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1.
J Environ Manage ; 366: 121828, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-39002464

RESUMO

Control of algal blooms and associated biologically-induced water quality risks in drinking reservoirs is problematic. Copper sulphate (CuSO4) treatment is one intervention that has been utilised for >100 years. Evidence indicates a favourable short-term reduction in Cyanobacterial biomass (e.g. bloom termination), but here we indicate that it may also increase longer-term water quality risk. In 2022, we investigated the impacts of CuSO4 spraying on Cyanobacterial communities and nutrient levels within a drinking water supply reservoir using environmental DNA (eDNA) to assess community shifts, alongside monitoring nutrient fractions, orthophosphate (OP) and total phosphate (TP), post-treatment. CuSO4 application successfully reduced Cyanobacterial abundance, however elimination of Cyanobacteria resulted in a shift in bacterial dominance favouring Planctomycetota throughout the summer and a combination of Actinobacteriota and Verrucomicrobiota, throughout autumn. As Cyanobacterial abundance recovered post-treatment, Cyanobacterial genera demonstrated greater diversity compared to only three Cyanobacterial genera present across samples pre-treatment, and included taxa associated with water quality risk (e.g. taste and odour (T&O) metabolite and toxin producers). The increase in Cyanobacteria post-treatment was attributed to an increase in biologically available nutrients, primarily a significant increase in OP. Overall, findings suggest that the significant shift in biodiversity likely induces a less stable ecosystem with greater plasticity of response to changing environmental and biogeochemical variables. Legacy implications of CuSO4 spraying, in terms of shifts in ecosystem and nutrient balance over time, may have implications for drinking water quality, but importantly also for reservoir management options. As such, the effects of CuSO4 spraying should be considered carefully before consideration as a contender for in-reservoir biological control.


Assuntos
Sulfato de Cobre , Cianobactérias , Qualidade da Água , Cianobactérias/efeitos dos fármacos , Eutrofização
2.
Mol Psychiatry ; 22(6): 920-930, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-27821870

RESUMO

Major depressive disorder (MDD) is associated with reduced concentrations of γ-aminobutyric acid (GABA) that are normalized by antidepressant therapies. Moreover, depressive-like phenotypes of GABAA receptor mutant mice can be reversed by treatment with conventional antidepressants drugs, as well as by subanesthetic doses of ketamine. Thus GABAergic deficits may causally contribute to depressive disorders, while antidepressant therapies may enhance GABAergic synaptic transmission. Here we tested the hypothesis that sustained enhancement of GABAergic transmission alone is sufficient to elicit antidepressant-like behavior, using disinhibition of GABAergic interneurons. We focused on somatostatin-positive (SST+) GABAergic interneurons because of evidence that their function is compromised in MDD. To disinhibit SST+ interneurons, we inactivated the γ2 subunit gene of GABAA receptors selectively in these neurons (SSTCre:γ2f/f mice). Loss of inhibitory synaptic input resulted in increased excitability of SST+ interneurons. In turn, pyramidal cell targets of SST+ neurons showed an increased frequency of spontaneous inhibitory postsynaptic currents. The behavior of SSTCre:γ2f/f mice mimicked the effects of anxiolytic and antidepressant drugs in a number of behavioral tests, without affecting performance in a spatial learning- and memory-dependent task. Finally, brain extracts of SSTCre:γ2f/f mice showed decreased phosphorylation of the eukaryotic elongation factor eEF2, reminiscent of the effects of ketamine. Importantly, these effects occurred without altered activity of the mammalian target of rapamycin pathway nor did they involve altered expression of SST. However, they were associated with reduced Ca2+/calmodulin-dependent auto-phosphorylation of eEF2 kinase, which controls the activity of eEF2 as its single target. Thus enhancing GABAergic inhibitory synaptic inputs from SST+ interneurons to pyramidal cells and corresponding chronic reductions in the synaptic excitation:inhibition ratio represents a novel strategy for antidepressant therapies that reproduces behavioral and biochemical end points of rapidly acting antidepressants.


Assuntos
Neurônios GABAérgicos/metabolismo , Neurônios GABAérgicos/fisiologia , Potenciais Pós-Sinápticos Inibidores/fisiologia , Animais , Ansiolíticos/farmacologia , Antidepressivos/uso terapêutico , Encéfalo/metabolismo , Transtorno Depressivo Maior/tratamento farmacológico , GABAérgicos/metabolismo , GABAérgicos/uso terapêutico , Potenciais Pós-Sinápticos Inibidores/efeitos dos fármacos , Interneurônios/fisiologia , Ketamina/farmacologia , Camundongos , Camundongos Transgênicos , Receptores de GABA-A/metabolismo , Somatostatina/metabolismo , Transmissão Sináptica/fisiologia , Ácido gama-Aminobutírico/metabolismo
3.
Org Biomol Chem ; 14(3): 963-9, 2016 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-26620576

RESUMO

The one-pot borylation/Suzuki reaction is a very efficient means of accessing cross-coupling products of two aryl-halide partners that generally requires the use of specific catalysts or ligands and/or relatively long reaction times. This new microwave-assisted method provides a quick one-pot borylation/Suzuki reaction protocol that we applied to the synthesis of various bi- or poly-aryl scaffolds, including a variety of aryl and heteroaryl ring systems and the core frameworks of kinase inhibitors vemurafenib and GDC-0879.


Assuntos
Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacologia , Proteínas Quinases/metabolismo , Catálise , Relação Dose-Resposta a Droga , Indenos/química , Indóis/química , Micro-Ondas , Estrutura Molecular , Compostos Organometálicos/química , Paládio/química , Inibidores de Proteínas Quinases/química , Pirazóis/química , Relação Estrutura-Atividade , Sulfonamidas/química , Vemurafenib
4.
Diabet Med ; 31(12): 1702-7, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25131724

RESUMO

AIMS: To determine if diabetic lipaemia is caused by loss of function mutations in the lipoprotein lipase gene, LPL. METHODS: We conducted a case-control study over 2 years in two tertiary care hospitals in South Australia. Six patients with a history of diabetic lipaemia and 12 control subjects, with previous diabetic ketoacidosis and peak triglyceride concentrations < 2.4 mmol/l were included. Participants were well at the time of study investigations. RESULTS: Only one patient with lipaemia had a loss of function mutation in LPL and no functional mutations in APOC2 or GPIHBP1 were identified. The mean lipoprotein lipase concentration was lower in patients with diabetic lipaemia than in control subjects (306 vs. 484 µg/l, P = 0.04). The mean fasting C-peptide concentration was higher in patients with diabetic lipaemia than in control subjects (771 vs. 50 pmol/l; P = 0.001). CONCLUSIONS: Lipoprotein lipase deficiency in patients with a history of diabetic lipaemia was predominantly quantitative, rather than secondary to mutations in LPL, APOC2 or GPIHBP1. The majority of patients with severe hypertriglyceridaemia in diabetic ketoacidosis may have ketosis-prone Type 2, rather than Type 1, diabetes.


Assuntos
Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Hiperlipidemias/genética , Lipase Lipoproteica/genética , Adulto , Idoso , Apolipoproteína C-II/genética , Estudos de Casos e Controles , HDL-Colesterol/metabolismo , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 2/complicações , Cetoacidose Diabética/metabolismo , Feminino , Genótipo , Humanos , Hiperlipidemias/etiologia , Hiperlipidemias/metabolismo , Hipertrigliceridemia/etiologia , Hipertrigliceridemia/genética , Hipertrigliceridemia/metabolismo , Lipase Lipoproteica/metabolismo , Masculino , Pessoa de Meia-Idade , Mutação , Receptores de Lipoproteínas/genética , Estudos Retrospectivos , Adulto Jovem
6.
Water Res ; 232: 119693, 2023 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-36764104

RESUMO

Geosmin synthase (geoA) and 2-MIB cyclase (mic) are key biosynthetic genes responsible for the production of taste and odour (T&O) compounds, geosmin and 2-MIB. These T&O compounds are becoming an increasing global problem for drinking water supplies. It is thought that geosmin and 2-MIB may be linked to, or exacerbated by, a variety of different environmental and nutrient triggers. However, to the best of our knowledge, no studies to date have evaluated the combined effects of seasonality, temperature, and nutrient concentrations on geoA and mic copy numbers in conjunction with T&O concentrations. In this study, environmental triggers behind geosmin and 2-MIB production were investigated in nine reservoirs across Wales, U.K. between July 2019 - August 2020. The abundance of geoA and mic were quantified through quantitative Polymerase Chain Reaction (qPCR). Temporal changes in geoA and geosmin concentrations revealed geoA to be an indicator of monthly geosmin concentrations, although only when geosmin concentrations exceeded 100 ng L-1. Model analysis of a reservoir with elevated geosmin concentrations revealed geoA to be significantly associated with mean temperature (p < 0.001) and the nutrients dissolved reactive silicate (p < 0.001), dissolved iron (p < 0.001), total inorganic nitrogen to phosphorous ratio (TIN:TP) (p < 0.001) and ammonium to nitrate ratio (NH4+:NO3-) (p < 0.001). Sulphate also demonstrated a significant positive linear relationship with geoA (p < 0.001). For mic analysis, NH4+:NO3- was significantly associated with mic (p < 0.05) and an association with dissolved reactive silicate was also observed (p = 0.084). Within this study we also report extreme variance in gene copy numbers between the study seasons. No consistent relationship could be determined for mic copy numbers mL-1 and 2-MIB (ng L-1). The findings from this study indicate that TIN:TP and NH4+:NO3- serve as good predictors for elevated geoA and mic, along with negative linear relationships observed for mean temperature and dissolved reactive silicate. Overall, our findings demonstrate the importance of nutrient concentrations, nutrient ratios and temperature for evidence based predictive capacity of taste and odour events in drinking water reservoirs.


Assuntos
Água Potável , Paladar , Canfanos , Água Potável/análise , Naftóis/análise , Nutrientes/análise , Odorantes/análise
7.
Scand J Trauma Resusc Emerg Med ; 31(1): 100, 2023 Dec 13.
Artigo em Inglês | MEDLINE | ID: mdl-38093335

RESUMO

INTRODUCTION: Survival from refractory out of hospital cardiac arrest (OHCA) without timely return of spontaneous circulation (ROSC) utilising conventional advanced cardiac life support (ACLS) therapies is dismal. CHEER3 was a safety and feasibility study of pre-hospital deployed extracorporeal membrane oxygenation (ECMO) during cardiopulmonary resuscitation (ECPR) for refractory OHCA in metropolitan Australia. METHODS: This was a single jurisdiction, single-arm feasibility study. Physicians, with pre-existing ECMO expertise, responded to witnessed OHCA, age < 65 yrs, within 30 min driving-time, using an ECMO equipped rapid response vehicle. If pre-hospital ECPR was undertaken, patients were transported to hospital for investigations and therapies including emergent coronary catheterisation, and standard intensive care (ICU) therapy until either cardiac and neurological recovery or palliation occurred. Analyses were descriptive. RESULTS: From February 2020 to May 2023, over 117 days, the team responded to 709 "potential cardiac arrest" emergency calls. 358 were confirmed OHCA. Time from emergency call to scene arrival was 27 min (15-37 min). 10 patients fulfilled the pre-defined inclusion criteria and all were successfully cannulated on scene. Time from emergency call to ECMO initiation was 50 min (35-62 min). Time from decision to ECMO support was 16 min (11-26 min). CPR duration was 46 min (32-62 min). All 10 patients were transferred to hospital for investigations and therapy. 4 patients (40%) survived to hospital discharge neurologically intact (CPC 1/2). CONCLUSION: Pre-hospital ECPR was feasible, using an experienced ECMO team from a single-centre. Overall survival was promising in this highly selected group. Further prospective studies are now warranted.


Assuntos
Reanimação Cardiopulmonar , Parada Cardíaca Extra-Hospitalar , Humanos , Idoso , Estudos Prospectivos , Estudos de Viabilidade , Austrália , Parada Cardíaca Extra-Hospitalar/terapia , Hospitais , Reperfusão , Estudos Retrospectivos
8.
J Chem Ecol ; 38(7): 836-45, 2012 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-22692410

RESUMO

Chinavia and Nezara spp. stink bugs (Heteroptera: Pentatomidae) include over100 species, with highest diversity in Afrotropical and Neotropical regions. Species thus far studied in these genera utilize trans-(Z)-(4 S)-bisabolene epoxide (BE) and cis-(Z)-(4 S)-BE as major sex pheromone components, with species specificity ensured by different ratios of the two compounds. Gas chromatography (GC) and coupled GC-mass spectrometry (GC-MS) analyses of a volatiles from C. ubica males revealed the presence of two BE isomers in approximately a 90:10 ratio, which were shown by microprobe (1) H NMR to be cis-(Z)-BE and trans-(Z)-BE isomers, respectively. Analyses of volatiles from C. impicticornis males suggested the presence of a single isomer, trans-(Z)-BE, in high purity (>90 %). The absolute configurations of the isomers produced by C. ubica and C. impicticornis were determined using chiral GC analysis (ß-DEX column). Oxidative microchemistry of synthetic standards of cis-(Z)-(4 S)-BE and trans-(Z)-(4R)-BE, and volatiles from male of C. ubica, revealed the absolute stereochemistry of the cis-(Z)-BE to be (1R,2 S,4 S) [cis-(Z)-(4 S) for short]. Similarly, analyses of trans-(Z)-(4 S)-BE and cis-(Z)-(4R)-BE standards, and volatiles from males of C. ubica and C. impicticornis, revealed the absolute stereochemistry of the trans-(Z)-BE to be (1 S,2R,4 S) [trans-(Z)-(4 S) for short]. Olfactometer bioassays with synthetic BEs confirmed attraction of female C. ubica and C. impicticornis to conspecific synthetic pheromone, but not to heterospecific synthetic pheromone. Chinavia impicticornis appeared not to discriminate behaviorally between the conspecific pheromone and its enantiomer. Coupled GC-electroantennography with antennae from females suggested that C. ubica and C. impicticornis possess olfactory receptors for both cis-(Z)-(4 S)-BE and trans-(Z)-(4 S)-BE. The results in this study confirm that C. ubica and C. impicticornis, as for other Chinavia and Nezara spp., utilize cis-(Z)-(4 S)-BE and trans-(Z)-(4 S)-BE as sex pheromone components, with different ratios guaranteeing species specificity. Furthermore, the results suggest that the absolute stereochemistry of BEs may be less important for conspecific recognition than the relative stereochemistry between the epoxide group and the alkyl substituent on the bisabolene ring.


Assuntos
Comunicação Animal , Heterópteros/fisiologia , Atrativos Sexuais/química , Animais , Antenas de Artrópodes/fisiologia , Feminino , Isomerismo , Masculino , Atrativos Sexuais/fisiologia , Especificidade da Espécie
9.
OTO Open ; 6(4): 2473974X221134267, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36329804

RESUMO

Objective: Tracheostomy is a common procedure that requires management by a multidisciplinary team of health care providers across a range of surgical and nonsurgical specialties. Nonsurgical health care providers have demonstrated a lack of knowledge and confidence in tracheostomy care, which improve with tracheostomy education programs. However, tracheostomy care is rarely included in preresidency medical education. The purpose of this study is to evaluate the effectiveness of a tracheostomy care video on third-year medical students' knowledge of and confidence in performing tracheostomy care. Methods: Prior to beginning clinical rotations, third-year medical students completed a 10-question tracheostomy care knowledge test (100 points total) and 11-question confidence survey (110 points total). After watching an 18-minute teaching video on tracheostomy care, students repeated the knowledge test and confidence survey. Results: An overall 147 medical students completed the educational module. After they watched the tracheostomy education video, their average score on the knowledge test improved from 57.8 to 88.9 out of 100 (P < .0001), and their average rating in confidence improved from 12.7 to 49.1 out of 110 (P < .0001). Students rated the helpfulness of the video a 7.4 out of 10. Discussion: Medical students' knowledge of tracheostomy care and confidence in caring for patients with tracheostomies improved after watching the video. Tracheostomy education should be included in early medical education so that future physicians of various specialties can better care for this patient population. Implications for Practice: Internet-published videos are an accessible educational resource with great potential application to various topics within otolaryngology, including tracheostomy care.

10.
Ann Clin Biochem ; 45(Pt 1): 102-5, 2008 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-18275685

RESUMO

Lipoprotein lipase (LPL) is the key enzyme in the catabolism of triglyceride-rich lipoproteins in the circulation. Familial LPL deficiency is characterized by hypertriglyceridaemia and absence of LPL activity. We report a case of LPL deficiency in a 43-year-old woman, who initially presented in childhood with chylomicronaemia syndrome. At that time, her plasma triglyceride concentration was approximately 30 mmol/L and post-heparin lipolytic activity was very low. In addition to having the known missense mutation LPL G188E, the patient was also found to have a novel nonsense mutation in exon 8, namely LPL W394X. The novel substitution in exon 8 (c.1262G > A) predicts a truncated protein product of 393 amino acids that lacks the carboxylterminal 12% of the mature LPL. Trp(394) is part of a cluster of exposed tryptophan residues in the carboxyl-terminal domain of LPL important for binding lipid substrate. Of 11 members from her three-generation family, three were heterozygotes for G188E (mean plasma triglyceride, 3.5 +/- 2.0 mmol/L), whereas six were heterozygotes for W394X (triglyceride, 4.3 +/- 1.8 mmol/L). In summary, we describe a case of familial LPL deficiency caused by compound heterozygosity for known (G188E) and novel (W394X) LPL gene mutations.


Assuntos
Hiperlipoproteinemia Tipo I/enzimologia , Hiperlipoproteinemia Tipo I/genética , Lipase Lipoproteica/genética , Adulto , Idoso , Aminoácidos/genética , Criança , Feminino , Humanos , Hiperlipoproteinemia Tipo I/sangue , Lipase Lipoproteica/metabolismo , Masculino , Pessoa de Meia-Idade , Mutação/genética , Linhagem
11.
J Inherit Metab Dis ; 30(6): 990, 2007 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-18027103

RESUMO

Abetalipoproteinaemia (ABL) and homozygous familial hypobetalipoproteinaemia (FHBL) are rare inherited disorders associated with low or undetectable levels of apolipoprotein B (apoB)-containing lipoproteins. Patients present with the symptoms and sequelae of fat malabsorption, including fat-soluble vitamin deficiencies. We describe two novel mutations: one an APOB gene mutation causing FHBL and the other a microsomal triglyceride transfer protein (MTP) gene mutation causing ABL. Two siblings of consanguineous parents were homozygous for an apoB mutation 4339delT causing an apoB-30.9 truncation. In another family, a boy born to consanguineous parents was homozygous for a 319 bp in-frame deletion of MTP exon 15 (c.2076-39_2303 + 52del319). All three children presented with malabsorption and liver dysfunction and had similar very low serum lipid, apoB, and fat-soluble vitamin levels. The FHBL parents had low serum lipid and apoB profiles distinguishing the disorder from the normal levels in ABL parents. Future patients presenting with FHBL or ABL should be genotyped to provide further insight into the varying clinical severity related to molecular heterogenicity in these two conditions.


Assuntos
Abetalipoproteinemia/genética , Apolipoproteínas B/genética , Proteínas de Transporte/genética , Hipobetalipoproteinemias/genética , Consanguinidade , Análise Mutacional de DNA/métodos , Éxons , Saúde da Família , Feminino , Deleção de Genes , Genótipo , Homozigoto , Humanos , Fígado/patologia , Masculino , Mutação
12.
Mol Cell Biol ; 2(5): 508-16, 1982 May.
Artigo em Inglês | MEDLINE | ID: mdl-6180308

RESUMO

The antibiotic chloramphenicol selectively inhibited mitochondrial protein synthesis in the ciliate protozoan Tetrahymena pyriformis GL. Secondary to the inhibition of mitochondrial protein synthesis was an inhibition of nuclear RNA synthesis at a time before inhibition of cellular protein and DNA synthesis. Of the stable non-polyadenylated RNA species in Tetrahymena, the addition of chloramphenicol resulted specifically in the inhibition of synthesis of 28S + 17S and 5S rRNA transcripts. By contrast, syntheses of 4S tRNA and 21S mitochondrial rRNA were not as extensively inhibited. The addition of 60 microM hemin before the addition of chloramphenicol partially protected against the inhibition of RNA synthesis. These data indicate that continued synthesis of nucleus-directed rRNA is linked to the synthesis of mitochondrial proteins in Tetrahymena.


Assuntos
Núcleo Celular/metabolismo , Regulação da Expressão Gênica , Mitocôndrias/metabolismo , RNA Ribossômico/biossíntese , Tetrahymena pyriformis/genética , Animais , Cloranfenicol/farmacologia , DNA/biossíntese , Hemina/farmacologia , Cinética , Biossíntese de Proteínas , RNA/biossíntese , RNA de Transferência/biossíntese
13.
Plant Sci ; 262: 165-168, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28716411

RESUMO

Accelerated soil-nitrifier activity and rapid nitrification are the cause of declining nitrogen-use efficiency (NUE) and enhanced nitrous oxide (N2O) emissions from farming. Biological nitrification inhibition (BNI) is the ability of certain plant roots to suppress soil-nitrifier activity, through production and release of nitrification inhibitors. The power of phytochemicals with BNI-function needs to be harnessed to control soil-nitrifier activity and improve nitrogen-cycling in agricultural systems. Transformative biological technologies designed for genetic mitigation are needed, so that BNI-enabled crop-livestock and cropping systems can rein in soil-nitrifier activity, to help reduce greenhouse gas (GHG) emissions and globally make farming nitrogen efficient and less harmful to environment. This will reinforce the adaptation or mitigation impact of other climate-smart agriculture technologies.


Assuntos
Agricultura/métodos , Gases de Efeito Estufa , Produtos Agrícolas/metabolismo , Produtos Agrícolas/fisiologia , Nitrificação , Óxido Nitroso/metabolismo , Sorghum/genética , Sorghum/metabolismo , Triticum/genética , Triticum/metabolismo
14.
Br J Sports Med ; 40(3): 275-9, 2006 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-16505089

RESUMO

BACKGROUND: Achilles tendinopathy is a common condition, which can become chronic and interfere with athletic performance. The proteinase inhibitor aprotinin (as injection) has been found to improve recovery in patellar tendinopathy (evidence level 1b) and Achilles tendinopathy. Internationally this therapy is being used based on this limited knowledge base. AIM: To evaluate whether aprotinin injections decrease time to recovery in Achilles tendinopathy. METHOD: A prospective, randomised, double blind, placebo controlled trial was performed comparing saline (0.9%) plus local anaesthetic injections and eccentric exercises with aprotinin (30,000 kIU) plus local anaesthetic injection and eccentric exercise. Three injections were given, each a week apart. In total, 26 patients, with 33 affected tendons, were enrolled for this study. RESULTS: At no follow up point (2, 4, 12, or 52 weeks) was there any statistically significant difference between the treatment group and placebo. This included VISA-A scores and secondary outcome measures. However, a trend for improvement over placebo was noted. CONCLUSION: In this study on Achilles tendinopathy, aprotinin was not shown to offer any statistically significant benefit over placebo. Larger multicentre trials are needed to evaluate the efficacy of aprotinin in Achilles tendinopathy.


Assuntos
Tendão do Calcâneo , Aprotinina/uso terapêutico , Inibidores de Proteases/uso terapêutico , Esportes , Tendinopatia/tratamento farmacológico , Adulto , Idoso , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Resultado do Tratamento
15.
Cancer Res ; 60(24): 6805-10, 2000 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-11156369

RESUMO

Vascular endothelial-cadherin (VE-cad) is an endothelial cell-specific adhesion molecule that is crucial for proper assembly of vascular tubes. Here we show that a monoclonal antibody (BV13) directed to the extracellular region of VE-cad inhibits formation of adherens junctions and capillary-like structures by endothelial cells and blocks angiogenesis in the mouse cornea and in Matrigel plugs in vivo. Systemic administration of BV13 markedly decreases the growth of s.c. Lewis lung or human A431 epidermoid tumors and strongly suppresses the growth of Lewis lung metastases. These data demonstrate that VE-cad is essential for postnatal angiogenesis and thus validate VE-cad as a novel target for antiangiogenesis agents.


Assuntos
Anticorpos Monoclonais/farmacologia , Caderinas/imunologia , Divisão Celular/efeitos dos fármacos , Metástase Neoplásica , Neovascularização Patológica , Neovascularização Fisiológica/efeitos dos fármacos , Animais , Antígenos CD , Carcinoma Pulmonar de Lewis/tratamento farmacológico , Adesão Celular , Colágeno/metabolismo , Córnea/efeitos dos fármacos , Relação Dose-Resposta a Droga , Combinação de Medicamentos , Endotélio/metabolismo , Humanos , Imunoglobulina G/metabolismo , Imuno-Histoquímica , Marcação In Situ das Extremidades Cortadas , Laminina/metabolismo , Neoplasias Pulmonares/tratamento farmacológico , Camundongos , Camundongos Nus , Transplante de Neoplasias , Molécula-1 de Adesão Celular Endotelial a Plaquetas/metabolismo , Antígeno Nuclear de Célula em Proliferação/metabolismo , Proteoglicanas/metabolismo , Fatores de Tempo , Células Tumorais Cultivadas
16.
Cancer Res ; 59(20): 5209-18, 1999 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-10537299

RESUMO

Tumor angiogenesis is mediated by tumor-secreted angiogenic growth factors that interact with their surface receptors expressed on endothelial cells. Vascular endothelial growth factor (VEGF) and its receptor [fetal liver kinase 1 (Flk-1)/kinase insert domain-containing receptor] play an important role in vascular permeability and tumor angiogenesis. Previously, we reported on the development of anti-Flk-1 and antikinase insert domain-containing receptor monoclonal antibodies (mAbs) that potently inhibit VEGF binding and receptor signaling. Here, we report the effect of anti-Flk-1 mAb (DC101) on angiogenesis and tumor growth. Angiogenesis in vivo was examined using a growth factor supplemented (basic fibroblast growth factor + VEGF) Matrigel plug and an alginate-encapsulated tumor cell (Lewis lung) assay in C57BL/6 mice. Systemic administration of DC101 every 3 days markedly reduced neovascularization of Matrigel plugs and tumor-containing alginate beads in a dose-dependent fashion. Histological analysis of Matrigel plugs showed reduced numbers of endothelial cells and vessel structures. Several mouse tumors and human tumor xenografts in athymic mice were used to examine the effect of anti-Flk-1 mAb treatment on tumor angiogenesis and growth. Anti-Flk-1 mAb treatment significantly suppressed the growth of primary murine Lewis lung, 4T1 mammary, and B16 melanoma tumors and growth of Lewis lung metastases. DC101 also completely inhibited the growth of established epidermoid, glioblastoma, pancreatic, and renal human tumor xenografts. Histological examination of anti-Flk-1 mAb-treated tumors showed evidence of decreased microvessel density, tumor cell apoptosis, decreased tumor cell proliferation, and extensive tumor necrosis. These findings support the conclusion that anti-Flk-1 mAb treatment inhibits tumor growth by suppression of tumor-induced neovascularization and demonstrate the potential for therapeutic application of anti-VEGF receptor antibody in the treatment of angiogenesis-dependent tumors.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Neoplasias Experimentais/terapia , Neovascularização Patológica/prevenção & controle , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Receptores de Fatores de Crescimento/antagonistas & inibidores , Animais , Apoptose , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Nus , Necrose , Transplante de Neoplasias , Neoplasias Experimentais/irrigação sanguínea , Neoplasias Experimentais/patologia , Receptores de Fatores de Crescimento do Endotélio Vascular , Transplante Heterólogo
17.
Phytochemistry ; 125: 73-87, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-26923852

RESUMO

The rice C-glycosyltransferase (OsCGT) is one of only a small number of characterised plant C-glycosyltransferases (CGT) known. The enzyme C-glucosylates a 2-hydroxyflavanone substrate with UDP-glucose as the sugar donor to produce C-glucosyl-2-hydroxyflavanones. We tested substrate specificity of the enzyme, using synthetic 2-hydroxyflavanones, and showed it has the potential to generate known natural CGFs that have been isolated from rice and also other plants. In addition, we synthesised novel, unnatural 2-hydroxyflavanone substrates to test the B-ring chemical space of substrate accepted by the OsCGT and demonstrated the OsCGT capacity as a synthetic reagent to generate significant quantities of known and novel CGFs. Many B-ring analogues are tolerated within a confined steric limit. Finally the OsCGT was used to generate novel mono-C-glucosyl-2-hydroxyflavanones as putative biosynthetic intermediates to examine the potential of Desmodium incanum biosynthetic CGTs to produce novel di-C-glycosylflavones, compounds implicated in the allelopathic biological activity of Desmodium against parasitic weeds from the Striga genus.


Assuntos
Flavonas/metabolismo , Glicosídeos/metabolismo , Glicosiltransferases/metabolismo , Oryza , Raízes de Plantas/metabolismo , Flavonas/química , Glicosídeos/química , Estrutura Molecular , Oryza/química , Oryza/enzimologia , Oryza/genética
18.
Biochim Biophys Acta ; 1459(2-3): 346-55, 2000 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-11004450

RESUMO

The combined action of ammonia monooxygenase, AMO, (NH(3)+2e(-)+O(2)-->NH(2)OH) and hydroxylamine oxidoreductase, HAO, (NH(2)OH+H(2)O-->HNO(2)+4e(-)+4H(+)) accounts for ammonia oxidation in Nitrosomonas europaea. Pathways for electrons from HAO to O(2), nitrite, NO, H(2)O(2) or AMO are reviewed and some recent advances described. The membrane cytochrome c(M)552 is proposed to participate in the path between HAO and ubiquinone. A bc(1) complex is shown to mediate between ubiquinol and the terminal oxidase and is shown to be downstream of HAO. A novel, red, low-potential, periplasmic copper protein, nitrosocyanin, is introduced. Possible mechanisms for the inhibition of ammonia oxidation in cells by protonophores are summarized. Genes for nitrite- and NO-reductase but not N(2)O or nitrate reductase are present in the genome of Nitrosomonas. Nitrite reductase is not repressed by growth on O(2); the flux of nitrite reduction is controlled at the substrate level.


Assuntos
Amônia/química , Nitrosomonas/metabolismo , Sequência de Aminoácidos , Amônia/metabolismo , Grupo dos Citocromos c/química , Grupo dos Citocromos c/metabolismo , Transporte de Elétrons , Complexo III da Cadeia de Transporte de Elétrons/química , Complexo III da Cadeia de Transporte de Elétrons/metabolismo , Heme/química , Modelos Químicos , Dados de Sequência Molecular , Nitritos/química , Nitrosomonas/ultraestrutura , Oxirredutases/antagonistas & inibidores , Oxirredutases/metabolismo , Prótons , Ubiquinona/química
19.
J Insect Physiol ; 51(12): 1366-75, 2005 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-16226273

RESUMO

Lutzomyia longipalpis adult males form leks on or near hosts and release (1S,3S,7R)-3-methyl-alpha-himachalene from their tergal glands to lure females to the same site for mating and feeding. Here we have examined whether the male-produced attractant could also serve as a male aggregation stimulus. High resolution chiral capillary gas chromatography analysis of male tergal gland extracts, synthetic (1S,3S,7R)-3-methyl-alpha-himachalene, and a synthetic mixture of all isomers of 3-methyl-alpha-himachalene, was coupled to electrophysiological recordings from ascoid sensillum receptor cells in antennae of male and female sandflies. Receptor cells of both sexes responded only to the main component of the male tergal gland extract that eluted at the same retention time as (1S,3S,7R)-3-methyl-alpha-himachalene. Furthermore, of the eight 3-methyl-alpha-himachalene isomers in the synthetic mixture only the fraction containing (1S,3S,7R)-3-methyl-alpha-himachalene, co-eluting with an isomer of (1S*,3S*,7S*)-3-methyl-alpha-himachalene, elicited an electrophysiological response from male and female ascoid sensillum receptor cells. Both males and females flew upwind in a wind tunnel towards a filter paper disk treated with either 4-6 male equivalents of the tergal gland extract, pure (1S,3S,7R)-3-methyl-alpha-himachalene or the synthetic mixture of eight isomers. This indicates that (1S,3S,7R)-3-methyl-alpha-himachalene derived from L. longipalpis males may have a dual function in causing male aggregation as well as serving as a sex pheromone for females.


Assuntos
Atividade Motora/efeitos dos fármacos , Psychodidae/química , Células Receptoras Sensoriais/efeitos dos fármacos , Sesquiterpenos/química , Atrativos Sexuais/química , Potenciais de Ação/efeitos dos fármacos , Potenciais de Ação/fisiologia , Animais , Brasil , Cromatografia Gasosa , Misturas Complexas , Eletrofisiologia , Masculino , Psychodidae/efeitos dos fármacos , Sesquiterpenos/farmacologia , Atrativos Sexuais/farmacologia
20.
Ir Med J ; 98(4): 105-7, 2005 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-15938552

RESUMO

A survey of 50 general practitioners and 50 practice nurses reviewed current practice in relation to intramuscular injections in the deltoid region of adults. The great majority of practitioners used the site for the intramuscular injection of vaccines and a wide range of other medications. The injection techniques employed by the two groups were similar. The great majority of respondents used either the middle one third or the upper half of the muscle. A significant minority of both groups used inappropriate depths of injection. Awareness of the structures which are at risk from injections in the region was poor in both groups. There is an urgent need to establish reliable protocols for the administration of safe, effective intramuscular injections at the deltoid site and to train practitioners in their use.


Assuntos
Injeções Intramusculares , Profissionais de Enfermagem , Médicos de Família , Padrões de Prática Médica , Humanos , Irlanda , Ombro , Inquéritos e Questionários
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