The kiss1/gpr54 signaling system is considered to be a critical regulator of reproduction in most vertebrates. However this presumption has not been tested vigorously in non-mammalian vertebrates. Distinct from mammals, multiple kiss1/gpr54 paralogous genes (kiss/kissr) have been identified in non-mammalian vertebrates, raising the possibility of functional redundancy among these genes. In this study, we have systematically generated the zebrafish kiss1(-/-), kiss2(-/-) and kiss1(-/-);kiss2(-/-) mutant lines as well as the kissr1(-/-), kissr2(-/-) and kissr1(-/-);kissr2(-/-) mutant lines using transcription activator like effector nucleases (TALENs). We have demonstrated that spermatogenesis and folliculogenesis as well as reproductive capability are not impaired in all of these six mutant lines. Collectively, our results indicate that kiss/kissr signaling is not absolutely required for zebrafish reproduction, suggesting that the kiss/kissr systems play non-essential roles for reproduction in certain non-mammalian vertebrates. These findings also demonstrated that fish and mammals have evolved different strategies for neuroendocrine control of reproduction.
A compact multifunctional optical correlator system for pulse width measurement of ultrashort ultraviolet (UV) pulses has been designed and experimentally demonstrated. Both autocorrelation and cross-correlation functions are measured using a single nonlinear crystal, and the switching between two measurements requires no adjustment of phase matching and detector. The system can measure UV pulse widths from sub-picoseconds to 100 ps, and it involves no auxiliary pulse in the measurement. The measurement results on a burst-mode picosecond UV laser show a high-quality performance on speed, accuracy, resolution, and dynamic range. The proposed correlator can be applied to measure any ultrashort UV pulses produced through sum-frequency generation or second-harmonic generation.
A two-dimensional (2D) low bandgap polymer () based on dithieno[3,2-b:2',3'-d]silole (DTS) with phenyl substitution on the bridging silicon atom and thiazolo[5,4-d]thiazole (TTz) was designed and synthesized for photovoltaic applications. The impact of conjugated side chains on the optical, electrochemical and energy levels of the polymer was studied. The phenyl substituted DTS polymer exhibited a 0.16 eV down-shifted highest occupied molecular orbital (HOMO) energy level and ca. 0.1 eV narrowed bandgap in comparison to the corresponding polymers with alkyl substitution on the silicon bridge. The influence of the blend weight ratio, the PFN layer, mixed solvent, THF exposure and polar solvent treatment and thermal annealing on the performance of :PC71BM devices was studied. ?:?PC71BM (1?:?1, weight ratio) devices delivered the highest power conversion efficiency of 2.14% by using the PFN layer and THF annealing. Thermal annealing was found to exert a negative effect on the device performance. The morphology evolution of blend films processed with different solvents explained the difference in device performance. The results indicate that phenyl substitution is an effective way to tune the HOMO and bandgap of polymer donors for enhanced photovoltaic performance with the as-demonstrated 2D-conjugated DTS structure.
Solar thermal fuels (STF) store the energy of sunlight, which can then be released later in the form of heat, offering an emission-free and renewable solution for both solar energy conversion and storage. However, this approach is currently limited by the lack of low-cost materials with high energy density and high stability. In this Letter, we present an ab initio high-throughput computational approach to accelerate the design process and allow for searches over a broad class of materials. The high-throughput screening platform we have developed can run through large numbers of molecules composed of earth-abundant elements and identifies possible metastable structures of a given material. Corresponding isomerization enthalpies associated with the metastable structures are then computed. Using this high-throughput simulation approach, we have discovered molecular structures with high isomerization enthalpies that have the potential to be new candidates for high-energy density STF. We have also discovered physical principles to guide further STF materials design through structural analysis. More broadly, our results illustrate the potential of using high-throughput ab initio simulations to design materials that undergo targeted structural transitions.
Achaete scute-like 2 (Ascl2), a basic helix-loop-helix (bHLH) transcription factor, is a downstream target of Wnt signaling that controls the fate of intestinal cryptic stem cells and colon cancer progenitor cells. However, its involvement in colon cancer and downstream molecular events is largely undefined; in particular, the mechanism by which Ascl2 regulates the plasticity of epithelial-mesenchymal transition (EMT) and mesenchymal-epithelial transition (MET) programs in colon cancer cells remains unknown. In this study, we systematically demonstrate that Ascl2 loss-of-function in colon cancer cells promotes MET by de-repressing the expression of miR-200s (i.e., miR-200b, miR-200a, miR-429, miR-200c and miR-141) and further activating their expression through a transcriptional mechanism that involves direct binding to the most proximal E-box (E-box2) in the miR-200b-a-429 promoter. Activation of miR-200s due to Ascl2 deficiency led to the inhibition of Zeb1/2 expression and the alteration of epithelial and mesenchymal features. Transfection of miR-200b, miR-200a and miR-429 inhibitors into Ascl2-deficient colon cancer cells promoted the epithelial-mesenchymal transition in a reversible manner. Transfection of miR-200a or miR-429 inhibitors into Ascl2-deficient colon cancer cells increased cellular proliferation and migration. Ascl2 mRNA levels and miRNA-200a, miRNA-200b, miRNA-200c, miRNA-141 or miRNA-429 levels in the colon cancerous samples were inversely correlated. These results provide the first evidence of a link between Ascl2 and miR-200s in the regulation of EMT-MET plasticity in colon cancer.
The RNA-binding protein fused-in-sarcoma (FUS) has been associated with amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD), two neurodegenerative disorders that share similar clinical and pathological features. Both missense mutations and overexpression of wild-type FUS protein can be pathogenic in human patients. To study the molecular and cellular basis by which FUS mutations and overexpression cause disease, we generated novel transgenic mice globally expressing low levels of human wild-type protein (FUS(WT)) and a pathological mutation (FUS(R521G)). FUS(WT) and FUS(R521G) mice that develop severe motor deficits also show neuroinflammation, denervated neuromuscular junctions, and premature death, phenocopying the human diseases. A portion of FUS(R521G) mice escape early lethality; these escapers have modest motor impairments and altered sociability, which correspond with a reduction of dendritic arbors and mature spines. Remarkably, only FUS(R521G) mice show dendritic defects; FUS(WT) mice do not. Activation of metabotropic glutamate receptors 1/5 in neocortical slices and isolated synaptoneurosomes increases endogenous mouse FUS and FUS(WT) protein levels but decreases the FUS(R521G) protein, providing a potential biochemical basis for the dendritic spine differences between FUS(WT) and FUS(R521G) mice.
Age-related macular degeneration (AMD) is a late-onset, neurodegenerative disease. Genes related to lipid metabolism are important in AMD pathogenesis. Recently, a variant rs2075650 located in lipid metabolism-related locus APOE/TOMM40 was identified to be associated with advanced AMD and early AMD, respectively, in two genome-wide association studies with European ancestry, while no association study between rs2075650 and overall advanced AMD in Chinese population has been conducted before. We evaluated the potential effect of this variant on advanced AMD in a Han Chinese cohort with 204 advanced AMD patients and 1536 healthy controls. The results suggested that rs2075650 was neither associated with advanced AMD in allele level (P?=?0.348) nor in genotype level (P?=?0.890 under additive model with age and sex adjusted). In conclusion, our study did not confirm the impact of rs2075650 on advanced AMD risk, indicating that rs2075650 is unlikely a superior marker for APOE/TOMM40 susceptible region with advanced AMD in Han Chinese population.
A one-pot, three-component cascade reaction between pyridine, ?-acylmethylbromide, and maleic anhydride leading to direct access of 1-bromoindolizines in high yields has been developed. This protocol is accomplished via a reaction sequence of 1,3-dipolar cycloaddition of the pyridinium ylide with maleic anhydride, oxidative decarboxylation of the primary cycloadduct, and dehydrogenative bromination of the resulting 1-unsubstituted indolizine. Copper chloride was used as a catalyst and oxygen as the terminal oxidant. This reaction represents the first example of transition-metal-catalyzed direct dehydrogenative bromination of indolizine at the C-1 position. Moreover, the obtained 1-bromoindolizines can be transformed to other 1-substituted indolizines such as 1-arylindolizines via a simple reaction process.
The pivotal role of gonadotropin signaling in regulating gonadal development and functions has attracted much research attention in the past 2 decades. However, the precise physiological role of gonadotropin signaling is still largely unknown in fish. In this study, we have established both LH ?-subunit (lhb) and LH receptor (lhr) knockout zebrafish lines by transcription activator-like effector nucleases. Intriguingly, both homozygous lhb and lhr mutant male fish are fertile. The fertilization rate, sperm motility, and histological structure of the testis were not affected in either lhb or lhr mutant males. On the contrary, homozygous lhb mutant females are infertile, whereas homozygous lhr mutant females are fertile. Folliculogenesis was not affected in either lhb or lhr mutants, but oocyte maturation and ovulation were disrupted in lhb mutant, whereas only ovulation was affected in lhr mutant. Differential expression of genes in the ovary involved in steroidogenesis, oocyte maturation, and ovulation was found between the lhb and lhr mutants. These data demonstrate the essential role of LH signaling in oocyte maturation and ovulation, and support the notion that LH acts through the FSH receptor in the absence of LH receptor. Moreover, the defects of lhb mutant could be partially restored by administration of human chorionic gonadotropin. This in vivo evidence in the present study demonstrates, for the first time in any vertebrate species, that LH signaling is indispensable in female reproduction but not in male reproduction. LH signaling is demonstrated to control oocyte maturation and ovulation in the ovary.
To study the effect of Compound Ezhu Powder (CEP) on serum levels of CA125 and CA19-9, and the expression of cyclin D protein in endometriosis patients, thus providing theoretical evidence for clinical application of CEP.
Na(+)-K(+)-2Cl(-) co-transporter isoform 1 (NKCC1) mRNA and protein decrease with increasing age in the cochlear lateral wall of C57BL/6J (C57) mice. The down-regulation of NKCC1 may influence the K(+) transport efficiency and the homeostasis of ion transport cells, and cause the irreversible damage of cochlear cells in old C57 mice. Our results indicate that NKCC1 may play an important role in the pathogenesis of age-related hearing loss (AHL).
This paper presents an integrated model aimed at obtaining robust and reliable results in decision level multisensor data fusion applications. The proposed model is based on the connection of Dempster-Shafer evidence theory and an extreme learning machine. It includes three main improvement aspects: a mass constructing algorithm to build reasonable basic belief assignments (BBAs); an evidence synthesis method to get a comprehensive BBA for an information source from several mass functions or experts; and a new way to make high-precision decisions based on an extreme learning machine (ELM). Compared to some universal classification methods, the proposed one can be directly applied in multisensor data fusion applications, but not only for conventional classifications. Experimental results demonstrate that the proposed model is able to yield robust and reliable results in multisensor data fusion problems. In addition, this paper also draws some meaningful conclusions, which have significant implications for future studies.
In the application of a micro-/nano-mechanical resonator, the position of an accreted particle and the resonant frequencies are measured by two different physical systems. Detecting the particle position sometimes can be extremely difficult or even impossible, especially when the particle is as small as an atom or a molecule. Using the resonant frequencies to determine the mass and position of an accreted particle formulates an inverse problem. The Dirac delta function and Galerkin method are used to model and formulate an eigenvalue problem of a beam with an accreted particle. An approximate method is proposed by ignoring the off-diagonal elements of the eigenvalue matrix. Based on the approximate method, the mass and position of an accreted particle can be decoupled and uniquely determined by measuring at most three resonant frequencies. The approximate method is demonstrated to be very accurate when the particle mass is small, which is the application scenario for much of the mass sensing of micro-/nano-mechanical resonators. By solving the inverse problem, the position measurement becomes unnecessary, which is of some help to the mass sensing application of a micro-/nano-mechanical resonator by reducing two measurement systems to one. How to apply the method to the general scenario of multiple accreted particles is also discussed.
Allopolyploids generally undergo bivalent pairing at meiosis because only homologous chromosomes pair up. On the other hand, several studies have documented abnormal chromosome behavior during mitosis and meiosis in allopolyploids plants leading to the production of gametes with complete paternal or maternal chromosomes. Polyploidy is relatively rare in animals compared with plants; thus, chromosome behavior at meiosis in the allopolyploid animals is poorly understood.
The association between large-artery atherosclerosis and leukoaraiosis (LA) has been increasingly reported with inconsistent conclusion. This systematic review examines the relationship between LA and carotid atherosclerosis, manifested as atherosclerotic stenosis, plaques and increased intima-media thickness (IMT). PubMed, Embase, and Web of Science were searched for articles published up to February 2014. Thirty-two studies that examined the relationship between LA and carotid atherosclerosis were included. All statistical analysis was conducted with Review Manager 5.2.4. Finally, 32 studies including 17,721 patients were identified. There were 7 (30%) out of 23 studies reporting significant association between LA and carotid stenosis; 11 (79%) out of 14 studies reporting significant association between LA and carotid plaque; all 9 studies reporting significant association between LA and carotid IMT; one study showing an association between LA and CAWT (similar to the role of the IMT). The quantitative meta-analysis of 10 studies showed that carotid atherosclerosis was not associated with LA (OR: 1.10; 95% CI: 0.61-1.98). A significant association was found between LA and carotid plaque (OR = 3.53; 95% CI = 1.83-6.79), and the result of IMT group showed that IMT increased risk of LA (MD = 0.11; 95% CI = 0.01-0.22). This systematic review suggested that LA has a tendency of association with carotid plaques but no association with simple carotid stenosis.
The establishment of the tetraploid organism is difficult but useful in genetics and breeding. In the present study, we have artificially established an autotetraploid fish line (F2-F8) derived from the distant hybridization of Carassius auratus red var. (RR, 2n = 100) (female) × Megalobrama amblycephala (BB, 2n = 48) (male). The autotetraploid line (F2-F8) possess four sets of chromosomes from red crucian carp (RRRR, 4n = 200) and produce diploid ova and diploid sperm, which maintains the formation of the autotetraploid line. The F2 of the autotetraploid fish result from the fertilization of the autodiploidy diploid eggs and diploid sperm from the females and males of F1 hybrids (RRBB, 4n = 148), which exhibit abnormal chromosome behavior during meiosis as revealed by gynogenesis and backcrossing. This is the first report concerning the establishment of an autotetraploid fish line derived from distant hybridization. The autotetraploid fish line provides an important gamete source for the production of triploids and tetraploids. The autotetraploid fish line also provides an ideal system to investigate the poorly understood mechanisms that drive diploidization in autotetraploids and to study the hybrid progenies' characteristics, including the appearance of new traits that promote a diversity of traits and facilitate adaptation.
Postcataract endophthalmitis treatment through eye drops is of low corneal bioavailability and short residence time. The dominant NSAIDs therapy also suffers from severe ocular irritancy and low patients compliance. This study dispersed bovine serum albumin (BSA) coated meloxicam (MX) nanocrystals encapsulating nanoaggregates (BSA-MX-NA) in contact lenses to reduce drug ocular irritancy and increased drug release duration. The BSA-MX-NA (?100nm) were prepared using acid-base neutralization in aqueous solutions and were dispersed in poly(hydroxylethyl methacrylate) gels, which are common contact lens materials. Drug release studies showed that the gels released the drug for about 5 days. The proposed drug transport mechanism is a diffusion process which can be described by the Ritger-Peppas model with the diffusional exponent n of 0.4768. The drug release can be affected by the gel thickness and the cross-linking degree. A 400 micro thick gels with 100?L cross-linker TEGDMA leads to an adequate meloxicam release for therapeutic application. The ocular irritation studies showed that BSA-MX-NA loaded p-HEMA gels are significantly less irritating to the ocular tissues as compared to marketed MX solutions. The developed contact lenses loaded with BSA-MX-NA could be very useful for extended delivery in postcataract endophthalmitis treatment.
In this paper, a novel stepwise-acid-active multifunctional mesoporous silica nanoparticle (MSN-(SA)TAT&(DMA)K11) was developed as a drug carrier. The MSN-(SA)TAT&(DMA)K11 is able to reverse its surface charge from negative to positive in the mildly acidic tumor extracellular environment. Then, the fast endo/lysosomal escape and subsequent nucleus targeting as well as intranuclear drug release can be realized after cellular internalization. Because of the difference in acidity between the tumor extracellular environment and that of endo/lysosomes, this multifunctional MSN-(SA)TAT&(DMA)K11 exhibits a stepwise-acid-active drug delivery with a tumor-specific nucleus-targeted property.
Previous studies have shown that some phytoestrogens inhibits proliferation and induces apoptosis in estrogen-dependent cancers via estrogen receptor (ER)-mediated signaling pathway. In view of the expression of ER in human osteosarcoma cells, the purpose of this study is to investigate whether formononetin and calycosin, two of the major isoflavones in Radix astragali, could also elicit anti-tumor activity against osteosarcoma, along with the underlying mechanism.
The deployment of a coronary stent near complex lesions can sometimes lead to incomplete stent apposition (ISA), an undesirable side effect of coronary stent implantation. Three-dimensional computational fluid dynamics (CFD) calculations are performed on simplified stent models (with either square or circular cross-section struts) inside an idealised coronary artery to analyse the effect of different levels of ISA to the change in haemodynamics inside the artery. The clinical significance of ISA is reported using haemodynamic metrics like wall shear stress (WSS) and wall shear stress gradient (WSSG). A coronary stent with square cross-sectional strut shows different levels of reverse flow for malapposition distance (MD) between 0mm and 0.12 mm. Chaotic blood flow is usually observed at late diastole and early systole for MD=0mm and 0.12 mm but are suppressed for MD=0.06 mm. The struts with circular cross section delay the flow chaotic process as compared to square cross-sectional struts at the same MD and also reduce the level of fluctuations found in the flow field. However, further increase in MD can lead to chaotic flow not only at late diastole and early systole, but it also leads to chaotic flow at the end of systole. In all cases, WSS increases above the threshold value (0.5 Pa) as MD increases due to the diminishing reverse flow near the artery wall. Increasing MD also results in an elevated WSSG as flow becomes more chaotic, except for square struts at MD=0.06 mm.
Sitafloxacin is a new fluoroquinolone antimicrobial agent with high activity. In this article, we reported a simple, rapid and specific LC-MS/MS method for accurate determination of sitafloxacin concentrations in human urine from healthy volunteers in detail. A two-step dilution method for the analysis of sitafloxacin in human urine using LC coupled to positive MS/MS has been developed and validated according to US FDA guidelines and Chinese State Food and Drug Administration (CFDA) guidelines for the validation of bioanalytical methods. The method uses 50 ?L of urine and covers a working range from 0.025 to 20 ?g/mL with a LLOQ of 0.025 ?g/mL. This new LC-MS/MS assay is sensitive and specific.
The objectives of this study were to evaluate sexual dimorphism for facial features within Chinese and African American populations and to compare the facial morphology by sex between these 2 populations.
Artesun-Plus is a fixed-dose combination antimalarial agent containing artesunate and amodiaquine. The current study was conducted to compare the pharmacokinetic and safety profiles of Artesun-Plus and the WHO-designated comparator product Artesunate Amodiaquine Winthrop. To overcome the high intrasubject variability of artesunate, the study applied a two-sequence and four-period crossover (2 by 4), replicate study design to assess bioequivalence between the two products in 31 healthy male Chinese volunteers under fasting conditions. The results showed that the values of the geometric mean ratios of maximum concentration of drug in plasma (Cmax) and area under the concentration-time curve from time zero to the last blood sample collection (AUC0-last) for the artesunate component in the test and reference products were 95.9% and 93.9%, respectively, and that the corresponding 90% confidence intervals were 84.5% to 108.7% and 87.2% to 101.1%, while the geometric mean ratios for the amodiaquine component in the test and reference products were 95.0% and 100.0%, respectively, and the corresponding 90% confidence intervals were 86.7% to 104.1% and 93.5% to 107.0%. In conclusion, bioequivalence between the two artesunate and amodiaquine fixed-dose combination products was demonstrated for both components. The study also confirmed high intrasubject variability, especially for artesunate: the coefficients of variation (CV) of Cmax values for the test and reference products were 39.2% and 43.7%, respectively, while those for amodiaquine were 30.6% and 30.2%, respectively.
Acute diarrhea is the most common infectious disease worldwide and its causes vary from one region to another. We aimed to analyze the spectrum and epidemiological characteristics of pathogens from 22,386 outpatients with acute diarrhea on the basis of surveillance data from Shanghai, China, during 2006-2011. The following 8 pathogens were isolated and identified using standard methods: Salmonella, Shigella, Vibrio cholerae, V. parahaemolyticus, enteropathogenic Escherichia coli, enterotoxigenic E. coli, enteroinvasive E. coli, and enterohemorrhagic E. coli. In total, 2,234 strains of pathogens were obtained and the overall isolation rate of these 8 pathogens gradually decreased from 17.1% in 2006 to 7.4% in 2011. V. parahaemolyticus was the most frequently identified pathogen, followed by Shigella and Salmonella. The isolation rate of V. parahaemolyticus notably varied by season, whereas Salmonella and Shigella infections showed little seasonal variation. Age-related variation was also observed. V. parahaemolyticus infection occurred more often in patients aged 20-40 years. S. enterica serovar Enteritidis and S. flexneri were the most common serotypes of Salmonella and Shigella, respectively. The descending trend observed in the isolation rate of pathogens from the current surveillance suggests an urgent requirement or improvement.
A novel algorithm for automatic foreground extraction based on difference of Gaussian (DoG) is presented. In our algorithm, DoG is employed to find the candidate keypoints of an input image in different color layers. Then, a keypoints filter algorithm is proposed to get the keypoints by removing the pseudo-keypoints and rebuilding the important keypoints. Finally, Normalized cut (Ncut) is used to segment an image into several regions and locate the foreground with the number of keypoints in each region. Experiments on the given image data set demonstrate the effectiveness of our algorithm.
Krüppel-like factor 9 (KLF9) is known to be a tumor suppressor gene in colorectal tumors and glioblastoma; however, the functional status and significance of KLF9 in hepatocellular carcinoma (HCC) is unclear. We report here that KLF9 is downregulated in HCC tissues. Restoration of KLF9 significantly inhibited growth and caused apoptosis in SK-Hep1 and HepG2 cells. We found that KLF9 positively regulated p53 levels by directly binding to GC boxes within the proximal region of the p53 promoter. Moreover, in the presence of cycloheximide, KLF9 significantly increased p53 stability in HCC cells. Remarkably, ectopic expression of KLF9 was sufficient to delay the onset of tumors and to promote regression of the established tumors in vivo, suggesting that KLF9 plays a critical role in HCC development and that pharmacological or genetic activation of KLF9 may have potential in the treatment of HCC.
Xylitol fermentation production from corncob acid hydrolysate has become an attractive and promising process. However, corncob acid hydrolysate cannot be directly used as fermentation substrate owing to various inhibitors. In this work, soaking in aqueous ammonia (SAA) pretreatment was employed to reduce the inhibitors in acid hydrolysate. After detoxification, the corncob acid hydrolysate was fermented by immobilized Candida tropicalis cell to produce xylitol. Results revealed that SAA pretreatment showed high delignification and efficient removal of acetyl group compounds without effect on cellulose and xylan content. Acetic acid was completely removed, and the content of phenolic compounds was reduced by 80%. Furthermore, kinetic behaviors of xylitol production by immobilized C. tropicalis cell were elucidated from corncob acid hydrolysate detoxified with SAA pretreatment and two-step adsorption method, respectively. The immobilized C. tropicalis cell showed higher productivity efficiency using the corncob acid hydrolysate as fermentation substrate after detoxification with SAA pretreatment than by two-step adsorption method in the five successive batch fermentation rounds. After the fifth round fermentation, about 60 g xylitol/L fermentation substrate was obtained for SAA pretreatment detoxification, while about 30 g xylitol/L fermentation substrate was obtained for two-step adsorption detoxification.
Polydatin (PD), a resveratrol glucoside extracted from the perennial herbage Polygonum cuspidatum, has been suggested to have wide cardioprotective effects. This study aimed to explore the direct antihypertrophic role of PD in cultured neonatal rat ventricular myocytes (NRVMs) and its therapeutic effects against pressure overload (PO)-induced hypertrophic remodeling and heart failure. Furthermore, we investigated the mechanisms underlying the actions of PD. Treatment of NRVMs with phenylephrine for 72 h induced myocyte hypertrophy, where the cell surface area and protein levels of atrial natriuretic peptide and ?-myosin heavy chain (?-MHC) were significantly increased. The amplitude of systolic Ca(2+) transient was increased, and sarcoplasmic reticulum Ca(2+) recycling was prolonged. Concomitantly, calcineurin activity was increased and NFAT protein was imported into the nucleus. PD treatment restored Ca(2+) handling and inhibited calcineurin-NFAT signaling, thus attenuating the hypertrophic remodeling in NRVMs. PO-induced cardiac hypertrophy was produced by transverse aortic constriction (TAC) in C57BL/6 mice, where the left ventricular posterior wall thickness and heart-to-body weight ratio were significantly increased. The cardiac function was increased at 5 wk of TAC, but significantly decreased at 13 wk of TAC. The amplitude of Ca(2+) transient and calcineurin activity were increased at 5 wk of TAC. PD treatment largely abolished TAC-induced hypertrophic remodeling by inhibiting the Ca(2+)-calcineurin pathway. Surprisingly, PD did not inhibit myocyte contractility despite that the amplitude of Ca(2+) transient was decreased. The cardiac function remained intact at 13 wk of TAC. In conclusion, PD is beneficial against PO-induced cardiac hypertrophy and heart failure largely through inhibiting the Ca(2+)-calcineurin pathway without compromising cardiac contractility.
Cytochrome P450 2E1 (CYP2E1) might be involved in the development of bladder cancer. However, previous studies of any association between CYP2E1 RsaI/PstI polymorphism and bladder cancer risk have yielded conflicting results. In this study, we performed a more precise estimation of the relationship by a meta-analysis based on the currently available evidence from the literature.
The support vector machine (SVM) is one of the most widely used approaches for data classification and regression. SVM achieves the largest distance between the positive and negative support vectors, which neglects the remote instances away from the SVM interface. In order to avoid a position change of the SVM interface as the result of an error system outlier, C-SVM was implemented to decrease the influences of the system's outliers. Traditional C-SVM holds a uniform parameter C for both positive and negative instances; however, according to the different number proportions and the data distribution, positive and negative instances should be set with different weights for the penalty parameter of the error terms. Therefore, in this paper, we propose density-based penalty parameter optimization of C-SVM. The experiential results indicated that our proposed algorithm has outstanding performance with respect to both precision and recall.
BackgroundOffspring of pregnancy complicated with gestational diabetes (GDM) are at high risk for metabolic diseases. The mechanisms behind the association of intrauterine exposure to GDM and high risk of health problems in later life remain largely unknown. The aim of this study was to clarify the alteration in methylation levels at differentially methylated regions (DMRs) of GNAS and IGF2 in fetuses of GDM women and to explore the possible mechanisms linking maternal GDM with high risk of metabolic diseases in later life of GDM offspring.MethodsThe methylation levels were detected in 7 CpG sites of GNAS DMRs and 6 sites of IGF2 DMRs. Methylation levels were significantly higher at sites 4, 5 and 7 of GNAS DMR in GDM compared to normal pregnancy (P¿=¿0.007, 0.008 and 0.008, respectively). The methylation level at site 4 of GNAS was significantly correlated with the presence of GDM (P¿=¿0.003), the methylation levels at site 5 and 7 were significantly correlated with the presence of GDM (P¿=¿0.002 for both) and gestational age (P¿=¿0.027 for both). There were no significant difference in any sites of IGF2 DMR (P¿>¿0.05 for all).ResultsLymphocytes were isolated from umbilical cord blood of infants born to 87 women with GDM and 81 women with normal pregnancy. Genomic DNA was extracted and DNA methylation levels of GNAS and IGF2 DMRs were determined by Massarray quantitative methylation analysis.ConclusionsWe concluded maternal GDM-induced hypermethylation at GNAS DMR and this condition may be among the mechanisms associating maternal GDM with increased risk of metabolic diseases in later life of offspring.
Abstract In this study, a thermoresponsive gel for minocycline (MCL) with chitosan/?-glycerophosphate (C/?-GP) was formulated and its characterization, in vitro release, stability, toxicity and pharmacodynamics were investigated. The formulation containing MCL was prepared by pouring the chitosan solution directly onto the sterilized drug powder and stirring before mixing with the ?-glycerophosphate (?-GP) solution. The final preparations contained 0.5% (w/v) chitosan, 1.8% (w/v) ?-GP and 2% (w/v) MCL. The drug content of prepared gels was in the range of 92-99%, and the pH value of the optimized formulation was found to be 5.6-6.2. The gelation temperature of the prepared C/?-GP thermogelling solutions was 37?°C. Color, consistency, pH, viscosity and drug content of the in situ gels were found to be consistent, and no signs of separation and deterioration were observed over a period of 90 d. In vivo studies showed that rats' liver and kidney tissue sections were normal, with no structural damage. The constituents of the in situ gels formulation had a well-sustained release efficacy on the animal model of periodontitis.
Identification of patients who are at high risk of adverse cardiovascular events after an acute coronary syndrome (ACS) remains a major challenge in clinical cardiology. We hypothesized that quantifying variability in electrocardiogram (ECG) morphology may improve risk stratification post-ACS.
Morphine has been widely used as a clinical anesthetic and analgesic. However, abuse of morphine might result in psychological and physiological dependence. Previous studies have indicated that memory mechanisms play critical roles in morphine dependence.
The topmouth culter (Erythroculter ilishaeformis) is a predatory cyprinid fish that distributes widely in the East Asia. Here we report the liver transcriptome in this organism as a model of predatory fish. Sequencing of 5Gb raw reads led to 27,741 unigenes and produced 11,131 annotatable genes. A total of 7093 (63.7%) genes were found to have putative functions by gene ontology analysis. Importantly, a blast search revealed 4033 culter genes that were orthologous to the zebrafish. Extracted from 38 candidate positive selection genes, 4 genes exhibit strong positive selection based on the ratio of nonsynonymous (Ka) to synonymous substitutions (Ks). In addition, the four genes also indicated the strong positive selection by comparing them between blunt snout bream (Megalobrama amblycephala) and zebrafish. These genes were involved in activator of gene expression, metabolic processes and development. The transcriptome variation may be reflective of natural selection in the early life history of Cyprinidae. Based on Ks ratios, date of the separation between topmouth culter and zebrafish is approximately 64millionyears ago. We conclude that natural selection acts in diversifying the genomes between topmouth culter and zebrafish.
Cracks are an important indicator reflecting the safety status of infrastructures. This paper presents an automatic crack detection and classification methodology for subway tunnel safety monitoring. With the application of high-speed complementary metal-oxide-semiconductor (CMOS) industrial cameras, the tunnel surface can be captured and stored in digital images. In a next step, the local dark regions with potential crack defects are segmented from the original gray-scale images by utilizing morphological image processing techniques and thresholding operations. In the feature extraction process, we present a distance histogram based shape descriptor that effectively describes the spatial shape difference between cracks and other irrelevant objects. Along with other features, the classification results successfully remove over 90% misidentified objects. Also, compared with the original gray-scale images, over 90% of the crack length is preserved in the last output binary images. The proposed approach was tested on the safety monitoring for Beijing Subway Line 1. The experimental results revealed the rules of parameter settings and also proved that the proposed approach is effective and efficient for automatic crack detection and classification.
The structures of many important functional oxides contain networks of metal-oxygen polyhedral units i.e. MOn. The correlation between the configurations and connectivities of these MOn to properties is essentially important to be well established to conduct the design, synthesis and application of new MOn-based functional materials. In this paper, we report on an atomic-scale solution-chemistry approach that for the first time enables TiO6 octahedral network control starting from metastable brookite TiO2 through simultaneously tuning pH values and interfering ions (Fe(3+), Sc(3+), and Sm(3+)). The relationship between solution chemistry and the resultant configuration/connectivity of TiO6 octahedra in TiO2 and lepidocrocite titanate is mapped out. Apart from differing crystalline phases and morphologies, atomic-scale TiO6 octahedral control also endows numerous defect dipoles for giant dielectric responses. The structural and property evolutions are well interpreted by the associated H(+)/OH(-) species in solution and/or defect states associated with Fe(3+) occupation within TiO6 octahedra. This work therefore provides fundamental new insights into controlling TiO6 octahedral arrangement essential for atomic-scale structure-property design.
BackgroundPreeclampsia reduces placental expression and activity of 11ß-hydroxysteroid dehydrogenase type 2 (HSD11B2), leading to an increase in fetal glucocordicoids. The latter has been proposed to be associated with low birth weight and high risk of metabolic diseases in later life of the offspring. This investigation aims to delineate the alteration in methylation levels at CpG sites of HSD11B2 promoter.ResultsMethylation levels of HSD9-2, HSD9-3, HSD23-2 and HSD23-3 and the mean methylation level were significantly lower in preeclampsia than in normal pregnancy (P¿=¿0.002, 0.031, 0.047 and 0.001, respectively and P¿<¿0.001 in mean). The mean methylation level was significantly correlated with preeclampsia after the adjustment of birth weight, maternal age, gestational age at delivery and fetal gender (r¿=¿0.325, P¿<¿0.001).ConclusionsPreeclampsia reduced methylation level at fetal HSD11B2 promoter. A positive correlation existed between HSD11B2 promoter methylation and preeclampsia. Our findings suggest that the methyaltion status of HSD11B2 promoter is a potentially accessible biomarker for preeclampsia. However, further studies are required to address the mechanisms of thehypomethylation at HSD11B2 promoter and the significance of the hypomethylation in the development of metabolic diseases of the fetals born to preeclamptic women.
This study was designed to discuss the effects of 3, 3'-diindolylmethane (DIM) on methionine-choline-deficient (MCD)-diet induced mouse nonalcoholic steatohepatitis (NASH) and the potential mechanisms. NASH mice were administrated with or without DIM at different concentrations for 8weeks. Both the in-vivo and in-vitro effects of DIM on Treg/Th17 imbalance during NASH progression were analyzed. The in-vivo blocking of CD25 or IL-17 was performed to respectively deplete respective function of Treg or Th17 subset. Besides, with the assistance of AhR antagonist CH223191 and anti-TLR4 neutralizing antibody, we designed the in-vitro DIM-incubation experiments to discuss the roles of aryl hydrocarbon receptor (AhR) (CYP1A1, CYP1B1) and toll-like receptor 4 (TLR4) on DIM's effects when shifting Treg/Th17 imbalance. Notably, in NASH mouse models, DIM alleviated hepatic steatosis and inflammation, and shifted the Treg/Th17 imbalance from MCD diet-induced Th17 dominance to Treg dominance. In-vitro, DIM not only significantly up-regulated the mRNAs of Foxp3 (Treg-specific) in purified spleen CD4(+) T cells, but also enhanced the immunosuppressive function of these Treg cells. Besides, DIM significantly up-regulated the proteins of CYP1A1 and CYP1B1 whereas down-regulated those of TLR4 on CD4(+) T cells from MCD-diet mice. Moreover, blocking AhR attenuated while blocking TLR4 enhanced the effects of DIM when regulating Treg/Th17 imbalance. Conclusively, DIM could be used as a potential therapeutic candidate to treat NASH based on its dramatic induction of Treg dominance to alleviate intra-hepatic inflammation, suggesting us a clue that the dietary cruciferous vegetables (containing abundant DIM) might exist as a protective factor for patients with NASH-related liver diseases.
Resistance to chemotherapy is the major cause of colorectal cancer (CRC) treatment failure. The cytokine IL-22, which is produced by T cells and NK cells, is associated with tumorigenesis and tumor progression in cancers. However, the role of IL-22 in chemoresistance has not been investigated. We found that IL-22 levels in tumor tissues and peripheral blood were associated with chemoresistance and indicate poor prognosis for patients who received FOLFOX chemotherapy. In CRC cells, IL-22 was able to attenuate the cytotoxic and apoptosis-inducing effects of 5-FU and OXA by activating the STAT3 pathway and subsequently increasing the expression of anti-apoptotic genes. In addition, IL-22 conferred resistance to 5-FU and OXA by inducing IL-8 autocrine expression through STAT3 activation. Our findings identify IL-22 as a novel chemoresistance cytokine and may be a useful prognostic biomarker for CRC patients receiving FOLFOX chemotherapy.
The large yellow croaker, Larimichthys crocea, is one of the most economically important marine fish species endemic to China. Its wild stocks have severely suffered from overfishing, and the aquacultured species are vulnerable to various marine pathogens. Here we report the creation of a draft genome of a wild large yellow croaker using a whole-genome sequencing strategy. We estimate the genome size to be 728?Mb with 19,362 protein-coding genes. Phylogenetic analysis shows that the stickleback is most closely related to the large yellow croaker. Rapidly evolving genes under positive selection are significantly enriched in pathways related to innate immunity. We also confirm the existence of several genes and identify the expansion of gene families that are important for innate immunity. Our results may reflect a well-developed innate immune system in the large yellow croaker, which could aid in the development of wild resource preservation and mariculture strategies.
Many studies have demonstrated that chemoradiotherapy followed by surgery (CRTS) prolongs the 5-year survival rate of resectable esophageal carcinoma patients. However, the effect of CRTS on postoperative complications, local recurrence and distant metastasis remains controversial. We performed a systematic review of the literature and conducted a meta-analysis to assess the postoperative efficacy of CRTS compared with surgery alone (SA).
Insulin resistance, diabetes and many kinds of cancers are common in overweight and obese individuals. The tumor suppressor p53 is important in securing genetic stability, but its role in the regulation of metabolic processes and cell differentiation remains unclear. We have investigated the role of p53 in adipocyte differentiation. Using 3T3-L1 cells, a mouse embryonic fibroblast preadipocyte model and DIO rat model, p53 expression and function during adipocyte differentiation were investigated. p53 expression increased on the second and fourth day of adipocyte differentiation and decreased thereafter. Its overexpression in 3T3-L1 preadipocytes markedly reduced adipogenesis and marker gene expression. p53 activity was weakened in DIO rat abdominal adipose tissue because of an decreased expression of its activated phosphorylated form. In contrast, p53 knockout enhanced adipogenesis and the expression of marker genes, but significantly reduced insulin-stimulated Akt phosphorylation. These results indicate that p53 partly suppresses preadipocyte differentiation and adipogenesis by regulating adipocyte gene expression and Akt signaling.
BackgroundOur previous studies demonstrated that S100A16 promotes adipogenesis and is involved in weight gain attenuation induced by dietary calcium. Till now, the function of S100A16 in the breast cancer remains to be elucidated.ResultsIn this study, we observed that S100A16 was expressed in higher levels in human breast cancer tissues compared with paired adjacent non-cancerous tissues. Further examination showed that overexpression of S100A16 in MCF-7 cells could increase cell proliferation and colony formation. One major mechanistic change was that S100A16 was able to up-regulate the transcription factors Notch1, ZEB1, and ZEB2, which had the capacities to directly repress the expression of epithelial markers E-cadherin and ß-catenin but increase mesenchymal markers N-cadherin and vimentin, a characterized phenotype of epithelial-mensenchymal transition (EMT). In addition to display with morphologic change, migration and invasion were increased in S100A16 over-expressed MCF-7 cells. Importantly, knockdown of Notch1 by specific siRNA could reverse the EMT induced by S100A16 overexpression, which confirmed that Notch1 played a critical role in the process of EMT induced by S100A16.ConclusionsAll together, our data indicated that S100A16 had a potential function to regulate some embryonic transcription factors to promote EMT in breast cancer cells which may be an important target site for the therapy of breast cancer.
Cornelia de Lange syndrome (CdLS) is a clinically and genetically heterogeneous developmental disorder. The clinical features of CdLS include growth retardation, intellectual disability, limb defects, typical facial dysmorphism and other systemic involvement. Here, we present the clinical and genetic characterization of a sporadic CdLS trio. The proband is a 7-year-old girl with typical CdLS, and both parents are apparently healthy. Whole-exome sequencing of the patient and of both her unaffected parents revealed a previously unobserved de novo mutation in exon 6 of the HDAC8 gene (chrX: 71684483, c.586 A>T; p.M196K). Thus, we have further founded that the p.M196K mutation in HDAC8 is a relevant causal mutation for CdLS.
A multifunctional enveloped nanodevice based on mesoporous silica nanoparticle (MSN) was delicately designed for subcellular co-delivery of drug and therapeutic peptide to tumor cells. Mesoporous silica MCM-41 nanoparticles were used as the core for loading antineoplastic drug topotecan (TPT). The surface of nanoparticles was decorated with mitochondria-targeted therapeutic agent (Tpep) containing triphenylphosphonium (TPP) and antibiotic peptide (KLAKLAK)2 via disulfide linkage, followed by coating with a charge reversal polyanion poly(ethylene glycol)-blocked-2,3-dimethylmaleic anhydride-modified poly(L-lysine) (PEG-PLL(DMA)) via electrostatic interaction. It was found that the outer shielding layer could be removed at acidic tumor microenvironment due to the degradation of DMA blocks and the cellular uptake was significantly enhanced by the formation of cationic nanoparticles. After endocytosis, due to the cleavage of disulfide bonds in the presence of intracellular glutathione (GSH), pharmacological agents (Tpep and TPT) could be released from the nanoparticles and subsequently induce specific damage of tumor cell mitochondria and nucleus respectively with remarkable synergistic antitumor effect.
The demonstration of bystander effect, which means injured cells propagate damage to neighboring cells, in whole organisms has clear implication of the potential relevance of the non-targeted response to human health. Here we show that 10 ?M lead acetate, the optimum concentration for inducing apoptosis confirmed by the expression levels of Bax and Bcl-2, can also induce rat pheochromocytoma (PC12) cells to exert bystander effects to neighboring cells. In a novel co-culture system, GFP-PC12 (Pb(2+)) cells, which were stable transfected with EF1A-eGFP and pre-exposed with lead acetate, were co-cultured with unexposed PC12 cells at a 1:5 ratio. Parachute assays demonstrated the functional gap-junctional intercellular communication (GJIC) formed between Pb(2+)-exposed and unexposed cells. The Pb(2+)-exposed cells induced very similar effects on neighboring unexposed cells to apoptosis coincide with intracellular ROS generation and the collapse of mitochondrial membrane potential (??m). Furthermore, carbenoxolone (CBX), a blocker of GJIC, inhibited the bystander effects. The results indicate that the Pb(2+)-induced insults propagate through GJIC between PC12 cells, while inducing the bystander cells to apoptosis via ROS-mitochondria-dependent apoptotic signaling.
The peptide QRFP plays an important role in the regulation of vertebrate feeding behavior. In this study, we cloned the full length cDNA of a QRFP precursor in a teleost fish, the orange-spotted grouper (Epinephelus coioides). Sequence analysis has shown that the functional regions of QRFP in other vertebrates (QRFP-25 and QRFP-7) are conserved in orange-spotted grouper. RT-PCR demonstrated that the pre-processed mRNA of QRFP is widely expressed in orange-spotted grouper. Three days of food deprivation did not change the hypothalamic pre-processed QRFP expression. However, QRFP expression significantly increased when the fish were reefed after three days of fasting. Intraperitoneal injection of QRFP-25 peptide to orange-spotted grouper suppressed expression of orexin, but elevated expression of pro-opiomelanocortin (POMC) in the hypothalamus. We also investigated the effects of QRFP-25 on the expression of reproductive genes. The peptide suppressed the expression of seabream-type gonadotropin-releasing hormones (sbGnRH), luteinizing hormone beta subunit (LH?) and follicle-stimulating hormone beta subunit (FSH?) in vivo, as well as inhibited the expression of LH? and FSH? in pituitary cells in primary culture. Our results indicate that QRFP may play an inhibitory role in the regulation of feeding behavior and reproduction in orange-spotted grouper.
Eight single-isomer ammonium-?-cyclodextrin derivatives with different side chains were successfully developed as chiral selectors for the chiral separation of selected racemates in capillary electrophoresis. The number of substituted groups at N-atom as well as the alkyl chain length greatly influenced the chiral separation. With the numbers of hydroxylalkyl groups at N-atom growing, the aqueous solubility of resolving agents were distinctly decreased and chiral separation ability was also significantly reduced. The apparent complex stability constants between CDs and analytes were further determined. The best enantioseparations of hydroxyl acids was achieved with the use of mono-6(A) -(3-hydroxypropyl)-1-ammonium-?-cyclodextrin chloride and mono-6(A) -(3-methoxypropyl)-1-ammonium-?-cyclodextrin chloride. The nuclear magnetic resonance experiments were carried out using them with mandelic acid as guest molecules, revealing the inclusion pattern as well as electrostatic interactions and hydrogen bonding interactions as additional chiral driving force. The contribution of potential interaction sites in the sidearm could enhance the enantioseparations.
Analysis of the related risks of disease provides a scientific basis for disease prevention and treatment, hospital management, and policy formulation by the changes in disease spectrum of patients in hospital. Retrospective analysis was made to the first diagnosis, age, gender, daily average cost of hospitalized patients, and other factors in the First Affiliated Hospital of Nanjing Medical University during 2006-2013. The top 4 cases were as follows: cardiovascular disease, malignant tumors, lung infections, and noninsulin dependent diabetes mellitus. By the age of disease analysis, we found a younger age trend of cardiovascular disease, and the age of onset of cancer or diabetes was somewhat postponed. The average daily cost of hospitalization and the average daily cost of the main noncommunicable diseases were both on the rise. Noncommunicable diseases occupy an increasingly important position in the constitution of the disease, and they caused an increasing medical burden. People should pay attention to health from the aspects of lifestyle changing. Hospitals should focus on building the appropriate discipline. On the other hand, an integrated government response is required to tackle key risks. Multiple interventions are needed to lower the burden of these diseases and to improve national health.
Individuals with gallbladder carcinoma (GBC), the most aggressive malignancy of the biliary tract, have a poor prognosis. Here we report the identification of somatic mutations for GBC in 57 tumor-normal pairs through a combination of exome sequencing and ultra-deep sequencing of cancer-related genes. The mutation pattern is defined by a dominant prevalence of C>T mutations at TCN sites. Genes with a significant frequency (false discovery rate (FDR)<0.05) of non-silent mutations include TP53 (47.1%), KRAS (7.8%) and ERBB3 (11.8%). Moreover, ErbB signaling (including EGFR, ERBB2, ERBB3, ERBB4 and their downstream genes) is the most extensively mutated pathway, affecting 36.8% (21/57) of the GBC samples. Multivariate analyses further show that cases with ErbB pathway mutations have a worse outcome (P=0.001). These findings provide insight into the somatic mutational landscape in GBC and highlight the key role of the ErbB signaling pathway in GBC pathogenesis.
Distant hybridization can combine together the genomes of different species, which leads to changes of the offspring in phenotypes and genotypes. In this study, we successfully establish a fertile hybrid lineage by intergeneric hybridization of female blunt snout bream (BSB, Megalobrama amblycephala)×male topmouth culter (TC, Culter alburnus) and investigate some important biological traits of this lineage including the morphological traits, chromosomal number, karyotype, DNA content, gonadal development, egg and milt yield, sperm shape and density, fertilization rate and early survival rate. The results show that: (1) the diploid and triploid hybrids coexist in F1 and only diploid hybrids are found in F2, in which the diploid hybrids of F1 and F2 possess 48 chromosomes with one chromosome set of BSB and one chromosome set of TC, and the triploid hybrids of F1 possess 72 chromosomes with two chromosome sets of BSB and one chromosome set of TC. (2) All the tested males and females of the diploid F1 and F2 hybrids have the normal gonadal development and produce mature sperm and egg, respectively, which are fertilized with each other to form F2 and F3 hybrids, respectively, and finally form a diploid hybrid lineage (F1-F3). (3) The good fertility of the F1 and F2 hybrids of female BSB×male TC potentially provides reproductive base to make the hybrid lineage propagate from one generation to another. The formation of the hybrid lineage (F1-F3) also provides an ideal model to research the reproductive rules of distant hybrid progeny.
Foam cell formation is the hallmark of atherosclerosis. Both telmisartan and autophagy protect against the development of atherosclerosis. However, it has yet to be elucidated whether telmisartan prevents vascular smooth muscle cell (VSMC)-derived foam cell formation. Vascular smooth muscle cells isolated from the thoracic aorta of male C57BL/6J mice were used for this study. To induce foam cell formation, primary VSMCs were incubated in 80 ?g/ml oxLDL for 24 h. LC3, beclin-1, PPAR?, AMPK, p-AMPK, mTOR and p-mTOR expression were determined via Western blot. Lipid accumulation was evaluated via oil red O staining and intracellular total cholesterol level measurement. Our study demonstrated that telmisartan dose-dependently increased the expression of beclin-1, the LC3II/LC3I ratio and the quantity of GFP-labeled autophagosomes, displaying a peak effect at 10 ?M. In control siRNA-transfected VSMCs, telmisartan (10 ?M) decreased lipid droplet accumulation and the total cholesterol level significantly. In contrast, in Atg7 siRNA-transfected VSMCs, telmisartan failed to attenuate lipid accumulation. In addition, telmisartan dose-dependently increased the expression of PPAR? and p-AMPK and decreased the expression of p-mTOR. GW9662 attenuated the telmisartan-induced increase in PPAR? expression, the LC3-II/LC3-I ratio and p-AMPK expression and the telmisartan-induced decrease in p-mTOR expression. Compound C restored mTOR activity and abolished the increase in the LC3-II/LC3-I ratio. Rapamycin significantly reduced p-mTOR expression and increased the LC3-II/LC3-I ratio. In conclusion, this study provides evidence that the chronic pharmacological activation of the PPAR?-mediated autophagy pathway using telmisartan may represent a promising therapeutic strategy for atherosclerosis.
Distant hybridization refers to crosses between two different species or higher-ranking taxa that enables interspecific genome transfer and leads to changes in phenotypes and genotypes of the resulting progeny. If progeny derived from distant hybridization are bisexual and fertile, they can form a hybrid lineage through self-mating, with major implications for evolutionary biology, genetics, and breeding. Here, we review and summarize the published literature, and present our results on fish distant hybridization. Relevant problems involving distant hybridization between orders, families, subfamilies, genera, and species of animals are introduced and discussed, with an additional focus on fish distant hybrid lineages, genetic variation, patterns, and applications. Our review serves as a useful reference for evolutionary biology research and animal genetic breeding.
The insulin-like growth factor (Igf) family is an evolutionarily conserved system essential for normal growth and development in vertebrates. Unlike mammals, four distinct Igf ligands (Igf1, Igf2a, Igf2b and Igf3) and two Igf type 1 receptors (Igf1ra and Igf1rb) are present in zebrafish. However, the localization of these multiple ligands and receptors especially the recently discovered igf3 during early development of zebrafish is poorly understood. In this study, detailed expression patterns of these components of the Igf system during embryogenesis of zebrafish were analyzed. It was found that igf1 is specifically expressed in the trigeminal ganglia region from 18 hpf to 72 hpf, while igf2a is restricted to the caudal regions of the notochord from 14 hpf to 18 hpf as well as in the midbrain, dorsal hind brain and otic vesicle at 24 hpf. On the other hand, igf2a is highly expressed in the midbrain and pharyngeal arch region at 48 hpf, followed by its appearance in the liver and brain at 72 hpf, while igf2b is restricted to the floor plate and hypochord from 12 hpf to 18 hpf, and strong expression is also detected in the midbrain and dorsal hind brain at 24 hpf. The teleost specific igf3 is highly expressed in the pharyngeal arch region before 24 hpf, but is then restricted to the sternohyoideus after 48 hpf. The receptor subtype igf1ra is ubiquitously expressed before 24 hpf but is confined to the brain at 72 hpf. However, igf1rb is widely expressed before 10 hpf, but is more confined to the brain region at 24 hpf and 72 hpf. This dynamic temporal-spatial expression during embryogenesis of zebrafish, together with the unique and overlapping expression patterns of the Igf ligands and receptors suggest the coordination of the divergent functions of the Igf system during early development in zebrafish.
Copy number variations of FCGR3B are associated with several immune related diseases such as systemic lupus erythematosus, rheumatoid arthritis and primary Sjögren's syndrome. Little is known about the association between FCGR3B copy number variants and psoriasis.
Elevated uric acid causes direct injury to pancreatic ?-cells. In this study, we examined the effects of luteolin, an important antioxidant, on uric acid-induced ?-cell dysfunction. We first evaluated the effect of luteolin on nitric oxide (NO) formation in uric acid-stimulated Min6 cells using the Griess method. Next, we performed transient transfection and reporter assays to measure transcriptional activity of nuclear factor (NF)-?B. Western blotting assays were also performed to assess the effect of luteolin on the expression of MafA and inducible NO synthase (iNOS) in uric acid-treated cells. Finally, we evaluated the effect of luteolin on uric acid-induced inhibition of glucose-stimulated insulin secretion (GSIS) in Min6 cells and freshly isolated mouse pancreatic islets. We found that luteolin significantly inhibited uric acid-induced NO production, which was well correlated with reduced expression of iNOS mRNA and protein. Furthermore, decreased activity of NF-?B was implicated in inhibition by luteolin of increased iNOS expression induced by uric acid. Besides, luteolin significantly increased MafA expression in Min6 cells exposed to uric acid, which was reversed by overexpression of iNOS. Moreover, luteolin prevented uric acid-induced inhibition of GSIS in both Min6 cells and mouse islets. In conclusion, luteolin protects pancreatic ?-cells from uric acid-induced dysfunction and may confer benefit on the protection of pancreatic ?-cells in hyperuricemia-associated diabetes.
Traumatic brain injury (TBI) is a major cause of disability or death worldwide, especially in the young. Thus, effective medication with few side effects needs to be developed. This work aimed to explore the potential benefits of formononetin (FN) on TBI rodent model and to discuss the regarding mechanism. These findings showed that FN effectively increased the activities of glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD) in brain tissue of TBI rats (P<0.01), while it reduced intracephalic malonaldehyde (MDA), tumor necrosis factor-? (TNF-?) and interleukin-6 (IL-6) concentrations (P<0.01). Meanwhile, the hydrocephalus in the TBI rat was alleviated, and the injured nerve cell of the lesioned brain was reduced as showed in hematoxylin-eosin (HE) staining assay. In addition, the endogenous mRNA level of cyclooxygenase-2 (COX-2) in the brain of the TBI rat was significantly down-regulated (P<0.01). Furthermore, the protein expression of nuclear factor E2-related factor 2 (Nrf2) was effectively up-regulated (P<0.01). Taken together, we conclude that formononetin mediates the promising anti-TBI effects against neurocyte damage, which the underlying mechanisms are associated with inhibiting intracephalic inflammatory response and oxidative stress for neuroprotection.
We retrospectively investigated the prognostic factors of acute myeloid leukemia (AML) in 152 Chinese patients with de novo AML who were older than 60 years of age and who received treatment at our hospital. Log-rank test showed that 6 parameters including older age, higher white blood cell (WBC) counts, lactate dehydrogenase (LDH) and bone marrow (BM) blasts at diagnosis, unfavorable risk cytogenetics, and non-mutated CEBP? were significant adverse prognostic factors of overall survival (OS) for elderly AML patients (P ?=? 0.0013, 0.0358, 0.0132, 0.0242, 0.0236 and 0.0130, respectively). Moreover, older age and higher LDH were significant adverse predictors for relapse-free survival (RFS) (P ?=? 0.0447 and 0.0470, respectively). Univariate analysis revealed similar results for OS to those of the log-rank test and only higher LDH at diagnosis was a significant adverse predictor for RFS (P ?=? 0.028, HR: 1.979, 95%CI: 1.075-3.644). In multivariate analysis, we identified 2 trends towards independent prognostic factors for OS, including BM blasts at diagnosis (P ?=? 0.057, HR: 1.676, 95%CI: 0.984-2.854) and mutation status of CEBP? (P ?=? 0.064, HR: 4.173, 95%CI: 0.918-18.966). Our data indicated that older age, gender and a previous history of hematologic diseases resulted in lower complete remission rate (P ?=? 0.012, 0.051 and 0.086, respectively). We further developed an easy scoring system for predicting prognosis and response to induction therapy in older AML patients. Patients who had lower scores showed significantly longer OS and RFS (P ?=? 0.0006 and 0.1001, respectively) and higher CR rate (P ?=? 0.014). Our research is limited by its retrospective nature and the results from our study need to be further validated by prospective randomized clinical trials.
The molecular interactions between pancreatic lipase (PL) and four tea polyphenols (EGCG analogs), like (-)-epigallocatechin gallate (EGCG), (-)-gallocatechin gallate (GCG), (-)-epicatechin gallate (ECG), and (-)-epigallocatechin (EC), were studied from PL activity, conformation, kinetics and thermodynamics. It was observed that EGCG analogs inhibited PL activity, and their inhibitory rates decreased by the order of EGCG>GCG>ECG>EC. PL activity at first decreased rapidly and then slowly with the increase of EGCG analogs concentrations. ?-Helix content of PL secondary structure decreased dependent on EGCG analogs concentration by the order of EGCG>GCG>ECG>EC. EGCG, ECG, and EC could quench PL fluorescence both dynamically and statically, while GCG only quenched statically. EGCG analogs would induce PL self-assembly into complexes and the hydrodynamic radii of the complexes possessed a close relationship with the inhibitory rates. Kinetics analysis showed that EGCG analogs non-competitively inhibited PL activity and did not bind to PL catalytic site. DSC measurement revealed that EGCG analogs decreased the transition midpoint temperature of PL enzyme, suggesting that these compounds reduced PL enzyme thermostability. In vitro renaturation through urea solution indicated that interactions between PL and EGCG analogs were weak and non-covalent.
Pressure ulcers are very common in hospital patients. Though many studies have been reported in many countries, the large-scale benchmarking prevalence of pressure ulcers in China is not available. The aim of this study is to quantify the prevalence of pressure ulcers and the incidence of hospital-acquired pressure ulcers and analyze risk factors in hospitalized patients in China. A multi-central cross-sectional survey was conducted in one university hospital and 11 general hospitals in China. The Minimum Data Set (MDS) recommended by European Pressure Ulcer Advisory Panel (EUPAP) was used to collect information of inpatients. All patients stayed in hospital more than 24 hours and older than 18 years signed consent form and were included. Data from 39952 out of 40415 (98.85%) inpatients were analyzed. Of the 39952 patients, 631 patients (including 1024 locations) had pressure ulcers. The prevalence rate of pressure ulcers in 12 hospitals was 1.58% (0.94-2.97%). The incidence of hospital-acquired pressure ulcers (HAPU) was 0.63% (0.20-1.20%). The most common locations developed pressure ulcers were sacrum, heels, and iliac crests. The common stages of pressure ulcers were stage I and II. Patients in Intensive Care Unit, Geriatric and Neurological Department were easier to develop pressure ulcers. The prevalence and incidence of pressure ulcers in China was lower than that reported in European and other countries. The stages of pressure ulcers in China were different than that reported in European countries. Our study provides with a baseline value for intensive research on pressure ulcer in China.
Flapping wings continuously create and send vortices into their wake, while imparting downward momentum into the surrounding fluid. However, experimental studies concerning the details of the three-dimensional vorticity distribution and evolution in the far wake are limited. In this study, the three-dimensional vortex wake structure in both the near and far field of a dynamically scaled flapping wing was investigated experimentally, using volumetric three-component velocimetry. A single wing, with shape and kinematics similar to those of a fruitfly, was examined. The overall result of the wing action is to create an integrated vortex structure consisting of a tip vortex (TV), trailing-edge shear layer (TESL) and leading-edge vortex. The TESL rolls up into a root vortex (RV) as it is shed from the wing, and together with the TV, contracts radially and stretches tangentially in the downstream wake. The downwash is distributed in an arc-shaped region enclosed by the stretched tangential vorticity of the TVs and the RVs. A closed vortex ring structure is not observed in the current study owing to the lack of well-established starting and stopping vortex structures that smoothly connect the TV and RV. An evaluation of the vorticity transport equation shows that both the TV and the RV undergo vortex stretching while convecting downwards: a three-dimensional phenomenon in rotating flows. It also confirms that convection and secondary tilting and stretching effects dominate the evolution of vorticity.
To construct a recombinant lentiviral vector containing integrin ?1 shRNA to provide an effective tool for integrin ?1 gene effect and a possible mechanism of Sombati cell of clinical refractory epilepsy.
To observe the efficacy of Danzhi Xiaoyao Pill (DXP) in anovulation infertility patients with polycystic ovary syndrome (PCOS) of pathogenic fire derived from stagnation of Gan-qi (PFDSG) complicated insulin resistance (IR).
To increase the dissolution rate and extent of valsartan, valsartan nanosuspensions have been prepared. Controlled precipitation assisted with sonication is utilized to prepare valsartan nanosuspensions, the concentration of the drug, stabilizer and costablizer had a great effect on the stability of the preparation according to the pre-experiment. So the method of central composite design-response surface is used to optimize the prescription based on the above three factors and the particle size as the response value. The software Origin 8.0 is used to draw the view of the three-dimensional effects and 2D contour map, to get the optimal prescription area. Valsartan nanosuspensions were prepared. The mean diameter and zeta potential are about 216.6 nm and -57.7 mV, respectively. Compared with the microsuspensions and commercial preparation, the dissolution of valsartan nanosuspensions was faster and the bioavailability can be enhanced to some extent.
Colloidal dispersions with a short-range attraction and long-range repulsion can exhibit an intriguing intermediate range order, manifested in scattering experiments as a low-q peak in the structure factor. Monte Carlo simulations are performed on fluids that exhibit intermediate range order to explicitly determine its connection to a possible state of microphase separation, equilibrium clustering. This is accomplished by decomposing the structure factor into cluster-cluster, monomer-monomer, and cross-correlations that cannot be extracted from experimental scattering patterns. Our simulation results indicate that the intermediate range order arises from either monomeric or cluster species, depending on solution conditions, and reflects the presence of a preferred length scale that is not trivially related to the interparticle potential. Further, criteria are established to define monomer, cluster, and percolated states in these systems that facilitate further studies. Combining scattering techniques with simulations provides an effective method for identifying clustered states in complex fluids.
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