Heat-stress cognate 70 (Hsc70) is a host factor that helps hepatitis C virus (HCV) to complete its life cycle in infected hepatocytes. Using Hsc70 as a target for HCV inhibition, a series of novel N-substituted benzyl matrinic/sophoridinic acid derivatives was synthesized and evaluated for their anti-HCV activity in vitro. Among these analogues, compound 7c possessing N-p-methylbenzyl afforded an appealing ability to inhibit HCV replication with SI value over 53. Furthermore, it showed a good oral pharmacokinetic profile with area-under-curve (AUC) of 13.4 µM·h, and a considerably good safety in oral administration in mice (LD50>1000 mg/kg). As 7c suppresses HCV replication via an action mode distinctly different from that of the marketed anti-HCV drugs, it has been selected as a new mechanism anti-HCV candidate for further investigation, with an advantage of no or decreased chance to induce drug-resistant mutations.
The cerebrovasuclar artery disease as a common complication of type-2 diabetes mellitus (T2DM) caused huge economic burden and lives threatening to patients. We evaluated the prevalence and morphology of carotid and cerebrovascular atherosclerotic plaques in T2DM patients with transient ischemic attack (TIA) or stroke using multidetector CT (MDCT).
64-MDCT and dual-source CT (DSCT) angiographies were performed in 195 T2DM patients with TIA or stroke (mean age 65.7+/-12.8 years; 118 men) between January 2009 to August 2011. During the process, plaque type, its distribution, extensive and obstructive natures were determined for each segment derived from the patients.
Atherosclerotic plaques were detected in 183 (93.8%) patients. A total of 1056 segments with plaque were identified, of which 450 (42.6%) were non-calcified, 192 (18.2%) were mixed and 414 (39.2%) calcified ones. Among them, 562 (53.2%) resulted in mild stenosis, 291 (27.6%) moderate stenosis, 170 (16.1%) severe stenosis and 33 (3.1%) occlusion. Non-calcified plaques contributed 91.8% to non-obstructive lumen narrowing, while mixed and calcified plaques contributed 89.0% and 65.0% respectively.
MDCT angiography detected a high prevalence of plaques in T2DM patients with TIA or stroke. A relatively high proportion of plaques were non-calcified, as well as with non-obstructive stenosis. MDCT angiography might further enhance the detection and management of carotid and cerebrovascular atherosclerosis in T2DM patients with TIA and stroke
The gene encoding the GroEL chaperonin is duplicated in nearly 30% of bacterial genomes; and although duplicated groEL genes have been comprehensively determined to have distinct physiological functions in different species, the mechanisms involved have not been characterized to date. Myxococcus xanthus DK1622 has two copies of the groEL gene, each of which can be deleted without affecting cell viability; however, the deletion of either gene does result in distinct defects in the cellular heat-shock response, predation, and development. In this study, we show that, from the expression levels of different groELs, the distinct functions of groEL1 and groEL2 in predation and development are probably the result of the substrate selectivity of the paralogous GroEL chaperonins, whereas the lethal effect of heat shock due to the deletion of groEL1 is caused by a decrease in the total groEL expression level. Following a bioinformatics analysis of the composition characteristics of GroELs from different bacteria, we performed region-swapping assays in M. xanthus, demonstrating that the differences in the apical and the C-terminal equatorial regions determine the substrate specificity of the two GroELs. Site-directed mutagenesis experiments indicated that the GGM repeat sequence at the C-terminus of GroEL1 plays an important role in functional divergence. Divergent functions of duplicated GroELs, which have similar patterns of variation in different bacterial species, have thus evolved mainly via alteration of the apical and the C-terminal equatorial regions. We identified the specific substrates of strain DK1622's GroEL1 and GroEL2 using immunoprecipitation and mass spectrometry techniques. Although 68 proteins bound to both GroEL1 and GroEL2, 83 and 46 proteins bound exclusively to GroEL1 or GroEL2, respectively. The GroEL-specific substrates exhibited distinct molecular sizes and secondary structures, providing an encouraging indication for GroEL evolution for functional divergence.
GroEL is a type I chaperonin, involved in protein folding, assembly, and transport. It is a major group of heat-shock proteins that are over-expressed at high temperatures and has fundamental roles in growth and survival at non-permissive temperatures. Because of its importance in many cellular processes, the groEL gene is ubiquitously distributed in bacteria. Most bacterial species possess a single groEL gene, while others (close to 30% of sequenced bacterial genomes) have two or more groEL copies. Many studies have described the functional divergence of duplicated groEL genes in different bacterial species, but the involved mechanisms have not yet been characterized. Myxobacteria are characterized by their unique multicellular behaviors. Myxococcus xanthus DK1622, the model strain of myxobacteria, possesses a large genome (9.14 Mb), containing many gene duplications, including two copies of the groEL gene. Gene duplications and their functional divergence are suggested for complex cellular behaviors, which, however, have not yet been testified. In this paper, using combined proteomic and genetic approaches, we explored how the duplicated groEL genes of M. xanthus DK1622 evolved to fit the functional divergence for social behaviors.
Apelin, a novel adipokine, is the specific endogenous ligand of G protein-coupled receptor APJ. Consistent with its putative role as an adipokine, apelin has been linked to states of insulin resistance. However, the function of apelin in hepatic insulin resistance, a vital part of insulin resistance, and its underlying mechanisms still remains unclear. Here we define the impacts of apelin on TNF-α-induced reduction of glycogen synthesis in the hepatocytes. Our studies indicate that apelin reversed TNF-α-induced reduction of glycogen synthesis in HepG2 cells, mouse primary hepatocytes and liver tissues of C57BL/6J mice by improving JNK-IRS1-AKT-GSK pathway. Moreover, Western blot revealed that APJ, but not apelin, expressed in the hepatocytes and liver tissues of mice. We found that F13A, a competitive antagonist for G protein-coupled receptor APJ, suppressed the effects of apelin on TNF-α-induced reduction of glycogen synthesis in the hepatocytes, suggesting APJ is involved in the function of apelin. In conclusion, we show novel evidence suggesting that apelin ameliorates TNF-α-induced reduction of glycogen synthesis in the hepatocytes through G protein-coupled receptor APJ. Apelin appears as a beneficial adipokine with anti-insulin resistance properties, and thus as a promising therapeutic target in metabolic disorders.
GSTP1, which is one major group of the glutathione S-transferase family, plays an important role in the metabolism of carcinogens and toxins, reducing damage of DNA as a suppressor of carcinogenesis. The 341C>T polymorphism of the GSTP1 has been implicated in cancer risk through cutting down its metabolic detoxification activities. However, results from previous studies remain conflicting rather than conclusive. To clarify the correlation and provide more statistical evidence for detecting the significance of 341C>T, a meta-analysis was conducted.
The relevant studies were identified through searching of PubMed, Embase, ISI Web of Knowledge and China National Knowledge Infrastructure in August 2012, and selected based on the established inclusion criteria for publications, then a meta-analysis was performed to quantitatively summarize the association of GSTP1 341C>T polymorphism with cancer susceptibility. Stratified analyses were employed to identify the source of heterogeneity. Publication bias was evaluated as well as sensitivity analysis. Based on 28 case-control studies with 13249 cases and 16798 controls, the pooled results indicated that the variant genotypes significantly increased the risk of cancer in homozygote comparison (TT versus CC: P = 0.012, OR = 1.40, 95% CI: 1.08–1.81, Phet. = 0.575), and recessive model (TT versus CT/CC: P = 0.012, OR = 1.40, 95% CI: 1.08–1.81, Phet. = 0.562). This was confirmed when stratified analyses were conducted according to ethnicity, source of control, matched control, quality score and cancer types. Moreover, significantly increased risk of cancer was also found in lung cancer (heterozygote comparison and dominant model). The stability of these observations was confirmed by a sensitivity analysis. Begger's funnel plot and Egger's test did not reveal any publication bias.
This meta-analysis suggests that the GSTP1 341C>T polymorphism may contribute to genetic susceptibility to cancer, especially to lung cancer, and in Asian population. Nevertheless, additional well-designed studies focusing on different ethnicity and cancer types are needed to provide a more exact and comprehensive conclusion.
Heterotrimeric G-proteins, comprising Gα and Gβγ subunits, couple metabotropic receptors to various downstream effectors and contribute to assembling and trafficking receptor based signaling complexes. A G-protein β-subunit, Gβ3 plays a critical role in several physiological processes as a polymorphism in its gene is associated with a risk factor for several disorders. Retinal ON bipolar cells express Gβ3, and they provide an excellent system to study its role. In the ON bipolar cells, mGluR6 inverts the photoreceptor’s signal via a cascade in which glutamate released from photoreceptors closes the TRPM1 channel. This cascade is essential for vision since deficiencies in its proteins lead to complete congenital stationary night blindness. Here we report that Gβ3 participates in the G-protein heterotrimer that couples mGluR6 to TRPM1. Gβ3 deletion in mouse greatly reduces the light response under both scotopic and photopic conditions, but it does not eliminate it. In addition, Gβ3 deletion causes mislocalization and downregulation of most cascade elements and modulators. Furthermore, Gβ3 may play a role in synaptic maintenance since in its absence, the number of invaginating rod bipolar dendrites is greatly reduced, a deficit that was not observed at 3 weeks, the end of the developmental period.
Gnb3; G-protein cascade; mGluR6; TRPM1; RGS
Magnetoelectric multiferroics are materials that have coupled magnetic and electric dipole orders, which can bring novel physical phenomena and offer possibilities for new device functions. In this report, single-crystalline Bi4.2K0.8Fe2O9+δ nanobelts which are isostructural with the high-temperature superconductor Bi2Sr2CaCu2O8+δ are successfully grown by a hydrothermal method. The regular stacking of the rock salt slabs and the BiFeO3-like perovskite blocks along the c axis of the crystal makes the Bi4.2K0.8Fe2O9+δ nanobelts have a natural magnetoelectric–dielectric superlattice structure. The most striking result is that the bulk material made of the Bi4.2K0.8Fe2O9+δ nanobelts is of multiferroicity near room temperature accompanied with a structure anomaly. When an external magnetic field is applied, the electric polarization is greatly suppressed, and correspondingly, a large negative magnetocapacitance coefficient is observed around 270 K possibly due to the magnetoelectric coupling effect. Our result provides contributions to the development of single phase multiferroics.
To study outcomes of concurrent chemoradiotherapy (CCRT) or radiotherapy (RT) alone followed by radical surgery in patients with local advanced cervical cancer.
A retrospective approach was carried out in 174 Chinese patients with International Federation of Obstetricians and Gynaecologists stage IB2–IIIB cervical carcinoma. A total of 121 patients were treated with CCRT, while the remaining 53 patients received RT alone, and the regimen of chemotherapy was weekly cisplatin (40 mg/m2). Pathological response, overall survival (OS), progression-free survival (PFS), and complications were analyzed.
The median age was 45 years and the mean primary tumor diameter was 4.8 ± 1.0 cm. Pathological complete response (CR) was achieved in 53 patients (30.5%). The CR rate was relatively higher in the CCRT group (31.4% vs 28.3%, P = 0.724), particularly when tumor diameter was less than 5 cm (38.2% vs 30.8%, P = 0.623). With median follow-up of 24 months, patients with CR had improved 3-year OS (100% vs 83.6%, P = 0.018) and 3-year PFS (93.1% vs 83.2%, P = 0.035) compared to patients with residual disease. CCRT was associated with significantly improved 3-year PFS (92.0% vs 76.5%, P = 0.032) compared to RT alone in patients with tumor diameter less than 5 cm. Thirty-seven patients (21.3%) experienced more than grade 2 toxicity, and one patient (0.6%) developed grade 3 uronephrosis. Data thus indicated that pathologic response, tumor size, and lymph-node involvement were highly correlated with clinical outcomes of the local advanced cervical disease.
Preoperative CCRT achieved outcomes superior to RT alone, depending on the pathologic response, tumor size and lymph-node involvement as major prognostic factors.
local advanced cervical carcinoma; concurrent chemoradiotherapy; radical hysterectomy; pelvic lymphadenectomy; prognostic factors
There is a growing interest in the health-promoting effects of natural substances obtained from plants. Although luteolin has been identified as a potential therapeutic and preventive agent for cancer because of its potent cancer cell-killing activity, the molecular mechanisms have not been well elucidated. This study provides evidence of an alternative target for luteolin and sheds light on the mechanism of its physiological benefits. Treatment of 786-O renal cell carcinoma (RCC) cells (as well as A498 and ACHN) with luteolin caused cell apoptosis and death. This cytotoxicity was caused by the downregulation of Akt and resultant upregulation of apoptosis signal-regulating kinase-1 (Ask1), p38, and c-Jun N-terminal kinase (JNK) activities, probably via protein phosphatase 2A (PP2A) activation. In addition to being a concurrent substrate of caspases and event of cell death, heat shock protein-90 (HSP90) cleavage might also play a role in driving further cellular alterations and cell death, at least in part, involving an Akt-related mechanism. Due to the high expression of HSP90 and Akt-related molecules in RCC and other cancer cells, our findings suggest that PP2A activation might work in concert with HSP90 cleavage to inactivate Akt and lead to a vicious caspase-dependent apoptotic cycle in luteolin-treated 786-O cells.
In the title compound, C19H18F3NO4, which was designed and synthesized as a dual-site inhibitor of insect AChE (acetylcholinesterase), the dihedral angle between the methylcarbamate group and the benzene ring is 72.47 (6)°. In the crystal, inversion dimers are linked by pairs of N—H⋯O hydrogen bonds.
The use of colistin in the treatment of life-threatening Gram-negative infections is associated with a high rate of nephrotoxicity that is dose limiting. This study aimed to examine the nephroprotective effect of ascorbic acid against colistin-induced nephrotoxicity.
Rats were treated intravenously twice daily with saline, colistin (cumulative dose of 36.5 mg/kg), a combination of ascorbic acid (50 or 200 mg/kg) and colistin, or ascorbic acid (200 mg/kg) over 7 days. Colistin-induced apoptosis was examined in rats over 5 days and in vitro using rat renal proximal tubular cells NRK-52E over 24 h with and without ascorbic acid. The effect of co-administered ascorbic acid on colistin pharmacokinetics was investigated.
The 24 h urinary excretion of N-acetyl-β-d-glucosaminidase, a sensitive marker for tubular damage, was significantly lower (P < 0.0001) in the colistin/ascorbic acid 200 mg/kg group. Significant histological abnormalities (P < 0.01) were detected only in the kidneys of the colistin group, which also had the highest percentage (30.6 ± 7.8%) of apoptotic cells (P < 0.005). In the cell culture studies, the percentage of apoptotic cells was significantly higher in the presence of 0.1 mM colistin alone (51.8 ± 2.0%; P < 0.0001) than in the presence of ascorbic acid, which decreased the apoptotic effect in a concentration-dependent manner. Ascorbic acid (200 mg/kg) altered colistin pharmacokinetics, as the total body clearance decreased from 3.78 ± 0.36 mL/min/kg (colistin group) to 2.46 ± 0.57 mL/min/kg (P = 0.0024).
This is the first study demonstrating the protective effect of ascorbic acid against colistin-induced nephrotoxicity and tubular apoptosis. Co-administration of ascorbic acid has the potential to increase the therapeutic index of colistin.
polymyxin E; vitamin C; rat kidney tubular cells
Genotype imputation is an important tool in human genetics studies, which uses reference sets with known genotypes and prior knowledge on linkage disequilibrium and recombination rates to infer un-typed alleles for human genetic variations at a low cost. The reference sets used by current imputation approaches are based on HapMap data, and/or based on recently available next-generation sequencing (NGS) data such as data generated by the 1000 Genomes Project. However, with different coverage and call rates for different NGS data sets, how to integrate NGS data sets of different accuracy as well as previously available reference data as references in imputation is not an easy task and has not been systematically investigated. In this study, we performed a comprehensive assessment of three strategies on using NGS data and previously available reference data in genotype imputation for both simulated data and empirical data, in order to obtain guidelines for optimal reference set construction. Briefly, we considered three strategies: strategy 1 uses one NGS data as a reference; strategy 2 imputes samples by using multiple individual data sets of different accuracy as independent references and then combines the imputed samples with samples based on the high accuracy reference selected when overlapping occurs; and strategy 3 combines multiple available data sets as a single reference after imputing each other. We used three software (MACH, IMPUTE2 and BEAGLE) for assessing the performances of these three strategies. Our results show that strategy 2 and strategy 3 have higher imputation accuracy than strategy 1. Particularly, strategy 2 is the best strategy across all the conditions that we have investigated, producing the best accuracy of imputation for rare variant. Our study is helpful in guiding application of imputation methods in next generation association analyses.
Tilapia is the common name for a group of cichlid fishes and is one of the most important aquacultured freshwater food fish. Mozambique tilapia and its hybrids, including red tilapia are main representatives of salt tolerant tilapias. A linkage map is an essential framework for mapping QTL for important traits, positional cloning of genes and understanding of genome evolution.
We constructed a consensus linkage map of Mozambique tilapia and red tilapia using 95 individuals from two F1 families and 401 microsatellites including 282 EST-derived markers. In addition, we conducted comparative mapping and searched for sex-determining loci on the whole genome. These 401 microsatellites were assigned to 22 linkage groups. The map spanned 1067.6 cM with an average inter-marker distance of 3.3 cM. Comparative mapping between tilapia and stickleback, medaka, pufferfish and zebrafish revealed clear homologous relationships between chromosomes from different species. We found evidence for the fusion of two sets of two independent chromosomes forming two new chromosome pairs, leading to a reduction of 24 chromosome pairs in their ancestor to 22 pairs in tilapias. The XY sex determination locus in Mozambique tilapia was mapped on LG1, and verified in five families containing 549 individuals. The major XY sex determination locus in red tilapia was located on LG22, and verified in two families containing 275 individuals.
A first-generation linkage map of salt tolerant tilapia was constructed using 401 microsatellites. Two separate fusions of two sets of two independent chromosomes may lead to a reduction of 24 chromosome pairs in their ancestor to 22 pairs in tilapias. The XY sex-determining loci from Mozambique tilapia and red tilapia were mapped on LG1 and LG22, respectively. This map provides a useful resource for QTL mapping for important traits and comparative genome studies. The DNA markers linked to the sex-determining loci could be used in the selection of YY males for breeding all-male populations of salt tolerant tilapia, as well as in studies on mechanisms of sex determination in fish.
Tilapia; Salt tolerance; Breeding; Sex; Growth
Peroxisome proliferator-activated receptor-γ (PPAR-γ) has recently emerged as potential therapeutic agents for cerebral ischemia-reperfusion (I/R) injury because of anti-neuronal apoptotic actions. However, whether PPAR-γ activation mediates neuronal autophagy in such conditions remains unclear. Therefore, in this study, we investigated the role of PPAR-γ agonist 15-PGJ2 on neuronal autophagy induced by I/R. The expression of autophagic-related protein in ischemic cortex such as LC3-II, Beclin 1, cathepsin-B and LAMP1 increased significantly after cerebral I/R injury. Furthermore, increased punctate LC3 labeling and cathepsin-B staining occurred in neurons. Treatment with PPAR-γ agonist 15d-PGJ2 decreased not only autophagic-related protein expression in ischemic cortex, but also immunoreactivity of LC3 and cathepsin-B in neurons. Autophagic inhibitor 3-methyladenine (3-MA) decreased LC3-II levels, reduced the infarct volume, and mimicked some protective effect of 15d-PGJ2 against cerebral I/R injury. These results indicate that PPAR-γ agonist 15d-PGJ2 exerts neuroprotection by inhibiting neuronal autophagy after cerebral I/R injury. Although the molecular mechanisms underlying PPAR-γ agonist in mediating neuronal autophagy remain to be determined, neuronal autophagy may be a new target for PPAR-γ agonist treatment in cerebral I/R injury.
Some recent clinical reports have shown that the combination of oxymatrine, a phyto-derived drug, with lamivudine (3TC) could improve its curative effect against hepatitis B virus (HBV) infection. However, the experimental data in support of this combination strategy are lacking. In this study, we investigated the anti-HBV activity of the combination of 3TC and either oxymatrine or matrine on HepG2 2.2.15 in vitro. The activities of the combination and the solo compound, each in different concentrations, were compared on the 3rd, 6th, and 9th experimental days. The cytotoxicity results showed that the nontoxic concentrations of both oxymatrine and matrine to HepG2 2.2.15 cells were 800 μg/mL. We found that the single use of oxymatrine below 100 μg/ml, matrine below 200 μg/ml, and 3TC below 30 μg/ml showed weak inhibitory effects on the secretion of hepatitis B surface antigen (HBsAg), hepatitis B e antigen (HBeAg), and HBV-DNA in culture media; the combination of 3TC (30 μg/ml) with oxymatrine (100 μg/ml) or matrine (100 μg/ml) showed significant inhibitory effects that were higher than or equivalent to the single use of 3TC at 100 μg/ml. The results provide a new impetus to develop novel, multicomponent anti-HBV drugs through the combination of natural products with nucleoside analogs to enhance their activity.
The docosahexaenoic (DHA), a ω-3 fatty acid, could play a beneficial inhibition of the incidence and progress of a series of human diseases including cancer. It has been report that DHA is involved in cell apoptosis. Recent studies show that the signal transduction pathway links with bcl-2, bax, caspase-3 and MMP-9 molecules. Therefore, we tested the relationship between DHA and cell apoptosis in human hepatocellular carcinoma cells (Bel-7402 cells). We show here that DHA induces Bel-7402 cells apoptosis after pre-treating cells with DHA. DHA down-regulates the protein expression of Bcl-2 and Bim mRNA level, and up-regulates caspase-3 activity and Bax expression level. We also found that DHA inhibits Bel-7402 cells migration. Basic on our studies, DHA may play a role in tumor invasion and survival.
Docosahexaenoic (DHA); Bcl-2; caspase-3; MMP-9
This study aimed to evaluate the efficacy, toxicity and tolerability of simultaneous modulated accelerated radiation therapy (SMART)-intensity modulated radiotherapy (IMRT) plus cisplatin and 5-fluorouracil (5-FU) chemotherapy for patients with advanced nasopharyngeal cancer (NPC). Forty-five patients with stage II–IV NPC, determined by the American Joint Committee on Cancer system, were treated with prescribed doses of 72 Gy total to the gross tumor volume, 60 Gy to the clinical target volume and metastatic nodal station, and 54 Gy to the clinically-negative neck region. Before radiotherapy, two cycles of cisplatin (30 mg/m2/day on days 1–3) plus 5-FU (400 mg/m2/day on days 1–5) were delivered every three weeks for two cycles. Patients received two cycles of cisplatin (30 mg/m2 day on days 1–3) every three weeks during radiotherapy. In addition, two cycles of cisplatin and 5-FU were given after radiation. All patients completed the prescribed radiotherapy and all scheduled cycles of chemotherapy. Thirty of the 45 patients (66.6%) had a complete response at the end of treatment. Grade 3 mucositis occurred in 4/45 patients (8.8%) and grade 3 dermatitis occurred in 5/45 (11.1%) during radiotherapy. Grade 3 neutropenia occurred in 6/45 (13.3%) during concurrent chemotherapy. There was no treatment-related mortality. After a median follow-up time of 51 months, only three patients’ treatments had failed. Local and distant failure rates were 1.5 and 3.0%, respectively. SMART-IMRT plus cisplatin and 5-FU chemotherapy showed promising activity with manageable toxicity. It is a feasible regimen and improves locoregional disease control.
nasopharyngeal cancer; induction chemotherapy; concurrent chemoradiotherapy; SMART-IMRT; cisplatin
We have recently demonstrated that intra-articular (IA) administration of human recombinant lubricin, LUB:1, significantly inhibited cartilage degeneration and pain in the rat meniscal tear model of post-traumatic arthritis. In this report, we show that after a single IA injection to naïve rats and rats that underwent unilateral meniscal tear, [125I]LUB:1 had a tri-phasic disposition profile, with the alpha, beta, and gamma half-life estimates of 4.5 h, 1.5 days, and 2.1 weeks, respectively. We hypothesize that the terminal phase kinetics was related to [125I]LUB:1 binding to its ligands. [125I]LUB:1 was detected on articular cartilage surfaces as long as 28 days after single IA injection. Micro-autoradiography analysis suggested that [125I]LUB:1 tended to localize to damaged joint surfaces in rats with meniscal tear. After a single intravenous (IV) dose to rats, [125I]LUB:1 was eliminated rapidly from the systemic circulation, with a mean total body clearance of 154 mL/h/kg and a mean elimination half-life (t1/2) of 6.7 h. Overall, LUB:1 has met a desired disposition profile of a potential therapeutic intended for an IA administration: target tissue (knee) retention and fast elimination from the systemic circulation after a single IA or IV dose.
lubricin; osteoarthritis; pharmacokinetics; Biomedicine; Biotechnology; Pharmacy; Pharmacology/Toxicology; Biochemistry, general
The objective of this study was to design and assess measurement instruments that accurately measure the levels of stigma among individuals with a primarily collectivist culture. A cross-sectional study was conducted among middle school students and their parents or guardians in a rural area of China. Exploratory and confirmatory factor analyses were used to examine and determine the latent factors of the sub-scales of stigma respectively among students and their parents. Factor analyses identified three sub-scales: HIV public stigma (7 items), drug-use public stigma (9 items), and fear of HIV infection (7 items). There were no items with cross-loading onto multiple factors, supporting the distinctness of the constructs that these scales were meant to measure. Goodness of fit indices indicated that a three-factor solution fit the data at an acceptable level in the student sample (χ2/degree ratio = 1.98, CFI = 0.92, RMSEA = 0.055, SRMR = 0.057) and in the parent sample (χ2/degree ratio = 1.95, CFI = 0.91, RMSEA = 0.06, SRMR = 0.059). Reliability of the three scales was excellent (Cronbach’s alpha: 0.78–0.92 for students; 0.80–0.94 for parents or guardians) and stable across split samples and for the data as a whole. The scales are brief and suitable for use in developing countries where the collectivist culture prevails.
HIV public stigma; drug-use public stigma; measurement scale; psychometric assessment; Chinese
The spaceflight environment presents unique challenges to terrestrial biology, including but not limited to the direct effects of gravity. As we near the end of the Space Shuttle era, there remain fundamental questions about the response and adaptation of plants to orbital spaceflight conditions. We address a key baseline question of whether gene expression changes are induced by the orbital environment, and then we ask whether undifferentiated cells, cells presumably lacking the typical gravity response mechanisms, perceive spaceflight. Arabidopsis seedlings and undifferentiated cultured Arabidopsis cells were launched in April, 2010, as part of the BRIC-16 flight experiment on STS-131. Biologically replicated DNA microarray and averaged RNA digital transcript profiling revealed several hundred genes in seedlings and cell cultures that were significantly affected by launch and spaceflight. The response was moderate in seedlings; only a few genes were induced by more than 7-fold, and the overall intrinsic expression level for most differentially expressed genes was low. In contrast, cell cultures displayed a more dramatic response, with dozens of genes showing this level of differential expression, a list comprised primarily of heat shock–related and stress-related genes. This baseline transcriptome profiling of seedlings and cultured cells confirms the fundamental hypothesis that survival of the spaceflight environment requires adaptive changes that are both governed and displayed by alterations in gene expression. The comparison of intact plants with cultures of undifferentiated cells confirms a second hypothesis: undifferentiated cells can detect spaceflight in the absence of specialized tissue or organized developmental structures known to detect gravity. Key Words: Tissue culture—Microgravity—Low Earth orbit—Space Shuttle—Microarray. Astrobiology 12, 40–56.
Although the overall prognosis in childhood acute lymphoblastic leukaemia (ALL) is good, outcome after relapse is poor. Recurrence is frequently characterised by the occurrence of disease at extramedullary sites such as the central nervous system and testes. Subpopulations of blasts able to migrate to such areas may have a survival advantage and give rise to disease recurrence. Gene expression profiling of 85 diagnostic pre-B-ALL bone marrow samples revealed higher 5T4 oncofoetal antigen transcript levels in cytogenetic high-risk subgroups of patients (p < 0.001). Flow cytometric analysis determined that bone marrow from relapse patients have a significantly higher percentage of 5T4 positive leukemic blasts than healthy donors (p = 0.005). The high-risk Sup-B15 pre-B-ALL line showed heterogeneity in 5T4 expression, and the derived, 5T4+ (Sup5T4) and 5T4− (Sup) subline cells, displayed differential spread to the omentum and ovaries following intraperitoneal inoculation of immunocompromised mice. Consistent with this, Sup5T4 compared to Sup cells show increased invasion in vitro concordant with increased LFA-1 and VLA-4 integrin expression, adhesion to extracellular matrix and secretion of matrix metalloproteases (MMP-2/-9). We also show that 5T4 positive Sup-B15 cells are susceptible to 5T4 specific superantigen antibody-dependent cellular toxicity providing support for targeted immunotherapy in high risk pre-B-ALL.
Pre-B cell acute lymphoblastic leukemia; childhood cancer; 5T4 oncofoetal antigen; immunotherapy; CXCR4; CXCL12; chemotaxis; invasion
The ridgetail white prawn Exopalaemon carinicauda is one of the most important commercial species in eastern China. However, little information of immune genes in E. carinicauda has been reported. To identify distinctive genes associated with immunity, an expressed sequence tag (EST) library was constructed from hemocytes of E. carinicauda. A total of 3411 clones were sequenced, yielding 2853 ESTs and the average sequence length is 436 bp. The cluster and assembly analysis yielded 1053 unique sequences including 329 contigs and 724 singletons. Blast analysis identified 593 (56.3%) of the unique sequences as orthologs of genes from other organisms (E-value < 1e-5). Based on the COG and Gene Ontology (GO), 593 unique sequences were classified. Through comparison with previous studies, 153 genes assembled from 367 ESTs have been identified as possibly involved in defense or immune functions. These genes are categorized into seven categories according to their putative functions in shrimp immune system: antimicrobial peptides, prophenoloxidase activating system, antioxidant defense systems, chaperone proteins, clottable proteins, pattern recognition receptors and other immune-related genes. According to EST abundance, the major immune-related genes were thioredoxin (141, 4.94% of all ESTs) and calmodulin (14, 0.49% of all ESTs). The EST sequences of E. carinicauda hemocytes provide important information of the immune system and lay the groundwork for development of molecular markers related to disease resistance in prawn species.
► The ridgetail white prawn Exopalaemon carinicauda. ► Expressed sequence tag (EST) library of hemocytes in E. carinicauda. ► Discovery of immune-related genes.
Exopalaemon carinicauda; Hemocytes; Expressed sequence tags; Immune-related gene
Does the brain activity underlying the production of deception differ depending on whether or not one believes their deception can be detected? To address this question, we had participants commit a mock theft in a laboratory setting, and then interrogated them while they underwent functional MRI (fMRI) scanning. Crucially, during some parts of the interrogation participants believed a lie-detector was activated, whereas in other parts they were told it was switched-off. We were thus able to examine the neural activity associated with the contrast between producing true vs. false claims, as well as the independent contrast between believing that deception could and could not be detected. We found increased activation in the right amygdala and inferior frontal gyrus (IFG), as well as the left posterior cingulate cortex (PCC), during the production of false (compared to true) claims. Importantly, there was a significant interaction between the effects of deception and belief in the left temporal pole and right hippocampus/parahippocampal gyrus, where activity increased during the production of deception when participants believed their false claims could be detected, but not when they believed the lie-detector was switched-off. As these regions are associated with binding socially complex perceptual input and memory retrieval, we conclude that producing deceptive behavior in a context in which one believes this deception can be detected is associated with a cognitively taxing effort to reconcile contradictions between one's actions and recollections.
mock-crime; deception; beliefs; lie-detection; fMRI
In this study, we evaluate the effect of HO-1 upregulation on blood pressure and cardiac function in the new model of infarct spontaneous hypertensive rats (ISHR). Male spontaneous hypertensive rats (SHR) at 13 weeks (n = 40) and age-matched male Wistar (WT) rats (n = 20) were divided into six groups: WT (sham + normal saline (NS)), WT (sham + Co(III) Protoporphyrin IX Chloride (CoPP)), SHR (myocardial infarction (MI) + NS), SHR (MI + CoPP), SHR (MI + CoPP + Tin Mesoporphyrin IX Dichloride (SnMP)), SHR (sham + NS); CoPP 4.5 mg/kg, SnMP 15 mg/kg, for six weeks, one/week, i.p., n = 10/group. At the sixth week, echocardiography (UCG) and hemodynamics were performed. Then, blood samples and heart tissue were collected. Copp treatment in the SHR (MI + CoPP) group lowered blood pressure, decreased infarcted area, restored cardiac function (left ventricular ejection fraction (LVEF), left ventricular fraction shortening (LVFS), +dp/dtmax, (−dp/dtmax)/left ventricular systolic pressure (LVSP)), inhibited cardiac hypertrophy and ventricular enlargement (downregulating left ventricular end-systolic diameter (LVEDD), left ventricular end-systolic diameter (LVESD) and heart weight/body weight (HW/BW)), lowered serum CRP, IL-6 and Glu levels and increased serum TB, NO and PGI2 levels. Western blot and immunohistochemistry showed that HO-1 expression was elevated in the SHR (MI + CoPP) group, while co-administration with SnMP suppressed the benefit functions mentioned above. In conclusion, HO-1 upregulation can lower blood pressure and improve post-infarct cardiac function in the ISHR model. These functions may be involved in the inhibition of inflammation and the ventricular remodeling process and in the amelioration of glucose metabolism and endothelial dysfunction.
hypertension; myocardial infarction; heme oxygenase; bilirubin