To investigate the impact of establishing regional collaborative network on reperfusion time and prognosis of patients with ST-segment elevated myocardial infarction (STEMI) admitting to community hospitals without percutaneous coronary intervention (PCI) capacity (Non-PCI hospital).
Fouling control is one of the critical issues in membrane filtration and plays a very important role in water/wastewater treatment. Better understanding of the underlying fouling mechanisms entails novel characterization techniques that can realize a real-time non-invasive observation and provide high resolution images recording the formation of a fouling layer. This work presents a characterization method based on optical coherence tomography (OCT), which is able to detect the internal structures and motions by analyzing the interference signals. An OCT system was incorporated with a lab-scale membrane filtration system, and the growth of the fouling layer was observed by using the structural imaging. Taking advantage of the Doppler effects, the OCT-based characterization also provided the velocity profiles of the fluid field, which are of great value in analyzing the formation of the cake layer. The characterization results clearly reveal for the first time the evolution of the morphology of the cake layer under different micro-hydrodynamic environments. This study demonstrates that OCT-based characterization is a powerful tool for investigating the dynamic processes during membrane fouling.
The mechanism of dual 1,3-dipolar cycloaddition reaction of CO2 with isocyanides and alkynes was studied using DFT calculations. The calculations show that this three-component reaction takes place from the nucleophilic attack of isocyanides to alkynes with the generation of 1,3-dipolar active species, which requires the largest energy barrier (24.3 kcal mol(-1)) and can be regarded as the rate-determining step for the entire reaction. From 1,3-dipolar species, the desired spiro compound is obtained through the energy-favorable dual 1,3-dipolar cycloaddition channel, including successive asynchronous concerted cycloaddition of CO2 with the 1,3-dipole and cycloaddition of 1,3-dipole with the resultant lactone. Additionally, the competing nucleophilic addition of 1,3-dipole with alkynes could lead to the production of 1,5-dipolar intermediate, which will alternatively react with isocyanides or CO2 and generate several byproducts. The investigations on the substituent effect of both substrates indicate that the substituents on alkynes play the more significant roles in controlling the rate and selectivity of the reaction than those on isocyanides. The moderate electron-withdrawing and conjugate groups on alkynes not only favor the generation of the 1,3-dipole, but also stabilize the negative charge on these species without losing reactivity.
We analyze the effects of turbulence on the detection probability spectrum and the mode weight of the orbital angular momentum (OAM) for Whittaker-Gaussian (WG) laser beams in weak non-Kolmogorov turbulence channels. Our numerical results show that WG beam is a better light source for mitigating the effects of turbulence with several adjustable parameters. The real parameters of WG beams ? and W0, which have significant effects on the mode weight, have no influence on the detection probability spectrum. Larger signal OAM quantum number, shorter wavelength, smaller beamwidth and coherence length will lead to the lower detection probability of the signal OAM mode.
Previous studies have found that Danhong injection (DHI), an extensively used herbal extract preparation in China, might be a powerful vasodilator. The aims of the present study were to determine the vascular activity of DHI and its effects on arteries of different sizes. The results showed that DHI significantly inhibited rat-hindquarters and rabbit-ear vasoconstriction elicited by norepinephrine (NE) perfusion, and markedly relaxed KCl-contracted and NE-contracted rat abdominal aortic and mesenteric artery rings. The endothelium made only a minor contribution to the vasorelaxant effect of DHI on artery segments. The vasorelaxant effect of DHI varied with the artery size, with larger arteries exhibiting a more sensitive and potent vasodilator response. DHI relaxed NE-induced vasoconstriction probably via inhibition of the intracellular Ca release through the inositol triphosphate receptor system in the abdominal aorta and mesenteric artery, along with blockage of extracellular Ca influx through the receptor-linked Ca channels in the mesenteric artery. In addition, DHI completely relaxed KCl-induced contraction in both of the arteries, suggesting that inhibition of Ca influx through voltage-gated Ca channels is involved in the vasorelaxant effect of DHI. This elucidation of the vascular effects of DHI and the underlying mechanisms could lead to improved clinical applications.
Background. Reports on the association of prediabetes with all-cause mortality and cardiovascular mortality are inconsistent. Objective. To evaluate the risk of all-cause and cardiovascular mortality in association with impaired fasting glucose (IFG) and impaired glucose tolerance (IGT). Methods. Prospective cohort studies with data on prediabetes and mortality were included. The relative risks (RRs) of all-cause and cardiovascular mortality were calculated and reported with 95% confidence intervals (95% CIs). Results. Twenty-six studies were included. The risks of all-cause and cardiovascular mortality were increased in participants with prediabetes defined as IFG of 110-125 mg/dL (IFG 110) (RR 1.12, 95% CI 1.05-1.20; and RR 1.19, 95% CI 1.05-1.35, respectively), IGT (RR 1.33, 95% CI 1.24-1.42; RR 1.23, 95% CI 1.11-1.36, respectively), or combined IFG 110 and/or IGT (RR 1.21, 95% CI 1.11-1.32; RR 1.21, 95% CI 1.07-1.36, respectively), but not when IFG was defined as 100-125 mg/dL (RR 1.07, 95% CI 0.92-1.26; and RR 1.16, 95% CI 0.94-1.42, respectively). Conclusions. Prediabetes, defined as IFG 110, IGT, or combined IFG 110 and/or IGT, was associated with increased all-cause and cardiovascular mortality.
Polycystic ovarian syndrome (PCOS), the most common female endocrine disorder of unknown etiology, is characterized by reproductive abnormalities and associated metabolic conditions comprising insulin resistance, type 2 diabetes mellitus, and dyslipidemia. We previously reported that transgenic overexpression of nerve growth factor (NGF), a marker of sympathetic hyperactivity, directed to the ovary by the mouse 17?-hydroxylase/C17-20 lyase promoter (17NF mice), results in ovarian abnormalities similar to those seen in PCOS women. To investigate whether ovarian overproduction of NGF also induces common metabolic alterations of PCOS, we assessed glucose homeostasis by glucose tolerance test, plasma insulin levels, and body composition by dual-energy x-ray absorptiometry scan in young female 17NF mice and wild-type mice. 17NF mice exhibited increased body weight and alterations in body fat distribution with a greater accumulation of visceral fat compared with sc fat (P < .01). 17NF mice also displayed glucose intolerance (P < .01), decreased insulin-mediated glucose disposal (P < .01), and hyperinsulinemia (P < .05), which, similar to PCOS patients, occurred independently of body weight. Additionally, 17NF mice exhibited increased sympathetic outflow observed as increased interscapular brown adipose tissue temperature. This change was evident during the dark period (7 pm to 7 am) and occurred concomitant with increased interscapular brown adipose tissue uncoupling protein 1 expression. These findings suggest that overexpression of NGF in the ovary may suffice to cause both reproductive and metabolic alterations characteristic of PCOS and support the hypothesis that sympathetic hyperactivity may contribute to the development and/or progression of PCOS.
While Scanning Tunneling Microscopy (STM) has evolved as an ideal tool to study surface chemistry at the atomic scale, the identification of adsorbed species is often not straightforward. This paper describes a way to reliably identify H2O, CO and O2 on the TiO2 anatase (101) surface with STM. These molecules are of a key importance in the surface chemistry of this and many other (photo-) catalytic materials. They exhibit a wide variety of contrasts in STM images, depending on the tip condition. With clean, metallic tips the molecules appear very similar, i.e., as bright, dimer-like features located in the proximity of surface Ti5c atoms. However, each species exhibits a specific response to the electric field applied by the STM tip. It is shown that this tip-adsorbate interaction can be used to reliably ascertain the identity of such species. The tip-adsorbate interactions, together with comparison of experimental and calculated STM images, are used to analyse and revisit the assignments of molecular adsorbed species reported in recent studies.
In premenopausal and menopausal women in particular, suboptimal estrogens have been linked to the development of the metabolic syndrome as major contributors to fat accumulation. At the same time, estrogens have been described to have a role in regulating body metabolic status. We evaluated how endogenous or administered estrogens impact on the changes associated with high-fat diet (HFD) consumption in 2 different paradigms; ovarian-intact and in ovariectomized mice. When estradiol (E2) was cyclically administered to ovarian-intact HFD-fed mice for 12 weeks, animals gained significantly less weight than ovarian-intact vehicle controls (P < .01). This difference was mainly due to a reduced caloric intake but not to an increase in energy expenditure or locomotor activity. This E2 treatment regime to mice exposed to HFD was overall able to avoid the increase of visceral fat content to levels of those found in mice fed a regular chow diet. In the ovariectomized model, the main body weight and fat content reducing action of E2 was not only through decreasing food intake but also by increasing the whole-body energy expenditure, locomotor activity, and by inducing fat oxidation. Importantly, these animals became responsive to the anorexigenic effects of leptin in contrast to the vehicle-treated and the pair-fed control groups (P < .01). Further, in vitro hypothalamic secretion experiments revealed that treatment of obese mice with E2 is able to modulate the secretion of appetite-regulating neuropeptides; namely, E2 increased the secretion of the anorectic neuropeptide ?-melanocyte-stimulating hormone and decreased the secretion of the orexigenic neuropetides neuropeptide Y and Agouti-related peptide. In conclusion, differences in response to E2 treatment of HFD-fed animals depend on their endogenous estrogenic status. Overall, E2 administration overcomes arcuate leptin resistance and partially prevents fat accumulation on these mice.
Fabrication of bioactive and mechanical matched bone substitutes is crucial for clinical application in bone defects repair. In this study, nano-hydroxyapatite/polyamide (nHA/PA) composite was coated on injection-moulded PA by a chemical corrosion and phase-inversion technique. The shear strength, gradient composition and pore structure of the bioactive coating were characterized. Osteoblast-like MG63 cells were cultured on pure PA and composite-coated PA samples. The cells' adhesion, spread and proliferation were determined using MTT assay and microscopy. The results confirm that the samples with the nHA/PA composite coating have better cytocompatibility and have no negative effects on cells. To investigate the in vivo biocompatibility, both pure PA and composite-coated PA cylinders were implanted in the trochlea of rabbit femurs and studied histologically, and the bonding ability with bone were determined using push-out tests. The results show that composite-coated implants exhibit better biocompatibility and the shear strength of the composite-coated implants with host bone at 12 weeks can reach 3.49±0.42 MPa, which is significantly higher than that of pure PA implants. These results indicate that composite-coated PA implants have excellent biocompatibility and bonding abilities with host bone and they have the potential to be applied in repair of bone defects.
Tetrandrine (TET) is a bisbenzylisoquinoline alkaloid extracted from Stephania tetrandra Moore. Recent studies have suggested that TET can reduce the inflammatory response in microglia, but the mechanisms remain unclear. The aim of this study is to investigate whether TET can inhibit lipopolysaccharide (LPS)-induced microglial activation and clarify its possible mechanisms.
MoS2 is a layered two-dimensional material with strong spin-orbit coupling and long spin lifetime, which is promising for electronic and spintronic applications. However, because of its large band gap and small electron affinity, a considerable Schottky barrier exists between MoS2 and contact metal, hindering the further study of spin transport and spin injection in MoS2. Although substantial progress has been made in improving device performance, the existence of metal-semiconductor Schottky barrier has not yet been fully understood. Here, we investigate permalloy (Py) contacts to both multilayer and monolayer MoS2. Ohmic contact is developed between multilayer MoS2 and Py electrodes with a negative Schottky barrier, which yields a high field-effect mobility exceeding 55?cm(2)V(-1)s(-1) at low temperature. Further, by applying back gate voltage and inserting different thickness of Al2O3 layer between the metal and monolayer MoS2, we have achieved a good tunability of the Schottky barrier height (down to zero). These results are important in improving the performance of MoS2 transistor devices; and it may pave the way to realize spin transport and spin injection in MoS2.
Activated microglia were considered to be the toxic inflammatory mediators that induce neuron degeneration after brain ischemia. Hypoxia can enhance the expression of hypoxia-inducible factor-1? (HIF-1?) in microglia and cause microglial activation. However, intermittent hypoxia has been reported recently to be capable of protecting the body from myocardial ischemia. We established a high-altitude environment as the hypoxic condition in this study. The hypoxic condition displayed a neuroprotective effect after brain ischemia, and mice exposed to this condition presented better neurological performance and smaller infarct size. At the same time, a high level of HIF-1?, low level of isoform of nitric oxide synthase, and a reduction in microglial activation were also seen in ischemic focus of hypoxic mice. However, this neuroprotective effect could be blocked by 2-methoxyestradiol, the HIF-1? inhibitor. Our finding suggested that HIF-1? expression was involved in microglial activation in vitro and was regulated by oxygen supply. The microglia were inactivated by re-exposure to hypoxia, which might be due to overexpression of HIF-1?. These results indicated that hypoxic conditions can be exploited to achieve maximum neuroprotection after brain ischemia. This mechanism possibly lies in microglial inactivation through regulation of the expression of HIF-1?.
This study examined the relation between long-term music training and child development based on 250 Chinese elementary school students' academic development of first language (L1), second language (L2), and mathematics. We found that musician children outperformed non-musician children only on musical achievement and second language development. Additionally, although music training appeared to be correlated with children's final academic development of L1, L2, and mathematics, it did not independently contribute to the development of L1 or mathematical skills. Our findings suggest caution in interpreting the positive findings on the non-musical cognitive benefits of music learning.
Although the repositioning maneuvers are usually very effective in patients with BPPV, some patients still complain residual dizziness. Danhong injection (DHI), a traditional Chinese medicine, can effectively dilate blood vessels and improve microcirculation, and has been proven to be effective in improving cervical vertigo and posterior circulation ischemic vertigo. The aim of this study was to evaluate the effects of DHI on residual dizziness after successful repositioning treatment in patients with BPPV.
The drug DMXAA (5,6-dimethylxanthenone-4-acetic acid) showed therapeutic promise against solid tumors in mouse models but subsequently failed in human clinical trials. DMXAA was later discovered to activate mouse, but not human, STING, an adaptor protein in the cyclic dinucleotide cGAMP-mediated signaling pathway, inducing type I interferon expression. To facilitate the development of compounds that target human STING, we combined structural, biophysical, and cellular assays to study mouse and human chimeric proteins and their interaction with DMXAA. We identified a single substitution (G230I) that enables a DMXAA-induced conformational transition of hSTING from an inactive "open" to an active "closed" state. We also identified a substitution within the binding pocket (Q266I) that cooperates with G230I and the previously identified S162A binding-pocket point substitution, rendering hSTING highly sensitive to DMXAA. These findings should facilitate the reciprocal engineering of DMXAA analogs that bind and stimulate wild-type hSTING and their exploitation for vaccine-adjuvant and anticancer drug development.
Dendritic cells (DCs) are potent antigen-presenting cells (APCs) that are characterized by the ability to take up and process antigens and prime T cell responses. Mesenchymal stem cells (MSCs) are multipotent cells that have been shown to have immunomodulatory abilities, including inhibition of DC maturation and function in vivo and in vitro; however, the underlying mechanism is far from clear. In this study we found that MSCs can inhibit the maturation and function of bone marrow-derived DCs by releasing TSG-6. In the presence of MSCs, lower expression of mature DC surface phenotype (CD80, CD86, MHC-II, and CD11c) was observed. In addition, typical DC functions, such as the production of IL-12 and the ability to prime T cells, were decreased when co-cultured with MSCs. In contrast, knockdown of TSG-6 reduced the inhibitory effect of MSCs on DC. Moreover, we found that TSG-6 can suppress the activation of MAPKs, and NF-?B signaling pathways within DCs during Lipopolysaccharides (LPS) stimulation. In conclusion, we suggest that TSG-6 plays an important role in MSCs-mediated immunosuppressive effect on DC.
HDGF is overexpressed in gliomas as compared to normal brain. We therefore analyzed the molecular mechanisms of HDGF action in gliomas. HDGF was downregulated in normal brain tissue as compared to glioma specimens at both the mRNA and the protein levels. In glioma samples, increased HDGF expression was associated with disease progression. Knocking down HDGF expression not only significantly decreased cellular proliferation, migration, invasion, and tumorigenesis, but also markedly enhanced TMZ-induced cytotoxicity and apoptosis in glioma cells. Mechanistic analyses revealed that CCND1, c-myc, and TGF-? were downregulated after stable HDGF knockdown in the U251 and U87 glioma cells. HDGF knockdown restored E-cadherin expression and suppressed mesenchymal cell markers such as vimentin, ?-catenin, and N-cadherin. The expression of cleaved caspase-3 increased, while Bcl-2 decreased in each cell line following treatment with shHDGF and TMZ, as compared to TMZ alone. Furthermore, RNAi-based knockdown study revealed that HDGF is probably involved in the activation of both the PI3K/Akt and the TGF-? signaling pathways. Together, our data suggested that HDGF regulates glioma cell growth, apoptosis and epithelial-mesenchymal transition (EMT) probably through the Akt and the TGF-? signaling pathways. These results provide evidence that targeting HDGF or its downstream targets may lead to novel therapies for gliomas.
Refractive surgery not only leads to tissue injury but also evokes mechanical stress increase of the cornea. How the mechanical stress affects the corneal matrix remodeling, specifically, matrix metalloproteinases (MMPs) and their inhibitors (tissue inhibitors of metalloproteinases; TIMPs) is not well understood. In this study, cultured rabbit corneal fibroblasts in vitro were subjected to regimen of 5%, 10%, or 15% equibiaxial stretch at 0.1 Hz for 3 or 24?h. MMP-2 protein level was measured by gelatin zymography and Western blotting. MMP-2, membrane type 1 MMP (MT1-MMP), and TIMP-2 mRNA levels were quantified by real-time quantitative PCR. Extracellular regulated protein kinase (ERK) phosphorylation protein levels were assessed by Western blotting. Our results showed that a 15% stretch resulted in increases in MMP-2 protein, MMP-2 mRNA, and MT1-MMP mRNA levels, but a decrease in TIMP-2 mRNA level. However, a 5% stretch caused decreases in MMP-2 protein and mRNA level, but an increase in TIMP-2 mRNA level, and no change in MT1-MMP mRNA level. A 15% stretch also caused a significant increase in ERK1/2 phosphorylation. Inhibition of the mitogenactivated protein kinase (MEK) pathway with PD98059 attenuated stretch-induced increase in MMP-2 production and ERK activity. These results suggest that small-magnitude stretching may promote corneal matrix synthetic events, whereas large-magnitude stretching promotes corneal matrix degradation by changing the balance between MMPs and TIMPs in corneal fibroblasts. Large-magnitude stretch-induced increase in pro-MMP-2 production was in an ERK-dependent manner.
Astrocytes play an important role in the pathogenesis of glaucoma. Abnormal activation and/or proliferation of astrocytes, termed astrogliosis, have been observed during optic nerve degeneration. Our previous study identified signal transducer and activator of transcription 3 (STAT3) signaling as an important regulator of astrogliosis in the optic nerve in a rat transient ischemia/reperfusion model. In this study, we used pharmacological inhibition of STAT3 activation in the same model to assess whether it could attenuate reactive astrogliosis and to observe its influence on optic nerve damage and retinal ganglion cell (RGC) damage. Our findings show that retrobulbar inhibition of STAT3 in optic nerve head astrocytes leads to (a) increased nerve fiber bundle survival in the optic nerve, (b) increased nerve fiber bundle and RGC survival in the retina, (c) decreased astrocyte reactivation in the optic nerve (d) decreased remodeling of astrocytes in the optic nerve, and (e) no influence of astrocyte reactivation inside the retina. Taken together, the Janus kinase/STAT3 pathway contributes to astrocyte reactivation in the optic nerve, which plays a pivotal role in neurodegeneration after transient ischemia/reperfusion in vivo. Inhibition of this pathway provides a potential therapeutic strategy for the treatment of glaucomatous neuropathy, and could extend to other neurodegenerative diseases.
Microglia are the primary immunocompetent cells in brain tissue and microglia-mediated inflammation is associated with the pathogenesis of various neuronal disorders. Recently, many studies have shown that mesenchymal stem cells (MSCs) display a remarkable ability to modulate inflammatory and immune responses through the release of a variety of bioactive molecules, thereby protecting the central nervous system. Previously, we reported that MSCs have the ability to modulate inflammatory responses in a traumatic brain injury model and that the potential mechanisms may be partially attributed to upregulated TNF-? stimulated gene/protein 6 (TSG-6) expression. However, whether TSG-6 exerts an anti-inflammatory effect by affecting microglia is not fully understood. In this study, we investigated the anti-inflammatory effects of MSCs and TSG-6 in an in vitro lipopolysaccharide (LPS)-induced BV2 microglial activation model. We found that MSCs and TSG-6 significantly inhibited the expression of pro-inflammatory mediators in activated microglia. However, MSC effects on microglia were attenuated when TSG-6 expression was silenced. In addition, we found that the activation of nuclear factor (NF)-?B and mitogen-activated protein kinase (MAPK) pathways in LPS-stimulated BV2 microglial cells was significantly inhibited by TSG-6. Furthermore, we found that the presence of CD44 in BV2 microglial cells was essential for MSC- and TSG-6-mediated inhibition of pro-inflammatory gene expression and of NF-?B and MAPK activation in BV2 microglial cells. The results of this study suggest that MSCs can modulate microglia activation through TSG-6 and that TSG-6 attenuates the inflammatory cascade in activated microglia. Our study indicates that novel mechanisms are responsible for the immunomodulatory effect of MSCs on microglia and that MSCs, as well as TSG-6, might be promising therapeutic agents for the treatment of neurotraumatic injuries or neuroinflammatory diseases associated with microglial activation.
High-quality thin films of the topological insulator Bi2-x Sbx Se3 are grown by molecular beam epitaxy. A metal-insulator transition along with strong surface states - revealed by Shubnikov-de Haas oscillations - is observed as the Sb concentration is increased. This system represents a widely tunable platform for achieving high surface conduction, suppressing the bulk influence, and manipulating the band structure of topological insulators.
Recently, extensive efforts have been devoted to the investigations of negative differential resistance (NDR) behavior in graphene. Here, by performing fully self-consistent density functional theory calculations combined with non-equilibrium Green's function technique, we investigate the transport properties of three molecules from conjugated molecule, one-dimension alkane chain, and single molecule magnet, which are sandwiched between two N-doped zigzag and armchair graphene nanoribbons (GNRs). We observe robust NDR effect in all examined molecular junctions including benzene, alkane, and planar four-coordinated Fe complex. Through the analyses of the calculated electronic structures and the bias-dependent transmission coefficients, we find that the narrow density of states of N-doped GNRs and the bias-dependent effective coupling between the discrete frontier molecular orbitals and the subbands of N-doped GNRs are responsible for the observed NDR phenomenon. These theoretical findings imply that N-doped GNRs hold great potential for building NDR devices based on various molecules.
A 73-year-old man, in clinical remission 17 years after radiation therapy for a localized low-grade follicular lymphoma (FL), developed extensive lymphadenopathy, ascites, and splenomegaly with splenic masses. Axillary lymph node biopsy showed FL composed of nodules of centrocytes side by side with nodules of immunoblasts rather than centroblasts. Immunophenotyping revealed conventional FL markers (BCL-2, BCL-6, and CD10) as well as MUM-1 in the immunoblastic component, suggesting postgerminal center differentiation. Fluorescence in situ hybridization showed t(14;18) in both centrocytic and immunoblastic components and a copy gain of BCL-6 predominantly in the immunoblastic component. Areas of centrocytic and of immunoblastic nodules were macrodissected separately and underwent molecular evaluation for immunoglobulin heavy chain gene rearrangement. Identical base-pair peaks were found, attesting to their clonal identity. This case represents a very unusual example of transformation of a low-grade FL to a nodular immunoblastic FL.
Kinesin-1 is a dimeric ATP-dependent motor protein that moves towards microtubules (+) ends. This movement is driven by two conformations (docked and undocked) of the two motor domains carboxy-terminal peptides (named neck linkers), in correlation with the nucleotide bound to each motor domain. Despite extensive data on kinesin-1, the structural connection between its nucleotide cycle and movement has remained elusive, mostly because the structure of the critical tubulin-bound apo-kinesin state was unknown. Here we report the 2.2?Å structure of this complex. From its comparison with detached kinesin-ADP and tubulin-bound kinesin-ATP, we identify three kinesin motor subdomains that move rigidly along the nucleotide cycle. Our data reveal how these subdomains reorient on binding to tubulin and when ATP binds, leading respectively to ADP release and to neck linker docking. These results establish a framework for understanding the transformation of chemical energy into mechanical work by (+) end-directed kinesins.
Amycolatopsis orientalis is the type species of the genus and its industrial strain HCCB10007, derived from ATCC 43491, has been used for large-scale production of the vital antibiotic vancomycin. However, to date, neither the complete genomic sequence of this species nor a systemic characterization of the vancomycin biosynthesis cluster (vcm) has been reported. With only the whole genome sequence of Amycolatopsis mediterranei available, additional complete genomes of other species may facilitate intra-generic comparative analysis of the genus.
Beige adipocytes in white adipose tissue (WAT) are similar to classical brown adipocytes in that they can burn lipids to produce heat. Thus, an increase in beige adipocyte content in WAT browning would raise energy expenditure and reduce adiposity. Here we report that adipose-specific inactivation of Notch1 or its signaling mediator Rbpj in mice results in browning of WAT and elevated expression of uncoupling protein 1 (Ucp1), a key regulator of thermogenesis. Consequently, as compared to wild-type mice, Notch mutants exhibit elevated energy expenditure, better glucose tolerance and improved insulin sensitivity and are more resistant to high fat diet-induced obesity. By contrast, adipose-specific activation of Notch1 leads to the opposite phenotypes. At the molecular level, constitutive activation of Notch signaling inhibits, whereas Notch inhibition induces, Ppargc1a and Prdm16 transcription in white adipocytes. Notably, pharmacological inhibition of Notch signaling in obese mice ameliorates obesity, reduces blood glucose and increases Ucp1 expression in white fat. Therefore, Notch signaling may be therapeutically targeted to treat obesity and type 2 diabetes.
In the light of the relationship between the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism and thyroid cancer (TC) exist objection, a meta-analysis of the MTHFR C677T polymorphism with thyroid cancer risk was performed. All the available studies were identified through a search of the PubMed, Embase, Web of Science, and Chinese Biomedical Literature Database (CBM) up to March 2014. The association between the MTHFR C677T polymorphism and thyroid cancer risk was conducted by odds ratios (ORs) and 95 % confidence intervals (95 % CIs). A total of five independent studies with 2,554 cases and 2,671 controls were included in our meta-analysis. Significant association was found between MTHFR C677T polymorphism and thyroid cancer risk in recessive model in overall populations (TT vs.
We previously reported and revised the nasopharyngeal epithelium specific protein CCDC19 and identified it as a potential tumour suppressor in nasopharyngeal carcinoma. The purpose of this study was to investigate the involvement of CCDC19 in the pathogenesis of human non-small cell lung cancers (NSCLC). Down-regulated CCDC19 expression was observed in NSCLC tissues and cells compared to normal tissues. However, reduced protein expression did not correlate with the status of NSCLC progression. Instead, we observed that patients with lower CCDC19 expression had a shorter overall survival than did patients with higher CCDC19 expression. Lentiviral-mediated CCDC19 overexpression significantly suppressed cell proliferation and cell cycle transition from G1 to S and G2 phases in NSCLC cells. Knocking down CCDC19 expression significantly restored the ability of cell growth in CCDC19 overexpressing NSCLC cells. Mechanistically CCDC19 functions as a potential tumour suppressor by stimulating miR-184 suppression of C-Myc thus blocking cell growth mediated by the PI3K/AKT/C-Jun pathway. Our studies are the first to demonstrate that reduced expression of CCDC19 is an unfavourable factor in NSCLC.
Modified vaccinia virus Ankara (MVA) is an attenuated poxvirus that has been engineered as a vaccine against infectious agents and cancers. Our goal is to understand how MVA modulates innate immunity in dendritic cells (DCs), which can provide insights to vaccine design. In this study, using murine bone marrow-derived dendritic cells, we assessed type I interferon (IFN) gene induction and protein secretion in response to MVA infection. We report that MVA infection elicits the production of type I IFN in murine conventional dendritic cells (cDCs), but not in plasmacytoid dendritic cells (pDCs). Transcription factors IRF3 (IFN regulatory factor 3) and IRF7, and the positive feedback loop mediated by IFNAR1 (IFN alpha/beta receptor 1), are required for the induction. MVA induction of type I IFN is fully dependent on STING (stimulator of IFN genes) and the newly discovered cytosolic DNA sensor cGAS (cyclic guanosine monophosphate-adenosine monophosphate synthase). MVA infection of cDCs triggers phosphorylation of TBK1 (Tank-binding kinase 1) and IRF3, which is abolished in the absence of cGAS and STING. Furthermore, intravenous delivery of MVA induces type I IFN in wild-type mice, but not in mice lacking STING or IRF3. Treatment of cDCs with inhibitors of endosomal and lysosomal acidification or the lysosomal enzyme Cathepsin B attenuated MVA-induced type I IFN production, indicating that lysosomal enzymatic processing of virions is important for MVA sensing. Taken together, our results demonstrate a critical role of the cGAS/STING-mediated cytosolic DNA-sensing pathway for type I IFN induction in cDCs by MVA. We present evidence that vaccinia virulence factors E3 and N1 inhibit the activation of IRF3 and the induction of IFNB gene in MVA-infected cDCs.
The present study focussed on investigating CD59-like molecules of Fasciola hepatica. A cDNA encoding a CD59-like protein (termed FhCD59-1) identified previously in the membrane fraction of the F. hepatica tegument was isolated. This homologue was shown to encode a predicted open reading frame (ORF) of 122 amino acids (aa) orthologous to human CD59 with a 25 aa signal peptide, a mature protein containing 10 cysteines and a conserved CD59/Ly-6 family motif "CCXXXXCN". An analysis of cDNAs from two different adult specimens of F. hepatica revealed seven variable types of FhCD59-1 sequences, designated FhCD59-1.1 to FhCD59-1.7, which had 94.3-99.7% amino acid sequence identity upon pairwise comparison. Molecular modeling of FhCD59-1.1 with human CD59 confirmed the presence of the three-finger protein domain found in the CD59 family and predicted three disulphide bonds in the F. hepatica sequence. The interrogation of F. hepatica databases identified two additional sequences, designated FhCD59-2 and FhCD59-3, which had only 23.4-29.5% amino acid identity to FhCD59-1.1. Orthologues of the inferred CD59 protein sequences of F. hepatica were also identified in other flatworms, including Fasciola gigantica, Fascioloides magna, Schistosoma haematobium, Schistosoma japonicum, Schistosoma mansoni, Clonorchis sinensis, Opisthorchis viverrini, Taenia solium, Echinococcus granulosus and the free living Schmidtea mediterannea. The results revealed a considerable degree of sequence complexity in the CD59-like sequence families in F. hepatica and flatworms. Phylogenetic analysis of CD59-like aa sequences from F. hepatica and flatworms showed that FhCD59-2 clustered with the known surface-associated protein SmCD59-2 of S. mansoni. Relatively well-supported clades specific to schistosomes, fasciolids and opisthorchiids were identified. The qPCR analysis of gene transcription showed that the relative expression of these 3 FhCD59-like sequences varied by 11-47-fold during fluke maturation, from the newly excysted juvenile (NEJ) to the adult stage. These findings suggest that different FhCD59-like sequences play distinct roles during the development of F. hepatica.
The success of using glycolytic inhibitors for cancer treatment relies on better understanding the roles of each frequently deregulated glycolytic genes in cancer. This report analyzed the involvement of a key glycolytic enzyme, alpha-enolase (ENO1), in tumor progression and prognosis of human glioma.
Many strains of Amycolatopsis, such as Amycolatopsis orientalis, A. balhimycina, and A. mediterranei, are important antibiotic producers. Three indigenous plasmids, pMEA100, pMEA300, and pA387, found in this genus have been sequenced. However, only some vectors based on pA387 have been widely applied in Amycolatopsis research. An indigenous plasmid, pXL100, was isolated from the vancomycin producer A. orientalis HCCB10007. Sequence analysis of pXL100 revealed its total length to be 33,499?bp and GC content to be 68.9%. A 2830-bp fragment containing three ORFs has been identified as essential for replication in A. orientalis, but it has no significant similarity to any known replicons. A vector, pLYZW7-3, was constructed based on the pXL100 replicon and could be transferred into A. mediterranei and A. orientalis by electroporation or conjugation with high frequency. A mutant with a disrupted gene was successfully complemented with the pLYZW7-3 vector, indicating that the vector is potentially useful in Amycolatopsis research.
This study proposes a mathematical model to estimate the initial tension forces of the extraocular muscles (EOMs). These forces are responsible for the mechanical equilibrium of the eye suspended in primary position. The passive contributions were obtained using the corresponding Cauchy stress-stretch relationships based on the previous clinical experimental data; whereas the active contributions were obtained using an optimum method with weakening the effect of innervation. The initial tension forces of the EOMs were estimated to be 48.8±14.2mN for the lateral rectus, 89.2±31.6mN for the medial rectus, 50.6±17.6mN for the superior rectus, 46.2±13.4mN for the inferior rectus, 15.6±8.3mN for the superior oblique, and 17.1±12.1mN for the inferior oblique.
MiR-17-92 cluster and its paralogues have emerged as crucial regulators of many oncogenes and tumor suppressors. Transforming growth factor-? receptor II (TGF?R2), as an important tumor suppressor, is involved in various cancer types. However, it is in cancer that only two miRNAs of this cluster and its paralogues have been reported so far to regulate TGF?R2. MiR-93 is oncogenic, but its targetome in cancer has not been fully defined. The role of miR-93 in nasopharyngeal carcinoma (NPC) still remains largely unknown.
Coronary chronic total occlusion (CTO) is the last stage of coronary artery atherosclerosis. Percutaneous coronary intervention (PCI) is a therapeutic procedure used to recanalize vessels with total occlusion. However, successful recanalization of CTO is still not optimal, and the key influence factors are still uncertainty. Therefore, a scientific evaluation on the effective of PCI for CTO treatment is necessary.
Resolvin D1 (RvD1), an endogenous lipid mediator derived from docosahexaenoic acid, has been reported to promote a biphasic activity in anti-inflammatory response and regulate inflammatory resolution. The present study aimed to determine the endogenous expression pattern of RvD1 in a rat model of self-resolution of lipopolysaccharide (LPS)-induced acute respiratory distress syndrome (ARDS) and inflammation. The ARDS model was induced by administrating LPS (2mg/kg) via tracheotomy in 138 male Sprague-Dawley rats. At specified time points, lung injury and inflammation were respectively assessed by lung histology and analysis of bronchoalveolar lavage fluid and cytokine levels. The expression of endogenous RvD1 was detected by high performance liquid chromatography and tandem mass spectrometry. The results showed that histological lung injury peaked between 6h (LPS6h) and day 3, followed by recovery over 4-10days after LPS administration. Lung tissue polymorph nuclear cell (PMN) was significantly increased at LPS6h, and peaked between 6h to day 2. The levels of interleukin (IL)-6 and IL-10 were significantly increased at LPS6h and remained higher over day 10 as compared to baseline. Intriguingly, the endogenous RvD1 expression was decreased gradually during the first 3days, followed by almost completely recovery over days 9-10. The finding indicated that endogenous RvD1 underwent a decrease in expression followed by gradual increase that was basically coincident with the lung injury recovery in a rat model of self-resolution LPS-induced ARDS and inflammation. Our results may help define the optimal therapeutic window for endogenous RvD1 to prevent or treat LPS-induced ARDS and inflammation.
A highly selective assay was developed for screening compounds that bind to the porcine recombinant ?2-adrenoceptor (?2-AR) with affinity chromatography coupled to quadrupole time-of-flight mass spectrometry (Q-TOF-MS). The methodology involved selective screening with immobilized ?2-AR, a highly accurate identification via Q-TOF-MS, and a functional evaluation of the screened compounds with a sensitive myograph system. Ferulic acid, hydroxysafflor yellow A (HSYA), and naringin were confirmed to be the bioactive compounds in Huoxue capsule that specifically bound to the ?2-AR. These compounds produced a concentration-dependent relaxation of arteries that were contracted by treatment with phenylephrine, and the relaxation caused by these compounds was attenuated in the presence of ICI 118551, a type of ?2-AR antagonist. Our data indicate that the use of an immobilized receptor is potentially an alternative method for the rapid screening of bioactive compounds in a complex matrix because of its high specificity. ?2-AR affinity chromatography was valuable in focusing attention on the further investigation of ferulic acid, HSYA, and naringin as ?2-AR agonists.
Human amniotic membrane-derived mesenchymal stem cells (AMSCs) are considered a novel and promising source of stem cells for cell replacement-based therapy. Current research is mostly limited to investigating the cellular differentiation potential of AMSCs, while few have focused on their immunosuppressive properties. This study is aimed at exploring and evaluating the immunosuppressive effect of human AMSCs on the viability and migratory properties of microglia. We found, from results of cell viability assays, that AMSCs can reduce the activity of inflammatory cells by secreting nitric oxide (NO). Also, based on results from wound healing and transwell migration assays, we show that AMSCs can inhibit the migration of human microglia as well as the mouse microglial cell line BV2, suggesting that they have the ability to inhibit the recruitment of certain immune cells to injury sites. Furthermore, we found that NO contributes significantly to this inhibitory effect. Our study provides evidence that human AMSCs can have detrimental effects on the viability and migration of microglia, through secretion of NO. This mechanism may contribute to anti-inflammatory processes in the central nervous system.
Studies of prehypertension and mortality are controversial after adjusting for other cardiovascular risk factors. This meta-analysis sought to evaluate the association of prehypertension with all-cause and cardiovascular disease (CVD) mortality.
Lipoprotein associated phospholipase A2 (Lp-PLA2) is a novel biomarker for cardiovascular risk prediction. Whether increased Lp-PLA2 level is associated with re-stenosis after stent-placement is unclear.
The immunological effects of heat shock proteins (HSPs) had been found in humans and mice, but scarce data of endotoxin-free Hsp70 were reported in tilapia. In the current study, we reported that tHsp70 alone and antigen-tHsp70 compound increased the proliferations of lymphocytes and macrophages, significantly increased the NO release and phagocytotic ability of macrophages (p<0.05), and enhanced the levels of immune-related genes in lymphocytes and macrophages in a dose- and/or time-dependent manner. On the other hand, tHsp70 not only helped to reduce the proliferation inhibitions induced by the ECP treatment, but also assisted antigens to enhance the vaccine-induced protection against Streptococcus iniae (p<0.05). We described, for the first time, a critical role of endotoxin-free tHsp70 on activation of tilapia lymphocytes and macrophages post S. iniae exposure and its up-regulation effects on vaccine-induced protection. Our research highlights the immunological enhancement action of Hsp70 in teleost immunity.
Accurate assessment of coronary chronic total occlusion (CTO) lesion is essential to design an appropriate procedural strategy before revascularization. The present study aims to evaluate the significance of a single multislice computed tomography (MSCT) examination in patients with CTO lesion. We retrospectively analyzed the clinical data of 23 CTO lesions in twenty patients underwent computed tomography coronary angiography (CTCA) and SPECT. The CTCA was more powerful and sensitive to determine the CTO lesion length (100% v.s 47.8%) and to identify the length and location of calcification in occluded vessels compared with the coronary angiography (CAG). The LVEF measured by MSCT was comparable to that from the gated SPECT. Myocardial perfusion imaging showed that the location of the early defect region identified by MSCT was corresponded to the nuclide filling defect on the stressed 201thallium-SPECT imaging. The late hyperenhancement on MSCT was presented as incomplete nuclide filling on the 99mTc-MIBI imaging. The results suggested that a single MSCT examination in previous myocardial infarction without revascularization facilitates to provide some valuable information on the nature of the occluded lesion, myocardial perfusion and globe cardiac function, which would be helpful to design appropriate revascularization strategy in these subjects.
This study aimed to determine the protective effects of tetrandrine (Tet) on murine ischemia-injured retinal ganglion cells (RGCs). For this, we used serum deprivation cell model, glutamate and hydrogen peroxide (H2O2)-induced RGC-5 cell death models, and staurosporine-differentiated neuron-like RGC-5 in vitro. We also investigated cell survival of purified primary-cultured RGCs treated with Tet. An in vivo retinal ischemia/reperfusion model was used to examine RGC survival after Tet administration 1 day before ischemia. We found that Tet affected RGC-5 survival in a dose- and time-dependent manner. Compared to dimethyl sulfoxide treatment, Tet increased the numbers of RGC-5 cells by 30% at 72 hours. After 48 hours, Tet protected staurosporine-induced RGC-5 cells from serum deprivation-induced cell death and significantly increased the relative number of cells cultured with 1 mM H2O2 (P<0.01). Several concentrations of Tet significantly prevented 25-mM-glutamate-induced cell death in a dose-dependent manner. Tet also increased primary RGC survival after 72 and 96 hours. Tet administration (10 ?M, 2 ?L) 1 day before retinal ischemia showed RGC layer loss (greater survival), which was less than those in groups with phosphate-buffered saline intravitreal injection plus ischemia in the central (P=0.005, n=6), middle (P=0.018, n=6), and peripheral (P=0.017, n=6) parts of the retina. Thus, Tet conferred protective effects on serum deprivation models of staurosporine-differentiated neuron-like RGC-5 cells and primary cultured murine RGCs. Furthermore, Tet showed greater in vivo protective effects on RGCs 1 day after ischemia. Tet and ciliary neurotrophic factor maintained the mitochondrial transmembrane potential (??m) of primary cultured RGCs and inhibited the expression of activated caspase-3 and bcl-2 in ischemia/reperfusion-insult retinas.
Artesunate, an anti-malarial drug, elicits an inhibitory effect on pulmonary carcinoma. However, the mechanisms of artesunate activity on pulmonary carcinoma have not been completely elucidated. The aim of this study is to investigate the effect of artesunate on the invasion of human lung adenocarcinoma A549 cells.
Array comparative genomic hybridization (aCGH) has yet to be fully leveraged in a prognostic setting in chronic lymphocytic leukemia (CLL). Genomic imbalance was assessed in 288 CLL specimens using a targeted array. Based on 20 aberrations in a hierarchical manner, all 228 treatment-naive specimens were classified into a group with poor outcome (20.6%) exhibiting at least one aberration that was univariately associated with adverse outcome (gain: 2p, 3q, 8q, 17q, loss: 7q, 8p, 11q, 17p, 18p), good outcome (32.5%) showing 13q14 loss without any of the other 10 aberrations (gain: 1p, 7p, 12, 18p, 18q, 19, loss: 4p, 5p, 6q, 7p) or intermediate outcome (remainder). The three groups were significantly separated with respect to time to first treatment and overall survival (p < 0.001), and validation of the stratification scheme was performed in two independent datasets. Gain of 3q and 8q, and 17p loss were determined to be independent unfavorable prognostic biomarkers. TP53, NOTCH1 and SF3B1 mutations correlated with the presence of one poor outcome aCGH marker, at a considerably higher frequency than when only considering poor risk aberrations routinely detected by fluorescence in situ hybridization (FISH). These data support genomic imbalance evaluation in CLL by aCGH to assist in risk stratification.
The mechanism and stereochemistry of the hydrophosphonylation of an ?-ketoester with dimethylphosphonate (DMHP) catalyzed by a thiourea-cinchona organocatalyst have been studied by the ONIOM method. The calculations show that the catalytic cycle is a three-step process, including the deprotonation of DMHP, C-P bond formation via nucleophilic addition and proton transfer with the regeneration of the catalyst. The deprotonation of DMHP mediated by the basicity of the quinuclidine nitrogen atom is the rate-determining step for the entire reaction. The activation of the ?-ketoester by the thiourea or protonated cinchona moiety of the bifunctional catalyst is comparatively investigated, and the former is energy-preferred. AIM combined with NBO analysis indicate that the multiple hydrogen bonds play essential roles in activating substrates, facilitating charge transfer and stabilizing transition states and intermediates. The stereochemistry of the reaction is controlled by the C-P bond formation step and originated from the chiral induction of the multiple hydrogen-bonding interactions. The bulkier substituent groups on the chiral scaffold of the catalyst may increase rigidity of the catalyst and the asymmetric induction to the substrates. The calculations predict that alkyl substituted ?-ketoesters might also be converted to chiral ?-hydroxyl phosphonates with high enantioselectivity.
Oxygen (O2) adsorbed on metal oxides is important in catalytic oxidation reactions, chemical sensing, and photocatalysis. Strong adsorption requires transfer of negative charge from oxygen vacancies (V(O)s) or dopants, for example. With scanning tunneling microscopy, we observed, transformed, and, in conjunction with theory, identified the nature of O2 molecules on the (101) surface of anatase (titanium oxide, TiO2) doped with niobium. V(O)s reside exclusively in the bulk, but we pull them to the surface with a strongly negatively charged scanning tunneling microscope tip. O2 adsorbed as superoxo (O2(-)) at fivefold-coordinated Ti sites was transformed to peroxo (O2(2-)) and, via reaction with a VO, placed into an anion surface lattice site as an (O2)O species. This so-called bridging dimer also formed when O2 directly reacted with V(O)s at or below the surface.
Bone marrow mesenchymal stem cells (MSCs) transplantation improved cardiac function and reduced myocardial fibrosis in both ischemic and non-ischemic cardiomyopathies. We evaluated the effects of repeated peripheral vein injection of MSCs on collagen network remodeling and myocardial TGF-?1, AT1, CYP11B2 (aldosterone synthase) gene expressions in a rat model of doxorubicin (DOX)-induced dilated cardiomyopathy (DCM). Thirty-eight out of 53 SD rats survived at 10 weeks post-DOX injection (2.5 mg/kg/week for 6 weeks, i.p.) were divided into DCM blank (without treatment, n = 12), DCM placebo (intravenous tail injection of 0.5 mL serum-free culture medium every other day for ten times, n = 13), and DCM plus MSCs group (intravenous tail injection of 5 × 10(6) MSCs dissolved in 0.5 mL serum-free culture medium every other day for 10 times, n = 13). Ten untreated rats served as normal controls. At 20 weeks after DOX injection, echocardiography, myocardial collagen content, myocardial expressions of types I and III collagen, TGF-?1, AT1, and CYP11B2 were compared among groups. At 20 weeks post-DOX injection, 8 rats (67 %) survived in DCM blank group, 9 rats (69 %) survived in DCM placebo group while 13 rats (100 %) survived in DCM plus MSCs group. Left ventricular end-diastolic diameter was significantly higher and ejection fraction was significantly lower in DCM blank and DCM placebo groups compared to normal control rats, which were significantly improved in DCM plus MSCs group (all p < 0.05 vs. DCM blank and DCM placebo groups). Moreover, myocardial collagen volume fraction, types I and III collagen, myocardial mRNA expressions of TGF-?1, AT1, CYP11B2, and collagen I/III ratio were all significantly lower in DCM plus MSCs group compared to DCM blank and DCM placebo groups (all p < 0.05). Repeated intravenous MSCs transplantation could improve cardiac function by attenuating myocardial collagen network remodeling possibly through downregulating renin-angiotensin-aldosterone system in DOX-induced DCM rats.
Background and Aim. Incidence of coronary restenosis after stent placement is high. Our study was going to investigate whether Lp(a) elevation was potential for predicting coronary restenosis and whether the effects of Lp(a) elevation on coronary restenosis were dependent on LDL-C level. Methods and Results. Totally 832 participants eligible for stent placement were enrolled and followed up for monitoring clinical end points. Baseline characteristics were collected. According to the cut point of Lp(a), participants were divided into low Lp(a) group (Lp(a) < 30?mg/dL) and high Lp(a) group (Lp(a) ? 30?mg/dL). Furthermore, based on baseline LDL-C level, participants were divided into LDL-C < 1.8?mmol/L and ?1.8?mmol/L subgroups. Clinical end points including major adverse cardiovascular events (MACE), cardiovascular death, nonfatal myocardial infarction, ischemic stroke, and coronary revascularization (CR) were compared. Patients in high Lp(a) groups more frequently presented with acute coronary syndrome and three vessel stenoses. In subgroup of LDL-C < 1.8?mmol/L, no significant differences of cardiovascular outcomes were found between low and high Lp(a) groups. While in the subgroup of LDL-C ? 1.8?mmol/L, incidences of MACE and CR were significantly higher in high Lp(a) group, and odds ratio for CR was 2.05. Conclusion. With baseline LDL-C and Lp(a) elevations, incidence of CR is significantly increased after stent placement.
S100A8/A9 proteins are members of EF-hand calcium-binding proteins secreted by neutrophils and activated monocytes. S100A8/A9 has cell growth-promoting activity at low concentrations by binding to the receptor for advanced glycation end products (RAGE). In this study, we report for the first time that S100A8/A9 promoted the invasion of breast cancer cells depending on RAGE. In addition, RAGE binding to S100A8/A9 promoted the phosphorylation of LIN-11, Isl1, and MEC-3 protein domain kinase, as well as cofilin. This phosphorylation is a critical step in cofilin recycling and actin polymerization. Interestingly, RAGE binding to S100A8/A9 enhanced cell mesenchymal properties and induced epithelial-mesenchymal transition. Mechanistically, RAGE binding to S100A8/A9 stabilized Snail through the NF-?B signaling pathway. Based on these observations, RAGE expression in breast cancer cells was associated with lymph node and distant metastases in patients with invasive ductal carcinoma. Moreover, RAGE binding to S100A8/A9 promoted lung metastasis in vivo. In summary, our in vitro and in vivo results indicated that RAGE binding to S100A8/A9 played an important role in breast cancer invasion/metastasis. This study identified both RAGE and S100A8/A9 as potential anti-invasion targets for therapeutic intervention in breast cancer.
Captive nonhuman primates have been identified as common hosts of Enterocytozoon bieneusi, Giardia duodenalis, Cryptosporidium hominis, and Cyclospora spp., thus are potential reservoirs of some enteric parasites in humans. However, few studies have examined the source and human-infective potential of enteric parasites in laboratory nonhuman primates. In the present work, 205 fecal specimens were collected from three groups of captive Macaca fascicularis kept in different densities in a laboratory animal facility in Guangxi, China, and examined by PCR for E. bieneusi, G. duodenalis, Cryptosporidium spp., and Cyclospora spp. The infection rates of E. bieneusi and G. duodenalis were 11.3% and 1.2% in Group 1 (young animals kept individually; n=168), 72.2% and 11.1% in Group 2 (young animals kept in groups; n=18), and 31.6% and 5.3% in Group 3 (adults kept in groups; n=19), respectively. Sequence analysis of PCR products showed the presence of five E. bieneusi genotypes, with genotype D (in 16/36 genotyped specimens) and a new genotype (in 15/36 genotyped specimens) as the dominant genotypes. All five E. bieneusi genotypes belonged to the zoonotic group (Group 1). The G. duodenalis genotypes (assemblages AII and B) in five specimens and C. hominis subtype (IdA14) in one specimen were also known human-pathogens, although the Cyclospora seen in one animal appeared to be unique to macaque monkeys. The higher infection rate in younger animals reared in groups and common occurrence of zoonotic genotypes indicated that human-pathogenic E. bieneusi could be transmitted efficiently in captive nonhuman primates, and group-housing was a risk factor for transmission of zoonotic pathogens in young nonhuman primates in research facilities.
Recently, angiotensin-converting enzyme inhibitor (ACEI) has gained increasing attention for its anti-atherosclerosis activity, but the underlying mechanism is unknown. In our study, we used rabbits fed with high-fat forage, as an atherosclerosis model to investigate the effect of fosinopril, which is an ACEI. Animals which received both high-fat forage and fosinopril, were maintained as the drug-treated group. Ultrasonography and Sudan III staining were used to determine the process of atherosclerosis. The expression of TLR4 and activity NF-?B were determined using western blot, RT-PCR and ELISA. The results showed that the atherosclerotic plaque was visible at sixteen weeks. More importantly, the atherosclerotic plaque was significantly decreased after fosinopril treatment. In the atherosclerosis model, the levels of TLR4 and NF-?B were increased, but this increased expression was inhibited in the fosinopril treated group. Our results demonstrated that TLR4 could be used as a potential biomarker for atherosclerosis and ACEI has the potential to be a new anti-atherosclerotic drug.
In the current study we used electroencephalography (EEG) to investigate the relation between musical tempo perception and the oscillatory activity in specific brain regions, and the scalp EEG networks in the theta, alpha, and beta bands. The results showed that the theta power at the frontal midline decreased with increased arousal level related to tempo. The alpha power induced by original music at the bilateral occipital-parietal regions was stronger than that by tempo-transformed music. The beta power did not change with tempo. At the network level, the original music-related alpha network had high global efficiency and the optimal path length. This study was the first to use EEG to investigate multi-oscillatory activities and the data support the tempo-specific timing hypothesis.
Prdm16 determines the bidirectional fate switch of skeletal muscle/brown adipose tissue (BAT) and regulates the thermogenic gene program of subcutaneous white adipose tissue (SAT) in mice. Here we show that miR-133a, a microRNA that is expressed in both BAT and SATs, directly targets the 3 UTR of Prdm16. The expression of miR-133a dramatically decreases along the commitment and differentiation of brown preadipocytes, accompanied by the upregulation of Prdm16. Overexpression of miR-133a in BAT and SAT cells significantly inhibits, and conversely inhibition of miR-133a upregulates, Prdm16 and brown adipogenesis. More importantly, double knockout of miR-133a1 and miR-133a2 in mice leads to elevations of the brown and thermogenic gene programs in SAT. Even 75% deletion of miR-133a (a1(-/-)a2(+/-) ) genes results in browning of SAT, manifested by the appearance of numerous multilocular UCP1-expressing adipocytes within SAT. Additionally, compared to wildtype mice, miR-133a1(-/-)a2(+/-) mice exhibit increased insulin sensitivity and glucose tolerance, and activate the thermogenic gene program more robustly upon cold exposure. These results together elucidate a crucial role of miR-133a in the regulation of adipocyte browning in vivo.
Binding of dsDNA by cyclic GMP-AMP (cGAMP) synthase (cGAS) triggers formation of the metazoan second messenger c[G(2,5)pA(3,5)p], which binds the signaling protein STING with subsequent activation of the interferon (IFN) pathway. We show that human hSTING(H232) adopts a "closed" conformation upon binding c[G(2,5)pA(3,5)p] and its linkage isomer c[G(2,5)pA(2,5)p], as does mouse mSting(R231) on binding c[G(2,5)pA(3,5)p], c[G(3,5)pA(3,5)p] and the antiviral agent DMXAA, leading to similar "closed" conformations. Comparing hSTING to mSting, 2,5-linkage-containing cGAMP isomers were more specific triggers of the IFN pathway compared to the all-3,5-linkage isomer. Guided by structural information, we identified a unique point mutation (S162A) placed within the cyclic-dinucleotide-binding site of hSTING that rendered it sensitive to the otherwise mouse-specific drug DMXAA, a conclusion validated by binding studies. Our structural and functional analysis highlights the unexpected versatility of STING in the recognition of natural and synthetic ligands within a small-molecule pocket created by the dimerization of STING.
Programmed cell death 4 (PDCD4), a novel tumor suppressor, inhibits cell proliferation, migration and invasion as well as promotes cell apoptosis in tumors. However, the molecular mechanism of its tumor-suppressive function remains largely unknown in tumors including nasopharyngeal carcinoma (NPC). In this study, downregulated PDCD4 expression was significantly associated with the status of NPC progression and poor prognosis. PDCD4 markedly suppressed the ability of cell proliferation and cell survival by modulating C-MYC-controlled cell cycle and BCL-2-mediated mitochondrion apoptosis resistance signals, and oncogenic transcription factor C-JUN in NPC. Furthermore, miR-184, a tumor-suppressive miRNA modulated by PDCD4 directly targeting BCL2 and C-MYC, participated in PDCD4-mediated suppression of cell proliferation and survival in NPC. Further, we found that PDCD4 decreased the binding of C-Jun to the AP-1 element on the miR-184 promoter regions by PI3K/AKT/JNK/C-Jun pathway and stimulated miR-184 expression. In clinical fresh specimens, reduced PDCD4 mRNA level was positively correlated with miR-184 expression in NPC. Our studies are the first to demonstrate that PDCD4 as tumor suppressor regulated miR-184-mediated direct targeting of BCL2 and C-MYC via PI3K/AKT and JNK/C-Jun pathway attenuating cell proliferation and survival in NPC.
A worldwide epidemic of obesity and its associated metabolic disorders raise the significance of adipocytes, their origins and characteristics. Our previous study has demonstrated that interscapular brown adipose tissue (BAT), but not intramuscular adipose, is derived from the Pax3-expressing cell lineage. Here, we show that various depots of subcutaneous (SAT) and visceral adipose tissue (VAT) are highly heterogeneous in the Pax3 lineage origin. Interestingly, the relative abundance of Pax3 lineage cells in SAT depots is inversely correlated to expression of BAT signature genes including Prdm16, Pgc1a (Ppargc1a) and Ucp1. FACS analysis further demonstrates that adipocytes differentiated from non-Pax3 lineage preadipocytes express higher levels of BAT and beige adipocyte signature genes compared with the Pax3 lineage adipocytes within the same depots. Although both Pax3 and non-Pax3 lineage preadipocytes can give rise to beige adipocytes, the latter contributes more significantly. Consistently, genetic ablation of Pax3 lineage cells in SAT leads to increased expression of beige cell markers. Finally, non-Pax3 lineage beige adipocytes are more responsive to cAMP-agonist-induced Ucp1 expression. Taken together, these results demonstrate widespread heterogeneity in Pax3 lineage origin, and its inverse association with BAT gene expression within and among subcutaneous adipose depots.
The purpose of this study was to examine the correlation between nuclear expression of cyclin-dependent kinase 4 (CDK4) and clinicopathological data in nasopharyngeal carcinoma (NPC), including patient survival.
Brown adipose tissues (BAT) are derived from a myogenic factor 5 (Myf5)-expressing cell lineage and white adipose tissues (WAT) predominantly arise from non-Myf5 lineages, although a subpopulation of adipocytes in some WAT depots can be derived from the Myf5 lineage. However, the functional implication of the Myf5- and non-Myf5-lineage cells in WAT is unclear. We found that the Myf5-lineage constitution in subcutaneous WAT depots is negatively correlated to the expression of classical BAT and newly defined beige/brite adipocyte-specific genes. Consistently, fluorescent-activated cell sorting (FACS)-purified Myf5-lineage adipo-progenitors give rise to adipocytes expressing lower levels of BAT-specific Ucp1, Prdm16, Cidea, and Ppargc1a genes and beige adipocyte-specific CD137, Tmem26, and Tbx1 genes compared with the non-Myf5-lineage adipocytes from the same depots. Ablation of the Myf5-lineage progenitors in WAT stromal vascular cell (SVC) cultures leads to increased expression of BAT and beige cell signature genes. Strikingly, the Myf5-lineage cells in WAT are heterogeneous and contain distinct adipogenic [stem cell antigen 1(Sca1)-positive] and myogenic (Sca1-negative) progenitors. The latter differentiate robustly into myofibers in vitro and in vivo, and they restore dystrophin expression after transplantation into mdx mouse, a model for Duchenne muscular dystrophy. These results demonstrate the heterogeneity and functional differences of the Myf5- and non-Myf5-lineage cells in the white adipose tissue.
Atherosclerotic cardiovascular diseases (CVD) are still the leading cause of morbidity and mortality worldwide, although optimal medical therapy has been prescribed for primary and secondary preventions. Residual cardiovascular risk for some population groups is still considerably high although target low density lipoprotein-cholesterol (LDL-C) level has been achieved. During the past few decades, compelling pieces of evidence from clinical trials and meta-analyses consistently illustrate that lipoprotein(a) (Lp(a)) is a significant risk factor for atherosclerosis and CVD due to its proatherogenic and prothrombotic features. However, the lack of effective medication for Lp(a) reduction significantly hampers randomized, prospective, and controlled trials conducting. Based on previous findings, for patients with LDL-C in normal range, Lp(a) may be a useful marker for identifying and evaluating the residual cardiovascular risk, and aggressively lowering LDL-C level than current guidelines recommendation may be reasonable for patients with particularly high Lp(a) level.
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