RESUMO
Concurrent cocaine and alcohol use is among the most frequent drug combination, and among the most dangerous in terms of deleterious outcomes. Cocaine increases extracellular monoamines by blocking dopamine (DA), norepinephrine (NE) and serotonin (5-HT) transporters (DAT, NET and SERT, respectively). Likewise, ethanol also increases extracellular monoamines, however evidence suggests that ethanol does so independently of DAT, NET and SERT. Organic cation transporter 3 (OCT3) is an emergent key player in the regulation of monoamine signaling. Using a battery of in vitro, in vivo electrochemical, and behavioral approaches, as well as wild-type and constitutive OCT3 knockout mice, we show that ethanol's actions to inhibit monoamine uptake are dependent on OCT3. These findings provide a novel mechanistic basis whereby ethanol enhances the neurochemical and behavioral effects of cocaine and encourage further research into OCT3 as a target for therapeutic intervention in the treatment of ethanol and ethanol/cocaine use disorders.
Assuntos
Transtornos Relacionados ao Uso de Cocaína , Cocaína , Camundongos , Animais , Dopamina , Etanol/farmacologia , Proteínas de Transporte , Cocaína/farmacologia , Serotonina , Camundongos Knockout , Cátions , Proteínas da Membrana Plasmática de Transporte de Dopamina , Proteínas da Membrana Plasmática de Transporte de SerotoninaRESUMO
Corneal wound healing is integral for resolution of corneal disease or for post-operative healing. However, corneal scarring that may occur secondary to this process can significantly impair vision. Tissue transglutaminase 2 (TGM2) inhibition has shown promising antifibrotic effects and thus holds promise to prevent or treat corneal scarring. The commercially available ocular solution for treatment of ocular manifestations of Cystinosis, Cystaran®, contains the TGM2 inhibitor cysteamine hydrochloride (CH). The purpose of this study is to assess the safety of CH on corneal epithelial and stromal wounds, its effects on corneal wound healing, and its efficacy against corneal scarring following wounding. Quantitative polymerase chain reaction (qPCR) and immunohistochemistry (IHC) were first used to quantify and localize TGM2 expression in the cornea. Subsequently, (i) the in vitro effects of CH at 0.163, 1.63, and 16.3 mM on corneal epithelial cell migration was assessed with an epithelial cell migration assay, and (ii) the in vivo effects of application of 1.63 mM CH on epithelial and stromal wounds was assessed in a rabbit model with ophthalmic examinations, inflammation scoring, color and fluorescein imaging, optical coherence tomography (OCT), and confocal biomicroscopy. Post-mortem assessment of corneal tissue post-stromal wounding included biomechanical characterization (atomic force microscopy (AFM)), histology (H&E staining), and determining incidence of myofibroblasts (immunostaining against α-SMA) in wounded corneal tissue. TGM2 expression was highest in corneal epithelial cells. Application of the TGM2 inhibitor CH did not affect in vitro epithelial cell migration at the two lower concentrations tested. At 16.3 mM, decreased cell migration was observed. In vivo application of CH at 57 mM was well tolerated and did not adversely affect wound healing. No difference in corneal scarring was found between CH treated and vehicle control eyes. This study shows that the TGM2 inhibitor CH, at the FDA-approved dose, is well tolerated in a rabbit model of corneal wound healing and does not adversely affect epithelial or stromal wound healing. This supports the safe use of this medication in Cystinosis patients with open corneal wounds. CH did not have an effect on corneal scarring in this study, suggesting that Cystaran® administration to patients with corneal wounds is unlikely to decrease corneal fibrosis.
Assuntos
Lesões da Córnea , Cisteamina , Cistinose , Epitélio Corneano , Animais , Coelhos , Cicatriz/metabolismo , Córnea/efeitos dos fármacos , Córnea/metabolismo , Doenças da Córnea/patologia , Lesões da Córnea/tratamento farmacológico , Lesões da Córnea/metabolismo , Cisteamina/farmacologia , Cisteamina/uso terapêutico , Cisteamina/metabolismo , Cistinose/metabolismo , Cistinose/patologia , Epitélio Corneano/patologia , Proteína 2 Glutamina gama-Glutamiltransferase/antagonistas & inibidores , Cicatrização/efeitos dos fármacosRESUMO
Peronospora belbahrii is an oomycete and the cause of basil downy mildew, one of the most destructive diseases affecting basil production worldwide. Disease management is challenging due to wind-dispersed sporangia and contaminated seed; therefore, identifying P. belbahrii in seed lots before sale or planting or in the field before symptoms develop could allow for timely deployment of disease management strategies. In this study, a draft genome assembly and next-generation sequencing reads for P. belbahrii, as well as publicly available DNA-seq and RNA-seq reads of several other downy mildew pathogens, were incorporated into a bioinformatics pipeline to predict P. belbahrii-specific diagnostic markers. The specificity of each candidate marker was validated against a diverse DNA collection of P. belbahrii, host tissue, and related oomycetes using PCR. Two species-specific markers were identified and used as templates to develop a highly sensitive probe-based real-time quantitative PCR (qPCR) assay that could detect P. belbahrii in leaf tissue and seed samples. Both markers were capable of reliably detecting as low as 500 fg/µl of P. belbahrii genomic DNA and as few as 10 sporangia. The qPCR assay was then validated with seed samples collected from a basil cultivar experiment. In total, 48 seed samples were collected and tested; P. belbahrii was detected in samples of all cultivars at estimated concentrations of 600 fg/µl up to 250 pg/µl and at as few as 10 sporangia up to >1,000 sporangia. The markers and assays are valuable for diagnostics and identifying P. belbahrii-contaminated seed lots to mitigate the effects of future basil downy mildew epidemics.
Assuntos
Ocimum basilicum , Oomicetos , Peronospora , Oomicetos/genética , Peronospora/genética , Doenças das Plantas , Folhas de PlantaRESUMO
BACKGROUND: Autologous haematopoietic stem cell transplantation (AHSCT) is an effective treatment for patients with multiple sclerosis (MS) who have highly active disease, despite the use of standard disease-modifying therapies (DMTs). However, the optimal time for offering AHSCT to patients with 'aggressive' MS is yet to be established. OBJECTIVES: The objective was to explore the safety and efficacy of AHSCT as a first-line DMT in patients with 'aggressive' MS. METHODS: All patients with 'aggressive' MS who received AHSCT as a first-line DMT in five European and North American centres were retrospectively evaluated. RESULTS: Twenty patients were identified. The median interval between diagnosis and AHSCT was 5 (1-20) months. All had multiple poor prognostic markers with a median pre-transplant Expanded Disability Status Scale (EDSS) score of 5.0 (1.5-9.5). After a median follow-up of 30 (12-118) months, the median EDSS score improved to 2.0 (0-6.5, p < 0.0001). No patient had further relapses. Three had residual magnetic resonance imaging (MRI) disease activities in the first 6 months post-transplant, but no further new or enhancing lesions were observed in subsequent scans. CONCLUSION: AHSCT is safe and effective as a first-line DMT in inducing rapid and sustained remission in patients with 'aggressive' MS.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Esclerose Múltipla , Humanos , Esclerose Múltipla/terapia , Estudos Retrospectivos , Transplante Autólogo , Resultado do TratamentoRESUMO
Pseudoperonospora humuli is an obligate oomycete pathogen of hop (Humulus lupulus) that causes downy mildew, an important disease in most production regions in the Northern Hemisphere. The pathogen can cause a systemic infection in hop, overwinter in the root system, and infect propagation material. Substantial yield loss may occur owing to P. humuli infection of strobiles (seed cones), shoots, and cone-bearing branches. Fungicide application and cultural practices are the primary methods to manage hop downy mildew. However, effective, sustainable, and cost-effective management of downy mildew can be improved by developing early detection systems to inform on disease risk and timely fungicide application. However, no species-specific diagnostic assays or genomic resources are available for P. humuli. The genome of the P. humuli OR502AA isolate was partially sequenced using Illumina technology and assembled with ABySS. The assembly had a minimum scaffold length of 500 bp and an N50 (median scaffold length of the assembled genome) of 19.2 kbp. A total number of 18,656 genes were identified using MAKER standard gene predictions. Additionally, transcriptome assemblies were generated using RNA-seq and Trinity for seven additional P. humuli isolates. Bioinformatics analyses of next generation sequencing reads of P. humuli and P. cubensis (a closely related sister species) identified 242 candidate species-specific P. humuli genes that could be used as diagnostic molecular markers. These candidate genes were validated using polymerase chain reaction against a diverse collection of isolates from P. humuli, P. cubensis, and other oomycetes. Overall, four diagnostic markers were found to be uniquely present in P. humuli. These candidate markers identified through comparative genomics can be used for pathogen diagnostics in propagation material, such as rhizomes and vegetative cuttings, or adapted for biosurveillance of airborne sporangia, an important source of inoculum in hop downy mildew epidemics.
Assuntos
Oomicetos , Doenças das Plantas/microbiologia , Perfilação da Expressão Gênica , Humulus , Oomicetos/genética , Oomicetos/patogenicidade , PeronosporaRESUMO
STUDY QUESTION: What is the cumulative live birth rate following ICSI cycles compared with IVF cycles for couples with non-male factor infertility? SUMMARY ANSWER: ICSI resulted in a similar cumulative live birth rate compared with IVF for couples with non-male factor infertility. WHAT IS KNOWN ALREADY: The ICSI procedure was developed for couples with male factor infertility. There has been an increased use of ICSI regardless of the cause of infertility. Cycle-based statistics show that there is no difference in pregnancy rates between ICSI and IVF in couples with non-male factor infertility. However, evidence indicates that ICSI is associated with an increased risk of adverse perinatal outcomes. STUDY DESIGN, SIZE, DURATION: A population-based cohort of 14 693 women, who had their first ever stimulated cycle with fertilization performed for at least one oocyte by either IVF or ICSI between July 2009 and June 2014 in Victoria, Australia was evaluated retrospectively. The pregnancy and birth outcomes following IVF or ICSI were recorded for the first oocyte retrieval (fresh stimulated cycle and associated thaw cycles) until 30 June 2016, or until a live birth was achieved, or until all embryos from the first oocyte retrieval had been used. PARTICIPANTS/MATERIALS, SETTING, METHODS: Demographic, treatment characteristics and resulting outcome data were obtained from the Victorian Assisted Reproductive Treatment Authority. Data items in the VARTA dataset were collected from all fertility clinics in Victoria. Women were grouped by whether they had undergone IVF or ICSI. The primary outcome was the cumulative live birth rate, which was defined as live deliveries (at least one live birth) per woman after the first oocyte retrieval. A discrete-time survival model was used to evaluate the cumulative live birth rate following IVF and ICSI. The adjustment was made for year of treatment in which fertilization occurred, the woman's and male partner's age at first stimulated cycle, parity and the number of oocytes retrieved in the first stimulated cycle. MAIN RESULTS AND THE ROLE OF CHANCE: A total of 4993 women undergoing IVF and 8470 women undergoing ICSI had 7980 and 13 092 embryo transfers, resulting in 1848 and 3046 live deliveries, respectively. About one-fifth of the women (19.0% of the IVF group versus 17.9% of the ICSI group) had three or more cycles during the study period. For couples who achieved a live delivery, the median time from oocyte retrieval to live delivery was 8.9 months in both IVF (range: 4.2-66.5) and ICSI group (range: 4.5-71.3) (P = 0.474). Fertilization rate per oocyte retrieval was higher in the IVF than in the ICSI group (59.8 versus 56.2%, P < 0.001). The overall cumulative live birth rate was 37.0% for IVF and 36.0% for ICSI. The overall likelihood of a live birth for women undergoing ICSI was not significantly different to that for women undergoing IVF (adjusted hazard ratio (AHR): 0.99, 95% CI: 0.92-1.06). For couples with a known cause of infertility, non-male factor infertility (female factor only or unexplained infertility) was reported for 64.0% in the IVF group and 36.8% in the ICSI group (P < 0.001). Among couples with non-male factor infertility, ICSI resulted in a similar cumulative live birth rate compared with IVF (AHR: 0.96, 95% CI: 0.85-1.10). LIMITATIONS, REASONS FOR CAUTION: Data were not available on clinic-specific protocols and processes for IVF and ICSI and the potential impact of these technique aspects on clinical outcomes. The reported causes of infertility were based on the treating clinician's classification which may vary between clinicians. WIDER IMPLICATIONS OF THE FINDINGS: This population-based study found ICSI resulted in a lower fertilization rate per oocyte retrieved and a similar cumulative live birth rate compared to conventional IVF. These data suggest that ICSI offers no advantage over conventional IVF in terms of live birth rate for couples with non-male factor infertility. STUDY FUNDING/COMPETING INTEREST(S): No specific funding was received to undertake this study. There is no conflict of interest, except that M.B. is a shareholder in Genea Ltd. TRIAL REGISTRATION NUMBER: N/A.
Assuntos
Coeficiente de Natalidade , Fertilização in vitro , Infertilidade/terapia , Nascido Vivo , Injeções de Esperma Intracitoplásmicas , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Recuperação de Oócitos , Gravidez , Resultado da Gravidez , Taxa de Gravidez , Estudos RetrospectivosRESUMO
Research shows that when students arrive at university they are often not prepared for independent learning. New students enter a period of transition during their first year, which is often characterised by emotional destabilisation, as they move towards becoming more self-regulating in their new learning environment. In this small-scale qualitative study, data from an in-depth pair interview were triangulated with data from a questionnaire, to explore participants' experiences of self-regulated learning in the first year of a Dental Surgery course. Five threshold concepts relating to learning in transition emerged from the analysis of the data. These concepts were as follows: learning how to learn using a range of self-chosen sources instead of a single textbook, learning how to organise incoming information without guidance, distinguishing between main ideas and detail during revision, coping with a heavy workload, and knowing what to expect from examinations and coursework. Strong emotions (feeling confused, overwhelmed and scared) were associated with negotiating these threshold concepts. However, the study illustrates how the participants adopted new cognitive and metacognitive strategies to become more self-regulating over time. The findings of the study suggest that lecturers, tutors, study advisers and peers all have an important role to play in explicitly guiding first-year students as they grapple with troublesome threshold concepts relating to self-regulated learning. Furthermore, structural changes to the content-heavy, lecture-based curricula often associated with first-year Medical and Dental courses would help ease students' transition to independent learning, which may make an impact on student attainment.
Assuntos
Educação em Odontologia/métodos , Autoaprendizagem como Assunto , Estudantes de Odontologia , Atitude , Feminino , Humanos , Entrevistas como Assunto , Masculino , Estudantes de Odontologia/psicologia , Inquéritos e Questionários , Reino UnidoRESUMO
Poor litter quality is a potential challenge to footpad health as well as the primary cause of ammonia volatilization. High ambient ammonia concentration is one of the most significant factors negatively affecting poultry production today. Some minerals have been reported to reduce ammonia release from poultry litter. Silicon dioxide, a highly pure and natural mineral, shows promise in decreasing ammonia volatilization and improving litter quality. The objective of the current study was to investigate the effects of feed-borne silicon dioxide on litter quality and how this impacts bird performance, general health and footpad health throughout a 12-wk posthatching turkey study. Supplementing the diet with silicon dioxide was found to significantly improve turkey BW gain and the efficiency of feed conversion. The severity of footpad dermatitis was monitored throughout the experimental period but no significant effect of diet was seen. The feeding of silicon dioxide reduced litter pH which decreased the conversion of NH4⺠to NH3 thereby reducing nitrogen losses from litter. It was concluded that, under our study conditions, the feeding of 0.02% silicon dioxide offers potential economic benefits to turkey producers.
Assuntos
Ração Animal/análise , Dieta/veterinária , Dióxido de Silício/farmacologia , Perus/crescimento & desenvolvimento , Fenômenos Fisiológicos da Nutrição Animal , Animais , Dermatite/patologia , Dermatite/veterinária , Suplementos Nutricionais , Pisos e Cobertura de Pisos , Doenças do Pé/veterinária , Abrigo para Animais , Doenças das Aves Domésticas/patologia , Dióxido de Silício/administração & dosagemRESUMO
Bleeding Assessment Tools (BATs) have been developed to aid in the standardized evaluation of bleeding symptoms. The Vicenza Bleeding Questionnaire (BQ), published in 2005, established a common framework and scoring key that has undergone subsequent modification over the years, culminating in the publication of the ISTH-BAT in 2010. Understanding the normal range of bleeding scores is critical when assessing the utility of a BAT. Within the context of The Merging Project, a bioinformatics system was created to facilitate the merging of legacy data derived from four different (but all Vicenza-based) BATs; the MCMDM1-VWD BQ, the Condensed MCMDM-1VWD BQ, the Pediatric Bleeding Questionnaire and the ISTH-BAT. Data from 1040 normal adults and 328 children were included in the final analysis, which showed that the normal range is 0-3 for adult males, 0-5 for adult females and 0-2 in children for both males and females. Therefore, the cut-off for a positive or abnormal BS is ≥4 in adult males, ≥6 in adult females and ≥3 in children. This information can now be used to objectively assess bleeding symptoms as normal or abnormal in future studies.
Assuntos
Hemorragia/sangue , Hemorragia/diagnóstico , Adolescente , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Biologia Computacional/métodos , Feminino , Hemofilia A/sangue , Hemofilia A/diagnóstico , Hemorragia/etiologia , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Valores de Referência , Índice de Gravidade de Doença , Inquéritos e Questionários , Adulto Jovem , Doenças de von Willebrand/sangue , Doenças de von Willebrand/diagnósticoRESUMO
The thoracic duct (TD) transports ingested fat, drains lymph from the gastrointestinal vascular bed, and delivers the lymph to central veins in the neck. Preliminary evidence suggests that diversion of TD lymph may mitigate the severity of end-organ dysfunction in critical illness. Variations in the anatomy of the TD may determine whether reliable and safe cannulation of the duct, a necessary step for diversion, is possible. A systematic review was undertaken using the Google Scholar, MEDLINE, PubMed, and Scopus databases until 31st March, 2013. Both English and non-English articles were searched for, and surgical, cadaveric, and radiologic studies were included. Fifty-seven articles from the past 102 years were retrieved. There are significant variations in the anatomy of the TD in terms of its formation at the cisterna chyli, its course through the thorax, and its termination in the venous system. The most common site of termination is at the internal jugular vein (46%), followed by the jugulosubclavian angle (32%), and the subclavian vein (18%). An improved understanding of the anatomy of the TD would help surgeons to avoid inadvertent injury and potentially afford new opportunities for diagnosis and intervention in patients with critical illness.
Assuntos
Ducto Torácico/anatomia & histologia , Variação Anatômica , Humanos , Pescoço/anatomia & histologiaAssuntos
Alelos , Substituição de Aminoácidos , Códon , Doenças de von Willebrand/sangue , Doenças de von Willebrand/genética , Fator de von Willebrand/genética , Fator de von Willebrand/metabolismo , Biomarcadores , Pré-Escolar , Genótipo , Humanos , Masculino , Mutação , Linhagem , Doenças de von Willebrand/diagnósticoRESUMO
BACKGROUND: Photodynamic therapy (PDT) causes tissue damage that initiates a local inflammatory response. Post-PDT reactions are considered to assist in mobilising the immune system thereby affecting tumour recurrence. The initiating process of the PDT-dependent tissue reaction remains to be determined. METHODS: Primary cultures of human lung cells were established. The photoreaction mediated by pyropheophorbide-a, at specific subcellular sites and levels resulting in the release of alarmins by epithelial cells (Eps), was defined by immunoblot analyses and expression profiling. The activity of Ep-derived factors to stimulate expression of proinflammatory mediators, including IL-6, and to enhance neutrophil binding by fibroblasts (Fbs) was determined by functional bioassays. RESULTS: Epithelial cells release IL-1ß as the primary Fb-stimulatory activity under basal conditions. Intracellular IL-1α, externalised following photoreaction, accounts for most of the PDT-mediated Fb activation. Expression of IL-1 is subject to increase or loss during oncogenic transformation resulting in altered alarmin functions mobilisable by PDT. Photoreaction by a cell surface-bound photosensitiser (PS) is 10-fold more effective than PSs localised to mitochondria or lysosomes. High-dose intracellular, but not cell surface, photoreaction inactivates IL-1 and reduces Fb stimulation. CONCLUSION: These in vitro data suggest that the subcellular site and intensity of photoreaction influence the magnitude of the stromal cell response to the local damage and, in part, support the relationship of PDT dose and level of post-PDT inflammatory response observed in vivo.
Assuntos
Mediadores da Inflamação/metabolismo , Interleucina-1alfa/metabolismo , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Fotoquimioterapia/métodos , Animais , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Humanos , Pulmão/citologia , RatosAssuntos
Hemofilia A/complicações , Hemorragia/complicações , Qualidade de Vida , Adolescente , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Autorrelato , Inquéritos e Questionários , Adulto JovemRESUMO
BACKGROUND: The calcium-binding protein S100A12 is highly up-regulated in the serum and sputum of patients with allergic asthma and is suggested to be a biomarker and pathologic mediator of asthma. OBJECTIVE: To test the role of S100A12 in mediating airway inflammation in a mouse model of allergic lung inflammation. METHODS: Transgenic (TG) mice that express human S100A12 and wild-type (WT) littermates were sensitized and challenged with ovalbumin (OVA) and assessed for inflammation, lung structure, and function. RESULTS: Following OVA sensitization and challenge, S100A12 TG mice showed reduced peribronchial and perivascular inflammation, mucus production, and eosinophilia as well as attenuated airway responsiveness to contractile agonist compared with WT sensitized and challenged animals. This is explained, at least in part, by remodelled airways in S100A12 TG mice with thinning of the airway smooth muscle. S100A12 exposure induced Fas expression and activation of caspase 3 in cultured airway smooth muscle cells, suggesting that airway smooth muscle abnormalities observed in S100A12 TG mice may be mediated through myocyte apoptosis. CONCLUSION AND CLINICAL RELEVANCE: S100A12 is one of the most abundant proteins found in the airways of human asthmatics, and it was postulated that S100A12 could mediate the inflammatory process. Our study shows for the first time that TG expression of S100A12 in the lung of mice does not exacerbate lung inflammation in a model of OVA-induced allergic inflammation. We speculate that the high levels of S100/calgranulins found in bronchoalveolar lavage fluid of asthmatics and of OVA-treated TG S100A12 mice do not significantly mediate pulmonary inflammation.
Assuntos
Hipersensibilidade , Pneumonia , Sistema Respiratório , Proteínas S100/genética , Proteínas S100/imunologia , Remodelação das Vias Aéreas/genética , Remodelação das Vias Aéreas/imunologia , Animais , Apoptose/genética , Apoptose/imunologia , Líquido da Lavagem Broncoalveolar/imunologia , Broncoconstrição/genética , Broncoconstrição/imunologia , Quimiocinas/metabolismo , Modelos Animais de Doenças , Humanos , Hipersensibilidade/genética , Hipersensibilidade/imunologia , Hipersensibilidade/patologia , Imunidade Humoral/genética , Imunidade Humoral/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Miócitos de Músculo Liso/imunologia , Ovalbumina/imunologia , Pneumonia/genética , Pneumonia/imunologia , Pneumonia/patologia , Mucosa Respiratória/imunologia , Mucosa Respiratória/patologia , Sistema Respiratório/imunologia , Sistema Respiratório/patologia , Proteínas S100/metabolismo , Proteína S100A12RESUMO
T cells respond in a V beta-restricted fashion to bacterial enterotoxins bound to major histocompatibility complex (MHC) class II molecules. The requirement for CD4 in MHC class II-restricted T cell responses is very well established. We have assessed the role of CD4 in the T cell response to the bacterial enterotoxins Staphylococcal enterotoxin A (SEA), SEB, and toxic shock syndrome toxin 1. Three CD4- murine T cell hybridomas were transfected with the human CD4 molecule and assayed for interleukin 2 production in the presence of accessory cells bearing human MHC class II molecules and of the appropriate enterotoxin. The results clearly indicate that CD4- cells responded even to suboptimal concentrations of enterotoxin(s) equally well as CD4+ cells. Furthermore, expression of CD4 did not result in the acquisition of previously undetectable reactivity to enterotoxins. These results suggest that unlike the case with antigen-specific responses, formation of a T cell receptor-CD3/CD4 supramolecular complex is not always essential for T cell activation by bacterial enterotoxins.
Assuntos
Toxinas Bacterianas/imunologia , Antígenos CD4/fisiologia , Enterotoxinas/imunologia , Linfócitos T/imunologia , Animais , Células Apresentadoras de Antígenos/imunologia , Antígenos CD4/genética , Linhagem Celular , Citometria de Fluxo , Antígenos de Histocompatibilidade Classe II/imunologia , Humanos , Hibridomas/imunologia , Interleucina-2/metabolismo , Ativação Linfocitária/imunologia , Staphylococcus , TransfecçãoRESUMO
PD-1 is an immunoinhibitory receptor expressed by activated T cells, B cells, and myeloid cells. Mice deficient in PD-1 exhibit a breakdown of peripheral tolerance and demonstrate multiple autoimmune features. We report here that the ligand of PD-1 (PD-L1) is a member of the B7 gene family. Engagement of PD-1 by PD-L1 leads to the inhibition of T cell receptor-mediated lymphocyte proliferation and cytokine secretion. In addition, PD-1 signaling can inhibit at least suboptimal levels of CD28-mediated costimulation. PD-L1 is expressed by antigen-presenting cells, including human peripheral blood monocytes stimulated with interferon gamma, and activated human and murine dendritic cells. In addition, PD-L1 is expressed in nonlymphoid tissues such as heart and lung. The relative levels of inhibitory PD-L1 and costimulatory B7-1/B7-2 signals on antigen-presenting cells may determine the extent of T cell activation and consequently the threshold between tolerance and autoimmunity. PD-L1 expression on nonlymphoid tissues and its potential interaction with PD-1 may subsequently determine the extent of immune responses at sites of inflammation.
Assuntos
Antígenos CD/imunologia , Antígenos de Superfície/imunologia , Antígeno B7-1/imunologia , Glicoproteínas de Membrana/imunologia , Sequência de Aminoácidos , Animais , Células Apresentadoras de Antígenos/imunologia , Antígenos CD/classificação , Antígenos CD/genética , Antígenos de Superfície/genética , Antígenos de Superfície/metabolismo , Proteínas Reguladoras de Apoptose , Antígeno B7-1/classificação , Antígeno B7-1/genética , Antígeno B7-2 , Sequência de Bases , Antígenos CD28/imunologia , Complexo CD3/imunologia , Divisão Celular , DNA Complementar , Expressão Gênica , Humanos , Ligantes , Glicoproteínas de Membrana/classificação , Glicoproteínas de Membrana/genética , Camundongos , Dados de Sequência Molecular , Receptor de Morte Celular Programada 1 , Transdução de Sinais/imunologia , Linfócitos T/citologiaRESUMO
FIZZ1 is an adipokine highly expressed under inflammatory conditions, and yet, little is known of its function. In this study we examine the expression and function of FIZZ1 in an ovalbumin mouse model of asthma. Trachea from naïve or ovalbumin-sensitised and -challenged mice were compared for transcriptional, functional and proteomic differences using gene microarrays, ex vivo tracheal contraction, immunohistochemistry and Western blot analysis. FIZZ1 was expressed in ovalbumin-treated, but not naïve, trachea. Naïve trachea incubated with recombinant FIZZ1 exhibited denuded epithelium and contractile hyperresponsiveness. The FIZZ1-incubated trachea also exhibited an associated increased expression of phospho-c-Raf, phospho-extracellular signal-regulated kinase 1/2, phospho-p38, MLCK and MLC-20. These data demonstrate that FIZZ1 regulates tracheal smooth muscle contraction through impairment of the epithelium and activation of the mitogen-activated protein kinase pathway in muscle.
Assuntos
Asma/fisiopatologia , Carbacol/farmacologia , Peptídeos e Proteínas de Sinalização Intercelular/fisiologia , Músculo Liso/fisiologia , Traqueia/fisiologia , Animais , Asma/imunologia , Líquido da Lavagem Broncoalveolar , Agonistas Colinérgicos/farmacologia , Modelos Animais de Doenças , Sinergismo Farmacológico , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/farmacologia , Lipopolissacarídeos/farmacologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Contração Muscular/efeitos dos fármacos , Contração Muscular/fisiologia , Músculo Liso/efeitos dos fármacos , Quinase de Cadeia Leve de Miosina/metabolismo , Ovalbumina/imunologia , Proteínas Recombinantes/farmacologia , Mucosa Respiratória/efeitos dos fármacos , Mucosa Respiratória/fisiologia , Organismos Livres de Patógenos Específicos , Traqueia/efeitos dos fármacosRESUMO
The prevalence of von Willebrand disease (VWD) is reported as approximately 1%; however, these estimates were not based on individuals with significant symptoms. Four thousand five hundred ninety-two unselected parents/children were asked: "Does your child have a problem with bleeding/bruising?"; 223 (5%) answered yes, 41 of whom were administered the validated Pediatric Bleeding Questionnaire and had VWF testing. Five were diagnosed with VWD (three type 1, one type 2A, one type 2B). The prevalence of bleeding/bruising in a general pediatric population is 5%; the prevalence of symptomatic VWD at the level of pediatric primary care is at least 1 in 1,000.
Assuntos
Atenção Primária à Saúde/estatística & dados numéricos , Doenças de von Willebrand/epidemiologia , Adolescente , Humanos , Valor Preditivo dos Testes , Prevalência , Estudos Prospectivos , Doenças de von Willebrand/sangue , Doenças de von Willebrand/diagnósticoRESUMO
Quantitative shape analysis of juvenile pyroclasts is applied in volcanology to reconstruct the dynamics and styles of eruptions, and to explore the details of tephra transport, dispersal, and emplacement. Morphometric analyses often include comparison of multiple data sets with a set of dimensionless shape parameters. Here we present "DendroScan", an open source Matlab program that provides the user with all the multivariate statistical methods needed to produce such morphometric comparisons. Serving as a statistical "toolbox", DendroScan conducts Levene-, t-, and equivalence tests, presenting the results in ad hoc interpretable graphs. Furthermore, it is designed to conduct dendrogrammatic analyses of particle morphometry, a recently developed approach for the inter-comparison of multiple morphometric data sets. DendroScan produces tree diagrams, in which the analysed samples are sorted according to their morphometric dissimilarity, allowing the user to identify, e.g., samples that are statistically equivalent. To demonstrate DendroScan's potential, ten experimental samples are compared with volcanic ash samples generated by the Havre 2012 deep-sea eruption in the Kermadec arc (New Zealand). We show how, using DendroScan-based results, information on the eruptive mechanism can be inferred, and how the cooling history of the experimental melt is reflected in the dissimilarity of thermally granulated fragments.
RESUMO
The corn earworm moth lays its eggs in the vicinity of triacetin, an ingredient of felt-tipped marking pens. Related compounds also induce this behavior. A bioassay was devised to measure the activity of chemicals as oviposition inducers.