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1.
Eur J Neurosci ; 59(4): 554-569, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36623837

RESUMO

The thalamic reticular nucleus (TRN) is crucial for the modulation of sleep-related oscillations. The caudal and rostral subpopulations of the TRN exert diverse activities, which arise from their interconnectivity with all thalamic nuclei, as well as other brain regions. Despite the recent characterization of the functional and genetic heterogeneity of the TRN, the implications of this heterogeneity for sleep regulation have not been assessed. Here, using a combination of optogenetics and electrophysiology in C57BL/6 mice, we demonstrate that caudal and rostral TRN modulations are associated with changes in cortical alpha and delta oscillations and have distinct effects on sleep stability. Tonic silencing of the rostral TRN elongates sleep episodes, while tonic silencing of the caudal TRN fragments sleep. Overall, we show evidence of distinct roles exerted by the rostral and caudal TRN in sleep regulation and oscillatory activity.


Assuntos
Sono , Núcleos Talâmicos , Camundongos , Animais , Camundongos Endogâmicos C57BL , Núcleos Talâmicos/fisiologia , Sono/fisiologia , Fenômenos Eletrofisiológicos
2.
Philos Trans A Math Phys Eng Sci ; 379(2206): 20200345, 2021 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-34334027

RESUMO

Trees belong to the largest living organisms on Earth and plants in general are one of our main renewable resources. Wood as a material has been used since the beginning of humankind. Today, forestry still provides raw materials for a variety of applications, for example in the building industry, in paper manufacturing and for various wood products. However, many parts of the tree, such as reaction wood, branches and bark are often discarded as forestry residues and waste wood, used as additives in composite materials or burned for energy production. More advanced uses of bark include the extraction of chemical substances for glues, food additives or healthcare, as well as the transformation to advanced carbon materials. Here, we argue that a proper understanding of the internal fibrous structure and the resulting mechanical behaviour of these forest residues allows for the design of materials with greatly varying properties and applications. We show that simple and cheap treatments can give tree bark a leather-like appearance that can be used for the construction of shelters and even the fabrication of woven textiles. This article is part of the theme issue 'Bio-derived and bioinspired sustainable advanced materials for emerging technologies (part 1)'.


Assuntos
Casca de Planta , Madeira , Carbono
3.
Macromol Rapid Commun ; 40(7): e1800896, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30811751

RESUMO

Inspired by the motions of plant tissues in response to external stimuli, significant attention has been devoted to the development of actuating polymeric materials. In particular, polymeric actuators driven by organic molecules have been designed due to their combined superiorities of tunable functional monomers, designable chemical structures, and variable structural anisotropy. Here, the recent progress is summarized in terms of material synthesis, structure design, polymer-solvent interaction, and actuating performance. In addition, various possibilities for practical applications, including the ability to sense chemical vapors and solvent isomers, and future directions to satisfy the requirement of sensing and smart systems are also highlighted.


Assuntos
Compostos Orgânicos/química , Polímeros/síntese química , Estrutura Molecular , Polímeros/química
4.
J Biol Chem ; 292(16): 6621-6632, 2017 04 21.
Artigo em Inglês | MEDLINE | ID: mdl-28213518

RESUMO

The behavioral and anatomical deficits seen in fragile X syndrome (FXS) are widely believed to result from imbalances in the relative strengths of excitatory and inhibitory neurotransmission. Although modified neuronal excitability is thought to be of significance, the contribution that alterations in GABAergic inhibition play in the pathophysiology of FXS are ill defined. Slow sustained neuronal inhibition is mediated by γ-aminobutyric acid type B (GABAB) receptors, which are heterodimeric G-protein-coupled receptors constructed from R1a and R2 or R1b and R2 subunits. Via the activation of Gi/o, they limit cAMP accumulation, diminish neurotransmitter release, and induce neuronal hyperpolarization. Here we reveal that selective deficits in R1a subunit expression are seen in Fmr1 knock-out mice (KO) mice, a widely used animal model of FXS, but the levels of the respective mRNAs were unaffected. Similar trends of R1a expression were seen in a subset of FXS patients. GABAB receptors (GABABRs) exert powerful pre- and postsynaptic inhibitory effects on neurotransmission. R1a-containing GABABRs are believed to mediate presynaptic inhibition in principal neurons. In accordance with this result, deficits in the ability of GABABRs to suppress glutamate release were seen in Fmr1-KO mice. In contrast, the ability of GABABRs to suppress GABA release and induce postsynaptic hyperpolarization was unaffected. Significantly, this deficit contributes to the pathophysiology of FXS as the GABABR agonist (R)-baclofen rescued the imbalances between excitatory and inhibitory neurotransmission evident in Fmr1-KO mice. Collectively, our results provided evidence that selective deficits in the activity of presynaptic GABABRs contribute to the pathophysiology of FXS.


Assuntos
Proteína do X Frágil da Deficiência Intelectual/genética , Síndrome do Cromossomo X Frágil/genética , Receptores de GABA-B/metabolismo , Idoso , Idoso de 80 Anos ou mais , Animais , Comportamento Animal , Modelos Animais de Doenças , Síndrome do Cromossomo X Frágil/metabolismo , Ácido Glutâmico/metabolismo , Hipocampo/metabolismo , Hipocampo/fisiopatologia , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neurônios/metabolismo , Fosforilação , RNA Mensageiro/metabolismo , Receptores de GABA-B/genética , Serina/química , Transdução de Sinais , Transmissão Sináptica , Ácido gama-Aminobutírico/metabolismo
5.
Ann Bot ; 121(2): 345-358, 2018 02 12.
Artigo em Inglês | MEDLINE | ID: mdl-29293865

RESUMO

Background and Aims: A key structural adaptation of vascular plants was the evolution of specialized vascular and mechanical tissues, innovations likely to have generated novel cell wall architectures. While collenchyma is a strengthening tissue typically found in growing organs of angiosperms, a similar tissue occurs in the petiole of the fern Asplenium rutifolium. Methods: The in situ cell wall (ultra)structure and composition of this tissue was investigated and characterized mechanically as well as structurally through nano-indentation and wide-angle X-ray diffraction, respectively. Key Results: Structurally the mechanical tissue resembles sclerenchyma, while its biomechanical properties and molecular composition both share more characteristics with angiosperm collenchyma. Cell wall thickening only occurs late during cell expansion or after cell expansion has ceased. Conclusions: If the term collenchyma is reserved for walls that thicken during expansive growth, the mechanical tissue in A. rutifolium represents sclerenchyma that mimics the properties of collenchyma and has the ability to modify its mechanical properties through sclerification. These results support the view that collenchyma does not occur in ferns and most probably evolved in angiosperms.


Assuntos
Parede Celular/fisiologia , Gleiquênias/citologia , Fenômenos Biomecânicos , Parede Celular/química , Parede Celular/ultraestrutura , Gleiquênias/fisiologia , Gleiquênias/ultraestrutura , Mananas/análise , Microscopia Eletrônica de Transmissão , Difração de Raios X
6.
Proc Natl Acad Sci U S A ; 112(11): 3523-8, 2015 Mar 17.
Artigo em Inglês | MEDLINE | ID: mdl-25733865

RESUMO

The K(+)/Cl(-) cotransporter (KCC2) allows adult neurons to maintain low intracellular Cl(-) levels, which are a prerequisite for efficient synaptic inhibition upon activation of γ-aminobutyric acid receptors. Deficits in KCC2 activity are implicated in epileptogenesis, but how increased neuronal activity leads to transporter inactivation is ill defined. In vitro, the activity of KCC2 is potentiated via phosphorylation of serine 940 (S940). Here we have examined the role this putative regulatory process plays in determining KCC2 activity during status epilepticus (SE) using knockin mice in which S940 is mutated to an alanine (S940A). In wild-type mice, SE induced by kainate resulted in dephosphorylation of S940 and KCC2 internalization. S940A homozygotes were viable and exhibited comparable basal levels of KCC2 expression and activity relative to WT mice. However, exposure of S940A mice to kainate induced lethality within 30 min of kainate injection and subsequent entrance into SE. We assessed the effect of the S940A mutation in cultured hippocampal neurons to explore the mechanisms underlying this phenotype. Under basal conditions, the mutation had no effect on neuronal Cl(-) extrusion. However, a selective deficit in KCC2 activity was seen in S940A neurons upon transient exposure to glutamate. Significantly, whereas the effects of glutamate on KCC2 function could be ameliorated in WT neurons with agents that enhance S940 phosphorylation, this positive modulation was lost in S940A neurons. Collectively our results suggest that phosphorylation of S940 plays a critical role in potentiating KCC2 activity to limit the development of SE.


Assuntos
Estado Epiléptico/metabolismo , Estado Epiléptico/patologia , Simportadores/metabolismo , Animais , Cloretos/metabolismo , Endocitose , Técnicas de Introdução de Genes , Glutamatos/farmacologia , Camundongos , Camundongos Mutantes Neurológicos , Proteínas Mutantes/metabolismo , Mutação/genética , Fosforilação , Fosfosserina/metabolismo , Proteína Fosfatase 1/antagonistas & inibidores , Proteína Fosfatase 1/metabolismo , Simportadores/genética , Ácido gama-Aminobutírico/metabolismo , Cotransportadores de K e Cl-
7.
J Neurosci ; 35(21): 8291-6, 2015 May 27.
Artigo em Inglês | MEDLINE | ID: mdl-26019342

RESUMO

GABA(A) receptors form Cl(-) permeable channels that mediate the majority of fast synaptic inhibition in the brain. The K(+)/Cl(-) cotransporter KCC2 is the main mechanism by which neurons establish low intracellular Cl(-) levels, which is thought to enable GABAergic inhibitory control of neuronal activity. However, the widely used KCC2 inhibitor furosemide is nonselective with antiseizure efficacy in slices and in vivo, leading to a conflicting scheme of how KCC2 influences GABAergic control of neuronal synchronization. Here we used the selective KCC2 inhibitor VU0463271 [N-cyclopropyl-N-(4-methyl-2-thiazolyl)-2-[(6-phenyl-3-pyridazinyl)thio]acetamide] to investigate the influence of KCC2 function. Application of VU0463271 caused a reversible depolarizing shift in E(GABA) values and increased spiking of cultured hippocampal neurons. Application of VU0463271 to mouse hippocampal slices under low-Mg(2+) conditions induced unremitting recurrent epileptiform discharges. Finally, microinfusion of VU0463271 alone directly into the mouse dorsal hippocampus rapidly caused epileptiform discharges. Our findings indicated that KCC2 function was a critical inhibitory factor ex vivo and in vivo.


Assuntos
Hipocampo/fisiologia , Inibidores de Simportadores de Cloreto de Sódio e Potássio/farmacologia , Simportadores/antagonistas & inibidores , Simportadores/fisiologia , Animais , Animais Recém-Nascidos , Células Cultivadas , Células HEK293 , Hipocampo/efeitos dos fármacos , Humanos , Potenciais da Membrana/efeitos dos fármacos , Potenciais da Membrana/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Técnicas de Cultura de Órgãos , Ratos , Ratos Sprague-Dawley , Transmissão Sináptica/efeitos dos fármacos , Transmissão Sináptica/fisiologia , Cotransportadores de K e Cl-
8.
J Exp Biol ; 218(Pt 6): 824-36, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25617457

RESUMO

Perhaps the most striking feature of billfishes is the extreme elongation of the premaxillary bones forming their rostra. Surprisingly, the exact role of this structure in feeding is still controversial. The goal of this study is to investigate the use of the rostrum from a functional, biomechanical and morphological standpoint to ultimately infer its possible role during feeding. Using beam theory, experimental and theoretical loading tests were performed on the rostra from two morphologically different billfish, the blue marlin (Makaira nigricans) and the swordfish (Xiphias gladius). Two loading regimes were applied (dorsoventral and lateral) to simulate possible striking behaviors. Histological samples and material properties of the rostra were obtained along their lengths to further characterize structure and mechanical performance. Intraspecific results show similar stress distributions for most regions of the rostra, suggesting that this structure may be designed to withstand continuous loadings with no particular region of stress concentration. Although material stiffness increased distally, flexural stiffness increased proximally owing to higher second moment of area. The blue marlin rostrum was stiffer and resisted considerably higher loads for both loading planes compared with that of the swordfish. However, when a continuous load along the rostrum was considered, simulating the rostrum swinging through the water, swordfish exhibited lower stress and drag during lateral loading. Our combined results suggest that the swordfish rostrum is suited for lateral swiping to incapacitate their prey, whereas the blue marlin rostrum is better suited to strike prey from a wider variety of directions.


Assuntos
Perciformes/anatomia & histologia , Perciformes/fisiologia , Comportamento Predatório , Crânio/anatomia & histologia , Animais , Fenômenos Biomecânicos , Teste de Materiais , Modelos Biológicos , Especificidade da Espécie
9.
J Neurochem ; 129(5): 884-94, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24494600

RESUMO

Aggregate-prone mutant proteins, such as α-synuclein and huntingtin, play a prominent role in the pathogenesis of various neurodegenerative disorders; thus, it has been hypothesized that reducing the aggregate-prone proteins may be a beneficial therapeutic strategy for these neurodegenerative disorders. Here, we identified two previously described glucosylceramide (GlcCer) synthase inhibitors, DL-threo-1-Phenyl-2-palmitoylamino-3-morpholino-1-propanol and Genz-123346(Genz), as enhancers of autophagy flux. We also demonstrate that GlcCer synthase inhibitors exert their effects on autophagy by inhibiting AKT-mammalian target of rapamycin (mTOR) signaling. More importantly, siRNA knock down of GlcCer synthase had the similar effect as pharmacological inhibition, confirming the on-target effect. In addition, we discovered that inhibition of GlcCer synthase increased the number and size of lysosomal/late endosomal structures. Although inhibition of GlcCer synthase decreases levels of mutant α-synuclein in neurons, it does so, according to our data, through autophagy-independent mechanisms. Our findings demonstrate a direct link between glycosphingolipid biosynthesis and autophagy in primary neurons, which may represent a novel pathway with potential therapeutic value for the treatment of Parkinson's disease. Inhibition of GlcCer synthase enhances autophagy by inhibiting AKT-mTOR signaling, and increases the number and size of lysosomal/late endosomal structures. Furthermore, inhibition of GlcCer synthase decreased levels of mutant α-synuclein in neurons, which may represent a potential therapeutic target for Parkinson's disease.


Assuntos
Autofagia/fisiologia , Inibidores Enzimáticos/farmacologia , Glucosiltransferases/antagonistas & inibidores , Neurônios/fisiologia , Animais , Western Blotting , Células Cultivadas , Dioxanos/farmacologia , Feminino , Glicoesfingolipídeos/biossíntese , Células HEK293 , Humanos , Masculino , Meperidina/análogos & derivados , Meperidina/farmacologia , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Proteína Oncogênica v-akt/metabolismo , Doença de Parkinson/genética , Fosforilação , Cultura Primária de Células , Pirrolidinas/farmacologia , RNA Interferente Pequeno/genética , Reação em Cadeia da Polimerase em Tempo Real
10.
J Neurochem ; 128(4): 561-76, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24117733

RESUMO

Genetic mutations in leucine-rich repeat kinase 2 (LRRK2) have been linked to autosomal dominant Parkinson's disease. The most prevalent mutation, G2019S, results in enhanced LRRK2 kinase activity that potentially contributes to the etiology of Parkinson's disease. Consequently, disease progression is potentially mediated by poorly characterized phosphorylation-dependent LRRK2 substrate pathways. To address this gap in knowledge, we transduced SH-SY5Y neuroblastoma cells with LRRK2 G2019S via adenovirus, then determined quantitative changes in the phosphoproteome upon LRRK2 kinase inhibition (LRRK2-IN-1 treatment) using stable isotope labeling of amino acids in culture combined with phosphopeptide enrichment and LC-MS/MS analysis. We identified 776 phosphorylation sites that were increased or decreased at least 50% in response to LRRK2-IN-1 treatment, including sites on proteins previously known to associate with LRRK2. Bioinformatic analysis of those phosphoproteins suggested a potential role for LRRK2 kinase activity in regulating pro-inflammatory responses and neurite morphology, among other pathways. In follow-up experiments, LRRK2-IN-1 inhibited lipopolysaccharide-induced tumor necrosis factor alpha (TNFα) and C-X-C motif chemokine 10 (CXCL10) levels in astrocytes and also enhanced multiple neurite characteristics in primary neuronal cultures. However, LRRK2-IN-1 had almost identical effects in primary glial and neuronal cultures from LRRK2 knockout mice. These data suggest LRRK2-IN-1 may inhibit pathways of perceived LRRK2 pathophysiological function independently of LRRK2 highlighting the need to use multiple pharmacological tools and genetic approaches in studies determining LRRK2 function.


Assuntos
Fosfoproteínas/genética , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteômica , Adenoviridae/genética , Animais , Astrócitos/metabolismo , Células Cultivadas , Quimiocina CXCL10/metabolismo , Ensaio de Imunoadsorção Enzimática , Humanos , Imuno-Histoquímica , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina , Lipopolissacarídeos/farmacologia , Espectrometria de Massas , Camundongos , Camundongos Knockout , Neuritos/efeitos dos fármacos , Neuritos/fisiologia , Fosforilação , Plasmídeos/genética , Cultura Primária de Células , Proteínas Serina-Treonina Quinases/genética , Transdução de Sinais/efeitos dos fármacos , Titânio/farmacologia , Fator de Necrose Tumoral alfa/metabolismo
11.
PNAS Nexus ; 3(4): pgae121, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38590971

RESUMO

Little is known about the contribution of 3D surface geometry to the development of multilayered tissues containing fibrous extracellular matrix components, such as those found in bone. In this study, we elucidate the role of curvature in the formation of chiral, twisted-plywood-like structures. Tissues consisting of murine preosteoblast cells (MC3T3-E1) were grown on 3D scaffolds with constant-mean curvature and negative Gaussian curvature for up to 32 days. Using 3D fluorescence microscopy, the influence of surface curvature on actin stress-fiber alignment and chirality was investigated. To gain mechanistic insights, we did experiments with MC3T3-E1 cells deficient in nuclear A-type lamins or treated with drugs targeting cytoskeleton proteins. We find that wild-type cells form a thick tissue with fibers predominantly aligned along directions of negative curvature, but exhibiting a twist in orientation with respect to older tissues. Fiber orientation is conserved below the tissue surface, thus creating a twisted-plywood-like material. We further show that this alignment pattern strongly depends on the structural components of the cells (A-type lamins, actin, and myosin), showing a role of mechanosensing on tissue organization. Our data indicate the importance of substrate curvature in the formation of 3D tissues and provide insights into the emergence of chirality.

12.
Int J Neuropsychopharmacol ; 16(3): 593-606, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-22717119

RESUMO

This study examined in naive or hemiparkinsonian rats the effect of various serotonin 2C (5-HT(2C)) receptor ligands differing in their intrinsic activity at 5-HT(2C) receptors on purposeless oral movements, a motor response integrated in the basal ganglia. Intraperitoneal administration of a non-selective [meta-chlorophenylpiperazine (m-CPP) 0.1-3 mg/kg], preferential [S-2-(6-chloro-5-fluoroindol-1-yl)-1-methylethylamine, Ro60-0175, 0.1-3 mg/kg] or selective [(7bR,10aR)-1,2,3,4,8,9,10,10a-octahydro-7bH-cyclopenta-[b][1,4]diazepino[6,7,1hi]indole, WAY163909, 0.3-10 mg/kg] 5-HT(2C) agonists enhanced oral bouts in naive rats. The 5-HT(2C) inverse agonists SB206553 [1-20 mg/kg; 5-methyl-1-(3-pyridylcarbamoyl)-1,2,3,5-tetrahydropyrrolo[2,3-f]indole] and S32006 [1-20 mg/kg; N-pyridin-3-yl-1,2-dihydro-3H-benzo[e]indole-3-carboxamide], but not the 5-HT(2C) antagonist SB243213 [1-10 mg/kg; 5-methyl-1-[[2-[(2-methyl-3-pyridyl)oxy]-5-pyridyl]carbamoyl]-6-trifluoromethylindoline], likewise dose-dependently enhanced oral movements. The effects induced by preferential 5-HT(2C) agonists and inverse agonists, but not by the cholinomimetic drug pilocarpine (5 mg/kg), were abolished by SB243213 underpinning its specificity. S32006-induced oral bouts was unaffected by the 5,7-dihydroxytryptamine lesions of 5-HT neurons. Nigrostriatal dopaminergic lesions potentiated oral effects induced by the agonists Ro60-0175 (3 mg/kg) and WAY163909 (1 mg/kg), but not by the inverse agonist SB206553 (10 mg/kg). The effect of Ro60-0175 in dopamine-lesioned rats was suppressed by SB243213. These data show that 5-HT(2C) agonists and full inverse agonists (but not neutral antagonists) perturb oral activity in rodents, paralleling studies of common antidepressant, anxiolytic and antipsychotic properties. The differential sensitivity of their actions to depletion of dopamine suggests recruitment of different contrasting neural mechanisms in the basal ganglia.


Assuntos
Modelos Animais de Doenças , Agonismo Inverso de Drogas , Doença de Parkinson Secundária/induzido quimicamente , Doença de Parkinson Secundária/fisiopatologia , Receptor 5-HT2C de Serotonina/fisiologia , Agonistas do Receptor 5-HT2 de Serotonina/toxicidade , Animais , Masculino , Transtornos dos Movimentos , Ligação Proteica/fisiologia , Ratos , Ratos Sprague-Dawley
13.
PNAS Nexus ; 2(1): pgac292, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36712928

RESUMO

Growing tissues are highly dynamic, and flow on sufficiently long timescales due to cell proliferation, migration, and tissue remodeling. As a consequence, growing tissues can often be approximated as viscous fluids. This means that the shape of microtissues growing in vitro is governed by their surface stress state, as in fluid droplets. Recent work showed that cells in the near-surface region of fibroblastic or osteoblastic microtissues contract with highly oriented actin filaments, thus making the surface properties highly anisotropic, in contrast to what is expected for an isotropic fluid. Here, we develop a model that includes mechanical anisotropy of the surface generated by contractile fibers and we show that mechanical equilibrium requires contractile filaments to follow geodesic lines on the surface. Constant pressure in the fluid forces these contractile filaments to be along geodesics with a constant normal curvature. We then take this into account to determine equilibrium shapes of rotationally symmetric bodies subjected to anisotropic surface stress states and derive a family of surfaces of revolution. A comparison with recently published shapes of microtissues shows that this theory accurately predicts both the surface shape and the direction of the actin filaments on the surface.

14.
Adv Mater ; 35(13): e2206110, 2023 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-36461812

RESUMO

Surface curvature both emerges from, and influences the behavior of, living objects at length scales ranging from cell membranes to single cells to tissues and organs. The relevance of surface curvature in biology is supported by numerous experimental and theoretical investigations in recent years. In this review, first, a brief introduction to the key ideas of surface curvature in the context of biological systems is given and the challenges that arise when measuring surface curvature are discussed. Giving an overview of the emergence of curvature in biological systems, its significance at different length scales becomes apparent. On the other hand, summarizing current findings also shows that both single cells and entire cell sheets, tissues or organisms respond to curvature by modulating their shape and their migration behavior. Finally, the interplay between the distribution of morphogens or micro-organisms and the emergence of curvature across length scales is addressed with examples demonstrating these key mechanistic principles of morphogenesis. Overall, this review highlights that curved interfaces are not merely a passive by-product of the chemical, biological, and mechanical processes but that curvature acts also as a signal that co-determines these processes.


Assuntos
Fenômenos Mecânicos , Membrana Celular , Morfogênese
15.
J Magn Reson Imaging ; 36(2): 344-54, 2012 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-22535702

RESUMO

PURPOSE: To assess test-retest stability of four functional magnetic resonance imaging (fMRI)-derived resting brain activity metrics: the seed-region-based functional connectivity (SRFC), independent component analysis (ICA)-derived network-based FC (NTFC), regional homogeneity (ReHo), and the amplitude of low frequency fluctuation (ALFF). METHODS: Simulations were used to assess the sensitivity of SRFC, ReHo, and ALFF to noise interference. Repeat resting blood oxygen level-dependent (BOLD) fMRI were acquired from 32 healthy subjects. The intraclass correlation coefficient (ICC) was used to assess the stability of the four metrics. RESULTS: Random noise yielded small random SRFC, small but consistent ReHo and ALFF. A neighborhood size greater than 20 voxels should be used for calculating ReHo in order to reduce the noise interference. Both the anterior cingulate cortex (ACC) and posterior cingulate cortex (PCC)-based SRFC were reproducible in more spatially extended regions than ICA NTFC. The two regional spontaneous brain activity (SBA) measures, ReHo and ALFF, showed test-retest reproducibility in almost the whole gray matter. CONCLUSION: SRFC, ReHo, and ALFF are robust to random noise interference. The neighborhood size for calculating ReHo should be larger than 20 voxels. ICC > 0.5 and cluster size > 11 should be used to assess the ICC maps for ACC/PCC SRFC, ReHo, and ALFF. BOLD fMRI-based SBA can be reliably measured using ACC/PCC SRFC, ReHo, and ALFF after 2 months.


Assuntos
Mapeamento Encefálico/métodos , Encéfalo/fisiologia , Circulação Cerebrovascular/fisiologia , Imageamento por Ressonância Magnética/métodos , Oxigênio/sangue , Descanso/fisiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Encéfalo/anatomia & histologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Adulto Jovem
16.
Handb Exp Pharmacol ; (213): 147-65, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-23027415

RESUMO

The 5-HT(2C) receptor is a highly complex, highly regulated receptor which is widely distributed throughout the brain. The 5-HT(2C) receptor couples to multiple signal transduction pathways leading to engagement of a number of intracellular signaling molecules. Moreover, there are multiple allelic variants of the 5-HT(2C) receptor and the receptor is subject to RNA editing in the coding regions. The complexity of this receptor is further emphasized by the studies suggesting the utility of either agonists or antagonists in the treatment of schizophrenia. While several 5-HT(2C) agonists have demonstrated clinical efficacy in obesity (lorcaserin, PRX-000933), the focus of this review is on the therapeutic potential of 5-HT(2C) agonists in schizophrenia. To this end, the preclinical profile of 5-HT(2C) agonists from a neurochemical, electrophysiological, and a behavioral perspective is indicative of antipsychotic-like efficacy without extrapyramidal symptoms or weight gain. Recently, the selective 5-HT(2C) agonist vabicaserin demonstrated clinical efficacy in a Phase II trial in schizophrenia patients without weight gain and with low EPS liability. These data are highly encouraging and suggest that 5-HT(2C) agonists are potential therapeutics for the treatment of psychiatric disorders.


Assuntos
Esquizofrenia/tratamento farmacológico , Agonistas do Receptor 5-HT2 de Serotonina/uso terapêutico , Compostos Heterocíclicos de 4 ou mais Anéis/uso terapêutico , Humanos , Edição de RNA , Pesquisa Translacional Biomédica
17.
Proc Math Phys Eng Sci ; 478(2257): 20210607, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-35153613

RESUMO

Bone injuries or defects that require invasive surgical treatment are a serious clinical issue, particularly when it comes to treatment success and effectiveness. Accordingly, bone tissue engineering (BTE) has been researching the use of computational fluid dynamics (CFD) analysis tools to assist in designing optimal scaffolds that better promote bone growth and repair. This paper aims to offer a comprehensive review of recent studies that use CFD analysis in BTE. The mechanical and fluidic properties of a given scaffold are coupled to each other via the scaffold architecture, meaning an optimization of one may negatively affect the other. For example, designs that improve scaffold permeability normally result in a decreased average wall shear stress. Linked with these findings, it appears there are very few studies in this area that state a specific application for their scaffolds and those that do are focused on in vitro bioreactor environments. Finally, this review also demonstrates a scarcity of studies that combine CFD with optimization methods to improve scaffold design. This highlights an important direction of research for the development of the next generation of BTE scaffolds.

18.
Materials (Basel) ; 15(20)2022 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-36295440

RESUMO

When designing scaffolds for bone tissue engineering (BTE), the wall shear stress (WSS), due to the fluid flow inside the scaffold, is an important factor to consider as it influences the cellular process involved in new tissue formation. The present work analyzed the average WSS in Schwartz diamond (SD) and gyroid (SG) scaffolds with different surface topologies and mesh elements using computational fluid dynamics (CFD) analysis. It was found that scaffold meshes with a smooth surface topology with tetrahedral elements had WSS levels 35% higher than the equivalent scaffold with a non-smooth surface topology with hexahedral elements. The present work also investigated the possibility of implementing the optimization algorithm simulated annealing to aid in the design of BTE scaffolds with a specific average WSS, with the outputs showing that the algorithm was able to reach WSS levels in the vicinity of 5 mPa (physiological range) within the established limit of 100 iterations. This proved the efficacy of combining CFD and optimization methods in the design of BTE scaffolds.

19.
J Pharmacol Exp Ther ; 337(3): 673-80, 2011 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-21402690

RESUMO

The 5-hydroxytryptamine 2C (5-HT(2C)) receptor subtype has received considerable attention as a target for drug discovery, having been implicated in a wide variety of disorders. Here, we describe the in vitro pharmacological profile of the novel 5-HT(2C) receptor-selective agonist vabicaserin [(-)-4,5,6,7,9,9a,10,11,12,12a-decahydrocyclopenta[c] [1,4]diazepino[6,7,1-ij]quinoline hydrochloride] (SCA-136), including a comprehensive strategy to assess 5-HT(2B) receptor selectivity using diverse preparations and assays of receptor activation. Vabicaserin displaced (125)I-(2,5-dimethoxy)phenylisopropylamine binding from human 5-HT(2C) receptor sites in Chinese hamster ovary cell membranes with a K(i) value of 3 nM and was >50-fold selective over a number of serotonergic, noradrenergic, and dopaminergic receptors. Binding affinity determined for the human 5-HT(2B) receptor subtype using [(3)H]5HT was 14 nM. Vabicaserin was a potent and full agonist (EC(50), 8 nM; E(max), 100%) in stimulating 5-HT(2C) receptor-coupled calcium mobilization and exhibited 5-HT(2A) receptor antagonism and 5-HT(2B) antagonist or partial agonist activity in transfected cells, depending on the level of receptor expression. In rat stomach fundus and human colonic longitudinal muscle endogenously expressing 5-HT(2B) receptors, vabicaserin failed to induce a 5-HT(2B) receptor-dependent contraction and produced a rightward shift of the 5-HT and α-methyl-5-HT concentration-response curves in these preparations, respectively, consistent with 5-HT(2B) competitive antagonism. Likewise, vabicaserin failed to induce a 5-HT(2B) receptor-mediated contraction in arteries from deoxycorticosterone acetate-salt-treated rats, a model of hypersensitized 5-HT(2B) receptor function, and produced a rightward shift in the 5-HT-induced response that was consistent with 5-HT(2B) receptor antagonism. In summary, vabicaserin is a novel, potent, and selective 5-HT(2C) receptor agonist.


Assuntos
Antipsicóticos/metabolismo , Antipsicóticos/farmacologia , Compostos Heterocíclicos de 4 ou mais Anéis/metabolismo , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Receptor 5-HT2C de Serotonina/metabolismo , Agonistas do Receptor 5-HT2 de Serotonina/metabolismo , Agonistas do Receptor 5-HT2 de Serotonina/farmacologia , Animais , Sítios de Ligação/efeitos dos fármacos , Células CHO , Linhagem Celular , Cricetinae , Cricetulus , Humanos , Masculino , Terapia de Alvo Molecular , Contração Muscular/efeitos dos fármacos , Músculo Liso/efeitos dos fármacos , Músculo Liso/fisiologia , Ligação Proteica/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Receptor 5-HT2A de Serotonina/metabolismo , Receptor 5-HT2B de Serotonina/metabolismo , Proteínas Recombinantes/metabolismo , Serotonina/análogos & derivados , Serotonina/metabolismo , Antagonistas do Receptor 5-HT2 de Serotonina/metabolismo , Antagonistas do Receptor 5-HT2 de Serotonina/farmacologia , Transdução de Sinais/efeitos dos fármacos
20.
J Pharmacol Exp Ther ; 338(1): 345-52, 2011 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-21508084

RESUMO

Metabotropic glutamate receptor 7 (mGluR7) remains the most elusive of the eight known mGluRs primarily because of the limited availability of tool compounds to interrogate its potential therapeutic utility. The discovery of N,N'-dibenzhydrylethane-1,2-diamine dihydrochloride (AMN082) as the first orally active, brain-penetrable, mGluR7-selective allosteric agonist by Mitsukawa and colleagues (Proc Natl Acad Sci USA 102:18712-18717, 2005) provides a means to investigate this receptor system directly. AMN082 demonstrates mGluR7 agonist activity in vitro and interestingly has a behavioral profile that supports utility across a broad spectrum of psychiatric disorders including anxiety and depression. The present studies were conducted to extend the in vitro and in vivo characterization of AMN082 by evaluating its pharmacokinetic and metabolite profile. Profiling of AMN082 in rat liver microsomes revealed rapid metabolism (t(1/2) < 1 min) to a major metabolite, N-benzhydrylethane-1,2-diamine (Met-1). In vitro selectivity profiling of Met-1 demonstrated physiologically relevant transporter binding affinity at serotonin transporter (SERT), dopamine transporter (DAT), and norepinephrine transporter (NET) (323, 3020, and 3410 nM, respectively); whereas the parent compound AMN082 had appreciable affinity at NET (1385 nM). AMN082 produced antidepressant-like activity and receptor occupancy at SERT up to 4 h postdose, a time point at which AMN082 is significantly reduced in brain and plasma while the concentration of Met-1 continues to increase in brain. Acute Met-1 administration produced antidepressant-like activity as would be expected from its in vitro profile as a mixed SERT, NET, DAT inhibitor. Taken together, these data suggest that the reported in vivo actions of AMN082 should be interpreted with caution, because they may involve other mechanisms in addition to mGluR7.


Assuntos
Compostos Benzidrílicos/farmacologia , Monoaminas Biogênicas/farmacologia , Receptores de Glutamato Metabotrópico/agonistas , Receptores de Glutamato Metabotrópico/fisiologia , Regulação Alostérica/efeitos dos fármacos , Regulação Alostérica/fisiologia , Animais , Compostos Benzidrílicos/metabolismo , Monoaminas Biogênicas/fisiologia , Células CHO , Cricetinae , Cricetulus , Células HEK293 , Humanos , Masculino , Camundongos , Ligação Proteica/fisiologia , Ratos , Ratos Sprague-Dawley
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