Breast-conserving surgery followed by radiation therapy has become the standard of care for early stage breast cancer. However, there are some patients that develop a local failure. We have previously shown that Bcl-2 overexpression was associated with an increased risk of local recurrence in patients with early stage breast cancer. The purpose of this study was to explore an approach to overcome radiation resistance by targeting pro-survival Bcl-2 family proteins in breast cancer cells. The breast cancer cell lines MCF-7, ZR-75-1 and MDA-MB231 were used in this study. siRNAs were employed to silence myeloid cell leukemia 1 (Mcl-1). A small molecule inhibitor of Bcl-2, ABT-737, was used to target anti-apoptotic Bcl-2 family proteins. Apoptosis was identified by FITC Annexin V, PI staining and Western blot analysis. The sensitivity to ionizing radiation and ABT-737 were measured by clonogenic assays. The effect of radiation and ABT-737 was also tested in a MCF-7 xenograft mouse model. Our data demonstrate that the combination of ABT-737 and radiation-induced apoptosis had an inhibitory effect on breast cancer cell proliferation. However, treatment with ABT-737 resulted in elevated Mcl-1 in breast cancer cell lines. Targeting Mcl-1 by siRNA sensitized MCF-7 cells to ABT-737. We revealed that radiation blunted Mcl-1 elevation induced by ABT-737, and that radiation downregulated Mcl-1 by promoting its degradation. Our results indicate that radiation and ABT-737 exert a synergistic effect on breast cancer cell lines through downregulating Mcl-1 and activating the bak-apoptotic pathway. These results support the combination of radiation and pro-survival Bcl-2 family inhibitor as a potential novel therapeutic strategy in the local-regional management of breast cancer.
Abstract Natural killer (NK) cells may modulate the pathogenesis of primary HIV-1 infection. However, the relationship between the number and function of NK cells during an acute HIV-1 infection and HIV-1 disease progression remains to be elucidated. In this study, we enrolled two distinct patient groups. One group progressed to where their CD4 cell counts fell below 200 cells/?l within 2 years (CD4Low group), while the CD4 cell counts of the other group remained above 500 cells/?l for over 2 years (CD4High group). We compared the number and function of NK cells during the first year of HIV-1 infection between the two distinct groups. We found that the number of total NK cells and the number of cells in the CD56(dim)CD16(pos) subset rapidly decreased in both groups during early HIV-1 infection. The absolute number of total NK cells and CD56(dim)CD16(pos) NK cells was significantly higher in the CD4High group when compared to the CD4Low group during the first month of infection. No significant difference between the numbers of CD56(bright)CD16(neg) NK cells of the two groups was observed. However, more CD56(neg)CD16(pos) NK cells were found in the CD4Low group than in the CD4High group. We also found that NK cell function increased within the first 3 months of HIV-1 infection in the CD4High group and then exhibited a decreasing trend. However, in the CD4Low group, NK cell function did not increase significantly within the first 3 months of HIV-1 infection but then gradually increased. We concluded, therefore, that robust NK functioning cells that are present during an acute HIV-1 infection might be beneficial in controlling HIV-1 disease progression.
The conversion of solar energy with simultaneous electric energy storage provides a promising means for optimizing energy utilization efficiency and reducing device volume. In this paper, a 3-dimensional mesoporous carbon coated branched TiO2 nanowire composite is rationally designed for direct conversion and storage of solar energy as electric double-layer capacitive energy. The 1-dimensional, crystalline TiO2 trunks serve as long light absorption and continuous charge transport pathways, and the high-density TiO2 branches can efficiently increase the contact area with the surface coated mesoporous carbon layers. In addition, the ordered and uniformed mesopores provide large pore sizes for electrolyte penetration, and a high surface area for charge absorption and storage. Under a 1-sun illumination and no external electric bias, this branched TiO2/mesoporous carbon composite exhibits specific capacitances of over 30 and 23.4 F g(-1), at current densities of 0.1 and 0.5 A g(-1), respectively. An excellent stability of >50 photocharging-electrical discharging cycles has also been demonstrated, suggesting the potential of further developing this hybrid material structure for simultaneous solar conversion and electric energy storage.
The diverse receptor families of the innate immune system activate signal transduction pathways that are important for host defence, but common themes to explain the operation of these pathways remain undefined. In this Opinion article, we propose - on the basis of recent structural and cell biological studies - the concept of supramolecular organizing centres (SMOCs) as location-specific higher-order signalling complexes in which increased local concentrations of signalling components promote the intrinsically weak allosteric interactions that are required for enzyme activation. We suggest that SMOCs are assembled on various membrane-bound organelles or other intracellular sites, which may assist signal amplification to reach a response threshold and potentially define the specificity of cellular responses that are induced in response to infectious and non-infectious insults.
Solid phase synthesis of 1,3,4-oxadiazin-5(6R)-one and 1,3,4-oxadiazol-2-one scaffolds from resin-bound acyl hydrazides is described. We demonstrate here that the reactions of resin-bound aryl or hetero-aromatic acyl hydrazides with 2-substituted-2-bromoacetic acids and 4-nitrophenyl chloroformate and subsequent treatment with DIEA lead to intramolecular cyclization reactions to produce six-membered 1,3,4-oxadiazin-5(6R)-ones and five-membered 1,3,4-oxadiazol-2-ones, respectively. We also show that acyl hydrazide-derived 1,3,4-oxadiazol-2-ones may be useful serine hydrolase inhibitors.
Non-obstructive azoospermia (NOA) is a complex and severe condition whose etiology remains largely unknown. In a genome-wide association study (GWAS) of NOA in Chinese men, few loci reached genome-wide significance, although this might be a result of genetic heterogeneity. Single nucleotide polymorphisms (SNPs) without genome-wide significance may also indicate genes that are essential for fertility, and multiple stage validation can lead to false-negative results. To perform large-scale functional screening of the genes surrounding these SNPs, we used in vivo RNA interference (RNAi) in Drosophila, which has a short maturation cycle and is suitable for high-throughput analysis. The analysis found that 7 (31.8%) of the 22 analyzed orthologous Drosophila genes were essential for male fertility. These genes corresponded to nine loci. Of these genes, leukocyte-antigen-related-like (Lar) is primarily required in germ cells to sustain spermatogenesis, whereas CG12404, doublesex-Mab-related 11E (dmrt11E), CG6769, estrogen-related receptor (ERR) and sulfateless (sfl) function in somatic cells. Interestingly, ERR and sfl are also required for testis morphogenesis. Our study thus demonstrates that SNPs without genome-wide significance in GWAS may also provide clues to disease-related genes and therefore warrant functional analysis.
The applications of photodynamic therapy (PDT) are usually limited by photosensitizer's side effect and the singlet oxygen's short half-life. Herein, we demonstrate a dual-targeting (both cellular and subcellular targeting) strategy to enhance the PDT efficacy. A cationic porphyrin derivative (MitoTPP) was synthesized as the mitochondrion-targeting photosensitizer, and the dual-targeting PDT system was then fabricated by encapsulating MitoTPP into the acid-responsive and folic acid (FA)-modified polymer micelles. Under acidic pH, the micelles swell as a result of protonation of tertiary amines and disruption of the nucleobase pairing, thereby causing the release of the photosensitizer. Confocal microscope observation shows that the dual-targeting and micelle-based PDT system can preferably enter folate receptor (FR)-positive cancer cells, and upon cellular internalization, the MitoTPP molecules are released from the micelles and selectively accumulate in mitochondria. Under light irradiation, the singlet oxygen generated by the photosensitizer causes the oxidant damage to the mitochondrial and subsequently the apoptosis of the cells, as evidenced by the loss of mitochondrial membrane potential. Cell viability assays indicate that dual-targeting micelle-based systems exhibit enhanced cytotoxicity toward FR-positive cells. This study may provide a new approach for effectively enhancing the action of PDT systems.
Lymphatic valves prevent the backflow of the lymph fluid and ensure proper lymphatic drainage throughout the body. Local accumulation of lymphatic fluid in tissues, a condition called lymphedema, is common in individuals with malformed lymphatic valves. The vascular endothelial growth factor receptor 3 (VEGFR3) is required for the development of lymphatic vascular system. The abundance of VEGFR3 in collecting lymphatic trunks is high before valve formation and, except at valve regions, decreases after valve formation. We found that in mesenteric lymphatics, the abundance of epsin 1 and 2, which are ubiquitin-binding adaptor proteins involved in endocytosis, was low at early stages of development. After lymphatic valve formation, the initiation of steady shear flow was associated with an increase in the abundance of epsin 1 and 2 in collecting lymphatic trunks, but not in valve regions. Epsin 1 and 2 bound to VEGFR3 and mediated the internalization and degradation of VEGFR3, resulting in termination of VEGFR3 signaling. Mice with lymphatic endothelial cell-specific deficiency of epsin 1 and 2 had dilated lymphatic capillaries, abnormally high VEGFR3 abundance in collecting lymphatics, immature lymphatic valves, and defective lymph drainage. Deletion of a single Vegfr3 allele or pharmacological suppression of VEGFR3 signaling restored normal lymphatic valve development and lymph drainage in epsin-deficient mice. Our findings establish a critical role for epsins in the temporal and spatial regulation of VEGFR3 abundance and signaling in collecting lymphatic trunks during lymphatic valve formation.
Described here are synthesis and biological evaluations of diversified groups of over 57 ertapenem prodrugs which include alkyl, methylenedioxy, carbonate, cyclic carbonate, carbamate esters, and esters containing active transport groups (e.g., carboxyl, amino acid, fatty acids, cholesterol) and macrocyclic lactones linking the two carboxyl groups. Many of the prodrugs were rapidly hydrolyzed in rat plasma but not in human plasma and were stable in simulated gastrointestinal fluid. The diethyl ester prodrug showed the best total absorption (>30%) by intredeudenal dosing in dogs, which could potentially be improved by formulation development. However, its slow rate of the hydrolysis to ertapenem also led to the presence of large amounts of circulating monoester metabolites, which pose significant development challenges. This study also suggests that the size of susbtituents at C-2 of carbapenem (e.g., benzoic acid of ertapenem) has significant impact on the absorption and the hydrolysis of the prodrugs.
Antibody response plays a crucial role against hepatitis C virus (HCV) infection and our understanding of this intricate progress in vivo is far from complete. We previously reported a novel and robust technique based on a large combinatorial viral antigen library displayed on the surface of the yeast Saccharomyces cerevisiae, allowing comprehensive profiling of polyclonal antibody responses in vivo in both qualitative and quantitative terms. Here, we report the generation and application of a combinatorial library of HCV JFH1 envelope glycoprotein to profile antibody response in four HCV chronically infected individuals. Systematic analysis of the location and frequency of antigenic fragments along the JFH1 envelope glycoprotein, we showed that the major binding antibody response was targeted to E2 (80.9-99.8%) while that against E1 was relatively small (0.3-19.0%). A total of five major antigenic domains (D1-D5) were identified; one was within the E1 and additional four within the E2, despite substantial variability among the different individuals. However, serum absorption with the yeast clones containing the antigenic domain D1 resulted in more reduction in neutralizing antibody activity against pseudotyped HCV than those in E2, suggesting that the E1 contained additional neutralizing epitopes. Our results have provided additional insghts into HCV-specific antibody response in human and should assist our better understanding of protective antibody immunity and to guide development of effective vaccines and therapeutics against HCV infection.
Increasing evidence reveals that diverse non-coding RNAs (ncRNAs) play critically important roles in viral infection. Viruses can use diverse ncRNAs to manipulate both cellular and viral gene expression to establish a host environment conducive to the completion of the viral life cycle. Many host cellular ncRNAs can also directly or indirectly influence viral replication and even target virus genomes. ViRBase (http://www.rna-society.org/virbase) aims to provide the scientific community with a resource for efficient browsing and visualization of virus-host ncRNA-associated interactions and interaction networks in viral infection. The current version of ViRBase documents more than 12 000 viral and cellular ncRNA-associated virus-virus, virus-host, host-virus and host-host interactions involving more than 460 non-redundant ncRNAs and 4400 protein-coding genes from between more than 60 viruses and 20 hosts. Users can query, browse and manipulate these virus-host ncRNA-associated interactions. ViRBase will be of help in uncovering the generic organizing principles of cellular virus-host ncRNA-associated interaction networks in viral infection.
To study the effects of alkaloids from Coptidis Rhizoma on low-density lipoprotein receptor (LDLR) mRNA expression and antihyperlipedemic levels. The LDLR mRNA expression were detected by real time fluorescence quantitative PCR, and the levels of total cholesterol (TC), triglyceride (TG), low density lipoprotein (LDL-c) and high-density lipoprotein cholesterol (HDL-c) in serum were measured at the first and last examination. The results show that, after the drug treatment, compared with the model group, each drug group showed a lipid-lowering effect. Especially, coptisine, palmatine, jatrorrhinze were significantly reduced TC, TG, LDL-c (P < 0.05, P < 0.01), and increased HDL-c (P < 0.01). In addition, they also increased mRNA expression of the LDLR in liver and HepG2 cells. The results showed that alkaloids from Coptidis Rhizoma can regulate lipid metabolism disorder, and coptisine have the best lipid-lowering effect.
RNA-seq has become a routine technique in differential expression (DE) identification. Scientists face a number of experimental design decisions, including the sample size. The power for detecting differential expression is affected by several factors, including the fraction of DE genes, distribution of the magnitude of DE, distribution of gene expression level, sequencing coverage and the choice of type I error control. The complexity and flexibility of RNA-seq experiments, the high-throughput nature of transcriptome-wide expression measurements and the unique characteristics of RNA-seq data make the power assessment particularly challenging.
In this paper, we propose a facile synthetic strategy for uniform bismuth@carbon (Bi@C) core-shell nanowires, which are prepared via controlled pyrolysis of Bi2S3@glucose-derived carbon-rich polysaccharide (GCP) nanowires under an inert atmosphere. Carbonization of GCP and pyrolysis of Bi2S3 into Bi occur at 500 °C and 600 °C, respectively, which increase the specific surface area and the pore volume of the nanowires, thus allowing accommodation of more lithium ions. Meanwhile, the carbon shell serves as a buffer layer to relieve large volume expansion-contraction during the electrochemical alloy formation, and can also efficiently reduce the aggregation of the nanowires. As a proof-of-concept, the Bi@C core-shell nanowire anodes manifest enhanced cycling stability (408 mA h g(-1) after 100 cycles at a current density of 100 mA g(-1)) and rate capacity (240 mA h g(-1) at a current density of 1 A g(-1)), much higher than pure bismuth microparticles and corresponding Bi2S3@C nanowires.
The spatial and temporal distribution of 16 polycyclic aromatic hydrocarbons (PAHs) has been investigated in water and sediments of Zhoushan coastal area every two months in 2012. The concentrations of total PAHs ranged from 382.3 to 816.9 ng x L(-1), with the mean value of 552.5 ng x L(-1) in water; whereas it ranged from 1017.9 to 3047.1 ng x g(-1), with the mean value of 2 022.4 ng x g(-1) in sediment. Spatial distribution showed that Yangshan and Yanwoshan offshore area had the maximum and minimum of total PAHs contents in water, while the maximum and minimum occurred at Yangshan and Zhujiajian Nansha offshore area in sediment. Temporal distribution revealed that total PAHs contents in water reached the maximum and minimum values in October and June, however in sediments these values were found in August and June, respectively. The PAHs pollution was affected by oil emission, charcoal and coal combustion. Using the biological threshold and exceeded coefficient method to assess the ecological risk of PAHs in Zhoushan coastal area, the result showed that sigma PAHs had a lower probability of potential risk, while there was a higher probability of potential risk for acenaphthylene monomer, and there might be ecological risk for acenaphthene and fluorene. Distribution of PAHs between sediment and water showed that Zhoushan coastal sediment enriched a lot of PAHs, meanwhile the enrichment coefficient (K(d) value) of sediment in Daishan island was larger than that in Zhoushan main island.
Wearable healthcare monitoring systems (WHMSs) have received significant interest from both academia and industry with the advantage of non-intrusive and ambulatory monitoring. The aim of this paper is to investigate the use of an adaptive filter to reduce motion artefact (MA) in physiological signals acquired by WHMSs. In our study, a WHMS is used to acquire ECG, respiration and triaxial accelerometer (ACC) signals during incremental treadmill and cycle ergometry exercises. With these signals, performances of adaptive MA cancellation are evaluated in both respiration and ECG signals. To achieve effective and robust MA cancellation, three axial outputs of the ACC are employed to estimate the MA by a bank of gradient adaptive Laguerre lattice (GALL) filter, and the outputs of the GALL filters are further combined with time-varying weights determined by a Kalman filter. The results show that for the respiratory signals, MA component can be reduced and signal quality can be improved effectively (the power ratio between the MA-corrupted respiratory signal and the adaptive filtered signal was 1.31 in running condition, and the corresponding signal quality was improved from 0.77 to 0.96). Combination of the GALL and Kalman filters can achieve robust MA cancellation without supervised selection of the reference axis from the ACC. For ECG, the MA component can also be reduced by adaptive filtering. The signal quality, however, could not be improved substantially just by the adaptive filter with the ACC outputs as the reference signals.
A new Exo III assisted strand-cleavage cycle and ligand-responsive quadruplex formation strategy for amplified and label-free detection of IFN-? was reported with a detection limit of 0.1 pM and a visual detection limit of 20 pM by the naked eye.
?Coinfection with human immunodeficiency virus (HIV) and hepatitis B virus (HBV) is common. Most studies have concentrated on the effects of chronic HIV infection on HBV infection; however, studies on the effects of acute HIV infection on HBV infection are especially important to elucidate the potential mechanisms leading to complications from HIV/HBV coinfection.
A new, simple, mild, atom economical homopolymerization method through Pd-catalyzed oxidative C-H/C-H coupling was developed for the preparation of a series of 5-alkyl[3,4-c]thienopyrrole-4,6-dione-based conjugated polymers.
Abstract The level of viral DNA in early HIV-1 infection is an important parameter in the prediction of disease progression. Few data have been published on the dynamics of HIV-1 DNA during the first year of HIV infection. In this study, two distinct HIV-1 patient groups were enrolled. Group 1 (CD4High group) maintained their CD4 above 450 cells/?L within 1 year, while Group 2 (CD4Low group) progressed to CD4 below 300 cells/?L. The amounts of total, 2-long terminal repeat (2-LTR) circular, and integrated HIV-1 DNA were determined in the peripheral blood mononuclear cells at 1, 3, 6, and 12 months after HIV infection. Reductions in the amount of total and integrated HIV-1 DNA were detected in the CD4High group during the first year of HIV infection but not in the CD4Low group. Disease progression may be related to the body's ability to control HIV-1 DNA during early HIV-1 infection.
Obesity has become a worldwide public health problem, which is mainly determined by excess energy intake and adipose tissue expansion. Adipose tissue expansion can occur through hyperplasia (adipocyte differentiation) or hypertrophy. Retinoic acid was shown to inhibit adipocyte differentiation. However, the molecular mechanism is unclear. In the study, we found that all-trans-retinoic acid (ATRA) inhibited 3T3-L1 adipocyte differentiation. We did not observe significant apoptosis in differentiated adipocytes treated by ATRA. ATRA increased ROS generation and disturbed redox balance. However, antioxidant treatment did not ameliorate the reduction of lipid accumulation induced by ATRA, indicating that ROS generation was not involved in ATRA-inhibited adipocyte differentiation. ATRA reduced C/EBP?, PPAR? and its target gene expression. In the presence of ATRA, retinoic acid receptor (RAR) ?/? expression was increased. Inhibition of RAR?, but not RAR?, blocked ATRA-induced reduction of PPAR?2 expression. ATRA induced a profound interaction between RAR? and C-Fos protein, reflected by Co-IP results. C-Fos was found to exhibit a differentiation-dependent DNA binding activity to PPAR?2 promoter. RAR? inhibitor significantly suppressed ATRA-inhibited DNA binding activity of C-Fos to PPAR?2 promoter, indicating that downregulation of C-Fos activity mediated activation of RAR?-exerted reduction of PPAR?2 expression and thus inhibition of adipocyte differentiation induced by ATRA. Taken together, these data demonstrates that RAR?-C-Fos-PPAR?2 signaling rather than ROS generation is critical for ATRA-inhibited adipocyte differentiation.
Inflammasomes are supramolecular signaling complexes that activate a subset of caspases known as inflammatory caspases such as caspase-1. Upon stimulation by microbial and damage-associated signals, inflammasomes assemble to elicit the first line of host defense by proteolytic maturation of cytokines IL-1? and IL-18, and by induction of pyroptotic cell death. Assembly of an inflammasome requires activation of an upstream sensor, a downstream effector, and in most cases an adaptor molecule such as apoptosis-associate speck-like protein containing a caspase recruitment domain (ASC). Depending on whether ASC is required, inflammasomes can be categorized into ASC-dependent and ASC-independent inflammasomes. Here, we review current understandings on the structures of inflammasomes, as probed by traditional structural methods, as well as biochemical, biophysical, and single molecule methods. The key structural scaffold for inflammasome assembly is composed of filaments of Pyrin domains (PYD) and caspase recruitment domains (CARD) in the sensor, adaptor and effector components. Nucleated polymerization appears to govern the ordered assembly process from activation of a PYD-containing sensor such as AIM2 by dsDNA or NLRP3 by extracellular particulates, to recruitment of the PYD and CARD-containing adaptor ASC, and finally to activation of CARD-containing caspase-1. The underlying filamentous architecture of inflammasomes and the cooperativity in the assembly may explain the "all-or-none" response in inflammasome activation. Inflammasomes are tightly regulated by a number of cytosolic inhibitors, which may change the morphology and assembly kinetics of inflammasomes. Biochemical and cellular studies suggest that PYD and CARD filaments possess prion-like properties in propagating inflammasome activation within and between cells. This article is protected by copyright. All rights reserved.
Noxious stimuli applied at doses close to but below the threshold of cell injury induce adaptive responses that provide a defense against additional stress. Epileptic preconditioning protects neurons against status epilepticus and ischemia; however, it is not known if the converse is true. During hypoxia/ischemia (H/I), lactate released from astrocytes is taken up by neurons and is stored for energy, a process mediated by monocarboxylate transporter 4 (MCT4) in astroglia. The present study investigated whether H/I preconditioning can provide protection to neurons against epilepsy through upregulation of MCT4 expression in astrocytes in vitro and in vivo. An oxygen/glucose deprivation protocol was used in primary astrocyte cultures, while rats were subjected to an intermittent hypoxia preconditioning (IHP) paradigm followed by lithium-pilocarpine-induced epilepsy as well as lactate transportation inhibitor injection, with a subsequent evaluation of protein expression as well as behavior. H/I induced an upregulation of MCT4 expression, while an IHP time course of 5 days provided the greatest protection against epileptic seizures, which was most apparent by 3 days after IHP. However, lactate transport function disturbances can block the protective effect induced by IHP. These findings provide a potential basis for the clinical treatment of epilepsy.
Receptor interaction protein kinase 1 (RIP1) is a molecular cell-fate switch. RIP1, together with Fas-associated protein with death domain (FADD) and caspase-8, forms the RIPoptosome that activates apoptosis. RIP1 also associates with RIP3 to form the necrosome that triggers necroptosis. The RIPoptosome assembles through interactions between the death domains (DDs) of RIP1 and FADD and between death effector domains (DEDs) of FADD and caspase-8. In this study, we analyzed the overall structure of the RIP1 DD/FADD DD complex, the core of the RIPoptosome, by negative-stain electron microscopy and modeling. The results show that RIP1 DD and FADD DD form a stable complex in vitro similar to the previously described Fas DD/FADD DD complex, suggesting that the RIPoptosome and the Fas death-inducing signaling complex share a common assembly mechanism. Both complexes adopt a helical conformation that requires type I, II, and III interactions between the death domains.
Cancer stem cell (CSC) or tumor initiating cell (TIC) plays an important role in tumor progression and metastasis. Biophysical forces in tumor microenvironment have an important effect on tumor formation and development. In this study, the potential effect of matrix stiffness on the biological characteristics of human head and neck squamous cell carcinoma (HNSCC) TICs, especially the enrichment of HNSCC TICs, was investigated under three-dimensional (3D) culture conditions by means of alginate gel (ALG) beads with different matrix stiffnesses. ALG beads with soft (21kPa), moderate (70kPa) and hard (105kPa) stiffness were generated by changing alginate concentration. It was found that significant HNSCC TIC enrichment was achieved in the ALG beads with moderate matrix stiffness (70kPa). The gene expression of stemness markers Oct3/4 and Nanog, TIC markers CD44 and ABCG2 was enhanced in cells under this moderate (70kPa) stiffness. HNSCC TIC proportion was also highly enriched under moderate matrix stiffness, accompanying with higher tumorigenicity, metastatic ability and drug resistance. And it was also found that the possible molecular mechanism underlying the regulated TIC properties by matrix stiffness under 3D culture conditions was significantly different from 2D culture condition. Therefore, the results achieved in this study indicated that 3D biophysical microenvironment had an important effect on TIC characteristics and alginate-based biomimetic scaffolds could be utilized as a proper platform to investigate the interaction between tumor cells and 3D microenvironment.
During HIV type-1 (HIV-1), hepatitis C virus (HCV), and hepatitis B virus (HBV) infections, altered iron balance correlates with morbidity. The liver-produced hormone hepcidin dictates systemic iron homeostasis. We measured hepcidin, iron parameters, cytokines, and inflammatory markers in three cohorts: plasma donors who developed acute HIV-1, HBV, or HCV viremia during the course of donations; HIV-1-positive individuals progressing from early to chronic infection; and chronically HIV-1-infected individuals (receiving antiretroviral therapy or untreated). Hepcidin increased and plasma iron decreased during acute HIV-1 infection, as viremia was initially detected. In patients transitioning from early to chronic HIV-1 infection, hepcidin in the first 60 d of infection positively correlated with the later plasma viral load set-point. Hepcidin remained elevated in individuals with untreated chronic HIV-1 infection and in subjects on ART. In contrast to HIV-1, there was no evidence of hepcidin up-regulation or hypoferremia during the primary viremic phases of HCV or HBV infection; serum iron marginally increased during acute HBV infection. In conclusion, hepcidin induction is part of the pathogenically important systemic inflammatory cascade triggered during HIV-1 infection and may contribute to the establishment and maintenance of viral set-point, which is a strong predictor of progression to AIDS and death. However, distinct patterns of hepcidin and iron regulation occur during different viral infections that have particular tissue tropisms and elicit different systemic inflammatory responses. The hypoferremia of acute infection is therefore a pathogen-specific, not universal, phenomenon.
Transmitted drug resistance (TDR) is an ongoing public health problem in HIV disease treatment. However, little is known about TDR among men who have sex with men (MSM) patients in China. In addition, TDR prevalence among patients with acute HIV infection (AHI) or early HIV infection (EHI) was believed higher than that of patients with chronic HIV infection (CHI), but as AHI is typically either unidentified or crudely defined in large populations, very few direct comparisons have been made. We did a retrospective analysis of TDR in 536 antiretroviral-naive MSM patients from our immunodeficiency clinics at You'an Hospital, Capital Medical University (CMU), in Beijing, China, 2008-2011. The cohort included 266 patients with AHI/EHI and 270 patients with CHI. We analyzed the subtype, estimated the TDR prevalence, and characterized the model of TDR and the predicted drug sensitivity. Additionally, we made a comparison of TDR between the patients with AHI/EHI and patients with CHI. Our results indicated that among the 536 patients, HIV-1 subtype CRF01_AE accounted for 52.1%, subtype B accounted for 24.8%, CRF07_BC/ CRF08_BC accounted for 21.6% (116/536), and 1.3% were denoted as unique recombinant forms (URFs). A total of 7.8% patients had one or more transmitted HIV-1 drug resistance mutations, representing 6.2% for PI-related mutations, 0.9% for NRTI-related mutations, and 1.7% for NNRTI-related mutations. Although patients with AHI/EHI had a higher TDR prevalence as compared to that of patients with CHI, the difference was not statistically significant. There was no significant difference in TDR model and predicted drug susceptibility between the two groups of patients either. This study provides important strategic information for public health planning by healthcare officials in China and warrants a comprehensive study with larger patient cohorts from various healthcare centers within China.
miR-132 was found to be overexpressed in glioma; however, its clinical significance has not been investigated. In the present study, we evaluated the association between miR-132 and clinicopathological parameters and prognosis. Quantitative real-time PCR was used to analyze the expression of miR-132 in 113 cases of glioma and 36 cases of normal brain tissues. The association of miR-132 expression with clinicopathological factors and prognosis of glioma patients were analyzed. The expression levels of miR-132 were significantly higher in glioma tissues than that in normal brain tissues (mean?±?SD, 4.448?±?1.857 vs. 1.936?±?0.543; P?0.001). The miR-132 expression level was classified as high or low in relation to the median value. High expression of miR-132 was found to significantly correlate with KPS score (P?=?0.001); extent of resection (P?=?0.009), and WHO grade (P?0.001). Kaplan-Meier analysis with the log-rank test indicated that high miR-132 expression had a significant impact on overall survival (17.3 vs. 56.2 %; P?=?0.04) and progression-free survival (11.7 vs. 50.5 %; P?=?0.012). In conclusion, this study identified high miR-132 expression as a biomarker of poor prognosis in patients diagnosed with glioma.
The role of DCs in primary HIV-1 infection remains uncertain. In this study, we enrolled two different groups of subjects with acute HIV-1 infection. One group progressed to CD4 counts below 200 cells/?l within 2 years of HIV-1 infection (CD4 Low Group), while the other group maintained CD4 counts above 500 cells/?l (CD4 High Group). We did not find statistical difference in the pDC number between the two groups during acute HIV-1 infection. However, the mDC number was significantly lower in the CD4 Low Group than in the CD4 High Group.
Recent studies have linked chemotherapy resistance to the altered expression of microRNAs (miRNAs). Thus, miRNA-based approaches to modulating sensitivity to temozolomide (TMZ) may overcome chemoresistance. The aim of the present study was to investigate whether miR-136 could modulates glioma cell sensitivity to TMZ.
Total knee arthroplasty (TKA) is a common form of orthopaedic surgery. Venous thromboembolism (VTE), which consists of deep venous thrombosis (DVT) and pulmonary embolism (PE), is a major and potentially fatal complication after TKA. The incidence of DVT after TKA is 40% to 80% and the incidence of PE is approximately 2%. It is generally agreed that thromboprophylaxis should be used in patients who undergo TKA. Both pharmacological and mechanical methods are used in the prevention of DVT. Pharmacological methods alter the blood coagulation profile and may increase the risk of bleeding complications. When pharmacological methods cannot be used the mechanical methods become crucial for VTE prophylaxis. Continuous passive motion (CPM) is provided through an external motorised device which enables a joint to move passively throughout a preset arc of motion. Despite the theoretical effectiveness and widespread use of CPM, there are still differing views on the effectiveness of CPM as prophylaxis against thrombosis after TKA. This is an update of the review first published in 2012.
The input of rice-photosynthesized carbon (C) into soil plays an important role in soil C cycling. A 13C-labelled microcosm experiment was carried out to quantify the input of photosynthesized C into soil C pools in a rice-soil system during the tillering stage. Growing rice (Oryza sativa L. ) was continuously fed with 13C-labeled CO, ( C-CO, ) in a closed chamber without nitrogen (NO), or at different rates of N supply (N10,N20, N30, N40 or N60). The results showed that there were significant differences in rice shoot (1.58 g plot-1 to 4.35 g plot-1) and root (1.05 g plot-1 to 2.44 g plot-1 ) biomass among the N treatments after labeling for 18 days. The amounts of 13C in shoots and roots ranged from 44.0 g plot-1 to 157.6 g.plot-1 and 8.3 g.plot-1 to 49.4 g.plot-1, respectively, and generally followed the order of N60 > N40 > N20 > N10 > NO. The contents of rice-planted 13C-SOC, 13C-DOC and 13C-MBC in soil carbon pool were much higher than those of CK (without rice and N supply). The amount of 13C-SOC ranged from 11.1 g plot - to 23.7 gplot-1 , depending on the rate of N addition, accounting for 10.2% -18. 1% of the net assimilation. The amounts of 13C-DOC and 13C-MBC ranged from 4. 82-14.51 microg kg-1 and 526. 1-1 478.8 microg kg-1 , both depending on the N application rate. In addition, at 18-day of labeling, the 13C-SOC, 13C-DOC and 13C-MBC concentration was positively correlated with the rice biomass. Therefore, our results suggest that paddy soils can probably sequester more C from the atmosphere if more photosynthesized C enters the soils and N application can stimulate C rhizodeposition during the tillering stage.
The effects of heightened microbial translocation on B cells during HIV infection are unknown. We examined the in vitro effects of HIV and lipopolysaccharide (LPS) on apoptosis of CD27+ IgD- memory B (mB) cells from healthy controls. In vivo analysis was conducted on a cohort of 82 HIV+ donors and 60 healthy controls. In vitro exposure of peripheral blood mononuclear cells (PBMCs) to LPS and HIV led to mB cell death via the Fas/Fas ligand (FasL) pathway. Plasmacytoid dendritic cells (pDCs) produced FasL in response to HIV via binding to CD4 and chemokine coreceptors. HIV and LPS increased Fas expression on mB cells in PBMCs, which was dependent on the presence of pDCs and monocytes. Furthermore, mB cells purified from PBMCs and pretreated with both HIV and LPS were more sensitive to apoptosis when cocultured with HIV-treated pDCs. Blocking the interferon receptor (IFNR) prevented HIV-stimulated FasL production in pDCs, HIV-plus-LPS-induced Fas expression, and apoptosis of mB cells. In vivo or ex vivo, HIV+ donors have higher levels of plasma LPS, Fas expression on mB cells, and mB cell apoptosis than controls. Correspondingly, in HIV+ donors, but not in controls, a positive correlation was found between plasma FasL and HIV RNA levels and between Fas expression on mB cells and plasma LPS levels. This work reveals a novel mechanism of mB cell apoptosis mediated by LPS and HIV through the Fas/FasL pathway, with key involvement of pDCs and type I IFN, suggesting a role for microbial translocation in HIV pathogenesis.
Among the three main divisions of marine macroalgae (Chlorophyta, Phaeophyta and Rhodophyta), marine green algae are valuable sources of structurally diverse bioactive compounds and remain largely unexploited in nutraceutical and pharmaceutical areas. Recently, a great deal of interest has been developed to isolate novel sulfated polysaccharides (SPs) from marine green algae because of their numerous health beneficial effects. Green seaweeds are known to synthesize large quantities of SPs and are well established sources of these particularly interesting molecules such as ulvans from Ulva and Enteromorpha, sulfated rhamnans from Monostroma, sulfated arabinogalactans from Codium, sulfated galacotans from Caulerpa, and some special sulfated mannans from different species. These SPs exhibit many beneficial biological activities such as anticoagulant, antiviral, antioxidative, antitumor, immunomodulating, antihyperlipidemic and antihepatotoxic activities. Therefore, marine algae derived SPs have great potential for further development as healthy food and medical products. The present review focuses on SPs derived from marine green algae and presents an overview of the recent progress of determinations of their structural types and biological activities, especially their potential health benefits.
Agonists of mouse STING (TMEM173) shrink and even cure solid tumors by activating innate immunity; human STING (hSTING) agonists are needed to test this therapeutic hypothesis in humans. The endogenous STING agonist is 2'3'-cGAMP, a second messenger that signals the presence of cytosolic double-stranded DNA. We report activity-guided partial purification and identification of ecto-nucleotide pyrophosphatase/phosphodiesterase (ENPP1) to be the dominant 2'3'-cGAMP hydrolyzing activity in cultured cells. The hydrolysis activity of ENPP1 was confirmed using recombinant protein and was depleted in tissue extracts and plasma from Enpp1(-/-) mice. We synthesized a hydrolysis-resistant bisphosphothioate analog of 2'3'-cGAMP (2'3'-cG(s)A(s)MP) that has similar affinity for hSTING in vitro and is ten times more potent at inducing IFN-? secretion from human THP1 monocytes. Studies in mouse Enpp1(-/-) lung fibroblasts indicate that resistance to hydrolysis contributes substantially to its higher potency. 2'3'-cG(s)A(s)MP is therefore improved over natural 2'3'-cGAMP as a model agonist and has potential as a vaccine adjuvant and cancer therapeutic.
Receptor-mediated mitophagy is one of the major mechanisms of mitochondrial quality control essential for cell survival. We previously have identified FUNDC1 as a mitophagy receptor for selectively removing damaged mitochondria in mammalian systems. A critical unanswered question is how receptor-mediated mitophagy is regulated in response to cellular and environmental cues. Here, we report the striking finding that BCL2L1/Bcl-xL, but not BCL2, suppresses mitophagy mediated by FUNDC1 through its BH3 domain. Mechanistically, we demonstrate that BCL2L1, but not BCL2, interacts with and inhibits PGAM5, a mitochondrially localized phosphatase, to prevent the dephosphorylation of FUNDC1 at serine 13 (Ser13), which activates hypoxia-induced mitophagy. Our results showed that the BCL2L1-PGAM5-FUNDC1 axis is critical for receptor-mediated mitophagy in response to hypoxia and that BCL2L1 possesses unique functions distinct from BCL2.
Analysis of peptide components of protein hydrolysates is often difficult due to the lack of suitable analytical methods. In the present study, an UHPLC-Q-TOF MS/MS method was developed and used to identify peptides derived from the protein hydrolysate of Mactra veneriformis. The peptide sequences were deduced by de novo sequencing based on MS/MS fragmentation data. A total of 21 peptides, four nucleobases, and one nucleoside were identified from the hydrolysate using this method. These peptides were chemically synthesised and showed antioxidant activity in radical scavenging assays. This method is suitable for quick, sensitive, and accurate analysis of complex protein hydrolysates.
In this work, a new binding-induced and label-free colorimetric method for protein detection has been developed on the basis of an autonomous assembly of hemin/G-quadruplex DNAzyme amplification strategy. The system consists of two proximity probes carrying two aptamer sequences as recognition elements for target, and two hairpin structures include three-fourths and one-fourth of the G-quadruplex sequences in inactive configuration as functional elements. In the presence of target protein, two proximity probes bind to the protein simultaneously, forming a stable DNA-protein complex. Then the complex triggers an autonomous cross-opening of the two functional hairpin structures, leading to the formation of numerous hemin/G-quadruplex DNAzymes. The resulting DNAzymes catalyze the oxidation of colorless 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS(2-)) to the green-colored ABTS(•-) with the presence of H2O2, thus providing the amplified colorimetric detection of target. Using human ?-thrombin as the protein target, this binding-induced DNAzyme amplification colorimetric method affords high sensitivity with a detection limit of 1.9pM. Furthermore, this method might be further extended to sensitive detection of other proteins by simply replacing recognition elements of proximity probes.
Zinc finger protein, X-linked (ZFX) has been identified as a transcriptional factor and is implicated in the development of variant types of cancer. Furthermore, it has been reported that ZFX is essential for the survival and self-renewal of embryonic stem cells. To investigate the involvement of ZFX in squamous cell carcinoma of the tongue, in the present study, we explored the expression of ZFX in clinical specimens from patients with squamous cell carcinoma of the tongue and the correlation between ZFX expression and multiple clinical pathological parameters. We further evaluated the impact of ZFX knockdown on the proliferation, colony formation ability, cell cycle distribution and survival of two human tongue squamous cell carcinoma cell lines to explore its critical role in the development of squamous cell carcinoma of the tongue. Our results showed that ZFX expression was aberrantly higher in samples from patients with squamous cell carcinoma of the tongue and revealed that ZFX expression is positively correlated with tumor grade and stage. Consistent with these findings, we further found that ZFX knockdown impaired cell proliferation and colony formation ability and induced cell apoptosis and cell cycle arrest in two human tongue squamous cell carcinoma cell lines. Our results indicate that ZFX is essential for the development and progression of squamous cell carcinoma of the tongue and represents a potential target for the development of effective therapy.
Diabetes is affecting more than 25.8 million people in the United States, causing huge burden on the health care system and economy. Insulin injection, which is the predominant treatment for diabetes, is incapable of replenishing the lost insulin-producing beta cell in patients. Restoring beta cell mass through replacement therapy such as islet transplantation or beta cell regeneration through in vitro and in vivo strategies has attracted particular attentions in the field due to its potential to cure diabetes. In the aspect of islet transplantation, gene therapy, stem cell therapy, and more biocompatible immunosuppressive drugs have been tested in various preclinical animal models to improve the longevity and function of human islets against the posttransplantation challenges. In the islet regeneration aspect, insulin-producing cells have been generated through in vitro transdifferentiation of stem cells and other types of cells and demonstrated to be capable of glycemic control. Moreover, several biomarkers including cell-surface receptors, soluble factors, and transcriptional factors have been identified or rediscovered in mediating the process of beta cell proliferation in rodents. This review summarizes the current progress and hurdles in the preclinical efforts in resurrecting beta cells. It may provide some useful insights into the future drug discovery for antidiabetic purposes.
Novel amphiphilic polypeptoid-polyester diblock copolymers based on poly(sarcosine) (PSar) and poly(?-caprolactone) (PCL) are synthesized by a one-pot glovebox-free approach. In this method, sarcosine N-carboxy anhydride (Sar-NCA) is firstly polymerized in the presence of benzylamine under N2 flow, then the resulting poly(sarcosine) is used in situ as the macro-initiator for the ring-opening polymerization (ROP) of ?-caprolactone using tin(II) octanoate as a catalyst. The degree of poly-merization of each block is controlled by various feed ratios of monomer/initiator. The diblock copolymers with controlled molecular weight and narrow molecular weight distributions (?M < 1.2) are characterized by (1) H NMR, (13) C NMR, and size-exclusion chromatography. The self-assembly behavior of PSar-b-PCL in water is investigated by dynamic light scattering (DLS) and transmission electron microscopy. DLS results reveal that the diblock copolymers associate into nanoparticles with average hydrodynamic diameters (DH ) around 100 nm in water, which may be used as drug delivery carriers.
Foxp3+ regulatory T cells (Tregs) are essential to maintain immune homeostasis, yet controversy exists about the stability of this cell population. Bcl6-deficient (Bcl6-/-) mice develop severe and spontaneous Th2-type inflammation and Bcl6-deficient Tregs are ineffective at controlling Th2 responses. We used a lineage tracing approach to analyze the fate of Tregs in these mice. In the periphery of Bcl6-/- mice, increased numbers of Foxp3-negative "exTreg" cells were found, particularly in the CD25+ population. ExTregs from Bcl6-/- mice expressed increased IL-17 and extremely elevated levels of Th2 cytokines compared to wild-type exTregs. While Tregs normally express only low levels of cytokines, Tregs from Bcl6-/- mice secreted higher levels of IL-4, IL-5, IL-13 and IL-17 than wild-type conventional T cells. Next, Treg-specific conditional Bcl6-deficient (Bcl6(Foxp3-/-) ) mice were analyzed. Bcl6(Foxp3-/-) mice do not develop inflammatory disease, indicating a requirement for non-Treg cells for the inflammation in Bcl6-/- mice, and have normal numbers of exTregs. We induced Th2-type allergic airway inflammation in Bcl6(Foxp3-/-) mice, and found that while exTreg cytokine expression was normal, Bcl6-deficient Tregs expressed higher levels of the Th2-specific regulator Gata3 than Bcl6+ Tregs. Bcl6(Foxp3-/-) mice had increased numbers of Th2 cells after induction of airway inflammation and increased T cells in the broncho-alveolar lavage (BAL) fluid. These data show both Treg-intrinsic and Treg-extrinsic roles for Bcl6 in controlling Treg stability and Th2 inflammation, and support the idea that Bcl6 expression in Tregs is critical for controlling Th2 responses. This article is protected by copyright. All rights reserved.
Active DNA demethylation in mammals involves TET-mediated iterative oxidation of 5-methylcytosine (5mC)/5-hydroxymethylcytosine (5hmC) and subsequent excision repair of highly oxidized cytosine bases 5-formylcytosine (5fC)/5-carboxylcytosine (5caC) by thymine DNA glycosylase (TDG). However, quantitative and high-resolution analysis of active DNA demethylation activity remains challenging. Here, we describe M.SssI methylase-assisted bisulfite sequencing (MAB-seq), a method that directly maps 5fC/5caC at single-base resolution. Genome-wide MAB-seq allows systematic identification of 5fC/5caC in Tdg-depleted embryonic stem cells, thereby generating a base-resolution map of active DNA demethylome. A comparison of 5fC/5caC and 5hmC distribution maps indicates that catalytic processivity of TET enzymes correlates with local chromatin accessibility. MAB-seq also reveals strong strand asymmetry of active demethylation within palindromic CpGs. Integrating MAB-seq with other base-resolution mapping methods enables quantitative measurement of cytosine modification states at key transitioning steps of the active DNA demethylation cascade and reveals a regulatory role of 5fC/5caC excision repair in this step-wise process.
Diabetic nephropathy (DN), as one of the chronic complications of diabetes, is the major cause of end-stage renal disease. However, the pathogenesis of this disease is not fully understood. In recent years, research on microRNAs (miRNAs) has become a hotspot because of their critical role in regulating posttranscriptional levels of protein-coding genes that may serve as key pathogenic factors in diseases. Several miRNAs were found to participate in the pathogenesis of DN, while others showed renal protective effects. Therefore, targeting miRNAs that are involved in DN may have a good prospect in the treatment of the disease. The aim of this review is to summarize DN-related miRNAs and provide potential targets for diagnostic strategies and therapeutic intervention.
Two-dimensional layered materials, such as molybdenum disulfide, are emerging as an exciting material system for future electronics due to their unique electronic properties and atomically thin geometry. Here we report a systematic investigation of MoS2 transistors with optimized contact and device geometry, to achieve self-aligned devices with performance including an intrinsic gain over 30, an intrinsic cut-off frequency fT up to 42?GHz and a maximum oscillation frequency fMAX up to 50?GHz, exceeding the reported values for MoS2 transistors to date (fT~0.9?GHz, fMAX~1?GHz). Our results show that logic inverters or radio frequency amplifiers can be formed by integrating multiple MoS2 transistors on quartz or flexible substrates with voltage gain in the gigahertz regime. This study demonstrates the potential of two-dimensional layered semiconductors for high-speed flexible electronics.
The freshwater crab Sinopotamon henanense was exposed to Cd (50, 100 and 500?gl(-1)) and Zn (100 and 1000?gl(-1)) either on their own or in combination. At 14 and 28days the hepatopancreas were taken and total metal and metallothionein (MT) in transcript abundance were assessed. In addition, following homogenization of the hepatopancreas differential centrifugation, NaOH digestion and heat denaturation steps were carried out to identify subcellular compartmentalization, defined as metal-sensitive fraction [MSF-organelles and heat-denaturable proteins (HDP)] and biologically detoxified metals [BDM-heat-stable proteins (HSP) and metal-rich granules (MRG)]. The results showed that concentration of the non-essential metal Cd was more responsive to waterborne metal exposures than the concentration of essential metal Zn; the latter metal was better regulated and exhibited only 2-3 fold increases relative to the control. Of the six fractions, the HSP fraction was the predominant metal-binding compartment for Cd. The proportion and accumulation of Cd in this fraction increased with the single Cd exposures, which suggest that metallothionein-like proteins play a key role in metal detoxification in the hepatopancreas of S. henanense. It was surprising that more Zn was in the HSP fraction than Cd, but its contribution did not increase progressively with the single Zn exposures. Despite the increases in Cd in the HSP fraction during single Cd exposures, some accumulation of Cd was observed in putative MSF (e.g., mitochondria), which showed that metal detoxification was incomplete. The results demonstrated that the Cd content decreased in metal mixture groups especially when mixed with higher Zn, while the Cd accumulation in MSF was also reduced when Zn was added, which suggested that Zn might alleviate the toxic effects of Cd through changing the subcellular distribution of Cd. MT mRNA expression was also determined in our report, the results showed that both Cd and Zn had the ability of inducing MT mRNA expression. Additionally, the MT mRNA transcription level was enhanced when Cd was mixed with Zn. We suggest, therefore, that MT synthesis following increased MT mRNA expression is one of the mechanisms in which Zn reduced the bioaccumulation of Cd.
Concurrent garbage collectors (CGC) have recently obtained extensive concern on multicore platform. Excellent designed CGC can improve the efficiency of runtime systems by exploring the full potential processing resources of multicore computers. Two major performance critical components for designing CGC are studied in this paper, stack scanning and heap compaction. Since the lock-based algorithms do not scale well, we present a lock-free solution for constructing a highly concurrent garbage collector. We adopt CAS/MCAS synchronization primitives to guarantee that the programs will never be blocked by the collector thread while the garbage collection process is ongoing. The evaluation results of this study demonstrate that our approach achieves competitive performance.
The cardiac progenitor cells (CPCs) in the anterior heart field (AHF) are located in the pharyngeal mesoderm (PM), where they expand, migrate and eventually differentiate into major cell types found in the heart, including cardiomyocytes. The mechanisms by which these progenitors are able to expand within the PM microenvironment without premature differentiation remain largely unknown. Through in silico data mining, genetic loss-of-function studies, and in vivo genetic rescue studies, we identified N-cadherin and interaction with canonical Wnt signals as a critical component of the microenvironment that facilitates the expansion of AHF-CPCs in the PM. CPCs in N-cadherin mutant embryos were observed to be less proliferative and undergo premature differentiation in the PM. Notably, the phenotype of N-cadherin deficiency could be partially rescued by activating Wnt signaling, suggesting a delicate functional interaction between the adhesion role of N-cadherin and Wnt signaling in the early PM microenvironment. This study suggests a new mechanism for the early renewal of AHF progenitors where N-cadherin provides additional adhesion for progenitor cells in the PM, thereby allowing Wnt paracrine signals to expand the cells without premature differentiation.Cell Research advance online publication 4 November 2014; doi:10.1038/cr.2014.142.
A combined process comprised of ex-situ nitrification in an aged refuse bioreactor (designated as A bioreactor) and in-situ denitrification in a fresh refuse bioreactor (designated as F bioreactor) was constructed for investigating N2O emission during the stabilization of municipal solid waste (MSW). The results showed that N2O concentration in the F bioreactor varied from undetectable to about 130 ppm, while it was much higher in the A bioreactor with the concentration varying from undetectable to about 900 ppm. The greatly differences of continuous monitoring of N2O emission after leachate cross recirculation in each period were primarily attributed to the stabilization degree of MSW. Moreover, the variation of N2O concentration was closely related to the leachate quality in both bioreactors and it was mainly affected by the COD and COD/TN ratio of leachate from the F bioreactor, as well as the DO, ORP, and NO3(-)-N of leachate from the A bioreactor.
Gastrointestinal stromal tumors (GISTs) are rare mesenchymal neoplasms of the gastrointestinal tract. Less than 1% occurs in the esophagus. Surgery is the primary treatment for patients with GISTs. We report a 29-year-old male was admitted after the detection of a posterior mediastinal mass during work-up with routine examination. He did not have any disease-related symptoms. The physical examination was unremarkable. Chest computed tomographic scan, the barium esophagogram and endoscopic esophageal ultrasound showed benign neoplasm. The patient was performed an enucleation surgery through the right posterolateral thoracotomy. The pathology revealed a 13.0 cm × 12.0 cm × 5.0 cm mass. The tumor was CD117 (C-kit), PDGFRA and DOG1 positive. These findings were consistent with a GIST of the esophagus. So the diagnosis of GIST of esophagus was confirmed. The pathological diagnosis of low grade of GIST of esophagus was confirmed. The patient has no evidence of recurrence and is in good clinical conditions up-to date, five years after surgery.
?? T cells play important roles in innate immunity as the first-line of defense against infectious diseases. Human immunodeficiency virus (HIV) infection disrupts the balance between V?1 T cells and V?2 T cells and causes dysfunction among ?? T cells. However, the biological mechanisms and clinical consequences of this disruption require further investigation. In this study, we performed a comprehensive analysis of phenotype and function of memory ?? T cells in cohorts of Chinese individuals with HIV infection. We found a dynamic change in memory V?2 ?? T cells, skewed toward an activated and terminally differentiated effector memory phenotype TEMRA V?2 ?? T cell, which may account for the dysfunction of V?2 ?? T cells in HIV disease. In addition, we found that IL-17-producing ?? T cells were significantly increased in HIV-infected patients with fast disease progression and positively correlated with HLA-DR(+) ?? T cells and CD38(+)HLA-DR(+) ?? T cells. This suggests the IL-17 signaling pathway is involved in ?? T-cell activation and HIV pathogenesis. Our findings provide novel insights into the role of V?2 T cells during HIV pathogenesis and represent a sound basis on which to consider immune therapies with these cells.Cellular & Molecular Immunology advance online publication, 15 September 2014; doi:10.1038/cmi.2014.77.
Trans-autophosphorylation is among the most prevalent means of protein kinase activation, yet its molecular basis is poorly defined. In Toll-like receptor and interleukin-1 receptor signaling pathways, the kinase IRAK4 is recruited to the membrane-proximal adaptor MyD88 through death domain (DD) interactions, forming the oligomeric Myddosome and mediating NF-?B activation. Here we show that unphosphorylated IRAK4 dimerizes in solution with a KD of 2.5 ?M and that Myddosome assembly greatly enhances IRAK4 kinase domain (KD) autophosphorylation at sub-KD concentrations. The crystal structure of the unphosphorylated IRAK4(KD) dimer captures a conformation that appears to represent the actual trans-autophosphorylation reaction, with the activation loop phosphosite of one IRAK4 monomer precisely positioned for phosphotransfer by its partner. We show that dimerization is crucial for IRAK4 autophosphorylation in vitro and ligand-dependent signaling in cells. These studies identify a mechanism for oligomerization-driven allosteric autoactivation of IRAK4 that may be general to other kinases activated by autophosphorylation.
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