Recent Updates in the Treatment of Neurodegenerative Disorders Using Natural Compounds

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Mahmood Rasool

2014-01-01

Full Text Available Neurodegenerative diseases are characterized by protein aggregates and inflammation as well as oxidative stress in the central nervous system (CNS. Multiple biological processes are linked to neurodegenerative diseases such as depletion or insufficient synthesis of neurotransmitters, oxidative stress, abnormal ubiquitination. Furthermore, damaging of blood brain barrier (BBB in the CNS also leads to various CNS-related diseases. Even though synthetic drugs are used for the management of Alzheimer’s disease, Parkinson’s disease, autism, and many other chronic illnesses, they are not without side effects. The attentions of researchers have been inclined towards the phytochemicals, many of which have minimal side effects. Phytochemicals are promising therapeutic agents because many phytochemicals have anti-inflammatory, antioxidative as well as anticholinesterase activities. Various drugs of either synthetic or natural origin applied in the treatment of brain disorders need to cross the BBB before they can be used. This paper covers various researches related to phytochemicals used in the management of neurodegenerative disorders.

The cytoskeleton as a novel therapeutic target for old neurodegenerative disorders.

Science.gov (United States)

Eira, Jessica; Silva, Catarina Santos; Sousa, Mónica Mendes; Liz, Márcia Almeida

2016-06-01

Cytoskeleton defects, including alterations in microtubule stability, in axonal transport as well as in actin dynamics, have been characterized in several unrelated neurodegenerative conditions. These observations suggest that defects of cytoskeleton organization may be a common feature contributing to neurodegeneration. In line with this hypothesis, drugs targeting the cytoskeleton are currently being tested in animal models and in human clinical trials, showing promising effects. Drugs that modulate microtubule stability, inhibitors of posttranslational modifications of cytoskeletal components, specifically compounds affecting the levels of tubulin acetylation, and compounds targeting signaling molecules which regulate cytoskeleton dynamics, constitute the mostly addressed therapeutic interventions aiming at preventing cytoskeleton damage in neurodegenerative disorders. In this review, we will discuss in a critical perspective the current knowledge on cytoskeleton damage pathways as well as therapeutic strategies designed to revert cytoskeleton-related defects mainly focusing on the following neurodegenerative disorders: Alzheimer's Disease, Parkinson's Disease, Huntington's Disease, Amyotrophic Lateral Sclerosis and Charcot-Marie-Tooth Disease. Copyright © 2016 Elsevier Ltd. All rights reserved.

Lower urinary tract dysfunction in patients with parkinsonism and other neurodegenerative disorders

DEFF Research Database (Denmark)

Winge, Kristian

2015-01-01

of incontinence in Alzheimer's disease, but higher cognitive function including attention and self-management may play a role. Incontinence is a major risk factor for loss of independence. The complex pathophysiologic mechanisms of neurodegenerative disorders and hence complex symptoms play important roles......Progressive neurodegenerative disorders are devastating diseases with often fatal outcomes. Lower urinary tract symptoms (LUTS) add to morbidity and increase the risk of becoming dependent on the help of others (e.g., nursing-home referral). In Parkinson's disease (PD), the specific loss...... in LUTS and patient quality of life. Nocturia, incontinence, and urgency as well as poor bladder emptying are the most common symptoms. These symptoms may interact with the core symptoms of the disorders, increasing the risk of incontinence and infection. In rarer neurogenerative disorder LUTS may...

Transposable elements in TDP-43-mediated neurodegenerative disorders.

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Wanhe Li

Full Text Available Elevated expression of specific transposable elements (TEs has been observed in several neurodegenerative disorders. TEs also can be active during normal neurogenesis. By mining a series of deep sequencing datasets of protein-RNA interactions and of gene expression profiles, we uncovered extensive binding of TE transcripts to TDP-43, an RNA-binding protein central to amyotrophic lateral sclerosis (ALS and frontotemporal lobar degeneration (FTLD. Second, we find that association between TDP-43 and many of its TE targets is reduced in FTLD patients. Third, we discovered that a large fraction of the TEs to which TDP-43 binds become de-repressed in mouse TDP-43 disease models. We propose the hypothesis that TE mis-regulation contributes to TDP-43 related neurodegenerative diseases.

Glucose 6 phosphatase dehydrogenase (G6PD and neurodegenerative disorders: Mapping diagnostic and therapeutic opportunities

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Manju Tiwari

2017-12-01

Full Text Available Glucose 6 phosphate dehydrogenase (G6PD is a key and rate limiting enzyme in the pentose phosphate pathway (PPP. The physiological significance of enzyme is providing reduced energy to specific cells like erythrocyte by maintaining co-enzyme nicotinamide adenine dinucleotide phosphate (NADPH. There are preponderance research findings that demonstrate the enzyme (G6PD role in the energy balance, and it is associated with blood-related diseases and disorders, primarily the anemia resulted from G6PD deficiency. The X-linked genetic deficiency of G6PD and associated non-immune hemolytic anemia have been studied widely across the globe. Recent advancement in biology, more precisely neuroscience has revealed that G6PD is centrally involved in many neurological and neurodegenerative disorders. The neuroprotective role of the enzyme (G6PD has also been established, as well as the potential of G6PD in oxidative damage and the Reactive Oxygen Species (ROS produced in cerebral ischemia. Though G6PD deficiency remains a global health issue, however, a paradigm shift in research focusing the potential of the enzyme in neurological and neurodegenerative disorders will surely open a new avenue in diagnostics and enzyme therapeutics. Here, in this study, more emphasis was made on exploring the role of G6PD in neurological and inflammatory disorders as well as non-immune hemolytic anemia, thus providing diagnostic and therapeutic opportunities.

Motor Phenotype in Neurodegenerative Disorders: Gait and Balance Platform Study Design Protocol for the Ontario Neurodegenerative Research Initiative (ONDRI).

Science.gov (United States)

Montero-Odasso, Manuel; Pieruccini-Faria, Frederico; Bartha, Robert; Black, Sandra E; Finger, Elizabeth; Freedman, Morris; Greenberg, Barry; Grimes, David A; Hegele, Robert A; Hudson, Christopher; Kleinstiver, Peter W; Lang, Anthony E; Masellis, Mario; McLaughlin, Paula M; Munoz, Douglas P; Strother, Stephen; Swartz, Richard H; Symons, Sean; Tartaglia, Maria Carmela; Zinman, Lorne; Strong, Michael J; McIlroy, William

2017-01-01

The association of cognitive and motor impairments in Alzheimer's disease and other neurodegenerative diseases is thought to be related to damage in the common brain networks shared by cognitive and cortical motor control processes. These common brain networks play a pivotal role in selecting movements and postural synergies that meet an individual's needs. Pathology in this "highest level" of motor control produces abnormalities of gait and posture referred to as highest-level gait disorders. Impairments in cognition and mobility, including falls, are present in almost all neurodegenerative diseases, suggesting common mechanisms that still need to be unraveled. To identify motor-cognitive profiles across neurodegenerative diseases in a large cohort of patients. Cohort study that includes up to 500 participants, followed every year for three years, across five neurodegenerative disease groups: Alzheimer's disease/mild cognitive impairment, frontotemporal degeneration, vascular cognitive impairment, amyotrophic lateral sclerosis, and Parkinson's disease. Gait and balance will be assessed using accelerometers and electronic walkways, evaluated at different levels of cognitive and sensory complexity, using the dual-task paradigm. Comparison of cognitive and motor performances across neurodegenerative groups will allow the identification of motor-cognitive phenotypes through the standardized evaluation of gait and balance characteristics. As part of the Ontario Neurodegenerative Research Initiative (ONDRI), the gait and balance platform aims to identify motor-cognitive profiles across neurodegenerative diseases. Gait assessment, particularly while dual-tasking, will help dissect the cognitive and motor contribution in mobility and cognitive decline, progression to dementia syndromes, and future adverse outcomes including falls and mortality.

Research progress on the pathogenesis of rapid eye movement sleep behavior disorder and neurodegenerative diseases

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Hai-yang JIANG

2017-10-01

Full Text Available Rapid eye movement sleep behavior disorder (RBD is a sleep disorder characterized by the disappearance of muscle relaxation and enacting one's dreams during rapid eye movement (REM, with most of the dreams being violent or aggressive. Prevalence of RBD, based on population, is 0.38%-2.01%, but it becomes much higher in patients with neurodegenerative diseases, especially α - synucleinopathies. RBD may herald the emergence of α-synucleinopathies by decades, thus it may be used as an effective early marker of neurodegenerative diseases. In this review, we summarized the progress on the pathogenesis of RBD and its relationship with neurodegenerative diseases. DOI: 10.3969/j.issn.1672-6731.2017.10.003

Longitudinal Study of Neurodegenerative Disorders

Science.gov (United States)

2018-01-31

MLD; Krabbe Disease; ALD; MPS I; MPS II; MPS III; Vanishing White Matter Disease; GM3 Gangliosidosis; PKAN; Tay-Sachs Disease; NP Deficiency; Osteopetrosis; Alpha-Mannosidosis; Sandhoff Disease; Niemann-Pick Diseases; MPS IV; Gaucher Disease; GAN; GM1 Gangliosidoses; Morquio Disease; S-Adenosylhomocysteine Hydrolase Deficiency; Batten Disease; Pelizaeus-Merzbacher Disease; Leukodystrophy; Lysosomal Storage Diseases; Purine Nucleoside Phosphorylase Deficiency; Multiple Sulfatase Deficiency Disease

Nanomechanical study of amorphous and polycrystalline ALD HfO2 thin films

Science.gov (United States)

K. Tapily; J.E. Jakes; D. Gu; H. Baumgart; A.A. Elmustafa

2011-01-01

Thin films of hafnium oxide (HfO2) were deposited by atomic layer deposition (ALD). The structural properties of the deposited films were characterised by transmission electron microscopy (TEM) and X-ray diffraction (XRD). We investigated the effect of phase transformations induced by thermal treatments on the mechanical properties of ALD HfO

Iron in neurodegenerative disorders: being in the wrong place at the wrong time?

Science.gov (United States)

Apostolakis, Sotirios; Kypraiou, Anna-Maria

2017-11-27

Brain iron deposits have been reported consistently in imaging and histologic examinations of patients with neurodegenerative disorders. While the origins of this finding have not been clarified yet, it is speculated that impaired iron homeostasis or deficient transport mechanisms result in the accumulation of this highly toxic metal ultimately leading to formation of reactive oxygen species and cell death. On the other hand, there are also those who support that iron is just an incidental finding, a by product of neuronal loss. A literature review has been performed in order to present the key findings in support of the iron hypothesis of neurodegeneration, as well as to identify conditions causing or resulting from iron overload and compare and contrast their features with the most prominent neurodegenerative disorders. There is an abundance of experimental and observational findings in support of the hypothesis in question; however, as neurodegeneration is a rare incident of commonly encountered iron-associated disorders of the nervous system, and this metal is found in non-neurodegenerative disorders as well, it is possible that iron is the result or even an incidental finding in neurodegeneration. Understanding the underlying processes of iron metabolism in the brain and particularly its release during cell damage is expected to provide a deeper understanding of the origins of neurodegeneration in the years to come.

REM behaviour disorder detection associated with neurodegenerative diseases

DEFF Research Database (Denmark)

Kempfner, Jacob; Sorensen, Gertrud; Zoetmulder, Marielle

2010-01-01

Abnormal skeleton muscle activity during REM sleep is characterized as REM Behaviour Disorder (RBD), and may be an early marker for different neurodegenerative diseases. Early detection of RBD is therefore highly important, and in this ongoing study a semi-automatic method for RBD detection......, a computerized algorithm has been attempted implemented. By analysing the REM and non-REM EMG activity, using advanced signal processing tools combined with a statistical classifier, it is possible to discriminate normal and abnormal EMG activity. Due to the small number of patients, the overall performance...

ALD TiO x as a top-gate dielectric and passivation layer for InGaZnO115 ISFETs

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Pavlidis, S.; Bayraktaroglu, B.; Leedy, K.; Henderson, W.; Vogel, E.; Brand, O.

2017-11-01

The suitability of atomic layer deposited (ALD) titanium oxide (TiO x ) as a top gate dielectric and passivation layer for indium gallium zinc oxide (InGaZnO115) ion sensitive field effect transistors (ISFETs) is investigated. TiO x is an attractive barrier material, but reports of its use for InGaZnO thin film transistor (TFT) passivation have been conflicting thus far. In this work, it is found that the passivated TFT’s behavior depends on the TiO x deposition temperature, affecting critical device characteristics such as threshold voltage, field-effect mobility and sub-threshold swing. An O2 annealing step is required to recover TFT performance post passivation. It is also observed that the positive bias stress response of the passivated TFTs improves compared the original bare device. Secondary ion mass spectroscopy excludes the effects of hydrogen doping and inter-diffusion as sources of the temperature-dependent performance change, therefore indicating that oxygen gettering induced by TiO x passivation is the likely source of oxygen vacancies and, consequently, carriers in the InGaZnO film. It is also shown that potentiometric sensing using ALD TiO x exhibits a near Nernstian response to pH change, as well as minimizes V TH drift in TiO x passivated InGaZnO TFTs immersed in an acidic liquid. These results add to the understanding of InGaZnO passivation effects and underscore the potential for low-temperature fabricated InGaZnO ISFETs to be used as high-performance mobile chemical sensors.

PLA2G6, encoding a phospholipase A2, is mutated in neurodegenerative disorders with high brain iron

Science.gov (United States)

Morgan, Neil V; Westaway, Shawn K; Morton, Jenny E V; Gregory, Allison; Gissen, Paul; Sonek, Scott; Cangul, Hakan; Coryell, Jason; Canham, Natalie; Nardocci, Nardo; Zorzi, Giovanna; Pasha, Shanaz; Rodriguez, Diana; Desguerre, Isabelle; Mubaidin, Amar; Bertini, Enrico; Trembath, Richard C; Simonati, Alessandro; Schanen, Carolyn; Johnson, Colin A; Levinson, Barbara; Woods, C Geoffrey; Wilmot, Beth; Kramer, Patricia; Gitschier, Jane; Maher, Eamonn R; Hayflick, Susan J

2007-01-01

Neurodegenerative disorders with high brain iron include Parkinson disease, Alzheimer disease and several childhood genetic disorders categorized as neuroaxonal dystrophies. We mapped a locus for infantile neuroaxonal dystrophy (INAD) and neurodegeneration with brain iron accumulation (NBIA) to chromosome 22q12-q13 and identified mutations in PLA2G6, encoding a calcium-independent group VI phospholipase A2, in NBIA, INAD and the related Karak syndrome. This discovery implicates phospholipases in the pathogenesis of neurodegenerative disorders with iron dyshomeostasis. PMID:16783378

Neuroimaging Biomarkers of Neurodegenerative Diseases and Dementia

OpenAIRE

Risacher, Shannon L.; Saykin, Andrew J.

2013-01-01

Neurodegenerative disorders leading to dementia are common diseases that affect many older and some young adults. Neuroimaging methods are important tools for assessing and monitoring pathological brain changes associated with progressive neurodegenerative conditions. In this review, the authors describe key findings from neuroimaging studies (magnetic resonance imaging and radionucleotide imaging) in neurodegenerative disorders, including Alzheimer’s disease (AD) and prodromal stages, famili...

Van gen naar ziekte; X-gebonden adrenoleukodystrofie

NARCIS (Netherlands)

Engelen, M.; Kemp, S.; van Geel, B. M.

2008-01-01

X-linked adrenoleukodystrophy (X-ALD) is the most common peroxisomal disorder, characterized by impaired peroxisomal beta-oxidation, subsequent accumulation of very long-chain fatty acids (> 22 carbon atoms), and mutations in the ABCD1 gene. Clinical manifestations, diagnostic procedures and

Hippocampal-Prefrontal Circuit and Disrupted Functional Connectivity in Psychiatric and Neurodegenerative Disorders

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Ming Li

2015-01-01

Full Text Available In rodents, the hippocampus has been studied extensively as part of a brain system responsible for learning and memory, and the prefrontal cortex (PFC participates in numerous cognitive functions including working memory, flexibility, decision making, and rewarding learning. The neuronal projections from the hippocampus, either directly or indirectly, to the PFC, referred to as the hippocampal-prefrontal cortex (Hip-PFC circuit, play a critical role in cognitive and emotional regulation and memory consolidation. Although in certain psychiatric and neurodegenerative diseases, structural connectivity viewed by imaging techniques has been consistently found to be associated with clinical phenotype and disease severity, the focus has moved towards the investigation of connectivity correlates of molecular pathology and coupling of oscillation. Moreover, functional and structural connectivity measures have been emerging as potential intermediate biomarkers for neuronal disorders. In this review, we summarize progress on the anatomic, molecular, and electrophysiological characters of the Hip-PFC circuit in cognition and emotion processes with an emphasis on oscillation and functional connectivity, revealing a disrupted Hip-PFC connectivity and electrical activity in psychiatric and neurodegenerative disorders as a promising candidate of neural marker for neuronal disorders.

Therapeutic Role and Drug Delivery Potential of Neuroinflammation as a Target in Neurodegenerative Disorders.

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Singh, Abhijeet; Chokriwal, Ankit; Sharma, Madan Mohan; Jain, Devendra; Saxena, Juhi; Stephen, Bjorn John

2017-08-16

Neuroinflammation, the condition associated with the hyperactivity of immune cells within the CNS (central nervous system), has recently been linked to a host range of neurodegenerative disorders. Targeting neuroinflammation could be of prime importance as recent research highlights the beneficial aspects associated with modulating the inflammatory mediators associated with the CNS. One of the main obstructions in neuroinflammatory treatments is the hindrance posed by the blood-brain barrier for the delivery of drugs. Hence, research has focused on novel modes of transport for drugs to cross the barrier through drug delivery and nanotechnology approaches. In this Review, we highlight the therapeutic advancement made in the field of neurodegenerative disorders by focusing on the effect neuroinflammation treatment has on these conditions.

Atomic layer deposition (ALD) for optical nanofabrication

Science.gov (United States)

Maula, Jarmo

2010-02-01

ALD is currently one of the most rapidly developing fields of thin film technology. Presentation gives an overview of ALD technology for optical film deposition, highlighting benefits, drawbacks and peculiarities of the ALD, especially compared to PVD. Viewpoint is practical, based on experience gained from tens of different applications over the last few decades. ALD is not competing, but enabling technology to provide coatings, which are difficult for traditional technologies. Examples of such cases are films inside of tubes; double side deposition on the substrate; large area accurate coatings; decorative coating for 3D parts; conformal coatings on high aspect ratio surfaces or inside porous structures. Novel materials can be easily engineered by making modifications on molecular level. ALD coats large surfaces effectively and fast. Opposite to common view, it actually provides high throughput (coated area/time), when used properly with a batch and/or in-line tools. It is possible to use ALD for many micrometers thick films or even produce thin parts with competitive cost. Besides optical films ALD provides large variety of features for nanofabrication. For example pin hole free films for passivation and barrier applications and best available films for conformal coatings like planarization or to improve surface smoothness. High deposition repeatability even with subnanometer film structures helps fabrication. ALD enters to production mostly through new products, not yet existing on the market and so the application IP field is reasonably open. ALD is an enabling, mature technology to fabricate novel optical materials and to open pathways for new applications.

Regulation Mechanism of the ald Gene Encoding Alanine Dehydrogenase in Mycobacterium smegmatis and Mycobacterium tuberculosis by the Lrp/AsnC Family Regulator AldR.

Science.gov (United States)

Jeong, Ji-A; Hyun, Jaekyung; Oh, Jeong-Il

2015-10-01

In the presence of alanine, AldR, which belongs to the Lrp/AsnC family of transcriptional regulators and regulates ald encoding alanine dehydrogenase in Mycobacterium smegmatis, changes its quaternary structure from a homodimer to an octamer with an open-ring conformation. Four AldR-binding sites (O2, O1, O4, and O3) with a consensus sequence of GA/T-N2-NWW/WWN-N2-A/TC were identified upstream of the M. smegmatis ald gene by means of DNase I footprinting analysis. O2, O1, and O4 are required for the induction of ald expression by alanine, while O3 is directly involved in the repression of ald expression. In addition to O3, both O1 and O4 are also necessary for full repression of ald expression in the absence of alanine, due to cooperative binding of AldR dimers to O1, O4, and O3. Binding of a molecule of the AldR octamer to the ald control region was demonstrated to require two AldR-binding sites separated by three helical turns between their centers and one additional binding site that is in phase with the two AldR-binding sites. The cooperative binding of AldR dimers to DNA requires three AldR-binding sites that are aligned with a periodicity of three helical turns. The aldR gene is negatively autoregulated independently of alanine. Comparative analysis of ald expression of M. smegmatis and Mycobacterium tuberculosis in conjunction with sequence analysis of both ald control regions led us to suggest that the expression of the ald genes in both mycobacterial species is regulated by the same mechanism. In mycobacteria, alanine dehydrogenase (Ald) is the enzyme required both to utilize alanine as a nitrogen source and to grow under hypoxic conditions by maintaining the redox state of the NADH/NAD(+) pool. Expression of the ald gene was reported to be regulated by the AldR regulator that belongs to the Lrp/AsnC (feast/famine) family, but the underlying mechanism was unknown. This study revealed the regulation mechanism of ald in Mycobacterium smegmatis and

Effect of ALD surface treatment on structural and optical properties of ZnO nanorods

Energy Technology Data Exchange (ETDEWEB)

Jang, Jin-Tak [Department of Nano Systems Engineering, Center for Nano Manufacturing, Inje University, Obang-dong, Gimhae, Gyeongnam 621-749 (Korea, Republic of); Ryu, Hyukhyun, E-mail: hhryu@inje.ac.kr [Department of Nano Systems Engineering, Center for Nano Manufacturing, Inje University, Obang-dong, Gimhae, Gyeongnam 621-749 (Korea, Republic of); Lee, Won-Jae [Department of Materials and Components Engineering, Dong-Eui University, 995 Eomgwangno, Busanjin-gu, Busan 614-714 (Korea, Republic of)

2013-07-01

In this study, we report on the improvement of the optical and structural properties of ZnO nanorods using atomic layer deposition (ALD) on seed ZnO nanorods. After the initial growth of ZnO seed nanorods by hydrothermal synthesis for 1 h, a ZnO layer with a thickness of 10 nm was deposited on the initial ZnO seed nanorods using ALD. Then ZnO was further grown by hydrothermal synthesis for 4 h. The samples were characterized using room temperature photoluminescence (PL), field emission-scanning electron microscopy (FE-SEM) and X-ray diffraction (XRD). From this experiment, it was found that the ZnO nanorods with the ALD surface treatment show improved optical and structural properties when compared with the ZnO nanorods grown only by hydrothermal synthesis. The ZnO nanorods with the ALD surface treatment show about 2.7 times higher XRD (0 0 2) peak intensity, about 2.64 times higher PL NBE peak intensity, and about 3.1 times better NBE/DLE ratio than the ZnO nanorods without an ALD surface treatment.

Properties of slow traps of ALD Al{sub 2}O{sub 3}/GeO{sub x}/Ge nMOSFETs with plasma post oxidation

Energy Technology Data Exchange (ETDEWEB)

Ke, M., E-mail: kiramn@mosfet.t.u-tokyo.ac.jp; Yu, X.; Chang, C.; Takenaka, M.; Takagi, S. [Department of Electrical Engineering and Information Systems, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8656, Japan and JST-CREST, K' s Gobancho 6F, 7 Gobancho, Chiyoda-ku, Tokyo 102-0076 (Japan)

2016-07-18

The realization of Ge gate stacks with a small amount of slow trap density as well as thin equivalent oxide thickness and low interface state density (D{sub it}) is a crucial issue for Ge CMOS. In this study, we examine the properties of slow traps, particularly the location of slow traps, of Al{sub 2}O{sub 3}/GeO{sub x}/n-Ge and HfO{sub 2}/Al{sub 2}O{sub 3}/GeO{sub x}/n-Ge MOS interfaces with changing the process and structural parameters, formed by atomic layer deposition (ALD) of Al{sub 2}O{sub 3} and HfO{sub 2}/Al{sub 2}O{sub 3} combined with plasma post oxidation. It is found that the slow traps can locate in the GeO{sub x} interfacial layer, not in the ALD Al{sub 2}O{sub 3} layer. Furthermore, we study the time dependence of channel currents in the Ge n-MOSFETs with 5-nm-thick Al{sub 2}O{sub 3}/GeO{sub x}/Ge gate stacks, with changing the thickness of GeO{sub x}, in order to further clarify the position of slow traps. The time dependence of the current drift and the effective time constant of slow traps do not change among the MOSFETs with the different thickness GeO{sub x}, demonstrating that the slow traps mainly exist near the interfaces between Ge and GeO{sub x}.

[Sense of smell, physiological ageing and neurodegenerative diseases: II. Ageing and neurodegenerative diseases].

Science.gov (United States)

Fusari, A; Molina, J A

The sense of smell, which was once studied because of its biological and evolutionary significance, is today one of the centres of interest in research on normal and pathological ageing. The latest scientific developments point to an inversely proportional relationship between age and olfactory sensitivity. In certain neurodegenerative diseases this sensory decline is one of the first symptoms of the disorder and is correlated with the progression of the disease. In this work we are going to review the scientific knowledge on loss of sense of smell in ageing and in neurodegenerative diseases, with special attention given to Alzheimer's and Parkinson's diseases. A survey of studies that have examined the olfactory deficits in ageing and in some neurodegenerative diseases offers conclusive results about the presence of these impairments in the early stages of these disorders and even among healthy elderly persons. Although a number of causes contribute to these sensory losses in physiological ageing, a common neurological foundation has been proposed for Alzheimer's and Parkinson's diseases. Nevertheless, despite certain initial similarities, the olfactory deficits shown in these disorders seem to be qualitatively different.

Enhancing the stability of copper chromite catalysts for the selective hydrogenation of furfural using ALD overcoating

Energy Technology Data Exchange (ETDEWEB)

Zhang, Hongbo; Lei, Yu; Kropf, A. Jeremy; Zhang, Guanghui; Elam, Jeffrey W.; Miller, Jeffrey T.; Sollberger, Fred; Ribeiro, Fabio; Akatay, M. Cem; Stach, Eric A.; Dumesic, James A.; Marshall, Christopher L.

2014-08-01

The stability of a gas-phase furfural hydrogenation catalyst (CuCr2O4 center dot CuO) was enhanced by depositing a thin Al2O3 layer using atomic layer deposition (ALD). Based on temperature-programed reduction (TPR) measurements, the reduction temperature of Cu was raised significantly, and the activation energy for furfural reduction was decreased following the ALD treatment. Thinner ALD layers yielded higher furfural hydrogenation activities. X-ray absorption fine structure (XAFS) spectroscopy studies indicated that Cu1+/Cu-0 are the active species for furfural reduction.

Recent developments in the MOCVD and ALD of rare earth oxides and silicates

International Nuclear Information System (INIS)

Jones, Anthony C.; Aspinall, Helen C.; Chalker, Paul R.; Potter, Richard J.; Kukli, Kaupo; Rahtu, Antti; Ritala, Mikko; Leskelae, Markku

2005-01-01

Lanthanide, or rare-earth oxides are currently being investigated as alternatives to SiO 2 as the dielectric insulating layer in sub-0.1 μm CMOS technology. Metalorganic chemical vapour deposition (MOCVD) and atomic layer deposition (ALD) are promising techniques for the deposition of these high-κ dielectric oxides and in this paper some of our recent research into the MOCVD and ALD of PrO x , La 2 O 3 , Gd 2 O 3 , Nd 2 O 3 and their related silicates are reviewed

Nucleation, Growth Mechanism, and Controlled Coating of ZnO ALD onto Vertically Aligned N-Doped CNTs.

Science.gov (United States)

Silva, R M; Ferro, M C; Araujo, J R; Achete, C A; Clavel, G; Silva, R F; Pinna, N

2016-07-19

Zinc oxide thin films were deposited on vertically aligned nitrogen-doped carbon nanotubes (N-CNTs) by atomic layer deposition (ALD) from diethylzinc and water. The study demonstrates that doping CNTs with nitrogen is an effective approach for the "activation" of the CNTs surface for the ALD of metal oxides. Conformal ZnO coatings are already obtained after 50 ALD cycles, whereas at lower ALD cycles an island growth mode is observed. Moreover, the process allows for a uniform growth from the top to the bottom of the vertically aligned N-CNT arrays. X-ray photoelectron spectroscopy demonstrates that ZnO nucleation takes place at the N-containing species on the surface of the CNTs by the formation of the Zn-N bonds at the interface between the CNTs and the ZnO film.

X-linked adrenoleukodystrophy: clinical and laboratory findings in 15 Brazilian patients

Directory of Open Access Journals (Sweden)

Carmen R. Vargas

2000-06-01

Full Text Available Adrenoleukodystrophy (X-ALD is an X-linked recessively inherited peroxisomal disorder, phenotypically heterogeneous, characterized by progressive white-matter demyelination of the central nervous system and adrenocortical insufficiency. We investigated 15 male X-ALD patients varying in age from 7 to 39, diagnosed among 108 suspected patients referred for investigation. Plasma levels of very long chain fatty acids (VLCFA were measured at our laboratory using gas chromatography (GC. Eleven cases of childhood X-ALD and four cases of adrenomyeloneuropathy (AMN were diagnosed. Adrenal leukodystrophy insufficiency and limb weakness were the most frequent symptoms, appearing in 12, 8 and 6 of the patients, respectively. Physician awareness of X-ALD seems inadequate to judge by age at diagnosis and lengthy interval between the start of symptoms and diagnosis. This is the first published series of Brazilian patients with X-ALD. We determined signs and symptoms relevant for diagnosis, as early identification seems important for treatment outcome. In addition, diagnosis identifies carriers, who could benefit from genetic counselling and prenatal diagnosis.Adrenoleucodistrofia (X-ALD é uma desordem peroxissomal com padrão de herança ligada ao X, fenotipicamente heterogênea, caracterizada por uma progressiva desmielinização da substância branca do sistema nervoso central e por insuficiência adrenal. Foram investigados por nós 15 pacientes do sexo masculino com sinais clínicos sugestivos de X-ALD, com idade entre 7 e 39 anos, diagnosticados entre 108 pacientes encaminhados para investigação por suspeita clínica. Os níveis plasmáticos dos ácidos graxos de cadeia muito longa (VLCFA foram dosados em nosso laboratório através de cromatografia gasosa (GC. Onze (73% casos da forma infantil de X-ALD (ALD e 4 (27% casos de adrenomieloneuropatia (AMN foram diagnosticados. Insuficiência leucodistrofia adrenal e fraqueza muscular foram os sinais mais

DNA damage in neurodegenerative diseases

Energy Technology Data Exchange (ETDEWEB)

Coppedè, Fabio, E-mail: fabio.coppede@med.unipi.it; Migliore, Lucia, E-mail: lucia.migliore@med.unipi.it

2015-06-15

Highlights: • Oxidative DNA damage is one of the earliest detectable events in the neurodegenerative process. • The mitochondrial DNA is more vulnerable to oxidative attack than the nuclear DNA. • Cytogenetic damage has been largely documented in Alzheimer's disease patients. • The question of whether DNA damage is cause or consequence of neurodegeneration is still open. • Increasing evidence links DNA damage and repair with epigenetic phenomena. - Abstract: Following the observation of increased oxidative DNA damage in nuclear and mitochondrial DNA extracted from post-mortem brain regions of patients affected by neurodegenerative diseases, the last years of the previous century and the first decade of the present one have been largely dedicated to the search of markers of DNA damage in neuronal samples and peripheral tissues of patients in early, intermediate or late stages of neurodegeneration. Those studies allowed to demonstrate that oxidative DNA damage is one of the earliest detectable events in neurodegeneration, but also revealed cytogenetic damage in neurodegenerative conditions, such as for example a tendency towards chromosome 21 malsegregation in Alzheimer's disease. As it happens for many neurodegenerative risk factors the question of whether DNA damage is cause or consequence of the neurodegenerative process is still open, and probably both is true. The research interest in markers of oxidative stress was shifted, in recent years, towards the search of epigenetic biomarkers of neurodegenerative disorders, following the accumulating evidence of a substantial contribution of epigenetic mechanisms to learning, memory processes, behavioural disorders and neurodegeneration. Increasing evidence is however linking DNA damage and repair with epigenetic phenomena, thereby opening the way to a very attractive and timely research topic in neurodegenerative diseases. We will address those issues in the context of Alzheimer's disease

DNA damage in neurodegenerative diseases

International Nuclear Information System (INIS)

Coppedè, Fabio; Migliore, Lucia

2015-01-01

Highlights: • Oxidative DNA damage is one of the earliest detectable events in the neurodegenerative process. • The mitochondrial DNA is more vulnerable to oxidative attack than the nuclear DNA. • Cytogenetic damage has been largely documented in Alzheimer's disease patients. • The question of whether DNA damage is cause or consequence of neurodegeneration is still open. • Increasing evidence links DNA damage and repair with epigenetic phenomena. - Abstract: Following the observation of increased oxidative DNA damage in nuclear and mitochondrial DNA extracted from post-mortem brain regions of patients affected by neurodegenerative diseases, the last years of the previous century and the first decade of the present one have been largely dedicated to the search of markers of DNA damage in neuronal samples and peripheral tissues of patients in early, intermediate or late stages of neurodegeneration. Those studies allowed to demonstrate that oxidative DNA damage is one of the earliest detectable events in neurodegeneration, but also revealed cytogenetic damage in neurodegenerative conditions, such as for example a tendency towards chromosome 21 malsegregation in Alzheimer's disease. As it happens for many neurodegenerative risk factors the question of whether DNA damage is cause or consequence of the neurodegenerative process is still open, and probably both is true. The research interest in markers of oxidative stress was shifted, in recent years, towards the search of epigenetic biomarkers of neurodegenerative disorders, following the accumulating evidence of a substantial contribution of epigenetic mechanisms to learning, memory processes, behavioural disorders and neurodegeneration. Increasing evidence is however linking DNA damage and repair with epigenetic phenomena, thereby opening the way to a very attractive and timely research topic in neurodegenerative diseases. We will address those issues in the context of Alzheimer's disease

Comparative Incidence of Conformational, Neurodegenerative Disorders.

Directory of Open Access Journals (Sweden)

Jesús de Pedro-Cuesta

Full Text Available The purpose of this study was to identify incidence and survival patterns in conformational neurodegenerative disorders (CNDDs.We identified 2563 reports on the incidence of eight conditions representing sporadic, acquired and genetic, protein-associated, i.e., conformational, NDD groups and age-related macular degeneration (AMD. We selected 245 papers for full-text examination and application of quality criteria. Additionally, data-collection was completed with detailed information from British, Swedish, and Spanish registries on Creutzfeldt-Jakob disease (CJD forms, amyotrophic lateral sclerosis (ALS, and sporadic rapidly progressing neurodegenerative dementia (sRPNDd. For each condition, age-specific incidence curves, age-adjusted figures, and reported or calculated median survival were plotted and examined.Based on 51 valid reported and seven new incidence data sets, nine out of eleven conditions shared specific features. Age-adjusted incidence per million person-years increased from ≤1.5 for sRPNDd, different CJD forms and Huntington's disease (HD, to 1589 and 2589 for AMD and Alzheimer's disease (AD respectively. Age-specific profiles varied from (a symmetrical, inverted V-shaped curves for low incidences to (b those increasing with age for late-life sporadic CNDDs and for sRPNDd, with (c a suggested, intermediate, non-symmetrical inverted V-shape for fronto-temporal dementia and Parkinson's disease. Frequently, peak age-specific incidences from 20-24 to ≥90 years increased with age at onset and survival. Distinct patterns were seen: for HD, with a low incidence, levelling off at middle age, and long median survival, 20 years; and for sRPNDd which displayed the lowest incidence, increasing with age, and a short median disease duration.These results call for a unified population view of NDDs, with an age-at-onset-related pattern for acquired and sporadic CNDDs. The pattern linking age at onset to incidence magnitude and survival might

Comparative Incidence of Conformational, Neurodegenerative Disorders

Science.gov (United States)

de Pedro-Cuesta, Jesús; Rábano, Alberto; Martínez-Martín, Pablo; Ruiz-Tovar, María; Alcalde-Cabero, Enrique; Almazán-Isla, Javier; Avellanal, Fuencisla; Calero, Miguel

2015-01-01

Background The purpose of this study was to identify incidence and survival patterns in conformational neurodegenerative disorders (CNDDs). Methods We identified 2563 reports on the incidence of eight conditions representing sporadic, acquired and genetic, protein-associated, i.e., conformational, NDD groups and age-related macular degeneration (AMD). We selected 245 papers for full-text examination and application of quality criteria. Additionally, data-collection was completed with detailed information from British, Swedish, and Spanish registries on Creutzfeldt-Jakob disease (CJD) forms, amyotrophic lateral sclerosis (ALS), and sporadic rapidly progressing neurodegenerative dementia (sRPNDd). For each condition, age-specific incidence curves, age-adjusted figures, and reported or calculated median survival were plotted and examined. Findings Based on 51 valid reported and seven new incidence data sets, nine out of eleven conditions shared specific features. Age-adjusted incidence per million person-years increased from ≤1.5 for sRPNDd, different CJD forms and Huntington's disease (HD), to 1589 and 2589 for AMD and Alzheimer's disease (AD) respectively. Age-specific profiles varied from (a) symmetrical, inverted V-shaped curves for low incidences to (b) those increasing with age for late-life sporadic CNDDs and for sRPNDd, with (c) a suggested, intermediate, non-symmetrical inverted V-shape for fronto-temporal dementia and Parkinson's disease. Frequently, peak age-specific incidences from 20–24 to ≥90 years increased with age at onset and survival. Distinct patterns were seen: for HD, with a low incidence, levelling off at middle age, and long median survival, 20 years; and for sRPNDd which displayed the lowest incidence, increasing with age, and a short median disease duration. Interpretation These results call for a unified population view of NDDs, with an age-at-onset-related pattern for acquired and sporadic CNDDs. The pattern linking age at onset to

Immune mediated disorders in women with a fragile X expansion and FXTAS.

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Jalnapurkar, Isha; Rafika, Nuva; Tassone, Flora; Hagerman, Randi

2015-01-01

Premutation alleles in fragile X mental retardation 1 (FMR1) can cause the late-onset neurodegenerative disorder, fragile X-associated tremor ataxia syndrome (FXTAS) and/or the fragile X-associated primary ovarian insufficiency in approximately 20% of heterozygotes. Heterozygotes of the FMR1 premutation have a higher incidence of immune mediated disorders such as autoimmune thyroid disorder, especially when accompanied by FXTAS motor signs. We describe the time course of symptoms of immune mediated disorders and the subsequent development of FXTAS in four women with an FMR1 CGG expansion, including three with the premutation and one with a gray zone expansion. These patients developed an immune mediated disorder followed by neurological symptoms that become consistent with FXTAS. In all patients we observed a pattern involving an initial appearance of disease symptoms-often after a period of heightened stress (depression, anxiety, divorce, general surgery) followed by the onset of tremor and/or ataxia. Immune mediated diseases are associated with the manifestations of FXTAS temporally, although further studies are needed to clarify this association. If a cause and effect relationship can be established, treatment of pre-existing immune mediated disorders may benefit patients with pathogenic FMR1 mutations. © 2014 Wiley Periodicals, Inc.

Mass spectrometry-based metabolomics: Targeting the crosstalk between gut microbiota and brain in neurodegenerative disorders.

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Luan, Hemi; Wang, Xian; Cai, Zongwei

2017-11-12

Metabolomics seeks to take a "snapshot" in a time of the levels, activities, regulation and interactions of all small molecule metabolites in response to a biological system with genetic or environmental changes. The emerging development in mass spectrometry technologies has shown promise in the discovery and quantitation of neuroactive small molecule metabolites associated with gut microbiota and brain. Significant progress has been made recently in the characterization of intermediate role of small molecule metabolites linked to neural development and neurodegenerative disorder, showing its potential in understanding the crosstalk between gut microbiota and the host brain. More evidence reveals that small molecule metabolites may play a critical role in mediating microbial effects on neurotransmission and disease development. Mass spectrometry-based metabolomics is uniquely suitable for obtaining the metabolic signals in bidirectional communication between gut microbiota and brain. In this review, we summarized major mass spectrometry technologies including liquid chromatography-mass spectrometry, gas chromatography-mass spectrometry, and imaging mass spectrometry for metabolomics studies of neurodegenerative disorders. We also reviewed the recent advances in the identification of new metabolites by mass spectrometry and metabolic pathways involved in the connection of intestinal microbiota and brain. These metabolic pathways allowed the microbiota to impact the regular function of the brain, which can in turn affect the composition of microbiota via the neurotransmitter substances. The dysfunctional interaction of this crosstalk connects neurodegenerative diseases, including Parkinson's disease, Alzheimer's disease and Huntington's disease. The mass spectrometry-based metabolomics analysis provides information for targeting dysfunctional pathways of small molecule metabolites in the development of the neurodegenerative diseases, which may be valuable for the

Support system and method for detecting neurodegenerative disorder

DEFF Research Database (Denmark)

2013-01-01

The present invention relates to a system and a method for detection of abnormal motor activity during REM sleep, and further to systems and method for assisting in detecting neurodegenerative disorders such as Parkinson's. One embodiment relates to a method for detection of abnormal motor activity...... during REM sleep comprising the steps of: performing polysomnographic recordings of a sleeping subject, thereby obtaining one or more electromyography (EMG) derivations, preferably surface EMG recordings, and one or more EEG derivations, and/or one or more electrooculargraphy (EOG) derivations, detecting...... one or more REM sleep stages, preferably based on the one or more EEG and/or EOG derivations, determining the level of muscle activity during the one or more REM sleep stages based on the one or more EMG derivations, wherein a subject having an increased level of muscle activity during REM sleep...

Neural stem cell therapy for neurodegenerative disorders: The role of neurotrophic support.

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Marsh, Samuel E; Blurton-Jones, Mathew

2017-06-01

Neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, and Huntington's disease currently affect tens of millions of people worldwide. Unfortunately, as the world's population ages, the incidence of many of these diseases will continue to rise and is expected to more than double by 2050. Despite significant research and a growing understanding of disease pathogenesis, only a handful of therapies are currently available and all of them provide only transient benefits. Thus, there is an urgent need to develop novel disease-modifying therapies to prevent the development or slow the progression of these debilitating disorders. A growing number of pre-clinical studies have suggested that transplantation of neural stem cells (NSCs) could offer a promising new therapeutic approach for neurodegeneration. While much of the initial excitement about this strategy focused on the use of NSCs to replace degenerating neurons, more recent studies have implicated NSC-mediated changes in neurotrophins as a major mechanism of therapeutic efficacy. In this mini-review we will discuss recent work that examines the ability of NSCs to provide trophic support to disease-effected neuronal populations and synapses in models of neurodegeneration. We will then also discuss some of key challenges that remain before NSC-based therapies for neurodegenerative diseases can be translated toward potential clinical testing. Copyright © 2017 Elsevier Ltd. All rights reserved.

Memory-rescuing effects of cannabidiol in an animal model of cognitive impairment relevant to neurodegenerative disorders.

Science.gov (United States)

Fagherazzi, Elen V; Garcia, Vanessa A; Maurmann, Natasha; Bervanger, Thielly; Halmenschlager, Luis H; Busato, Stefano B; Hallak, Jaime E; Zuardi, Antônio W; Crippa, José A; Schröder, Nadja

2012-02-01

Cannabidiol, the main nonpsychotropic constituent of Cannabis sativa, possesses a large number of pharmacological effects including anticonvulsive, sedative, hypnotic, anxiolytic, antipsychotic, anti-inflammatory, and neuroprotective, as demonstrated in clinical and preclinical studies. Many neurodegenerative disorders involve cognitive deficits, and this has led to interest in whether cannabidiol could be useful in the treatment of memory impairment associated to these diseases. We used an animal model of cognitive impairment induced by iron overload in order to test the effects of cannabidiol in memory-impaired rats. Rats received vehicle or iron at postnatal days 12-14. At the age of 2 months, they received an acute intraperitoneal injection of vehicle or cannabidiol (5.0 or 10.0 mg/kg) immediately after the training session of the novel object recognition task. In order to investigate the effects of chronic cannabidiol, iron-treated rats received daily intraperitoneal injections of cannabidiol for 14 days. Twenty-four hours after the last injection, they were submitted to object recognition training. Retention tests were performed 24 h after training. A single acute injection of cannabidiol at the highest dose was able to recover memory in iron-treated rats. Chronic cannabidiol improved recognition memory in iron-treated rats. Acute or chronic cannabidiol does not affect memory in control rats. The present findings provide evidence suggesting the potential use of cannabidiol for the treatment of cognitive decline associated with neurodegenerative disorders. Further studies, including clinical trials, are warranted to determine the usefulness of cannabidiol in humans suffering from neurodegenerative disorders.

High speed atmospheric pressure ALD for industrial scale solar cell passivation

NARCIS (Netherlands)

Vermang, B.; Rothschild, A.; Racz, A.; John, J.; Poortmans, J.; Mertens, R.; Poodt, P.; Tiba, M.V.; Roozeboom, F.

2010-01-01

A next generation material for surface passivation is atomic layer deposition (ALD) Al2O3. However, conventional time-resolved ALD is limited by its low deposition rate. Therefore, an experimental high-deposition-rate prototype ALD reactor based on the spatially-separated ALD principle has been

Integration of Nanobots Into Neural Circuits As a Future Therapy for Treating Neurodegenerative Disorders.

Science.gov (United States)

Saniotis, Arthur; Henneberg, Maciej; Sawalma, Abdul-Rahman

2018-01-01

Recent neuroscientific research demonstrates that the human brain is becoming altered by technological devices. Improvements in biotechnologies and computer based technologies are now increasing the likelihood for the development of brain augmentation devices in the next 20 years. We have developed the idea of an "Endomyccorhizae like interface" (ELI) nanocognitive device as a new kind of future neuroprosthetic which aims to facilitate neuronal network properties in individuals with neurodegenerative disorders. The design of our ELI may overcome the problems of invasive neuroprosthetics, post-operative inflammation, and infection and neuroprosthetic degradation. The method in which our ELI is connected and integrated to neuronal networks is based on a mechanism similar to endomyccorhizae which is the oldest and most widespread form of plant symbiosis. We propose that the principle of Endomyccorhizae could be relevant for developing a crossing point between the ELI and neuronal networks. Similar to endomyccorhizae the ELI will be designed to form webs, each of which connects multiple neurons together. The ELI will function to sense action potentials and deliver it to the neurons it connects to. This is expected to compensate for neuronal loss in some neurodegenerative disorders, such as Alzheimer's disease and Parkinson's disease.

Sleep disturbance in mental health problems and neurodegenerative disease

Directory of Open Access Journals (Sweden)

Anderson KN

2013-05-01

Full Text Available Kirstie N Anderson1 Andrew J Bradley2,3 1Department of Neurology, Newcastle Upon Tyne Hospitals NHS Trust, Newcastle Upon Tyne, UK; 2Eli Lilly and Company Limited, Lilly House, Basingstoke, UK; 3Institute of Neuroscience, Newcastle University, Newcastle Upon Tyne, UK Abstract: Sleep has been described as being of the brain, by the brain, and for the brain. This fundamental neurobiological behavior is controlled by homeostatic and circadian (24-hour processes and is vital for normal brain function. This review will outline the normal sleep–wake cycle, the changes that occur during aging, and the specific patterns of sleep disturbance that occur in association with both mental health disorders and neurodegenerative disorders. The role of primary sleep disorders such as insomnia, obstructive sleep apnea, and REM sleep behavior disorder as potential causes or risk factors for particular mental health or neurodegenerative problems will also be discussed. Keywords: sleep, mental health, neurodegenerative disorders, cognition

Glutamate and Neurodegenerative Disease

Science.gov (United States)

Schaeffer, Eric; Duplantier, Allen

As the main excitatory neurotransmitter in the mammalian central nervous system, glutamate is critically involved in most aspects of CNS function. Given this critical role, it is not surprising that glutamatergic dysfunction is associated with many CNS disorders. In this chapter, we review the literature that links aberrant glutamate neurotransmission with CNS pathology, with a focus on neurodegenerative diseases. The biology and pharmacology of the various glutamate receptor families are discussed, along with data which links these receptors with neurodegenerative conditions. In addition, we review progress that has been made in developing small molecule modulators of glutamate receptors and transporters, and describe how these compounds have helped us understand the complex pharmacology of glutamate in normal CNS function, as well as their potential for the treatment of neurodegenerative diseases.

Essential Tremor: A Neurodegenerative Disease?

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Julian Benito-Leon

2014-07-01

Full Text Available Background: Essential tremor (ET is one of the most common neurological disorders among adults, and is the most common of the many tremor disorders. It has classically been viewed as a benign monosymptomatic condition, yet over the past decade, a growing body of evidence indicates that ET is a progressive condition that is clinically heterogeneous, as it may be associated with a spectrum of clinical features, with both motor and non‐motor elements. In this review, I will describe the most significant emerging milestones in research which, when taken together, suggest that ET is a neurodegenerative condition.Methods: A PubMed search conducted in June 2014 crossing the terms “essential tremor” (ET and “neurodegenerative” yielded 122 entries, 20 of which included the term “neurodegenerative” in the article title. This was supplemented by articles in the author's files that pertained to this topic.Results/Discussion: There is an open and active dialogue in the medical community as to whether ET is a neurodegenerative disease, with considerable evidence in favor of this. Specifically, ET is a progressive disorder of aging associated with neuronal loss (reduction in Purkinje cells as well as other post‐mortem changes that occur in traditional neurodegenerative disorders. Along with this, advanced neuroimaging techniques are now demonstrating distinct structural changes, several of which are consistent with neuronal loss, in patients with ET. However, further longitudinal clinical and neuroimaging longitudinal studies to assess progression are required.

Coenzyme Q10 effects in neurodegenerative disease

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Meredith Spindler

2009-11-01

Full Text Available Meredith Spindler1, M Flint Beal1,2, Claire Henchcliffe1,21Department of Neurology, 2Department of Neuroscience, Weill Medical College of Cornell University, New York, NY, USAAbstract: Coenzyme Q10 (CoQ10 is an essential cofactor in the mitochondrial respiratory chain, and as a dietary supplement it has recently gained attention for its potential role in the treatment of neurodegenerative disease. Evidence for mitochondrial dysfunction in neurodegenerative disorders derives from animal models, studies of mitochondria from patients, identification of genetic defects in patients with neurodegenerative disease, and measurements of markers of oxidative stress. Studies of in vitro models of neuronal toxicity and animal models of neurodegenerative disorders have demonstrated potential neuroprotective effects of CoQ10. With this data in mind, several clinical trials of CoQ10 have been performed in Parkinson’s disease and atypical Parkinson’s syndromes, Huntington’s disease, Alzheimer disease, Friedreich’s ataxia, and amyotrophic lateral sclerosis, with equivocal findings. CoQ10 is widely available in multiple formulations and is very well tolerated with minimal adverse effects, making it an attractive potential therapy. Phase III trials of high-dose CoQ10 in large sample sizes are needed to further ascertain the effects of CoQ10 in neurodegenerative diseases.Keywords: coenzyme Q10, neurodegenerative disease, Parkinson’s disease, Huntington’s disease, mitochondrial dysfunction

Progression of abnormalities in adrenomyeloneuropathy and neurologically asymptomatic X-linked adrenoleukodystrophy despite treatment with "Lorenzo's oil"

NARCIS (Netherlands)

van Geel, B. M.; Assies, J.; Haverkort, E. B.; Koelman, J. H.; Verbeeten, B.; Wanders, R. J.; Barth, P. G.

1999-01-01

OBJECTIVES: X-linked adrenoleukodystrophy (X-ALD) is an inherited disorder of peroxisomal fatty acid oxidation, biochemically characterised by the accumulation of saturated very long chain fatty acids (VLCFAs), particularly hexacosanoic acid (C26:0). Dietary treatment with a 4:1 mixture of

The Enhanced Catalytic Performance and Stability of Rh/γ-Al₂O₃ Catalyst Synthesized by Atomic Layer Deposition (ALD) for Methane Dry Reforming.

Science.gov (United States)

Li, Yunlin; Jiang, Jing; Zhu, Chaosheng; Li, Lili; Li, Quanliang; Ding, Yongjie; Yang, Weijie

2018-01-22

Rh/γ-Al₂O₃ catalysts were synthesized by both incipient wetness impregnation (IWI) and atomic layer deposition (ALD). The TEM images of the two catalysts showed that the catalyst from ALD had smaller particle size, and narrower size distribution. The surface chemical states of both catalysts were investigated by both XPS and X-ray Absorption Near Edge Structure (XANES), and the catalyst from IWI had higher concentration of Rh 3+ than that from ALD. The catalytic performance of both catalysts was tested in the dry reforming of methane reaction. The catalyst from ALD showed a higher conversion and selectivity than that from IWI. The stability testing results indicated that the catalyst from ALD showed similar stability to that from IWI at 500 °C, but higher stability at 800 °C.

X-linked adrenoleukodystrophy in heterozygous female patients: women are not just carriers

Directory of Open Access Journals (Sweden)

Charles Marques Lourenço

2012-07-01

Full Text Available X-linked adrenoleukodystrophy (X-ALD is a recessive X-linked disorder associated with marked phenotypic variability. Female carriers are commonly thought to be normal or only mildly affected, but their disease still needs to be better described and systematized. OBJECTIVES: To review and systematize the clinical features of heterozygous women followed in a Neurogenetics Clinic. METHODS: We reviewed the clinical, biochemical, and neuroradiological data of all women known to have X-ADL. RESULTS: The nine women identified were classified into three groups: with severe and aggressive diseases; with slowly progressive, spastic paraplegia; and with mildly decreased vibratory sensation, brisk reflexes, and no complaints. Many of these women did not have a known family history of X-ALD. CONCLUSIONS: Heterozygous women with X-ADL have a wide spectrum of clinical manifestations, ranging from mild to severe phenotypes.

ALDS 1978 panel review. [PNL

Energy Technology Data Exchange (ETDEWEB)

Hall, D.L. (ed.)

1979-08-01

Pacific Northwest Laboratory (PNL) is examining the analysis of large data sets (ALDS). After one year's work, a panel was convened to evaluate the project. This document is the permanent record of that panel review. It consists of edited transcripts of presentations made to the panel by the PNL staff, a summary of the responses of the panel to these presentations, and PNL's plans for the development of the ALDS project. The representations of the PNL staff described various aspects of the project and/or the philosophy surrounding the project. Supporting materials appear in appendixes. 20 figures, 4 tables. (RWR)

Disordered APP metabolism and neurovasculature in trauma and aging: Combined risks for chronic neurodegenerative disorders.

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Ikonomovic, Milos D; Mi, Zhiping; Abrahamson, Eric E

2017-03-01

Traumatic brain injury (TBI), advanced age, and cerebral vascular disease are factors conferring increased risk for late onset Alzheimer's disease (AD). These conditions are also related pathologically through multiple interacting mechanisms. The hallmark pathology of AD consists of pathological aggregates of amyloid-β (Aβ) peptides and tau proteins. These molecules are also involved in neuropathology of several other chronic neurodegenerative diseases, and are under intense investigation in the aftermath of TBI as potential contributors to the risk for developing AD and chronic traumatic encephalopathy (CTE). The pathology of TBI is complex and dependent on injury severity, age-at-injury, and length of time between injury and neuropathological evaluation. In addition, the mechanisms influencing pathology and recovery after TBI likely involve genetic/epigenetic factors as well as additional disorders or comorbid states related to age and central and peripheral vascular health. In this regard, dysfunction of the aging neurovascular system could be an important link between TBI and chronic neurodegenerative diseases, either as a precipitating event or related to accumulation of AD-like pathology which is amplified in the context of aging. Thus with advanced age and vascular dysfunction, TBI can trigger self-propagating cycles of neuronal injury, pathological protein aggregation, and synaptic loss resulting in chronic neurodegenerative disease. In this review we discuss evidence supporting TBI and aging as dual, interacting risk factors for AD, and the role of Aβ and cerebral vascular dysfunction in this relationship. Evidence is discussed that Aβ is involved in cyto- and synapto-toxicity after severe TBI, and that its chronic effects are potentiated by aging and impaired cerebral vascular function. From a therapeutic perspective, we emphasize that in the fields of TBI- and aging-related neurodegeneration protective strategies should include preservation of

Integration of Nanobots Into Neural Circuits As a Future Therapy for Treating Neurodegenerative Disorders

Directory of Open Access Journals (Sweden)

Arthur Saniotis

2018-03-01

Full Text Available Recent neuroscientific research demonstrates that the human brain is becoming altered by technological devices. Improvements in biotechnologies and computer based technologies are now increasing the likelihood for the development of brain augmentation devices in the next 20 years. We have developed the idea of an “Endomyccorhizae like interface” (ELI nanocognitive device as a new kind of future neuroprosthetic which aims to facilitate neuronal network properties in individuals with neurodegenerative disorders. The design of our ELI may overcome the problems of invasive neuroprosthetics, post-operative inflammation, and infection and neuroprosthetic degradation. The method in which our ELI is connected and integrated to neuronal networks is based on a mechanism similar to endomyccorhizae which is the oldest and most widespread form of plant symbiosis. We propose that the principle of Endomyccorhizae could be relevant for developing a crossing point between the ELI and neuronal networks. Similar to endomyccorhizae the ELI will be designed to form webs, each of which connects multiple neurons together. The ELI will function to sense action potentials and deliver it to the neurons it connects to. This is expected to compensate for neuronal loss in some neurodegenerative disorders, such as Alzheimer's disease and Parkinson's disease.

Pain in Neurodegenerative Disease : Current Knowledge and Future Perspectives

NARCIS (Netherlands)

de Tommaso, Marina; Arendt-Nielsen, Lars; Defrin, Ruth; Kunz, Miriam; Pickering, Gisele; Valeriani, Massimiliano

2016-01-01

Neurodegenerative diseases are going to increase as the life expectancy is getting longer. The management of neurodegenerative diseases such as Alzheimer's disease (AD) and other dementias, Parkinson's disease (PD) and PD related disorders, motor neuron diseases (MND), Huntington's disease (HD),

Does Vitamin C Influence Neurodegenerative Diseases and Psychiatric Disorders?

Science.gov (United States)

Luchowska-Kocot, Dorota; Kiełczykowska, Małgorzata; Musik, Irena; Kurzepa, Jacek

2017-01-01

Vitamin C (Vit C) is considered to be a vital antioxidant molecule in the brain. Intracellular Vit C helps maintain integrity and function of several processes in the central nervous system (CNS), including neuronal maturation and differentiation, myelin formation, synthesis of catecholamine, modulation of neurotransmission and antioxidant protection. The importance of Vit C for CNS function has been proven by the fact that targeted deletion of the sodium-vitamin C co-transporter in mice results in widespread cerebral hemorrhage and death on post-natal day one. Since neurological diseases are characterized by increased free radical generation and the highest concentrations of Vit C in the body are found in the brain and neuroendocrine tissues, it is suggested that Vit C may change the course of neurological diseases and display potential therapeutic roles. The aim of this review is to update the current state of knowledge of the role of vitamin C on neurodegenerative diseases including Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, multiple sclerosis and amyotrophic sclerosis, as well as psychiatric disorders including depression, anxiety and schizophrenia. The particular attention is attributed to understanding of the mechanisms underlying possible therapeutic properties of ascorbic acid in the presented disorders. PMID:28654017

Development and validation of brain and spinal cord vector and cell-delivery techniques in pre-clinical minipig models of neurodegenerative disorders

Czech Academy of Sciences Publication Activity Database

Juhás, Štefan; Juhásová, Jana; Klíma, Jiří; Maršala, M.; Maršala, S.; Atsushi, Y.; Johe, K.; Motlík, Jan

2015-01-01

Roč. 78, Suppl 2 (2015), s. 9-10 ISSN 1210-7859. [Conference on Animal Models for neurodegenerative Diseases /3./. 08.11.2015-10.11.2015, Liblice] R&D Projects: GA MŠk ED2.1.00/03.0124; GA MŠk(CZ) 7F14308 Institutional support: RVO:67985904 Keywords : minipig models of neurodegenerative disorders * brin and spinal cord cell delivery techniques Subject RIV: EB - Genetics ; Molecular Biology

Open Science Meets Stem Cells: A New Drug Discovery Approach for Neurodegenerative Disorders.

Science.gov (United States)

Han, Chanshuai; Chaineau, Mathilde; Chen, Carol X-Q; Beitel, Lenore K; Durcan, Thomas M

2018-01-01

Neurodegenerative diseases are a challenge for drug discovery, as the biological mechanisms are complex and poorly understood, with a paucity of models that faithfully recapitulate these disorders. Recent advances in stem cell technology have provided a paradigm shift, providing researchers with tools to generate human induced pluripotent stem cells (iPSCs) from patient cells. With the potential to generate any human cell type, we can now generate human neurons and develop "first-of-their-kind" disease-relevant assays for small molecule screening. Now that the tools are in place, it is imperative that we accelerate discoveries from the bench to the clinic. Using traditional closed-door research systems raises barriers to discovery, by restricting access to cells, data and other research findings. Thus, a new strategy is required, and the Montreal Neurological Institute (MNI) and its partners are piloting an "Open Science" model. One signature initiative will be that the MNI biorepository will curate and disseminate patient samples in a more accessible manner through open transfer agreements. This feeds into the MNI open drug discovery platform, focused on developing industry-standard assays with iPSC-derived neurons. All cell lines, reagents and assay findings developed in this open fashion will be made available to academia and industry. By removing the obstacles many universities and companies face in distributing patient samples and assay results, our goal is to accelerate translational medical research and the development of new therapies for devastating neurodegenerative disorders.

Open Science Meets Stem Cells: A New Drug Discovery Approach for Neurodegenerative Disorders

Directory of Open Access Journals (Sweden)

Chanshuai Han

2018-02-01

Full Text Available Neurodegenerative diseases are a challenge for drug discovery, as the biological mechanisms are complex and poorly understood, with a paucity of models that faithfully recapitulate these disorders. Recent advances in stem cell technology have provided a paradigm shift, providing researchers with tools to generate human induced pluripotent stem cells (iPSCs from patient cells. With the potential to generate any human cell type, we can now generate human neurons and develop “first-of-their-kind” disease-relevant assays for small molecule screening. Now that the tools are in place, it is imperative that we accelerate discoveries from the bench to the clinic. Using traditional closed-door research systems raises barriers to discovery, by restricting access to cells, data and other research findings. Thus, a new strategy is required, and the Montreal Neurological Institute (MNI and its partners are piloting an “Open Science” model. One signature initiative will be that the MNI biorepository will curate and disseminate patient samples in a more accessible manner through open transfer agreements. This feeds into the MNI open drug discovery platform, focused on developing industry-standard assays with iPSC-derived neurons. All cell lines, reagents and assay findings developed in this open fashion will be made available to academia and industry. By removing the obstacles many universities and companies face in distributing patient samples and assay results, our goal is to accelerate translational medical research and the development of new therapies for devastating neurodegenerative disorders.

Fragile X-associated tremor/ataxia syndrome: another phenotype of the fragile X gene.

Science.gov (United States)

Hessl, David; Grigsby, Jim

2016-08-01

Neuropsychologists have an important role in evaluating patients with fragile X-associated disorders, but most practitioners are unaware of the recently identified neurodegenerative movement disorder known as fragile X-associated tremor ataxia syndrome (FXTAS). The objective of this editorial is to orient the reader to FXTAS and highlight the importance of clinical neuropsychology in describing the fragile X premutation phenotype and the role practitioners may have in assessing and monitoring patients with or at risk for neurodegeneration. We issued a call for papers for the special issue, highlighting the primary objective of familiarizing clinical neuropsychologists with FXTAS, and with the neuropsychological phenotype of both male and female asymptomatic carriers. Eight papers are included, including an overview of the fragile X-associated disorders (Grigsby), a review of the neuroradiological and neurological aspects of FXTAS and how the disorder compares to other movement disorders (O'Keefe et al.), a perspective on the prominence of white matter disease and dementia in FXTAS (Filley), and a review of mouse models of FXTAS (Foote). There are four research papers, including one on self-reported memory problems in FXTAS (Birch et al.), and three papers focused on the neuropsychiatric aspects of the fragile X premutation, a review (Bourgeois), an examination of autism-related traits (Schneider), and a research paper on executive functioning and psychopathology (Grigsby). The issue highlights the importance of awareness of fragile X-associated disorders for neuropsychologists, an awareness that must reach beyond neurodevelopmental aspects related to fragile X syndrome into the realm of neurodegenerative disease and aging.

Pharmacological Alternatives for the Treatment of Neurodegenerative Disorders: Wasp and Bee Venoms and Their Components as New Neuroactive Tools.

Science.gov (United States)

Silva, Juliana; Monge-Fuentes, Victoria; Gomes, Flávia; Lopes, Kamila; dos Anjos, Lilian; Campos, Gabriel; Arenas, Claudia; Biolchi, Andréia; Gonçalves, Jacqueline; Galante, Priscilla; Campos, Leandro; Mortari, Márcia

2015-08-18

Neurodegenerative diseases are relentlessly progressive, severely impacting affected patients, families and society as a whole. Increased life expectancy has made these diseases more common worldwide. Unfortunately, available drugs have insufficient therapeutic effects on many subtypes of these intractable diseases, and adverse effects hamper continued treatment. Wasp and bee venoms and their components are potential means of managing or reducing these effects and provide new alternatives for the control of neurodegenerative diseases. These venoms and their components are well-known and irrefutable sources of neuroprotectors or neuromodulators. In this respect, the present study reviews our current understanding of the mechanisms of action and future prospects regarding the use of new drugs derived from wasp and bee venom in the treatment of major neurodegenerative disorders, including Alzheimer's Disease, Parkinson's Disease, Epilepsy, Multiple Sclerosis and Amyotrophic Lateral Sclerosis.

C9orf72-related disorders: expanding the clinical and genetic spectrum of neurodegenerative diseases

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Paulo Victor Sgobbi de Souza

2015-03-01

Full Text Available Neurodegenerative diseases represent a heterogeneous group of neurological conditions primarily involving dementia, motor neuron disease and movement disorders. They are mostly related to different pathophysiological processes, notably in family forms in which the clinical and genetic heterogeneity are lush. In the last decade, much knowledge has been acumulated about the genetics of neurodegenerative diseases, making it essential in cases of motor neuron disease and frontotemporal dementia the repeat expansions of C9orf72 gene. This review analyzes the main clinical, radiological and genetic aspects of the phenotypes related to the hexanucleotide repeat expansions (GGGGCC of C9orf72 gene. Future studies will aim to further characterize the neuropsychological, imaging and pathological aspects of the extra-motor features of motor neuron disease, and will help to provide a new classification system that is both clinically and biologically relevant.

Bezafibrate for X-Linked Adrenoleukodystrophy

NARCIS (Netherlands)

Engelen, Marc; Tran, Luc; Ofman, Rob; Brennecke, Josephine; Moser, Ann B.; Dijkstra, Inge M. E.; Wanders, Ronald J. A.; Poll-The, Bwee Tien; Kemp, Stephan

2012-01-01

X-linked adrenoleukodystrophy (X-ALD) is caused by mutations in the ABCD1 gene and is characterized by impaired beta-oxidation of very-long-chain fatty acids (VLCFA) and subsequent VLCFA accumulation in tissues. In adulthood X-ALD most commonly manifests as a gradually progressive myelopathy,

Correlation of auditory brain stem response and the MRI measurements in neuro-degenerative disorders

International Nuclear Information System (INIS)

Kamei, Hidekazu

1989-01-01

The purpose of this study is to elucidate correlations of several MRI measurements of the cranium and brain, functioning as a volume conductor, to the auditory brain stem response (ABR) in neuro-degenerative disorders. The subjects included forty-seven patients with spinocerebellar degeneration (SCD) and sixteen of amyotrophic lateral sclerosis (ALS). Statistically significant positive correlations were found between I-V and III-V interpeak latencies (IPLs) and the area of cranium and brain in the longitudinal section of SCD patients, and between I-III and III-V IPLs and the area in the longitudinal section of those with ALS. And, also there were statistically significant correlations between the amplitude of the V wave and the area of brain stem as well as that of the cranium in the longitudinal section of SCD patients, and between the amplitude of the V wave and the area of the cerebrum in the longitudinal section of ALS. In conclusion, in the ABR, the IPLs were prolonged and the amplitude of the V wave was decreased while the MRI size of the cranium and brain increased. When the ABR is applied to neuro-degenerative disorders, it might be important to consider not only the conduction of the auditory tracts in the brain stem, but also the correlations of the size of the cranium and brain which act as a volume conductor. (author)

Correlation of auditory brain stem response and the MRI measurements in neuro-degenerative disorders

Energy Technology Data Exchange (ETDEWEB)

Kamei, Hidekazu (Tokyo Women' s Medical Coll. (Japan))

1989-06-01

The purpose of this study is to elucidate correlations of several MRI measurements of the cranium and brain, functioning as a volume conductor, to the auditory brain stem response (ABR) in neuro-degenerative disorders. The subjects included forty-seven patients with spinocerebellar degeneration (SCD) and sixteen of amyotrophic lateral sclerosis (ALS). Statistically significant positive correlations were found between I-V and III-V interpeak latencies (IPLs) and the area of cranium and brain in the longitudinal section of SCD patients, and between I-III and III-V IPLs and the area in the longitudinal section of those with ALS. And, also there were statistically significant correlations between the amplitude of the V wave and the area of brain stem as well as that of the cranium in the longitudinal section of SCD patients, and between the amplitude of the V wave and the area of the cerebrum in the longitudinal section of ALS. In conclusion, in the ABR, the IPLs were prolonged and the amplitude of the V wave was decreased while the MRI size of the cranium and brain increased. When the ABR is applied to neuro-degenerative disorders, it might be important to consider not only the conduction of the auditory tracts in the brain stem, but also the correlations of the size of the cranium and brain which act as a volume conductor. (author).

EMQN best practice guidelines for the molecular genetic testing and reporting of fragile X syndrome and other fragile X-associated disorders

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Biancalana, Valérie; Glaeser, Dieter; McQuaid, Shirley; Steinbach, Peter

2015-01-01

Different mutations occurring in the unstable CGG repeat in 5' untranslated region of FMR1 gene are responsible for three fragile X-associated disorders. An expansion of over ∼200 CGG repeats when associated with abnormal methylation and inactivation of the promoter is the mutation termed ‘full mutation' and is responsible for fragile X syndrome (FXS), a neurodevelopmental disorder described as the most common cause of inherited intellectual impairment. The term ‘abnormal methylation' is used here to distinguish the DNA methylation induced by the expanded repeat from the ‘normal methylation' occurring on the inactive X chromosomes in females with normal, premutation, and full mutation alleles. All male and roughly half of the female full mutation carriers have FXS. Another anomaly termed ‘premutation' is characterized by the presence of 55 to ∼200 CGGs without abnormal methylation, and is the cause of two other diseases with incomplete penetrance. One is fragile X-associated primary ovarian insufficiency (FXPOI), which is characterized by a large spectrum of ovarian dysfunction phenotypes and possible early menopause as the end stage. The other is fragile X-associated tremor/ataxia syndrome (FXTAS), which is a late onset neurodegenerative disorder affecting males and females. Because of the particular pattern and transmission of the CGG repeat, appropriate molecular testing and reporting is very important for the optimal genetic counselling in the three fragile X-associated disorders. Here, we describe best practice guidelines for genetic analysis and reporting in FXS, FXPOI, and FXTAS, including carrier and prenatal testing. PMID:25227148

The Enhanced Catalytic Performance and Stability of Rh/γ-Al2O3 Catalyst Synthesized by Atomic Layer Deposition (ALD for Methane Dry Reforming

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Yunlin Li

2018-01-01

Full Text Available Rh/γ-Al2O3 catalysts were synthesized by both incipient wetness impregnation (IWI and atomic layer deposition (ALD. The TEM images of the two catalysts showed that the catalyst from ALD had smaller particle size, and narrower size distribution. The surface chemical states of both catalysts were investigated by both XPS and X-ray Absorption Near Edge Structure (XANES, and the catalyst from IWI had higher concentration of Rh3+ than that from ALD. The catalytic performance of both catalysts was tested in the dry reforming of methane reaction. The catalyst from ALD showed a higher conversion and selectivity than that from IWI. The stability testing results indicated that the catalyst from ALD showed similar stability to that from IWI at 500 °C, but higher stability at 800 °C.

Synthetic prions and other human neurodegenerative proteinopathies.

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Le, Nhat Tran Thanh; Narkiewicz, Joanna; Aulić, Suzana; Salzano, Giulia; Tran, Hoa Thanh; Scaini, Denis; Moda, Fabio; Giachin, Gabriele; Legname, Giuseppe

2015-09-02

Transmissible spongiform encephalopathies (TSE) are a heterogeneous group of neurodegenerative disorders. The common feature of these diseases is the pathological conversion of the normal cellular prion protein (PrP(C)) into a β-structure-rich conformer-termed PrP(Sc). The latter can induce a self-perpetuating process leading to amplification and spreading of pathological protein assemblies. Much evidence suggests that PrP(Sc) itself is able to recruit and misfold PrP(C) into the pathological conformation. Recent data have shown that recombinant PrP(C) can be misfolded in vitro and the resulting synthetic conformers are able to induce the conversion of PrP(C) into PrP(Sc)in vivo. In this review we describe the state-of-the-art of the body of literature in this field. In addition, we describe a cell-based assay to test synthetic prions in cells, providing further evidence that synthetic amyloids are able to template conversion of PrP into prion inclusions. Studying prions might help to understand the pathological mechanisms governing other neurodegenerative diseases. Aggregation and deposition of misfolded proteins is a common feature of several neurodegenerative disorders, such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and other disorders. Although the proteins implicated in each of these diseases differ, they share a common prion mechanism. Recombinant proteins are able to aggregate in vitro into β-rich amyloid fibrils, sharing some features of the aggregates found in the brain. Several studies have reported that intracerebral inoculation of synthetic aggregates lead to unique pathology, which spread progressively to distal brain regions and reduced survival time in animals. Here, we review the prion-like features of different proteins involved in neurodegenerative disorders, such as α-synuclein, superoxide dismutase-1, amyloid-β and tau. Copyright © 2014 Elsevier B.V. All rights reserved.

Role of sigma-1 receptors in neurodegenerative diseases

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Linda Nguyen

2015-01-01

Full Text Available Neurodegenerative diseases with distinct genetic etiologies and pathological phenotypes appear to share common mechanisms of neuronal cellular dysfunction, including excitotoxicity, calcium dysregulation, oxidative damage, ER stress and mitochondrial dysfunction. Glial cells, including microglia and astrocytes, play an increasingly recognized role in both the promotion and prevention of neurodegeneration. Sigma receptors, particularly the sigma-1 receptor subtype, which are expressed in both neurons and glia of multiple regions within the central nervous system, are a unique class of intracellular proteins that can modulate many biological mechanisms associated with neurodegeneration. These receptors therefore represent compelling putative targets for pharmacologically treating neurodegenerative disorders. In this review, we provide an overview of the biological mechanisms frequently associated with neurodegeneration, and discuss how sigma-1 receptors may alter these mechanisms to preserve or restore neuronal function. In addition, we speculate on their therapeutic potential in the treatment of various neurodegenerative disorders.

Non-coding RNA and pseudogenes in neurodegenerative diseases: "The (unUsual Suspects"

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Valerio eCosta

2012-10-01

Full Text Available Neurodegenerative disorders and cancer are severe diseases threatening human health. The glaring differences between neurons and cancer cells mask the processes involved in their pathogenesis. Defects in cell cycle, DNA repair and cell differentiation can determine unlimited proliferation in cancer, or conversely, compromise neuronal plasticity, leading to cell death and neurodegeneration.Alteration in regulatory networks affecting gene expression contribute to human diseases' onset, including neurodegenerative disorders, and deregulation of non-coding RNAs - particularly microRNAs - is supposed to have a significant impact.Recently, competitive endogenous RNAs - acting as sponges - have been identified in cancer, indicating a new and intricate regulatory network. Given that neurodegenerative disorders and cancer share altered genes and pathways, and considering the emerging role of microRNAs in neurogenesis, we hypothesize competitive endogenous RNAs may be implicated in neurodegenerative diseases. Here we propose, and computationally predict, such regulatory mechanism may be shared between the diseases. It is predictable that similar regulation occurs in other complex diseases, and further investigation is needed.

Epidemic spreading model to characterize misfolded proteins propagation in aging and associated neurodegenerative disorders.

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Iturria-Medina, Yasser; Sotero, Roberto C; Toussaint, Paule J; Evans, Alan C

2014-11-01

Misfolded proteins (MP) are a key component in aging and associated neurodegenerative disorders. For example, misfolded Amyloid-ß (Aß) and tau proteins are two neuropathogenic hallmarks of Alzheimer's disease. Mechanisms underlying intra-brain MP propagation/deposition remain essentially uncharacterized. Here, is introduced an epidemic spreading model (ESM) for MP dynamics that considers propagation-like interactions between MP agents and the brain's clearance response across the structural connectome. The ESM reproduces advanced Aß deposition patterns in the human brain (explaining 46∼56% of the variance in regional Aß loads, in 733 subjects from the ADNI database). Furthermore, this model strongly supports a) the leading role of Aß clearance deficiency and early Aß onset age during Alzheimer's disease progression, b) that effective anatomical distance from Aß outbreak region explains regional Aß arrival time and Aß deposition likelihood, c) the multi-factorial impact of APOE e4 genotype, gender and educational level on lifetime intra-brain Aß propagation, and d) the modulatory impact of Aß propagation history on tau proteins concentrations, supporting the hypothesis of an interrelated pathway between Aß pathophysiology and tauopathy. To our knowledge, the ESM is the first computational model highlighting the direct link between structural brain networks, production/clearance of pathogenic proteins and associated intercellular transfer mechanisms, individual genetic/demographic properties and clinical states in health and disease. In sum, the proposed ESM constitutes a promising framework to clarify intra-brain region to region transference mechanisms associated with aging and neurodegenerative disorders.

Epidemic spreading model to characterize misfolded proteins propagation in aging and associated neurodegenerative disorders.

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Yasser Iturria-Medina

2014-11-01

Full Text Available Misfolded proteins (MP are a key component in aging and associated neurodegenerative disorders. For example, misfolded Amyloid-ß (Aß and tau proteins are two neuropathogenic hallmarks of Alzheimer's disease. Mechanisms underlying intra-brain MP propagation/deposition remain essentially uncharacterized. Here, is introduced an epidemic spreading model (ESM for MP dynamics that considers propagation-like interactions between MP agents and the brain's clearance response across the structural connectome. The ESM reproduces advanced Aß deposition patterns in the human brain (explaining 46∼56% of the variance in regional Aß loads, in 733 subjects from the ADNI database. Furthermore, this model strongly supports a the leading role of Aß clearance deficiency and early Aß onset age during Alzheimer's disease progression, b that effective anatomical distance from Aß outbreak region explains regional Aß arrival time and Aß deposition likelihood, c the multi-factorial impact of APOE e4 genotype, gender and educational level on lifetime intra-brain Aß propagation, and d the modulatory impact of Aß propagation history on tau proteins concentrations, supporting the hypothesis of an interrelated pathway between Aß pathophysiology and tauopathy. To our knowledge, the ESM is the first computational model highlighting the direct link between structural brain networks, production/clearance of pathogenic proteins and associated intercellular transfer mechanisms, individual genetic/demographic properties and clinical states in health and disease. In sum, the proposed ESM constitutes a promising framework to clarify intra-brain region to region transference mechanisms associated with aging and neurodegenerative disorders.

Olfactory memory impairment in neurodegenerative diseases.

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Bahuleyan, Biju; Singh, Satendra

2012-10-01

Olfactory disorders are noted in a majority of neurodegenerative diseases, but they are often misjudged and are rarely rated in the clinical setting. Severe changes in the olfactory tests are observed in Parkinson's disease. Olfactory deficits are an early feature in Alzheimer's disease and they worsen with the disease progression. Alterations in the olfactory function are also noted after severe head injuries, temporal lobe epilepsy, multiple sclerosis, and migraine. The purpose of the present review was to discuss the available scientific knowledge on the olfactory memory and to relate its impairment with neurodegenerative diseases.

Crystal Structure of Mycobacterium tuberculosis H37Rv AldR (Rv2779c), a Regulator of the ald Gene: DNA BINDING AND IDENTIFICATION OF SMALL MOLECULE INHIBITORS.

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Dey, Abhishek; Shree, Sonal; Pandey, Sarvesh Kumar; Tripathi, Rama Pati; Ramachandran, Ravishankar

2016-06-03

Here we report the crystal structure of M. tuberculosis AldR (Rv2779c) showing that the N-terminal DNA-binding domains are swapped, forming a dimer, and four dimers are assembled into an octamer through crystal symmetry. The C-terminal domain is involved in oligomeric interactions that stabilize the oligomer, and it contains the effector-binding sites. The latter sites are 30-60% larger compared with homologs like MtbFFRP (Rv3291c) and can consequently accommodate larger molecules. MtbAldR binds to the region upstream to the ald gene that is highly up-regulated in nutrient-starved tuberculosis models and codes for l-alanine dehydrogenase (MtbAld; Rv2780). Further, the MtbAldR-DNA complex is inhibited upon binding of Ala, Tyr, Trp and Asp to the protein. Studies involving a ligand-binding site G131T mutant show that the mutant forms a DNA complex that cannot be inhibited by adding the amino acids. Comparative studies suggest that binding of the amino acids changes the relative spatial disposition of the DNA-binding domains and thereby disrupt the protein-DNA complex. Finally, we identified small molecules, including a tetrahydroquinoline carbonitrile derivative (S010-0261), that inhibit the MtbAldR-DNA complex. The latter molecules represent the very first inhibitors of a feast/famine regulatory protein from any source and set the stage for exploring MtbAldR as a potential anti-tuberculosis target. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

ald of Mycobacterium tuberculosis Encodes both the Alanine Dehydrogenase and the Putative Glycine Dehydrogenase

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Giffin, Michelle M.; Modesti, Lucia; Raab, Ronald W.; Wayne, Lawrence G.

2012-01-01

The putative glycine dehydrogenase of Mycobacterium tuberculosis catalyzes the reductive amination of glyoxylate to glycine but not the reverse reaction. The enzyme was purified and identified as the previously characterized alanine dehydrogenase. The Ald enzyme was expressed in Escherichia coli and had both pyruvate and glyoxylate aminating activities. The gene, ald, was inactivated in M. tuberculosis, which resulted in the loss of all activities. Both enzyme activities were found associated with the cell and were not detected in the extracellular filtrate. By using an anti-Ald antibody, the protein was localized to the cell membrane, with a smaller fraction in the cytosol. None was detected in the extracellular medium. The ald knockout strain grew without alanine or glycine and was able to utilize glycine but not alanine as a nitrogen source. Transcription of ald was induced when alanine was the sole nitrogen source, and higher levels of Ald enzyme were measured. Ald is proposed to have several functions, including ammonium incorporation and alanine breakdown. PMID:22210765

Homogeneous transparent conductive ZnO:Ga by ALD for large LED wafers

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Szabó, Zoltán; Baji, Zsófia [MTA EK Institute of Technical Physics and Materials Science, Konkoly Thege M. út 29-33, 1121 Budapest (Hungary); Basa, Péter [Semilab Semiconductor Physics Laboratory Co. Ltd., Prielle K. u. 2, H-1117 Budapest (Hungary); Czigány, Zsolt; Bársony, István [MTA EK Institute of Technical Physics and Materials Science, Konkoly Thege M. út 29-33, 1121 Budapest (Hungary); Wang, Hsin-Ying [Epistar corporation No 5, Li-hsin 5th Rd., Hsinchu Science Park, Hsinchu 300, Taiwan (China); Volk, János, E-mail: volk@mfa.kfki.hu [MTA EK Institute of Technical Physics and Materials Science, Konkoly Thege M. út 29-33, 1121 Budapest (Hungary)

2016-08-30

Highlights: • Highly conductive, transparent GZO layers were deposited by ALD. • The ALD layers show superior thickness and sheet resistance homogeneity for 4” wafers. • A two-step ALD deposition technique was proposed and demonstrated to improve the quality of GZO/p-GaN interface. - Abstract: Highly conductive and uniform Ga doped ZnO (GZO) films were prepared by atomic layer deposition (ALD) as transparent conductive layers for InGaN/GaN LEDs. The optimal Ga doping concentration was found to be 3 at%. Even for 4” wafers, the TCO layer shows excellent homogeneity of film resistivity (0.8 %) according to Eddy current and spectroscopic ellipsometry mapping. This makes ALD a favourable technique over concurrent methods like MBE and PLD where the up-scaling is problematic. In agreement with previous studies, it was found that by an annealing treatment the quality of the GZO/p-GaN interface can be improved, although it causes the degradation of TCO conductivity. Therefore, a two-step ALD deposition technique was proposed and demonstrated: a “buffer layer” deposited and annealed first was followed by a second deposition step to maintain the high conductivity of the top layer.

7 Tesla proton magnetic resonance spectroscopic imaging in adult X-linked adrenoleukodystrophy

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Ratai, Eva; Kok, Trina; Wiggins, Christopher; Wiggins, Graham; Grant, Ellen; Gagoski, Borjan; O'Neill, Gilmore; Adalsteinsson, Elfar; Eichler, Florian

2010-01-01

Background Adult patients with X-linked adrenoleukodystrophy (X-ALD) remain at risk for progressive neurological deterioration. Phenotypes vary in their pathology, ranging from axonal degeneration to inflammatory demyelination. The severity of symptoms is poorly explained by conventional imaging. Objective To test the hypothesis that neurochemistry in normal appearing brain differs among adult phenotypes of X-ALD, and that neurochemical changes correlate with the severity of symptoms. Patients and Methods Using a 7 Tesla scanner we performed structural and proton MRSI in 13 adult patients with X-ALD, including 4 patients with adult cerebral ALD (ACALD), 5 with adrenomyeloneuropathy (AMN) and 4 female heterozygotes. Studies were also performed in nine healthy controls. Results Among adult X-ALD phenotypes, MI/Cr was 46% higher and Cho/Cr 21% higher in normal appearing white matter of ACALD compared to AMN (p Tesla proton MRSI reveals differences in the neurochemistry of ACALD but is unable to distinguish AMN from female heterozygotes. MI/Cr correlates with the severity of the symptoms and may be a meaningful biomarker in adult X-ALD. PMID:19001168

Integration of technology-based outcome measures in clinical trials of Parkinson and other neurodegenerative diseases.

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Artusi, Carlo Alberto; Mishra, Murli; Latimer, Patricia; Vizcarra, Joaquin A; Lopiano, Leonardo; Maetzler, Walter; Merola, Aristide; Espay, Alberto J

2018-01-01

We sought to review the landscape of past, present, and future use of technology-based outcome measures (TOMs) in clinical trials of neurodegenerative disorders. We systematically reviewed PubMed and ClinicalTrials.gov for published and ongoing clinical trials in neurodegenerative disorders employing TOMs. In addition, medical directors of selected pharmaceutical companies were surveyed on their companies' ongoing efforts and future plans to integrate TOMs in clinical trials as primary, secondary, or exploratory endpoints. We identified 164 published clinical trials indexed in PubMed that used TOMs as outcome measures in Parkinson disease (n = 132) or other neurodegenerative disorders (n = 32). The ClinicalTrials.gov search yielded 42 clinical trials using TOMs, representing 2.7% of ongoing trials. Sensor-based technology accounted for over 75% of TOMs applied. Gait and physical activity were the most common targeted domains. Within the next 5 years, 83% of surveyed pharmaceutical companies engaged in neurodegenerative disorders plan to deploy TOMs in clinical trials. Although promising, TOMs are underutilized in clinical trials of neurodegenerative disorders. Validating relevant endpoints, standardizing measures and procedures, establishing a single platform for integration of data and algorithms from different devices, and facilitating regulatory approvals should advance TOMs integration into clinical trials. Copyright © 2017 Elsevier Ltd. All rights reserved.

Spatial atmospheric ALD of functional layers for CIGS Solar Cells

NARCIS (Netherlands)

Illiberi, A.; Frijters, C.; Balder, J. E.; Poodt, P.; Roozeboom, F.

2015-01-01

Spatial Atmospheric Atomic Layer Deposition combines the advantages of temporal ALD, i.e. excellent control of film composition and uniformity over large area substrates, with high growth rates (up to nm/s). In this paper we present a short overview of our research activity carried out on S-ALD of

Spatial atmospheric ALD of functional layers for CIGS Solar Cells

NARCIS (Netherlands)

Illiberi, A.; Frijters, C.; Balder, J.E.; Poodt, P.W.G.; Roozeboom, F.

2015-01-01

Spatial Atmosperic Atomic Layer Depositon combines the advantages of temporal ALD, i.e. excellent control of film composition and uniformity over large area substrates, with high growth rages (up tot nm/s). In this paper we present a short overview of our research acctivity carried out on S-ALD of

Controllable ALD synthesis of platinum nanoparticles by tuning different synthesis parameters

International Nuclear Information System (INIS)

Wang, Chuandao; Lin, Yuyuan; Marks, Laurence; Hu, Linhua; Poeppelmeier, Kenneth; Stair, Peter

2017-01-01

Pt nanoparticles were successfully deposited using three different atomic layer deposition (ALD) methods, e.g. AB-type, ABC-type and static ABC-type ALD, on two different types of strontium titanate nanocuboids (STO-NCs) samples in a reaction temperature window of 125 °C–300 °C. The influence of reaction temperature, number of ALD cycles, type of substrate, 2nd reagent and type of ALD method on Pt nanoparticle deposition are comprehensively studied and discussed in this work. Varying the reaction temperature and number of cycles across the three different ALD methods affects Pt particle size, density, and loading. Surface termination of STO-NCs substrate will change deposited Pt nanoparticle growth orientation and thermodynamic shape. The B reagent besides platinum precursor can lead to different ligand decomposition mechanism when Pt precursors are exposed: oxygen allows more effective ligand combustion compared to water, however, the Pt particles are more oxidized according to XPS studies. We expect this work provides a way for tailoring nanoparticles with desired size, dispersion, exposed surfaces and chemical state etc, which helps controlling and optimizing their performance when applied as catalysts or nanosensors. (paper)

Genetic dissection of a cell-autonomous neurodegenerative disorder: lessons learned from mouse models of Niemann-Pick disease type C

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Manuel E. Lopez

2013-09-01

Full Text Available Understanding neurodegenerative disease progression and its treatment requires the systematic characterization and manipulation of relevant cell types and molecular pathways. The neurodegenerative lysosomal storage disorder Niemann-Pick disease type C (NPC is highly amenable to genetic approaches that allow exploration of the disease biology at the organismal, cellular and molecular level. Although NPC is a rare disease, genetic analysis of the associated neuropathology promises to provide insight into the logic of disease neural circuitry, selective neuron vulnerability and neural-glial interactions. The ability to control the disorder cell-autonomously and in naturally occurring spontaneous animal models that recapitulate many aspects of the human disease allows for an unparalleled dissection of the disease neurobiology in vivo. Here, we review progress in mouse-model-based studies of NPC disease, specifically focusing on the subtype that is caused by a deficiency in NPC1, a sterol-binding late endosomal membrane protein involved in lipid trafficking. We also discuss recent findings and future directions in NPC disease research that are pertinent to understanding the cellular and molecular mechanisms underlying neurodegeneration in general.

Relationships between Rapid Eye Movement Sleep Behavior Disorder and Neurodegenerative Diseases: Clinical Assessments, Biomarkers, and Treatment

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Li, Min; Wang, Li; Liu, Jiang-Hong; Zhan, Shu-Qin

2018-01-01

Objective: Rapid eye movement sleep behavior disorder (RBD) is characterized by dream enactment and loss of muscle atonia during rapid eye movement sleep. RBD is closely related to α-synucleinopathies including Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy. Many studies have investigated the markers of imaging and neurophysiological, genetic, cognitive, autonomic function of RBD and their predictive value for neurodegenerative diseases. This report reviewed the progress of these studies and discussed their limitations and future research directions. Data Sources: Using the combined keywords: “RBD”, “neurodegenerative disease”, “Parkinson disease”, and “magnetic resonance imaging”, the PubMed/MEDLINE literature search was conducted up to January 1, 2018. Study Selection: A total of 150 published articles were initially identified citations. Of the 150 articles, 92 articles were selected after further detailed review. This study referred to all the important English literature in full. Results: Single-nucleotide polymorphisms in SCARB2 (rs6812193) and MAPT (rs12185268) were significantly associated with RBD. The olfactory loss, autonomic dysfunction, marked electroencephalogram slowing during both wakefulness and rapid eye movement sleep, and cognitive impairments were potential predictive markers for RBD conversion to neurodegenerative diseases. Traditional structural imaging studies reported relatively inconsistent results, whereas reduced functional connectivity between the left putamen and substantia nigra and dopamine transporter uptake demonstrated by functional imaging techniques were relatively consistent findings. Conclusions: More longitudinal studies should be conducted to evaluate the predictive value of biomarkers of RBD. Moreover, because the glucose and dopamine metabolisms are not specific for assessing cognitive cognition, the molecular metabolism directly related to cognition should be investigated

Effect of growth temperature on the epitaxial growth of ZnO on GaN by ALD

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Särkijärvi, Suvi; Sintonen, Sakari; Tuomisto, Filip; Bosund, Markus; Suihkonen, Sami; Lipsanen, Harri

2014-07-01

We report on the epitaxial growth of ZnO on GaN template by atomic layer deposition (ALD). Diethylzinc (DEZn) and water vapour (H2O) were used as precursors. The structure and the quality of the grown ZnO layers were studied with scanning electron microscope (SEM), X-ray diffraction (XRD), photoluminescence (PL) measurements and positron annihilation spectroscopy. The ZnO films were confirmed epitaxial, and the film quality was found to improve with increasing deposition temperature in the vicinity of the threshold temperature of two dimensional growth. We conclude that high quality ZnO thin films can be grown by ALD. Interestingly only separate Zn-vacancies were observed in the films, although ZnO thin films typically contain fairly high density of surface pits and vacancy clusters.

Repurposing of Copper(II)-chelating Drugs for the Treatment of Neurodegenerative Diseases.

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Lanza, Valeria; Milardi, Danilo; Di Natale, Giuseppe; Pappalardo, Giuseppe

2018-02-12

There is mounting urgency to find new drugs for the treatment of neurodegenerative disorders. A large number of reviews have exhaustively described either the molecular or clinical aspects of neurodegenerative diseases such as Alzheimer's (AD) and Parkinson's (PD). Conversely, reports outlining how known drugs in use for other diseases can also be effective as therapeutic agents in neurodegenerative diseases are less reported. This review focuses on the current uses of some copper(II) chelating molecules as potential drug candidates in neurodegeneration. Starting from the well-known harmful relationships existing between the dyshomeostasis and mis-management of metals and AD onset, we surveyed the experimental work reported in the literature, which deals with the repositioning of metal-chelating drugs in the field of neurodegenerative diseases. The reviewed papers were retrieved from common literature and their selection was limited to those describing the biomolecular aspects associated with neuroprotection. In particular, we emphasized the copper(II) coordination abilities of the selected drugs. Copper, together with zinc and iron, are known to play a key role in regulating neuronal functions. Changes in copper homeostasis are crucial for several neurodegenerative disorders. The studies included in this review may provide an overview on the current strategies aimed at repurposing copper (II) chelating drugs for the treatment of neurodegenerative disorders. Starting from the exemplary case of clioquinol repurposing, we discuss the challenge and the opportunities that repurposing of other metal-chelating drugs may provide (e.g. PBT-2, metformin and cyclodipeptides) in the treatment of neurodegenerative disease. In order to improve the success rate of drug repositioning, comprehensive studies on the molecular mechanism and therapeutic efficacy are still required. The present review upholds that drug repurposing makes significant advantages over drug discovery since

Cell based-gene delivery approaches for the treatment of spinal cord injury and neurodegenerative disorders.

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Taha, Masoumeh Fakhr

2010-03-01

Cell based-gene delivery has provided an important therapeutic strategy for different disorders in the recent years. This strategy is based on the transplantation of genetically modified cells to express specific genes and to target the delivery of therapeutic factors, especially for the treatment of cancers and neurological, immunological, cardiovascular and heamatopoietic disorders. Although, preliminary reports are encouraging, and experimental studies indicate functionally and structurally improvements in the animal models of different disorders, universal application of this strategy for human diseases requires more evidence. There are a number of parameters that need to be evaluated, including the optimal cell source, the most effective gene/genes to be delivered, the optimal vector and method of gene delivery into the cells and the most efficient route for the delivery of genetically modified cells into the patient. Also, some obstacles have to be overcome, including the safety and usefulness of the approaches and the stability of the improvements. Here, recent studies concerning with the cell-based gene delivery for spinal cord injury and some neurodegenerative disorders such as amyotrophic lateral sclerosis, Parkinson's disease and Alzheimer's disease are briefly reviewed, and their exciting consequences are discussed.

Amino acids as dietary excitotoxins: a contribution to understanding neurodegenerative disorders.

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Meldrum, B

1993-01-01

The possibility that some acidic amino acids occurring naturally or as additives in the diet can act as excitotoxins producing central nervous system pathology has been the subject of extensive debate in the last 20 years and is here reviewed. High doses of glutamate, aspartate or related excitatory amino acids given in isolation to neonatal rodents produce acute degeneration organs. Neuropathology resulting from consumption of glutamate or aspartate has not been described in man. Various unusual amino acids of plant origin can produce acute excitotoxic syndromes. In man domoate (consumed in mussels that have fed on (Nitschia pungens) can produce an acute syndrome associated with limbic system lesions and anterograde amnesia. Kainate and domoate produce similar syndromes in rodents; acromelate produces spinal pathology. The mechanisms and manifestations of chronic excitotoxicity are less clearly established. A combination of impaired energy metabolism or impaired buffering of calcium and free radicals and endogenous or exogenous excitotoxins may contribute to neuronal loss in human neurodegenerative disorders.

Cerebral correlates of psychotic syndromes in neurodegenerative diseases.

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Jellinger, Kurt A

2012-05-01

Psychosis has been recognized as a common feature in neurodegenerative diseases and a core feature of dementia that worsens most clinical courses. It includes hallucinations, delusions including paranoia, aggressive behaviour, apathy and other psychotic phenomena that occur in a wide range of degenerative disorders including Alzheimer's disease, synucleinopathies (Parkinson's disease, dementia with Lewy bodies), Huntington's disease, frontotemporal degenerations, motoneuron and prion diseases. Many of these psychiatric manifestations may be early expressions of cognitive impairment, but often there is a dissociation between psychotic/behavioural symptoms and the rather linear decline in cognitive function, suggesting independent pathophysiological mechanisms. Strictly neuropathological explanations are likely to be insufficient to explain them, and a large group of heterogeneous factors (environmental, neurochemical changes, genetic factors, etc.) may influence their pathogenesis. Clinico-pathological evaluation of behavioural and psychotic symptoms (PS) in the setting of neurodegenerative and dementing disorders presents a significant challenge for modern neurosciences. Recognition and understanding of these manifestations may lead to the development of more effective preventive and therapeutic options that can serve to delay long-term progression of these devastating disorders and improve the patients' quality of life. A better understanding of the pathophysiology and distinctive pathological features underlying the development of PS in neurodegenerative diseases may provide important insights into psychotic processes in general. © 2011 The Author Journal of Cellular and Molecular Medicine © 2011 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd.

The emergence of designed multiple ligands for neurodegenerative disorders.

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Geldenhuys, Werner J; Youdim, Moussa B H; Carroll, Richard T; Van der Schyf, Cornelis J

2011-09-01

The incidence of neurodegenerative diseases has seen a constant increase in the global population, and is likely to be the result of extended life expectancy brought about by better health care. Despite this increase in the incidence of neurodegenerative diseases, there has been a dearth in the introduction of new disease-modifying therapies that are approved to prevent or delay the onset of these diseases, or reverse the degenerative processes in brain. Mounting evidence in the peer-reviewed literature shows that the etiopathology of these diseases is extremely complex and heterogeneous, resulting in significant comorbidity and therefore unlikely to be mitigated by any drug acting on a single pathway or target. A recent trend in drug design and discovery is the rational design or serendipitous discovery of novel drug entities with the ability to address multiple drug targets that form part of the complex pathophysiology of a particular disease state. In this review we discuss the rationale for developing such multifunctional drugs (also called designed multiple ligands or DMLs), and why these drug candidates seem to offer better outcomes in many cases compared to single-targeted drugs in pre-clinical studies for neurodegenerative diseases such as Alzheimer's and Parkinson's disease. Examples are drawn from the literature of drug candidates that have already reached the market, some unsuccessful attempts, and others that are still in the drug development pipeline. Copyright © 2011. Published by Elsevier Ltd.

Microbiota-Brain-Gut Axis and Neurodegenerative Diseases.

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Quigley, Eamonn M M

2017-10-17

The purposes of this review were as follows: first, to provide an overview of the gut microbiota and its interactions with the gut and the central nervous system (the microbiota-gut-brain axis) in health, second, to review the relevance of this axis to the pathogenesis of neurodegenerative diseases, such as Parkinson's disease, and, finally, to assess the potential for microbiota-targeted therapies. Work on animal models has established the microbiota-gut-brain axis as a real phenomenon; to date, the evidence for its operation in man has been limited and has been confronted by considerable logistical challenges. Animal and translational models have incriminated a disturbed gut microbiota in a number of CNS disorders, including Parkinson's disease; data from human studies is scanty. While a theoretical basis can be developed for the use of microbiota-directed therapies in neurodegenerative disorders, support is yet to come from high-quality clinical trials. In theory, a role for the microbiota-gut-brain axis is highly plausible; clinical confirmation is awaited.

Fragile X-associated tremor/ataxia syndrome.

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Hoem, Gry; Koht, Jeanette

2017-10-31

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a hereditary neurodegenerative disorder caused by a mutation on the X chromosome. The major signs and symptoms are tremor, ataxia and parkinsonism. Up to one in 2 000 persons over 50 years of age will develop the syndrome. There is reason to believe that too few individuals in Norway undergo testing for this condition.

Assessing Executive Dysfunction in Neurodegenerative Disorders: A Critical Review of Brief Neuropsychological Tools

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Helena S. Moreira

2017-11-01

Full Text Available Executive function (EF has been defined as a multifaceted construct that involves a variety of high-level cognitive abilities such as planning, working memory, mental flexibility, and inhibition. Being able to identify deficits in EF is important for the diagnosis and monitoring of several neurodegenerative disorders, and thus their assessment is a topic of much debate. In particular, there has been a growing interest in the development of neuropsychological screening tools that can potentially provide a reliable quick measure of EF. In this review, we critically discuss the four screening tools of EF currently available in the literature: Executive Interview-25 (EXIT 25, Frontal Assessment Battery (FAB, INECO Frontal Screening (IFS, and FRONTIER Executive Screen (FES. We first describe their features, and then evaluate their psychometric properties, the existing evidence on their neural correlates, and the empirical work that has been conducted in clinical populations. We conclude that the four screening tools generally present appropriate psychometric properties, and are sensitive to impairments in EF in several neurodegenerative conditions. However, more research will be needed mostly with respect to normative data and neural correlates, and to determine the extent to which these tools add specific information to the one provided by global cognition screening tests. More research directly comparing the available tools with each other will also be important to establish in which conditions each of them can be most useful.

Aptamer and its applications in neurodegenerative diseases.

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Qu, Jing; Yu, Shuqing; Zheng, Yuan; Zheng, Yan; Yang, Hui; Zhang, Jianliang

2017-02-01

Aptamers are small single-stranded DNA or RNA oligonucleotide fragments or small peptides, which can bind to targets by high affinity and specificity. Because aptamers are specific, non-immunogenic and non-toxic, they are ideal materials for clinical applications. Neurodegenerative disorders are ravaging the lives of patients. Even though the mechanism of these diseases is still elusive, they are mainly characterized by the accumulation of misfolded proteins in the central nervous system. So it is essential to develop potential measures to slow down or prevent the onset of these diseases. With the advancements of the technologies, aptamers have opened up new areas in this research field. Aptamers could bind with these related target proteins to interrupt their accumulation, subsequently blocking or preventing the process of neurodegenerative diseases. This review presents recent advances in the aptamer generation and its merits and limitations, with emphasis on its applications in neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, transmissible spongiform encephalopathy, Huntington's disease and multiple sclerosis.

Prions, prion-like prionoids, and neurodegenerative disordersVacancy

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Ashok Verma

2016-01-01

Full Text Available Prion diseases or transmissible spongiform encephalopathies are fatal neurodegenerative diseases characterized by the aggregation and deposition of the misfolded prion protein in the brain. α-synuclein (α-syn-associated multiple system atrophy has been recently shown to be caused by a bona fide α-syn prion strain. Several other misfolded native proteins such as β-amyloid, tau and TDP-43 share some aspects of prions although none of them is shown to be transmissible in nature or in experimental animals. However, these prion-like “prionoids” are causal to a variety of neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. The remarkable recent discovery of at least two new α-syn prion strains and their transmissibility in transgenic mice and in vitro cell models raises a distinct question as to whether some specific strain of other prionoids could have the capability of disease transmission in a manner similar to prions. In this overview, we briefly describe human and other mammalian prion diseases and comment on certain similarities between prion and prionoid and the possibility of prion-like transmissibility of some prionoid strains.

LSTM for diagnosis of neurodegenerative diseases using gait data

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Zhao, Aite; Qi, Lin; Li, Jie; Dong, Junyu; Yu, Hui

2018-04-01

Neurodegenerative diseases (NDs) usually cause gait disorders and postural disorders, which provides an important basis for NDs diagnosis. By observing and analyzing these clinical manifestations, medical specialists finally give diagnostic results to the patient, which is inefficient and can be easily affected by doctors' subjectivity. In this paper, we propose a two-layer Long Short-Term Memory (LSTM) model to learn the gait patterns exhibited in the three NDs. The model was trained and tested using temporal data that was recorded by force-sensitive resistors including time series, such as stride interval and swing interval. Our proposed method outperforms other methods in literature in accordance with accuracy of the predicted diagnostic result. Our approach aims at providing the quantitative assessment so that to indicate the diagnosis and treatment of these neurodegenerative diseases in clinic

Neuroimmune regulation of microglial activity involved in neuroinflammation and neurodegenerative diseases.

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González, Hugo; Elgueta, Daniela; Montoya, Andro; Pacheco, Rodrigo

2014-09-15

Neuroinflammation constitutes a fundamental process involved in the progression of several neurodegenerative disorders, such as Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis and multiple sclerosis. Microglial cells play a central role in neuroinflammation, promoting neuroprotective or neurotoxic microenvironments, thus controlling neuronal fate. Acquisition of different microglial functions is regulated by intercellular interactions with neurons, astrocytes, the blood-brain barrier, and T-cells infiltrating the central nervous system. In this study, an overview of the regulation of microglial function mediated by different intercellular communications is summarised and discussed. Afterward, we focus in T-cell-mediated regulation of neuroinflammation involved in neurodegenerative disorders. Copyright © 2014 Elsevier B.V. All rights reserved.

Lentiviral hematopoietic cell gene therapy for X-linked adrenoleukodystrophy.

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Cartier, Nathalie; Hacein-Bey-Abina, Salima; Bartholomae, Cynthia C; Bougnères, Pierre; Schmidt, Manfred; Kalle, Christof Von; Fischer, Alain; Cavazzana-Calvo, Marina; Aubourg, Patrick

2012-01-01

X-linked adrenoleukodystrophy (X-ALD) is a severe genetic demyelinating disease caused by a deficiency in ALD protein, an adenosine triphosphate-binding cassette transporter encoded by the ABCD1 gene. When performed at an early stage of the disease, allogeneic hematopoietic stem cell transplantation (HCT) can arrest the progression of cerebral demyelinating lesions. To overcome the limitations of allogeneic HCT, hematopoietic stem cell (HSC) gene therapy strategy aiming to perform autologous transplantation of lentivirally corrected cells was developed. We demonstrated the preclinical feasibility of HSC gene therapy for ALD based on the correction of CD34+ cells from X-ALD patients using an HIV1-derived lentiviral vector. These results prompted us to initiate an HSC gene therapy trial in two X-ALD patients who had developed progressive cerebral demyelination, were candidates for allogeneic HCT, but had no HLA-matched donors or cord blood. Autologous CD34+ cells were purified from the peripheral blood after G-CSF stimulation, genetically corrected ex vivo with a lentiviral vector encoding wild-type ABCD1 cDNA, and then reinfused into the patients after they had received full myeloablative conditioning. Over 3 years of follow-up, the hematopoiesis remained polyclonal in the two patients treated with 7-14% of granulocytes, monocytes, and T and B lymphocytes expressing the lentivirally encoded ALD protein. There was no evidence of clonal dominance or skewing based on the retrieval of lentiviral insertion repertoire in different hematopoietic lineages by deep sequencing. Cerebral demyelination was arrested 14 and 16months, respectively, in the two treated patients, without further progression up to the last follow-up, a clinical outcome that is comparable to that observed after allogeneic HCT. Longer follow-up of these two treated patients and HSC gene therapy performed in additional ALD patients are however needed to evaluate the safety and efficacy of lentiviral HSC

Excitatory amino acid neurotoxicity and neurodegenerative disease.

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Meldrum, B; Garthwaite, J

1990-09-01

The progress over the last 30 years in defining the role of excitatory amino acids in normal physiological function and in the abnormal neuronal activity of epilepsy has been reviewed in earlier articles in this series. In the last five years it has become clear that excitatory amino acids also play a role in a wide range of neurodegenerative processes. The evidence is clearest where the degenerative process is acute, but is more controversial for slow degenerative processes. In this article Brian Meldrum and John Garthwaite review in vivo and in vitro studies of the cytotoxicity of amino acids and summarize the contribution of such toxicity to acute and chronic neurodegenerative disorders.

Redox Imbalance and Viral Infections in Neurodegenerative Diseases

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Dolores Limongi

2016-01-01

Full Text Available Reactive oxygen species (ROS are essential molecules for many physiological functions and act as second messengers in a large variety of tissues. An imbalance in the production and elimination of ROS is associated with human diseases including neurodegenerative disorders. In the last years the notion that neurodegenerative diseases are accompanied by chronic viral infections, which may result in an increase of neurodegenerative diseases progression, emerged. It is known in literature that enhanced viral infection risk, observed during neurodegeneration, is partly due to the increase of ROS accumulation in brain cells. However, the molecular mechanisms of viral infection, occurring during the progression of neurodegeneration, remain unclear. In this review, we discuss the recent knowledge regarding the role of influenza, herpes simplex virus type-1, and retroviruses infection in ROS/RNS-mediated Parkinson’s disease (PD, Alzheimer’s disease (AD, and amyotrophic lateral sclerosis (ALS.

Characterization of ALD grown TixAlyN and TixAlyC thin films

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Kinnunen, S. A.; Malm, J.; Arstila, K.; Lahtinen, M.; Sajavaara, T.

2017-09-01

Atomic layer deposition (ALD) was used to grow TixAlyN and TixAlyC thin films using trimethylaluminum (TMA), titanium tetrachloride and ammonia as precursors. Deposition temperature was varied between 325 °C and 500 °C. Films were also annealed in vacuum and N2-atmosphere at 600-1000 °C. Wide range of characterization methods was used including time-of-flight elastic recoil detection analysis (ToF-ERDA), X-ray diffractometry (XRD), X-ray reflectometry (XRR), Raman spectroscopy, ellipsometry, helium ion microscopy (HIM), atomic force microscopy (AFM) and 4-point probe measurement for resistivity. Deposited films were roughly 100 nm thick and contained mainly desired elements. Carbon, chlorine and hydrogen were found to be the main impurities.

Quantitative analysis on electrooculography (EOG) for neurodegenerative disease

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Liu, Chang-Chia; Chaovalitwongse, W. Art; Pardalos, Panos M.; Seref, Onur; Xanthopoulos, Petros; Sackellares, J. C.; Skidmore, Frank M.

2007-11-01

Many studies have documented abnormal horizontal and vertical eye movements in human neurodegenerative disease as well as during altered states of consciousness (including drowsiness and intoxication) in healthy adults. Eye movement measurement may play an important role measuring the progress of neurodegenerative diseases and state of alertness in healthy individuals. There are several techniques for measuring eye movement, Infrared detection technique (IR). Video-oculography (VOG), Scleral eye coil and EOG. Among those available recording techniques, EOG is a major source for monitoring the abnormal eye movement. In this real-time quantitative analysis study, the methods which can capture the characteristic of the eye movement were proposed to accurately categorize the state of neurodegenerative subjects. The EOG recordings were taken while 5 tested subjects were watching a short (>120 s) animation clip. In response to the animated clip the participants executed a number of eye movements, including vertical smooth pursued (SVP), horizontal smooth pursued (HVP) and random saccades (RS). Detection of abnormalities in ocular movement may improve our diagnosis and understanding a neurodegenerative disease and altered states of consciousness. A standard real-time quantitative analysis will improve detection and provide a better understanding of pathology in these disorders.

NSAIDs and cardiovascular drugs in neurodegenerative and cerebrovascular diseases

NARCIS (Netherlands)

M.D.M. Haag (Mendel)

2009-01-01

textabstractNeurodegenerative and cerebrovascular diseases are frequent in elderly populations and comprise primarily of dementia (mainly Alzheimer disease (AD)), Parkinson disease (PD) and stroke. The prevalence of these neurological disorders rises with older age. From 55 years to 90 years and

Low temperature plasma-enhanced ALD TiN ultrathin films for Hf{sub 0.5}Zr{sub 0.5}O{sub 2}-based ferroelectric MIM structures

Energy Technology Data Exchange (ETDEWEB)

Kozodaev, M.G.; Chernikova, A.G.; Markeev, A.M. [Moscow Institute of Physics and Technology, Institutsky Lane 9, Dolgoprudny, Moscow Region 141700 (Russian Federation); Lebedinskii, Y.Y. [Moscow Institute of Physics and Technology, Institutsky Lane 9, Dolgoprudny, Moscow Region 141700 (Russian Federation); National Research Nuclear University MEPhI, Moscow Engineering Physics Institute, Kashirskoye Shosse 31, 115409 Moscow (Russian Federation); Polyakov, S.N. [Technological Institute for Superhard and Novel Carbon Materials, Tsentral' naya str. 7a, 142190, Troitsk, Moscow (Russian Federation)

2017-06-15

In this work chemical and electrical properties of TiN films, grown by low temperature plasma-enhanced atomic layer deposition (PE-ALD) process from TiCl{sub 4} and NH{sub 3}, were investigated. Electrical resistivity as low as 250 μOhm x cm, as well as the lowest Cl impurity content, was achieved at 320 C. Full-ALD Hf{sub 0.5}Zr{sub 0.5}O{sub 2}-based metal-ferroelectric-metal capacitor with TiN electrodes was fabricated and its electrical properties were investigated. It was also shown that the proposed PE-ALD process provides an early film continuity, which was confirmed by ultrathin fully continuous film growth. Such ultrathin (3 nm) and fully continuous TiN film was also successfully implemented as the top electrode to Hf{sub 0.5}Zr{sub 0.5}O{sub 2}-based ferroelectric capacitor. Angle-resolved X-ray photoelectron spectroscopy (AR-XPS) was used for its thickness determination and a visible wake-up effect in underlying Hf{sub 0.5}Zr{sub 0.5}O{sub 2} layer was clearly observed. (copyright 2017 WILEY-VCH Verlag GmbH and Co. KGaA, Weinheim)

Convergent molecular defects underpin diverse neurodegenerative diseases.

Science.gov (United States)

Tofaris, George K; Buckley, Noel J

2018-02-19

In our ageing population, neurodegenerative disorders carry an enormous personal, societal and economic burden. Although neurodegenerative diseases are often thought of as clinicopathological entities, increasing evidence suggests a considerable overlap in the molecular underpinnings of their pathogenesis. Such overlapping biological processes include the handling of misfolded proteins, defective organelle trafficking, RNA processing, synaptic health and neuroinflammation. Collectively but in different proportions, these biological processes in neurons or non-neuronal cells lead to regionally distinct patterns of neuronal vulnerability and progression of pathology that could explain the disease symptomology. With the advent of patient-derived cellular models and novel genetic manipulation tools, we are now able to interrogate this commonality despite the cellular complexity of the brain in order to develop novel therapeutic strategies to prevent or arrest neurodegeneration. Here, we describe broadly these concepts and their relevance across neurodegenerative diseases. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Gemfibrozil, a lipid-lowering drug, induces suppressor of cytokine signaling 3 in glial cells: implications for neurodegenerative disorders.

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Ghosh, Arunava; Pahan, Kalipada

2012-08-03

Glial inflammation is an important feature of several neurodegenerative disorders. Suppressor of cytokine signaling (SOCS) proteins play a crucial role in inhibiting cytokine signaling and inflammatory gene expression in various cell types, including glial cells. However, mechanisms by which SOCS genes could be up-regulated are poorly understood. This study underlines the importance of gemfibrozil, a Food and Drug Administration-approved lipid-lowering drug, in up-regulating the expression of SOCS3 in glial cells. Gemfibrozil increased the expression of Socs3 mRNA and protein in mouse astroglia and microglia in both a time- and dose-dependent manner. Interestingly, gemfibrozil induced the activation of type IA phosphatidylinositol (PI) 3-kinase and AKT. Accordingly, inhibition of PI 3-kinase and AKT by chemical inhibitors abrogated gemfibrozil-mediated up-regulation of SOCS3. Furthermore, we demonstrated that gemfibrozil induced the activation of Krüppel-like factor 4 (KLF4) via the PI 3-kinase-AKT pathway and that siRNA knockdown of KLF4 abrogated gemfibrozil-mediated up-regulation of SOCS3. Gemfibrozil also induced the recruitment of KLF4 to the distal, but not proximal, KLF4-binding site of the Socs3 promoter. This study delineates a novel property of gemfibrozil in up-regulating SOCS3 in glial cells via PI 3-kinase-AKT-mediated activation of KLF4 and suggests that gemfibrozil may find therapeutic application in neuroinflammatory and neurodegenerative disorders.

Cannabinoids and value-based decision making: Implications for neurodegenerative disorders

NARCIS (Netherlands)

Lee, AM; Oleson, E.B.; Diergaarde, L.; Cheer, J.F.; Pattij, T.

2012-01-01

In recent years, disturbances in cognitive function have been increasingly recognized as important symptomatic phenomena in neurodegenerative diseases, including Parkinson's disease (PD). Value-based decision making in particular is an important executive cognitive function that is not only impaired

S-Nitrosylation and uncompetitive/fast off-rate (UFO) drug therapy in neurodegenerative disorders of protein misfolding.

Science.gov (United States)

Nakamura, T; Lipton, S A

2007-07-01

Although activation of glutamate receptors is essential for normal brain function, excessive activity leads to a form of neurotoxicity known as excitotoxicity. Key mediators of excitotoxic damage include overactivation of N-methyl-D-aspartate (NMDA) receptors, resulting in excessive Ca(2+) influx with production of free radicals and other injurious pathways. Overproduction of free radical nitric oxide (NO) contributes to acute and chronic neurodegenerative disorders. NO can react with cysteine thiol groups to form S-nitrosothiols and thus change protein function. S-nitrosylation can result in neuroprotective or neurodestructive consequences depending on the protein involved. Many neurodegenerative diseases manifest conformational changes in proteins that result in misfolding and aggregation. Our recent studies have linked nitrosative stress to protein misfolding and neuronal cell death. Molecular chaperones - such as protein-disulfide isomerase, glucose-regulated protein 78, and heat-shock proteins - can provide neuroprotection by facilitating proper protein folding. Here, we review the effect of S-nitrosylation on protein function under excitotoxic conditions, and present evidence that NO contributes to degenerative conditions by S-nitrosylating-specific chaperones that would otherwise prevent accumulation of misfolded proteins and neuronal cell death. In contrast, we also review therapeutics that can abrogate excitotoxic damage by preventing excessive NMDA receptor activity, in part via S-nitrosylation of this receptor to curtail excessive activity.

Nanoporous silver cathode surface treated by atomic layer deposition of CeO_x for low-temperature solid oxide fuel cells

International Nuclear Information System (INIS)

Neoh, Ke Chean; Han, Gwon Deok; Kim, Manjin; Kim, Jun Woo; Choi, Hyung Jong; Park, Suk Won; Shim, Joon Hyung

2016-01-01

We evaluated the performance of solid oxide fuel cells (SOFCs) with a 50 nm thin silver (Ag) cathode surface treated with cerium oxide (CeO_x) by atomic layer deposition (ALD). The performances of bare and ALD-treated Ag cathodes were evaluated on gadolinia-doped ceria (GDC) electrolyte supporting cells with a platinum (Pt) anode over 300 °C–450 °C. Our work confirms that ALD CeO_x treatment enhances cathodic performance and thermal stability of the Ag cathode. The performance difference between cells using a Ag cathode optimally treated with an ALD CeO_x surface and a reference Pt cathode is about 50% at 450 °C in terms of fuel cell power output in our experiment. The bare Ag cathode completely agglomerated into islands during fuel cell operation at 450 °C, while the ALD CeO_x treatment effectively protects the porosity of the cathode. We also discuss the long-term stability of ALD CeO_x-treated Ag cathodes related to the microstructure of the layers. (paper)

Selective Spatial Processing Deficits in an At-Risk Subgroup of the Fragile X Premutation

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Hocking, Darren R.; Kogan, Cary S.; Cornish, Kim M.

2012-01-01

Until a decade ago, it was assumed that males with the fragile X premutation were unaffected by any cognitive phenotype. Here we examined the extent to which CGG repeat toxicity extends to visuospatial functioning in male fragile X premutation carriers who are asymptomatic for a late-onset neurodegenerative disorder, fragile X-associated…

Olfactory Memory Impairment in Neurodegenerative Diseases

OpenAIRE

Bahuleyan, Biju; Singh, Satendra

2012-01-01

Olfactory disorders are noted in a majority of neurodegenerative diseases, but they are often misjudged and are rarely rated in the clinical setting. Severe changes in the olfactory tests are observed in Parkinson's disease. Olfactory deficits are an early feature in Alzheimer's disease and they worsen with the disease progression. Alterations in the olfactory function are also noted after severe head injuries, temporal lobe epilepsy, multiple sclerosis, and migraine. The purpose of the prese...

Old Things New View: Ascorbic Acid Protects the Brain in Neurodegenerative Disorders

Directory of Open Access Journals (Sweden)

Adriana Covarrubias-Pinto

2015-11-01

Full Text Available Ascorbic acid is a key antioxidant of the Central Nervous System (CNS. Under brain activity, ascorbic acid is released from glial reservoirs to the synaptic cleft, where it is taken up by neurons. In neurons, ascorbic acid scavenges reactive oxygen species (ROS generated during synaptic activity and neuronal metabolism where it is then oxidized to dehydroascorbic acid and released into the extracellular space, where it can be recycled by astrocytes. Other intrinsic properties of ascorbic acid, beyond acting as an antioxidant, are important in its role as a key molecule of the CNS. Ascorbic acid can switch neuronal metabolism from glucose consumption to uptake and use of lactate as a metabolic substrate to sustain synaptic activity. Multiple evidence links oxidative stress with neurodegeneration, positioning redox imbalance and ROS as a cause of neurodegeneration. In this review, we focus on ascorbic acid homeostasis, its functions, how it is used by neurons and recycled to ensure antioxidant supply during synaptic activity and how this antioxidant is dysregulated in neurodegenerative disorders.

QCM gas sensor characterization of ALD-grown very thin TiO2 films

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Boyadjiev, S.; Georgieva, V.; Vergov, L.; Szilágyi, I. M.

2018-03-01

The paper presents a technology for preparation and characterization of titanium dioxide (TiO2) thin films suitable for gas sensor applications. Applying atomic layer deposition (ALD), very thin TiO2 films were deposited on quartz resonators, and their gas sensing properties were studied using the quartz crystal microbalance (QCM) method. The TiO2 thin films were grown using Ti(iOPr)4 and water as precursors. The surface of the films was observed by scanning electron microscopy (SEM), coupled with energy dispersive X-ray analysis (EDX) used for a composition study. The research was focused on the gas-sensing properties of the films. Films of 10-nm thickness were deposited on quartz resonators with Au electrodes and the QCMs were used to build highly sensitive gas sensors, which were tested for detecting NO2. Although very thin, these ALD-grown TiO2 films were sensitive to NO2 already at room temperature and could register as low concentrations as 50 ppm, while the sorption was fully reversible, and the sensors could be fully recovered. With the technology presented, the manufacturing of gas sensors is simple, fast and cost-effective, and suitable for energy-effective portable equipment for real-time environmental monitoring of NO2.

Fragile X-associated disorders: Don't miss them.

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Birch, Rachael C; Cohen, Jonathan; Trollor, Julian N

2017-01-01

Fragile X-associated disorders are a family of inherited disorders caused by expansions in the Fragile X Mental Retardation 1 (FMR1) gene. Premutation expansions of the FMR1 gene confer risk for fragile X-associated primary ovarian insufficiency and fragile X-associated tremor ataxia syndrome, as well as other medical and psychiatric comorbidities. Premutation expansions of the FMR1 gene are common in the general population. However, fragile X-associated disorders are frequently under-recognised and often misdiagnosed. The aim of this article is to describe fragile X-associated disorders and identify specific considerations for general practitioners (GPs) during identification and management of these disorders. GPs have a critical role in the identification of fragile X-associated disorders, as well as coordination of complex care needs. Prompt recognition and appropriate management of these disorders and potential medical and psychiatric comorbidities will have important implications not only for the affected patient, but also other family members who may be at risk.

Recent trends in the transdermal delivery of therapeutic agents used for the management of neurodegenerative diseases.

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Ita, Kevin

2017-06-01

With the increasing proportion of the global geriatric population, it becomes obvious that neurodegenerative diseases will become more widespread. From an epidemiological standpoint, it is necessary to develop new therapeutic agents for the management of Alzheimer's disease, Parkinson's disease, multiple sclerosis and other neurodegenerative disorders. An important approach in this regard involves the use of the transdermal route. With transdermal drug delivery systems (TDDS), it is possible to modulate the pharmacokinetic profiles of these medications and improve patient compliance. Transdermal drug delivery has also been shown to be useful for drugs with short half-life and low or unpredictable bioavailability. In this review, several transdermal drug delivery enhancement technologies are being discussed in relation to the delivery of medications used for the management of neurodegenerative disorders.

Fragile X syndrome and fragile X-associated tremor ataxia syndrome.

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Hall, Deborah A; Berry-Kravis, Elizabeth

2018-01-01

Fragile X-associated disorders encompass several conditions, which are caused by expansion mutations in the fragile X mental retardation 1 (FMR1) gene. Fragile X syndrome is the most common inherited etiology of intellectual disability and results from a full mutation or >200 CGG repeats in FMR1. It is associated with developmental delay, autism spectrum disorder, and seizures. Fragile X-associated tremor/ataxia syndrome is a progressive neurodegenerative disease that occurs in premutation carriers of 55-200 CGG repeats in FMR1 and is characterized by kinetic tremor, gait ataxia, parkinsonism, executive dysfunction, and neuropathy. Fragile X-associated primary ovarian insufficiency also occurs in premutation carrier women and manifests with infertility and early menopause. The diseases constituting fragile X-associated disorders differ mechanistically, due to the distinct molecular properties of premutation versus full mutations. Fragile X syndrome occurs when there is a lack of fragile X mental retardation protein (FMRP) due to FMR1 methylation and silencing. In fragile X-associated tremor ataxia syndrome, a toxic gain of function is postulated with the production of excess CGG repeat-containing FMR1 mRNA, abnormal translation of the repeat sequence leading to production of polyglycine, polyalanine, and other polypeptides and to outright deficits in translation leading to reduced FMRP at larger premutation sizes. The changes in underlying brain chemistry due to FMR1 mutations have led to therapeutic studies in these disorders, with some progress being made in fragile X syndrome. This paper also summarizes indications for testing, genetic counseling issues, and what the future holds for these disorders. Copyright © 2018 Elsevier B.V. All rights reserved.

Autism Spectrum Disorder and Fragile X Syndrome

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... only after another family member has been diagnosed. Autism Spectrum Disorder and Fragile X Syndrome Fragile X syndrome is ... gene cause of ASD What Is Autism Spectrum Disorder? Autism spectrum disorder (ASD) is a behavioral diagnosis. The range ...

Repeat-mediated genetic and epigenetic changes at the FMR1 locus in the Fragile X-related disorders

Science.gov (United States)

Usdin, Karen; Hayward, Bruce E.; Kumari, Daman; Lokanga, Rachel A.; Sciascia, Nicholas; Zhao, Xiao-Nan

2014-01-01

The Fragile X-related disorders are a group of genetic conditions that include the neurodegenerative disorder, Fragile X-associated tremor/ataxia syndrome (FXTAS), the fertility disorder, Fragile X-associated primary ovarian insufficiency (FXPOI) and the intellectual disability, Fragile X syndrome (FXS). The pathology in all these diseases is related to the number of CGG/CCG-repeats in the 5′ UTR of the Fragile X mental retardation 1 (FMR1) gene. The repeats are prone to continuous expansion and the increase in repeat number has paradoxical effects on gene expression increasing transcription on mid-sized alleles and decreasing it on longer ones. In some cases the repeats can simultaneously both increase FMR1 mRNA production and decrease the levels of the FMR1 gene product, Fragile X mental retardation 1 protein (FMRP). Since FXTAS and FXPOI result from the deleterious consequences of the expression of elevated levels of FMR1 mRNA and FXS is caused by an FMRP deficiency, the clinical picture is turning out to be more complex than once appreciated. Added complications result from the fact that increasing repeat numbers make the alleles somatically unstable. Thus many individuals have a complex mixture of different sized alleles in different cells. Furthermore, it has become apparent that the eponymous fragile site, once thought to be no more than a useful diagnostic criterion, may have clinical consequences for females who inherit chromosomes that express this site. This review will cover what is currently known about the mechanisms responsible for repeat instability, for the repeat-mediated epigenetic changes that affect expression of the FMR1 gene, and for chromosome fragility. It will also touch on what current and future options are for ameliorating some of these effects. PMID:25101111

The role of the immune system in neurodegenerative disorders: Adaptive or maladaptive?

Science.gov (United States)

Doty, Kevin R; Guillot-Sestier, Marie-Victoire; Town, Terrence

2015-08-18

Neurodegenerative diseases share common features, including catastrophic neuronal loss that leads to cognitive or motor dysfunction. Neuronal injury occurs in an inflammatory milieu that is populated by resident and sometimes, infiltrating, immune cells - all of which participate in a complex interplay between secreted inflammatory modulators and activated immune cell surface receptors. The importance of these immunomodulators is highlighted by the number of immune factors that have been associated with increased risk of neurodegeneration in recent genome-wide association studies. One of the more difficult tasks for designing therapeutic strategies for immune modulation against neurodegenerative diseases is teasing apart beneficial from harmful signals. In this regard, learning more about the immune components of these diseases has yielded common themes. These unifying concepts should eventually enable immune-based therapeutics for treatment of Alzheimer׳s and Parkinson׳s diseases and amyotrophic lateral sclerosis. Targeted immune modulation should be possible to temper maladaptive factors, enabling beneficial immune responses in the context of neurodegenerative diseases. This article is part of a Special Issue entitled SI: Neuroimmunology in Health And Disease. Copyright © 2014 Elsevier B.V. All rights reserved.

Fluorinated graphene and hexagonal boron nitride as ALD seed layers for graphene-based van der Waals heterostructures

International Nuclear Information System (INIS)

Guo, Hongwei; Liu, Yunlong; Xu, Yang; Meng, Nan; Luo, Jikui; Wang, Hongtao; Hasan, Tawfique; Wang, Xinran; Yu, Bin

2014-01-01

Ultrathin dielectric materials prepared by atomic-layer-deposition (ALD) technology are commonly used in graphene electronics. Using the first-principles density functional theory calculations with van der Waals (vdW) interactions included, we demonstrate that single-side fluorinated graphene (SFG) and hexagonal boron nitride (h-BN) exhibit large physical adsorption energy and strong electrostatic interactions with H 2 O-based ALD precursors, indicating their potential as the ALD seed layer for dielectric growth on graphene. In graphene-SFG vdW heterostructures, graphene is n-doped after ALD precursor adsorption on the SFG surface caused by vertical intrinsic polarization of SFG. However, graphene-h-BN vdW heterostructures help preserving the intrinsic characteristics of the underlying graphene due to in-plane intrinsic polarization of h-BN. By choosing SFG or BN as the ALD seed layer on the basis of actual device design needs, the graphene vdW heterostructures may find applications in low-dimensional electronics. (paper)

Neurodegenerative Dementia

International Nuclear Information System (INIS)

Allard, Michelle

2006-01-01

Full text: With increasing life expectancy across the world, the number of elderly people at risk of developing dementia is growing rapidly. Thus, progressive neurodegenerative disorders such as dementia represent a growing public health concern. These diseases are characterized by a progressive loss in most of the cognitive functions. The promise, possibly in a near future, of disease-modifying therapies has made the characterization of the early stages of dementia a topic of major interest. The assessment of these early stages is a challenge for neuroimaging studies. In order to conceive prevention trials; it is of major outcome to fully understand the mechanisms of the cognitive system impairment and its evolution, with a particular reference to the symptomatic pre-dementia stage, when subjects just begin to depart from normality. In this article we review recent progress in neuroimaging, and their potentiality for increasing a diagnostic accuracy. (author)

Role of Different Alpha-Synuclein Strains in Synucleinopathies, Similarities with other Neurodegenerative Diseases

OpenAIRE

Melki, Ronald

2015-01-01

Abstract Misfolded protein aggregates are the hallmark of several neurodegenerative diseases in humans. The main protein constituent of these aggregates and the regions within the brain that are affected differ from one neurodegenerative disorder to another. A plethora of reports suggest that distinct diseases have in common the ability of protein aggregates to spread and amplify within the central nervous system. This review summarizes briefly what is known about the nature of the protein ag...

Enhanced Corrosion Resistance of PVD-CrN Coatings by ALD Sealing Layers

Science.gov (United States)

Wan; Zhang, Teng Fei; Ding, Ji Cheng; Kim, Chang-Min; Park, So-Won; Yang, Yang; Kim, Kwang-Ho; Kwon, Se-Hun

2017-04-01

Multilayered hard coatings with a CrN matrix and an Al2O3, TiO2, or nanolaminate-Al2O3/TiO2 sealing layer were designed by a hybrid deposition process combined with physical vapor deposition (PVD) and atomic layer deposition (ALD). The strategy was to utilize ALD thin films as pinhole-free barriers to seal the intrinsic defects to protect the CrN matrix. The influences of the different sealing layers added in the coatings on the microstructure, surface roughness, and corrosion behaviors were investigated. The results indicated that the sealing layer added by ALD significantly decreased the average grain size and improved the corrosion resistance of the CrN coatings. The insertion of the nanolaminate-Al2O3/TiO2 sealing layers resulted in a further increase in corrosion resistance, which was attributed to the synergistic effect of Al2O3 and TiO2, both acting as excellent passivation barriers to the diffusion of corrosive substances.

Bio-effectiveness of the main flavonoids of Achillea millefolium in the pathophysiology of neurodegenerative disorders- a review

Directory of Open Access Journals (Sweden)

Fatemeh Ayoobi

2017-06-01

Full Text Available The Achillea millefolium L. (Yarrow is a common herb which is widely being used, worldwide. Achillea is being used for treatment of many disorders since centuries. It is considered safe for supplemental use and flavonoids such as kaempferol, luteolin and apigenin are of main constituents present in Achillea. Most of both antioxidant and anti-inflammatory properties of this herb have been attributed to its flavonoid content. Oxidative and inflammatory processes play important roles in pathogenesis of neurodegenerative diseases. Present review was aimed to review the latest literature evidences regarding application of Achillea and/or its three main flavonoid constituents on epilepsy, Alzheimer's disease, multiple sclerosis, Parkinson's disease and stroke.

Cerebral correlates of psychotic syndromes in neurodegenerative diseases

OpenAIRE

Jellinger, Kurt A

2012-01-01

Abstract Psychosis has been recognized as a common feature in neurodegenerative diseases and a core feature of dementia that worsens most clinical courses. It includes hallucinations, delusions including paranoia, aggressive behaviour, apathy and other psychotic phenomena that occur in a wide range of degenerative disorders including Alzheimer?s disease, synucleinopathies (Parkinson?s disease, dementia with Lewy bodies), Huntington?s disease, frontotemporal degenerations, motoneuron and prion...

Movement and Other Neurodegenerative Syndromes in Patients with Systemic Rheumatic Diseases: A Case Series of 8 Patients and Review of the Literature.

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Menezes, Rikitha; Pantelyat, Alexander; Izbudak, Izlem; Birnbaum, Julius

2015-08-01

Patients with rheumatic diseases can present with movement and other neurodegenerative disorders. It may be underappreciated that movement and other neurodegenerative disorders can encompass a wide variety of disease entities. Such disorders are strikingly heterogeneous and lead to a wider spectrum of clinical injury than seen in Parkinson's disease. Therefore, we sought to stringently phenotype movement and other neurodegenerative disorders presenting in a case series of rheumatic disease patients. We integrated our findings with a review of the literature to understand mechanisms which may account for such a ubiquitous pattern of clinical injury.Seven rheumatic disease patients (5 Sjögren's syndrome patients, 2 undifferentiated connective tissue disease patients) were referred and could be misdiagnosed as having Parkinson's disease. However, all of these patients were ultimately diagnosed as having other movement or neurodegenerative disorders. Findings inconsistent with and more expansive than Parkinson's disease included cerebellar degeneration, dystonia with an alien-limb phenomenon, and nonfluent aphasias.A notable finding was that individual patients could be affected by cooccurring movement and other neurodegenerative disorders, each of which could be exceptionally rare (ie, prevalence of ∼1:1000), and therefore with the collective probability that such disorders were merely coincidental and causally unrelated being as low as ∼1-per-billion. Whereas our review of the literature revealed that ubiquitous patterns of clinical injury were frequently associated with magnetic resonance imaging (MRI) findings suggestive of a widespread vasculopathy, our patients did not have such neuroimaging findings. Instead, our patients could have syndromes which phenotypically resembled paraneoplastic and other inflammatory disorders which are known to be associated with antineuronal antibodies. We similarly identified immune-mediated and inflammatory markers of injury

Reverse engineering human neurodegenerative disease using pluripotent stem cell technology.

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Liu, Ying; Deng, Wenbin

2016-05-01

With the technology of reprogramming somatic cells by introducing defined transcription factors that enables the generation of "induced pluripotent stem cells (iPSCs)" with pluripotency comparable to that of embryonic stem cells (ESCs), it has become possible to use this technology to produce various cells and tissues that have been difficult to obtain from living bodies. This advancement is bringing forth rapid progress in iPSC-based disease modeling, drug screening, and regenerative medicine. More and more studies have demonstrated that phenotypes of adult-onset neurodegenerative disorders could be rather faithfully recapitulated in iPSC-derived neural cell cultures. Moreover, despite the adult-onset nature of the diseases, pathogenic phenotypes and cellular abnormalities often exist in early developmental stages, providing new "windows of opportunity" for understanding mechanisms underlying neurodegenerative disorders and for discovering new medicines. The cell reprogramming technology enables a reverse engineering approach for modeling the cellular degenerative phenotypes of a wide range of human disorders. An excellent example is the study of the human neurodegenerative disease amyotrophic lateral sclerosis (ALS) using iPSCs. ALS is a progressive neurodegenerative disease characterized by the loss of upper and lower motor neurons (MNs), culminating in muscle wasting and death from respiratory failure. The iPSC approach provides innovative cell culture platforms to serve as ALS patient-derived model systems. Researchers have converted iPSCs derived from ALS patients into MNs and various types of glial cells, all of which are involved in ALS, to study the disease. The iPSC technology could be used to determine the role of specific genetic factors to track down what's wrong in the neurodegenerative disease process in the "disease-in-a-dish" model. Meanwhile, parallel experiments of targeting the same specific genes in human ESCs could also be performed to control

Preparation and characterization of ALD deposited ZnO thin films studied for gas sensors

Energy Technology Data Exchange (ETDEWEB)

Boyadjiev, S.I., E-mail: boiajiev@gmail.com [MTA-BME Technical Analytical Chemistry Research Group, Szent Gellért tér 4, Budapest, H-1111 (Hungary); Georgi Nadjakov Institute of Solid State Physics, Bulgarian Academy of Sciences, 72 Tzarigradsko Chaussee Blvd., 1784 Sofia (Bulgaria); Georgieva, V. [Georgi Nadjakov Institute of Solid State Physics, Bulgarian Academy of Sciences, 72 Tzarigradsko Chaussee Blvd., 1784 Sofia (Bulgaria); Yordanov, R. [Department of Microelectronics, Technical University of Sofia, 8 Kliment Ohridski Blvd., 1756 Sofia (Bulgaria); Raicheva, Z. [Georgi Nadjakov Institute of Solid State Physics, Bulgarian Academy of Sciences, 72 Tzarigradsko Chaussee Blvd., 1784 Sofia (Bulgaria); Szilágyi, I.M. [MTA-BME Technical Analytical Chemistry Research Group, Szent Gellért tér 4, Budapest, H-1111 (Hungary); Budapest University of Technology and Economics, Department of Inorganic and Analytical Chemistry, Szent Gellért tér 4, Budapest, H-1111 (Hungary)

2016-11-30

Highlights: • For the first time the gas sensing towards NO{sub 2} of very thin ALD ZnO films is studied. • The very thin ALD ZnO films showed excellent sensitivity to NO{sub 2} at room temperature. • These very thin film ZnO-based QCM sensors very well register even low concentrations. • The sensors have fully reversible sorption and are able to be recovered in short time. • Described fast and cost-effective ALD deposition of ZnO thin films for QCM gas sensor. - Abstract: Applying atomic layer deposition (ALD), very thin zinc oxide (ZnO) films were deposited on quartz resonators, and their gas sensing properties were studied using the quartz crystal microbalance (QCM) method. The gas sensing of the ZnO films to NO{sub 2} was tested in the concentration interval between 10 and 5000 ppm. On the basis of registered frequency change of the QCM, for each concentration the sorbed mass was calculated. Further characterization of the films was carried out by various techniques, i.e. by SEM-EDS, XRD, ellipsometry, and FTIR spectroscopy. Although being very thin, the films were gas sensitive to NO{sub 2} already at room temperature and could register very well as low concentrations as 100 ppm, while the sorption was fully reversible. Our results for very thin ALD ZnO films show that the described fast, simple and cost-effective technology could be implemented for producing gas sensors working at room temperature and being capable to detect in real time low concentrations of NO{sub 2}.

FDTD-based Transcranial Magnetic Stimulation model applied to specific neurodegenerative disorders.

Science.gov (United States)

Fanjul-Vélez, Félix; Salas-García, Irene; Ortega-Quijano, Noé; Arce-Diego, José Luis

2015-01-01

Non-invasive treatment of neurodegenerative diseases is particularly challenging in Western countries, where the population age is increasing. In this work, magnetic propagation in human head is modelled by Finite-Difference Time-Domain (FDTD) method, taking into account specific characteristics of Transcranial Magnetic Stimulation (TMS) in neurodegenerative diseases. It uses a realistic high-resolution three-dimensional human head mesh. The numerical method is applied to the analysis of magnetic radiation distribution in the brain using two realistic magnetic source models: a circular coil and a figure-8 coil commonly employed in TMS. The complete model was applied to the study of magnetic stimulation in Alzheimer and Parkinson Diseases (AD, PD). The results show the electrical field distribution when magnetic stimulation is supplied to those brain areas of specific interest for each particular disease. Thereby the current approach entails a high potential for the establishment of the current underdeveloped TMS dosimetry in its emerging application to AD and PD. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Electrocatalytic activity of Pt grown by ALD on carbon nanotubes for Si-based DMFC applications

DEFF Research Database (Denmark)

Johansson, Alicia Charlotte; Dalslet, Bjarke Thomas; Yang, R.B.

2012-01-01

in a top-flow ALD reactor at 250°C, using MeCpPtMe3 and O2 as precursors. The anode was tested for the methanol oxidation reaction (MOR) in a three-electrode electrochemical set-up and it showed improved catalytic activity compared to a reference sample of Pt deposited on flat Si. It is demonstrated......We present an anode design for silicon-based direct methanol fuel cell (DMFC) applications. Platinum was deposited conformally by atomic layer deposition (ALD) onto vertically aligned, nitrogendoped multi-walled carbon nanotubes (MWCNTs) grown on porous silicon. The deposition was carried out...... that ALD could be a MEMS compatible deposition technique for Si-based fuel cell applications. © The Electrochemical Society....

Evaluation of retinoids for induction of the redundant gene ABCD2 as an alternative treatment option in X-linked adrenoleukodystrophy.

Directory of Open Access Journals (Sweden)

Franziska D Weber

Full Text Available X-linked adrenoleukodystrophy (X-ALD, the most common peroxisomal disorder, is a clinically heterogeneous disease that can manifest as devastating inflammatory cerebral demyelination (CALD leading to death of affected males. Currently, the only curative treatment is allogeneic hematopoietic stem cell transplantation (HSCT. However, HSCT is only effective when performed at an early stage because the inflammation may progress for eighteen months after HSCT. Thus, alternative treatment options able to immediately halt the progression are urgently needed. X-ALD is caused by mutations in the ABCD1 gene, encoding the peroxisomal membrane protein ABCD1, resulting in impaired very long-chain fatty acid metabolism. The related ABCD2 protein is able to functionally compensate for ABCD1-deficiency both in vitro and in vivo. Recently, we demonstrated that of the cell types derived from CD34+ stem cells, predominantly monocytes but not lymphocytes are metabolically impaired in X-ALD. As ABCD2 is virtually not expressed in these cells, we hypothesize that a pharmacological up-regulation of ABCD2 should compensate metabolically and halt the inflammation in CALD. Retinoids are anti-inflammatory compounds known to act on ABCD2. Here, we investigated the capacity of selected retinoids for ABCD2 induction in human monocytes/macrophages. In THP-1 cells, 13-cis-retinoic acid reached the highest, fivefold, increase in ABCD2 expression. To test the efficacy of retinoids in vivo, we analyzed ABCD2 mRNA levels in blood cells isolated from acne patients receiving 13-cis-retinoic acid therapy. In treated acne patients, ABCD2 mRNA levels were comparable to pre-treatment levels in monocytes and lymphocytes. Nevertheless, when primary monocytes were in vitro differentiated into macrophages and treated with 13-cis-retinoic acid, we observed a fourfold induction of ABCD2. However, the level of ABCD2 induction obtained by retinoids alone is probably not of therapeutic relevance

Seeking environmental causes of neurodegenerative disease and envisioning primary prevention.

Science.gov (United States)

Spencer, Peter S; Palmer, Valerie S; Kisby, Glen E

2016-09-01

Pathological changes of the aging brain are expressed in a range of neurodegenerative disorders that will impact increasing numbers of people across the globe. Research on the causes of these disorders has focused heavily on genetics, and strategies for prevention envision drug-induced slowing or arresting disease advance before its clinical appearance. We discuss a strategic shift that seeks to identify the environmental causes or contributions to neurodegeneration, and the vision of primary disease prevention by removing or controlling exposure to culpable agents. The plausibility of this approach is illustrated by the prototypical neurodegenerative disease amyotrophic lateral sclerosis and parkinsonism-dementia complex (ALS-PDC). This often-familial long-latency disease, once thought to be an inherited genetic disorder but now known to have a predominant or exclusive environmental origin, is in the process of disappearing from the three heavily affected populations, namely Chamorros of Guam and Rota, Japanese residents of Kii Peninsula, Honshu, and Auyu and Jaqai linguistic groups on the island of New Guinea in West Papua, Indonesia. Exposure via traditional food and/or medicine (the only common exposure in all three geographic isolates) to one or more neurotoxins in seed of cycad plants is the most plausible if yet unproven etiology. Neurotoxin dosage and/or subject age at exposure might explain the stratified epidemic of neurodegenerative disease on Guam in which high-incidence ALS peaked and declined before that of PD, only to be replaced today by a dementing disorder comparable to Alzheimer's disease. Exposure to the Guam environment is also linked to the delayed development of ALS among a subset of Chamorro and non-Chamorro Gulf War/Era veterans, a summary of which is reported here for the first time. Lessons learned from this study and from 65 years of research on ALS-PDC include the exceptional value of initial, field-based informal investigation of

Operando SXRD of E-ALD deposited sulphides ultra-thin films: Crystallite strain and size

Science.gov (United States)

Giaccherini, Andrea; Russo, Francesca; Carlà, Francesco; Guerri, Annalisa; Picca, Rosaria Anna; Cioffi, Nicola; Cinotti, Serena; Montegrossi, Giordano; Passaponti, Maurizio; Di Benedetto, Francesco; Felici, Roberto; Innocenti, Massimo

2018-02-01

Electrochemical Atomic Layer Deposition (E-ALD), exploiting surface limited electrodeposition of atomic layers, can easily grow highly ordered ultra-thin films and 2D structures. Among other compounds CuxZnyS grown by means of E-ALD on Ag(111) has been found particularly suitable for the solar energy conversion due to its band gap (1.61 eV). However its growth seems to be characterized by a micrometric thread-like structure, probably overgrowing a smooth ultra-thin films. On this ground, a SXRD investigation has been performed, to address the open questions about the structure and the growth of CuxZnyS by means of E-ALD. The experiment shows a pseudo single crystal pattern as well as a powder pattern, confirming that part of the sample grows epitaxially on the Ag(111) substrate. The growth of the film was monitored by following the evolution of the Bragg peaks and Debye rings during the E-ALD steps. Breadth and profile analysis of the Bragg peaks lead to a qualitative interpretation of the growth mechanism. This study confirms that Zn lead to the growth of a strained Cu2S-like structure, while the growth of the thread-like structure is probably driven by the release of the stress from the epitaxial phase.

Peroxiredoxin distribution in the mouse brain with emphasis on neuronal populations affected in neurodegenerative disorders.

Science.gov (United States)

Goemaere, Julie; Knoops, Bernard

2012-02-01

Redox changes are observed in neurodegenerative diseases, ranging from increased levels of reactive oxygen/nitrogen species and disturbance of antioxidant systems, to nitro-oxidative damage. By reducing hydrogen peroxide, peroxynitrite, and organic hydroperoxides, peroxiredoxins (Prdxs) represent a major potential protective barrier against nitro-oxidative insults in the brain. While recent works have investigated the putative role of Prdxs in neurodegenerative disorders, less is known about their expression in the healthy brain. Here we used immunohistochemistry to map basal expression of Prdxs throughout C57BL/6 mouse brain. We first confirmed the neuronal localization of Prdx2-5 and the glial expression of Prdx1, Prdx4, and Prdx6. Then we performed an in-depth analysis of neuronal Prdx distribution in the brain. Our results show that Prdx2-5 are widely detected in the different neuronal populations, and especially well expressed in the olfactory bulb, in the cerebral cortex, in pons nuclei, in the red nucleus, in all cranial nerve nuclei, in the cerebellum, and in motor neurons of the spinal cord. In contrast, Prdx expression is very low in the dopaminergic neurons of substantia nigra pars compacta and in the CA1/2 pyramidal cells of hippocampus. This low basal expression may contribute to the vulnerability of these neurons to nitro-oxidative attacks occurring in Parkinson's disease and Alzheimer's disease. In addition, we found that Prdx expression levels are unevenly distributed among neurons of a determined region and that distinct regional patterns of expression are observed between isoforms, reinforcing the hypothesis of the nonredundant function of Prdxs. Copyright © 2011 Wiley-Liss, Inc.

Investigating the Trimethylaluminium/Water ALD Process on Mesoporous Silica by In Situ Gravimetric Monitoring

Directory of Open Access Journals (Sweden)

Verena E. Strempel

2018-05-01

Full Text Available A low amount of AlOx was successfully deposited on an unordered, mesoporous SiO2 powder using 1–3 ALD (Atomic Layer Deposition cycles of trimethylaluminium and water. The process was realized in a self-built ALD setup featuring a microbalanceand a fixed particle bed. The reactor temperature was varied between 75, 120, and 200 °C. The self-limiting nature of the deposition was verified by in situ gravimetric monitoring for all temperatures. The coated material was further analyzed by nitrogen sorption, inductively coupled plasma-optical emission spectroscopy, powder X-ray diffraction, high-resolution transmission electron microscopy, attenuated total reflection Fourier transformed infrared spectroscopy, and elemental analysis. The obtained mass gains correspond to average growth between 0.81–1.10 Å/cycle depending on substrate temperature. In addition, the different mass gains during the half-cycles in combination with the analyzed aluminum content after one, two, and three cycles indicate a change in the preferred surface reaction of the trimethylaluminium molecule from a predominately two-ligand exchange with hydroxyl groups to more single-ligand exchange with increasing cycle number. Nitrogen sorption isotherms demonstrate (1 homogeneously coated mesopores, (2 a decrease in surface area, and (3 a reduction of the pore size. The experiment is successfully repeated in a scale-up using a ten times higher substrate batch size.

Role of 4-hydroxy-2-nonenal (HNE) in the pathogenesis of alzheimer disease and other selected age-related neurodegenerative disorders.

Science.gov (United States)

Di Domenico, Fabio; Tramutola, Antonella; Butterfield, D Allan

2017-10-01

Oxidative stress is involved in various and numerous pathological states including several age-related neurodegenerative diseases. Peroxidation of the membrane lipid bilayer is one of the major sources of free radical-mediated injury that directly damages neurons causing increased membrane rigidity, decreased activity of membrane-bound enzymes, impairment of membrane receptors and altered membrane permeability and eventual cell death. Moreover, the peroxidation of polyunsaturated fatty acids leads to the formation of aldehydes, which can act as toxic by-products. One of the most abundant and cytotoxic lipid -derived aldehydes is 4-hydroxy 2-nonenal (HNE). HNE toxicity is mainly due to the alterations of cell functions by the formation of covalent adducts of HNE with proteins. A key marker of lipid peroxidation, HNE-protein adducts, were found to be elevated in brain tissues and body fluids of Alzheimer disease, Parkinson disease, Huntington disease and amyotrophic lateral sclerosis subjects and/or models of the respective age-related neurodegenerative diseases. Although only a few proteins were identified as common targets of HNE modification across all these listed disorders, a high overlap of these proteins occurs concerning the alteration of common pathways, such as glucose metabolism or mitochondrial function that are known to contribute to cognitive decline. Within this context, despite the different etiological and pathological mechanisms that lead to the onset of different neurodegenerative diseases, the formation of HNE-protein adducts might represent the shared leit-motif, which aggravates brain damage contributing to disease specific clinical presentation and decline in cognitive performance observed in each case. Copyright © 2016 Elsevier Inc. All rights reserved.

Isoprostanes and Neuroprostanes as Biomarkers of Oxidative Stress in Neurodegenerative Diseases

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Elżbieta Miller

2014-01-01

Full Text Available Accumulating data shows that oxidative stress plays a crucial role in neurodegenerative disorders. The literature data indicate that in vivo or postmortem cerebrospinal fluid and brain tissue levels of F2-isoprostanes (F2-IsoPs especially F4-neuroprotanes (F4-NPs are significantly increased in some neurodegenerative diseases: multiple sclerosis, Alzheimer's disease, Huntington's disease, and Creutzfeldt-Jakob disease. Central nervous system is the most metabolically active organ of the body characterized by high requirement for oxygen and relatively low antioxidative activity, what makes neurons and glia highly susceptible to destruction by reactive oxygen/nitrogen species and neurodegeneration. The discovery of F2-IsoPs and F4-NPs as markers of lipid peroxidation caused by the free radicals has opened up new areas of investigation regarding the role of oxidative stress in the pathogenesis of human neurodegenerative diseases. This review focuses on the relationship between F2-IsoPs and F4-NPs as biomarkers of oxidative stress and neurodegenerative diseases. We summarize the knowledge of these novel biomarkers of oxidative stress and the advantages of monitoring their formation to better define the involvement of oxidative stress in neurological diseases.

Dynamic Modeling for the Design and Cyclic Operation of an Atomic Layer Deposition (ALD Reactor

Directory of Open Access Journals (Sweden)

Curtisha D. Travis

2013-08-01

Full Text Available A laboratory-scale atomic layer deposition (ALD reactor system model is derived for alumina deposition using trimethylaluminum and water as precursors. Model components describing the precursor thermophysical properties, reactor-scale gas-phase dynamics and surface reaction kinetics derived from absolute reaction rate theory are integrated to simulate the complete reactor system. Limit-cycle solutions defining continuous cyclic ALD reactor operation are computed with a fixed point algorithm based on collocation discretization in time, resulting in an unambiguous definition of film growth-per-cycle (gpc. A key finding of this study is that unintended chemical vapor deposition conditions can mask regions of operation that would otherwise correspond to ideal saturating ALD operation. The use of the simulator for assisting in process design decisions is presented.

Sirtuins and Their Roles in Brain Aging and Neurodegenerative Disorders.

Science.gov (United States)

Jęśko, Henryk; Wencel, Przemysław; Strosznajder, Robert P; Strosznajder, Joanna B

2017-03-01

Sirtuins (SIRT1-SIRT7) are unique histone deacetylases (HDACs) whose activity depends on NAD + levels and thus on the cellular metabolic status. SIRTs regulate energy metabolism and mitochondrial function. They orchestrate the stress response and damage repair. Through these functions sirtuins modulate the course of aging and affect neurodegenerative diseases. SIRTSs interact with multiple signaling proteins, transcription factors (TFs) and poly(ADP-ribose) polymerases (PARPs) another class of NAD + -dependent post-translational protein modifiers. The cross-talk between SIRTs TFs and PARPs is a highly promising research target in a number of brain pathologies. This review describes updated results on sirtuins in brain aging/neurodegeneration. It focuses on SIRT1 but also on the roles of mitochondrial SIRTs (SIRT3, 4, 5) and on SIRT6 and SIRT2 localized in the nucleus and in cytosol, respectively. The involvement of SIRTs in regulation of insulin-like growth factor signaling in the brain during aging and in Alzheimer's disease was also focused. Moreover, we analyze the mechanism(s) and potential significance of interactions between SIRTs and several TFs in the regulation of cell survival and death. A critical view is given on the application of SIRT activators/modulators in therapy of neurodegenerative diseases.

aldB, an RpoS-dependent gene in Escherichia coli encoding an aldehyde dehydrogenase that is repressed by Fis and activated by Crp.

Science.gov (United States)

Xu, J; Johnson, R C

1995-06-01

Escherichia coli aldB was identified as a gene that is negatively regulated by Fis but positively regulated by RpoS. The complete DNA sequence determined in this study indicates that aldB encodes a 56.3-kDa protein which shares a high degree of homology with an acetaldehyde dehydrogenase encoded by acoD of Alcaligenes eutrophus and an aldehyde dehydrogenase encoded by aldA of Vibrio cholerae and significant homology with a group of other aldehyde dehydrogenases from prokaryotes and eukaryotes. Expression of aldB is maximally induced during the transition from exponential phase to stationary phase. Its message levels are elevated three- to fourfold by a fis mutation and abolished by an rpoS mutation. In addition, the expression of an aldB-lacZ fusion was decreased about 20-fold in the absence of crp. DNase I footprinting analysis showed that five Fis binding sites and one Crp binding site are located within the aldB promoter region, suggesting that Fis and Crp are acting directly to control aldB transcription. AldB expression is induced by ethanol, but in contrast to that of most of the RpoS-dependent genes, the expression of aldB is not altered by an increase in medium osmolarity.

The Influence of Adipose Tissue on Brain Development, Cognition, and Risk of Neurodegenerative Disorders.

Science.gov (United States)

Letra, Liliana; Santana, Isabel

2017-01-01

The brain is a highly metabolic organ and thus especially vulnerable to changes in peripheral metabolism, including those induced by obesity-associated adipose tissue dysfunction. In this context, it is likely that the development and maturation of neurocognitive circuits may also be affected and modulated by metabolic environmental factors, beginning in utero. It is currently recognized that maternal obesity, either pre-gestational or gestational, negatively influences fetal brain development and elevates the risk of cognitive impairment and neuropsychiatric disorders in the offspring. During infancy and adolescence, obesity remains a limiting factor for healthy neurodevelopment, especially affecting executive functions but also attention, visuospatial ability, and motor skills. In middle age, obesity seems to induce an accelerated brain aging and thus may increase the risk of age-related neurodegenerative diseases such as Alzheimer's disease. In this chapter we review and discuss experimental and clinical evidence focusing on the influence of adipose tissue dysfunction on neurodevelopment and cognition across lifespan, as well as some possible mechanistic links, namely the role of the most well studied adipokines.

Fetal programming of the human brain: is there a link with insurgence of neurodegenerative disorders in adulthood?

Science.gov (United States)

Faa, G; Marcialis, M A; Ravarino, A; Piras, M; Pintus, M C; Fanos, V

2014-01-01

In recent years, evidence is growing on the role played by gestational factors in shaping brain development and on the influence of intrauterine experiences on later development of neurodegenerative diseases including Parkinson's (PD) and Alzheimer's disease (AD). The nine months of intrauterine development and the first three years of postnatal life are appearing to be extremely critical for making connections among neurons and among neuronal and glial cells that will shape a lifetime of experience. Here, the multiple epigenetic factors acting during gestation - including maternal diet, malnutrition, stress, hypertension, maternal diabetes, fetal hypoxia, prematurity, low birth weight, prenatal infection, intrauterine growth restriction, drugs administered to the mother or to the baby - are reported, and their ability to modulate brain development, resulting in interindividual variability in the total neuronal and glial burden at birth is discussed. Data from recent literature suggest that prevention of neurodegeneration should be identified as the one method to halt the diffusion of neurodegenerative diseases. The "two hits" hypothesis, first introduced for PD and successfully applied to AD and other neurodegenerative human pathologies, should focus our attention on a peculiar period of our life: the intrauterine and perinatal periods. The first hit to our nervous system occurs early in life, determining a PD or AD imprinting to our brain that will condition our resistance or, alternatively, our susceptibility to develop a neurodegenerative disease later in life. In conclusion, how early life events contribute to late-life development of adult neurodegenerative diseases, including PD and AD, is emerging as a new fascinating research focus. This assumption implies that research on prevention of neurodegenerative diseases should center on events taking place early in life, during gestation and in the perinatal periods, thus presenting a new challenge to

Protection against neurodegenerative disease on Earth and in space

Science.gov (United States)

Takamatsu, Yoshiki; Koike, Wakako; Takenouchi, Takato; Sugama, Shuei; Wei, Jianshe; Waragai, Masaaki; Sekiyama, Kazunari; Hashimoto, Makoto

2016-01-01

All living organisms have evolutionarily adapted themselves to the Earth’s gravity, and failure to adapt to gravity changes may lead to pathological conditions. This perspective may also apply to abnormal aging observed in bedridden elderly patients with aging-associated diseases such as osteoporosis and sarcopenia. Given that bedridden elderly patients are partially analogous to astronauts in that both cannot experience the beneficial effects of gravity on the skeletal system and may suffer from bone loss and muscle weakness, one may wonder whether there are gravity-related mechanisms underlying diseases among the elderly. In contrast to numerous studies of the relevance of microgravity in skeletal disorders, little attention has been paid to neurodegenerative diseases. Therefore, the objective of this paper is to discuss the possible relevance of microgravity in these diseases. We particularly noted a proteomics paper showing that levels of hippocampal proteins, including β-synuclein and carboxyl-terminal ubiquitin hydrolase L1, which have been linked to familial neurodegenerative diseases, were significantly decreased in the hippocampus of mice subjected to hindlimb suspension, a model of microgravity. We suggest that microgravity-induced neurodegeneration may be further exacerbated by diabetes and other factors. On the basis of this view, prevention of neurodegenerative diseases through ‘anti-diabetes’ and ‘hypergravity’ approaches may be important as a common therapeutic approach on Earth and in space. Collectively, neurodegenerative diseases and space medicine may be linked to each other more strongly than previously thought. PMID:28725728

Application of PIXE in medical study. Environmental minerals and neurodegenerative disorders

International Nuclear Information System (INIS)

Yoshida, S.

1999-01-01

Comparative study on amyotrophic lateral sclerosis (ALS) and parkinsonism-dementia (PDC) in the Kii Peninsula of Japan and Guam was conducted to evaluate the participatory role of environmental minerals in the pathogenesis of the above neurodegenerative diseases, using particle-induced x-ray emission (PIXE) spectrometry and morphometric-statistical analysis. A significantly high content of Al in the hippocampus and spinal cord or Kii and Guamanian ALS/PD cases was found with a positive correlation for Fe and Cu, and a negative correlation for Zn. The numbers of hippocampal neurons in Guamanian PDC, Alzheimer's disease, and Parkinson's disease were significantly decreased with a high Al content. Al content significantly and positively correlated with the number of Alzheimer's neurofibrillary tangles (NFTs) in the hippocampus of ALS cases and controls in both foci, especially in Guamanian cases. The slope of best linear regression of Guamanian cases was markedly steeper than that of Japanese cases (p < 0,001), Morin staining for Al showed green fluorescence on the nucleolus, cytoplasm, and NFT in the hippocampus of Kii ALS cases. These findings suggest that Guamanian and Kii people have a predisposition to develop ALS/PDC precipitated by their geological/geochemical environmental status, i.e., a prolonged low intake or Ca and Mg together with excess exposure to Al and other environmental minerals. (author)

Application of PIXE in medical study. Environmental minerals and neurodegenerative disorders

Energy Technology Data Exchange (ETDEWEB)

Yoshida, S. [Department of Neurology, Wakayama Medical College, Wakayama (Japan)

1999-07-01

Comparative study on amyotrophic lateral sclerosis (ALS) and parkinsonism-dementia (PDC) in the Kii Peninsula of Japan and Guam was conducted to evaluate the participatory role of environmental minerals in the pathogenesis of the above neurodegenerative diseases, using particle-induced x-ray emission (PIXE) spectrometry and morphometric-statistical analysis. A significantly high content of Al in the hippocampus and spinal cord or Kii and Guamanian ALS/PD cases was found with a positive correlation for Fe and Cu, and a negative correlation for Zn. The numbers of hippocampal neurons in Guamanian PDC, Alzheimer's disease, and Parkinson's disease were significantly decreased with a high Al content. Al content significantly and positively correlated with the number of Alzheimer's neurofibrillary tangles (NFTs) in the hippocampus of ALS cases and controls in both foci, especially in Guamanian cases. The slope of best linear regression of Guamanian cases was markedly steeper than that of Japanese cases (p < 0,001), Morin staining for Al showed green fluorescence on the nucleolus, cytoplasm, and NFT in the hippocampus of Kii ALS cases. These findings suggest that Guamanian and Kii people have a predisposition to develop ALS/PDC precipitated by their geological/geochemical environmental status, i.e., a prolonged low intake or Ca and Mg together with excess exposure to Al and other environmental minerals. (author)

The Big Bluff of Amyotrophic Lateral Sclerosis Diagnosis: The Role of Neurodegenerative Disease Mimics.

Science.gov (United States)

Bicchi, Ilaria; Emiliani, Carla; Vescovi, Angelo; Martino, Sabata

2015-01-01

Neurodegenerative diseases include a significant number of pathologies affecting the nervous system. Generally, the primary cause of each disease is specific; however, recently, it was shown that they may be correlated at molecular level. This aspect, together with the exhibition of similar symptoms, renders the diagnosis of these disorders difficult. Amyotrophic lateral sclerosis is one of these pathologies. Herein, we report several cases of amyotrophic lateral sclerosis misdiagnosed as a consequence of features that are common to several neurodegenerative diseases, such as Parkinson's, Huntington's and Alzheimer's disease, spinal muscular atrophy, progressive bulbar palsy, spastic paraplegia and frontotemporal dementia, and mostly with the lysosomal storage disorder GM2 gangliosidosis. Overall reports highlight that the differential diagnosis for amyotrophic lateral sclerosis should include correlated mechanisms. © 2015 S. Karger AG, Basel.

Home video monitoring system for neurodegenerative diseases based on commercial HD cameras

NARCIS (Netherlands)

Abramiuc, B.; Zinger, S.; De With, P.H.N.; De Vries-Farrouh, N.; Van Gilst, M.M.; Bloem, B.; Overeem, S.

2016-01-01

Neurodegenerative disease (ND) is an umbrella term for chronic disorders that are characterized by severe joint cognitive-motor impairments, which are difficult to evaluate on a frequent basis. HD cameras in the home environment could extend and enhance the diagnosis process and could lead to better

Plasma-assisted ALD for the conformal deposition of SiO2 : process, material and electronic properties

NARCIS (Netherlands)

Dingemans, G.; Helvoirt, van C.A.A.; Pierreux, D.; Keuning, W.; Kessels, W.M.M.

2012-01-01

Plasma-assisted atomic layer deposition (ALD) was used to deposit SiO2 films in the temperature range of Tdep = 50–400°C on Si(100). H2Si[N(C2H5)2]2 and an O2 plasma were used as Si precursor and oxidant, respectively. The ALD growth process and material properties were characterized in detail.

Advances in epigenetics and epigenomics for neurodegenerative diseases.

Science.gov (United States)

Qureshi, Irfan A; Mehler, Mark F

2011-10-01

In the post-genomic era, epigenetic factors-literally those that are "over" or "above" genetic ones and responsible for controlling the expression and function of genes-have emerged as important mediators of development and aging; gene-gene and gene-environmental interactions; and the pathophysiology of complex disease states. Here, we provide a brief overview of the major epigenetic mechanisms (ie, DNA methylation, histone modifications and chromatin remodeling, and non-coding RNA regulation). We highlight the nearly ubiquitous profiles of epigenetic dysregulation that have been found in Alzheimer's and other neurodegenerative diseases. We also review innovative methods and technologies that enable the characterization of individual epigenetic modifications and more widespread epigenomic states at high resolution. We conclude that, together with complementary genetic, genomic, and related approaches, interrogating epigenetic and epigenomic profiles in neurodegenerative diseases represent important and increasingly practical strategies for advancing our understanding of and the diagnosis and treatment of these disorders.

A puzzling combination: disorder X order

International Nuclear Information System (INIS)

Hasenfratz, P.

1979-01-01

There are several examples indicating that the operator combination 'disorder X order' creates anomalous spin and/or statistics. In 2 + 1 dimensions there is a similar anomaly related to the disorder operator carrying Z(N) topological charge believed to have an important role in quark confinement. The conventionally defined total angular momentum has an anomalous term 1/2 sigma 3 ((1/√3) lambda 8 ) and can take the values 1/2 (1/3) in the presence of 'disorder X order' in 2 + 1 dimensional SU(2) (SU(3)) gauge theories. It is argued that the existence of a stable soliton solution or the introduction of Higgs fields are not important for the anomaly. (Auth.)

Insights into chirality distributions of single-walled carbon nanotubes grown on different CoxMg1-xO solid solutions

DEFF Research Database (Denmark)

He, Maoshuai; Jiang, Hua; Kauppi, Inkeri

2014-01-01

Low-temperature chemical vapor deposition (CVD) growth of single-walled carbon nanotubes (SWNTs) was achieved on two different types of Co xMg1-xO catalysts prepared by different techniques: atomic layer deposition (ALD) and impregnation. The chirality distribution of SWNTs grown on the ALD......-prepared CoxMg1-xO catalyst is wider than that of SWNTs grown on the impregnation-prepared CoxMg 1-xO catalyst. The different chirality distributions of SWNTs are related to their different growth modes. The ALD-prepared CoxMg 1-xO catalyzes the growth of SWNTs by "tip growth" mode, as revealed by in situ...... for the synthesis of SWNTs with high chiral-selectivity. In addition, impregnation-prepared Co xMg1-xO catalysts calcinated at different temperatures were systematically studied and their catalytic performances in synthesizing carbon nanotubes were elucidated. This work illustrates the influence of metal...

REM Sleep Behavior Disorder: Updated Review of the Core Features, the RBD-Neurodegenerative Disease Association, Evolving Concepts, Controversies, and Future Directions

Science.gov (United States)

Boeve, Bradley F.

2010-01-01

Rapid eye movement (REM) sleep behavior disorder (RBD) is a parasomnia manifested by vivid, often frightening dreams associated with simple or complex motor behavior during REM sleep. Patients appear to “act out their dreams,” in which the exhibited behaviors mirror the content of the dreams, and the dream content often involves a chasing or attacking theme. The polysomnographic features of RBD include increased electromyographic tone +/- dream enactment behavior during REM sleep. Management with counseling and pharmacologic measures is usually straight-forward and effective. In this review, the terminology, clinical and polysomnographic features, demographic and epidemiologic features, diagnostic criteria, differential diagnosis, and management strategies are discussed. Recent data on the suspected pathophysiologic mechanisms of RBD are also reviewed. The literature and our institutional experience on RBD are next discussed, with an emphasis on the RBD-neurodegenerative disease association and particularly the RBD-synucleinopathy association. Several issues relating to evolving concepts, controversies, and future directions are then reviewed, with an emphasis on idiopathic RBD representing an early feature of a neurodegenerative disease and particularly an evolving synucleinopathy. Planning for future therapies that impact patients with idiopathic RBD is reviewed in detail. PMID:20146689

Nanoscale semiconductor Pb{sub 1-x}Sn{sub x}Se (x = 0.2) thin films synthesized by electrochemical atomic layer deposition

Energy Technology Data Exchange (ETDEWEB)

Lin Shaoxiong; Zhang Xin; Shi Xuezhao; Wei Jinping; Lu Daban; Zhang Yuzhen; Kou Huanhuan [Department of Chemistry, Lanzhou University, Lanzhou 730000 (China); Wang Chunming, E-mail: wangcm@lzu.edu.cn [Department of Chemistry, Lanzhou University, Lanzhou 730000 (China)

2011-04-15

In this paper the fabrication and characterization of IV-VI semiconductor Pb{sub 1-x}Sn{sub x}Se (x = 0.2) thin films on gold substrate by electrochemical atomic layer deposition (EC-ALD) method at room temperature are reported. Cyclic voltammetry (CV) is used to determine approximate deposition potentials for each element. The amperometric I-t technique is used to fabricate the semiconductor alloy. The elements are deposited in the following sequence: (Se/Pb/Se/Pb/Se/Pb/Se/Pb/Se/Sn ...), each period is formed using four ALD cycles of PbSe followed by one cycle of SnSe. Then the deposition manner above is cyclic repeated till a satisfactory film with expected thickness of Pb{sub 1-x}Sn{sub x}Se is obtained. The morphology of the deposit is observed by field emission scanning electron microscopy (FE-SEM). X-ray diffraction (XRD) pattern is used to study its crystalline structure; X-ray photoelectron spectroscopy (XPS) of the deposit indicates an approximate ratio 1.0:0.8:0.2 of Se, Pb and Sn, as the expected stoichiometry for the deposit. Open-circuit potential (OCP) studies indicate a good p-type property, and the good optical activity makes it suitable for fabricating a photoelectric switch.

In Vivo Profiling Reveals a Competent Heat Shock Response in Adult Neurons: Implications for Neurodegenerative Disorders.

Directory of Open Access Journals (Sweden)

Alisia Carnemolla

Full Text Available The heat shock response (HSR is the main pathway used by cells to counteract proteotoxicity. The inability of differentiated neurons to induce an HSR has been documented in primary neuronal cultures and has been proposed to play a critical role in ageing and neurodegeneration. However, this accepted dogma has not been demonstrated in vivo. We used BAC transgenic mice generated by the Gene Expression Nervous System Atlas project to investigate the capacity of striatal medium sized spiny neurons to induce an HSR as compared to that of astrocytes and oligodendrocytes. We found that all cell populations were competent to induce an HSR upon HSP90 inhibition. We also show the presence and relative abundance of heat shock-related genes and proteins in these striatal cell populations. The identification of a competent HSR in adult neurons supports the development of therapeutics that target the HSR pathway as treatments for neurodegenerative disorders.

Role of agmatine in neurodegenerative diseases and epilepsy.

Science.gov (United States)

Moretti, Morgana; Matheus, Filipe C; de Oliveira, Paulo A; Neis, Vivian B; Ben, Juliana; Walz, Roger; Rodrigues, Ana Lucia S; Prediger, Rui Daniel

2014-06-01

Agmatine, a cationic polyamine synthesized after decarboxylation of L-arginine by the enzyme arginine decarboxylase, is an endogenous neuromodulator that emerges as a potential agent to manage diverse central nervous system (CNS) disorders. Consistent with its neuromodulatory and neuroprotective properties, there is increasing number of preclinical studies demonstrating the beneficial effects of exogenous agmatine administration on depression, anxiety, hypoxic ischemia, nociception, morphine tolerance, memory, Parkinson`s disease, Alzheimer`s disease, traumatic brain injury related alterations/disorders and epilepsy. The aim of this review is to summarize the knowledge about the effects of agmatine in CNS and point out its potential as new pharmacological treatment for diverse neurological and neurodegenerative diseases. Moreover, some molecular mechanisms underlying the neuroprotective effects of agmatine will be discussed.

Bioinformatics Mining and Modeling Methods for the Identification of Disease Mechanisms in Neurodegenerative Disorders

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Martin Hofmann-Apitius

2015-12-01

Full Text Available Since the decoding of the Human Genome, techniques from bioinformatics, statistics, and machine learning have been instrumental in uncovering patterns in increasing amounts and types of different data produced by technical profiling technologies applied to clinical samples, animal models, and cellular systems. Yet, progress on unravelling biological mechanisms, causally driving diseases, has been limited, in part due to the inherent complexity of biological systems. Whereas we have witnessed progress in the areas of cancer, cardiovascular and metabolic diseases, the area of neurodegenerative diseases has proved to be very challenging. This is in part because the aetiology of neurodegenerative diseases such as Alzheimer´s disease or Parkinson´s disease is unknown, rendering it very difficult to discern early causal events. Here we describe a panel of bioinformatics and modeling approaches that have recently been developed to identify candidate mechanisms of neurodegenerative diseases based on publicly available data and knowledge. We identify two complementary strategies—data mining techniques using genetic data as a starting point to be further enriched using other data-types, or alternatively to encode prior knowledge about disease mechanisms in a model based framework supporting reasoning and enrichment analysis. Our review illustrates the challenges entailed in integrating heterogeneous, multiscale and multimodal information in the area of neurology in general and neurodegeneration in particular. We conclude, that progress would be accelerated by increasing efforts on performing systematic collection of multiple data-types over time from each individual suffering from neurodegenerative disease. The work presented here has been driven by project AETIONOMY; a project funded in the course of the Innovative Medicines Initiative (IMI; which is a public-private partnership of the European Federation of Pharmaceutical Industry Associations

An overview of the molecular mechanisms and novel roles of Nrf2 in neurodegenerative disorders.

Science.gov (United States)

Yang, Yang; Jiang, Shuai; Yan, Juanjuan; Li, Yue; Xin, Zhenlong; Lin, Yan; Qu, Yan

2015-02-01

Recently, growing evidence has demonstrated that nuclear factor erythroid 2-related factor 2 (Nrf2) is a pivotal regulator of endogenous defense systems that function via the activation of a set of protective genes, and this is particularly clear in the central nervous system (CNS). Therefore, it is highly useful to summarize the current literature on the molecular mechanisms and role of Nrf2 in the CNS. In this review, we first briefly introduce the molecular features of Nrf2. We then discuss the regulation, cerebral actions, upstream modulators and downstream targets of Nrf2 pathway. Following this background, we expand our discussion to the role of Nrf2 in several major neurodegenerative disorders (NDDs) such as Alzheimer's disease, Parkinson's disease, Huntington's disease, multiple sclerosis and amyotrophic lateral sclerosis. Lastly, we discuss some potential future directions. The information reviewed here may be significant in the design of further experimental research and increase the potential of Nrf2 as a therapeutic target in the future. Copyright © 2014 Elsevier Ltd. All rights reserved.

The influence of surface preparation on low temperature HfO2 ALD on InGaAs (001) and (110) surfaces

International Nuclear Information System (INIS)

Kent, Tyler; Edmonds, Mary; Kummel, Andrew C.; Tang, Kechao; Negara, Muhammad Adi; McIntyre, Paul; Chobpattana, Varistha; Mitchell, William; Sahu, Bhagawan; Galatage, Rohit; Droopad, Ravi

2015-01-01

Current logic devices rely on 3D architectures, such as the tri-gate field effect transistor (finFET), which utilize the (001) and (110) crystal faces simultaneously thus requiring passivation methods for the (110) face in order to ensure a pristine 3D surface prior to further processing. Scanning tunneling microscopy (STM), x-ray photoelectron spectroscopy (XPS), and correlated electrical measurement on MOSCAPs were utilized to compare the effects of a previously developed in situ pre-atomic layer deposition (ALD) surface clean on the InGaAs (001) and (110) surfaces. Ex situ wet cleans are very effective on the (001) surface but not the (110) surface. Capacitance voltage indicated the (001) surface with no buffered oxide etch had a higher C max hypothesized to be a result of poor nucleation of HfO 2 on the native oxide. An in situ pre-ALD surface clean employing both atomic H and trimethylaluminum (TMA) pre-pulsing, developed by Chobpattana et al. and Carter et al. for the (001) surface, was demonstrated to be effective on the (110) surface for producing low D it high C ox MOSCAPs. Including TMA in the pre-ALD surface clean resulted in reduction of the magnitude of the interface state capacitance. The XPS studies show the role of atomic H pre-pulsing is to remove both carbon and oxygen while STM shows the role of TMA pre-pulsing is to eliminate H induced etching. Devices fabricated at 120 °C and 300 °C were compared

NeuroX, a fast and efficient genotyping platform for investigation of neurodegenerative diseases

NARCIS (Netherlands)

Nalls, M.A.; Bras, J.; Hernandez, D.G.; Keller, M.F.; Majounie, E.; Renton, A.E.; Saad, M.; Jansen, I.E.; Guerreiro, R.; Lubbe, S.; Plagnol, V.; Gibbs, J.R.; Schulte, C.; Pankratz, N.; Sutherland, M.; Bertram, L.; Lill, C.M.; DeStefano, A.L.; Faroud, T.; Eriksson, N.; Tung, J.Y.; Edsall, C.; Nichols, N.; Brooks, J.; Arepalli, S.; Pliner, H.; Letson, C.; Heutink, P.; Martinez, M.; Gasser, T.; Traynor, B.J.; Wood, N.; Hardy, J.; Singleton, A.B.

2015-01-01

Our objective was to design a genotyping platform that would allow rapid genetic characterization of samples in the context of genetic mutations and risk factors associated with common neurodegenerative diseases. The platform needed to be relatively affordable, rapid to deploy, and use a common and

The aldehyde dehydrogenase, AldA, is essential for L-1,2-propanediol utilization in laboratory-evolved Escherichia coli

DEFF Research Database (Denmark)

Aziz, Ramy K.; Monk, Jonathan M.; Andrews, Kathleen A.

2017-01-01

is highly conserved among members of the family Enterobacteriacea. To test this hypothesis, we first performed computational model simulation, which confirmed the essentiality of the aldA gene for 1,2-PDO utilization by the evolved PDO-degrading E. coli. Next, we deleted the aldA gene from the evolved...

Enhancement of fiber-optic low-coherence Fabry-Pérot interferometer with ZnO ALD films

Science.gov (United States)

Hirsch, Marzena; Listewnik, Paulina; Jedrzejewska-Szczerska, Małgorzata

2018-04-01

In this paper investigation of the enhanced fiber-optic low coherence Fabry-Pérot interferometer with zinc oxide (ZnO) film deposited by atomic layer deposition (ALD) was presented. Model of the interferometer, which was constructed of single-mode optical fiber with applied ZnO ALD films, was built. The interferometer was also examined by means of experiment. Measurements were performed for both reflective and transmission modes, using wavelengths of 1300 nm and 1500 nm. The measurements with the air cavity showed the best performance in terms of a visibility of the interference signal can be achieved for small cavity lengths ( 50μm) in both configurations. Combined with the enhancement of reflectance of the interferometer mirrors due to the ALD film, proposed construction could be successfully applied in refractive index (RI) sensor that can operate with improved visibility of the signal even in 1.3-1.5 RI range as well as with small volume samples, as shown by the modeling.

Newborn screening for X-linked adrenoleukodystrophy: further evidence high throughput screening is feasible.

Science.gov (United States)

Theda, Christiane; Gibbons, Katy; Defor, Todd E; Donohue, Pamela K; Golden, W Christopher; Kline, Antonie D; Gulamali-Majid, Fizza; Panny, Susan R; Hubbard, Walter C; Jones, Richard O; Liu, Anita K; Moser, Ann B; Raymond, Gerald V

2014-01-01

X-linked adrenoleukodystrophy (ALD) is characterized by adrenal insufficiency and neurologic involvement with onset at variable ages. Plasma very long chain fatty acids are elevated in ALD; even in asymptomatic patients. We demonstrated previously that liquid chromatography tandem mass spectrometry measuring C26:0 lysophosphatidylcholine reliably identifies affected males. We prospectively applied this method to 4689 newborn blood spot samples; no false positives were observed. We show that high throughput neonatal screening for ALD is methodologically feasible. Copyright © 2013 Elsevier Inc. All rights reserved.

Astrocytes and endoplasmic reticulum stress: A bridge between obesity and neurodegenerative diseases.

Science.gov (United States)

Martin-Jiménez, Cynthia A; García-Vega, Ángela; Cabezas, Ricardo; Aliev, Gjumrakch; Echeverria, Valentina; González, Janneth; Barreto, George E

2017-11-01

Endoplasmic reticulum (ER) is a subcellular organelle involved in protein folding and processing. ER stress constitutes a cellular process characterized by accumulation of misfolded proteins, impaired lipid metabolism and induction of inflammatory responses. ER stress has been suggested to be involved in several human pathologies, including neurodegenerative diseases and obesity. Different studies have shown that both neurodegenerative diseases and obesity trigger similar cellular responses to ER stress. Moreover, both diseases are assessed in astrocytes as evidences suggest these cells as key regulators of brain homeostasis. However, the exact contributions to the effects of ER stress in astrocytes in the various neurodegenerative diseases and its relation with obesity are not well known. Here, we discuss recent advances in the understanding of molecular mechanisms that regulate ER stress-related disorders in astrocytes such as obesity and neurodegeneration. Moreover, we outline the correlation between the activated proteins of the unfolded protein response (UPR) in these pathological conditions in order to identify possible therapeutic targets for ER stress in astrocytes. We show that ER stress in astrocytes shares UPR activation pathways during both obesity and neurodegenerative diseases, demonstrating that UPR related proteins like ER chaperone GRP 78/Bip, PERK pathway and other exogenous molecules ameliorate UPR response and promote neuroprotection. Copyright © 2017 Elsevier Ltd. All rights reserved.

Histochemical approaches to assess cell-to-cell transmission of misfolded proteins in neurodegenerative diseases

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G. Natale

2013-03-01

Full Text Available Formation, aggregation and transmission of abnormal proteins are common features in neurodegenerative disorders including Parkinson’s disease, Alzheimer’s disease, amyotrophic lateral sclerosis, and Huntington’s disease. The mechanisms underlying protein alterations in neurodegenerative diseases remain controversial. Novel findings highlighted altered protein clearing systems as common biochemical pathways which generate protein misfolding, which in turn causes protein aggregation and protein spreading. In fact, proteinaceous aggregates are prone to cell-to-cell propagation. This is reminiscent of what happens in prion disorders, where the prion protein misfolds thus forming aggregates which spread to neighbouring cells. For this reason, the term prionoids is currently used to emphasize how several misfolded proteins are transmitted in neurodegenerative diseases following this prion-like pattern. Histochemical techniques including the use of specific antibodies covering both light and electron microscopy offer a powerful tool to describe these phenomena and investigate specific molecular steps. These include: prion like protein alterations; glycation of prion-like altered proteins to form advanced glycation end-products (AGEs; mechanisms of extracellular secretion; interaction of AGEs with specific receptors placed on neighbouring cells (RAGEs. The present manuscript comments on these phenomena aimed to provide a consistent scenario of the available histochemical approaches to dissect each specific step.

Application of a diagnostic methodology by quantification of 26:0 lysophosphatidylcholine in dried blood spots for Japanese newborn screening of X-linked adrenoleukodystrophy

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Chen Wu

2017-09-01

Full Text Available X-linked adrenoleukodystrophy (X-ALD is a rare inherited metabolic disease that results in the accumulation of very long chain fatty acids (VLCFA in plasma and all tissues. Recent studies regarding cerebral X-ALD (CALD treatment emphasize the importance of its early diagnosis. 26:0 lysophosphatidylcholine (LysoPC is a sensitive biomarker for newborn screening of X-ALD, while its application for Japanese DBS is unclear. Therefore, we evaluated the feasibility of 20:0 LysoPC and 24:0 LysoPC along with 26:0 LysoPC for diagnosing X-ALD in a cohort of newborns (n = 604, healthy adults (n = 50 and patients (n = 4. Results indicated that 26:0 LysoPC had strong significance for discrimination of patients by the amounts of 2.0 to 4.0 and 0.1 to 1.9 pmol/punch for patients and newborns/healthy adults, respectively. Based on these values, we recommend that further diagnostic confirmation is essential if the amount of 26:0 LysoPC in DBS is above 1.7 pmol/punch.

Transgenic nonhuman primates for neurodegenerative diseases

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Chan Anthony WS

2004-06-01

Full Text Available Abstract Animal models that represent human diseases constitute an important tool in understanding the pathogenesis of the diseases, and in developing effective therapies. Neurodegenerative diseases are complex disorders involving neuropathologic and psychiatric alterations. Although transgenic and knock-in mouse models of Alzheimer's disease, (AD, Parkinson's disease (PD and Huntington's disease (HD have been created, limited representation in clinical aspects has been recognized and the rodent models lack true neurodegeneration. Chemical induction of HD and PD in nonhuman primates (NHP has been reported, however, the role of intrinsic genetic factors in the development of the diseases is indeterminable. Nonhuman primates closely parallel humans with regard to genetic, neuroanatomic, and cognitive/behavioral characteristics. Accordingly, the development of NHP models for neurodegenerative diseases holds greater promise for success in the discovery of diagnoses, treatments, and cures than approaches using other animal species. Therefore, a transgenic NHP carrying a mutant gene similar to that of patients will help to clarify our understanding of disease onset and progression. Additionally, monitoring disease onset and development in the transgenic NHP by high resolution brain imaging technology such as MRI, and behavioral and cognitive testing can all be carried out simultaneously in the NHP but not in other animal models. Moreover, because of the similarity in motor repertoire between NHPs and humans, it will also be possible to compare the neurologic syndrome observed in the NHP model to that in patients. Understanding the correlation between genetic defects and physiologic changes (e.g. oxidative damage will lead to a better understanding of disease progression and the development of patient treatments, medications and preventive approaches for high risk individuals. The impact of the transgenic NHP model in understanding the role which

Implications of glial nitric oxyde in neurodegenerative diseases

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Jose Enrique eYuste

2015-08-01

Full Text Available Nitric oxide (NO is a pleiotropic janus-faced molecule synthesized by nitric oxide synthases (NOS which plays a critical role in a number of physiological and pathological processes in humans. The physiological roles of NO depend on its local concentrations, as well as its availability and the nature of downstream target molecules. Its double-edged sword action has been linked to neurodegenerative disorders. Excessive NO production, as the evoked by inflammatory signals, has been identified as one of the major causative reasons for the pathogenesis of several neurodegenerative diseases. Moreover, excessive NO synthesis under neuroinflammation leads to the formation of reactive nitrogen species and neuronal cell death. There is an intimate relation between microglial activation, NO and neuroinflammation in the human brain. The role of NO in neuroinflammation has been defined in animal models where this neurotransmitter can modulate the inflammatory process acting on key regulatory pathways, such as those associated with excitotoxicity processes induced by glutamate accumulation and microglial activation. Activated glia express inducible NOS and produce NO that triggers calcium mobilization from the endoplasmic reticulum, activating the release of vesicular glutamate from astroglial cells resulting in neuronal death. This change in microglia potentially contributes to the increased age-associated susceptibility and neurodegeneration. In the current review, information is provided about the role of NO, glial activation and age-related processes in the central nervous system (CNS that may be helpful in the isolation of new therapeutic targets for aging and neurodegenerative diseases.

Neuronal network disintegration: common pathways linking neurodegenerative diseases.

Science.gov (United States)

Ahmed, Rebekah M; Devenney, Emma M; Irish, Muireann; Ittner, Arne; Naismith, Sharon; Ittner, Lars M; Rohrer, Jonathan D; Halliday, Glenda M; Eisen, Andrew; Hodges, John R; Kiernan, Matthew C

2016-11-01

Neurodegeneration refers to a heterogeneous group of brain disorders that progressively evolve. It has been increasingly appreciated that many neurodegenerative conditions overlap at multiple levels and therefore traditional clinicopathological correlation approaches to better classify a disease have met with limited success. Neuronal network disintegration is fundamental to neurodegeneration, and concepts based around such a concept may better explain the overlap between their clinical and pathological phenotypes. In this Review, promoters of overlap in neurodegeneration incorporating behavioural, cognitive, metabolic, motor, and extrapyramidal presentations will be critically appraised. In addition, evidence that may support the existence of large-scale networks that might be contributing to phenotypic differentiation will be considered across a neurodegenerative spectrum. Disintegration of neuronal networks through different pathological processes, such as prion-like spread, may provide a better paradigm of disease and thereby facilitate the identification of novel therapies for neurodegeneration. 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/.

Building an integrated neurodegenerative disease database at an academic health center.

Science.gov (United States)

Xie, Sharon X; Baek, Young; Grossman, Murray; Arnold, Steven E; Karlawish, Jason; Siderowf, Andrew; Hurtig, Howard; Elman, Lauren; McCluskey, Leo; Van Deerlin, Vivianna; Lee, Virginia M-Y; Trojanowski, John Q

2011-07-01

It is becoming increasingly important to study common and distinct etiologies, clinical and pathological features, and mechanisms related to neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and frontotemporal lobar degeneration. These comparative studies rely on powerful database tools to quickly generate data sets that match diverse and complementary criteria set by them. In this article, we present a novel integrated neurodegenerative disease (INDD) database, which was developed at the University of Pennsylvania (Penn) with the help of a consortium of Penn investigators. Because the work of these investigators are based on Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and frontotemporal lobar degeneration, it allowed us to achieve the goal of developing an INDD database for these major neurodegenerative disorders. We used the Microsoft SQL server as a platform, with built-in "backwards" functionality to provide Access as a frontend client to interface with the database. We used PHP Hypertext Preprocessor to create the "frontend" web interface and then used a master lookup table to integrate individual neurodegenerative disease databases. We also present methods of data entry, database security, database backups, and database audit trails for this INDD database. Using the INDD database, we compared the results of a biomarker study with those using an alternative approach by querying individual databases separately. We have demonstrated that the Penn INDD database has the ability to query multiple database tables from a single console with high accuracy and reliability. The INDD database provides a powerful tool for generating data sets in comparative studies on several neurodegenerative diseases. Copyright © 2011 The Alzheimer's Association. Published by Elsevier Inc. All rights reserved.

Effect of Neuroinflammation on Synaptic Organization and Function in the Developing Brain: Implications for Neurodevelopmental and Neurodegenerative Disorders

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Amin Mottahedin

2017-07-01

Full Text Available The brain is a plastic organ where both the intrinsic CNS milieu and extrinsic cues play important roles in shaping and wiring neural connections. The perinatal period constitutes a critical time in central nervous system development with extensive refinement of neural connections, which are highly sensitive to fetal and neonatal compromise, such as inflammatory challenges. Emerging evidence suggests that inflammatory cells in the brain such as microglia and astrocytes are pivotal in regulating synaptic structure and function. In this article, we will review the role of glia cells in synaptic physiology and pathophysiology, including microglia-mediated elimination of synapses. We propose that activation of the immune system dynamically affects synaptic organization and function in the developing brain. We will discuss the role of neuroinflammation in altered synaptic plasticity following perinatal inflammatory challenges and potential implications for neurodevelopmental and neurodegenerative disorders.

Targeting Microglial KATP Channels to Treat Neurodegenerative Diseases: A Mitochondrial Issue

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Manuel J. Rodríguez

2013-01-01

Full Text Available Neurodegeneration is a complex process involving different cell types and neurotransmitters. A common characteristic of neurodegenerative disorders is the occurrence of a neuroinflammatory reaction in which cellular processes involving glial cells, mainly microglia and astrocytes, are activated in response to neuronal death. Microglia do not constitute a unique cell population but rather present a range of phenotypes closely related to the evolution of neurodegeneration. In a dynamic equilibrium with the lesion microenvironment, microglia phenotypes cover from a proinflammatory activation state to a neurotrophic one directly involved in cell repair and extracellular matrix remodeling. At each moment, the microglial phenotype is likely to depend on the diversity of signals from the environment and of its response capacity. As a consequence, microglia present a high energy demand, for which the mitochondria activity determines the microglia participation in the neurodegenerative process. As such, modulation of microglia activity by controlling microglia mitochondrial activity constitutes an innovative approach to interfere in the neurodegenerative process. In this review, we discuss the mitochondrial KATP channel as a new target to control microglia activity, avoid its toxic phenotype, and facilitate a positive disease outcome.

Potential application of lithium in Parkinson’s and other neurodegenerative diseases

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Carol A Lazzara

2015-10-01

Full Text Available Lithium, the long-standing hallmark treatment for bipolar disorder, has recently been identified as a potential neuroprotective agent in neurodegeneration. Here we focus on introducing numerous in vitro and in vivo studies that have shown lithium treatment to be efficacious in reducing oxidative stress and inflammation, increasing autophagy, inhibiting apoptosis, and decreasing the accumulation of α-synulcein, with an emphasis on Parkinson’s disease. A number of biological pathways have been shown to be involved in causing these neuroprotective effects. The inhibition of GSK-3β has been the mechanism most studied; however, other modes of action include the regulation of apoptotic proteins and glutamate excitotoxicity as well as down-regulation of Calpain-1. This review provides a framework of the neuroprotective effects of lithium in neurodegenerative diseases and the putative mechanisms by which lithium provides the protection. Lithium-only treatment may not be a suitable therapeutic option for neurodegenerative diseases due to inconsistent efficacy and potential side-effects, however, the use of low dose lithium in combination with other potential or existing therapeutic compounds may be a promising approach to reduce symptoms and disease progression in neurodegenerative diseases.

Role of farnesoid X receptor and bile acids in alcoholic liver disease

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Sharon Manley

2015-03-01

Full Text Available Alcoholic liver disease (ALD is one of the major causes of liver morbidity and mortality worldwide. Chronic alcohol consumption leads to development of liver pathogenesis encompassing steatosis, inflammation, fibrosis, cirrhosis, and in extreme cases, hepatocellular carcinoma. Moreover, ALD may also associate with cholestasis. Emerging evidence now suggests that farnesoid X receptor (FXR and bile acids also play important roles in ALD. In this review, we discuss the effects of alcohol consumption on FXR, bile acids and gut microbiome as well as their impacts on ALD. Moreover, we summarize the findings on FXR, FoxO3a (forkhead box-containing protein class O3a and PPARα (peroxisome proliferator-activated receptor alpha in regulation of autophagy-related gene transcription program and liver injury in response to alcohol exposure.

Plasma-assisted ALD of LiPO(N) for solid state batteries

NARCIS (Netherlands)

Put, B.; Mees, M.J.; Hornsveld, N.; Sepúlveda, A.; Vereecken, P.M.; Kessels, W.M.M.; Creatore, M.

2016-01-01

All solid state 3D batteries are pursued for their increased safety and high power capabilities. At present conformai coating of the solid electrolyte remains one of the key hurdles for the implementation of such devices. In the present work we investigate atomic layer deposition (ALD) as means of

Lipid Involvement in Neurodegenerative Diseases of the Motor System: Insights from Lysosomal Storage Diseases.

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Dodge, James C

2017-01-01

Lysosomal storage diseases (LSDs) are a heterogeneous group of rare inherited metabolic diseases that are frequently triggered by the accumulation of lipids inside organelles of the endosomal-autophagic-lysosomal system (EALS). There is now a growing realization that disrupted lysosomal homeostasis (i.e., lysosomal cacostasis) also contributes to more common neurodegenerative disorders such as Parkinson disease (PD). Lipid deposition within the EALS may also participate in the pathogenesis of some additional neurodegenerative diseases of the motor system. Here, I will highlight the lipid abnormalities and clinical manifestations that are common to LSDs and several diseases of the motor system, including amyotrophic lateral sclerosis (ALS), atypical forms of spinal muscular atrophy, Charcot-Marie-Tooth disease (CMT), hereditary spastic paraplegia (HSP), multiple system atrophy (MSA), PD and spinocerebellar ataxia (SCA). Elucidating the underlying basis of intracellular lipid mislocalization as well as its consequences in each of these disorders will likely provide innovative targets for therapeutic research.

AlGaN/GaN MISHEMTs with AlN gate dielectric grown by thermal ALD technique.

Science.gov (United States)

Liu, Xiao-Yong; Zhao, Sheng-Xun; Zhang, Lin-Qing; Huang, Hong-Fan; Shi, Jin-Shan; Zhang, Chun-Min; Lu, Hong-Liang; Wang, Peng-Fei; Zhang, David Wei

2015-01-01

Recently, AlN plasma-enhanced atomic layer deposition (ALD) passivation technique had been proposed and investigated for suppressing the dynamic on-resistance degradation behavior of high-electron-mobility transistors (HEMTs). In this paper, a novel gate dielectric and passivation technique for GaN-on-Si AlGaN/GaN metal-insulator-semiconductor high-electron-mobility transistors (MISHEMTs) is presented. This technique features the AlN thin film grown by thermal ALD at 400°C without plasma enhancement. A 10.6-nm AlN thin film was grown upon the surface of the HEMT serving as the gate dielectric under the gate electrode and as the passivation layer in the access region at the same time. The MISHEMTs with thermal ALD AlN exhibit enhanced on/off ratio, reduced channel sheet resistance, reduction of gate leakage by three orders of magnitude at a bias of 4 V, reduced threshold voltage hysteresis of 60 mV, and suppressed current collapse degradation.

Hemoglobin mRNA Changes in the Frontal Cortex of Patients with Neurodegenerative Diseases

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Silvia Vanni

2018-01-01

Full Text Available Background: Hemoglobin is the major protein found in erythrocytes, where it acts as an oxygen carrier molecule. In recent years, its expression has been reported also in neurons and glial cells, although its role in brain tissue remains still unknown. Altered hemoglobin expression has been associated with various neurodegenerative disorders. Here, we investigated hemoglobin mRNA levels in brains of patients affected by variant, iatrogenic, and sporadic forms of Creutzfeldt-Jakob disease (vCJD, iCJD, sCJD, respectively and in different genetic forms of prion diseases (gPrD in comparison to Alzheimer's disease (AD subjects and age-matched controls.Methods: Total RNA was obtained from the frontal cortex of vCJD (n = 20, iCJD (n = 11, sCJD (n = 23, gPrD (n = 30, and AD (n = 14 patients and age-matched controls (n = 30. RT-qPCR was performed for hemoglobin transcripts HBB and HBA1/2 using four reference genes for normalization. In addition, expression analysis of the specific erythrocyte marker ALAS2 was performed in order to account for blood contamination of the tissue samples. Hba1/2 and Hbb protein expression was then investigated with immunofluorescence and confocal microscope analysis.Results: We observed a significant up-regulation of HBA1/2 in vCJD brains together with a significant down-regulation of HBB in iCJD. In addition, while in sporadic and genetic forms of prion disease hemoglobin transcripts did not shown any alterations, both chains display a strong down-regulation in AD brains. These results were confirmed also at a protein level.Conclusions: These data indicate distinct hemoglobin transcriptional responses depending on the specific alterations occurring in different neurodegenerative diseases. In particular, the initial site of misfolding event (central nervous system vs. peripheral tissue—together with specific molecular and conformational features of the pathological agent of the disease—seem to dictate the peculiar

Hemoglobin mRNA Changes in the Frontal Cortex of Patients with Neurodegenerative Diseases.

Science.gov (United States)

Vanni, Silvia; Zattoni, Marco; Moda, Fabio; Giaccone, Giorgio; Tagliavini, Fabrizio; Haïk, Stéphane; Deslys, Jean-Philippe; Zanusso, Gianluigi; Ironside, James W; Carmona, Margarita; Ferrer, Isidre; Kovacs, Gabor G; Legname, Giuseppe

2018-01-01

Background: Hemoglobin is the major protein found in erythrocytes, where it acts as an oxygen carrier molecule. In recent years, its expression has been reported also in neurons and glial cells, although its role in brain tissue remains still unknown. Altered hemoglobin expression has been associated with various neurodegenerative disorders. Here, we investigated hemoglobin mRNA levels in brains of patients affected by variant, iatrogenic, and sporadic forms of Creutzfeldt-Jakob disease (vCJD, iCJD, sCJD, respectively) and in different genetic forms of prion diseases (gPrD) in comparison to Alzheimer's disease (AD) subjects and age-matched controls. Methods: Total RNA was obtained from the frontal cortex of vCJD ( n = 20), iCJD ( n = 11), sCJD ( n = 23), gPrD ( n = 30), and AD ( n = 14) patients and age-matched controls ( n = 30). RT-qPCR was performed for hemoglobin transcripts HBB and HBA1/2 using four reference genes for normalization. In addition, expression analysis of the specific erythrocyte marker ALAS2 was performed in order to account for blood contamination of the tissue samples. Hba1/2 and Hbb protein expression was then investigated with immunofluorescence and confocal microscope analysis. Results: We observed a significant up-regulation of HBA1/2 in vCJD brains together with a significant down-regulation of HBB in iCJD. In addition, while in sporadic and genetic forms of prion disease hemoglobin transcripts did not shown any alterations, both chains display a strong down-regulation in AD brains. These results were confirmed also at a protein level. Conclusions: These data indicate distinct hemoglobin transcriptional responses depending on the specific alterations occurring in different neurodegenerative diseases. In particular, the initial site of misfolding event (central nervous system vs. peripheral tissue)-together with specific molecular and conformational features of the pathological agent of the disease-seem to dictate the peculiar hemoglobin

Developments in plasma enhanced spatial ALD for high throughput applications [3.04

NARCIS (Netherlands)

Creyghton, Y.; Illiberi, A.; Mione, M.; Boekel, W. van; Debernardi, N.; Seitz, M.; Bruele, F. van den; Poodt, P.; Roozeboom,F.

2016-01-01

Atomic layer deposition by means of spatial separation of reactive gases is emerging as an industrial manufacturing technology. Integration of non-thermal plasma in spatial ALD machines will further expand the process window towards lower operation temperatures and specific materials requiring

Impact of Plant-Derived Flavonoids on Neurodegenerative Diseases.

Science.gov (United States)

Costa, Silvia Lima; Silva, Victor Diogenes Amaral; Dos Santos Souza, Cleide; Santos, Cleonice Creusa; Paris, Irmgard; Muñoz, Patricia; Segura-Aguilar, Juan

2016-07-01

Neurodegenerative disorders have a common characteristic that is the involvement of different cell types, typically the reactivity of astrocytes and microglia, characterizing gliosis, which in turn contributes to the neuronal dysfunction and or death. Flavonoids are secondary metabolites of plant origin widely investigated at present and represent one of the most important and diversified among natural products phenolic groups. Several biological activities are attributed to this class of polyphenols, such as antitumor activity, antioxidant, antiviral, and anti-inflammatory, among others, which give significant pharmacological importance. Our group have observed that flavonoids derived from Brazilian plants Dimorphandra mollis Bent., Croton betulaster Müll. Arg., e Poincianella pyramidalis Tul., botanical synonymous Caesalpinia pyramidalis Tul. also elicit a broad spectrum of responses in astrocytes and neurons in culture as activation of astrocytes and microglia, astrocyte associated protection of neuronal progenitor cells, neuronal differentiation and neuritogenesis. It was observed the flavonoids also induced neuronal differentiation of mouse embryonic stem cells and human pluripotent stem cells. Moreover, with the objective of seeking preclinical pharmacological evidence of these molecules, in order to assess its future use in the treatment of neurodegenerative disorders, we have evaluated the effects of flavonoids in preclinical in vitro models of neuroinflammation associated with Parkinson's disease and glutamate toxicity associated with ischemia. In particular, our efforts have been directed to identify mechanisms involved in the changes in viability, morphology, and glial cell function induced by flavonoids in cultures of glial cells and neuronal cells alone or in interactions and clarify the relation with their neuroprotective and morphogetic effects.

From Narcissistic Personality Disorder to Frontotemporal Dementia: A Case Report

OpenAIRE

Michele Poletti; Ubaldo Bonuccelli

2011-01-01

Premorbid personality characteristics could have a pathoplastic effect on behavioral symptoms and personality changes related to neurodegenerative diseases. Patients with personality disorders, in particular of the dramatic cluster, may present functional frontolimbic abnormalities. May these neurobiological vulnerabilities linked to a premorbid personality disorder predispose or represent a risk factor to subsequently develop a neurodegenerative disorder? Are subjects with personality disord...

Nonpeptide neurotrophic agents useful in the treatment of neurodegenerative diseases such as Alzheimer's disease

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Masaaki Akagi

2015-02-01

Full Text Available Developed regions, including Japan, have become “aged societies,” and the number of adults with senile dementias, such as Alzheimer's disease (AD, Parkinson's disease, and Huntington's disease, has also increased in such regions. Neurotrophins (NTs may play a role in the treatment of AD because endogenous neurotrophic factors (NFs prevent neuronal death. However, peptidyl compounds have been unable to cross the blood–brain barrier in clinical studies. Thus, small molecules, which can mimic the functions of NFs, might be promising alternatives for the treatment of neurodegenerative diseases. Natural products, such as or nutraceuticals or those used in traditional medicine, can potentially be used to develop new therapeutic agents against neurodegenerative diseases. In this review, we introduced the neurotrophic activities of polyphenols honokiol and magnolol, which are the main constituents of Magnolia obovata Thunb, and methanol extracts from Zingiber purpureum (BANGLE, which may have potential therapeutic applications in various neurodegenerative disorders.

Contribution towards ALD and MOCVD of rare earth oxides and hafnium oxide. From precursor evaluation to process development and thin film characterization

International Nuclear Information System (INIS)

Xu, Ke

2013-01-01

This PhD thesis is consisted of two major parts: precursor development for ALD and MOCVD applications as well as thin film deposition using ALD and MOCVD with self developed precursors. The first part of this work presents the synthesis, characterization and detailed thermal property investigations of different novel group IV and rare earth precursor classes (guandinate, guanidine and ketoiminate). The second part of this work presents the ALD and MOCVD depositions using various guanidinate precursors for forming corresponding metal oxide thin films. The overall motivation of this work is to fulfill the lack of precursors of rare earth and group IV elements for ALD and MOCVD applications that satisfy the stringent requirements for the modern microelectronic and optoelectronic technologies. The aspect of the precursor engineering part is focusing on influence of ligand sphere on precursors' chemical and thermal properties. In this way, we successfully introduced guanidine and ketoiminate as potential ligands for the precursor design. The thin film deposition part of this work is ALD of rare earth oxides and group IV oxides employing literature known compounds which were previously developed in our research group. The main focus was dedicated to the process optimization, the characterization of the structural, morphological, compositional and functional properties of the deposited thin films. Certain film properties were discussed comparatively with the corresponding thin films deposited with literature known precursors. It was already shortly demonstrated in Chapter 6 that the guanidine ligand showed potential interest as suitable ligand for precursor engineering. This titan guanidine precursor [Ti(NC(NMe 2 ) 2 ) 4 ] (GD1) possesses higher thermal stability compared to its parent amide, [Ti(NMe 2 ) 4 ], while reactivity against water is not significantly affected. It could be very interesting to transfer this ligand for the precursor development of rare earth

Interplay among gut microbiota, intestinal mucosal barrier and enteric neuro-immune system: a common path to neurodegenerative diseases?

Science.gov (United States)

Pellegrini, Carolina; Antonioli, Luca; Colucci, Rocchina; Blandizzi, Corrado; Fornai, Matteo

2018-05-24

Neurological diseases, such as Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis (ALS) and multiple sclerosis, are often associated with functional gastrointestinal disorders. These gastrointestinal disturbances may occur at all stages of the neurodegenerative diseases, to such an extent that they are now considered an integral part of their clinical picture. Several lines of evidence support the contention that, in central neurodegenerative diseases, changes in gut microbiota and enteric neuro-immune system alterations could contribute to gastrointesinal dysfunctions as well as initiation and upward spreading of the neurologic disorder. The present review has been intended to provide a comprehensive overview of the available knowledge on the role played by enteric microbiota, mucosal immune system and enteric nervous system, considered as an integrated network, in the pathophysiology of the main neurological diseases known to be associated with intestinal disturbances. In addition, based on current human and pre-clinical evidence, our intent was to critically discuss whether changes in the dynamic interplay between gut microbiota, intestinal epithelial barrier and enteric neuro-immune system are a consequence of the central neurodegeneration or might represent the starting point of the neurodegenerative process. Special attention has been paid also to discuss whether alterations of the enteric bacterial-neuro-immune network could represent a common path driving the onset of the main neurodegenerative diseases, even though each disease displays its own distinct clinical features.

Anoxic limestone drain (ALD) treatment of acid pit waters; Tratamiento de aguas acidas de mina mediante drenaje anoxico en caliza (ALD)

Energy Technology Data Exchange (ETDEWEB)

Ramirez Masferrer, J. A.

2001-07-01

As a consequence of the weathering, the pyrite is combined together with the oxygen and water, Mine Acid Drainage is produced, with rather low pH and dissolved metals. In order to treat this kind of polluted water it could be good to increase its alkalinity (capacity to neutralize the acid). There are several ways to increase the water alkalinity. One of them is the ALD. limestone beds buried through which the polluted water flows, in which carbonates are dissolved. (mostly calcium carbonate), in a media lacking of oxygen. (Author) 11 refs.

Congo red and protein aggregation in neurodegenerative diseases.

Science.gov (United States)

Frid, Petrea; Anisimov, Sergey V; Popovic, Natalija

2007-01-01

Congo red is a commonly used histological dye for amyloid detection. The specificity of this staining results from Congo red's affinity for binding to fibril proteins enriched in beta-sheet conformation. Unexpectedly, recent investigations indicate that the dye also possesses the capacity to interfere with processes of protein misfolding and aggregation, stabilizing native protein monomers or partially folded intermediates, while reducing concentration of more toxic protein oligomers. Inhibitory effects of Congo red upon amyloid toxicity may also range from blockade of channel formation and interference with glycosaminoglycans binding or immune functions, to the modulation of gene expression. Particularly, Congo red exhibits ameliorative effect in models of neurodegenerative disorders, such as Alzheimer's, Parkinson's, Huntington's and prion diseases. Another interesting application of Congo red analogues is the development of imaging probes. Based on their small molecular size and penetrability through blood-brain barrier, Congo red congeners can be used for both antemortem and in vivo visualization and quantification of brain amyloids. Therefore, understanding mechanisms involved in dye-amyloidal fibril binding and inhibition of aggregation will provide instructive guides for the design of future compounds, potentially useful for monitoring and treating neurodegenerative diseases.

The iron-binding protein lactotransferrin is present in pathologic lesions in a variety of neurodegenerative disorders: a comparative immunohistochemical analysis.

Science.gov (United States)

Leveugle, B; Spik, G; Perl, D P; Bouras, C; Fillit, H M; Hof, P R

1994-07-04

Lactotransferrin is a glycoprotein that specifically binds and transports iron. This protein is also believed to transport other metals such as aluminum. Several lines of evidence indicate that iron and aluminum are involved in the pathogenesis of many dementing diseases. In this context, the analysis of the iron-binding protein distribution in the brains of patients affected by neurodegenerative disorders is of particular interest. In the present study, the distribution of lactotransferrin was analyzed by immunohistochemistry in the cerebral cortex from patients presenting with Alzheimer's disease, Down syndrome, amyotrophic lateral sclerosis/parkinsonism-dementia complex of Guam, sporadic amyotrophic lateral sclerosis, or Pick's disease. The results show that lactotransferrin accumulates in the characteristic lesions of the different pathologic conditions investigated. For instance, in Alzheimer's disease and Guamanian cases, a subpopulation of neurofibrillary tangles was intensely labeled in the hippocampal formation and inferior temporal cortex. Senile plaques and Pick bodies were also consistently labeled. These staining patterns were comparable to those obtained with antibodies to the microtubule-associated protein tau and the amyloid beta A4 protein, although generally fewer neurofibrillary tangles were positive for lactotransferrin than for tau protein. Neuronal cytoplasmic staining with lactotransferrin antibodies, was observed in a subpopulation of pyramidal neurons in normal aging, and was more pronounced in Alzheimer's disease, Guamanian cases, Pick's disease, and particularly in Down syndrome. Lactotransferrin was also strongly associated with Betz cells and other motoneurons in the primary motor cortex of control, Alzheimer's disease, Down syndrome, Guamanian and Pick's disease cases. These same lactotransferrin-immunoreactive motoneurons were severely affected in the cases with amyotrophic lateral sclerosis. It is possible that in these

Edible and Medicinal Mushrooms: Emerging Brain Food for the Mitigation of Neurodegenerative Diseases.

Science.gov (United States)

Phan, Chia-Wei; David, Pamela; Sabaratnam, Vikineswary

2017-01-01

There is an exponential increase in dementia in old age at a global level because of increasing life expectancy. The prevalence of neurodegenerative diseases such as dementia and Alzheimer's disease (AD) will continue to rise steadily, and is expected to reach 42 million cases worldwide in 2020. Despite the advancement of medication, the management of these diseases remains largely ineffective. Therefore, it is vital to explore novel nature-based nutraceuticals to mitigate AD and other age-related neurodegenerative disorders. Mushrooms and their extracts appear to hold many health benefits, including immune-modulating effects. A number of edible mushrooms have been shown to contain rare and exotic compounds that exhibit positive effects on brain cells both in vitro and in vivo. In this review, we summarize the scientific information on edible and culinary mushrooms with regard to their antidementia/AD active compounds and/or pharmacological test results. The bioactive components in these mushrooms and the underlying mechanism of their activities are discussed. In short, these mushrooms may be regarded as functional foods for the mitigation of neurodegenerative diseases.

Cerebral Blood Flow and A beta-Amyloid Estimates by WARAM Analysis of [C-11]PiB Uptake Distinguish among and between Neurodegenerative Disorders and Aging

DEFF Research Database (Denmark)

Rodell, Anders B.; O'Keefe, Graeme; Rowe, Christopher C.

2017-01-01

Alzheimer’s disease, and healthy volunteers. The method introduces two approaches to the identification of brain pathology related to amyloid accumulation, (1) a novel analysis of amyloid binding based on the late washout of the tracer from brain tissue, and (2) the simultaneous estimation of absolute...... metabolism and reduction of blood flow by neurovascular coupling in neurodegenerative disorders, including Alzheimer’s disease. Methods: Previously reported images of [11C]PiB retention in brain of 29 subjects with cognitive impairment or dementia [16 Alzheimer’s Disease (AD), eight subjects with dementia...

High functioning male with fragile X syndrome and fragile X-associated tremor/ataxia syndrome.

Science.gov (United States)

Basuta, Kirin; Schneider, Andrea; Gane, Louise; Polussa, Jonathan; Woodruff, Bryan; Pretto, Dalyir; Hagerman, Randi; Tassone, Flora

2015-09-01

Fragile X syndrome (FXS) affects individuals with more than 200 CGG repeats (full mutation) in the fragile X mental retardation 1 (FMR1) gene. Those born with FXS experience cognitive and social impairments, developmental delays, and some features of autism spectrum disorders. Carriers of a premutation (55-200 CGG repeats) are generally not severely affected early in life; however, are at high risk of developing the late onset neurodegenerative disorder, Fragile X-associated Tremor/Ataxia Syndrome (FXTAS), or Fragile X-associated Primary Ovarian Insufficiency (FXPOI), and may have other medical conditions such as developmental delay, autism spectrum disorders, hypertension, anxiety, and immune-mediated disorders. Here we present a case of a 58-year-old man with a borderline IQ, average memory skills, and executive function deficits. He met criteria for multiple psychiatric diagnoses and presented with tremor and ataxia, meeting criteria for FXTAS. Molecular testing unveiled a completely unmethylated FMR1 full mutation in peripheral blood mononucleated cells with elevated FMR1 mRNA and premutation alleles of different sizes in two other tissues (primary fibroblasts and sperm), indicating the presence of allele instability based on both inter- and intra-tissue mosaicism. The observation of FXTAS in this case of a full mutation mosaic man suggests that the pathogenic mechanism underlying this disorder is not observed exclusively in premutation carriers as it was originally thought. The concomitant presence of features of FXS and late onset neurological deterioration with probable FXTAS likely result from a combined molecular pathology of elevated FMR1 mRNA levels, a molecular hallmark of FXTAS and low FMRP expression that leads to FXS. © 2015 Wiley Periodicals, Inc.

Combination Comprising Parthenolide For Use In The Treatment Of Alzheimer's Disease And Other Neurodegenerative Disorders

KAUST Repository

Bajic, Vladimir B.; Essack, Magbubah

2015-01-01

The present invention generally concerns particular methods and compositions for treatment of a neurodegenerative disease, such as Alzheimer's Disease. In particular embodiments, there is a composition comprising Parthenolide and a second agent

Confocal Synaptology: Synaptic Rearrangements in Neurodegenerative Disorders and upon Nervous System Injury

Directory of Open Access Journals (Sweden)

Maja Vulovic

2018-02-01

Full Text Available The nervous system is a notable exception to the rule that the cell is the structural and functional unit of tissue systems and organs. The functional unit of the nervous system is the synapse, the contact between two nerve cells. As such, synapses are the foci of investigations of nervous system organization and function, as well as a potential readout for the progression of various disorders of the nervous system. In the past decade the development of antibodies specific to presynaptic terminals has enabled us to assess, at the optical, laser scanning microscopy level, these subcellular structures, and has provided a simple method for the quantification of various synapses. Indeed, excitatory (glutamatergic and inhibitory synapses can be visualized using antibodies against the respective vesicular transporters, and choline-acetyl transferase (ChAT immunoreactivity identifies cholinergic synapses throughout the central nervous system. Here we review the results of several studies in which these methods were used to estimate synaptic numbers as the structural equivalent of functional outcome measures in spinal cord and femoral nerve injuries, as well as in genetic mouse models of neurodegeneration, including Alzheimer’s disease (AD. The results implicate disease- and brain region-specific changes in specific types of synapses, which correlate well with the degree of functional deficit caused by the disease process. Additionally, results are reproducible between various studies and experimental paradigms, supporting the reliability of the method. To conclude, this quantitative approach enables fast and reliable estimation of the degree of the progression of neurodegenerative changes and can be used as a parameter of recovery in experimental models.

aldB, an RpoS-dependent gene in Escherichia coli encoding an aldehyde dehydrogenase that is repressed by Fis and activated by Crp.

OpenAIRE

Xu, J; Johnson, R C

1995-01-01

Escherichia coli aldB was identified as a gene that is negatively regulated by Fis but positively regulated by RpoS. The complete DNA sequence determined in this study indicates that aldB encodes a 56.3-kDa protein which shares a high degree of homology with an acetaldehyde dehydrogenase encoded by acoD of Alcaligenes eutrophus and an aldehyde dehydrogenase encoded by aldA of Vibrio cholerae and significant homology with a group of other aldehyde dehydrogenases from prokaryotes and eukaryotes...

Effect of electromagnetic radiations on neurodegenerative diseases- technological revolution as a curse in disguise.

Science.gov (United States)

Hasan, Gulam M; Sheikh, Ishfaq A; Karim, Sajjad; Haque, Absarul; Kamal, Mohammad A; Chaudhary, Adeel G; Azhar, Essam; Mirza, Zeenat

2014-01-01

In the present developed world, all of us are flooded with electromagnetic radiations (EMR) emanating from generation and transmission of electricity, domestic appliances and industrial equipments, to telecommunications and broadcasting. We have been exposed to EMR for last many decades; however their recent steady increase from artificial sources has been reported as millions of antennas and satellites irradiate the global population round the clock, year round. Needless to say, these are so integral to modern life that interaction with them on a daily basis is seemingly inevitable; hence, the EMR exposure load has increased to a point where their health effects are becoming a major concern. Delicate and sensitive electrical system of human body is affected by consistent penetration of electromagnetic frequencies causing DNA breakages and chromosomal aberrations. Technological innovations came with Pandora's Box of hazardous consequences including neurodegenerative disorders, hearing disabilities, diabetes, congenital abnormalities, infertility, cardiovascular diseases and cancer to name few, all on a sharp rise. Electromagnetic non-ionizing radiations pose considerable health threat with prolonged exposure. Mobile phones are usually held near to the brain and manifest progressive structural or functional alterations in neurons leading to neurodegenerative diseases and neuronal death. This has provoked awareness among both the general public and scientific community and international bodies acknowledge that further systematic research is needed. The aim of the present review was to have an insight in whether and how cumulative electro-magnetic field exposure is a risk factor for neurodegenerative disorders.

Clinical outcomes of neonatal onset proximal versus distal urea cycle disorders do not differ.

Science.gov (United States)

Ah Mew, Nicholas; Krivitzky, Lauren; McCarter, Robert; Batshaw, Mark; Tuchman, Mendel

2013-02-01

To compare the clinical course and outcome of patients diagnosed with one of 4 neonatal-onset urea cycle disorders (UCDs): deficiency of carbamyl phosphate synthase 1 (CPSD), ornithine transcarbamylase (OTCD), argininosuccinate synthase (ASD), or argininosuccinate lyase (ALD). Clinical, biochemical, and neuropsychological data from 103 subjects with neonatal-onset UCDs were derived from the Longitudinal Study of Urea Cycle Disorders, an observational protocol of the Urea Cycle Disorders Consortium, one of the Rare Disease Clinical Research Networks. Some 88% of the subjects presented clinically by age 7 days. Peak ammonia level was 963 μM in patients with proximal UCDs (CPSD or OTCD), compared with 589 μM in ASD and 573 μM in ALD. Roughly 25% of subjects with CPSD or OTCD, 18% of those with ASD, and 67% of those with ALD had a "honeymoon period," defined as the time interval from discharge from initial admission to subsequent admission for hyperammonemia, greater than 1 year. The proportion of patients with a poor outcome (IQ/Developmental Quotient <70) was greatest in ALD (68%), followed by ASD (54%) and CPSD/OTCD (47%). This trend was not significant, but was observed in both patients aged <4 years and those aged ≥ 4 years. Poor cognitive outcome was not correlated with peak ammonia level or duration of initial admission. Neurocognitive outcomes do not differ between patients with proximal UCDs and those with distal UCDs. Factors other than hyperammonemia may contribute to poor neurocognitive outcome in the distal UCDs. Copyright © 2013 Mosby, Inc. All rights reserved.

Role of Ionizing Radiation in Neurodegenerative Diseases

Directory of Open Access Journals (Sweden)

Neel K. Sharma

2018-05-01

Full Text Available Ionizing radiation (IR from terrestrial sources is continually an unprotected peril to human beings. However, the medical radiation and global radiation background are main contributors to human exposure and causes of radiation sickness. At high-dose exposures acute radiation sickness occurs, whereas chronic effects may persist for a number of years. Radiation can increase many circulatory, age related and neurodegenerative diseases. Neurodegenerative diseases occur a long time after exposure to radiation, as demonstrated in atomic bomb survivors, and are still controversial. This review discuss the role of IR in neurodegenerative diseases and proposes an association between neurodegenerative diseases and exposure to IR.

Role of Ionizing Radiation in Neurodegenerative Diseases

Science.gov (United States)

Sharma, Neel K.; Sharma, Rupali; Mathur, Deepali; Sharad, Shashwat; Minhas, Gillipsie; Bhatia, Kulsajan; Anand, Akshay; Ghosh, Sanchita P.

2018-01-01

Ionizing radiation (IR) from terrestrial sources is continually an unprotected peril to human beings. However, the medical radiation and global radiation background are main contributors to human exposure and causes of radiation sickness. At high-dose exposures acute radiation sickness occurs, whereas chronic effects may persist for a number of years. Radiation can increase many circulatory, age related and neurodegenerative diseases. Neurodegenerative diseases occur a long time after exposure to radiation, as demonstrated in atomic bomb survivors, and are still controversial. This review discuss the role of IR in neurodegenerative diseases and proposes an association between neurodegenerative diseases and exposure to IR. PMID:29867445

Clinical manifest x-linked recessive adrenoleukodystrophy in a female

DEFF Research Database (Denmark)

Jack, Gyda Hlin Skuladottir; Malm-Willadsen, Karolina; Frederiksen, Anja

2013-01-01

Adrenoleukodystrophy (ALD) is a rare X-linked inherited leukodystrophy with a reduced capacity for degradation of very long chain fatty acids (VLCFAs). The intracellular accumulation of VLCFA leads to demyelination in the central nervous system (CNS) and cell destruction in the adrenal glands. ALD...... examination revealed decreased sensitivity in the feet, particularly to touch. Deep tendon reflexes in the lower limbs were brisk, and Babinski's sign was present bilaterally. Multiple sclerosis (MS) was excluded, and all clinical and biochemical tests were normal. After two years of progressing symptoms...

Toxic AGE (TAGE Theory for the Pathophysiology of the Onset/Progression of NAFLD and ALD

Directory of Open Access Journals (Sweden)

Masayoshi Takeuchi

2017-06-01

Full Text Available Non-alcoholic fatty liver disease (NAFLD and alcoholic liver disease (ALD are among the most common causes of chronic liver diseases in the westernized world. NAFLD and ALD are frequently accompanied by extrahepatic complications, including hepatocellular carcinoma and cardiovascular diseases, which have a negative impact on patient survival. The chronic ingestion of an excessive daily diet containing sugar/high-fructose corn syrup increases the level of the fructose/glucose metabolite, glyceraldehyde (GA, while the chronic consumption of an excessive number of alcoholic beverages increases the level of the alcohol metabolite, acetaldehyde (AA in the liver. GA and AA are known to react non-enzymatically with the ε- or α-amino groups of proteins, thereby generating advanced glycation end-products (AGEs, GA-AGEs, and AA-AGEs, respectively in vivo. The interaction between GA-AGEs and the receptor for AGEs (RAGE alters intracellular signaling, gene expression, and the release of pro-inflammatory molecules and also elicits the production of reactive oxygen species by human hepatocytes and hepatic stellate cells, all of which may contribute to the pathological changes associated with chronic liver diseases. We herein discuss the pathophysiological roles of GA-AGEs and AA-AGEs (toxic AGEs, TAGE and a related novel theory for preventing the onset/progression of NAFLD and ALD.

Recurrent Anion Gap Acidosis: An Unusual Presentation of X-Linked Adrenoleukodystrophy in a Five-year-old Male.

Science.gov (United States)

Schwab, Joel; Pena, Loren; Sigman, Laura; Waggoner, Darrel

2010-01-01

We are presenting a five-year-old male with recurrent anion gap acidosis. During his last admission, it was detected that he had elevated VLCFA and the evaluation discovered that he had X-linked Adrenooleukodystrophy. He had the Addisonian only phenotype without any clinical or radiographic CNS findings. We were unable to find any other reports of this presentation of ALD. If the work-up of recurrent anion gap acidosis does not uncover an etiology, X-linked ALD should be considered in the differential diagnosis.

A case of adrenoleukodystrophy presenting with manic symptoms in a patient on steroids for Addison's disease.

Science.gov (United States)

Jyothi, K S; George, Cyriac; Shaji, K S

2016-01-01

Adrenoleukodystrophy (ALD) is an X-linked disorder with diverse clinical presentations. A 30-year-old male, previously diagnosed with Addison's disease, on steroid supplementation for 18 years, presented to us with manic symptoms for 4 years. He was found to have white matter hypodensities in computed tomography head and had white matter signal changes in magnetic resonance imaging, and therefore a diagnosis of ALD was made.

Polypathology and dementia after brain trauma: Does brain injury trigger distinct neurodegenerative diseases, or should they be classified together as traumatic encephalopathy?

Science.gov (United States)

Washington, Patricia M; Villapol, Sonia; Burns, Mark P

2016-01-01

Neuropathological studies of human traumatic brain injury (TBI) cases have described amyloid plaques acutely after a single severe TBI, and tau pathology after repeat mild TBI (mTBI). This has helped drive the hypothesis that a single moderate to severe TBI increases the risk of developing late-onset Alzheimer's disease (AD), while repeat mTBI increases the risk of developing chronic traumatic encephalopathy (CTE). In this review we critically assess this position-examining epidemiological and case control human studies, neuropathological evidence, and preclinical data. Epidemiological studies emphasize that TBI is associated with the increased risk of developing multiple types of dementia, not just AD-type dementia, and that TBI can also trigger other neurodegenerative conditions such as Parkinson's disease. Further, human post-mortem studies on both single TBI and repeat mTBI can show combinations of amyloid, tau, TDP-43, and Lewy body pathology indicating that the neuropathology of TBI is best described as a 'polypathology'. Preclinical studies confirm that multiple proteins associated with the development of neurodegenerative disease accumulate in the brain after TBI. The chronic sequelae of both single TBI and repeat mTBI share common neuropathological features and clinical symptoms of classically defined neurodegenerative disorders. However, while the spectrum of chronic cognitive and neurobehavioral disorders that occur following repeat mTBI is viewed as the symptoms of CTE, the spectrum of chronic cognitive and neurobehavioral symptoms that occur after a single TBI is considered to represent distinct neurodegenerative diseases such as AD. These data support the suggestion that the multiple manifestations of TBI-induced neurodegenerative disorders be classified together as traumatic encephalopathy or trauma-induced neurodegeneration, regardless of the nature or frequency of the precipitating TBI. Copyright © 2015 Elsevier Inc. All rights reserved.

La sélection d'Aldébaran

Directory of Open Access Journals (Sweden)

Françoise Acquier

2014-09-01

Full Text Available Aldébaran est une revue électronique en libre accès qui propose une sélection de ressources documentaires en sciences humaines à travers des notices de sites et des conseils de recherche. Les notices présentées dans ce numéro ont été rédigées par Françoise Acquier (CRESSON, Grenoble, Fabrice Melka (IMAF, Julien Gillet (Cléo et Véronique Ginouvès (MMSH USR3125. Afriterra. The Cartographic Free Library http://aldebaran.revues.org/6775 La fondation Afriterra, à but non lucratif, est une bibl...

AMPD2 Regulates GTP Synthesis and is Mutated in a Potentially-Treatable Neurodegenerative Brainstem Disorder

Science.gov (United States)

Akizu, Naiara; Cantagrel, Vincent; Schroth, Jana; Cai, Na; Vaux, Keith; McCloskey, Douglas; Naviaux, Robert K.; Vleet, Jeremy Van; Fenstermaker, Ali G.; Silhavy, Jennifer L.; Scheliga, Judith S.; Toyama, Keiko; Morisaki, Hiroko; Sonmez, Fatma Mujgan; Celep, Figen; Oraby, Azza; Zaki, Maha S.; Al-Baradie, Raidah; Faqeih, Eissa; Saleh, Mohammad; Spencer, Emily; Rosti, Rasim Ozgur; Scott, Eric; Nickerson, Elizabeth; Gabriel, Stacey; Morisaki, Takayuki; Holmes, Edward W.; Gleeson, Joseph G.

2013-01-01

Purine biosynthesis and metabolism, conserved in all living organisms, is essential for cellular energy homeostasis and nucleic acids synthesis. The de novo synthesis of purine precursors is under tight negative feedback regulation mediated by adenosine and guanine nucleotides. We describe a new distinct early-onset neurodegenerative condition resulting from mutations in the adenosine monophosphate deaminase 2 gene (AMPD2). Patients have characteristic brain imaging features of pontocerebellar hypoplasia (PCH), due to loss of brainstem and cerebellar parenchyma. We found that AMPD2 plays an evolutionary conserved role in the maintenance of cellular guanine nucleotide pools by regulating the feedback inhibition of adenosine derivatives on de novo purine synthesis. AMPD2 deficiency results in defective GTP-dependent initiation of protein translation, which can be rescued by administration of purine precursors. These data suggest AMPD2-related PCH as a new, potentially treatable early-onset neurodegenerative disease. PMID:23911318

[Investigation of Genetic Aetiology in Neurodegenerative Ataxias: Recommendations from the Group of Neurogenetics of Centro Hospitalar São João, Portugal].

Science.gov (United States)

Gomes, Tiago; Guimaraes, Joana; Leão, Miguel

2017-06-30

In recent decades, a long and increasing list of monogenic neurodegenerative ataxias has been identified, allowing for better characterization of the pathophysiology, phenotype and prognosis of this heterogeneous group of disorders, while also revealing potential new therapeutic targets. However, the heterogeneity and complexity of the genotype-phenotype relationships and the high costs of molecular genetics often make it difficult for clinicians to decide on a molecular investigation based on an unbiased rational plan. Clinical history is essential to guide the diagnostic workup, but often the phenotype does not hold enough specificity to allow for predicting the genotype. The Group of Neurogenetics of the Centro Hospitalar São João, a multidisciplinary team of neurologists and geneticists with special interest in neurogenetic disorders, devised consensus recommendations for the investigation of the genetic aetiology of neurodegenerative ataxias in clinical practice, based on international consensus documents (currently containing potentially outdated information) and published scientific evidence on this topic. At the time these recommendations were written, there were around 10 well described autosomal recessive loci and more than 27 autosomal dominant loci for neurodegenerative ataxias. This document covers, in a pragmatic way, the rational process used for the genetic diagnosis of neurodegenerative ataxias, with specific recommendations for the various groups of these heterogeneous diseases, per the Portuguese reality.

Potential contribution of the neurodegenerative disorders risk loci to cognitive performance in an elderly male gout population.

Science.gov (United States)

Han, Lin; Jia, Zhaotong; Cao, Chunwei; Liu, Zhen; Liu, Fuqiang; Wang, Lin; Ren, Wei; Sun, Mingxia; Wang, Baoping; Li, Changgui; Chen, Li

2017-09-01

Cognitive impairment has been described in elderly subjects with high normal concentrations of serum uric acid. However, it remains unclear if gout confers an increased poorer cognition than those in individuals with asymptomatic hyperuricemia. The present study aimed at evaluating cognitive function in patients suffering from gout in an elderly male population, and further investigating the genetic contributions to the risk of cognitive function.This study examined the cognitive function as assessed by Mini-Mental State Examination (MMSE) and the Montreal Cognitive Assessment (MoCA) in 205 male gout patients and 204 controls. The genetic basis of these cognitive measures was evaluated by genome-wide association study (GWAS) data in 102 male gout patients. Furthermore, 7 loci associated with cognition in GWAS were studied for correlation with gout in 1179 male gout patients and 1848 healthy male controls.Compared with controls, gout patients had significantly lower MoCA scores [22.78 ± 3.01 vs 23.42 ± 2.95, P = .023, adjusted by age, body mass index (BMI), education, and emotional disorder]. GWAS revealed 7 single-nucleotide polymorphisms (SNPs) associations with MoCA test at a level of conventional genome-wide significance (P gout in further analysis (all P > .05).Elderly male subjects with gout exhibit accelerated decline in cognition performance. Several neurodegenerative disorders risk loci were identified for genetic contributors to cognitive performance in our Chinese elderly male gout population. Larger prospective studies of the cognitive performance and genetic analysis in gout subjects are recommended.

Activation of farnesoid X receptor attenuates hepatic injury in a murine model of alcoholic liver disease

International Nuclear Information System (INIS)

Wu, Weibin; Zhu, Bo; Peng, Xiaomin; Zhou, Meiling; Jia, Dongwei; Gu, Jianxin

2014-01-01

Highlights: •FXR activity was impaired by chronic ethanol ingestion in a murine model of ALD. •Activation of FXR attenuated alcohol-induced liver injury and steatosis. •Activation of FXR attenuated cholestasis and oxidative stress in mouse liver. -- Abstract: Alcoholic liver disease (ALD) is a common cause of advanced liver disease, and considered as a major risk factor of morbidity and mortality worldwide. Hepatic cholestasis is a pathophysiological feature observed in all stages of ALD. The farnesoid X receptor (FXR) is a member of the nuclear hormone receptor superfamily, and plays an essential role in the regulation of bile acid, lipid and glucose homeostasis. However, the role of FXR in the pathogenesis and progression of ALD remains largely unknown. Mice were fed Lieber-DeCarli ethanol diet or an isocaloric control diet. We used a specific agonist of FXR WAY-362450 to study the effect of pharmacological activation of FXR in alcoholic liver disease. In this study, we demonstrated that FXR activity was impaired by chronic ethanol ingestion in a murine model of ALD. Activation of FXR by specific agonist WAY-362450 protected mice from the development of ALD. We also found that WAY-362450 treatment rescued FXR activity, suppressed ethanol-induced Cyp2e1 up-regulation and attenuated oxidative stress in liver. Our results highlight a key role of FXR in the modulation of ALD development, and propose specific FXR agonists for the treatment of ALD patients

Activation of farnesoid X receptor attenuates hepatic injury in a murine model of alcoholic liver disease

Energy Technology Data Exchange (ETDEWEB)

Wu, Weibin [Department of Biochemistry and Molecular Biology, Shanghai Medical College, Fudan University, Shanghai 200032 (China); Institutes of Biomedical Science, Fudan University, Shanghai 200032 (China); Zhu, Bo; Peng, Xiaomin [Department of Biochemistry and Molecular Biology, Shanghai Medical College, Fudan University, Shanghai 200032 (China); Zhou, Meiling, E-mail: meilingzhou2012@gmail.com [Department of Radiology, Zhongshan Hospital of Fudan University and Shanghai Institute of Medical Imaging, Shanghai 200032 (China); Jia, Dongwei, E-mail: jiadongwei@fudan.edu.cn [Department of Biochemistry and Molecular Biology, Shanghai Medical College, Fudan University, Shanghai 200032 (China); Gu, Jianxin [Department of Biochemistry and Molecular Biology, Shanghai Medical College, Fudan University, Shanghai 200032 (China); Institutes of Biomedical Science, Fudan University, Shanghai 200032 (China)

2014-01-03

Highlights: •FXR activity was impaired by chronic ethanol ingestion in a murine model of ALD. •Activation of FXR attenuated alcohol-induced liver injury and steatosis. •Activation of FXR attenuated cholestasis and oxidative stress in mouse liver. -- Abstract: Alcoholic liver disease (ALD) is a common cause of advanced liver disease, and considered as a major risk factor of morbidity and mortality worldwide. Hepatic cholestasis is a pathophysiological feature observed in all stages of ALD. The farnesoid X receptor (FXR) is a member of the nuclear hormone receptor superfamily, and plays an essential role in the regulation of bile acid, lipid and glucose homeostasis. However, the role of FXR in the pathogenesis and progression of ALD remains largely unknown. Mice were fed Lieber-DeCarli ethanol diet or an isocaloric control diet. We used a specific agonist of FXR WAY-362450 to study the effect of pharmacological activation of FXR in alcoholic liver disease. In this study, we demonstrated that FXR activity was impaired by chronic ethanol ingestion in a murine model of ALD. Activation of FXR by specific agonist WAY-362450 protected mice from the development of ALD. We also found that WAY-362450 treatment rescued FXR activity, suppressed ethanol-induced Cyp2e1 up-regulation and attenuated oxidative stress in liver. Our results highlight a key role of FXR in the modulation of ALD development, and propose specific FXR agonists for the treatment of ALD patients.

Adrenomieloneuropatia--jedna z postaci adrenoleukodystrofii sprzezonej z chromosomem X--badania rodziny

NARCIS (Netherlands)

Rzeski, M.; Kuran, W.; Mierzewska, H.; Vreken, P.; Wanders, R. J.; Zaremba, J.

1999-01-01

A family with adrenoleucodystrophy linked to chromosome X (X-ALD) is reported. Three patients, one man (proband) and two female monozygotic twins, had adrenomyeloneuropathy (AMN) which is a form of the disease. The proband had characteristic changes in MRI with demyelination of the white matter in

Disorder effects on free excitons in CdSsub(1-x)Sesub(x) mixed crystals

International Nuclear Information System (INIS)

Goede, O.; Hennig, D.; John, L.

1979-01-01

In CdSsub(1-x)Sesub(x) mixed crystals the energies and transition probability ratios for free A, B, and C excitons are obtained as a function of the composition x by reflection and emission measurements at 77 K. The observation of the disorder-allowed A(GAMMA 6 ) exciton transition, the bowing of the energy difference between A and C exciton, and the broadening of the exciton lines clearly demonstrate the importance of disorder effects in these mixed crystals. This conclusion is further supported by the stress-induced enhancement of the A(GAMMA 6 ) exciton transition probability by uniaxial stress parallel to the c-axis of the mixed crystals. The experimental results are discussed on the basis of an effective exciton Hamiltonian consisting of a quasi-cubic VCA-Hamiltonian for wurtzite-type mixed crystals and an additional lower-symmetric term which describes the disorder effects phenomenologically by two fluctuating crystal fields parallel and perpendicular to the c-axis, respectively. (author)

AMPD2 regulates GTP synthesis and is mutated in a potentially treatable neurodegenerative brainstem disorder.

Science.gov (United States)

Akizu, Naiara; Cantagrel, Vincent; Schroth, Jana; Cai, Na; Vaux, Keith; McCloskey, Douglas; Naviaux, Robert K; Van Vleet, Jeremy; Fenstermaker, Ali G; Silhavy, Jennifer L; Scheliga, Judith S; Toyama, Keiko; Morisaki, Hiroko; Sonmez, Fatma M; Celep, Figen; Oraby, Azza; Zaki, Maha S; Al-Baradie, Raidah; Faqeih, Eissa A; Saleh, Mohammed A M; Spencer, Emily; Rosti, Rasim Ozgur; Scott, Eric; Nickerson, Elizabeth; Gabriel, Stacey; Morisaki, Takayuki; Holmes, Edward W; Gleeson, Joseph G

2013-08-01

Purine biosynthesis and metabolism, conserved in all living organisms, is essential for cellular energy homeostasis and nucleic acid synthesis. The de novo synthesis of purine precursors is under tight negative feedback regulation mediated by adenosine and guanine nucleotides. We describe a distinct early-onset neurodegenerative condition resulting from mutations in the adenosine monophosphate deaminase 2 gene (AMPD2). Patients have characteristic brain imaging features of pontocerebellar hypoplasia (PCH) due to loss of brainstem and cerebellar parenchyma. We found that AMPD2 plays an evolutionary conserved role in the maintenance of cellular guanine nucleotide pools by regulating the feedback inhibition of adenosine derivatives on de novo purine synthesis. AMPD2 deficiency results in defective GTP-dependent initiation of protein translation, which can be rescued by administration of purine precursors. These data suggest AMPD2-related PCH as a potentially treatable early-onset neurodegenerative disease. Copyright © 2013 Elsevier Inc. All rights reserved.

Neurodevelopmental Versus Neurodegenerative Model of Schizophrenia and Bipolar Disorder: Comparison with Physiological Brain Development and Aging.

Science.gov (United States)

Buoli, Massimiliano; Serati, Marta; Caldiroli, Alice; Cremaschi, Laura; Altamura, Alfredo Carlo

2017-03-01

Available data support a contribution of both neurodevelopmental and neurodegenerative factors in the etiology of schizophrenia (SCH) and bipolar disorder (BD). Of note, one of the most important issue of the current psychiatric research is to identify the specific factors that contribute to impaired brain development and neurodegeneration in SCH and BD, and especially how these factors alter normal brain development and physiological aging process. Our hypothesis is that only specific damages, taking place in precise brain development stages, are associated with future SCH /BD onset and that neurodegeneration consists of an acceleration of brain aging after SCH /BD onset. In support of our hypothesis, the results of the present narrative mini-review shows as neurodevelopmental damages generally contribute to neuropsychiatric syndromes (e.g. hypothyroidism or treponema pallidum), but only some of them are specifically associated with adult SCH and BD (e.g. toxoplasma or substance abuse), particularly if they happen in specific stages of brain development. On the other hand, cognitive impairment and brain changes, associated with long duration of SCH /BD, look like what happens during aging: memory, executive domains and prefrontal cortex are implicated both in aging and in SCH /BD progression. Future research will explore possible validity of this etiological model for SCH and BD.

Clinical, molecular, and pharmacological aspects of FMR1 related disorders.

Science.gov (United States)

Pugin, A; Faundes, V; Santa María, L; Curotto, B; Aliaga, S; Salas, I; Soto, P; Bravo, P; Peña, M I; Alliende, M A

2017-05-01

Fragile X syndrome, the most common inherited cause of intellectual disability, is associated with a broad spectrum of disorders across different generations of a single family. This study reviews the clinical manifestations of fragile X-associated disorders as well as the spectrum of mutations of the fragile X mental retardation 1 gene (FMR1) and the neurobiology of the fragile X mental retardation protein (FMRP), and also provides an overview of the potential therapeutic targets and genetic counselling. This disorder is caused by expansion of the CGG repeat (>200 repeats) in the 5 prime untranslated region of FMR1, resulting in a deficit or absence of FMRP. FMRP is an RNA-binding protein that regulates the translation of several genes that are important in synaptic plasticity and dendritic maturation. It is believed that CGG repeat expansions in the premutation range (55 to 200 repeats) elicit an increase in mRNA levels of FMR1, which may cause neuronal toxicity. These changes manifest clinically as developmental problems such as autism and learning disabilities as well as neurodegenerative diseases including fragile X-associated tremor/ataxia syndrome (FXTAS). Advances in identifying the molecular basis of fragile X syndrome may help us understand the causes of neuropsychiatric disorders, and they will probably contribute to development of new and specific treatments. Copyright © 2014 Sociedad Española de Neurología. Publicado por Elsevier España, S.L.U. All rights reserved.

Methods for the prognosus and suagnosis of neurodegenerative diseases

OpenAIRE

Naranjo, José Ramón; Mellström, Britt; Rábano, Alberto

2014-01-01

[EN] The present invention corresponds to the field of neurobiology and relates to methods for predicting the appearance of a neurodegenerative disease in a subject, for diagnosing the prodromic stage of a neurodegenerative disease in a subject, for predicting whether a subject diagnosed of a prodromic stage of a neurodegenerative disease will develop said neurodegenerative disease and for selecting a subject for a therapy for the prevention and/or treatment of a prodromic stage of a neurode...

La sélection d'Aldébaran

Directory of Open Access Journals (Sweden)

Françoise Acquier

2013-12-01

Full Text Available Aldébaran est une revue électronique en libre accès qui propose une sélection de ressources documentaires en sciences humaines à travers des notices de sites et des conseils de recherche. Les notices présentées dans ce numéro ont été rédigées par Véronique Ginouvès (MMSH USR3125 et Françoise Acquier (CRESSON. Arab Cinema Directory [http://aldebaran.revues.org/6945] Le site  « Arab Cinema Directory » rassemble des informations sur plus de 6 500 films arabes depuis les années 1930 jusqu'à auj...

The human epilepsy mutation GABRG2(Q390X) causes chronic subunit accumulation and neurodegeneration.

Science.gov (United States)

Kang, Jing-Qiong; Shen, Wangzhen; Zhou, Chengwen; Xu, Dong; Macdonald, Robert L

2015-07-01

Genetic epilepsy and neurodegenerative diseases are two common neurological disorders that are conventionally viewed as being unrelated. A subset of patients with severe genetic epilepsies who have impaired development and often go on to die of their disease respond poorly to anticonvulsant drug therapy, suggesting a need for new therapeutic targets. Previously, we reported that multiple GABAA receptor epilepsy mutations result in protein misfolding and abnormal receptor trafficking. We have now developed a model of a severe human genetic epileptic encephalopathy, the Gabrg2(+/Q390X) knock-in mouse. We found that, in addition to impairing inhibitory neurotransmission, mutant GABAA receptor γ2(Q390X) subunits accumulated and aggregated intracellularly, activated caspase 3 and caused widespread, age-dependent neurodegeneration. These findings suggest that the fundamental protein metabolism and cellular consequences of the epilepsy-associated mutant γ2(Q390X) ion channel subunit are not fundamentally different from those associated with neurodegeneration. Our results have far-reaching relevance for the identification of conserved pathological cascades and mechanism-based therapies that are shared between genetic epilepsies and neurodegenerative diseases.

Pig Models of Neurodegenerative Disorders: Utilization in Cell Replacement-Based Preclinical Safety and Efficacy Studies

Czech Academy of Sciences Publication Activity Database

Doležalová, D.; Hruška-Plocháň, M.; Bjarkam, C. R.; Sorensen, J. C. H.; Cunningham, M.; Weingarten, D.; Ciacci, J. D.; Juhás, Štefan; Juhásová, Jana; Motlík, Jan; Hefferan, M. P.; Hazel, T.; Johe, K.; Carromeu, C.; Muotri, A.; Bui, J. D.; Strnádel, J.; Marsala, M.

2014-01-01

Roč. 522, č. 12 (2014), s. 2784-2801 ISSN 0021-9967 R&D Projects: GA TA ČR(CZ) TA01011466; GA MŠk ED2.1.00/03.0124 Institutional support: RVO:67985904 Keywords : pig * neurodegenerative models * stem cells Subject RIV: FH - Neurology Impact factor: 3.225, year: 2014

From narcissistic personality disorder to frontotemporal dementia: a case report.

Science.gov (United States)

Poletti, Michele; Bonuccelli, Ubaldo

2011-01-01

Premorbid personality characteristics could have a pathoplastic effect on behavioral symptoms and personality changes related to neurodegenerative diseases. Patients with personality disorders, in particular of the dramatic cluster, may present functional frontolimbic abnormalities. May these neurobiological vulnerabilities linked to a premorbid personality disorder predispose or represent a risk factor to subsequently develop a neurodegenerative disorder? Are subjects with personality disorders more at risk to develop a dementia than mentally healthy subjects? This topic is discussed presenting the clinical case of a patient who suffered of a probable Narcissistic Personality Disorder and subsequently developed a clinically diagnosed Frontotemporal Dementia.

Curcumin and neurodegenerative diseases

Science.gov (United States)

Monroy, Adriana; Lithgow, Gordon J.; Alavez, Silvestre

2013-01-01

Over the last ten years curcumin has been reported to be effective against a wide variety of diseases and is characterized as having anti-carcinogenic, hepatoprotective, thrombosuppressive, cardioprotective, anti-arthritic, and anti-infectious properties. Recent studies performed in both vertebrate and invertebrate models have been conducted to determine whether curcumin was also neuroprotective. The efficacy of curcumin in several pre-clinical trials for neurodegenerative diseases has created considerable excitement mainly due to its lack of toxicity and low cost. This suggests that curcumin could be a worthy candidate for nutraceutical intervention. Since aging is a common risk factor for neurodegenerative diseases, it is possible that some compounds that target aging mechanisms could also prevent these kinds of diseases. One potential mechanism to explain several of the general health benefits associated with curcumin is that it may prevent aging-associated changes in cellular proteins that lead to protein insolubility and aggregation. This loss in protein homeostasis is associated with several age-related diseases. Recently, curcumin has been found to help maintain protein homeostasis and extend lifespan in the model invertebrate Caenorhabditis elegans. Here, we review the evidence from several animal models that curcumin improves healthspan by preventing or delaying the onset of various neurodegenerative diseases. PMID:23303664

The applications of pharmacogenomics to neurological disorders.

Science.gov (United States)

Gilman, C; McSweeney, C; Mao, Y

2014-01-01

The most common neurological disorders, including neurodegenerative diseases and psychiatric disorders, have received recent attention with regards to pharmacogenomics and personalized medicine. Here, we will focus on a neglected neurodegenerative disorder, cerebral ischemic stroke (CIS), and highlight recent advances in two disorders, Parkinson's disease (PD) and Alzheimer's diseases (AD), that possess both similar and distinct mechanisms in regards to potential therapeutic targets. In the first part of this review, we will focus primarily on mechanisms that are somewhat specific to each disorder which are involved in neurodegeneration (i.e., protease pathways, calcium homeostasis, reactive oxygen species regulation, DNA repair mechanisms, neurogenesis regulation, mitochondrial function, etc.). In the second part of this review, we will discuss the applications of the genome-wide technology on pharmacogenomics of mental illnesses including schizophrenia (SCZ), autism spectrum disorders (ASD), attention deficit hyperactivity disorder (ADHD), and obsessive compulsive disorder (OCD).

Investigation of Genetic Aetiology in Neurodegenerative Ataxias: Recommendations from the Group of Neurogenetics of Centro Hospitalar São João, Portugal

Directory of Open Access Journals (Sweden)

Tiago Gomes

2017-06-01

Full Text Available In recent decades, a long and increasing list of monogenic neurodegenerative ataxias has been identified, allowing for better characterization of the pathophysiology, phenotype and prognosis of this heterogeneous group of disorders, while also revealing potential new therapeutic targets. However, the heterogeneity and complexity of the genotype-phenotype relationships and the high costs of molecular genetics often make it difficult for clinicians to decide on a molecular investigation based on an unbiased rational plan. Clinical history is essential to guide the diagnostic workup, but often the phenotype does not hold enough specificity to allow for predicting the genotype. The Group of Neurogenetics of the Centro Hospitalar São João, a multidisciplinary team of neurologists and geneticists with special interest in neurogenetic disorders, devised consensus recommendations for the investigation of the genetic aetiology of neurodegenerative ataxias in clinical practice, based on international consensus documents (currently containing potentially outdated information and published scientific evidence on this topic. At the time these recommendations were written, there were around 10 well described autosomal recessive loci and more than 27 autosomal dominant loci for neurodegenerative ataxias. This document covers, in a pragmatic way, the rational process used for the genetic diagnosis of neurodegenerative ataxias, with specific recommendations for the various groups of these heterogeneous diseases, per the Portuguese reality.

Signs of testicular insufficiency in adrenomyeloneuropathy and neurologically asymptomatic X-linked adrenoleukodystrophy: a retrospective study

NARCIS (Netherlands)

Assies, J.; Gooren, L. J.; van Geel, B.; Barth, P. G.

1997-01-01

X-linked adrenoleukodystrophy (X-ALD) is characterized by central nervous system demyelination, and impaired steroidogenesis in the adrenal cortex and testis. Most patients develop adrenocortical insufficiency. We studied retrospectively the frequency and severity of testicular dysfunction in 26 men

The interplay between iron accumulation, mitochondrial dysfunction and inflammation during the execution step of neurodegenerative disorders

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Pamela J. Urrutia

2014-03-01

Full Text Available A growing set of observations points to mitochondrial dysfunction, iron accumulation, oxidative damage and chronic inflammation as common pathognomonic signs of a number of neurodegenerative diseases that includes Alzheimer's disease, Huntington disease, amyotrophic lateral sclerosis, Friedrich’s ataxia and Parkinson’s disease. Particularly relevant for neurodegenerative processes is the relationship between mitochondria and iron. The mitochondrion upholds the synthesis of iron-sulfur clusters and heme, the most abundant iron-containing prosthetic groups in a large variety of proteins, so a fraction of incoming iron must go through this organelle before reaching its final destination. In turn, the mitochondrial respiratory chain is the source of reactive oxygen species (ROS derived from leaks in the electron transport chain. The co-existence of both iron and ROS in the secluded space of the mitochondrion makes this organelle particularly prone to hydroxyl radical-mediated damage. In addition, a connection between the loss of iron homeostasis and inflammation is starting to emerge; thus, inflammatory cytokines like TNF-alpha and IL-6 induce the synthesis of the divalent metal transporter 1 and promote iron accumulation in neurons and microglia. Here, we review the recent literature on mitochondrial iron homeostasis and the role of inflammation on mitochondria dysfunction and iron accumulation on the neurodegenerative process that lead to cell death in Parkinson’s disease. We also put forward the hypothesis that mitochondrial dysfunction, iron accumulation and inflammation are part of a synergistic self-feeding cycle that ends in apoptotic cell death, once the antioxidant cellular defense systems are finally overwhelmed.

Combination Comprising Parthenolide For Use In The Treatment Of Alzheimer's Disease And Other Neurodegenerative Disorders

KAUST Repository

Bajic, Vladimir B.

2015-06-18

The present invention generally concerns particular methods and compositions for treatment of a neurodegenerative disease, such as Alzheimer\\'s Disease. In particular embodiments, there is a composition comprising Parthenolide and a second agent, including an inhibitor of TLR4/MD-2/CD14, nAChR agonist, Resatorvid, Curcumin, Tilorone or a Tilorone analog, or a combination thereof.

Governance assessment of a protected area : the case of the Alde Feanen National Park

NARCIS (Netherlands)

Lordkipanidze, Maia; Bressers, Hans; Lulofs, Kris

2018-01-01

This paper addresses the challenge of appropriate governance of complexity and diversity in the Dutch national park of Alde Feanen. The issue is how to enhance ecosystem resilience. Our focus relates to a navigable waterway within the park that affects the natural values of the area. The governance

Ultrahigh capacitance density for multiple ALD-grown MIM capacitor stacks in 3-D silicon

NARCIS (Netherlands)

Klootwijk, J.H.; Jinesh, K.B.; Dekkers, W.; Verhoeven, J.F.C.; Heuvel, van den F.C.; Kim, H.-D.; Blin, D.; Verheijen, M.A.; Weemaes, R.G.R.; Kaiser, M.; Ruigrok, J.J.M.; Roozeboom, F.

2008-01-01

"Trench" capacitors containing multiple metal-insulator-metal (MIM) layer stacks are realized by atomic-layer deposition (ALD), yielding an ultrahigh capacitance density of 440 nF/mm2 at a breakdown voltage VBD > 6 V. This capacitance density on silicon is at least 10 times higher than the values

Tremor in neurodegenerative ataxias, Huntington disease and tic disorder.

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Rudzińska, M; Krawczyk, M; Wójcik-Pędziwiatr, M; Szczudlik, A; Tomaszewski, T

2013-01-01

Tremor is the most prevalent movement disorder, defined as rhythmic oscillations of a body part, caused by alternating or synchronic contractions of agonistic or antagonistic muscles. The aim of the study was to assess prevalence and to characterize parameters of tremor accompanying de-generative ataxias, Huntington disease (HD) and tic disorders in comparison with a control group. Forty-three patients with degenerative ataxias, 28 with HD and 26 with tic disorders together with 51 healthy controls were included in the study. For each participant, clinical and instrumental assessment (accelerometer, electromyography [EMG], graphic tablet) of hand tremor was performed. Frequency and severity of tremor were assessed in three positions: at rest (rest tremor), with hands extended (postural tremor), during the 'finger-to-nose' test and during Archimedes spiral drawing (kinetic tremor). Based on the mass load test, the type of tremor was determined as essential tremor type or enhanced physiological tremor type. The incidence of tremor in the accelerometry in patients with degenerative ataxia (50%) significantly differs from controls (10%) (p = 0.001). The dominant tremor was postural, low-intense, with 7-Hz frequency, essential tremor (23%) or other tremor type (23%), while enhanced physiological tremor was the least frequent (2%). Tremor in patients with HD and tic disorders was found in 10% and 20% of patients, respectively, similarly to the control group. Tremor was mild, postural and of essential tremor type, less frequently of enhanced physiological tremor type. No correlation between severity of tremor and severity of disease was found. The prevalence of tremor is considerably higher among patients with degenerative ataxias compared with HD, tic disorder and the control group. The most common type of tremor accompanying ataxias, HD and tic disorders is essential tremor type.

Susceptibility weighted imaging in the evaluation of movement disorders

International Nuclear Information System (INIS)

Hingwala, D.R.; Kesavadas, C.; Thomas, B.; Kapilamoorthy, T.R.

2013-01-01

Movement disorders are neurodegenerative disorders associated with abnormalities of brain iron deposition. In this presentation, we aim to describe the role of susceptibility weighted imaging (SWI) in the imaging of patients with movement disorders and differentiate between the various disorders. SWI is a high-resolution, fully velocity-encoded gradient-echo magnetic resonance imaging (MRI) sequence that consists of using both magnitude and phase information. We describe briefly the physics behind this sequence and the post-processing techniques used. The anatomy of the midbrain and basal ganglia in normal subjects on SWI is covered. A number of neurodegenerative disorders are associated with abnormal iron deposition, which can be detected due to the susceptibility effects

The AMC Linear Disability Score (ALDS): a cross-sectional study with a new generic instrument to measure disability applied to patients with peripheral arterial disease

NARCIS (Netherlands)

Met, R.; Reekers, J.A.; Koelemay, M.J.W.; Legemate, D.A.; de Haan, R.J.

2009-01-01

Background: The AMC Linear Disability Score (ALDS) is a calibrated generic itembank to measure the level of physical disability in patients with chronic diseases. The ALDS has already been validated in different patient populations suffering from chronic diseases. The aim of this study was to assess

Neuroprotective effects of the anti-cancer drug sunitinib in models of HIV neurotoxicity suggests potential for the treatment of neurodegenerative disorders.

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Wrasidlo, Wolf; Crews, Leslie A; Tsigelny, Igor F; Stocking, Emily; Kouznetsova, Valentina L; Price, Diana; Paulino, Amy; Gonzales, Tania; Overk, Cassia R; Patrick, Christina; Rockenstein, Edward; Masliah, Eliezer

2014-12-01

Anti-retrovirals have improved and extended the life expectancy of patients with HIV. However, as this population ages, the prevalence of cognitive changes is increasing. Aberrant activation of kinases, such as receptor tyrosine kinases (RTKs) and cyclin-dependent kinase 5 (CDK5), play a role in the mechanisms of HIV neurotoxicity. Inhibitors of CDK5, such as roscovitine, have neuroprotective effects; however, CNS penetration is low. Interestingly, tyrosine kinase inhibitors (TKIs) display some CDK inhibitory activity and ability to cross the blood-brain barrier. We screened a small group of known TKIs for a candidate with additional CDK5 inhibitory activity and tested the efficacy of the candidate in in vitro and in vivo models of HIV-gp120 neurotoxicity. Among 12 different compounds, sunitinib inhibited CDK5 with an IC50 of 4.2 μM. In silico analysis revealed that, similarly to roscovitine, sunitinib fitted 6 of 10 features of the CDK5 pharmacophore. In a cell-based model, sunitinib reduced CDK5 phosphorylation (pCDK5), calpain-dependent p35/p25 conversion and protected neuronal cells from the toxic effects of gp120. In glial fibrillary acidic protein-gp120 transgenic (tg) mice, sunitinib reduced levels of pCDK5, p35/p25 and phosphorylated tau protein, along with amelioration of the neurodegenerative pathology. Compounds such as sunitinib with dual kinase inhibitory activity could ameliorate the cognitive impairment associated with chronic HIV infection of the CNS. Moreover, repositioning existing low MW compounds holds promise for the treatment of patients with neurodegenerative disorders. © 2014 The British Pharmacological Society.

Circadian Rhythms, Sleep, and Disorders of Aging.

Science.gov (United States)

Mattis, Joanna; Sehgal, Amita

2016-04-01

Sleep-wake cycles are known to be disrupted in people with neurodegenerative disorders. These findings are now supported by data from animal models for some of these disorders, raising the question of whether the disrupted sleep/circadian regulation contributes to the loss of neural function. As circadian rhythms and sleep consolidation also break down with normal aging, changes in these may be part of what makes aging a risk factor for disorders like Alzheimer's disease (AD). Mechanisms underlying the connection between circadian/sleep dysregulation and neurodegeneration remain unclear, but several recent studies provide interesting possibilities. While mechanistic analysis is under way, it is worth considering treatment of circadian/sleep disruption as a means to alleviate symptoms of neurodegenerative disorders. Copyright © 2016 Elsevier Ltd. All rights reserved.

Pharmacogenetics in Neurodegenerative Diseases: Implications for Clinical Trials.

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Tortelli, Rosanna; Seripa, Davide; Panza, Francesco; Solfrizzi, Vincenzo; Logroscino, Giancarlo

2016-01-01

Pharmacogenetics has become extremely important over the last 20 years for identifying individuals more likely to be responsive to pharmacological interventions. The role of genetic background as a predictor of drug response is a young and mostly unexplored field in neurodegenerative diseases. Mendelian mutations in neurodegenerative diseases have been used as models for early diagnosis and intervention. On the other hand, genetic polymorphisms or risk factors for late-onset Alzheimer's disease (AD) or other neurodegenerative diseases, probably influencing drug response, are hardly taken into account in randomized clinical trial (RCT) design. The same is true for genetic variants in cytochrome P450 (CYP), the principal enzymes influencing drug metabolism. A better characterization of individual genetic background may optimize clinical trial design and personal drug response. This chapter describes the state of the art about the impact of genetic factors in RCTs on neurodegenerative disease, with AD, frontotemporal dementia, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease as examples. Furthermore, a brief description of the genetic bases of drug response focusing on neurodegenerative diseases will be conducted. The role of pharmacogenetics in RCTs for neurodegenerative diseases is still a young, unexplored, and promising field. Genetic tools allow increased sophistication in patient profiling and treatment optimization. Pharmaceutical companies are aware of the value of collecting genetic data during their RCTs. Pharmacogenetic research is bidirectional with RCTs: efficacy data are correlated with genetic polymorphisms, which in turn define subjects for treatment stratification. © 2016 S. Karger AG, Basel.

No Geographic Correlation between Lyme Disease and Death Due to 4 Neurodegenerative Disorders, United States, 2001-2010.

Science.gov (United States)

Forrester, Joseph D; Kugeler, Kiersten J; Perea, Anna E; Pastula, Daniel M; Mead, Paul S

2015-11-01

Associations between Lyme disease and certain neurodegenerative diseases have been proposed, but supportive evidence for an association is lacking. Similar geographic distributions would be expected if 2 conditions were etiologically linked. Thus, we compared the distribution of Lyme disease cases in the United States with the distributions of deaths due to Alzheimer disease, amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), and Parkinson disease; no geographic correlations were identified. Lyme disease incidence per US state was not correlated with rates of death due to ALS, MS, or Parkinson disease; however, an inverse correlation was detected between Lyme disease and Alzheimer disease. The absence of a positive correlation between the geographic distribution of Lyme disease and the distribution of deaths due to Alzheimer disease, ALS, MS, and Parkinson disease provides further evidence that Lyme disease is not associated with the development of these neurodegenerative conditions.

N-3 PUFAs and neuroinflammatory processes in cognitive disorders

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Leyrolle Quentin

2016-01-01

Full Text Available With the ageing population and increased cases of neurodegenerative diseases, there is a crucial need for the development of new nutritional approaches to prevent and delay the onset of cognitive decline. Neuroinflammatory processes contribute to neuronal damage that underpins neurodegenerative disorders. Growing evidence sheds light on the use of dietary n-3 long chain polyunsaturated fatty acids to improve cognitive performances and reduce the neuroinflammatory responses occurring with age and neurodegenerative pathologies. This review will summarise the most recent information related to the impact and mechanisms underlying the neuroinflammatory processes in cognitive disorders. We will also discuss the mechanisms underlying n-3 polyunsaturated fatty acids effect on neuroinflammation and memory decline.

A new look at auranofin, dextromethorphan and rosiglitazone for reduction of glia-mediated inflammation in neurodegenerative diseases

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Jocelyn M Madeira

2015-01-01

Full Text Available Neurodegenerative disorders including Alzheimer′s disease are characterized by chronic inflammation in the central nervous system. The two main glial types involved in inflammatory reactions are microglia and astrocytes. While these cells normally protect neurons by providing nutrients and growth factors, disease specific stimuli can induce glial secretion of neurotoxins. It has been hypothesized that reducing glia-mediated inflammation could diminish neuronal loss. This hypothesis is supported by observations that chronic use of non-steroidal anti-inflammatory drugs (NSAIDs is linked with lower incidences of neurodegenerative disease. It is possible that the NSAIDs are not potent enough to appreciably reduce chronic neuroinflammation after disease processes are fully established. Gold thiol compounds, including auranofin, comprise another class of medications effective at reducing peripheral inflammation. We have demonstrated that auranofin inhibits human microglia- and astrocyte-mediated neurotoxicity. Other drugs which are currently used to treat peripheral inflammatory conditions could be helpful in neurodegenerative disease. Three different classes of anti-inflammatory compounds, which have a potential to inhibit neuroinflammation are highlighted below.

Amnestic Disorders

NARCIS (Netherlands)

Kessels, R.P.C.; Savage, G.; Cautin, R.L.; Lilienfeld, S.O.

2015-01-01

Amnestic disorders may involve deficits in the encoding or storage of information in memory, or in retrieval of information from memory. Etiologies vary and include traumatic brain injury, neurodegenerative disease, and psychiatric illness. Different forms of amnesia can be distinguished:

Neuroleptic malignant syndrome during zuclopenthixol therapy in X-linked cerebral adrenoleukodystrophy.

NARCIS (Netherlands)

Rubio Gozalbo, M.E.; Waardenburg, D.A. van; Forget, P.P.; Spaapen, L.J.; Verrips, A.; Vroomen, P.C.

2001-01-01

An 8 year-old boy with X-ALD under treatment with simvastatin developed a severe adverse reaction when the dose of his other medication, zuclopenthixol was increased. Both drugs were withdrawn after a diagnosis of neuroleptic malignant syndrome was made.

Beer and bread to brains and beyond: can yeast cells teach us about neurodegenerative disease?

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Gitler, Aaron D

2008-01-01

For millennia, humans have harnessed the astonishing power of yeast, producing such culinary masterpieces as bread, beer and wine. Therefore, in this new millennium, is it very farfetched to ask if we can also use yeast to unlock some of the modern day mysteries of human disease? Remarkably, these seemingly simple cells possess most of the same basic cellular machinery as the neurons in the brain. We and others have been using the baker's yeast, Saccharomyces cerevisiae, as a model system to study the mechanisms of devastating neurodegenerative diseases such as Parkinson's, Huntington's, Alzheimer's and amyotrophic lateral sclerosis. While very different in their pathophysiology, they are collectively referred to as protein-misfolding disorders because of the presence of misfolded and aggregated forms of various proteins in the brains of affected individuals. Using yeast genetics and the latest high-throughput screening technologies, we have identified some of the potential causes underpinning these disorders and discovered conserved genes that have proven effective in preventing neuron loss in animal models. Thus, these genes represent new potential drug targets. In this review, I highlight recent work investigating mechanisms of cellular toxicity in a yeast Parkinson's disease model and discuss how similar approaches are being applied to additional neurodegenerative diseases.

Neurodegenerative diseases: exercising towards neurogenesis and neuroregeneration

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Eng-Tat Ang

2010-07-01

Full Text Available Currently, there is still no effective therapy for neurodegenerative diseases (NDD such as Alzheimer’s disease (AD and Parkinson’s disease (PD despite intensive research and on-going clinical trials. Collectively, these diseases account for the bulk of health care burden associated with age-related neurodegenerative disorders. There is therefore an urgent need to further research into the molecular pathogenesis, histological differentiation, and clinical management of NDD. Importantly, there is also an urgency to understand the similarities and differences between these two diseases so as to identify the common or different upstream and downstream signaling pathways. In this review, the role iron play in NDD will be highlighted, as iron is key to a common underlying pathway in the production of oxidative stress. There is increasing evidence to suggest that oxidative stress predisposed cells to undergo damage to DNA, protein and lipid, and as such a common factor involved in the pathogenesis of AD and PD. The challenge then is to minimize elevated and uncontrolled oxidative stress levels while not affecting basal iron metabolism, as iron plays vital roles in sustaining cellular function. However, overload of iron results in increased oxidative stress due to the Fenton reaction. We discuss evidence to suggest that sustained exercise and diet restriction may be ways to slow the rate of neurodegeneration, by perhaps promoting neurogenesis or antioxidant-related pathways. It is also our intention to cover NDD in a broad sense, in the context of basic and clinical sciences to cater for both clinician’s and the scientist’s needs, and to highlight current research investigating exercise as a therapeutic or preventive measure.

Control of CydB and GltA1 expression by the SenX3 RegX3 two component regulatory system of Mycobacterium tuberculosis.

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Gretta Roberts

Full Text Available Two component regulatory systems are used widely by bacteria to coordinate changes in global gene expression profiles in response to environmental signals. The SenX3-RegX3 two component system of Mycobacterium tuberculosis has previously been shown to play a role in virulence and phosphate-responsive control of gene expression. We demonstrate that expression of SenX3-RegX3 is controlled in response to growth conditions, although the absolute changes are small. Global gene expression profiling of a RegX3 deletion strain and wild-type strain in different culture conditions (static, microaerobic, anaerobic, as well as in an over-expressing strain identified a number of genes with changed expression patterns. Among those were genes previously identified as differentially regulated in aerobic culture, including ald (encoding alanine dehydrogenase cyd,encoding a subunit of the cytochrome D ubiquinol oxidase, and gltA1, encoding a citrate synthase. Promoter activity in the upstream regions of both cydB and gltA1 was altered in the RegX3 deletion strain. DNA-binding assays confirmed that RegX3 binds to the promoter regions of ald, cydB and gltA1 in a phosphorylation-dependent manner. Taken together these data suggest a direct role for the SenX-RegX3 system in modulating expression of aerobic respiration, in addition to its role during phosphate limitation.

Desenvolvimento e caracterização de filmes de base celulósica incorporados com aldeído cinâmico

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Franceline Aparecida Lopes

2014-03-01

Full Text Available Filmes antimicrobianos foram desenvolvidos com a incorporação de aldeído cinâmico nas concentrações de 5%, 10% e 20% v/p. Suas atividades de inibição do crescimento foram avaliadas para as bactérias Staphylococcus aureus, Listeria monocytogenes e Escherichia coli e para os fungos Fusarium oxysporum e Aspergillus flavus. As propriedades mecânicas dos filmes também foram avaliadas. Para as bactérias, à exceção de E. coli, foram observados halos de inibição que aumentaram proporcionalmente ao aumento da concentração de aldeído cinâmico no filme. A espessura média dos filmes utilizados, independentemente da concentração, foi de 32,47 µm e a média de deformação relativa na carga máxima dos filmes foi de 2,05% a 8 ºC e 1,73% a 25 ºC. O filme contendo 10% de aldeído cinâmico apresentou carga máxima de deformação de 108,27 N (Newton, significativamente menor (p<0,05 que os filmes com 0% e 5%. Os resultados mostraram que o uso de filmes incorporados com aldeído cinâmico é uma alternativa como embalagem ativa para o controle do crescimento de micro-organismos em produtos alimentícios.

[Changes in olfaction during ageing and in certain neurodegenerative diseases: up-to-date].

Science.gov (United States)

Bianchi, A-J; Guépet-Sordet, H; Manckoundia, P

2015-01-01

Olfaction is a complex sensory system, and increasing interest is being shown in the link between olfaction and cognition, notably in the elderly. In this literature review, we revisit the specific neurophysiological features of the olfactory system and odorants that lead to a durable olfactory memory and an emotional memory, for which the implicit component produces subconscious olfactory conditioning. Olfaction is known to affect cognitive abilities and mood. We also consider the impairment of olfactory function due to ageing and to neurodegenerative diseases, in particular Alzheimer's disease and Parkinson's disease, through anatomopathological changes in the peripheral and central olfactory structures. The high frequency of these olfactory disorders as well as their early occurrence in Alzheimer disease and Parkinson disease are in favour of their clinical detection in subjects suffering from these two neurodegenerative diseases. Finally, we analyse the impact of olfactory stimulation on cognitive performance and attention. Current observational data from studies in elderly patients with Alzheimer-type dementia are limited to multiple sensory stimulation methods, such as the Snoezelen method, and aromatherapy. These therapies have shown benefits for dementia-related mood and behaviour disorders in the short term, with few side effects. Since olfactory chemosensory stimulation may be beneficial, it may be proposed in patients with dementia, especially Alzheimer-type dementia, as a complementary or even alternative therapy to existing medical strategies. Copyright © 2014 Société nationale française de médecine interne (SNFMI). Published by Elsevier SAS. All rights reserved.

Mapping Neurodegenerative Disease Onset and Progression.

Science.gov (United States)

Seeley, William W

2017-08-01

Brain networks have been of long-standing interest to neurodegeneration researchers, including but not limited to investigators focusing on conventional prion diseases, which are known to propagate along neural pathways. Tools for human network mapping, however, remained inadequate, limiting our understanding of human brain network architecture and preventing clinical research applications. Until recently, neuropathological studies were the only viable approach to mapping disease onset and progression in humans but required large autopsy cohorts and laborious methods for whole-brain sectioning and staining. Despite important advantages, postmortem studies cannot address in vivo, physiological, or longitudinal questions and have limited potential to explore early-stage disease except for the most common disorders. Emerging in vivo network-based neuroimaging strategies have begun to address these issues, providing data that complement the neuropathological tradition. Overall, findings to date highlight several fundamental principles of neurodegenerative disease anatomy and pathogenesis, as well as some enduring mysteries. These principles and mysteries provide a road map for future research. Copyright © 2017 Cold Spring Harbor Laboratory Press; all rights reserved.

Extremely low frequency electromagnetic fields stimulation modulates autoimmunity and immune responses: a possible immuno-modulatory therapeutic effect in neurodegenerative diseases

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Fabio Guerriero

2016-01-01

Full Text Available Increasing evidence shows that extremely low frequency electromagnetic fields (ELF-EMFs stimulation is able to exert a certain action on autoimmunity and immune cells. In the past, the efficacy of pulsed ELF-EMFs in alleviating the symptoms and the progression of multiple sclerosis has been supported through their action on neurotransmission and on the autoimmune mechanisms responsible for demyelination. Regarding the immune system, ELF-EMF exposure contributes to a general activation of macrophages, resulting in changes of autoimmunity and several immunological reactions, such as increased reactive oxygen species-formation, enhanced phagocytic activity and increased production of chemokines. Transcranial electromagnetic brain stimulation is a non-invasive novel technique used recently to treat different neurodegenerative disorders, in particular Alzheimer's disease. Despite its proven value, the mechanisms through which EMF brain-stimulation exerts its beneficial action on neuronal function remains unclear. Recent studies have shown that its beneficial effects may be due to a neuroprotective effect on oxidative cell damage. On the basis of in vitro and clinical studies on brain activity, modulation by ELF-EMFs could possibly counteract the aberrant pro-inflammatory responses present in neurodegenerative disorders reducing their severity and their onset. The objective of this review is to provide a systematic overview of the published literature on EMFs and outline the most promising effects of ELF-EMFs in developing treatments of neurodegenerative disorders. In this regard, we review data supporting the role of ELF-EMF in generating immune-modulatory responses, neuromodulation, and potential neuroprotective benefits. Nonetheless, we reckon that the underlying mechanisms of interaction between EMF and the immune system are still to be completely understood and need further studies at a molecular level.

Ketogenic Diet in Neuromuscular and Neurodegenerative Diseases

Science.gov (United States)

Damiani, Ernesto; Bosco, Gerardo

2014-01-01

An increasing number of data demonstrate the utility of ketogenic diets in a variety of metabolic diseases as obesity, metabolic syndrome, and diabetes. In regard to neurological disorders, ketogenic diet is recognized as an effective treatment for pharmacoresistant epilepsy but emerging data suggests that ketogenic diet could be also useful in amyotrophic lateral sclerosis, Alzheimer, Parkinson's disease, and some mitochondriopathies. Although these diseases have different pathogenesis and features, there are some common mechanisms that could explain the effects of ketogenic diets. These mechanisms are to provide an efficient source of energy for the treatment of certain types of neurodegenerative diseases characterized by focal brain hypometabolism; to decrease the oxidative damage associated with various kinds of metabolic stress; to increase the mitochondrial biogenesis pathways; and to take advantage of the capacity of ketones to bypass the defect in complex I activity implicated in some neurological diseases. These mechanisms will be discussed in this review. PMID:25101284

Electrical response of electron selective atomic layer deposited TiO2‑x heterocontacts on crystalline silicon substrates

Science.gov (United States)

Ahiboz, Doğuşcan; Nasser, Hisham; Aygün, Ezgi; Bek, Alpan; Turan, Raşit

2018-04-01

Integration of oxygen deficient sub-stoichiometric titanium dioxide (TiO2‑x) thin films as the electron transporting-hole blocking layer in solar cell designs are expected to reduce fabrication costs by eliminating high temperature processes while maintaining high conversion efficiencies. In this paper, we conducted a study to reveal the electrical properties of TiO2‑x thin films grown on crystalline silicon (c-Si) substrates by atomic layer deposition (ALD) technique. Effect of ALD substrate temperature, post deposition annealing, and doping type of the c-Si substrate on the interface states and TiO2‑x bulk properties were extracted by performing admittance (C-V, G-V) and current-voltage (J-V) measurements. Moreover, the asymmetry in C-V and J-V measurements between the p-n type and n-n TiO2‑x-c-Si heterojunction types were examined and the electron transport selectivity of TiO2‑x was revealed.

CMOS compatible thin-film ALD tungsten nanoelectromechanical devices

Science.gov (United States)

Davidson, Bradley Darren

This research focuses on the development of a novel, low-temperature, CMOS compatible, atomic-layer-deposition (ALD) enabled NEMS fabrication process for the development of ALD Tungsten (WALD) NEMS devices. The devices are intended for use in CMOS/NEMS hybrid systems, and NEMS based micro-processors/controllers capable of reliable operation in harsh environments not accessible to standard CMOS technologies. The majority of NEMS switches/devices to date have been based on carbon-nano-tube (CNT) designs. The devices consume little power during actuation, and as expected, have demonstrated actuation voltages much smaller than MEMS switches. Unfortunately, NEMS CNT switches are not typically CMOS integrable due to the high temperatures required for their growth, and their fabrication typically results in extremely low and unpredictable yields. Thin-film NEMS devices offer great advantages over reported CNT devices for several reasons, including: higher fabrication yields, low-temperature (CMOS compatible) deposition techniques like ALD, and increased control over design parameters/device performance metrics, i.e., device geometry. Furthermore, top-down, thin-film, nano-fabrication techniques are better capable of producing complicated device geometries than CNT based processes, enabling the design and development of multi-terminal switches well-suited for low-power hybrid NEMS/CMOS systems as well as electromechanical transistors and logic devices for use in temperature/radiation hard computing architectures. In this work several novel, low-temperature, CMOS compatible fabrication technologies, employing WALD as a structural layer for MEMS or NEMS devices, were developed. The technologies developed are top-down nano-scale fabrication processes based on traditional micro-machining techniques commonly used in the fabrication of MEMS devices. Using these processes a variety of novel WALD NEMS devices have been successfully fabricated and characterized. Using two different

Relationships between Rapid Eye Movement Sleep Behavior Disorder and Neurodegenerative Diseases: Clinical Assessments, Biomarkers, and Treatment

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Min Li

2018-01-01

Conclusions: More longitudinal studies should be conducted to evaluate the predictive value of biomarkers of RBD. Moreover, because the glucose and dopamine metabolisms are not specific for assessing cognitive cognition, the molecular metabolism directly related to cognition should be investigated. There is a need for more treatment trials to determine the effectiveness of interventions of RBD on preventing the conversion to neurodegenerative diseases.

Mitochondrial Mutations in Subjects with Psychiatric Disorders

NARCIS (Netherlands)

V. Sequeira (Vasco); S.M. Rollins; C. Magnan (Christophe); M. van Oven (Mannis); P. Baldi (Pierre); R.M. Myers (Richard M.); J.D. Barchas (Jack D.); A.F. Schatzberg (Alan F); S.J. Watson (Stanley J); H. Akil (Huda); W.E. Bunney (William E.); M.P. Vawter (Marquis)

2015-01-01

textabstractA considerable body of evidence supports the role of mitochondrial dysfunction in psychiatric disorders and mitochondrial DNA (mtDNA) mutations are known to alter brain energy metabolism, neurotransmission, and cause neurodegenerative disorders. Genetic studies focusing on common nuclear

Recent advances in assays for the fragile X-related disorders.

Science.gov (United States)

Hayward, Bruce E; Kumari, Daman; Usdin, Karen

2017-10-01

The fragile X-related disorders are a group of three clinical conditions resulting from the instability of a CGG-repeat tract at the 5' end of the FMR1 transcript. Fragile X-associated tremor/ataxia syndrome (FXTAS) and fragile X-associated primary ovarian insufficiency (FXPOI) are disorders seen in carriers of FMR1 alleles with 55-200 repeats. Female carriers of these premutation (PM) alleles are also at risk of having a child who has an FMR1 allele with >200 repeats. Most of these full mutation (FM) alleles are epigenetically silenced resulting in a deficit of the FMR1 gene product, FMRP. This results in fragile X Syndrome (FXS), the most common heritable cause of intellectual disability and autism. The diagnosis and study of these disorders is challenging, in part because the detection of alleles with large repeat numbers has, until recently, been either time-consuming or unreliable. This problem is compounded by the mosaicism for repeat length and/or DNA methylation that is frequently seen in PM and FM carriers. Furthermore, since AGG interruptions in the repeat tract affect the risk that a FM allele will be maternally transmitted, the ability to accurately detect these interruptions in female PM carriers is an additional challenge that must be met. This review will discuss some of the pros and cons of some recently described assays for these disorders, including those that detect FMRP levels directly, as well as emerging technologies that promise to improve the diagnosis of these conditions and to be useful in both basic and translational research settings.

A missense change in the ATG4D gene links aberrant autophagy to a neurodegenerative vacuolar storage disease.

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Kaisa Kyöstilä

2015-04-01

Full Text Available Inherited neurodegenerative disorders are debilitating diseases that occur across different species. We have performed clinical, pathological and genetic studies to characterize a novel canine neurodegenerative disease present in the Lagotto Romagnolo dog breed. Affected dogs suffer from progressive cerebellar ataxia, sometimes accompanied by episodic nystagmus and behavioral changes. Histological examination revealed unique pathological changes, including profound neuronal cytoplasmic vacuolization in the nervous system, as well as spheroid formation and cytoplasmic aggregation of vacuoles in secretory epithelial tissues and mesenchymal cells. Genetic analyses uncovered a missense change, c.1288G>A; p.A430T, in the autophagy-related ATG4D gene on canine chromosome 20 with a highly significant disease association (p = 3.8 x 10-136 in a cohort of more than 2300 Lagotto Romagnolo dogs. ATG4D encodes a poorly characterized cysteine protease belonging to the macroautophagy pathway. Accordingly, our histological analyses indicated altered autophagic flux in affected tissues. The knockdown of the zebrafish homologue atg4da resulted in a widespread developmental disturbance and neurodegeneration in the central nervous system. Our study describes a previously unknown canine neurological disease with particular pathological features and implicates the ATG4D protein as an important autophagy mediator in neuronal homeostasis. The canine phenotype serves as a model to delineate the disease-causing pathological mechanism(s and ATG4D function, and can also be used to explore treatment options. Furthermore, our results reveal a novel candidate gene for human neurodegeneration and enable the development of a genetic test for veterinary diagnostic and breeding purposes.

Sulforaphane as a Potential Protective Phytochemical against Neurodegenerative Diseases

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Andrea Tarozzi

2013-01-01

Full Text Available A wide variety of acute and chronic neurodegenerative diseases, including ischemic/traumatic brain injury, Alzheimer’s disease, and Parkinson's disease, share common characteristics such as oxidative stress, misfolded proteins, excitotoxicity, inflammation, and neuronal loss. As no drugs are available to prevent the progression of these neurological disorders, intervention strategies using phytochemicals have been proposed as an alternative form of treatment. Among phytochemicals, isothiocyanate sulforaphane, derived from the hydrolysis of the glucosinolate glucoraphanin mainly present in Brassica vegetables, has demonstrated neuroprotective effects in several in vitro and in vivo studies. In particular, evidence suggests that sulforaphane beneficial effects could be mainly ascribed to its peculiar ability to activate the Nrf2/ARE pathway. Therefore, sulforaphane appears to be a promising compound with neuroprotective properties that may play an important role in preventing neurodegeneration.

The impact of autism spectrum disorder symptoms on gesture use in fragile X syndrome and Down syndrome

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Emily Lorang

2017-12-01

Full Text Available Background & aims This study compared gesture rate and purpose in participants with Down syndrome and fragile X syndrome, and the impact of autism spectrum disorder symptoms on each syndrome. Methods Twenty individuals with fragile X syndrome and 20 individuals with Down syndrome between nine and 22 years of age participated in this study. We coded gesture rate and purpose from an autism spectrum disorder evaluation, the Autism Diagnostic Observation Schedule – Second Edition. Results We did not find between-group differences (Down syndrome compared to fragile X syndrome in gesture rate or purpose. Notably, as autism spectrum disorder symptoms increased, the group with Down syndrome produced a lower rate of gestures, but used gestures for the same purpose. Gesture rate did not change based on autism spectrum disorder symptoms in the participants with fragile X syndrome, but as autism spectrum disorder symptoms increased, the participants with fragile X syndrome produced a larger proportion of gestures to regulate behavior and a smaller proportion for joint attention/social interaction. Conclusions Overall, the amount or purpose of gestures did not differentiate individuals with Down syndrome and fragile X syndrome. However, the presence of autism spectrum disorder symptoms had a significant and unique impact on these genetic disorders. In individuals with Down syndrome, the presence of more autism spectrum disorder symptoms resulted in a reduction in the rate of gesturing, but did not change the purpose. However, in fragile X syndrome, the rate of gestures remained the same, but the purpose of those gestures changed based on autism spectrum disorder symptoms. Implications Autism spectrum disorder symptoms differentially impact gestures in Down syndrome and fragile X syndrome. Individuals with Down syndrome and more autism spectrum disorder symptoms are using gestures less frequently. Therefore, clinicians may need to consider children with

Comparing XPS on bare and capped ZrN films grown by plasma enhanced ALD: Effect of ambient oxidation

Science.gov (United States)

Muneshwar, Triratna; Cadien, Ken

2018-03-01

In this article we compare x-ray photoelectron spectroscopy (XPS) measurements on bare- and capped- zirconium nitride (ZrN) films to investigate the effect of ambient sample oxidation on the detected bound O in the form of oxide ZrO2 and/or oxynitride ZrOxNy. ZrN films in both bare- and Al2O3/AlN capped- XPS samples were grown by plasma-enhanced atomic layer deposition (PEALD) technique using tetrakis dimethylamino zirconium (TDMAZr) precursor, forming gas (5% H2, rest N2) inductively coupled plasma (ICP), and as received research grade process gases under identical process conditions. Capped samples were prepared by depositing 1 nm thick PEALD AlN on ZrN, followed by additional deposition of 1 nm thick ALD Al2O3, without venting of ALD reactor. On bare ZrN sample at room temperature, spectroscopic ellipsometry (SE) measurements with increasing ambient exposure times (texp) showed a self-limiting surface oxidation with the oxide thickness (dox) approaching 3.7 ± 0.02 nm for texp > 120 min. In XPS data measured prior to sample sputtering (tsput = 0), ZrO2 and ZrOxNy were detected in bare- samples, whereas only ZrN and Al2O3/AlN from capping layer were detected in capped- samples. For bare-ZrN samples, appearance of ZrO2 and ZrOxNy up to sputter depth (dsput) of 15 nm in depth-profile XPS data is in contradiction with measured dox = 3.7 nm, but explained from sputtering induced atomic inter-diffusion within analyzed sample. Appearance of artifacts in the XPS spectra from moderately sputtered (dsput = 0.2 nm and 0.4 nm) capped-ZrN sample, provides an evidence to ion-bombardment induced modifications within analyzed sample.

Perpendicular magnetic anisotropy of CoFeB\\Ta bilayers on ALD HfO2

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Bart F. Vermeulen

2017-05-01

Full Text Available Perpendicular magnetic anisotropy (PMA is an essential condition for CoFe thin films used in magnetic random access memories. Until recently, interfacial PMA was mainly known to occur in materials stacks with MgO\\CoFe(B interfaces or using an adjacent crystalline heavy metal film. Here, PMA is reported in a CoFeB\\Ta bilayer deposited on amorphous high-κ dielectric (relative permittivity κ=20 HfO2, grown by atomic layer deposition (ALD. PMA with interfacial anisotropy energy Ki up to 0.49 mJ/m2 appears after annealing the stacks between 200°C and 350°C, as shown with vibrating sample magnetometry. Transmission electron microscopy shows that the decrease of PMA starting from 350°C coincides with the onset of interdiffusion in the materials. High-κ dielectrics are potential enablers for giant voltage control of magnetic anisotropy (VCMA. The absence of VCMA in these experiments is ascribed to a 0.6 nm thick magnetic dead layer between HfO2 and CoFeB. The results show PMA can be easily obtained on ALD high-κ dielectrics.

Overnutrition Determines LPS Regulation of Mycotoxin Induced Neurotoxicity in Neurodegenerative Diseases

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Ian James Martins

2015-12-01

Full Text Available Chronic neurodegenerative diseases are now associated with obesity and diabetes and linked to the developing and developed world. Interests in healthy diets have escalated that may prevent neurodegenerative diseases such as Parkinson’s and Alzheimer’s disease. The global metabolic syndrome involves lipoprotein abnormalities and insulin resistance and is the major disorder for induction of neurological disease. The effects of bacterial lipopolysaccharides (LPS on dyslipidemia and NAFLD indicate that the clearance and metabolism of fungal mycotoxins are linked to hypercholesterolemia and amyloid beta oligomers. LPS and mycotoxins are associated with membrane lipid disturbances with effects on cholesterol interacting proteins, lipoprotein metabolism, and membrane apo E/amyloid beta interactions relevant to hypercholesterolemia with close connections to neurological diseases. The influence of diet on mycotoxin metabolism has accelerated with the close association between mycotoxin contamination from agricultural products such as apple juice, grains, alcohol, and coffee. Cholesterol efflux in lipoproteins and membrane cholesterol are determined by LPS with involvement of mycotoxin on amyloid beta metabolism. Nutritional interventions such as diets low in fat/carbohydrate/cholesterol have become of interest with relevance to low absorption of lipophilic LPS and mycotoxin into lipoproteins with rapid metabolism of mycotoxin to the liver with the prevention of neurodegeneration.

MOCVD and ALD of rare earth containing multifunctional materials. From precursor chemistry to thin film deposition and applications

International Nuclear Information System (INIS)

Milanov, Andrian Petrov

2010-01-01

The present thesis deals with the development of metal-organic complexes of rare elements. They should be used as novel precursors for the production of rare earth thin films by metal-organic chemical vapor deposition (MOCVD) and Atomic Layer Deposition (ALD). Within the work two precursor classes were examined, the tris-Malonato-complexes as well as the tris-Guanidinato-complexes of a series of rare earth metals. The latter showed excellent properties regarding to their volatility, their thermal stability, the defined decomposition and high reactivity towards water. They have been successfully used as precursors for the MOCVD of rare earth oxide layers. By using of a gadolinium guanidinate it could also be shown that the rare earth guanidinates are promising precursors for ALD of rare earth oxide and MOCVD of rare earth nitride layers. [de

Implication of Caspase-3 as a Common Therapeutic Target for Multineurodegenerative Disorders and Its Inhibition Using Nonpeptidyl Natural Compounds

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Saif Khan

2015-01-01

Full Text Available Caspase-3 has been identified as a key mediator of neuronal apoptosis. The present study identifies caspase-3 as a common player involved in the regulation of multineurodegenerative disorders, namely, Alzheimer’s disease (AD, Parkinson’s disease (PD, Huntington’s disease (HD, and amyotrophic lateral sclerosis (ALS. The protein interaction network prepared using STRING database provides a strong evidence of caspase-3 interactions with the metabolic cascade of the said multineurodegenerative disorders, thus characterizing it as a potential therapeutic target for multiple neurodegenerative disorders. In silico molecular docking of selected nonpeptidyl natural compounds against caspase-3 exposed potent leads against this common therapeutic target. Rosmarinic acid and curcumin proved to be the most promising ligands (leads mimicking the inhibitory action of peptidyl inhibitors with the highest Gold fitness scores 57.38 and 53.51, respectively. These results were in close agreement with the fitness score predicted using X-score, a consensus based scoring function to calculate the binding affinity. Nonpeptidyl inhibitors of caspase-3 identified in the present study expeditiously mimic the inhibitory action of the previously identified peptidyl inhibitors. Since, nonpeptidyl inhibitors are preferred drug candidates, hence, discovery of natural compounds as nonpeptidyl inhibitors is a significant transition towards feasible drug development for neurodegenerative disorders.

Low-temperature atomic layer deposition of MoO{sub x} for silicon heterojunction solar cells

Energy Technology Data Exchange (ETDEWEB)

Macco, B.; Vos, M.F.J.; Thissen, N.F.W.; Bol, A.A. [Department of Applied Physics, Eindhoven University of Technology, Eindhoven (Netherlands); Kessels, W.M.M. [Department of Applied Physics, Eindhoven University of Technology, Eindhoven (Netherlands); Solliance Solar Research, Eindhoven (Netherlands)

2015-07-15

The preparation of high-quality molybdenum oxide (MoO{sub x}) is demonstrated by plasma-enhanced atomic layer deposition (ALD) at substrate temperatures down to 50 C. The films are amorphous, slightly substoichiometric with respect to MoO{sub 3}, and free of other elements apart from hydrogen (<11 at%). The films have a high transparency in the visible region and their compatibility with a-Si:H passivation schemes is demonstrated. It is discussed that these aspects, in conjunction with the low processing temperature and the ability to deposit very thin conformal films, make this ALD process promising for the future application of MoO{sub x} in hole-selective contacts for silicon heterojunction solar cells. (copyright 2015 WILEY-VCH Verlag GmbH and Co. KGaA, Weinheim)

In silico studies in drug research against neurodegenerative diseases.

Science.gov (United States)

Makhouri, Farahnaz Rezaei; Ghasemi, Jahan B

2017-08-22

Neurodegenerative diseases such as Alzheimer's disease (AD), progressive neurodegenerative forms of Huntington's disease, Parkinson's disease (PD), amyotrophic lateral sclerosis, spinal cerebellar ataxias, and spinal and bulbar muscular atrophy are described by slow and selective dysfunction and degeneration of neurons and axons in the central nervous system (CNS). Computer-aided or in silico design methods have matured into powerful tools for reducing the number of ligands that should be screened in experimental assays. In the present review, the authors provide a basic background about neurodegenerative diseases and in silico techniques in the drug research. Furthermore, they review the various in silico studies reported against various targets in neurodegenerative diseases, including homology modeling, molecular docking, virtual high-throughput screening, quantitative structure activity relationship (QSAR), hologram quantitative structure activity relationship (HQSAR), 3D pharmacophore mapping, proteochemometrics modeling (PCM), fingerprints, fragment-based drug discovery, Monte Carlo simulation, molecular dynamic (MD) simulation, quantum-mechanical methods for drug design, support vector machines, and machine learning approaches. Neurodegenerative diseases have a multifactorial pathoetiological origin, so scientists have become persuaded that a multi-target therapeutic strategy aimed at the simultaneous targeting of multiple proteins (and therefore etiologies) involved in the development of a disease is recommended in future. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Aspirin-Mediated Acetylation Protects Against Multiple Neurodegenerative Pathologies by Impeding Protein Aggregation.

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Ayyadevara, Srinivas; Balasubramaniam, Meenakshisundaram; Kakraba, Samuel; Alla, Ramani; Mehta, Jawahar L; Shmookler Reis, Robert J

2017-12-10

Many progressive neurological disorders, including Alzheimer's disease (AD), Huntington's disease, and Parkinson's disease (PD), are characterized by accumulation of insoluble protein aggregates. In prospective trials, the cyclooxygenase inhibitor aspirin (acetylsalicylic acid) reduced the risk of AD and PD, as well as cardiovascular events and many late-onset cancers. Considering the role played by protein hyperphosphorylation in aggregation and neurodegenerative diseases, and aspirin's known ability to donate acetyl groups, we asked whether aspirin might reduce both phosphorylation and aggregation by acetylating protein targets. Aspirin was substantially more effective than salicylate in reducing or delaying aggregation in human neuroblastoma cells grown in vitro, and in Caenorhabditis elegans models of human neurodegenerative diseases in vivo. Aspirin acetylates many proteins, while reducing phosphorylation, suggesting that acetylation may oppose phosphorylation. Surprisingly, acetylated proteins were largely excluded from compact aggregates. Molecular-dynamic simulations indicate that acetylation of amyloid peptide energetically disfavors its association into dimers and octamers, and oligomers that do form are less compact and stable than those comprising unacetylated peptides. Hyperphosphorylation predisposes certain proteins to aggregate (e.g., tau, α-synuclein, and transactive response DNA-binding protein 43 [TDP-43]), and it is a critical pathogenic marker in both cardiovascular and neurodegenerative diseases. We present novel evidence that acetylated proteins are underrepresented in protein aggregates, and that aggregation varies inversely with acetylation propensity after diverse genetic and pharmacologic interventions. These results are consistent with the hypothesis that aspirin inhibits protein aggregation and the ensuing toxicity of aggregates through its acetyl-donating activity. This mechanism may contribute to the neuro-protective, cardio

Contribution of glucocorticoids and glucocorticoid receptors to the regulation of neurodegenerative processes.

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Vyas, Sheela; Maatouk, Layal

2013-12-01

Isolation of glucocorticoids (GCs) from adrenal glands followed by synthesis led rapidly to their first clinical application, about 70 years ago, for treatment of rheumatoid arthritis. To this day GCs are used in diseases that have an inflammatory component. However, their use is carefully monitored because of harmful side effects. GCs are also synonymous with stress and adaptation. In CNS, GC binds and activates high affinity mineralocorticoid receptor (MR) and low affinity glucocorticoid receptor (GR). GR, whose expression is ubiquitous, is only activated when GC levels rise as during circadian peak and in response to stress. Numerous recent studies have yielded important and new insights on the mechanisms concerning pulsatile secretory pattern of GCs as well as various processes that tightly control their synthesis via hypothalamic-pituitary-adrenal (HPA) axis involving regulated release of corticotropin-releasing hormone (CRH) and adrenocorticotropic hormone (ACTH) from hypothalamus and pituitary, respectively. GR modulates neuronal functions and viability through both genomic and non-genomic actions, and importantly its transcriptional regulatory activity is tightly locked with GC secretory pattern. There is increasing evidence pointing to involvement of GC-GR in neurodegenerative disorders. Patients with Alzheimer's or Parkinson's or Huntington's disease show chronically high cortisol levels suggesting changes occurring in controls of HPA axis. In experimental models of these diseases, chronic stress or GC treatment was found to exacerbate both the clinical symptoms and neurodegenerative processes. However, recent evidence also shows that GC-GR can exert neuroprotective effects. Thus, for any potential therapeutic strategies in these neurodegenerative diseases we need to understand the precise modifications both in HPA axis and in GR activity and find ways to harness their protective actions.

CsPbBr{sub 3} QD/AlO{sub x} inorganic nanocomposites with exceptional stability in water, light, and heat

Energy Technology Data Exchange (ETDEWEB)

Loiudice, Anna; Saris, Seryio; Buonsanti, Raffaella [Department of Chemical Sciences and Engineering, EPFL Valais Wallis, Sion (Switzerland); Oveisi, Emad; Alexander, Duncan T.L. [Interdisciplinary Centre for Electron Microscopy (CIME), EPFL, Lausanne (Switzerland)

2017-08-28

Herein, the assembly of CsPbBr{sub 3} QD/AlO{sub x} inorganic nanocomposites, by using atomic layer deposition (ALD) for the growth of the amorphous alumina matrix (AlO{sub x}), is described as a novel protection scheme for such QDs. The nucleation and growth of AlO{sub x} on the QD surface was thoroughly investigated by miscellaneous techniques, which highlighted the importance of the interaction between the ALD precursors and the QD surface to uniformly coat the QDs while preserving the optoelectronic properties. These nanocomposites show exceptional stability towards exposure to air (for at least 45 days), irradiation under simulated solar spectrum conditions (for at least 8 h), and heat (up to 200 C in air), and finally upon immersion in water. This method was extended to the assembly of CsPbBr{sub x}I{sub 3-x} QD/AlO{sub x} and CsPbI{sub 3} QD/AlO{sub x} nanocomposites, which were more stable than the pristine QD films. (copyright 2017 Wiley-VCH Verlag GmbH and Co. KGaA, Weinheim)

Farnesoid X Receptor Agonist Treatment Alters Bile Acid Metabolism but Exacerbates Liver Damage in a Piglet Model of Short-Bowel Syndrome.

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Pereira-Fantini, Prue M; Lapthorne, Susan; Gahan, Cormac G M; Joyce, Susan A; Charles, Jenny; Fuller, Peter J; Bines, Julie E

2017-07-01

Options for the prevention of short-bowel syndrome-associated liver disease (SBS-ALDs) are limited and often ineffective. The farnesoid X receptor (FXR) is a newly emerging pharmaceutical target and FXR agonists have been shown to ameliorate cholestasis and metabolic disorders. The aim of this study was to assess the efficacy of obeticholic acid (OCA) treatment in preventing SBS-ALDs. Piglets underwent 75% small-bowel resection (SBS) or sham surgery (sham) and were assigned to either a daily dose of OCA (2.4 mg/kg/day) or were untreated. Clinical measures included weight gain and stool studies. Histologic features were assessed. Ultraperformance liquid chromatography tandem mass spectrometry was used to determine bile acid composition in end point bile and portal serum samples. Gene expression of key FXR targets was assessed in intestinal and hepatic tissues via quantitative polymerase chain reaction. OCA-treated SBS piglets showed decreased stool fat and altered liver histology when compared with nontreated SBS piglets. OCA prevented SBS-associated taurine depletion, however, further analysis of bile and portal serum samples indicated that OCA did not prevent SBS-associated alterations in bile acid composition. The expression of FXR target genes involved in bile acid transport and synthesis increased within the liver of SBS piglets after OCA administration whereas, paradoxically, intestinal expression of FXR target genes were decreased by OCA administration. Administration of OCA in SBS reduced fat malabsorption and altered bile acid composition, but did not prevent the development of SBS-ALDs. We postulate that extensive small resection impacts the ability of the remnant intestine to respond to FXR activation.

Effects of Ashwagandha (roots of Withania somnifera) on neurodegenerative diseases.

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Kuboyama, Tomoharu; Tohda, Chihiro; Komatsu, Katsuko

2014-01-01

Neurodegenerative diseases commonly induce irreversible destruction of central nervous system (CNS) neuronal networks, resulting in permanent functional impairments. Effective medications against neurodegenerative diseases are currently lacking. Ashwagandha (roots of Withania somnifera Dunal) is used in traditional Indian medicine (Ayurveda) for general debility, consumption, nervous exhaustion, insomnia, and loss of memory. In this review, we summarize various effects and mechanisms of Ashwagandha extracts and related compounds on in vitro and in vivo models of neurodegenerative diseases such as Alzheimer's disease and spinal cord injury.

Plasma-Assisted ALD TiN/Al2O3 stacks for MIMIM Trench Capacitor Applications

NARCIS (Netherlands)

Hoogeland, D.; Jinesh, K.B.; Voogt, F.C.; Besling, W.F.A.; Lamy, Y.; Roozeboom, F.; Sanden, van de M.C.M.; Kessels, W.M.M.; Gendt, de S.

2009-01-01

In this paper we report on the overall plasma-assisted ALD processes of Al2O3 and TiN conducted in a single reactor chamber and at a single temperature (340 oC). The individual Al2O3 and TiN films in the stack were consecutively deposited in such a way that they were separated by purge intervals

Structural and XPS studies of PSi/TiO2 nanocomposites prepared by ALD and Ag-assisted chemical etching

International Nuclear Information System (INIS)

Iatsunskyi, Igor; Kempiński, Mateusz; Nowaczyk, Grzegorz; Jancelewicz, Mariusz; Pavlenko, Mykola; Załęski, Karol; Jurga, Stefan

2015-01-01

Highlights: • Porous silicon/TiO 2 nanocomposites have been investigated. • Morphology and chemical composition of PSi/TiO 2 nanocomposites were established. • Valence-band XPS maximums for PSi/TiO 2 nanocomposites were found and analyzed. - Abstract: PSi/TiO 2 nanocomposites fabricated by atomic layer deposition (ALD) and metal-assisted chemical etching (MACE) were investigated. The morphology and phase structure of PSi/TiO 2 nanocomposites were studied by means of scanning electron microscopy (SEM), transmission electron microscopy (TEM) with an energy dispersive X-ray spectroscopy (EDX) and Raman spectroscopy. The mean size of TiO 2 nanocrystals was determined by TEM and Raman spectroscopy. X-ray photoelectron spectroscopy (XPS) was used to analyze the chemical elemental composition by observing the behavior of the Ti 2p, O 1s and Si 2p lines. TEM, Raman spectroscopy and XPS binding energy analysis confirmed the formation of TiO 2 anatase phase inside the PSi matrix. The XPS valence band analysis was performed in order to investigate the modification of PSi/TiO 2 nanocomposites electronic structure. Surface defects states of Ti 3+ at PSi/TiO 2 nanocomposites were identified by analyzing of XPS valence band spectra

Effects of annealing temperature on the characteristics of ALD-deposited HfO2 in MIM capacitors

International Nuclear Information System (INIS)

Jeong, S.-W.; Lee, H.J.; Kim, K.S.; You, M.T.; Roh, Y.; Noguchi, T.; Xianyu, W.; Jung, J.

2006-01-01

We have investigated the annealing effects of HfO 2 films deposited by an atomic layer deposition (ALD) method on the electrical and physical properties in the Si/SiO 2 /Pt/ALD-HfO 2 /Pd metal-insulator-metal (MIM) capacitors. If the annealing temperature for HfO 2 films was restricted below 500 deg. C, an annealing step using a rapid thermal processor (RTP) improves the electrical properties such as the dissipation factor and the dielectric constant. On the other hand, annealing at 700 deg. C degrades the electrical characteristics in general; the dissipation factor increases over the frequency range of 1∼4 MHz, and the leakage current increases up to 2 orders at the low electric field regions. We found that the degradation of electrical properties is due to the grain growth in the HfO 2 film (i.e., poly-crystallization of the film) by the high temperature annealing processing. We suggested that the annealing temperature must be restricted below 500 deg. C to obtain the high quality high-k film for the MIM capacitors

Neurodegenerative diseases of the central motor system in MRI

International Nuclear Information System (INIS)

Alfke, K.

2005-01-01

Neurodegenerative diseases of the central motor system often lead to discrete but functionally important parenchymal abnormalities in various parts of the brain. MRI is the most sensitive imaging method to detect these abnormalities. Various neurodegenerative diseases are presented with their clinical symptoms and MRI findings. Criteria for differential diagnosis are provided as well. (orig.)

A new concept for spatially divided Deep Reactive Ion Etching with ALD-based passivation

International Nuclear Information System (INIS)

Roozeboom, F; Kniknie, B; Lankhorst, A M; Winands, G; Knaapen, R; Smets, M; Poodt, P; Dingemans, G; Keuning, W; Kessels, W M M

2012-01-01

Conventional Deep Reactive Ion Etching (DRIE) is a plasma etch process with alternating half-cycles of 1) Si-etching with SF 6 to form gaseous SiF x etch products, and 2) passivation with C 4 F 8 that polymerizes as a protecting fluorocarbon deposit on the sidewalls and bottom of the etched features. In this work we report on a novel alternative and disruptive technology concept of Spatially-divided Deep Reactive Ion Etching, S-DRIE, where the process is converted from the time-divided into the spatially divided regime. The spatial division can be accomplished by inert gas bearing 'curtains' of heights down to ∼20 μm. These curtains confine the reactive gases to individual (often linear) injection slots constructed in a gas injector head. By horizontally moving the substrate back and forth under the head one can realize the alternate exposures to the overall cycle. A second improvement in the spatially divided approach is the replacement of the CVD-based C 4 F 8 passivation steps by ALD-based oxide (e.g. SiO 2 ) deposition cycles. The method can have industrial potential in cost-effective creation of advanced 3D interconnects (TSVs), MEMS manufacturing and advanced patterning, e.g., in nanoscale transistor line edge roughness using Atomic Layer Etching.

Infectivity versus Seeding in Neurodegenerative Diseases Sharing a Prion-Like Mechanism

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Natalia Fernández-Borges

2013-01-01

Full Text Available Prions are considered the best example to prove that the biological information can be transferred protein to protein through a conformational change. The term “prion-like” is used to describe molecular mechanisms that share similarities with the mammalian prion protein self-perpetuating aggregation and spreading characteristics. Since prions are presumably composed only of protein and are infectious, the more similar the mechanisms that occur in the different neurodegenerative diseases, the more these processes will resemble an infection. In vitro and in vivo experiments carried out during the last decade in different neurodegenerative disorders such as Alzheimer's disease (AD, Parkinson's diseases (PD, and amyotrophic lateral sclerosis (ALS have shown a convergence toward a unique mechanism of misfolded protein propagation. In spite of the term “infection” that could be used to explain the mechanism governing the diversity of the pathological processes, other concepts as “seeding” or “de novo induction” are being used to describe the in vivo propagation and transmissibility of misfolded proteins. The current studies are demanding an extended definition of “disease-causing agents” to include those already accepted as well as other misfolded proteins. In this new scenario, “seeding” would be a type of mechanism by which an infectious agent can be transmitted but should not be used to define a whole “infection” process.

Oxidative stress treatment for clinical trials in neurodegenerative diseases.

Science.gov (United States)

Ienco, Elena Caldarazzo; LoGerfo, Annalisa; Carlesi, Cecilia; Orsucci, Daniele; Ricci, Giulia; Mancuso, Michelangelo; Siciliano, Gabriele

2011-01-01

Oxidative stress is a metabolic condition arising from imbalance between the production of potentially reactive oxygen species and the scavenging activities. Mitochondria are the main providers but also the main scavengers of cell oxidative stress. The role of mitochondrial dysfunction and oxidative stress in the pathogenesis of neurodegenerative diseases is well documented. Therefore, therapeutic approaches targeting mitochondrial dysfunction and oxidative damage hold great promise in neurodegenerative diseases. Despite this evidence, human experience with antioxidant neuroprotectants has generally been negative with regards to the clinical progress of disease, with unclear results in biochemical assays. Here we review the antioxidant approaches performed so far in neurodegenerative diseases and the future challenges in modern medicine.

ALD-Developed Plasmonic Two-Dimensional Au-WO3-TiO2 Heterojunction Architectonics for Design of Photovoltaic Devices.

Science.gov (United States)

Karbalaei Akbari, Mohammad; Hai, Zhenyin; Wei, Zihan; Detavernier, Christophe; Solano, Eduardo; Verpoort, Francis; Zhuiykov, Serge

2018-03-28

Electrically responsive plasmonic devices, which benefit from the privilege of surface plasmon excited hot carries, have supported fascinating applications in the visible-light-assisted technologies. The properties of plasmonic devices can be tuned by controlling charge transfer. It can be attained by intentional architecturing of the metal-semiconductor (MS) interfaces. In this study, the wafer-scaled fabrication of two-dimensional (2D) TiO 2 semiconductors on the granular Au metal substrate is achieved using the atomic layer deposition (ALD) technique. The ALD-developed 2D MS heterojunctions exhibited substantial enhancement of the photoresponsivity and demonstrated the improvement of response time for 2D Au-TiO 2 -based plasmonic devices under visible light illumination. To circumvent the undesired dark current in the plasmonic devices, a 2D WO 3 nanofilm (∼0.7 nm) was employed as the intermediate layer on the MS interface to develop the metal-insulator-semiconductor (MIS) 2D heterostructure. As a result, 13.4% improvement of the external quantum efficiency was obtained for fabricated 2D Au-WO 3 -TiO 2 heterojunctions. The impedancometry measurements confirmed the modulation of charge transfer at the 2D MS interface using MIS architectonics. Broadband photoresponsivity from the UV to the visible light region was observed for Au-TiO 2 and Au-WO 3 -TiO 2 heterostructures, whereas near-infrared responsivity was not observed. Consequently, considering the versatile nature of the ALD technique, this approach can facilitate the architecturing and design of novel 2D MS and MIS heterojunctions for efficient plasmonic devices.

Growth Kinetics and Oxidation Mechanism of ALD TiN Thin Films Monitored by In Situ Spectroscopic Ellipsometry

NARCIS (Netherlands)

Van Hao, B.; Groenland, A.W.; Aarnink, Antonius A.I.; Wolters, Robertus A.M.; Schmitz, Jurriaan; Kovalgin, Alexeij Y.

2011-01-01

Spectroscopic ellipsometry (SE) was employed to investigate the growth of atomic layer deposited (ALD) TiN thin films from titanium chloride (TiCl4) and ammonia (NH3) and the followed oxidation in dry oxygen. Two regimes were found in the growth including a transient stage prior to a linear regime.

Interface Energy Alignment of Atomic-Layer-Deposited VOx on Pentacene: an in Situ Photoelectron Spectroscopy Investigation.

Science.gov (United States)

Zhao, Ran; Gao, Yuanhong; Guo, Zheng; Su, Yantao; Wang, Xinwei

2017-01-18

Ultrathin atomic-layer-deposited (ALD) vanadium oxide (VO x ) interlayer has recently been demonstrated for remarkably reducing the contact resistance in organic electronic devices (Adv. Funct. Mater. 2016, 26, 4456). Herein, we present an in situ photoelectron spectroscopy investigation (including X-ray and ultraviolet photoelectron spectroscopies) of ALD VO x grown on pentacene to understand the role of the ALD VO x interlayer for the improved contact resistance. The in situ photoelectron spectroscopy characterizations allow us to monitor the ALD growth process of VO x and trace the evolutions of the work function, pentacene HOMO level, and VO x defect states during the growth. The initial VO x growth is found to be partially delayed on pentacene in the first ∼20 ALD cycles. The underneath pentacene layer is largely intact after ALD. The ALD VO x is found to contain a high density of defect states starting from 0.67 eV below the Fermi level, and the energy level of these defect states is in excellent alignment with the HOMO level of pentacene, which therefore allows these VO x defect states to provide an efficient hole-injection pathway at the contact interface.

Targeting Specific HATs for Neurodegenerative Disease Treatment: Translating Basic Biology to Therapeutic Possibilities

Directory of Open Access Journals (Sweden)

Sheila K. Pirooznia

2013-03-01

Full Text Available Dynamic epigenetic regulation of neurons is emerging as a fundamental mechanism by which neurons adapt their transcriptional responses to specific developmental and environmental cues. While defects within the neural epigenome have traditionally been studied in the context of early developmental and heritable cognitive disorders, recent studies point to aberrant histone acetylation status as a key mechanism underlying acquired inappropriate alterations of genome structure and function in post-mitotic neurons during the aging process. Indeed, it is becoming increasingly evident that chromatin acetylation status can be impaired during the lifetime of neurons through mechanisms related to loss of function of histone acetyltransferase (HATs activity. Several HATs have been shown to participate in vital neuronal functions such as regulation of neuronal plasticity and memory formation. As such, dysregulation of such HATs has been implicated in the pathogenesis associated with age-associated neurodegenerative diseases and cognitive decline. In order to counteract the loss of HAT function in neurodegenerative diseases, the current therapeutic strategies involve the use of small molecules called histone deacetylase (HDAC inhibitors that antagonize HDAC activity and thus enhance acetylation levels. Although this strategy has displayed promising therapeutic effects, currently used HDAC inhibitors lack target specificity, raising concerns about their applicability. With rapidly evolving literature on HATs and their respective functions in mediating neuronal survival and higher order brain function such as learning and memory, modulating the function of specific HATs holds new promises as a therapeutic tool in neurodegenerative diseases. In this review, we focus on the recent progress in research regarding epigenetic histone acetylation mechanisms underlying neuronal activity and cognitive function. We discuss the current understanding of specific HDACs and

Synopsis on Managment Strategies for Neurodegenerative Disorders: Challenges from Bench to Bedside in Successful Drug Discovery and Development.

Science.gov (United States)

Bhat, Sheraz Ahmad; Kamal, Mohammad Amjad; Yarla, Nagendra Sastry; Ashraf, Ghulam Md

2017-01-01

The maintenance of health requires successful cell functioning, which in turn depends upon the proper and active conformation of proteins besides other biomolecules. However, occasionally these proteins may misfold and lead to the appearance and progression of protein conformational diseases. These diseases apart from others include several neurodegenerative disorders (NDDs) such as Alzheimer's disease, Parkinson disease, Huntington's disease, multiple sclerosis, amyotrophic lateral sclerosis, and other lesser known diseases. Although much knowledge has been gained, these NDDs still warrant advance research in the elucidation of their mechanisms as well as effective therapeutic interventions and proper management. There is an ever-growing and urgent need to improve the diagnosis and management of NDDs due to their devastating nature, serious social impact and neuropsychiatric symptoms. It is also envisioned that we may be able to encourage, develop, and strengthen the cell defenses against amyloid toxicity and prevent neuronal destruction and consequently neurodegeneration. In this review, the implications of protein misfolding and aggregation in NDDs are discussed along with some of the most recent findings on the curative and beneficial effects of natural molecules such as polyphenols. This paper also reviews the anti-aggregation and protective effects of some organic and peptidic compounds duly supported experimentally, as prospective future therapeutics for NDDs. The synopses presented in this review shall prove helpful in further understanding of the causes, cures and management of lethal NDDs. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Fragile X syndrome and fragile X-associated disorders [version 1; referees: 2 approved

Directory of Open Access Journals (Sweden)

Akash Rajaratnam

2017-12-01

Full Text Available Fragile X syndrome (FXS is caused by a full mutation on the FMR1 gene and a subsequent lack of FMRP, the protein product of FMR1. FMRP plays a key role in regulating the translation of many proteins involved in maintaining neuronal synaptic connections; its deficiency may result in a range of intellectual disabilities, social deficits, psychiatric problems, and dysmorphic physical features. A range of clinical involvement is also associated with the FMR1 premutation, including fragile X-associated tremor ataxia syndrome, fragile X-associated primary ovarian insufficiency, psychiatric problems, hypertension, migraines, and autoimmune problems. Over the past few years, there have been a number of advances in our knowledge of FXS and fragile X-associated disorders, and each of these advances offers significant clinical implications. Among these developments are a better understanding of the clinical impact of the phenomenon known as mosaicism, the revelation that various types of mutations can cause FXS, and improvements in treatment for FXS.

Low temperature formation of higher-k cubic phase HfO{sub 2} by atomic layer deposition on GeO{sub x}/Ge structures fabricated by in-situ thermal oxidation

Energy Technology Data Exchange (ETDEWEB)

Zhang, R., E-mail: zhang@mosfet.t.u-tokyo.ac.jp [School of Engineering, The University of Tokyo, 2-11-16 Yayoi, Bunkyo-ku, Tokyo 113-8656 (Japan); Department of Information Science and Electronic Engineering, Zhejiang University, 38 Zheda Road, Hangzhou 310027 (China); Huang, P.-C.; Taoka, N.; Yokoyama, M.; Takenaka, M.; Takagi, S. [School of Engineering, The University of Tokyo, 2-11-16 Yayoi, Bunkyo-ku, Tokyo 113-8656 (Japan)

2016-02-01

We have demonstrated a low temperature formation (300 °C) of higher-k HfO{sub 2} using atomic layer deposition (ALD) on an in-situ thermal oxidation GeO{sub x} interfacial layer. It is found that the cubic phase is dominant in the HfO{sub 2} film with an epitaxial-like growth behavior. The maximum permittivity of 42 is obtained for an ALD HfO{sub 2} film on a 1-nm-thick GeO{sub x} form by the in-situ thermal oxidation. It is suggested from physical analyses that the crystallization of cubic phase HfO{sub 2} can be induced by the formation of six-fold crystalline GeO{sub x} structures in the underlying GeO{sub x} interfacial layer.

Amyloid PET in neurodegenerative diseases with dementia.

Science.gov (United States)

Camacho, V; Gómez-Grande, A; Sopena, P; García-Solís, D; Gómez Río, M; Lorenzo, C; Rubí, S; Arbizu, J

2018-05-15

Alzheimer's disease (AD) is a neurodegenerative condition characterized by progressive cognitive decline and memory loss, and is the most common form of dementia. Amyloid plaques with neurofibrillary tangles are a neuropathological hallmark of AD that produces synaptic dysfunction and culminates later in neuronal loss. Amyloid PET is a useful, available and non-invasive technique that provides in vivo information about the cortical amyloid burden. In the latest revised criteria for the diagnosis of AD biomarkers were defined and integrated: pathological and diagnostic biomarkers (increased retention on fibrillar amyloid PET or decreased Aβ 1-42 and increased T-Tau or P-Tau in CSF) and neurodegeneration or topographical biomarkers (temporoparietal hypometabolism on 18 F-FDG PET and temporal atrophy on MRI). Recently specific recommendations have been created as a consensus statement on the appropriate use of the imaging biomarkers, including amyloid PET: early-onset cognitive impairment/dementia, atypical forms of AD, mild cognitive impairment with early age of onset, and to differentiate between AD and other neurodegenerative diseases that occur with dementia. Amyloid PET is also contributing to the development of new therapies for AD, as well as in research studies for the study of other neurodegenerative diseases that occur with dementia where the deposition of Aβ amyloid is involved in its pathogenesis. In this paper, we review some general concepts and study the use of amyloid PET in depth and its relationship with neurodegenerative diseases and other diagnostic techniques. Copyright © 2018 Sociedad Española de Medicina Nuclear e Imagen Molecular. Publicado por Elsevier España, S.L.U. All rights reserved.

Potential contribution of the neurodegenerative disorders risk loci to cognitive performance in an elderly male gout population

Science.gov (United States)

Han, Lin; Jia, Zhaotong; Cao, Chunwei; Liu, Zhen; Liu, Fuqiang; Wang, Lin; Ren, Wei; Sun, Mingxia; Wang, Baoping; Li, Changgui; Chen, Li

2017-01-01

Abstract Cognitive impairment has been described in elderly subjects with high normal concentrations of serum uric acid. However, it remains unclear if gout confers an increased poorer cognition than those in individuals with asymptomatic hyperuricemia. The present study aimed at evaluating cognitive function in patients suffering from gout in an elderly male population, and further investigating the genetic contributions to the risk of cognitive function. This study examined the cognitive function as assessed by Mini-Mental State Examination (MMSE) and the Montreal Cognitive Assessment (MoCA) in 205 male gout patients and 204 controls. The genetic basis of these cognitive measures was evaluated by genome-wide association study (GWAS) data in 102 male gout patients. Furthermore, 7 loci associated with cognition in GWAS were studied for correlation with gout in 1179 male gout patients and 1848 healthy male controls. Compared with controls, gout patients had significantly lower MoCA scores [22.78 ± 3.01 vs 23.42 ± 2.95, P = .023, adjusted by age, body mass index (BMI), education, and emotional disorder]. GWAS revealed 7 single-nucleotide polymorphisms (SNPs) associations with MoCA test at a level of conventional genome-wide significance (P gene (Padjusted = 4.2 × 10−9, Padjusted = 4.7 × 10–9) at 14q22. The next best signal was in RELN gene (rs155333, Padjusted = 1.3 × 10–8) at 7q22, while the other variants at rs17458357 (Padjusted = 3.98 × 10–8), rs2572683 (Padjusted = 8.9 × 10–8), rs12555895 (Padjusted = 2.6 × 10–8), and rs3764030 (Padjusted = 9.4 × 10–8) were also statistically significant. The 7 SNPs were not associated with gout in further analysis (all P > .05). Elderly male subjects with gout exhibit accelerated decline in cognition performance. Several neurodegenerative disorders risk loci were identified for genetic contributors to cognitive performance in our

Affective disorders in neurological diseases

DEFF Research Database (Denmark)

Nilsson, F M; Kessing, L V; Sørensen, T M

2003-01-01

OBJECTIVE: To investigate the temporal relationships between a range of neurological diseases and affective disorders. METHOD: Data derived from linkage of the Danish Psychiatric Central Register and the Danish National Hospital Register. Seven cohorts with neurological index diagnoses and two...... of affective disorder was lower than the incidence in the control groups. CONCLUSION: In neurological diseases there seems to be an increased incidence of affective disorders. The elevated incidence was found to be particularly high for dementia and Parkinson's disease (neurodegenerative diseases)....

Skin disorders in Parkinson's disease

DEFF Research Database (Denmark)

Ravn, Astrid-Helene; Thyssen, Jacob P; Egeberg, Alexander

2017-01-01

Parkinson's disease (PD) is one of the most common neurodegenerative disorders, characterized by a symptom triad comprising resting tremor, rigidity, and akinesia. In addition, non-motor symptoms of PD are well recognized and often precede the overt motor manifestations. Cutaneous manifestations...

The causative role and therapeutic potential of the kynurenine pathway in neurodegenerative disease.

Science.gov (United States)

Amaral, Marta; Outeiro, Tiago F; Scrutton, Nigel S; Giorgini, Flaviano

2013-06-01

Metabolites of the kynurenine pathway (KP), which arise from the degradation of tryptophan, have been studied in detail for over a century and garnered the interest of the neuroscience community in the late 1970s and early 1980s with work uncovering the neuromodulatory potential of this pathway. Much research in the following decades has found that perturbations in the levels of KP metabolites likely contribute to the pathogenesis of several neurodegenerative diseases. More recently, it has become apparent that targeting KP enzymes, in particular kynurenine 3-monooxygenase (KMO), may hold substantial therapeutic potential for these disorders. Here we provide an overview of the KP, the neuroactive properties of KP metabolites and their role in neurodegeneration. We also discuss KMO as a therapeutic target for these disorders, and our recent resolution of the crystallographic structure of KMO, which will permit the development of new and improved KMO inhibitors which may ultimately expedite clinical application of these compounds.

THE MITOCHONDRIAL DERANGEMENTS IN NEURONAL DEGENER ATION AND NEURODEGENERATIVE DISEASES

Institute of Scientific and Technical Information of China (English)

Xue, Qi-ming; Gao, Feng; Chen, Qin-tang

2000-01-01

@@There are diverse concepts on the pathogenesis of neuronal degeneration and the neurodegenerative diseases. Among them there are different factors which might influence the initiation of neuronal degeneration as well as the pathogenesis of neurodegenerative diseases, such as Alzheimer′s disease, Parkinson′s disease, motor neuron disease, and so on.

Ion irradiation induced order-to-disorder transformations in δ-phase Sc4-xZr3+xO12+x/2

International Nuclear Information System (INIS)

Zhang, J.; Wang, Y.Q.; Tang, M.; Valdez, J.A.; Sickafus, K.E.

2010-01-01

The purpose of this study is to investigate the role of stoichiometry on crystal structure transformations in derivative fluorite compounds known as delta (δ) phase. In this study, polycrystalline δ-phase ceramic pellets were prepared with stoichiometries given by Sc 4-x Zr 3+x O 12+x/2 (x = 0, 0.77 and 1.20) . The pressed and polished pellets were then irradiated under cryogenic conditions with 200 keV Ne + ions to fluences ranging from 1-5 x 10 14 Ne/cm 2 . An order-to-disorder (O-D) transformation was observed for all compositions, as determined using grazing incidence X-ray diffraction (GIXRD). However, the transformation threshold dose was found to systematically decrease with increasing ZrO 2 content: ∼0.2, ∼0.16, and ∼0.08 dpa for Sc 4-x Zr 3+x O 12+x/2 with x = 0, 0.77, and 1.20, respectively. These irradiation-induced phase transformation results are discussed in terms of the crystal structure of the δ-phase.

A Three-Step Atomic Layer Deposition Process for SiN x Using Si2Cl6, CH3NH2, and N2 Plasma.

Science.gov (United States)

Ovanesyan, Rafaiel A; Hausmann, Dennis M; Agarwal, Sumit

2018-06-06

We report a novel three-step SiN x atomic layer deposition (ALD) process using Si 2 Cl 6 , CH 3 NH 2 , and N 2 plasma. In a two-step process, nonhydrogenated chlorosilanes such as Si 2 Cl 6 with N 2 plasmas lead to poor-quality SiN x films that oxidize rapidly. The intermediate CH 3 NH 2 step was therefore introduced in the ALD cycle to replace the NH 3 plasma step with a N 2 plasma, while using Si 2 Cl 6 as the Si precursor. This three-step process lowers the atomic H content and improves the film conformality on high-aspect-ratio nanostructures as Si-N-Si bonds are formed during a thermal CH 3 NH 2 step in addition to the N 2 plasma step. During ALD, the reactive surface sites were monitored using in situ surface infrared spectroscopy. Our infrared spectra show that, on the post-N 2 plasma-treated SiN x surface, Si 2 Cl 6 reacts primarily with the surface -NH 2 species to form surface -SiCl x ( x = 1, 2, or 3) bonds, which are the reactive sites during the CH 3 NH 2 cycle. In the N 2 plasma step, reactive -NH 2 surface species are created because of the surface H available from the -CH 3 groups. At 400 °C, the SiN x films have a growth per cycle of ∼0.9 Å with ∼12 atomic percent H. The films grown on high-aspect-ratio nanostructures have a conformality of ∼90%.

Conceptualizing neurodevelopmental disorders through a mechanistic understanding of fragile X syndrome and Williams syndrome.

Science.gov (United States)

Fung, Lawrence K; Quintin, Eve-Marie; Haas, Brian W; Reiss, Allan L

2012-04-01

The overarching goal of this review is to compare and contrast the cognitive-behavioral features of fragile X syndrome (FraX) and Williams syndrome and to review the putative neural and molecular underpinnings of these features. Information is presented in a framework that provides guiding principles for conceptualizing gene-brain-behavior associations in neurodevelopmental disorders. Abnormalities, in particular cognitive-behavioral domains with similarities in underlying neurodevelopmental correlates, occur in both FraX and Williams syndrome including aberrant frontostriatal pathways leading to executive function deficits, and magnocellular/dorsal visual stream, superior parietal lobe, inferior parietal lobe, and postcentral gyrus abnormalities contributing to deficits in visuospatial function. Compelling cognitive-behavioral and neurodevelopmental contrasts also exist in these two disorders, for example, aberrant amygdala and fusiform cortex structure and function occurring in the context of contrasting social behavioral phenotypes, and temporal cortical and cerebellar abnormalities potentially underlying differences in language function. Abnormal dendritic development is a shared neurodevelopmental morphologic feature between FraX and Williams syndrome. Commonalities in molecular machinery and processes across FraX and Williams syndrome occur as well - microRNAs involved in translational regulation of major synaptic proteins; scaffolding proteins in excitatory synapses; and proteins involved in axonal development. Although the genetic variations leading to FraX and Williams syndrome are different, important similarities and contrasts in the phenotype, neurocircuitry, molecular machinery, and cellular processes in these two disorders allow for a unique approach to conceptualizing gene-brain-behavior links occurring in neurodevelopmental disorders.

Developmental Vulnerability of Synapses and Circuits Associated with Neuropsychiatric Disorders

OpenAIRE

Penzes, Peter; Buonanno, Andres; Passafarro, Maria; Sala, Carlo; Sweet, Robert A.

2013-01-01

Psychiatric and neurodegenerative disorders, including intellectual disability (ID), autism spectrum disorders (ASD), schizophrenia (SZ), and Alzheimer's disease (AD), pose an immense burden to society. Symptoms of these disorders become manifest at different stages of life: early childhood, adolescence, and late adulthood, respectively. Progress has been made in recent years toward understanding the genetic substrates, cellular mechanisms, brain circuits, and endophenotypes of these disorder...

Cellular and Molecular Aspects of the β-N-Methylamino-l-alanine (BMAA Mode of Action within the Neurodegenerative Pathway: Facts and Controversy

Directory of Open Access Journals (Sweden)

Nicolas Delcourt

2017-12-01

Full Text Available The implication of the cyanotoxin β-N-methylamino-l-alanine (BMAA in long-lasting neurodegenerative disorders is still a matter of controversy. It has been alleged that chronic ingestion of BMAA through the food chain could be a causative agent of amyotrophic lateral sclerosis (ALS and several related pathologies including Parkinson syndrome. Both in vitro and in vivo studies of the BMAA mode of action have focused on different molecular targets, demonstrating its toxicity to neuronal cells, especially motoneurons, and linking it to human neurodegenerative diseases. Historically, the hypothesis of BMAA-induced excitotoxicity following the stimulation of glutamate receptors has been established. However, in this paradigm, most studies have shown acute, rather than chronic effects of BMAA. More recently, the interaction of this toxin with neuromelanin, a pigment present in the nervous system, has opened a new research perspective. The issues raised by this toxin are related to its kinetics of action, and its possible incorporation into cellular proteins. It appears that BMAA neurotoxic activity involves different targets through several mechanisms known to favour the development of neurodegenerative processes.

Flavonoid-Based Therapies in the Early Management of Neurodegenerative Diseases12

Science.gov (United States)

Solanki, Isha; Parihar, Priyanka; Mansuri, Mohammad Lukman; Parihar, Mordhwaj S

2015-01-01

During the past several years, there has been enormous progress in the understanding of the causative factors that initiate neuronal damage in various neurodegenerative diseases, including Alzheimer disease, Parkinson disease, multiple sclerosis, amyotrophic lateral sclerosis, and Huntington disease. Preventing neuronal damage and neuronal death will have a huge clinical benefit. However, despite major advances in causative factors that trigger these neurodegenerative diseases, to date there have been no therapies available that benefit patients who suffer from these diseases. Because most neurodegenerative diseases are late-onset and remain asymptomatic for most of the phases, the therapies initiated in advanced stages of the disease have limited value to patients. It may be possible to prevent or halt the disease progression to a great extent if therapies start at the initial stage of the disease. Such therapies may restore neuronal function by reducing or even eliminating the primary stressor. Flavonoids are key compounds for the development of a new generation of therapeutic agents that are clinically effective in treating neurodegenerative diseases. Regular consumption of flavonoids has been associated with a reduced risk of neurodegenerative diseases. In addition to their antioxidant properties, these polyphenolic compounds exhibit neuroprotective properties by their interaction with cellular signaling pathways followed by transcription and translation that mediate cell function under both normal and pathologic conditions. This review focuses on human intervention studies as well as animal studies on the role of various flavonoids in the prevention of neurodegenerative diseases. PMID:25593144

Influence of annealing temperature on the structural, optical and mechanical properties of ALD-derived ZnO thin films

International Nuclear Information System (INIS)

Yen, C.-Y.; Jian, S.-R.; Chen, G.-J.; Lin, C.-M.; Lee, H.-Y.; Ke, W.-C.; Liao, Y.-Y.; Yang, P.-F.; Wang, C.-T.; Lai, Y.-S.; Jang, Jason S.-C.; Juang, J.-Y.

2011-01-01

ZnO thin films grown on Si(1 1 1) substrates by using atomic layer deposition (ALD) were annealed at the temperatures ranging from 300 to 500 deg. C. The X-ray diffraction (XRD) results show that the annealed ZnO thin films are highly (0 0 2)-oriented, indicating a well ordered microstructure. The film surface examined by the atomic force microscopy (AFM), however, indicated that the roughness increases with increasing annealing temperature. The photoluminescence (PL) spectrum showed that the intensity of UV emission was strongest for films annealed at 500 deg. C. The mechanical properties of the resultant ZnO thin films investigated by nanoindentation reveal that the hardness decreases from 9.2 GPa to 7.2 GPa for films annealed at 300 deg. C and 500 deg. C, respectively. On the other hand, the Young's modulus for the former is 168.6 GPa as compared to a value of 139.5 GPa for the latter. Moreover, the relationship between the hardness and film grain size appear to follow closely with the Hall-Petch equation.

Degradation of misfolded proteins in neurodegenerative diseases: therapeutic targets and strategies.

Science.gov (United States)

Ciechanover, Aaron; Kwon, Yong Tae

2015-03-13

Mammalian cells remove misfolded proteins using various proteolytic systems, including the ubiquitin (Ub)-proteasome system (UPS), chaperone mediated autophagy (CMA) and macroautophagy. The majority of misfolded proteins are degraded by the UPS, in which Ub-conjugated substrates are deubiquitinated, unfolded and cleaved into small peptides when passing through the narrow chamber of the proteasome. The substrates that expose a specific degradation signal, the KFERQ sequence motif, can be delivered to and degraded in lysosomes via the CMA. Aggregation-prone substrates resistant to both the UPS and the CMA can be degraded by macroautophagy, in which cargoes are segregated into autophagosomes before degradation by lysosomal hydrolases. Although most misfolded and aggregated proteins in the human proteome can be degraded by cellular protein quality control, some native and mutant proteins prone to aggregation into β-sheet-enriched oligomers are resistant to all known proteolytic pathways and can thus grow into inclusion bodies or extracellular plaques. The accumulation of protease-resistant misfolded and aggregated proteins is a common mechanism underlying protein misfolding disorders, including neurodegenerative diseases such as Huntington's disease (HD), Alzheimer's disease (AD), Parkinson's disease (PD), prion diseases and Amyotrophic Lateral Sclerosis (ALS). In this review, we provide an overview of the proteolytic pathways in neurons, with an emphasis on the UPS, CMA and macroautophagy, and discuss the role of protein quality control in the degradation of pathogenic proteins in neurodegenerative diseases. Additionally, we examine existing putative therapeutic strategies to efficiently remove cytotoxic proteins from degenerating neurons.

Neurodegenerative disease mutations in TREM2 reveal a functional surface and distinct loss-of-function mechanisms

Energy Technology Data Exchange (ETDEWEB)

Kober, Daniel L.; Alexander-Brett, Jennifer M.; Karch, Celeste M.; Cruchaga, Carlos; Colonna, Marco; Holtzman, Michael J.; Brett, Thomas J. (WU-MED)

2016-12-20

Genetic variations in the myeloid immune receptor TREM2 are linked to several neurodegenerative diseases. To determine how TREM2 variants contribute to these diseases, we performed structural and functional studies of wild-type and variant proteins. Our 3.1 Å TREM2 crystal structure revealed that mutations found in Nasu-Hakola disease are buried whereas Alzheimer’s disease risk variants are found on the surface, suggesting that these mutations have distinct effects on TREM2 function. Biophysical and cellular methods indicate that Nasu-Hakola mutations impact protein stability and decrease folded TREM2 surface expression, whereas Alzheimer’s risk variants impact binding to a TREM2 ligand. Additionally, the Alzheimer’s risk variants appear to epitope map a functional surface on TREM2 that is unique within the larger TREM family. These findings provide a guide to structural and functional differences among genetic variants of TREM2, indicating that therapies targeting the TREM2 pathway should be tailored to these genetic and functional differences with patient-specific medicine approaches for neurodegenerative disorders.

Mechanisms of action of brain insulin against neurodegenerative diseases.

Science.gov (United States)

Ramalingam, Mahesh; Kim, Sung-Jin

2014-06-01

Insulin, a pancreatic hormone, is best known for its peripheral effects on the metabolism of glucose, fats and proteins. There is a growing body of evidence linking insulin action in the brain to neurodegenerative diseases. Insulin present in central nervous system is a regulator of central glucose metabolism nevertheless this glucoregulation is not the main function of insulin in the brain. Brain is known to be specifically vulnerable to oxidative products relative to other organs and altered brain insulin signaling may cause or promote neurodegenerative diseases which invalidates and reduces the quality of life. Insulin located within the brain is mostly of pancreatic origin or is produced in the brain itself crosses the blood-brain barrier and enters the brain via a receptor-mediated active transport system. Brain Insulin, insulin receptor and insulin receptor substrate-mediated signaling pathways play important roles in the regulation of peripheral metabolism, feeding behavior, memory and maintenance of neural functions such as neuronal growth and differentiation, neuromodulation and neuroprotection. In the present review, we would like to summarize the novel biological and pathophysiological roles of neuronal insulin in neurodegenerative diseases and describe the main signaling pathways in use for therapeutic strategies in the use of insulin to the cerebral tissues and their biological applications to neurodegenerative diseases.

Computed tomography of neurodegenerative disease in childhood

International Nuclear Information System (INIS)

Kataoka, Kenkichi; Nakagawa, Yoshihiro; Hojo, Hiroatsu

1984-01-01

Serial computed tomographic scans were performed on seven children with neurodegenerative disorders. In two cases of white-matter diseases (Krabbe's disease and metachromatic leukodystrophy), diffuse, low-density lesions of white matter were visible in the early stage of the diseases. In one case of adrenoleukodystrophy, regional low-density lesions of the white matter around the posterior horns and peculiar high-density strip lesions were visible in the early stage. In two cases of storage-type gray-matter diseases (Tay-Sachs' and infantile Gaucher's disease), there were no abnormalities in the early stage, but diffuse cortical atrophies in the late stage. In one case of Leigh's disease, there were small, low-density lesions of the basal ganglia and multiple low-density lesions of the gray matter in the early stage. In one case of subacute sclerosing panencephalitis, there were no abnormalities in the early stage, but small, low-density lesions of the basal ganglia and diffuse cerebral atrophies in the late stage. Diagnostic values were recognized dominantly in two cases of adrenoleukodystrophy and Leigh's disease. In the other cases, however, serial CT scans were useful in the diagnostic process. (author)

X-ray scattering of calcite thin films deposited by atomic layer deposition: Studies in air and in calcite saturated water solution

Energy Technology Data Exchange (ETDEWEB)

Wang, Peng [Lujan Neutron Scattering Center, Los Alamos National Laboratory, P.O. Box 1663, Los Alamos, NM 87545 (United States); Hudak, Michael R.; Lerner, Allan [Earth and Environmental Sciences Division, Los Alamos National Laboratory, P.O. Box 1663, Los Alamos, NM 87545 (United States); Grubbs, Robert K. [Sandia National Laboratories, P.O. Box 5800, Albuquerque, NM 87185 (United States); Wang, Shanmin [Lujan Neutron Scattering Center, Los Alamos National Laboratory, P.O. Box 1663, Los Alamos, NM 87545 (United States); Zhang, Zhan; Karapetrova, Evguenia [Advance Photon Source, Argonne National Laboratory, 9700S Cass Ave, Argonne, IL 60439 (United States); Hickmott, Donald [Earth and Environmental Sciences Division, Los Alamos National Laboratory, P.O. Box 1663, Los Alamos, NM 87545 (United States); Majewski, Jaroslaw, E-mail: jarek@lanl.gov [Lujan Neutron Scattering Center, Los Alamos National Laboratory, P.O. Box 1663, Los Alamos, NM 87545 (United States)

2014-08-28

Carbonates are one of the most abundant groups of minerals in earth systems and are important in many geological settings and industrial processes. Calcite (CaCO{sub 3}) thin films produced by atomic layer deposition offer a method to evaluate the surficial properties of carbonates as well as interactions at the carbonate–fluid interface. Using synchrotron X-ray reflectivity and X-ray diffraction, these films are observed to be porous, polycrystalline, and have crystallites oriented with the major (104) calcite cleavage plane parallel to the surface of the z-cut single crystal quartz substrate. An Al{sub 2}O{sub 3} buffer layer, present between quartz and the calcite film, does not affect the as-deposited film, but does influence how the films reorganize in contact with fluid. Without a buffer layer, calcite reorients its crystallites to have populations of (006) and (030) parallel to the substrate, while those with an Al{sub 2}O{sub 3} buffer layer become more amorphous. Amorphous films may represent an analog to amorphous calcium carbonate and provide insights into that material's thermophysical behavior. Due to a higher percentage of pore spaces available for fluid infiltration, films deposited at higher temperature make the calcite thin films more susceptible to amorphization. These films are chemically similar, but structurally dissimilar to bulk natural calcite. Nevertheless, they can be a complementary system to traditional single crystal X-ray surface scattering studies on carbonates, particularly for important but less common minerals, to evaluate mineral–fluid interfacial interactions. - Highlights: • Atomic layer deposition (ALD) used to produce calcite films. • Calcite film orientation and crystallinity depend on ALD parameters. • ALD calcite films can be both crystalline and amorphous. • Interaction of water with films can re-orient or amorphize the films. • ALD calcite films may be useful to study carbonate–fluid interfacial

X-ray scattering of calcite thin films deposited by atomic layer deposition: Studies in air and in calcite saturated water solution

International Nuclear Information System (INIS)

Wang, Peng; Hudak, Michael R.; Lerner, Allan; Grubbs, Robert K.; Wang, Shanmin; Zhang, Zhan; Karapetrova, Evguenia; Hickmott, Donald; Majewski, Jaroslaw

2014-01-01

Carbonates are one of the most abundant groups of minerals in earth systems and are important in many geological settings and industrial processes. Calcite (CaCO 3 ) thin films produced by atomic layer deposition offer a method to evaluate the surficial properties of carbonates as well as interactions at the carbonate–fluid interface. Using synchrotron X-ray reflectivity and X-ray diffraction, these films are observed to be porous, polycrystalline, and have crystallites oriented with the major (104) calcite cleavage plane parallel to the surface of the z-cut single crystal quartz substrate. An Al 2 O 3 buffer layer, present between quartz and the calcite film, does not affect the as-deposited film, but does influence how the films reorganize in contact with fluid. Without a buffer layer, calcite reorients its crystallites to have populations of (006) and (030) parallel to the substrate, while those with an Al 2 O 3 buffer layer become more amorphous. Amorphous films may represent an analog to amorphous calcium carbonate and provide insights into that material's thermophysical behavior. Due to a higher percentage of pore spaces available for fluid infiltration, films deposited at higher temperature make the calcite thin films more susceptible to amorphization. These films are chemically similar, but structurally dissimilar to bulk natural calcite. Nevertheless, they can be a complementary system to traditional single crystal X-ray surface scattering studies on carbonates, particularly for important but less common minerals, to evaluate mineral–fluid interfacial interactions. - Highlights: • Atomic layer deposition (ALD) used to produce calcite films. • Calcite film orientation and crystallinity depend on ALD parameters. • ALD calcite films can be both crystalline and amorphous. • Interaction of water with films can re-orient or amorphize the films. • ALD calcite films may be useful to study carbonate–fluid interfacial interactions

The disordering phase transformation in (Ni/sub 70/Fe/sub 30/)/sub 3/(V/sub 98-x/Al/sub x/Ti/sub 2/) alloys with O ≤ x ≤ 80

International Nuclear Information System (INIS)

Das Gupta, A.; Horton, J.A.

1985-01-01

The sequence of disordering transformation processes in the A/sub 3/B type alloy series (Ni/sub 70/Fe/sub 30/)/sub 3/(V/sub 98-x/Al/sub x/Ti/sub 2/), currently under development for high-temperature structural applications, was studied by differential scanning calorimetry (DSC), x-ray diffraction, optical microscopy, and transmission electron microscopy (TEM). Results of DSC show that in all alloys there are two endothermic stages of phase transformation from the ordered to the disordered state. With increasing chi, the disordering transition temperature, T/sub c/, reaches a maximum --1000 0 C at chi ≅ 50 and then decreases. Interrupted heating, followed by water quenching, was used to characterize the crystal structure and the microstructure of the intermediate phases. For the x = 20 alloy, TEM observations showed ordered regions of DO/sub 22/ phase in a matrix of disordered fcc (Al) phase at intermediate temperatures. The ordered domains transformed morphologically into cuboid like regions at higher temperatures. From a combined study by all the techniques, the authors conclude that in alloy with x between 0 and 20, the sequence of phase transformations from heating is: DO/sub 2/ → DO/sub 22/ + Al → Al, whereas in alloys with x > 40, the major sequence is Ll/sub 2/ + B/sub 2/ → Ll/sub 2/ + Al → Al

Molecular Imaging and Precision Medicine in Dementia and Movement Disorders.

Science.gov (United States)

Mallik, Atul K; Drzezga, Alexander; Minoshima, Satoshi

2017-01-01

Precision medicine (PM) has been defined as "prevention and treatment strategies that take individual variability into account." Molecular imaging (MI) is an ideally suited tool for PM approaches to neurodegenerative dementia and movement disorders (MD). Here we review PM approaches and discuss how they may be applied to other associated neurodegenerative dementia and MD. With ongoing major therapeutic research initiatives that include the use of molecular imaging, we look forward to established interventions targeted to specific molecular pathophysiology and expect the potential benefit of MI PM approaches in neurodegenerative dementia and MD will only increase. Copyright © 2016 Elsevier Inc. All rights reserved.

Gas Diffusion Barriers Prepared by Spatial Atmospheric Pressure Plasma Enhanced ALD.

Science.gov (United States)

Hoffmann, Lukas; Theirich, Detlef; Pack, Sven; Kocak, Firat; Schlamm, Daniel; Hasselmann, Tim; Fahl, Henry; Räupke, André; Gargouri, Hassan; Riedl, Thomas

2017-02-01

In this work, we report on aluminum oxide (Al 2 O 3 ) gas permeation barriers prepared by spatial ALD (SALD) at atmospheric pressure. We compare the growth characteristics and layer properties using trimethylaluminum (TMA) in combination with an Ar/O 2 remote atmospheric pressure plasma for different substrate velocities and different temperatures. The resulting Al 2 O 3 films show ultralow water vapor transmission rates (WVTR) on the order of 10 -6 gm -2 d -1 . In notable contrast, plasma based layers already show good barrier properties at low deposition temperatures (75 °C), while water based processes require a growth temperature above 100 °C to achieve equally low WVTRs. The activation energy for the water permeation mechanism was determined to be 62 kJ/mol.

Atomic layer deposited nanocrystalline tungsten carbides thin films as a metal gate and diffusion barrier for Cu metallization

Energy Technology Data Exchange (ETDEWEB)

Kim, Jun Beom; Kim, Soo-Hyun, E-mail: soohyun@ynu.ac.kr [School of Materials Science and Engineering, Yeungnam University, Gyeongsan-si 712-749 (Korea, Republic of); Han, Won Seok [UP Chemical 576, Chilgoedong, Pyeongtaek-si, Gyeonggi-do 459-050 (Korea, Republic of); Lee, Do-Joong [School of Engineering, Brown University, Providence, Rhode Island 02912 (United States)

2016-07-15

Tungsten carbides (WC{sub x}) thin films were deposited on thermally grown SiO{sub 2} substrates by atomic layer deposition (ALD) using a fluorine- and nitrogen-free W metallorganic precursor, tungsten tris(3-hexyne) carbonyl [W(CO)(CH{sub 3}CH{sub 2}C ≡ CCH{sub 2}CH{sub 3}){sub 3}], and N{sub 2} + H{sub 2} plasma as the reactant at deposition temperatures between 150 and 350 °C. The present ALD-WC{sub x} system showed an ALD temperature window between 200 and 250 °C, where the growth rate was independent of the deposition temperature. Typical ALD characteristics, such as self-limited film growth and a linear dependency of the film grown on the number of ALD cycles, were observed, with a growth rate of 0.052 nm/cycle at a deposition temperature of 250 °C. The ALD-WC{sub x} films formed a nanocrystalline structure with grains, ∼2 nm in size, which consisted of hexagonal W{sub 2}C, WC, and nonstoichiometric cubic β-WC{sub 1−x} phase. Under typical deposition conditions at 250 °C, an ALD-WC{sub x} film with a resistivity of ∼510 μΩ cm was deposited and the resistivity of the ALD-WC{sub x} film could be reduced even further to ∼285 μΩ cm by further optimizing the reactant pulsing conditions, such as the plasma power. The step coverage of ALD-WC{sub x} film was ∼80% on very small sized and dual trenched structures (bottom width of 15 nm and aspect ratio of ∼6.3). From ultraviolet photoelectron spectroscopy, the work function of the ALD-WC{sub x} film was determined to be 4.63 eV. Finally, the ultrathin (∼5 nm) ALD-WC{sub x} film blocked the diffusion of Cu, even up to 600 °C, which makes it a promising a diffusion barrier material for Cu interconnects.

High-energy X-ray diffraction studies of disordered materials

International Nuclear Information System (INIS)

Kohara, Shinji; Suzuya, Kentaro

2003-01-01

With the arrival of the latest generation of synchrotron sources and the introduction of advanced insertion devices (wigglers and undulators), the high-energy (E≥50 keV) X-ray diffraction technique has become feasible, leading to new approaches in the quantitative study of the structure of disordered materials. High-energy X-ray diffraction has several advantages: higher resolution in real space due to a wide range of scattering vector Q, smaller correction terms (especially the absorption correction), reduction of truncation errors, the feasibility of running under extreme environments, including high-temperatures and high-pressures, and the ability to make direct comparisons between X-ray and neutron diffraction data. Recently, high-energy X-ray diffraction data have been combined with neutron diffraction data from a pulsed source to provide more detailed and reliable structural information than that hitherto available

Safety and efficacy of ALD403, an antibody to calcitonin gene-related peptide, for the prevention of frequent episodic migraine

DEFF Research Database (Denmark)

Dodick, David W; Goadsby, Peter J; Silberstein, Stephen D

2014-01-01

BACKGROUND: Calcitonin gene-related peptide (CGRP) is crucial in the pathophysiology of migraine. We assessed the safety, tolerability, and efficacy of ALD403, a genetically engineered humanised anti-CGRP antibody, for migraine prevention. METHODS: In this randomised, double-blind, placebo-contro...

Disorder controlled electrical transport properties of NdCo1−xNiO3

International Nuclear Information System (INIS)

Kumar, Vinod; Kumar, Rajesh; Shukla, D.K.; Kumar, Ravi

2013-01-01

Highlights: •Single phase NdCo 1−x Ni x O 3 were prepared using solid state reaction method. •Drastic improvement in room temperature conductivity for substituted samples. •Arrhenius and VRH conduction models employed to explain electrical transport. •Disorder induced charge carrier localization dominates in the substituted samples. -- Abstract: The effect of Ni substitution on structural and electrical transport has been investigated in NdCo 1−x Ni x O 3 system for 0 ⩽ x ⩽ 0.5. The Rietveld refinement of XRD data confirms orthorhombic, Pbnm symmetry for all the samples. The lattice parameters and hence unit cell volume is found to increase linearly with increase in Ni concentration. Substitution of Ni leads to the increase in conductivity and samples have been found to display semiconducting behavior in measured range of temperature. The explanation for the variation of resistivity with substitution and temperature has been provided on the basis of substitutional disorder and spin state related effects. Arrhenius and variable range hopping conduction approaches have been used to explain the temperature variation of resistivity. These results suggest that disorder-induced localization of charge carriers dominate the electrical transport in the substituted samples

Pathophysiological Role of Neuroinflammation in Neurodegenerative Diseases and Psychiatric Disorders

Directory of Open Access Journals (Sweden)

Heeok Hong

2016-05-01

Full Text Available Brain diseases and disorders such as Alzheimer disease, Parkinson disease, depression, schizophrenia, autism, and addiction lead to reduced quality of daily life through abnormal thoughts, perceptions, emotional states, and behavior. While the underlying mechanisms remain poorly understood, human and animal studies have supported a role of neuroinflammation in the etiology of these diseases. In the central nervous system, an increased inflammatory response is capable of activating microglial cells, leading to the release of pro-inflammatory cytokines including interleukin (IL-1β, IL-6, and tumor necrosis factor-α. In turn, the pro-inflammatory cytokines aggravate and propagate neuroinflammation, degenerating healthy neurons and impairing brain functions. Therefore, activated microglia may play a key role in neuroinflammatory processes contributing to the pathogenesis of psychiatric disorders and neurodegeneration.

Translocator Protein-18 kDa (TSPO Positron Emission Tomography (PET Imaging and Its Clinical Impact in Neurodegenerative Diseases

Directory of Open Access Journals (Sweden)

Anne-Claire Dupont

2017-04-01

Full Text Available In vivo exploration of activated microglia in neurodegenerative diseases is achievable by Positron Emission Tomography (PET imaging, using dedicated radiopharmaceuticals targeting the translocator protein-18 kDa (TSPO. In this review, we emphasized the major advances made over the last 20 years, thanks to TSPO PET imaging, to define the pathophysiological implication of microglia activation and neuroinflammation in neurodegenerative diseases, including Parkinson’s disease, Huntington’s disease, dementia, amyotrophic lateral sclerosis, multiple sclerosis, and also in psychiatric disorders. The extent and upregulation of TSPO as a molecular biomarker of activated microglia in the human brain is now widely documented in these pathologies, but its significance, and especially its protective or deleterious action regarding the disease’s stage, remains under debate. Thus, we exposed new and plausible suggestions to enhance the contribution of TSPO PET imaging for biomedical research by exploring microglia’s role and interactions with other cells in brain parenchyma. Multiplex approaches, associating TSPO PET radiopharmaceuticals with other biomarkers (PET imaging of cellular metabolism, neurotransmission or abnormal protein aggregates, but also other imaging modalities, and peripheral cytokine levels measurement and/or metabolomics analysis was considered. Finally, the actual clinical impact of TSPO PET imaging as a routine biomarker of neuroinflammation was put into perspective regarding the current development of diagnostic and therapeutic strategies for neurodegenerative diseases.

Availability of endogenous peptides limits expression of an M3a-Ld major histocompatibility complex class I chimera

Science.gov (United States)

1994-01-01

Taking advantage of our understanding of the peptide specificity of the major histocompatibility complex class I-b molecule M3a, we sought to determine why these molecules are poorly represented on the cell surface. To this end we constructed a chimeric molecule with the alpha 1 and alpha 2 domains of M3a and alpha 3 of Ld thereby allowing use of available monoclonal antibodies to quantify surface expression. Transfected, but not control, B10.CAS2 (H-2M3b) cells were lysed readily by M3a-restricted monoclonal cytotoxic T lymphocytes. Thus, the chimera bound, trafficked, and presented endogenous mitochondrial peptides. However, despite high levels of M3a-Ld mRNA, transfectants were negative by surface staining. This finding was consistent with inefficient trafficking to the cell surface. Incubation at 26 degrees C, thought to permit trafficking of unoccupied heavy (H) chains, resulted in detectable cell surface expression of chimeric molecules. Incubation with exogenous peptide at 26 degrees C (but not at 37 degrees C) greatly enhanced expression of M3a-Ld molecules in a dose- dependent manner, suggesting stabilization of unoccupied molecules. Stable association of beta 2-microglobulin with the chimeric H chain was observed in labeled cell lysates only in the presence of exogenous specific peptide, indicating that peptide is required for the formation of a ternary complex. These results indicate that surface expression of M3a-Ld is limited largely by the steady-state availability of endogenous peptides. Since most known M3a-binding peptides are N- formylated, native M3a may normally be expressed at high levels only during infection by intracellular bacteria. PMID:8270862

Characterizing a neurodegenerative syndrome: primary progressive apraxia of speech.

Science.gov (United States)

Josephs, Keith A; Duffy, Joseph R; Strand, Edythe A; Machulda, Mary M; Senjem, Matthew L; Master, Ankit V; Lowe, Val J; Jack, Clifford R; Whitwell, Jennifer L

2012-05-01

Apraxia of speech is a disorder of speech motor planning and/or programming that is distinguishable from aphasia and dysarthria. It most commonly results from vascular insults but can occur in degenerative diseases where it has typically been subsumed under aphasia, or it occurs in the context of more widespread neurodegeneration. The aim of this study was to determine whether apraxia of speech can present as an isolated sign of neurodegenerative disease. Between July 2010 and July 2011, 37 subjects with a neurodegenerative speech and language disorder were prospectively recruited and underwent detailed speech and language, neurological, neuropsychological and neuroimaging testing. The neuroimaging battery included 3.0 tesla volumetric head magnetic resonance imaging, [(18)F]-fluorodeoxyglucose and [(11)C] Pittsburg compound B positron emission tomography scanning. Twelve subjects were identified as having apraxia of speech without any signs of aphasia based on a comprehensive battery of language tests; hence, none met criteria for primary progressive aphasia. These subjects with primary progressive apraxia of speech included eight females and four males, with a mean age of onset of 73 years (range: 49-82). There were no specific additional shared patterns of neurological or neuropsychological impairment in the subjects with primary progressive apraxia of speech, but there was individual variability. Some subjects, for example, had mild features of behavioural change, executive dysfunction, limb apraxia or Parkinsonism. Voxel-based morphometry of grey matter revealed focal atrophy of superior lateral premotor cortex and supplementary motor area. Voxel-based morphometry of white matter showed volume loss in these same regions but with extension of loss involving the inferior premotor cortex and body of the corpus callosum. These same areas of white matter loss were observed with diffusion tensor imaging analysis, which also demonstrated reduced fractional anisotropy

Supply Chain difficulties in the Operational Leasing industry : A case study of ALD Automotive

OpenAIRE

Forslöf, Oscar; Jazic, Armen

2012-01-01

Abstract In today’s competitive world companies strive to be best in class and at the same time have high revenue. They try to sell the best products, deliver the best service and at the same time reduce costs in order to make high profits. They strive for high efficiency at all levels of the organization as well as reduced costs where possible. This report examines a company in the operational leasing industry, ALD Automotive. The company is a part of Société Générale, a Financial Services c...

Effects of out-of-plane disorder on the superconductivity of Bi{sub 2}Sr{sub 2-x}La{sub x}CuO{sub 6+{delta}}

Energy Technology Data Exchange (ETDEWEB)

Roehler, Juergen; Trabant, Christoph; Frielingsdorf, Johanna; Djemour, Rabia [Universitaet Koeln, 50937 Koeln (Germany); Martovitsky, Victor [Lebedev-Institute, 119991 Moscow (Russian Federation); Dudy, Lenart; Dwelk, Helmut; Krapf, Alica [Humboldt Universitaet Berlin, 12489 Berlin (Germany)

2008-07-01

The effects of out-of-plane substitutional order/disorder on cuprate superconductivity remains to a large extent an unresolved issue. We have investigated the connection between superconductivity and the lattice effects arising from the heterovalent doping of Bi{sub 2}Sr{sub 2-x}La{sub x}CuO{sub 6+{delta}}, x = 0.8-0.1. Decreasing lanthanum content tunes the compound through the entire underdoped and overdoped regimes. Cu-K and La- K EXAFS served as local structural probes, and single crystal X-ray diffraction for the determination of the basic unit cell, and the symmetry of the supercell. The oxygen atoms in the CuO{sub 2} planes were found significantly disordered, dependent on doping, and to exhibit minimum disorder around x{sub opt}=0.33. But the degree of substitutional disorder in the out-of-plane La environment turned out independent on the concentration of the La dopants, the superstructure symmetry, and the crystal growth parameters, whereas T{sub c} depends sensitively on them. No evidence was found for possible concentration dependent site changes of the La dopant from the nominal Sr to the Bi sites. We discuss the probably crucial role of the interstitial oxygen atoms for the superconducting properties of the Bi{sub 2}Sr{sub 2-x}La{sub x}CuO{sub 6+{delta}} system.

Fast method for reactor and feature scale coupling in ALD and CVD

Science.gov (United States)

Yanguas-Gil, Angel; Elam, Jeffrey W.

2017-08-08

Transport and surface chemistry of certain deposition techniques is modeled. Methods provide a model of the transport inside nanostructures as a single-particle discrete Markov chain process. This approach decouples the complexity of the surface chemistry from the transport model, thus allowing its application under general surface chemistry conditions, including atomic layer deposition (ALD) and chemical vapor deposition (CVD). Methods provide for determination of determine statistical information of the trajectory of individual molecules, such as the average interaction time or the number of wall collisions for molecules entering the nanostructures as well as to track the relative contributions to thin-film growth of different independent reaction pathways at each point of the feature.

Fragile X-Associated Tremor/Ataxia Syndrome (FXTAS) Motor Dysfunction Modeled in Mice.

Science.gov (United States)

Foote, Molly; Arque, Gloria; Berman, Robert F; Santos, Mónica

2016-10-01

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorder that affects some carriers of the fragile X premutation (PM). In PM carriers, there is a moderate expansion of a CGG trinucleotide sequence (55-200 repeats) in the fragile X gene (FMR1) leading to increased FMR1 mRNA and small to moderate decreases in the fragile X mental retardation protein (FMRP) expression. The key symptoms of FXTAS include cerebellar gait ataxia, kinetic tremor, sensorimotor deficits, neuropsychiatric changes, and dementia. While the specific trigger(s) that causes PM carriers to progress to FXTAS pathogenesis remains elusive, the use of animal models has shed light on the underlying neurobiology of the altered pathways involved in disease development. In this review, we examine the current use of mouse models to study PM and FXTAS, focusing on recent advances in the field. Specifically, we will discuss the construct, face, and predictive validities of these PM mouse models, the insights into the underlying disease mechanisms, and potential treatments.

Fragile X-associated Tremor/Ataxia Syndrome (FXTAS) Motor Dysfunction Modeled in Mice

Science.gov (United States)

Foote, Molly; Arque, Gloria; Berman, Robert F.; Santos, Mónica

2016-01-01

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late onset neurodegenerative disorder that affects some carriers of the Fragile X premutation (PM). In PM carriers there is a moderate expansion of a CGG trinucleotide sequence (55-200 repeats) in the fragile X gene (FMR1) leading to increased FMR1 mRNA and small to moderate decreases in the Fragile X Mental Retardation Protein (FMRP) expression. The key symptoms of FXTAS include cerebellar gait ataxia, kinetic tremor, sensorimotor deficits, neuropsychiatric changes, and dementia. While the specific trigger(s) that cause PM carriers to progress to FXTAS pathogenesis remains elusive, the use of animal models has shed light on the underlying neurobiology of the altered pathways involved in disease development. In this review, we examine the current use of mouse models to study PM and FXTAS, focusing on recent advances in the field. Specifically we will discuss the construct, face and predictive validities of these PM mouse models, the insights into the underlying disease mechanisms and potential treatments. PMID:27255703

Long term clinical and neurophysiological effects of cerebellar transcranial direct current stimulation in patients with neurodegenerative ataxia.

Science.gov (United States)

Benussi, Alberto; Dell'Era, Valentina; Cotelli, Maria Sofia; Turla, Marinella; Casali, Carlo; Padovani, Alessandro; Borroni, Barbara

Neurodegenerative cerebellar ataxias represent a group of disabling disorders for which we currently lack effective therapies. Cerebellar transcranial direct current stimulation (tDCS) is a non-invasive technique, which has been demonstrated to modulate cerebellar excitability and improve symptoms in patients with cerebellar ataxias. The present study investigated whether a two-weeks' treatment with cerebellar anodal tDCS could improve symptoms in patients with neurodegenerative cerebellar ataxia and could modulate cerebello-motor connectivity, at short and long term. We performed a double-blind, randomized, sham controlled trial with cerebellar tDCS (5 days/week for 2 weeks) in twenty patients with ataxia. Each patient underwent a clinical evaluation pre- and post-anodal tDCS or sham stimulation. A follow-up evaluation was performed at one and three months. Cerebello-motor connectivity was evaluated using transcranial magnetic stimulation (TMS) at baseline and at follow-up. Patients who underwent anodal tDCS showed a significant improvement in all performance scores (scale for the assessment and rating of ataxia, international cooperative ataxia rating scale, 9-hole peg test, 8-m walking time) and in cerebellar brain inhibition compared to patients who underwent sham stimulation. A two-weeks' treatment with anodal cerebellar tDCS improves symptoms in patients with ataxia and restores physiological cerebellar brain inhibition pathways. Cerebellar tDCS might represent a promising future therapeutic and rehabilitative approach in patients with neurodegenerative ataxia. Copyright © 2016 Elsevier Inc. All rights reserved.

Bipolar disorder, a precursor of Parkinson's disease?

Directory of Open Access Journals (Sweden)

Tânia M.S. Novaretti

Full Text Available ABSTRACT Parkinson's disease is a neurodegenerative disorder predominantly resulting from dopamine depletion in the substantia nigra pars compacta. Some psychiatric disorders may have dopaminergic dysfunction as their substrate. We describe a well-documented case of Parkinson's disease associated with Bipolar Disorder. Although there is some knowledge about the association between these diseases, little is known about its pathophysiology and correlation. We believe that among various hypotheses, many neurotransmitters are linked to this pathophysiology.

The Emerging Role of Proteomics in Precision Medicine: Applications in Neurodegenerative Diseases and Neurotrauma.

Science.gov (United States)

Alaaeddine, Rana; Fayad, Mira; Nehme, Eliana; Bahmad, Hisham F; Kobeissy, Firas

2017-01-01

Inter-individual variability in response to pharmacotherapy has provoked a higher demand to personalize medical decisions. As the field of pharmacogenomics has served to translate personalized medicine from concept to practice, the contribution of the "omics" disciplines to the era of precision medicine seems to be vital in improving therapeutic outcomes. Although we have observed significant advances in the field of genomics towards personalized medicine , the field of proteomics-with all its capabilities- is still in its infancy towards the area of personalized precision medicine. Neurodegenerative diseases and neurotrauma are among the areas where the implementation of neuroproteomics approaches has enabled neuroscientists to broaden their understanding of neural disease mechanisms and characteristics. It has been shown that the influence of epigenetics, genetics and environmental factors were among the recognized factors contributing to the diverse presentation of a single disease as well as its treatment establishing the factor-disease interaction. Thus, management of these variable single disease presentation/outcome necessitated the need for factoring the influence of epigenetics, genetics, epigenetics, and other factors on disease progression to create a custom treatment plan unique to each individual. In fact, neuroproteomics with its high ability to decipher protein alterations along with their post translational modifications (PTMs) can be an ideal tool for personalized medicine goals including: discovery of molecular mechanisms underlying disease pathobiology, development of novel diagnostics, enhancement of pharmacological neurotherapeutic approaches and finally, providing a "proteome identity" for patients with certain disorders and diseases. So far, neuroproteomics approaches have excelled in the areas of biomarker discovery arena where several diagnostic, prognostic and injury markers have been identified with a direct impact on the

Higher-level gait disorders: an open frontier.

Science.gov (United States)

Nutt, John G

2013-09-15

The term higher-level gait disorders (HLGD) defines a category of balance and gait disorders that are not explained by deficits in strength, tone, sensation, or coordination. HLGD are characterized by various combinations of disequilibrium and impaired locomotion. A plethora of new imaging techniques are beginning to determine the neural circuits that are the basis of these disorders. Although a variety of neurodegenerative and other pathologies can produce HLGD, the most common cause appears to be microvascular disease that causes white-matter lesions and thereby disrupts balance/locomotor circuits. © 2013 Movement Disorder Society.

Exosomes: vehicles for the transfer of toxic proteins associated with neurodegenerative diseases?

Science.gov (United States)

Bellingham, Shayne A; Guo, Belinda B; Coleman, Bradley M; Hill, Andrew F

2012-01-01

Exosomes are small membranous vesicles secreted by a number of cell types including neurons and can be isolated from conditioned cell media or bodily fluids such as urine and plasma. Exosome biogenesis involves the inward budding of endosomes to form multivesicular bodies (MVB). When fused with the plasma membrane, the MVB releases the vesicles into the extracellular environment as exosomes. Proposed functions of these vesicles include roles in cell-cell signaling, removal of unwanted proteins, and the transfer of pathogens between cells. One such pathogen which exploits this pathway is the prion, the infectious particle responsible for the transmissible neurodegenerative diseases such as Creutzfeldt-Jakob disease (CJD) of humans or bovine spongiform encephalopathy (BSE) of cattle. Similarly, exosomes are also involved in the processing of the amyloid precursor protein (APP) which is associated with Alzheimer's disease. Exosomes have been shown to contain full-length APP and several distinct proteolytically cleaved products of APP, including Aβ. In addition, these fragments can be modulated using inhibitors of the proteases involved in APP cleavage. These observations provide further evidence for a novel pathway in which PrP and APP fragments are released from cells. Other proteins such as superoxide dismutase I and alpha-synuclein (involved in amyotrophic lateral sclerosis and Parkinson's disease, respectively) are also found associated with exosomes. This review will focus on the role of exosomes in neurodegenerative disorders and discuss the potential of these vesicles for the spread of neurotoxicity, therapeutics, and diagnostics for these diseases.

Structural Analyses of Phase Stability in Amorphous and Partially Crystallized Ge-Rich GeTe Films Prepared by Atomic Layer Deposition.

Science.gov (United States)

Gwon, Taehong; Mohamed, Ahmed Yousef; Yoo, Chanyoung; Park, Eui-Sang; Kim, Sanggyun; Yoo, Sijung; Lee, Han-Koo; Cho, Deok-Yong; Hwang, Cheol Seong

2017-11-29

The local bonding structures of Ge x Te 1-x (x = 0.5, 0.6, and 0.7) films prepared through atomic layer deposition (ALD) with Ge(N(Si(CH 3 ) 3 ) 2 ) 2 and ((CH 3 ) 3 Si) 2 Te precursors were investigated using Ge K-edge X-ray absorption spectroscopy (XAS). The results of the X-ray absorption fine structure analyses show that for all of the compositions, the as-grown films were amorphous with a tetrahedral Ge coordination of a mixture of Ge-Te and Ge-Ge bonds but without any signature of Ge-GeTe decomposition. The compositional evolution in the valence band electronic structures probed through X-ray photoelectron spectroscopy suggests a substantial chemical influence of additional Ge on the nonstoichiometric GeTe. This implies that the ALD process can stabilize Ge-abundant bonding networks like -Te-Ge-Ge-Te- in amorphous GeTe. Meanwhile, the XAS results on the Ge-rich films that had undergone post-deposition annealing at 350 °C show that the parts of the crystalline Ge-rich GeTe became separated into Ge crystallites and rhombohedral GeTe in accordance with the bulk phase diagram, whereas the disordered GeTe domains still remained, consistent with the observations of transmission electron microscopy and Raman spectroscopy. Therefore, amorphousness in GeTe may be essential for the nonsegregated Ge-rich phases and the low growth temperature of the ALD enables the achievement of the structurally metastable phases.

Delineating the Profile of Autism Spectrum Disorder Characteristics in Cornelia de Lange and Fragile X Syndromes

Science.gov (United States)

Moss, Joanna; Oliver, Chris; Nelson, Lisa; Richards, Caroline; Hall, Scott

2013-01-01

An atypical presentation of autism spectrum disorder is noted in Cornelia de Lange and Fragile X syndromes, but there are few detailed empirical descriptions. Participants in this study were individuals with Cornelia de Lange syndrome (n = 130, M age = 17.19), Fragile X syndrome (n = 182, M age = 16.94), and autism spectrum disorder (n = 142, M…

Molecular Chaperone Dysfunction in Neurodegenerative Diseases and Effects of Curcumin

Directory of Open Access Journals (Sweden)

Panchanan Maiti

2014-01-01

Full Text Available The intra- and extracellular accumulation of misfolded and aggregated amyloid proteins is a common feature in several neurodegenerative diseases, which is thought to play a major role in disease severity and progression. The principal machineries maintaining proteostasis are the ubiquitin proteasomal and lysosomal autophagy systems, where heat shock proteins play a crucial role. Many protein aggregates are degraded by the lysosomes, depending on aggregate size, peptide sequence, and degree of misfolding, while others are selectively tagged for removal by heat shock proteins and degraded by either the proteasome or phagosomes. These systems are compromised in different neurodegenerative diseases. Therefore, developing novel targets and classes of therapeutic drugs, which can reduce aggregates and maintain proteostasis in the brains of neurodegenerative models, is vital. Natural products that can modulate heat shock proteins/proteosomal pathway are considered promising for treating neurodegenerative diseases. Here we discuss the current knowledge on the role of HSPs in protein misfolding diseases and knowledge gained from animal models of Alzheimer’s disease, tauopathies, and Huntington’s diseases. Further, we discuss the emerging treatment regimens for these diseases using natural products, like curcumin, which can augment expression or function of heat shock proteins in the cell.

Taking snapshots of photoexcited molecules in disordered media using pulsed synchrotron x-rays

International Nuclear Information System (INIS)

Chen, L.X.

2004-01-01

Photoexcited molecules are quintessential reactants in photochemistry. Structures of these photoexcited molecules in disordered media in which a majority of photochemical reactions take place remained elusive for decades owing to a lack of suitable X-ray sources, despite their importance in understanding fundamental aspects in photochemistry. As new pulsed X-ray sources become available, short-lived excited-state molecular structures in disordered media can now be captured by using laser-pulse pump, X-ray pulse-probe techniques of third-generation synchrotron sources with time resolutions of 30-100 ps, as demonstrated by examples in this review. These studies provide unprecedented information on structural origins of molecular properties in the excited states. By using other ultrafast X-ray facilities that will be completed in the near future, time-resolution for the excited-state structure measurements should reach the femtosecond timescales, which will make 'molecular movies' of bond breaking or formation, and vibrational relaxation, a reality.

Association between environmental exposure to pesticides and neurodegenerative diseases

Energy Technology Data Exchange (ETDEWEB)

Parron, Tesifon [University of Almeria, Department of Neurosciences and Health Sciences, Almeria (Spain); Andalusian Council of Health at Almeria province, Almeria (Spain); Requena, Mar [Andalusian Council of Health at Almeria province, Almeria (Spain); Hernandez, Antonio F., E-mail: ajerez@ugr.es [University of Granada School of Medicine, Granada (Spain); Alarcon, Raquel [Andalusian Council of Health at Almeria province, Almeria (Spain)

2011-11-15

Preliminary studies have shown associations between chronic pesticide exposure in occupational settings and neurological disorders. However, data on the effects of long-term non-occupational exposures are too sparse to allow any conclusions. This study examines the influence of environmental pesticide exposure on a number of neuropsychiatric conditions and discusses their underlying pathologic mechanisms. An ecological study was conducted using averaged prevalence rates of Alzheimer's disease, Parkinson's disease, multiple sclerosis, cerebral degeneration, polyneuropathies, affective psychosis and suicide attempts in selected Andalusian health districts categorized into areas of high and low environmental pesticide exposure based on the number of hectares devoted to intensive agriculture and pesticide sales per capita. A total of 17,429 cases were collected from computerized hospital records (minimum dataset) between 1998 and 2005. Prevalence rates and the risk of having Alzheimer's disease, Parkinson's disease, multiple sclerosis and suicide were significantly higher in districts with greater pesticide use as compared to those with lower pesticide use. The multivariate analyses showed that the population living in areas with high pesticide use had an increased risk for Alzheimer's disease and suicide attempts and that males living in these areas had increased risks for polyneuropathies, affective disorders and suicide attempts. In conclusion, this study supports and extends previous findings and provides an indication that environmental exposure to pesticides may affect the human health by increasing the incidence of certain neurological disorders at the level of the general population. -- Highlights: Black-Right-Pointing-Pointer Environmental exposure to pesticides and neurodegenerative-psychiatric disorders. Black-Right-Pointing-Pointer Increased risk for Alzheimer's disease and suicide attempts in high exposure areas. Black

Pharmacological Alternatives for the Treatment of Neurodegenerative Disorders: Wasp and Bee Venoms and Their Components as New Neuroactive Tools

OpenAIRE

Silva, Juliana; Monge-Fuentes, Victoria; Gomes, Fl?via; Lopes, Kamila; dos Anjos, Lilian; Campos, Gabriel; Arenas, Claudia; Biolchi, Andr?ia; Gon?alves, Jacqueline; Galante, Priscilla; Campos, Leandro; Mortari, M?rcia

2015-01-01

Neurodegenerative diseases are relentlessly progressive, severely impacting affected patients, families and society as a whole. Increased life expectancy has made these diseases more common worldwide. Unfortunately, available drugs have insufficient therapeutic effects on many subtypes of these intractable diseases, and adverse effects hamper continued treatment. Wasp and bee venoms and their components are potential means of managing or reducing these effects and provide new alternatives for...

New Therapeutic Drugs from Bioactive Natural Molecules: the Role of Gut Microbiota Metabolism in Neurodegenerative Diseases.

Science.gov (United States)

Di Meo, Francesco; Donato, Stella; Di Pardo, Alba; Maglione, Vittorio; Filosa, Stefania; Crispi, Stefania

2018-04-03

The gut-brain axis is considered a neuroendocrine system, which connects brain and gastrointestinal tract and plays an important role in stress response. The homeostasis of gut-brain axis is important for healthy conditions and its alterations are associated to neurological disorders and neurodegenerative diseases. Gut microbiota is a dynamic ecosystem that can be altered by external factors such as diet composition, antibiotics or xenobiotics. Recent advances in gut microbiota analyses indicate that the gut bacterial community plays a key role in maintaining normal brain functions. Recent metagenomic analyses have elucidated that the relationship between gut and brain, either in normal or in pathological conditions, reflects the existence of a "microbiota-gut-brain" axis. Gut microbiota composition can be influenced by dietary ingestion of probiotics or natural bioactive molecules such as prebiotics and polyphenols. Their derivatives coming from microbiota metabolism can affect both gut bacterial composition and brain biochemistry. Modifications of microbiota composition by natural bioactive molecules could be used to restore the altered brain functions, which characterize neurodegenerative diseases, leading to consider these compounds as novel therapeutic strategies for the treatment of neuropathologies. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

X-ray evaluation of lymph flow disorders in posttraumatic lower limb edema

International Nuclear Information System (INIS)

Chepelenko, G.V.; Sveshnikov, A.A.; Mukhamedzhanov, I.Kh.

1985-01-01

X-ray examination showed that in 41 patients with lower limb traumas and their complications (chronic osteomyelitis, articular contracture, osseous defects) disorders in the permeability of the superficial medial collector were detected at the trauma level. Enlarged sizes, rearrangement of the structure and cumulative defects of the inguinal and illiac lymph nodes were simultaneously revealed. Disorders of the lymph flow in the femoral vessels were found in the distal part of the injured bone zone in half of the examined patients. In 8 patients the above disorders caused edema developing at the trauma level

Plants traditionally used in age-related brain disorders (dementia): an ethanopharmacological survey.

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Natarajan, Suganthy; Shunmugiah, Karutha Pandian; Kasi, Pandima Devi

2013-04-01

Epidemiological studies have shown that despite mortality due to communicable diseases, poverty and human conflicts, the incidence of dementia increases in the developing world in tandem with the ageing population. Although some FDA approved drugs are available for the treatment of dementia, the outcomes are often unsatisfactory. In traditional practices of medicine, numerous plants have been used to treat cognitive disorders, including neurodegenerative diseases such as Alzheimer's disease (AD) and other memory-related disorders. In western medicine most of the drugs used for the treatment of neurodegenerative disorders are derived from plant sources. This article reviews plants and their active constituents that have been used for their reputed cognitive-enhancing and antidementia effects. A literature survey in Science Direct, Pubmed, and Google Scholar was performed to gather information regarding drug discovery from plants sources for the treatment of congnitive disorders and dementia. More than forty herbal remedies were identified with cholinesterase inhibitory, anti-inflammatory, or antioxidant activities. Bioactive compounds include alkaloids, flavonoids, steroids, saponins, terpenoids, and essential oils. About eleven herbal plants with multipotent activity against AD are discussed. Literature surveys show that most of the research has been conducted on herbal remedies effect on cholinesterase inhibitory and antioxidant activities. Studies regarding the effect of herbal drugs on β-secretase inhibitory activity and antiaggregation property are lacking. This review provides leads for identifying potential new drugs from plant sources for the treatment of neurodegenerative disorders.

Heterozygosity for the Mood Disorder-Associated Variant Gln460Arg Alters P2X7 Receptor Function and Sleep Quality.

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Metzger, Michael W; Walser, Sandra M; Dedic, Nina; Aprile-Garcia, Fernando; Jakubcakova, Vladimira; Adamczyk, Marek; Webb, Katharine J; Uhr, Manfred; Refojo, Damian; Schmidt, Mathias V; Friess, Elisabeth; Steiger, Axel; Kimura, Mayumi; Chen, Alon; Holsboer, Florian; Arzt, Eduardo; Wurst, Wolfgang; Deussing, Jan M

2017-11-29

A single nucleotide polymorphism substitution from glutamine (Gln, Q) to arginine (Arg, R) at codon 460 of the purinergic P2X7 receptor (P2X7R) has repeatedly been associated with mood disorders. The P2X7R-Gln460Arg variant per se is not compromised in its function. However, heterologous expression of P2X7R-Gln460Arg together with wild-type P2X7R has recently been demonstrated to impair receptor function. Here we show that this also applies to humanized mice coexpressing both human P2X7R variants. Primary hippocampal cells derived from heterozygous mice showed an attenuated calcium uptake upon agonist stimulation. While humanized mice were unaffected in their behavioral repertoire under basal housing conditions, mice that harbor both P2X7R variants showed alterations in their sleep quality resembling signs of a prodromal disease stage. Also healthy heterozygous human subjects showed mild changes in sleep parameters. These results indicate that heterozygosity for the wild-type P2X7R and its mood disorder-associated variant P2X7R-Gln460Arg represents a genetic risk factor, which is potentially able to convey susceptibility to mood disorders. SIGNIFICANCE STATEMENT Depression and bipolar disorder are the most common mood disorders. The P2X7 receptor (P2X7R) regulates many cellular functions. Its polymorphic variant Gln460Arg has repeatedly been associated with mood disorders. Genetically engineered mice, with human P2X7R, revealed that heterozygous mice (i.e., they coexpress the disease-associated Gln460Arg variant together with its normal version) have impaired receptor function and showed sleep disturbances. Human participants with the heterozygote genotype also had subtle alterations in their sleep profile. Our findings suggest that altered P2X7R function in heterozygote individuals disturbs sleep and might increase the risk for developing mood disorders. Copyright © 2017 the authors 0270-6474/17/3711688-13$15.00/0.

Formation of Micro- and Nanostructures on the Nanotitanium Surface by Chemical Etching and Deposition of Titania Films by Atomic Layer Deposition (ALD

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Denis V. Nazarov

2015-12-01

Full Text Available In this study, an integrated approach was used for the preparation of a nanotitanium-based bioactive material. The integrated approach included three methods: severe plastic deformation (SPD, chemical etching and atomic layer deposition (ALD. For the first time, it was experimentally shown that the nature of the etching medium (acidic or basic Piranha solutions and the etching time have a significant qualitative impact on the nanotitanium surface structure both at the nano- and microscale. The etched samples were coated with crystalline biocompatible TiO2 films with a thickness of 20 nm by Atomic Layer Deposition (ALD. Comparative study of the adhesive and spreading properties of human osteoblasts MG-63 has demonstrated that presence of nano- and microscale structures and crystalline titanium oxide on the surface of nanotitanium improve bioactive properties of the material.

Modeling cognitive deficits following neurodegenerative diseases and traumatic brain injuries with deep convolutional neural networks.

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Lusch, Bethany; Weholt, Jake; Maia, Pedro D; Kutz, J Nathan

2018-06-01

The accurate diagnosis and assessment of neurodegenerative disease and traumatic brain injuries (TBI) remain open challenges. Both cause cognitive and functional deficits due to focal axonal swellings (FAS), but it is difficult to deliver a prognosis due to our limited ability to assess damaged neurons at a cellular level in vivo. We simulate the effects of neurodegenerative disease and TBI using convolutional neural networks (CNNs) as our model of cognition. We utilize biophysically relevant statistical data on FAS to damage the connections in CNNs in a functionally relevant way. We incorporate energy constraints on the brain by pruning the CNNs to be less over-engineered. Qualitatively, we demonstrate that damage leads to human-like mistakes. Our experiments also provide quantitative assessments of how accuracy is affected by various types and levels of damage. The deficit resulting from a fixed amount of damage greatly depends on which connections are randomly injured, providing intuition for why it is difficult to predict impairments. There is a large degree of subjectivity when it comes to interpreting cognitive deficits from complex systems such as the human brain. However, we provide important insight and a quantitative framework for disorders in which FAS are implicated. Copyright © 2018 Elsevier Inc. All rights reserved.

Friends or Foes: Matrix Metalloproteinases and Their Multifaceted Roles in Neurodegenerative Diseases.

Science.gov (United States)

Brkic, Marjana; Balusu, Sriram; Libert, Claude; Vandenbroucke, Roosmarijn E

2015-01-01

Neurodegeneration is a chronic progressive loss of neuronal cells leading to deterioration of central nervous system (CNS) functionality. It has been shown that neuroinflammation precedes neurodegeneration in various neurodegenerative diseases. Matrix metalloproteinases (MMPs), a protein family of zinc-containing endopeptidases, are essential in (neuro)inflammation and might be involved in neurodegeneration. Although MMPs are indispensable for physiological development and functioning of the organism, they are often referred to as double-edged swords due to their ability to also inflict substantial damage in various pathological conditions. MMP activity is strictly controlled, and its dysregulation leads to a variety of pathologies. Investigation of their potential use as therapeutic targets requires a better understanding of their contributions to the development of neurodegenerative diseases. Here, we review MMPs and their roles in neurodegenerative diseases: Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), and multiple sclerosis (MS). We also discuss MMP inhibition as a possible therapeutic strategy to treat neurodegenerative diseases.

Friends or Foes: Matrix Metalloproteinases and Their Multifaceted Roles in Neurodegenerative Diseases

Directory of Open Access Journals (Sweden)

Marjana Brkic

2015-01-01

Full Text Available Neurodegeneration is a chronic progressive loss of neuronal cells leading to deterioration of central nervous system (CNS functionality. It has been shown that neuroinflammation precedes neurodegeneration in various neurodegenerative diseases. Matrix metalloproteinases (MMPs, a protein family of zinc-containing endopeptidases, are essential in (neuroinflammation and might be involved in neurodegeneration. Although MMPs are indispensable for physiological development and functioning of the organism, they are often referred to as double-edged swords due to their ability to also inflict substantial damage in various pathological conditions. MMP activity is strictly controlled, and its dysregulation leads to a variety of pathologies. Investigation of their potential use as therapeutic targets requires a better understanding of their contributions to the development of neurodegenerative diseases. Here, we review MMPs and their roles in neurodegenerative diseases: Alzheimer’s disease (AD, Parkinson’s disease (PD, amyotrophic lateral sclerosis (ALS, Huntington’s disease (HD, and multiple sclerosis (MS. We also discuss MMP inhibition as a possible therapeutic strategy to treat neurodegenerative diseases.

Genetic enhancement of macroautophagy in vertebrate models of neurodegenerative diseases.

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Ejlerskov, Patrick; Ashkenazi, Avraham; Rubinsztein, David C

2018-04-03

Most of the neurodegenerative diseases that afflict humans manifest with the intraneuronal accumulation of toxic proteins that are aggregate-prone. Extensive data in cell and neuronal models support the concept that such proteins, like mutant huntingtin or alpha-synuclein, are substrates for macroautophagy (hereafter autophagy). Furthermore, autophagy-inducing compounds lower the levels of such proteins and ameliorate their toxicity in diverse animal models of neurodegenerative diseases. However, most of these compounds also have autophagy-independent effects and it is important to understand if similar benefits are seen with genetic strategies that upregulate autophagy, as this strengthens the validity of this strategy in such diseases. Here we review studies in vertebrate models using genetic manipulations of core autophagy genes and describe how these improve pathology and neurodegeneration, supporting the validity of autophagy upregulation as a target for certain neurodegenerative diseases. Copyright © 2018 Elsevier Inc. All rights reserved.

Effect of allogenic thymic cells on radioleukaemogenesis in AKR-T1ALD mice

International Nuclear Information System (INIS)

Legrand, E.; Sankar-Mistry, P.; Kressmann, M.C.

1975-01-01

When AKR mice are irradiated with a sub-lethal dose (4 times 175 R), thymic lymphosarcomas (L.S.) occur earlier than in controls. This accelerated leukaemogenesis is not inhibited by syngenic restoration with bone marrows cells (BM). Using the AKR/T1ALD substrain which bears 38 chromosomes with 1 metacentric markers, it has been shown that AKR radio-chimaeras restored by T1ALD BM developed two kinds of L.S.: early (radiation-induced) L.S. originating mainly from host cells surviving irradiation and late L.S. from donor cells. The experiments were to investigate the potential influence of normal allogenic thymic cells, with or without syngenic B.M., on the incidence, latency and origin of LS appearing in irradiated AKR recipients. Adding C3H allogenic thymic cells to syngenic B.M. increases the percentage of early L.S. whose latencies are unchanged. Besides, when C3H thymic cells are injected to irradiated controls without syngenic B.M. cells, L.S. are seen to occur significantly earlier than in just the irradiated animals alone. In radio-chimaeras restored by allogenic thymic cells and syngenic B.M., except in one case, all the L.S. were seen to originate from B.M. cells. The interpretation of these results depends on the possible role of allogenic thymic cells on host cells surviving the irradiation, or the exogeneous B.M. In the first case, allogenic thymocytes could induce a graft versus host reaction increasing the post-irradiation depletion of lymphoid system and hastening thymic endoregeneration which is supposed to be the first step towards leukaemogenesis. The second hypothesis, which seems the most likely, would be that C1H thymic cells could selectively act on host cells surviving irradiation and enhance the differenciation of haemopoietic precursors at the expense of the lymphoid cells [fr

Ladinia linguistica in una monumentale opera: Atlante linguistico del ladino dolomitico e dei dialetti limitrofi - ALD-1, Dr. Ludwig Reichert Verlag, Wiesbaden 1998

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Mitja Skubic

2000-12-01

Full Text Available L'apparizione dell'atlante linguistico di un territorio romanzo va salutata con gioia, come una festa della ricerca scientifica in tale settore. E il sentimenta di gioia ci pervade quando sfogliamo i primi quattro volumi, in folio, dell 'ALD. Non solo per la mole e l'ampia concezione dell'opera, ma altrettanto e più ancora per il ricco materiale che l' ALD offre. A tutta l' equipe scientifica guidata dal rinomato romanista salisburghese prof. Hans Goebl che assieme a Lois Craffonara é anche ideatore dell 'opera, nonché ai collaboratori e all'editore vadano i nostri sinceri ringraziamenti. Ci sia permesso di aggiungere che la nostra rivista si pregia d'aver potuto ospitare alcuni studi scientifici del prof. Goebl, come anche del suo stretto collaboratore prof. Roland Bauer.

Ladinia linguistica in una monumentale opera: atlante lunguistico del ladino dolomitico e dei dialetti limitrofi - ald-1, Dr. Ludwig Reichert Verlag, Wiesbaden 1998.

Directory of Open Access Journals (Sweden)

Mitja Skubic

2015-08-01

Full Text Available L'apparizione dell'atlante linguistico di un territorio romanzo va salutata con gioia, come una festa della ricerca scientifica in tale settore. E il sentimento di gioia ci pervade quando sfogliamo i primi quattro vol umi, in folio, deli' ALD. Non sol oper la mole e l'ampia concezione dell'opera, ma altrettanto e più ancora per il ricco materiale che l 'ALD offre. A tutta l' équipe scientifica guidata dal rinomato romanista salisburghese prof. Hans Goebl che assieme a Lois Craffonara e anche ideatore deli' opera, nonché ai collaboratori è all'editore vadano i nostri sinceri ringraziamenti. Ci sia permesso di aggiungere che la nostra rivista si pregia d'aver potuto ospitare alcuni studi scientifici del prof. Goebl, come anche del suo stretto collaboratore prof. Roland Bauer.

TRPM2, calcium and neurodegenerative diseases

Science.gov (United States)

Xie, Yu-Feng; MacDonald, John F; Jackson, Michael F

2010-01-01

NMDA receptor overactivation triggers intracellular Ca2+ dysregulation, which has long been thought to be critical for initiating excitotoxic cell death cascades associated with stroke and neurodegenerative disease. The inability of NMDA receptor antagonists to afford neuroprotection in clinical stroke trials has led to a re-evaluation of excitotoxic models of cell death and has focused research efforts towards identifying additional Ca2+ influx pathways. Recent studies indicate that TRPM2, a member of the TRPM subfamily of Ca2+-permeant, non-selective cation channel, plays an important role in mediating cellular responses to a wide range of stimuli that, under certain situations, can induce cell death. These include reactive oxygen and nitrogen species, tumour necrosis factor as well as soluble oli-gomers of amyloid beta. However, the molecular basis of TRPM2 channel involvement in these processes is not fully understood. In this review, we summarize recent studies about the regulation of TRPM2, its interaction with calcium and the possible implications for neurodegenerative diseases. PMID:21383889

Basic pathologies of neurodegenerative dementias and their relevance for state-of-the-art molecular imaging studies

International Nuclear Information System (INIS)

Drzezga, Alexander

2008-01-01

Rising life-expectancy in the modern society has resulted in a rapidly growing prevalence of dementia, particularly of Alzheimer's disease (AD). Dementia turns into one of the most common age-related disorders with deleterious consequences for the concerned patients and their relatives, as well as worrying effects on the socio-economic systems. These facts justify strengthened scientific efforts to identify the pathologic origin of dementing disorders, to improve diagnosis, and to interfere therapeutically with the disease progression. In the recent years, remarkable progress has been made concerning the identification of molecular mechanisms underlying the pathology of neurodegenerative disorders. Growing evidence indicates that a common basis of many neurodegenerative dementias can be found in increased production, misfolding and pathological aggregation of proteins, such as ss-amyloid, tau protein, a-synuclein, or the recently described ubiquitinated TDP-43. This progressive insight in pathological processes is paralleled by the development of new therapeutic approaches. However, the exact contribution or mechanism of different pathologies with regard to the development of disease is not yet sufficiently clear. Considerable overlap of pathologies has been documented in different types of clinically defined dementias post mortem, and it has been difficult to correlate post mortem histopathology data with disease-expression during life. Molecular imaging procedures may play a valuable role to circumvent this limitation. In general, methods of molecular imaging have recently experienced an impressive advance, with numerous new and improved technologies emerging. These exciting tools may play a key role in the future regarding the evaluation of pathomechanisms, preclinical evaluation of new diagnostic procedures in animal models, selection of patients for clinical trials, and therapy monitoring. In this overview, molecular key pathologies, which are currently

Autism Spectrum Disorder in a Girl with a De Novo X;19 Balanced Translocation

Science.gov (United States)

Baruffi, Marcelo Razera; de Souza, Deise Helena; Bicudo da Silva, Rosana Aparecida; Ramos, Ester Silveira; Moretti-Ferreira, Danilo

2012-01-01

Balanced X-autosome translocations are rare, and female carriers are a clinically heterogeneous group of patients, with phenotypically normal women, history of recurrent miscarriage, gonadal dysfunction, X-linked disorders or congenital abnormalities, and/or developmental delay. We investigated a patient with a de novo X;19 translocation. The six-year-old girl has been evaluated due to hyperactivity, social interaction impairment, stereotypic and repetitive use of language with echolalia, failure to follow parents/caretakers orders, inconsolable outbursts, and persistent preoccupation with parts of objects. The girl has normal cognitive function. Her measurements are within normal range, and no other abnormalities were found during physical, neurological, or dysmorphological examinations. Conventional cytogenetic analysis showed a de novo balanced translocation, with the karyotype 46,X,t(X;19)(p21.2;q13.4). Replication banding showed a clear preference for inactivation of the normal X chromosome. The translocation was confirmed by FISH and Spectral Karyotyping (SKY). Although abnormal phenotypes associated with de novo balanced chromosomal rearrangements may be the result of disruption of a gene at one of the breakpoints, submicroscopic deletion or duplication, or a position effect, X; autosomal translocations are associated with additional unique risk factors including X-linked disorders, functional autosomal monosomy, or functional X chromosome disomy resulting from the complex X-inactivation process. PMID:23074688

Autism Spectrum Disorder in a Girl with a De Novo X;19 Balanced Translocation

Directory of Open Access Journals (Sweden)

Marcelo Razera Baruffi

2012-01-01

Full Text Available Balanced X-autosome translocations are rare, and female carriers are a clinically heterogeneous group of patients, with phenotypically normal women, history of recurrent miscarriage, gonadal dysfunction, X-linked disorders or congenital abnormalities, and/or developmental delay. We investigated a patient with a de novo X;19 translocation. The six-year-old girl has been evaluated due to hyperactivity, social interaction impairment, stereotypic and repetitive use of language with echolalia, failure to follow parents/caretakers orders, inconsolable outbursts, and persistent preoccupation with parts of objects. The girl has normal cognitive function. Her measurements are within normal range, and no other abnormalities were found during physical, neurological, or dysmorphological examinations. Conventional cytogenetic analysis showed a de novo balanced translocation, with the karyotype 46,X,t(X;19(p21.2;q13.4. Replication banding showed a clear preference for inactivation of the normal X chromosome. The translocation was confirmed by FISH and Spectral Karyotyping (SKY. Although abnormal phenotypes associated with de novo balanced chromosomal rearrangements may be the result of disruption of a gene at one of the breakpoints, submicroscopic deletion or duplication, or a position effect, X; autosomal translocations are associated with additional unique risk factors including X-linked disorders, functional autosomal monosomy, or functional X chromosome disomy resulting from the complex X-inactivation process.

Pin1 and neurodegeneration: a new player for prion disorders?

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Elisa Isopi

2015-07-01

Full Text Available Pin1 is a peptidyl-prolyl isomerase that catalyzes the cis/trans conversion of phosphorylated proteins at serine or threonine residues which precede a proline. The peptidyl-prolyl isomerization induces a conformational change of the proteins involved in cell signaling process. Pin1 dysregulation has been associated with some neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease and Huntington's disease. Proline-directed phosphorylation is a common regulator of these pathologies and a recent work showed that it is also involved in prion disorders. In fact, prion protein phosphorylation at the Ser-43-Pro motif induces prion protein conversion into a disease-associated form. Furthermore, phosphorylation at Ser-43-Pro has been observed to increase in the cerebral spinal fluid of sporadic Creutzfeldt-Jakob Disease patients. These findings provide new insights into the pathogenesis of prion disorders, suggesting Pin1 as a potential new player in the disease. In this paper, we review the mechanisms underlying Pin1 involvement in the aforementioned neurodegenerative pathologies focusing on the potential role of Pin1 in prion disorders.

Atomic Layer Deposition Re Ective Coatings For Future Astronomical Space Telescopes And The Solar Corona Viewed Through The Minxss (Miniature X-Ray Solar Spectrometer) Cubesats

Science.gov (United States)

Moore, Christopher Samuel

2017-11-01

Advances in technology and instrumentation open new windows for observing astrophysical objects. The first half of my dissertation involves the development of atomic layer deposition (ALD) coatings to create high reflectivity UV mirrors for future satellite astronomical telescopes. Aluminum (Al) has intrinsic reflectance greater than 80% from 90 – 2,000 nm, but develops a native aluminum oxide (Al2O3) layer upon exposure to air that readily absorbs light below 250 nm. Thus, Al based UV mirrors must be protected by a transmissive overcoat. Traditionally, metal-fluoride overcoats such as MgF2 and LiF are used to mitigate oxidation but with caveats. We utilize a new metal fluoride (AlF3) to protect Al mirrors deposited by ALD. ALD allows for precise thickness control, conformal and near stoichiometric thin films. We prove that depositing ultra-thin ( 3 nm) ALD ALF3 to protect Al mirrors after removing the native oxide layer via atomic layer etching (ALE) enhances the reflectance near 90 nm from 5% to 30%.X-ray detector technology with high readout rates are necessary for the relatively bright Sun, particularly during large flares. The hot plasma in the solar corona generates X-rays, which yield information on the physical conditions of the plasma. The second half of my dissertation includes detector testing, characterization and solar science with the Miniature X-ray Solar Spectrometer (MinXSS) CubeSats. The MinXSS CubeSats employ Silicon Drift Diode (SDD) detectors called X123, which generate full sun spectrally resolved ( 0.15 FWHM at 5.9 keV) measurements of the sparsely measured, 0.5 – 12 keV range. The absolute radiometric calibration of the MinXSS instrument suite was performed at the National Institute for Standards and Technology (NIST) Synchrotron Ultraviolet Radiation Facility (SURF) and spectral resolution determined from radioactive sources. I used MinXSS along with data from the Geostationary Operational Environmental Satellites (GOES), Reuven Ramaty

From bench to bed: putative animal models of REM sleep behavior disorder (RBD).

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Krenzer, Martina; Lu, Jun; Mayer, Geert; Oertel, Wolfgang

2013-04-01

REM behavior disorder (RBD) is a parasomnia characterized by REM sleep without atonia, leading to abnormal and potentially injurious behavior during REM sleep. It is considered one of the most specific predictors of neurodegenerative disorders, such as Parkinson's disease. In this paper, we provide an overview of animal models contributing to our current understanding of REM-associated atonia, and, as a consequence, the pathophysiology of RBD. The generator of REM-associated atonia is located in glutamatergic neurons of the pontine sublaterodorsal nucleus (SLD), as shown in cats, rats and mice. These findings are supported by clinical cases of patients with lesions of the homologous structure in humans. Glutamatergic SLD neurons, presumably in conjunction with others, project to (a) the ventromedial medulla, where they either directly target inhibitory interneurons to alpha motor neurons or are relayed, and (b) the spinal cord directly. At the spinal level, alpha motor neurons are inhibited by GABAergic and glycinergic interneurons. Our current understanding is that lesions of the glutamatergic SLD are the key factor for REM sleep behavior disorder. However, open questions remain, e.g. other features of RBD (such as the typically aggressive dream content) or the frequent progression from idiopathic RBD to neurodegenerative disorders, to name only a few. In order to elucidate these questions, a constant interaction between basic and clinical researchers is required, which might, ultimately, create an early therapeutic window for neurodegenerative disorders.

Morbidities in rapid eye movement sleep behavior disorder

DEFF Research Database (Denmark)

Jennum, Poul; Mayer, Geert; Ju, Yo-El

2013-01-01

Idiopathic rapid eye movement (REM) sleep behavior disorder (iRBD, RBD without any obvious comorbid major neurological disease), is strongly associated with numerous comorbid conditions. The most prominent is that with neurodegenerative disorders, especially synuclein-mediated disorders, above all...... function, neuropsychiatric manifestations and sleep complaints. Furthermore, patients with PD and RBD may have worse prognosis in terms of impaired cognitive function and overall morbidity/mortality; in dementia, the presence of RBD is strongly associated with clinical hallmarks and pathological findings...

Understanding the role of P2X7 in affective disorders – are glial cells the major players?

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Leanne eStokes

2015-07-01

Full Text Available The pathophysiology of several psychiatric disorders has been linked to biomarkers of inflammation generating a theory of major depressive disorder as an inflammatory disease and infection and autoimmunity as major risk factors for schizophrenia. The idea of pro-inflammatory cytokines altering behavior is now well accepted however many questions remain. Microglia can produce a plethora of inflammatory cytokines and these cells appear to be critical in the link between inflammatory changes and depressive disorders. Microglia play a known role in sickness behavior which has many components of depressive-like behavior such as social withdrawal, sleep alterations, and anorexia. Numerous candidate genes have been identified for psychiatric disorders in the last decade. Single nucleotide polymorphisms in the human P2X7 gene have been linked to bipolar disorder, depression, and to the severity of depressive symptoms. P2X7 is a ligand-gated cation channel expressed on microglia with lower levels found on astrocytes and on some neuronal populations. In microglia P2X7 is a major regulator of pro-inflammatory cytokines of the interleukin-1 family. Genetic deletion of P2X7 in mice is protective for depressive behavior in addition to inflammatory responses. P2X7-/- mice have been shown to demonstrate anti-depressive-like behavior in forced swim and tail suspension behavioral tests and stressor-induced behavioral responses were blunted. Both neurochemical (norepinephrine, serotonin, dopamine and inflammatory changes have been observed in the brains of P2X7-/- mice. This review will discuss the recent evidence for involvement of P2X7 in the pathophysiology of depressive disorders and propose mechanisms by which altered signaling through this ion channel may affect the inflammatory state of the brain.

Assisted delivery of antisense therapeutics in animal models of heritable neurodegenerative and neuromuscular disorders: a systematic review and meta-analysis.

Science.gov (United States)

van der Bent, M Leontien; Paulino da Silva Filho, Omar; van Luijk, Judith; Brock, Roland; Wansink, Derick G

2018-03-08

Antisense oligonucleotide (AON)-based therapies hold promise for a range of neurodegenerative and neuromuscular diseases and have shown benefit in animal models and patients. Success in the clinic is nevertheless still limited, due to unfavourable biodistribution and poor cellular uptake of AONs. Extensive research is currently being conducted into the formulation of AONs to improve delivery, but thus far there is no consensus on which of those strategies will be the most effective. This systematic review was designed to answer in an unbiased manner which delivery strategies most strongly enhance the efficacy of AONs in animal models of heritable neurodegenerative and neuromuscular diseases. In total, 95 primary studies met the predefined inclusion criteria. Study characteristics and data on biodistribution and toxicity were extracted and reporting quality and risk of bias were assessed. Twenty studies were eligible for meta-analysis. We found that even though the use of delivery systems provides an advantage over naked AONs, it is not yet possible to select the most promising strategies. Importantly, standardisation of experimental procedures is warranted in order to reach conclusions about the most efficient delivery strategies. Our best practice guidelines for future experiments serve as a step in that direction.

Synergy between plasma-assisted ALD and roll-to-roll atmospheric pressure PE-CVD processing of moisture barrier films on polymers

NARCIS (Netherlands)

Starostin, S.A.; Keuning, W.; Schalken, J.R.G.; Creatore, M.; Kessels, W.M.M.; Bouwstra, J.B.; Sanden, van de M.C.M.; Vries, de H.W.

2016-01-01

The synergy between fast (1600 nm · min−1), roll-to-roll plasma-enhanced chemical vapor deposited (PE-CVD) SiO2 layers and plasma-assisted atomic layer deposited (PA-ALD) ultra-thin Al2O3 films has been investigated in terms of moisture permeation barrier properties. The effective and intrinsic

Synergy Between Plasma-Assisted ALD and Roll-to-Roll Atmospheric Pressure PE-CVD Processing of Moisture Barrier Films on Polymers

NARCIS (Netherlands)

Starostin, S. A.; Keuning, W.; Schalken, J.; Creatore, M.; Kessels, W. M. M.; Bouwstra, J. B.; van de Sanden, M. C. M.; de Vries, H. W.

2016-01-01

The synergy between fast (1600 nm · min−1), roll-to-roll plasma-enhanced chemical vapor deposited (PE-CVD) SiO2 layers and plasma-assisted atomic layer deposited (PA-ALD) ultra-thin Al2O3 films has been investigated in terms of moisture permeation barrier properties. The effective and intrinsic

Paraneoplastic autoimmune movement disorders.

Science.gov (United States)

Lim, Thien Thien

2017-11-01

To provide an overview of paraneoplastic autoimmune disorders presenting with various movement disorders. The spectrum of paraneoplastic autoimmune disorders has been expanding with the discovery of new antibodies against cell surface and intracellular antigens. Many of these paraneoplastic autoimmune disorders manifest as a form of movement disorder. With the discovery of new neuronal antibodies, an increasing number of idiopathic or neurodegenerative movement disorders are now being reclassified as immune-mediated movement disorders. These include anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis which may present with orolingual facial dyskinesia and stereotyped movements, CRMP-5 IgG presenting with chorea, anti-Yo paraneoplastic cerebellar degeneration presenting with ataxia, anti-VGKC complex (Caspr2 antibodies) neuromyotonia, opsoclonus-myoclonus-ataxia syndrome, and muscle rigidity and episodic spasms (amphiphysin, glutamic acid decarboxylase, glycine receptor, GABA(A)-receptor associated protein antibodies) in stiff-person syndrome. Movement disorders may be a presentation for paraneoplastic autoimmune disorders. Recognition of these disorders and their common phenomenology is important because it may lead to the discovery of an occult malignancy. Copyright © 2017 Elsevier Ltd. All rights reserved.

Effects of O2 plasma post-treatment on ZnO: Ga thin films grown by H2O-thermal ALD

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Lee, Yueh-Lin; Chuang, Jia-Hao; Huang, Tzu-Hsuan; Ho, Chong-Long; Wu, Meng-Chyi

2013-03-01

Transparent conducting oxides have been widely employed in optoelectronic devices using the various deposition methods such as sputtering, thermal evaporator, and e-gun evaporator technologies.1-3 In this work, gallium doped zinc oxide (ZnO:Ga) thin films were grown on glass substrates via H2O-thermal atomic layer deposition (ALD) at different deposition temperatures. ALD-GZO thin films were constituted as a layer-by-layer structure by stacking zinc oxides and gallium oxides. Diethylzinc (DEZ), triethylgallium (TEG) and H2O were used as zinc, gallium precursors and oxygen source, respectively. Furthermore, we investigated the influences of O2 plasma post-treatment power on the surface morphology, electrical and optical property of ZnO:Ga films. As the result of O2 plasma post-treatment, the characteristics of ZnO:Ga films exhibit a smooth surface, low resistivity, high carrier concentration, and high optical transmittance in the visible spectrum. However, the transmittance decreases with O2 plasma power in the near- and mid-infrared regions.

Synthesis, characterization, and thermal properties of homoleptic rare-earth guanidinates: promising precursors for MOCVD and ALD of rare-earth oxide thin films.

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Milanov, Andrian P; Fischer, Roland A; Devi, Anjana

2008-12-01

Eight novel homoleptic tris-guanidinato complexes M[(N(i)Pr)(2)CNR(2)](3) [M = Y (a), Gd (b), Dy (c) and R = Me (1), Et (2), (i)Pr (3)] have been synthesized and characterized by NMR, CHN-analysis, mass spectrometry and infrared spectroscopy. Single crystal structure analysis revealed that all the compounds are monomers with the rare-earth metal center coordinated to six nitrogen atoms of the three chelating guanidinato ligands in a distorted trigonal prism geometry. With the use of TGA/DTA and isothermal TGA analysis, the thermal characteristics of all the complexes were studied in detail to evaluate their suitability as precursors for thin film deposition by MOCVD and ALD. The (i)Pr-Me(2)N-guanidinates of Y, Gd and Dy (1a-c) showed excellent thermal characteristics in terms of thermal stability and volatility. Additionally, the thermal stability of the (i)Pr-Me(2)N-guanidinates of Y and Dy (1a, c) in solution was investigated by carrying out NMR decomposition experiments and both the compounds were found to be remarkably stable. All these studies indicate that (i)Pr-Me(2)N-guanidinates of Y, Gd and Dy (1a-c) have the prerequisites for MOCVD and ALD applications which were confirmed by the successful deposition of Gd(2)O(3) and Dy(2)O(3) thin films on Si(100) substrates. The MOCVD grown films of Gd(2)O(3) and Dy(2)O(3) were highly oriented in the cubic phase, while the ALD grown films were amorphous.

[Fragile X syndrome and white matter abnormalities: Case study of two brothers].

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Wallach, E; Bieth, E; Sevely, A; Cances, C

2017-03-01

Fragile X syndrome is the most usual cause of hereditary intellectual deficiency. Typical symptoms combine intellectual deficiency, social anxiety, intense emotional vigilance, and a characteristic facial dysmorphy. This is subsequent to a complete mutation of the FMR1 gene, considering a semidominant transmission linked to the unstable X. The expansion of the CGG triplet greater than 200 units combined with a high methylation pattern lead to a transcriptional silence of the FMR1 gene, and the protein product, the FMRP, is not synthesized. This protein is involved in synaptic plasticity. Brain MRI can show an increased volume of the caudate nucleus and hippocampus, combined with hypoplasia of the cerebellar vermis. Fragile X Associated Tremor Ataxia Syndrome (FXTAS) syndrome is a neurodegenerative disorder occurring in carriers of the premutation in FMR1. Brain MRI shows an increased T2 signal in the middle cerebellar peduncles. This syndrome is linked to a premutation in the FMR1 gene. We report here the case of two brothers presenting a typical fragile X symptomatology. Brain MRI showed hyperintensities of the middle cerebellar peduncles. Such MRI findings support the assumption of a genetic mosaicism. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Metallothionein in Brain Disorders

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Daniel Juárez-Rebollar

2017-01-01

Full Text Available Metallothioneins are a family of proteins which are able to bind metals intracellularly, so their main function is to regulate the cellular metabolism of essential metals. There are 4 major isoforms of MTs (I–IV, three of which have been localized in the central nervous system. MT-I and MT-II have been localized in the spinal cord and brain, mainly in astrocytes, whereas MT-III has been found mainly in neurons. MT-I and MT-II have been considered polyvalent proteins whose main function is to maintain cellular homeostasis of essential metals such as zinc and copper, but other functions have also been considered: detoxification of heavy metals, regulation of gene expression, processes of inflammation, and protection against free radicals generated by oxidative stress. On the other hand, the MT-III has been related in events of pathogenesis of neurodegenerative diseases such as Parkinson and Alzheimer. Likewise, the participation of MTs in other neurological disorders has also been reported. This review shows recent evidence about the role of MT in the central nervous system and its possible role in neurodegenerative diseases as well as in brain disorders.

Tau imaging in neurodegenerative diseases

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Dani, M.; Edison, P. [Imperial College London, Neurology Imaging Unit, Division of Neuroscience, London (United Kingdom); Brooks, D.J. [Imperial College London, Neurology Imaging Unit, Division of Neuroscience, London (United Kingdom); Aarhus University, Institute of Clinical Medicine, Aarhus (Denmark)

2016-06-15

Aggregated tau protein is a major neuropathological substrate central to the pathophysiology of neurodegenerative diseases such as Alzheimer's disease (AD), frontotemporal dementia, progressive supranuclear palsy, corticobasal degeneration and chronic traumatic encephalopathy. In AD, it has been shown that the density of hyperphosphorylated tau tangles correlates closely with neuronal dysfunction and cell death, unlike β-amyloid. Until now, diagnostic and pathologic information about tau deposition has only been available from invasive techniques such as brain biopsy or autopsy. The recent development of selective in-vivo tau PET imaging ligands including [{sup 18}F]THK523, [{sup 18}F]THK5117, [{sup 18}F]THK5105 and [{sup 18}F]THK5351, [{sup 18}F]AV1451(T807) and [{sup 11}C]PBB3 has provided information about the role of tau in the early phases of neurodegenerative diseases, and provided support for diagnosis, prognosis, and imaging biomarkers to track disease progression. Moreover, the spatial and longitudinal relationship of tau distribution compared with β - amyloid and other pathologies in these diseases can be mapped. In this review, we discuss the role of aggregated tau in tauopathies, the challenges posed in developing selective tau ligands as biomarkers, the state of development in tau tracers, and the new clinical information that has been uncovered, as well as the opportunities for improving diagnosis and designing clinical trials in the future. (orig.)

Chronic traumatic encephalopathy and other neurodegenerative proteinopathies

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Maria Carmela Tartaglia

2014-01-01

Full Text Available Chronic traumatic encephalopathy (CTE is described as a slowly progressive neurodegenerative disease believed to result from multiple concussions. Traditionally, concussions were considered benign events and although most people recover fully, about 10% develop a post-concussive syndrome with persisting neurological, cognitive and neuropsychiatric symptoms. CTE was once thought to be unique to boxers, but it has now been observed in many different athletes having suffered multiple concussions as well as in military personal after repeated blast injuries. Much remains unknown about the development of CTE but its pathological substrate is usually tau, similar to that seen in Alzheimer’s disease and frontotemporal lobar degeneration. The aim of this perspective is to compare and contrast clinical and pathological CTE with the other neurodegenerative proteinopathies and highlight that there is an urgent need for understanding the relationship between concussion and the development of CTE as it may provide a window into the development of a proteinopathy and thus new avenues for treatment.

Sequestration of DROSHA and DGCR8 by Expanded CGG RNA Repeats Alters MicroRNA Processing in Fragile X-Associated Tremor/Ataxia Syndrome

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Chantal Sellier

2013-03-01

Full Text Available Fragile X-associated tremor/ataxia syndrome (FXTAS is an inherited neurodegenerative disorder caused by the expansion of 55–200 CGG repeats in the 5′ UTR of FMR1. These expanded CGG repeats are transcribed and accumulate in nuclear RNA aggregates that sequester one or more RNA-binding proteins, thus impairing their functions. Here, we have identified that the double-stranded RNA-binding protein DGCR8 binds to expanded CGG repeats, resulting in the partial sequestration of DGCR8 and its partner, DROSHA, within CGG RNA aggregates. Consequently, the processing of microRNAs (miRNAs is reduced, resulting in decreased levels of mature miRNAs in neuronal cells expressing expanded CGG repeats and in brain tissue from patients with FXTAS. Finally, overexpression of DGCR8 rescues the neuronal cell death induced by expression of expanded CGG repeats. These results support a model in which a human neurodegenerative disease originates from the alteration, in trans, of the miRNA-processing machinery.

KKR-CPA calculations of density of states and soft X-ray emission from disordered Li-Mg alloys

International Nuclear Information System (INIS)

Rajput, S.S.; Singru, R.M.; Prasad, R.

1994-01-01

The density of states (DOS) and soft X-ray spectra from disordered Li 1-x Mg x alloys have been calculated by using the charge self-consistent KKR-CPA method. We find that the DOS at the Fermi energy (E F ) shows an interesting behaviour as a function of x; it first increases in the range x=0.0 to 0.14, then shows a flat behaviour in the range x approx. 0.14 to 0.20 and finally decreases smoothly from x=0.20 to 0.60. We show that this behaviour of the DOS is related to the development of a neck in the Fermi surface and its smearing due to disorder scattering. Theoretical results for the soft X-ray emission spectra are compared with experimental results and are found to be in good accord. (author). 14 refs, 4 figs, 1 tab

Neural correlates of apathy in patients with neurodegenerative disorders, acquired brain injury, and psychiatric disorders

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Kos, Claire; van Tol, Marie-Jose; Marsman, Jan-Bernard C.; Knegtering, Henderikus; Aleman, Andre

2016-01-01

Apathy can be described as a loss of goal-directed purposeful behavior and is common in a variety of neurological and psychiatric disorders. Although previous studies investigated associations between abnormal brain functioning and apathy, it is unclear whether the neural basis of apathy is similar

A rare mitochondrial disorder: Leigh sydrome - a case report

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Shrikhande Dhananjay Y

2010-09-01

Full Text Available Abstract Leigh syndrome is a rare progressive neurodegenerative, mitochondrial disorder of childhood with only a few cases documented from India. The clinical presentation of Leigh syndrome is highly variable. However, in most cases it presents as a progressive neurological disease with motor and intellectual developmental delay and signs and symptoms of brain stem and/or basal ganglia involvement. Raised lactate levels in blood and/or cerebrospinal fluid is noted. It is the neuroimaging, mainly the Magnetic Resonance Imaging showing characteristic symmetrical necrotic lesions in the basal ganglia and/or brain stem that leads to the diagnosis. Here, we report a case of 7 months old female child presenting to us with status epilepticus, delayed developmental milestones and regression of the achieved milestones suspected to be a case of neurodegenerative disorder, which on MRI was diagnosed as Leigh syndrome.

Quantum and superconducting fluctuations effects in disordered Nb 1- xTa x thin films above Tc

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Giannouri, M.; Papastaikoudis, C.

1999-05-01

Disordered Nb 1- xTa x thin films are prepared with e-gun coevaporation. The influence of the β-phase of tantalum in the critical temperature Tc is observed as a function of the substrate temperature. The measurements of transverse magnetoresistance at various isothermals are interpreted in terms of weak-localization and superconducting fluctuations. From the fitting procedure, the phase breaking rate τφ-1 and the Larkin parameter βL are estimated as a function of temperature. Conclusions about the dominant inelastic scattering mechanisms at various temperature regions as well as for the dominant mechanism of superconducting fluctuations near the transition temperature are extracted.

Repeat-mediated epigenetic dysregulation of the FMR1 gene in the fragile X-related disorders.

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Usdin, Karen; Kumari, Daman

2015-01-01

The fragile X-related disorders are members of the Repeat Expansion Diseases, a group of genetic conditions resulting from an expansion in the size of a tandem repeat tract at a specific genetic locus. The repeat responsible for disease pathology in the fragile X-related disorders is CGG/CCG and the repeat tract is located in the 5' UTR of the FMR1 gene, whose protein product FMRP, is important for the proper translation of dendritic mRNAs in response to synaptic activation. There are two different pathological FMR1 allele classes that are distinguished only by the number of repeats. Premutation alleles have 55-200 repeats and confer risk of fragile X-associated tremor/ataxia syndrome and fragile X-associated primary ovarian insufficiency. Full mutation alleles on the other hand have >200 repeats and result in fragile X syndrome, a disorder that affects learning and behavior. Different symptoms are seen in carriers of premutation and full mutation alleles because the repeat number has paradoxical effects on gene expression: Epigenetic changes increase transcription from premutation alleles and decrease transcription from full mutation alleles. This review will cover what is currently known about the mechanisms responsible for these changes in FMR1 expression and how they may relate to other Repeat Expansion Diseases that also show repeat-mediated changes in gene expression.

Fragile X-associated tremor/ataxia syndrome: phenotypic comparisons with other movement disorders.

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Robertson, Erin E; Hall, Deborah A; McAsey, Andrew R; O'Keefe, Joan A

2016-08-01

The purpose of this paper is to review the typical cognitive and motor impairments seen in fragile X-associated tremor/ataxia syndrome (FXTAS), essential tremor (ET), Parkinson disease (PD), spinocerebellar ataxias (SCAs), multiple system atrophy (MSA), and progressive supranuclear palsy (PSP) in order to enhance diagnosis of FXTAS patients. We compared the cognitive and motor phenotypes of FXTAS with each of these other movement disorders. Relevant neuropathological and neuroimaging findings are also reviewed. Finally, we describe the differences in age of onset, disease severity, progression rates, and average lifespan in FXTAS compared to ET, PD, SCAs, MSA, and PSP. We conclude with a flow chart algorithm to guide the clinician in the differential diagnosis of FXTAS. By comparing the cognitive and motor phenotypes of FXTAS with the phenotypes of ET, PD, SCAs, MSA, and PSP we have clarified potential symptom overlap while elucidating factors that make these disorders unique from one another. In summary, the clinician should consider a FXTAS diagnosis and testing for the Fragile X mental retardation 1 (FMR1) gene premutation if a patient over the age of 50 (1) presents with cerebellar ataxia and/or intention tremor with mild parkinsonism, (2) has the middle cerebellar peduncle (MCP) sign, global cerebellar and cerebral atrophy, and/or subcortical white matter lesions on MRI, or (3) has a family history of fragile X related disorders, intellectual disability, autism, premature ovarian failure and has neurological signs consistent with FXTAS. Peripheral neuropathy, executive function deficits, anxiety, or depression are supportive of the diagnosis. Distinct profiles in the cognitive and motor domains between these movement disorders may guide practitioners in the differential diagnosis process and ultimately lead to better medical management of FXTAS patients.

The ELISA-measured increase in cerebrospinal fluid tau that discriminates Alzheimer's disease from other neurodegenerative disorders is not attributable to differential recognition of tau assembly forms.

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O'Dowd, Seán T; Ardah, Mustafa T; Johansson, Per; Lomakin, Aleksey; Benedek, George B; Roberts, Kinley A; Cummins, Gemma; El Agnaf, Omar M; Svensson, Johan; Zetterberg, Henrik; Lynch, Timothy; Walsh, Dominic M

2013-01-01

Elevated cerebrospinal fluid concentrations of tau discriminate Alzheimer's disease from other neurodegenerative conditions. The reasons for this are unclear. While commercial assay kits are widely used to determine total-tau concentrations, little is known about their ability to detect different aggregation states of tau. We demonstrate that the leading commercial enzyme-linked immunosorbent assay reliably detects aggregated and monomeric tau and evinces good recovery of both species when added into cerebrospinal fluid. Hence, the disparity between total-tau levels encountered in Alzheimer's disease and other neurodegenerative conditions is not due to differential recognition of tau assembly forms or the extent of degeneration.

When cytokinin, a plant hormone, meets the adenosine A2A receptor: a novel neuroprotectant and lead for treating neurodegenerative disorders?

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Yi-Chao Lee

Full Text Available It is well known that cytokinins are a class of phytohormones that promote cell division in plant roots and shoots. However, their targets, biological functions, and implications in mammalian systems have rarely been examined. In this study, we show that one cytokinin, zeatin riboside, can prevent pheochromocytoma (PC12 cells from serum deprivation-induced apoptosis by acting on the adenosine A(2A receptor (A(2A-R, which was blocked by an A(2A-R antagonist and a protein kinase A (PKA inhibitor, demonstrating the functional ability of zeatin riboside by mediating through A(2A-R signaling event. Since the A(2A-R was implicated as a therapeutic target in treating Huntington's disease (HD, a cellular model of HD was applied by transfecting mutant huntingtin in PC12 cells. By using filter retardation assay and confocal microscopy we found that zeatin riboside reversed mutant huntingtin (Htt-induced protein aggregations and proteasome deactivation through A(2A-R signaling. PKA inhibitor blocked zeatin riboside-induced suppression of mutant Htt aggregations. In addition, PKA activated proteasome activity and reduced mutant Htt protein aggregations. However, a proteasome inhibitor blocked both zeatin riboside-and PKA activator-mediated suppression of mutant Htt aggregations, confirming mediation of the A(2A-R/PKA/proteasome pathway. Taken together, zeatin riboside might have therapeutic potential as a novel neuroprotectant and a lead for treating neurodegenerative disorders.

Assessment of Olfactory Function in MAPT-Associated Neurodegenerative Disease Reveals Odor-Identification Irreproducibility as a Non-Disease-Specific, General Characteristic of Olfactory Dysfunction.

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Markopoulou, Katerina; Chase, Bruce A; Robowski, Piotr; Strongosky, Audrey; Narożańska, Ewa; Sitek, Emilia J; Berdynski, Mariusz; Barcikowska, Maria; Baker, Matt C; Rademakers, Rosa; Sławek, Jarosław; Klein, Christine; Hückelheim, Katja; Kasten, Meike; Wszolek, Zbigniew K

2016-01-01

Olfactory dysfunction is associated with normal aging, multiple neurodegenerative disorders, including Parkinson's disease, Lewy body disease and Alzheimer's disease, and other diseases such as diabetes, sleep apnea and the autoimmune disease myasthenia gravis. The wide spectrum of neurodegenerative disorders associated with olfactory dysfunction suggests different, potentially overlapping, underlying pathophysiologies. Studying olfactory dysfunction in presymptomatic carriers of mutations known to cause familial parkinsonism provides unique opportunities to understand the role of genetic factors, delineate the salient characteristics of the onset of olfactory dysfunction, and understand when it starts relative to motor and cognitive symptoms. We evaluated olfactory dysfunction in 28 carriers of two MAPT mutations (p.N279K, p.P301L), which cause frontotemporal dementia with parkinsonism, using the University of Pennsylvania Smell Identification Test. Olfactory dysfunction in carriers does not appear to be allele specific, but is strongly age-dependent and precedes symptomatic onset. Severe olfactory dysfunction, however, is not a fully penetrant trait at the time of symptom onset. Principal component analysis revealed that olfactory dysfunction is not odor-class specific, even though individual odor responses cluster kindred members according to genetic and disease status. Strikingly, carriers with incipient olfactory dysfunction show poor inter-test consistency among the sets of odors identified incorrectly in successive replicate tests, even before severe olfactory dysfunction appears. Furthermore, when 78 individuals without neurodegenerative disease and 14 individuals with sporadic Parkinson's disease were evaluated twice at a one-year interval using the Brief Smell Identification Test, the majority also showed inconsistency in the sets of odors they identified incorrectly, independent of age and cognitive status. While these findings may reflect the

Assessment of Olfactory Function in MAPT-Associated Neurodegenerative Disease Reveals Odor-Identification Irreproducibility as a Non-Disease-Specific, General Characteristic of Olfactory Dysfunction.

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Katerina Markopoulou

Full Text Available Olfactory dysfunction is associated with normal aging, multiple neurodegenerative disorders, including Parkinson's disease, Lewy body disease and Alzheimer's disease, and other diseases such as diabetes, sleep apnea and the autoimmune disease myasthenia gravis. The wide spectrum of neurodegenerative disorders associated with olfactory dysfunction suggests different, potentially overlapping, underlying pathophysiologies. Studying olfactory dysfunction in presymptomatic carriers of mutations known to cause familial parkinsonism provides unique opportunities to understand the role of genetic factors, delineate the salient characteristics of the onset of olfactory dysfunction, and understand when it starts relative to motor and cognitive symptoms. We evaluated olfactory dysfunction in 28 carriers of two MAPT mutations (p.N279K, p.P301L, which cause frontotemporal dementia with parkinsonism, using the University of Pennsylvania Smell Identification Test. Olfactory dysfunction in carriers does not appear to be allele specific, but is strongly age-dependent and precedes symptomatic onset. Severe olfactory dysfunction, however, is not a fully penetrant trait at the time of symptom onset. Principal component analysis revealed that olfactory dysfunction is not odor-class specific, even though individual odor responses cluster kindred members according to genetic and disease status. Strikingly, carriers with incipient olfactory dysfunction show poor inter-test consistency among the sets of odors identified incorrectly in successive replicate tests, even before severe olfactory dysfunction appears. Furthermore, when 78 individuals without neurodegenerative disease and 14 individuals with sporadic Parkinson's disease were evaluated twice at a one-year interval using the Brief Smell Identification Test, the majority also showed inconsistency in the sets of odors they identified incorrectly, independent of age and cognitive status. While these findings may

Risk Factors for Neurodegeneration in Idiopathic REM sleep Behavior Disorder: A Multicenter Study

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Postuma, RB; Iranzo, A; Hogl, B; Arnulf, I; Ferini-Strambi, L; Manni, R; Miyamoto, T.; Oertel, W; Dauvilliers, Y; Ju, Y; Puligheddu, M; Sonka, K; Pelletier, A; Santamaria, J; Frauscher, B; Leu-Semenescu, S; Zucconi, M; Terzaghi, M; Miyamoto, M.; Unger, MM; Carlander, B; Fantini, ML; Montplaisir, JY

2018-01-01

Objective To assess whether risk factors for Parkinson’s disease and Dementia with Lewy bodies increase rate of defined neurodegenerative disease in idiopathic REM sleep behavior disorder Methods 12 centers administered a detailed questionnaire assessing risk factors for neurodegenerative synucleinopathy to patients with idiopathic REM sleep behavior disorder. Variables included demographics, lifestyle factors, pesticide exposures, occupation, co-morbid conditions, medication use, family history, and autonomic/motor symptoms. After 4-years follow-up, patients were assessed for dementia or parkinsonism. Disease risk was assessed with Kaplan-Meier analysis, and epidemiologic variables were compared between convertors and those still idiopathic using logistic regression. Results Of 305 patients, follow-up information was available for 279, of whom 93 (33.3%) developed defined neurodegenerative disease. Disease risk was 25% at 3 years, and 41% after 5 years. Patients who converted were older (difference=4.5 years, pconversion. Although occupation was similar between groups, those who converted had a lower likelihood of pesticide exposure (occupational insecticide=2.3% vs. 9.0%). Convertors were more likely to report family history of dementia (OR=2.09), without significant differences in Parkinson’s disease or sleep disorders. Medication exposures and medical history were similar between groups. Autonomic and motor symptoms were more common among those who converted. Risk factors for primary dementia and parkinsonism were generally similar, except for a notably higher clonazepam use in dementia convertors (OR=2.6). Interpretation Patients with idiopathic RBD are at very high risk of neurodegenerative synucleinopathy. Risk factor profiles between convertors and non-convertors have both important commonalities and differences. PMID:25767079

REM sleep behavior disorder in Parkinson′s disease: A case from India confirmed with polysomnographic data

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Ravi Gupta

2013-01-01

Full Text Available Rapid eye movement (REM sleep behavior disorder is a condition characterized by dream enactment. This condition may accompany neurodegenerative disorders. However, only a few reports from India are available, that too, without any polysomnographic evidence. We are reporting a case of REM sleep behavior disorder with polysomnographic evidence.

Dissecting the Molecular Mechanisms of Neurodegenerative Diseases through Network Biology

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Jose A. Santiago

2017-05-01

Full Text Available Neurodegenerative diseases are rarely caused by a mutation in a single gene but rather influenced by a combination of genetic, epigenetic and environmental factors. Emerging high-throughput technologies such as RNA sequencing have been instrumental in deciphering the molecular landscape of neurodegenerative diseases, however, the interpretation of such large amounts of data remains a challenge. Network biology has become a powerful platform to integrate multiple omics data to comprehensively explore the molecular networks in the context of health and disease. In this review article, we highlight recent advances in network biology approaches with an emphasis in brain-networks that have provided insights into the molecular mechanisms leading to the most prevalent neurodegenerative diseases including Alzheimer’s (AD, Parkinson’s (PD and Huntington’s diseases (HD. We discuss how integrative approaches using multi-omics data from different tissues have been valuable for identifying biomarkers and therapeutic targets. In addition, we discuss the challenges the field of network medicine faces toward the translation of network-based findings into clinically actionable tools for personalized medicine applications.

Progress of the relationship between serum uric acid and neurodegenerative diseases

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Yang FU

2018-04-01

Full Text Available Serum uric acid (sUA, a natural antioxidant in human body, has been found to be related to the occurrence and development of various neurodegenerative diseases in recent years, including Parkinson's disease (PD, multiple system atrophy (MSA, Alzheimer's disease (AD and amyotrophic lateral sclerosis (ALS. Increasing of sUA level has been found to reduce the incidence of PD and ALS, but the relationship between sUA and AD, MSA remains largely unknown. The in vitro studies and animal experiments revealed that sUA can enhance the antioxidant capacity of neurons and delay neurodegeneration and apoptosis. This paper mainly reviews the progress in epidemiological and basic studies of the relationship between sUA and neurodegenerative diseases in recent years, and aims to provide a reference for future novel prevention and treatment strategies for neurodegenerative diseases. DOI: 10.3969/j.issn.1672-6731.2018.03.010

High-school football and late-life risk of neurodegenerative syndromes, 1956–1970

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Janssen, Pieter HH; Mandrekar, Jay; Mielke, Michelle M; Ahlskog, J. Eric; Boeve, Bradley F; Josephs, Keith; Savica, Rodolfo

2017-01-01

BACKGROUND Repeated head trauma has been associated with risk of neurodegenerative diseases. Few studies have evaluated the long-term risk of neurodegenerative diseases in collision sports like football. OBJECTIVE To assess whether athletes who played American varsity high-school football between 1956 and 1970 have an increased risk of neurodegenerative diseases later in life. PATIENTS AND METHODS We identified all male varsity football players between 1956 and 1970 in the public high schools of Rochester, Minnesota, compared to non-football-playing male varsity swimmers, wrestlers or basketball players. Using the records-linkage system of the Rochester Epidemiology Project, we ascertained the incidence of late-life neurodegenerative diseases: dementia, parkinsonism, or amyotrophic lateral sclerosis. We also recorded medical record-documented head trauma during high school years. RESULTS We identified 296 varsity football players and 190 athletes engaging in other sports. Football players had an increased risk of medically documented head trauma, especially if they played football for more than one year. Compared to non-football athletes, football players did not have an increased risk of neurodegenerative disease overall, nor the individual conditions of dementia, parkinsonism, or amyotrophic lateral sclerosis. CONCLUSION In this community based study, varsity high school football players from 1956 to 1970 did not have an increased risk of developing neurodegenerative diseases compared with athletes engaged in other varsity sports. This was from an era where there was a generally nihilistic view of concussion dangers, less protective equipment and without prohibition of spearing (head-first tackling). However, size and strength of players from prior eras may not be comparable to current high-school athletes. PMID:27979411

The Report on 2 Cases of Fragile X Syndrome Comorbid with Attention Deficit/Hyperactivity Disorder

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Katayoun Khoushabi

2000-07-01

Full Text Available The term “fragile X syndrome” is named after a constriction recognizable on chromosome (at Xq 27.3 cultured at chromosome media without folic acid. The unstable part includes repetition of 3 nucleotides which is intensified at subsequent generation (DNA amplification and gives rise to a more severe phenotype in the individual. About 20% of males have normal fragile X syndrome. The daughters of these individuals have abnormal chromosomes (carrier and their grandchildren will be marked. In typical syndrome, the boys will suffer from mental retardation, macrocephalia, large or protruding ears, elongated face, and macroorchidism. In terms of behavioral comorbidity, symptoms are similar to pervasive developmental disorder such as autism and attention deficit/hyperactivity disorder. The impairments in cognitive abilities are manifested as learning difficulties to severe problems. Our patients were 2 boys (6 and 7 years old referred due to their hyperactivity. In physical examination, attention deficit/hyperactivity disorder as well as fragile X syndrome were confirmed. In chromosome culture test, the constriction at Xq 27.3 was specified.

Ocimum basilicum improve chronic stress-induced neurodegenerative changes in mice hippocampus.

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Ayuob, Nasra Naeim; El Wahab, Manal Galal Abd; Ali, Soad Shaker; Abdel-Tawab, Hanem Saad

2018-01-22

Alzheimer's disease (AD), one of the progressive neurodegenerative diseases might be associated with exposure to stress and altered living conditions. This study aimed to evaluate the effectiveness of Ocimum basilicum (OB) essential oils in improving the neurodegenerative-like changes induced in mice after exposed to chronic unpredictable mild stress (CUMS). Forty male Swiss albino mice divided into four groups (n = 10); the control, CUMS, CUMS + Fluoxetine, CUMS + OB were used. Behavioral tests, serum corticosterone level, hippocampus protein level of the glucocorticoid receptors (GRs) and brain-dreived neurotropic factor (BDNF) were determined after exposure to CUMS. Hippocampus was histopathologically examined. Data were analyzed using statistical package for the social sciences (SPSS) and P value of less than 0.05 was considered significant. OB diminished the depression manifestation as well as impaired short term memory observed in the mice after exposure to the CUMS as evidenced by the forced swimming and elevated plus maze test. OB also up-regulated the serum corticosterone level, hippocampal protein level of the glucocorticoid receptor and the brain-derived neurotropic factor and reduced the neurodegenerative and atrophic changes induced in the hippocampus after exposure to CUMS. Essential oils of OB alleviated the memory impairment and hippocampal neurodegenerative changes induced by exposure to the chronic unpredictable stress indicating that it is the time to test its effectiveness on patients suffering from Alzheimer disease.

[Zr(NEtMe)2(guan-NEtMe)2] as a novel ALD precursor: ZrO2 film growth and mechanistic studies

NARCIS (Netherlands)

Blanquart, T.; Niinistö, J.; Aslam, N.; Banerjee, M.; Tomczak, Y.; Gavagnin, M.; Longo, V.; Puukilainen, E.; Wanzenboeck, H.D.; Kessels, W.M.M.; Devi, A.; Hoffmann-Eifert, S.; Ritala, M.; Leskelä, M.

2013-01-01

[Zr(NEtMe)2(guan-NEtMe2)2], a recently developed compound, was investigated as a novel precursor for the atomic layer deposition (ALD) of ZrO2. With water as the oxygen source, the growth rate remained constant over a wide temperature range, whereas with ozone the growth rate increased steadily with

Magnetism and electrical transport properties of La{sub 1-x-y}Pr{sub y}Ca{sub x}MnO{sub 3} (x ∼ 0.42, y ∼ 0.40) thin films: role of microstructural disorder

Energy Technology Data Exchange (ETDEWEB)

Agarwal, Vasudha; Sharma, Geetanjali; Siwach, P.K.; Maurya, K.K.; Singh, H.K. [Dr. K.S. Krishnan Marg, CSIR-National Physical Laboratory, New Delhi (India)

2015-06-15

We report the effect of substrate-induced lattice disorder on the balance between the coexisting antiferromagnetic/charge-ordered insulating (AFM/COI) and ferromagnetic metallic (FMM) phases and the dynamics of the phase transition in the strongly phase-separated single-crystalline La{sub 1-x-y}Pr{sub y}Ca{sub x}MnO{sub 3} (x ∼ 0.42, y ∼ 0.40) thin films. At lower degree of disorder, the delicate balance between AFM/COI and FMM phases gives rise to a magnetically disordered/non-equilibrium magnetic liquid, which shows a strong supercooling behaviour and colossal thermal hysteresis in temperature dependence of magnetization (M-T) and resistivity (ρ-T). At lower temperatures, the disordered liquid freezes to yield a randomly frozen glassy state. The enhanced lattice disorder quenches the non-FM phases and promotes AFM/COI-FMM phase transition, which in turn reduces the magnetic frustration and lowers the degree of supercooling. The enhanced FMM fraction also unblocks the blocked magnetic states and results in the vanishing of the pronounced minimum in the ρ-T curve observed well above the glass transition. Our results show that the impact of enhanced lattice disorder is in many ways similar to that of the extrinsic magneto-thermodynamic perturbations. (orig.)

Investigation of structural and electrical properties of vanadium substituted disordered pyrochlore-type Ho{sub 2−x}V{sub x}Zr{sub 2}O{sub 7} nanostructure

Energy Technology Data Exchange (ETDEWEB)

Karamat, Nazia, E-mail: naziakaramatgoraya@yahoo.com [Institute of Chemical Sciences, Bahauddin Zakariya University, Multan (Pakistan); Ashiq, Muhammad Naeem, E-mail: naeemashiqqau@yahoo.com [Institute of Chemical Sciences, Bahauddin Zakariya University, Multan (Pakistan); Najam-ul-Haq, Muhammad [Institute of Chemical Sciences, Bahauddin Zakariya University, Multan (Pakistan); Ali, Irshad; Iqbal, M. Asif; Irfan, Muhammad [Department of Physics, Bahauddin Zakariya University, Multan (Pakistan); Abbas, Yasir; Athar, Muhammad [Institute of Chemical Sciences, Bahauddin Zakariya University, Multan (Pakistan)

2014-04-01

Graphical abstract: - Highlights: • Normal microemulsion method has been used for the synthesis of zirconates nanomaterials. • Structure shifted towards highly disordered pyrochlore state with substitution. • The electrical resistivity increase with the vanadium content. • The dielectric constant show resonance behavior. • The synthesized materials are suitable for microwave devices. - Abstract: Disordered pyrochlore system with composition Ho{sub 2−x}V{sub x}Zr{sub 2}O{sub 7} (where x = 0, 0.25, 0.50, 0.75 and 1) has been synthesized by the normal microemulsion route to examine the effect of vanadium substitution on structural and electrical properties. The prepared compounds are characterized by several techniques including X-ray diffraction (XRD), Fourier transform infrared (FTIR) spectroscopy, energy dispersive X-ray fluorescence (ED-XRF), energy dispersive spectra (EDS), scanning electron microscopy (SEM), temperature dependent electrical and frequency dependent dielectric measurements. The XRD analysis confirms the formation of disordered pyrochlore phase with crystallite size 7–30 nm while a second phase is also observed in the highly substituted materials. The increase in resistivity is attributed to the removal of low energy pathway due to cation disordering. The dielectric constant decreases due to lowering of dipole moment with substitution and its resonance behavior shifted toward higher frequencies. The electrical and dielectric measurements suggest that materials are suitable for high frequency electronic devices, such as oscillators, resonators and frequency filters.

Altered structural brain connectome in young adult fragile X premutation carriers.

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Leow, Alex; Harvey, Danielle; Goodrich-Hunsaker, Naomi J; Gadelkarim, Johnson; Kumar, Anand; Zhan, Liang; Rivera, Susan M; Simon, Tony J

2014-09-01

Fragile X premutation carriers (fXPC) are characterized by 55-200 CGG trinucleotide repeats in the 5' untranslated region on the Xq27.3 site of the X chromosome. Clinically, they are associated with the fragile X-Associated Tremor/Ataxia Syndrome, a late-onset neurodegenerative disorder with diffuse white matter neuropathology. Here, we conducted first-ever graph theoretical network analyses in fXPCs using 30-direction diffusion-weighted magnetic resonance images acquired from 42 healthy controls aged 18-44 years (HC; 22 male and 20 female) and 46 fXPCs (16 male and 30 female). Globally, we found no differences between the fXPCs and HCs within each gender for all global graph theoretical measures. In male fXPCs, global efficiency was significantly negatively associated with the number of CGG repeats. For nodal measures, significant group differences were found between male fXPCs and male HCs in the right fusiform and the right ventral diencephalon (for nodal efficiency), and in the left hippocampus [for nodal clustering coefficient (CC)]. In female fXPCs, CC in the left superior parietal cortex correlated with counting performance in an enumeration task. Copyright © 2014 Wiley Periodicals, Inc.

Neural correlates of apathy in patients with neurodegenerative disorders, acquired brain injury, and psychiatric disorders.

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Kos, Claire; van Tol, Marie-José; Marsman, Jan-Bernard C; Knegtering, Henderikus; Aleman, André

2016-10-01

Apathy can be described as a loss of goal-directed purposeful behavior and is common in a variety of neurological and psychiatric disorders. Although previous studies investigated associations between abnormal brain functioning and apathy, it is unclear whether the neural basis of apathy is similar across different pathological conditions. The purpose of this systematic review was to provide an extensive overview of the neuroimaging literature on apathy including studies of various patient populations, and evaluate whether the current state of affairs suggest disorder specific or shared neural correlates of apathy. Results suggest that abnormalities within fronto-striatal circuits are most consistently associated with apathy across the different pathological conditions. Of note, abnormalities within the inferior parietal cortex were also linked to apathy, a region previously not included in neuroanatomical models of apathy. The variance in brain regions implicated in apathy may suggest that different routes towards apathy are possible. Future research should investigate possible alterations in different processes underlying goal-directed behavior, ranging from intention and goal-selection to action planning and execution. Copyright © 2016. Published by Elsevier Ltd.

Chameleon sequences in neurodegenerative diseases.

Science.gov (United States)

Bahramali, Golnaz; Goliaei, Bahram; Minuchehr, Zarrin; Salari, Ali

2016-03-25

Chameleon sequences can adopt either alpha helix sheet or a coil conformation. Defining chameleon sequences in PDB (Protein Data Bank) may yield to an insight on defining peptides and proteins responsible in neurodegeneration. In this research, we benefitted from the large PDB and performed a sequence analysis on Chameleons, where we developed an algorithm to extract peptide segments with identical sequences, but different structures. In order to find new chameleon sequences, we extracted a set of 8315 non-redundant protein sequences from the PDB with an identity less than 25%. Our data was classified to "helix to strand (HE)", "helix to coil (HC)" and "strand to coil (CE)" alterations. We also analyzed the occurrence of singlet and doublet amino acids and the solvent accessibility in the chameleon sequences; we then sorted out the proteins with the most number of chameleon sequences and named them Chameleon Flexible Proteins (CFPs) in our dataset. Our data revealed that Gly, Val, Ile, Tyr and Phe, are the major amino acids in Chameleons. We also found that there are proteins such as Insulin Degrading Enzyme IDE and GTP-binding nuclear protein Ran (RAN) with the most number of chameleons (640 and 405 respectively). These proteins have known roles in neurodegenerative diseases. Therefore it can be inferred that other CFP's can serve as key proteins in neurodegeneration, and a study on them can shed light on curing and preventing neurodegenerative diseases. Copyright © 2016 Elsevier Inc. All rights reserved.

Chameleon sequences in neurodegenerative diseases

International Nuclear Information System (INIS)

Bahramali, Golnaz; Goliaei, Bahram; Minuchehr, Zarrin; Salari, Ali

2016-01-01

Chameleon sequences can adopt either alpha helix sheet or a coil conformation. Defining chameleon sequences in PDB (Protein Data Bank) may yield to an insight on defining peptides and proteins responsible in neurodegeneration. In this research, we benefitted from the large PDB and performed a sequence analysis on Chameleons, where we developed an algorithm to extract peptide segments with identical sequences, but different structures. In order to find new chameleon sequences, we extracted a set of 8315 non-redundant protein sequences from the PDB with an identity less than 25%. Our data was classified to “helix to strand (HE)”, “helix to coil (HC)” and “strand to coil (CE)” alterations. We also analyzed the occurrence of singlet and doublet amino acids and the solvent accessibility in the chameleon sequences; we then sorted out the proteins with the most number of chameleon sequences and named them Chameleon Flexible Proteins (CFPs) in our dataset. Our data revealed that Gly, Val, Ile, Tyr and Phe, are the major amino acids in Chameleons. We also found that there are proteins such as Insulin Degrading Enzyme IDE and GTP-binding nuclear protein Ran (RAN) with the most number of chameleons (640 and 405 respectively). These proteins have known roles in neurodegenerative diseases. Therefore it can be inferred that other CFP's can serve as key proteins in neurodegeneration, and a study on them can shed light on curing and preventing neurodegenerative diseases.

Chameleon sequences in neurodegenerative diseases

Energy Technology Data Exchange (ETDEWEB)

Bahramali, Golnaz [Institute of Biochemistry and Biophysics, University of Tehran, Tehran (Iran, Islamic Republic of); Goliaei, Bahram, E-mail: goliaei@ut.ac.ir [Institute of Biochemistry and Biophysics, University of Tehran, Tehran (Iran, Islamic Republic of); Minuchehr, Zarrin, E-mail: minuchehr@nigeb.ac.ir [Department of Systems Biotechnology, National Institute of Genetic Engineering and Biotechnology, (NIGEB), Tehran (Iran, Islamic Republic of); Salari, Ali [Department of Systems Biotechnology, National Institute of Genetic Engineering and Biotechnology, (NIGEB), Tehran (Iran, Islamic Republic of)

2016-03-25

Chameleon sequences can adopt either alpha helix sheet or a coil conformation. Defining chameleon sequences in PDB (Protein Data Bank) may yield to an insight on defining peptides and proteins responsible in neurodegeneration. In this research, we benefitted from the large PDB and performed a sequence analysis on Chameleons, where we developed an algorithm to extract peptide segments with identical sequences, but different structures. In order to find new chameleon sequences, we extracted a set of 8315 non-redundant protein sequences from the PDB with an identity less than 25%. Our data was classified to “helix to strand (HE)”, “helix to coil (HC)” and “strand to coil (CE)” alterations. We also analyzed the occurrence of singlet and doublet amino acids and the solvent accessibility in the chameleon sequences; we then sorted out the proteins with the most number of chameleon sequences and named them Chameleon Flexible Proteins (CFPs) in our dataset. Our data revealed that Gly, Val, Ile, Tyr and Phe, are the major amino acids in Chameleons. We also found that there are proteins such as Insulin Degrading Enzyme IDE and GTP-binding nuclear protein Ran (RAN) with the most number of chameleons (640 and 405 respectively). These proteins have known roles in neurodegenerative diseases. Therefore it can be inferred that other CFP's can serve as key proteins in neurodegeneration, and a study on them can shed light on curing and preventing neurodegenerative diseases.

ALD grown nanostructured ZnO thin films: Effect of substrate temperature on thickness and energy band gap

Directory of Open Access Journals (Sweden)

Javed Iqbal

2016-10-01

Full Text Available Nanostructured ZnO thin films with high transparency have been grown on glass substrate by atomic layer deposition at various temperatures ranging from 100 °C to 300 °C. Efforts have been made to observe the effect of substrate temperature on the thickness of the deposited thin films and its consequences on the energy band gap. A remarkably high growth rate of 0.56 nm per cycle at a substrate temperature of 200 °C for ZnO thin films have been achieved. This is the maximum growth rate for ALD deposited ZnO thin films ever reported so far to the best of our knowledge. The studies of field emission scanning electron microscopy and X-ray diffractometry patterns confirm the deposition of uniform and high quality nanosturtured ZnO thin films which have a polycrystalline nature with preferential orientation along (100 plane. The thickness of the films deposited at different substrate temperatures was measured by ellipsometry and surface profiling system while the UV–visible and photoluminescence spectroscopy studies have been used to evaluate the optical properties of the respective thin films. It has been observed that the thickness of the thin film depends on the substrate temperatures which ultimately affect the optical and structural parameters of the thin films.

A study of the disorder in heavily doped Ba1-xLaxF2+x by neutron scattering, ionic conductivity and specific heat measurements

DEFF Research Database (Denmark)

Andersen, Niels Hessel; Clausen, Kurt Nørgaard; Kjems, Jørgen

1986-01-01

The ionic disorder in single crystals of the fluorite-type solid solutions Ba1-xLaxF2+x (with x=0.209 and x=0.492) has been studied in the temperature range from room temperature to 800 degrees C by diffuse neutron scattering, ionic conductivity, and specific heat measurements. From the diffuse...... neutron scattering it was found that the disorder was dominated by 222 clusters, which at low temperatures (T>10-10s), in agreement with NMB results which suggest a jump frequency below 75 MHz. The temperatures at which the steepest slopes are found in the loss of correlations and in the conductivity...... coincide at approximately 650 degrees C. At this temperature no clear anomaly is observed in the specific heat. Based on these findings the authors propose a conduction mechanisms where F- ions are moving through the lattice by means of rearrangements of the 222 clusters....

Nutraceutical Potential of Phenolics from ′Brava′ and ′Mansa′ Extra-Virgin Olive Oils on the Inhibition of Enzymes Associated to Neurodegenerative Disorders in Comparison with Those of ′Picual′ and ′Cornicabra′

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María Figueiredo-González

2018-03-01

Full Text Available The increasing interest in the Mediterranean diet is based on the protective effects against several diseases, including neurodegenerative disorders. Polyphenol-rich functional foods have been proposed to be unique supplementary and nutraceutical treatments for these disorders. Extra-virgin olive oils (EVOOs obtained from ′Brava′ and ′Mansa′, varieties recently identified from Galicia (northwestern Spain, were selected for in vitro screening to evaluate their capacity to inhibit key enzymes involved in Alzheimer′s disease (AD (acetylcholinesterase (AChE, butyrylcholinesterase (BuChE and 5-lipoxygenase (5-LOX, major depressive disorder (MDD and Parkinson′s disease (PD (monoamine oxidases: hMAO-A and hMAO-B respectively. ′Brava′ oil exhibited the best inhibitory activity against all enzymes, when they are compared to ′Mansa′ oil: BuChE (IC50 = 245 ± 5 and 591 ± 23 mg·mL−1, 5-LOX (IC50 = 45 ± 7 and 106 ± 14 mg·mL−1, hMAO-A (IC50 = 30 ± 1 and 72 ± 10 mg·mL−1 and hMAO-B (IC50 = 191 ± 8 and 208 ± 14 mg·mL−1, respectively. The inhibitory capacity of the phenolic extracts could be associated with the content of secoiridoids, lignans and phenolic acids.

Diode behavior in ultra-thin low temperature ALD grown zinc-oxide on silicon

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Nazek El-Atab

2013-10-01

Full Text Available A thin-film ZnO(n/Si(p+ heterojunction diode is demonstrated. The thin film ZnO layer is deposited by Atomic Layer Deposition (ALD at different temperatures on a p-type silicon substrate. Atomic force microscopy (AFM AC-in-Air method in addition to conductive AFM (CAFM were used for the characterization of ZnO layer and to measure the current-voltage characteristics. Forward and reverse bias n-p diode behavior with good rectification properties is achieved. The diode with ZnO grown at 80°C exhibited the highest on/off ratio with a turn-on voltage (VON ∼3.5 V. The measured breakdown voltage (VBR and electric field (EBR for this diode are 5.4 V and 3.86 MV/cm, respectively.

Maillard reaction versus other nonenzymatic modifications in neurodegenerative processes.

Science.gov (United States)

Pamplona, Reinald; Ilieva, Ekaterina; Ayala, Victoria; Bellmunt, Maria Josep; Cacabelos, Daniel; Dalfo, Esther; Ferrer, Isidre; Portero-Otin, Manuel

2008-04-01

Nonenzymatic protein modifications are generated from direct oxidation of amino acid side chains and from reaction of the nucleophilic side chains of specific amino acids with reactive carbonyl species. These reactions give rise to specific markers that have been analyzed in different neurodegenerative diseases sharing protein aggregation, such as Alzheimer's disease, Pick's disease, Parkinson's disease, dementia with Lewy bodies, Creutzfeldt-Jakob disease, and amyotrophic lateral sclerosis. Collectively, available data demonstrate that oxidative stress homeostasis, mitochondrial function, and energy metabolism are key factors in determining the disease-specific pattern of protein molecular damage. In addition, these findings suggest the lack of a "gold marker of oxidative stress," and, consequently, they strengthen the need for a molecular dissection of the nonenzymatic reactions underlying neurodegenerative processes.

Olfaction in Neurologic and Neurodegenerative Diseases: A Literature Review

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Godoy, Maria Dantas Costa Lima

2015-01-01

Full Text Available Introduction Loss of smell is involved in various neurologic and neurodegenerative diseases, such as Parkinson disease and Alzheimer disease. However, the olfactory test is usually neglected by physicians at large. Objective The aim of this study was to review the current literature about the relationship between olfactory dysfunction and neurologic and neurodegenerative diseases. Data Synthesis Twenty-seven studies were selected for analysis, and the olfactory system, olfaction, and the association between the olfactory dysfunction and dementias were reviewed. Furthermore, is described an up to date in olfaction. Conclusion Otolaryngologist should remember the importance of olfaction evaluation in daily practice. Furthermore, neurologists and physicians in general should include olfactory tests in the screening of those at higher risk of dementia.

Cathepsin X in serum from patients with colorectal cancer: relation to prognosis

Science.gov (United States)

Vizin, Tjasa; Christensen, Ib Jarle; Nielsen, Hans Jørgen; Kos, Janko

2012-01-01

Background Up-regulation of lysosomal cysteine protease cathepsin X (Cat X) is associated with disorders of the immune system and neurodegenerative diseases, while its role in the development and progression of cancer is less understood. Enhanced secretion of pro-Cat X was observed in malignant processes, and therefore, the level of total serum Cat X rather than the active enzyme may better reflect the tumour status. Patients and methods Seventy-seven patients with colorectal cancer (CRC) were included in a retrospective study. Blood samples were collected prior to therapy. Using ELISA, the values of total Cat X were measured in serum. Groups of healthy persons (n=77), patients with adenomas (n=77) and patients with non-neoplastic findings (n=77) were included. Results Significant differences between the group of colorectal patients and the groups of healthy persons, adenoma patients and patients with non-malignant findings could not be shown (p=0.89). Within the group of CRC, higher levels of total Cat X significantly correlated to shorter overall survival (HR=2.08, 95% CI:1.07–4.05, p=0.028). Conclusions Total serum Cat X could be a useful prognostic indicator for determining survival of patients with CRC. Increased serum levels of total Cat X may reflect more aggressive tumour cell phenotypes and suggest the involvement of Cat X in processes involved in later stages of tumour progression. PMID:23077459

Superconductivity, Pairing Symmetry, and Disorder in the Doped Topological Insulator Sn_1-xIn_xTe for x >= 0.10.

Energy Technology Data Exchange (ETDEWEB)

Smylie, M. P.; Claus, H.; Kwok, W. -K.; Louden, E. R.; Eskildsen, M. R.; Sefat, A. S.; Zhong, R. D.; Schneeloch, J.; Gu, G. D.; Bokari, E.; Niraula, P. M.; Kayani, A.; Dewhurst, C. D.; Snezhko, A.; Welp, U.

2018-01-19

The temperature dependence of the London penetration depth Delta lambda(T) in the superconducting doped topological crystalline insulator Sn1-xInxTe was measured down to 450 mK for two different doping levels, x approximate to 0.45 (optimally doped) and x approximate to 0.10 (underdoped), bookending the range of cubic phase in the compound. The results indicate no deviation from fully gapped BCS-like behavior, eliminating several candidate unconventional gap structures. Critical field values below 1 K and other superconducting parameters are also presented. The introduction of disorder by repeated particle irradiation with 5 MeV protons does not enhance T-c, indicating that ferroelectric interactions do not compete with superconductivity.

Medicinal Plants in Neurodegenerative Diseases: Perspective of Traditional Persian Medicine.

Science.gov (United States)

Farzaei, Mohammad Hosein; Shahpiri, Zahra; Mehri, Mohammad Reza; Bahramsoltani, Roodabeh; Rezaei, Mahdi; Raeesdana, Azade; Rahimi, Roja

2018-01-01

Neurodegenerative diseases are a progressive loss of structure and/or function of neurons. Weak therapeutic response and progressive nature of the diseases, as well as a wide range of side effects caused by conventional therapeutic approaches make patients seek for complementary and alternative medicine. The aim of the present paper is to discuss the neuropharmacological basis of medicinal plants and their principle phytochemicals which have been used in traditional Persian medicine for different types of neurodegenerative diseases. Medicinal plants introduced in traditional Persian medicine perform beneficial effects in neurodegenerative diseases via various cellular and molecular mechanisms including suppression of apoptosis mediated by an increase in the expression of anti-apoptotic agents (e.g. Bcl-2) as well as a decrease in the expression and activity of proapoptotic proteins (e.g. Bax, caspase 3 and 9). Alleviating inflammatory responses and suppressing the expression and function of pro-inflammatory cytokines like Tumor necrosis factor α and interleukins, as well as improvement in antioxidative performance mediated by superoxide dismutase and catalase, are among other neuroprotective mechanisms of traditional medicinal plants. Modulation of transcription, transduction, intracellular signaling pathways including ERK, p38, and MAPK, with upstream regulatory activity on inflammatory cascades, apoptosis and oxidative stress associated pathways, play an essential role in the preventive and therapeutic potential of the plants in neurodegenerative diseases. Medicinal plants used in traditional Persian medicine along with their related phytochemicals by affecting various neuropharmacological pathways can be considered as future drugs or adjuvant therapies with conventional pharmacotherapeutics; though, further clinical studies are necessary for the confirmation of their safety and efficacy. Copyright© Bentham Science Publishers; For any queries, please email at

The tip of the iceberg: RNA-binding proteins with prion-like domains in neurodegenerative disease

Science.gov (United States)

King, Oliver D.; Gitler, Aaron D.; Shorter, James

2012-01-01

Prions are self-templating protein conformers that are naturally transmitted between individuals and promote phenotypic change. In yeast, prion-encoded phenotypes can be beneficial, neutral or deleterious depending upon genetic background and environmental conditions. A distinctive and portable ‘prion domain’ enriched in asparagine, glutamine, tyrosine and glycine residues unifies the majority of yeast prion proteins. Deletion of this domain precludes prionogenesis and appending this domain to reporter proteins can confer prionogenicity. An algorithm designed to detect prion domains has successfully identified 19 domains that can confer prion behavior. Scouring the human genome with this algorithm enriches a select group of RNA-binding proteins harboring a canonical RNA recognition motif (RRM) and a putative prion domain. Indeed, of 210 human RRM-bearing proteins, 29 have a putative prion domain, and 12 of these are in the top 60 prion candidates in the entire genome. Startlingly, these RNA-binding prion candidates are inexorably emerging, one by one, in the pathology and genetics of devastating neurodegenerative disorders, including: amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U), Alzheimer’s disease and Huntington’s disease. For example, FUS and TDP-43, which rank 1st and 10th among RRM-bearing prion candidates, form cytoplasmic inclusions in the degenerating motor neurons of ALS patients and mutations in TDP-43 and FUS cause familial ALS. Recently, perturbed RNA-binding proteostasis of TAF15, which is the 2nd ranked RRM-bearing prion candidate, has been connected with ALS and FTLD-U. We strongly suspect that we have now merely reached the tip of the iceberg. We predict that additional RNA-binding prion candidates identified by our algorithm will soon surface as genetic modifiers or causes of diverse neurodegenerative conditions. Indeed, simple prion-like transfer mechanisms involving the

Improving ethanol yield in acetate-reducing Saccharomyces cerevisiae by cofactor engineering of 6-phosphogluconate dehydrogenase and deletion of ALD6.

Science.gov (United States)

Papapetridis, Ioannis; van Dijk, Marlous; Dobbe, Arthur P A; Metz, Benjamin; Pronk, Jack T; van Maris, Antonius J A

2016-04-26

Acetic acid, an inhibitor of sugar fermentation by yeast, is invariably present in lignocellulosic hydrolysates which are used or considered as feedstocks for yeast-based bioethanol production. Saccharomyces cerevisiae strains have been constructed, in which anaerobic reduction of acetic acid to ethanol replaces glycerol formation as a mechanism for reoxidizing NADH formed in biosynthesis. An increase in the amount of acetate that can be reduced to ethanol should further decrease acetic acid concentrations and enable higher ethanol yields in industrial processes based on lignocellulosic feedstocks. The stoichiometric requirement of acetate reduction for NADH implies that increased generation of NADH in cytosolic biosynthetic reactions should enhance acetate consumption. Replacement of the native NADP(+)-dependent 6-phosphogluconate dehydrogenase in S. cerevisiae by a prokaryotic NAD(+)-dependent enzyme resulted in increased cytosolic NADH formation, as demonstrated by a ca. 15% increase in the glycerol yield on glucose in anaerobic cultures. Additional deletion of ALD6, which encodes an NADP(+)-dependent acetaldehyde dehydrogenase, led to a 39% increase in the glycerol yield compared to a non-engineered strain. Subsequent replacement of glycerol formation by an acetate reduction pathway resulted in a 44% increase of acetate consumption per amount of biomass formed, as compared to an engineered, acetate-reducing strain that expressed the native 6-phosphogluconate dehydrogenase and ALD6. Compared to a non-acetate reducing reference strain under the same conditions, this resulted in a ca. 13% increase in the ethanol yield on glucose. The combination of NAD(+)-dependent 6-phosphogluconate dehydrogenase expression and deletion of ALD6 resulted in a marked increase in the amount of acetate that was consumed in these proof-of-principle experiments, and this concept is ready for further testing in industrial strains as well as in hydrolysates. Altering the cofactor

High-energy synchrotron x-ray diffraction studies on disordered materials. From ambient condition to an extreme condition

International Nuclear Information System (INIS)

Kohara, Shinji; Ohishi, Yasuo; Suzuya, Kentaro; Takata, Masaki

2007-01-01

High-energy x-rays from synchrotron radiation source allow us to measure high-quality diffraction data of the disordered materials from under ambient condition to an extreme condition, which is necessary to reveal the detailed structure of glass, liquid, and amorphous materials. We introduce the high-energy x-ray diffraction beamline and dedicated diffractometer for glass, liquid, and amorphous materials with the recent developments of ancillary equipments. Furthermore our recent studies on the structures of disordered materials reviewed. (author)

A novel human model of the neurodegenerative disease GM1 gangliosidosis using induced pluripotent stem cells demonstrates inflammasome activation.

Science.gov (United States)

Son, Mi-Young; Kwak, Jae Eun; Seol, Binna; Lee, Da Yong; Jeon, Hyejin; Cho, Yee Sook

2015-09-01

GM1 gangliosidosis (GM1) is an inherited neurodegenerative disorder caused by mutations in the lysosomal β-galactosidase (β-gal) gene. Insufficient β-gal activity leads to abnormal accumulation of GM1 gangliosides in tissues, particularly in the central nervous system, resulting in progressive neurodegeneration. Here, we report an in vitro human GM1 model, based on induced pluripotent stem cell (iPSC) technology. Neural progenitor cells differentiated from GM1 patient-derived iPSCs (GM1-NPCs) recapitulated the biochemical and molecular phenotypes of GM1, including defective β-gal activity and increased lysosomes. Importantly, the characterization of GM1-NPCs established that GM1 is significantly associated with the activation of inflammasomes, which play a critical role in the pathogenesis of various neurodegenerative diseases. Specific inflammasome inhibitors potently alleviated the disease-related phenotypes of GM1-NPCs in vitro and in vivo. Our data demonstrate that GM1-NPCs are a valuable in vitro human GM1 model and suggest that inflammasome activation is a novel target pathway for GM1 drug development. Copyright © 2015 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Dysregulated Translational Control: From Brain Disorders to Psychoactive Drugs

Directory of Open Access Journals (Sweden)

Emanuela eSantini

2011-11-01

Full Text Available In the last decade, a plethora of studies utilizing pharmacological, biochemical, and genetic approaches have shown that precise translational control is required for long-lasting synaptic plasticity and the formation of long-term memory. Moreover, more recent studies indicate that alterations in translational control are a common pathophysiological feature of human neurological disorders, including developmental disorders, neuropsychiatric disorders, and neurodegenerative diseases. Finally, translational control mechanisms are susceptible to modification by psychoactive drugs. Taken together, these findings point to a central role for translational control in the regulation of synaptic function and behavior.

Order-disorder in ferroelectric PbZr1-xTixO3 system base solid solutions

International Nuclear Information System (INIS)

Redichkina, N.B.; Kupriyanov, M.F.; Dudek, Yu.; Abdulvakhidov, K.G.

1995-01-01

Effect of close order in PbZr 1-x Tr x O 3 system is studied by roentgen infraction method. It is shown that possible effects of crystal-chemical order-disorder shoved be accounted for by analysis of dependence of physical properties on real structural state parameters. Refs. 17, fig. 1

Collective effects of interface roughness and alloy disorder in InxGa1-xN/GaN multiple quantum wells

International Nuclear Information System (INIS)

Zeng, K.C.; Smith, M.; Lin, J.Y.; Jiang, H.X.

1998-01-01

The collective effects of alloy disorder and interface roughness on optical properties of In x Ga 1-x N/GaN multiple quantum wells (MQWs) have been studied. The results are compared with those of GaN/AlGaN MQWs and InGaN epilayers. In x Ga 1-x N/GaN MQWs emit a broad and asymmetrical photoluminescence (PL) band, while GaN/AlGaN MQWs and InGaN epilayers emit narrower and Gaussian-shaped PL bands. Furthermore, the decay of excitons at low temperatures in In x Ga 1-x N/GaN MQWs follows a nonexponential function even at the lower-energy side of the PL spectral peak, while those in GaN/AlGaN MQWs and in InGaN epilayers follow a single exponential function. Both alloy disorder and interface roughness have to be included in order to interpret the PL emission spectrum and the decay dynamics in In x Ga 1-x N/GaN MQWs. Important parameters of the In x Ga 1-x N/GaN MQWs, σ x ,σ L , and dτ/dL, denoting the alloy disorder, the interface roughness, and the rate of changing of the exciton decay lifetime with well width, respectively, have been deduced. The method developed here can be used to determine σ x ,σ L , and dτ/dL in any MQW systems with wells being alloy materials. copyright 1998 American Institute of Physics

Autonomic symptoms in idiopathic REM behavior disorder

DEFF Research Database (Denmark)

Ferini-Strambi, Luigi; Oertel, Wolfgang; Dauvilliers, Yves

2014-01-01

Patients with idiopathic REM sleep behavior disorder (iRBD) are at very high risk of developing neurodegenerative synucleinopathies, which are disorders with prominent autonomic dysfunction. Several studies have documented autonomic dysfunction in iRBD, but large-scale assessment of autonomic...... symptoms has never been systematically performed. Patients with polysomnography-confirmed iRBD (318 cases) and controls (137 healthy volunteers and 181 sleep center controls with sleep diagnoses other than RBD) were recruited from 13 neurological centers in 10 countries from 2008 to 2011. A validated scale...

Scientific basis for the use of Indian ayurvedic medicinal plants in the treatment of neurodegenerative disorders: ashwagandha.

Science.gov (United States)

Ven Murthy, M R; Ranjekar, Prabhakar K; Ramassamy, Charles; Deshpande, Manasi

2010-09-01

nontoxic medication that normalizes physiological functions, disturbed by chronic stress, through correction of imbalances in the neuroendocrine and immune systems [9, 10]. The scientific research that has been carried out on Ashwagandha and other ayurvedic herbal medicines may be classified into three major categories, taking into consideration the endogenous or exogenous phenomena that are known to cause physiological disequilibrium leading to the pathological state; (A) pharmacological and therapeutic effects of extracts, purified compounds or multi-herbal mixtures on specific non-neurological diseases; (B) pharmacological and therapeutic effects of extracts, purified compounds or multi-herbal mixtures on neurodegenerative disorders; and (C) biochemical, physiological and genetic studies on the herbal plants themselves, in order to distinguish between those originating from different habitats, or to improve the known medicinal quality of the indigenous plant. Some of the major points on its use in the treatment of neurodegenerative disorders are described below.

Progranulin: at the interface of neurodegenerative and metabolic diseases.

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Nguyen, Andrew D; Nguyen, Thi A; Martens, Lauren Herl; Mitic, Laura L; Farese, Robert V

2013-12-01

Progranulin is a widely expressed, cysteine-rich, secreted glycoprotein originally discovered for its growth factor-like properties. Its subsequent identification as a causative gene for frontotemporal dementia (FTD), a devastating early-onset neurodegenerative disease, has catalyzed a surge of new discoveries about progranulin function in the brain. More recently, progranulin was recognized as an adipokine involved in diet-induced obesity and insulin resistance, revealing its metabolic function. We review here progranulin biology in both neurodegenerative and metabolic diseases. In particular, we highlight the growth factor-like, trophic, and anti-inflammatory properties of progranulin as potential unifying themes in these seemingly divergent conditions. We also discuss potential therapeutic options for raising progranulin levels to treat progranulin-deficient FTD, as well as the possible consequences of such treatment. Copyright © 2013 Elsevier Ltd. All rights reserved.

Astrocytes in neurodegenerative diseases (I): function and molecular description.

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Guillamón-Vivancos, T; Gómez-Pinedo, U; Matías-Guiu, J

2015-03-01

Astrocytes have been considered mere supporting cells in the CNS. However, we now know that astrocytes are actively involved in many of the functions of the CNS and may play an important role in neurodegenerative diseases. This article reviews the roles astrocytes play in CNS development and plasticity; control of synaptic transmission; regulation of blood flow, energy, and metabolism; formation of the blood-brain barrier; regulation of the circadian rhythms, lipid metabolism and secretion of lipoproteins; and in neurogenesis. Astrocyte markers and the functions of astrogliosis are also described. Astrocytes play an active role in the CNS. A good knowledge of astrocytes is essential to understanding the mechanisms of neurodegenerative diseases. Copyright © 2012 Sociedad Española de Neurología. Published by Elsevier Espana. All rights reserved.

Beneficial Role of Coffee and Caffeine in Neurodegenerative Diseases: A Minireview

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Yenisetti SC

2016-06-01

Full Text Available Coffee is among the most widespread and healthiest beverages in the world. Coffee typically contains more caffeine than most other beverages, and is widely and frequently consumed. Thus, it contributes significantly to the overall caffeine consumption within the general population, particularly in adults. Controversies regarding its benefits and risks still exist as reliable evidence is becoming available supporting its health-promoting potential. Several lines of evidence have highlighted the beneficial effects towards several disease conditions including Type II diabetes, hepatitis C virus, hepatocellular carcinoma, nonalcoholic fatty liver disease and neurodegenerative disorders such as Alzheimer's disease (AD, Parkinson's disease (PD and Amyotrophic Lateral Sclerosis (ALS. The health-promoting properties of coffee are largely attributed to its rich phytochemistry, including caffeine, chlorogenic acid, caffeic acid, and hydroxy hydroquinone. In this minireview, an attempt has been made to discuss the various evidences which are mainly derived from animal and cell models. Various mechanisms chiefly responsible for the beneficial effects of caffeine have also been briefly outlined. A short note on the undesirable effects of excessive coffee intakes is also presented.

Atomic layer deposition of ruthenium on plasma-treated vertically aligned carbon nanotubes for high-performance ultracapacitors.

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Kim, Jun Woo; Kim, Byungwoo; Park, Suk Won; Kim, Woong; Shim, Joon Hyung

2014-10-31

It is challenging to realize a conformal metal coating by atomic layer deposition (ALD) because of the high surface energy of metals. In this study, ALD of ruthenium (Ru) on vertically aligned carbon nanotubes (CNTs) was carried out. To activate the surface of CNTs that lack surface functional groups essential for ALD, oxygen plasma was applied ex situ before ALD. X-ray photoelectron spectroscopy and Raman spectroscopy confirmed surface activation of CNTs by the plasma pretreatment. Transmission electron microscopy analysis with energy-dispersive x-ray spectroscopy composition mapping showed that ALD Ru grew conformally along CNTs walls. ALD Ru/CNTs were electrochemically oxidized to ruthenium oxide (RuOx) that can be a potentially useful candidate for use in the electrodes of ultracapacitors. Electrode performance of RuOx/CNTs was evaluated using cyclic voltammetry and galvanostatic charge-discharge measurements.

Liposomes for Targeted Delivery of Active Agents against Neurodegenerative Diseases (Alzheimer's Disease and Parkinson's Disease

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Carlos Spuch

2011-01-01

Full Text Available Neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease represent a huge unmet medical need. The prevalence of both diseases is increasing, but the efficacy of treatment is still very limited due to various factors including the blood brain barrier (BBB. Drug delivery to the brain remains the major challenge for the treatment of all neurodegenerative diseases because of the numerous protective barriers surrounding the central nervous system. New therapeutic drugs that cross the BBB are critically needed for treatment of many brain diseases. One of the significant factors on neurotherapeutics is the constraint of the blood brain barrier and the drug release kinetics that cause peripheral serious side effects. Contrary to common belief, neurodegenerative and neurological diseases may be multisystemic in nature, and this presents numerous difficulties for their potential treatment. Overall, the aim of this paper is to summarize the last findings and news related to liposome technology in the treatment of neurodegenerative diseases and demonstrate the potential of this technology for the development of novel therapeutics and the possible applications of liposomes in the two most widespread neurodegenerative diseases, Alzheimer's disease and Parkinson's disease.

Mitochondrial mutations in subjects with psychiatric disorders.

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Adolfo Sequeira

Full Text Available A considerable body of evidence supports the role of mitochondrial dysfunction in psychiatric disorders and mitochondrial DNA (mtDNA mutations are known to alter brain energy metabolism, neurotransmission, and cause neurodegenerative disorders. Genetic studies focusing on common nuclear genome variants associated with these disorders have produced genome wide significant results but those studies have not directly studied mtDNA variants. The purpose of this study is to investigate, using next generation sequencing, the involvement of mtDNA variation in bipolar disorder, schizophrenia, major depressive disorder, and methamphetamine use. MtDNA extracted from multiple brain regions and blood were sequenced (121 mtDNA samples with an average of 8,800x coverage and compared to an electronic database containing 26,850 mtDNA genomes. We confirmed novel and rare variants, and confirmed next generation sequencing error hotspots by traditional sequencing and genotyping methods. We observed a significant increase of non-synonymous mutations found in individuals with schizophrenia. Novel and rare non-synonymous mutations were found in psychiatric cases in mtDNA genes: ND6, ATP6, CYTB, and ND2. We also observed mtDNA heteroplasmy in brain at a locus previously associated with schizophrenia (T16519C. Large differences in heteroplasmy levels across brain regions within subjects suggest that somatic mutations accumulate differentially in brain regions. Finally, multiplasmy, a heteroplasmic measure of repeat length, was observed in brain from selective cases at a higher frequency than controls. These results offer support for increased rates of mtDNA substitutions in schizophrenia shown in our prior results. The variable levels of heteroplasmic/multiplasmic somatic mutations that occur in brain may be indicators of genetic instability in mtDNA.

A Low-Cost Method for Coating of Selective Laser Melting (SLM) Manufacturing of Complex High-Precision Components for Spaceflight Applications Using Atomic Layer Deposition (ALD), Phase I

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National Aeronautics and Space Administration — This proposal is intended to perform basic research using Atomic Layer Deposition (ALD) as a means of coating various substrate materials with a variety of metallic...

Molecular Pathways Bridging Frontotemporal Lobar Degeneration and Psychiatric Disorders

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Roberta eZanardini

2016-02-01

Full Text Available The overlap of symptoms between neurodegenerative and psychiatric diseases has been reported. Neuropsychiatric alterations are commonly observed in dementia, especially in the behavioral variant of frontotemporal dementia (bvFTD, which is the most common clinical FTD subtype. At the same time, psychiatric disorders, like schizophrenia, can display symptoms of dementia, including features of frontal dysfunction with relative sparing of memory. In the present review we discuss common molecular features in these pathologies with a special focus on FTD. Molecules like Brain Derived Neurotrophic Factor (BDNF and progranulin are linked to the pathophysiology of both neurodegenerative and psychiatric diseases. In these brain-associated illnesses, the presence of disease-associated variants in BDNF and progranulin (GRN genes cause a reduction of circulating proteins levels, through alterations in proteins expression or secretion. For these reasons, we believe that prevention and therapy of psychiatric and neurological disorders could be achieved enhancing both BDNF and progranulin levels thanks to drug discovery efforts.

PENN neurodegenerative disease research - in the spirit of Benjamin Franklin.

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Trojanowski, John Q

2008-01-01

Benjamin Franklin (1706-1790) was entrepreneur, statesman, supporter of the public good as well as inventor, and his most significant invention was the University of Pennsylvania (PENN). Franklin outlined his plans for a college providing practical and classical instruction to prepare youth for real-world pursuits in his 'Proposals Relating to the Education of Youth in Pensilvania' (1749), and Franklin's spirit of learning to serve society guides PENN to the present day. This is evidenced by the series of articles in this special issue of Neurosignals, describing research conducted by seasoned and newly recruited PENN faculty, addressing consequences of the longevity revolution which defines our epoch at the dawn of this millennium. While aging affects all organ systems, the nervous system is most critical to successful aging. Thus, the articles in this special issue of Neurosignals focus on research at PENN that is designed to prevent or ameliorate aging-related neurodegenerative disorders such as Alzheimer's and Parkinson's disease, amyotrophic lateral sclerosis and frontotemporal dementia. This research could enhance our chances of aging successfully in the continuing longevity revolution, and the essay here provides context and background on this research.

The Contribution of Optical Coherence Tomography in Neuromyelitis Optica Spectrum Disorders

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Mateo, Javier; Esteban, Olivia; Martínez, Mireya; Grzybowski, Andrzej; Ascaso, Francisco Javier

2017-01-01

Neuromyelitis optica spectrum disorders (NMOSD) comprises a group of central nervous system disorders of inflammatory autoimmune origin that mainly affect the optic nerves and the spinal cord and can cause severe visual and general disability. The clinical signs are similar to those of multiple sclerosis (MS), with the result that it is often difficult to differentiate between the two, thus leading to misdiagnosis. As the treatment and prognosis of NMOSD and MS are different, it is important to make an accurate and early diagnosis of NMOSD. Optical coherence tomography (OCT) is a non-invasive technique that enables a quantitative study of the changes that the optic nerve and the macula undergo in several neurodegenerative diseases. Many studies have shown that some of these changes, such as retinal nerve fiber layer thinning or microcystic macular edema, can be related to alterations in the brain due to neurodegenerative disorders. The purpose of this mini-review is to show how OCT can be useful for the diagnosis of NMOSD and follow-up of affected patients, as well as for the differential diagnosis with MS. PMID:29085325

Heat shock protein 90 in neurodegenerative diseases

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Rodina Anna

2010-06-01

Full Text Available Abstract Hsp90 is a molecular chaperone with important roles in regulating pathogenic transformation. In addition to its well-characterized functions in malignancy, recent evidence from several laboratories suggests a role for Hsp90 in maintaining the functional stability of neuronal proteins of aberrant capacity, whether mutated or over-activated, allowing and sustaining the accumulation of toxic aggregates. In addition, Hsp90 regulates the activity of the transcription factor heat shock factor-1 (HSF-1, the master regulator of the heat shock response, mechanism that cells use for protection when exposed to conditions of stress. These biological functions therefore propose Hsp90 inhibition as a dual therapeutic modality in neurodegenerative diseases. First, by suppressing aberrant neuronal activity, Hsp90 inhibitors may ameliorate protein aggregation and its associated toxicity. Second, by activation of HSF-1 and the subsequent induction of heat shock proteins, such as Hsp70, Hsp90 inhibitors may redirect neuronal aggregate formation, and protect against protein toxicity. This mini-review will summarize our current knowledge on Hsp90 in neurodegeneration and will focus on the potential beneficial application of Hsp90 inhibitors in neurodegenerative diseases.

Cytogenetic abnormalities and fragile-x syndrome in Autism Spectrum Disorder

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Reddy Kavita S

2005-01-01

Full Text Available Abstract Background Autism is a behavioral disorder with impaired social interaction, communication, and repetitive and stereotypic behaviors. About 5–10 % of individuals with autism have 'secondary' autism in which an environmental agent, chromosome abnormality, or single gene disorder can be identified. Ninety percent have idiopathic autism and a major gene has not yet been identified. We have assessed the incidence of chromosome abnormalities and Fragile X syndrome in a population of autistic patients referred to our laboratory. Methods Data was analyzed from 433 patients with autistic traits tested using chromosome analysis and/or fluorescence in situ hybridization (FISH and/or molecular testing for fragile X syndrome by Southern and PCR methods. Results The median age was 4 years. Sex ratio was 4.5 males to 1 female [354:79]. A chromosome (cs abnormality was found in 14/421 [3.33 %] cases. The aberrations were: 4/14 [28%] supernumerary markers; 4/14 [28%] deletions; 1/14 [7%] duplication; 3/14 [21%] inversions; 2/14 [14%] translocations. FISH was performed on 23 cases for reasons other than to characterize a previously identified cytogenetic abnormality. All 23 cases were negative. Fragile-X testing by Southern blots and PCR analysis found 7/316 [2.2 %] with an abnormal result. The mutations detected were: a full mutation (fM and abnormal methylation in 3 [43 %], mosaic mutations with partial methylation of variable clinical significance in 3 [43%] and a permutation carrier [14%]. The frequency of chromosome and fragile-X abnormalities appears to be within the range in reported surveys (cs 4.8-1.7%, FRAX 2–4%. Limitations of our retrospective study include paucity of behavioral diagnostic information, and a specific clinical criterion for testing. Conclusions Twenty-eight percent of chromosome abnormalities detected in our study were subtle; therefore a high resolution cytogenetic study with a scrutiny of 15q11.2q13, 2q37 and Xp23

Drosophila as an In Vivo Model for Human Neurodegenerative Disease

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McGurk, Leeanne; Berson, Amit; Bonini, Nancy M.

2015-01-01

With the increase in the ageing population, neurodegenerative disease is devastating to families and poses a huge burden on society. The brain and spinal cord are extraordinarily complex: they consist of a highly organized network of neuronal and support cells that communicate in a highly specialized manner. One approach to tackling problems of such complexity is to address the scientific questions in simpler, yet analogous, systems. The fruit fly, Drosophila melanogaster, has been proven tremendously valuable as a model organism, enabling many major discoveries in neuroscientific disease research. The plethora of genetic tools available in Drosophila allows for exquisite targeted manipulation of the genome. Due to its relatively short lifespan, complex questions of brain function can be addressed more rapidly than in other model organisms, such as the mouse. Here we discuss features of the fly as a model for human neurodegenerative disease. There are many distinct fly models for a range of neurodegenerative diseases; we focus on select studies from models of polyglutamine disease and amyotrophic lateral sclerosis that illustrate the type and range of insights that can be gleaned. In discussion of these models, we underscore strengths of the fly in providing understanding into mechanisms and pathways, as a foundation for translational and therapeutic research. PMID:26447127

Regulatory Role of Circular RNAs and Neurological Disorders.

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Floris, Gabriele; Zhang, Longbin; Follesa, Paolo; Sun, Tao

2017-09-01

Circular RNAs (circRNAs) are a class of long noncoding RNAs that are characterized by the presence of covalently linked ends and have been found in all life kingdoms. Exciting studies in regulatory roles of circRNAs are emerging. Here, we summarize classification, characteristics, biogenesis, and regulatory functions of circRNAs. CircRNAs are found to be preferentially expressed along neural genes and in neural tissues. We thus highlight the association of circRNA dysregulation with neurodegenerative diseases such as Alzheimer's disease. Investigation of regulatory role of circRNAs will shed novel light in gene expression mechanisms during development and under disease conditions and may identify circRNAs as new biomarkers for aging and neurodegenerative disorders.

Recommendations for the Design of Serious Games in Neurodegenerative Diseases.

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Ben-Sadoun, Grégory; Manera, Valeria; Alvarez, Julian; Sacco, Guillaume; Robert, Philippe

2018-01-01

The use of Serious Games (SG) in the health domain is expanding. In the field of Neurodegenerative Diseases (ND) such as Alzheimer's Disease, SG are currently employed to provide alternative solutions for patients' treatment, stimulation, and rehabilitation. The design of SG for people with ND implies collaborations between professionals in ND and professionals in SG design. As the field is quite young, professionals specialized in both ND and SG are still rare, and recommendations for the design of SG for people with ND are still missing. This perspective paper aims to provide recommendations in terms of ergonomic choices for the design of SG aiming at stimulating people with ND, starting from the existing SG already tested in this population: "MINWii", "Kitchen and Cooking", and "X-Torp". We propose to rely on nine ergonomic criteria: eight ergonomic criteria inspired by works in the domain of office automation: Compatibility, Guidance, Workload, Adaptability, Consistency, Significance of codes, Explicit control and Error management; and one ergonomic criterion related to videogame: the game rules. Perspectives derived from this proposal are also discussed.

Thin-barrier enhancement-mode AlGaN/GaN MIS-HEMT using ALD Al2O3 as gate insulator

International Nuclear Information System (INIS)

Wang Zheli; Zhou Jianjun; Kong Yuechan; Kong Cen; Dong Xun; Yang Yang; Chen Tangsheng

2015-01-01

A high-performance enhancement-mode (E-mode) gallium nitride (GaN)-based metal–insulator–semiconductor high electron mobility transistor (MIS-HEMT) that employs a 5-nm-thick aluminum gallium nitride (Al 0.3 Ga 0.7 N) as a barrier layer and relies on silicon nitride (SiN) passivation to control the 2DEG density is presented. Unlike the SiN passivation, aluminum oxide (Al 2 O 3 ) by atomic layer deposition (ALD) on AlGaN surface would not increase the 2DEG density in the heterointerface. ALD Al 2 O 3 was used as gate insulator after the depletion by etching of the SiN in the gate region. The E-mode MIS-HEMT with gate length (L G ) of 1 μm showed a maximum drain current density (I DS ) of 657 mA/mm, a maximum extrinsic transconductance (g m ) of 187 mS/mm and a threshold voltage (V th ) of 1 V. Comparing with the corresponding E-mode HEMT, the device performances had been greatly improved due to the insertion of Al 2 O 3 gate insulator. This provided an excellent way to realize E-mode AlGaN/GaN MIS-HEMTs with both high V th and I DS . (paper)

Electron density distribution and disordered crystal structure of 8H-SiAlON, Si3−xAl1+xOxN5−x (x∼2.2)

International Nuclear Information System (INIS)

Banno, Hiroki; Asaka, Toru; Fukuda, Koichiro

2014-01-01

The 8H-SiAlON crystal with general formula Si 3−x Al 1+x O x N 5−x was characterized using laboratory X-ray powder diffraction (CuKα 1 ), transmission electron microscopy and energy dispersive X-ray spectroscopy. The [Si: Al] molar ratios were determined to be [0.21(1): 0.79(1)], corresponding to x=2.2(1). The Si 0.8(1) Al 3.2(1) O 2.2(1) N 2.8(1) compound is hexagonal with space group P6 3 /mmc (Z=2). The unit-cell dimensions are a=0.298877(8) nm, c=2.30872(5) nm and V=0.178602(8) nm 3 . The initial structural model was successfully derived by the charge-flipping method and further refined by the Rietveld method. The final structural model showed the positional disordering of two of the three (Si,Al) sites. The maximum-entropy method-based pattern fitting (MPF) method was used to confirm the validity of the split-atom model, in which conventional structure bias caused by assuming intensity partitioning was minimized. The reliability indices calculated from the MPF were R wp =4.74%, S (=R wp /R e )=1.30, R p =3.40%, R B =1.04% and R F =0.74%. The disordered crystal structure was successfully described by overlapping four types of domains with ordered atom arrangements. The distribution of atomic positions in each of the domains can be achieved in the space group P6 3 mc. Two of the four types of domains are related by a pseudo-symmetry inversion, and the two remaining domains also have each other the inversion pseudo-symmetry. - Graphical abstract: Bird's eye view of electron densities up to 49.3% (0.071 nm −3 ) of the maximum on the plane parallel to (110) with the corresponding atomic arrangements of Si 0.8 Al 3.2 O 2.2 N 2.8 . - Highlights: • Crystal structure of Si 0.8 Al 3.2 O 2.2 N 2.8 is determined by laboratory X-ray powder diffraction. • The atom arrangements are represented by the split-atom model. • The maximum-entropy method-based pattern fitting method is used to confirm the validity of the model. • The disordered structure is described

Having a Coffee Break: The Impact of Caffeine Consumption on Microglia-Mediated Inflammation in Neurodegenerative Diseases.

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Madeira, Maria H; Boia, Raquel; Ambrósio, António F; Santiago, Ana R

2017-01-01

Caffeine is the major component of coffee and the most consumed psychostimulant in the world and at nontoxic doses acts as a nonselective adenosine receptor antagonist. Epidemiological evidence suggests that caffeine consumption reduces the risk of several neurological and neurodegenerative diseases. However, despite the beneficial effects of caffeine consumption in human health and behaviour, the mechanisms by which it impacts the pathophysiology of neurodegenerative diseases still remain to be clarified. A promising hypothesis is that caffeine controls microglia-mediated neuroinflammatory response associated with the majority of neurodegenerative conditions. Accordingly, it has been already described that the modulation of adenosine receptors, namely, the A 2A receptor, affords neuroprotection through the control of microglia reactivity and neuroinflammation. In this review, we will summarize the main effects of caffeine in the modulation of neuroinflammation in neurodegenerative diseases.

Influence of nonmagnetic disorder on specific heat and electrical resistivity in Kondo lattice system CePd{sub 1−x}Ge{sub x}In

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Gnida, D., E-mail: d.gnida@int.pan.wroc.pl [Institute of Low Temperature and Structure Research, Polish Academy of Sciences, 50-950 Wrocław (Poland); Dominyuk, N.; Zaremba, V. [Inorganic Chemistry Department, Ivan Franko Lviv National University, Kyryla and Mephodiya Str. 6, 79005 Lviv (Ukraine); Kaczorowski, D. [Institute of Low Temperature and Structure Research, Polish Academy of Sciences, 50-950 Wrocław (Poland)

2015-02-15

Highlights: • Interplay of Kondo and RKKY interactions in the presence of nonmagnetic disorder. • Suppression of the coherent Kondo state by nonmagnetic impurities. • Observation of quantum interference phenomena in Ce-based Kondo system. • Coexistence of incoherent Kondo effect and Altshuler-Aronov quantum correction. - Abstract: The alloy system CePd{sub 1−x}Ge{sub x}In with 0.1⩽x⩽0.4 was investigated by means of heat capacity and electrical resistivity measurements. Its low-temperature behavior has been found to be governed by the interplay of Kondo effect and Ruderman-Kittel-Kasuya-Yosida (RKKY) interactions in the presence of atomic disorder in nonmagnetic atoms sublattice. The coherent Kondo state, observed for CePdIn, gradually vanishes with increasing the Ge-content. The incoherent Kondo state, which characterizes Ge-rich alloys, appears very sensitive to applied magnetic field. The observed systematic changes in the temperature- and field-dependent electrical transport in CePd{sub 1−x}Ge{sub x}In manifest the important role of quantum correction due to electron-electron interactions in weakly localized regime.

FXTAS in an unmethylated mosaic male with fragile X syndrome from Chile.

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Santa María, L; Pugin, A; Alliende, M A; Aliaga, S; Curotto, B; Aravena, T; Tang, H-T; Mendoza-Morales, G; Hagerman, R; Tassone, F

2014-10-01

Carriers of an FMR1 premutation allele (55-200 CGG repeats) often develop the neurodegenerative disorders, fragile X-associated tremor/ataxia syndrome (FXTAS). Neurological signs of FXTAS, parkinsonism and rapid onset of cognitive decline have not been reported in individuals with an unmethylated full mutation (FM). Here, we report a Chilean family affected with FXS, inherited from a parent carrier of an FMR1 unmethylated full mosaic allele, who presented with a fast progressing FXTAS. This case suggests that the definition of FXTAS may need to be broadened to not only include those with a premutation but also those with an expanded allele in FM range with a lack of methylation leading to elevated FMR1-mRNA expression levels and subsequent RNA toxicity. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Progranulin in neurodegenerative disease.

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Petkau, Terri L; Leavitt, Blair R

2014-07-01

Loss-of-function mutations in the progranulin gene are a common cause of familial frontotemporal dementia (FTD). The purpose of this review is to summarize the role of progranulin in health and disease, because the field is now poised to begin examining therapeutics that alter endogenous progranulin levels. We first review the clinical and neuropathological phenotype of FTD patients carrying mutations in the progranulin gene, which suggests that progranulin-mediated neurodegeneration is multifactorial and influenced by other genetic and/or environmental factors. We then examine evidence for the role of progranulin in the brain with a focus on mouse model systems. A better understanding of the complexity of progranulin biology in the brain will help guide the development of progranulin-modulating therapies for neurodegenerative disease. Copyright © 2014 Elsevier Ltd. All rights reserved.

[Retinal imaging of the macula and optic disc in neurodegenerative diseases].

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Turski, G N; Schmitz-Valckenberg, S; Holz, F G; Finger, R P

2017-02-01

Due to current demographic trends, the prevalence of mild cognitive impairment and dementia is expected to increase considerably. For potential new therapies it is important to identify patients at risk as early as possible. Currently, there is no population-based screening. Therefore, identification of biomarkers that will help screen the population at risk is urgently needed. Thus, a literature review on retinal pathology in neurodegenerative diseases was performed. PubMed was searched for studies published up to August 2016 using the following keywords: "mild cognitive impairment", "dementia", "eye", "ocular biomarkers", "OCT" and "OCT angiography". Relevant publications were selected and summarized qualitatively. Multiple studies using noninvasive in vivo optical coherence tomography (OCT) imaging showed nonspecific retinal pathological changes in patients with neurodegenerative diseases such as mild cognitive impairment, Alzheimer's and Parkinson's disease. Pathological changes in macular volume, optic nerve fiber layer thickness and the ganglion cell complex were observed. However, based on available evidence, no ocular biomarkers for neurodegeneration which could be integrated in routine clinical diagnostics have been identified. The potential use of OCT in the early diagnostic workup and monitoring of progression of neurodegenerative diseases needs to be further explored in longitudinal studies with large cohorts.

Having a Coffee Break: The Impact of Caffeine Consumption on Microglia-Mediated Inflammation in Neurodegenerative Diseases

Directory of Open Access Journals (Sweden)

Maria H. Madeira

2017-01-01

Full Text Available Caffeine is the major component of coffee and the most consumed psychostimulant in the world and at nontoxic doses acts as a nonselective adenosine receptor antagonist. Epidemiological evidence suggests that caffeine consumption reduces the risk of several neurological and neurodegenerative diseases. However, despite the beneficial effects of caffeine consumption in human health and behaviour, the mechanisms by which it impacts the pathophysiology of neurodegenerative diseases still remain to be clarified. A promising hypothesis is that caffeine controls microglia-mediated neuroinflammatory response associated with the majority of neurodegenerative conditions. Accordingly, it has been already described that the modulation of adenosine receptors, namely, the A2A receptor, affords neuroprotection through the control of microglia reactivity and neuroinflammation. In this review, we will summarize the main effects of caffeine in the modulation of neuroinflammation in neurodegenerative diseases.

The Mircen project, neuro-degenerative disease: mechanisms, therapeutics and imaging research Unit URA Cea Cnrs 2210

International Nuclear Information System (INIS)

Hantraye, Ph.

2006-01-01

During the post-genomic era, significant advances in our understanding of the molecular basis of disease have been made. The power of functional and molecular imaging in translating this knowledge into effective therapy is now being more and more recognized. Thus, molecular imaging plays a vital role in the early identification of disease-related molecular markers, in the development of molecular-targeted therapies, and in monitoring phenotypic response to therapy both in experimental animals and in human patients. In this context, MIRCen (acronym for Molecular Imaging Research Center ) provides a comprehensive resource available to empower basic, translational, and clinical research through the application of imaging and drug, cell, and gene based technologies. The MIR center will be dedicated to the development of pre-clinical trials for the treatment of various seriously debilitating diseases such as neuro-degenerative diseases, cardiac and hepatic disorders, and infectious diseases (AIDS). Despite the fact that many of these pathologies are still incurable, recent advances in drug, cell and gene therapy point to the feasibility of new therapeutic approaches. The long term goals of MIRCen are therefore to develop and validate: - pertinent animal models for neuro-degenerative, hepatic, cardiac and infectious diseases in rodents as well as non-human primates, - novel technologies for in vivo sensing and imaging of disease-related molecular events,- drug, gene and cell based palliative and or curative therapeutic strategies aiming at protecting and /or restoring damaged or lost functions. (author)

Neuropsychological profile of a Filipino gentleman with X-linked dystonia-parkinsonism: a case report of Lubag disease.

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Howe, Laura L S; Kellison, Ida L; Fernandez, Hubert H; Okun, Michael S; Bowers, Dawn

2009-01-01

X-Linked Dystonia-Parkinsonism (XDP or "Lubag") is a progressive neurodegenerative disorder unique to the Island of Panay in the Philippines. Imaging and autopsy studies have suggested involvement of the caudate and putamen in late stages. Because the clinical presentation of patients with XDP resembles that of patients with Parkinson disease or dystonia, it is reasonable to predict the neuropsychological profile might be similar; however, the neuropsychological profile of a XDP patient has not previously been published. We present the neuropsychological findings of a 67-year-old gentleman with a 10-year history of XDP who presented with parkinsonian and dystonic symptoms. He was evaluated for suitability for deep brain stimulation surgery. Neuropsychological findings demonstrated diffuse impairment involving memory, visuospatial, language, and executive functioning.

Neural Substrates of Spontaneous Narrative Production in Focal Neurodegenerative Disease

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Gola, Kelly A.; Thorne, Avril; Veldhuisen, Lisa D.; Felix, Cordula M.; Hankinson, Sarah; Pham, Julie; Shany-Ur, Tal; Schauer, Guido P.; Stanley, Christine M.; Glenn, Shenly; Miller, Bruce L.; Rankin, Katherine P.

2016-01-01

Conversational storytelling integrates diverse cognitive and socio-emotional abilities that critically differ across neurodegenerative disease groups and may have diagnostic relevance and predict anatomic changes. The present study employed mixed methods discourse and quantitative analyses to delineate patterns of storytelling across focal neurodegenerative disease groups, and to clarify the neuroanatomical contributions to common storytelling characteristics in these patients. Transcripts of spontaneous social interactions of 46 participants (15 behavioral variant frontotemporal dementia (bvFTD), 7 semantic variant primary progressive aphasia (svPPA), 12 Alzheimer's disease (AD), and 12 healthy older normal controls) were analysed for storytelling characteristics and frequency, and videos of the interactions were rated for patients' social attentiveness. Compared to controls, svPPAs also told more stories and autobiographical stories, and perseverated on aspects of self during storytelling. ADs told fewer autobiographical stories than NCs, and svPPAs and bvFTDs failed to attend to social cues. Storytelling characteristics were associated with a processing speed and mental flexibility, and voxel-based anatomic analysis of structural magnetic resonance imaging revealed that temporal organization, evaluations, and social attention correlated with atrophy corresponding to known intrinsic connectivity networks, including the default mode, limbic, salience, and stable task control networks. Differences in spontaneous storytelling among neurodegenerative groups elucidated diverse cognitive, socio-emotional, and neural contributions to narrative production, with implications for diagnostic screening and therapeutic intervention. PMID:26485159

Sublethal RNA Oxidation as a Mechanism for Neurodegenerative Disease

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Mark A. Smith

2008-05-01

Full Text Available Although cellular RNA is subjected to the same oxidative insults as DNA and other cellular macromolecules, oxidative damage to RNA has not been a major focus in investigations of the biological consequences of free radical damage. In fact, because it is largely single-stranded and its bases lack the protection of hydrogen bonding and binding by specific proteins, RNA may be more susceptible to oxidative insults than is DNA. Oxidative damage to protein-coding RNA or non-coding RNA will, in turn, potentially cause errors in proteins and/or dysregulation of gene expression. While less lethal than mutations in the genome, such sublethal insults to cells might be associated with underlying mechanisms of several chronic diseases, including neurodegenerative disease. Recently, oxidative RNA damage has been described in several neurodegenerative diseases including Alzheimer disease, Parkinson disease, dementia with Lewy bodies, and prion diseases. Of particular interest, oxidative RNA damage can be demonstrated in vulnerable neurons early in disease, suggesting that RNA oxidation may actively contribute to the onset of the disease. An increasing body of evidence suggests that, mechanistically speaking, the detrimental effects of oxidative RNA damage to protein synthesis are attenuated, at least in part, by the existence of protective mechanisms that prevent the incorporation of the damaged ribonucleotides into the translational machinery. Further investigations aimed at understanding the processing mechanisms related to oxidative RNA damage and its consequences may provide significant insights into the pathogenesis of neurodegenerative and other degenerative diseases and lead to better therapeutic strategies.

Targeted pharmacological treatment of autism spectrum disorders: fragile X and Rett syndromes

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Hansen eWang

2015-02-01

Full Text Available Autism spectrum disorders (ASDs are genetically and clinically heterogeneous and lack effective medications to treat their core symptoms. Studies of syndromic ASDs caused by single gene mutations have provided insights into the pathophysiology of autism. Fragile X and Rett syndromes belong to the syndromic ASDs in which preclinical studies have identified rational targets for drug therapies focused on correcting underlying neural dysfunction. These preclinical discoveries are increasingly translating into exciting human clinical trials. Since there are significant molecular and neurobiological overlaps among ASDs, targeted treatments developed for fragile X and Rett syndromes may be helpful for autism of different etiologies. Here, we review the targeted pharmacological treatment of fragile X and Rett syndromes and discuss related issues in both preclinical studies and clinical trials of potential therapies for the diseases.

Targeted pharmacological treatment of autism spectrum disorders: fragile X and Rett syndromes

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Wang, Hansen; Pati, Sandipan; Pozzo-Miller, Lucas; Doering, Laurie C.

2015-01-01

Autism spectrum disorders (ASDs) are genetically and clinically heterogeneous and lack effective medications to treat their core symptoms. Studies of syndromic ASDs caused by single gene mutations have provided insights into the pathophysiology of autism. Fragile X and Rett syndromes belong to the syndromic ASDs in which preclinical studies have identified rational targets for drug therapies focused on correcting underlying neural dysfunction. These preclinical discoveries are increasingly translating into exciting human clinical trials. Since there are significant molecular and neurobiological overlaps among ASDs, targeted treatments developed for fragile X and Rett syndromes may be helpful for autism of different etiologies. Here, we review the targeted pharmacological treatment of fragile X and Rett syndromes and discuss related issues in both preclinical studies and clinical trials of potential therapies for the diseases. PMID:25767435

Study on discriminant analysis by military mental disorder prediction scale for mental disorder of new recruits

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Li-yi ZHANG

2011-11-01

Full Text Available Objective To examine the predictive role of the Military Mental Disorder Prediction Scale on the mental disorder of new recruits.Methods The present study examined 115 new recruits diagnosed with mental disorder and 115 healthy new recruits.The recruits were tested using the Military Mental Disorder Prediction Scale.The discriminant function was built by discriminant analysis method.The current study analyzed the predictive value of 11 factors(family medical record and past medical record(X1,growth experience(X2,introversion(X3,stressor(X4,poor mental defense(X5,social support(X6,psychosis(X7,depression(X8,mania(X9,neurosis(X10,and personality disorder(X11 aside from lie factor on the mental disorder of new recruits.Results The mental disorder group has higher total score and factor score in family medical record and past medical record,introversion,stressor,poor mental defense,social support,psychosis,depression,mania,neurosis,personality disorder,and lie than those of the contrast group(P < 0.01.For the score of growth experience factor,that of the mental disorder group is higher than the score of the contrast group(P < 0.05.All 11 factors except the lie factor in the Mental Disorder Prediction Scale are taken as independent variables by enforced introduction to obtain the Fisher linear discriminant function as follows: The mental disorder group=-7.014-0.278X1+1.556X2+1.563X3+0.878X4+0.183X5-0.845X6-0.562X7-0.353X8+1.246X9-0.505X10+1.029X11.The contrast group=-2.971+0.056X1+2.194X2+0.707X3+0.592X4-0.086X5-0.888X6-0.133X7-0.360X8+0.654X9-0.467X10+0.308X11.The discriminant function has an accuracy rate of 76.5% on the new recruits with mental disorders and 100% on the healthy new recruits.The total accurate discrimination rate is 88.3% and the total inaccurate discrimination rate is 11.7%.Conclusion The Military Mental Disorder Prediction Scale has a high accuracy rate on the prediction of mental disorder of new recruits and is worthy of

Prediction of neurodegenerative diseases from functional brain imaging data

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Mudali, Deborah

2016-01-01

Neurodegenerative diseases are a challenge, especially in the developed society where life expectancy is high. Since these diseases progress slowly, they are not easy to diagnose at an early stage. Moreover, they portray similar disease features, which makes them hard to differentiate. In this

Brain Aggregates: An Effective In Vitro Cell Culture System Modeling Neurodegenerative Diseases.

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Ahn, Misol; Kalume, Franck; Pitstick, Rose; Oehler, Abby; Carlson, George; DeArmond, Stephen J

2016-03-01

Drug discovery for neurodegenerative diseases is particularly challenging because of the discrepancies in drug effects between in vitro and in vivo studies. These discrepancies occur in part because current cell culture systems used for drug screening have many limitations. First, few cell culture systems accurately model human aging or neurodegenerative diseases. Second, drug efficacy may differ between dividing and stationary cells, the latter resembling nondividing neurons in the CNS. Brain aggregates (BrnAggs) derived from embryonic day 15 gestation mouse embryos may represent neuropathogenic processes in prion disease and reflect in vivo drug efficacy. Here, we report a new method for the production of BrnAggs suitable for drug screening and suggest that BrnAggs can model additional neurological diseases such as tauopathies. We also report a functional assay with BrnAggs by measuring electrophysiological activities. Our data suggest that BrnAggs could serve as an effective in vitro cell culture system for drug discovery for neurodegenerative diseases. © 2016 American Association of Neuropathologists, Inc. All rights reserved.

Mitochondrial dysfunction in the neuro-degenerative and cardio-degenerative disease, Friedreich's ataxia.

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Chiang, Shannon; Kalinowski, Danuta S; Jansson, Patric J; Richardson, Des R; Huang, Michael L-H

2017-08-04

Mitochondrial homeostasis is essential for maintaining healthy cellular function and survival. The detrimental involvement of mitochondrial dysfunction in neuro-degenerative diseases has recently been highlighted in human conditions, such as Parkinson's, Alzheimer's and Huntington's disease. Friedreich's ataxia (FA) is another neuro-degenerative, but also cardio-degenerative condition, where mitochondrial dysfunction plays a crucial role in disease progression. Deficient expression of the mitochondrial protein, frataxin, is the primary cause of FA, which leads to adverse alterations in whole cell and mitochondrial iron metabolism. Dys-regulation of iron metabolism in these compartments, results in the accumulation of inorganic iron deposits in the mitochondrial matrix that is thought to potentiate oxidative damage observed in FA. Therefore, the maintenance of mitochondrial homeostasis is crucial in the progression of neuro-degenerative conditions, particularly in FA. In this review, vital mitochondrial homeostatic processes and their roles in FA pathogenesis will be discussed. These include mitochondrial iron processing, mitochondrial dynamics (fusion and fission processes), mitophagy, mitochondrial biogenesis, mitochondrial energy production and calcium metabolism. Copyright © 2017 Elsevier Ltd. All rights reserved.

Neuroproteases in peptide neurotransmission and neurodegenerative diseases: applications to drug discovery research.

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Hook, Vivian Y H

2006-01-01

The nervous system represents a key area for development of novel therapeutic agents for the treatment of neurological and neurodegenerative diseases. Recent research has demonstrated the critical importance of neuroproteases for the production of specific peptide neurotransmitters and for the production of toxic peptides in major neurodegenerative diseases that include Alzheimer, Huntington, and Parkinson diseases. This review illustrates the successful criteria that have allowed identification of proteases responsible for converting protein precursors into active peptide neurotransmitters, consisting of dual cysteine protease and subtilisin-like protease pathways in neuroendocrine cells. These peptide neurotransmitters are critical regulators of neurologic conditions, including analgesia and cognition, and numerous behaviors. Importantly, protease pathways also represent prominent mechanisms in neurodegenerative diseases, especially Alzheimer, Huntington, and Parkinson diseases. Recent studies have identified secretory vesicle cathepsin B as a novel beta-secretase for production of the neurotoxic beta-amyloid (Abeta) peptide of Alzheimer disease. Moreover, inhibition of cathepsin B reduces Abeta peptide levels in brain. These neuroproteases potentially represent new drug targets that should be explored in future pharmaceutical research endeavors for drug discovery.

Strong composition-dependent disorder in InAs1-xNx alloys

International Nuclear Information System (INIS)

Benaissa, H.; Zaoui, A.; Ferhat, M.

2009-01-01

We investigate the main causes of disorder in the InAs 1-x N x alloys (x = 0, 0.03125, 0.0625, 0.09375, 0.125, 0.25, 0.5, 0.75, 0.875, 0.90625, 0.9375, 0.96875 and 1). The calculation is based on the density-functional theory in the local-density approximation. We use a plane wave-expansion non-norm conserving ab initio Vanderbilt pseudopotentials. To avoid the difficulty of considering the huge number of atomic configurations, we use an appropriate strategy in which we consider four configurations for a given composition where the N atoms are not randomly distributed. We mainly show that the band gap decreases (increases) rapidly with increasing (decreasing) compositions of N. As a consequence the optical band gap bowing is found to be strong and composition dependent. The obtained compounds, from these alloys, may change from semi-conducting to metal (passing to a negative bowing) and could be useful for device applications, especially at certain composition.

Humoral activity of cord blood-derived stem/progenitor cells: implications for stem cell-based adjuvant therapy of neurodegenerative disorders.

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Edyta Paczkowska

that CM from SPCs favorable influence neural cell proliferation and survival. Understanding the mechanisms governing the characterization and humoral activity of subsets of SPCs may yield new therapeutic strategies that might be more effective in treating neurodegenerative disorders.

Electron beam induced oxygen disordering in YBa2Cu3O7-x superconductors

International Nuclear Information System (INIS)

Basu, S.N.; Roy, T.; Mitchell, T.E.; Nastasi, M.

1990-01-01

Thin foils of bulk YBa 2 Cu 3 O 7-x (YBCO) superconductors were subjected to electron irradiation in a transmission electron microscope (TEM). The resulting disordering of the oxygen atoms and vacancies in the Cu-O planes was monitored by measuring the splitting of the (110) diffraction spots in the [001] diffraction pattern. Samples were irradiated at 83 K with 100, 150, 200 and 300 kV electrons. The 100 kV electrons did not cause any disordering, even after prolonged irradiation. The results of the higher energy irradiations showed an excellent fit to a disordering model, indicating a lack of radiation assisted reordering at 83 K. This was further confirmed by the insensitivity of the disordering to the dose rate of 300 kV electrons at 83 K. However, at 300 K, an increase in the dose rate of 300 kV electrons increased the disordering rate, indicating that radiation assisted reordering was occurring at that temperature

Gas diffusion ultrabarriers on polymer substrates using Al2O3 atomic layer deposition and SiN plasma-enhanced chemical vapor deposition

International Nuclear Information System (INIS)

Carcia, P. F.; McLean, R. S.; Groner, M. D.; Dameron, A. A.; George, S. M.

2009-01-01

Thin films grown by Al 2 O 3 atomic layer deposition (ALD) and SiN plasma-enhanced chemical vapor deposition (PECVD) have been tested as gas diffusion barriers either individually or as bilayers on polymer substrates. Single films of Al 2 O 3 ALD with thicknesses of ≥10 nm had a water vapor transmission rate (WVTR) of ≤5x10 -5 g/m 2 day at 38 deg. C/85% relative humidity (RH), as measured by the Ca test. This WVTR value was limited by H 2 O permeability through the epoxy seal, as determined by the Ca test for the glass lid control. In comparison, SiN PECVD films with a thickness of 100 nm had a WVTR of ∼7x10 -3 g/m 2 day at 38 deg. C/85% RH. Significant improvements resulted when the SiN PECVD film was coated with an Al 2 O 3 ALD film. An Al 2 O 3 ALD film with a thickness of only 5 nm on a SiN PECVD film with a thickness of 100 nm reduced the WVTR from ∼7x10 -3 to ≤5x10 -5 g/m 2 day at 38 deg. C/85% RH. The reduction in the permeability for Al 2 O 3 ALD on the SiN PECVD films was attributed to either Al 2 O 3 ALD sealing defects in the SiN PECVD film or improved nucleation of Al 2 O 3 ALD on SiN.

High School Football and Late-Life Risk of Neurodegenerative Syndromes, 1956-1970.

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Janssen, Pieter H H; Mandrekar, Jay; Mielke, Michelle M; Ahlskog, J Eric; Boeve, Bradley F; Josephs, Keith; Savica, Rodolfo

2017-01-01

To assess whether athletes who played American varsity high school football between 1956 and 1970 have an increased risk of neurodegenerative diseases later in life. We identified all male varsity football players between 1956 and 1970 in the public high schools of Rochester, Minnesota, and non-football-playing male varsity swimmers, wrestlers, and basketball players. Using the medical records linkage system of the Rochester Epidemiology Project, we ascertained the incidence of late-life neurodegenerative diseases: dementia, parkinsonism, and amyotrophic lateral sclerosis. We also recorded medical record-documented head trauma during high school years. We identified 296 varsity football players and 190 athletes engaging in other sports. Football players had an increased risk of medically documented head trauma, especially if they played football for more than 1 year. Compared with nonfootball athletes, football players did not have an increased risk of neurodegenerative disease overall or of the individual conditions of dementia, parkinsonism, and amyotrophic lateral sclerosis. In this community-based study, varsity high school football players from 1956 to 1970 did not have an increased risk of neurodegenerative diseases compared with athletes engaged in other varsity sports. This was from an era when there was a generally nihilistic view of concussion dangers, less protective equipment, and no prohibition of spearing (head-first tackling). However, the size and strength of players from previous eras may not be comparable with that of current high school athletes. Copyright © 2016 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.

The Role of Sigma-1 Receptor, an Intracellular Chaperone in Neurodegenerative Diseases.

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Penke, Botond; Fulop, Livia; Szucs, Maria; Frecska, Ede

2018-01-01

Widespread protein aggregation occurs in the living system under stress or during aging, owing to disturbance of endoplasmic reticulum (ER) proteostasis. Many neurodegenerative diseases may have a common mechanism: the failure of protein homeostasis. Perturbation of ER results in unfolded protein response (UPR). Prolonged chronical UPR may activate apoptotic pathways and cause cell death. Research articles on Sigma-1 receptor were reviewed. ER is associated to mitochondria by the mitochondria-associated ER-membrane, MAM. The sigma-1 receptor (Sig-1R), a well-known ER-chaperone localizes in the MAM. It serves for Ca2+-signaling between the ER and mitochondria, involved in ion channel activities and especially important during neuronal differentiation. Sig-1R acts as central modulator in inter-organelle signaling. Sig-1R helps cell survival by attenuating ER-stress. According to sequence based predictions Sig-1R is a 223 amino acid protein with two transmembrane (2TM) domains. The X-ray structure of the Sig-1R [1] showed a membrane-bound trimeric assembly with one transmembrane (1TM) region. Despite the in vitro determined assembly, the results of in vivo studies are rather consistent with the 2TM structure. The receptor has unique and versatile pharmacological profile. Dimethyl tryptamine (DMT) and neuroactive steroids are endogenous ligands that activate Sig-1R. The receptor has a plethora of interacting client proteins. Sig-1R exists in oligomeric structures (dimer-trimer-octamer-multimer) and this fact may explain interaction with diverse proteins. Sig-1R agonists have been used in the treatment of different neurodegenerative diseases, e.g. Alzheimer's and Parkinson's diseases (AD and PD) and amyotrophic lateral sclerosis. Utilization of Sig-1R agents early in AD and similar other diseases has remained an overlooked therapeutic opportunity. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Pt thermal atomic layer deposition for silicon x-ray micropore optics.

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Takeuchi, Kazuma; Ezoe, Yuichiro; Ishikawa, Kumi; Numazawa, Masaki; Terada, Masaru; Ishi, Daiki; Fujitani, Maiko; Sowa, Mark J; Ohashi, Takaya; Mitsuda, Kazuhisa

2018-04-20

We fabricated a silicon micropore optic using deep reactive ion etching and coated by Pt with atomic layer deposition (ALD). We confirmed that a metal/metal oxide bilayer of Al 2 O 3 ∼10  nm and Pt ∼20  nm was successfully deposited on the micropores whose width and depth are 20 μm and 300 μm, respectively. An increase of surface roughness of sidewalls of the micropores was observed with a transmission electron microscope and an atomic force microscope. X-ray reflectivity with an Al Kα line at 1.49 keV before and after the deposition was measured and compared to ray-tracing simulations. The surface roughness of the sidewalls was estimated to increase from 1.6±0.2  nm rms to 2.2±0.2  nm rms. This result is consistent with the microscope measurements. Post annealing of the Pt-coated optic at 1000°C for 2 h showed a sign of reduced surface roughness and better angular resolution. To reduce the surface roughness, possible methods such as the annealing after deposition and a plasma-enhanced ALD are discussed.

The Contribution of Optical Coherence Tomography in Neuromyelitis Optica Spectrum Disorders

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Javier Mateo

2017-09-01

Full Text Available Neuromyelitis optica spectrum disorders (NMOSD comprises a group of central nervous system disorders of inflammatory autoimmune origin that mainly affect the optic nerves and the spinal cord and can cause severe visual and general disability. The clinical signs are similar to those of multiple sclerosis (MS, with the result that it is often difficult to differentiate between the two, thus leading to misdiagnosis. As the treatment and prognosis of NMOSD and MS are different, it is important to make an accurate and early diagnosis of NMOSD. Optical coherence tomography (OCT is a non-invasive technique that enables a quantitative study of the changes that the optic nerve and the macula undergo in several neurodegenerative diseases. Many studies have shown that some of these changes, such as retinal nerve fiber layer thinning or microcystic macular edema, can be related to alterations in the brain due to neurodegenerative disorders. The purpose of this mini-review is to show how OCT can be useful for the diagnosis of NMOSD and follow-up of affected patients, as well as for the differential diagnosis with MS.

Expressions of renin, angiotensin II and aldosterone in patients with viral hepatitis or hepatic cirrhosis

International Nuclear Information System (INIS)

Huo Ying; Zhu Yalin; Liu Yun

2008-01-01

Objective: To explore the changes of renin, angiotensin and aldosterone system in patients with hepatic disorders. Methods: Plasma renin activity (PRA), AT-II and Ald levels were measured with RIA in 31 patients with viral hepatitis, 35 patients with hepatic cirrhosis and 38 controls. Results: The levels of PRA, AT-II and Ald in patients with viral hepatitis were slightly but non-significantly higher than those in controls (P>0.05). The levels of PRA, AT-II and Ald in patients with cirrhosis were significantly higher than those in controls (P<0.01). Conclusion: RAAS was activated during progression of hepatic disorders and participated in the development of hepatic fibrosis. (authors)

Loss of Neuroprotective Factors in Neurodegenerative Dementias: The End or the Starting Point?

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Benussi, Luisa; Binetti, Giuliano; Ghidoni, Roberta

2017-01-01

Recent clinical, genetic and biochemical experimental evidences highlight the existence of common molecular pathways underlying neurodegenerative diseases. In this review, we will explore a key common pathological mechanism, i.e., the loss of neuroprotective factors, across the three major neurodegenerative diseases leading to dementia: Alzheimer's disease (AD), Frontotemporal dementia (FTD) and Lewy body dementia (LBD). We will report evidences that the Brain Derived Neurotrophic Factor (BDNF), the most investigated and characterized brain neurotrophin, progranulin, a multi-functional adipokine with trophic and growth factor properties, and cystatin C, a neuroprotective growth factor, are reduced in AD, FTD, and LBD. Moreover, we will review the molecular mechanism underlying the loss of neuroprotective factors in neurodegenerative diseases leading to dementia, with a special focus on endo-lysosomal pathway and intercellular communication mediated by extracellular vesicles. Exploring the shared commonality of disease mechanisms is of pivotal importance to identify novel potential therapeutic targets and to develop treatments to delay, slow or block disease progression. PMID:29249935

Loss of Neuroprotective Factors in Neurodegenerative Dementias: The End or the Starting Point?

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Luisa Benussi

2017-12-01

Full Text Available Recent clinical, genetic and biochemical experimental evidences highlight the existence of common molecular pathways underlying neurodegenerative diseases. In this review, we will explore a key common pathological mechanism, i.e., the loss of neuroprotective factors, across the three major neurodegenerative diseases leading to dementia: Alzheimer's disease (AD, Frontotemporal dementia (FTD and Lewy body dementia (LBD. We will report evidences that the Brain Derived Neurotrophic Factor (BDNF, the most investigated and characterized brain neurotrophin, progranulin, a multi-functional adipokine with trophic and growth factor properties, and cystatin C, a neuroprotective growth factor, are reduced in AD, FTD, and LBD. Moreover, we will review the molecular mechanism underlying the loss of neuroprotective factors in neurodegenerative diseases leading to dementia, with a special focus on endo-lysosomal pathway and intercellular communication mediated by extracellular vesicles. Exploring the shared commonality of disease mechanisms is of pivotal importance to identify novel potential therapeutic targets and to develop treatments to delay, slow or block disease progression.

Beneficial Effects of Green Tea Catechins on Neurodegenerative Diseases

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Monira Pervin

2018-05-01

Full Text Available Tea is one of the most consumed beverages in the world. Green tea, black tea, and oolong tea are made from the same plant Camellia sinensis (L. O. Kuntze. Among them, green tea has been the most extensively studied for beneficial effects on diseases including cancer, obesity, diabetes, and inflammatory and neurodegenerative diseases. Several human observational and intervention studies have found beneficial effects of tea consumption on neurodegenerative impairment, such as cognitive dysfunction and memory loss. These studies supported the basis of tea’s preventive effects of Parkinson’s disease, but few studies have revealed such effects on Alzheimer’s disease. In contrast, several human studies have not reported these favorable effects with regard to tea. This discrepancy may be due to incomplete adjustment of confounding factors, including the method of quantifying consumption, beverage temperature, cigarette smoking, alcohol consumption, and differences in genetic and environmental factors, such as race, sex, age, and lifestyle. Thus, more rigorous human studies are required to understand the neuroprotective effect of tea. A number of laboratory experiments demonstrated the benefits of green tea and green tea catechins (GTCs, such as epigallocatechin gallate (EGCG, and proposed action mechanisms. The targets of GTCs include the abnormal accumulation of fibrous proteins, such as Aβ and α-synuclein, inflammation, elevated expression of pro-apoptotic proteins, and oxidative stress, which are associated with neuronal cell dysfunction and death in the cerebral cortex. Computational molecular docking analysis revealed how EGCG can prevent the accumulation of fibrous proteins. These findings suggest that GTCs have the potential to be used in the prevention and treatment of neurodegenerative diseases and could be useful for the development of new drugs.

ALD Produced B{sub 2}O{sub 3}, Al{sub 2}O{sub 3} and TiO{sub 2} Coatings on Gd{sub 2}O{sub 3} Burnable Poison Nanoparticles and Carbonaceous TRISO Coating Layers

Energy Technology Data Exchange (ETDEWEB)

Weimer, Alan

2012-11-26

This project will demonstrate the feasibility of using atomic layer deposition (ALD) to apply ultrathin neutron-absorbing, corrosion-resistant layers consisting of ceramics, metals, or combinations thereof, on particles for enhanced nuclear fuel pellets. Current pellet coating technology utilizes chemical vapor deposition (CVD) in a fluidized bed reactor to deposit thick, porous layers of C (or PyC) and SiC. These graphitic/carbide materials degrade over time owing to fission product bombardment, active oxidation, thermal management issues, and long-term irradiation effects. ALD can be used to deposit potential ceramic barrier materials of interest, including ZrO{sub 2}, Y{sub 2}O{sub 3}:ZrO{sub 2} (YSZ), Al{sub 2}O{sub 3}, and TiO{sub 2}, or neutron-absorbing materials, namely B (in BN or B{sub 2}O{sub 3}) and Gd (in Gd{sub 2}O{sub 3}). This project consists of a two-pronged approach to integrate ALD into the next-generation nuclear plant (NGNP) fuel pellet manufacturing process:

Percutaneous Endoscopic Gastrostomy Tube Insertion in Neurodegenerative Disease: A Retrospective Study and Literature Review

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Pamela Sarkar

2017-05-01

Full Text Available Background/Aims With the notable exceptions of dementia, stroke, and motor neuron disease, relatively little is known about the safety and utility of percutaneous endoscopic gastrostomy (PEG tube insertion in patients with neurodegenerative disease. We aimed to determine the safety and utility of PEG feeding in the context of neurodegenerative disease and to complete a literature review in order to identify whether particular factors need to be considered to improve safety and outcome. Methods A retrospective case note review of patients referred for PEG insertion by neurologists in a single neuroscience center was conducted according to a pre-determined set of standards. For the literature review, we identified references from searches of PubMed, mainly with the search items “percutaneous endoscopic gastrostomy” and “neurology” or “neurodegenerative disease.” Results Short-term mortality and morbidity associated with PEG in patients with neurological disease were significant. Age greater than 75 years was associated with poor outcome, and a trend toward adverse outcome was observed in patients with low serum albumin. Conclusions This study highlights the relatively high risk of PEG in patients with neurodegenerative disease. We present points for consideration to improve outcome in this particularly vulnerable group of patients.

Recommendations for the Design of Serious Games in Neurodegenerative Diseases

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Grégory Ben-Sadoun

2018-02-01

Full Text Available The use of Serious Games (SG in the health domain is expanding. In the field of Neurodegenerative Diseases (ND such as Alzheimer’s Disease, SG are currently employed to provide alternative solutions for patients’ treatment, stimulation, and rehabilitation. The design of SG for people with ND implies collaborations between professionals in ND and professionals in SG design. As the field is quite young, professionals specialized in both ND and SG are still rare, and recommendations for the design of SG for people with ND are still missing. This perspective paper aims to provide recommendations in terms of ergonomic choices for the design of SG aiming at stimulating people with ND, starting from the existing SG already tested in this population: “MINWii”, “Kitchen and Cooking”, and “X-Torp”. We propose to rely on nine ergonomic criteria: eight ergonomic criteria inspired by works in the domain of office automation: Compatibility, Guidance, Workload, Adaptability, Consistency, Significance of codes, Explicit control and Error management; and one ergonomic criterion related to videogame: the game rules. Perspectives derived from this proposal are also discussed.

Fragile X-associated tremor/ataxia syndrome (FXTAS): Pathology and mechanisms

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Hagerman, Paul

2013-01-01

Since its discovery in 2001, our understanding of fragile X-associated tremor/ataxia syndrome (FXTAS) has undergone a remarkable transformation. Initially characterized rather narrowly as an adult-onset movement disorder, the definition of FXTAS is broadening; moreover, the disorder is now recognized as only one facet of a much broader clinical pleiotropy among children and adults who carry premutation alleles of the FMR1 gene. Furthermore, the intranuclear inclusions of FXTAS, once thought to be a CNS-specific marker of the disorder, are now known to be widely distributed in multiple non-CNS tissues; this observation fundamentally changes our concept of the disease, and may provide the basis for understanding the diverse medical problems associated with the premutation. Recent work on the pathogenic mechanisms underlying FXTAS indicates that the origins of the late-onset neurodegenerative disorder actually lie in early development, raising the likelihood that all forms of clinical involvement among premutation carriers have a common underlying mechanistic basis. There has also been great progress in our understanding of the triggering event(s) in FXTAS pathogenesis, which is now thought to involve sequestration of one or more nuclear proteins involved with microRNA biogenesis. Moreover, there is mounting evidence that mitochondrial dysregulation contributes to the decreased cell function and loss of viability, evident in mice even during the neonatal period. Taken together, these recent findings offer hope for early interventions for FXTAS, well before the onset of overt disease, and for the treatment of other forms of clinical involvement among premutation carriers. PMID:23793382

Possible Role of the Transglutaminases in the Pathogenesis of Alzheimer's Disease and Other Neurodegenerative Diseases

OpenAIRE

Martin, Antonio; De Vivo, Giulia; Gentile, Vittorio

2011-01-01

Transglutaminases are ubiquitous enzymes which catalyze posttranslational modifications of proteins. Recently, transglutaminase-catalyzed post-translational modification of proteins has been shown to be involved in the molecular mechanisms responsible for human diseases. Transglutaminase activity has been hypothesized to be involved also in the pathogenetic mechanisms responsible for several human neurodegenerative diseases. Alzheimer's disease and other neurodegenerative diseases, such as Pa...

Sensitive Electrochemical Detection of Native and Aggregated x-Synuclein Protein Involved in Parkinson's Disease

NARCIS (Netherlands)

Masarik, Michal; Stobiecka, Agata; Kizek, René; Jelen, Frantisek; Pechan, Zdenk; Hoyer, Wolfgang; Subramaniam, Vinod; Palecek, Emil

2004-01-01

The aggregation of α-synuclein, a 14 kDa protein, is involved in several human neurodegenerative disorders, including Parkinson's disease. We studied native and in vitro aggregated α-synuclein by circular dichroism (CD), atomic force microscopy (AFM) and electrochemical methods. We used constant

High-resolution inelastic X-ray scattering to study the high-frequency atomic dynamics of disordered systems

International Nuclear Information System (INIS)

Monaco, G.

2008-01-01

The use of momentum-resolved inelastic X-ray scattering with meV energy resolution to study the high-frequency atomic dynamics in disordered systems is here reviewed. The typical realization of this experiment is described together with some common models used to interpret the measured spectra and to extract parameters of interest for the investigation of disordered systems. With the help of some selected examples, the present status of the field is discussed. Particular attention is given to those results which are still open for discussion or controversial, and which will require further development of the technique to be fully solved. Such an instrumental development seems nowadays possible at the light of recently proposed schemes for advanced inelastic X-ray scattering spectrometers. (author)

Evaluation of Alternative Atomistic Models for the Incipient Growth of ZnO by Atomic Layer Deposition

Energy Technology Data Exchange (ETDEWEB)

Chu, Manh-Hung; Tian, Liang; Chaker, Ahmad; Skopin, Evgenii; Cantelli, Valentina; Ouled, Toufik; Boichot, Raphaël; Crisci, Alexandre; Lay, Sabine; Richard, Marie-Ingrid; Thomas, Olivier; Deschanvres, Jean-Luc; Renevier, Hubert; Fong, Dillon; Ciatto, Gianluca

2017-03-20

ZnO thin films are interesting for applications in several technological fields, including optoelectronics and renewable energies. Nanodevice applications require controlled synthesis of ZnO structures at nanometer scale, which can be achieved via atomic layer deposition (ALD). However, the mechanisms governing the initial stages of ALD had not been addressed until very recently. Investigations into the initial nucleation and growth as well as the atomic structure of the heterointerface are crucial to optimize the ALD process and understand the structure-property relationships for ZnO. We have used a complementary suite of in situ synchrotron x-ray techniques to investigate both the structural and chemical evolution during ZnO growth by ALD on two different substrates, i.e., SiO2 and Al2O3, which led us to formulate an atomistic model of the incipient growth of ZnO. The model relies on the formation of nanoscale islands of different size and aspect ratio and consequent disorder induced in the Zn neighbors' distribution. However, endorsement of our model requires testing and discussion of possible alternative models which could account for the experimental results. In this work, we review, test, and rule out several alternative models; the results confirm our view of the atomistic mechanisms at play, which influence the overall microstructure and resulting properties of the final thin film.

A Fragment-Based Method of Creating Small-Molecule Libraries to Target the Aggregation of Intrinsically Disordered Proteins.

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Joshi, Priyanka; Chia, Sean; Habchi, Johnny; Knowles, Tuomas P J; Dobson, Christopher M; Vendruscolo, Michele

2016-03-14

The aggregation process of intrinsically disordered proteins (IDPs) has been associated with a wide range of neurodegenerative disorders, including Alzheimer's and Parkinson's diseases. Currently, however, no drug in clinical use targets IDP aggregation. To facilitate drug discovery programs in this important and challenging area, we describe a fragment-based approach of generating small-molecule libraries that target specific IDPs. The method is based on the use of molecular fragments extracted from compounds reported in the literature to inhibit of the aggregation of IDPs. These fragments are used to screen existing large generic libraries of small molecules to form smaller libraries specific for given IDPs. We illustrate this approach by describing three distinct small-molecule libraries to target, Aβ, tau, and α-synuclein, which are three IDPs implicated in Alzheimer's and Parkinson's diseases. The strategy described here offers novel opportunities for the identification of effective molecular scaffolds for drug discovery for neurodegenerative disorders and to provide insights into the mechanism of small-molecule binding to IDPs.

Conversational assessment in memory clinic encounters: interactional profiling for differentiating dementia from functional memory disorders.

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Jones, Danielle; Drew, Paul; Elsey, Christopher; Blackburn, Daniel; Wakefield, Sarah; Harkness, Kirsty; Reuber, Markus

2016-01-01

In the UK dementia is under-diagnosed, there is limited access to specialist memory clinics, and many of the patients referred to such clinics are ultimately found to have functional (non-progressive) memory disorders (FMD), rather than a neurodegenerative disorder. Government initiatives on 'timely diagnosis' aim to improve the rate and quality of diagnosis for those with dementia. This study seeks to improve the screening and diagnostic process by analysing communication between clinicians and patients during initial specialist clinic visits. Establishing differential conversational profiles could help the timely differential diagnosis of memory complaints. This study is based on video- and audio recordings of 25 initial consultations between neurologists and patients referred to a UK memory clinic. Conversation analysis was used to explore recurrent communicative practices associated with each diagnostic group. Two discrete conversational profiles began to emerge, to help differentiate between patients with dementia and functional memory complaints, based on (1) whether the patient is able to answer questions about personal information; (2) whether they can display working memory in interaction; (3) whether they are able to respond to compound questions; (4) the time taken to respond to questions; and (5) the level of detail they offer when providing an account of their memory failure experiences. The distinctive conversational profiles observed in patients with functional memory complaints on the one hand and neurodegenerative memory conditions on the other suggest that conversational profiling can support the differential diagnosis of functional and neurodegenerative memory disorders.

Therapeutic potential of systemic brain rejuvenation strategies for neurodegenerative disease [version 1; referees: 3 approved

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Alana M. Horowitz

2017-08-01

Full Text Available Neurodegenerative diseases are a devastating group of conditions that cause progressive loss of neuronal integrity, affecting cognitive and motor functioning in an ever-increasing number of older individuals. Attempts to slow neurodegenerative disease advancement have met with little success in the clinic; however, a new therapeutic approach may stem from classic interventions, such as caloric restriction, exercise, and parabiosis. For decades, researchers have reported that these systemic-level manipulations can promote major functional changes that extend organismal lifespan and healthspan. Only recently, however, have the functional effects of these interventions on the brain begun to be appreciated at a molecular and cellular level. The potential to counteract the effects of aging in the brain, in effect rejuvenating the aged brain, could offer broad therapeutic potential to combat dementia-related neurodegenerative disease in the elderly. In particular, results from heterochronic parabiosis and young plasma administration studies indicate that pro-aging and rejuvenating factors exist in the circulation that can independently promote or reverse age-related phenotypes. The recent demonstration that human umbilical cord blood similarly functions to rejuvenate the aged brain further advances this work to clinical translation. In this review, we focus on these blood-based rejuvenation strategies and their capacity to delay age-related molecular and functional decline in the aging brain. We discuss new findings that extend the beneficial effects of young blood to neurodegenerative disease models. Lastly, we explore the translational potential of blood-based interventions, highlighting current clinical trials aimed at addressing therapeutic applications for the treatment of dementia-related neurodegenerative disease in humans.

Lack of miRNA misregulation at early pathological stages in Drosophila neurodegenerative disease models

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Anita eReinhardt

2012-10-01

Full Text Available Late onset neurodegenerative diseases represent a major public health concern as the population in many countries ages. Both frequent diseases such as Alzheimer disease (AD, 14% incidence for 80-84 year old Europeans or Parkinson disease (PD, 1.4% prevalence for > 55 years old share, with other low-incidence neurodegenerative pathologies such as spinocerebellar ataxias (SCAs, 0.01% prevalence and frontotemporal lobar degeneration (FTLD, 0.02% prevalence, a lack of efficient treatment in spite of important research efforts. Besides significant progress, studies with animal models have revealed unexpected complexities in the degenerative process, emphasizing a need to better understand the underlying pathological mechanisms. Recently, microRNAs, a class of small regulatory non-coding RNAs, have been implicated in some neurodegenerative diseases. The current data supporting a role of miRNAs in PD, tauopathies, dominant ataxias and FTLD will first be discussed to emphasize the different levels of the pathological processes which may be affected by miRNAs. To investigate a potential involvement of miRNA dysregulation in the early stages of these neurodegenerative diseases we have used Drosophila models for 7 diseases (PD, 3 FTLD, 3 dominant ataxias that recapitulate many features of the human diseases. We performed deep sequencing of head small RNAs after 3 days of pathological protein expression in the fly head neurons. We found no evidence for a statistically significant difference in miRNA expression in this early stage of the pathological process. In addition, we could not identify small non coding CAG repeat RNAs (sCAG in polyQ disease models. Thus our data suggest that transcriptional deregulation of miRNAs or sCAG is unlikely to play a significant role in the initial stages of neurodegenerative diseases.