEP might be an interesting potential target to treat or to be protective for AD making it indispensable to understand the regulation of NEP. Interestingly, it is discussed that the APP intracellular domain (AICD), one of the cleavage products of APP processing, which has high similarities to Notch receptor processing, might be involved in the transcriptional regulation of NEP. However, the mechanisms of NEP regulation by AICD, which might be helpful to develop new therapeutic strategies, are up to now controversially discussed and summarized in the second part of this review. In addition, we review the impact of AICD not only in the transcriptional regulation of NEP but also of further genes. PMID:24391587

Distinct neural systems underlying reduced emotional enhancement for positive and negative stimuli in early Alzheimer's disease

PubMed Central

Mistridis, Panagiota; Taylor, Kirsten I.; Kissler, Johanna M.; Monsch, Andreas U.; Kressig, Reto W.; Kivisaari, Sasa L.

2014-01-01

Emotional information is typically better remembered than neutral content, and previous studies suggest that this effect is subserved particularly by the amygdala together with its interactions with the hippocampus. However, it is not known whether amygdala damage affects emotional memory performance at immediate and delayed recall, and whether its involvement is modulated by stimulus valence. Moreover, it is unclear to what extent more distributed neocortical regions involved in e.g., autobiographical memory, also contribute to emotional processing. We investigated these questions in a group of patients with Alzheimer's disease (AD), which affects the amygdala, hippocampus and neocortical regions. Healthy controls (n = 14), patients with AD (n = 15) and its putative prodrome amnestic mild cognitive impairment (n = 11) completed a memory task consisting of immediate and delayed free recall of a list of positive, negative and neutral words. Memory performance was related to brain integrity in region of interest and whole-brain voxel-based morphometry analyses. In the brain-behavioral analyses, the left amygdala volume predicted the immediate recall of both positive and negative material, whereas at delay, left and right amygdala volumes were associated with performance with positive and negative words, respectively. Whole-brain analyses revealed additional associations between left angular gyrus integrity and the immediate recall of positive words as well as between the orbitofrontal cortex and the delayed recall of negative words. These results indicate that emotional memory impairments in AD may be underpinned by damage to regions implicated in emotional processing as well as frontoparietal regions, which may exert their influence via autobiographical memories and organizational strategies. PMID:24478669

The efficiency of geophysical adjoint codes generated by automatic differentiation tools

NASA Astrophysics Data System (ADS)

Vlasenko, A. V.; Köhl, A.; Stammer, D.

2016-02-01

The accuracy of numerical models that describe complex physical or chemical processes depends on the choice of model parameters. Estimating an optimal set of parameters by optimization algorithms requires knowledge of the sensitivity of the process of interest to model parameters. Typically the sensitivity computation involves differentiation of the model, which can be performed by applying algorithmic differentiation (AD) tools to the underlying numerical code. However, existing AD tools differ substantially in design, legibility and computational efficiency. In this study we show that, for geophysical data assimilation problems of varying complexity, the performance of adjoint codes generated by the existing AD tools (i) Open_AD, (ii) Tapenade, (iii) NAGWare and (iv) Transformation of Algorithms in Fortran (TAF) can be vastly different. Based on simple test problems, we evaluate the efficiency of each AD tool with respect to computational speed, accuracy of the adjoint, the efficiency of memory usage, and the capability of each AD tool to handle modern FORTRAN 90-95 elements such as structures and pointers, which are new elements that either combine groups of variables or provide aliases to memory addresses, respectively. We show that, while operator overloading tools are the only ones suitable for modern codes written in object-oriented programming languages, their computational efficiency lags behind source transformation by orders of magnitude, rendering the application of these modern tools to practical assimilation problems prohibitive. In contrast, the application of source transformation tools appears to be the most efficient choice, allowing handling even large geophysical data assimilation problems. However, they can only be applied to numerical models written in earlier generations of programming languages. Our study indicates that applying existing AD tools to realistic geophysical problems faces limitations that urgently need to be solved to allow the continuous use of AD tools for solving geophysical problems on modern computer architectures.

Modified allocation capacitated planning model in blood supply chain management

NASA Astrophysics Data System (ADS)

Mansur, A.; Vanany, I.; Arvitrida, N. I.

2018-04-01

Blood supply chain management (BSCM) is a complex process management that involves many cooperating stakeholders. BSCM involves four echelon processes, which are blood collection or procurement, production, inventory, and distribution. This research develops an optimization model of blood distribution planning. The efficiency of decentralization and centralization policies in a blood distribution chain are compared, by optimizing the amount of blood delivered from a blood center to a blood bank. This model is developed based on allocation problem of capacitated planning model. At the first stage, the capacity and the cost of transportation are considered to create an initial capacitated planning model. Then, the inventory holding and shortage costs are added to the model. These additional parameters of inventory costs lead the model to be more realistic and accurate.

Involving patients in a multidisciplinary European consensus process and in the development of a 'patient summary of the consensus document for colon and rectal cancer care'.

PubMed

Boelens, Petra G; Taylor, Claire; Henning, Geoffrey; Marang-van de Mheen, Perla J; Espin, Eloy; Wiggers, Theo; Gore-Booth, Jola; Moss, Barbara; Valentini, Vincenzo; van de Velde, Cornelis J H

2014-01-01

High-quality cancer care should be accessible for patients and healthcare professionals. Involvement of patients as partners in guideline formation and consensus processes is still rarely found. EURECCA, short for European Registration of Cancer Care, is the platform to improve outcomes of cancer care by reducing variation in the diagnostic and treatment process. EURECCA acknowledges the important role of patients in implementation of consensus information in clinical practice. The aim of this article is to describe the process of involving patients in the consensus process and in developing the patient summary of the consensus for colon and rectal cancer care. The Delphi method for achieving consensus was used. Three online voting rounds and one tele-voting round were offered to an expert panel of oncology professionals and patient representatives. At four different stages, patients and/or patient representatives were involved in the process: (1) during the consensus process, (2) lecturing about the role of the patient, (3) development of the patient summary, and (4) testing the patient summary. Representatives were invited to the voting and commenting rounds of this process and given an equal vote. Although patients were not consulted during the planning stages of this process, patient involvement increased following the panel's discussion of the implementation of the consensus among the patient population. After the consensus meeting, the patient summary was written by patient representatives, oncologists and nurses. A selection of proactive patients reviewed the draft patient summary; responses were positive and several patient-reported outcomes were added. Questionnaires to evaluate the use and implementation of the patient summary in daily practice are currently being developed and tested. Patient consultation will be needed in future planning for selection of topics. The present study may function as a model for future consensus processes to involve patients at different stages and to implement both patient and healthcare professional versions in daily practice.

Copper and the oxidation of hemoglobin: a comparison of horse and human hemoglobins.

PubMed

Rifkind, J M; Lauer, L D; Chiang, S C; Li, N C

1976-11-30

Oxidation studies of hemoglobin by Cu(II) indicate that for horse hemoglobin, up to a Cu(II)/heme molar ratio of 0.5, all of the Cu(II) added is used to rapidly oxidize the heme. On the other hand, most of the Cu(II) added to human hemoglobin at low Cu(II)/heme molar ratios is unable to oxidize the heme. Only at Cu(II)/heme molar ratios greater than 0.5 does the amount of oxidation per added Cu(II) approach that of horse hemoglobin. At the same time, binding studies indicate that human hemoglobin has an additional binding site involving one copper for every two hemes, which has a higher copper affinity than the single horse hemoglobin binding site. The Cu(II) oxidation of human hemoglobin is explained utilizing this additional binding site by a mechanism where a transfer of electrons cannot occur between the heme and the Cu(II) bound to the high affinity human binding site. The electron transfer must involve the Cu(II) bound to the lower affinity human hemoglobin binding site, which is similar to the only horse hemoglobin site. The involvement of beta-2 histidine in the binding of this additional copper is indicated by a comparison of the amino acid sequences of various hemoglobins which possess the additional site, with the amino acid sequences of hemoglobins which do not possess the additional site. Zn(II), Hg(II), and N-ethylmaleimide (NEM) are found to decrease the Cu(II) oxidation of hemoglobin. The sulfhydryl reagents, Hg(II) and NEM, produce a very dramatic decrease in the rate of oxidation, which can only be explained by an effect on the rate for the actual transfer of electrons between the Cu(II) and the Fe(II). The effect of Zn(II) is much smaller and can, for the most part, be explained by the increased oxygen affinity, which affects the ligand dissociation process that must precede the electron transfer process.

Linking Alzheimer's disease to insulin resistance: the FoxO response to oxidative stress.

PubMed

Manolopoulos, K N; Klotz, L-O; Korsten, P; Bornstein, S R; Barthel, A

2010-11-01

Oxidative stress is an important determinant not only in the pathogenesis of Alzheimer's disease (AD), but also in insulin resistance (InsRes) and diabetic complications. Forkhead box class O (FoxO) transcription factors are involved in both insulin action and the cellular response to oxidative stress, thereby providing a potential integrative link between AD and InsRes. For example, the expression of intra- and extracellular antioxidant enzymes, such as manganese-superoxide dismutase and selenoprotein P, is regulated by FoxO proteins, as is the expression of important hepatic enzymes of gluconeogenesis. Here, we review the molecular mechanisms involved in the pathogenesis of AD and InsRes and discuss the function of FoxO proteins in these processes. Both InsRes and oxidative stress may promote the transcriptional activity of FoxO proteins, resulting in hyperglycaemia and a further increased production of reactive oxygen species (ROS). The consecutive activation of c-Jun N-terminal kinases and inhibition of Wingless (Wnt) signalling may result in the formation of β-amyloid plaques and τ protein phosphorylation. Wnt inhibition may also result in a sustained activation of FoxO proteins with induction of apoptosis and neuronal loss, thereby completing a vicious circle from oxidative stress, InsRes and hyperglycaemia back to the formation of ROS and consecutive neurodegeneration. In view of their central function in this model, FoxO proteins may provide a potential molecular target for the treatment of both InsRes and AD.

Mitochondrial dysfunction: the missing link between aging and sporadic Alzheimer's disease.

PubMed

Grimm, Amandine; Friedland, Kristina; Eckert, Anne

2016-04-01

Alzheimer's disease (AD) is a progressive neurodegenerative disease that represents the most common form of dementia among the elderly. Despite the fact that AD was studied for decades, the underlying mechanisms that trigger this neuropathology remain unresolved. Since the onset of cognitive deficits occurs generally within the 6th decade of life, except in rare familial case, advancing age is the greatest known risk factor for AD. To unravel the pathogenesis of the disease, numerous studies use cellular and animal models based on genetic mutations found in rare early onset familial AD (FAD) cases that represent less than 1 % of AD patients. However, the underlying process that leads to FAD appears to be distinct from that which results in late-onset AD. As a genetic disorder, FAD clearly is a consequence of malfunctioning/mutated genes, while late-onset AD is more likely due to a gradual accumulation of age-related malfunction. Normal aging and AD are both marked by defects in brain metabolism and increased oxidative stress, albeit to varying degrees. Mitochondria are involved in these two phenomena by controlling cellular bioenergetics and redox homeostasis. In the present review, we compare the common features observed in both brain aging and AD, placing mitochondrial in the center of pathological events that separate normal and pathological aging. We emphasize a bioenergetic model for AD including the inverse Warburg hypothesis which postulates that AD is a consequence of mitochondrial deregulation leading to metabolic reprogramming as an initial attempt to maintain neuronal integrity. After the failure of this compensatory mechanism, bioenergetic deficits may lead to neuronal death and dementia. Thus, mitochondrial dysfunction may represent the missing link between aging and sporadic AD, and represent attractive targets against neurodegeneration.

Alzheimer's disease, cerebrovascular dysfunction and the benefits of exercise: from vessels to neurons.

PubMed

Lange-Asschenfeldt, Christian; Kojda, Georg

2008-06-01

Exercise training promotes extensive cardiovascular changes and adaptive mechanisms in both the peripheral and cerebral vasculature, such as improved organ blood flow, induction of antioxidant pathways, and enhanced angiogenesis and vascular regeneration. Clinical studies have demonstrated a reduction of morbidity and mortality from cardiovascular disease among exercising individuals. However, evidence from recent large clinical trials also suggests a substantial reduction of dementia risk - particularly regarding Alzheimer's disease (AD) - with regular exercise. Enhanced neurogenesis and improved synaptic plasticity have been implicated in this beneficial effect. However, recent research has revealed that vascular and specifically endothelial dysfunction is essentially involved in the disease process and profoundly aggravates underlying neurodegeneration. Moreover, vascular risk factors (VRFs) are probably determinants of incidence and course of AD. In this review, we emphasize the interconnection between AD and VRFs and the impact of cerebrovascular and endothelial dysfunction on AD pathophysiology. Furthermore, we describe the molecular mechanisms of the beneficial effects of exercise on the vasculature such as activation of the vascular nitric oxide (NO)/endothelial NO synthase (eNOS) pathway, upregulation of antioxidant enzymes, and angiogenesis. Finally, recent prospective clinical studies dealing with the effect of exercise on the risk of incident AD are briefly reviewed. We conclude that, next to upholding neuronal plasticity, regular exercise may counteract AD pathophysiology by building a vascular reserve.

Current status of renin-aldosterone angiotensin system-targeting anti-hypertensive drugs as therapeutic options for Alzheimer's disease.

PubMed

Ashby, Emma Louise; Kehoe, Patrick G

2013-10-01

Hypertension is a modifiable risk factor for Alzheimer's disease (AD) and other dementias. Yet, despite this well-documented association, few of the current strategies to treat AD are directed at this possible target. The renin-aldosterone angiotensin system (RAAS) is a centrally active modifiable pathway that is involved in cerebral blood flow regulation. Currently, three classes of RAAS-targeting drugs are licensed for treatment of peripheral hypertension--angiotensin-converting enzyme inhibitors (ACE-Is), angiotensin II receptor blockers (ARBs) and direct renin inhibitors (DRIs). All of these are generally well tolerated and have been shown to offer varying degrees of protection on aspects of cognition and dementia, thus making them an attractive therapeutic option for AD. This review summarises existing evidence regarding the plausibility of using RAAS-targeting drugs as a strategy to treat AD and highlights unresolved aspects to such approaches, namely the potential impact of altering angiotensin II-mediated processes in the central nervous system. Continued biochemical research of the RAAS pathway in combination with formal investigation of current RAAS-modifying drugs in randomised clinical trials is now necessary to determine their therapeutic value in AD.

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

Spike-adding in parabolic bursters: The role of folded-saddle canards

NASA Astrophysics Data System (ADS)

Desroches, Mathieu; Krupa, Martin; Rodrigues, Serafim

2016-09-01

The present work develops a new approach to studying parabolic bursting, and also proposes a novel four-dimensional canonical and polynomial-based parabolic burster. In addition to this new polynomial system, we also consider the conductance-based model of the Aplysia R15 neuron known as the Plant model, and a reduction of this prototypical biophysical parabolic burster to three variables, including one phase variable, namely the Baer-Rinzel-Carillo (BRC) phase model. Revisiting these models from the perspective of slow-fast dynamics reveals that the number of spikes per burst may vary upon parameter changes, however the spike-adding process occurs in an explosive fashion that involves special solutions called canards. This spike-adding canard explosion phenomenon is analysed by using tools from geometric singular perturbation theory in tandem with numerical bifurcation techniques. We find that the bifurcation structure persists across all considered systems, that is, spikes within the burst are incremented via the crossing of an excitability threshold given by a particular type of canard orbit, namely the true canard of a folded-saddle singularity. However there can be a difference in the spike-adding transitions in parameter space from one case to another, according to whether the process is continuous or discontinuous, which depends upon the geometry of the folded-saddle canard. Using these findings, we construct a new polynomial approximation of the Plant model, which retains all the key elements for parabolic bursting, including the spike-adding transitions mediated by folded-saddle canards. Finally, we briefly investigate the presence of spike-adding via canards in planar phase models of parabolic bursting, namely the theta model by Ermentrout and Kopell.

Total flavonoid extract from Dracoephalum moldavica L. attenuates β-amyloid-induced toxicity through anti-amyloidogenesic and neurotrophic pathways.

PubMed

Liu, Qing-Shan; Jiang, Hai-Lun; Wang, Yu; Wang, Lin-Lin; Zhang, Jun-Xia; He, Cheng-Hui; Shao, Shuai; Zhang, Tian-Tai; Xing, Jian-Guo; Liu, Rui

2018-01-15

Alzheimer's disease (AD) is an incurable neurodegenerative disorder characterized by global cognitive impairment that involves accumulation of amyloid-beta peptides (Aβ) in the brain. Herbal approaches can be used as alternative medicines to slow the progression of AD. This study aimed to determine the beneficial effects and potential underlying mechanisms of total flavonoid extract from Dracoephalum moldavica L. (TFDM) for attenuating Alzheimer-related deficits induced by Aβ. We used amyloid precursor protein (APP) and presenilin 1 (PS1) double transgenic mice and copper-injured APP Swedish mutation overexpressing SH-SY5Y cells to evaluate the beneficial effects of TFDM. Further, identifying the mechanisms of action was conducted on anti-amyloidogenic and neurotrophic transductions. Our results indicated that TFDM treatment ameliorated cognitive impairments and neurodegeneration and improved the antioxidant defense system in APP/PS1 mice. TFDM also reduced Aβ burden by relieving Aβ deposition, decreasing insoluble Aβ levels, and inhibiting β-amyloidogenic processing pathway involving downregulation of β-secretase and β-C-terminal fragment in the brain. In the in vitro model of AD, TFDM treatment protected injured cells, and combined with the beneficial effects of decreasing APP levels, lowered Aβ 1-42 and regulated the redox imbalance. Moreover, TFDM preserved the extracellular signal-regulated kinase/cAMP response element-binding protein/brain-derived neurotrophic factor pathway both in vitro and in vivo. In conclusion, TFDM clearly demonstrated neuroprotective effects by restoring the anti-amyloidogenic and neurotrophic transductions in the context of AD-associated deficits. These findings indicate the potential use of herb-based substances as supplements or potential alternative supplements for attenuating the progression of AD. Copyright © 2017. Published by Elsevier Inc.

Pharmacological Inhibition of O-GlcNAcase Enhances Autophagy in Brain through an mTOR-Independent Pathway.

PubMed

Zhu, Yanping; Shan, Xiaoyang; Safarpour, Farzaneh; Erro Go, Nancy; Li, Nancy; Shan, Alice; Huang, Mina C; Deen, Matthew; Holicek, Viktor; Ashmus, Roger; Madden, Zarina; Gorski, Sharon; Silverman, Michael A; Vocadlo, David J

2018-03-05

The glycosylation of nucleocytoplasmic proteins with O-linked N-acetylglucosamine residues (O-GlcNAc) is conserved among metazoans and is particularly abundant within brain. O-GlcNAc is involved in diverse cellular processes ranging from the regulation of gene expression to stress response. Moreover, O-GlcNAc is implicated in various diseases including cancers, diabetes, cardiac dysfunction, and neurodegenerative diseases. Pharmacological inhibition of O-GlcNAcase (OGA), the sole enzyme that removes O-GlcNAc, reproducibly slows neurodegeneration in various Alzheimer's disease (AD) mouse models manifesting either tau or amyloid pathology. These data have stimulated interest in the possibility of using OGA-selective inhibitors as pharmaceuticals to alter the progression of AD. The mechanisms mediating the neuroprotective effects of OGA inhibitors, however, remain poorly understood. Here we show, using a range of methods in neuroblastoma N2a cells, in primary rat neurons, and in mouse brain, that selective OGA inhibitors stimulate autophagy through an mTOR-independent pathway without obvious toxicity. Additionally, OGA inhibition significantly decreased the levels of toxic protein species associated with AD pathogenesis in the JNPL3 tauopathy mouse model as well as the 3×Tg-AD mouse model. These results strongly suggest that OGA inhibitors act within brain through a mechanism involving enhancement of autophagy, which aids the brain in combatting the accumulation of toxic protein species. Our study supports OGA inhibition being a feasible therapeutic strategy for hindering the progression of AD and other neurodegenerative diseases. Moreover, these data suggest more targeted strategies to stimulate autophagy in an mTOR-independent manner may be found within the O-GlcNAc pathway. These findings should aid the advancement of OGA inhibitors within the clinic.

Multimodal Magnetic Resonance Imaging in Alzheimer's Disease Patients at Prodromal Stage.

PubMed

Eustache, Pierre; Nemmi, Federico; Saint-Aubert, Laure; Pariente, Jeremie; Péran, Patrice

2016-01-01

One objective of modern neuroimaging is to identify markers that can aid in diagnosis, monitor disease progression, and impact long-term drug analysis. In this study, physiopathological modifications in seven subcortical structures of patients with mild cognitive impairment (MCI) due to Alzheimer's disease (AD) were characterized by simultaneously measuring quantitative magnetic resonance parameters that are sensitive to complementary tissue characteristics (e.g., volume atrophy, shape changes, microstructural damage, and iron deposition). Fourteen MCI patients and fourteen matched, healthy subjects underwent 3T-magnetic resonance imaging with whole-brain, T1-weighted, T2*-weighted, and diffusion-tensor imaging scans. Volume, shape, mean R2*, mean diffusivity (MD), and mean fractional anisotropy (FA) in the thalamus, hippocampus, putamen, amygdala, caudate nucleus, pallidum, and accumbens were compared between MCI patients and healthy subjects. Comparisons were then performed using voxel-based analyses of R2*, MD, FA maps, and voxel-based morphometry to determine which subregions showed the greatest difference for each parameter. With respect to the micro- and macro-structural patterns of damage, our results suggest that different and distinct physiopathological processes are present in the prodromal phase of AD. MCI patients had significant atrophy and microstructural changes within their hippocampi and amygdalae, which are known to be affected in the prodromal stage of AD. This suggests that the amygdala is affected in the same, direct physiopathological process as the hippocampus. Conversely, atrophy alone was observed within the thalamus and putamen, which are not directly involved in AD pathogenesis. This latter result may reflect another mechanism, whereby atrophy is linked to indirect physiopathological processes.

Modeling adsorption of copper(II), cobalt(II) and nickel(II) metal ions from aqueous solution onto a new carboxylated sugarcane bagasse. Part II: Optimization of monocomponent fixed-bed column adsorption.

PubMed

Xavier, Amália Luísa Pedrosa; Adarme, Oscar Fernando Herrera; Furtado, Laís Milagres; Ferreira, Gabriel Max Dias; da Silva, Luis Henrique Mendes; Gil, Laurent Frédéric; Gurgel, Leandro Vinícius Alves

2018-04-15

In the second part of this series of studies, the monocomponent adsorption of Cu 2+ , Co 2+ and Ni 2+ onto STA adsorbent in a fixed-bed column was investigated and optimized using a 2 2 central composite design. The process variables studied were: initial metal ion concentration and spatial time, and the optimized responses were: adsorption capacity of the bed (Q max ), efficiency of the adsorption process (EAP), and effective use of the bed (H). The higher Q max for Cu 2+ , Co 2+ and Ni 2+ were 1.060, 0.800 and 1.029 mmol/g, respectively. The breakthrough curves were modeled by the original Thomas and Bohart-Adams models. The changes in enthalpy (Δ ads H°) of adsorption of the metal ions onto STA were determined by isothermal titration calorimetry (ITC). The values of Δ ads H° were in the range of 3.0-6.8 kJ/mol, suggesting that the adsorption process involved physisorption. Desorption (E des ) and re-adsorption (E re-ads ) of metal ions from the STA adsorbent were also investigated in batch mode, and the optimum conditions were applied for three cycles of adsorption/desorption in a fixed bed column. For these cycles, the lowest values of E des and E re-ads were 95 and 92.3%, respectively, showing that STA is a promising candidate for real applications on a large scale. Copyright © 2018 Elsevier Inc. All rights reserved.

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

Scrudato, R.J.; Chiarenzelli, J.R.

An electrochemical peroxidation (ECP) process has been developed and used to degrade polychlorinated biphenyls (PCB) and volatile organic compounds (VOC)-contaminated water, sludge, and sediments at a New York State Federal and State Superfund Site. The process involves passing an oscillating low-amperage (<10 amps) current through steel electrodes immersed in an acidified water or sediment slurry into which hydrogen peroxide (<1,000 ppm) is added. The generated free radicals attack organic compounds, including organo-metallic complexes and refractory compounds including PCBs. PCB degradation ranged from about 30% to 80% in experiments involving Federal Superfund Site sediments; total PCBs were reduced by {approximately}97% tomore » 68%, respectively, in water and slurry collected from a State Superfund subsurface storage tank. VOC bench-scale experiments involved chloroethane, 1,1-dichloroethane, dichloromethane, 1,1,1-trichloroethane, and acetone and after a 3-min ECP treatment, degradation ranged from >94% to about 99.9%. Results indicate the ECP is a viable process to degrade organic contaminants in water and sediment suspensions. Because the treated water suspensions are acidified, select trace metal sorbed to the particulates is solubilized and therefore can be segregated from the particulates, offering a process that simultaneously degrades organic contaminants and separates trace metals. 19 refs., 1 fig., 4 tabs.« less

FUEL COMPOSITION FOR NUCLEAR REACTORS

DOEpatents

Andersen, J.C.

1963-08-01

A process for making refractory nuclear fuel elements involves heating uranium and silicon powders in an inert atmosphere to 1600 to 1800 deg C to form USi/sub 3/; adding silicon carbide, carbon, 15% by weight of nickel and aluminum, and possibly also molybdenum and silicon powders; shaping the mixture; and heating to 1700 to 2050 deg C again in an inert atmosphere. Information on obtaining specific compositions is included. (AEC)

The Role of Reading in a Japanese Language Program: A Response to the MLA Ad Hoc Committee's Report (2007)

ERIC Educational Resources Information Center

Marcus, Ginger

2010-01-01

Reading is defined as a socio-cultural act negotiated between text and reader, and the act of reading is considered to be a cognitive process that involves knowledge not only of symbols/letters, vocabulary and structure, but also of culture. In other words, in order to understand the intentions of the author and to formulate meaning, the second…

TQM: the essential concepts.

PubMed

Chambers, D W

1998-01-01

This is an introduction to the major concepts in total quality management, a loose collection of management approaches that focus on continuous improvement of processes, guided by routine data collection and adjustment of the processes. Customer focus and involvement of all members of an organization are also characteristics commonly found in TQM. The seventy-five-year history of the movement is sketched from its beginning in statistical work on quality assurance through the many improvements and redefinitions added by American and Japanese thinkers. Essential concepts covered include: control cycles, focus on the process rather than the defects, the GEAR model, importance of the customer, upstream quality, just-in-time, kaizen, and service quality.

Quantitative Balance and Gait Measurement in Patients with Frontotemporal Dementia and Alzheimer Diseases: A Pilot Study

PubMed Central

Velayutham, Selva Ganapathy; Chandra, Sadanandavalli Retnaswami; Bharath, Srikala; Shankar, Ravi Girikamatha

2017-01-01

Introduction: Alzhiemers disease and Frontotemporal dementia are common neurodegenerative dementias with a wide prevalence. Falls are a common cause of morbidity in these patients. Identifying subclinical involvement of these parameters might serve as a tool in differential analysis of these distinct parameters involved in these conditions and also help in planning preventive strategies to prevent falls. Patients and Methods: Eight patients in age and gender matched patients in each group were compared with normal controls. Standardizes methods of gait and balance aseesment were done in all persons. Results: Results revealed subclinical involvement of gait and balancesin all groups specially during divided attention. The parameters were significantly more affected in patients. Patients with AD and FTD had involement of over all ambulation index balance more affected in AD patients FTD patients showed step cycle, stride length abnormalities. Discussion: There is balance and gait involvement in normal ageing as well as patients with AD and FTD. The pattern of involvement in AD correlates with WHERE pathway involvement and FTD with frontal subcortical circuits involvement. Conclusion: Identification the differential patterns of involvement in subclinical stage might help to differentiate normal ageing and the different types of cortical dementias. This could serve as an additional biomarker and also assist in initiating appropriate training methods to prevent future falls. PMID:28515555

Life cycle assessment of two emerging sewage sludge-to-energy systems: evaluating energy and greenhouse gas emissions implications.

PubMed

Cao, Yucheng; Pawłowski, Artur

2013-01-01

A "cradle-to-grave" life cycle assessment was conducted to examine the energy and greenhouse gas (GHG) emission footprints of two emerging sludge-to-energy systems. One system employs a combination of anaerobic digestion (AD) and fast pyrolysis for bioenergy conversion, while the other excludes AD. Each system was divided into five process phases: plant construction, sludge pretreatment, sludge-to-bioenergy conversion, bioenergy utilizations and biochar management. Both systems achieved energy and GHG emission benefits, and the AD-involving system performed better than the AD-excluding system (5.30 vs. 0.63 GJ/t sludge in net energy gain and 0.63 vs. 0.47 t CO(2)eq/t sludge in emission credit for base case). Detailed contribution and sensitivity analyses were conducted to identify how and to what degree the different life-cycle phases are responsible for the energy and emission impacts. The energy and emission performances were significantly affected by variations in bioenergy production, energy requirement for sludge drying and end use of bioenergy. Copyright © 2012 Elsevier Ltd. All rights reserved.

Causality constraints on corrections to the graviton three-point coupling

DOE PAGES

Camanho, Xián O.; Edelstein, José D.; Maldacena, Juan; ...

2016-02-03

In this paper, we consider higher derivative corrections to the graviton three-point coupling within a weakly coupled theory of gravity. Lorentz invariance allows further structures beyond the one present in the Einstein theory. We argue that these are constrained by causality. We devise a thought experiment involving a high energy scattering process which leads to causality violation if the graviton three-point vertex contains the additional structures. This violation cannot be fixed by adding conventional particles with spins J ≤ 2. But, it can be fixed by adding an in finite tower of extra massive particles with higher spins, J > 2. In AdS theories this implies a constraint on the conformal anomaly coefficients |more » $$\\frac{a-c}{c}$$|≲ $$\\frac{1}{2}$$ $${^Δ}_{gap}$$ in terms of Δgap, the dimension of the lightest single trace operator with spin J > 2. Lastly, for inflation, or de Sitter-like solutions, it indicates the existence of massive higher spin particles if the gravity wave non-gaussianity deviates significantly from the one computed in the Einstein theory.« less

Current and emerging topical therapies for atopic dermatitis.

PubMed

Udkoff, Jeremy; Waldman, Andrea; Ahluwalia, Jusleen; Borok, Jenna; Eichenfield, Lawrence F

The pathogenesis of atopic dermatitis (AD) involves epidermal barrier dysfunction and T helper cell type 2 (T h 2) lymphocyte-driven inflammation. Cytokines, such as interleukin 4 (IL-4) and IL-13, are important in this reaction. They stimulate B cells to produce immunoglobulin E, causing atopic disease. This process has been well characterized, and new therapies for AD, such as phosphodiesterase 4 (PDE-4) inhibitors, T h 2-expressed chemoattractant receptor-homologous molecule antagonists, and Janus kinase inhibitors, work by antagonizing this cellular pathway. Recently, there have been many advances in treatment strategies and novel therapies for AD. This review summarizes the clinical evidence supporting the use of current and emerging topical treatments for AD, as well as their safety and efficacy profiles. Crisaborole, a novel PDE-4 inhibitor, is of particular note because phase III clinical trials were recently completed, as summarized here. It is prudent for dermatologists to be current with updates in the field because therapies are constantly changing. In addition to the academic interest, this results in improvement of patient care and advancement of the field. Copyright © 2017 Elsevier Inc. All rights reserved.

Destination memory in Alzheimer's Disease: when I imagine telling Ronald Reagan about Paris.

PubMed

El Haj, Mohamad; Postal, Virginie; Allain, Philippe

2013-01-01

Destination memory refers to remembering the destination of information that people output. This present paper establishes a new distinction between external and internal processes within this memory system for both normal aging and Alzheimer's Disease (AD). Young adults, older adults, and mild AD patients were asked either to tell facts (i.e., external destination memory condition) or to imagine telling facts (i.e., internal destination memory condition) to pictures of famous people. The experiment established three major findings. First, the destination memory performance of the AD patients was significantly poorer than that of older adults, which in turn was poorer than that of the young adults. Furthermore, internal destination processes were more prone to being forgotten than external destination memory processes. In other words, participants had more difficulty in remembering whether they had previously imagined telling the facts to the pictures or not (i.e., imagined condition) than in remembering whether they had previously told the facts to the pictures or not (i.e., enacted condition). Second, significant correlations were detected between performances on destination memory and several executive measures such as the Stroop, the Plus-Minus and the Binding tasks. Third, among the executive measures, regression analyses showed that performance on the Stroop task was a main factor in explaining variance in destination memory performance. Our findings reflect the difficulty in remembering the destination of internally generated information. They also demonstrate the involvement of inhibitory processes in destination memory. Copyright © 2011 Elsevier Ltd. All rights reserved.

Hand stereotypies distinguish Rett syndrome from autism disorder.

PubMed

Goldman, Sylvie; Temudo, Teresa

2012-07-01

Rett syndrome (RTT) and autism disorder (AD) are 2 neurodevelopmental disorders of early life that share phenotypic features, one being hand stereotypies. Distinguishing RTT from AD often represents a challenge, and given their distinct long-term prognoses, this issue may have far-reaching implications. With the advances in genetic testing, the contribution of clinical manifestations in distinguishing RTT from AD has been overlooked. A comparison of hand stereotypies in 20 children with RTT and 20 with AD was performed using detailed analyses of videotaped standardized observations. Striking differences are observed between RTT and AD children. In RTT, hand stereotypies are predominantly complex, continuous, localized to the body midline, and involving mouthing. Conversely, in AD children, hand stereotypies are simple, bilateral, intermittent, and often involving objects. These results provide important clinical signs useful to the differential diagnosis of RTT versus AD, especially when genetic testing for RTT is not an option. Copyright © 2012 Movement Disorder Society.

Label-free Proteomic Analysis of Exosomes Derived from Inducible Hepatitis B Virus-Replicating HepAD38 Cell Line*

PubMed Central

Jia, Xiaofang; Chen, Jieliang; Megger, Dominik A.; Zhang, Xiaonan; Kozlowski, Maya; Zhang, Lijun; Fang, Zhong; Li, Jin; Chu, Qiaofang; Wu, Min; Li, Yaming; Sitek, Barbara; Yuan, Zhenghong

2017-01-01

Hepatitis B virus (HBV) infection is a major health problem worldwide. Recent evidence suggests that some viruses can manipulate the infection process by packing specific viral and cellular components into exosomes, small nanometer-sized (30–150 nm) vesicles secreted from various cells. However, the impact of HBV replication on the content of exosomes produced by hepatocytes has not been fully delineated. In this work, an HBV-inducible cell line HepAD38 was used to directly compare changes in the protein content of exosomes secreted from HepAD38 cells with or without HBV replication. Exosomes were isolated from supernantants of HepAD38 cells cultured with or without doxycycline (dox) and their purity was confirmed by transmission electron microscopy (TEM) and Western immunoblotting assays. Ion-intensity based label-free LC-MS/MS quantitation technologies were applied to analyze protein content of exosomes from HBV replicating cells [referred as HepAD38 (dox−)-exo] and from HBV nonreplicating cells [referred as HepAD38 (dox+)-exo]. A total of 1412 exosomal protein groups were identified, among which the abundance of 35 proteins was significantly changed following HBV replication. Strikingly, 5 subunit proteins from the 26S proteasome complex, including PSMC1, PSMC2, PSMD1, PSMD7 and PSMD14 were consistently enhanced in HepAD38 (dox−)-exo. Bioinformatic analysis of differential exosomal proteins confirmed the significant enrichment of components involved in the proteasomal catabolic process. Proteasome activity assays further suggested that HepAD38 (dox−)-exo had enhanced proteolytic activity compared with HepAD38 (dox+)-exo. Furthermore, human peripheral monocytes incubated with HepAD38 (dox−)-exo induced a significantly lower level of IL-6 secretion compared with IL-6 levels from HepAD38 (dox+)-exo. Irreversible inhibition of proteasomal activity within exosomes restored higher production of IL-6 by monocytes, suggesting that transmission of proteasome subunit proteins by HepAD38 (dox−)-exo might modulate the production of pro-inflammatory molecules in the recipient monocytes. These results revealed the composition and potential function of exosomes produced during HBV replication, thus providing a new perspective on the role of exosomes in HBV-host interaction. PMID:28242843

Label-free Proteomic Analysis of Exosomes Derived from Inducible Hepatitis B Virus-Replicating HepAD38 Cell Line.

PubMed

Jia, Xiaofang; Chen, Jieliang; Megger, Dominik A; Zhang, Xiaonan; Kozlowski, Maya; Zhang, Lijun; Fang, Zhong; Li, Jin; Chu, Qiaofang; Wu, Min; Li, Yaming; Sitek, Barbara; Yuan, Zhenghong

2017-04-01

Hepatitis B virus (HBV) infection is a major health problem worldwide. Recent evidence suggests that some viruses can manipulate the infection process by packing specific viral and cellular components into exosomes, small nanometer-sized (30-150 nm) vesicles secreted from various cells. However, the impact of HBV replication on the content of exosomes produced by hepatocytes has not been fully delineated. In this work, an HBV-inducible cell line HepAD38 was used to directly compare changes in the protein content of exosomes secreted from HepAD38 cells with or without HBV replication. Exosomes were isolated from supernantants of HepAD38 cells cultured with or without doxycycline (dox) and their purity was confirmed by transmission electron microscopy (TEM) and Western immunoblotting assays. Ion-intensity based label-free LC-MS/MS quantitation technologies were applied to analyze protein content of exosomes from HBV replicating cells [referred as HepAD38 (dox - )-exo] and from HBV nonreplicating cells [referred as HepAD38 (dox + )-exo]. A total of 1412 exosomal protein groups were identified, among which the abundance of 35 proteins was significantly changed following HBV replication. Strikingly, 5 subunit proteins from the 26S proteasome complex, including PSMC1, PSMC2, PSMD1, PSMD7 and PSMD14 were consistently enhanced in HepAD38 (dox - )-exo. Bioinformatic analysis of differential exosomal proteins confirmed the significant enrichment of components involved in the proteasomal catabolic process. Proteasome activity assays further suggested that HepAD38 (dox - )-exo had enhanced proteolytic activity compared with HepAD38 (dox + )-exo. Furthermore, human peripheral monocytes incubated with HepAD38 (dox - )-exo induced a significantly lower level of IL-6 secretion compared with IL-6 levels from HepAD38 (dox + )-exo. Irreversible inhibition of proteasomal activity within exosomes restored higher production of IL-6 by monocytes, suggesting that transmission of proteasome subunit proteins by HepAD38 (dox - )-exo might modulate the production of pro-inflammatory molecules in the recipient monocytes. These results revealed the composition and potential function of exosomes produced during HBV replication, thus providing a new perspective on the role of exosomes in HBV-host interaction. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

Simulation of anaerobic digestion processes using stochastic algorithm.

PubMed

Palanichamy, Jegathambal; Palani, Sundarambal

2014-01-01

The Anaerobic Digestion (AD) processes involve numerous complex biological and chemical reactions occurring simultaneously. Appropriate and efficient models are to be developed for simulation of anaerobic digestion systems. Although several models have been developed, mostly they suffer from lack of knowledge on constants, complexity and weak generalization. The basis of the deterministic approach for modelling the physico and bio-chemical reactions occurring in the AD system is the law of mass action, which gives the simple relationship between the reaction rates and the species concentrations. The assumptions made in the deterministic models are not hold true for the reactions involving chemical species of low concentration. The stochastic behaviour of the physicochemical processes can be modeled at mesoscopic level by application of the stochastic algorithms. In this paper a stochastic algorithm (Gillespie Tau Leap Method) developed in MATLAB was applied to predict the concentration of glucose, acids and methane formation at different time intervals. By this the performance of the digester system can be controlled. The processes given by ADM1 (Anaerobic Digestion Model 1) were taken for verification of the model. The proposed model was verified by comparing the results of Gillespie's algorithms with the deterministic solution for conversion of glucose into methane through degraders. At higher value of 'τ' (timestep), the computational time required for reaching the steady state is more since the number of chosen reactions is less. When the simulation time step is reduced, the results are similar to ODE solver. It was concluded that the stochastic algorithm is a suitable approach for the simulation of complex anaerobic digestion processes. The accuracy of the results depends on the optimum selection of tau value.

Targeting synaptic dysfunction in Alzheimer's disease by administering a specific nutrient combination.

PubMed

van Wijk, Nick; Broersen, Laus M; de Wilde, Martijn C; Hageman, Robert J J; Groenendijk, Martine; Sijben, John W C; Kamphuis, Patrick J G H

2014-01-01

Synapse loss and synaptic dysfunction are pathological processes already involved in the early stages of Alzheimer's disease (AD). Synapses consist principally of neuronal membranes, and the neuronal and synaptic losses observed in AD have been linked to the degeneration and altered composition and structure of these membranes. Consequently, synapse loss and membrane-related pathology provide viable targets for intervention in AD. The specific nutrient combination Fortasyn Connect (FC) is designed to ameliorate synapse loss and synaptic dysfunction in AD by addressing distinct nutritional needs believed to be present in these patients. This nutrient combination comprises uridine, docosahexaenoic acid, eicosapentaenoic acid, choline, phospholipids, folic acid, vitamins B12, B6, C, and E, and selenium, and is present in Souvenaid, a medical food intended for use in early AD. It has been hypothesized that FC counteracts synaptic loss and reduces membrane-related pathology in AD by providing nutritional precursors and cofactors that act together to support neuronal membrane formation and function. Preclinical studies formed the basis of this hypothesis which is being validated in a broad clinical study program investigating the potential of this nutrient combination in AD. Memory dysfunction is one key early manifestation in AD and is associated with synapse loss. The clinical studies to date show that the FC-containing medical food improves memory function and preserves functional brain network organization in mild AD compared with controls, supporting the hypothesis that this intervention counteracts synaptic dysfunction. This review provides a comprehensive overview of basic scientific studies that led to the creation of FC and of its effects in various preclinical models.

Implication of the nutritional and nonnutritional factors in the context of preservation of cognitive performance in patients with dementia/depression and Alzheimer disease.

PubMed

Aliev, Gjumrakch; Ashraf, Ghulam Md; Kaminsky, Yury G; Sheikh, Ishfaq Ahmed; Sudakov, Sergey K; Yakhno, Nikolay N; Benberin, Valery V; Bachurin, Sergey O

2013-11-01

It has been postulated that Alzheimer disease (AD) is a systemic process, which involves multiple pathophysiological factors. A combination of pharmacotherapy and nonpharmacological interventions has been proposed to treat AD and other dementia. The nonpharmacological interventions include but are not limited to increasing sensory input through physical and mental activities, in order to modify cerebral blood flow and implementing nutritional interventions such as diet modification and vitamins and nutraceuticals therapy to vitalize brain functioning. This article highlights the recent research findings regarding novel treatment strategies aimed at modifying natural course of the disease and delaying cognitive decline through simultaneous implementation of pharmacological and nonpharmacological modulators as standardized treatment protocols.

Docosahexaenoic Acid and the Aging Brain1–3

PubMed Central

Lukiw, Walter J.; Bazan, Nicolas G.

2008-01-01

The dietary essential PUFA docosahexaenoic acid [DHA; 22:6(n-3)] is a critical contributor to cell structure and function in the nervous system, and deficits in DHA abundance are associated with cognitive decline during aging and in neurodegenerative disease. Recent studies underscore the importance of DHA-derived neuroprotectin D1 (NPD1) in the homeostatic regulation of brain cell survival and repair involving neurotrophic, antiapoptotic and antiinflammatory signaling. Emerging evidence suggests that NPD1 synthesis is activated by growth factors and neurotrophins. Evolving research indicates that NPD1 has important determinant and regulatory interactions with the molecular-genetic mechanisms affecting β-amyloid precursor protein (βAPP) and amyloid beta (Aβ) peptide neurobiology. Deficits in DHA or its peroxidation appear to contribute to inflammatory signaling, apoptosis, and neuronal dysfunction in Alzheimer disease (AD), a common and progressive age-related neurological disorder unique to structures and processes of the human brain. This article briefly reviews our current understanding of the interactions of DHA and NPD1 on βAPP processing and Aβ peptide signaling and how this contributes to oxidative and pathogenic processes characteristic of aging and AD pathology. PMID:19022980

Advancing three-dimensional MEMS by complimentary laser micro manufacturing

NASA Astrophysics Data System (ADS)

Palmer, Jeremy A.; Williams, John D.; Lemp, Tom; Lehecka, Tom M.; Medina, Francisco; Wicker, Ryan B.

2006-01-01

This paper describes improvements that enable engineers to create three-dimensional MEMS in a variety of materials. It also provides a means for selectively adding three-dimensional, high aspect ratio features to pre-existing PMMA micro molds for subsequent LIGA processing. This complimentary method involves in situ construction of three-dimensional micro molds in a stand-alone configuration or directly adjacent to features formed by x-ray lithography. Three-dimensional micro molds are created by micro stereolithography (MSL), an additive rapid prototyping technology. Alternatively, three-dimensional features may be added by direct femtosecond laser micro machining. Parameters for optimal femtosecond laser micro machining of PMMA at 800 nanometers are presented. The technical discussion also includes strategies for enhancements in the context of material selection and post-process surface finish. This approach may lead to practical, cost-effective 3-D MEMS with the surface finish and throughput advantages of x-ray lithography. Accurate three-dimensional metal microstructures are demonstrated. Challenges remain in process planning for micro stereolithography and development of buried features following femtosecond laser micro machining.

Multiple cytokines are involved in the early events leading to the Alzheimer’s disease pathology

PubMed Central

Wilberding, Akiko; Morimoto, Kaori; Satoh, Haruhisa; Harano, Keiko; Harano, Teruo; Arita, Seizaburo; Tooyama, Ikuo; Konishi, Yoshihiro

2009-01-01

It is likely that neuroinflammation begins well before detectable cognitive impairment in Alzheimer’s disease (AD) occurs. Clarifying the alterations occurring prior to the clinical manifestation of overt AD dementia may provide valuable insight into the early diagnosis and management of AD. Herein, to address the issue that neuroinflammation precedes development of AD pathology, we analyzed cytokine expression profiles of the brain, with focus on non-demented control patients with increasing AD pathology, referred to as high pathology control (HPC) cases, who provide an intermediate subset between AD and normal control cases referred to as low pathology control (LPC) cases. With a semi-quantitative analysis of cytokine mRNA, among 15 cytokines and their related molecules tested, we found the involvement of eight: interleukin-1(IL-1) receptor antagonist (IL-1ra), IL-1 converting enzyme (ICE), IL-2, IL-6, IL-8, tumor necrosis factor (TNF) α, macrophage-colony stimulating factor (M-CSF) and transforming growth factor (TGF) β1 during the development from LPC to HPC, while decreases in IL-1ra, IL-8, MCP-1 and TNFα, and an increase in TACE were implicated in the later development from HPC to AD. These findings indicate that neuroinflammation precedes the clinical manifestation of overt dementia, rather than being involved at the later stages of AD. PMID:22586434

A Systematic Investigation into Aging Related Genes in Brain and Their Relationship with Alzheimer's Disease.

PubMed

Meng, Guofeng; Zhong, Xiaoyan; Mei, Hongkang

2016-01-01

Aging, as a complex biological process, is accompanied by the accumulation of functional loses at different levels, which makes age to be the biggest risk factor to many neurological diseases. Even following decades of investigation, the process of aging is still far from being fully understood, especially at a systematic level. In this study, we identified aging related genes in brain by collecting the ones with sustained and consistent gene expression or DNA methylation changes in the aging process. Functional analysis with Gene Ontology to these genes suggested transcriptional regulators to be the most affected genes in the aging process. Transcription regulation analysis found some transcription factors, especially Specificity Protein 1 (SP1), to play important roles in regulating aging related gene expression. Module-based functional analysis indicated these genes to be associated with many well-known aging related pathways, supporting the validity of our approach to select aging related genes. Finally, we investigated the roles of aging related genes on Alzheimer's Disease (AD). We found that aging and AD related genes both involved some common pathways, which provided a possible explanation why aging made the brain more vulnerable to Alzheimer's Disease.

Regulated Proteolytic Processing of Reelin through Interplay of Tissue Plasminogen Activator (tPA), ADAMTS-4, ADAMTS-5, and Their Modulators

PubMed Central

Krstic, Dimitrije; Rodriguez, Myriam; Knuesel, Irene

2012-01-01

The extracellular signaling protein Reelin, indispensable for proper neuronal migration and cortical layering during development, is also expressed in the adult brain where it modulates synaptic functions. It has been shown that proteolytic processing of Reelin decreases its signaling activity and promotes Reelin aggregation in vitro, and that proteolytic processing is affected in various neurological disorders, including Alzheimer's disease (AD). However, neither the pathophysiological significance of dysregulated Reelin cleavage, nor the involved proteases and their modulators are known. Here we identified the serine protease tissue plasminogen activator (tPA) and two matrix metalloproteinases, ADAMTS-4 and ADAMTS-5, as Reelin cleaving enzymes. Moreover, we assessed the influence of several endogenous protease inhibitors, including tissue inhibitors of metalloproteinases (TIMPs), α-2-Macroglobulin, and multiple serpins, as well as matrix metalloproteinase 9 (MMP-9) on Reelin cleavage, and described their complex interplay in the regulation of this process. Finally, we could demonstrate that in the murine hippocampus, the expression levels and localization of Reelin proteases largely overlap with that of Reelin. While this pattern remained stable during normal aging, changes in their protein levels coincided with accelerated Reelin aggregation in a mouse model of AD. PMID:23082219

Pilot users in agile development processes: motivational factors.

PubMed

Johannessen, Liv Karen; Gammon, Deede

2010-01-01

Despite a wealth of research on user participation, few studies offer insights into how to involve multi-organizational users in agile development methods. This paper is a case study of user involvement in developing a system for electronic laboratory requisitions using agile methodologies in a multi-organizational context. Building on an interpretive approach, we illuminate questions such as: How does collaboration between users and developers evolve and how might it be improved? What key motivational aspects are at play when users volunteer and continue contributing in the face of considerable added burdens? The study highlights how agile methods in themselves appear to facilitate mutually motivating collaboration between user groups and developers. Lessons learned for leveraging the advantages of agile development processes include acknowledging the substantial and ongoing contributions of users and their roles as co-designers of the system.

Cryptococcus neoformans ADS lyase is an enzyme essential for virulence whose crystal structure reveals features exploitable in antifungal drug design.

PubMed

Chitty, Jessica L; Blake, Kirsten L; Blundell, Ross D; Koh, Y Q Andre E; Thompson, Merinda; Robertson, Avril A B; Butler, Mark S; Cooper, Matthew A; Kappler, Ulrike; Williams, Simon J; Kobe, Bostjan; Fraser, James A

2017-07-14

There is significant clinical need for new antifungal agents to manage infections with pathogenic species such as Cryptococcus neoformans Because the purine biosynthesis pathway is essential for many metabolic processes, such as synthesis of DNA and RNA and energy generation, it may represent a potential target for developing new antifungals. Within this pathway, the bifunctional enzyme adenylosuccinate (ADS) lyase plays a role in the formation of the key intermediates inosine monophosphate and AMP involved in the synthesis of ATP and GTP, prompting us to investigate ADS lyase in C. neoformans. Here, we report that ADE13 encodes ADS lyase in C. neoformans. We found that an ade13 Δ mutant is an adenine auxotroph and is unable to successfully cause infections in a murine model of virulence. Plate assays revealed that production of a number of virulence factors essential for dissemination and survival of C. neoformans in a host environment was compromised even with the addition of exogenous adenine. Purified recombinant C. neoformans ADS lyase shows catalytic activity similar to its human counterpart, and its crystal structure, the first fungal ADS lyase structure determined, shows a high degree of structural similarity to that of human ADS lyase. Two potentially important amino acid differences are identified in the C. neoformans crystal structure, in particular a threonine residue that may serve as an additional point of binding for a fungal enzyme-specific inhibitor. Besides serving as an antimicrobial target, C. neoformans ADS lyase inhibitors may also serve as potential therapeutics for metabolic disease; rather than disrupt ADS lyase, compounds that improve the stability the enzyme may be used to treat ADS lyase deficiency disease. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

Abnormalities of neural circuitry in Alzheimer's disease: hippocampus and cortical cholinergic innervation.

PubMed

Geula, C

1998-07-01

Severe pathology in Alzheimer's disease (AD) results in marked disruption of cortical circuitry. Formation of neurofibrillary tangles, neuronal loss, decrease in dendritic extent, and synaptic depletion combine to halt communication among various cortical areas, resulting in anatomic isolation and fragmentation of many cortical zones. The clinical manifestation of this disruption is severe and debilitating cognitive dysfunction, often accompanied by psychiatric and behavioral disturbances and a diminished ability to perform activities of daily living. However, different cortical circuits are not equally vulnerable to AD pathology. In particular, two cortical systems that appear to be involved in the neural processing of memory are selectively vulnerable to degeneration in AD. One consists of connections between the hippocampus and its neighboring cortical structures within the temporal lobe. The second is the cortical cholinergic system that originates in neurons within the basal forebrain and innervates the entire cortical mantle. The circuitry in these systems shows early and severe degenerative changes in the course of AD. The selective vulnerability of these circuits is the probable reason for the early and marked loss of memory observed in these patients. This review presents current knowledge of the general pattern of cortical circuitry, followed by a summary of abnormalities of this circuitry in AD. The cortical circuits that exhibit selective pathology in AD are described in greater detail. Therapeutic implications of the abnormal circuitry in AD are also discussed. For therapies to be effective, early diagnosis of AD is necessary. Future efforts at AD therapy must be combined with an equally intense effort to develop tools capable of early diagnosis of AD, preferably at a preclinical stage before the onset of cognitive symptoms.

Oxidative Stress and Hypoxia Contribute to Alzheimer's Disease Pathogenesis: Two Sides of the Same Coin

PubMed Central

Guglielmotto, Michela; Tamagno, Elena; Danni, Oliviero

2009-01-01

While it is well established that stroke and cerebral hypoperfusion are risk factors for Alzheimer's disease (AD), the molecular link between ischemia/hypoxia and amyloid precursor protein (APP) processing has only been recently established. Here we review the role of the release of reactive oxygen species (ROS) by the mitochondrial electron chain in response to hypoxia, providing evidence that hypoxia fosters the amyloidogenic APP processing through a biphasic mechanism that up-regulates β-secretase activity, which involves an early release of ROS and an activation of HIF-1α. PMID:19705038

Consumers responses to coupons in direct-to-consumer advertising of prescription drugs.

PubMed

Bhutada, Nilesh S; Cook, Christopher L; Perri, Matthew

2009-01-01

A study was conducted to understand the influence of coupons and consumers' level of involvement in direct-to-consumer advertising. Consumers exposed to prescription drug advertising with a coupon had significantly more favorable ad and brand-related attitudes, and intention to inquire about the drug to their doctor. However, there was no significant difference in perceived product risk between consumers exposed to the ad with a coupon and consumers exposed to the ad without a coupon. Highly involved consumers had significantly more favorable ad, brand, and coupon-related attitudes, drug inquiry intention, and perceptions about the risks associated with the drug.

A common biological mechanism in cancer and Alzheimer’s disease?

PubMed Central

Behrens, Maria I; Lendon, Corinne; Roe, Catherine M.

2009-01-01

Cancer and Alzheimer’s disease (AD) are two common disorders for which the final pathophysiological mechanism is not yet clearly defined. In a prospective longitudinal study we have previously shown an inverse association between AD and cancer, such that the rate of developing cancer in general with time was significantly slower in participants with AD, while participants with a history of cancer had a slower rate of developing AD. In cancer, cell regulation mechanisms are disrupted with augmentation of cell survival and/or proliferation, whereas conversely, AD is associated with increased neuronal death, either caused by, or concomitant with, beta amyloid (Aβ) and tau deposition. The possibility that perturbations of mechanisms involved in cell survival/death regulation could be involved in both disorders is discussed. Genetic polymorphisms, DNA methylation or other mechanisms that induce changes in activity of molecules with key roles in determining the decision to “repair and live”- or “die” could be involved in the pathogenesis of the two disorders. As examples, the role of p53, Pin1 and the Wnt signaling pathway are discussed as potential candidates that, speculatively, may explain inverse associations between AD and cancer. PMID:19519301

Mechanisms of low-power noncoherent photon upconversion in metalloporphyrin-organic blue emitter systems in solution.

PubMed

Sugunan, Sunish K; Tripathy, Umakanta; Brunet, Sophie M K; Paige, Matthew F; Steer, Ronald P

2009-07-30

The mechanisms of noncoherent photon upconversion that involve triplet-triplet annihilation (TTA) in solution have been investigated for two model systems. ZnTPP (meso-tetraphenylporphine zinc) is used as the model visible light-absorbing metalloporphyrin because its S(1) fluorescence intensity can be used to monitor the initial rate of porphyrin triplet state production and because its S(2) fluorescence intensity can be used as a direct measure of the rate of porphyrin TTA. When perylene, which has a triplet energy lower than that of ZnTPP, is added as a signaling blue emitter (BE), the mechanism of photon upconversion involves triplet energy transfer from the porphyrin to the BE followed by TTA in the BE to form the fluorescent perylene S(1) state. The kinetics of this process have been characterized and are unremarkable. When coumarin 343 (C343), which has photophysical properties similar to those of perylene except that it has a much higher triplet energy than ZnTPP, is added as the signaling BE, emission from the ZnTPP S(2) state is quenched and fluorescence from the C343 grows in. Contrary to previous suggestions, the mechanism of photon upconversion in this system does not involve singlet energy transfer from the porphyrin S(2) state to the BE. Instead, ground-state C343 complexes with the ZnTPP triplet to form a triplet exciplex, which then undergoes TTA with a second ZnTPP triplet to give the fluorescent state of the BE in a three-center process.

A note on the entropy of rotating BPS AdS7 × S4 black holes

NASA Astrophysics Data System (ADS)

Hosseini, Seyed Morteza; Hristov, Kiril; Zaffaroni, Alberto

2018-05-01

In this note we show that the entropy of BPS, rotating, electrically charged AdS7 × S 4 black holes can be obtained by an extremization principle involving a particular combination of anomaly coefficients of the six-dimensional N=(2,0) theory. This result extends our previous finding for BPS, rotating AdS5 × S 5 black holes.

Screening Utility of the King-Devick Test in Mild Cognitive Impairment and Alzheimer Disease Dementia.

PubMed

Galetta, Kristin M; Chapman, Kimberly R; Essis, Maritza D; Alosco, Michael L; Gillard, Danielle; Steinberg, Eric; Dixon, Diane; Martin, Brett; Chaisson, Christine E; Kowall, Neil W; Tripodis, Yorghos; Balcer, Laura J; Stern, Robert A

2017-01-01

The King-Devick (K-D) test is a 1 to 2 minute, rapid number naming test, often used to assist with detection of concussion, but also has clinical utility in other neurological conditions (eg, Parkinson disease). The K-D involves saccadic eye and other eye movements, and abnormalities thereof may be an early indicator of Alzheimer disease (AD)-associated cognitive impairment. No study has tested the utility of the K-D in AD and we sought to do so. The sample included 206 [135 controls, 39 mild cognitive impairment (MCI), and 32 AD dementia] consecutive subjects from the Boston University Alzheimer's Disease Center registry undergoing their initial annual evaluation between March 2013 and July 2015. The K-D was administered during this period. Areas under the receiver operating characteristic curves generated from logistic regression models revealed the K-D test distinguished controls from subjects with cognitive impairment (MCI and AD dementia) [area under the curve (AUC)=0.72], MCI (AUC=0.71) and AD dementia (AUC=0.74). K-D time scores between 48 and 52 seconds were associated with high sensitivity (>90.0%) and negative predictive values (>85.0%) for each diagnostic group. The K-D correlated strongly with validated attention, processing speed, and visual scanning tests. The K-D test may be a rapid and simple effective screening tool to detect cognitive impairment associated with AD.

Evolution of Chloroplast Transcript Processing in Plasmodium and Its Chromerid Algal Relatives

PubMed Central

Dorrell, Richard G.; Drew, James; Nisbet, R. Ellen R.; Howe, Christopher J.

2014-01-01

It is well understood that apicomplexan parasites, such as the malaria pathogen Plasmodium, are descended from free-living algae, and maintain a vestigial chloroplast that has secondarily lost all genes of photosynthetic function. Recently, two fully photosynthetic relatives of parasitic apicomplexans have been identified, the ‘chromerid’ algae Chromera velia and Vitrella brassicaformis, which retain photosynthesis genes within their chloroplasts. Elucidating the processes governing gene expression in chromerid chloroplasts might provide valuable insights into the origins of parasitism in the apicomplexans. We have characterised chloroplast transcript processing pathways in C. velia, V. brassicaformis and P. falciparum with a focus on the addition of an unusual, 3′ poly(U) tail. We demonstrate that poly(U) tails in chromerids are preferentially added to transcripts that encode proteins that are directly involved in photosynthetic electron transfer, over transcripts for proteins that are not involved in photosynthesis. To our knowledge, this represents the first chloroplast transcript processing pathway to be associated with a particular functional category of genes. In contrast, Plasmodium chloroplast transcripts are not polyuridylylated. We additionally present evidence that poly(U) tail addition in chromerids is involved in the alternative processing of polycistronic precursors covering multiple photosynthesis genes, and appears to be associated with high levels of transcript abundance. We propose that changes to the chloroplast transcript processing machinery were an important step in the loss of photosynthesis in ancestors of parasitic apicomplexans. PMID:24453981

Phosphodiesterase Inhibition to Target the Synaptic Dysfunction in Alzheimer's Disease

NASA Astrophysics Data System (ADS)

Bales, Kelly R.; Plath, Niels; Svenstrup, Niels; Menniti, Frank S.

Alzheimer's Disease (AD) is a disease of synaptic dysfunction that ultimately proceeds to neuronal death. There is a wealth of evidence that indicates the final common mediator of this neurotoxic process is the formation and actions on synaptotoxic b-amyloid (Aβ). The premise in this review is that synaptic dysfunction may also be an initiating factor in for AD and promote synaptotoxic Aβ formation. This latter hypothesis is consistent with the fact that the most common risk factors for AD, apolipoprotein E (ApoE) allele status, age, education, and fitness, encompass suboptimal synaptic function. Thus, the synaptic dysfunction in AD may be both cause and effect, and remediating synaptic dysfunction in AD may have acute effects on the symptoms present at the initiation of therapy and also slow disease progression. The cyclic nucleotide (cAMP and cGMP) signaling systems are intimately involved in the regulation of synaptic homeostasis. The phosphodiesterases (PDEs) are a superfamily of enzymes that critically regulate spatial and temporal aspects of cyclic nucleotide signaling through metabolic inactivation of cAMP and cGMP. Thus, targeting the PDEs to promote improved synaptic function, or 'synaptic resilience', may be an effective and facile approach to new symptomatic and disease modifying therapies for AD. There continues to be a significant drug discovery effort aimed at discovering PDE inhibitors to treat a variety of neuropsychiatric disorders. Here we review the current status of those efforts as they relate to potential new therapies for AD.

An Island of Stability: Art Images and Natural Scenes - but Not Natural Faces - Show Consistent Esthetic Response in Alzheimer's-Related Dementia.

PubMed

Graham, Daniel J; Stockinger, Simone; Leder, Helmut

2013-01-01

Alzheimer's disease (AD) causes severe impairments in cognitive function but there is evidence that aspects of esthetic perception are somewhat spared, at least in early stages of the disease. People with early Alzheimer's-related dementia have been found to show similar degrees of stability over time in esthetic judgment of paintings compared to controls, despite poor explicit memory for the images. Here we expand on this line of inquiry to investigate the types of perceptual judgments involved, and to test whether people in later stages of the disease also show evidence of preserved esthetic judgment. Our results confirm that, compared to healthy controls, there is similar esthetic stability in early stage AD in the absence of explicit memory, and we report here that people with later stages of the disease also show similar stability compared to controls. However, while we find that stability for portrait paintings, landscape paintings, and landscape photographs is not different compared to control group performance, stability for face photographs - which were matched for identity with the portrait paintings - was significantly impaired in the AD group. We suggest that partially spared face-processing systems interfere with esthetic processing of natural faces in ways that are not found for artistic images and landscape photographs. Thus, our work provides a novel form of evidence regarding face-processing in healthy and diseased aging. Our work also gives insights into general theories of esthetics, since people with AD are not encumbered by many of the semantic and emotional factors that otherwise color esthetic judgment. We conclude that, for people with AD, basic esthetic judgment of artistic images represents an "island of stability" in a condition that in most other respects causes profound cognitive disruption. As such, esthetic response could be a promising route to future therapies.

An Island of Stability: Art Images and Natural Scenes – but Not Natural Faces – Show Consistent Esthetic Response in Alzheimer’s-Related Dementia

PubMed Central

Graham, Daniel J.; Stockinger, Simone; Leder, Helmut

2013-01-01

Alzheimer’s disease (AD) causes severe impairments in cognitive function but there is evidence that aspects of esthetic perception are somewhat spared, at least in early stages of the disease. People with early Alzheimer’s-related dementia have been found to show similar degrees of stability over time in esthetic judgment of paintings compared to controls, despite poor explicit memory for the images. Here we expand on this line of inquiry to investigate the types of perceptual judgments involved, and to test whether people in later stages of the disease also show evidence of preserved esthetic judgment. Our results confirm that, compared to healthy controls, there is similar esthetic stability in early stage AD in the absence of explicit memory, and we report here that people with later stages of the disease also show similar stability compared to controls. However, while we find that stability for portrait paintings, landscape paintings, and landscape photographs is not different compared to control group performance, stability for face photographs – which were matched for identity with the portrait paintings – was significantly impaired in the AD group. We suggest that partially spared face-processing systems interfere with esthetic processing of natural faces in ways that are not found for artistic images and landscape photographs. Thus, our work provides a novel form of evidence regarding face-processing in healthy and diseased aging. Our work also gives insights into general theories of esthetics, since people with AD are not encumbered by many of the semantic and emotional factors that otherwise color esthetic judgment. We conclude that, for people with AD, basic esthetic judgment of artistic images represents an “island of stability” in a condition that in most other respects causes profound cognitive disruption. As such, esthetic response could be a promising route to future therapies. PMID:23471005

Factors influencing clicking of banner ads on the WWW.

PubMed

Cho, Chang-Hoan

2003-04-01

This paper explores various factors influencing the clicking of banner ads on the WWW. The study indicates that several important variables affect the clicking of banner ads: (1) level of product involvement, (2) congruency between the content of a vehicle and the product category of a banner ad, (3) attitude toward the vehicle, and (4) overall attitude toward web advertising. For methodology, this study employed a between-group experimental design and measured real click-through rates with the aid of an online data collection technology called FileMaker Pro. Results of logistic regressions show that people are more likely to click banner ads if they are highly involved with products, perceive high synergy between web pages and ads, have a favorable attitude toward a vehicle, or have a favorable attitude toward web advertising in general. A total of 756 subjects participated in this research.

Extraction and purification of high added value compounds from by-products of the winemaking chain using alternative/nonconventional processes/technologies.

PubMed

Yammine, Sami; Brianceau, Sylène; Manteau, Sébastien; Turk, Mohammad; Ghidossi, Rémy; Vorobiev, Eugène; Mietton-Peuchot, Martine

2018-05-24

Grape byproducts are today considered as a cheap source of valuable compounds since existent technologies allow the recovery of target compounds and their recycling. The goal of the current article is to explore the different recovery stages used by both conventional and alternative techniques and processes. Alternative pre-treatments techniques reviewed are: ultrasounds, pulsed electric fields and high voltage discharges. In addition, nonconventional solvent extraction under high pressure, specifically, supercritical fluid extraction and subcritical water extraction are discussed. Finally alternative purification technologies, for example membrane processing were also examined. The intent is to describe the mechanisms involved by these alternative technologies and to summarize the work done on the improvement of the extraction process of phenolic compounds from winery by-products. With a focus on the developmental stage of each technology, highlighting the research need and challenges to be overcome for an industrial implementation of these unitary operations in the overall extraction process. A critical comparison of conventional and alternative techniques will be reviewed for ethe pre-treatment of raw material, the diffusion of polyphenols and the purification of these high added value compounds. This review intends to give the reader some key answers (costs, advantages, drawbacks) to help in the choice of alternative technologies for extraction purposes.

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.

Affective and executive network processing associated with persuasive antidrug messages.

PubMed

Ramsay, Ian S; Yzer, Marco C; Luciana, Monica; Vohs, Kathleen D; MacDonald, Angus W

2013-07-01

Previous research has highlighted brain regions associated with socioemotional processes in persuasive message encoding, whereas cognitive models of persuasion suggest that executive brain areas may also be important. The current study aimed to identify lateral prefrontal brain areas associated with persuasive message viewing and understand how activity in these executive regions might interact with activity in the amygdala and medial pFC. Seventy adolescents were scanned using fMRI while they watched 10 strongly convincing antidrug public service announcements (PSAs), 10 weakly convincing antidrug PSAs, and 10 advertisements (ads) unrelated to drugs. Antidrug PSAs compared with nondrug ads more strongly elicited arousal-related activity in the amygdala and medial pFC. Within antidrug PSAs, those that were prerated as strongly persuasive versus weakly persuasive showed significant differences in arousal-related activity in executive processing areas of the lateral pFC. In support of the notion that persuasiveness involves both affective and executive processes, functional connectivity analyses showed greater coactivation between the lateral pFC and amygdala during PSAs known to be strongly (vs. weakly) convincing. These findings demonstrate that persuasive messages elicit activation in brain regions responsible for both emotional arousal and executive control and represent a crucial step toward a better understanding of the neural processes responsible for persuasion and subsequent behavior change.

Reliability of an interactive computer program for advance care planning.

PubMed

Schubart, Jane R; Levi, Benjamin H; Camacho, Fabian; Whitehead, Megan; Farace, Elana; Green, Michael J

2012-06-01

Despite widespread efforts to promote advance directives (ADs), completion rates remain low. Making Your Wishes Known: Planning Your Medical Future (MYWK) is an interactive computer program that guides individuals through the process of advance care planning, explaining health conditions and interventions that commonly involve life or death decisions, helps them articulate their values/goals, and translates users' preferences into a detailed AD document. The purpose of this study was to demonstrate that (in the absence of major life changes) the AD generated by MYWK reliably reflects an individual's values/preferences. English speakers ≥30 years old completed MYWK twice, 4 to 6 weeks apart. Reliability indices were assessed for three AD components: General Wishes; Specific Wishes for treatment; and Quality-of-Life values (QoL). Twenty-four participants completed the study. Both the Specific Wishes and QoL scales had high internal consistency in both time periods (Knuder Richardson formula 20 [KR-20]=0.83-0.95, and 0.86-0.89). Test-retest reliability was perfect for General Wishes (κ=1), high for QoL (Pearson's correlation coefficient=0.83), but lower for Specific Wishes (Pearson's correlation coefficient=0.57). MYWK generates an AD where General Wishes and QoL (but not Specific Wishes) statements remain consistent over time.

Reliability of an Interactive Computer Program for Advance Care Planning

PubMed Central

Levi, Benjamin H.; Camacho, Fabian; Whitehead, Megan; Farace, Elana; Green, Michael J

2012-01-01

Abstract Despite widespread efforts to promote advance directives (ADs), completion rates remain low. Making Your Wishes Known: Planning Your Medical Future (MYWK) is an interactive computer program that guides individuals through the process of advance care planning, explaining health conditions and interventions that commonly involve life or death decisions, helps them articulate their values/goals, and translates users' preferences into a detailed AD document. The purpose of this study was to demonstrate that (in the absence of major life changes) the AD generated by MYWK reliably reflects an individual's values/preferences. English speakers ≥30 years old completed MYWK twice, 4 to 6 weeks apart. Reliability indices were assessed for three AD components: General Wishes; Specific Wishes for treatment; and Quality-of-Life values (QoL). Twenty-four participants completed the study. Both the Specific Wishes and QoL scales had high internal consistency in both time periods (Knuder Richardson formula 20 [KR-20]=0.83–0.95, and 0.86–0.89). Test-retest reliability was perfect for General Wishes (κ=1), high for QoL (Pearson's correlation coefficient=0.83), but lower for Specific Wishes (Pearson's correlation coefficient=0.57). MYWK generates an AD where General Wishes and QoL (but not Specific Wishes) statements remain consistent over time. PMID:22512830

17β-Estradiol Induces Overproliferation in Adenomyotic Human Uterine Smooth Muscle Cells of the Junctional Zone Through Hyperactivation of the Estrogen Receptor-Enhanced RhoA/ROCK Signaling Pathway.

PubMed

Sun, Fu-Qing; Duan, Hua; Wang, Sha; Li, Jin-Jiao

2015-11-01

Adenomyosis (ADS) is a common estrogen-dependent gynecological disease with unknown etiology. Recent models favor abnormal thickening of the junctional zone (JZ) may be the causative factor in the development of ADS. RhoA, a small guanosine triphosphatase which controls multiple cellular processes, is involved in the control of cell proliferation. Here we demonstrate that treatment of human uterine smooth muscle cells (SMCs) of the JZ with 17β-estradiol (E2) increased expression of RhoA and its downstream effectors (-associated coiled coil containing protein kinase [ROCK] 1 and ROCK2). Compared with non-ADS cells, RhoA, ROCK1, and ROCK2 were overexpressed and hyperactivated in ADS cells. These effects were suppressed in the presence of ICI 182,780, supporting an estrogen receptor (ER)-dependent mechanism. Hyperactivation of ER-enhanced RhoA/ROCK signaling was associated with overproliferation in ADS human uterine SMCs of the JZ. Moreover, E2-induced overproliferation was accompanied by downregulation of cyclin-dependent kinases inhibitors (CKIs; p21(Waf1/Cip1) and p27(Kip1)) and upregulation of cyclin-dependent kinases (CDKs) and cyclins (cyclin D1, cyclin E1, CDK2, CDK4, and CDK6). © The Author(s) 2015.

Ultra-processed foods and added sugars in the US diet: evidence from a nationally representative cross-sectional study

PubMed Central

Martínez Steele, Eurídice; Baraldi, Larissa Galastri; Louzada, Maria Laura da Costa; Moubarac, Jean-Claude; Mozaffarian, Dariush; Monteiro, Carlos Augusto

2016-01-01

Objectives To investigate the contribution of ultra-processed foods to the intake of added sugars in the USA. Ultra-processed foods were defined as industrial formulations which, besides salt, sugar, oils and fats, include substances not used in culinary preparations, in particular additives used to imitate sensorial qualities of minimally processed foods and their culinary preparations. Design Cross-sectional study. Setting National Health and Nutrition Examination Survey 2009–2010. Participants We evaluated 9317 participants aged 1+ years with at least one 24 h dietary recall. Main outcome measures Average dietary content of added sugars and proportion of individuals consuming more than 10% of total energy from added sugars. Data analysis Gaussian and Poisson regressions estimated the association between consumption of ultra-processed foods and intake of added sugars. All models incorporated survey sample weights and adjusted for age, sex, race/ethnicity, family income and educational attainment. Results Ultra-processed foods comprised 57.9% of energy intake, and contributed 89.7% of the energy intake from added sugars. The content of added sugars in ultra-processed foods (21.1% of calories) was eightfold higher than in processed foods (2.4%) and fivefold higher than in unprocessed or minimally processed foods and processed culinary ingredients grouped together (3.7%). Both in unadjusted and adjusted models, each increase of 5 percentage points in proportional energy intake from ultra-processed foods increased the proportional energy intake from added sugars by 1 percentage point. Consumption of added sugars increased linearly across quintiles of ultra-processed food consumption: from 7.5% of total energy in the lowest quintile to 19.5% in the highest. A total of 82.1% of Americans in the highest quintile exceeded the recommended limit of 10% energy from added sugars, compared with 26.4% in the lowest. Conclusions Decreasing the consumption of ultra-processed foods could be an effective way of reducing the excessive intake of added sugars in the USA. PMID:26962035

Category Cued Recall Evokes a Generate-Recognize Retrieval Process

PubMed Central

Hunt, R. Reed; Smith, Rebekah E.; Toth, Jeffrey P.

2015-01-01

The experiments reported here were designed to replicate and extend McCabe, Roediger, and Karpicke’s (2011) finding that retrieval in category cued recall involves both controlled and automatic processes. The extension entailed identifying whether distinctive encoding affected one or both of these two processes. The first experiment successfully replicated McCabe et al., but the second, which added a critical baseline condition, produced data inconsistent with a two independent process model of recall. The third experiment provided evidence that retrieval in category cued recall reflects a generate-recognize strategy, with the effect of distinctive processing being localized to recognition. Overall, the data suggest that category cued recall evokes a generate-recognize retrieval strategy and that the sub-processes underlying this strategy can be dissociated as a function of distinctive versus relational encoding processes. PMID:26280355

Current concepts on selected plant secondary metabolites with promising inhibitory effects against enzymes linked to Alzheimer's disease.

PubMed

Orhan, I Erdogan

2012-01-01

Alzheimer's disease (AD) has become one of the deadliest diseases for human beings with special incidence in elderly population. It is a progressive neurodegenerative disease and the most prevalent cause of dementia. The neuropathology of AD has not been fully elucidated yet, however, cholinergic hypothesis is the most accepted theory nowadays, resulting from the cholinergic deficit emerging in the brains of AD patients. Shortage of the neurotransmitters, acetylcholine and butyrylcholine has been demonstrated, and therefore, inhibition of the enzymes; acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) that break down acetylcholine and butyrylcholine has become a standard approach for AD treatment. However, cholinesterase inhibitors are only effective in symptomatic treatment and have no ability to impede the disease. The pathogenesis of AD is highly complex and another hypothesis is the formation of amyloid plaques containing beta-amyloid peptide, which causes neurolesions in the brains of AD patients. Beta-amyloid peptide is generated after the sequential cleavage of amyloid precursor protein, especially by the beta- and gamma-secretase in the amyloidogenic pathway. The secretases involved in the processing of amyloid precursor protein are of particular interest and, consequently, the inhibition of secretase enzyme family of protease type has become another desired treatment strategy for AD. On the other hand, medicinal plants are attractive sources for drug research and development as they produce chemically-varying molecules with preferred biological activities. The aim of this article is to review the available data on selected inhibitors from plant secondary metabolites with emphasis on cholinesterase, prolyl endopeptidase, and secretase enzyme families as being the current treatments of AD.

Gender effects in alcohol dependence: an fMRI pilot study examining affective processing.

PubMed

Padula, Claudia B; Anthenelli, Robert M; Eliassen, James C; Nelson, Erik; Lisdahl, Krista M

2015-02-01

Alcohol dependence (AD) has global effects on brain structure and function, including frontolimbic regions regulating affective processing. Preliminary evidence suggests alcohol blunts limbic response to negative affective stimuli and increases activation to positive affective stimuli. Subtle gender differences are also evident during affective processing. Fourteen abstinent AD individuals (8 F, 6 M) and 14 healthy controls (9 F, 5 M), ages 23 to 60, were included in this facial affective processing functional magnetic resonance imaging pilot study. Whole-brain linear regression analyses were performed, and follow-up analyses examined whether AD status significantly predicted depressive symptoms and/or coping. Fearful Condition-The AD group demonstrated reduced activation in the right medial frontal gyrus, compared with controls. Gender moderated the effects of AD in bilateral inferior frontal gyri. Happy Condition-AD individuals had increased activation in the right thalamus. Gender moderated the effects of AD in the left caudate, right middle frontal gyrus, left paracentral lobule, and right lingual gyrus. Interactive AD and gender effects for fearful and happy faces were such that AD men activated more than control men, but AD women activated less than control women. Enhanced coping was associated with greater activation in right medial frontal gyrus during fearful condition in AD individuals. Abnormal affective processing in AD may be a marker of alcoholism risk or a consequence of chronic alcoholism. Subtle gender differences were observed, and gender moderated the effects of AD on neural substrates of affective processing. AD individuals with enhanced coping had brain activation patterns more similar to controls. Results help elucidate the effects of alcohol, gender, and their interaction on affective processing. Copyright © 2015 by the Research Society on Alcoholism.

Gender Effects in Alcohol Dependence: An fMRI Pilot Study Examining Affective Processing

PubMed Central

Padula, Claudia B.; Anthenelli, Robert M.; Eliassen, James C.; Nelson, Erik; Lisdahl, Krista M.

2017-01-01

Background Alcohol dependence (AD) has global effects on brain structure and function, including frontolimbic regions regulating affective processing. Preliminary evidence suggests alcohol blunts limbic response to negative affective stimuli and increases activation to positive affective stimuli. Subtle gender differences are also evident during affective processing. Methods Fourteen abstinent AD individuals (8 F, 6 M) and 14 healthy controls (9 F, 5 M), ages 23 to 60, were included in this facial affective processing functional magnetic resonance imaging pilot study. Whole-brain linear regression analyses were performed, and follow-up analyses examined whether AD status significantly predicted depressive symptoms and/or coping. Results Fearful Condition—The AD group demonstrated reduced activation in the right medial frontal gyrus, compared with controls. Gender moderated the effects of AD in bilateral inferior frontal gyri. Happy Condition—AD individuals had increased activation in the right thalamus. Gender moderated the effects of AD in the left caudate, right middle frontal gyrus, left paracentral lobule, and right lingual gyrus. Interactive AD and gender effects for fearful and happy faces were such that AD men activated more than control men, but AD women activated less than control women. Enhanced coping was associated with greater activation in right medial frontal gyrus during fearful condition in AD individuals. Conclusions Abnormal affective processing in AD may be a marker of alcoholism risk or a consequence of chronic alcoholism. Subtle gender differences were observed, and gender moderated the effects of AD on neural substrates of affective processing. AD individuals with enhanced coping had brain activation patterns more similar to controls. Results help elucidate the effects of alcohol, gender, and their interaction on affective processing. PMID:25684049

Caspase-2 cleavage of tau reversibly impairs memory.

PubMed

Zhao, Xiaohui; Kotilinek, Linda A; Smith, Benjamin; Hlynialuk, Chris; Zahs, Kathleen; Ramsden, Martin; Cleary, James; Ashe, Karen H

2016-11-01

In Alzheimer's disease (AD) and other tauopathies, the tau protein forms fibrils, which are believed to be neurotoxic. However, fibrillar tau has been dissociated from neuron death and network dysfunction, suggesting the involvement of nonfibrillar species. Here we describe a novel pathological process in which caspase-2 cleavage of tau at Asp314 impairs cognitive and synaptic function in animal and cellular models of tauopathies by promoting the missorting of tau to dendritic spines. The truncation product, Δtau314, resists fibrillation and is present at higher levels in brains from cognitively impaired mice and humans with AD. The expression of tau mutants that resisted caspase-2 cleavage prevented tau from infiltrating spines, dislocating glutamate receptors and impairing synaptic function in cultured neurons, and it prevented memory deficits and neurodegeneration in mice. Decreasing the levels of caspase-2 restored long-term memory in mice that had existing deficits. Our results suggest an overall treatment strategy for re-establishing synaptic function and restoring memory in patients with AD by preventing tau from accumulating in dendritic spines.

Expression of IL-33 in chronic lesional skin of canine atopic dermatitis.

PubMed

Asahina, Ryota; Nishida, Hidetaka; Kamishina, Hiroaki; Maeda, Sadatoshi

2018-06-01

In humans, interleukin (IL)-33 plays a critical role in the enhancement of allergic skin inflammation. However, it currently remains unclear whether IL-33 is involved in the pathogenesis of canine atopic dermatitis (cAD). To examine the expression of IL-33 in chronic lesional skin of cAD. Eight dogs with spontaneous cAD and five healthy dogs were used. The transcription of il-33 in chronic lesional skin of cAD was quantified by quantitative reverse transcription PCR. The expression of IL-33 was evaluated immunohistochemically using an anti-human IL-33 monoclonal antibody with cross-reactivity to canine IL-33. The transcription levels of il-33 in chronic lesional skin of cAD were significantly higher than those in normal skin of healthy dogs. Keratinocytes were a major cellular source of IL-33 production in chronic lesional skin of cAD. The results indicate that IL-33 is involved in chronic lesional skin of cAD. © 2018 ESVD and ACVD.

Academic dishonesty in higher education: students' perceptions and involvement in an African institution.

PubMed

Saana, Sixtus Bieranye Bayaa Martin; Ablordeppey, Ephraim; Mensah, Napoleon Jackson; Karikari, Thomas K

2016-04-25

Integrity in academic work is a critical benchmark of every profession. For this reason, special attention should be devoted to addressing academic dishonesty (AD) in higher education to prevent the potential transfer of these practices to the workplace. In order to effectively address AD in Africa, further information about correlates of, and barriers to, the effectiveness of existing AD-controlling measures is needed. In Ghana, little is known about AD from the perspective of students. Here, we present a first report of Ghanaian undergraduate students' self-reported understanding of, and support for, institutional AD regulations, their involvement in specific dishonest behaviours, as well as their motivation factors. Approximately 92% of respondents said they were aware of institutional regulations on AD. However, only 31% rated their understanding as high. Respondents believed that their lecturers had better understanding of, and support for, these regulations than the students (p < 0.001 and p < 0.0001 respectively). Approximately 40% of respondents had witnessed their colleagues engage in AD before, but the majority (94%) had never reported these acts. The pursuit of good grades, high academic load and pressure to please family and guardians were the leading causes of AD. Cheating during examinations and inappropriately sharing answers in the preparation of assignments were some of the highly-occurring forms of AD. Respondents believed that copying colleagues' work without their permission was a serious offense but doing so with their permission was not. Our findings suggest that the sampled students consent to cheating-they believed that they committed no misconduct once the parties involved had agreed on the act. Considering these misconceptions, institutions should do more to help their students better understand the different forms of AD and how to avoid them.

Adenosine/nitric oxide crosstalk in the branchial circulation of Squalus acanthias and Anguilla anguilla.

PubMed

Pellegrino, D; Tota, B; Randall, D J

2005-10-01

The potent vasomodulator adenosine (AD), thanks to the interaction with by A(1) and A(2) receptors, dilates systemic, coronary and cerebral vasculatures but exert a constrictor action in several vessels of respiratory organs. Recent investigations suggest that nitric oxide (NO) contributes to AD effects. In fish, both NO and AD induce atypical effects compared to mammals. Since there is very little information on the role of NO and its involvement in mediating the actions of AD in fish, we have analysed this question in the branchial vasculature of the elasmobranch Squalus acanthias and the teleost Anguilla anguilla using an isolated perfused head and a branchial basket preparation, respectively. In both dogfish and eel, AD dose-response curves showed a biphasic effect: vasoconstriction (pico to nanomolar range) and vasodilation (micromolar range). Both effects were abolished by the classic xanthine inhibitor theophylline (Theo) and also by specific antagonists of A(1) and A(2) receptor subtypes. To analyse the involvement of the NO/cGMP system in the AD responses, we tested a NOS inhibitor, l-NIO, and a specific soluble guanylate cyclase (sGC) blocker, ODQ. In both dogfish and eel preparations l-NIO abrogated all vasomotor effects of AD, whereas ODQ blocked the AD-mediated vasoconstriction without affecting the vasorelaxant response. This indicates that only AD-induced vasoconstriction is mediated by a NO-cGMP-dependent mechanism. By using the NO donor SIN-1, we showed a dose-dependent vasoconstrictory effect which was completely blocked by ODQ. These results provide compelling evidence that the vasoactive role of AD in the branchial circulation of S. acanthias and A. anguilla involves a NO signalling.

Multifactorial Analysis of a Biomarker Pool for Alzheimer Disease Risk in a North Indian Population.

PubMed

Talwar, Puneet; Grover, Sandeep; Sinha, Juhi; Chandna, Puneet; Agarwal, Rachna; Kushwaha, Suman; Kukreti, Ritushree

2017-01-01

Alzheimer disease (AD) is a progressive neurodegenerative disease with a complex multifactorial etiology. Here, we aim to identify a biomarker pool comprised of genetic variants and blood biomarkers as predictor of AD risk. We performed a case-control study involving 108 cases and 159 non-demented healthy controls to examine the association of multiple biomarkers with AD risk. The APOE genotyping revealed that ε4 allele frequency was significantly high (p value = 0.0001, OR = 2.66, 95% CI 1.58-4.46) in AD as compared to controls, whereas ε2 (p = 0.0430, OR = 0.29, CI 0.07-1.10) was overrepresented in controls. In biochemical assays, significant differences in levels of total copper, free copper, zinc, copper/zinc ratio, iron, epidermal growth factor receptor (EGFR), leptin, and albumin were also observed. The AD risk score (ADRS) as a linear combination of 6 candidate markers involving age, education status, APOE ε4 allele, levels of iron, Cu/Zn ratio, and EGFR was created using stepwise linear discriminant analysis. The area under the ROC curve of the ADRS panel for predicting AD risk was significantly high (AUC = 0.84, p < 0.0001, 95% CI 0.78-0.89, sensitivity = 70.0%, specificity = 83.8%) compared to individual parameters. These findings support the multifactorial etiology of AD and demonstrate the ability of a panel involving 6 biomarkers to discriminate AD cases from non-demented healthy controls. © 2017 S. Karger AG, Basel.

Project Facilitate: An Inservice Education Program for Educators and Parents.

ERIC Educational Resources Information Center

Worthington, Lou Anne; Wortham, Joycelyn Foy; Smith, Cynthia Ruth Blocker; Patterson, David

1997-01-01

Describes "Project Facilitate," an inservice education program that provides educators and parents with a comprehensive overview of attention deficit hyperactivity disorder (AD/HD). The program involves the use of four self-instructional content manuals: AD/HD general knowledge base, legal issues and AD/HD, assessment of children with AD/HD, and…

Added sugars and ultra-processed foods in Spanish households (1990-2010).

PubMed

Latasa, P; Louzada, M L D C; Martinez Steele, E; Monteiro, C A

2017-12-26

To study the association between ultra-processed foods acquisitions and added sugar content of total food purchases in Spanish households in 2010. Changes over time (1990-2000-2010) in ultra-processed food purchases and added sugars content of total food purchases are also compared. We used data from three nationally representative Household Budget Surveys (HBS) conducted in 1990, 2000 and 2010. Number of studied households was 21,012, 33,730 and 22,116, respectively. Purchased foods and drinks were classified according to NOVA food groups as ultra-processed foods, processed foods, unprocessed or minimally processed foods, or processed culinary ingredients. Linear and Poisson regressions were used to estimate the association between quintiles of energy contribution of ultra-processed foods and added sugars contents of total food purchases in 2010. Changes over time were assessed using tests of linear trend and Student's t test. In 2010, ultra-processed foods represented 31.7% of daily energy acquisitions and 80.4% of all added sugars. Added sugars content of food purchases raised from 7.3% in the lowest to 18.2% in the highest quintiles of energy contribution of ultra-processed foods. The risk of exceeding 10% energy from added sugars quadrupled between the lowest and highest quintiles. The percentage of ultra-processed foods on all food purchases almost tripled between 1990 and 2010 (from 11.0 to 31.7%), paralleling the increase of added sugars content (from 8.4 to 13.0%). Cutting down exceeding added sugars availability in Spain may require a reduction in ultra-processed food purchasing.

Application of Ferulic Acid for Alzheimer’s Disease: Combination of Text Mining and Experimental Validation

PubMed Central

Meng, Guilin; Meng, Xiulin; Ma, Xiaoye; Zhang, Gengping; Hu, Xiaolin; Jin, Aiping; Liu, Xueyuan

2018-01-01

Alzheimer’s disease (AD) is an increasing concern in human health. Despite significant research, highly effective drugs to treat AD are lacking. The present study describes the text mining process to identify drug candidates from a traditional Chinese medicine (TCM) database, along with associated protein target mechanisms. We carried out text mining to identify literatures that referenced both AD and TCM and focused on identifying compounds and protein targets of interest. After targeting one potential TCM candidate, corresponding protein-protein interaction (PPI) networks were assembled in STRING to decipher the most possible mechanism of action. This was followed by validation using Western blot and co-immunoprecipitation in an AD cell model. The text mining strategy using a vast amount of AD-related literature and the TCM database identified curcumin, whose major component was ferulic acid (FA). This was used as a key candidate compound for further study. Using the top calculated interaction score in STRING, BACE1 and MMP2 were implicated in the activity of FA in AD. Exposure of SHSY5Y-APP cells to FA resulted in the decrease in expression levels of BACE-1 and APP, while the expression of MMP-2 and MMP-9 increased in a dose-dependent manner. This suggests that FA induced BACE1 and MMP2 pathways maybe novel potential mechanisms involved in AD. The text mining of literature and TCM database related to AD suggested FA as a promising TCM ingredient for the treatment of AD. Potential mechanisms interconnected and integrated with Aβ aggregation inhibition and extracellular matrix remodeling underlying the activity of FA were identified using in vitro studies. PMID:29896095

Application of Ferulic Acid for Alzheimer's Disease: Combination of Text Mining and Experimental Validation.

PubMed

Meng, Guilin; Meng, Xiulin; Ma, Xiaoye; Zhang, Gengping; Hu, Xiaolin; Jin, Aiping; Zhao, Yanxin; Liu, Xueyuan

2018-01-01

Alzheimer's disease (AD) is an increasing concern in human health. Despite significant research, highly effective drugs to treat AD are lacking. The present study describes the text mining process to identify drug candidates from a traditional Chinese medicine (TCM) database, along with associated protein target mechanisms. We carried out text mining to identify literatures that referenced both AD and TCM and focused on identifying compounds and protein targets of interest. After targeting one potential TCM candidate, corresponding protein-protein interaction (PPI) networks were assembled in STRING to decipher the most possible mechanism of action. This was followed by validation using Western blot and co-immunoprecipitation in an AD cell model. The text mining strategy using a vast amount of AD-related literature and the TCM database identified curcumin, whose major component was ferulic acid (FA). This was used as a key candidate compound for further study. Using the top calculated interaction score in STRING, BACE1 and MMP2 were implicated in the activity of FA in AD. Exposure of SHSY5Y-APP cells to FA resulted in the decrease in expression levels of BACE-1 and APP, while the expression of MMP-2 and MMP-9 increased in a dose-dependent manner. This suggests that FA induced BACE1 and MMP2 pathways maybe novel potential mechanisms involved in AD. The text mining of literature and TCM database related to AD suggested FA as a promising TCM ingredient for the treatment of AD. Potential mechanisms interconnected and integrated with Aβ aggregation inhibition and extracellular matrix remodeling underlying the activity of FA were identified using in vitro studies.

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.

[Relationship between multi-slice spiral CT angiography imaging features and in-hospital death of patients with aortic dissection].

PubMed

Xiao, Z Y; Wang, H J; Yao, C L; Gu, G R; Xue, Y; Yin, J; Chen, J; Zhang, C; Tong, C Y; Song, Z J

2017-03-24

Objective: To explore the imaging manifestations of multi-slice spiral CT angiography (CTA) and relationship with in-hospital death in patients with aortic dissection (AD). Methods: The clinical data of 429 patients with AD who underwent CTA in Zhongshan Hospital of Fudan University between January 2009 and January 2016 were retrospectively analyzed. AD patients were divided into 2 groups, including operation group who underwent surgery or interventional therapy (370 cases) and non-operation group who underwent medical conservative treatment(59 cases). The multi-slice spiral CTA imaging features of AD were analyzed, and multivariate logistic regression analysis was used to investigate the relationship between imaging manifestations and in-hospital death in AD patients. Results: There were 12 cases (3.24%) of in-hospital death in operation group, and 28 cases (47.46%) of in-hospital death in non-operation group( P <0.001). AD involved different vascular branches. Multi-slice spiral CTA can clearly show the dissection of true and false lumen, and intimal tear was detected in 363 (84.62%) cases, outer wall calcification was revealed in 63 (14.69%) cases, and thrombus formation was present in 227 (52.91%) cases. The multivariate logistic regression analysis showed that the number of branch vessels involved ( OR =1.374, 95% CI 1.081-1.745, P =0.009) and tearing false lumen range( OR =2.059, 95% CI 1.252-3.385, P =0.004) were independent risk factors of in-hospital death in AD patients, and the number of branch vessels involved ( OR =1.600, 95% CI 1.062-2.411, P =0.025) was independent risk factor of in-hospital death in the operation group, while the tearing false lumen range ( OR =2.315, 95% CI 1.019-5.262, P =0.045) was independent risk factor of in-hospital death of non-operation group. Conclusions: Multi-slice spiral CTA can clearly show the entire AD, true and false lumen, intimal tear, wall calcification and thrombosis of AD patients. The number of branch vessels involved and tearing false lumen range are the independent risk factors of in-hospital death in AD patients.

Identification of the key molecules involved in chronic copper exposure-aggravated memory impairment in transgenic mice of Alzheimer's disease using proteomic analysis.

PubMed

Yu, Jun; Luo, Xiaobin; Xu, Hua; Ma, Quan; Yuan, Jianhui; Li, Xuling; Chang, Raymond Chuen-Chung; Qu, Zhongsen; Huang, Xinfeng; Zhuang, Zhixiong; Liu, Jianjun; Yang, Xifei

2015-01-01

Alzheimer's disease (AD) is the most common neurodegenerative disease characterized by a progressive impairment of cognitive functions including spatial learning and memory. Excess copper exposure accelerates the development of AD; however, the potential mechanisms by which copper exacerbates the symptoms of AD remain unknown. In this study, we explored the effects of chronic copper exposure on cognitive function by treating 6 month-old triple AD transgenic (3xTg-AD) mice with 250 ppm copper sulfate in drinking water for 6 months, and identified several potential key molecules involved in the effects of chronic copper exposure on memory by proteomic analysis. The behavioral test showed that chronic copper exposure aggravated memory impairment of 3xTg-AD mice. Two-dimensional fluorescence difference gel electrophoresis (2D-DIGE) coupled with mass spectrometry revealed a total of 44 differentially expressed proteins (18 upregulated and 26 down-regulated) in hippocampus between the wild-type (WT) mice and non-exposed 3xTg-AD mice. A total of 40 differentially expressed proteins were revealed (20 upregulated and 20 down-regulated) in hippocampus between copper exposed and non-exposed 3xTg-AD mice. Among these differentially expressed proteins, complexin-1 and complexin-2, two memory associated proteins, were significantly decreased in hippocampus of 3xTg-AD mice compared with the WT mice. Furthermore, the expression of these two proteins was further down-regulated in 3xTg-AD mice when exposed to copper. The abnormal expression of complexin-1 and complexin-2 identified by proteomic analysis was verified by western blot analysis. Taken together, our data showed that chronic copper exposure accelerated memory impairment and altered the expression of proteins in hippocampus in 3xTg-AD mice. The functional analysis on the differentially expressed proteins suggested that complexin-1 and complexin-2 may be the key molecules involved in chronic copper exposure-aggravated memory impairment in AD.

Knowledge-driven computational modeling in Alzheimer's disease research: Current state and future trends.

PubMed

Geerts, Hugo; Hofmann-Apitius, Martin; Anastasio, Thomas J

2017-11-01

Neurodegenerative diseases such as Alzheimer's disease (AD) follow a slowly progressing dysfunctional trajectory, with a large presymptomatic component and many comorbidities. Using preclinical models and large-scale omics studies ranging from genetics to imaging, a large number of processes that might be involved in AD pathology at different stages and levels have been identified. The sheer number of putative hypotheses makes it almost impossible to estimate their contribution to the clinical outcome and to develop a comprehensive view on the pathological processes driving the clinical phenotype. Traditionally, bioinformatics approaches have provided correlations and associations between processes and phenotypes. Focusing on causality, a new breed of advanced and more quantitative modeling approaches that use formalized domain expertise offer new opportunities to integrate these different modalities and outline possible paths toward new therapeutic interventions. This article reviews three different computational approaches and their possible complementarities. Process algebras, implemented using declarative programming languages such as Maude, facilitate simulation and analysis of complicated biological processes on a comprehensive but coarse-grained level. A model-driven Integration of Data and Knowledge, based on the OpenBEL platform and using reverse causative reasoning and network jump analysis, can generate mechanistic knowledge and a new, mechanism-based taxonomy of disease. Finally, Quantitative Systems Pharmacology is based on formalized implementation of domain expertise in a more fine-grained, mechanism-driven, quantitative, and predictive humanized computer model. We propose a strategy to combine the strengths of these individual approaches for developing powerful modeling methodologies that can provide actionable knowledge for rational development of preventive and therapeutic interventions. Development of these computational approaches is likely to be required for further progress in understanding and treating AD. Copyright © 2017 the Alzheimer's Association. Published by Elsevier Inc. All rights reserved.

What Is Inflammatory Breast Cancer? Revisiting the Case Definition

DTIC Science & Technology

2010-03-03

d’orange 7 14% Warmth 6 12% Thick mass 3 6% Other 12 24% Initial clinical diagnoses for 10 women were infection, including nine diagnoses of mastitis ...antibiotics since it may be inadvisable to biopsy an infectious process, but clinically , it is important to note that mastitis is generally seen in...invasion and recently added those with clinical involvement of more than 3/4 of the breast. We established a registry to collect information and specimens

Overcoming the barriers to effective treatment for attention-deficit/hyperactivity disorder: a neuro-educational approach.

PubMed

Monastra, Vincent J

2005-10-01

Despite specific diagnostic criteria, published practice guidelines for assessing patients, and the availability of effective pharmacological treatments for children diagnosed with attention-deficit/hyperactivity disorder (AD/HD), a review of prescription practices in the United States indicates that as few as 25-50% of these patients receive even minimal medical treatment for this condition. Because untreated children with AD/HD are at increased risk for psychoactive substance abuse, criminal behavior, and other social problems as adults, the provision of effective care during childhood is essential. In order to clarify the factors impeding treatment during childhood and develop a targeted intervention to overcome these barriers, two studies involving 1514 families were conducted. Each family included one child diagnosed with AD/HD. Factors associated with treatment failure or non-compliance with medical advice included: dissatisfaction with a diagnostic process limited to brief observation, interview, and review of behavior rating scales; fear of stimulant medication; lack of medication response within the first month; development of side-effects during the first month; lack of understanding of the reasons stimulants were being prescribed for a child, and insufficient clinical response. Based on these findings, an intervention program consisting of a comprehensive evaluation process (that included neuropsychological and neurophysiological tests of attention, and medical screening for other health problems associated with inattention and hyperactivity) and parent education about the medical causes of AD/HD, the biochemical action of medications, the relationship between dietary habits and attention, and the educational rights of children with AD/HD was conducted. Following completion of this three session intervention, 95% of patients complied with medical recommendations, initiated pharmacological treatment, and continued medication for a 2-year follow-up period. Three percent of the patients were diagnosed and treated for other medical conditions.

Local amygdala structural differences with 3T MRI in patients with Alzheimer disease

PubMed Central

Cavedo, E.; Boccardi, M.; Ganzola, R.; Canu, E.; Beltramello, A.; Caltagirone, C.; Thompson, P.M.

2011-01-01

Objective: Histologic studies show that the amygdala is affected by Alzheimer disease (AD) pathology, and its medial aspect is the most involved. We aimed to assess in vivo local structural differences in the amygdala of patients with AD using high-field MRI. Methods: A total of 19 patients with AD (mean age 76, SD 6 years, mean Mini-Mental State Examination score [MMSE] 13, SD 4) and 19 healthy elderly controls (age 74, SD 5, MMSE 29, SD 1) were enrolled. The radial atrophy mapping technique was used to reconstruct the 3-dimensional surface of the amygdala. Maps of surface tissue loss in patients with AD vs controls were computed and statistically tested with permutation tests thresholded at p < 0.05, to correct for multiple comparisons. A digital atlas of the amygdalar nuclei was used to infer which nuclei were involved. Results: Both amygdalar volumes were significantly smaller in patients with AD (right 1,508 mm3, SD 418; left 1,646, SD 419) than controls (right 2,129 mm3, SD 316; left 2,077, SD 376; p < 0.002). In the dorsomedial part, significant local tissue loss (20%–30%) was mapped in the medial and central nuclei. Ventrally, the lateral nucleus (La) and the basolateral ventral medial nucleus (BLVM) were also involved (20%–30% loss). Conclusions: We found in vivo local structural differences in the amygdala of patients with AD. The nuclei involved have known connections to the hippocampus (BLVM, La) and olfactory system (medial nucleus) and with cholinergic pathways (central nucleus). This pattern is consistent with the known pathophysiology of neural systems affected by AD. PMID:21339500

Innate immune system and inflammation in Alzheimer's disease: from pathogenesis to treatment.

PubMed

Serpente, Maria; Bonsi, Rossana; Scarpini, Elio; Galimberti, Daniela

2014-01-01

Immune activation and inflammation, likely triggered by amyloid-beta (Aβ) deposition, play a remarkable role in the pathogenesis of Alzheimer's disease (AD), which is the most frequent cause of dementia in the elderly. The principal cellular elements of the brain innate immune system likely to be involved in such processes are microglia. In an attempt to search for new disease-modifying drugs, the immune system has been addressed, with the aim of removing deposition of Aβ or tau by developing vaccines and humanized monoclonal antibodies. The aim of this review is to summarize the current evidence regarding the role played by microglia and inflammatory molecules in the pathogenesis of AD. In addition, we will discuss the main active and passive immunotherapeutic approaches. © 2014 S. Karger AG, Basel.

Category cued recall evokes a generate-recognize retrieval process.

PubMed

Hunt, R Reed; Smith, Rebekah E; Toth, Jeffrey P

2016-03-01

The experiments reported here were designed to replicate and extend McCabe, Roediger, and Karpicke's (2011) finding that retrieval in category cued recall involves both controlled and automatic processes. The extension entailed identifying whether distinctive encoding affected 1 or both of these 2 processes. The first experiment successfully replicated McCabe et al., but the second, which added a critical baseline condition, produced data inconsistent with a 2 independent process model of recall. The third experiment provided evidence that retrieval in category cued recall reflects a generate-recognize strategy, with the effect of distinctive processing being localized to recognition. Overall, the data suggest that category cued recall evokes a generate-recognize retrieval strategy and that the subprocesses underlying this strategy can be dissociated as a function of distinctive versus relational encoding processes. (c) 2016 APA, all rights reserved).

Effective Ad-Hoc Committees.

ERIC Educational Resources Information Center

Young, David G.

1983-01-01

Ad-hoc committees may be symbolic, informational, or action committees. A literature survey indicates such committees' structural components include a suprasystem and three subsystems involving linkages, production, and implementation. Other variables include size, personal factors, and timing. All the factors carry implications about ad-hoc…

[Evaluation of temporality semantic knowledge in normal aging and in mild and moderate stages of Alzheimer's disease].

PubMed

Rivasseau Jonveaux, T; Batt, M; Empereur, F; Braun, M; Trognon, A

2015-04-01

Episodic and semantic processes are involved in temporality used in daily life. Episodic memory permits one to place an event on the time axis, while semantic memory makes us aware of the time segmentation and its symbolic representation. Memory of the knowledge connected to the passing of time is materialized on the calendar and can be seen symbolically on the dial of a clock. In AD, semantic memory processes are preserved longer than processes related to episodic memory. We wonder whether the specific field of knowledge about time is altered during AD. We validated a specific evaluation with a control group (354 healthy subjects). Then we applied this battery to assess AD patients to appreciate the feasibility of this tool for this population. We then compared 22 AD patients with a control group matched for age, sex and educational level. Our clinical scale of temporal semantic knowledge consists of four parts: (a) hour reading with a.m. and p.m. hours; (b) using a clock: 12 clock faces with the hour numbers already placed: the patient draws hour and minute hands for various hours; (c) temporal segmentation: exploration of the knowledge on daytime scale and of the calendar; (d) time duration estimation: calculate how long the interview has lasted after indicating the time of its beginning and its end, then the time between 10.40 to 12.00. While age and educational level had an influence on all the scores, in the two groups control and patients, gender did not. Temporal segmentation, independent of the cultural level, revealed the best acquired knowledge in our control population. All the scores differentiated patients from control subjects. The temporal semantic knowledge correlated with the AD severity seemed to be correlated with the attention, verbal comprehension, and some components of executive functions, but was not related to the clock drawing test result. Depression did not have any influence on this scale in our AD group. The temporal semantic knowledge clinical scale shows differential alterations, notably in hour reading and using a clock, and less in temporal segmentation. Temporal semantic knowledge is altered in AD. The diagnosis and follow-up of these alterations allow professionals and caregivers to consider adaptations of the patient's environment according to their needs. Copyright © 2013 L’Encéphale, Paris. Published by Elsevier Masson SAS. All rights reserved.

Evaluating public involvement in research design and grant development: Using a qualitative document analysis method to analyse an award scheme for researchers.

PubMed

Baxter, Susan; Muir, Delia; Brereton, Louise; Allmark, Christine; Barber, Rosemary; Harris, Lydia; Hodges, Brian; Khan, Samaira; Baird, Wendy

2016-01-01

The National Institute for Health Research (NIHR) Research Design Service (RDS) for Yorkshire and Humber has been running a public involvement funding scheme since 2008. This scheme awards researchers a small amount of money to help them get involvement from patients and/or the public. Involvement activities take place at the time when researchers are planning studies, and when they are completing application forms to request funding for a proposed research project. After the public involvement activities researchers are asked to write a report for the RDS describing what they did with the public involvement funding. This study analysed those reports using an approach which included members of a public involvement panel in the data analysis process. The aim of the work was to see what the views and experiences of researchers who received funding were, and what might be learned for the future of the scheme. Twenty five reports were analysed. Four main themes were identified, these described: the added value of public involvement; aspects to consider when planning and designing public involvement; different roles of public contributors; and aspects of valuing public member contributions. The group approach to analysis was successful in enabling involvement of a variety of individuals in the process. The findings of the study provide evidence of the value of public involvement during the development of applications for research funding. The results also indicate that researchers recognise the variety in potential roles for the public in research, and acknowledge how involvement adds value to studies. Background A regional Research Design Service, funded by the National Institute for Health Research, introduced a small grant in 2008, to support public involvement (often known as patient and public involvement [PPI]) activities during the development of applications for research funding. Successful applicants are requested to submit a report detailing how the grant money was used, including a description of the aims and outcomes of the public involvement activities. The purpose of this study was to analyse the content of these reports. We aimed to find out what researcher views and experiences of public involvement activities were, and what lessons might be learned. Methods We used an innovative method of data analysis, drawing on group participatory approaches, qualitative content analysis, and Framework Analysis to sort and label the content of the reports. We developed a framework of categories and sub-categories (or themes and sub-themes) from this process. Results Twenty five documents were analysed. Four main themes were identified in the data: the added value of public involvement; planning and designing involvement; the role of public members; and valuing public member contributions. Within these themes, sub-themes related to the timing of involvement (prior to the research study/intended during the research study), and also specific benefits of public involvement such as: validating ideas; ensuring appropriate outcomes; ensuring the acceptability of data collection methods/tools and advice regarding research processes. Other sub-themes related to: finding and approaching public members; timing of events; training/support; the format of sessions; setting up public involvement panels: use of public contributors in analysis and interpretation of data; and using public members to assist with dissemination and translation into practice. Conclusions The analysis of reports submitted by researchers following involvement events provides evidence of the value of public involvement during the development of applications for research funding, and details a method for involving members of the public in data analysis which could be of value to other researchers The findings of the analysis indicate recognition amongst researchers of the variety in potential roles for public members in research, and also an acknowledgement of how involvement adds value to studies.

Oxidative stress in Alzheimer disease and mild cognitive impairment: evidence from human data provided by redox proteomics.

PubMed

Swomley, Aaron M; Butterfield, D Allan

2015-10-01

Alzheimer disease (AD) is a neurodegenerative disease with many known pathological features, yet there is still much debate into the exact cause and mechanisms for progression of this degenerative disorder. The amyloid-beta (Aβ)-induced oxidative stress hypothesis postulates that it is the oligomeric Aβ that inserts into membrane systems to initiate much of the oxidative stress observed in brain during the progression of the disease. In order to study the effects of oxidative stress on tissue from patients with AD and amnestic mild cognitive impairment (MCI), we have developed a method called redox proteomics that identifies specific brain proteins found to be selectively oxidized. Here, we discuss experimental findings of oxidatively modified proteins involved in three key cellular processes implicated in the pathogenesis of AD progression: energy metabolism, cell signaling and neurotransmission, as well as the proteasomal degradation pathways and antioxidant response systems. These proteomics studies conducted by our laboratory and others in the field shed light on the molecular changes imposed on the cells of AD and MCI brain, through the deregulated increase in oxidative/nitrosative stress inflicted by Aβ and mitochondrial dysfunction.

Reversible Nuclear-Lipid-Droplet Morphology Induced by Oleic Acid: A Link to Cellular-Lipid Metabolism

PubMed Central

Lagrutta, Lucía C.; Montero-Villegas, Sandra; Layerenza, Juan P.; Sisti, Martín S.; García de Bravo, Margarita M.

2017-01-01

Neutral lipids—involved in many cellular processes—are stored as lipid droplets (LD), those mainly cytosolic (cLD) along with a small nuclear population (nLD). nLD could be involved in nuclear-lipid homeostasis serving as an endonuclear buffering system that would provide or incorporate lipids and proteins involved in signalling pathways as transcription factors and as enzymes of lipid metabolism and nuclear processes. Our aim was to determine if nLD constituted a dynamic domain. Oleic-acid (OA) added to rat hepatocytes or HepG2 cells in culture produced cellular-phenotypic LD modifications: increases in TAG, CE, C, and PL content and in cLD and nLD numbers and sizes. LD increments were reversed on exclusion of OA and were prevented by inhibition of acyl-CoA synthetase (with Triacsin C) and thus lipid biosynthesis. Under all conditions, nLD corresponded to a small population (2–10%) of total cellular LD. The anabolism triggered by OA, involving morphologic and size changes within the cLD and nLD populations, was reversed by a net balance of catabolism, upon eliminating OA. These catabolic processes included lipolysis and the mobilization of hydrolyzed FA from the LD to cytosolic-oxidation sites. These results would imply that nLD are actively involved in nuclear processes that include lipids. In conclusion, nLD are a dynamic nuclear domain since they are modified by OA through a reversible mechanism in combination with cLD; this process involves acyl-CoA-synthetase activity; ongoing TAG, CE, and PL biosynthesis. Thus, liver nLD and cLD are both dynamic cellular organelles. PMID:28125673

Aberrant Subcellular Neuronal Calcium Regulation in Aging and Alzheimer’s Disease

PubMed Central

Camandola, Simonetta; Mattson, Mark P.

2010-01-01

In this mini-review/opinion article we describe evidence that multiple cellular and molecular alterations in Alzheimer’s disease (AD) pathogenesis involve perturbed cellular calcium regulation, and that alterations in synaptic calcium handling may be early and pivotal events in the disease process. With advancing age neurons encounter increased oxidative stress and impaired energy metabolism, which compromise the function of proteins that control membrane excitability and subcellular calcium dynamics. Altered proteolytic cleavage of the β-amyloid precursor protein (APP) in response to the aging process in combination with genetic and environmental factors results in the production and accumulation of neurotoxic forms of amyloid β-peptide (Aβ ). Aβ undergoes a self-aggregation process and concomitantly generates reactive oxygen species that can trigger membrane-associated oxidative stress which, in turn, impairs the functions of ion-motive ATPases and glutamate and glucose transporters thereby rendering neurons vulnerable to excitotoxicity and apoptosis. Mutations in presenilin-1 that cause early-onset AD increase Aβ production, but also result in an abnormal increase in the size of endoplasmic reticulum calcium stores. Some of the events in the neurodegenerative cascade can be counteracted in animal models by manipulations that stabilize neuronal calcium homeostasis including dietary energy restriction, agonists of glucagon-like peptide 1 receptors and drugs that activate mitochondrial potassium channels. Emerging knowledge of the actions of calcium upstream and downstream of Aβ provides opportunities to develop novel preventative and therapeutic interventions for AD. PMID:20950656

Analysis of production flow process with lean manufacturing approach

NASA Astrophysics Data System (ADS)

Siregar, Ikhsan; Arif Nasution, Abdillah; Prasetio, Aji; Fadillah, Kharis

2017-09-01

This research was conducted on the company engaged in the production of Fast Moving Consumer Goods (FMCG). The production process in the company are still exists several activities that cause waste. Non value added activity (NVA) in the implementation is still widely found, so the cycle time generated to make the product will be longer. A form of improvement on the production line is by applying lean manufacturing method to identify waste along the value stream to find non value added activities. Non value added activity can be eliminated and reduced by utilizing value stream mapping and identifying it with activity mapping process. According to the results obtained that there are 26% of value-added activities and 74% non value added activity. The results obtained through the current state map of the production process of process lead time value of 678.11 minutes and processing time of 173.94 minutes. While the results obtained from the research proposal is the percentage of value added time of 41% of production process activities while non value added time of the production process of 59%. While the results obtained through the future state map of the production process of process lead time value of 426.69 minutes and processing time of 173.89 minutes.

Magnetic resonance imaging biomarkers for the early diagnosis of Alzheimer's disease: a machine learning approach.

PubMed

Salvatore, Christian; Cerasa, Antonio; Battista, Petronilla; Gilardi, Maria C; Quattrone, Aldo; Castiglioni, Isabella

2015-01-01

Determination of sensitive and specific markers of very early AD progression is intended to aid researchers and clinicians to develop new treatments and monitor their effectiveness, as well as to lessen the time and cost of clinical trials. Magnetic Resonance (MR)-related biomarkers have been recently identified by the use of machine learning methods for the in vivo differential diagnosis of AD. However, the vast majority of neuroimaging papers investigating this topic are focused on the difference between AD and patients with mild cognitive impairment (MCI), not considering the impact of MCI patients who will (MCIc) or not convert (MCInc) to AD. Morphological T1-weighted MRIs of 137 AD, 76 MCIc, 134 MCInc, and 162 healthy controls (CN) selected from the Alzheimer's disease neuroimaging initiative (ADNI) cohort, were used by an optimized machine learning algorithm. Voxels influencing the classification between these AD-related pre-clinical phases involved hippocampus, entorhinal cortex, basal ganglia, gyrus rectus, precuneus, and cerebellum, all critical regions known to be strongly involved in the pathophysiological mechanisms of AD. Classification accuracy was 76% AD vs. CN, 72% MCIc vs. CN, 66% MCIc vs. MCInc (nested 20-fold cross validation). Our data encourage the application of computer-based diagnosis in clinical practice of AD opening new prospective in the early management of AD patients.

The influence of viewing an entertainment-education program on cornea donation intention: a test of the theory of planned behavior.

PubMed

Bae, Hyuhn-Suhck; Kang, Seok

2008-01-01

This study was designed to examine the role of issue involvement and the 3 components of the theory of planned behavior in predicting intentions to sign a cornea donor card. This study also compares viewers and nonviewers of an entertainment-education program in terms of issue involvement and the theory of planned behavior. The breakdown of effects for the latent constructs confirms that issue involvement is an important intermediary in the persuasion process. Issue involvement is a common causal antecedent of attitude, subjective norm, and perceived behavioral control, the last 2 of which, in turn, predict intentions, whereas attitude does not. The revised path model confirms that involvement directly influences intentions. In the comparison of viewers with nonviewers, viewers exhibit a significantly higher degree of involvement, attitude toward cornea donation, subjective norm, perceived behavioral control, and intention to sign a cornea donor card. The overall findings of this study suggest that adding issue involvement in the theory of planned behavior enhances the explanatory power of the theory in predicting intentions.

AhR mediates an anti-inflammatory feedback mechanism in human Langerhans cells involving FcεRI and IDO.

PubMed

Koch, S; Stroisch, T J; Vorac, J; Herrmann, N; Leib, N; Schnautz, S; Kirins, H; Förster, I; Weighardt, H; Bieber, T

2017-11-01

Aryl hydrocarbon receptor (AhR), an important regulator of immune responses, is activated by UVB irradiation in the skin. Langerhans cells (LC) in the epidermis of patients with atopic dermatitis (AD) carry the high-affinity receptor for IgE, FcεRI, and are crucially involved in the pathogenesis of AD by inducing inflammatory responses and regulating tolerogenic processes. We investigated AhR and AhR repressor (AhRR) expression and functional consequences of AhR activation in human ex vivo skin cells and in in vitro-generated LC. Epidermal cells from healthy skin were analyzed for their expression of AhR and AhRR. LC generated from CD34 + hematopoietic stem cells (CD34LC) were treated with the UV photoproduct and AhR ligand 6-formylindolo[3,2-b]carbazole (FICZ). Cell surface receptors, transcription factors, and the tolerogenic tryptophan-degrading enzyme indoleamine 2,3-dioxygenase (IDO) were analyzed using flow cytometry and quantitative PCR. Epidermal LC and CD34LC express AhR and AhRR. AhR was also found in keratinocytes, which lack AhRR. AhR activation of LC by FICZ caused downregulation of FcεRI in CD34LC without affecting their maturation. AhR-mediated regulation of FcεRI did not involve any known transcription factors related to this receptor. Furthermore, we could show upregulation of IDO mediated by AhR engagement. Our study shows that AhR activation by FICZ reduces FcεRI and upregulates IDO expression in LC. This AhR-mediated anti-inflammatory feedback mechanism may dampen the allergen-induced inflammation in AD. © 2017 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.

Development of a countywide recycling program for Polk County, Wisconsin

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

Not Available

Designing a recycling program for a rural county presents many more challenges in terms of transportation of materials and funding sources. Rural counties and communities typically have much smaller budgets and resources to draw from. In order to create a program that could realistically be implemented and also have widespread support, it was decided to allow ample time for public involvement in the design process. A multi-faceted approach was adopted to facilitate participation by individuals involved in solid waste handling and the general public. The approach included the use of surveys, formation of an advisory committee, public meetings, presentations tomore » civic groups, personal contacts, news releases, and a logo contest. The public involvement turned out to be invaluable. Throughout the year, many concepts and ideas were presented for feedback. Consequently, some aspects of the program were modified, some were scrapped altogether, and a few new ideas were added. Undoubtedly, the process of refinement will continue as the program moves into the implementation phase. The extensive public involvement has resulted in strong support for the countywide program from many sectors, including private haulers and recycling businesses, local officials and county board supervisors, civic groups, environmental groups, and the general public.« less

The Black Hole Firewall and Top-Down Constructions of AdS/CFT

NASA Astrophysics Data System (ADS)

Almheiri, Ahmed Eid Khamis Thani

In the first part of this dissertation we argue that the following statements cannot be all true: (i) Black hole formation and evaporation is a unitary process as viewed by external observers, (ii) Physics outside some microscopic distance away from the event horizon is described by local effective quantum field theory, (iii) A black hole is a quantum system with a finite number of states given by the exponential of the Bekenstein Hawking entropy, and (iv) An infalling observer's experience in the vicinity of the horizon is well described by local effective quantum field theory in the infalling reference frame. We argue that the most conservative resolution is that an infalling observer will see drastic violations of effective field theory far away from the singularity, and encounter high energy quanta, a firewall, just behind the black hole event horizon. We address counter proposals to the firewall which involve, in one way or another, radical modifications of quantum mechanics or locality, and argue that they are unsatisfactory in their current formulation. We conclude this part with an investigation into the existence of firewalls in the two dimensional Einstein-dilaton gravity model of CGHS. We find that black holes in such models do not develop firewalls, but rather evaporate down to form small mass remnants. We elaborate on why this is inevitable in two dimensions and argue against a similar conclusion in higher dimensions. In the second part of this dissertation we construct AdS2 and AdS3 magnetic brane solutions within the abelian truncations of AdS4 x orbifolded S7 and AdS5 x S5 supergravity. We find a class of supersymmetric solutions of the bulk theory to assure stability. We perform a preliminary analysis demonstrating the stability of some nonsupersymmetric embeddings. We identify the dual field theory and compare the thermal entropies across the duality. We end with an investigatation into the effects of backreaction on holography in AdS2. We study a classically solvable toy model that contains an IR AdS2 throat, and find that backreaction behaves as a strongly relevant perturbation deep in the AdS2 region.

Ultra-processed foods and added sugars in the US diet: evidence from a nationally representative cross-sectional study.

PubMed

Martínez Steele, Eurídice; Baraldi, Larissa Galastri; Louzada, Maria Laura da Costa; Moubarac, Jean-Claude; Mozaffarian, Dariush; Monteiro, Carlos Augusto

2016-03-09

To investigate the contribution of ultra-processed foods to the intake of added sugars in the USA. Ultra-processed foods were defined as industrial formulations which, besides salt, sugar, oils and fats, include substances not used in culinary preparations, in particular additives used to imitate sensorial qualities of minimally processed foods and their culinary preparations. Cross-sectional study. National Health and Nutrition Examination Survey 2009-2010. We evaluated 9317 participants aged 1+ years with at least one 24 h dietary recall. Average dietary content of added sugars and proportion of individuals consuming more than 10% of total energy from added sugars. Gaussian and Poisson regressions estimated the association between consumption of ultra-processed foods and intake of added sugars. All models incorporated survey sample weights and adjusted for age, sex, race/ethnicity, family income and educational attainment. Ultra-processed foods comprised 57.9% of energy intake, and contributed 89.7% of the energy intake from added sugars. The content of added sugars in ultra-processed foods (21.1% of calories) was eightfold higher than in processed foods (2.4%) and fivefold higher than in unprocessed or minimally processed foods and processed culinary ingredients grouped together (3.7%). Both in unadjusted and adjusted models, each increase of 5 percentage points in proportional energy intake from ultra-processed foods increased the proportional energy intake from added sugars by 1 percentage point. Consumption of added sugars increased linearly across quintiles of ultra-processed food consumption: from 7.5% of total energy in the lowest quintile to 19.5% in the highest. A total of 82.1% of Americans in the highest quintile exceeded the recommended limit of 10% energy from added sugars, compared with 26.4% in the lowest. Decreasing the consumption of ultra-processed foods could be an effective way of reducing the excessive intake of added sugars in the USA. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

On Gamma Ray Instrument On-Board Data Processing Real-Time Computational Algorithm for Cosmic Ray Rejection

NASA Technical Reports Server (NTRS)

Kizhner, Semion; Hunter, Stanley D.; Hanu, Andrei R.; Sheets, Teresa B.

2016-01-01

Richard O. Duda and Peter E. Hart of Stanford Research Institute in [1] described the recurring problem in computer image processing as the detection of straight lines in digitized images. The problem is to detect the presence of groups of collinear or almost collinear figure points. It is clear that the problem can be solved to any desired degree of accuracy by testing the lines formed by all pairs of points. However, the computation required for n=NxM points image is approximately proportional to n2 or O(n2), becoming prohibitive for large images or when data processing cadence time is in milliseconds. Rosenfeld in [2] described an ingenious method due to Hough [3] for replacing the original problem of finding collinear points by a mathematically equivalent problem of finding concurrent lines. This method involves transforming each of the figure points into a straight line in a parameter space. Hough chose to use the familiar slope-intercept parameters, and thus his parameter space was the two-dimensional slope-intercept plane. A parallel Hough transform running on multi-core processors was elaborated in [4]. There are many other proposed methods of solving a similar problem, such as sampling-up-the-ramp algorithm (SUTR) [5] and algorithms involving artificial swarm intelligence techniques [6]. However, all state-of-the-art algorithms lack in real time performance. Namely, they are slow for large images that require performance cadence of a few dozens of milliseconds (50ms). This problem arises in spaceflight applications such as near real-time analysis of gamma ray measurements contaminated by overwhelming amount of traces of cosmic rays (CR). Future spaceflight instruments such as the Advanced Energetic Pair Telescope instrument (AdEPT) [7-9] for cosmos gamma ray survey employ large detector readout planes registering multitudes of cosmic ray interference events and sparse science gamma ray event traces' projections. The AdEPT science of interest is in the gamma ray events and the problem is to detect and reject the much more voluminous cosmic ray projections, so that the remaining science data can be telemetered to the ground over the constrained communication link. The state-of-the-art in cosmic rays detection and rejection does not provide an adequate computational solution. This paper presents a novel approach to the AdEPT on-board data processing burdened with the CR detection top pole bottleneck problem. This paper is introducing the data processing object, demonstrates object segmentation and distribution for processing among many processing elements (PEs) and presents solution algorithm for the processing bottleneck - the CR-Algorithm. The algorithm is based on the a priori knowledge that a CR pierces the entire instrument pressure vessel. This phenomenon is also the basis for a straightforward CR simulator, allowing the CR-Algorithm performance testing. Parallel processing of the readout image's (2(N+M) - 4) peripheral voxels is detecting all CRs, resulting in O(n) computational complexity. This algorithm near real-time performance is making AdEPT class spaceflight instruments feasible.

Micro RNA as a potential blood-based epigenetic biomarker for Alzheimer's disease.

PubMed

Fransquet, Peter D; Ryan, Joanne

2018-06-06

As the prevalence of Alzheimer's disease (AD) increases, the search for a definitive, easy to access diagnostic biomarker has become increasingly important. Micro RNA (miRNA), involved in the epigenetic regulation of protein synthesis, is a biological mark which varies in association with a number of disease states, possibly including AD. Here we comprehensively review methods and findings from 26 studies comparing the measurement of miRNA in blood between AD cases and controls. Thirteen of these studies used receiver operator characteristic (ROC) analysis to determine the diagnostic accuracy of identified miRNA to predict AD, and three studies did this with a machine learning approach. Of 8098 individually measured miRNAs, 23 that were differentially expressed between AD cases and controls were found to be significant in two or more studies. Only six of these were consistent in their direction of expression between studies (miR-107, miR-125b, miR-146a, miR-181c, miR-29b, and miR-342), and they were all shown to be down regulated in individuals with AD compared to controls. Of these directionally concordant miRNAs, the strongest evidence was for miR-107 which has also been shown in previous studies to be involved in the dysregulation of proteins involved in aspects of AD pathology, as well as being consistently downregulated in studies of AD brains. We conclude that imperative to the discovery of reliable and replicable miRNA biomarkers of AD, standardised methods of measurements, appropriate statistical analysis, utilization of large datasets with machine learning approaches, and comprehensive reporting of findings is urgently needed. Copyright © 2017. Published by Elsevier Inc.

Decreased levels of guanosine 3', 5'-monophosphate (cGMP) in cerebrospinal fluid (CSF) are associated with cognitive decline and amyloid pathology in Alzheimer's disease.

PubMed

Ugarte, Ana; Gil-Bea, Francisco; García-Barroso, Carolina; Cedazo-Minguez, Ángel; Ramírez, M Javier; Franco, Rafael; García-Osta, Ana; Oyarzabal, Julen; Cuadrado-Tejedor, Mar

2015-06-01

Levels of the cyclic nucleotides guanosine 3', 5'-monophosphate (cGMP) or adenosine 3', 5'-monophosphate (cAMP) that play important roles in memory processes are not characterized in Alzheimer's disease (AD). The aim of this study was to analyse the levels of these nucleotides in cerebrospinal fluid (CSF) samples from patients diagnosed with clinical and prodromal stages of AD and study the expression level of the enzymes that hydrolyzed them [phosphodiesterases (PDEs)] in the brain of AD patients vs. For cGMP and cAMP CSF analysis, the cohort (n = 79) included cognitively normal participants (subjective cognitive impairment), individuals with stable mild cognitive impairment or AD converters (sMCI and cMCI), and mild AD patients. A high throughput liquid chromatography-tandem mass spectrometry method was used. Interactions between CSF cGMP or cAMP with mini-mental state examination (MMSE) score, CSF Aβ(1-42) and CSF p-tau were analysed. For PDE4, 5, 9 and 10 expression analysis, brains of AD patients vs. controls (n = 7 and n = 8) were used. cGMP, and not cAMP levels, were significantly lower in the CSF of patients diagnosed with mild AD when compared with nondemented controls. CSF levels of cGMP showed a significant association with MMSE-diagnosed clinical dementia and with CSF biomarker Aβ42 in AD patients. Significant increase in PDE5 expression was detected in temporal cortex of AD patients compared with that of age-matched healthy control subjects. No changes in the expression of others PDEs were detected. These results support the potential involvement of cGMP in the pathological and clinical development of AD. The cGMP reduction in early stages of AD might participate in the aggravation of amyloid pathology and cognitive decline. © 2014 British Neuropathological Society.

Leukocyte Telomere Length in Alzheimer's Disease Patients with a Different Rate of Progression.

PubMed

Tedone, Enzo; Arosio, Beatrice; Colombo, Federico; Ferri, Evelyn; Asselineau, Delphine; Piette, Francois; Gussago, Cristina; Belmin, Joel; Pariel, Sylvie; Benlhassan, Khadija; Casati, Martina; Bornand, Anne; Rossi, Paolo Dionigi; Mazzola, Paolo; Annoni, Giorgio; Doulazmi, Mohamed; Mariani, Jean; Porretti, Laura; Bray, Dorothy H; Mari, Daniela

2015-01-01

Age and short leukocyte telomeres have been associated with a higher risk of Alzheimer's disease (AD). Inflammation is involved in AD and it is suggested that anti-inflammatory interleukin-10 (IL-10) may partly antagonize these processes. The aim is to correlate telomere length (TL) in peripheral blood mononuclear cells (PBMC) from patients with AD to disease progression rate. Moreover, we evaluated whether TL was associated with IL-10 production by unstimulated or amyloid-β (Aβ)-stimulated PBMC. We enrolled 31 late-onset AD and 20 age-matched healthy elderly (HE). After a two-year follow-up period, patients were retrospectively evaluated as slow-progressing (ADS) (Mini Mental State Examination (MMSE) decline over the two years of follow-up ≤3 points) or fast progressing AD (ADF) (MMSE decline ≥5 points). TL was measured by flow cytometry and in vitro IL-10 production by enzyme-linked immunosorbent assay. TL (mean±SD) for HE, ADS, and ADF was 2.3±0.1, 2.0±0.1, and 2.5±0.1 Kb, respectively. ADS showed a shorter TL compared to HE (p = 0.034) and to ADF (p = 0.005). MMSE decline correlated with TL in AD (R2 = 0.284; p = 0.008). We found a significant difference in IL-10 production between unstimulated and Aβ-stimulated PBMC from ADS (40.7±13.7 versus 59.0±27.0; p = 0.004) but not from ADF (39.7±14.4 versus 42.2±22.4). HE showed a trend toward significance (47.1±25.4 versus 55.3±27.9; p = 0.10). PBMC from ADF may be characterized by an impaired response induced by Aβ and by a reduced proliferative response responsible for the longer telomeres. TL might be a contributing factor in predicting the rate of AD progression.

Anti-IL17 treatment ameliorates Down syndrome phenotypes in mice.

PubMed

Rueda, Noemí; Vidal, Verónica; García-Cerro, Susana; Narcís, Josep Oriol; Llorens-Martín, María; Corrales, Andrea; Lantigua, Sara; Iglesias, Marcos; Merino, Jesús; Merino, Ramón; Martínez-Cué, Carmen

2018-05-16

Down syndrome (DS) is characterized by structural and functional anomalies that are present prenatally and that lead to intellectual disabilities. Later in life, the cognitive abilities of DS individuals progressively deteriorate due to the development of Alzheimer's disease (AD)-associated neuropathology (i.e., β-amyloid (Aβ) plaques, neurofibrillary tangles (NFTs), neurodegeneration, synaptic pathology, neuroinflammation and increased oxidative stress). Increasing evidence has shown that among these pathological processes, neuroinflammation plays a predominant role in AD etiopathology. In AD mouse models, increased neuroinflammation appears earlier than Aβ plaques and NFTs, and in DS and AD models, neuroinflammation exacerbates the levels of soluble and insoluble Aβ species, favoring neurodegeneration. The Ts65Dn (TS) mouse, the most commonly used murine model of DS, recapitulates many alterations present in both DS and AD individuals, including enhanced neuroinflammation. In this study, we observed an altered neuroinflammatory milieu in the hippocampus of the TS mouse model. Pro-inflammatory mediators that were elevated in the hippocampus of this model included pro-inflammatory cytokine IL17A, which has a fundamental role in mediating brain damage in neuroinflammatory processes. Here, we analyzed the ability of an anti-IL17A antibody to reduce the neuropathological alterations that are present in TS mice during early neurodevelopmental stages (i.e., hippocampal neurogenesis and hypocellularity) or that are aggravated in later-life stages (i.e., cognitive abilities, cholinergic neuronal loss and increased cellular senescence, APP expression, Aβ peptide expression and neuroinflammation). Administration of anti-IL17 for 5 months, starting at the age of 7 months, partially improved the cognitive abilities of the TS mice, reduced the expression of several pro-inflammatory cytokines and the density of activated microglia and normalized the APP and Aβ 1-42 levels in the hippocampi of the TS mice. These results suggest that IL17-mediated neuroinflammation is involved in several AD phenotypes in TS mice and provide a new therapeutic target to reduce these pathological characteristics. Copyright © 2018 Elsevier Inc. All rights reserved.

mTOR in Down syndrome: Role in Aß and tau neuropathology and transition to Alzheimer disease-like dementia.

PubMed

Di Domenico, Fabio; Tramutola, Antonella; Foppoli, Cesira; Head, Elizabeth; Perluigi, Marzia; Butterfield, D Allan

2018-01-01

The mammalian target of rapamycin (mTOR) is a serine/threonine protein kinase involved in the regulation of protein synthesis and degradation, longevity and cytoskeletal formation. The mTOR pathway represents a key growth and survival pathway involved in several diseases such as cancer, obesity, cardiovascular disease and neurodegenerative diseases. Numerous studies linked the alterations of mTOR pathway to age-dependent cognitive decline, pathogenesis of Alzheimer disease (AD) and AD-like dementia in Down syndrome (DS). DS is the most frequent chromosomal abnormality that causes intellectual disability. The neuropathology of AD in DS is complex and involves impaired mitochondrial function, defects in neurogenesis, increased oxidative stress, altered proteostasis and autophagy networks as a result of triplication of chromosome 21(chr 21). The chr21 gene products are considered a principal neuropathogenic moiety in DS. Several genes involved respectively in the formation of senile plaques and neurofibrillary tangles (NFT), two main pathological hallmarks of AD, are mapped on chr21. Further, in subjects with DS the activation of mTOR signaling contributes to Aβ generation and the formation of NFT. This review discusses recent research highlighting the complex role of mTOR associated with the presence of two hallmarks of AD pathology, senile plaques (composed mostly of fibrillar Aß peptides), and NFT (composed mostly of hyperphosphorylated tau protein). Oxidative stress, associated with chr21-related Aβ and mitochondrial alterations, may significantly contribute to this linkage of mTOR to AD-like neuropathology in DS. Copyright © 2017 Elsevier Inc. All rights reserved.

Inventories of Delaware's coastal vegetation and land-use utilizing digital processing of ERTS-1 imagery

NASA Technical Reports Server (NTRS)

Klemas, V. (Principal Investigator); Bartlett, D.; Rogers, R.; Reed, L.

1974-01-01

The author has identified the following significant results. Analysis of ERTS-1 color composite images using analogy processing equipment confirmed that all the major wetlands plant species were distinguishable at ERTS-1 scale. Furthermore, human alterations of the coastal zone were easily recognized since such alterations typically involve removal of vegetative cover resulting in a change of spectral signature. The superior spectral resolution of the CCTs as compared with single band or composite imagery has indeed provided good discrimination through digital analysis of the CCTs with the added advantage of rapid production of thematic maps and data.

Study of soft magnetic iron cobalt based alloys processed by powder injection molding

NASA Astrophysics Data System (ADS)

Silva, Aline; Lozano, Jaime A.; Machado, Ricardo; Escobar, Jairo A.; Wendhausen, Paulo A. P.

As a near net shape process, powder injection molding (PIM) opens new possibilities to process Fe-Co alloys for magnetic applications. Due to the fact that PIM does not involve plastic deformation of the material during processing, we envisioned the possibility of eliminating vanadium (V), which is generally added to Fe-Co alloys to improve the ductility in order to enable its further shaping by conventional processes such as forging and cold rolling. In our investigation we have found out two main futures related to the elimination of V, which lead to a cost-benefit gain in manufacturing small magnetic components where high-saturation induction is needed at low frequencies. Firstly, the elimination of V enables the achievement of much better magnetic properties when alloys are processed by PIM. Secondly, a lower sintering temperature can be used when the alloy is processed starting with elemental Fe and Co powders without the addition of V.

Why pleiotropic interventions are needed for Alzheimer's disease.

PubMed

Frautschy, Sally A; Cole, Greg M

2010-06-01

Alzheimer's disease (AD) involves a complex pathological cascade thought to be initially triggered by the accumulation of beta-amyloid (Abeta) peptide aggregates or aberrant amyloid precursor protein (APP) processing. Much is known of the factors initiating the disease process decades prior to the onset of cognitive deficits, but an unclear understanding of events immediately preceding and precipitating cognitive decline is a major factor limiting the rapid development of adequate prevention and treatment strategies. Multiple pathways are known to contribute to cognitive deficits by disruption of neuronal signal transduction pathways involved in memory. These pathways are altered by aberrant signaling, inflammation, oxidative damage, tau pathology, neuron loss, and synapse loss. We need to develop stage-specific interventions that not only block causal events in pathogenesis (aberrant tau phosphorylation, Abeta production and accumulation, and oxidative damage), but also address damage from these pathways that will not be reversed by targeting prodromal pathways. This approach would not only focus on blocking early events in pathogenesis, but also adequately correct for loss of synapses, substrates for neuroprotective pathways (e.g., docosahexaenoic acid), defects in energy metabolism, and adverse consequences of inappropriate compensatory responses (aberrant sprouting). Monotherapy targeting early single steps in this complicated cascade may explain disappointments in trials with agents inhibiting production, clearance, or aggregation of the initiating Abeta peptide or its aggregates. Both plaque and tangle pathogenesis have already reached AD levels in the more vulnerable brain regions during the "prodromal" period prior to conversion to "mild cognitive impairment (MCI)." Furthermore, many of the pathological events are no longer proceeding in series, but are going on in parallel. By the MCI stage, we stand a greater chance of success by considering pleiotropic drugs or cocktails that can independently limit the parallel steps of the AD cascade at all stages, but that do not completely inhibit the constitutive normal functions of these pathways. Based on this hypothesis, efforts in our laboratories have focused on the pleiotropic activities of omega-3 fatty acids and the anti-inflammatory, antioxidant, and anti-amyloid activity of curcumin in multiple models that cover many steps of the AD pathogenic cascade (Cole and Frautschy, Alzheimers Dement 2:284-286, 2006).

Automatic process control in anaerobic digestion technology: A critical review.

PubMed

Nguyen, Duc; Gadhamshetty, Venkataramana; Nitayavardhana, Saoharit; Khanal, Samir Kumar

2015-10-01

Anaerobic digestion (AD) is a mature technology that relies upon a synergistic effort of a diverse group of microbial communities for metabolizing diverse organic substrates. However, AD is highly sensitive to process disturbances, and thus it is advantageous to use online monitoring and process control techniques to efficiently operate AD process. A range of electrochemical, chromatographic and spectroscopic devices can be deployed for on-line monitoring and control of the AD process. While complexity of the control strategy ranges from a feedback control to advanced control systems, there are some debates on implementation of advanced instrumentations or advanced control strategies. Centralized AD plants could be the answer for the applications of progressive automatic control field. This article provides a critical overview of the available automatic control technologies that can be implemented in AD processes at different scales. Copyright © 2015 Elsevier Ltd. All rights reserved.

Sexual Orientation as a Peripheral Cue in Advertising: Effects of Models' Sexual Orientation, Argument Strength, and Involvement on Responses to Magazine Ads.

PubMed

Ivory, Adrienne Holz

2017-10-12

This study examines how sexual orientation of couples featured in magazine advertisements affects heterosexual viewers' responses using the elaboration likelihood model as a framework. A 3 × 2 × 2 × 3 experiment tested effects of sexual orientation, argument strength, involvement, and attitudes toward homosexuality on heterosexuals' attitudes toward the couple, advertisement, brand, and product, purchase intentions, and recall. Results indicate that consumers were accepting of ads with lesbian portrayals. Participants showed more negative attitudes toward gay male portrayals, but attitudes toward heterosexual and lesbian ads were similar. This effect was moderated by participants' attitudes toward homosexuals. Low-involvement consumers showed more negative attitudes toward homosexual portrayals than toward heterosexual portrayals, indicating that sexual orientation may have served as a peripheral cue negatively impacting attitudes toward the couple and ad under low elaboration. These effects were not observed for attitudes toward the brand and product, purchase intentions, or recall.

Components of Adenovirus Genome Packaging

PubMed Central

Ahi, Yadvinder S.; Mittal, Suresh K.

2016-01-01

Adenoviruses (AdVs) are icosahedral viruses with double-stranded DNA (dsDNA) genomes. Genome packaging in AdV is thought to be similar to that seen in dsDNA containing icosahedral bacteriophages and herpesviruses. Specific recognition of the AdV genome is mediated by a packaging domain located close to the left end of the viral genome and is mediated by the viral packaging machinery. Our understanding of the role of various components of the viral packaging machinery in AdV genome packaging has greatly advanced in recent years. Characterization of empty capsids assembled in the absence of one or more components involved in packaging, identification of the unique vertex, and demonstration of the role of IVa2, the putative packaging ATPase, in genome packaging have provided compelling evidence that AdVs follow a sequential assembly pathway. This review provides a detailed discussion on the functions of the various viral and cellular factors involved in AdV genome packaging. We conclude by briefly discussing the roles of the empty capsids, assembly intermediates, scaffolding proteins, portal vertex and DNA encapsidating enzymes in AdV assembly and packaging. PMID:27721809

The autonomic higher order processing nuclei of the lower brain stem are among the early targets of the Alzheimer's disease-related cytoskeletal pathology.

PubMed

Rüb, U; Del Tredici, K; Schultz, C; Thal, D R; Braak, E; Braak, H

2001-06-01

The nuclei of the pontine parabrachial region (medial parabrachial nucleus, MPB; lateral parabrachial nucleus, LPB; subpeduncular nucleus, SPP) together with the intermediate zone of the medullary reticular formation (IRZ) are pivotal relay stations within central autonomic regulatory feedback systems. This study was undertaken to investigate the evolution of the Alzheimer's disease-related cytoskeletal pathology in these four sites of the lower brain stem. We examined the MPB, LPB, SPP and IRZ in 27 autopsy cases and classified the cortical Alzheimer-related cytoskeletal anomalies according to an established staging system (neurofibrillary tangle/neuropil threads [NFT/NT] stages I-VI). The lesions were visualized either with the antibody AT8, which is immunospecific for the abnormally phosphorylated form of the cytoskeletal protein tau, or with a modified Gallyas silver iodide stain. The MPB, SPB, and IRZ display cytoskeletal pathology in stage I and the LPB in stage II, whereby bothstages correspond to the preclinical phase of Alzheimer's disease (AD). In stages III-IV (incipient AD), the MPB and SPP are severely affected. In all of the stage III-IV cases, the lesions in the LPB and IRZ are well developed. In stages V and VI (clinical phase of AD), the MPB and SPP are filled with the abnormal intraneuronal material. At stages V-VI, the LPB is moderately involved and the IRZ shows severe damage. The pathogenesis of the AD-related cytoskeletal lesions in the nuclei of the pontine parabrachial region and in the IRZ conforms with the cortical NFT/NT staging sequence I-VI. In the event that the cytoskeletal pathology observed in this study impairs the function of the nerve cells involved, it is conceivable that autonomic mechanisms progressively deteriorate with advancing cortical NFT/NT stages. This relationship remains to be established, but it could provide insights into the illusive correlation between the AD-related cytoskeletal pathology and the function of affected neurons.

Functional microRNAs in Alzheimer’s disease and cancer: differential regulation of common mechanisms and pathways

PubMed Central

Holohan, Kelly N.; Lahiri, Debomoy K.; Schneider, Bryan P.; Foroud, Tatiana; Saykin, Andrew J.

2013-01-01

Two of the main research priorities in the United States are cancer and neurodegenerative diseases, which are attributed to abnormal patterns of cellular behavior. MicroRNAs (miRNA) have been implicated as regulators of cellular metabolism, and thus are an active topic of investigation in both disease areas. There is presently a more extensive body of work on the role of miRNAs in cancer compared to neurodegenerative diseases, and therefore it may be useful to examine whether there is any concordance between the functional roles of miRNAs in these diseases. As a case study, the roles of miRNAs in Alzheimer’s disease (AD) and their functions in various cancers will be compared. A number of miRNA expression patterns are altered in individuals with AD compared with healthy older adults. Among these, some have also been shown to correlate with neuropathological changes including plaque and tangle accumulation, as well as expression levels of other molecules known to be involved in disease pathology. Importantly, these miRNAs have also been shown to have differential expression and or functional roles in various types of cancer. To examine possible intersections between miRNA functions in cancer and AD, we review the current literature on these miRNAs in cancer and AD, focusing on their roles in known biological pathways. We propose a pathway-driven model in which some molecular processes show an inverse relationship between cancer and neurodegenerative disease (e.g., proliferation and apoptosis) whereas others are more parallel in their activity (e.g., immune activation and inflammation). A critical review of these and other molecular mechanisms in cancer may shed light on the pathophysiology of AD, and highlight key areas for future research. Conclusions from this work may be extended to other neurodegenerative diseases for which some molecular pathways have been identified but which have not yet been extensively researched for miRNA involvement. PMID:23335942

Recollection and familiarity in amnesic mild cognitive impairment.

PubMed

Serra, Laura; Bozzali, Marco; Cercignani, Mara; Perri, Roberta; Fadda, Lucia; Caltagirone, Carlo; Carlesimo, Giovanni A

2010-05-01

To investigate whether, in patients with amnesic mild cognitive impairment (a-MCI), recognition deficits are mainly due to a selective impairment of recollection rather than familiarity. Nineteen patients with a-MCI and 23 sex-, age-, and education-matched healthy controls underwent two experimental investigations, using the Process Dissociation Procedure (PDP) and the Remember/Know (R/K) procedure, to assess the differential contribution of recollection and familiarity to their recognition performance. Both experimental procedures revealed a selective preservation of familiarity in a-MCI patients. Moreover, the R/K procedure showed a statistically significant impairment of recollection in a-MCI patients for words that were either read or anagrammed during the study phase. A-MCI is known to be commonly associated with a high risk of conversion to Alzheimer's disease (AD). Several previous studies have demonstrated a characteristic impairment of episodic memory in a-MCI, with an early dysfunction of recognition. Our findings are consistent with the knowledge of neurodegeneration occurring in AD, which is characterized, at the earliest disease stages, by a selective involvement of the entorhinal cortex. Moreover, the current study supports the dual process model of recognition, which hypothesizes recollection and familiarity to be independent processes associated with distinct anatomical substrates.

Lean six sigma methodologies improve clinical laboratory efficiency and reduce turnaround times.

PubMed

Inal, Tamer C; Goruroglu Ozturk, Ozlem; Kibar, Filiz; Cetiner, Salih; Matyar, Selcuk; Daglioglu, Gulcin; Yaman, Akgun

2018-01-01

Organizing work flow is a major task of laboratory management. Recently, clinical laboratories have started to adopt methodologies such as Lean Six Sigma and some successful implementations have been reported. This study used Lean Six Sigma to simplify the laboratory work process and decrease the turnaround time by eliminating non-value-adding steps. The five-stage Six Sigma system known as define, measure, analyze, improve, and control (DMAIC) is used to identify and solve problems. The laboratory turnaround time for individual tests, total delay time in the sample reception area, and percentage of steps involving risks of medical errors and biological hazards in the overall process are measured. The pre-analytical process in the reception area was improved by eliminating 3 h and 22.5 min of non-value-adding work. Turnaround time also improved for stat samples from 68 to 59 min after applying Lean. Steps prone to medical errors and posing potential biological hazards to receptionists were reduced from 30% to 3%. Successful implementation of Lean Six Sigma significantly improved all of the selected performance metrics. This quality-improvement methodology has the potential to significantly improve clinical laboratories. © 2017 Wiley Periodicals, Inc.

Evaluation of inflammation-related genes polymorphisms in Mexican with Alzheimer’s disease: a pilot study

PubMed Central

Toral-Rios, Danira; Franco-Bocanegra, Diana; Rosas-Carrasco, Oscar; Mena-Barranco, Francisco; Carvajal-García, Rosa; Meraz-Ríos, Marco Antonio; Campos-Peña, Victoria

2015-01-01

Amyloid peptide is able to promote the activation of microglia and astrocytes in Alzheimer’s disease (AD), and this stimulates the production of pro-inflammatory cytokines. Inflammation contributes to the process of neurodegeneration and therefore is a key factor in the development of AD. Some of the most important proteins involved in AD inflammation are: clusterin (CLU), complement receptor 1 (CR1), C reactive protein (CRP), tumor necrosis factor α (TNF-α), the interleukins 1α (IL-1α), 6 (IL-6), 10 (IL-10) and cyclooxygenase 2 (COX-2). In particular, COX-2 is encoded by the prostaglandin-endoperoxide synthase 2 gene (PTGS2). Since variations in the genes that encode these proteins may modify gene expression or function, it is important to investigate whether these variations may change the developing AD. The aim of this study was to determine whether the presence of polymorphisms in the genes encoding the aforementioned proteins is associated in Mexican patients with AD. Fourteen polymorphisms were genotyped in 96 subjects with AD and 100 controls; the differences in allele, genotype and haplotype frequencies were analyzed. Additionally, an ancestry analysis was conducted to exclude differences in genetic ancestry among groups as a confounding factor in the study. Significant differences in frequencies between AD and controls were found for the single-nucleotide polymorphism (SNP) rs20417 within the PTGS2 gene. Ancestry analysis revealed no significant differences in the ancestry of the compared groups, and the association was significant even after adjustment for ancestry and correction for multiple testing, which strengthens the validity of the results. We conclude that this polymorphism plays an important role in the development of the AD pathology and further studies are required, including their proteins. PMID:26041990

Osteoporosis and alzheimer pathology: Role of cellular stress response and hormetic redox signaling in aging and bone remodeling

PubMed Central

Cornelius, Carolin; Koverech, Guido; Crupi, Rosalia; Di Paola, Rosanna; Koverech, Angela; Lodato, Francesca; Scuto, Maria; Salinaro, Angela T.; Cuzzocrea, Salvatore; Calabrese, Edward J.; Calabrese, Vittorio

2014-01-01

Alzheimer’s disease (AD) and osteoporosis are multifactorial progressive degenerative disorders. Increasing evidence shows that osteoporosis and hip fracture are common complication observed in AD patients, although the mechanisms underlying this association remain poorly understood. Reactive oxygen species (ROS) are emerging as intracellular redox signaling molecules involved in the regulation of bone metabolism, including receptor activator of nuclear factor-κB ligand-dependent osteoclast differentiation, but they also have cytotoxic effects that include lipoperoxidation and oxidative damage to proteins and DNA. ROS generation, which is implicated in the regulation of cellular stress response mechanisms, is an integrated, highly regulated, process under control of redox sensitive genes coding for redox proteins called vitagenes. Vitagenes, encoding for proteins such as heat shock proteins (Hsps) Hsp32, Hsp70, the thioredoxin, and the sirtuin protein, represent a systems controlling a complex network of intracellular signaling pathways relevant to life span and involved in the preservation of cellular homeostasis under stress conditions. Consistently, nutritional anti-oxidants have demonstrated their neuroprotective potential through a hormetic-dependent activation of vitagenes. The biological relevance of dose–response affects those strategies pointing to the optimal dosing to patients in the treatment of numerous diseases. Thus, the heat shock response has become an important hormetic target for novel cytoprotective strategies focusing on the pharmacological development of compounds capable of modulating stress response mechanisms. Here we discuss possible signaling mechanisms involved in the activation of vitagenes which, relevant to bone remodeling and through enhancement of cellular stress resistance provide a rationale to limit the deleterious consequences associated to homeostasis disruption with consequent impact on the aging process. PMID:24959146

Added value of involving patients in the first step of multidisciplinary guideline development: a qualitative interview study among infertile patients.

PubMed

den Breejen, Elvira M E; Hermens, Rosella P M G; Galama, Wienke H; Willemsen, Wim N P; Kremer, Jan A M; Nelen, Willianne L D M

2016-06-01

Patient involvement in scoping the guideline is emphasized, but published initiatives actively involving patients are generally limited to the writing and reviewing phase. To assess patients' added value to the scoping phase of a multidisciplinary guideline on infertility. Qualitative interview study. We conducted interviews among 12 infertile couples and 17 professionals. We listed and compared the couples' and professionals' key clinical issues (=care aspects that need improvement) to be addressed in the guideline according to four domains: current guidelines, professionals, patients and organization of care. Main key clinical issues suggested by more than three quarters of the infertile couples and/or at least two professionals were identified and compared. Overall, we identified 32 key clinical issues among infertile couples and 23 among professionals. Of the defined main key clinical issues, infertile couples mentioned eight issues that were not mentioned by the professionals. These main key clinical issues mainly concerned patient-centred (e.g. poor information provision and poor alignment of care) aspects of care on the professional and organizational domain. Both groups mentioned two main key clinical issues collectively that were interpreted differently: the lack of emotional support and respect for patients' values. Including patients from the first phase of the guideline development process leads to valuable additional main key clinical issues for the next step of a multidisciplinary guideline development process and broadens the scope of the guideline, particularly regarding patient-centredness and organizational issues from a patients' perspective. © The Author 2016. Published by Oxford University Press in association with the International Society for Quality in Health Care; all rights reserved.

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.

Text mining and its potential applications in systems biology.

PubMed

Ananiadou, Sophia; Kell, Douglas B; Tsujii, Jun-ichi

2006-12-01

With biomedical literature increasing at a rate of several thousand papers per week, it is impossible to keep abreast of all developments; therefore, automated means to manage the information overload are required. Text mining techniques, which involve the processes of information retrieval, information extraction and data mining, provide a means of solving this. By adding meaning to text, these techniques produce a more structured analysis of textual knowledge than simple word searches, and can provide powerful tools for the production and analysis of systems biology models.

Close-Spaced High Temperature Knudsen Flow.

DTIC Science & Technology

1984-06-15

study of discharge processes in Knudsen mode (collisionless), thermionic energy converters. Areas of research involve mechanism for reducing the...The mechanisms we have chosen to study are: reduction of space-charge through a very close inter- electrode gap (less than 10 microns); transport and...AD-AI4U 471 :NNTIM R~ A Rl M ,i; ,11 , i J)W R8 1070 1 I~ "i E~Hhhh IIt Ll ~ : RASOR ASSOCIATES, INC.- AFOSR.TR. 84-1070 NSR-22-2 CLOSE -SPACED HIGH

BPS objects in D = 7 supergravity and their M-theory origin

NASA Astrophysics Data System (ADS)

Dibitetto, Giuseppe; Petri, Nicolò

2017-12-01

We study several different types of BPS flows within minimal N=1 , D = 7 supergravity with SU(2) gauge group and non-vanishing topological mass. After reviewing some known domain wall solutions involving only the metric and the ℝ+ scalar field, we move to considering more general flows involving a "dyonic" profile for the 3-form gauge potential. In this context, we consider flows featuring a Mkw3 as well as an AdS3 slicing, write down the corresponding flow equations, and integrate them analytically to obtain many examples of asymptotically AdS7 solutions in presence of a running 3-form. Furthermore, we move to adding the possibility of non-vanishing vector fields, find the new corresponding flows and integrate them numerically. Finally, we discuss the eleven-dimensional interpretation of the aforementioned solutions as effective descriptions of M2 - M5 bound states.

Alzheimer’s disease is not “brain aging”: neuropathological, genetic, and epidemiological human studies

PubMed Central

Head, Elizabeth; Schmitt, Frederick A.; Davis, Paulina R.; Neltner, Janna H.; Jicha, Gregory A.; Abner, Erin L.; Smith, Charles D.; Van Eldik, Linda J.; Kryscio, Richard J.; Scheff, Stephen W.

2011-01-01

Human studies are reviewed concerning whether “aging”-related mechanisms contribute to Alzheimer’s disease (AD) pathogenesis. AD is defined by specific neuropathology: neuritic amyloid plaques and neocortical neurofibrillary tangles. AD pathology is driven by genetic factors related not to aging per se, but instead to the amyloid precursor protein (APP). In contrast to genes involved in APP-related mechanisms, there is no firm connection between genes implicated in human “accelerated aging” diseases (progerias) and AD. The epidemiology of AD in advanced age is highly relevant but deceptively challenging to address given the low autopsy rates in most countries. In extreme old age, brain diseases other than AD approximate AD prevalence while the impact of AD pathology appears to peak by age 95 and decline thereafter. Many distinct brain diseases other than AD afflict older human brains and contribute to cognitive impairment. Additional prevalent pathologies include cerebrovascular disease and hippocampal sclerosis, both high-morbidity brain diseases that appear to peak in incidence later than AD chronologically. Because of these common brain diseases of extreme old age, the epidemiology differs between clinical “dementia” and the subset of dementia cases with AD pathology. Additional aging-associated mechanisms for cognitive decline such as diabetes and synapse loss have been linked to AD and these hypotheses are discussed. Criteria are proposed to define an “aging-linked” disease, and AD fails all of these criteria. In conclusion, it may be most fruitful to focus attention on specific pathways involved in AD rather than attributing it to an inevitable consequence of aging. PMID:21516511

The cognitive mechanisms underlying perspective taking between conversational partners: Evidence from speakers with Alzheimer’s disease

PubMed Central

Wardlow, Liane; Ivanova, Iva; Gollan, Tamar H.

2014-01-01

Successful communication requires speakers to consider their listeners’ perspectives. Little is known about how this ability changes in Alzheimer’s Disease (AD) although such knowledge could reveal the cognitive mechanisms fundamental to perspective-taking ability, and reveal which cognitive deficits are fundamental to communication disorders in AD. Patients with mild to moderate AD and age and education matched controls were tested in a communicative perspective-taking task, and on measures of executive control, general cognitive functioning, and lexical retrieval. Patients’ ability to perform the perspective-taking task was significantly correlated with performance on measures of general cognitive functioning, visual scanning and construction, response conflict and attention. Measures of lexical retrieval tended not to be correlated with performance on the communication task with one exception: semantic but not letter fluency predicted a derived score of perspective-taking ability. These findings broaden our understanding of the cognitive mechanisms underlying perspective taking, and suggest that impairments in perspective taking in AD occur during utterance planning, and at a relatively early processing stage which involves rapid visual scanning and problem solving, rather than during retrieval of lexical items needed to speak. More broadly, these data reveal executive function and semantic deficits, but not problems with lexical retrieval, as more fundamental to the basis of cognitive changes associated with AD. PMID:24467889

Dysregulated Pathway Identification of Alzheimer's Disease Based on Internal Correlation Analysis of Genes and Pathways.

PubMed

Kong, Wei; Mou, Xiaoyang; Di, Benteng; Deng, Jin; Zhong, Ruxing; Wang, Shuaiqun

2017-11-20

Dysregulated pathway identification is an important task which can gain insight into the underlying biological processes of disease. Current pathway-identification methods focus on a set of co-expression genes and single pathways and ignore the correlation between genes and pathways. The method proposed in this study, takes into account the internal correlations not only between genes but also pathways to identifying dysregulated pathways related to Alzheimer's disease (AD), the most common form of dementia. In order to find the significantly differential genes for AD, mutual information (MI) is used to measure interdependencies between genes other than expression valves. Then, by integrating the topology information from KEGG, the significant pathways involved in the feature genes are identified. Next, the distance correlation (DC) is applied to measure the pairwise pathway crosstalks since DC has the advantage of detecting nonlinear correlations when compared to Pearson correlation. Finally, the pathway pairs with significantly different correlations between normal and AD samples are known as dysregulated pathways. The molecular biology analysis demonstrated that many dysregulated pathways related to AD pathogenesis have been discovered successfully by the internal correlation detection. Furthermore, the insights of the dysregulated pathways in the development and deterioration of AD will help to find new effective target genes and provide important theoretical guidance for drug design. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

New Functions of APC/C Ubiquitin Ligase in the Nervous System and Its Role in Alzheimer's Disease.

PubMed

Fuchsberger, Tanja; Lloret, Ana; Viña, Jose

2017-05-14

The E3 ubiquitin ligase Anaphase Promoting Complex/Cyclosome (APC/C) regulates important processes in cells, such as the cell cycle, by targeting a set of substrates for degradation. In the last decade, APC/C has been related to several major functions in the nervous system, including axon guidance, synaptic plasticity, neurogenesis, and neuronal survival. Interestingly, some of the identified APC/C substrates have been related to neurodegenerative diseases. There is an accumulation of some degradation targets of APC/C in Alzheimer's disease (AD) brains, which suggests a dysregulation of the protein complex in the disorder. Moreover, recently evidence has been provided for an inactivation of APC/C in AD. It has been shown that oligomers of the AD-related peptide, Aβ, induce degradation of the APC/C activator subunit cdh1, in vitro in neurons in culture and in vivo in the mouse hippocampus. Furthermore, in the AD mouse model APP/PS1, lower cdh1 levels were observed in pyramidal neurons in CA1 when compared to age-matched wildtype mice. In this review, we provide a complete list of APC/C substrates that are involved in the nervous system and we discuss their functions. We also summarize recent studies that show neurobiological effects in cdh1 knockout mouse models. Finally, we discuss the role of APC/C in the pathophysiology of AD.

Harvesting Social Signals to Inform Peace Processes Implementation and Monitoring

PubMed Central

Nigam, Aastha; Dambanemuya, Henry K.; Joshi, Madhav; Chawla, Nitesh V.

2017-01-01

Abstract Peace processes are complex, protracted, and contentious involving significant bargaining and compromising among various societal and political stakeholders. In civil war terminations, it is pertinent to measure the pulse of the nation to ensure that the peace process is responsive to citizens' concerns. Social media yields tremendous power as a tool for dialogue, debate, organization, and mobilization, thereby adding more complexity to the peace process. Using Colombia's final peace agreement and national referendum as a case study, we investigate the influence of two important indicators: intergroup polarization and public sentiment toward the peace process. We present a detailed linguistic analysis to detect intergroup polarization and a predictive model that leverages Tweet structure, content, and user-based features to predict public sentiment toward the Colombian peace process. We demonstrate that had proaccord stakeholders leveraged public opinion from social media, the outcome of the Colombian referendum could have been different. PMID:29235916

Harvesting Social Signals to Inform Peace Processes Implementation and Monitoring.

PubMed

Nigam, Aastha; Dambanemuya, Henry K; Joshi, Madhav; Chawla, Nitesh V

2017-12-01

Peace processes are complex, protracted, and contentious involving significant bargaining and compromising among various societal and political stakeholders. In civil war terminations, it is pertinent to measure the pulse of the nation to ensure that the peace process is responsive to citizens' concerns. Social media yields tremendous power as a tool for dialogue, debate, organization, and mobilization, thereby adding more complexity to the peace process. Using Colombia's final peace agreement and national referendum as a case study, we investigate the influence of two important indicators: intergroup polarization and public sentiment toward the peace process. We present a detailed linguistic analysis to detect intergroup polarization and a predictive model that leverages Tweet structure, content, and user-based features to predict public sentiment toward the Colombian peace process. We demonstrate that had proaccord stakeholders leveraged public opinion from social media, the outcome of the Colombian referendum could have been different.

The White-hat Bot: A Novel Botnet Defense Strategy

DTIC Science & Technology

2012-06-14

etc. I will briefly discuss one common exploit here. One fraudulent activity 4 perpetuated by botnets involves ad services such as Google’s AdSense ...which pays website owners revenue for posting the AdSense banner on their web site (Google, 2012). The AdSense banner displays messages from...botmaster creates a bot that is programmed to visit the botmaster’s own websites to click on the advertisements displayed in the AdSense banners. Since

The relevance of hippocampal subfield integrity and clock drawing test performance for the diagnosis of Alzheimer's disease and mild cognitive impairment.

PubMed

Hirjak, Dusan; Sambataro, Fabio; Remmele, Barbara; Kubera, Katharina M; Schröder, Johannes; Seidl, Ulrich; Thomann, Anne K; Maier-Hein, Klaus H; Wolf, Robert C; Thomann, Philipp A

2017-08-31

The clock drawing test (CDT) is one of the worldwide most used screening tests for Alzheimer's disease (AD). MRI studies have identified temporo-parietal regions being involved in CDT impairment. However, the contributions of specific hippocampal subfields and adjacent extrahippocampal structures to CDT performance in AD and mild cognitive impairment (MCI) have not been investigated so far. It is unclear whether morphological alterations or CDT score, or a combination of both, are able to predict AD. 38 AD patients, 38 MCI individuals and 31 healthy controls underwent neuropsychological assessment and MRI at 3 Tesla. FreeSurfer 5.3 was used to perform hippocampal parcellation. We used a collection of statistical methods to better understand the relationship between CDT and hippocampal formation. We also tested the clinical feasibility of this relationship when predicting AD. Impaired CDT performance in AD was associated with widespread atrophy of the cornu ammonis, presubiculum, and subiculum, whereas MCI subjects showed CDT-related alterations of the CA4-dentate gyrus and subiculum. CDT correlates in AD and MCI showed regional and quantitative overlap. Importantly, CDT score was the best predictor of AD. Our findings lend support for an involvement of different hippocampal subfields in impaired CDT performance in AD and MCI. CDT seems to be more efficient than subfield imaging for predicting AD.

Molecular Mechanisms for Herpes Simplex Virus Type 1 Pathogenesis in Alzheimer’s Disease

PubMed Central

Harris, Steven A.; Harris, Elizabeth A.

2018-01-01

This review focuses on research in the areas of epidemiology, neuropathology, molecular biology and genetics that implicates herpes simplex virus type 1 (HSV-1) as a causative agent in the pathogenesis of sporadic Alzheimer’s disease (AD). Molecular mechanisms whereby HSV-1 induces AD-related pathophysiology and pathology, including neuronal production and accumulation of amyloid beta (Aβ), hyperphosphorylation of tau proteins, dysregulation of calcium homeostasis, and impaired autophagy, are discussed. HSV-1 causes additional AD pathologies through mechanisms that promote neuroinflammation, oxidative stress, mitochondrial damage, synaptic dysfunction, and neuronal apoptosis. The AD susceptibility genes apolipoprotein E (APOE), phosphatidylinositol binding clathrin assembly protein (PICALM), complement receptor 1 (CR1) and clusterin (CLU) are involved in the HSV lifecycle. Polymorphisms in these genes may affect brain susceptibility to HSV-1 infection. APOE, for example, influences susceptibility to certain viral infections, HSV-1 viral load in the brain, and the innate immune response. The AD susceptibility gene cholesterol 25-hydroxylase (CH25H) is upregulated in the AD brain and is involved in the antiviral immune response. HSV-1 interacts with additional genes to affect cognition-related pathways and key enzymes involved in Aβ production, Aβ clearance, and hyperphosphorylation of tau proteins. Aβ itself functions as an antimicrobial peptide (AMP) against various pathogens including HSV-1. Evidence is presented supporting the hypothesis that Aβ is produced as an AMP in response to HSV-1 and other brain infections, leading to Aβ deposition and plaque formation in AD. Epidemiologic studies associating HSV-1 infection with AD and cognitive impairment are discussed. Studies are reviewed supporting subclinical chronic reactivation of latent HSV-1 in the brain as significant in the pathogenesis of AD. Finally, the rationale for and importance of clinical trials treating HSV-1-infected MCI and AD patients with antiviral medication is discussed. PMID:29559905

Alzheimer's as a Systems-Level Disease Involving the Interplay of Multiple Cellular Networks.

PubMed

Castrillo, Juan I; Oliver, Stephen G

2016-01-01

Alzheimer's disease (AD), and many neurodegenerative disorders, are multifactorial in nature. They involve a combination of genomic, epigenomic, interactomic and environmental factors. Progress is being made, and these complex diseases are beginning to be understood as having their origin in altered states of biological networks at the cellular level. In the case of AD, genomic susceptibility and mechanisms leading to (or accompanying) the impairment of the central Amyloid Precursor Protein (APP) processing and tau networks are widely accepted as major contributors to the diseased state. The derangement of these networks may result in both the gain and loss of functions, increased generation of toxic species (e.g., toxic soluble oligomers and aggregates) and imbalances, whose effects can propagate to supra-cellular levels. Although well sustained by empirical data and widely accepted, this global perspective often overlooks the essential roles played by the main counteracting homeostatic networks (e.g., protein quality control/proteostasis, unfolded protein response, protein folding chaperone networks, disaggregases, ER-associated degradation/ubiquitin proteasome system, endolysosomal network, autophagy, and other stress-protective and clearance networks), whose relevance to AD is just beginning to be fully realized. In this chapter, an integrative perspective is presented. Alzheimer's disease is characterized to be a result of: (a) intrinsic genomic/epigenomic susceptibility and, (b) a continued dynamic interplay between the deranged networks and the central homeostatic networks of nerve cells. This interplay of networks will underlie both the onset and rate of progression of the disease in each individual. Integrative Systems Biology approaches are required to effect its elucidation. Comprehensive Systems Biology experiments at different 'omics levels in simple model organisms, engineered to recapitulate the basic features of AD may illuminate the onset and sequence of events underlying AD. Indeed, studies of models of AD in simple organisms, differentiated cells in culture and rodents are beginning to offer hope that the onset and progression of AD, if detected at an early stage, may be stopped, delayed, or even reversed, by activating or modulating networks involved in proteostasis and the clearance of toxic species. In practice, the incorporation of next-generation neuroimaging, high-throughput and computational approaches are opening the way towards early diagnosis well before irreversible cell death. Thus, the presence or co-occurrence of: (a) accumulation of toxic Aβ oligomers and tau species; (b) altered splicing and transcriptome patterns; (c) impaired redox, proteostatic, and metabolic networks together with, (d) compromised homeostatic capacities may constitute relevant 'AD hallmarks at the cellular level' towards reliable and early diagnosis. From here, preventive lifestyle changes and tailored therapies may be investigated, such as combined strategies aimed at both lowering the production of toxic species and potentiating homeostatic responses, in order to prevent or delay the onset, and arrest, alleviate, or even reverse the progression of the disease.

Pain in Alzheimer's disease: A study of behavior and neural correlates

NASA Astrophysics Data System (ADS)

Beach, Paul Anthony

Alzheimer's disease (AD) is a devastating neurodegenerative disease characterized by insidious and progressive impairment of cognition, emotion, and memory. Though pain in patients with AD is a major medical concern it is under diagnosed and under treated in patients, compared to cognitively healthy elderly. Further complicating matters, subjective self-report of pain by becomes increasingly compromised with disease progression; this often leaves clinicians and caregivers no choice but to rely on discerning pain from behavior alone. Patients also report pain at a lower frequency and intensity than healthy seniors (HS). These findings, coupled with recognition that AD pathology affects many pain processing brain regions, have prompted examination of whether AD alters pain perception. While there is evidence that AD actually predisposes heightened perception of pain, several issues remain: experimental work is limited to a handful of studies, whose results have been inconsistent; few examinations of pain in AD have included patients with advanced disease; the neural mechanism underlying altered pain in AD is not clear. I addressed these gaps in the literature by examining subjective, behavioral, and autonomic pain responses in 33 HS and 38 patients with varying severities of AD. A subset of these subjects (24 HS and 20 AD) were scanned, using fMRI. I then determined how the functional connectivity of various resting-state networks (RSNs) were associated with measured pain responses. I found that AD patients rated low-level stimuli as more painful than HS. Also, patients, regardless of severity, showed greater degrees of pain behaviors than HS - both with respect to global behaviors as measured by a clinical pain scale and facial responses as measured by an experimental tool. In contrast, autonomic responses were blunted with advancing AD. Altered pain responses in AD were associated with altered function of RSNs involved in attention and internal mentation, affect, somatosensation, and interoception (p<0.05, FWE corrected). These findings provide further evidence and an improved understanding of the neural basis for heightened pain sensitivity in patients with AD. They also emphasize the necessity to improve pain assessment and treatment strategies for a vulnerable patient population set to expand greatly in the coming decades.

Spinning AdS loop diagrams: two point functions

NASA Astrophysics Data System (ADS)

Giombi, Simone; Sleight, Charlotte; Taronna, Massimo

2018-06-01

We develop a systematic approach to evaluating AdS loop amplitudes with spinning legs based on the spectral (or "split") representation of bulk-to-bulk propagators, which re-expresses loop diagrams in terms of spectral integrals and higher-point tree diagrams. In this work we focus on 2pt one-loop Witten diagrams involving totally symmetric fields of arbitrary mass and integer spin. As an application of this framework, we study the contribution to the anomalous dimension of higher-spin currents generated by bubble diagrams in higher-spin gauge theories on AdS.

Secure ADS-B authentication system and method

NASA Technical Reports Server (NTRS)

Viggiano, Marc J (Inventor); Valovage, Edward M (Inventor); Samuelson, Kenneth B (Inventor); Hall, Dana L (Inventor)

2010-01-01

A secure system for authenticating the identity of ADS-B systems, including: an authenticator, including a unique id generator and a transmitter transmitting the unique id to one or more ADS-B transmitters; one or more ADS-B transmitters, including a receiver receiving the unique id, one or more secure processing stages merging the unique id with the ADS-B transmitter's identification, data and secret key and generating a secure code identification and a transmitter transmitting a response containing the secure code and ADSB transmitter's data to the authenticator; the authenticator including means for independently determining each ADS-B transmitter's secret key, a receiver receiving each ADS-B transmitter's response, one or more secure processing stages merging the unique id, ADS-B transmitter's identification and data and generating a secure code, and comparison processing comparing the authenticator-generated secure code and the ADS-B transmitter-generated secure code and providing an authentication signal based on the comparison result.

Current Concepts of Neurodegenerative Mechanisms in Alzheimer's Disease.

PubMed

Magalingam, Kasthuri Bai; Radhakrishnan, Ammu; Ping, Ng Shee; Haleagrahara, Nagaraja

2018-01-01

Neurodegenerative diseases are hereditary or sporadic conditions that result in the progressive loss of the structure and function of neurons as well as neuronal death. Although a range of diseases lie under this umbrella term, Alzheimer's disease (AD) and Parkinson's disease (PD) are the most common neurodegenerative diseases that affect a large population around the globe. Alzheimer's disease is characterized by the abnormal accumulation of extracellular amyloid- β plaques and intraneuronal neurofibrillary tangles in brain regions and manifests as a type of dementia in aged individuals that results in memory loss, multiple cognitive abnormalities, and intellectual disabilities that interfere with quality of life. Since the discovery of AD, a wealth of new information has emerged that delineates the causes, mechanisms of disease, and potential therapeutic agents, but an effective remedy to cure the diseases has not been identified yet. This could be because of the complexity of the disease process, as it involves various contributing factors that include environmental factors and genetic predispositions. This review summarizes the current understanding on neurodegenerative mechanisms that lead to the emergence of the pathology of AD.

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

Elucidation of non-intentionally added substances migrating from polyester-polyurethane lacquers using automated LC-HRMS data processing.

PubMed

Omer, Elsa; Cariou, Ronan; Remaud, Gérald; Guitton, Yann; Germon, Hélène; Hill, Paul; Dervilly-Pinel, Gaud; Le Bizec, Bruno

2018-03-08

An untargeted strategy aiming at identifying non-intentionally added substances (NIAS) migrating from coatings was developed. This innovative approach was applied to two polyester-polyurethane lacquers, for which suppliers previously provided the identity of the monomers involved. Lacquers were extracted with acetonitrile and analyzed by liquid chromatography-high resolution mass spectrometry (LC-HRMS). Data, acquired in the full scan mode, were processed using an open-source R-environment (xcms and CAMERA packages) to list the detected features and deconvolute them in groups related to individual compounds. The most intense groups, accounting for more than 85% of cumulated feature intensities, were then investigated. A homemade database, populated with predicted polyester oligomer combinations from a relevant selection of diols and diacids, enabled highlighting the presence of 14 and 17 cyclic predicted polyester oligomers in the two lacquers, including three mutual combinations explained by common known monomers. Combination hypotheses were strengthened by chromatographic considerations and by the investigation of fragmentation patterns. Regarding unpredicted migrating substances, four monomers were hypothesised to explain several polyester or caprolactam oligomer series. Finally, considering both predicted and tentatively elucidated unpredicted oligomers, it was possible to assign hypotheses to features representing up to 82% and 90% of the cumulated intensities in the two lacquers, plus 9% and 3% (respectively) originating from the procedural blank. Graphical abstract Elucidation of non-intentionally added substances.

Chromium cycling in soils and water: links, gaps, and methods.

PubMed

Bartlett, R J

1991-05-01

The major links in the cycling of chromium in soils and in natural waters are between chromium(III) and chromium (VI). Between the larger links are lesser links involving processes of mobilization and oxidation of CrIII and reduction of CrVI. The gaps are mainly in our understanding of the factors that control these processes. If soluble CrIII is added to an "average" soil, a portion of it will become immediately oxidized by manganese oxides to CrVI. The rest of the CrIII may remain reduced for long periods of time, even in the presence of electron-accepting manganese oxides. However, this less available CrIII can be mobilized by low molecular weight organic complexers and then oxidized where redox conditions are optimal. Usually part of any CrVI added to a soil or sediment will be reduced instantly, especially under acid conditions. On the other hand, high concentrations of polluting CrVI may quickly exhaust the readily available reducing power of the matrix material and excess CrVI, the thermodynamically stable form in air, may persist for years in soils or lagoons without reduction. Cleanup of chromium pollution must involve the surrounding of both CrIII and CrVI with excesses of slowly available reducing substances and sealing them permanently from inputs of atmospheric oxygen. Monitoring the effectiveness of the measures is mandatory, but fortunately the chemical testing for CrVI in soil and water is simple and problem free compared with most colorimetric determinations.

Engineering of biotin-prototrophy in Pichia pastoris for robust production processes.

PubMed

Gasser, Brigitte; Dragosits, Martin; Mattanovich, Diethard

2010-11-01

Biotin plays an essential role as cofactor for biotin-dependent carboxylases involved in essential metabolic pathways. The cultivation of Pichia pastoris, a methylotrophic yeast that is successfully used as host for the production of recombinant proteins, requires addition of high dosage of biotin. As biotin is the only non-salt media component used during P. pastoris fermentation (apart from the carbon source), nonconformities during protein production processes are usually attributed to poor quality of the added biotin. In order to avoid dismissed production runs due to biotin quality issues, we engineered the biotin-requiring yeast P. pastoris to become a biotin-prototrophic yeast. Integration of four genes involved in the biotin biosynthesis from brewing yeast into the P. pastoris genome rendered P. pastoris biotin-prototrophic. The engineered strain has successfully been used as production host for both intracellular and secreted heterologous proteins in fed-batch processes, employing mineral media without vitamins. Another field of application for these truly prototrophic hosts is the production of biochemicals and small metabolites, where defined mineral media leads to easier purification procedures. Copyright © 2010 Elsevier Inc. All rights reserved.

Neurolinguistic approach to natural language processing with applications to medical text analysis.

PubMed

Duch, Włodzisław; Matykiewicz, Paweł; Pestian, John

2008-12-01

Understanding written or spoken language presumably involves spreading neural activation in the brain. This process may be approximated by spreading activation in semantic networks, providing enhanced representations that involve concepts not found directly in the text. The approximation of this process is of great practical and theoretical interest. Although activations of neural circuits involved in representation of words rapidly change in time snapshots of these activations spreading through associative networks may be captured in a vector model. Concepts of similar type activate larger clusters of neurons, priming areas in the left and right hemisphere. Analysis of recent brain imaging experiments shows the importance of the right hemisphere non-verbal clusterization. Medical ontologies enable development of a large-scale practical algorithm to re-create pathways of spreading neural activations. First concepts of specific semantic type are identified in the text, and then all related concepts of the same type are added to the text, providing expanded representations. To avoid rapid growth of the extended feature space after each step only the most useful features that increase document clusterization are retained. Short hospital discharge summaries are used to illustrate how this process works on a real, very noisy data. Expanded texts show significantly improved clustering and may be classified with much higher accuracy. Although better approximations to the spreading of neural activations may be devised a practical approach presented in this paper helps to discover pathways used by the brain to process specific concepts, and may be used in large-scale applications.

Involvement of suppressor of cytokine signaling-1 in globular adiponectin-induced granulocyte colony-stimulating factor in RAW 264 cell.

PubMed

Fujimoto, Akie; Akifusa, Sumio; Hirofuji, Takao; Yamashita, Yoshihisa

2011-09-01

We previously demonstrated that treatment with a globular type of adiponectin (gAd) induced expression of granulocyte colony-stimulating factor (G-CSF) via the MEK/ERK signaling pathway in a murine macrophage cell line, RAW 264. In the present study, we investigated whether suppressor of cytokine signaling-1 (SOCS1) has roles in the regulation of gAd-induced G-CSF generation. Intracellular G-CSF generation induced by gAd treatment peaked after 10h and then attenuated. SOCS1 mRNA and protein were expressed at 1h and 4h after gAd treatment, respectively. Overexpression of SOCS1 reduced G-CSF generation and phosphorylation of ERK, JNK, and p38 MAPK in gAd-treated cells. While gAd treatment induced the translocation of STAT3 to the nucleus under control conditions, STAT3 stayed in the cytosol when SOCS1 was overexpressed. Additionally, knockdown of SOCS1 by interfering RNA caused levels of G-CSF to continue to rise beyond 10h after gAd treatment. These results suggest that SOCS1 is involved in providing negative feedback for gAd-induced production of G-CSF. Copyright © 2011 Elsevier Ltd. All rights reserved.

New surface smoothing technologies for manufacturing of complex shaped glass components

NASA Astrophysics Data System (ADS)

Henkel, Sebastian; Schwager, Anne-Marie; Bliedtner, Jens; Götze, Kerstin; Rädlein, Edda; Schulze, Christian; Gerhardt, Martin; Fuhr, Michael

2017-10-01

The production of complex glass components with 2.5D or 3D-structures involves great effort and the need for advanced CNC-technology. Especially the final surface treatment, for generation of transparent surfaces, represents a timeconsuming and costly process. The ultrasonic-assisted grinding procedure is used to generate arbitrary shaped components and freeform-surfaces. The special kinematic principle, containing a high-frequency tool oscillation, enables efficient manufacturing processes. Surfaces produced in this way allow for application of novel smoothing methods, providing considerable advantages compared to classic polishing. It is shown, that manufacturing of transparent glass surfaces with low roughness down to Rq = 10 nm is possible, using an ultra-fine grinding process. By adding a CO2-laser polishing process, roughness can be reduced even further with a very short polishing time.

Atopic dermatitis and vitamin D: facts and controversies*

PubMed Central

Mesquita, Kleyton de Carvalho; Igreja, Ana Carolina de Souza Machado; Costa, Izelda Maria Carvalho

2013-01-01

Patients with atopic dermatitis have genetically determined risk factors that affect the barrier function of the skin and immune responses that interact with environmental factors. Clinically, this results in an intensely pruriginous and inflamed skin that allows the penetration of irritants and allergens and predisposes patients to colonization and infection by microorganisms. Among the various etiological factors responsible for the increased prevalence of atopic diseases over the past few decades, the role of vitamin D has been emphasized. As the pathogenesis of AD involves a complex interplay of epidermal barrier dysfunction and dysregulated immune response, and vitamin D is involved in both processes, it is reasonable to expect that vitamin D's status could be associated with atopic dermatitis' risk or severity. Such association is suggested by epidemiological and experimental data. In this review, we will discuss the evidence for and against this controversial relationship, emphasizing the possible etiopathogenic mechanisms involved. PMID:24474104

Comprehensive analysis of differentially expressed profiles of Alzheimer’s disease associated circular RNAs in an Alzheimer’s disease mouse model

PubMed Central

Huang, Jin-Lan; Qin, Mei-Chun; Zhou, Yan; Xu, Zhe-Hao; Yang, Si-man; Zhang, Fan; Zhong, Jing; Liang, Ming-Kun; Chen, Ben; Zhang, Wen-Yan

2018-01-01

Circular RNAs (circRNAs), a novel kind of non-coding RNA, have received increasing attention for their involvement in pathogenesis of Alzheimer’s disease (AD); however, few studies have reported in the characterization and function of AD associated circRNAs. Here the expression profiles of circRNAs in 5- and 10-month-old SAMP8 mice were identified using circRNA microarray and found that 85 dysregulated circRNAs were observed in 10-month-old SAMP8 versus control mice and 231 circRNAs exhibited differential expression in 10-month-old SAMP8 versus 5-month-old SAMP8. One most significantly dysregulated circRNA, mmu_circRNA_017963, was select for Gene Oncology (GO) and pathway analysis. The results showed that mmu_circRNA_017963 was strongly related with autophagosome assembly, exocytosis, apoptotic process, transport and RNA splicing and highly associated with synaptic vesicle cycle, spliceosome, glycosaminoglycan and SNARE interactions in vesicular transport pathways. Collectively, this study was the first to describe circRNAs expression in different ages of SAMP8 and will contribute to the understanding of the regulatory roles of circRNAs in AD pathogenesis and provide a valuable resource for the diagnosis and therapy of AD. PMID:29448241

Ebselen inhibits iron-induced tau phosphorylation by attenuating DMT1 up-regulation and cellular iron uptake.

PubMed

Xie, Ling; Zheng, Wei; Xin, Na; Xie, Jing-Wei; Wang, Tao; Wang, Zhan-You

2012-08-01

Dysregulation of iron homeostasis is involved in the pathological process of Alzheimer's disease (AD). We have recently reported that divalent metal transporter 1 (DMT1) is upregulated in an AD transgenic mouse brain, and that silencing of DMT1, which reduces cellular iron influx, results in inhibition of amyloidogenesis in vitro, suggesting a potential target of DMT1 for AD therapy. In the present study, we tested the hypothesis that inhibition of DMT1 with ebselen, a DMT1 transport inhibitor, could affect tau phosphorylation. Human neuroblastoma SH-SY5Y cells were pre-treated with ebselen and then treated with ferrous sulfate (dissolved in ascorbic acid), and the effects of ebselen on tau phosphorylation and the relative signaling pathways were examined. Our results showed that ebselen decreased iron influx, reduced iron-induced ROS production, inhibited the activities of cyclin-dependent kinase 5 and glycogen synthase kinase 3β, and ultimately attenuated the levels of tau phosphorylation at the sites of Thr205, Ser396 and Thr231. The present study indicates that the neuroprotective effect of ebselen on AD is not only related to its antioxidant activity as reported previously, but is also associated with a reduction in tau phosphorylation by inhibition of DMT1. Copyright © 2012 Elsevier Ltd. All rights reserved.

Evolution of Neurodegeneration Imaging Biomarkers from Clinically Normal to Dementia in the Alzheimer Disease Spectrum

PubMed Central

Knopman, David S.; Jack, Clifford R.; Lundt, Emily S.; Weigand, Stephen D.; Vemuri, Prashanthi; Lowe, Val J.; Kantarci, Kejal; Gunter, Jeffrey L.; Senjem, Matthew L.; Mielke, Michelle M.; Machulda, Mary M.; Roberts, Rosebud O.; Boeve, Bradley F.; Jones, David T.; Petersen, Ronald C.

2016-01-01

The availability of antemortem biomarkers for Alzheimer’s Disease (AD) enables monitoring the evolution of neurodegenerative processes in real time. Pittsburgh compound B (PIB) positron emission tomography (PET) was used to select participants in the Mayo Clinic Study of Aging and the Mayo Alzheimer’s Disease Research Center with elevated β-amyloid, designated as “A+,” and hippocampal volume and 18fluorodeoxyglucose (FDG) positron emission tomography were used to characterize participants as having evidence of neurodegeneration (“N+”) at the baseline evaluation. There were 145 clinically normal (CN) A+ individuals, 62 persons with mild cognitive impairment (MCI) who were A+ and 20 with A+ AD dementia. Over a period of 1–6 years, MCI A+N+ individuals showed declines in medial temporal, lateral temporal, lateral parietal, and to a lesser extent, medial parietal regions for both FDG standardized uptake value ratio (SUVR) and grey matter (GM) volume that exceeded declines seen in the CN A+N+ group. The AD dementia group showed declines in the same regions on FDG SUVR and GM volume with rates that exceeded that in MCI A+N+. Expansion of regional involvement and faster rate of neurodegeneration characterizes progression in the AD pathway. PMID:27460147

Evolution of neurodegeneration-imaging biomarkers from clinically normal to dementia in the Alzheimer disease spectrum.

PubMed

Knopman, David S; Jack, Clifford R; Lundt, Emily S; Weigand, Stephen D; Vemuri, Prashanthi; Lowe, Val J; Kantarci, Kejal; Gunter, Jeffrey L; Senjem, Matthew L; Mielke, Michelle M; Machulda, Mary M; Roberts, Rosebud O; Boeve, Bradley F; Jones, David T; Petersen, Ronald C

2016-10-01

The availability of antemortem biomarkers for Alzheimer's disease (AD) enables monitoring the evolution of neurodegenerative processes in real time. Pittsburgh compound B (PIB) positron emission tomography (PET) was used to select participants in the Mayo Clinic Study of Aging and the Mayo Alzheimer's Disease Research Center with elevated β-amyloid, designated as "A+," and hippocampal volume and (18)fluorodeoxyglucose (FDG) positron emission tomography were used to characterize participants as having evidence of neurodegeneration ("N+") at the baseline evaluation. There were 145 clinically normal (CN) A+ individuals, 62 persons with mild cognitive impairment (MCI) who were A+ and 20 with A+ AD dementia. Over a period of 1-6 years, MCI A+N+ individuals showed declines in medial temporal, lateral temporal, lateral parietal, and to a lesser extent, medial parietal regions for both FDG standardized uptake value ratio and gray matter volume that exceeded declines seen in the CN A+N+ group. The AD dementia group showed declines in the same regions on FDG standardized uptake value ratio and gray matter volume with rates that exceeded that in MCI A+N+. Expansion of regional involvement and faster rate of neurodegeneration characterizes progression in the AD pathway. Copyright © 2016 Elsevier Inc. All rights reserved.

Immunogenicity of DNA- and recombinant protein-based Alzheimer disease epitope vaccines.

PubMed

Davtyan, Hayk; Bacon, Andrew; Petrushina, Irina; Zagorski, Karen; Cribbs, David H; Ghochikyan, Anahit; Agadjanyan, Michael G

2014-01-01

Alzheimer disease (AD) process involves the accumulation of amyloid plaques and tau tangles in the brain, nevertheless the attempts at targeting the main culprits, neurotoxic β-amyloid (Aβ) peptides, have thus far proven unsuccessful for improving cognitive function. Important lessons about anti-Aβ immunotherapeutic strategies were learned from the first active vaccination clinical trials. AD progression could be safely prevented or delayed if the vaccine (1) induces high titers of antibodies specific to toxic forms of Aβ; (2) does not activate the harmful autoreactive T cells that may induce inflammation; (3) is initiated before or at least at the early stages of the accumulation of toxic forms of Aβ. Data from the recent passive vaccination trials with bapineuzumab and solanezumab also indicated that anti-Aβ immunotherapy might be effective in reduction of the AD pathology and even improvement of cognitive and/or functional performance in patients when administered early in the course of the disease. For the prevention of AD the active immunization strategy may be more desirable than passive immunotherapy protocol and it can offer the potential for sustainable clinical and commercial advantages. Here we discuss the active vaccine approaches, which are still in preclinical development and vaccines that are already in clinical trials.

From Nose to Memory: The Involuntary Nature of Odor-evoked Autobiographical Memories in Alzheimer's Disease.

PubMed

El Haj, Mohamad; Gandolphe, Marie Charlotte; Gallouj, Karim; Kapogiannis, Dimitrios; Antoine, Pascal

2017-12-25

Research suggests that odors may serve as a potent cue for autobiographical retrieval. We tested this hypothesis in Alzheimer's disease (AD) and investigated whether odor-evoked autobiographical memory is an involuntary process that shares similarities with music-evoked autobiographical memory. Participants with mild AD and controls were asked to retrieve 2 personal memories after odor exposure, after music exposure, and in an odor-and music-free condition. AD participants showed better specificity, emotional experience, mental time travel, and retrieval time after odor and music exposure than in the control condition. Similar beneficial effects of odor and music exposure were observed for autobiographical characteristics (i.e., specificity, emotional experience, and mental time travel), except for retrieval time which was more improved after odor than after music exposure. Interestingly, regression analyses suggested executive involvement in memories evoked in the control condition but not in those evoked after music or odor exposure. These findings suggest the involuntary nature of odor-evoked autobiographical memory in AD. They also suggest that olfactory cuing could serve as a useful and ecologically valid tool to stimulate autobiographical memory, at least in the mild stage of the disease. © The Author(s) 2017. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

ADS genes for reducing saturated fatty acid levels in seed oils

DOEpatents

Heilmann, Ingo H; Shanklin, John

2014-03-18

The present invention relates to enzymes involved in lipid metabolism. In particular, the present invention provides coding sequences for Arabidopsis Desaturases (ADS), the encoded ADS polypeptides, and methods for using the sequences and encoded polypeptides, where such methods include decreasing and increasing saturated fatty acid content in plant seed oils.

ADS genes for reducing saturated fatty acid levels in seed oils

DOEpatents

Heilmann, Ingo H.; Shanklin, John

2010-02-02

The present invention relates to enzymes involved in lipid metabolism. In particular, the present invention provides coding sequences for Arabidopsis Desaturases (ADS), the encoded ADS polypeptides, and methods for using the sequences and encoded polypeptides, where such methods include decreasing and increasing saturated fatty acid content in plant seed oils.

Verbal Repetitions and Echolalia in Alzheimer's Discourse

ERIC Educational Resources Information Center

Da Cruz, Fernanda Miranda

2010-01-01

This article reports on an investigation of echolalic repetition in Alzheimer's disease (AD). A qualitative analysis of data from spontaneous conversations with MHI, a woman with AD, is presented. The data come from the DALI Corpus, a corpus of spontaneous conversations involving subjects with AD. This study argues that echolalic effects can be…

Parent ads in the National Youth Anti-Drug Media Campaign.

PubMed

Stephenson, Michael T; Quick, Brian L

2005-12-01

The National Youth Anti-Drug Media Campaign aims not only to reduce drug use by teens and preteens, but also to arm parents with knowledge about specific parenting practices known to reduce the risk of teen drug use. Among the documented successes of the campaign to date was a small, but direct effect on some parenting practices, including parent-child discussions about drug use. To reach a deeper understanding about the substance of the parental ads, we content analyzed the message strategies employed in the campaign's parent ads over the inaugural 5 years of the campaign. Each ad was coded for its major theme, minor subtheme, and featured drug. Among seven possible major themes, the parental anti-drug ads largely featured four: enhance the risk of their child's drug use, encourage monitoring practices, promote parent-child discussions about drug use, or advocate positive involvement behaviors. Moreover, most parental messages addressed marijuana use or addressed drug use in general. Marijuana and inhalant ads largely were risk based, while general drug messages focused on monitoring, parent-child discussions or positive involvement practices.

Protease and Protease-Activated Receptor-2 Signaling in the Pathogenesis of Atopic Dermatitis

PubMed Central

Lee, Sang Eun; Jeong, Se Kyoo

2010-01-01

Proteases in the skin are essential to epidermal permeability barrier homeostasis. In addition to their direct proteolytic effects, certain proteases signal to cells by activating protease-activated receptors (PARs), the G-protein-coupled receptors. The expression of functional PAR-2 on human skin and its role in inflammation, pruritus, and skin barrier homeostasis have been demonstrated. Atopic dermatitis (AD) is a multifactorial inflammatory skin disease characterized by genetic barrier defects and allergic inflammation, which is sustained by gene-environmental interactions. Recent studies have revealed aberrant expression and activation of serine proteases and PAR-2 in the lesional skin of AD patients. The imbalance between proteases and protease inhibitors associated with genetic defects in the protease/protease inhibitor encoding genes, increase in skin surface pH, and exposure to proteolytically active allergens contribute to this aberrant protease/PAR-2 signaling in AD. The increased protease activity in AD leads to abnormal desquamation, degradation of lipid-processing enzymes and antimicrobial peptides, and activation of primary cytokines, thereby leading to permeability barrier dysfunction, inflammation, and defects in the antimicrobial barrier. Moreover, up-regulated proteases stimulate PAR-2 in lesional skin of AD and lead to the production of cytokines and chemokines involved in inflammation and immune responses, itching sensation, and sustained epidermal barrier perturbation with easier allergen penetration. In addition, PAR-2 is an important sensor for exogenous danger molecules, such as exogenous proteases from various allergens, and plays an important role in AD pathogenesis. Together, these findings suggest that protease activity or PAR-2 may be a future target for therapeutic intervention for the treatment of AD. PMID:20879045

Recent Findings in Alzheimer Disease and Nutrition Focusing on Epigenetics.

PubMed

Athanasopoulos, Dimitrios; Karagiannis, George; Tsolaki, Magda

2016-09-01

Alzheimer disease (AD) is a chronic neurodegenerative disease with no effective cure so far. The current review focuses on the epigenetic mechanisms of AD and how nutrition can influence the course of this disease through regulation of gene expression, according to the latest scientific findings. The search strategy was the use of scientific databases such as PubMed and Scopus in order to find relative research or review articles published in the years 2012-2015. By showing the latest data of various nutritional compounds, this study aims to stimulate the scientific community to recognize the value of nutrition in this subject. Epigenetics is becoming a very attractive subject for researchers because it can shed light on unknown aspects of complex diseases like AD. DNA methylation, histone modifications, and microRNAs are the principal epigenetic mechanisms involved in AD pathophysiology. Nutrition is an environmental factor that is related to AD through epigenetic pathways. Vitamin B-12, for instance, can alter the one-carbon metabolism and thus interfere in the DNA methylation process. The research results might seem ambiguous about the clinical role of nutrition, but there is strengthening evidence that proper nutrition can not only change epigenetic biomarker levels but also prevent the development of late-onset AD and attenuate cognition deficit. Nutrition might grow to become a preventive and even therapeutic alternative against AD, especially if combined with other antidementia interventions, brain exercise, physical training, etc. Epigenetic biomarkers can be a very helpful tool to help researchers find the exact nutrients needed to create specific remedies, and perhaps the same biomarkers can be used even in patient screening in the future. © 2016 American Society for Nutrition.

Recent Findings in Alzheimer Disease and Nutrition Focusing on Epigenetics12

PubMed Central

2016-01-01

Alzheimer disease (AD) is a chronic neurodegenerative disease with no effective cure so far. The current review focuses on the epigenetic mechanisms of AD and how nutrition can influence the course of this disease through regulation of gene expression, according to the latest scientific findings. The search strategy was the use of scientific databases such as PubMed and Scopus in order to find relative research or review articles published in the years 2012–2015. By showing the latest data of various nutritional compounds, this study aims to stimulate the scientific community to recognize the value of nutrition in this subject. Epigenetics is becoming a very attractive subject for researchers because it can shed light on unknown aspects of complex diseases like AD. DNA methylation, histone modifications, and microRNAs are the principal epigenetic mechanisms involved in AD pathophysiology. Nutrition is an environmental factor that is related to AD through epigenetic pathways. Vitamin B-12, for instance, can alter the one-carbon metabolism and thus interfere in the DNA methylation process. The research results might seem ambiguous about the clinical role of nutrition, but there is strengthening evidence that proper nutrition can not only change epigenetic biomarker levels but also prevent the development of late-onset AD and attenuate cognition deficit. Nutrition might grow to become a preventive and even therapeutic alternative against AD, especially if combined with other antidementia interventions, brain exercise, physical training, etc. Epigenetic biomarkers can be a very helpful tool to help researchers find the exact nutrients needed to create specific remedies, and perhaps the same biomarkers can be used even in patient screening in the future. PMID:27633107

Carbon Nanotube Bonding Strength Enhancement Using Metal "Wicking" Process

NASA Technical Reports Server (NTRS)

Lamb, James L.; Dickie, Matthew R.; Kowalczyk, Robert S.; Liao, Anna; Bronikowski, Michael J.

2012-01-01

Carbon nanotubes grown from a surface typically have poor bonding strength at the interface. A process has been developed for adding a metal coat to the surface of carbon nano tubes (CNTs) through a wicking process, which could lead to an enhanced bonding strength at the interface. This process involves merging CNTs with indium as a bump-bonding enhancement. Classical capillary theory would not normally allow materials that do not wet carbon or graphite to be drawn into the spacings by capillary action because the contact angle is greater than 90 degrees. However, capillary action can be induced through JPL's ability to fabricate oriented CNT bundles to desired spacings, and through the use of deposition techniques and temperature to control the size and mobility of the liquid metal streams and associated reservoirs. A reflow and plasma cleaning process has also been developed and demonstrated to remove indium oxide, and to obtain smooth coatings on the CNT bundles.

A promoter polymorphism in the monoamine oxidase A gene is associated with the pineal MAOA activity in Alzheimer's disease patients.

PubMed

Wu, Ying-Hui; Fischer, David F; Swaab, Dick F

2007-09-05

Monoamine oxidase A (MAOA) is involved in the pathogenesis of mood disorders and Alzheimer's disease (AD). MAOA activity and gene expression have been found to be up-regulated in different brain areas of AD patients, including the pineal gland. Increased pineal MAOA activity might contribute to the reduced pineal melatonin production in AD. A promoter polymorphism of a variable number tandem repeats (VNTR) in the MAOA gene shows to affect MAOA transcriptional activity in vitro. Here we examined in 63 aged controls and 44 AD patients the effects of the MAOA-VNTR on MAOA gene expression and activity in the pineal gland as endophenotypes, and on melatonin production. AD patients carrying long MAOA-VNTR genotype (consisting of 3.5- or 4-repeat alleles) showed higher MAOA gene expression and activity than the short-genotyped (i.e., 3-repeat allele) AD patients. Moreover, the AD-related up-regulation of MAOA showed up only among long-genotype bearing subjects. There was no significant effect of the MAOA-VNTR on MAOA activity or gene expression in controls, or on melatonin production in both controls and AD patients. Our data suggest that the MAOA-VNTR affects the activity and gene expression of MAOA in the brain of AD patients, and is involved in the changes of monoamine metabolism.

A review on the role of moisturizers for atopic dermatitis

PubMed Central

Hebert, Adelaide Ann; Dizon, Maria Victoria; Van Bever, Hugo; Tiongco-Recto, Marysia; Kim, Kyu-Han; Soebono, Hardyanto; Munasir, Zakiudin; Diana, Inne Arline; Luk, David Chi Kang

2016-01-01

Effective management of atopic dermatitis (AD) involves the treatment of a defective skin barrier. Patients with AD are therefore advised to use moisturizers regularly. To date, there are few comparative studies involving moisturizers in patients with AD, and no classification system exists to objectively determine which types of moisturizers are best suited to specific AD phenotypes. With this in mind, a group of experts from allergy and immunology, adult and pediatric dermatology, and pediatrics centers within Southeast Asia met to review current data and practice, and to develop recommendations regarding the use of moisturizers in patients with AD within the Asia-Pacific region. Chronicity and severity of AD, along with patient age, treatment compliance, and economic background should all be taken into account when selecting an appropriate moisturizer for AD patients. Other considerations include adjuvant properties of the product, cosmetic acceptability, and availability over the counter. Well-defined clinical phenotypes of AD could optimally benefit from specific moisturizers. It is hoped that future studies may identify such differences by means of filaggrin mutation subtypes, confocal microscopic evaluation, pH, transepidermal water loss or presence of allergy specific IgE. Recommendations to improve the regular use of moisturizers among AD patients include measures that focus on treatment compliance, patient and caregiver education, appropriate treatment goals, avoidance of sensitizing agents, and collaboration with other relevant specialists. PMID:27141486

Pharmacogenomics and therapeutic prospects in dementia.

PubMed

Cacabelos, Ramón

2008-03-01

Dementia is a major problem of health in developed countries. Alzheimer's disease (AD) is the main cause of dementia, accounting for 50-70% of the cases, followed by vascular dementia (30-40%) and mixed dementia (15-20%). Approximately 10-15% of direct costs in dementia are attributed to pharmacological treatment, and only 10-20% of the patients are moderate responders to conventional anti-dementia drugs, with questionable cost-effectiveness. Primary pathogenic events underlying the dementia process include genetic factors in which more than 200 different genes distributed across the human genome are involved, accompanied by progressive cerebrovascular dysfunction and diverse environmental factors. Mutations in genes directly associated with the amyloid cascade (APP, PS1, PS2) are only present in less than 5% of the AD population; however, the presence of the APOE-4 allele in the apolipoprotein E (APOE) gene represents a major risk factor for more than 40% of patients with dementia. Genotype-phenotype correlation studies and functional genomics studies have revealed the association of specific mutations in primary loci (APP, PS1, PS2) and/or APOE-related polymorphic variants with the phenotypic expression of biological traits. It is estimated that genetics accounts for 20-95% of variability in drug disposition and pharmacodynamics. Recent studies indicate that the therapeutic response in AD is genotype-specific depending upon genes associated with AD pathogenesis and/or genes responsible for drug metabolism (CYPs). In monogenic-related studies, APOE-4/4 carriers are the worst responders. In trigenic (APOE-PS1-PS2 clusters)-related studies the best responders are those patients carrying the 331222-, 341122-, 341222-, and 441112- genomic profiles. The worst responders in all genomic clusters are patients with the 441122+ genotype, indicating the powerful, deleterious effect of the APOE-4/4 genotype on therapeutics in networking activity with other AD-related genes. Cholinesterase inhibitors of current use in AD are metabolized via CYP-related enzymes. These drugs can interact with many other drugs which are substrates, inhibitors or inducers of the cytochrome P-450 system; this interaction elicits liver toxicity and other adverse drug reactions. CYP2D6-related enzymes are involved in the metabolism of more than 20% of CNS drugs. The distribution of the CYP2D6 genotypes differentiates four major categories of CYP2D6-related metabolyzer types: (a) Extensive Metabolizers (EM)(*1/*1, *1/*10)(51.61%); (b) Intermediate Metabolizers (IM) (*1/*3, *1/*4, *1/*5, *1/*6, *1/*7, *10/*10, *4/*10, *6/*10, *7/*10) (32.26%); (c) Poor Metabolizers (PM) (*4/*4, *5/*5) (9.03%); and (d) Ultra-rapid Metabolizers (UM) (*1xN/*1, *1xN/*4, Dupl) (7.10%). PMs and UMs tend to show higher transaminase activity than EMs and IMs. EMs and IMs are the best responders, and PMs and UMs are the worst responders to pharmacological treatments in AD. It seems very plausible that the pharmacogenetic response in AD depends upon the interaction of genes involved in drug metabolism and genes associated with AD pathogenesis. The establishment of clinical protocols for the practical application of pharmacogenetic strategies in AD will foster important advances in drug development, pharmacological optimization and cost-effectiveness of drugs, and personalized treatments in dementia.

Advertising Content, Platform Characteristics and the Appeal of Beer Advertising on a Social Networking Site.

PubMed

Noel, Jonathan K; Babor, Thomas F; Grady, James J

2018-03-15

The current study was conducted to investigate how changes in the content of a social media ad, user engagement values associated with the ad and user-generated comments (UGCs) associated with the ad can influence the appeal (i.e. source appeal, informational appeal and emotional appeal) of a social media ad. Facebook beer ads that violated the guidelines of a relevant marketing code were rated as more emotionally appealing compared to Facebook beer ads that did not violated the guidelines. Increased emotional appeal in beer advertising increases the probability that the ad will be remembered and influence future drinking occasions. A 2 (ad regulatory compliance: compliant vs. non-compliant) × 2 (user engagement: low vs. high) × 2 (UGC congruence: pro- vs anti-alcohol) mixed factorial experiment was conducted with 120 young adults, 21-24 years old. Each participant viewed four Facebook beer ads that were previously evaluated for thematic content and regulatory compliance. Participants were randomized to view either high or low user engagement values and either pro- or anti-drinking user-generated comments. After each ad exposure, ad appeal was assessed. Statistical analysis was conducted using hierarchical linear modeling. Models were adjusted for demographics, Alcohol Use Disorders Identification Test (AUDIT) scores and Facebook involvement. Source appeal (P = 0.034) and informational appeal (P < 0.001) were significantly higher among ads that were compliant with existing advertising regulations. Emotional appeal was significantly higher among ads that were non-compliant (P = 0.004). The effect of user engagement and UGCs were non-significant (p's > 0.05). Additionally, AUDIT scores (p's < 0.01) and Facebook involvement scores (p's < 0.01) were positively associated with all forms of ad appeal. The appeal of Facebook beer ads may be primarily determined by ad content. Increased emotional appeal in advertising caused by non-compliant advertising may increase the probability that the ad will be remembered and influence future drinking occasions.

To what extent are the wishes of a signatory reflected in their advance directive: a qualitative analysis

PubMed Central

2014-01-01

Background Advance directives (ADs) are assumed to reflect the patients’ preferences, even if these are not clearly expressed. Research into whether this assumption is correct has been lacking. This study explores to what extent ADs reflect the true wishes of the signatories. Methods Semi-structured interviews (INT), pretest. Transcribed INT and the contents of ADs were inductively categorised (Mayring) and triangulated. Software: MAXQDA 2007. Participants: Patients receiving palliative care (PPC), healthy (H) and chronically ill (CI) individuals with an AD completed ≥3 months prior to recruitment. Results Between 08/2008 and 07/2009, 53 individuals (20 H, 17 CI, 16 PPC) were interviewed (mean age 63.2 years (55–70 years)), 34% male). Most important (in)consistencies between preferences as expressed in INT compared to ADs included preconditions for termination/rejection of life-sustaining measures, refusal of/demand for medical interventions and the nomination of proxies. Standardized AD forms were rarely tailored to the individual. We found a high tendency to use set phrases, such as want to die with dignity or do not want to suffer/vegetate. Likely events in the course of an existing progressive disease were not covered, even in ADs of PPC close to death. Conclusions Only some of the incongruities between verbally expressed preferences and the contents of the AD can be put down to use of standardized forms or lack of medical knowledge. Nevertheless, the non-involvement of a doctor in the process of making an AD must be seen as potentially problematic and seeking medical advice should be promoted by politics and physicians. Standardised forms should encourage amendments and present space for free text entries for all aspects covered. Set phrases need to be defined by the individual to enable them to be translated into a specific course of action. PMID:24981101

Reduced cGMP levels in CSF of AD patients correlate with severity of dementia and current depression.

PubMed

Hesse, Raphael; Lausser, Ludwig; Gummert, Pauline; Schmid, Florian; Wahler, Anke; Schnack, Cathrin; Kroker, Katja S; Otto, Markus; Tumani, Hayrettin; Kestler, Hans A; Rosenbrock, Holger; von Arnim, Christine A F

2017-03-09

Alzheimer's disease (AD) is a neurodegenerative disorder, primarily affecting memory. That disorder is thought to be a consequence of neuronal network disturbances and synapse loss. Decline in cognitive function is associated with a high burden of neuropsychiatric symptoms (NPSs) such as depression. The cyclic nucleotides cyclic adenosine-3',5'-monophosphate (cAMP) and cyclic guanosine-3',5'-monophosphate (cGMP) are essential second messengers that play a crucial role in memory processing as well as synaptic plasticity and are potential therapeutic targets. Biomarkers that are able to monitor potential treatment effects and that reflect the underlying pathology are of crucial interest. In this study, we measured cGMP and cAMP in cerebrospinal fluid (CSF) in a cohort of 133 subjects including 68 AD patients and 65 control subjects. To address the association with disease progression we correlated cognitive status with cyclic nucleotide levels. Because a high burden of NPSs is associated with decrease in cognitive function, we performed an exhaustive evaluation of AD-relevant marker combinations in a depressive subgroup. We show that cGMP, but not cAMP, levels in the CSF of AD patients are significantly reduced compared with the control group. Reduced cGMP levels in AD patients correlate with memory impairment based on Mini-Mental State Examination score (r = 0.17, p = 0.048) and tau as a marker of neurodegeneration (r = -0.28, p = 0.001). Moreover, we were able to show that AD patients suffering from current depression show reduced cGMP levels (p = 0.07) and exhibit a higher degree of cognitive impairment than non-depressed AD patients. These results provide further evidence for an involvement of cGMP in AD pathogenesis and accompanying co-morbidities, and may contribute to elucidating synaptic plasticity alterations during disease progression.

Hippocampal subfield volumetry in mild cognitive impairment, Alzheimer's disease and semantic dementia.

PubMed

La Joie, Renaud; Perrotin, Audrey; de La Sayette, Vincent; Egret, Stéphanie; Doeuvre, Loïc; Belliard, Serge; Eustache, Francis; Desgranges, Béatrice; Chételat, Gaël

2013-01-01

Hippocampal atrophy is a well-known feature of Alzheimer's disease (AD), but sensitivity and specificity of hippocampal volumetry are limited. Neuropathological studies have shown that hippocampal subfields are differentially vulnerable to AD; hippocampal subfield volumetry may thus prove to be more accurate than global hippocampal volumetry to detect AD. CA1, subiculum and other subfields were manually delineated from 40 healthy controls, 18 AD, 17 amnestic Mild Cognitive Impairment (aMCI), and 8 semantic dementia (SD) patients using a previously developed high resolution MRI procedure. Non-parametric group comparisons and receiver operating characteristic (ROC) analyses were conducted. Complementary analyses were conducted to evaluate differences of hemispheric asymmetry and anterior-predominance between AD and SD patients and to distinguish aMCI patients with or without β-amyloid deposition as assessed by Florbetapir-TEP. Global hippocampi were atrophied in all three patient groups and volume decreases were maximal in the CA1 subfield (22% loss in aMCI, 27% in both AD and SD; all p < 0.001). In aMCI, CA1 volumetry was more accurate than global hippocampal measurement to distinguish patients from controls (areas under the ROC curve = 0.88 and 0.76, respectively; p = 0.05) and preliminary analyses suggest that it was independent from the presence of β-amyloid deposition. In patients with SD, whereas the degree of CA1 and subiculum atrophy was similar to that found in AD patients, hemispheric and anterior-posterior asymmetry were significantly more marked than in AD with greater involvement of the left and anterior hippocampal subfields. The findings suggest that CA1 measurement is more sensitive than global hippocampal volumetry to detect structural changes at the pre-dementia stage, although the predominance of CA1 atrophy does not appear to be specific to AD pathophysiological processes.

Phytochemicals as inhibitors of NF-κB for treatment of Alzheimer's disease.

PubMed

Seo, Ean-Jeong; Fischer, Nicolas; Efferth, Thomas

2018-03-01

Alzheimer's disease (AD) is the most prevalent form of dementia. The exact pathophysiology of this disease remains incompletely understood and safe and effective therapies are required. AD is highly correlated with neuroinflammation and oxidative stress in brain causing neuronal loss. Nuclear factor of activated B-cells (NF-κB) is involved in physiological inflammatory processes and thus representing a promising target for inflammation-based AD therapy. Phytochemicals are able to interfere with the NF-κB pathway. They inhibit the phosphorylation or the ubiquitination of signaling molecules, and thus, inhibit the degradation of IκB. The translocation of NF-κB to the nucleus and subsequent transcription of pro-inflammatory cytokines are inhibited by the actions of phytochemicals. Additionally, natural compounds preventing the interaction of NF-κB can block NF-κB's transcriptional activity by inhibiting its binding to target DNA. Many polyphenols including curcumin, resveratrol, pterostilbene, punicalagin, macranthoin G, salidroside, 4-O-methylhonokiol, lycopene, genistein, obovatol and gallic acid were reported as potent NF-κB inhibitors for AD treatment. Several alkaloids such as galantamine, glaucocalyxin B, tetrandrine, berberine, oridonin, anatabine have been shown anti-inflammatory effects in AD models in vitro as well as in vivo. Besides, vitamins, tanshinone IIA, artemisinin, dihydroasparagusic acid, geniposide, xanthoceraside, l-theranine, 1,8-cineole and paeoniflorin were described as promising NF-κB inhibitors. In conclusion, natural products from plants represent interesting candidates for AD treatment. They may qualify as promising compounds for the development of derivatives providing enhanced pharmacological features. Copyright © 2017 Elsevier Ltd. All rights reserved.

Distinct molecular signatures of mild extrinsic and intrinsic atopic dermatitis.

PubMed

Martel, Britta C; Litman, Thomas; Hald, Andreas; Norsgaard, Hanne; Lovato, Paola; Dyring-Andersen, Beatrice; Skov, Lone; Thestrup-Pedersen, Kristian; Skov, Søren; Skak, Kresten; Poulsen, Lars K

2016-06-01

Atopic dermatitis (AD) is a common inflammatory skin disease with underlying defects in epidermal function and immune responses. In this study, we used microarray analysis to investigate differences in gene expression in lesional skin from patients with mild extrinsic or intrinsic AD compared to skin from healthy controls and from lesional psoriasis skin. The primary aim was to identify differentially expressed genes involved in skin barrier formation and inflammation, and to compare our results with those reported for patients with moderate and severe AD. In contrast to severe AD, expression of the majority of genes associated with skin barrier formation was unchanged or upregulated in patients with mild AD compared to normal healthy skin. Among these, no significant differences in the expression of filaggrin (FLG) and loricrin at both mRNA and protein level were found in lesional skin from patients with mild AD, despite the presence of heterozygous FLG mutations in the majority of patients with mild extrinsic AD. Several inflammation-associated genes such as S100A9, MMP12, CXCL10 and CCL18 were highly expressed in lesional skin from patients with mild psoriasis and were also increased in patients with mild extrinsic and intrinsic AD similar to previous reports for severe AD. Interestingly, expression of genes involved in inflammatory responses in intrinsic AD resembled that of psoriasis more than that of extrinsic AD. Overall, differences in expression of inflammation-associated genes found among patients with mild intrinsic and extrinsic AD correlated with previous findings for patients with severe intrinsic and extrinsic AD. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Epigenetics—Beyond the Genome in Alcoholism

PubMed Central

Starkman, Bela G.; Sakharkar, Amul J.; Pandey, Subhash C.

2012-01-01

Genetic and environmental factors play a role in the development of alcoholism. Whole-genome expression profiling has highlighted the importance of several genes that may contribute to alcohol abuse disorders. In addition, more recent findings have added yet another layer of complexity to the overall molecular mechanisms involved in a predisposition to alcoholism and addiction by demonstrating that processes related to genetic factors that do not manifest as DNA sequence changes (i.e., epigenetic processes) play a role. Both acute and chronic ethanol exposure can alter gene expression levels in specific neuronal circuits that govern the behavioral consequences related to tolerance and dependence. The unremitting cycle of alcohol consumption often includes satiation and self-medication with alcohol, followed by excruciating withdrawal symptoms and the resultant relapse, which reflects both the positive and negative affective states of alcohol addiction. Recent studies have indicated that behavioral changes induced by acute and chronic ethanol exposure may involve chromatin remodeling resulting from covalent histone modifications and DNA methylation in the neuronal circuits involving a brain region called the amygdala. These findings have helped identify enzymes involved in epigenetic mechanisms, such as the histone deacetylase, histone acetyltransferase, and DNA methyltransferase enzymes, as novel therapeutic targets for the development of future pharmacotherapies for the treatment of alcoholism. PMID:23134045

Epigenetics-beyond the genome in alcoholism.

PubMed

Starkman, Bela G; Sakharkar, Amul J; Pandey, Subhash C

2012-01-01

Genetic and environmental factors play a role in the development of alcoholism. Whole-genome expression profiling has highlighted the importance of several genes that may contribute to alcohol abuse disorders. In addition, more recent findings have added yet another layer of complexity to the overall molecular mechanisms involved in a predisposition to alcoholism and addiction by demonstrating that processes related to genetic factors that do not manifest as DNA sequence changes (i.e., epigenetic processes) play a role. Both acute and chronic ethanol exposure can alter gene expression levels in specific neuronal circuits that govern the behavioral consequences related to tolerance and dependence. The unremitting cycle of alcohol consumption often includes satiation and self-medication with alcohol, followed by excruciating withdrawal symptoms and the resultant relapse, which reflects both the positive and negative affective states of alcohol addiction. Recent studies have indicated that behavioral changes induced by acute and chronic ethanol exposure may involve chromatin remodeling resulting from covalent histone modifications and DNA methylation in the neuronal circuits involving a brain region called the amygdala. These findings have helped identify enzymes involved in epigenetic mechanisms, such as the histone deacetylase, histone acetyltransferase, and DNA methyltransferase enzymes, as novel therapeutic targets for the development of future pharmacotherapies for the treatment of alcoholism.

Differential brain responses to cries of infants with autistic disorder and typical development: an fMRI study.

PubMed

Venuti, Paola; Caria, Andrea; Esposito, Gianluca; De Pisapia, Nicola; Bornstein, Marc H; de Falco, Simona

2012-01-01

This study used fMRI to measure brain activity during adult processing of cries of infants with autistic disorder (AD) compared to cries of typically developing (TD) infants. Using whole brain analysis, we found that cries of infants with AD compared to those of TD infants elicited enhanced activity in brain regions associated with verbal and prosodic processing, perhaps because altered acoustic patterns of AD cries render them especially difficult to interpret, and increased activity in brain regions associated with emotional processing, indicating that AD cries also elicit more negative feelings and may be perceived as more aversive and/or arousing. Perceived distress engendered by AD cries related to increased activation in brain regions associated with emotional processing. This study supports the hypothesis that cry is an early and meaningful anomaly displayed by children with AD. It could be that cries associated with AD alter parent-child interactions much earlier than the time that reliable AD diagnosis normally occurs. Copyright © 2012 Elsevier Ltd. All rights reserved.

Research About the Corosive Effects of FeCl3 in the Aeration Wastewater Basin

NASA Astrophysics Data System (ADS)

Panaitescu, C.; Petrescu, M. G.

2018-01-01

Biological aeration of industrial wastewater is a very impressive process in the treatment of wastewater. The involvement of chemical reagents in this process, however, implies the intensification of the corrosion processes due to both pollutants in the wastewater and the chemical reactions that occur when the coagulation / flocculation reagents are added. This paper explores the action of ferric chloride (FeCl3) on metallic parts in the aeration basin. The most affected structures are metal. At the classical basins the aeration systems were made of P295GH materials. The corrosion produced is uneven. The analysis of the high degree of corrosion was done according to the national and international standards. Finally, the paper supports the replacement of the existing aeration system with an anticorrosive material.

Decreased sudomotor function is involved in the formation of atopic eczema in the cubital fossa.

PubMed

Takahashi, Aya; Murota, Hiroyuki; Matsui, Saki; Kijima, Akiko; Kitaba, Shun; Lee, Jeong-Beom; Katayama, Ichiro

2013-12-01

Eczema in the cubital fossa, which is susceptible to sweat, is frequently observed in atopic dermatitis (AD). However, there has been no direct evidence that sweating causes eczema in the cubital fossa. To investigate this issue, axon reflex-mediated sweating volume (AXR) and skin barrier function in the cubital fossa were measured in subjects with AD and in healthy volunteers, and were applied to clinical feature of the cubital fossa. AXR in the cubital fossa decreased in AD subjects; it positively correlated only with water-holding capacity in healthy subjects but not in patients with in AD. Furthermore, AD subjects with lichenoid eczema and either prurigo or papules over the cubital fossa showed extremely decreased AXR. These results suggest that decreased sweating is a major source of water in the stratum corneum, and decreased sudomotor function may be involved in both the cause and aggravation of representative atopic eczema in the cubital fossa.

Ultra-processed foods and added sugars in the Chilean diet (2010).

PubMed

Cediel, Gustavo; Reyes, Marcela; da Costa Louzada, Maria Laura; Martinez Steele, Euridice; Monteiro, Carlos A; Corvalán, Camila; Uauy, Ricardo

2018-01-01

To assess the consumption of ultra-processed foods and analyse its association with the content of added sugars in the Chilean diet. Cross-sectional study of national dietary data obtained through 24 h recalls and classified into food groups according to the extent and purpose of food processing (NOVA classification). Chile. A probabilistic sample of 4920 individuals (aged 2 years or above) studied in 2010 by a national dietary survey (Encuesta Nacional de Consumo Alimentario). Ultra-processed foods represented 28·6 (se 0·5) % of total energy intake and 58·6 (se 0·9) % of added sugars intake. The mean percentage of energy from added sugars increased from 7·7 (se 0·3) to 19·7 (se 0·5) % across quintiles of the dietary share of ultra-processed foods. After adjusting for several potential sociodemographic confounders, a 5 percentage point increase in the dietary share of ultra-processed foods determined a 1 percentage point increase in the dietary content of added sugars. Individuals in the highest quintile were three times more likely (OR=2·9; 95 % CI 2·4, 3·4) to exceed the 10 % upper limit for added sugars recommended by the WHO compared with those in the lowest quintile, after adjusting for sociodemographic variables. This association was strongest among individuals aged 2-19 years (OR=3·9; 95 % CI 2·7, 5·9). In Chile, ultra-processed foods are important contributors to total energy intake and to the consumption of added sugars. Actions aimed at limiting consumption of ultra-processed foods are being implemented as effective ways to achieve WHO dietary recommendations to limit added sugars and processed foods, especially for children and adolescents.

The role of the user within the medical device design and development process: medical device manufacturers' perspectives

PubMed Central

2011-01-01

Background Academic literature and international standards bodies suggest that user involvement, via the incorporation of human factors engineering methods within the medical device design and development (MDDD) process, offer many benefits that enable the development of safer and more usable medical devices that are better suited to users' needs. However, little research has been carried out to explore medical device manufacturers' beliefs and attitudes towards user involvement within this process, or indeed what value they believe can be added by doing so. Methods In-depth interviews with representatives from 11 medical device manufacturers are carried out. We ask them to specify who they believe the intended users of the device to be, who they consult to inform the MDDD process, what role they believe the user plays within this process, and what value (if any) they believe users add. Thematic analysis is used to analyse the fully transcribed interview data, to gain insight into medical device manufacturers' beliefs and attitudes towards user involvement within the MDDD process. Results A number of high-level themes emerged, relating who the user is perceived to be, the methods used, the perceived value and barriers to user involvement, and the nature of user contributions. The findings reveal that despite standards agencies and academic literature offering strong support for the employment formal methods, manufacturers are still hesitant due to a range of factors including: perceived barriers to obtaining ethical approval; the speed at which such activity may be carried out; the belief that there is no need given the 'all-knowing' nature of senior health care staff and clinical champions; a belief that effective results are achievable by consulting a minimal number of champions. Furthermore, less senior health care practitioners and patients were rarely seen as being able to provide valuable input into the process. Conclusions Medical device manufacturers often do not see the benefit of employing formal human factors engineering methods within the MDDD process. Research is required to better understand the day-to-day requirements of manufacturers within this sector. The development of new or adapted methods may be required if user involvement is to be fully realised. PMID:21356097

Safety behavior: Job demands, job resources, and perceived management commitment to safety.

PubMed

Hansez, Isabelle; Chmiel, Nik

2010-07-01

The job demands-resources model posits that job demands and resources influence outcomes through job strain and work engagement processes. We test whether the model can be extended to effort-related "routine" safety violations and "situational" safety violations provoked by the organization. In addition we test more directly the involvement of job strain than previous studies which have used burnout measures. Structural equation modeling provided, for the first time, evidence of predicted relationships between job strain and "routine" violations and work engagement with "routine" and "situational" violations, thereby supporting the extension of the job demands-resources model to safety behaviors. In addition our results showed that a key safety-specific construct 'perceived management commitment to safety' added to the explanatory power of the job demands-resources model. A predicted path from job resources to perceived management commitment to safety was highly significant, supporting the view that job resources can influence safety behavior through both general motivational involvement in work (work engagement) and through safety-specific processes.

Synthesis of perm-selective membranes by grafting acrylic acid into air-irradiated Teflon-FEP films

NASA Astrophysics Data System (ADS)

Bozzi, Annick; Chapiro, Adolphe

Grafting acrylic acid into air-irradiated Teflon-FEP films was investigated. Pre-irradiation doses ranged from 0.5 to 10 kGy. Grafting occurred at 45 or 60°C. Homopolymerization inhibitors, ferrous ions or methylene blue, were added to the system. It was found that after completion of the reaction, within 40-100 min, membranes were obtained with very low electric resistivities. The influence of added inhibitors, pre-irradiation dose and grafting temperature was studied. From the results it is concluded that the initiating centers in air-irradiated Teflon-FEP are, on the one hand, peroxides of structure POOP', in which P is a polymeric radical and Pprime; a small fragment, and on the other trapped PO .2 radicals. The latter only react after losing their oxygen. In the presence of polymerization inhibitors, initiation involves a redox process which reduces the overall activation energy.

Emergence of an apical epithelial cell surface in vivo

PubMed Central

Sedzinski, Jakub; Hannezo, Edouard; Tu, Fan; Biro, Maté; Wallingford, John B.

2016-01-01

Epithelial sheets are crucial components of all metazoan animals, enclosing organs and protecting the animal from its environment. Epithelial homeostasis poses unique challenges, as addition of new cells and loss of old cells must be achieved without disrupting the fluid-tight barrier and apicobasal polarity of the epithelium. Several studies have identified cell biological mechanisms underlying extrusion of cells from epithelia, but far less is known of the converse mechanism by which new cells are added. Here, we combine molecular, pharmacological and laser-dissection experiments with theoretical modelling to characterize forces driving emergence of an apical surface as single nascent cells are added to a vertebrate epithelium in vivo. We find that this process involves the interplay between cell-autonomous actin-generated pushing forces in the emerging cell and mechanical properties of neighboring cells. Our findings define the forces driving this cell behavior, contributing to a more comprehensive understanding of epithelial homeostasis. PMID:26766441

The Fate of Nascent APP in Hippocampal Neurons: A Live Cell Imaging Study.

PubMed

DelBove, Claire E; Deng, Xian-Zhen; Zhang, Qi

2018-06-21

Amyloid precursor protein (APP) is closely associated with Alzheimer's disease (AD) because its proteolytic products form amyloid plaques and its mutations are linked to familial AD patients. As a membrane protein, APP is involved in neuronal development and plasticity. However, it remains unclear how nascent APP is distributed and transported to designated membrane compartments to execute its diverse functions. Here, we employed a dual-tagged APP fusion protein in combination with a synaptic vesicle marker to study the surface trafficking and cleavage of APP in hippocampal neurons immediately after its synthesis. Using long-term time-lapse imaging, we found that a considerable amount of nascent APP was directly transported to the somatodendritic surface, from which it propagates to distal neurites. Some APP in the plasma membrane was endocytosed and some was cleaved by α-secretase. Hence, we conclude that surface transportation of APP is a major step preceding its proteolytic processing and neuritic distribution.

A Brief History of Educational "Value-Added": How Did We Get to Where We Are?

ERIC Educational Resources Information Center

Saunders, Lesley

1999-01-01

Explains how and why the economics concept "value added" came to be used in an educational context, focusing on early usage in the United Kingdom. The term has been developed, used, and defined in various, conflicting ways. Some ambiguities cannot be eliminated. Value-added effectiveness measures involve value judgments. (44 references)…

Mechanisms that synergistically regulate η-secretase processing of APP and Aη-α protein levels: relevance to pathogenesis and treatment of Alzheimer's disease.

PubMed

Ward, Joseph; Wang, Haizhi; Saunders, Aleister J; Tanzi, Rudolph E; Zhang, Can

2017-02-01

The pathophysiology of Alzheimer's disease (AD) is characterized by the formation of cerebral β-amyloid plaque from a small peptide amyloid-β (Aβ). Aβ is generated from the canonical amyloid-β precursor protein (APP) proteolysis pathway through β- and γ-secretases. Decreasing Aβ levels through targeting APP processing is a very promising direction in clinical trials for AD. A novel APP processing pathway was recently identified, in which η-secretase processing of APP occurs and results in the generation of the carboxy-terminal fragment-η (CTF-η or η-CTF) (Wang et al., 2015) and Aη-α peptide (Willem et al., 2015). η-Secretase processing of APP may be up-regulated by at least two mechanisms: either through inhibition of lysosomal-cathepsin degradation pathway (Wang et al., 2015) or through inhibition of BACE1 that competes with η-secretase cleavage of APP (Willem et al., 2015). A thorough characterization of η-processing of APP is critical for a better understanding of AD pathogenesis and insights into results of clinical trials of AD. Here we further investigated η-secretase processing of APP using well-characterized cell models of AD. We found that these two mechanisms act synergistically toward increasing η-secretase processing of APP and Aη-α levels. Furthermore, we evaluated the effects of several other known secretase modulators on η-processing of APP. The results of our study should advance the understanding of pathophysiology of AD, as well as enhance the knowledge in developing effective AD treatments or interventions related to η-secretase processing of APP.

Preparation of 4-amino-2,4-dioxobutanoic acid

DOEpatents

Unkefer, Pat J.; Martinez, Rodolfo A.; Glass, David R.

2015-06-02

A process for synthesizing 4-amino-2,4-dioxobutanoic acid involves reacting diethyl oxalate with sodium ethoxide in ethanol to form a reaction mixture, and afterward adding ethyl cyanoacetate to the reaction mixture and allowing a reaction to proceed under conditions suitable to form a first reaction product of the formula diethyl-2-cyano-3-hydroxy-butenedioate, and then isolating the diethyl-2-cyano-3-hydroxybutenedioate, and afterward reacting the diethyl-2-cyano-3-hydroxy-butenedioate with aqueous sodium hydroxide under conditions suitable to form 4-amino-2,4-dioxobutanoic acid.

Structural dynamics technology research in NASA: Perspective on future needs

NASA Technical Reports Server (NTRS)

1979-01-01

The perspective of a NASA ad hoc study group on future research needs in structural dynamics within the aerospace industry is presented. The common aspects of the design process across the industry are identified and the role of structural dynamics is established through a discussion of various design considerations having their basis in structural dynamics. The specific structural dynamics issues involved are identified and assessed as to their current technological status and trends. Projections of future requirements based on this assessment are made and areas of research to meet them are identified.

Preparation of 4-amino-2,4-dioxobutanoic acid

DOEpatents

Unkefer, Pat J.; Martinez, Rodolfo A.; Glass, David R.

2016-03-22

A process for synthesizing 4-amino-2,4-dioxobutanoic acid involves reacting diethyl oxalate with an alkoxide in ethanol to form a reaction mixture, and afterward adding ethyl cyanoacetate to the reaction mixture and allowing a reaction to proceed under conditions suitable to form a first reaction product of the formula diethyl 2-cyano-3-hydroxy-butenedioate, and then isolating the diethyl 2-cyano-3-hydroxy-butenedioate, and afterward reacting the diethyl-2-cyano-3-hydroxy-butenedioate with an aqueous hydroxide under conditions suitable to form 4-amino-2,4-dioxobutanoic acid.

Inflammation occurs early during the Abeta deposition process in TgCRND8 mice.

PubMed

Dudal, Sherri; Krzywkowski, Pascale; Paquette, Julie; Morissette, Céline; Lacombe, Diane; Tremblay, Patrick; Gervais, Francine

2004-08-01

Alzheimer's disease (AD) is characterized by a progressive cognitive decline leading to dementia and involves the deposition of amyloid-beta (Abeta) peptides into senile plaques. Other neuropathological features that accompany progression of the disease include a decrease in synaptic density, neurofibrillary tangles, dystrophic neurites, inflammation, and neuronal cell loss. In this study, we report the early kinetics of brain amyloid deposition and its associated inflammation in an early onset transgenic mouse model of AD (TgCRND8) harboring the human amyloid precursor protein gene with the Indiana and Swedish mutations. Both diffuse and compact plaques were detected as early as 9-10 weeks of age. Abeta-immunoreactive (Abeta-IR) plaques (4G8-positive) appeared first in the neocortex and amygdala, then in the hippocampal formation, and lastly in the thalamus. Compact plaques (ThioS-positive) with an amyloid core were observed as early as diffuse plaques were detected, but in lower numbers. Amyloid deposition increased progressively with age. The formation of plaques was concurrent with the appearance of activated microglial cells and shortly followed by the clustering of activated astrocytes around plaques at 13-14 weeks of age. This TgCRND8 mouse model allows for a rapid, time-dependent study of the relationship between the fibrillogenic process and the inflammatory response during the brain amyloidogenic process.

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

The prevalence of mutations in the gene encoding filaggrin in the population of Polish patients with atopic dermatitis

PubMed Central

Kaczmarek-Skamira, Elżbieta; Romańska-Gocka, Krystyna; Czajkowski, Rafał; Kałużna, Lucyna; Zegarska, Barbara

2016-01-01

Introduction The genetic background of atopic dermatitis (AD) is complex, involves many genes and their participation varies in varied populations, and depends on the intensity and course of a disease. Changes in the nucleotide sequence of the FLG gene and a reduced number or a deficit of the functional product of processed profilaggrin can be one of risk factors for atopic dermatitis. Aim To determine the prevalence of R501X and 2282del4 mutations of the FLG gene in patients with AD. Material and methods The studied group included 60 patients with clinically diagnosed AD, and the control group included 61 healthy volunteers. The study protocol included collection of biological material for tests, DNA isolation and evaluation of its quality and quantity, and PCR amplification of the isolated genetic material. Results In the studied group, both changes in the nucleotide sequence of the FLG gene were detected and in the control group no tested mutations were detected. In 18 (30%) patients with AD, 22 mutations (4 heterozygous and 1 homozygous ones of R501X and 10 heterozygous and 7 homozygous ones of 2282del4) were detected. Conclusions A high rate of mutations of the FLG gene in patients with clinically diagnosed AD and pathologically dry skin was observed in the studied population. The 2282del4 mutation occurred more often than R501X. PMID:27279822

[Early episodic memory impairments in Alzheimer's disease].

PubMed

Ergis, A-M; Eusop-Roussel, E

2008-05-01

Patients with Alzheimer's disease (AD) show early episodic memory impairments. Such deficits reflect specific impairments affecting one or several stages of encoding, storage and retrieval processes. However, AD patients not only have great difficulty retrieving memories and information but also suffer from distortions of memory, as intrusions and false recognitions. Intrusions can be defined as the unintentional recall of inappropriate information in a laboratory-learning tasks such as word-list recall and story recall. False recognition refers to the erroneous recognition of information that was not previously presented. The first objective of this review is to present studies from the literature that allowed a better understanding of the nature of episodic memory deficits in AD, and to examine recent research on false memories. The second part of this review is aimed at presenting recent research conducted on prospective memory (PM) in Alzheimer's disease. Prospective memory situations involve forming intentions and then realizing those intentions at some appropriate time in the future. Everyday examples of prospective memory include remembering to buy bread on the way home from work, remembering to give friends a message upon next encountering them, and remembering to take medication. Patients suffering from AD show difficulties in performing prospective tasks in daily life, according to the complaints of their care givers, and these difficulties are massively present at the first stages of the disease. Nevertheless, very few studies have been dedicated to this subject, although the evaluation of PM could be helpful for the early diagnosis of AD.

Rule induction performance in amnestic mild cognitive impairment and Alzheimer's dementia: examining the role of simple and biconditional rule learning processes.

PubMed

Oosterman, Joukje M; Heringa, Sophie M; Kessels, Roy P C; Biessels, Geert Jan; Koek, Huiberdina L; Maes, Joseph H R; van den Berg, Esther

2017-04-01

Rule induction tests such as the Wisconsin Card Sorting Test require executive control processes, but also the learning and memorization of simple stimulus-response rules. In this study, we examined the contribution of diminished learning and memorization of simple rules to complex rule induction test performance in patients with amnestic mild cognitive impairment (aMCI) or Alzheimer's dementia (AD). Twenty-six aMCI patients, 39 AD patients, and 32 control participants were included. A task was used in which the memory load and the complexity of the rules were independently manipulated. This task consisted of three conditions: a simple two-rule learning condition (Condition 1), a simple four-rule learning condition (inducing an increase in memory load, Condition 2), and a complex biconditional four-rule learning condition-inducing an increase in complexity and, hence, executive control load (Condition 3). Performance of AD patients declined disproportionately when the number of simple rules that had to be memorized increased (from Condition 1 to 2). An additional increment in complexity (from Condition 2 to 3) did not, however, disproportionately affect performance of the patients. Performance of the aMCI patients did not differ from that of the control participants. In the patient group, correlation analysis showed that memory performance correlated with Condition 1 performance, whereas executive task performance correlated with Condition 2 performance. These results indicate that the reduced learning and memorization of underlying task rules explains a significant part of the diminished complex rule induction performance commonly reported in AD, although results from the correlation analysis suggest involvement of executive control functions as well. Taken together, these findings suggest that care is needed when interpreting rule induction task performance in terms of executive function deficits in these patients.

Complexity and Selectivity of γ-Secretase Cleavage on Multiple Substrates: Consequences in Alzheimer's Disease and Cancer.

PubMed

Medoro, Alessandro; Bartollino, Silvia; Mignogna, Donatella; Passarella, Daniela; Porcile, Carola; Pagano, Aldo; Florio, Tullio; Nizzari, Mario; Guerra, Germano; Di Marco, Roberto; Intrieri, Mariano; Raimo, Gennaro; Russo, Claudio

2018-01-01

The processing of the amyloid-β protein precursor (AβPP) by β- and γ-secretases is a pivotal event in the genesis of Alzheimer's disease (AD). Besides familial mutations on the AβPP gene, or upon its overexpression, familial forms of AD are often caused by mutations or deletions in presenilin 1 (PSEN1) and 2 (PSEN2) genes: the catalytic components of the proteolytic enzyme γ-secretase (GS). The "amyloid hypothesis", modified over time, states that the aberrant processing of AβPP by GS induces the formation of specific neurotoxic soluble amyloid-β (Aβ) peptides which, in turn, cause neurodegeneration. This theory, however, has recently evidenced significant limitations and, in particular, the following issues are debated: 1) the concept and significance of presenilin's "gain of function" versus "loss of function"; and 2) the presence of several and various GS substrates, which interact with AβPP and may influence Aβ formation. The latter consideration is suggestive: despite the increasing number of GS substrates so far identified, their reciprocal interaction with AβPP itself, even in the AD field, is significantly unexplored. On the other hand, GS is also an important pharmacological target in the cancer field; inhibitors or GS activity are investigated in clinical trials for treating different tumors. Furthermore, the function of AβPP and PSENs in brain development and in neuronal migration is well known. In this review, we focused on a specific subset of GS substrates that directly interact with AβPP and are involved in its proteolysis and signaling, by evaluating their role in neurodegeneration and in cell motility or proliferation, as a possible connection between AD and cancer.

The Transport of Plasma and Magnetic Flux in Giant Planet Magnetospheres

NASA Astrophysics Data System (ADS)

Russell, C. T.

2013-05-01

Both Jupiter and Saturn have moons that add significant quantities of neutrals and/or dust beyond geosynchronous orbit. This material becomes charged and interacts with the planetary plasma that is "orbiting" the planets at near corotational speeds, driven by the planetary ionospheres. Since this speed is greater than the keplerian orbital speed at these distances, the net force on the newly added charged mass is outward. The charged material is held in place by the magnetic field which stretches to the amount needed to balance centripetal and centrifugal forces. The currents involved in this process close in the ionosphere which is an imperfect conductor and the feet of the field lines hence slip poleward and the material near the equator moves outward. This motion allows the magnetosphere to divest itself of the added mass by transferring it to the magnetotail. The magnetotail in turn can rid itself of the newly added mass by the process of reconnection, interior to the region of added mass, freeing an island of magnetized plasma which then moves down the magnetotail no longer connected to the magnetosphere. This maintains a quasi-stationary conservation of mass in the magnetosphere with roughly constant mass and "periodic" disturbances. However, there is one other steady state the magnetosphere needs to maintain. It needs to replace the mass loaded flux tubes with emptied flux tubes. Thus the "emptied" flux tubes in the tail must move inward against the outgoing mass-loaded flux tubes. That they are buoyant is a help in this regard but it appears also to be helpful if the returning flux separates into thin flux tubes, just like air bubbles rising in a container with a leak in the bottom. In this way the magnetospheres of Jupiter and Saturn maintain their dynamic, steady-state convection patterns.

Glycines from the APP GXXXG/GXXXA Transmembrane Motifs Promote Formation of Pathogenic Aβ Oligomers in Cells

PubMed Central

Decock, Marie; Stanga, Serena; Octave, Jean-Noël; Dewachter, Ilse; Smith, Steven O.; Constantinescu, Stefan N.; Kienlen-Campard, Pascal

2016-01-01

Alzheimer’s disease (AD) is the most common neurodegenerative disorder characterized by progressive cognitive decline leading to dementia. The amyloid precursor protein (APP) is a ubiquitous type I transmembrane (TM) protein sequentially processed to generate the β-amyloid peptide (Aβ), the major constituent of senile plaques that are typical AD lesions. There is a growing body of evidence that soluble Aβ oligomers correlate with clinical symptoms associated with the disease. The Aβ sequence begins in the extracellular juxtamembrane region of APP and includes roughly half of the TM domain. This region contains GXXXG and GXXXA motifs, which are critical for both TM protein interactions and fibrillogenic properties of peptides derived from TM α-helices. Glycine-to-leucine mutations of these motifs were previously shown to affect APP processing and Aβ production in cells. However, the detailed contribution of these motifs to APP dimerization, their relation to processing, and the conformational changes they can induce within Aβ species remains undefined. Here, we describe highly resistant Aβ42 oligomers that are produced in cellular membrane compartments. They are formed in cells by processing of the APP amyloidogenic C-terminal fragment (C99), or by direct expression of a peptide corresponding to Aβ42, but not to Aβ40. By a point-mutation approach, we demonstrate that glycine-to-leucine mutations in the G29XXXG33 and G38XXXA42 motifs dramatically affect the Aβ oligomerization process. G33 and G38 in these motifs are specifically involved in Aβ oligomerization; the G33L mutation strongly promotes oligomerization, while G38L blocks it with a dominant effect on G33 residue modification. Finally, we report that the secreted Aβ42 oligomers display pathological properties consistent with their suggested role in AD, but do not induce toxicity in survival assays with neuronal cells. Exposure of neurons to these Aβ42 oligomers dramatically affects neuronal differentiation and, consequently, neuronal network maturation. PMID:27242518

A framework to understand the variations of PSD-95 expression in brain aging and in Alzheimer's disease.

PubMed

Savioz, Armand; Leuba, Geneviève; Vallet, Philippe G

2014-11-01

The postsynaptic density protein PSD-95 is a major element of synapses. PSD-95 is involved in aging, Alzheimer's disease (AD) and numerous psychiatric disorders. However, contradictory data about PSD-95 expression in aging and AD have been reported. Indeed in AD versus control brains PSD-95 varies according to regions, increasing in the frontal cortex, at least in a primary stage, and decreasing in the temporal cortex. In contrast, in transgenic mouse models of aging and AD PSD-95 expression is decreased, in behaviorally aged impaired versus unimpaired rodents it can decrease or increase and finally, it is increased in rodents grown in enriched environments. Different factors explain these contradictory results in both animals and humans, among others concomitant psychiatric endophenotypes, such as depression. The possible involvement of PSD-95 in reactive and/or compensatory mechanisms during AD progression is underscored, at least before the occurrence of important synaptic elimination. Thus, in AD but not in AD transgenic mice, enhanced expression might precede the diminution commonly observed in advanced aging. A two-compartments cell model, separating events taking place in cell bodies and synapses, is presented. Overall these data suggest that AD research will progress by untangling pathological from protective events, a prerequisite for effective therapeutic strategies. Copyright © 2014 Elsevier B.V. All rights reserved.

Genome-wide copy number variation (CNV) in patients with autoimmune Addison's disease

PubMed Central

2011-01-01

Background Addison's disease (AD) is caused by an autoimmune destruction of the adrenal cortex. The pathogenesis is multi-factorial, involving genetic components and hitherto unknown environmental factors. The aim of the present study was to investigate if gene dosage in the form of copy number variation (CNV) could add to the repertoire of genetic susceptibility to autoimmune AD. Methods A genome-wide study using the Affymetrix GeneChip® Genome-Wide Human SNP Array 6.0 was conducted in 26 patients with AD. CNVs in selected genes were further investigated in a larger material of patients with autoimmune AD (n = 352) and healthy controls (n = 353) by duplex Taqman real-time polymerase chain reaction assays. Results We found that low copy number of UGT2B28 was significantly more frequent in AD patients compared to controls; conversely high copy number of ADAM3A was associated with AD. Conclusions We have identified two novel CNV associations to ADAM3A and UGT2B28 in AD. The mechanism by which this susceptibility is conferred is at present unclear, but may involve steroid inactivation (UGT2B28) and T cell maturation (ADAM3A). Characterization of these proteins may unravel novel information on the pathogenesis of autoimmunity. PMID:21851588

A variant of the sigma receptor type-1 gene is a protective factor for Alzheimer disease.

PubMed

Uchida, Naohiko; Ujike, Hiroshi; Tanaka, Yuji; Sakai, Ayumu; Yamamoto, Mitsutoshi; Fujisawa, Yoshikatsu; Kanzaki, Akihiro; Kuroda, Shigetoshi

2005-12-01

Some preclinical evidence suggests that the sigma receptor type 1, which plays several roles in learning and memory, may also be involved in the pathogenesis of Alzheimer disease (AD). The authors provide here genetic evidence that the sigma receptor type 1 (SIGMAR1) gene is involved in susceptibility to AD. Two polymorphisms of the SIGMAR1 gene, G-241T/C-240T and Q2P, were analyzed in a Japanese sample of 239 patients with AD and 227 comparisons subjects. These two polymorphisms were in complete linkage disequilibrium with each other, resulting in only two haplotypes, GC-241-240Q2 and TT-241-240P2. There was a significant association between AD and the TT-241-240P2 haplotype of the SIGMAR1 gene and its homozygote, found with late-onset, but not early-onset AD. After stratification by epsilon4 allele status of the apolipoprotein E gene, TT-241-240P2 homozygosity of the SIGMAR1 gene reduced the risk of AD in epsilon4 allele carriers by three-fourths. The present study suggests that the TT-241-240P2 haplotype of the SIGMAR1 gene, which decreases expression of the gene, may have a protective role against susceptibility to AD.

Therapeutic correction of ApoER2 splicing in Alzheimer's disease mice using antisense oligonucleotides.

PubMed

Hinrich, Anthony J; Jodelka, Francine M; Chang, Jennifer L; Brutman, Daniella; Bruno, Angela M; Briggs, Clark A; James, Bryan D; Stutzmann, Grace E; Bennett, David A; Miller, Steven A; Rigo, Frank; Marr, Robert A; Hastings, Michelle L

2016-04-01

Apolipoprotein E receptor 2 (ApoER2) is an apolipoprotein E receptor involved in long-term potentiation, learning, and memory. Given its role in cognition and its association with the Alzheimer's disease (AD) risk gene, apoE, ApoER2 has been proposed to be involved in AD, though a role for the receptor in the disease is not clear. ApoER2 signaling requires amino acids encoded by alternatively spliced exon 19. Here, we report that the balance of ApoER2 exon 19 splicing is deregulated in postmortem brain tissue from AD patients and in a transgenic mouse model of AD To test the role of deregulated ApoER2 splicing in AD, we designed an antisense oligonucleotide (ASO) that increases exon 19 splicing. Treatment of AD mice with a single dose of ASO corrected ApoER2 splicing for up to 6 months and improved synaptic function and learning and memory. These results reveal an association between ApoER2 isoform expression and AD, and provide preclinical evidence for the utility of ASOs as a therapeutic approach to mitigate Alzheimer's disease symptoms by improving ApoER2 exon 19 splicing. © 2016 The Authors. Published under the terms of the CC BY 4.0 license.

Effects of Specific Multi-Nutrient Enriched Diets on Cerebral Metabolism, Cognition and Neuropathology in AβPPswe-PS1dE9 Mice

PubMed Central

Jansen, Diane; Zerbi, Valerio; Arnoldussen, Ilse A. C.; Wiesmann, Maximilian; Rijpma, Anne; Fang, Xiaotian T.; Dederen, Pieter J.; Mutsaers, Martina P. C.; Broersen, Laus M.; Lütjohann, Dieter; Miller, Malgorzata; Joosten, Leo A. B.; Heerschap, Arend; Kiliaan, Amanda J.

2013-01-01

Recent studies have focused on the use of multi-nutrient dietary interventions in search of alternatives for the treatment and prevention of Alzheimer's disease (AD). In this study we investigated to which extent long-term consumption of two specific multi-nutrient diets can modulate AD-related etiopathogenic mechanisms and behavior in 11-12-month-old AβPPswe-PS1dE9 mice. Starting from 2 months of age, male AβPP-PS1 mice and wild-type littermates were fed either a control diet, the DHA+EPA+UMP (DEU) diet enriched with uridine monophosphate (UMP) and the omega-3 fatty acids docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), or the Fortasyn® Connect (FC) diet enriched with the DEU diet plus phospholipids, choline, folic acid, vitamins and antioxidants. We performed behavioral testing, proton magnetic resonance spectroscopy, immunohistochemistry, biochemical analyses and quantitative real-time PCR to gain a better understanding of the potential mechanisms by which these multi-nutrient diets exert protective properties against AD. Our results show that both diets were equally effective in changing brain fatty acid and cholesterol profiles. However, the diets differentially affected AD-related pathologies and behavioral measures, suggesting that the effectiveness of specific nutrients may depend on the dietary context in which they are provided. The FC diet was more effective than the DEU diet in counteracting neurodegenerative aspects of AD and enhancing processes involved in neuronal maintenance and repair. Both diets elevated interleukin-1β mRNA levels in AβPP-PS1 and wild-type mice. The FC diet additionally restored neurogenesis in AβPP-PS1 mice, decreased hippocampal levels of unbound choline-containing compounds in wild-type and AβPP-PS1 animals, suggesting diminished membrane turnover, and decreased anxiety-related behavior in the open field behavior. In conclusion, the current data indicate that specific multi-nutrient diets can influence AD-related etiopathogenic processes. Intervention with the FC diet might be of interest for several other neurodegenerative and neurological disorders. PMID:24086523

Electrochemical pretreatment of waste activated sludge: effect of process conditions on sludge disintegration degree and methane production.

PubMed

Ye, Caihong; Yuan, Haiping; Dai, Xiaohu; Lou, Ziyang; Zhu, Nanwen

2016-11-01

Waste activated sludge (WAS) requires a long digestion time because of a rate-limiting hydrolysis step - the first phase of anaerobic digestion (AD). Pretreatment can be used prior to AD to facilitate the hydrolysis step and improve the efficiency of WAS digestion. This study evaluated a novel application of electrochemical (EC) technology employed as the pretreatment method prior to AD of WAS, focusing on the effect of process conditions on sludge disintegration and subsequent AD process. A superior process condition of EC pretreatment was obtained by reaction time of 30 min, electrolysis voltage of 20 V, and electrode distance of 5 cm, under which the disintegration degree of WAS ranged between 9.02% and 9.72%. In the subsequent batch AD tests, 206 mL/g volatile solid (VS) methane production in EC pretreated sludge was obtained, which was 20.47% higher than that of unpretreated sludge. The AD time was 19 days shorter for EC pretreated sludge compared to the unpretreated sludge. Additionally, the EC + AD reactor achieved 41.84% of VS removal at the end of AD. The analysis of energy consumption showed that EC pretreatment could be effective in enhancing sludge AD with reduced energy consumption when compared to other pretreatment methods.

Higher Curvature Gravity from Entanglement in Conformal Field Theories.

PubMed

Haehl, Felix M; Hijano, Eliot; Parrikar, Onkar; Rabideau, Charles

2018-05-18

By generalizing different recent works to the context of higher curvature gravity, we provide a unifying framework for three related results: (i) If an asymptotically anti-de Sitter (AdS) spacetime computes the entanglement entropies of ball-shaped regions in a conformal field theory using a generalized Ryu-Takayanagi formula up to second order in state deformations around the vacuum, then the spacetime satisfies the correct gravitational equations of motion up to second order around the AdS background. (ii) The holographic dual of entanglement entropy in higher curvature theories of gravity is given by the Wald entropy plus a particular correction term involving extrinsic curvatures. (iii) Conformal field theory relative entropy is dual to gravitational canonical energy (also in higher curvature theories of gravity). Especially for the second point, our novel derivation of this previously known statement does not involve the Euclidean replica trick.

Higher Curvature Gravity from Entanglement in Conformal Field Theories

NASA Astrophysics Data System (ADS)

Haehl, Felix M.; Hijano, Eliot; Parrikar, Onkar; Rabideau, Charles

2018-05-01

By generalizing different recent works to the context of higher curvature gravity, we provide a unifying framework for three related results: (i) If an asymptotically anti-de Sitter (AdS) spacetime computes the entanglement entropies of ball-shaped regions in a conformal field theory using a generalized Ryu-Takayanagi formula up to second order in state deformations around the vacuum, then the spacetime satisfies the correct gravitational equations of motion up to second order around the AdS background. (ii) The holographic dual of entanglement entropy in higher curvature theories of gravity is given by the Wald entropy plus a particular correction term involving extrinsic curvatures. (iii) Conformal field theory relative entropy is dual to gravitational canonical energy (also in higher curvature theories of gravity). Especially for the second point, our novel derivation of this previously known statement does not involve the Euclidean replica trick.

TREM2 p.H157Y Variant and the Risk of Alzheimer's Disease: A Meta-Analysis Involving 14,510 Subjects.

PubMed

Jiang, Teng; Hou, Jian-Kang; Gao, Qing; Yu, Jin-Tai; Zhou, Jun-Shan; Zhao, Hong-Dong; Zhang, Ying-Dong

2016-01-01

We recently revealed that p.H157Y (rs2234255), a rare coding variant of triggering receptor expressed on myeloid cells 2 gene (TREM2), was associated with Alzheimer's disease (AD) susceptibility in Han Chinese. Contrastingly, although p.H157Y was previously identified in both AD cases and controls by several sequencing studies, no association of this variant with disease susceptibility was reported. To gain a credible conclusion on the association between p.H157Y and AD risk, a meta-analysis involving 7,102 cases and 7,408 controls was conducted. Our results indicated that p.H157Y was associated with an increased risk of AD (OR=3.65, 95% CI: 1.61-8.28; P=0.002), further establishing TREM2 as an important susceptibility gene for this disease.

Could ecosystem management provide a new framework for Alzheimer's disease?

PubMed

Hubin, Ellen; Vanschoenwinkel, Bram; Broersen, Kerensa; De Deyn, Peter P; Koedam, Nico; van Nuland, Nico A; Pauwels, Kris

2016-01-01

Alzheimer's disease (AD) is a progressive neurodegenerative brain disorder that involves a plethora of molecular pathways. In the context of therapeutic treatment and biomarker profiling, the amyloid-beta (Aβ) peptide constitutes an interesting research avenue that involves interactions within a complex mixture of Aβ alloforms and other disease-modifying factors. Here, we explore the potential of an ecosystem paradigm as a novel way to consider AD and Aβ dynamics in particular. We discuss the example that the complexity of the Aβ network not only exhibits interesting parallels with the functioning of complex systems such as ecosystems but that this analogy can also provide novel insights into the neurobiological phenomena in AD and serve as a communication tool. We propose that combining network medicine with general ecosystem management principles could be a new and holistic approach to understand AD pathology and design novel therapies. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Lessons from the Desert

DTIC Science & Technology

1993-04-14

involvement in Operations DESERT SHIELD and STORM. The 498th was a unique unit, well-suited for the gamut of operations conducted by the 2AD (FWD) during its...Division (Forward), during that unit’s involvement in Operations DESERT SHIELD and STORM. The 498th was a unique unit, well-suited for the gamut of...well-suited fir the gamut of operations conducted by 2AD (FWD) during its stay in Southwest Asia (SWA) . I commanded the 498th Support Battalion from

A stable partitioned FSI algorithm for rigid bodies and incompressible flow. Part I: Model problem analysis

NASA Astrophysics Data System (ADS)

Banks, J. W.; Henshaw, W. D.; Schwendeman, D. W.; Tang, Qi

2017-08-01

A stable partitioned algorithm is developed for fluid-structure interaction (FSI) problems involving viscous incompressible flow and rigid bodies. This added-mass partitioned (AMP) algorithm remains stable, without sub-iterations, for light and even zero mass rigid bodies when added-mass and viscous added-damping effects are large. The scheme is based on a generalized Robin interface condition for the fluid pressure that includes terms involving the linear acceleration and angular acceleration of the rigid body. Added-mass effects are handled in the Robin condition by inclusion of a boundary integral term that depends on the pressure. Added-damping effects due to the viscous shear forces on the body are treated by inclusion of added-damping tensors that are derived through a linearization of the integrals defining the force and torque. Added-damping effects may be important at low Reynolds number, or, for example, in the case of a rotating cylinder or rotating sphere when the rotational moments of inertia are small. In this first part of a two-part series, the properties of the AMP scheme are motivated and evaluated through the development and analysis of some model problems. The analysis shows when and why the traditional partitioned scheme becomes unstable due to either added-mass or added-damping effects. The analysis also identifies the proper form of the added-damping which depends on the discrete time-step and the grid-spacing normal to the rigid body. The results of the analysis are confirmed with numerical simulations that also demonstrate a second-order accurate implementation of the AMP scheme.

Analysis of the times involved in processing and communication in a lower limb simulation system controlled by SEMG

NASA Astrophysics Data System (ADS)

Profumieri, A.; Bonell, C.; Catalfamo, P.; Cherniz, A.

2016-04-01

Virtual reality has been proposed for different applications, including the evaluation of new control strategies and training protocols for upper limb prostheses and for the study of new rehabilitation programs. In this study, a lower limb simulation environment commanded by surface electromyography signals is evaluated. The time delays generated by the acquisition and processing stages for the signals that would command the knee joint, were measured and different acquisition windows were analysed. The subjective perception of the quality of simulation was also evaluated when extra delays were added to the process. The results showed that the acquisition window is responsible for the longest delay. Also, the basic implemented processes allowed for the acquisition of three signal channels for commanding the simulation. Finally, the communication between different applications is arguably efficient, although it depends on the amount of data to be sent.

A systematic process for persuasive mobile healthcare applications

NASA Astrophysics Data System (ADS)

Qasim, Mustafa Moosa; Ahmad, Mazida; Omar, Mazni; Zulkifli, Abdul Nasir; Bakar, Juliana Aida Abu

2017-10-01

In recent years there has been an increased focus on persuasive design of mobile in the healthcare domain. However, most of the studies did not follow systematic processes while analysis and designing the persuasive technology applications, and they also failed to provide some of the relevant information needed to design the persuasive applications. Adding to this is a need for more guidance in order to set how the persuasive guidelines can be implemented, which also means that there is a need for a way to transform the persuasive components into software requirements and functionalities. Therefore, this paper proposes a general systematic process to be used independently of the problem domain in order to analyze the customers' significant requirements. Such domain is the obesity problem among Malaysian children, and the most significant treatment of this case is parents' involvement. To this end, this paper will apply a systematic process in monitoring the children's obesity status among parents.

Liquid crystalline spinning of spider silk

NASA Astrophysics Data System (ADS)

Vollrath, Fritz; Knight, David P.

2001-03-01

Spider silk has outstanding mechanical properties despite being spun at close to ambient temperatures and pressures using water as the solvent. The spider achieves this feat of benign fibre processing by judiciously controlling the folding and crystallization of the main protein constituents, and by adding auxiliary compounds, to create a composite material of defined hierarchical structure. Because the `spinning dope' (the material from which silk is spun) is liquid crystalline, spiders can draw it during extrusion into a hardened fibre using minimal forces. This process involves an unusual internal drawdown within the spider's spinneret that is not seen in industrial fibre processing, followed by a conventional external drawdown after the dope has left the spinneret. Successful copying of the spider's internal processing and precise control over protein folding, combined with knowledge of the gene sequences of its spinning dopes, could permit industrial production of silk-based fibres with unique properties under benign conditions.

An investigation of the molecular mechanisms engaged before and after the development of Alzheimer disease neuropathology in Down syndrome: a proteomics approach.

PubMed

Cenini, Giovanna; Fiorini, Ada; Sultana, Rukhsana; Perluigi, Marzia; Cai, Jian; Klein, Jon B; Head, Elizabeth; Butterfield, D Allan

2014-11-01

Down syndrome (DS) is one of the most common causes of intellectual disability, owing to trisomy of all or part of chromosome 21. DS is also associated with the development of Alzheimer disease (AD) neuropathology after the age of 40 years. To better clarify the cellular and metabolic pathways that could contribute to the differences in DS brain, in particular those involved in the onset of neurodegeneration, we analyzed the frontal cortex of DS subjects with or without significant AD pathology in comparison with age-matched controls, using a proteomics approach. Proteomics represents an advantageous tool to investigate the molecular mechanisms underlying the disease. From these analyses, we investigated the effects that age, DS, and AD neuropathology could have on protein expression levels. Our results show overlapping and independent molecular pathways (including energy metabolism, oxidative damage, protein synthesis, and autophagy) contributing to DS, to aging, and to the presence of AD pathology in DS. Investigation of pathomechanisms involved in DS with AD may provide putative targets for therapeutic approaches to slow the development of AD. Copyright © 2014 Elsevier Inc. All rights reserved.

The zinc dyshomeostasis hypothesis of Alzheimer's disease.

PubMed

Craddock, Travis J A; Tuszynski, Jack A; Chopra, Deepak; Casey, Noel; Goldstein, Lee E; Hameroff, Stuart R; Tanzi, Rudolph E

2012-01-01

Alzheimer's disease (AD) is the most common form of dementia in the elderly. Hallmark AD neuropathology includes extracellular amyloid plaques composed largely of the amyloid-β protein (Aβ), intracellular neurofibrillary tangles (NFTs) composed of hyper-phosphorylated microtubule-associated protein tau (MAP-tau), and microtubule destabilization. Early-onset autosomal dominant AD genes are associated with excessive Aβ accumulation, however cognitive impairment best correlates with NFTs and disrupted microtubules. The mechanisms linking Aβ and NFT pathologies in AD are unknown. Here, we propose that sequestration of zinc by Aβ-amyloid deposits (Aβ oligomers and plaques) not only drives Aβ aggregation, but also disrupts zinc homeostasis in zinc-enriched brain regions important for memory and vulnerable to AD pathology, resulting in intra-neuronal zinc levels, which are either too low, or excessively high. To evaluate this hypothesis, we 1) used molecular modeling of zinc binding to the microtubule component protein tubulin, identifying specific, high-affinity zinc binding sites that influence side-to-side tubulin interaction, the sensitive link in microtubule polymerization and stability. We also 2) performed kinetic modeling showing zinc distribution in extra-neuronal Aβ deposits can reduce intra-neuronal zinc binding to microtubules, destabilizing microtubules. Finally, we 3) used metallomic imaging mass spectrometry (MIMS) to show anatomically-localized and age-dependent zinc dyshomeostasis in specific brain regions of Tg2576 transgenic, mice, a model for AD. We found excess zinc in brain regions associated with memory processing and NFT pathology. Overall, we present a theoretical framework and support for a new theory of AD linking extra-neuronal Aβ amyloid to intra-neuronal NFTs and cognitive dysfunction. The connection, we propose, is based on β-amyloid-induced alterations in zinc ion concentration inside neurons affecting stability of polymerized microtubules, their binding to MAP-tau, and molecular dynamics involved in cognition. Further, our theory supports novel AD therapeutic strategies targeting intra-neuronal zinc homeostasis and microtubule dynamics to prevent neurodegeneration and cognitive decline.

Cycle Checkpoint Abnormalities during Dementia: A Plausible Association with the Loss of Protection against Oxidative Stress in Alzheimer’s Disease

PubMed Central

Katsel, Pavel; Tan, Weilun; Fam, Peter; Purohit, Dushyant P.; Haroutunian, Vahram

2013-01-01

Background Increasing evidence suggests an association between neuronal cell cycle (CCL) events and the processes that underlie neurodegeneration in Alzheimer’s disease (AD). Elevated levels of oxidative stress markers and mitochondrial dysfunction are also among early events in AD. Recent studies have reported the role of CCL checkpoint proteins and tumor suppressors, such as ATM and p53 in the control of glycolysis and oxidative metabolism in cancer, but their involvement in AD remains uncertain. Methods and Findings In this postmortem study, we measured gene expression levels of eight CCL checkpoint proteins in the superior temporal cortex (STC) of persons with varying severities of AD dementia and compare them to those of cognitively normal controls. To assess whether the CCL changes associated with cognitive impairment in AD are specific to dementia, gene expression of the same proteins was also measured in STC of persons with schizophrenia (SZ), which is also characterized by mitochondrial dysfunction. The expression of CCL-checkpoint and DNA damage response genes: MDM4, ATM and ATR was strongly upregulated and associated with progression of dementia (cognitive dementia rating, CDR), appearing as early as questionable or mild dementia (CDRs 0.5–1). In addition to gene expression changes, the downstream target of ATM-p53 signaling - TIGAR, a p53-inducible protein, the activation of which can regulate energy metabolism and protect against oxidative stress was progressively decreased as severity of dementia evolved, but it was unaffected in subjects with SZ. In contrast to AD, different CCL checkpoint proteins, which include p53, CHEK1 and BRCA1 were significantly downregulated in SZ. Conclusions These results support the activation of an ATM signaling and DNA damage response network during the progression of AD dementia, while the progressive decrease in the levels of TIGAR suggests loss of protection initiated by ATM-p53 signaling against intensifying oxidative stress in AD. PMID:23861893

The Situation-Specific Theory of Heart Failure Self-Care: Revised and Updated.

PubMed

Riegel, Barbara; Dickson, Victoria Vaughan; Faulkner, Kenneth M

2016-01-01

Since the situation-specific theory of heart failure (HF) self-care was published in 2008, we have learned much about how and why patients with HF take care of themselves. This knowledge was used to revise and update the theory. The purpose of this article was to describe the revised, updated situation-specific theory of HF self-care. Three major revisions were made to the existing theory: (1) a new theoretical concept reflecting the process of symptom perception was added; (2) each self-care process now involves both autonomous and consultative elements; and (3) a closer link between the self-care processes and the naturalistic decision-making process is described. In the revised theory, HF self-care is defined as a naturalistic decision-making process with person, problem, and environmental factors that influence the everyday decisions made by patients and the self-care actions taken. The first self-care process, maintenance, captures those behaviors typically referred to as treatment adherence. The second self-care process, symptom perception, involves body listening, monitoring signs, as well as recognition, interpretation, and labeling of symptoms. The third self-care process, management, is the response to symptoms when they occur. A total of 5 assumptions and 8 testable propositions are specified in this revised theory. Prior research illustrates that all 3 self-care processes (ie, maintenance, symptom perception, and management) are integral to self-care. Further research is greatly needed to identify how best to help patients become experts in HF self-care.

Non-equilibrium condensation process in holographic superconductor with nonlinear electrodynamics

NASA Astrophysics Data System (ADS)

Liu, Yunqi; Gong, Yungui; Wang, Bin

2016-02-01

We study the non-equilibrium condensation process in a holographic superconductor with nonlinear corrections to the U (1) gauge field. We start with an asymptotic Anti-de-Sitter (AdS) black hole against a complex scalar perturbation at the initial time, and solve the dynamics of the gravitational systems in the bulk. When the black hole temperature T is smaller than a critical value T c , the scalar perturbation grows exponentially till saturation, the final state of spacetime approaches to a hairy black hole. In the bulk theory, we find the clue of the influence of nonlinear corrections in the gauge filed on the process of the scalar field condensation. We show that the bulk dynamics in the non-equilibrium process is completely consistent with the observations on the boundary order parameter. Furthermore we examine the time evolution of horizons in the bulk non-equilibrium transformation process from the bald AdS black hole to the AdS hairy hole. Both the evolution of apparent and event horizons show that the original AdS black hole configuration requires more time to finish the transformation to become a hairy black hole if there is nonlinear correction to the electromagnetic field. We generalize our non-equilibrium discussions to the holographic entanglement entropy and find that the holographic entanglement entropy can give us further understanding of the influence of the nonlinearity in the gauge field on the scalar condensation.

Impact of celebrity pitch in direct-to-consumer advertising of prescription drugs.

PubMed

Bhutada, Nilesh S; Menon, Ajit M; Deshpande, Aparna D; Perri, Matthew

2012-01-01

Online surveys were conducted to determine the impact of endorser credibility, endorser effectiveness, and consumers' involvement in direct-to-consumer advertising. In a randomized posttest only study, using the elaboration likelihood model, survey participants (U.S. adults) were either exposed to a fictitious prescription drug ad with a celebrity or a noncelebrity endorser. There was no significant difference in credibility and effectiveness between the celebrity and the noncelebrity endorser. High involvement consumers viewed the ad more favorably and exhibited significantly stronger drug inquiry intentions during their next doctor visit. Further, consumers' involvement did not moderate the effect of celebrity endorser.

Neurolinguistic Approach to Natural Language Processing with Applications to Medical Text Analysis

PubMed Central

Matykiewicz, Paweł; Pestian, John

2008-01-01

Understanding written or spoken language presumably involves spreading neural activation in the brain. This process may be approximated by spreading activation in semantic networks, providing enhanced representations that involve concepts that are not found directly in the text. Approximation of this process is of great practical and theoretical interest. Although activations of neural circuits involved in representation of words rapidly change in time snapshots of these activations spreading through associative networks may be captured in a vector model. Concepts of similar type activate larger clusters of neurons, priming areas in the left and right hemisphere. Analysis of recent brain imaging experiments shows the importance of the right hemisphere non-verbal clusterization. Medical ontologies enable development of a large-scale practical algorithm to re-create pathways of spreading neural activations. First concepts of specific semantic type are identified in the text, and then all related concepts of the same type are added to the text, providing expanded representations. To avoid rapid growth of the extended feature space after each step only the most useful features that increase document clusterization are retained. Short hospital discharge summaries are used to illustrate how this process works on a real, very noisy data. Expanded texts show significantly improved clustering and may be classified with much higher accuracy. Although better approximations to the spreading of neural activations may be devised a practical approach presented in this paper helps to discover pathways used by the brain to process specific concepts, and may be used in large-scale applications. PMID:18614334

Focal atrophy in Dementia with Lewy Bodies on MRI: a distinct pattern from Alzheimer's disease

PubMed Central

Whitwell, Jennifer L; Weigand, Stephen D; Shiung, Maria M; Boeve, Bradley F; Ferman, Tanis J; Smith, Glenn E; Knopman, David S; Petersen, Ronald C; Benarroch, Eduardo E; Josephs, Keith A; Jack, Clifford R

2009-01-01

SUMMARY Dementia with Lewy Bodies (DLB) is the second most common cause of degenerative dementia after Alzheimer's disease (AD). However, unlike in AD the patterns of cerebral atrophy associated with DLB have not been well established. The aim of this study was to identify a signature pattern of cerebral atrophy in DLB and to compare it to the pattern found in AD. Seventy-two patients that fulfilled clinical criteria for probable DLB were age and gender-matched to 72 patients with probable AD and 72 controls. Voxel-based morphometry (VBM) was used to assess patterns of grey matter atrophy in the DLB and AD groups, relative to controls, after correction for multiple comparisons (p<0.05). Study specific templates and prior probability maps were used to avoid normalization and segmentation bias. Region-of-interest (ROI) analyses were also performed comparing loss of the midbrain, substantia innominata (SI), temporoparietal cortex and hippocampus between the groups. The DLB group showed very little cortical involvement on VBM with regional grey matter loss observed primarily in the dorsal midbrain, SI and hypothalamus. In comparison, the AD group showed a widespread pattern of grey matter loss involving the temporoparietal association cortices and the medial temporal lobes. The SI and dorsal midbrain were involved in AD however they were not identified as a cluster of loss discrete from uninvolved surrounding areas, as observed in the DLB group. On direct comparison between the two groups, the AD group showed greater loss in the medial temporal lobe and inferior temporal regions than the DLB group. The ROI analysis showed reduced SI and midbrain grey matter in both the AD and DLB groups. The SI grey matter was reduced more in AD than DLB, yet the midbrain was reduced more in DLB than AD. The hippocampus and temporoparietal cortex showed significantly greater loss in the AD group compared to the DLB group. A pattern of relatively focused atrophy of the midbrain, hypothalamus and SI, with a relative sparing of the hippocampus and temporoparietal cortex, is therefore suggestive of DLB and may aid in the differentiation of DLB from AD. These findings support recent pathological studies showing an ascending pattern of Lewy Body progression from brainstem to basal areas of the brain. Damage to this network of structures in DLB may affect a number of different neurotransmitter systems which in turn may contribute to a number of the core clinical features of DLB. PMID:17267521

Adenovirus receptors and their implications in gene delivery

PubMed Central

Sharma, Anurag; Li, Xiaoxin; Bangari, Dinesh S.; Mittal, Suresh K.

2010-01-01

Adenoviruses (Ads) have gained popularity as gene delivery vectors for therapeutic and prophylactic applications. Ad entry into host cells involves specific interactions between cell surface receptors and viral capsid proteins. Several cell surface molecules have been identified as receptors for Ad attachment and entry. Tissue tropism of Ad vectors is greatly influenced by their receptor usage. A variety of strategies have been investigated to modify Ad vector tropism by manipulating the receptor-interacting moieties. Many such strategies are aimed at targeting and/or detargeting of Ad vectors. In this review, we discuss the various cell surface molecules that are implicated as receptors for virus attachment and internalization. Special emphasis is given to Ad types that are utilized as gene delivery vectors. Various strategies to modify Ad tropism using the knowledge of Ad receptors are also discussed. PMID:19647886

Binary chromatographic data and estimation of adsorbent porosities. [data for system n-heptane/n-pentane

NASA Technical Reports Server (NTRS)

Meisch, A. J.

1972-01-01

Data for the system n-pentane/n-heptane on porous Chromosorb-102 adsorbent were obtained at 150, 175, and 200 C for mixtures containing zero to 100% n-pentane by weight. Prior results showing limitations on superposition of pure component data to predict multicomponent chromatograms were verified. The thermodynamic parameter MR0 was found to be a linear function of sample composition. A nonporous adsorbent failed to separate the system because of large input sample dispersions. A proposed automated data processing scheme involving magnetic tape recording of the detector signals and processing by a minicomputer was rejected because of resolution limitations of the available a/d converters. Preliminary data on porosity and pore size distributions of the adsorbents were obtained.

Family Process and Peer Deviance Influences on Adolescent Aggression: Longitudinal Effects across Early and Middle Adolescence

PubMed Central

Benson, Mark J.; Buehler, Cheryl

2012-01-01

Beginning in sixth grade, 416 adolescents and their parents participated in four waves of data collection involving family observations and multiple-reporter assessments. Ecological theory and the Process-Person-Context-Time (PPCT) model guided the hypotheses and analyses. Lagged, growth curve models revealed that both hostile family interactions and peer deviance affiliation predicted adolescent aggression in the subsequent year. Family warmth played only a minor role in protecting against adolescent aggression. In hostile or low warmth families, peer deviance affiliation linked to a declining aggression trajectory consistent with the arena of comfort hypothesis. The longitudinal findings suggest a non-additive, synergistic interplay between family and peer contexts across time in adding nuance to the understanding adolescent aggression. PMID:22497273

[Marketing approval and market surveillance of medical devices in Germany: Where does policy integration take place?].

PubMed

Lang, Achim

2014-01-01

Since 2011 new regulatory measures regarding medical devices have been set up with the aim to eliminate obstacles to innovations and to find more coordinated ways to marketing authorisation and market surveillance. This essay investigates whether these new and existing coordination mechanisms build up to a Joined-up Government approach. The analysis shows that the regulatory process should be adjusted along several dimensions. First, many organisations lack awareness regarding their stakeholders and focus solely on their immediate organisational activities. Second, the regulatory process (marketing authorisation and market surveillance) is too fragmented for an effective communication to take place. Finally, the underlying strategy process is an ad-hoc approach lacking continuity and continued involvement of, in particular, the responsible federal ministries. Copyright © 2013. Published by Elsevier GmbH.

Spent coffee enhanced biomethane potential via an integrated hydrothermal carbonization-anaerobic digestion process.

PubMed

Codignole Luz, Fábio; Volpe, Maurizio; Fiori, Luca; Manni, Alessandro; Cordiner, Stefano; Mulone, Vincenzo; Rocco, Vittorio

2018-05-01

This study reports the implications of using spent coffee hydrochar as substrate for anaerobic digestion (AD) processes. Three different spent coffee hydrochars produced at 180, 220 and 250 °C, 1 h residence time, were investigated for their biomethane potential in AD process inoculated with cow manure. Spent coffee hydrochars were characterized in terms of ultimate, proximate and higher heating value (HHV), and their theoretical bio-methane yield evaluated using Boyle-Buswell equation and compared to the experimental values. The results were then analyzed using the modified Gompertz equation to determine the main AD evolution parameters. Different hydrochar properties were related to AD process performances. AD of spent coffee hydrochars produced at 180 °C showed the highest biomethane production rate (46 mL CH 4 /gVS . d), a biomethane potential of 491 mL/gVS (AD lasting 25 days), and a biomethane gas daily composition of about 70%. Copyright © 2018 Elsevier Ltd. All rights reserved.

Protecting cognition from aging and Alzheimer's disease: a computerized cognitive training combined with reminiscence therapy.

PubMed

Barban, Francesco; Annicchiarico, Roberta; Pantelopoulos, Stelios; Federici, Alessia; Perri, Roberta; Fadda, Lucia; Carlesimo, Giovanni Augusto; Ricci, Claudia; Giuli, Simone; Scalici, Francesco; Turchetta, Chiara Stella; Adriano, Fulvia; Lombardi, Maria Giovanna; Zaccarelli, Chiara; Cirillo, Giulio; Passuti, Simone; Mattarelli, Paolo; Lymperopoulou, Olga; Sakka, Paraskevi; Ntanasi, Eva; Moliner, Reyes; Garcia-Palacios, Azucena; Caltagirone, Carlo

2016-04-01

The aim of this paper was to assess the efficacy of process-based cognitive training (pb-CT) combined with reminiscence therapy (RT) in patients with mild Alzheimer's disease (mAD) and mild cognitive impairment (MCI) and in healthy elderly (HE) subjects. This multicenter, randomized, controlled trial involved 348 participants with mAD, MCI, and HE from four European countries. Participants were randomly assigned to two arms of a crossover design: those in arm A underwent 3 months of computerized pb-CT for memory and executive functions combined with RT and 3 months of rest; those in arm B underwent the reverse. The primary outcome was the effect of the training on memory and executive functions performance. The secondary outcome was the effect of the training on functional abilities in mAD assessed with the instrumental activities of daily living. We found a significant effect of the training for memory in all three groups on delayed recall of the Rey Auditory Verbal Learning Test and for executive functions in HE on the phonological fluency test. MCI and HE participants maintained these effects at follow-up. MCI and mAD participants also showed a significant effect of the training on the Mini-mental state examination scale. Participants with mAD showed more stable instrumental activities of daily living during the training versus the rest period. Our results corroborate the positive effect of pb-CT and its maintenance primarily on memory in HE and MCI participants that did not seem to be potentiated by RT. Moreover, our results are very promising for the mAD participants. Copyright © 2015 John Wiley & Sons, Ltd.

Deconstructing the Age-Prevalence Curve of Alcohol Dependence: Why “Maturing Out” is only a Small Piece of the Puzzle

PubMed Central

Vergés, Alvaro; Jackson, Kristina M.; Bucholz, Kathleen K.; Grant, Julia D.; Trull, Timothy J.; Wood, Phillip K.; Sher, Kenneth J.

2012-01-01

Epidemiological studies have consistently demonstrated that heavy alcohol use and alcohol dependence (AD), tend to increase in adolescence and emerging adulthood and then show a large decline in the late 20s, a phenomenon called “maturing out”. This decline has been explained as an effect of “role incompatibility” in which involvement in new roles and activities interferes with a heavy drinking lifestyle. However, maturing out has been conceived mostly as a decrease in offset, with little attention paid to reductions in new onset or recurrence across decades of life. Moreover, although role incompatibility processes have been studied with young samples, little is known about the effect of life transitions (e.g., marriage, parenthood, changes in employment status) on AD later in life and whether similar effects are observed. Using longitudinal data from the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC), a nationally representative epidemiologic survey, we examined the patterns of stability and change in AD across the lifespan and the differential effect of life transitions on AD across different age strata. Results showed that persistence of alcohol dependence tended to increase with age, although not dramatically, and that onset and recurrence tended to decrease with age. Moreover, the effects of life transitions on the course of AD varied across the lifespan and were different for men and women. These results indicate that life transitions differentially affect the patterns of stability and change in younger versus older people, have a different impact for men and women, and highlight the need to consider the unique aspects of each stage of adult development on the course of AD. PMID:22060948

Effects of education on the progression of early- versus late-stage mild cognitive impairment.

PubMed

Ye, Byoung Seok; Seo, Sang Won; Cho, Hanna; Kim, Seong Yoon; Lee, Jung-Sun; Kim, Eun-Joo; Lee, Yunhwan; Back, Joung Hwan; Hong, Chang Hyung; Choi, Seong Hye; Park, Kyung Won; Ku, Bon D; Moon, So Young; Kim, Sangyun; Han, Seol-Heui; Lee, Jae-Hong; Cheong, Hae-Kwan; Na, Duk L

2013-04-01

Highly educated participants with normal cognition show lower incidence of Alzheimer's disease (AD) than poorly educated participants, whereas longitudinal studies involving AD have reported that higher education is associated with more rapid cognitive decline. We aimed to evaluate whether highly educated amnestic mild cognitive impairment (aMCI) participants show more rapid cognitive decline than those with lower levels of education. A total of 249 aMCI patients enrolled from 31 memory clinics using the standard assessment and diagnostic processes were followed with neuropsychological evaluation (duration 17.2 ± 8.8 months). According to baseline performances on memory tests, participants were divided into early-stage aMCI (-1.5 to -1.0 standard deviation (SD)) and late-stage aMCI (below -1.5 SD) groups. Risk of AD conversion and changes in neuropsychological performances according to the level of education were evaluated. Sixty-two patients converted to AD over a mean follow-up of 1.43 years. The risk of AD conversion was higher in late-stage aMCI than early-stage aMCI. Cox proportional hazard models showed that aMCI participants, and late-stage aMCI participants in particular, with higher levels of education had a higher risk of AD conversion than those with lower levels of education. Late-stage aMCI participants with higher education showed faster cognitive decline in language, memory, and Clinical Dementia Rating Sum of Boxes (CDR-SOB) scores. On the contrary, early-stage aMCI participants with higher education showed slower cognitive decline in MMSE and CDR-SOB scores. Our findings suggest that the protective effects of education against cognitive decline remain in early-stage aMCI and disappear in late-stage aMCI.

Defects of filaggrin-like proteins in both lesional and nonlesional atopic skin.

PubMed

Pellerin, Laurence; Henry, Julie; Hsu, Chiung-Yueh; Balica, Stéfana; Jean-Decoster, Catherine; Méchin, Marie-Claire; Hansmann, Britta; Rodriguez, Elke; Weindinger, Stefan; Schmitt, Anne-Marie; Serre, Guy; Paul, Carle; Simon, Michel

2013-04-01

Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by a disturbed epidermal barrier. In a subset of patients, this is explained by nonsense mutations in the gene encoding filaggrin (FLG). We sought to evaluate the respective role of FLG mutations and proinflammatory cytokines and to assess the expression of FLG, hornerin (HRNR), and FLG2, 2 FLG-like proteins, which are involved in epidermal barrier functions, in normal skin and both lesional and nonlesional skin of patients with AD. An FLG-genotyped cohort of 73 adults with AD and 73 aged-matched control subjects was analyzed by using immunohistochemistry and immunoblotting. Normal primary human keratinocytes were differentiated in either the absence or presence of IL-4, IL-13, and IL-25. Compared with control subjects, FLG, HRNR, and FLG2 were detected at significantly lower levels in the skin of patients with AD, irrespective of their FLG genotype. The reduction was greater in lesional compared with nonlesional skin. In addition, the proFLG/FLG ratio was found to be higher in the skin of wild-type patients than in control subjects. Cytokine treatment of keratinocytes induced a dramatic reduction in FLG, FLG2, and HRNR expression both at the mRNA and protein levels. The stratum corneum of lesional but also clinically unaffected skin of adults with AD is abnormal, with reduced expression of FLG and FLG-like proteins. In addition to nonsense mutations, proinflammatory cytokines and some defects in the proFLG processing can contribute to the FLG downregulation. Our study suggests that skin inflammation reduces the expression of FLG-like proteins, contributing to the AD-related epidermal barrier dysfunction. Copyright © 2013 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.

Tailored nutritional guidance for home-dwelling AD families: the Feasibility of and Elements Promoting Positive Changes in Diet (NuAD-Trial).

PubMed

Puranen, T M; Pitkala, K H; Suominen, M H

2015-04-01

To describe the process and feasibility of our randomised, controlled intervention study (NuAD trial) that positively affected the nutrition and quality of life, and prevented falls of home-dwelling persons with Alzheimer disease (AD). This qualitative study comprised 40 persons with AD and spousal caregivers of our trial. Our intervention during one year involved tailored nutritional guidance for these couples. The nutritionist's field notes (about 100 pages) and the participant feedback questionnaires (N = 28) served to analyse the feasibility of intervention, factors promoting the application of intervention and challenges hindering it. Thematic content analysis served to analyse our data with the grounded theory approach. We identified several positive elements promoting better nutrition: positive attitudes on nutrition to participants including a participant-centred approach, positive feedback, findings of food diaries and practical suggestions. Home visits by the nutritionist were convenient and participants felt that someone cares. Group meetings which included protein-rich snacks strengthened the nutritional message by enabling discussions and socialising. The oral nutritional supplements (ONS) helped participants to regain their energy and to motivate them to exercise and make changes in their diets. Obstacles to making changes in diets included participants' false ideas about nutrition, especially with regard to weight gain. Health problems and functional limitations hampered food management, and some families had inveterate eating habits. The positive feedback from participants indicated the feasibility of our tailored nutritional guidance. Assessment-based, tailored nutritional guidance implemented with a personal and positive approach may inspire and empower AD families to make positive changes in their diets, leading them to improved nutrition and quality of life.

Evaluating the Economic Impact of Smart Care Platforms: Qualitative and Quantitative Results of a Case Study

PubMed Central

Van der Auwermeulen, Thomas; Van Ooteghem, Jan; Jacobs, An; Verbrugge, Sofie; Colle, Didier

2016-01-01

Background In response to the increasing pressure of the societal challenge because of a graying society, a gulf of new Information and Communication Technology (ICT) supported care services (eCare) can now be noticed. Their common goal is to increase the quality of care while decreasing its costs. Smart Care Platforms (SCPs), installed in the homes of care-dependent people, foster the interoperability of these services and offer a set of eCare services that are complementary on one platform. These eCare services could not only result in more quality care for care receivers, but they also offer opportunities to care providers to optimize their processes. Objective The objective of the study was to identify and describe the expected added values and impacts of integrating SCPs in current home care delivery processes for all actors. In addition, the potential economic impact of SCP deployment is quantified from the perspective of home care organizations. Methods Semistructured and informal interviews and focus groups and cocreation workshops with service providers, managers of home care organizations, and formal and informal care providers led to the identification of added values of SCP integration. In a second step, process breakdown analyses of home care provisioning allowed defining the operational impact for home care organization. Impacts on 2 different process steps of providing home care were quantified. After modeling the investment, an economic evaluation compared the business as usual (BAU) scenario versus the integrated SCP scenario. Results The added value of SCP integration for all actors involved in home care was identified. Most impacts were qualitative such as increase in peace of mind, better quality of care, strengthened involvement in care provisioning, and more transparent care communication. For home care organizations, integrating SCPs could lead to a decrease of 38% of the current annual expenses for two administrative process steps namely, care rescheduling and the billing for care provisioning. Conclusions Although integrating SCP in home care processes could affect both the quality of life of the care receiver and informal care giver, only scarce and weak evidence was found that supports this assumption. In contrast, there exists evidence that indicates the lack of the impact on quality of life of the care receiver while it increases the cost of care provisioning. However, our cost-benefit quantification model shows that integrating SCPs in home care provisioning could lead to a considerable decrease of costs for care administrative tasks. Because of this cost decreasing impact, we believe that the integration of SCPs will be driven by home care organizations instead of the care receivers themselves. PMID:27799137

Evaluating the Economic Impact of Smart Care Platforms: Qualitative and Quantitative Results of a Case Study.

PubMed

Vannieuwenborg, Frederic; Van der Auwermeulen, Thomas; Van Ooteghem, Jan; Jacobs, An; Verbrugge, Sofie; Colle, Didier

2016-10-31

In response to the increasing pressure of the societal challenge because of a graying society, a gulf of new Information and Communication Technology (ICT) supported care services (eCare) can now be noticed. Their common goal is to increase the quality of care while decreasing its costs. Smart Care Platforms (SCPs), installed in the homes of care-dependent people, foster the interoperability of these services and offer a set of eCare services that are complementary on one platform. These eCare services could not only result in more quality care for care receivers, but they also offer opportunities to care providers to optimize their processes. The objective of the study was to identify and describe the expected added values and impacts of integrating SCPs in current home care delivery processes for all actors. In addition, the potential economic impact of SCP deployment is quantified from the perspective of home care organizations. Semistructured and informal interviews and focus groups and cocreation workshops with service providers, managers of home care organizations, and formal and informal care providers led to the identification of added values of SCP integration. In a second step, process breakdown analyses of home care provisioning allowed defining the operational impact for home care organization. Impacts on 2 different process steps of providing home care were quantified. After modeling the investment, an economic evaluation compared the business as usual (BAU) scenario versus the integrated SCP scenario. The added value of SCP integration for all actors involved in home care was identified. Most impacts were qualitative such as increase in peace of mind, better quality of care, strengthened involvement in care provisioning, and more transparent care communication. For home care organizations, integrating SCPs could lead to a decrease of 38% of the current annual expenses for two administrative process steps namely, care rescheduling and the billing for care provisioning. Although integrating SCP in home care processes could affect both the quality of life of the care receiver and informal care giver, only scarce and weak evidence was found that supports this assumption. In contrast, there exists evidence that indicates the lack of the impact on quality of life of the care receiver while it increases the cost of care provisioning. However, our cost-benefit quantification model shows that integrating SCPs in home care provisioning could lead to a considerable decrease of costs for care administrative tasks. Because of this cost decreasing impact, we believe that the integration of SCPs will be driven by home care organizations instead of the care receivers themselves. ©Frederic Vannieuwenborg, Thomas Van der Auwermeulen, Jan Van Ooteghem, An Jacobs, Sofie Verbrugge, Didier Colle. Originally published in JMIR Medical Informatics (http://medinform.jmir.org), 31.10.2016.

Data Quality Screening Service

NASA Technical Reports Server (NTRS)

Strub, Richard; Lynnes, Christopher; Hearty, Thomas; Won, Young-In; Fox, Peter; Zednik, Stephan

2013-01-01

A report describes the Data Quality Screening Service (DQSS), which is designed to help automate the filtering of remote sensing data on behalf of science users. Whereas this process often involves much research through quality documents followed by laborious coding, the DQSS is a Web Service that provides data users with data pre-filtered to their particular criteria, while at the same time guiding the user with filtering recommendations of the cognizant data experts. The DQSS design is based on a formal semantic Web ontology that describes data fields and the quality fields for applying quality control within a data product. The accompanying code base handles several remote sensing datasets and quality control schemes for data products stored in Hierarchical Data Format (HDF), a common format for NASA remote sensing data. Together, the ontology and code support a variety of quality control schemes through the implementation of the Boolean expression with simple, reusable conditional expressions as operands. Additional datasets are added to the DQSS simply by registering instances in the ontology if they follow a quality scheme that is already modeled in the ontology. New quality schemes are added by extending the ontology and adding code for each new scheme.

Therapeutic patient education in atopic dermatitis: worldwide experiences.

PubMed

Stalder, Jean-Francois; Bernier, Claire; Ball, Alan; De Raeve, Linda; Gieler, Uwe; Deleuran, Mette; Marcoux, Danielle; Eichenfield, Lawrence F; Lio, Peter; Lewis-Jones, Sue; Gelmetti, Carlo; Takaoka, Roberto; Chiaverini, Christine; Misery, Laurent; Barbarot, Sébastien

2013-01-01

Therapeutic patient education (TPE) has proven effective in increasing treatment adherence and improving quality of life (QoL) for patients with numerous chronic diseases, especially atopic dermatitis (AD). This study was undertaken to identify worldwide TPE experiences in AD treatment. Experts from 23 hospitals, located in 11 countries, responded to a questionnaire on 10 major items. Patients in TPE programs were mainly children and adolescents with moderate to severe AD or markedly affected QoL. Individual and collective approaches were used. Depending on the center, the number of sessions varied from one to six (corresponding to 2 to 12 hours of education), and 20 to 200 patients were followed each year. Each center's education team comprised multidisciplinary professionals (e.g., doctors, nurses, psychologists). Evaluations were based on clinical assessment, QoL, a satisfaction index, or some combination of the three. When funding was obtained, it came from regional health authorities (France), insurance companies (Germany), donations (United States), or pharmaceutical firms (Japan, Italy). The role of patient associations was always highlighted, but their involvement in the TPE process varied from one country to another. Despite the nonexhaustive approach, our findings demonstrate the increasing interest in TPE for managing individuals with AD. In spite of the cultural and financial differences between countries, there is a consensus among experts to integrate education into the treatment of eczema. © 2013 Wiley Periodicals, Inc.

The biomarker-based diagnosis of Alzheimer's disease. 1-ethical and societal issues.

PubMed

Porteri, Corinna; Albanese, Emiliano; Scerri, Charles; Carrillo, Maria C; Snyder, Heather M; Martensson, Birgitta; Baker, Mark; Giacobini, Ezio; Boccardi, Marina; Winblad, Bengt; Frisoni, Giovanni B; Hurst, Samia

2017-04-01

There is great interest in the use of biomarkers to assist in the timely identification of Alzheimer's disease (AD) in individuals with mild symptoms. However, the inclusion of AD biomarkers in clinical criteria poses socioethical challenges. The Geneva Task Force for the Roadmap of Alzheimer's Biomarkers was established to deliver a systematic strategic research agenda (aka roadmap) to promote efficient and effective validation of AD biomarkers and to foster their uptake in clinical practice. In this article, we summarize the workshop discussion of the Geneva Task Force "ethical and societal issues" working group, which comprised bioethicists, clinicians, health economists, and representatives of those affected by AD. The working group identified the following key issues that need to be included in the roadmap: improving access to services through timely diagnosis, the need for a diagnostic research protocol before moving to clinical routine, recruitment in diagnostic research protocols in the absence of effective therapy, respect for the autonomy of the individual with mild cognitive impairment in information and consent process and the right not to know biomarkers results, need for counseling programs, disclosure of the diagnosis in a structured environment and the involvement of family members, health policies including the individuals' views and the protection of their interests, and the economic costs for society. Copyright © 2016 Elsevier Inc. All rights reserved.

Autism, Alzheimer disease, and fragile X

PubMed Central

Sokol, D.K.; Maloney, B.; Long, J.M.; Ray, B.

2011-01-01

The present review highlights an association between autism, Alzheimer disease (AD), and fragile X syndrome (FXS). We propose a conceptual framework involving the amyloid-β peptide (Aβ), Aβ precursor protein (APP), and fragile X mental retardation protein (FMRP) based on experimental evidence. The anabolic (growth-promoting) effect of the secreted α form of the amyloid-β precursor protein (sAPPα) may contribute to the state of brain overgrowth implicated in autism and FXS. Our previous report demonstrated that higher plasma sAPPα levels associate with more severe symptoms of autism, including aggression. This molecular effect could contribute to intellectual disability due to repression of cell–cell adhesion, promotion of dense, long, thin dendritic spines, and the potential for disorganized brain structure as a result of disrupted neurogenesis and migration. At the molecular level, APP and FMRP are linked via the metabotropic glutamate receptor 5 (mGluR5). Specifically, mGluR5 activation releases FMRP repression of APP mRNA translation and stimulates sAPP secretion. The relatively lower sAPPα level in AD may contribute to AD symptoms that significantly contrast with those of FXS and autism. Low sAPPα and production of insoluble Aβ would favor a degenerative process, with the brain atrophy seen in AD. Treatment with mGluR antagonists may help repress APP mRNA translation and reduce secretion of sAPP in FXS and perhaps autism. PMID:21482951

3D Maps from Multiple MRI Illustrate Changing Atrophy Patterns as Subjects Progress from MCI to AD

PubMed Central

Whitwell, Jennifer L; Przybelski, Scott; Weigand, Stephen D; Knopman, David S; Boeve, Bradley F; Petersen, Ronald C; Jack, Clifford R

2009-01-01

Summary Mild cognitive impairment (MCI), particularly the amnestic subtype (aMCI), is considered as a transitional stage between normal aging and a diagnosis of clinically probable Alzheimer's disease (AD). The aMCI construct is particularly useful as it provides an opportunity to assess a clinical stage which in most subjects represents prodromal AD. The aim of this study was to assess the progression of cerebral atrophy over multiple serial MRI during the period from aMCI to conversion to AD. Thirty-three subjects were selected that fulfilled clinical criteria for aMCI and had three serial MRI scans: the first scan approximately three years before conversion to AD, the second scan approximately one year before conversion, and the third scan at the time of conversion from aMCI to AD. A group of 33 healthy controls were age and gender-matched to the study cohort. Voxel-based morphometry (VBM) was used to assess patterns of grey matter atrophy in the aMCI subjects at each time-point compared to the control group. Customized templates and prior probability maps were used to avoid normalization and segmentation bias. The pattern of grey matter loss in the aMCI subject scans that were three years before conversion was focused primarily on the medial temporal lobes, including the amygdala, anterior hippocampus and entorhinal cortex, with some additional involvement of the fusiform gyrus, compared to controls. The extent and magnitude of the cerebral atrophy further progressed by the time the subjects were one year before conversion. At this point atrophy in the temporal lobes spread to include the middle temporal gyrus, and extended into more posterior regions of the temporal lobe to include the entire extent of the hippocampus. The parietal lobe also started to become involved. By the time the subjects had converted to a clinical diagnosis of AD the pattern of grey matter atrophy had become still more widespread with more severe involvement of the medial temporal lobes and the temporoparietal association cortices and, for the first time, substantial involvement of the frontal lobes. This pattern of progression fits well with the Braak and Braak neurofibrillary pathological staging scheme in AD. It suggests that the earliest changes occur in the anterior medial temporal lobe and fusiform gyrus, and that these changes occur at least three years before conversion to AD. These results also suggest that 3-dimensional patterns of grey matter atrophy may help to predict the time to conversion in subjects with aMCI. PMID:17533169

Abatement of waste gases and water during the processes of semiconductor fabrication.

PubMed

Wen, Rui-mei; Liang, Jun-wu

2002-10-01

The purpose of this article is to examine the methods and equipment for abating waste gases and water produced during the manufacture of semiconductor materials and devices. Three separating methods and equipment are used to control three different groups of electronic wastes. The first group includes arsine and phosphine emitted during the processes of semiconductor materials manufacture. The abatement procedure for this group of pollutants consists of adding iodates, cupric and manganese salts to a multiple shower tower (MST) structure. The second group includes pollutants containing arsenic, phosphorus, HF, HCl, NO2, and SO3 emitted during the manufacture of semiconductor materials and devices. The abatement procedure involves mixing oxidants and bases in an oval column with a separator in the middle. The third group consists of the ions of As, P and heavy metals contained in the waste water. The abatement procedure includes adding CaCO3 and ferric salts in a flocculation-sedimentation compact device equipment. Test results showed that all waste gases and water after the abatement procedures presented in this article passed the discharge standards set by the State Environmental Protection Administration of China.

White matter microstructure damage in tremor-dominant Parkinson's disease patients.

PubMed

Luo, ChunYan; Song, Wei; Chen, Qin; Yang, Jing; Gong, QiYong; Shang, Hui-Fang

2017-07-01

Resting tremor is one of the cardinal motor features of Parkinson's disease (PD). Several lines of evidence suggest resting tremor may have different underlying pathophysiological processes from those of bradykinesia and rigidity. The current study aims to identify white matter microstructural abnormalities associated with resting tremor in PD. We recruited 60 patients with PD (30 with tremor-dominant PD and 30 with nontremor-dominant PD) and 26 normal controls. All participants underwent clinical assessment and diffusion tensor MRI. We used tract-based spatial statistics to investigate white matter integrity across the entire white matter tract skeleton. Compared with both healthy controls and the nontremor-dominant PD patients, the tremor-dominant PD patients were characterized by increased mean diffusivity (MD) and axial diffusivity (AD) along multiple white matter tracts, mainly involving the cerebello-thalamo-cortical (CTC) pathway. The mean AD value in clusters with significant difference was correlated with resting tremor score in the tremor-dominant PD patients. There was no significant difference between the nontremor-dominant PD patients and controls. Our results support the notion that resting tremor in PD is a distinct condition in which significant microstructural white matter changes exist and provide evidence for the involvement of the CTC in tremor genesis of PD.

Independent Deficits of Visual Word and Motion Processing in Aging and Early Alzheimer's Disease

PubMed Central

Velarde, Carla; Perelstein, Elizabeth; Ressmann, Wendy; Duffy, Charles J.

2013-01-01

We tested whether visual processing impairments in aging and Alzheimer's disease (AD) reflect uniform posterior cortical decline, or independent disorders of visual processing for reading and navigation. Young and older normal controls were compared to early AD patients using psychophysical measures of visual word and motion processing. We find elevated perceptual thresholds for letters and word discrimination from young normal controls, to older normal controls, to early AD patients. Across subject groups, visual motion processing showed a similar pattern of increasing thresholds, with the greatest impact on radial pattern motion perception. Combined analyses show that letter, word, and motion processing impairments are independent of each other. Aging and AD may be accompanied by independent impairments of visual processing for reading and navigation. This suggests separate underlying disorders and highlights the need for comprehensive evaluations to detect early deficits. PMID:22647256

Age-related changes in core body temperature and activity in triple-transgenic Alzheimer’s disease (3xTgAD) mice

PubMed Central

Knight, Elysse M.; Brown, Timothy M.; Gümüsgöz, Sarah; Smith, Jennifer C. M.; Waters, Elizabeth J.; Allan, Stuart M.; Lawrence, Catherine B.

2013-01-01

SUMMARY Alzheimer’s disease (AD) is characterised, not only by cognitive deficits and neuropathological changes, but also by several non-cognitive behavioural symptoms that can lead to a poorer quality of life. Circadian disturbances in core body temperature and physical activity are reported in AD patients, although the cause and consequences of these changes are unknown. We therefore characterised circadian patterns of body temperature and activity in male triple transgenic AD mice (3xTgAD) and non-transgenic (Non-Tg) control mice by remote radiotelemetry. At 4 months of age, daily temperature rhythms were phase advanced and by 6 months of age an increase in mean core body temperature and amplitude of temperature rhythms were observed in 3xTgAD mice. No differences in daily activity rhythms were seen in 4- to 9-month-old 3xTgAD mice, but by 10 months of age an increase in mean daily activity and the amplitude of activity profiles for 3xTgAD mice were detected. At all ages (4–10 months), 3xTgAD mice exhibited greater food intake compared with Non-Tg mice. The changes in temperature did not appear to be solely due to increased food intake and were not cyclooxygenase dependent because the temperature rise was not abolished by chronic ibuprofen treatment. No β-amyloid (Aβ) plaques or neurofibrillary tangles were noted in the hypothalamus of 3xTgAD mice, a key area involved in temperature regulation, although these pathological features were observed in the hippocampus and amygdala of 3xTgAD mice from 10 months of age. These data demonstrate age-dependent changes in core body temperature and activity in 3xTgAD mice that are present before significant AD-related neuropathology and are analogous to those observed in AD patients. The 3xTgAD mouse might therefore be an appropriate model for studying the underlying mechanisms involved in non-cognitive behavioural changes in AD. PMID:22864021

Age-related changes in core body temperature and activity in triple-transgenic Alzheimer's disease (3xTgAD) mice.

PubMed

Knight, Elysse M; Brown, Timothy M; Gümüsgöz, Sarah; Smith, Jennifer C M; Waters, Elizabeth J; Allan, Stuart M; Lawrence, Catherine B

2013-01-01

Alzheimer's disease (AD) is characterised, not only by cognitive deficits and neuropathological changes, but also by several non-cognitive behavioural symptoms that can lead to a poorer quality of life. Circadian disturbances in core body temperature and physical activity are reported in AD patients, although the cause and consequences of these changes are unknown. We therefore characterised circadian patterns of body temperature and activity in male triple transgenic AD mice (3xTgAD) and non-transgenic (Non-Tg) control mice by remote radiotelemetry. At 4 months of age, daily temperature rhythms were phase advanced and by 6 months of age an increase in mean core body temperature and amplitude of temperature rhythms were observed in 3xTgAD mice. No differences in daily activity rhythms were seen in 4- to 9-month-old 3xTgAD mice, but by 10 months of age an increase in mean daily activity and the amplitude of activity profiles for 3xTgAD mice were detected. At all ages (4-10 months), 3xTgAD mice exhibited greater food intake compared with Non-Tg mice. The changes in temperature did not appear to be solely due to increased food intake and were not cyclooxygenase dependent because the temperature rise was not abolished by chronic ibuprofen treatment. No β-amyloid (Aβ) plaques or neurofibrillary tangles were noted in the hypothalamus of 3xTgAD mice, a key area involved in temperature regulation, although these pathological features were observed in the hippocampus and amygdala of 3xTgAD mice from 10 months of age. These data demonstrate age-dependent changes in core body temperature and activity in 3xTgAD mice that are present before significant AD-related neuropathology and are analogous to those observed in AD patients. The 3xTgAD mouse might therefore be an appropriate model for studying the underlying mechanisms involved in non-cognitive behavioural changes in AD.

Pediatric neurology: the diagnostic process.

PubMed

Neville, Brian G R

2013-01-01

Pediatric neurology comprises a very large of number of conditions exhibiting symptoms and signs in several functional domains arising from damage and dysfunction to the developing nervous system. The diagnostic process involves ensuring that data from all possible domains are sought including those that are unaffected. The subsequent analysis involves fitting these data into patterns of classical natural history and rigorous investigation of the aspects that do not appear to fit. There may be a pattern of illness that is immediately recognized or something that is a fairly close fit. However, the aim is to develop a pathogenic sequence for the condition particularly so that conditions that have been lumped together for convenience are separated into distinct disease entities. The major presentations of pediatric neurology of fixed central motor impairments (the cerebral palsies), the epilepsies, and the progressive degenerative diseases are in the process of being split into such pathogenic sequences so that definitive treatments and possible primary prevention can be added to aims of simple diagnostic recognition. Much of this is at an early stage and pediatric neurology is still a young and fast developing specialty. Copyright © 2013 Elsevier B.V. All rights reserved.

Polyphenols in foods are more complex than often thought.

PubMed

Cheynier, Véronique

2005-01-01

Dietary polyphenols show a great diversity of structures, ranging from rather simple molecules (monomers and oligomers) to polymers. Higher-molecular-weight structures (with molecular weights of > 500) are usually designated as tannins, which refers to their ability to interact with proteins. Among them, condensed tannins (proanthocyanidins) are particularly important because of their wide distribution in plants and their contributions to major food qualities. All phenolic compounds are highly unstable and rapidly transformed into various reaction products when the plant cells are damaged (for instance, during food processing), thus adding to the complexity of dietary polyphenol composition. The polyphenol composition of plant-derived foods and beverages depends on that of the raw material used but also on the extraction process and subsequent biochemical and chemical reactions of plant polyphenols. The occurrence of specific tannin-like compounds (ie, thearubigins and theaflavins) arising from enzymatic oxidation is well documented in black tea. Various chemical reactions involving anthocyanins and/or flavanols have been demonstrated to occur during red wine aging. Current knowledge regarding the reaction mechanisms involved in some of these processes and the structures of the resulting products is reviewed. Their effects on organoleptic and nutritional quality are also discussed.

Witten diagrams revisited: the AdS geometry of conformal blocks

DOE PAGES

Hijano, Eliot; Kraus, Per; Perlmutter, Eric; ...

2016-01-25

Here, we develop a new method for decomposing blocks. The steps involved are elementary, requiring no explicit integration, and operate directly in position space. Central to this construction is an appealingly simple answer to the question: what object in AdS computes a conformal block? The answer is a "geodesic Witten diagram", which is essentially an ordinary exchange Witten diagram, except that the cubic vertices are not integrated over all of AdS, but only over bulk geodesics connecting the boundary operators. In particular, we also consider the case of four-point functions of scalar operators, and show how to easily reproduce existingmore » results for the relevant conformal blocks in arbitrary dimension.« less

A stable partitioned FSI algorithm for rigid bodies and incompressible flow. Part II: General formulation

NASA Astrophysics Data System (ADS)

Banks, J. W.; Henshaw, W. D.; Schwendeman, D. W.; Tang, Qi

2017-08-01

A stable partitioned algorithm is developed for fluid-structure interaction (FSI) problems involving viscous incompressible flow and rigid bodies. This added-mass partitioned (AMP) algorithm remains stable, without sub-iterations, for light and even zero mass rigid bodies when added-mass and viscous added-damping effects are large. The scheme is based on a generalized Robin interface condition for the fluid pressure that includes terms involving the linear acceleration and angular acceleration of the rigid body. Added mass effects are handled in the Robin condition by inclusion of a boundary integral term that depends on the pressure. Added-damping effects due to the viscous shear forces on the body are treated by inclusion of added-damping tensors that are derived through a linearization of the integrals defining the force and torque. Added-damping effects may be important at low Reynolds number, or, for example, in the case of a rotating cylinder or rotating sphere when the rotational moments of inertia are small. In this second part of a two-part series, the general formulation of the AMP scheme is presented including the form of the AMP interface conditions and added-damping tensors for general geometries. A fully second-order accurate implementation of the AMP scheme is developed in two dimensions based on a fractional-step method for the incompressible Navier-Stokes equations using finite difference methods and overlapping grids to handle the moving geometry. The numerical scheme is verified on a number of difficult benchmark problems.

Epidemiology and Clinical Features of Atopic Dermatitis in Kerman, a Desert Area of Iran

PubMed Central

Esfandiarpour, Iraj; Sedaghatmanesh, Maryam; Saviz, Mahdieh

2014-01-01

Background Epidemiologic studies of atopic dermatitis (AD) in desert areas are still lacking. Objective The aim of this study was to investigate the epidemiology of AD in children in Kerman city, a desert area in Iran. Methods We evaluated preschool children (age, 2 to 7 years) and primary school students (age, greater than 7 up to 12 years) in Kerman. We selected 865 students to estimate the prevalence and assess other features of AD such as distribution of lesions, personal history, family history of atopy, aggravating factors, associated symptoms, and morphological variants. Results The prevalence of AD was 9.1% in our study population. The prevalence of AD was 9.17% and 9.09% in males and females, respectively. The prevalence of AD in the age range of 2 to 7 years was 13.53% and 8.33% among children aged greater than 7 up to 12 years. In total, 82.27% of the patients were in chronic stage of the disease, and 31.6% had a personal history of other atopic diseases. At least one first-degree family member with atopy was seen in 46.83% of the patients. The most common sites of involvement were the head and neck. The most involved areas in the limbs were extensor surfaces. The most frequent morphological variant of AD was the common type. Conclusion The prevalence of AD in Kerman was higher than in other Iranian cities but lower than that in developed countries. Diversity in the clinical features of AD has been observed among different studies, and the diagnostic criteria of AD should be adapted in proportion to the studied area. PMID:24648683

Anaerobic digestion of food waste: A review focusing on process stability.

PubMed

Li, Lei; Peng, Xuya; Wang, Xiaoming; Wu, Di

2018-01-01

Food waste (FW) is rich in biomass energy, and increasing numbers of national programs are being established to recover energy from FW using anaerobic digestion (AD). However process instability is a common operational issue for AD of FW. Process monitoring and control as well as microbial management can be used to control instability and increase the energy conversion efficiency of anaerobic digesters. Here, we review research progress related to these methods and identify existing limitations to efficient AD; recommendations for future research are also discussed. Process monitoring and control are suitable for evaluating the current operational status of digesters, whereas microbial management can facilitate early diagnosis and process optimization. Optimizing and combining these two methods are necessary to improve AD efficiency. Copyright © 2017 Elsevier Ltd. All rights reserved.

Assessment of socioemotional processes facilitates the distinction between frontotemporal lobar degeneration and Alzheimer's disease.

PubMed

Narme, Pauline; Mouras, Harold; Roussel, Martine; Devendeville, Agnès; Godefroy, Olivier

2013-01-01

We explored the value of a battery of socioemotional tasks for differentiating between frontotemporal lobar degeneration (FTLD) and Alzheimer's disease (AD). Patients with FTLD (n = 13) or AD (n = 13) and healthy controls (n = 26) underwent a neuropsychological assessment and the socioemotional battery (an empathy questionnaire, an emotion recognition task, and theory of mind tasks). Socioemotional processes were markedly impaired in FTLD but relatively unaffected in mild AD. The computed Socioemotional Index discriminated more accurately between FTLD from AD than behavioral and executive assessments did. Furthermore, impairments in socioemotional processes were correlated with indifference to others.

Energy Production and Transmutation of Nuclear Waste by Accelerator Driven Systems

NASA Astrophysics Data System (ADS)

Zhivkov, P. K.

2018-05-01

There is a significant amount of highly radiotoxic long-life nuclear waste (NW) produced by NPP (Nuclear Power Plants). Transmutation is a process which transforms NW into less radiotoxic nuclides with a shorter period of half-life by spallation neutrons or radiative capture of neutrons produced by ADS (Accelerator Driven System). In the processes of transmutation new radioactive nuclides are produced. ADS is big energy consumer equipment. It is a method for production of a high-flux and high-energy neutron field. All these processes occur in ADS simultaneously. ADS is able to transmute actinides and produce energy simultaneously. The article considers the energy production problems in ADS. Several ideas are developed regarding the solution of the global energy supply.

Discourse changes in early Alzheimer disease, mild cognitive impairment, and normal aging.

PubMed

Chapman, Sandra Bond; Zientz, Jennifer; Weiner, Myron; Rosenberg, Roger; Frawley, William; Burns, Mary Hope

2002-01-01

The purpose of this study was to determine the sensitivity of discourse gist measures to the early cognitive-linguistic changes in Alzheimer disease (AD) and in the preclinical stages. Differences in discourse abilities were examined in 25 cognitively normal adults, 24 adults with mild probable AD, and 20 adults with mild cognitive impairment (MCI) at gist and detail levels of discourse processing. The authors found that gist and detail levels of discourse processing were significantly impaired in persons with AD and MCI as compared with normal control subjects. Gist-level discourse processing abilities showed minimal overlap between cognitively normal control subjects and those with mild AD. Moreover, the majority of the persons with MCI performed in the range of AD on gist measures. These findings indicate that discourse gist measures hold promise as a diagnostic complement to enhance early detection of AD. Further studies are needed to determine how early the discourse gist deficits arise in AD.

Deficient symbol processing in Alzheimer disease.

PubMed

Toepper, Max; Steuwe, Carolin; Beblo, Thomas; Bauer, Eva; Boedeker, Sebastian; Thomas, Christine; Markowitsch, Hans J; Driessen, Martin; Sammer, Gebhard

2014-01-01

Symbols and signs have been suggested to improve the orientation of patients suffering from Alzheimer disease (AD). However, there are hardly any studies that confirm whether AD patients benefit from signs or symbols and which symbol characteristics might improve or impede their symbol comprehension. To address these issues, 30 AD patients and 30 matched healthy controls performed a symbol processing task (SPT) with 4 different item categories. A repeated-measures analysis of variance was run to identify impact of different item categories on performance accuracy in both the experimental groups. Moreover, SPT scores were correlated with neuropsychological test scores in a broad range of other cognitive domains. Finally, diagnostic accuracy of the SPT was calculated by a receiver-operating characteristic curve analysis. Results revealed a global symbol processing dysfunction in AD that was associated with semantic memory and executive deficits. Moreover, AD patients showed a disproportional performance decline at SPT items with visual distraction. Finally, the SPT total score showed high sensitivity and specificity in differentiating between AD patients and healthy controls. The present findings suggest that specific symbol features impede symbol processing in AD and argue for a diagnostic benefit of the SPT in neuropsychological assessment.

Involving Latina/o parents in patient-centered outcomes research: Contributions to research study design, implementation and outcomes.

PubMed

Pérez Jolles, Mónica; Martinez, Maria; Garcia, San Juanita; Stein, Gabriela L; Thomas, Kathleen C

2017-10-01

Comparative effectiveness research (CER) is supported by policymakers as a way to provide service providers and patients with evidence-based information to make better health-care decisions and ultimately improve services for patients. However, Latina/o patients are rarely involved as study advisors, and there is a lack of documentation on how their voices contribute to the research process when they are included as collaborators. The purpose of this article was to contribute to the literature by presenting concrete contributions of Latina/o parent involvement to study design, implementation and outcomes in the context of a CER study called Padres Efectivos (Parent Activation). Researchers facilitated a collaborative relationship with parents by establishing a mentor parent group. The contributions of parent involvement in the following stages of the research process are described: (i) proposal development, (ii) implementation of protocols, (iii) analysis plan and (iv) dissemination of results. Mentor parents' contributions helped tailor the content of the intervention to their needs during proposal, increased recruitment, validated the main outcome measure and added two important outcome measures, emphasized the importance of controlling for novice treatment status and developed innovative dissemination strategies. Mentor parents' guidance to the researchers has contributed to reaching recruitment goals, strengthened the study protocol, expanded findings, supported broad ownership of study implications and enriched the overall study data collection efforts. These findings can inform future research efforts seeking an active Latino parent collaboration and the timely incorporation of parent voices in each phase of the research process. © 2017 The Authors Health Expectations Published by John Wiley & Sons Ltd.

The evolution of and challenges for industrial radiation processing—2012

NASA Astrophysics Data System (ADS)

Berejka, A. J.; Cleland, M. R.; Walo, M.

2014-01-01

The evolution of industrial radiation processing is traced from Roentgen's discovery of X-radiation in 1895 by following the development of high current, electron beam accelerators (EB) throughout the twentieth century. Although Becquerel soon followed Roentgen with his discovery of what became to be known as radioactivity, electrical sources for ionizing radiation dominate industrial processing with there being more than ten times as many industrial installations using high current EB equipment than the facilities relying upon large concentrations of radioactive isotopes. In the 1950s, the discovery that ionizing radiation would enhance the value of what has become the world's largest volume commodity plastic, polyethylene (PE), opened the way for full scale commercial use of high current EB equipment. While the crosslinking of the PE insulation on wire became one of the first major industrial applications, other uses of EB processing soon followed. In the 1970s, low-energy, self-shielded EB equipment made the surface curing of inks, coatings and adhesives more industrially viable. In the early part of the twenty-first century, new market applications involving the low-energy EB surface decontamination of packaging materials emerged. This new area poses challenges for the metrology needed to control industrial processes, in that there is limited EB penetration into what have been used as dosimeters by industry. Major industrial use of radiation process is now over 50 years old. Because of the diversity of end-uses and the fact that the use of ionizing radiation in industry is a process technique, it is hard to quantify the value-added to numerous commercial products that benefit from this energy efficient process. It may be in excess of a trillion Euros in value-added to articles of commerce. In this milieu, there are some broad-based opportunities for research which are noted.

Lipoperoxidation is selectively involved in progressive supranuclear palsy.

PubMed

Odetti, P; Garibaldi, S; Norese, R; Angelini, G; Marinelli, L; Valentini, S; Menini, S; Traverso, N; Zaccheo, D; Siedlak, S; Perry, G; Smith, M A; Tabaton, M

2000-05-01

Progressive supranuclear palsy (PSP) is a neurodegenerative disorder characterized by extensive neurofibrillary tangle (NFT) formation and neuronal loss in selective neuronal populations. Currently, no clues to the biological events underlying the pathological process have emerged. In Alzheimer disease (AD), which shares with PSP the occurrence of NFTs, advanced glycation end products (AGEs) as well as oxidation adducts have been found to be increased in association with neurofibrillary pathology. The presence and the amount of lipid and protein oxidation markers, as well as of pyrraline and pentosidine. 2 major AGEs, was assessed by biochemical, immunochemical, and immunocytochemical analysis in midbrain tissue from 5 PSP cases, 6 sporadic AD cases, and 6 age-matched control cases. The levels of 4-hydroxynonenal (HNE) and thiobarbituric acid reactive substances (TBARS), 2 major products of lipid peroxidation, were significantly increased by 1.6-fold (p < 0.04) and 3.9-fold (p < 0.01), respectively, in PSP compared with control tissues, whereas in AD only TBARS were significantly increased. In PSP tissue the intensity of neuronal HNE immunoreactivity was proportional to the extent of abnormal aggregated tau protein. The amount of protein oxidation products and AGEs was instead similar in PSP and control tissues. In AD, a higher but not significant level of pyrraline and pentosidine was measured, whereas the level of carbonyl groups was doubled. These findings indicate that in PSP, unlike in AD, lipid peroxidation is selectively associated with NFT formation. The intraneuronal accumulation of toxic aldehydes may contribute to hamper tau degradation, leading to its aggregation in the PSP specific abnormal filaments.

Imaginary parts of coupled electron and phonon propagators

NASA Astrophysics Data System (ADS)

Schwartzman, K.; Lawrence, W. E.

1988-01-01

Quasiparticle and phonon damping rates due to the electron-phonon and Coulomb interactions are obtained directly from the self-energy formalism of strong-coupling theory. This accounts for all processes involving phonon or quasiparticle decay into a single particle-hole pair, or quasiparticle decay by emission or absorption of a single real phonon. The two quasiparticle decay modes are treated on a common footing, without ad hoc separation, by accounting fully for the dynamics of the phonon propagator and the Coulomb vertex-the latter by expansion of the four-point Coulomb vertex function. The results are shown to be expressible in terms of only the physical (i.e., fully renormalized) energies and coupling constants, and are written in terms of spectral functions such as α2F(ω) and its generalizations. Expansion of these in powers of a phonon linewidth parameter distinguishes (in lowest orders) between quasiparticle decay modes involving real and virtual phonons. However, the simplest prescription for calculating decay rates involves an effective scattering amplitude in which this distinction is not made.

Categorial Compositionality II: Universal Constructions and a General Theory of (Quasi-)Systematicity in Human Cognition

PubMed Central

Phillips, Steven; Wilson, William H.

2011-01-01

A complete theory of cognitive architecture (i.e., the basic processes and modes of composition that together constitute cognitive behaviour) must explain the systematicity property—why our cognitive capacities are organized into particular groups of capacities, rather than some other, arbitrary collection. The classical account supposes: (1) syntactically compositional representations; and (2) processes that are sensitive to—compatible with—their structure. Classical compositionality, however, does not explain why these two components must be compatible; they are only compatible by the ad hoc assumption (convention) of employing the same mode of (concatenative) compositionality (e.g., prefix/postfix, where a relation symbol is always prepended/appended to the symbols for the related entities). Architectures employing mixed modes do not support systematicity. Recently, we proposed an alternative explanation without ad hoc assumptions, using category theory. Here, we extend our explanation to domains that are quasi-systematic (e.g., aspects of most languages), where the domain includes some but not all possible combinations of constituents. The central category-theoretic construct is an adjunction involving pullbacks, where the primary focus is on the relationship between processes modelled as functors, rather than the representations. A functor is a structure-preserving map (or construction, for our purposes). An adjunction guarantees that the only pairings of functors are the systematic ones. Thus, (quasi-)systematicity is a necessary consequence of a categorial cognitive architecture whose basic processes are functors that participate in adjunctions. PMID:21857816

A comprehensive analysis on preservation patterns of gene co-expression networks during Alzheimer's disease progression.

PubMed

Ray, Sumanta; Hossain, Sk Md Mosaddek; Khatun, Lutfunnesa; Mukhopadhyay, Anirban

2017-12-20

Alzheimer's disease (AD) is a chronic neuro-degenerative disruption of the brain which involves in large scale transcriptomic variation. The disease does not impact every regions of the brain at the same time, instead it progresses slowly involving somewhat sequential interaction with different regions. Analysis of the expression patterns of the genes in different regions of the brain influenced in AD surely contribute for a enhanced comprehension of AD pathogenesis and shed light on the early characterization of the disease. Here, we have proposed a framework to identify perturbation and preservation characteristics of gene expression patterns across six distinct regions of the brain ("EC", "HIP", "PC", "MTG", "SFG", and "VCX") affected in AD. Co-expression modules were discovered considering a couple of regions at once. These are then analyzed to know the preservation and perturbation characteristics. Different module preservation statistics and a rank aggregation mechanism have been adopted to detect the changes of expression patterns across brain regions. Gene ontology (GO) and pathway based analysis were also carried out to know the biological meaning of preserved and perturbed modules. In this article, we have extensively studied the preservation patterns of co-expressed modules in six distinct brain regions affected in AD. Some modules are emerged as the most preserved while some others are detected as perturbed between a pair of brain regions. Further investigation on the topological properties of preserved and non-preserved modules reveals a substantial association amongst "betweenness centrality" and "degree" of the involved genes. Our findings may render a deeper realization of the preservation characteristics of gene expression patterns in discrete brain regions affected by AD.

The relationship between stress and Alzheimer's disease.

PubMed

Justice, Nicholas J

2018-02-01

Stress is critically involved in the development and progression of disease. From the stress of undergoing treatments to facing your own mortality, the physiological processes that stress drives have a serious detrimental effect on the ability to heal, cope and maintain a positive quality of life. This is becoming increasingly clear in the case of neurodegenerative diseases. Neurodegenerative diseases involve the devastating loss of cognitive and motor function which is stressful in itself, but can also disrupt neural circuits that mediate stress responses. Disrupting these circuits produces aberrant emotional and aggressive behavior that causes long-term care to be especially difficult. In addition, added stress drives progression of the disease and can exacerbate symptoms. In this review, I describe how neural and endocrine pathways activated by stress interact with ongoing neurodegenerative disease from both a clinical and experimental perspective.

Re-engineering the mission life cycle with ABC and IDEF

NASA Technical Reports Server (NTRS)

Mandl, Daniel; Rackley, Michael; Karlin, Jay

1994-01-01

The theory behind re-engineering a business process is to remove the non-value added activities thereby lowering the process cost. In order to achieve this, one must be able to identify where the non-value added elements are located which is not a trivial task. This is because the non-value added elements are often hidden in the form of overhead and/or pooled resources. In order to be able to isolate these non-value added processes from among the other processes, one must first decompose the overall top level process into lower layers of sub-processes. In addition, costing data must be assigned to each sub-process along with the value the sub-process adds towards the final product. IDEF0 is a Federal Information Processing Standard (FIPS) process-modeling tool that allows for this functional decomposition through structured analysis. In addition, it illustrates the relationship of the process and the value added to the product or service. The value added portion is further defined in IDEF1X which is an entity relationship diagramming tool. The entity relationship model is the blueprint of the product as it moves along the 'assembly line' and therefore relates all of the parts to each other and the final product. It also relates the parts to the tools that produce the product and all of the paper work that is used in their acquisition. The use of IDEF therefore facilitates the use of Activity Based Costing (ABC). ABC is an essential method in a high variety, product-customizing environment, to facilitate rapid response to externally caused change. This paper describes the work being done in the Mission Operations Division to re-engineer the development and operation life cycle of Mission Operations Centers using these tools.

Visual discrimination predicts naming and semantic association accuracy in Alzheimer disease.

PubMed

Harnish, Stacy M; Neils-Strunjas, Jean; Eliassen, James; Reilly, Jamie; Meinzer, Marcus; Clark, John Greer; Joseph, Jane

2010-12-01

Language impairment is a common symptom of Alzheimer disease (AD), and is thought to be related to semantic processing. This study examines the contribution of another process, namely visual perception, on measures of confrontation naming and semantic association abilities in persons with probable AD. Twenty individuals with probable mild-moderate Alzheimer disease and 20 age-matched controls completed a battery of neuropsychologic measures assessing visual perception, naming, and semantic association ability. Visual discrimination tasks that varied in the degree to which they likely accessed stored structural representations were used to gauge whether structural processing deficits could account for deficits in naming and in semantic association in AD. Visual discrimination abilities of nameable objects in AD strongly predicted performance on both picture naming and semantic association ability, but lacked the same predictive value for controls. Although impaired, performance on visual discrimination tests of abstract shapes and novel faces showed no significant relationship with picture naming and semantic association. These results provide additional evidence to support that structural processing deficits exist in AD, and may contribute to object recognition and naming deficits. Our findings suggest that there is a common deficit in discrimination of pictures using nameable objects, picture naming, and semantic association of pictures in AD. Disturbances in structural processing of pictured items may be associated with lexical-semantic impairment in AD, owing to degraded internal storage of structural knowledge.

Study on the optimal moisture adding rate of brown rice during germination by using segmented moisture conditioning method.

PubMed

Cao, Yinping; Jia, Fuguo; Han, Yanlong; Liu, Yang; Zhang, Qiang

2015-10-01

The aim of this study was to find out the optimal moisture adding rate of brown rice during the process of germination. The process of water addition in brown rice could be divided into three stages according to different water absorption speeds in soaking process. Water was added with three different speeds in three stages to get the optimal water adding rate in the whole process of germination. Thus, the technology of segmented moisture conditioning which is a method of adding water gradually was put forward. Germinated brown rice was produced by using segmented moisture conditioning method to reduce the loss of water-soluble nutrients and was beneficial to the accumulation of gamma aminobutyric acid. The effects of once moisture adding amount in three stages on the gamma aminobutyric acid content in germinated brown rice and germination rate of brown rice were investigated by using response surface methodology. The optimum process parameters were obtained as follows: once moisture adding amount of stage I with 1.06 %/h, once moisture adding amount of stage II with 1.42 %/h and once moisture adding amount of stage III with 1.31 %/h. The germination rate under the optimum parameters was 91.33 %, which was 7.45 % higher than that of germinated brown rice produced by soaking method (84.97 %). The content of gamma aminobutyric acid in germinated brown rice under the optimum parameters was 29.03 mg/100 g, which was more than two times higher than that of germinated brown rice produced by soaking method (12.81 mg/100 g). The technology of segmented moisture conditioning has potential applications for studying many other cereals.

Role of Sirt1 during the ageing process: relevance to protection of synapses in the brain.

PubMed

Godoy, Juan A; Zolezzi, Juan M; Braidy, Nady; Inestrosa, Nibaldo C

2014-12-01

Ageing is a stochastic process associated with a progressive decline in physiological functions which predispose to the pathogenesis of several neurodegenerative diseases. The intrinsic complexity of ageing remains a significant challenge to understand the cause of this natural phenomenon. At the molecular level, ageing is thought to be characterized by the accumulation of chronic oxidative damage to lipids, proteins and nucleic acids caused by free radicals. Increased oxidative stress and misfolded protein formations, combined with impaired compensatory mechanisms, may promote neurodegenerative disorders with age. Nutritional modulation through calorie restriction has been shown to be effective as an anti-ageing factor, promoting longevity and protecting against neurodegenerative pathology in yeast, nematodes and murine models. Calorie restriction increases the intracellular levels of the essential pyridine nucleotide, nicotinamide adenine dinucleotide (NAD(+)), a co-substrate for the sirtuin 1 (Sirt1, silent mating-type information regulator 2 homolog 1) activity and a cofactor for oxidative phosphorylation and ATP synthesis. Promotion of intracellular NAD(+) anabolism is speculated to induce neuroprotective effects against amyloid-β-peptide (Aβ) toxicity in some models for Alzheimer's disease (AD). The NAD(+)-dependent histone deacetylase, Sirt1, has been implicated in the ageing process. Sirt1 serves as a deacetylase for numerous proteins involved in several cellular pathways, including stress response and apoptosis, and plays a protective role in neurodegenerative disorders, such as AD.

C145 as a short-latency electrophysiological index of cognitive compensation in Alzheimer's disease

PubMed Central

Chapman, Robert M.; Porsteinsson, Anton P.; Gardner, Margaret N.; Mapstone, Mark; McCrary, John W.; Sandoval, Tiffany C.; Guillily, Maria D.; DeGrush, Elizabeth; Reilly, Lindsey A.

2012-01-01

Brain plasticity and cognitive compensation in the elderly are of increasing interest, and Alzheimer's disease (AD) offers an opportunity to elucidate how the brain may overcome damage. We provide neurophysiological evidence of a short-latency ERP component (C145) linked to stimulus relevancy that may reflect cognitive compensation in early-stage Alzheimer's disease (AD). Thirty-six subjects with early-stage, mild AD and 36 like-aged normal elderly (Controls) had their EEG recorded while performing our Number-Letter task, a cognitive/perceptual paradigm that manipulates stimulus relevancies. ERP components, including C145, were extracted from ERPs using Principal Components Analysis. C145 amplitudes and spatial distributions were compared among Controls, AD subjects with high performance on the Number-Letter task, and AD subjects with low performance. Compared to AD subjects, Control subjects showed enhanced C145 processing of visual stimuli in the occipital region where differential processing of relevant stimuli occurred. AD high performers recruited central brain areas in processing task relevancy. Controls and AD low performers did not show a significant task relevancy effect in these areas. We conclude that short-latency ERP components can detect electrophysiological differences in early-stage AD that reflect altered cognition. Differences in C145 amplitudes between AD and normal elderly groups regarding brain locations and types of task effects suggest compensatory mechanisms can occur in the AD brain to overcome loss of normal functionality, and this early compensation may have a profound effect on the cognitive efficiency of AD individuals. PMID:22886016

Historical Y. pestis Genomes Reveal the European Black Death as the Source of Ancient and Modern Plague Pandemics.

PubMed

Spyrou, Maria A; Tukhbatova, Rezeda I; Feldman, Michal; Drath, Joanna; Kacki, Sacha; Beltrán de Heredia, Julia; Arnold, Susanne; Sitdikov, Airat G; Castex, Dominique; Wahl, Joachim; Gazimzyanov, Ilgizar R; Nurgaliev, Danis K; Herbig, Alexander; Bos, Kirsten I; Krause, Johannes

2016-06-08

Ancient DNA analysis has revealed an involvement of the bacterial pathogen Yersinia pestis in several historical pandemics, including the second plague pandemic (Europe, mid-14(th) century Black Death until the mid-18(th) century AD). Here we present reconstructed Y. pestis genomes from plague victims of the Black Death and two subsequent historical outbreaks spanning Europe and its vicinity, namely Barcelona, Spain (1300-1420 cal AD), Bolgar City, Russia (1362-1400 AD), and Ellwangen, Germany (1485-1627 cal AD). Our results provide support for (1) a single entry of Y. pestis in Europe during the Black Death, (2) a wave of plague that traveled toward Asia to later become the source population for contemporary worldwide epidemics, and (3) the presence of an historical European plague focus involved in post-Black Death outbreaks that is now likely extinct. Copyright © 2016 Elsevier Inc. All rights reserved.

Deep brain stimulation for the treatment of Alzheimer disease and dementias.

PubMed

Laxton, Adrian W; Lozano, Andres M

2013-01-01

To review the use of deep brain stimulation (DBS) for treatment of dementia. A PubMed literature search was conducted to identify all studies that have investigated the use of DBS for treatment of dementia. Three studies examined the use of DBS for dementia. One study involved fornix DBS for Alzheimer disease (AD), and two studies involved DBS of the nucleus basalis of Meynert, one to treat AD and one to treat Parkinson disease dementia. Evidence for the use of DBS to treat dementia is preliminary and limited. Fornix and nucleus basalis of Meynert DBS can influence activity in the pathologic neural circuits that underlie AD and Parkinson disease dementia. Further investigation into the potential clinical effects of DBS for dementia is warranted. Copyright © 2013 Elsevier Inc. All rights reserved.

Clinical applications of cognitive event-related potentials in Alzheimer's disease.

PubMed

Olichney, John M; Hillert, Dieter G

2004-02-01

This article has reviewed several abnormalities in the cognitive ERPs of AD patients. These abnormalities are prominent from latencies of approximately 200 msec and later. In contrast, sensory-dependent evoked potentials, such as N100, are generally normal in AD. This finding is as one familiar with the neuropathology of AD would predict. Predilection sites in early AD include the medial temporal lobe, other limbic areas, and multimodal association cortices with sparing of primary sensory areas. Unimodal association cortex is involved in AD, but not as heavily as multimodal cortex. Particular advantages of studying a given ERP paradigm or component depend largely on the specific application or hypothesis being tested. A P300 paradigm can be useful in detecting a disorder of attention or in quantifying the effects of drugs that improve attention, such as the cholinesterase inhibitors. For the early diagnosis of AD or other memory disorders, a word-repetition paradigm with an explicit recognition task or one that fosters associative learning would be recommended. This article has discussed potential use of N400 in tracking disease progression. ERPs provide a flexible and powerful technique, with superb temporal resolution, which can be used as a probe into subtle "subclinical" abnormalities of cognitive processes. Despite being applied to AD for about 25 years since the early P300 studies, the full potential of ERPs in helping diagnose and treat AD patients has yet to be realized. In this era of rapidly evolving brain-imaging techniques, electrophysiologic data are important in advancing understanding of cognition. Brain-mapping techniques that can inform where and when key cognitive processes occur are finally emerging. A final example of potential clinical application of cognitive ERPs is in the development of rational combinational treatment of cognitive enhancing drugs. Along these lines, P300 investigations in epilepsy proved helpful in ranking the cognitive side effects of anticonvulsant drugs. Drug studies that use 2 x 2 combinational designs, which compare the effects of drug A, drug B, with A + B, are currently prohibitively expensive for full-scale clinical trials in AD. It is likely that precise ERP measures could hasten drug development in several ways. Smaller samples could be used, at lower cost, to test the cognitive effects of each specific drug combination. Optimal doses of combinational therapy perhaps could be identified by repeated within-subject ERP measures. Longitudinal changes in the ERP hold promise as a marker of individual responsivity to a particular agent, which could have diagnostic utility (eg, testing response to cholinergic or dopaminergic therapy). This horizon and many others remain wide open for well-planned explorations.

Crocin improved amyloid beta induced long-term potentiation and memory deficits in the hippocampal CA1 neurons in freely moving rats.

PubMed

Hadipour, Mohammadmehdi; Kaka, Gholamreza; Bahrami, Farideh; Meftahi, Gholam Hossein; Pirzad Jahromi, Gila; Mohammadi, Alireza; Sahraei, Hedayat

2018-05-01

Extracellular beta-amyloid (Aβ) accumulation and deposition is the main factor, which causes synaptic loss and eventually cells death in Alzheimer's disease (AD). Memory loss and long-term potentiation (LTP) dysfunction in the hippocampus are involved in the AD. The involvement of crocin, as the main and active constituent of saffron extract in learning and memory processes, has been proposed. Here we investigated the probable therapeutic effect of crocin on memory, LTP, and neuronal apoptosis using in vivo Aβ models of the AD. The Aβ peptide (1-42) was bilaterally administered into the frontal-cortex using stereotaxic apparatus. Five hours after surgery, rats were given intraperitoneal crocin (30 mg/kg) daily, which repeated for 12 days. Barnes maze results showed that administration of crocin significantly improves spatial memory indicators such as latency time to achieving the target hole and the number of errors when compared to Aβ-group. Passive avoidance test revealed that crocin significantly increased the step-through-latency compared to Aβ-treated alone. These learning deficits in Aβ-treated animals correlated with a reduction of LTP in hippocampal CA1 synapses in freely moving rats, which crocin improved population spike amplitude and mean field excitatory postsynaptic potentials (fEPSP) slope reduction induced by Aβ. Neuronal apoptosis was detected by TUNEL assay and the expression levels of c-Fos proteins were examined by Western blotting. Crocin significantly reduced the number of TUNEL-positive cells in the CA1 region and decreased c-Fos in the hippocampus compared to Aβ-group. In vivo Aβ treatment altered significantly the electrophysiological properties of CA1 neurons and crocin further confirmed a neuroprotective action against Aβ toxicity. © 2018 Wiley Periodicals, Inc.

78 FR 24673 - Airworthiness Directives; The Boeing Company Airplanes

Federal Register 2010, 2011, 2012, 2013, 2014

2013-04-26

... involving lithium ion battery failures that resulted in release of flammable electrolytes, heat damage, and... prompted by recent incidents involving lithium ion battery failures that resulted in release of flammable... modification of the battery system, or other actions. That AD resulted from recent incidents involving lithium...

78 FR 12231 - Airworthiness Directives; The Boeing Company Airplanes

Federal Register 2010, 2011, 2012, 2013, 2014

2013-02-22

... actions. This AD was prompted by recent incidents involving lithium ion battery failures that resulted in... recent incidents involving lithium ion battery failures that resulted in release of flammable... adoption of this rule because of recent incidents involving lithium ion battery failures that resulted in...

Cognitive load, stress, and disinhibited eating.

PubMed

Lattimore, Paul; Maxwell, Linda

2004-11-01

The impact of cognitive distraction on eating behaviour was examined in restrained and unrestrained eaters. It was predicted that restrained eaters would eat more than unrestrained eaters following high cognitive load when it involves processing of ego-threat information independent of self-reported anxiety. There were 119 female participants randomly allocated to one of four experimental conditions whereby cognitive load and ego threat were manipulated using modified colour-naming Stroop (CNS) tasks. Anxiety ratings were made prior to and following experimental tasks. After performing Stroop tasks, participants consumed snack foods ad libitum. Restrained eaters consumed significantly more food when high cognitive load was ego threatening than when it involved processing and memorisation of colour nouns and consumed significantly more than unrestrained eaters in a high cognitive load ego-threat condition. Posttask anxiety was greater than baseline across all conditions. Task difficulty was greater under high cognitive load than low cognitive load as indicated by Stroop response times. These results indicated that the escape theory of disinhibited eating is conceptually subsumed by a more generalisable limited cognitive capacity model.

Quantitation of substance-P and its metabolites in plasma and synovial fluid from patients with arthritis.

PubMed

Joyce, T J; Yood, R A; Carraway, R E

1993-09-01

Substance-P (SP) and its metabolites, SP-(1-7) and SP-(5-11), were quantitated in arthritic synovial fluids and plasma using a validated procedure. This process involved collection into appropriate enzyme inhibitors, extraction with acid-acetone, high pressure liquid chromatography, and RIA using region-specific antisera. Our results demonstrate that the levels of authentic SP in these fluids are less than 3.5 pmol/L, which is 50- to 10,000-fold less than those previously reported by others. These discrepant findings were not attributable to degradation, because added SP was recovered in good yield, and the measured levels of the metabolites SP-(1-7) and SP-(5-11) were also extremely low. In search of an explanation, we noted that many of the earlier reports involved direct assay of these fluids (without extraction and chromatography). Further work indicated that proteolytic enzymes (e.g. protease 24.11) present in these unextracted fluids can give rise to artifactually high SP measurements. We conclude that if SP is released within the joint space and if it participates in the inflammatory reaction and/or healing process, it most likely does so in a local fashion, which would not involve its accumulation in synovial fluid or plasma.

Adenovirus vector induced innate immune responses: impact upon efficacy and toxicity in gene therapy and vaccine applications.

PubMed

Hartman, Zachary C; Appledorn, Daniel M; Amalfitano, Andrea

2008-03-01

Extensively characterized, modified, and employed for a variety of purposes, adenovirus (Ad) vectors are generally regarded as having great potential by many applied virologists who wish to manipulate and use viral biology to achieve beneficial clinical outcomes. Despite widespread functional prominence and utility (i.e., Ad-based clinical trials have begun to progress to critical Phase III levels, it has recently become apparent that investigations regarding the innate immune response to Ads may reveal not only reasons behind previous failures, but also reveal novel insights that will allow for safer, more efficacious uses of this important gene transfer platform. Insights gained by the exploration of Ad induced innate immune responses will likely be most important to the fields of vaccine development, since Ad-based vaccines are regarded as one of the more promising vaccine platforms in development today. Adenovirus is currently known to interact with several different extracellular, intracellular, and membrane-bound innate immune sensing systems. Past and recent studies involving manipulation of the Ad infectious cycle as well as use of different mutants have shed light on some of the initiation mechanisms underlying Ad induced immune responses. More recent studies using microarray-based analyses, genetically modified cell lines and/or mouse mutants, and advanced generation Ad vectors have revealed important new insights into the scope and mechanism of this cellular defensive response. This review is an attempt to synthesize these studies, update Ad biologists to the current knowledge surrounding these increasingly important issues, as well as highlight areas where future research should be directed. It should also serve as a sobering reality to researchers exploring the use of any gene transfer vector, as to the complexities potentially involved when contemplating use of such vectors for human applications.

Adenovirus vector induced Innate Immune responses: Impact upon efficacy and toxicity in gene therapy and vaccine applications

PubMed Central

Hartman, Zachary C.; Appledorn, Daniel M.; Amalfitano, Andrea

2013-01-01

Extensively characterized, modified, and employed for a variety of purposes, Adenovirus (Ad) vectors are generally regarded as having great potential by many applied virologists who wish to manipulate and use viral biology to achieve beneficial clinical outcomes. Despite widespread functional prominence and utility, (i.e.: Ad based clinical trials have begun to progress to critical Phase III levels, it has recently become apparent that investigations regarding the innate immune response to Ads may reveal not only reasons behind previous failures, but also reveal novel insights that will allow for safer, more efficacious uses of this important gene transfer platform. Insights gained by the exploration of Ad induced innate immune responses will likely be most important to the fields of vaccine development, since Ad based vaccines are highly acknowledged as one of the more promising vaccine platforms in development today. Adenovirus is currently known to interact with several different extracellular, intracellular, and membrane bound innate immune sensing systems. Past and recent studies involving manipulation of the Ad infectious cycle as well as use of different mutants have shed light on some of the initiation mechanisms underlying Ad induced immune responses. More recent studies using microarray based analyses, genetically modified cell lines and/or mouse mutants, and advanced generation Ad vectors have revealed important new insights into the scope and mechanism of this cellular defensive response. This review is an attempt to synthesize these studies, update Ad biologists to the current knowledge surrounding these increasingly important issues, as well point areas where future research should be directed. It should also serve as a sobering reality to researchers exploring the use of any gene transfer vector, as to the complexities potentially involved when contemplating use of such vectors for human applications. PMID:18036698

The Principal Axis Approach to Value-Added Calculation

ERIC Educational Resources Information Center

He, Qingping; Tymms, Peter

2014-01-01

The assessment of the achievement of students and the quality of schools has drawn increasing attention from educational researchers, policy makers, and practitioners. Various test-based accountability and feedback systems involving the use of value-added techniques have been developed for evaluating the effectiveness of individual teaching…

A stable partitioned FSI algorithm for rigid bodies and incompressible flow. Part I: Model problem analysis

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

Banks, J. W.; Henshaw, W. D.; Schwendeman, D. W.

A stable partitioned algorithm is developed for fluid-structure interaction (FSI) problems involving viscous incompressible flow and rigid bodies. This added-mass partitioned (AMP) algorithm remains stable, without sub-iterations, for light and even zero mass rigid bodies when added-mass and viscous added-damping effects are large. The scheme is based on a generalized Robin interface condition for the fluid pressure that includes terms involving the linear acceleration and angular acceleration of the rigid body. Added mass effects are handled in the Robin condition by inclusion of a boundary integral term that depends on the pressure. Added-damping effects due to the viscous shear forcesmore » on the body are treated by inclusion of added-damping tensors that are derived through a linearization of the integrals defining the force and torque. Added-damping effects may be important at low Reynolds number, or, for example, in the case of a rotating cylinder or rotating sphere when the rotational moments of inertia are small. In this second part of a two-part series, the general formulation of the AMP scheme is presented including the form of the AMP interface conditions and added-damping tensors for general geometries. A fully second-order accurate implementation of the AMP scheme is developed in two dimensions based on a fractional-step method for the incompressible Navier-Stokes equations using finite difference methods and overlapping grids to handle the moving geometry. Here, the numerical scheme is verified on a number of difficult benchmark problems.« less

A stable partitioned FSI algorithm for rigid bodies and incompressible flow. Part I: Model problem analysis

DOE PAGES

Banks, J. W.; Henshaw, W. D.; Schwendeman, D. W.; ...

2017-01-20

A stable partitioned algorithm is developed for fluid-structure interaction (FSI) problems involving viscous incompressible flow and rigid bodies. This added-mass partitioned (AMP) algorithm remains stable, without sub-iterations, for light and even zero mass rigid bodies when added-mass and viscous added-damping effects are large. The scheme is based on a generalized Robin interface condition for the fluid pressure that includes terms involving the linear acceleration and angular acceleration of the rigid body. Added mass effects are handled in the Robin condition by inclusion of a boundary integral term that depends on the pressure. Added-damping effects due to the viscous shear forcesmore » on the body are treated by inclusion of added-damping tensors that are derived through a linearization of the integrals defining the force and torque. Added-damping effects may be important at low Reynolds number, or, for example, in the case of a rotating cylinder or rotating sphere when the rotational moments of inertia are small. In this second part of a two-part series, the general formulation of the AMP scheme is presented including the form of the AMP interface conditions and added-damping tensors for general geometries. A fully second-order accurate implementation of the AMP scheme is developed in two dimensions based on a fractional-step method for the incompressible Navier-Stokes equations using finite difference methods and overlapping grids to handle the moving geometry. Here, the numerical scheme is verified on a number of difficult benchmark problems.« less

Association of apolipoprotein E allele {epsilon}4 with late-onset sporadic Alzheimer`s disease

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

Lucotte, G.; David, F.; Berriche, S.

1994-09-15

Apolipoprotein E, type {epsilon}4 allele (ApoE {epsilon}4), is associated with late-onset sporadic Alzheimer`s disease (AD) in French patients. The association is highly significant (0.45 AD versus 0.12 controls for {epsilon}4 allele frequencies). These data support the involvement of ApoE {epsilon}4 allele as a very important risk factor for the clinical expression of AD. 22 refs., 1 fig., 3 tabs.

Leader genes in osteogenesis: a theoretical study.

PubMed

Orlando, Bruno; Giacomelli, Luca; Ricci, Massimiliano; Barone, Antonio; Covani, Ugo

2013-01-01

Little is still known about the molecular mechanisms involved in the process of osteogenesis. In this paper, the leader genes approach, a new bioinformatics method which has already been experimentally validated, is adopted in order to identify the genes involved in human osteogenesis. Interactions among genes are then calculated and genes are ranked according to their relative importance in this process. In total, 167 genes were identified as being involved in osteogenesis. Genes were divided into 4 groups, according to their main function in the osteogenic processes: skeletal development; cell adhesion and proliferation; ossification; and calcium ion binding. Seven genes were consistently identified as leader genes (i.e. the genes with the greatest importance in osteogenesis), while 14 were found to have slightly less importance (class B genes). It was interesting to notice that the larger part of leader and class B genes belonged to the cell adhesion and proliferation or to the ossification sub-groups. This finding suggested that these two particular sub-processes could play a more important role in osteogenesis. Moreover, among the 7 leader genes, it is interesting to notice that RUNX2, BMP2, SPARC, PTH play a direct role in bone formation, while the 3 other leader genes (VEGF, IL6, FGF2) seem to be more connected with an angiogenetic process. Twenty-nine genes have no known interactions (orphan genes). From these results, it may be possible to plan an ad hoc experimentation, for instance by microarray analyses, focused on leader, class B and orphan genes, with the aim to shed new light on the molecular mechanisms underlying osteogenesis. Copyright © 2012 Elsevier Ltd. All rights reserved.

The Role of Clinical Proteomics, Lipidomics, and Genomics in the Diagnosis of Alzheimer's Disease.

PubMed

Martins, Ian James

2016-03-31

The early diagnosis of Alzheimer's disease (AD) has become important to the reversal and treatment of neurodegeneration, which may be relevant to premature brain aging that is associated with chronic disease progression. Clinical proteomics allows the detection of various proteins in fluids such as the urine, plasma, and cerebrospinal fluid for the diagnosis of AD. Interest in lipidomics has accelerated with plasma testing for various lipid biomarkers that may with clinical proteomics provide a more reproducible diagnosis for early brain aging that is connected to other chronic diseases. The combination of proteomics with lipidomics may decrease the biological variability between studies and provide reproducible results that detect a community's susceptibility to AD. The diagnosis of chronic disease associated with AD that now involves genomics may provide increased sensitivity to avoid inadvertent errors related to plasma versus cerebrospinal fluid testing by proteomics and lipidomics that identify new disease biomarkers in body fluids, cells, and tissues. The diagnosis of AD by various plasma biomarkers with clinical proteomics may now require the involvement of lipidomics and genomics to provide interpretation of proteomic results from various laboratories around the world.

Methylglyoxal induces tau hyperphosphorylation via promoting AGEs formation.

PubMed

Li, Xiao-Hong; Xie, Jia-Zhao; Jiang, Xia; Lv, Bing-Ling; Cheng, Xiang-Shu; Du, Lai-Ling; Zhang, Jia-Yu; Wang, Jian-Zhi; Zhou, Xin-Wen

2012-12-01

The hyperphosphorylated tau is a major protein component of neurofibrillary tangle, which is one of hallmarks of Alzheimer's disease (AD). While the level of methylglyoxal (MG) is significantly increased in the AD brains, the role of MG in tau phosphorylation is still not reported. Here, we found that MG could induce tau hyperphosphorylation at multiple AD-related sites in neuroblastoma 2a cells under maintaining normal cell viability. MG treatment increased the level of advanced glycation end products (AGEs) and the receptor of AGEs (RAGE). Glycogen synthesis kinase-3β (GSK-3β) and p38 MAPK were activated, whereas the level and activity of JNK, Erk1/2, cdk5, and PP2A were not altered after MG treatment. Simultaneous inhibition of GSK-3β or p38 attenuated the MG-induced tau hyperphosphorylation. Aminoguanidine, a blocker of AGEs formation, could effectively reverse the MG-induced tau hyperphosphorylation. These data suggest that MG induces AD-like tau hyperphosphorylation through AGEs formation involving RAGE up-regulation and GSK-3β activation and p38 activation is also partially involved in MG-induced tau hyperphosphorylation. Thus, targeting MG may be a promising therapeutic strategy to prevent AD-like tau hyperphosphorylation.

Association between Mitofusin 2 Gene Polymorphisms and Late-Onset Alzheimer's Disease in the Korean Population

PubMed Central

Kim, Young Jong; Park, Jin Kyung; Kang, Won Sub; Kim, Su Kang; Han, Changsu; Na, Hae Ri; Park, Hae Jeong; Kim, Jong Woo; Kim, Young Youl; Park, Moon Ho

2017-01-01

Objective Mitochondrial dysfunction is a prominent and early feature of Alzheimer's disease (AD). The morphologic changes observed in the AD brain could be caused by a failure of mitochondrial fusion mechanisms. The aim of this study was to investigate whether genetic polymorphisms of two genes involved in mitochondrial fusion mechanisms, optic atrophy 1 (OPA1) and mitofusin 2 (MFN2), were associated with AD in the Korean population by analyzing genotypes and allele frequencies. Methods One coding single nucleotide polymorphism (SNP) in the MFN2, rs1042837, and two coding SNPs in the OPA1, rs7624750 and rs9851685, were compared between 165 patients with AD (83 men and 82 women, mean age 72.3±4.41) and 186 healthy control subjects (82 men and 104 women, mean age 76.5±5.98). Results Among these three SNPs, rs1042837 showed statistically significant differences in allele frequency, and genotype frequency in the co-dominant 1 model and in the dominant model. Conclusion These results suggest that the rs1042837 polymorphism in MFN2 may be involved in the pathogenesis of AD. PMID:28096879

Design of production process main shaft process with lean manufacturing to improve productivity

NASA Astrophysics Data System (ADS)

Siregar, I.; Nasution, A. A.; Andayani, U.; Anizar; Syahputri, K.

2018-02-01

This object research is one of manufacturing companies that produce oil palm machinery parts. In the production process there is delay in the completion of the Main shaft order. Delays in the completion of the order indicate the low productivity of the company in terms of resource utilization. This study aimed to obtain a draft improvement of production processes that can improve productivity by identifying and eliminating activities that do not add value (non-value added activity). One approach that can be used to reduce and eliminate non-value added activity is Lean Manufacturing. This study focuses on the identification of non-value added activity with value stream mapping analysis tools, while the elimination of non-value added activity is done with tools 5 whys and implementation of pull demand system. Based on the research known that non-value added activity on the production process of the main shaft is 9,509.51 minutes of total lead time 10,804.59 minutes. This shows the level of efficiency (Process Cycle Efficiency) in the production process of the main shaft is still very low by 11.89%. Estimation results of improvement showed a decrease in total lead time became 4,355.08 minutes and greater process cycle efficiency that is equal to 29.73%, which indicates that the process was nearing the concept of lean production.

[Health impact assessment of occupational health policy reform at a multinational chemical company in Japan].

PubMed

Fujino, Yoshihisa; Nagata, Tomohisa; Kuroki, Naomi; Dohi, Seitaro; Uehara, Masamichi; Oyama, Ichiro; Kajiki, Shigeyuki; Mori, Koji

2009-09-01

A health impact assessment (HIA) was conducted to identify potential health impacts arising from policy reform of occupational health and safety at S-chemical company, a multinational global company that employs about 13,000 workers. A multidisciplinary team of health professionals including occupational physicians, an epidemiologist, and public health researchers oversaw the HIA. A project manager from S-company was also involved in the whole HIA process. A literature review, profiling using annual health examination data and interviews with stakeholders and key informants were undertaken in order to identify possible impacts. A range of positive and negative health impacts were identified and develop recommendations for implementation of the new occupational health policy were proposed. The HIA added value to the planning process for the occupational health policy reform.

17 CFR 240.17Ad-2 - Turnaround, processing, and forwarding of items.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 17 Commodity and Securities Exchanges 3 2011-04-01 2011-04-01 false Turnaround, processing, and forwarding of items. 240.17Ad-2 Section 240.17Ad-2 Commodity and Securities Exchanges SECURITIES AND EXCHANGE... be filed with the Comptroller of the Currency shall be filed with the Office of the Comptroller of...

17 CFR 240.17Ad-2 - Turnaround, processing, and forwarding of items.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 17 Commodity and Securities Exchanges 3 2010-04-01 2010-04-01 false Turnaround, processing, and forwarding of items. 240.17Ad-2 Section 240.17Ad-2 Commodity and Securities Exchanges SECURITIES AND EXCHANGE... be filed with the Comptroller of the Currency shall be filed with the Office of the Comptroller of...

Silicon and germanium nanoparticles with tailored surface chemistry as novel inorganic fiber brightening agents.

PubMed

Deb-Choudhury, Santanu; Prabakar, Sujay; Krsinic, Gail; Dyer, Jolon M; Tilley, Richard D

2013-07-31

Low-molecular-weight organic molecules, such as coumarins and stilbenes, are used commercially as fluorescent whitening agents (FWAs) to mask photoyellowing and to brighten colors in fabrics. FWAs achieve this by radiating extra blue light, thus changing the hue and also adding to the brightness. However, organic FWAs can rapidly photodegrade in the presence of ultraviolet (UV) radiation, exacerbating the yellowing process through a reaction involving singlet oxygen species. Inorganic nanoparticles, on the other hand, can provide a similar brightening effect with the added advantage of photostability. We report a targeted approach in designing new inorganic silicon- and germanium-based nanoparticles, functionalized with hydrophilic (amine) surface terminations as novel inorganic FWAs. When applied on wool, by incorporation in a sol-gel Si matrix, the inorganic FWAs improved brightness properties, demonstrated enhanced photostability toward UV radiation, especially the germanium nanoparticles, and also generated considerably lower levels of reactive oxygen species compared to a commercial stilbene-based organic FWA, Uvitex NFW.

Low Temperature Testing of a Radiation Hardened CMOS 8-Bit Flash Analog-to-Digital (A/D) Converter

NASA Technical Reports Server (NTRS)

Gerber, Scott S.; Hammond, Ahmad; Elbuluk, Malik E.; Patterson, Richard L.; Overton, Eric; Ghaffarian, Reza; Ramesham, Rajeshuni; Agarwal, Shri G.

2001-01-01

Power processing electronic systems, data acquiring probes, and signal conditioning circuits are required to operate reliably under harsh environments in many of NASA:s missions. The environment of the space mission as well as the operational requirements of some of the electronic systems, such as infrared-based satellite or telescopic observation stations where cryogenics are involved, dictate the utilization of electronics that can operate efficiently and reliably at low temperatures. In this work, radiation-hard CMOS 8-bit flash A/D converters were characterized in terms of voltage conversion and offset in the temperature range of +25 to -190 C. Static and dynamic supply currents, ladder resistance, and gain and offset errors were also obtained in the temperature range of +125 to -190 C. The effect of thermal cycling on these properties for a total of ten cycles between +80 and - 150 C was also determined. The experimental procedure along with the data obtained are reported and discussed in this paper.

Strain-specific Fibril Propagation by an Aβ Dodecamer

NASA Astrophysics Data System (ADS)

Dean, Dexter N.; Das, Pradipta K.; Rana, Pratip; Burg, Franklin; Levites, Yona; Morgan, Sarah E.; Ghosh, Preetam; Rangachari, Vijayaraghavan

2017-01-01

Low molecular weight oligomers of amyloid-β (Aβ) have emerged as the primary toxic agents in the etiology of Alzheimer disease (AD). Polymorphism observed within the aggregation end products of fibrils are known to arise due to microstructural differences among the oligomers. Diversity in aggregate morphology correlates with the differences in AD, cementing the idea that conformational strains of oligomers could be significant in phenotypic outcomes. Therefore, it is imperative to determine the ability of strains to faithfully propagate their structure. Here we report fibril propagation of an Aβ42 dodecamer called large fatty acid-derived oligomers (LFAOs). The LFAO oligomeric strain selectively induces acute cerebral amyloid angiopathy (CAA) in neonatally-injected transgenic CRND8 mice. Propagation in-vitro occurs as a three-step process involving the association of LFAO units. LFAO-seeded fibrils possess distinct morphology made of repeating LFAO units that could be regenerated upon sonication. Overall, these data bring forth an important mechanistic perspective into strain-specific propagation of oligomers that has remained elusive thus far.

Structure-activity relationships of β-hairpin mimics as modulators of amyloid β-peptide aggregation.

PubMed

Tonali, Nicolo; Kaffy, Julia; Soulier, Jean-Louis; Gelmi, Maria Luisa; Erba, Emanuela; Taverna, Myriam; van Heijenoort, Carine; Ha-Duong, Tap; Ongeri, Sandrine

2018-05-18

Aggregation of amyloid proteins is currently involved in more than 20 serious human diseases that are actually untreated, such as Alzheimer's disease (AD). Despite many efforts made to target the amyloid cascade in AD, finding an aggregation inhibiting compound and especially modulating early oligomerization remains a relevant and challenging strategy. We report herein the first examples of small and non-peptide mimics of acyclic beta-hairpins, showing an ability to delay the fibrillization of amyloid-β (Aβ 1-42 ) peptide and deeply modify its early oligomerization process. Modifications providing better druggability properties such as increased hydrophilicity and reduced peptidic character were performed. We also demonstrate that an appropriate balance between flexibility and stability of the β-hairpin must be reached to adapt to the different shape of the various aggregated forms of the amyloid peptide. This strategy can be investigated to target other challenging amyloid proteins. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

Mechanisms linking brain insulin resistance to Alzheimer's disease

PubMed Central

Matioli, Maria Niures P.S.; Nitrini, Ricardo

2015-01-01

Several studies have indicated that Diabetes Mellitus (DM) can increase the risk of developing Alzheimer's disease (AD). This review briefly describes current concepts in mechanisms linking DM and insulin resistance/deficiency to AD. Insulin/insulin-like growth factor (IGF) resistance can contribute to neurodegeneration by several mechanisms which involve: energy and metabolism deficits, impairment of Glucose transporter-4 function, oxidative and endoplasmic reticulum stress, mitochondrial dysfunction, accumulation of AGEs, ROS and RNS with increased production of neuro-inflammation and activation of pro-apoptosis cascade. Impairment in insulin receptor function and increased expression and activation of insulin-degrading enzyme (IDE) have also been described. These processes compromise neuronal and glial function, with a reduction in neurotransmitter homeostasis. Insulin/IGF resistance causes the accumulation of AβPP-Aβ oligomeric fibrils or insoluble larger aggregated fibrils in the form of plaques that are neurotoxic. Additionally, there is production and accumulation of hyper-phosphorylated insoluble fibrillar tau which can exacerbate cytoskeletal collapse and synaptic disconnection. PMID:29213950

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

Tang, Q; Xie, S

This report describes the Atmospheric Radiation Measurement (ARM) Best Estimate (ARMBE) 2-dimensional (2D) gridded surface data (ARMBE2DGRID) value-added product. Spatial variability is critically important to many scientific studies, especially those that involve processes of great spatial variations at high temporal frequency (e.g., precipitation, clouds, radiation, etc.). High-density ARM sites deployed at the Southern Great Plains (SGP) allow us to observe the spatial patterns of variables of scientific interests. The upcoming megasite at SGP with its enhanced spatial density will facilitate the studies at even finer scales. Currently, however, data are reported only at individual site locations at different time resolutionsmore » for different datastreams. It is difficult for users to locate all the data they need and requires extra effort to synchronize the data. To address these problems, the ARMBE2DGRID value-added product merges key surface measurements at the ARM SGP sites and interpolates the data to a regular 2D grid to facilitate the data application.« less

Semiclassical S-matrix for black holes

DOE PAGES

Bezrukov, Fedor; Levkov, Dmitry; Sibiryakov, Sergey

2015-12-01

In this study, we propose a semiclassical method to calculate S-matrix elements for two-stage gravitational transitions involving matter collapse into a black hole and evaporation of the latter. The method consistently incorporates back-reaction of the collapsing and emitted quanta on the metric. We illustrate the method in several toy models describing spherical self-gravitating shells in asymptotically flat and AdS space-times. We find that electrically neutral shells reflect via the above collapse-evaporation process with probability exp(–B), where B is the Bekenstein-Hawking entropy of the intermediate black hole. This is consistent with interpretation of exp(B) as the number of black hole states.more » The same expression for the probability is obtained in the case of charged shells if one takes into account instability of the Cauchy horizon of the intermediate Reissner-Nordström black hole. As a result, our semiclassical method opens a new systematic approach to the gravitational S-matrix in the non-perturbative regime.« less

Early-Onset Severe Encephalopathy with Epilepsy: The BRAT1 Gene Should Be Added to the List of Causes.

PubMed

van de Pol, Laura A; Wolf, Nicole I; van Weissenbruch, Mirjam M; Stam, Cornelie J; Weiss, Janneke M; Waisfisz, Quinten; Kevelam, Sietske H; Bugiani, Mariana; van de Kamp, Jiddeke M; van der Knaap, Marjo S

2015-12-01

A variety of pathologies can underlie early-onset severe encephalopathy with epilepsy. To aid the diagnostic process in such patients we present an overview of causes, including the rapidly expanding list of genes involved. When no explanation is found, whole-exome sequencing (WES) can be used in an attempt to identify gene defects in patients suspected to suffer from a genetic form. We describe three siblings, born to consanguineous parents, with a lethal severe epileptic encephalopathy with early-infantile onset, including their magnetic resonance imaging, electroencephalography and, in one case, neuropathological findings. Using WES a homozygous frameshift mutation in the BRAT1 gene, c.638dup p.(Val214Glyfs*189), was identified. We present our cases in the context of all published cases with mutations in the BRAT1 gene and conclude that BRAT1 should be added to the growing list of genes related to early-onset severe encephalopathy with epilepsy. Georg Thieme Verlag KG Stuttgart · New York.

The Added-Value of Using Participatory Approaches to Assess the Acceptability of Surveillance Systems: The Case of Bovine Tuberculosis in Belgium

PubMed Central

Calba, Clémentine; Goutard, Flavie Luce; Vanholme, Luc; Antoine-Moussiaux, Nicolas; Hendrikx, Pascal; Saegerman, Claude

2016-01-01

Context and Objective Bovine tuberculosis (bTB) surveillance in Belgium is essential to maintain the officially free status and to preserve animal and public health. An evaluation of the system is thus needed to ascertain the surveillance provides a precise description of the current situation in the country. The evaluation should assess stakeholders’ perceptions and expectations about the system due to the fact that the acceptability has an influence on the levels of sensitivity and timeliness of the surveillance system. The objective of the study was to assess the acceptability of the bTB surveillance in Belgium, using participatory tools and the OASIS flash tool (‘analysis tool for surveillance systems’). Methods For the participatory process, focus group discussions and individual interviews were implemented with representatives involved with the system, both from cattle and wildlife part of the surveillance. Three main tools were used: (i) relational diagrams associated with smileys, (ii) flow diagrams associated with proportional piling, and (iii) impact diagrams associated with proportional piling. A total of six criteria were assessed, among which five were scored on a scale from -1 to +1. For the OASIS flash tool, one full day meeting with representatives from stakeholders involved with the surveillance was organised. A total of 19 criteria linked to acceptability were scored on a scale from 0 to 3. Results and Conclusion Both methods highlighted a medium acceptability of the bTB surveillance. The main elements having a negative influence were the consequences of official notification of a bTB suspect case in a farm, the low remuneration paid to private veterinarians for execution of intradermal tuberculin tests and the practical difficulties about the containment of the animals. Based on the two evaluation processes, relevant recommendations to improve the surveillance were made. Based on the comparison between the two evaluation processes, the added value of the participatory approach was highlighted. PMID:27462705

Activated forms of astrocytes with higher GLT-1 expression are associated with cognitive normal subjects with Alzheimer pathology in human brain.

PubMed

Kobayashi, Eiji; Nakano, Masako; Kubota, Kenta; Himuro, Nobuaki; Mizoguchi, Shougo; Chikenji, Takako; Otani, Miho; Mizue, Yuka; Nagaishi, Kanna; Fujimiya, Mineko

2018-01-26

Although the cognitive impairment in Alzheimer's disease (AD) is believed to be caused by amyloid-β (Aβ) plaques and neurofibrillary tangles (NFTs), several postmortem studies have reported cognitive normal subjects with AD brain pathology. As the mechanism underlying these discrepancies has not been clarified, we focused the neuroprotective role of astrocytes. After examining 47 donated brains, we classified brains into 3 groups, no AD pathology with no dementia (N-N), AD pathology with no dementia (AD-N), and AD pathology with dementia (AD-D), which represented 41%, 21%, and 38% of brains, respectively. No differences were found in the accumulation of Aβ plaques or NFTs in the entorhinal cortex (EC) between AD-N and AD-D. Number of neurons and synaptic density were increased in AD-N compared to those in AD-D. The astrocytes in AD-N possessed longer or thicker processes, while those in AD-D possessed shorter or thinner processes in layer I/II of the EC. Astrocytes in all layers of the EC in AD-N showed enhanced GLT-1 expression in comparison to those in AD-D. Therefore these activated forms of astrocytes with increased GLT-1 expression may exert beneficial roles in preserving cognitive function, even in the presence of Aβ and NFTs.

Worldsheet scattering in AdS3/CFT2

NASA Astrophysics Data System (ADS)

Sundin, Per; Wulff, Linus

2013-07-01

We confront the recently proposed exact S-matrices for AdS 3/ CFT 2 with direct worldsheet calculations. Utilizing the BMN and Near Flat Space (NFS) expansions for strings on AdS 3 × S 3 × S 3 × S 1 and AdS 3 × S 3 × T 4 we compute both tree-level and one-loop scattering amplitudes. Up to some minor issues we find nice agreement in the tree-level sector. At the one-loop level however we find that certain non-zero tree-level processes, which are not visible in the exact solution, contribute, via the optical theorem, and give an apparent mismatch for certain amplitudes. Furthermore we find that a proposed one-loop modification of the dressing phase correctly reproduces the worldsheet calculation while the standard Hernandez-Lopez phase does not. We also compute several massless to massless processes.

Impaired Processing of Serial Order Determines Working Memory Impairments in Alzheimer's Disease.

PubMed

De Belder, Maya; Santens, Patrick; Sieben, Anne; Fias, Wim

2017-01-01

Working memory (WM) problems are commonly observed in Alzheimer's disease (AD), but the affected mechanisms leading to impaired WM are still insufficiently understood. The ability to efficiently process serial order in WM has been demonstrated to be fundamental to fluent daily life functioning. The decreased capability to mentally process serial position in WM has been put forward as the underlying explanation for generally compromised WM performance. Determine which mechanisms, such as order processing, are responsible for deficient WM functioning in AD. A group of AD patients (n = 32) and their partners (n = 25), assigned to the control group, were submitted to an extensive battery of neuropsychological and experimental tasks, assessing general cognitive state and functioning of several aspects related to serial order WM. The results revealed an impaired ability to bind item information to serial position within WM in AD patients compared to controls. It was additionally observed that AD patients experienced specific difficulties with directing spatial attention when searching for item information stored in WM. The processing of serial order and the allocation of attentional resources are both disrupted, explaining the generally reduced WM functioning in AD patients. Further studies should now clarify whether this observation could explain disease-related problems for other cognitive functions such as verbal expression, auditory comprehension, or planning.

Syntheses and properties of the major hydroxy metabolites in humans of blonanserin AD-5423, a novel antipsychotic agent.

PubMed

Ochi, Takeshi; Sakamoto, Masato; Minamida, Akira; Suzuki, Kenji; Ueda, Tomohiko; Une, Teruaki; Toda, Hiroshi; Matsumoto, Kazuya; Terauchi, Yoshiaki

2005-02-15

Two major metabolites in humans of blonanserin, 2-(4-ethyl-1-piperazinyl)-4-(4-fluorophenyl)-5,6,7,8,9,10-hexahydrocycloocta-[b]pyridine (code name AD-5423), were synthesized. The first, 7-hydroxylated AD-5423, was synthesized through a four-step process starting from 4-fluorobenzoylacetonitrile (1), and the second, 8-hydroxylated AD-5423, a nine-step process also from 1. The optical resolution, structures, and receptor binding properties of the metabolites were documented.

Conventional freezing plus high pressure-low temperature treatment: Physical properties, microbial quality and storage stability of beef meat.

PubMed

Fernández, Pedro P; Sanz, Pedro D; Molina-García, Antonio D; Otero, Laura; Guignon, Bérengère; Vaudagna, Sergio R

2007-12-01

Meat high-hydrostatic pressure treatment causes severe decolouration, preventing its commercialisation due to consumer rejection. Novel procedures involving product freezing plus low-temperature pressure processing are here investigated. Room temperature (20°C) pressurisation (650MPa/10min) and air blast freezing (-30°C) are compared to air blast freezing plus high pressure at subzero temperature (-35°C) in terms of drip loss, expressible moisture, shear force, colour, microbial quality and storage stability of fresh and salt-added beef samples (Longissimus dorsi muscle). The latter treatment induced solid water transitions among ice phases. Fresh beef high pressure treatment (650MPa/20°C/10min) increased significantly expressible moisture while it decreased in pressurised (650MPa/-35°C/10min) frozen beef. Salt addition reduced high pressure-induced water loss. Treatments studied did not change fresh or salt-added samples shear force. Frozen beef pressurised at low temperature showed L, a and b values after thawing close to fresh samples. However, these samples in frozen state, presented chromatic parameters similar to unfrozen beef pressurised at room temperature. Apparently, freezing protects meat against pressure colour deterioration, fresh colour being recovered after thawing. High pressure processing (20°C or -35°C) was very effective reducing aerobic total (2-log(10) cycles) and lactic acid bacteria counts (2.4-log(10) cycles), in fresh and salt-added samples. Frozen+pressurised beef stored at -18°C during 45 days recovered its original colour after thawing, similarly to just-treated samples while their counts remain below detection limits during storage.

Biofilm formation and granule properties in anaerobic digestion at high salinity.

PubMed

Gagliano, M C; Ismail, S B; Stams, A J M; Plugge, C M; Temmink, H; Van Lier, J B

2017-09-15

For the anaerobic biological treatment of saline wastewater, Anaerobic Digestion (AD) is currently a possibility, even though elevated salt concentrations can be a major obstacle. Anaerobic consortia and especially methanogenic archaea are very sensitive to fluctuations in salinity. When working with Upflow Sludge Blanket Reactor (UASB) technology, in which the microorganisms are aggregated and retained in the system as a granular biofilm, high sodium concentration negatively affects aggregation and consequently process performances. In this research, we analysed the structure of the biofilm and granules formed during the anaerobic treatment of high salinity (at 10 and 20 g/L of sodium) synthetic wastewater at lab scale. The acclimated inoculum was able to accomplish high rates of organics removal at all the salinity levels tested. 16S rRNA gene clonal analysis and Fluorescence In Situ Hybridization (FISH) analyses identified the acetoclastic Methanosaeta harundinacea as the key player involved acetate degradation and microbial attachment/granulation. When additional calcium (1 g/L) was added to overcome the negative effect of sodium on microbial aggregation, during the biofilm formation process microbial attachment and acetate degradation decreased. The same result was observed on granules formation: while calcium had a positive effect on granules strength when added to UASB reactors, Methanosaeta filaments were not present and the degradation of the partially acidified substrate was negatively influenced. This research demonstrated the possibility to get granulation at high salinity, bringing to the forefront the importance of a selection towards Methanosaeta cells growing in filamentous form to obtain strong and healthy granules. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

Morphometric alterations of Golgi apparatus in Alzheimer's disease are related to tau hyperphosphorylation.

PubMed

Antón-Fernández, Alejandro; Aparicio-Torres, Guillermo; Tapia, Silvia; DeFelipe, Javier; Muñoz, Alberto

2017-01-01

The Golgi apparatus (GA) is a highly dynamic organelle, which is mainly involved in the post-translational processing and targeting of cellular proteins and which undergoes significant morphological changes in response to different physiological and pathological conditions. In the present study, we have analyzed the possible alterations of GA in neurons from the temporal neocortex and hippocampus of Alzheimer's disease (AD) patients, using double immunofluorescence techniques, confocal microscopy and 3D quantification techniques. We found that in AD patients, the percentage of temporal neocortical and CA1 hippocampal pyramidal neurons with a highly altered GA is much higher (approximately 65%) in neurons with neurofibrillary tangles (NFT) than in NFT-free neurons (approximately 6%). Quantitative analysis of the surface area and volume of GA elements in neurons revealed that, compared with NFT-free neurons, NFT-bearing neurons had a reduction of approximately one half in neocortical neurons and one third in CA1 neurons. In both regions, neurons with a pre-tangle stage of phospho-tau accumulation had surface area and GA volume values that were intermediate, that is, between those of NFT-free and NFT-bearing neurons. These findings support the idea that the progressive accumulation of phospho-tau is associated with structural alterations of the GA including fragmentation and a decrease in the surface area and volume of GA elements. These alterations likely impact the processing and trafficking of proteins, which might contribute to neuronal dysfunction in AD. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

To what extent does adding tobacco to cannabis expose young users to nicotine?

PubMed

Bélanger, Richard E; Marclay, François; Berchtold, André; Saugy, Martial; Cornuz, Jacques; Suris, Joan-Carles

2013-11-01

To determine if mulling, the process of adding tobacco to cannabis for its consumption, exposes young cannabis users to significant levels of nicotine. This observational study performed in 2009-2010 among Swiss youths aged 16-25 years involved the completion of a self-administrated questionnaire and the collection of a urine sample on the same day. Measures of urinary cotinine were blindly performed using liquid chromatography coupled-mass spectrometry. A total of 197 eligible participants were divided in 3 groups based on their consumption profile in the past 5 days: 70 abstainers (ABS) not having used cigarettes or cannabis, 57 cannabis users adding tobacco to the cannabis they smoke (MUL) but not having smoked cigarettes, and 70 cigarette smokers (CIG) not having smoked cannabis. Exposure to nicotine was at its lowest among ABS with a mean (SE) cotinine level of 3.2 (1.4) ng/ml compared, respectively, with 214.6 (43.8) and 397.9 (57.4) for MUL and CIG (p < .001). While consumption profile appeared as the only significant factor of influence when examining nicotine exposure from the ABS and MUL participants on multivariate analysis, it did not result in substantial differences among MUL and CIG groups. Urinary cotinine levels found among MUL are high enough to indicate a significant exposure to nicotine originating from the mulling process. In line with our results, health professionals should pay attention to mulling as it is likely to influence cannabis and cigarette use as well as the efficacy of cessation interventions.

Metals and cholesterol: two sides of the same coin in Alzheimer’s disease pathology

PubMed Central

Wong, Bruce X.; Hung, Ya Hui; Bush, Ashley I.; Duce, James A.

2014-01-01

Alzheimer’s disease (AD) is a multifactorial neurodegenerative disease. It begins years prior to the onset of clinical symptoms, such as memory loss and cognitive decline. Pathological hallmarks of AD include the accumulation of β-amyloid in plaques and hyperphosphorylated tau in neurofibrillary tangles. Copper, iron, and zinc are abnormally accumulated and distributed in the aging brain. These metal ions can adversely contribute to the progression of AD. Dysregulation of cholesterol metabolism has also been implicated in the development of AD pathology. To date, large bodies of research have been carried out independently to elucidate the role of metals or cholesterol on AD pathology. Interestingly, metals and cholesterol affect parallel molecular and biochemical pathways involved in AD pathology. The possible links between metal dyshomeostasis and altered brain cholesterol metabolism in AD are reviewed. PMID:24860500

Holographic thermalization and generalized Vaidya-AdS solutions in massive gravity

NASA Astrophysics Data System (ADS)

Hu, Ya-Peng; Zeng, Xiao-Xiong; Zhang, Hai-Qing

2017-02-01

We investigate the effect of massive graviton on the holographic thermalization process. Before doing this, we first find out the generalized Vaidya-AdS solutions in the de Rham-Gabadadze-Tolley (dRGT) massive gravity by directly solving the gravitational equations. Then, we study the thermodynamics of these Vaidya-AdS solutions by using the Misner-Sharp energy and unified first law, which also shows that the massive gravity is in a thermodynamic equilibrium state. Moreover, we adopt the two-point correlation function at equal time to explore the thermalization process in the dual field theory, and to see how the graviton mass parameter affects this process from the viewpoint of AdS/CFT correspondence. Our results show that the graviton mass parameter will increase the holographic thermalization process.

DEMONSTRATION OF BIODEGRADATION OF DENSE, NONAQUEOUS-PHASE LIQUIDS (DNAPL)THROUGH BIOSTIMULATION AND BIOAUGMENTATION AT LAUNCH COMPLEX 34 IN CAPE CANAVERAL AIR FORCE STATION, FLORIDA

EPA Science Inventory

Biostimulation involves stimulating indigenous microbial cultures by adding nutrients whereas bioaugmentation involves introducing microbial cultures that are particularly adept at degrading these contaminants into the target aquifer. This demonstration involved biostimulation fo...

Flavour exposures after conditioned aversion or preference trigger different brain processes in anaesthetised pigs.

PubMed

Gaultier, A; Meunier-Salaün, M C; Malbert, C H; Val-Laillet, D

2011-11-01

We describe the behavioural consequences of conditioned flavour aversion and preference in pigs and have investigated the brain circuits involved in the representation of flavours with different hedonic values. The study was performed on eight 30-kg pigs. (i) Animals were negatively conditioned to an F- flavour added to a meal followed by LiCl intraduodenal (i.d.) injection, and positively conditioned to an F+ flavour added to a meal followed by NaCl i.d. injection. F+ and F- were thyme or cinnamon flavours. After each conditioning, the behavioural activities were recorded; (ii) One and 5 weeks later, animals were subjected to three two-choice food tests to investigate their preferences between F+, F- and a novel flavour (O); and (iii) Anaesthetised animals were subjected to three SPECT brain imaging sessions: control situation (no flavour) and exposure to F+ and to F-. The negative reinforcement induced a physical malaise and visceral illness. After a positive reinforcement, animals showed playing or feeding motivation and quietness. F+ was significantly preferred over O and F-, and O was significantly preferred over F-. Both F- and F+ induced some metabolic differences in neural circuits involved in sensory associative processes, learning and memory, emotions, reward and feeding motivation. Exposure to F+ induced a higher activity in corticolimbic and reward-related areas, while F- induced a deactivation of the basal nuclei and limbic thalamic nuclei. This study reveals the unconscious cognitive dimension evoked by food flavours according to the individual experience, and highlights the importance of the food sensory image on hedonism and anticipatory eating behaviour. © 2011 The Authors. European Journal of Neuroscience © 2011 Federation of European Neuroscience Societies and Blackwell Publishing Ltd.

Brain structural, functional, and cognitive correlates of recent versus remote autobiographical memories in amnestic Mild Cognitive Impairment

PubMed Central

Tomadesso, Clémence; Perrotin, Audrey; Mutlu, Justine; Mézenge, Florence; Landeau, Brigitte; Egret, Stéphanie; de la Sayette, Vincent; Jonin, Pierre-Yves; Eustache, Francis; Desgranges, Béatrice; Chételat, Gaël

2015-01-01

Deficits in autobiographical memory appear earlier for recent than for remote life periods over the course of Alzheimer's disease (AD). The present study aims to further our understanding of this graded effect by investigating the cognitive and neural substrates of recent versus remote autobiographical memories in patients with amnestic Mild Cognitive Impairment (aMCI) thanks to an autobiographical fluency task. 20 aMCI patients and 25 Healthy elderly Controls (HC) underwent neuropsychological tests assessing remote (20-to-30 years old) and recent (the ten last years) autobiographical memory as well as episodic and semantic memory, executive function and global cognition. All patients also had a structural MRI and an FDG-PET scan. Correlations were assessed between each autobiographical memory score and the other tests as well as grey matter volume and metabolism. Within the aMCI, performances for the remote period correlated with personal semantic memory and episodic memory retrieval whereas performances for the recent period only correlated with episodic memory retrieval. Neuroimaging analyses revealed significant correlations between performances for the remote period and temporal pole and temporo-parietal cortex volumes and anterior cingulate gyrus metabolism, while performances for the recent period correlated with hippocampal volume and posterior cingulate, medial prefrontal and hippocampus metabolism. The brain regions related with the retrieval of events from the recent period showed greater atrophy/hypometabolism in aMCI patients compared to HC than those involved in remote memories. Recall of recent memories essentially relies on episodic memory processes and brain network while remote memories also involve other processes such as semantic memory. This is consistent with the semanticization of memories with time and may explain the better resistance of remote memory in AD. PMID:26106572

The functional neuroanatomy of multitasking: combining dual tasking with a short term memory task.

PubMed

Deprez, Sabine; Vandenbulcke, Mathieu; Peeters, Ron; Emsell, Louise; Amant, Frederic; Sunaert, Stefan

2013-09-01

Insight into the neural architecture of multitasking is crucial when investigating the pathophysiology of multitasking deficits in clinical populations. Presently, little is known about how the brain combines dual-tasking with a concurrent short-term memory task, despite the relevance of this mental operation in daily life and the frequency of complaints related to this process, in disease. In this study we aimed to examine how the brain responds when a memory task is added to dual-tasking. Thirty-three right-handed healthy volunteers (20 females, mean age 39.9 ± 5.8) were examined with functional brain imaging (fMRI). The paradigm consisted of two cross-modal single tasks (a visual and auditory temporal same-different task with short delay), a dual-task combining both single tasks simultaneously and a multi-task condition, combining the dual-task with an additional short-term memory task (temporal same-different visual task with long delay). Dual-tasking compared to both individual visual and auditory single tasks activated a predominantly right-sided fronto-parietal network and the cerebellum. When adding the additional short-term memory task, a larger and more bilateral frontoparietal network was recruited. We found enhanced activity during multitasking in components of the network that were already involved in dual-tasking, suggesting increased working memory demands, as well as recruitment of multitask-specific components including areas that are likely to be involved in online holding of visual stimuli in short-term memory such as occipito-temporal cortex. These results confirm concurrent neural processing of a visual short-term memory task during dual-tasking and provide evidence for an effective fMRI multitasking paradigm. © 2013 Elsevier Ltd. All rights reserved.

Brain structural, functional, and cognitive correlates of recent versus remote autobiographical memories in amnestic Mild Cognitive Impairment.

PubMed

Tomadesso, Clémence; Perrotin, Audrey; Mutlu, Justine; Mézenge, Florence; Landeau, Brigitte; Egret, Stéphanie; de la Sayette, Vincent; Jonin, Pierre-Yves; Eustache, Francis; Desgranges, Béatrice; Chételat, Gaël

2015-01-01

Deficits in autobiographical memory appear earlier for recent than for remote life periods over the course of Alzheimer's disease (AD). The present study aims to further our understanding of this graded effect by investigating the cognitive and neural substrates of recent versus remote autobiographical memories in patients with amnestic Mild Cognitive Impairment (aMCI) thanks to an autobiographical fluency task. 20 aMCI patients and 25 Healthy elderly Controls (HC) underwent neuropsychological tests assessing remote (20-to-30 years old) and recent (the ten last years) autobiographical memory as well as episodic and semantic memory, executive function and global cognition. All patients also had a structural MRI and an FDG-PET scan. Correlations were assessed between each autobiographical memory score and the other tests as well as grey matter volume and metabolism. Within the aMCI, performances for the remote period correlated with personal semantic memory and episodic memory retrieval whereas performances for the recent period only correlated with episodic memory retrieval. Neuroimaging analyses revealed significant correlations between performances for the remote period and temporal pole and temporo-parietal cortex volumes and anterior cingulate gyrus metabolism, while performances for the recent period correlated with hippocampal volume and posterior cingulate, medial prefrontal and hippocampus metabolism. The brain regions related with the retrieval of events from the recent period showed greater atrophy/hypometabolism in aMCI patients compared to HC than those involved in remote memories. Recall of recent memories essentially relies on episodic memory processes and brain network while remote memories also involve other processes such as semantic memory. This is consistent with the semanticization of memories with time and may explain the better resistance of remote memory in AD.

Effluent composition prediction of a two-stage anaerobic digestion process: machine learning and stoichiometry techniques.

PubMed

Alejo, Luz; Atkinson, John; Guzmán-Fierro, Víctor; Roeckel, Marlene

2018-05-16

Computational self-adapting methods (Support Vector Machines, SVM) are compared with an analytical method in effluent composition prediction of a two-stage anaerobic digestion (AD) process. Experimental data for the AD of poultry manure were used. The analytical method considers the protein as the only source of ammonia production in AD after degradation. Total ammonia nitrogen (TAN), total solids (TS), chemical oxygen demand (COD), and total volatile solids (TVS) were measured in the influent and effluent of the process. The TAN concentration in the effluent was predicted, this being the most inhibiting and polluting compound in AD. Despite the limited data available, the SVM-based model outperformed the analytical method for the TAN prediction, achieving a relative average error of 15.2% against 43% for the analytical method. Moreover, SVM showed higher prediction accuracy in comparison with Artificial Neural Networks. This result reveals the future promise of SVM for prediction in non-linear and dynamic AD processes. Graphical abstract ᅟ.

Solid anaerobic digestion: State-of-art, scientific and technological hurdles.

PubMed

André, Laura; Pauss, André; Ribeiro, Thierry

2018-01-01

In this paper, a state-of-art about solid anaerobic digestion (AD), focused on recent progress and trends of research is proposed. Solid anaerobic digestion should be the most appropriate process for degradation of by-products with high total solid (TS) content, especially lignocellulosic materials like agricultural waste (straw, manure), household waste and food waste. Solid AD is already widely used in waste water treatment plant for treating plant for sewage sludge but could be more developed for lignocellulosic materials with high TS content. Many research works were carried out in Europe on solid AD, focused on current hurdles (BMP, codigestion, inhibition, microbial population, rheology, water transfers, inoculum, etc.) in order to optimize the solid AD process. In conclusion, hurdles of solid AD process should and must be solved in order to propose better productivity and profitability of such system operating with high TS content (>15%), favouring reliable industrial processes. Copyright © 2017 Elsevier Ltd. All rights reserved.

EPIBLASTER-fast exhaustive two-locus epistasis detection strategy using graphical processing units

PubMed Central

Kam-Thong, Tony; Czamara, Darina; Tsuda, Koji; Borgwardt, Karsten; Lewis, Cathryn M; Erhardt-Lehmann, Angelika; Hemmer, Bernhard; Rieckmann, Peter; Daake, Markus; Weber, Frank; Wolf, Christiane; Ziegler, Andreas; Pütz, Benno; Holsboer, Florian; Schölkopf, Bernhard; Müller-Myhsok, Bertram

2011-01-01

Detection of epistatic interaction between loci has been postulated to provide a more in-depth understanding of the complex biological and biochemical pathways underlying human diseases. Studying the interaction between two loci is the natural progression following traditional and well-established single locus analysis. However, the added costs and time duration required for the computation involved have thus far deterred researchers from pursuing a genome-wide analysis of epistasis. In this paper, we propose a method allowing such analysis to be conducted very rapidly. The method, dubbed EPIBLASTER, is applicable to case–control studies and consists of a two-step process in which the difference in Pearson's correlation coefficients is computed between controls and cases across all possible SNP pairs as an indication of significant interaction warranting further analysis. For the subset of interactions deemed potentially significant, a second-stage analysis is performed using the likelihood ratio test from the logistic regression to obtain the P-value for the estimated coefficients of the individual effects and the interaction term. The algorithm is implemented using the parallel computational capability of commercially available graphical processing units to greatly reduce the computation time involved. In the current setup and example data sets (211 cases, 222 controls, 299468 SNPs; and 601 cases, 825 controls, 291095 SNPs), this coefficient evaluation stage can be completed in roughly 1 day. Our method allows for exhaustive and rapid detection of significant SNP pair interactions without imposing significant marginal effects of the single loci involved in the pair. PMID:21150885

78 FR 25666 - Airworthiness Directives; Airbus Airplanes

Federal Register 2010, 2011, 2012, 2013, 2014

2013-05-02

...) sensor blockage. The existing AD also provides for optional terminating action for the AFM revision, which involves replacing AoA sensor conic plates with AoA sensor flat plates. Since we issued that AD, we have determined that the replacement of AoA sensor conic plates is necessary to address the...

Mitochondrial accumulation of APP and Aβ: significance for Alzheimer disease pathogenesis

PubMed Central

Pavlov, Pavel F; Petersen, Camilla Hansson; Glaser, Elzbieta; Ankarcrona, Maria

2009-01-01

Accumulating evidence suggest that alterations in energy metabolism are among the earliest events that occur in the Alzheimer disease (AD) affected brain. Energy consumption is drastically decreased in the AD-affected regions of cerebral cortex and hippocampus pointing towards compromised mitochondrial function of neurons within specific brain regions. This is accompanied by an elevated production of reactive oxygen species contributing to increased rates of neuronal loss in the AD-affected brain regions. In this review, we will discuss the role of mitochondrial function and dysfunction in AD. We will focus on the consequences of amyloid precursor protein and amyloid-β peptide accumulation in mitochondria and their involvement in AD pathogenesis. PMID:19725915

77 FR 65506 - Airworthiness Directives; The Boeing Company Airplanes

Federal Register 2010, 2011, 2012, 2013, 2014

2012-10-29

...We propose to supersede an existing airworthiness directive (AD) that applies to certain The Boeing Company Model 757-200 and - 200PF series airplanes. The existing AD currently requires modification of the nacelle strut and wing structure, and repair of any damage found during the modification. Since we issued that AD, a compliance time error involving the optional threshold formula was discovered, which could allow an airplane to exceed the acceptable compliance time for addressing the unsafe condition. This proposed AD would specify a maximum compliance time limit that overrides the optional threshold formula results. We are proposing this AD to prevent fatigue cracking in primary strut structure and consequent reduced structural integrity of the strut.

Availability of added sugars in Brazil: distribution, food sources and time trends.

PubMed

Levy, Renata Bertazzi; Claro, Rafael Moreira; Bandoni, Daniel Henrique; Mondini, Lenise; Monteiro, Carlos Augusto

2012-03-01

To describe the regional and socio-economic distribution of consumption of added sugar in Brazil in 2002/03, particularly products, sources of sugar and trends in the past 15 years. The study used data from Household Budget Surveys since the 1980s about the type and quantity of food and beverages bought by Brazilian families. Different indicators were analyzed: % of sugar calories over the total diet energy and caloric % of table sugar fractions and sugar added to processed food/ sugar calories of diet. In 2002/03, of the total energy available for consumption, 16.7% came from added sugar in all regional and socio-economic strata. The table sugar/ sugar added to processed food ratio was inversely proportional to increase in income. Although this proportion fell in the past 15 years, sugar added to processed food doubled, especially in terms of consumption of soft drinks and cookies. Brazilians consume more sugar than the recommended levels determined by the WHO and the sources of consumption of sugar have changed significantly.

Proposed Framework for Determining Added Mass of Orion Drogue Parachutes

NASA Technical Reports Server (NTRS)

Fraire, Usbaldo, Jr.; Dearman, James; Morris, Aaron

2011-01-01

The Crew Exploration Vehicle (CEV) Parachute Assembly System (CPAS) project is executing a program to qualify a parachute system for a next generation human spacecraft. Part of the qualification process involves predicting parachute riser tension during system descent with flight simulations. Human rating the CPAS hardware requires a high degree of confidence in the simulation models used to predict parachute loads. However, uncertainty exists in the heritage added mass models used for loads predictions due to a lack of supporting documentation and data. Even though CPAS anchors flight simulation loads predictions to flight tests, extrapolation of these models outside the test regime carries the risk of producing non-bounding loads. A set of equations based on empirically derived functions of skirt radius is recommended as the simplest and most viable method to test and derive an enhanced added mass model for an inflating parachute. This will increase confidence in the capability to predict parachute loads. The selected equations are based on those published in A Simplified Dynamic Model of Parachute Inflation by Dean Wolf. An Ames 80x120 wind tunnel test campaign is recommended to acquire the reefing line tension and canopy photogrammetric data needed to quantify the terms in the Wolf equations and reduce uncertainties in parachute loads predictions. Once the campaign is completed, the Wolf equations can be used to predict loads in a typical CPAS Drogue Flight test. Comprehensive descriptions of added mass test techniques from the Apollo Era to the current CPAS project are included for reference.

Autism, Alzheimer disease, and fragile X: APP, FMRP, and mGluR5 are molecular links.

PubMed

Sokol, D K; Maloney, B; Long, J M; Ray, B; Lahiri, D K

2011-04-12

The present review highlights an association between autism, Alzheimer disease (AD), and fragile X syndrome (FXS). We propose a conceptual framework involving the amyloid-β peptide (Aβ), Aβ precursor protein (APP), and fragile X mental retardation protein (FMRP) based on experimental evidence. The anabolic (growth-promoting) effect of the secreted α form of the amyloid-β precursor protein (sAPPα) may contribute to the state of brain overgrowth implicated in autism and FXS. Our previous report demonstrated that higher plasma sAPPα levels associate with more severe symptoms of autism, including aggression. This molecular effect could contribute to intellectual disability due to repression of cell-cell adhesion, promotion of dense, long, thin dendritic spines, and the potential for disorganized brain structure as a result of disrupted neurogenesis and migration. At the molecular level, APP and FMRP are linked via the metabotropic glutamate receptor 5 (mGluR5). Specifically, mGluR5 activation releases FMRP repression of APP mRNA translation and stimulates sAPP secretion. The relatively lower sAPPα level in AD may contribute to AD symptoms that significantly contrast with those of FXS and autism. Low sAPPα and production of insoluble Aβ would favor a degenerative process, with the brain atrophy seen in AD. Treatment with mGluR antagonists may help repress APP mRNA translation and reduce secretion of sAPP in FXS and perhaps autism.

Decreased levels of PSD95 and two associated proteins and increased levels of BCl2 and caspase 3 in hippocampus from subjects with amnestic mild cognitive impairment: Insights into their potential roles for loss of synapses and memory, accumulation of Abeta, and neurodegeneration in a prodromal stage of Alzheimer's disease.

PubMed

Sultana, Rukhsana; Banks, William A; Butterfield, D Allan

2010-02-15

Alzheimer's disease (AD) is the most common form of dementia and is pathologically characterized by senile plaques, neurofibrillary tangles, synaptic disruption and loss, and progressive neuronal deficits. The exact mechanism(s) of AD pathogenesis largely remain unknown. With advances in technology diagnosis of a pre-AD stage referred to as amnestic mild cognitive impairment (MCI) has become possible. Amnestic MCI is characterized clinically by memory deficit, but normal activities of daily living and no dementia. In the present study, compared to controls, we observed in hippocampus from subjects with MCI a significantly decreased level of PSD95, a key synaptic protein, and also decreased levels of two proteins associated with PSD95, the N-methyl-D-aspartate receptor, subunit 2A (NR2A) and the low-density lipoprotein receptor-1 (LRP1). PSD95 and NR2A are involved in long-term potentiation, a key component of memory formation, and LRP1 is involved in efflux of amyloid beta-peptide (1-42). Abeta (1-42) conceivably is critical to the pathogenesis of MCI and AD, including the oxidative stress under which brain in both conditions exist. The data obtained from the current study suggest a possible involvement of these proteins in synaptic alterations, apoptosis and consequent decrements in learning and memory associated with the progression of MCI to AD. Copyright 2009 Wiley-Liss, Inc.

Abnormal Thiamine-Dependent Processes in Alzheimer’s Disease. Lessons from Diabetes

PubMed Central

Gibson, Gary E.; Hirsch, Joseph A.; Cirio, Rosanna T.; Jordan, Barry D.; Fonzetti, Pasquale; Elder, Jessica

2013-01-01

Reduced glucose metabolism is an invariant feature of Alzheimer’s Disease (AD) and an outstanding biomarker of disease progression. Glucose metabolism may be an attractive therapeutic target, whether the decline initiates AD pathophysiology or is a critical component of a cascade. The cause of cerebral regional glucose hypometabolism remains unclear. Thiamine-dependent processes are critical in glucose metabolism and are diminished in brains of AD patients at autopsy. Further, the reductions in thiamine-dependent processes are highly correlated to the decline in clinical dementia rating scales. In animal models, thiamine deficiency exacerbates plaque formation, promotes phosphorylation of tau and impairs memory. In contrast, treatment of mouse models of AD with the thiamine derivative benfotiamine diminishes plaques, decreases phosphorylation of tau and reverses memory deficits. Diabetes predisposes to AD, which suggests they may share some common mechanisms. Benfotiamine diminishes peripheral neuropathy in diabetic humans and animals. In diabetes, benfotiamine induces key thiamine-dependent enzymes of the pentose shunt to reduce accumulation of toxic metabolites including advanced glycation end products (AGE). Related mechanisms may lead to reversal of plaque formation by benfotiamine in animals. If so, the use of benfotiamine could provide a safe intervention to reverse biological and clinical processes of AD progression. PMID:22982063

Factors influencing the role of cardiac autonomic regulation in the service of cognitive control.

PubMed

Capuana, Lesley J; Dywan, Jane; Tays, William J; Elmers, Jamie L; Witherspoon, Richelle; Segalowitz, Sidney J

2014-10-01

Working from a model of neurovisceral integration, we examined whether adding response contingencies and motivational involvement would increase the need for cardiac autonomic regulation in maintaining effective cognitive control. Respiratory sinus arrhythmia (RSA) was recorded during variants of the Stroop color-word task. The Basic task involved "accepting" congruent items and "rejecting" words printed in incongruent colors (BLUE in red font); an added contingency involved rejecting a particular congruent word (e.g., RED in red font), or a congruent word repeated on an immediately subsequent trial. Motivation was increased by adding a financial incentive phase. Results indicate that pre-task RSA predicted accuracy best when response contingencies required the maintenance of a specific item in memory or on the Basic Stroop task when errors resulted in financial loss. Overall, RSA appeared to be most relevant to performance when the task encouraged a more proactive style of cognitive control, a control strategy thought to be more metabolically costly, and hence, more reliant on flexible cardiac autonomic regulation. Copyright © 2014 Elsevier B.V. All rights reserved.

Verbal repetitions and echolalia in Alzheimer's discourse.

PubMed

Da Cruz, Fernanda Miranda

2010-11-01

This article reports on an investigation of echolalic repetition in Alzheimer's disease (AD). A qualitative analysis of data from spontaneous conversations with MHI, a woman with AD, is presented. The data come from the DALI Corpus, a corpus of spontaneous conversations involving subjects with AD. This study argues that echolalic effects can be explained through an analysis of their formal linguistic aspects, such as intonational-prosodic and enunciative-syntactic features. The analysis shows that the description of echolalic repetitions in these terms can help find parameters for the description of the linguistic and communicative characteristics of AD. This analysis even shows how a previous speech turn serves as a base for the elaboration of the next turn by the participant with AD. It also contributes to the understanding of echolalic productions in AD.

Hypermultiplet gaugings and supersymmetric solutions from 11D and massive IIA supergravity on H^{(p,q)} spaces

NASA Astrophysics Data System (ADS)

Guarino, Adolfo

2018-03-01

Supersymmetric {AdS}4, {AdS}2 × Σ 2 and asymptotically AdS4 black hole solutions are studied in the context of non-minimal N=2 supergravity models involving three vector multiplets (STU-model) and Abelian gaugings of the universal hypermultiplet moduli space. Such models correspond to consistent subsectors of the {SO}(p,q) and {ISO}(p,q) gauged maximal supergravities that arise from the reduction of 11D and massive IIA supergravity on {H}^{(p,q)} spaces down to four dimensions. A unified description of all the models is provided in terms of a square-root prepotential and the gauging of a duality-hidden symmetry pair of the universal hypermultiplet. Some aspects of M-theory and massive IIA holography are mentioned in passing.

A Secure and Privacy-Preserving Targeted Ad-System

NASA Astrophysics Data System (ADS)

Androulaki, Elli; Bellovin, Steven M.

Thanks to its low product-promotion cost and its efficiency, targeted online advertising has become very popular. Unfortunately, being profile-based, online advertising methods violate consumers' privacy, which has engendered resistance to the ads. However, protecting privacy through anonymity seems to encourage click-fraud. In this paper, we define consumer's privacy and present a privacy-preserving, targeted ad system (PPOAd) which is resistant towards click fraud. Our scheme is structured to provide financial incentives to all entities involved.

A new method for placental/cord blood processing in the collection bag. I. Analysis of factors involved in red blood cell removal.

PubMed

Bertolini, F; Battaglia, M; Zibera, C; Baroni, G; Soro, V; Perotti, C; Salvaneschi, L; Robustelli della Cuna, G

1996-10-01

We describe a new procedure for large-scale CB processing in the collection bag, thus minimizing the risk of CB contamination. A solution of 6% hydroxyethyl starch (HES) was added directly to the CB containing bag. After RBC sedimentation at 4 degrees C, the WBC-rich supernatant was collected in a satellite bag and centrifuged. After supernatant removal, the cell pellet was resuspended and the percent recovery of total WBC, CD34+ progenitor cells, CFU-GM and cobblestone area-forming cells (CAFC) evaluated. Results obtained with three different types of CB collection bags (300, 600 and 1000 ml) were analyzed and compared with those of an open system in 50 ml tubes. CB processing procedures in 300 and 1000 ml bags were associated with better WBC, CFU, CD34+ cell and CAFC recovery (83-93%). This novel CB processing procedure appears to be easy, effective and particularly suitable for large-scale banking under GMP conditions.

Genomics of Dementia: APOE- and CYP2D6-Related Pharmacogenetics

PubMed Central

Cacabelos, Ramón; Martínez, Rocío; Fernández-Novoa, Lucía; Carril, Juan C.; Lombardi, Valter; Carrera, Iván; Corzo, Lola; Tellado, Iván; Leszek, Jerzy; McKay, Adam; Takeda, Masatoshi

2012-01-01

Dementia is a major problem of health in developed societies. Alzheimer's disease (AD), vascular dementia, and mixed dementia account for over 90% of the most prevalent forms of dementia. Both genetic and environmental factors are determinant for the phenotypic expression of dementia. AD is a complex disorder in which many different gene clusters may be involved. Most genes screened to date belong to different proteomic and metabolomic pathways potentially affecting AD pathogenesis. The ε4 variant of the APOE gene seems to be a major risk factor for both degenerative and vascular dementia. Metabolic factors, cerebrovascular disorders, and epigenetic phenomena also contribute to neurodegeneration. Five categories of genes are mainly involved in pharmacogenomics: genes associated with disease pathogenesis, genes associated with the mechanism of action of a particular drug, genes associated with phase I and phase II metabolic reactions, genes associated with transporters, and pleiotropic genes and/or genes associated with concomitant pathologies. The APOE and CYP2D6 genes have been extensively studied in AD. The therapeutic response to conventional drugs in patients with AD is genotype specific, with CYP2D6-PMs, CYP2D6-UMs, and APOE-4/4 carriers acting as the worst responders. APOE and CYP2D6 may cooperate, as pleiotropic genes, in the metabolism of drugs and hepatic function. The introduction of pharmacogenetic procedures into AD pharmacological treatment may help to optimize therapeutics. PMID:22482072

Infant Directed Speech Enhances Statistical Learning in Newborn Infants: An ERP Study

PubMed Central

Teinonen, Tuomas; Tervaniemi, Mari; Huotilainen, Minna

2016-01-01

Statistical learning and the social contexts of language addressed to infants are hypothesized to play important roles in early language development. Previous behavioral work has found that the exaggerated prosodic contours of infant-directed speech (IDS) facilitate statistical learning in 8-month-old infants. Here we examined the neural processes involved in on-line statistical learning and investigated whether the use of IDS facilitates statistical learning in sleeping newborns. Event-related potentials (ERPs) were recorded while newborns were exposed to12 pseudo-words, six spoken with exaggerated pitch contours of IDS and six spoken without exaggerated pitch contours (ADS) in ten alternating blocks. We examined whether ERP amplitudes for syllable position within a pseudo-word (word-initial vs. word-medial vs. word-final, indicating statistical word learning) and speech register (ADS vs. IDS) would interact. The ADS and IDS registers elicited similar ERP patterns for syllable position in an early 0–100 ms component but elicited different ERP effects in both the polarity and topographical distribution at 200–400 ms and 450–650 ms. These results provide the first evidence that the exaggerated pitch contours of IDS result in differences in brain activity linked to on-line statistical learning in sleeping newborns. PMID:27617967

Dysfunctional Sensory Modalities, Locus Coeruleus, and Basal Forebrain: Early Determinants that Promote Neuropathogenesis of Cognitive and Memory Decline and Alzheimer's Disease.

PubMed

Daulatzai, Mak Adam

2016-10-01

Sporadic Alzheimer's disease (AD) is a devastating neurodegenerative disorder. It is essential to unravel its etiology and pathogenesis. This should enable us to study the presymptomatic stages of the disease and to analyze and reverse the antemortem behavioral, memory, and cognitive dysfunction. Prima facie, an ongoing chronic vulnerability involving neural insult may lead normal elderly to mild cognitive impairment (MCI) and then to AD. Development of effective preventive and therapeutic strategies to thwart the disease pathology obviously requires a thorough delineation of underlying disruptive neuropathological processes. Our sensory capacity for touch, smell, taste, hearing, and vision declines with advancing age. Declines in different sensory attributes are considered here to be the primary "first-tier pathologies." Olfactory loss is among the first clinical signs of neurodegenerative diseases including AD and Parkinson's disease (PD). Sensory dysfunction in the aged promotes pathological disturbances in the locus coeruleus, basal forebrain, entorhinal cortex, hippocampus, and several key areas of neocortex and brainstem. Hence, sensory dysfunction is the pivotal factor that may upregulate cognitive and memory dysfunction. The age-related constellation of comorbid pathological factors may include apolipoprotein E (APOE) genotype, obesity, diabetes, hypertension, alcohol abuse, head trauma, and obstructive sleep apnea. The concepts and trajectories delineated here are the dynamic pillars of the current hypothesis presented-it postulates that the sensory decline, in conjunction with the above pathologies, is crucial in triggering neurodegeneration and promoting cognitive/memory dysfunction in aging and AD. The application of this thesis can be important in formulating new multifactorial preventive and treatment strategies (suggested here) in order to attenuate cognitive and memory decline and ameliorate pathological dysfunction in aging, MCI, and AD.

Predicting the conversion of mild cognitive impairment to Alzheimer's disease based on the volumetric measurements of the selected brain structures in magnetic resonance imaging.

PubMed

Nesteruk, Marta; Nesteruk, Tomasz; Styczyńska, Maria; Barczak, Anna; Mandecka, Monika; Walecki, Jerzy; Barcikowska-Kotowicz, Maria

2015-01-01

Mild cognitive impairment (MCI) is defined as abnormal cognitive state, but does not meet the criteria for the diagnosis of dementia. According to the new guidelines Alzheimer's disease (AD) involves not only dementia's phase but also predementia phase which is asymptomatic and pathological process in the brain is already present. For this reason it is very important to determine the suitability of markers which should be positive before onset of the first symptoms. One of these biomarkers is a structural magnetic resonance imaging with hippocampal volumetric assessment. The aim of this study was to investigate the usefulness of structural brain magnetic resonance imaging with volumetric assessment of the hippocampus and entorhinal cortex, posterior cingulate gyrus, parahippocampal gyrus, temporal gyri: superior, medial and inferior, to predict the conversion of MCI to AD. Magnetic resonance imaging of brain was performed at the baseline visit in 101 patients diagnosed with MCI. Clinic follow-ups were scheduled after 6.12 and 24 months. Amongst 101 patients with MCI, 17 (16.8%) converted into AD within two years of observation. All measured volumes were lower in converters than non-converters. Discriminant analysis was conducted and sensitivity for MCI conversion to AD was 64.7%, specificity 96.4%. 91% of patients were correctly classified (converter or non-converter). Volumetric measurements may help clinicians to predict MCI conversion to AD but due to low sensitivity it cannot be use separately. The study group requires further observation. Copyright © 2015 Polish Neurological Society. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.

Episodic Memory Dysfunction in Behavioral Variant Frontotemporal Dementia: A Clinical And FDG-PET Study.

PubMed

Fernández-Matarrubia, Marta; Matías-Guiu, Jordi A; Cabrera-Martín, María Nieves; Moreno-Ramos, Teresa; Valles-Salgado, María; Carreras, José Luis; Matías-Guiu, Jorge

2017-01-01

Episodic memory disturbance is still considered as an exclusion criterion for behavioral variant frontotemporal dementia (bvFTD), but growing evidence suggests that memory can be impaired. Our main purposes were to assess episodic memory in a group of bvFTD patients comparatively with Alzheimer's disease (AD) patients, and analyze the relationship between episodic memory and brain metabolism measured using positron emission tomography imaging with 18F-fluorodeoxyglucose (FDG-PET). Twenty-six bvFTD, 29 AD, and 24 healthy controls were included. Episodic memory was assessed by the Free and Cued Selective Reminding Test (FCSRT), which controls for effective encoding and measures memory consolidation processing. All participants underwent FDG-PET brain scans to provide data for voxel-based brain mapping analysis. Half of bvFTD patients had a deficit of total, free delayed, and total free delayed recall as severe as AD patients (amnestic-FTD). The other half had FCSRT scores similar to controls (non-amnestic-FTD). Imaging analyses revealed that amnestic-FTD showed bilateral lower metabolism than non-amnestic-FTD in anterior parahippocampal and inferior temporal gyri. Additionally, FCSRT total and total delayed scores were inversely correlated with parahippocampal metabolism in both bvFTD and AD. Besides, bvFTD showed an inverse association among FCSRT and inferior temporal metabolism. Our findings support that bvFTD could present a genuine amnesia affecting storage and consolidation abilities, which involves structures implicated in the Papez circuit, as occurs in AD, and also inferior temporal regions. These results contribute to understanding the mechanisms underpinning memory dysfunction in bvFTD, and may be relevant to further revisions of the current diagnostic criteria.

The AICD interacting protein DAB1 is up-regulated in Alzheimer frontal cortex brain samples and causes deregulation of proteins involved in gene expression changes.

PubMed

Müller, T; Loosse, C; Schrötter, A; Schnabel, A; Helling, S; Egensperger, R; Marcus, K

2011-08-01

AICD is the intracellular subdomain of the amyloid precursor protein thought to play a pivotal role as a potential transcription factor that might be of relevance for the pathophysiology of Alzheimer's disease. For its signal transduction potential AICD requires interacting proteins like FE65 and TIP60. However, many other proteins were described being able to bind to AICD. Here, we studied mRNA levels of AICD interacting proteins and found one of them (DAB1) strongly up-regulated in human post-mortem frontal cortex brain samples of AD patients. Subsequent cell culture experiments revealed that elevated DAB1 level results in the deregulation of the cellular proteome. We found the proliferation associated protein 2G4 as well as the guanine monophosphate synthetase (GMPS) significantly up-regulated in DAB1 over-expressing cells. Both proteins can be involved in cellular transcription processes supporting the hypothesis that DAB1 acts via modification of the AICD-dependent transcriptionally active complex. Of note, expression of the three components of the putative transcription complex (AICD, FE65, and TIP60 (AFT)) also revealed deregulation of the GMPS protein in an opposite fashion. Our results point to a putative relevance of AICD-dependent mechanisms in AD, caused by protein abundance changes of AICD interacting proteins, as shown for DAB1 in this work.