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1.
Rhinology ; 61(6): 519-530, 2023 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-37804121

RESUMO

BACKGROUND: Chronic rhinosinusitis (CRS) disease control is a global metric of disease status for CRS. While there is broad acceptance that it is an important treatment goal, there has been inconsistency in the criteria used to define CRS control. The objective of this study was to identify and develop consensus around essential criteria for assessment of CRS disease control. METHODS: Modified Delphi methodology consisting of three rounds to review a list of 24 possible CRS control criteria developed by a 12-person steering committee. The core authorship of the multidisciplinary EPOS 2020 guidelines was invited to participate. RESULTS: Thirty-two individuals accepted the invitation to participate and there was no dropout of participants throughout the entire study (3 rounds). Consensus essential criteria for assessment of CRS control were: overall symptom severity, need for CRS-related systemic corticosteroids in the prior 6 months, severity of nasal obstruction, and patient-reported CRS control. Near-consensus items were: nasal endoscopy findings, severity of smell loss, overall quality of life, impairment of normal activities and severity of nasal discharge. Participants’ comments provided insights into caveats of, and disagreements related to, near-consensus items. CONCLUSIONS: Overall symptom severity, use of CRS-related systemic corticosteroids, severity of nasal obstruction, and patient-reported CRS control are widely agreed upon essential criteria for assessment of CRS disease control. Consideration of near-consensus items to assess CRS control should be implemented with their intrinsic caveats in mind. These identified consensus CRS control criteria, together with evidence-based support, will provide a foundation upon which CRS control criteria with wide-spread acceptance can be developed.


Assuntos
Obstrução Nasal , Pólipos Nasais , Rinite , Sinusite , Humanos , Consenso , Qualidade de Vida , Técnica Delphi , Rinite/diagnóstico , Sinusite/diagnóstico , Sinusite/terapia , Corticosteroides , Doença Crônica , Pólipos Nasais/diagnóstico
2.
Rhinology ; 61(1): 85-89, 2023 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-36507741

RESUMO

Chronic rhinosinusitis (CRS) is known to affect around 5 % of the total population, with major impact on the quality of life of those severely affected (1). Despite a substantial burden on individuals, society and health economies, CRS often remains underdiagnosed, under-estimated and under-treated (2). International guidelines like the European Position Paper on Rhinosinusitis and Nasal Polyps (EPOS) (3) and the International Consensus statement on Allergy and Rhinology: Rhinosinusitis 2021 (ICAR) (4) offer physicians insight into the recommended treatment options for CRS, with an overview of effective strategies and guidance of diagnosis and care throughout the disease journey of CRS.


Assuntos
Hipersensibilidade , Pólipos Nasais , Rinite , Sinusite , Humanos , Rinite/diagnóstico , Rinite/terapia , Rinite/epidemiologia , Qualidade de Vida , Sinusite/diagnóstico , Sinusite/terapia , Sinusite/epidemiologia , Doença Crônica , Pólipos Nasais/diagnóstico , Pólipos Nasais/terapia
3.
Poult Sci ; 95(3): 612-21, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26755655

RESUMO

Fatty liver hemorrhagic syndrome (FLHS) is a metabolic condition of chicken and other birds caused by diverse nutritional, hormonal, environmental, and metabolic factors. Here we studied the effect of different diet composition on the induction of FLHS in single comb White Leghorn (WL) Hy-line laying hens. Seventy six (76) young WL (26 wks old) laying hens and 69 old hens (84 wks old) of the same breed were each divided into 4 treatment groups and provided 4 different diet treatments. The diet treatments included: control (C), 17.5% CP, 3.5% fat (F); normal protein, high fat (HF), 17.5% CP, 7% F; low protein, normal fat (LP), 13% CP, 3.5% F; and low protein, high fat (LPHF), 13% CP, 6.5% F. The diets containing high fat also had a higher ME of 3,000 kcal/kg of feed while the other 2 diets with normal fat had a regular lower amount of ME (2750 kcal/kg). Hen-day egg production (HDEP), ADFI, BW, egg weight, plasma enzymes indicating liver damage (alkaline phosphatase [ALP], aspartate aminotransferase [AST], gamma-glutamyl transferase [GGT]), liver and abdominal fat weight, liver color score (LCS), liver hemorrhagic score (LHS), liver fat content (LFC), liver histological examination, lipid peroxidation product in the liver, and genes indicating liver inflammation were evaluated. HDEP, ADFI, BW, and egg weight were significantly decreased in the LPHF diet group, while egg weight was also decreased in the LP diet group. In the young hens (LPHF group), ALP was found significantly higher at 30 d of diet treatment and was numerically higher throughout the experiment, while AST was significantly higher at 105 d of treatment. LCS, LHS, and LFC were significantly higher in young hens on the LPHF diet treatment. A liver histological examination shows more lipid vacuolization in the LPHF treatment diet. HF or LP alone had no significant effect on LFC, LHS, or LCS. We suggest that LP in the diet with higher ME from fat can be a possible natural cause for predisposing laying hens to FLHS.


Assuntos
Fenômenos Fisiológicos da Nutrição Animal , Galinhas , Dieta com Restrição de Proteínas/veterinária , Fígado Gorduroso/veterinária , Doenças das Aves Domésticas/fisiopatologia , Ração Animal/análise , Animais , Dieta com Restrição de Proteínas/efeitos adversos , Fígado Gorduroso/etiologia , Fígado Gorduroso/fisiopatologia , Feminino , Doenças das Aves Domésticas/etiologia
4.
Neuron ; 17(4): 759-67, 1996 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-8893032

RESUMO

Dynamic regulation of ion channel interactions with the cytoskeleton mediates aspects of synaptic plasticity, yet mechanisms for this process are largely unknown. Here, we report that two inwardly rectifying K+ channels, Kir 2.1 and 2.3, bind to PSD-95, a cytoskeletal protein of postsynaptic densities that clusters NMDA receptors and voltage-dependent K+ channels. Kir 2.3 colocalizes with PSD-95 in neuronal populations in forebrain, and a PSD-95/Kir 2.3 complex occurs in hippocampus. Within the C-terminal tail of Kir 2.3, a serine residue critical for interaction with PSD-95, is also a substrate for phosphorylation by protein kinase A (PKA). Stimulation of PKA in intact cells causes rapid dissociation of the channel from PSD-95. This work identifies a physiological mechanism for regulating ion channel interactions with the postsynaptic density.


Assuntos
Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Canais de Potássio Corretores do Fluxo de Internalização , Canais de Potássio/metabolismo , Sequência de Aminoácidos , Animais , Sítios de Ligação , Western Blotting , Calcimicina/farmacologia , Linhagem Celular , Colforsina/farmacologia , Humanos , Rim , Mamíferos , Dados de Sequência Molecular , Fragmentos de Peptídeos/química , Fragmentos de Peptídeos/imunologia , Fosforilação , Canais de Potássio/química , Proteínas Proto-Oncogênicas c-myc/química , Proteínas Proto-Oncogênicas c-myc/metabolismo , Proteínas Recombinantes/química , Proteínas Recombinantes/metabolismo , Homologia de Sequência de Aminoácidos , Acetato de Tetradecanoilforbol/farmacologia , Transfecção
5.
Neuron ; 20(1): 115-24, 1998 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-9459447

RESUMO

Nitric oxide (NO) produced by neuronal nitric oxide synthase (nNOS) is important for N-methyl-D-aspartate (NMDA) receptor-dependent neurotransmitter release, neurotoxicity, and cyclic GMP elevations. The coupling of NMDA receptor-mediated calcium influx and nNOS activation is postulated to be due to a physical coupling of the receptor and the enzyme by an intermediary adaptor protein, PSD95, through a unique PDZ-PDZ domain interaction between PSD95 and nNOS. Here, we report the identification of a novel nNOS-associated protein, CAPON, which is highly enriched in brain and has numerous colocalizations with nNOS. CAPON interacts with the nNOS PDZ domain through its C terminus. CAPON competes with PSD95 for interaction with nNOS, and overexpression of CAPON results in a loss of PSD95/nNOS complexes in transfected cells. CAPON may influence nNOS by regulating its ability to associate with PSD95/NMDA receptor complexes.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal , Proteínas de Transporte/fisiologia , Proteínas do Tecido Nervoso/fisiologia , Neurônios/enzimologia , Óxido Nítrico Sintase/metabolismo , Animais , Ligação Competitiva , Encéfalo/metabolismo , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Clonagem Molecular , Proteína 4 Homóloga a Disks-Large , Interações Medicamentosas , Guanilato Quinases , Peptídeos e Proteínas de Sinalização Intracelular , Proteínas de Membrana , Dados de Sequência Molecular , Proteínas do Tecido Nervoso/metabolismo , Óxido Nítrico Sintase/genética , Ratos , Ratos Sprague-Dawley , Distribuição Tecidual
6.
Cancer Res ; 51(16): 4360-6, 1991 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-1714342

RESUMO

The antineoplastic agents N,N',N''-triethylenethiophosphoramide (thioTEPA) and N,N',N''-triethylenephosphoramide (TEPA) were studied for their interaction with the DNA of L1210 cells in the presence and absence of rat hepatic microsomes and NADPH. Alkaline elution was used to study 3 types of DNA lesions. When L1210 cells were incubated with thioTEPA alone, or with thioTEPA in the presence of microsomes and NADPH, no single-strand breaks were detected. However, incubation of L1210 cells for 2 h with thioTEPA, at concentrations greater than or equal to 100 microM, caused a dose-dependent increase in interstrand cross-linking that reached a maximum by 2 h after drug exposure. In the presence of rat hepatic microsomes and NADPH, this cross-linking was eliminated, but a different DNA lesion, alkali-labile sites, was produced. These alkali-labile sites were partially reparable with maximum repair achieved by 2 h after removal of drug. ThioTEPA was greater than 85% consumed by the microsomal incubation conditions employed, and TEPA was the only product of the microsomal metabolism of thioTEPA. Alkaline elution studies of L1210 cells that had been incubated with TEPA, alone or in the presence of microsomes and NADPH, demonstrated an elution pattern identical to that produced by thioTEPA in the presence of microsomes and NADPH. Lymphoblastoid cell lines derived from patients with Fanconi's anemia were far more sensitive to thioTEPA and mechlorethamine hydrochloride than were lymphoblasts derived from normal humans, but this hypersensitivity was not noted with TEPA or bleomycin. This is consistent with the known hypersensitivity of cells from patients with Fanconi's anemia to agents that produce interstrand cross-links and with the alkaline elution studies described above. In contrast, lymphoblastoid cell lines derived from patients with ataxia telangiectasia were no more sensitive to thioTEPA than were lymphoblasts derived from normal humans but were far more sensitive to bleomycin. One of these cell lines proved hypersensitive to TEPA, whereas the other was no more sensitive to TEPA than were lymphoblasts from normal humans. Our data imply that thioTEPA produces interstrand cross-links but that TEPA, the primary metabolite of thioTEPA, produces DNA lesions that are alkali labile.


Assuntos
Divisão Celular/efeitos dos fármacos , Dano ao DNA , DNA de Neoplasias/efeitos dos fármacos , Tiotepa/farmacologia , Trietilenofosforamida/farmacologia , Animais , Arocloros/farmacologia , Biotransformação , Linhagem Celular , Reparo do DNA/efeitos dos fármacos , Replicação do DNA/efeitos dos fármacos , DNA de Neoplasias/isolamento & purificação , Humanos , Cinética , Leucemia L1210 , Camundongos , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/metabolismo , Ratos , Tiotepa/metabolismo , Trietilenofosforamida/metabolismo
7.
J Laryngol Otol ; 130(4): 380-7, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26991876

RESUMO

OBJECTIVE: This study aimed to develop a functional model of subglottic stenosis by inducing direct airway irritation in transplanted mouse laryngotracheal complexes. METHODS: Laryngotracheal complexes from C57BL/6 mice were harvested and divided into three groups: uninjured, mechanically injured and chemically injured. Donor laryngotracheal complexes from each group were placed in dorsal subcutaneous pockets of recipient mice. Each week, the transplanted laryngotracheal complexes were harvested, and tissues were fixed, sectioned, and stained with haematoxylin and eosin. Representative slides were reviewed by a blinded pathologist, to determine the formation of granulation tissue, and graded as to the degree of granulation formation. RESULTS: Direct airway irritation induced granulation tissue formation under the disrupted epithelium of airway mucosa; this was seen as early as two weeks after chemical injury. CONCLUSION: Results indicate that granulation tissue formation in a murine model may be an efficient tool for investigating the development and treatment of subglottic stenosis.


Assuntos
Tecido de Granulação/patologia , Laringoestenose/patologia , Animais , Modelos Animais de Doenças , Laringoestenose/induzido quimicamente , Laringe/patologia , Laringe/transplante , Camundongos , Camundongos Endogâmicos C57BL , Traqueia/patologia , Traqueia/transplante
8.
Neuroscience ; 76(2): 581-96, 1997 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-9015340

RESUMO

Agrin, a synaptic basal lamina protein, is essential for the formation of the vertebrate neuromuscular junction. Agrin's role in synaptogenesis in the central nervous system has, however, not been elucidated. Therefore, we performed immunohistochemical analysis of agrin localization in adult rat brain using agrin-specific polyclonal antibodies. Our results show that agrin immunoreactivity is detected in neuronal cells throughout the brain, and that agrin is expressed in many morphologically and neurochemically distinct neuronal populations. Within neurons, agrin-immunoreactive material is present in dendrites. To determine agrin isoform expression in the central nervous system, we analysed the pattern of expression of several isoforms during development of the rat brain. Our results indicate that alternative splicing of agrin is specifically regulated in the nervous system; isoforms of the Y=4 (i.e. Ag x,4,0, Ag x,4,8 and Ag x,4,19), Z=8 and Z=19 type are expressed exclusively in the nervous system. Agrin expression precedes synaptogenesis and is developmentally regulated in neural tissues. To evaluate stimuli that may be involved in the regulation of agrin expression, we monitored the patterns of isoform expression following a depolarizing stimulus. Our results show that agrin expression in the adult hippocampus is regulated in an activity-dependent manner, with kinetics of induction resembling a delayed early response gene.


Assuntos
Agrina/biossíntese , Química Encefálica/fisiologia , Encéfalo/crescimento & desenvolvimento , Envelhecimento/metabolismo , Animais , Encéfalo/anatomia & histologia , Eletrochoque , Imuno-Histoquímica , Hibridização In Situ , Isomerismo , Sondas de Oligonucleotídeos , Ratos , Ratos Sprague-Dawley , Convulsões/metabolismo
9.
Brain Res Dev Brain Res ; 114(1): 127-34, 1999 Apr 12.
Artigo em Inglês | MEDLINE | ID: mdl-10209250

RESUMO

To study a possible involvement of inwardly rectifying K+ 4.1 (Kir 4. 1) channels in neural cell development, RT-PCR, immunocytochemistry and whole-cell patch-clamp techniques were used to assess expression of Kir 4.1 channels in proliferating and differentiated NG108-15 cells. RT-PCR revealed co-expression of Kir 4.1 and rat ether-a-go-go-related gene (R-ERG) mRNAs in both proliferating and differentiated cells. The relative Kir 4.1 mRNA concentration increased markedly as cells progressed from undifferentiated to differentiated cells. Kir 4.1-immunoreactivity was barely detectable in undifferentiated cells, but clearly detected in differentiated cells, indicating that Kir 4.1 gene and protein expressions are developmentally regulated. However, corresponding Kir 4.1 current could not be detected in differentiated cells using whole-cell patch-clamp recording. The 'silent' channel/receptor, often found in tumor cells, may carry genetic defects, which prevent functional expression of the channel. NG108-15 may serve as unique model for studying the relationship between the expression of an ion channel gene and the electrophysiological phenotype it encodes.


Assuntos
Regulação da Expressão Gênica no Desenvolvimento , Regulação Neoplásica da Expressão Gênica , Neurônios/química , Neurônios/fisiologia , Canais de Potássio Corretores do Fluxo de Internalização , Canais de Potássio de Abertura Dependente da Tensão da Membrana , Canais de Potássio/genética , Animais , Bário/farmacologia , Química Encefálica/fisiologia , Primers do DNA , Canal de Potássio ERG1 , Canais de Potássio Éter-A-Go-Go , Glioma , Células Híbridas/citologia , Masculino , Potenciais da Membrana/efeitos dos fármacos , Potenciais da Membrana/fisiologia , Proteínas Associadas aos Microtúbulos/genética , Neuroblastoma , Neurônios/citologia , Técnicas de Patch-Clamp , Canais de Potássio/metabolismo , RNA Mensageiro/análise , Ratos , Ratos Sprague-Dawley , Reação em Cadeia da Polimerase Via Transcriptase Reversa
10.
Int J Psychoanal ; 63(Pt 2): 149-55, 1982.
Artigo em Inglês | MEDLINE | ID: mdl-7129763

RESUMO

In this paper I have focused attention on a particular group of patients who by the very nature of their narcissistic disorder often do not seek help until they are elderly. I have indicated through clinical material the nature of intrapsychic conflicts, a failure to achieve and work through depressive anxieties that interfere with the successful resolution of problems related to mourning; this does not allow for adequate adaptation to ageing and poses problems with regard to the evaluation and prognosis of such patients for psychoanalytic therapy.


Assuntos
Envelhecimento , Solidão , Teoria Psicanalítica , Isolamento Social , Atitude Frente a Morte , Transtorno Depressivo/terapia , Humanos , Masculino , Pessoa de Meia-Idade , Narcisismo , Prognóstico , Terapia Psicanalítica/métodos , Transferência Psicológica
11.
Child Welfare ; 65(5): 481-94, 1986.
Artigo em Inglês | MEDLINE | ID: mdl-3757594

RESUMO

This paper analyzes findings pertaining to quality of care issues concerning group home care for adolescents in the greater Los Angeles County area during 1978-1979. The issues include normalization, institutionalization, treatment goals, continuity of care, and qualifications of child welfare staff, particularly child care workers. Recommendations for improvement are offered.


Assuntos
Maus-Tratos Infantis , Casas para Recuperação/normas , Delinquência Juvenil/reabilitação , Garantia da Qualidade dos Cuidados de Saúde , Adolescente , Necessidades e Demandas de Serviços de Saúde , Humanos
12.
J Laryngol Otol ; 126(3): 267-70, 2012 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-22051053

RESUMO

OBJECTIVE: To demonstrate that patients who have been intubated for prolonged periods of time will have an increased likelihood of developing bacterial biofilm on their endotracheal tubes. METHODS: We collected endotracheal tubes from patients at the time of extubation, and analysed representative sections with scanning electron microscopy for morphologic evidence of biofilms. RESULTS: From September 2007 to September 2008, 32 endotracheal tubes were analysed with electron microscopy. Patients who had been intubated for 6 days or longer had a significantly higher percentage of endotracheal tubes that exhibited bacterial biofilms, compared with patients intubated for less than 6 days (88.9 versus 57.1 per cent, p = 0.0439). CONCLUSIONS: Longer duration of intubation is associated with a higher incidence of bacterial biofilm. Further research is needed to link the presence of bacterial biofilms to acquired laryngotracheal damage.


Assuntos
Biofilmes , Contaminação de Equipamentos , Intubação Intratraqueal/instrumentação , Pseudomonas/fisiologia , Staphylococcus aureus/fisiologia , Humanos , Intubação Intratraqueal/efeitos adversos , Mucosa Laríngea/microbiologia , Mucosa Laríngea/patologia , Laringoestenose/etiologia , Laringoestenose/microbiologia , Microscopia Eletrônica de Varredura , Pseudomonas/isolamento & purificação , Staphylococcus aureus/isolamento & purificação , Fatores de Tempo , Traqueia/microbiologia , Estenose Traqueal/etiologia , Estenose Traqueal/microbiologia
17.
J Laryngol Otol ; 122(4): 361-5, 2008 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-17697445

RESUMO

INTRODUCTION: The development of computer-aided systems for endoscopic sinus surgery has enabled surgical navigation through diseased or surgically altered sinus anatomy with increased confidence. However, conventional computer-aided systems do not provide intra-operative updated computed tomography imaging. We describe the technical aspects of the xCAT, a new intra-operative mobile volume computed tomography scanner. TECHNICAL REPORT: A patient with a malignant melanoma unwittingly removed at another hospital underwent surgery for removal of the lateral nasal wall and directed biopsies, in an attempt to identify the site of tumour origin. The procedure was performed with the GE InstaTrak 3500 Plus computer-aided system, updated with intra-operative computed tomography images. Intra-operative, updated images were integrated successfully into the InstaTrak system, and these images were consistent with the observed endoscopic anatomy. CONCLUSION: The xCAT intra-operative mobile volume computed tomography scanner is a technological advancement that can assist the endoscopic sinus surgeon when performing complex rhinological and skull base procedures.


Assuntos
Base do Crânio/diagnóstico por imagem , Base do Crânio/cirurgia , Cirurgia Assistida por Computador/instrumentação , Tomógrafos Computadorizados , Endoscopia/métodos , Desenho de Equipamento , Feminino , Humanos , Cuidados Intraoperatórios/instrumentação , Cuidados Intraoperatórios/métodos , Masculino , Melanoma/diagnóstico por imagem , Melanoma/cirurgia , Pessoa de Meia-Idade , Pólipos Nasais/cirurgia , Seios Paranasais/diagnóstico por imagem , Seios Paranasais/cirurgia , Sistemas Automatizados de Assistência Junto ao Leito , Técnicas Estereotáxicas , Cirurgia Assistida por Computador/métodos , Tomografia Computadorizada por Raios X
18.
Proc Natl Acad Sci U S A ; 91(26): 12994-8, 1994 Dec 20.
Artigo em Inglês | MEDLINE | ID: mdl-7809162

RESUMO

Molecular targets for the actions of nitric oxide (NO) have only been partially clarified. The dynamic properties of the iron-sulfur (Fe-S) cluster of the iron responsive-element binding protein (IRE-BP) suggested that it might serve as a target for NO produced in response to glutamatergic stimulation in neurons. In the present study, we demonstrate that N-methyl-D-aspartate, acting through NO, stimulates the RNA-binding function of the IRE-BP in brain slices while diminishing its aconitase activity. In addition, we demonstrate a selective localization of the IRE-BP in discrete neuronal structures, suggesting a potential role for this protein in the response of neurons to NO.


Assuntos
Óxido Nítrico/farmacologia , Proteínas de Ligação a RNA/metabolismo , Sinapses/efeitos dos fármacos , Aconitato Hidratase/genética , Aconitato Hidratase/metabolismo , Aminoquinolinas/farmacologia , Animais , Cerebelo , Citosol/enzimologia , Expressão Gênica , Guanilato Ciclase/antagonistas & inibidores , Hibridização In Situ , Técnicas In Vitro , Proteínas Reguladoras de Ferro , Proteínas Ferro-Enxofre/química , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias/enzimologia , N-Metilaspartato/farmacologia , Oligonucleotídeos Antissenso , Ligação Proteica/efeitos dos fármacos , RNA Mensageiro/genética , Ratos , Transdução de Sinais , Transmissão Sináptica/efeitos dos fármacos
19.
Proc Natl Acad Sci U S A ; 92(15): 6753-7, 1995 Jul 18.
Artigo em Inglês | MEDLINE | ID: mdl-7624316

RESUMO

We have cloned two inwardly rectifying K+ channels that occur selectively in neurons in the brain and are designated BIRK (brain inwardly rectifying K+) channels. BIRK1 mRNA is extremely abundant and is enriched in specific brainstem nuclei, BIRK1 displays a consensus phosphate-binding loop, and expression in Xenopus oocytes has shown that its conductance is inhibited by ATP and adenosine 5'-[gamma-thio]triphosphate. BIRK2 is far less abundant and is selectively localized in telencephalic neurons. BIRK2 has a consensus sequence for cAMP-dependent phosphorylation.


Assuntos
Tronco Encefálico/química , Canais de Potássio Corretores do Fluxo de Internalização , Canais de Potássio/genética , Telencéfalo/química , Trifosfato de Adenosina/análogos & derivados , Trifosfato de Adenosina/farmacologia , Sequência de Aminoácidos , Animais , Sequência de Bases , Northern Blotting , Encéfalo/anatomia & histologia , Compartimento Celular , Núcleo Celular/química , Clonagem Molecular , Condutividade Elétrica , Hibridização In Situ , Potenciais da Membrana/efeitos dos fármacos , Modelos Moleculares , Dados de Sequência Molecular , Potássio/metabolismo , Canais de Potássio/biossíntese , RNA Mensageiro/análise , Ratos , Proteínas Recombinantes/biossíntese , Análise de Sequência de DNA , Homologia de Sequência de Aminoácidos , Distribuição Tecidual , Xenopus
20.
Proc Natl Acad Sci U S A ; 95(4): 1432-7, 1998 Feb 17.
Artigo em Inglês | MEDLINE | ID: mdl-9465032

RESUMO

The complex of rapamycin with its intracellular receptor, FKBP12, interacts with RAFT1/FRAP/mTOR, the in vivo rapamycin-sensitive target and a member of the ataxia telangiectasia mutated (ATM)-related family of kinases that share homology with the catalytic domain of phosphatidylinositol 3-kinase. The function of RAFT1 in the rapamycin-sensitive pathway and its connection to downstream components of the pathway, such as p70 S6 kinase and 4E-BP1, are poorly understood. Here, we show that RAFT1 directly phosphorylates p70(S6k), 4E-BP1, and 4E-BP2 and that serum stimulates RAFT1 kinase activity with kinetics similar to those of p70(S6k) and 4E-BP1 phosphorylation. RAFT1 phosphorylates p70(S6k) on Thr-389, a residue whose phosphorylation is rapamycin-sensitive in vivo and necessary for S6 kinase activity. RAFT1 phosphorylation of 4E-BP1 on Thr-36 and Thr-45 blocks its association with the cap-binding protein, eIF-4E, in vitro, and phosphorylation of Thr-45 seems to be the major regulator of the 4E-BP1-eIF-4E interaction in vivo. RAFT1 phosphorylates p70(S6k) much more effectively than 4E-BP1, and the phosphorylation sites on the two proteins show little homology. This raises the possibility that, in vivo, an unidentified kinase analogous to p70(S6k) is activated by RAFT1 phosphorylation and acts at the rapamycin-sensitive phosphorylation sites of 4E-BP1.


Assuntos
Proteínas de Transporte/metabolismo , Fosfoproteínas/metabolismo , Fosfotransferases (Aceptor do Grupo Álcool) , Proteínas Quinases S6 Ribossômicas/metabolismo , Proteínas Adaptadoras de Transdução de Sinal , Sequência de Aminoácidos , Proteínas de Ciclo Celular , Proteínas de Ligação a DNA/metabolismo , Fator de Iniciação 4E em Eucariotos , Proteínas de Choque Térmico/metabolismo , Humanos , Dados de Sequência Molecular , Fatores de Iniciação de Peptídeos/metabolismo , Mapeamento de Peptídeos , Fosforilação , Fosfotreonina/metabolismo , Polienos/metabolismo , Sirolimo , Serina-Treonina Quinases TOR , Proteínas de Ligação a Tacrolimo
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