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1.
Cell Death Dis ; 14(10): 675, 2023 10 13.
Artigo em Inglês | MEDLINE | ID: mdl-37833248

RESUMO

Myoepithelium plays an important role in mammary gland development, but less is known about the molecular mechanism underlying how myoepithelium controls acinus differentiation during gestation. Herein, we found that loss of Kindlin-2 in myoepithelial cells impaired mammary morphogenesis, alveologenesis, and lactation. Using five genetically modified mouse lines combined with single-cell RNA sequencing, we found a Kindlin-2-Stat3-Dll1 signaling cascade in myoepithelial cells that inactivates Notch signaling in luminal cells and consequently drives luminal progenitor commitment to alveolar cells identity. Single-cell profiling revealed that Kindlin-2 loss significantly reduces the proportion of matured alveolar cells. Mechanistically, Kindlin-2 depletion in myoepithelial cells promotes Stat3 activation and upregulates Dll1, which activates the Notch pathway in luminal cells and inhibits luminal progenitor differentiation and maturation during gestation. Inhibition of Notch1 with tangeretin allowed luminal progenitors to regain commitment ability in the pregnant mice with Kindlin-2 depletion in myoepithelium. Taken together, we demonstrated that Kindlin-2 is essential to myoepithelium-controlled luminal progenitors to alveoli transition during gestation.


Assuntos
Células Epiteliais , Glândulas Mamárias Animais , Animais , Feminino , Camundongos , Gravidez , Diferenciação Celular , Células Epiteliais/metabolismo , Epitélio , Lactação
2.
Dalton Trans ; 52(39): 14132-14141, 2023 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-37747221

RESUMO

The optical characteristics of multimode luminescent materials like multimode luminescence (photoluminescence, afterglow, thermoluminescence) and a multi-excitation source (light, thermal, mechanical force) play crucial roles in optical data storage and readout, document security and anticounterfeiting. A higher level of advanced anticounterfeiting may rely on multimode anticounterfeiting materials that can realize multicolor luminescence. Here, a highly integrated multimode and multicolor Y7O6F9:Er3+,Eu3+ material is developed through multiplexing of dual lanthanides in fluorine oxide particles. In photoluminescence and photoluminescence/up-conversion luminescence modes, the material Y7O6F9:Er3+,Eu3+ has the characteristic of excitation wavelength and power dependence. In the photoluminescence mode, under excitation at 254 nm and 365 nm, Y7O6F9:Er3+ and Y7O6F9:Eu3+ showed bright red and green emissions, respectively. In the photoluminescence/up-conversion mode, under the increased excitation power from 0.2 to 2.0 W cm-2, the color of luminescence emission can be finely tuned from red to orange, yellow and green. Taking this unique excitation wavelength-power-dependent luminescence property into account, a multilevel anticounterfeiting device with the Lily pattern was designed. The device readily integrates the advantages of the excitation wavelength-dependent photoluminescence emissions and excitation power-dependent photoluminescence emissions in one overall device. These findings offer unique insight for designing highly integrated multimode, multicolor luminescence materials and advanced anticounterfeiting technology toward a wide variety of applications, particularly multilevel anticounterfeiting devices.

3.
J Fluoresc ; 2023 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-37721706

RESUMO

The development of portable and cost-effective sensing system for Hg2+ quantitation is highly demanded for environmental monitoring. Herein, an on-site, rapid and portable smartphone readout device based Hg2+ sensing system integrating nitrogen-doped carbon quantum dots (NCDs) modified paper strip was proposed, and the physicochemical properties of NCDs were characterized by high resolution TEM, FTIR, UV-vis absorption spectrum and fluorescence spectral analysis. The modified paper strip was prepared via "ink-jet" printing technology and exhibits sensitive fluorescence response to Hg2+ with fluorescence color of bright blue (at the excitation/emission wavelength of 365/440 nm). This portable smartphone-based sensing platform is highly selective and sensitive to Hg2+ with the limit of detection (LOD) of 10.6 nM and the concentration range of 0-130 nM. In addition, the recoveries of tap water and local lake water were in the range of 89.4% to 109%. The cost-effective sensing system based on smartphone shows a great potential for trace amounts of Hg2+ monitoring in environmental water samples.

4.
Cell Rep ; 42(8): 112886, 2023 08 29.
Artigo em Inglês | MEDLINE | ID: mdl-37527040

RESUMO

Cyclin-dependent kinase 4 (CDK4) and retinoblastoma protein (RB) are both important cell-cycle regulators that function in different scenarios. Here, we report that FERM domain-containing 8 (FRMD8) inhibits CDK4 activation and stabilizes RB, thereby causing cell-cycle arrest and inhibiting colorectal cancer (CRC) cell growth. FRMD8 interacts separately with CDK7 and CDK4, and it disrupts the interaction of CDK7 with CDK4, subsequently inhibiting CDK4 activation. FRMD8 competes with MDM2 to bind RB and attenuates MDM2-mediated RB degradation. Frmd8 deficiency in mice accelerates azoxymethane/dextran-sodium-sulfate-induced colorectal adenoma formation. The FRMD8 promoter is hypermethylated, and low expression of FRMD8 predicts poor prognosis in CRC patients. Further, we identify an LKCHE-containing FRMD8 peptide that blocks MDM2 binding to RB and stabilizes RB. Combined application of the CDK4 inhibitor and FRMD8 peptide leads to marked suppression of CRC cell growth. Therefore, using an LKCHE-containing peptide to interfere with the MDM2-RB interaction may have therapeutic value in CDK4/6 inhibitor-resistant patients.


Assuntos
Neoplasias do Colo , Quinases Ciclina-Dependentes , Animais , Camundongos , Neoplasias do Colo/genética , Quinase 4 Dependente de Ciclina/metabolismo , Quinases Ciclina-Dependentes/metabolismo , Fosforilação , Proteína do Retinoblastoma/metabolismo
5.
Dalton Trans ; 52(33): 11649-11657, 2023 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-37552091

RESUMO

In recent years, a series of persistent luminescence materials excitable by blue light have been developed and widely used in many fields such as optical information storage, AC-LEDs, anti-counterfeiting and bio-imaging. However, it is still a long-standing challenge to develop a superior red-emitting persistent phosphor that can be efficiently excited by blue light. In this work, a novel blue-light excited red-emitting persistent phosphor CaCd2Ga2Ge3O12:Pr3+ was successfully synthesized by using a solid-state method, showing excellent luminescence properties. Moreover, the phase purity, crystal structure, photoluminescence spectra, afterglow emission spectra, and three-dimensional thermoluminescence spectrum were successfully investigated. Under 294 nm excitation, photoluminescence spectra show a single orange emission and a series of peaks centered at 492, 537, 568, 614 and 664 nm, which correspond to the 3P0 → 3H4, 3P0 → 3H5, 3P2 → 3H6, 1D2 → 3H4, and 3P0 → 3F2 transitions of Pr3+, respectively. Interestingly, after blue light excitation, the afterglow luminescence exhibits red long emission, which is attributed to the 1D2 → 3H4 transition of Pr3+. Through thermoluminescence spectra and three-dimensional thermoluminescence spectra, we analyze the reasons for the different colors of photoluminescence and afterglow luminescence. The results imply that there are two types of traps, and the depth of shallow traps and deep traps is calculated to be 0.684 and 0.776 eV, respectively. It is worth noting that the photoluminescence is attributed to the 4f2 → 4f5d and f → f transitions of Pr3+, and the afterglow luminescence is ascribed to a tunneling-related process and the transition of electrons from the valence band to the conduction band. The obtained red-emitting persistent phosphors provide a promising pathway toward AC-LEDs, multi-cycle bio-imaging and other fields.

6.
Dalton Trans ; 52(7): 2145-2156, 2023 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-36722897

RESUMO

Luminescent anti-counterfeiting materials have drawn much attention in anti-counterfeiting applications due to their photochemical stability and emission patterns. However, conventional materials majorly use single-mode luminescence, leaving a growing demand for new materials to prevent counterfeiting. In this work, multi-mode anti-counterfeiting is guaranteed from a single luminescent material CaCd2Ga2Ge3O12:Tb3+,Yb3+via a high-temperature solid-state reaction. The experimental result showed that this single material features green luminescence with excellent photoluminescence, afterglow, thermoluminescence, and up-conversion luminescence, which are ascribed to Tb3+ transitions. Upon co-doping with Yb3+ as a sensitiser, the photo-stimuli responsiveness was achieved at 254 and 980 nm excitation sources, respectively, and the thermo-stimuli responsiveness was realised after exposure to UV of 254 nm for 10 s and heating at 45 °C, respectively. The band structure calculation, trap distribution, and effective trap depths were used to explain the luminescence mechanism. Based on the two-stimuli responsiveness and four-state emission performance, we prepared images of optical devices using silk screen printing technology. It was found that the images displayed green emission under different luminescence modes. The results prove that we successfully constructed an advanced luminescence anti-counterfeiting material.

7.
Inorg Chem ; 62(1): 75-86, 2023 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-36574356

RESUMO

The continuously growing significance of information security and authentication has put forward many new requirements and challenges for modern luminescent materials and anti-counterfeiting technologies. Recently, luminescent materials have attracted much attention in this field owing to their legibility, repeatability, multicolor, and multiple stimuli-responsive nature. In this work, the efficient multicolor and multimodal luminescence material CaCd2Ga2Ge3O12:Mn2+ was successfully designed and synthesized using the strategy of single-doped Mn2+ in a single matrix. Also, we combined the morphology, crystal structure, energy band calculation, luminescence properties, and trap analysis to study the optical data storage capacity of CaCd2Ga2Ge3O12:Mn2+. Interestingly, in the presence of the 254 nm UV lamp, the sample can exhibit a tunable emission color from bule to cyan to yellow by increasing the dopant concentration of Mn2+. Also, under the afterglow and thermoluminescence luminescence modes, it presented strong yellow emission centered at 558 nm. Based on the advantage of multiple tunable luminescence, samples were made into anti-counterfeiting ink and were used to print four optical devices through the screen printing technology. The results show that the material has excellent multicolor anti-counterfeiting properties under the three luminescence modes, which has contributed to the development of many kinds of luminescent anti-counterfeiting materials for security purposes.


Assuntos
Luminescência , Humanos , Manganês , Germânio , Cádmio , Cálcio
8.
Adv Mater ; 34(43): e2205414, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-36042002

RESUMO

Electrochemical generation of hydrogen peroxide (H2 O2 ) by two-electron oxygen reduction offers a green method to mitigate the current dependence on the energy-intensive anthraquinone process, promising its on-site applications. Unfortunately, in alkaline environments, H2 O2 is not stable and undergoes rapid decomposition. Making H2 O2 in acidic electrolytes can prevent its decomposition, but choices of active, stable, and selective electrocatalysts are significantly limited. Here, the selective and efficient two-electron reduction of oxygen toward H2 O2 in acid by a composite catalyst that is composed of black phosphorus (BP) nailed chemically on the metallic cobalt diselenide (CoSe2 ) surface is reported. It is found that this catalyst exhibits a 91% Faradic efficiency for H2 O2 product at an overpotential of 300 mV. Moreover, it can mediate oxygen to H2 O2 with a high production rate of ≈1530 mg L-1 h-1 cm-2 in a flow-cell reactor. Spectroscopic and computational studies together uncover a BP-induced surface charge redistribution in CoSe2 , which leads to a favorable surface electronic structure that weakens the HOO* adsorption, thus enhancing the kinetics toward H2 O2 formation.

9.
Cell Rep ; 40(8): 111210, 2022 08 23.
Artigo em Inglês | MEDLINE | ID: mdl-36001969

RESUMO

HOXB9 is an important transcription factor associated with unfavorable outcomes in patients with lung adenocarcinoma (LUAD). However, its degradation mechanism remains unclear. Here, we show that HOXB9 is a substrate of AMP kinase alpha (AMPKα). AMPK mediates HOXB9 T133 phosphorylation and downregulates the level of HOXB9 in mice and LUAD cells. Mechanistically, phosphorylated HOXB9 promoted E3 ligase Praja2-mediated HOXB9 degradation. Blocking HOXB9 phosphorylation by depleting AMPKα1/2 or employing the HOXB9 T133A mutant promoted tumor cell growth in cell culture and mouse xenografts via upregulation of HOXB9 and KRAS that is herein identified as a target of HOXB9. Clinically, AMPK activation levels in LUAD samples were positively correlated with pHOXB9 levels; higher pHOXB9 levels were associated with better survival of patients with LUAD. We thus present a HOXB9 degradation mechanism and demonstrate an AMPK-HOXB9-KRAS axis linking glucose-level-regulated AMPK activation to HOXB9 stability and KRAS gene expression, ultimately controlling LUAD progression.


Assuntos
Adenocarcinoma de Pulmão , Adenocarcinoma , Neoplasias Pulmonares , Proteínas Quinases Ativadas por AMP/metabolismo , Adenocarcinoma/patologia , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/patologia , Animais , Regulação Neoplásica da Expressão Gênica , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Humanos , Neoplasias Pulmonares/patologia , Camundongos , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteínas Proto-Oncogênicas p21(ras)/metabolismo
10.
Phys Chem Chem Phys ; 24(28): 17116-17120, 2022 Jul 21.
Artigo em Inglês | MEDLINE | ID: mdl-35791889

RESUMO

A good oxygen reduction reaction (ORR) catalyst should be stable and active under electrochemical reaction conditions. Niobium pentaoxide (Nb2O5) is known to be stable under ORR conditions. However it has a large band gap, which makes conductivity a challenge during the reaction. In this work, we aim to understand if surface modification of the 110 facet of niobium pentaoxide with transition metal doping has any effect on its ORR activity and conductivity. While the problem of conductivity in the case of transition metal oxides (TMOs) can be partially rectified by transition metal doping, it has negligible influence on the ORR activity of the doped systems.

11.
Adv Sci (Weinh) ; 9(27): e2201916, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35869034

RESUMO

Exploring low cost, highly active, and durable electrocatalysts for oxygen evolution reaction (OER) is of prime importance to boost energy conversion efficiency. Perovskite fluorides are emerging as alternative electrocatalysts for OER, however, their intrinsically active sites during real operation are still elusive. Herein, the self-reconstruction on newly designed NiFe coupled perovskite fluorides during OER process is demonstrated. In situ Raman spectroscopy, ex situ X-ray absorption spectroscopy, and theoretical calculation reveal that Fe incorporation can significantly activate the self-reconstruction of perovskite fluorides and efficiently lower the energy barrier of OER. Benefiting from self-reconstruction and low energy barrier, the KNi0.8 Fe0.2 F3 @nickel foam (KNFF2@NF) electrocatalyst delivers an ultralow overpotential of 258 mV to afford 100 mA cm-2 and an excellent durability for 100 h, favorably rivaling most the state-of-the-art OER electrocatalysts. This protocol provides the fundamental understanding on OER mechanism associated with surface reconstruction for perovskite fluorides.

12.
Nat Commun ; 13(1): 2382, 2022 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-35501341

RESUMO

The need for efficient ammonia synthesis is as urgent as ever. Over the past two decades, many attempts to find new catalysts for ammonia synthesis at mild conditions have been reported and, in particular, many new promoters of the catalytic rate have been introduced beyond the traditional K and Cs oxides. Herein, we provide an overview of recent experimental results for non-traditional promoters and develop a comprehensive model to explain how they work. The model has two components. First, we establish what is the most likely structure of the active sites in the presence of the different promoters. We then show that there are two effects dictating the catalytic activity. One is an electrostatic interaction between the adsorbed promoter and the N-N dissociation transition state. In addition, we identify a new promoter effect for magnetic catalysts giving rise to an anomalously large lowering of the activation energy opening the possibility of finding new ammonia synthesis catalysts.

13.
Nat Commun ; 13(1): 2294, 2022 Apr 28.
Artigo em Inglês | MEDLINE | ID: mdl-35484271

RESUMO

Developing non-noble catalysts with superior activity and durability for oxygen evolution reaction (OER) in acidic media is paramount for hydrogen production from water. Still, challenges remain due to the inadequate activity and stability of the OER catalyst. Here, we report a cost-effective and stable manganese oxybromide (Mn7.5O10Br3) catalyst exhibiting an excellent OER activity in acidic electrolytes, with an overpotential of as low as 295 ± 5 mV at a current density of 10 mA cm-2. Mn7.5O10Br3 maintains good stability under operating conditions for at least 500 h. In situ Raman spectroscopy, X ray absorption near edge spectroscopy, and density functional theory calculations confirm that a self-oxidized surface with enhanced electronic transmission capacity forms on Mn7.5O10Br3 and is responsible for both the high catalytic activity and long-term stability during catalysis. The development of Mn7.5O10Br3 as an OER catalyst provides crucial insights into the design of non-noble metal electrocatalysts for water oxidation.

14.
ACS Nano ; 16(4): 6334-6348, 2022 Apr 26.
Artigo em Inglês | MEDLINE | ID: mdl-35377139

RESUMO

The development of inexpensive and abundant catalysts with high activity, selectivity, and stability for the oxygen reduction reaction (ORR) is imperative for the widespread implementation of fuel cell devices. Herein, we present a combined theoretical-experimental approach to discover and design first-row transition metal antimonates as excellent electrocatalytic materials for the ORR. Theoretically, we identify first-row transition metal antimonates─MSb2O6, where M = Mn, Fe, Co, and Ni─as nonprecious metal catalysts with good oxygen binding energetics, conductivity, thermodynamic phase stability, and aqueous stability. Among the considered antimonates, MnSb2O6 shows the highest theoretical ORR activity based on the 4e- ORR kinetic volcano. Experimentally, nanoparticulate transition metal antimonate catalysts are found to have a minimum of a 2.5-fold enhancement in intrinsic mass activity (on transition metal mass basis) relative to the corresponding transition metal oxide at 0.7 V vs RHE in 0.1 M KOH. MnSb2O6 is the most active catalyst under these conditions, with a 3.5-fold enhancement on a per Mn mass activity basis and 25-fold enhancement on a surface area basis over its antimony-free counterpart. Electrocatalytic and material stability are demonstrated over a 5 h chronopotentiometry experiment in the stability window identified by theoretical Pourbaix analysis. This study further highlights the stable and electrically conductive antimonate structure as a framework to tune the activity and selectivity of nonprecious metal oxide active sites for ORR catalysis.

15.
ChemSusChem ; 14(18): 3967-3974, 2021 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-34324265

RESUMO

Cu2 S is a promising solar energy conversion material owing to its good optical properties, elemental earth abundance, and low cost. However, simple and cheap methods to prepare phase-pure and photo-active Cu2 S thin films are lacking. This study concerns the development of a cost-effective and high-throughput method that consists of dissolving high-purity commercial Cu2 S powder in a thiol-amine solvent mixture followed by spin coating and low-temperature annealing to obtain phase-pure crystalline low chalcocite Cu2 S thin films. After coupling with a CdS buffer layer, a TiO2 protective layer and a RuOx hydrogen evolution catalyst, the champion Cu2 S photocathode gives a photocurrent density of 2.5 mA cm-2 at -0.3 V vs. reversible hydrogen electrode (VRHE ), an onset potential of 0.42 VRHE , and high stability over 12 h in pH 7 buffer solution under AM1.5 G simulated sunlight illumination (100 mW cm-2 ). This is the first thiol-amine-based ink deposition strategy to prepare phase-pure Cu2 S thin films achieving decent photoelectrochemical performance, which will facilitate its future scalable application for solar-driven hydrogen fuel production.

16.
Cell Death Dis ; 12(6): 604, 2021 06 11.
Artigo em Inglês | MEDLINE | ID: mdl-34117213

RESUMO

Kindlin-2 is known to play important roles in the development of mesoderm-derived tissues including myocardium, smooth muscle, cartilage and blood vessels. However, nothing is known for the role of Kindlin-2 in mesoderm-derived reproductive organs. Here, we report that loss of Kindlin-2 in Sertoli cells caused severe testis hypoplasia, abnormal germ cell development and complete infertility in male mice. Functionally, loss of Kindlin-2 inhibits proliferation, increases apoptosis, impairs phagocytosis in Sertoli cells and destroyed the integration of blood-testis barrier structure in testes. Mechanistically, Kindlin-2 interacts with LATS1 and YAP, the key components of Hippo pathway. Kindlin-2 impedes LATS1 interaction with YAP, and depletion of Kindlin-2 enhances LATS1 interaction with YAP, increases YAP phosphorylation and decreases its nuclear translocation. For clinical relevance, lower Kindlin-2 expression and decreased nucleus localization of YAP was found in SCOS patients. Collectively, we demonstrated that Kindlin-2 in Sertoli cells is essential for sperm development and male reproduction.


Assuntos
Proteínas do Citoesqueleto/fisiologia , Fertilidade/genética , Proteínas Musculares/fisiologia , Testículo/crescimento & desenvolvimento , Animais , Células Cultivadas , Proteínas do Citoesqueleto/genética , Proteínas do Citoesqueleto/metabolismo , Células HEK293 , Humanos , Infertilidade Masculina/genética , Infertilidade Masculina/metabolismo , Infertilidade Masculina/patologia , Masculino , Camundongos , Camundongos Transgênicos , Proteínas Musculares/genética , Proteínas Musculares/metabolismo , Células de Sertoli/metabolismo , Células de Sertoli/fisiologia , Testículo/metabolismo
17.
Inorg Chem ; 59(21): 15681-15689, 2020 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-33064941

RESUMO

With the rapid development of technology, information security has always been considered a major challenge. In this work, the excellent combination of persistent luminescence, photoluminescence, up-conversion luminescence, and thermo-luminescence in a particular material Zn4B6O13:Tb3+,Yb3+ synthesized via a solid-state reaction is reported, which can be used for the information encryption and anti-counterfeiting. Tb3+ ions were chosen as the emitting centers for multimodal emissions, and Yb3+ codoping can be used as electron traps and sensitizer to adjust trap distribution and efficient up-conversion luminescence in rare-earth-doped luminescent materials. Besides, the as-prepared luminescent materials exhibit high thermal stability and excellent water resistance. On the basis of these properties, the samples were used to print luminescent images through a screen printing process on the film and banknote. The luminescent image in a film is showing different patterns and on a banknote is showing green emissions under different stimulations. These multimodal emissions demonstrate that the as-prepared sample is suitable for advanced information encryption and anti-counterfeiting.

18.
Huan Jing Ke Xue ; 41(2): 620-629, 2020 Feb 08.
Artigo em Chinês | MEDLINE | ID: mdl-32608720

RESUMO

Temporal evolution of black carbon (BC) in Nanjing was studied along with its main influencing factors. The multi-wavelength aethalometer (AE-33) was used to select the typical month of each season to observe BC mass concentration, combined with atmospheric pollutant data, meteorological elements, and boundary layer detection data. Seasonal, daily, weekly trends, and source characteristics of BC were analyzed. The results showed that the BC concentration in Nanjing had obvious seasonal changes, which were higher in spring and winter, in the decreasing order:spring[(3351±919) ng·m-3] > winter[(3234±2102) ng·m-3] > in autumn[(3064±967) ng·m-3] > summer[(2632±1705) ng·m-3]. The diurnal changes in BC during the four seasons are bimodal, with peaks at 06:00-08:00 and 21:00-23:00. The morning and evening peak distribution characteristics of BC in different seasons are different. The peak concentration of BC was highest in the early morning peak spring and the highest in the late peak winter. The morning peak timing of winter is 2 h behind other seasons, while the summer peak timing is 2 h ahead of other seasons. The effect of the wind speed on the seasonal distribution of BC diurnal variation is significantly larger than that on RH. The mechanism of the influence of the inversion layer on the concentration of atmospheric pollutants is complicated. The effects of height, thickness, and temperature of the inversion layer on the pollutants are different in different seasons. Weekly BC effects vary seasonally. The effect of RH and wind speed on the weekly BC effect is small, and the difference in the inversion layer is the main reason behind it. Liquid fuel combustion in Nanjing has a greater contribution to BC, whereas solid combustion contributes by a lesser extent.

19.
Theranostics ; 10(14): 6182-6200, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32483447

RESUMO

Rationale: Smooth muscle-motility disorders are mainly characterized by impaired contractility and functional intestinal obstruction. Some of these cases are caused by genetic mutations of smooth muscle genes ACTA2, ACTG2, MYH11, MYLK and LMOD1. Still the etiology is complex and multifactorial and the underlying pathology is poorly understood. Integrin interaction protein Kindlin-2 is widely expressed in striated and smooth muscle cells (SMC). However, the function of Kindlin-2 in the smooth muscle remains elusive. Methods: We generated two mouse models using different cre promoter transgenic mice, Kindlin-2fl/fl SM22α-cre+ (cKO mice) and Kindlin-2fl/fl; MYH-cre+ (iKO mice). Embryos and adult tissues were prepared for hematoxylin and eosin (H&E) staining, immunohistochemistry (IHC) and terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) apoptosis assay. We investigated ultrastructure changes of mouse smooth muscle using transmission electron microscopy (TEM) and measured smooth muscle contractile force in mounting aortic and intestinal rings using the multiwire myograph system (DMT 620M). In addition, cell traction force microscopy (CTFM) was applied to observe the functional change of primary SMC after Kindlin-2 depletion by RNAi. Results: Depletion of Kindlin-2 encoding gene Fermt2 in embryonic smooth muscles leads to apoptosis, downregulates the key components of SMC, impairs smooth muscle development, and finally causes embryonic death at E14.5. Tamoxifen-induced Kindlin-2-specific knockout in adult mouse smooth muscle showed decreased blood pressure, intestinal hypoperistalsis, and eventually died of intestinal obstruction. Kindlin-2 depletion also leads to downregulated Myh11, α-SMA, and CNN, shortened myofilament, broken myofibrils, and impaired contractility of the smooth muscles in iKO mice. Mechanistically, loss of Kindlin-2 decreases Ca2+ influx in primary vascular smooth muscle cells (PVSMC) by downregulating the expression of calcium-binding protein S100A14 and STIM1. Conclusion: We demonstrated that Kindlin-2 is essential for maintaining the normal structure and function of smooth muscles. Loss of Kindlin-2 impairs smooth muscle formation during embryonic development by inducing apoptosis and jeopardizes the contraction of adult smooth muscle by blocking Ca2+ influx that leads to intestinal obstruction. Mice with Kindlin-2 depletion in adult smooth muscle could be a potent animal model of intestinal obstruction for disease research, drug treatment and prognosis.


Assuntos
Proteínas de Ligação ao Cálcio/metabolismo , Proteínas do Citoesqueleto/deficiência , Obstrução Intestinal/patologia , Proteínas Musculares/deficiência , Músculo Liso/patologia , Animais , Movimento Celular , Proteínas do Citoesqueleto/genética , Modelos Animais de Doenças , Obstrução Intestinal/etiologia , Obstrução Intestinal/metabolismo , Camundongos , Camundongos Knockout , Contração Muscular , Proteínas Musculares/genética , Músculo Liso/metabolismo
20.
Cell Mol Biol (Noisy-le-grand) ; 66(3): 65-71, 2020 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-32538749

RESUMO

Intervertebral Disc (IVD) is a moderately moving joint that provides load transfer and flexibility to the entire spine. Although healthy IVD can balance the turnover of slow-synthesis matrices, this balance is often disrupted that leading to the development of degenerative diseases. The pathogenesis and treatment mechanism of Intervertebral Disc Degeneration (IDD) has always been the focus of scientific research, but its pathogenesis is still unknown. Therefore, this study is based on a modular approach to in-depth analysis and explore the genes of IDD, intended to identify the molecular process of disc degeneration. Firstly, the data related to Intervertebral Disc Degeneration and normal intervertebral disc were downloaded from the GEO database. The differential analysis of two kinds of data was performed to obtain differential gene expression profiles. Secondly, mapping those differential genes to Cytoscape to construct protein-protein interaction networks (PPIs). Then, the module gene was subjected to enrichment analysis of GO function and KEGG pathway. Finally, non-coding RNAs (ncRNAs) and transcription factors that regulate the module are predicted based on hypergeometric testing. In summary, we identified 22 co-expression modules, and the enrichment analysis results revealed that the module genes were significantly involved in the regulation of definite biotic procedures. In conclusion, we recognized the ncRNA pivot (including miR-193b-3p, CRNDE, etc.) and TF pivot (including E2F1, E2F4, etc.) that significantly regulate dysfunction modules.


Assuntos
Degeneração do Disco Intervertebral/etiologia , Ontologia Genética , Redes Reguladoras de Genes , Humanos , Disco Intervertebral/patologia , Degeneração do Disco Intervertebral/genética , Degeneração do Disco Intervertebral/patologia , RNA não Traduzido/genética , RNA não Traduzido/metabolismo , Fatores de Transcrição/metabolismo
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