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Durability of a lubricant-infused surface (LIS) is critical for heat transfer, especially in condensation-based applications. Although LIS promotes dropwise condensation, each departing droplet condensate acts as a lubricant-depleting agent due to the formation of wetting ridge and cloaking layer around the condensate, thus gradually leading to drop pinning on the underlying rough topography. Condensation heat transfer further deteriorates in the presence of non-condensable gases (NCGs) requiring special experimental arrangements to eliminate NCGs due to a decrease in the availability of nucleation sites. To address these issues while simultaneously improving heat-transfer performance of LIS in condensation-based systems, we report fabrication of both fresh LIS and a lubricant-depleted LIS using silicon porous nanochannel wicks as an underlying substrate. Strong capillarity in the nanochannels helps retain silicone oil (polydimethylsiloxane) on the surface even after it is severely depleted under tap water. The effect of oil viscosity was investigated for drop mobility and condensation heat transfer under ambient conditions, i.e., in the presence of NCGs. While fresh LIS prepared using 5 cSt silicone oil exhibited a low roll-off angle (â¼1°) and excellent water drop (5 µL) sliding velocity â¼66 mm s-1, it underwent rapid depletion as compared to higher viscosity oils. Condensation performed on depleted nanochannel LIS with higher viscosity oil (50 cSt) resulted in a heat-transfer coefficient (HTC) of â¼2.33 kW m-2 K-1, which is a â¼162% improvement over flat Si-LIS (50 cSt). Such LIS promote fast drop shedding as is evident from the little change in the fraction of drops with diameter <500 µm from â¼98% to only â¼93% after 4 h of condensation. Improvement in HTC was also seen in condensation experiments conducted for 3 days where a steady HTC of â¼1.46 kW m-2 K-1 was achieved over the last 2 days. The ability of reported LIS to maintain long-term hydrophobicity and dropwise condensation will aid in designing condensation-based systems with improved heat-transfer performance.
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This article addresses the issue of output-feedback consensus control of multiagent systems under the directed topology and subject to bounded external disturbances. By employing a smooth time-varying function, a distributed practical predefined-time (PPT) observer is developed to estimate the reference trajectory for the entire team (i.e., the leader's state) and a practical preset-time extended-state observer is also proposed to estimate bounded disturbances and unmeasurable system states. Next, a novel continuous and nonsingular PPT consensus control law is designed on the basis of the observers. Furthermore, the designed control protocol can achieve PPT stability, that is, consensus tracking errors are enforced to a neighborhood around zero within a predetermined time, which can be specified a priori, independent of initial states of agents and/or any other design parameters. Finally, illustrative numerical examples, including a comparative one, are provided to demonstrate the performance of the present predefined-time control approach.
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HYPOTHESIS: Transpiration occurs in 100 m tall redwood trees where water is passively pulled against gravity requiring the evaporating liquid meniscus in stomata pores to be under absolute negative pressures of -10 atm or higher. Disjoining pressure can significantly reduce pressure at meniscus in nanopores due to strong surface-liquid molecular interaction. Hence, disjoining pressure should be able to solely govern the transpiration process. SIMULATIONS: Expression of disjoining pressure in a water film is first developed from prior experimental findings. The expression is then implemented in a commercial CFD solver and validated against experimental data for water wicking in nanochannels of height varying from 59 nm to 1 µm. Following the implementation, the transpiration process is simulated in a 3D domain comprising of a nanopore connected to a tube with ground-based water tank, thus mimicking the stomata-xylem-soil pathway in a 100 m tall tree. FINDINGS: Disjoining pressure is found to induce absolute negative pressures as high as -23.5 atm at the evaporating meniscus and can also sustain high evaporation fluxes in nanopore before the meniscus completely dewets. This is the first report to integrate disjoining pressure into continuum simulations and study the transpiration process in a 100 m tall tree using such simulations.
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Transpiración de Plantas , Árboles , Transporte Biológico , Árboles/metabolismo , Agua/metabolismo , Xilema/metabolismoRESUMEN
The disjoining pressure of water was estimated from wicking experiments in 1D silicon dioxide nanochannels of heights of 59, 87, 124, and 1015 nm. The disjoining pressure was found to be as high as â¼1.5 MPa while exponentially decreasing with increasing channel height. Such a relation resulting from the curve fitting of experimentally derived data was implemented and validated in computational fluid dynamics. The implementation was then used to simulate bubble nucleation in a water-filled 59 nm nanochannel to determine the nucleation temperature. Simultaneously, experiments were conducted by nucleating a bubble in a similar 58 nm nanochannel by laser heating. The measured nucleation temperature was found to be in excellent agreement with the simulation, thus independently validating the disjoining pressure relation developed in this work. The methodology implemented here integrates experimental nanoscale physics into continuum simulations thus enabling numerical study of various phenomena where disjoining pressure plays an important role.
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Dióxido de Silicio , Agua , TemperaturaRESUMEN
Voltage-gated sodium channel Nav1.7 robustly expressed in peripheral nociceptive neurons has been considered as a therapeutic target for chronic pain, but there is no selective Nav1.7 inhibitor available for therapy of chronic pain. Ralfinamide has shown anti-nociceptive activity in animal models of inflammatory and neuropathic pain and is currently under phase III clinical trial for neuropathic pain. Based on ralfinamide, a novel small molecule (S)-2-((3-(4-((2-fluorobenzyl) oxy) phenyl) propyl) amino) propanamide (QLS-81) was synthesized. Here, we report the electrophysiological and pharmacodynamic characterization of QLS-81 as a Nav1.7 channel inhibitor with promising anti-nociceptive activity. In whole-cell recordings of HEK293 cells stably expressing Nav1.7, QLS-81 (IC50 at 3.5 ± 1.5 µM) was ten-fold more potent than its parent compound ralfinamide (37.1 ± 2.9 µM) in inhibiting Nav1.7 current. QLS-81 inhibition on Nav1.7 current was use-dependent. Application of QLS-81 (10 µM) caused a hyperpolarizing shift of the fast and slow inactivation of Nav1.7 channel about 7.9 mV and 26.6 mV, respectively, and also slowed down the channel fast and slow inactivation recovery. In dissociated mouse DRG neurons, QLS-81 (10 µM) inhibited native Nav current and suppressed depolarizing current pulse-elicited neuronal firing. Administration of QLS-81 (2, 5, 10 mg· kg-1· d-1, i.p.) in mice for 10 days dose-dependently alleviated spinal nerve injury-induced neuropathic pain and formalin-induced inflammatory pain. In addition, QLS-81 (10 µM) did not significantly affect ECG in guinea pig heart ex vivo; and administration of QLS-81 (10, 20 mg/kg, i.p.) in mice had no significant effect on spontaneous locomotor activity. Taken together, our results demonstrate that QLS-81, as a novel Nav1.7 inhibitor, is efficacious on chronic pain in mice, and it may hold developmental potential for pain therapy.
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Analgésicos/uso terapéutico , Fluorobencenos/uso terapéutico , Canal de Sodio Activado por Voltaje NAV1.7/metabolismo , Neuralgia/tratamiento farmacológico , Bloqueadores del Canal de Sodio Activado por Voltaje/uso terapéutico , Potenciales de Acción/efectos de los fármacos , Animales , Formaldehído , Ganglios Espinales/citología , Ganglios Espinales/efectos de los fármacos , Cobayas , Células HEK293 , Humanos , Inflamación/inducido químicamente , Inflamación/complicaciones , Masculino , Ratones Endogámicos C57BL , Neuralgia/inducido químicamente , Neuralgia/etiología , Neuronas/efectos de los fármacos , Nervios Espinales/lesionesRESUMEN
Droplet wicking and evaporation in porous nanochannels is experimentally studied on a heated surface at temperatures ranging from 35 to 90 °C. The fabricated geometry consists of cross-connected nanochannels of height 728 nm with micropores of diameter 2 µm present at every channel intersection; the pores allow water from a droplet placed on the top surface to wick into the channels. Droplet volume is also varied, and a total of 16 experimental cases are conducted. Wicking characteristics such as wicked distance, capillary pressure, viscous resistance, and propagation coefficients are obtained at all surface temperatures. Evaporation flux from the nanochannels/micropores is estimated from the droplet experiments but is also independently confirmed via a new set of experiments where water is continuously fed to the sample through a microtube so that it matches the evaporation rate. Heat flux as high as â¼294 W/cm2 is achieved from channels and pores. The experimental findings are applied to evaluate the use of porous nanochannel geometry in spray cooling application and is found to be capable of passively dissipating high heat fluxes upto â¼77 W/cm2 at temperatures below nucleation, thus highlighting the thermal management potential of the fabricated geometry.
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Cross-connected buried nanochannels of height â¼728 nm, with micropores of â¼2 µm diameter present at each intersection, are used in this work to numerically and experimentally study droplet-coupled evaporation dynamics at room temperature. The uniformly structured channels/pores, along with their well-defined porosity, allow for computational fluid dynamics simulations and experiments to be performed on the same geometry of samples. A water droplet is placed on top of the sample causing water to wick into the nanochannels through the micropores. After advancing, the meniscus front stabilizes when evaporation flux is balanced with the wicking flux, and it recedes once the water droplet is completely wicked in. Evaporation flux at the meniscus interface of channels/pores is estimated over time, while the flux at the water droplet interface is found to be negligible. When the meniscus recedes in the channels, local contact line regions are found to form underneath the pores, thus rapidly enhancing evaporation flux as a power-law function of time. Temporal variation of wicking flux velocity and pressure gradient in the nanochannels is also independently computed, from which the viscous resistance variation is estimated and compared to the theoretical prediction.
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In this work, molecular dynamics simulations show that liquid in a nanopore can be at thermodynamically stable high pressure even when connected to conventional bulk liquid. Such high pressure is associated with strong surface-liquid interaction. Evaporation of liquid in the pore creates a flow from the low pressure (bulk) region to the high pressure (nanopore) region. Such a counterintuitive flow occurs due to pressure being reduced in the pore from its thermodynamically stable state. The transition from high pressures to negative pressures in thin liquid films is also studied. This work provides insight into a possible mechanism of passive liquid transport in tall trees such as redwoods.
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Nonalcoholic steatohepatitis (NASH) is a leading cause of chronic liver disease worldwide and is characterized by steatosis, inflammation, and fibrosis. The molecular mechanisms underlying NASH development remain obscure. The nuclear receptor small heterodimer partner (Shp) plays a complex role in lipid metabolism and inflammation. Here, we sought to determine SHP's role in regulating steatosis and inflammation in NASH. Shp deletion in murine hepatocytes (ShpHep-/-) resulted in massive infiltration of macrophages and CD4+ T cells in the liver. ShpHep-/- mice developed reduced steatosis, but surprisingly increased hepatic inflammation and fibrosis after being fed a high-fat, -cholesterol, and -fructose (HFCF) diet. RNA-Seq analysis revealed that pathways involved in inflammation and fibrosis are significantly activated in the liver of ShpHep-/- mice fed a chow diet. After having been fed the HFCF diet, WT mice displayed up-regulated peroxisome proliferator-activated receptor γ (Pparg) signaling in the liver; however, this response was completely abolished in the ShpHep-/- mice. In contrast, livers of ShpHep-/- mice had consistent NF-κB activation. To further characterize the role of Shp specifically in the transition of steatosis to NASH, mice were fed the HFCF diet for 4 weeks, followed by Shp deletion. Surprisingly, Shp deletion after steatosis development exacerbated hepatic inflammation and fibrosis without affecting liver steatosis. Together, our results indicate that, depending on NASH stage, hepatic Shp plays an opposing role in steatosis and inflammation. Mechanistically, Shp deletion in hepatocytes activated NF-κB and impaired Pparg activation, leading to the dissociation of steatosis, inflammation, and fibrosis in NASH development.
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Inflamación/patología , Hígado/metabolismo , Hígado/patología , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Enfermedad del Hígado Graso no Alcohólico/patología , Receptores Citoplasmáticos y Nucleares/metabolismo , Animales , Dieta Alta en Grasa , Progresión de la Enfermedad , Eliminación de Gen , Ontología de Genes , Hepatocitos/metabolismo , Hepatocitos/patología , Cirrosis Hepática/genética , Cirrosis Hepática/patología , Ratones Endogámicos C57BL , Ratones Noqueados , FN-kappa B/metabolismo , Enfermedad del Hígado Graso no Alcohólico/genética , PPAR gamma/metabolismo , Transducción de Señal/genética , Transcriptoma/genéticaRESUMEN
Pool boiling is explicitly coupled with nanoscale evaporation by using buried nanochannels of height â¼728 nm and â¼100 nm to enhance critical heat flux (CHF) by â¼105%. Additional menisci and contact line formation in nanochannels are found to be the dominant factors of CHF enhancement. Wicking assists in creating the additional contact line but does not serve as the primary measurable factor in predicting such enhancement based on CFD simulations and wicking experiments. This work provides clarity on the roles of contact line and wicking in boiling heat transfer.
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With improved screening methods, the numbers of abnormal breast lesions diagnosed in women have been increasing over time. However, it remains unclear whether these breast lesions will develop into invasive cancers. To more effectively predict the outcome of breast lesions and determine a more appropriate course of treatment, it is important to understand the underlying mechanisms that regulate progression of non-invasive lesions to invasive breast cancers. A hallmark of invasive breast cancers is the accumulation of fibroblasts. Fibroblast proliferation and activation in the mammary gland is in part regulated by the Transforming Growth Factor beta1 pathway (TGF-ß). In animal models, TGF-ß suppression of CCL2 and CXCL1 chemokine expression is associated with metastatic progression of mammary carcinomas. Here, we show that transgenic overexpression of the Polyoma middle T viral antigen in the mouse mammary gland of C57BL/6 mice results in slow growing non-invasive lesions that progress to invasive carcinomas in a stage dependent manner. Invasive carcinomas are associated with accumulation of fibroblasts that show decreased TGF-ß expression and high levels of CXCL1, but not CCL2. Using co-transplant models, we show that decreased TGF-ß signaling in fibroblasts contribute to mammary carcinoma progression through enhancement of CXCL1/CXCR2 dependent mechanisms. Using cell culture models, we show that CXCL1 mediated mammary carcinoma cell invasion through NF-κB, AKT, Stat3 and p42/44MAPK dependent mechanisms. These studies provide novel mechanistic insight into the progression of pre-invasive lesions and identify new stromal biomarkers, with important prognostic implications.
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Mama/metabolismo , Mama/patología , Quimiocina CXCL1/metabolismo , Fibroblastos/metabolismo , Neoplasias Mamarias Animales/metabolismo , Neoplasias Mamarias Animales/patología , Animales , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Proliferación Celular/fisiología , Progresión de la Enfermedad , Femenino , Fibroblastos/patología , Humanos , Ratones , Ratones Endogámicos C57BL , Células RAW 264.7 , Receptores de Interleucina-8B/metabolismo , Transducción de Señal/fisiología , Factor de Crecimiento Transformador beta/metabolismoRESUMEN
The microlayer thin film is visualized in situ in a vapor bubble during pool boiling. Contrary to current understanding, bubbles originate on hydrophilic and silane-coated hydrophobic surfaces without a three-phase contact line, i.e., the microlayer completely covers the bubble base. The occurrence of such a wetted bubble base is found to be dependent on the liquid-solid interaction. As the bubble grows in time, the film decreases in thickness, eventually forming the contact line and dry region. During this drying out process, curvature at the center of the microlayer shows a cyclical behavior due to competing Marangoni and capillary flows, and is characterized as a "dryout viscosity". After the dry region forms, the mechanism of contact line/microlayer movement of a single bubble on the hydrophilic surface is experimentally determined, and a generalized expression of energy required for its unpinning and movement is defined.
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Nonalcoholic fatty liver disease (NAFLD) is a burgeoning health problem worldwide, ranging from nonalcoholic fatty liver (NAFL, steatosis without hepatocellular injury) to the more aggressive nonalcoholic steatohepatitis (NASH, steatosis with ballooning, inflammation, or fibrosis). Although many studies have greatly contributed to the elucidation of NAFLD pathogenesis, the disease progression from NAFL to NASH remains incompletely understood. Nuclear receptor small heterodimer partner (Nr0b2, SHP) is a transcriptional regulator critical for the regulation of bile acid, glucose, and lipid metabolism. Here, we show that SHP levels are decreased in the livers of patients with NASH and in diet-induced mouse NASH. Exposing primary mouse hepatocytes to palmitic acid and lipopolysaccharide in vitro, we demonstrated that the suppression of Shp expression in hepatocytes is due to c-Jun N-terminal kinase (JNK) activation, which stimulates c-Jun-mediated transcriptional repression of Shp Interestingly, in vivo induction of hepatocyte-specific SHP in steatotic mouse liver ameliorated NASH progression by attenuating liver inflammation and fibrosis, but not steatosis. Moreover, a key mechanism linking the anti-inflammatory role of hepatocyte-specific SHP expression to inflammation involved SHP-induced suppression of NF-κB p65-mediated induction of chemokine (C-C motif) ligand 2 (CCL2), which activates macrophage proinflammatory polarization and migration. In summary, our results indicate that a JNK/SHP/NF-κB/CCL2 regulatory network controls communications between hepatocytes and macrophages and contributes to the disease progression from NAFL to NASH. Our findings may benefit the development of new management or prevention strategies for NASH.
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Modelos Animales de Enfermedad , Inflamación/prevención & control , Cirrosis Hepática/prevención & control , Enfermedad del Hígado Graso no Alcohólico/fisiopatología , Receptores Citoplasmáticos y Nucleares/metabolismo , Animales , Células Cultivadas , Quimiocina CCL2/genética , Quimiocina CCL2/metabolismo , Hepatocitos/metabolismo , Hepatocitos/patología , Humanos , Inflamación/metabolismo , Inflamación/patología , Cirrosis Hepática/metabolismo , Cirrosis Hepática/patología , MAP Quinasa Quinasa 4/genética , MAP Quinasa Quinasa 4/metabolismo , Macrófagos/metabolismo , Macrófagos/patología , Masculino , Ratones , Ratones Endogámicos C57BL , FN-kappa B/genética , FN-kappa B/metabolismo , Receptores Citoplasmáticos y Nucleares/genéticaRESUMEN
Nonalcoholic fatty liver disease (NAFLD) is the most common type of chronic liver disease in the Western countries, affecting up to 25% of the general population and becoming a major health concern in both adults and children. NAFLD encompasses the entire spectrum of fatty liver disease in individuals without significant alcohol consumption, ranging from nonalcoholic fatty liver (NAFL) to nonalcoholic steatohepatitis (NASH) and cirrhosis. NASH is a manifestation of the metabolic syndrome and hepatic disorders with the presence of steatosis, hepatocyte injury (ballooning), inflammation, and, in some patients, progressive fibrosis leading to cirrhosis. The pathogenesis of NASH is a complex process and implicates cell interactions between liver parenchymal and nonparenchymal cells as well as crosstalk between various immune cell populations in liver. Lipotoxicity appears to be the central driver of hepatic cellular injury via oxidative stress and endoplasmic reticulum (ER) stress. This review focuses on the contributions of hepatocytes and nonparenchymal cells to NASH, assessing their potential applications to the development of novel therapeutic agents. Currently, there are limited pharmacological treatments for NASH; therefore, an increased understanding of NASH pathogenesis is pertinent to improve disease interventions in the future.
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Fibrosis/fisiopatología , Hígado/fisiopatología , Enfermedad del Hígado Graso no Alcohólico/fisiopatología , Tejido Parenquimatoso/fisiopatología , Consumo de Bebidas Alcohólicas/fisiopatología , Estrés del Retículo Endoplásmico/fisiología , Fibrosis/inmunología , Hepatocitos/patología , Humanos , Hígado/inmunología , Síndrome Metabólico/fisiopatología , Enfermedad del Hígado Graso no Alcohólico/inmunología , Estrés Oxidativo/inmunología , Estrés Oxidativo/fisiologíaRESUMEN
For over five decades, an enhancement in pool boiling heat transfer has been achieved by altering the surface wetting, wickability, roughness, nucleation site density, and providing separate liquid/vapor pathways. In this work, a new enhancement mechanism based on the early evaporation of the microlayer is discovered and validated. The microlayer is a thin liquid film present at the base of a vapor bubble. The presence of microridges on the silicon dioxide surface partitions the microlayer and disconnects it from the bulk liquid, causing it to evaporate sooner, thus leading to increase in the bubble growth rate, heat transfer, departure frequency, and critical heat flux (CHF). Compared to a plain surface, an â¼120% enhancement in CHF is obtained with only an â¼18% increase in surface area. A CHF enhancement map is developed on the basis of the ridge height and spacing, resulting in three regions of full, partial, and no enhancement. The new mechanism is validated by comparing the growth rate of a laser-created vapor bubble on a ridge-structured surface and a plain surface, and the corresponding prediction of the CHF enhancement is found to be in good agreement with the experimental boiling data. This discovery opens up a new field of CHF enhancement and can potentially be coupled with existing techniques to further push the limits of boiling heat transfer.
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Boiling, a dynamic and multiscale process, has been studied for several decades; however, a comprehensive understanding of the process is still lacking. The bubble ebullition cycle, which occurs over millisecond time-span, makes it extremely challenging to study near-surface interfacial characteristics of a single bubble. Here, we create a steady-state vapor bubble that can remain stable for hours in a pool of sub-cooled water using a femtosecond laser source. The stability of the bubble allows us to measure the contact-angle and perform in-situ imaging of the contact-line region and the microlayer, on hydrophilic and hydrophobic surfaces and in both degassed and regular (with dissolved air) water. The early growth stage of vapor bubble in degassed water shows a completely wetted bubble base with the microlayer, and the bubble does not depart from the surface due to reduced liquid pressure in the microlayer. Using experimental data and numerical simulations, we obtain permissible range of maximum heat transfer coefficient possible in nucleate boiling and the width of the evaporating layer in the contact-line region. This technique of creating and measuring fundamental characteristics of a stable vapor bubble will facilitate rational design of nanostructures for boiling enhancement and advance thermal management in electronics.
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Bile acid (BA) metabolism is tightly controlled by nuclear receptor signaling to coordinate regulation of BA synthetic enzymes and transporters. Here we reveal a molecular cascade consisting of the antiapoptotic protein BCL2, nuclear receptor Shp, and long non-coding RNA (lncRNA) H19 to maintain BA homeostasis. Bcl2 was overexpressed in liver of C57BL/6J mice using adenovirus mediated gene delivery for two weeks. Hepatic overexpression of Bcl2 caused drastic accumulation of serum BA and bilirubin levels and dysregulated BA synthetic enzymes and transporters. Bcl2 reactivation triggered severe liver injury, fibrosis and inflammation, which were accompanied by a significant induction of H19. Bcl2 induced rapid SHP protein degradation via the activation of caspase-8 pathway. The induction of H19 in Bcl2 overexpressed mice was contributed by a direct loss of Shp transcriptional repression. H19 knockdown or Shp re-expression largely rescued Bcl2-induced liver injury. Strikingly different than Shp, the expression of Bcl2 and H19 was hardly detectable in adult liver but was markedly increased in fibrotic/cirrhotic human and mouse liver. We demonstrated for the first time a detrimental effect of Bcl2 and H19 associated with cholestatic liver fibrosis and an indispensable role of Shp to maintain normal liver function.
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Ácidos y Sales Biliares/metabolismo , Hepatopatías/metabolismo , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , ARN Largo no Codificante/metabolismo , Receptores Citoplasmáticos y Nucleares/metabolismo , Animales , Ácidos y Sales Biliares/sangre , Caspasa 8/metabolismo , Línea Celular , Modelos Animales de Enfermedad , Regulación de la Expresión Génica , Células HT29 , Células HeLa , Células Hep G2 , Humanos , Hígado/metabolismo , Hepatopatías/patología , Ratones , Transducción de SeñalRESUMEN
Small heterodimer partner (SHP; NR0B2) is a unique orphan nuclear receptor (NR) that contains a putative ligand-binding domain but lacks a DNA-binding domain. SHP is a transcriptional corepressor affecting diverse metabolic processes including bile acid synthesis, cholesterol and lipid metabolism, glucose and energy homeostasis, and reproductive biology via interaction with multiple NRs and transcriptional factors (TFs). Hepatocellular carcinoma (HCC) is one of the most deadly human cancers worldwide with few therapeutic options and poor prognosis. Recently, it is becoming clear that SHP plays an antitumor role in the development of liver cancer. In this review, we summarize the most recent findings regarding the new SHP interaction partners, new structural insights into SHP's gene repressing activity, and SHP protein posttranslational modifications by bile acids. We also discuss the pleiotropic role of SHP in regulating cell proliferation, apoptosis, DNA methylation, and inflammation that are related to antitumor role of SHP in HCC. Improving our understanding of SHP's antitumor role in the development of liver cancer will provide new insights into developing novel treatments or prevention strategies. Future research will focus on developing more efficacious and specific synthetic SHP ligands for pharmaceutical applications in liver cancer and several metabolic diseases such as hypercholesterolemia, obesity, diabetes, and fatty liver disease.
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Fibroblasts are major cellular components of the breast cancer stroma, and influence the growth, survival and invasion of epithelial cells. Compared to normal tissue fibroblasts, carcinoma associated fibroblasts (CAFs) show increased expression of numerous soluble factors including growth factors and cytokines. However, the mechanisms regulating expression of these factors remain poorly understood. Recent studies have shown that breast CAFs overexpress the chemokine CXCL1, a key regulator of tumor invasion and chemo-resistance. Increased expression of CXCL1 in CAFs correlated with poor patient prognosis, and was associated with decreased expression of TGF-ß signaling components. The goal of these studies was to understand the role of TGF-ß in regulating CXCL1 expression in CAFs, using cell culture and biochemical approaches. We found that TGF-ß treatment decreased CXCL1 expression in CAFs, through Smad2/3 dependent mechanisms. Chromatin immunoprecipitation and site-directed mutagenesis assays revealed two new binding sites in the CXCL1 promoter important for Smad2/3 modulation of CXCL1 expression. Smad2/3 proteins also negatively regulated expression of Hepatocyte Growth Factor (HGF), which was found to positively regulate CXCL1 expression in CAFs through c-Met receptor dependent mechanisms. HGF/c-Met signaling in CAFs was required for activity of NF-κB, a transcriptional activator of CXCL1 expression. These studies indicate that TGF-ß negatively regulates CXCL1 expression in CAFs through Smad2/3 binding to the promoter, and through suppression of HGF/c-Met autocrine signaling. These studies reveal novel insight into how TGF-ß and HGF, key tumor promoting factors modulate CXCL1 chemokine expression in CAFs.
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Quimiocina CXCL1/metabolismo , Fibroblastos/metabolismo , Regulación de la Expresión Génica , Glándulas Mamarias Animales/citología , Transducción de Señal , Factor de Crecimiento Transformador beta1/farmacología , Animales , Mama/metabolismo , Mama/patología , Carcinoma Ductal de Mama/metabolismo , Carcinoma Ductal de Mama/patología , Femenino , Factor de Crecimiento de Hepatocito/metabolismo , Humanos , Glándulas Mamarias Animales/metabolismo , Ratones , Ratones Endogámicos C57BL , Mutagénesis Sitio-Dirigida , Regiones Promotoras Genéticas , Proteínas Proto-Oncogénicas c-met/metabolismo , ARN Interferente Pequeño/metabolismo , Proteína Smad2/metabolismo , Proteína smad3/metabolismo , Células Tumorales CultivadasRESUMEN
OBJECTIVE: To investigate the relationships of electrophysiological characteristics between speech evoked auditory brainstem response (s-ABR) and auditory mismatch negativity (MMN), so as to provide more clues for the mechanism of speech cognitive behavior. METHOD: Thirty-three ears in 33 normal hearing adults were included in this study. Their s-ABR were recorded with speech syllables /da/ at 80 dB HL intensity. Meanwhile, two MMNs were recorded with 1 kHz frequency deviant extent and 40 dB intensity deviant extent in them. The electrophysiological characteristics of s-ABRs and MMNs, as well as the relationships of MMN latencies between s-ABR parameters including latencies in time domain, fundamental frequency(F0) and first formants(F1) in frequency domain were analyzed statistically. RESULT: MMN latency of frequency deviance showed a negative correlation tendency with s-ABR transient components, and it showed a positive trend with sustained components of s-ABR. While MMN latency of intensity deviance showed a positive correlation with s-ABR latency of peak V, A and D respectively, and it negatively showed a correlation with s-ABR latency of other peak s and amplitude of F0 and FI respectively. Only the s-ABR latency of peak F and MMN latency of frequency deviance, and the F0 amplitude of s-ABR and MMN latency of intensity deviance were moderate correlation statistically. CONCLUSION: It was probably the neurons of frequency deviant MMN unmatched the characteristics of frequency with the neurons of s-ABR transient component, but well matched the characteristics of frequency with the neurons of s-ABR sustained component. Similarly, the neurons of intensity deviant MMN probably matched the characteristics of intensity with neurons of different components of s-ABR or not. These results may formed as a valuable clue for further investigation of speech perception and temporal processing abilities.