RESUMO
Spatially resolved emission inventories were used with an atmospheric dispersion model to predict ambient concentrations of methane, ethane, and propane in the Eagle Ford oil and gas production region in south central Texas; predicted concentrations were compared to ground level observations. Using a base case inventory, predicted median propane/ethane concentration ratios were 106% higher (95% CI: 83% higher-226% higher) than observations, while median ethane/methane concentration ratios were 112% higher (95% CI: 17% higher-228% higher) than observations. Predicted median propane and ethane concentrations were factors of 6.9 (95% CI: 3-15.2) and 3.4 (95% CI: 1.4-9) larger than observations, respectively. Predicted median methane concentrations were 7% higher (95% CI: 39% lower-37% higher) than observations. These comparisons indicate that sources of emissions with high propane/ethane ratios (condensate tank flashing) were likely overestimated in the inventories. Because sources of propane and ethane emissions are also sources of methane emissions, the results also suggest that sources of emissions with low ethane/methane ratios (midstream sources) were underestimated. This analysis demonstrates the value of using multiple light alkanes in attributing sources of methane emissions and evaluating the performance of methane emission inventories for oil and natural gas production regions.
Assuntos
Poluentes Atmosféricos , Alcanos , Etano , Metano , Gás Natural , TexasRESUMO
Blood pressure is critically controlled by angiotensins, which are vasopressor peptides specifically released by the enzyme renin from the tail of angiotensinogen-a non-inhibitory member of the serpin family of protease inhibitors. Although angiotensinogen has long been regarded as a passive substrate, the crystal structures solved here to 2.1 Å resolution show that the angiotensin cleavage site is inaccessibly buried in its amino-terminal tail. The conformational rearrangement that makes this site accessible for proteolysis is revealed in our 4.4 Å structure of the complex of human angiotensinogen with renin. The co-ordinated changes involved are seen to be critically linked by a conserved but labile disulphide bridge. Here we show that the reduced unbridged form of angiotensinogen is present in the circulation in a near 40:60 ratio with the oxidized sulphydryl-bridged form, which preferentially interacts with receptor-bound renin. We propose that this redox-responsive transition of angiotensinogen to a form that will more effectively release angiotensin at a cellular level contributes to the modulation of blood pressure. Specifically, we demonstrate the oxidative switch of angiotensinogen to its more active sulphydryl-bridged form in the maternal circulation in pre-eclampsia-the hypertensive crisis of pregnancy that threatens the health and survival of both mother and child.
Assuntos
Angiotensinogênio/química , Angiotensinogênio/metabolismo , Angiotensinas/metabolismo , Processamento de Proteína Pós-Traducional , Sequência de Aminoácidos , Angiotensinogênio/sangue , Angiotensinas/química , Pressão Sanguínea , Cristalografia por Raios X , Dissulfetos/química , Dissulfetos/metabolismo , Feminino , Humanos , Cinética , Modelos Moleculares , Dados de Sequência Molecular , Oxirredução , Estresse Oxidativo , Pré-Eclâmpsia/sangue , Pré-Eclâmpsia/metabolismo , Gravidez , Conformação Proteica , Renina/química , Renina/metabolismoRESUMO
Proteolytic release from the cell surface is an essential activation event for many growth factors and cytokines. TNF-α converting enzyme (TACE) is a membrane-bound metalloprotease responsible for solubilizing many pathologically significant membrane substrates and is an attractive therapeutic target for the treatment of cancer and arthritis. Prior attempts to antagonize cell-surface TACE activity have focused on small-molecule inhibition of the metalloprotease active site. Given the highly conserved nature of metalloprotease active sites, this paradigm has failed to produce a truly specific TACE inhibitor and continues to obstruct the clinical investigation of TACE activity. We report the bespoke development of a specific TACE inhibitory human antibody using "two-step" phage display. This approach combines calculated selection conditions with antibody variable-domain exchange to direct individual antibody variable domains to desired epitopes. The resulting "cross-domain" human antibody is a previously undescribed selective TACE antagonist and provides a unique alternative to small-molecule metalloprotease inhibition.
Assuntos
Proteínas ADAM/antagonistas & inibidores , Anticorpos/farmacologia , Desenho de Fármacos , Região Variável de Imunoglobulina/metabolismo , Modelos Moleculares , Proteínas ADAM/metabolismo , Proteína ADAM17 , Animais , Ensaio de Imunoadsorção Enzimática , Humanos , Região Variável de Imunoglobulina/genética , Camundongos , Mutagênese , Biblioteca de Peptídeos , Estrutura Terciária de Proteína/genética , Ressonância de Plasmônio de SuperfícieRESUMO
In Frongoch Mine (UK), it is unclear the distribution of metals on indigenous algae and whether these species of algae can accumulate metals. This study aimed to investigate the role of indigenous algae for metal removal from acid mine drainage and understand if metals can be adsorbed on the surface of algae or/and bioaccumulated in algae. A sequential extraction procedure was applied for algae samples collected from acid mine drainage (AMD) water to identify the forms in which metals are found in algae. Concentrations of Fe, Pb, Zn, Cu and Cd were evaluated in the algae and AMD samples were collected in June and October 2019. AMDs samples had a pH value ranging between 3.5 and 6.9 and high concentrations of Zn (351 mg/L) and Pb (4.22 mg/L) that exceeded the water quality standards (Water Framework Directive, 2015). Algae Ulothrix sp. and Oedogonium sp. were the two main species in the Frongoch AMDs. The concentrations of metals in algae ranged from 0.007 to 51 mg/g, and the bioconcentration factor of metals decreased in the following order: Fe > > Pb > > Cu > Cd > Zn. It was found that Zn, Cu and Cd were adsorbed onto the surface of and bioaccumulated in the algae, while Pb and Fe were mainly bioaccumulated in the algae. Indigenous algae can be considered as a biogeochemical barrier where metals are accumulating and can be used in bioremediation methods. Also, indigenous algae could be used as a bioindicator to assess water pollution at Frongoch Mine and other similar metal mines.
Assuntos
Metais Pesados , Poluentes Químicos da Água , Ácidos , Bioacumulação , Cádmio , Monitoramento Ambiental/métodos , Chumbo , Metais Pesados/análise , Plantas , Reino Unido , Poluentes Químicos da Água/análiseRESUMO
Improved food security and nutrition remain a notable global challenge. Yet, food security and nutrition are areas of strategic importance regarding the United Nations' Sustainable Development Goals. The increasingly weakening global food production systems pose a threat to sustainable improved food security and nutrition. Consequently, a significant population remains chronically hungry and severely malnourished. As a remedy, farm production diversity (FPD) remains a viable pathway through which household nutrition can be improved. However, evidence is mixed, or unavailable on how FPD is associated with key nutrition indicators like household dietary diversity, energy, iron, zinc, and vitamin A (micronutrients). We use the Uganda National Panel Survey (UNPS) data for rural households to analyze differential associations of sub-components of FPD on dietary diversity, energy, and micronutrient intake. Panel data models reveal that indeed crop species count, and animal species count (sub-components of FPD) are differently associated with household dietary diversity score (HDDS), energy, and vitamin A sourced from markets. Moreover, when volumes of these nutrition outcomes were disaggregated by source (own farm vs. markets), the animal species count was only positively significantly associated with nutrition outcomes sourced from consumption of produce from own farm. Associations were insignificant for nutrition indicators sourced from markets except vitamin A. The crop species count, however, consistently showed a strong positive and significant association with energy, and all studied micronutrients sourced from own farm produce consumption, as well as those sourced from markets except Vitamin A, which was negative but insignificant. Therefore, inclusive, pro-poor, and pro-nutrition rural policy initiatives in the context of rural Uganda and similar ones, could more widely improve household nutrition through prioritizing crop species diversification on own farms because crops fetch wider nutrition gains.
Assuntos
Abastecimento de Alimentos , Vitamina A , Humanos , Fazendas , Uganda , Dieta , Micronutrientes , População RuralAssuntos
Prótese do Joelho/efeitos adversos , Infecções por Mycoplasma , Mycoplasma hominis , Infecções Relacionadas à Prótese , Adulto , Feminino , Humanos , Infecções por Mycoplasma/diagnóstico , Infecções por Mycoplasma/microbiologia , Infecções Relacionadas à Prótese/diagnóstico , Infecções Relacionadas à Prótese/microbiologiaRESUMO
ADAM17 (where ADAM is 'a disintegrin and metalloproteinase') can rapidly modulate cell-surface signalling events by the proteolytic release of soluble forms of proligands for cellular receptors. Many regulatory pathways affect the ADAM17 sheddase activity, but the mechanisms for the activation are still not clear. We have utilized a cell-based ADAM17 assay to show that thiol isomerases, specifically PDI (protein disulfide isomerase), could be responsible for maintaining ADAM17 in an inactive form. Down-regulation of thiol isomerases, by changes in the redox environment (for instance as elicited by phorbol ester modulation of mitochondrial reactive oxygen species) markedly enhanced ADAM17 activation. On the basis of ELISA binding studies with novel fragment antibodies against ADAM17 we propose that isomerization of the disulfide bonds in ADAM17, and the subsequent conformational changes, form the basis for the modulation of ADAM17 activity. The shuffling of disulfide bond patterns in ADAMs has been suggested by a number of recent adamalysin crystal structures, with distinct disulfide bond patterns altering the relative orientations of the domains. Such a mechanism is rapid and reversible, and the role of thiol isomerases should be investigated further as a potential factor in the redox regulation of ADAM17.
Assuntos
Proteínas ADAM/metabolismo , Regulação para Baixo , Isomerases de Dissulfetos de Proteínas/metabolismo , Proteínas ADAM/genética , Proteína ADAM17 , Linhagem Celular Tumoral , Células HeLa , Humanos , Isomerases de Dissulfetos de Proteínas/genéticaRESUMO
BACKGROUND: Ras signaling regulates a number of important processes in the heart, including cell growth and hypertrophy. Although it is known that defective Ras signaling is associated with Noonan, Costello, and other syndromes that are characterized by tumor formation and cardiac hypertrophy, little is known about factors that may control it. Here we investigate the role of Ras effector Ras-association domain family 1 isoform A (RASSF1A) in regulating myocardial hypertrophy. METHODS AND RESULTS: A significant downregulation of RASSF1A expression was observed in hypertrophic mouse hearts, as well as in failing human hearts. To further investigate the role of RASSF1A in cardiac (patho)physiology, we used RASSF1A knock-out (RASSF1A(-)(/)(-)) mice and neonatal rat cardiomyocytes with adenoviral overexpression of RASSF1A. Ablation of RASSF1A in mice significantly enhanced the hypertrophic response to transverse aortic constriction (64.2% increase in heart weight/body weight ratio in RASSF1A(-)(/)(-) mice compared with 32.4% in wild type). Consistent with the in vivo data, overexpression of RASSF1A in cardiomyocytes markedly reduced the cellular hypertrophic response to phenylephrine stimulation. Analysis of molecular signaling events in isolated cardiomyocytes indicated that RASSF1A inhibited extracellular regulated kinase 1/2 activation, likely by blocking the binding of Raf1 to active Ras. CONCLUSIONS: Our data establish RASSF1A as a novel inhibitor of cardiac hypertrophy by modulating the extracellular regulated kinase 1/2 pathway.
Assuntos
Cardiomegalia/metabolismo , Cardiomegalia/patologia , Proliferação de Células , Transdução de Sinais/fisiologia , Proteínas Supressoras de Tumor/metabolismo , Adenoviridae/genética , Animais , Apoptose/fisiologia , Cardiomegalia/induzido quimicamente , Linhagem Celular , Células Cultivadas , Modelos Animais de Doenças , Regulação para Baixo , Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/patologia , Humanos , Masculino , Camundongos , Camundongos Knockout , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Fenilefrina/efeitos adversos , Proteínas Proto-Oncogênicas c-raf/metabolismo , Ratos , Ratos Sprague-Dawley , Proteínas Supressoras de Tumor/genética , Vasoconstritores/efeitos adversosRESUMO
We describe the first case report of posaconazole use as first line agent in the treatment of disseminated zygomycosis with prosthetic hip joint and pulmonary involvement due to Rhizopus microsporus. This infection occurred in a heavily immunosuppressed patient with systemic lupus erythematosus.
Assuntos
Antifúngicos/uso terapêutico , Rhizopus/isolamento & purificação , Triazóis/uso terapêutico , Zigomicose/tratamento farmacológico , Feminino , Prótese de Quadril , Humanos , Hospedeiro Imunocomprometido , Pneumopatias Fúngicas/tratamento farmacológico , Lúpus Eritematoso Sistêmico/complicações , Pessoa de Meia-Idade , Infecções Relacionadas à Prótese/tratamento farmacológicoRESUMO
In the present study, we have investigated the in vitro polymerization of human plasma AGT (angiotensinogen), a non-inhibitory member of the serpin (SERine Protease INhibitor) family. Polymerization of AGT is thought to contribute to a high molecular mass form of the protein in plasma that is increased in pregnancy and pregnancy-associated hypertension. The results of the present study demonstrate that the polymerization of AGT occurs through a novel mechanism which is primarily dependent on non-covalent linkages, while additional disulfide linkages formed after prolonged incubation are not essential for either formation or stability of polymers. We present the first analyses of AGT polymers by electron microscopy, CD spectroscopy, stability assays and sensitivity to proteinases and we conclude that their structure differs from the 'loop-sheet' polymers typical of inhibitory serpins. Histidine residues within the unique N-terminal extension of AGT appear to influence polymer formation, although polymer formation can still take place after their removal by renin. At a functional level, we show that AGT polymers are not substrates for renin, so polymerization of AGT in plasma would predictably lead to decreased formation of AngI (angiotensin I) with blood pressure lowering. Polymerization may therefore be an appropriate response to hypertension. The ability of AGT to protect its renin cleavage site through polymerization may explain why the AngI decapeptide has remained linked to the large and apparently inactive serpin body throughout evolution.
Assuntos
Angiotensinogênio/química , Modelos Moleculares , Angiotensinogênio/metabolismo , Angiotensinogênio/ultraestrutura , Dicroísmo Circular , Dimerização , Dissulfetos/química , Humanos , Concentração de Íons de Hidrogênio , Microscopia Eletrônica , Fosfatos/farmacologia , Conformação Proteica/efeitos dos fármacos , Dobramento de Proteína , Renina/metabolismo , Cloreto de Sódio/farmacologia , Temperatura , Ureia/farmacologiaRESUMO
Laryngeal cryptococcosis is a rare clinical entity. There have been a limited number of case reports in the literature with no consensus regarding optimal management. This review contributes two additional case reports of immunocompetent patients with cryptococcal infection of the larynx in whom exposure to high doses of inhaled corticosteroids is proposed as a significant risk factor. Twenty cases were identified from review of the literature. All patients presented with hoarseness and a spectrum of microlaryngoscopic features, often mimicking laryngeal malignancy. The majority of cases were treated with systemic antifungal therapy, three cases had surgical excision alone, and another three had a combination of medical and surgical management. Risk factor modification, in the form of a reduction in inhaled corticosteroid was employed in the two new cases, and in some previously published cases. Risk factor modification, such as reduction of inhaled corticosteroid dose, in addition to oral antifungal agents can be effective in managing cryptococcal laryngitis.
Assuntos
Filariose Linfática/diagnóstico , Adulto , Austrália , Dietilcarbamazina/uso terapêutico , Doxiciclina/administração & dosagem , Doxiciclina/uso terapêutico , Quimioterapia Combinada , Filariose Linfática/tratamento farmacológico , Filariose Linfática/patologia , Filaricidas/administração & dosagem , Filaricidas/uso terapêutico , Humanos , Masculino , Cordão Espermático/parasitologia , Cordão Espermático/patologiaRESUMO
Recent studies suggest that cells make stochastic choices with respect to differentiation or division. However, the molecular mechanism underlying such stochasticity is unknown. We previously proposed that the timing of vertebrate neuronal differentiation is regulated by molecular oscillations of a transcriptional repressor, HES1, tuned by a post-transcriptional repressor, miR-9. Here, we computationally model the effects of intrinsic noise on the Hes1/miR-9 oscillator as a consequence of low molecular numbers of interacting species, determined experimentally. We report that increased stochasticity spreads the timing of differentiation in a population, such that initially equivalent cells differentiate over a period of time. Surprisingly, inherent stochasticity also increases the robustness of the progenitor state and lessens the impact of unequal, random distribution of molecules at cell division on the temporal spread of differentiation at the population level. This advantageous use of biological noise contrasts with the view that noise needs to be counteracted.
Assuntos
Diferenciação Celular , Proliferação de Células , Regulação da Expressão Gênica , MicroRNAs/metabolismo , Neurônios/fisiologia , Células-Tronco/fisiologia , Fatores de Transcrição HES-1/metabolismo , Simulação por Computador , HumanosRESUMO
The brain-gut peptide neuromedin U (NMU) has been identified recently as a physiological regulator of food intake. To further investigate the central role of NMU in energy homeostasis, we examined the distribution of NMU transcript and the effect of intracerebroventricular administration on several physiological parameters and on the pattern of c-Fos activation. Here we report that intracerebroventricular administration of NMU to 24-h fasted rats resulted in a decrease in subsequent food intake and body weight gain. NMU administration activated neurons in several brain regions implicated in the regulation of feeding behavior. Activated cells included catecholaminergic neurons of the arcuate nucleus and brain stem. Distribution studies revealed NMU expression in the caudal brain stem (nucleus of the solitary tract and inferior olive) and pituitary, with significant levels in the pars tuberalis. This contradicts earlier published observations. In obese (fa/fa) Zucker rats, decreases in NMU expression were detected in the nucleus of the solitary tract, pars tuberalis, and pars distalis, whereas in the fasted rat, a decrease in NMU transcript was detected in the pars distalis. These results confirm the effects of NMU on feeding and suggest additional roles for NMU in neuroendocrine function.
Assuntos
Metabolismo Energético/efeitos dos fármacos , Homeostase/efeitos dos fármacos , Neuropeptídeos/farmacologia , Hipófise/efeitos dos fármacos , Hipófise/fisiologia , Animais , Temperatura Corporal/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Encéfalo/metabolismo , Ingestão de Alimentos/efeitos dos fármacos , Injeções Intraventriculares , Masculino , Neuropeptídeos/administração & dosagem , Neuropeptídeos/genética , Obesidade/metabolismo , Proteínas Proto-Oncogênicas c-fos/metabolismo , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Ratos Zucker , Magreza , Distribuição TecidualRESUMO
During the development of the nervous system, apicobasally polarized stem cells are characterized by a shorter cell cycle than nonpolar progenitors, leading to a lower differentiation potential of these cells. However, how polarization might be directly linked to the kinetics of the cell cycle is not understood. Here, we report that apicobasally polarized neuroepithelial cells in Xenopus laevis have a shorter cell cycle than nonpolar progenitors, consistent with mammalian systems. We show that the apically localized serine/threonine kinase aPKC directly phosphorylates an N-terminal site of the cell-cycle inhibitor p27Xic1 and reduces its ability to inhibit the cyclin-dependent kinase 2 (Cdk2), leading to shortening of G1 and S phases. Overexpression of activated aPKC blocks the neuronal differentiation-promoting activity of p27Xic1. These findings provide a direct mechanistic link between apicobasal polarity and the cell cycle, which may explain how proliferation is favored over differentiation in polarized neural stem cells.
Assuntos
Pontos de Checagem do Ciclo Celular/fisiologia , Polaridade Celular/fisiologia , Inibidor de Quinase Dependente de Ciclina p27/metabolismo , Proteína Quinase C/metabolismo , Proteínas de Xenopus/metabolismo , Animais , Diferenciação Celular/fisiologia , Divisão Celular/fisiologia , Quinase 2 Dependente de Ciclina/metabolismo , Fosforilação , Proteínas Serina-Treonina Quinases/metabolismo , Xenopus laevisRESUMO
SUMMARY: Postoperative pyoderma gangrenosum is a rare neutrophilic dermatosis that may be confused for necrotizing fasciitis. The inflammatory response is triggered by the trauma of surgery and thus must be managed nonsurgically. Clinical and pathological findings in the 2 diseases can be identical, leading to misdiagnosis and massive surgical defects from the ensuing surgery. This report documents a severe case of postsurgical pyoderma following an elective rotator cuff repair presenting with myositis and myonecrosis. The patient was initially treated as having an infection, which resulted in multiple aggressive surgical debridements. Despite this, the patient continued to deteriorate and was in a critical and hemodynamically unstable condition. Following administration of high-dose intravenous corticosteroids, the patient made a dramatic recovery and went on to have internal fixation of the shoulder and closure of the wound with a combination of a free flap and a rotational flap. Extensive myositis, as seen in this case, has not been previously reported in postoperative pyoderma gangrenosum variants. Clinicians should be aware that the presence of myositis and myonecrosis should not preclude this diagnosis.
RESUMO
Short-period (ultradian) oscillations of Hes1, a Notch signaling effector, are essential for maintaining neural progenitors in a proliferative state, while constitutive downregulation of Hes1 leads to neuronal differentiation. Hes1 oscillations are driven by autorepression, coupled with high instability of the protein and mRNA. It is unknown how Hes1 mRNA stability is controlled and furthermore, how cells exit oscillations in order to differentiate. Here, we identify a microRNA, miR-9, as a component of ultradian oscillations. We show that miR-9 controls the stability of Hes1 mRNA and that both miR-9 overexpression and lack of miR-9 dampens Hes1 oscillations. Reciprocally, Hes1 represses the transcription of miR-9, resulting in out-of-phase oscillations. However, unlike the primary transcript, mature miR-9 is very stable and thus accumulates over time. Given that raising miR-9 levels leads to dampening of oscillations, these findings provide support for a self-limiting mechanism whereby cells might terminate Hes1 oscillations and differentiate.