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1.
Neuroscience ; 398: 55-63, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30529693

RESUMO

Sleep disturbances are a common early symptom of neurodegenerative diseases, including Alzheimer's disease (AD) and other age-related dementias, and emerging evidence suggests that poor sleep may be an important contributor to development of amyloid pathology. Of the causes of sleep disturbances, it is estimated that 10-20% of adults in the United States have sleep-disordered breathing (SDB) disorder, with obstructive sleep apnea accounting for the majority of the SBD cases. The clinical and epidemiological data clearly support a link between sleep apnea and AD; yet, almost no experimental research is available exploring the mechanisms associated with this correlative link. Therefore, we exposed an AD-relevant mouse model (APP/PS1 KI) to chronic intermittent hypoxia (IH) (an experimental model of sleep apnea) to begin to describe one of the potential mechanisms by which SDB could increase the risk of dementia. Previous studies have found that astrogliosis is a contributor to neuropathology in models of chronic IH and AD; therefore, we hypothesized that a reactive astrocyte response might be a contributing mechanism in the neuroinflammation associated with sleep apnea. To test this hypothesis, 10-11-month-old wild-type (WT) and APP/PS1 KI mice were exposed to 10 hours of IH, daily for four weeks. At the end of four weeks brains were analyzed from amyloid burden and astrogliosis. No effect was found for chronic IH exposure on amyloid-beta levels or plaque load in the APP/PS1 KI mice. A significant increase in GFAP staining was found in the APP/PS1 KI mice following chronic IH exposure, but not in the WT mice. Profiling of genes associated with different phenotypes of astrocyte activation identified GFAP, CXCL10, and Ggta1 as significant responses activated in the APP/PS1 KI mice exposed to chronic IH.


Assuntos
Doença de Alzheimer/fisiopatologia , Astrócitos/fisiologia , Encéfalo/fisiopatologia , Gliose/fisiopatologia , Hipóxia/fisiopatologia , Síndromes da Apneia do Sono/fisiopatologia , Doença de Alzheimer/patologia , Animais , Astrócitos/patologia , Encéfalo/patologia , Modelos Animais de Doenças , Feminino , Regulação da Expressão Gênica , Gliose/patologia , Hipóxia/patologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Placa Amiloide/patologia , Placa Amiloide/fisiopatologia , Distribuição Aleatória , Síndromes da Apneia do Sono/patologia
2.
J Comp Physiol B ; 186(1): 45-57, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26438517

RESUMO

The Drosophila melanogaster heart is a popular model in which to study cardiac physiology and development. Progress has been made in understanding the role of endogenous compounds in regulating cardiac function in this model. It is well characterized that common neurotransmitters act on many peripheral and non-neuronal tissues as they flow through the hemolymph of insects. Many of these neuromodulators, including acetylcholine (ACh), have been shown to act directly on the D. melanogaster larval heart. ACh is a primary neurotransmitter in the central nervous system (CNS) of vertebrates and at the neuromuscular junctions on skeletal and cardiac tissue. In insects, ACh is the primary excitatory neurotransmitter of sensory neurons and is also prominent in the CNS. A full understanding regarding the regulation of the Drosophila cardiac physiology by the cholinergic system remains poorly understood. Here we use semi-intact D. melanogaster larvae to study the pharmacological profile of cholinergic receptor subtypes, nicotinic acetylcholine receptors (nAChRs) and muscarinic acetylcholine receptors (mAChRs), in modulating heart rate (HR). Cholinergic receptor agonists, nicotine and muscarine both increase HR, while nAChR agonist clothianidin exhibits no significant effect when exposed to an open preparation at concentrations as low as 100 nM. In addition, both nAChR and mAChR antagonists increase HR as well but also display capabilities of blocking agonist actions. These results provide evidence that both of these receptor subtypes display functional significance in regulating the larval heart's pacemaker activity.


Assuntos
Drosophila melanogaster/fisiologia , Frequência Cardíaca/efeitos dos fármacos , Coração/fisiologia , Receptores Colinérgicos/metabolismo , Acetilcolina/administração & dosagem , Acetilcolina/farmacologia , Animais , Agonistas Colinérgicos/administração & dosagem , Agonistas Colinérgicos/farmacologia , Antagonistas Colinérgicos/administração & dosagem , Antagonistas Colinérgicos/farmacologia , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Coração/efeitos dos fármacos , Larva/efeitos dos fármacos , Larva/fisiologia , Muscarina/administração & dosagem , Muscarina/farmacologia , Nicotina/administração & dosagem , Nicotina/farmacologia , Receptores Colinérgicos/classificação , Receptores Colinérgicos/genética
3.
Artigo em Inglês | MEDLINE | ID: mdl-26232582

RESUMO

The commonly used mood altering drug fluoxetine (Prozac) in humans has a low occurrence in reports of harmful effects from overdose; however, individuals with altered metabolism of the drug and accidental overdose have led to critical conditions and even death. We addressed direct actions of high concentrations on synaptic transmission at neuromuscular junctions (NMJs), neural properties, and cardiac function unrelated to fluoxetine's action as a selective 5-HT reuptake inhibitor. There appears to be action in blocking action potentials in crayfish axons, enhanced occurrences of spontaneous synaptic vesicle fusion events in the presynaptic terminals at NMJs of both Drosophila and crayfish. In rodent neurons, cytoplasmic Ca(2+) rises by fluoxetine and is thapsigargin dependent. The Drosophila larval heart showed a dose dependent effect in cardiac arrest. Acute paralytic behavior in crayfish occurred at a systemic concentration of 2mM. A high percentage of death as well as slowed development occurred in Drosophila larvae consuming food containing 100µM fluoxetine. The release of Ca(2+) from the endoplasmic reticulum in neurons and the cardiac tissue as well as blockage of voltage-gated Na(+) channels in neurons could explain the effects on the whole animal as well as the isolated tissues. The use of various animal models in demonstrating the potential mechanisms for the toxic effects with high doses of fluoxetine maybe beneficial for acute treatments in humans. Future studies in determining how fluoxetine is internalized in cells and if there are subtle effects of these mentioned mechanisms presented with chronic therapeutic doses are of general interest.


Assuntos
Astacoidea/efeitos dos fármacos , Drosophila melanogaster/efeitos dos fármacos , Fluoxetina/toxicidade , Miócitos Cardíacos/efeitos dos fármacos , Junção Neuromuscular/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Inibidores Seletivos de Recaptação de Serotonina/toxicidade , Animais , Astacoidea/metabolismo , Comportamento Animal/efeitos dos fármacos , Sinalização do Cálcio/efeitos dos fármacos , Células Cultivadas , Relação Dose-Resposta a Droga , Drosophila melanogaster/metabolismo , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Parada Cardíaca/induzido quimicamente , Parada Cardíaca/metabolismo , Camundongos , Modelos Animais , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Junção Neuromuscular/metabolismo , Junção Neuromuscular/patologia , Neurônios/metabolismo , Neurônios/patologia , Terminações Pré-Sinápticas/efeitos dos fármacos , Terminações Pré-Sinápticas/metabolismo , Medição de Risco , Especificidade da Espécie , Fatores de Tempo
4.
Int J Exerc Sci ; 3(3): 117-125, 2010.
Artigo em Inglês | MEDLINE | ID: mdl-27182337

RESUMO

Graded exercise testing (GXT), per a cycle-ergometer (CE), offers safety and monitoring advantages over treadmill (TM) GXT. Unfortunately, CE-VO2max and some other cardiorespiratory (CR) variables are frequently lower than TM-GXT values. It has been difficult to compare TM and CE-GXT values. However, it was hypothesized that standing towards the conclusion of the CE-GXT (Stand-CE) might increase CE values to those equal to TM-GXT. If Stand-CE and TM-GXT CR values were equal, Stand-CE-GXT could become the method of choice for GXT for the general population. The purpose of this investigation was to investigate the effect of Stand-CE on CR variables. An intentionally diverse sample (N = 34, 24 males and 10 females, aged 18-54 y, with VO2max values 25-76 ml/kg/min) representing the "apparently healthy" general population participated. Volunteers completed two GXT trials, one per TM (Bruce protocol) and the other per a MET-TM-matched CE-GXT where initially seated participants stood and pedaled after their respiratory exchange ratio (RER) reached 1.0. Eighteen participants underwent a third MET-TM-matched trial where they remained seated throughout GXT (Sit-CE). Trials were counter-balanced with at least 48 h between GXT. There were significant statistical differences (p < 0.05) between TM and Stand-CE per matched-samples T-test (N = 34) on the following variables: VEmax (TM = 115 ± 24.4 l/min, Stand-CE = 99.4 ± 28.1), VCO2max (TM = 4.26 ± 0.9 l/min, Stand-CE = 3.56 ± 0.84), VO2max (TM = 44.9 ± 9.1 ml/kg/min, Stand-CE = 39.3 ± 9.0), METSmax (TM = 12.8 ± 2.6 METS, Stand-CE = 11.2 ± 2.5), and HRmax (TM = 175 ± 13 bpm, Stand-CE = 166 ± 12). One-way repeated measures ANOVA (N = 18) demonstrated no statistical differences among all trials: VEmax (TM = 112.8 ± 25.3 l/min, Stand-CE = 102.3 ± 25.2, Sit-CE = 107.3 ± 33.1), VCO2max (TM = 4.17 ± 0.99 l/min, Stand-CE = 3.62 ± 0.80, Sit-CE = 3.55 ± 0.83), VO2max (TM = 47.1 ± 9.8 ml/kg/min, Stand-CE = 42.0 ± 9.0, Sit-CE = 43.3 ± 8.9), METSmax (TM = 13.5 ± 2.8 METS, Stand-CE = 12.0 ± 2.6, Sit-CE = 12.4 ± 2.5), and HRmax (TM = 176 ± 13 bpm, Stand-CE = 171 ± 12, Sit-CE = 173 ± 11). Results of this investigation suggest that TM-GXT CR values are larger than Stand-CE, and Stand-CE values are not different from Sit-CE. Future studies will test validity of these findings per gender, aerobic training status, in populations that are highly skilled with TM and CE (tri-athletes), children, the elderly, and diseased populations.

5.
Nat Mater ; 8(3): 235-42, 2009 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-19219032

RESUMO

Graphene shows promise as a future material for nanoelectronics owing to its compatibility with industry-standard lithographic processing, electron mobilities up to 150 times greater than Si and a thermal conductivity twice that of diamond. The electronic structure of graphene nanoribbons (GNRs) and quantum dots (GQDs) has been predicted to depend sensitively on the crystallographic orientation of their edges; however, the influence of edge structure has not been verified experimentally. Here, we use tunnelling spectroscopy to show that the electronic structure of GNRs and GQDs with 2-20 nm lateral dimensions varies on the basis of the graphene edge lattice symmetry. Predominantly zigzag-edge GQDs with 7-8 nm average dimensions are metallic owing to the presence of zigzag edge states. GNRs with a higher fraction of zigzag edges exhibit a smaller energy gap than a predominantly armchair-edge ribbon of similar width, and the magnitudes of the measured GNR energy gaps agree with recent theoretical calculations.

6.
Nanotechnology ; 19(1): 015704, 2008 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-21730545

RESUMO

We have developed a method for depositing graphene monolayers and bilayers with minimum lateral dimensions of 2-10 nm by the mechanical exfoliation of graphite onto the Si(100)-2 × 1:H surface. Room temperature, ultrahigh vacuum tunneling spectroscopy measurements of nanometer-sized single layer graphene reveal a size-dependent energy gap ranging from 0.1 to 1 eV. Furthermore, the number of graphene layers can be directly determined from scanning tunneling microscopy topographic contours. This atomistic study provides an experimental basis for probing the electronic structure of nanometer-sized graphene which can assist the development of graphene-based nanoelectronics.

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