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An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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El Niño and La Niña, collectively referred to as the El Niño-Southern Oscillation (ENSO), are not only highly consequential1-6 but also strongly nonlinear7-14. For example, the maximum warm anomalies of El Niño, which occur in the equatorial eastern Pacific Ocean, are larger than the maximum cold anomalies of La Niña, which are centred in the equatorial central Pacific Ocean7-9. The associated atmospheric nonlinear thermal damping cools the equatorial Pacific during El Niño but warms it during La Niña15,16. Under greenhouse warming, climate models project an increase in the frequency of strong El Niño and La Niña events, but the change differs vastly across models17, which is partially attributed to internal variability18-23. Here we show that like a butterfly effect24, an infinitesimal random perturbation to identical initial conditions induces vastly different initial ENSO variability, which systematically affects its response to greenhouse warming a century later. In experiments with higher initial variability, a greater cumulative oceanic heat loss from ENSO thermal damping reduces stratification of the upper equatorial Pacific Ocean, leading to a smaller increase in ENSO variability under subsquent greenhouse warming. This self-modulating mechanism operates in two large ensembles generated using two different models, each commencing from identical initial conditions but with a butterfly perturbation24,25; it also operates in a large ensemble generated with another model commencing from different initial conditions25,26 and across climate models participating in the Coupled Model Intercomparison Project27,28. Thus, if the greenhouse-warming-induced increase in ENSO variability29 is initially suppressed by internal variability, future ENSO variability is likely to be enhanced, and vice versa. This self-modulation linking ENSO variability across time presents a different perspective for understanding the dynamics of ENSO variability on multiple timescales in a changing climate.
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SignificanceThe western Pacific subtropical high (WPSH) channels moisture from the tropics that underpins the East Asian summer climate. Interannual variability of the WPSH dominates climate extremes in the densely populated countries of East Asia. In 2020, an anomalously strong WPSH led to catastrophic floods with hundreds of deaths, 28,000 homes destroyed, and tens of billions in economic damage in China alone. How the frequency of such strong WPSH events will change is of great societal concern. Our finding of an increase in future WPSH variability, translating into an increased frequency of climate extreme as seen in the 2020 episode, highlights the increased risks for the billions of people in the densely populated East Asia with profound socioeconomic consequences.
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BACKGROUND: Marfan syndrome (MFS) is associated with TGF (transforming growth factor) ß-stimulated ERK (extracellular signal-regulated kinase) activity in vascular smooth muscle cells (VSMCs), which adopt a mixed synthetic/contractile phenotype. In VSMCs, TGFß induces IL (interleukin) 11) that stimulates ERK-dependent secretion of collagens and MMPs (matrix metalloproteinases). Here, we examined the role of IL11 in the MFS aorta. METHODS: We used echocardiography, histology, immunostaining, and biochemical methods to study aortic anatomy, physiology, and molecular endophenotypes in Fbn1C1041G/+ mice, an established murine model of MFS (mMFS). mMFS mice were crossed to an IL11-tagged EGFP (enhanced green fluorescent protein; Il11EGFP/+) reporter strain or to a strain deleted for the IL11 receptor (Il11ra1-/-). In therapeutic studies, mMFS were administered an X209 (neutralizing antibody against IL11RA [IL11 receptor subunit alpha]) or IgG for 20 weeks and imaged longitudinally. RESULTS: IL11 mRNA and protein were elevated in the aortas of mMFS mice, as compared to controls. mMFS mice crossed to Il11EGFP/+ mice had increased IL11 expression in VSMCs, notably in the aortic root and ascending aorta. As compared to the mMFS parental strain, double mutant mMFS:Il11ra1-/- mice had reduced aortic dilatation and exhibited lesser fibrosis, inflammation, elastin breaks, and VSMC loss, which was associated with reduced aortic COL1A1 (collagen type I alpha 1 chain), IL11, MMP2/9, and phospho-ERK expression. To explore therapeutic targeting of IL11 signaling in MFS, we administered either a neutralizing antibody against IL11RA (X209) or an IgG control. After 20 weeks of antibody administration, as compared to IgG, mMFS mice receiving X209 had reduced thoracic and abdominal aortic dilation as well as lesser fibrosis, inflammation, elastin breaks, and VSMC loss. By immunoblotting, X209 was shown to reduce aortic COL1A1, IL11, MMP2/9, and phospho-ERK expression. CONCLUSIONS: In MFS, IL11 is upregulated in aortic VSMCs to cause ERK-related thoracic aortic dilatation, inflammation, and fibrosis. Therapeutic inhibition of IL11, imminent in clinical trials, might be considered as a new approach in MFS.
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Enfermedades de la Aorta , Síndrome de Marfan , Animales , Anticuerpos Neutralizantes/metabolismo , Anticuerpos Neutralizantes/farmacología , Aorta/metabolismo , Enfermedades de la Aorta/patología , Modelos Animales de Enfermedad , Elastina/metabolismo , Fibrosis , Inmunoglobulina G/metabolismo , Inflamación/metabolismo , Interleucina-11/metabolismo , Subunidad alfa del Receptor de Interleucina-11 , Síndrome de Marfan/complicaciones , Síndrome de Marfan/genética , Metaloproteinasa 2 de la Matriz/metabolismo , Ratones , Músculo Liso Vascular/metabolismo , Receptores de Interleucina-11/metabolismo , Factor de Crecimiento Transformador beta/metabolismoRESUMEN
BACKGROUND: Marfan Syndrome (MFS) is an inherited connective tissue disorder caused by mutations in the FBN1 (fibrillin-1) gene. Lung abnormalities are common in MFS, but their pathogenesis is poorly understood. IL11 (interleukin-11) causes aortic disease in a mouse model of MFS and was studied here in the lung. METHODS: We examined histological and molecular phenotypes in the lungs of Fbn1C1041G/+ mice (mouse model of Marfan Syndrome [mMFS]), an established mouse model of MFS. To identify IL11-expressing cells, we used immunohistochemistry on lungs of 4- and 16-week-old Fbn1C1041G/+:Il11EGFP/+ reporter mice. We studied the effects of IL11 inhibition by RT-qPCR, immunoblots and histopathology in lungs from genetic or pharmacologic models: (1) 16-week-old IL11 receptor (IL11RA) knockout mMFS mice (Fbn1C1041G/+:Il11ra1-/- mice) and (2) in mMFS mice administered IgG control or interleukin-11 receptor antibodies twice weekly from 4 to 24 weeks of age. RESULTS: mMFS lungs showed progressive loss and enlargement of distal airspaces associated with increased proinflammatory and profibrotic gene expression as well as matrix metalloproteinases 2, 9, and 12. IL11 was increased in mMFS lungs and localized to smooth muscle and endothelial cells in young mMFS mice in the Fbn1C1041G/+:Il11EGFP/+ reporter strain and in fibroblasts, in older mice. In mMFS mice, genetic (Fbn1C1041G/+:Il11ra1-/-) or pharmacologic (anti-interleukin-11 receptor) inhibition of IL11 signaling reduced lung emphysema, fibrosis, and inflammation. This protective effect was associated with reduced pathogenic ERK1/2 signaling and lower metalloproteinase 2, 9, and 12 expression. CONCLUSIONS: IL11 causes lung disease in mMFS. This reveals a shared IL11-driven disease mechanism in lung and aorta in MFS and suggests inhibition of IL11 signaling as a holistic approach for treating multiorgan morbidity in MFS.
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Interleucina-11 , Síndrome de Marfan , Enfisema Pulmonar , Animales , Ratones , Modelos Animales de Enfermedad , Células Endoteliales/metabolismo , Fibrilina-1/genética , Interleucina-11/genética , Subunidad alfa del Receptor de Interleucina-11 , Síndrome de Marfan/complicaciones , Síndrome de Marfan/genética , Síndrome de Marfan/patología , Metaloproteinasa 2 de la Matriz/genética , Ratones Noqueados , Enfisema Pulmonar/complicaciones , Enfisema Pulmonar/genéticaRESUMEN
OBJECTIVES: To determine the compliance of online vendors to the UK Opticians Act 1989 Section 27 requirements and safety regulations for cosmetic contact lens (CCL) sales and the quality of online CCL health information. METHODS: The top 50 websites selling CCLs on each three search engines, namely Google, Yahoo, and Bing, were selected. Duplicates were removed, and the remaining websites were systematically analyzed in February 2023. UK legal authorization for CCL sales was assessed using the Opticians Act Section 27 and safety regulations determined by the presence of Conformité Européene (CE) marking. The quality and reliability of online information was graded using the DISCERN (16-80) and JAMA (0-4) scores by two independent reviewers. RESULTS: Forty-seven eligible websites were analyzed. Only six (12.7%) met the UK legal authorization for CCL sales. Forty-nine different brands of CCLs were sold on these websites, of which 13 (26.5%) had no CE marking. The mean DISCERN and JAMA benchmark scores were 26 ± 12.2 and 1.3 ± 0.6, respectively (intraclass correlation scores: 0.99 for both). CONCLUSIONS: A significant number of websites provide consumers with easy, unsafe, and unregulated access to CCLs. Most online stores do not meet the requirements set out in the Opticians Act for CCL sales in the United Kingdom. A significant number of CCLs lack CE marking, while the average quality of information on websites selling CCLs is poor. Together, these pose a risk to consumers purchasing CCLs from unregulated websites, and therefore, further stringent regulations on the online sales of these products are needed.
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Información de Salud al Consumidor , Internet , Humanos , Reino Unido , Información de Salud al Consumidor/normas , Cosméticos/normas , Lentes de Contacto , Seguridad de Productos para el Consumidor/legislación & jurisprudencia , Seguridad de Productos para el Consumidor/normasRESUMEN
Fibrosis is a common pathology in cardiovascular disease. In the heart, fibrosis causes mechanical and electrical dysfunction and in the kidney, it predicts the onset of renal failure. Transforming growth factor ß1 (TGFß1) is the principal pro-fibrotic factor, but its inhibition is associated with side effects due to its pleiotropic roles. We hypothesized that downstream effectors of TGFß1 in fibroblasts could be attractive therapeutic targets and lack upstream toxicity. Here we show, using integrated imaging-genomics analyses of primary human fibroblasts, that upregulation of interleukin-11 (IL-11) is the dominant transcriptional response to TGFß1 exposure and required for its pro-fibrotic effect. IL-11 and its receptor (IL11RA) are expressed specifically in fibroblasts, in which they drive non-canonical, ERK-dependent autocrine signalling that is required for fibrogenic protein synthesis. In mice, fibroblast-specific Il11 transgene expression or Il-11 injection causes heart and kidney fibrosis and organ failure, whereas genetic deletion of Il11ra1 protects against disease. Therefore, inhibition of IL-11 prevents fibroblast activation across organs and species in response to a range of important pro-fibrotic stimuli. These results reveal a central role of IL-11 in fibrosis and we propose that inhibition of IL-11 is a potential therapeutic strategy to treat fibrotic diseases.
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Sistema Cardiovascular/metabolismo , Sistema Cardiovascular/patología , Fibrosis/metabolismo , Fibrosis/patología , Interleucina-11/metabolismo , Animales , Comunicación Autocrina , Células Cultivadas , Femenino , Fibroblastos/efectos de los fármacos , Fibroblastos/metabolismo , Fibroblastos/patología , Fibrosis/inducido químicamente , Corazón , Humanos , Interleucina-11/antagonistas & inhibidores , Interleucina-11/genética , Subunidad alfa del Receptor de Interleucina-11/deficiencia , Subunidad alfa del Receptor de Interleucina-11/genética , Riñón/patología , Masculino , Ratones , Ratones Noqueados , Persona de Mediana Edad , Miocardio/metabolismo , Miocardio/patología , Puntuaciones en la Disfunción de Órganos , Biosíntesis de Proteínas , Factor de Crecimiento Transformador beta1/metabolismo , Factor de Crecimiento Transformador beta1/farmacología , Transgenes/genéticaRESUMEN
BACKGROUND AND OBJECTIVE: We have previously described reversal of collateral ventilation (CV) in a severe chronic obstructive pulmonary disease (COPD) patient with endoscopic polymer foam (EPF), prior to endoscopic lung volume reduction (ELVR) with valves. The aim of this study was to investigate the efficacy of this in a larger cohort and compare outcomes with a similar cohort with no CV. METHODS: Patients with severe COPD, with the left upper lobe (LUL) targeted for ELVR, were assessed for CV with high resolution computed tomography (HRCT). If fissure completeness was >95% they were enrolled as controls for valves alone (endobronchial valve control group [EBV-CTRL]). If fissure completeness was 80%-95%, defects were mapped to the corresponding segment, where EPF was instilled following confirmation of CV with CHARTIS. EBVs were inserted 1 month afterwards. RESULTS: Fourteen patients were enrolled into both arms. After 6 months, there were significant improvements in both groups in forced expiratory volume in 1 s (FEV1; +19.7% EPF vs. +27.7% EBV-CTRL, p < 0.05); residual volume (RV; -16.2% EPF vs. -20.1% EBV-CTRL, p = NS); SGRQ (-15.1 EPF vs. -16.6 EBV-CTRL p = NS) and 6 min walk (+25.8% EPF [77.2 m] vs. +28.4% [82.3 m] EBV-CTRL p = NS). Patients with fissural defects mapped to the lingula had better outcomes than those mapped to other segments (FEV1 +22.9% vs. +16.3% p < 0.05). There were no serious adverse reactions to EPF. CONCLUSION: EPF successfully reverses CV in severe COPD patients with a left oblique fissure that is 80%-95% complete. Following EBV, outcomes are similar to patients with complete fissures undergoing ELVR with EBV alone. EPF therapy to reverse CV potentially increases the number of COPD patients suitable for ELVR with minimal adverse reactions.
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Enfermedad Pulmonar Obstructiva Crónica , Enfisema Pulmonar , Humanos , Neumonectomía/métodos , Enfisema Pulmonar/cirugía , Broncoscopía/métodos , Polímeros , Aerosoles y Gotitas Respiratorias , Enfermedad Pulmonar Obstructiva Crónica/cirugía , Volumen Espiratorio Forzado , Resultado del TratamientoRESUMEN
Cognitive Radio (CR) is a practical technique for overcoming spectrum inefficiencies by sensing and utilizing spectrum holes over a wide spectrum. In particular, cooperative spectrum sensing (CSS) determines the state of primary users (PUs) by cooperating with multiple secondary users (SUs) distributed around a Cognitive Radio Network (CRN), further overcoming various noise and fading issues in the radio environment. But it's still challenging to balance energy efficiency and good sensing performances in the existing CSS system, especially when the CRN consists of battery-limited sensors. This article investigates the application of machine learning technologies for cooperative spectrum sensing, especially through solving a multi-dimensional optimization that cannot be readily addressed by traditional approaches. Specifically, we develop a neural network, which involves parameters that are integral to the CSS performance, including a device sleeping rate for each sensor and thresholds used in the energy detection method, and a customized loss function based on the energy consumption of the CSS system and multiple penalty terms reflecting the system requirements. Using this formulation, energy consumption is to be minimized with the guarantee of reaching a certain probability of false alarm and detection in the CSS system. With the proposed method, comparison studies under different hard fusion rules ('OR' and 'AND') demonstrate its effectiveness in improving the CSS system performances, as well as its robustness in the face of changing global requirements. This paper also suggests the combination of the traditional and the proposed scheme to circumvent the respective inherent pitfalls of neural networks and the traditional semi-analytic methods.
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Redes de Comunicación de Computadores , Tecnología Inalámbrica , Algoritmos , Aprendizaje Automático , Fenómenos FísicosRESUMEN
Interleukin-11 (IL11) is important for fibrosis and inflammation, but its role in the pancreas is unclear. In pancreatitis, fibrosis, inflammation and organ dysfunction are associated with pancreatic stellate cell (PSC)-to-myofibroblast transformation. Here, we show that IL11 stimulation of PSCs, which specifically express IL11RA in the pancreas, results in transient STAT3 phosphorylation, sustained ERK activation and PSC activation. In contrast, IL6 stimulation of PSCs caused sustained STAT3 phosphorylation but did not result in ERK activation or PSC transformation. Pancreatitis factors, including TGFß, CTGF and PDGF, induced IL11 secretion from PSCs and a neutralising IL11RA antibody prevented PSC activation by these stimuli. This revealed an important ERK-dependent role for autocrine IL11 activity in PSCs. In mice, IL11 was increased in the pancreas after pancreatic duct ligation, and in humans, IL11 and IL11RA levels were elevated in chronic pancreatitis. Following pancreatic duct ligation, administration of anti-IL11RA to mice reduced pathologic (ERK, STAT, NF-κB) signalling, pancreatic atrophy, fibrosis and pro-inflammatory cytokine (TNFα, IL6 and IL1ß) levels. This is the first description of IL11-mediated activation of PSCs, and the data suggest IL11 as a stromal therapeutic target in pancreatitis.
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Interleucina-11 , Pancreatitis Crónica , Animales , Atrofia/patología , Modelos Animales de Enfermedad , Fibrosis , Inflamación/patología , Interleucina-6 , Ratones , Páncreas/patología , Células Estrelladas Pancreáticas/patología , Pancreatitis Crónica/patologíaRESUMEN
Titin-truncating variants (TTNtv) are the most common genetic cause of dilated cardiomyopathy. TTNtv occur in ~1% of the general population and causes subclinical cardiac remodeling in asymptomatic carriers. In rat models with either proximal or distal TTNtv, we previously showed altered cardiac metabolism at baseline and impaired cardiac function in response to stress. However, the molecular mechanism(s) underlying these effects remains unknown. In the current study, we used rat models of TTNtv to investigate the effect of TTNtv on autophagy and mitochondrial function, which are essential for maintaining cellular metabolic homeostasis and cardiac function. In both the proximal and distal TTNtv rat models, we found increased levels of LC3B-II and p62 proteins, indicative of diminished autophagic degradation. The accumulation of autophagosomes and p62 protein in cardiomyocytes was also demonstrated by electron microscopy and immunochemistry, respectively. Impaired autophagy in the TTNtv heart was associated with increased phosphorylation of mTOR and decreased protein levels of the lysosomal protease, cathepsin B. In addition, TTNtv hearts showed mitochondrial dysfunction, as evidenced by decreased oxygen consumption rate in cardiomyocytes, increased levels of reactive oxygen species and mitochondrial protein ubiquitination. We also observed increased acetylation of mitochondrial proteins associated with decreased NAD+/NADH ratio in the TTNtv hearts. mTORC1 inhibitor, rapamycin, was able to rescue the impaired autophagy in TTNtv hearts. In summary, TTNtv leads to impaired autophagy and mitochondrial function in the heart. These changes not only provide molecular mechanisms that underlie TTNtv-associated ventricular remodeling but also offer potential targets for its intervention.
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Autofagia/genética , Cardiomiopatía Dilatada/genética , Conectina/genética , Mitocondrias Cardíacas/metabolismo , Miocitos Cardíacos/metabolismo , Acetilación , Animales , Autofagosomas/metabolismo , Autofagosomas/ultraestructura , Cardiomiopatía Dilatada/metabolismo , Catepsina B/metabolismo , Células Cultivadas , Conectina/metabolismo , Masculino , Proteínas Asociadas a Microtúbulos/metabolismo , Mitocondrias Cardíacas/patología , Proteínas Mitocondriales/metabolismo , NAD/análogos & derivados , NAD/metabolismo , Ratas , Especies Reactivas de Oxígeno/metabolismo , Eliminación de Secuencia , Proteína Sequestosoma-1/metabolismo , Serina-Treonina Quinasas TOR/metabolismo , UbiquitinaciónRESUMEN
OBJECTIVES: Interleukin 11 (IL11) is highly upregulated in skin and lung fibroblasts from patients with systemic sclerosis (SSc). Here we tested whether IL11 is mechanistically linked with activation of human dermal fibroblasts (HDFs) from patients with SSc or controls. METHODS: We measured serum IL11 levels in volunteers and patients with early diffuse SSc and manipulated IL11 signalling in HDFs using gain- and loss-of-function approaches that we combined with molecular and cellular phenotyping. RESULTS: In patients with SSc, serum IL11 levels are elevated as compared with healthy controls. All transforming growth factor beta (TGFß) isoforms induced IL11 secretion from HDFs, which highly express IL11 receptor α-subunit and the glycoprotein 130 (gp130) co-receptor, suggestive of an autocrine loop of IL11 activity in HDFs. IL11 stimulated ERK activation in HDFs and resulted in HDF-to-myofibroblast transformation and extracellular matrix secretion. The pro-fibrotic action of IL11 in HDFs appeared unrelated to STAT3 activity, independent of TGFß upregulation and was not associated with phosphorylation of SMAD2/3. Inhibition of IL11 signalling using either a neutralizing antibody against IL11 or siRNA against IL11RA reduced TGFß-induced HDF proliferation, matrix production and cell migration, which was phenocopied by pharmacological inhibition of ERK. CONCLUSIONS: These data reveal that autocrine IL11-dependent ERK activity alone or downstream of TGFß stimulation promotes fibrosis phenotypes in dermal fibroblasts and suggest IL11 as a potential therapeutic target in SSc.
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Regulación de la Expresión Génica , Subunidad alfa del Receptor de Interleucina-11/genética , Interleucina-11/sangre , Sistema de Señalización de MAP Quinasas/genética , ARN/genética , Esclerodermia Sistémica/sangre , Piel/patología , Biomarcadores/sangre , Células Cultivadas , Ensayo de Inmunoadsorción Enzimática , Humanos , Subunidad alfa del Receptor de Interleucina-11/biosíntesis , Esclerodermia Sistémica/genética , Esclerodermia Sistémica/patología , Transducción de SeñalRESUMEN
Repetitive pulmonary injury causes fibrosis and inflammation that underlies chronic lung diseases such as idiopathic pulmonary fibrosis (IPF). Interleukin 11 (IL11) is important for pulmonary fibroblast activation but the contribution of fibroblast-specific IL11 activity to lung fibro-inflammation is not known. To address this gap in knowledge, we generated mice with loxP-flanked Il11ra1 and deleted the IL11 receptor in adult fibroblasts (CKO mice). In the bleomycin (BLM) model of lung fibrosis, CKO mice had reduced fibrosis, lesser fibroblast ERK activation, and diminished immune cell STAT3 phosphorylation. Following BLM injury, acute inflammation in CKO mice was similar to controls but chronic immune infiltrates and pro-inflammatory gene activation, including NF-kB phosphorylation, were notably reduced. Therapeutic prevention of IL11 activity with neutralizing antibodies mirrored the effects of genetic deletion of Il11ra1 in fibroblasts. These data reveal a new function for IL11 in pro-inflammatory lung fibroblasts and highlight the important contribution of the stroma to inflammation in pulmonary disease.
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Fibroblastos/metabolismo , Inflamación/metabolismo , Subunidad alfa del Receptor de Interleucina-11/metabolismo , Interleucina-11/metabolismo , Fibrosis Pulmonar/metabolismo , Animales , Bleomicina , Células Cultivadas , Enfermedad Crónica , Fibroblastos/citología , Fibroblastos/efectos de los fármacos , Humanos , Inflamación/genética , Interleucina-11/farmacología , Subunidad alfa del Receptor de Interleucina-11/genética , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , FN-kappa B/metabolismo , Fosforilación , Fibrosis Pulmonar/inducido químicamente , Fibrosis Pulmonar/genética , Transducción de Señal/efectos de los fármacos , Transducción de Señal/genéticaRESUMEN
BACKGROUND & AIMS: We studied the role of interleukin 11 (IL11) signaling in the pathogenesis of nonalcoholic steatohepatitis (NASH) using hepatic stellate cells (HSCs), hepatocytes, and mouse models of NASH. METHODS: We stimulated mouse and human fibroblasts, HSCs, or hepatocytes with IL11 and other cytokines and analyzed them by imaging, immunoblot, and functional assays and enzyme-linked immunosorbent assays. Mice were given injections of IL11. Mice with disruption of the interleukin 11 receptor subunit alpha1 gene (Il11ra1-/-) mice and Il11ra1+/+ mice were fed a high-fat methionine- and choline-deficient diet (HFMCD) or a Western diet with liquid fructose (WDF) to induce steatohepatitis; control mice were fed normal chow. db/db mice were fed with methionine- and choline-deficient diet for 12 weeks and C57BL/6 NTac were fed with HFMCD for 10 weeks or WDF for 16 weeks. Some mice were given intraperitoneal injections of anti-IL11 (X203), anti-IL11RA (X209), or a control antibody at different timepoints on the diets. Livers and blood were collected; blood samples were analyzed by biochemistry and liver tissues were analyzed by histology, RNA sequencing, immunoblots, immunohistochemistry, hydroxyproline, and mass cytometry time of flight assays. RESULTS: HSCs incubated with cytokines produced IL11, resulting in activation (phosphorylation) of ERK and expression of markers of fibrosis. Livers of mice given injections of IL11 became damaged, with increased markers of fibrosis, hepatocyte cell death and inflammation. Following the HFMCD or WDF, livers from Il11ra1-/- mice had reduced steatosis, fibrosis, expression of markers of inflammation and steatohepatitis, compared to and Il11ra1+/+ mice on the same diets. Depending on the time of administration of anti-IL11 or anti-IL11RA antibodies to wild-type mice on the HFMCD or WDF, or to db/db mice on the methionine and choline-deficient diet, the antibodies prevented, stopped, or reversed development of fibrosis and steatosis. Blood samples from Il11ra1+/+ mice fed the WDF and given injections of anti-IL11 or anti-IL11RA, as well as from Il11ra1-/- mice fed WDF, had lower serum levels of lipids and glucose than mice not injected with antibody or with disruption of Il11ra1. CONCLUSIONS: Neutralizing antibodies that block IL11 signaling reduce fibrosis, steatosis, hepatocyte death, inflammation and hyperglycemia in mice with diet-induced steatohepatitis. These antibodies also improve the cardiometabolic profile of mice and might be developed for the treatment of NASH.
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Anticuerpos Neutralizantes/farmacología , Hepatitis/prevención & control , Subunidad alfa del Receptor de Interleucina-11/metabolismo , Interleucina-11/antagonistas & inhibidores , Cirrosis Hepática Experimental/prevención & control , Hígado/efectos de los fármacos , Enfermedad del Hígado Graso no Alcohólico/prevención & control , Animales , Muerte Celular/efectos de los fármacos , Fibroblastos/efectos de los fármacos , Fibroblastos/metabolismo , Fibroblastos/patología , Células Estrelladas Hepáticas/efectos de los fármacos , Células Estrelladas Hepáticas/metabolismo , Células Estrelladas Hepáticas/patología , Hepatitis/genética , Hepatitis/metabolismo , Hepatitis/patología , Hepatocitos/efectos de los fármacos , Hepatocitos/metabolismo , Hepatocitos/patología , Humanos , Mediadores de Inflamación/metabolismo , Interleucina-11/metabolismo , Subunidad alfa del Receptor de Interleucina-11/deficiencia , Subunidad alfa del Receptor de Interleucina-11/genética , Hígado/metabolismo , Hígado/patología , Cirrosis Hepática Experimental/genética , Cirrosis Hepática Experimental/metabolismo , Cirrosis Hepática Experimental/patología , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , Enfermedad del Hígado Graso no Alcohólico/genética , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Enfermedad del Hígado Graso no Alcohólico/patología , Transducción de Señal/efectos de los fármacos , Células THP-1RESUMEN
BACKGROUND: Combination drug therapy for pulmonary arterial hypertension (PAH) is the international standard of care for most patients, however in Australia there are barriers to drug access. This study evaluates current treatment of PAH patients in Australia and the consistency of therapy with international guidelines. METHODS: Cross-sectional analysis of patients with Group 1 PAH enrolled in the Pulmonary Hypertension Society of Australia and New Zealand Registry (PHSANZ) at 31 December 2017. Drug treatment was classified as monotherapy or combination therapy and adequacy of treatment was determined by risk status assessment using the Registry to Evaluate Early and Long-Term PAH Disease Management (REVEAL) 2.0 risk calculator. Predictors of monotherapy were assessed using a generalised linear model with Poisson distribution and logarithmic link function. RESULTS: 1,046 patients met the criteria for analysis. Treatment was classified as monotherapy in 536 (51%) and combination therapy in 510 (49%) cases. Based on REVEAL 2.0, 184 (34%) patients on monotherapy failed to meet low-risk criteria and should be considered inadequately treated. Independent predictors of monotherapy included age greater than 60 years (risk ratio [RR] 1.23, 95% confidence interval [CI] 1.09-1.38; p=0.001), prevalent enrolment in the registry (RR 1.21 [95%CI 1.08-1.36]; p=0.001) and comorbid systemic hypertension (RR 1.17 [95%CI 1.03-1.32]; p=0.014), while idiopathic/heritable/drug-induced PAH subtype (RR 0.85 [95%CI 0.76-0.96]; p=0.006), functional class IV (RR 0.50 [95%CI 0.29-0.86]; p=0.012), increased right ventricular systolic pressure (RR 0.99 [95%CI 0.99-1.00]; p<0.001) and increased pulmonary vascular resistance (RR 0.96 [95%CI 0.95-0.98]; p<0.001) were less likely to be associated with monotherapy. CONCLUSIONS: Most Australian PAH patients are treated with monotherapy and a significant proportion remain at risk of poor outcomes. This is below the standard of care recommended by international guidelines and at risk patients should be escalated to combination therapy.
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Antihipertensivos/administración & dosificación , Hipertensión Arterial Pulmonar/tratamiento farmacológico , Sistema de Registros , Adulto , Anciano , Australia/epidemiología , Estudios Transversales , Relación Dosis-Respuesta a Droga , Quimioterapia Combinada , Femenino , Humanos , Masculino , Persona de Mediana Edad , Hipertensión Arterial Pulmonar/epidemiología , Adulto JovenRESUMEN
Point mutations in DNA are useful biomarkers that can provide critical classification of disease for accurate diagnosis and to inform clinical decisions. Conventional approaches to detect point mutations are usually based on technologies such as real-time polymerase chain reaction (PCR) or DNA sequencing, which are typically slow and require expensive lab-based equipment. While rapid isothermal strategies such as recombinase polymerase amplification (RPA) have been proposed, they tend to suffer from poor specificity in discriminating point mutations. Herein, we describe a novel strategy that enabled exquisite point mutation discrimination with isothermal DNA amplification, using mismatched primers in conjunction with a two-round enrichment process. As a proof of concept, the method was applied to the rapid and specific identification of drug-resistant Mycobacterium tuberculosis using RPA under specific conditions. The assay requires just picogram levels of genomic DNA input, is sensitive and specific enough to detect 10% point mutation loading, and can discriminate between closely related mutant variants within 30 min. The assay was subsequently adapted onto a low-cost 3D-printed isothermal device with real-time analysis capabilities to demonstrate a potential point-of-care application. Finally, the generic applicability of the strategy was shown by detecting three other clinically important cancer-associated point mutations. We believe that our assay shows potential in a broad range of healthcare screening processes for detecting and categorizing disease phenotypes at the point of care, thus reducing unnecessary therapy and cost in these contexts.
Asunto(s)
ADN Bacteriano/genética , Mycobacterium tuberculosis/efectos de los fármacos , Mycobacterium tuberculosis/genética , Mutación Puntual , Tuberculosis Resistente a Múltiples Medicamentos/microbiología , ADN Bacteriano/química , Técnicas de Amplificación de Ácido Nucleico/métodos , Sistemas de Atención de PuntoAsunto(s)
Antirreumáticos , Artritis , Hipertensión Arterial Pulmonar , Antirreumáticos/efectos adversos , Artritis/inducido químicamente , Artritis/diagnóstico , Artritis/tratamiento farmacológico , Humanos , Piperidinas , Pirimidinas/efectos adversos , Pirroles/efectos adversos , Resultado del TratamientoRESUMEN
Tuberculosis (TB) remains a global health threat, with over a third of the world population suffering from the disease, and 1.5 million deaths due to the disease in 2013 alone. Despite significant advances in TB detection strategies in recent years, a bigger push toward detecting TB in the shortest and easiest way possible at the point-of-care (POC) is still in demand. To this end, we have designed a simple yet rapid and sensitive bioassay that detects Mtb DNA electrochemically using colloidal gold nanoparticles. This assay couples rapid isothermal amplification of target DNA that is specific to Mtb with gold nanoparticle electrochemistry on disposable screen printed carbon electrodes. The assay is capable of detecting a positive differential pulse voltammetry (DPV) response from as low as 1 CFU of Mtb bacilli DNA input material, having shown its exquisite sensitivity over a conventional gel based readout. The translation of our assay onto a portable potentiostat was also demonstrated, with promising results. We believe that our assay has significant potential for translation into broader bioassay applications or development as a POC diagnostic tool.