Human Enterovirus 71 and Coxsackie A16 have caused many outbreaks in the last decade in mainland China, resulting in thousands of fatal cases. Seroepidemiology which provides important information to document population immunity is rare in China.
A cross sectional study of Enterovirus 71 (EV71) and Coxsackie A16 (CA16) seroprevalence was carried out in Guangdong, China, pre- and post- the 2010 hand, foot and mouth disease (HFMD) epidemic period. The levels of EV71 and CA16 specific antibodies were evaluated by a microneutralization test and the geometric mean titer (GMT) was calculated and compared. Our results indicated frequent infection by EV71 and CA16 in Guangdong before the 2010 epidemic. Only EV71 neutralizing antibody but not CA16 seroprevalence was significantly increased after the 2010 HFMD epidemic. Children less than 3 years old especially those aged 2 years showed the lowest positive rates for EV71 and CA16 NA before epidemic and the most significantly increased EV71 seroprevalence after epidemic. CA16 GMT values declined after the 2010 epidemic.
These results indicate EV71 was the major pathogen of HFMD in Guangdong during the 2010 epidemic. The infection occurs largely in children less than 3 years, who should have first priority to receive an EV71 vaccine.
Xeroderma pigmentosum group D (XPD) is an essential gene involved in the nucleotide excision repair (NER) pathway. Two commonly studied single nucleotide polymorphisms (SNPs) of XPD (Lys751Gln, A>C, rs13181; Asp312Asn, G>A, rs1799793) are implicated in the modulation of DNA repair capacity, thus related to the responses to platinum-based chemotherapy. Here we performed a meta-analysis to better evaluate the association between the two XPD SNPs and clinical outcome of platinum-based chemotherapy in non-small cell lung cancer (NSCLC) patients.
A comprehensive search of PubMed database was conducted to identify relevant articles. Primary outcomes included objective response (i.e., complete response + partial response vs. stable disease + progressive disease), progression-free survival (PFS) and overall survival (OS). The pooled and 95% confidence intervals (CIs) of ORs (odds ratios) and HRs (hazard ratios) were estimated using the fixed or random effect model.
Twenty-four studies were eligible according to the inclusion criteria. None of the XPD Lys751Gln/Asp312Asn polymorphisms was associated with objective response, PFS or OS in NSCLC patients treated with platinum drugs. However, in stratified analysis by ethnicity, the XPD Lys751Gln (A>C) polymorphism was not significantly associated with increased response in Caucasians (OR = 1.35, 95%CI = 1.0–1.83, P = 0.122 for heterogeneity) but was associated with decreased PFS in Asians (HR = 1.39, 95%CI = 1.07–1.81, P = 0.879 for heterogeneity). Furthermore, a statistically significant difference existed in the estimates of effect between the two ethnicities (P = 0.014 for TR; P<0.001 for PFS).
XPD Lys751Gln (A>C) may have inverse predictive and prognostic role in platinum-based treatment of NSCLC according to different ethnicities. Further studies are needed to validate our findings.
Paraganglioma is a rare neuroendocrine neoplasm observed in patients of all ages, with an estimated incidence of 3/1,000,000 population. It has long been recognized that some cases are familial. The majority of these tumors are benign, and the only absolute criterion for malignancy is the presence of metastases at sites where chromaffin tissue is not usually found. Some tumors show gross local invasion and recurrence, which may indeed kill the patient, but this does not necessarily associate with metastatic potential. Here, we report a case of vertebral metastatic paraganglioma that occurred 19 months after the patient had undergone partial cystectomy for urinary bladder paraganglioma. We believe this to be a rarely reported bone metastasis of paraganglioma arising originally within the urinary bladder. In this report, we also provide a summary of the general characteristics of this disease, together with progress in diagnosis, treatment, and prognosis.
Bone neoplasms; malignant paraganglioma; neuroendocrine peptide; neuroendocrine tumors; surgery; carcinoma
AIM: To investigate the mRNA expression of cyclooxygensae-2 (COX-2) in benign and malignant ascites, and to explore the difference in COX-2 mRNA expression among different diseases.
METHODS: A total of 36 samples were collected from the Fifth Affiliated Hospital of Sun Yat-Sen University and divided into two experimental groups: benign ascites (n = 21) and malignant ascites (n = 15). Benign ascites included cirrhotic ascites (n = 10) and tuberculous ascites (n = 5). Malignant ascites included oophoroma (n = 7), cancer of colon (n = 5), cancer of the liver (n = 6), gastric cancer (n = 2), and bladder carcinoma (n = 1). The mRNA expression of COX-2 in ascites was examined with reverse transcriptase polymerase chain reaction (RT-PCR) technology, and the positive rate of COX-2 mRNA was compared between different diseases.
RESULTS: The positive rate of COX-2 mRNA in malignant ascites was 42.9% (9/21), which was significantly higher than in benign ascites, 6.7% (1/15), difference being significant between these two groups (χ2 = 4.051, P = 0.044). The proportion of the positive rate in the malignant ascites was as follows: ovarian cancers 57.1% (4/7), colon cancer 40.0% (2/5), liver cancer 33.3% (2/6), gastric cancer 50.0% (1/2), and bladder cancer 0.00% (0/1). However, there was no significant difference in COX-2 mRNA expression among various tumors with malignant ascites (χ2 = 1.614, P = 0.806). Among the benign ascites, COX-2 mRNA levels were different between the tuberculous ascites (0/5) and cirrhotic ascites (1/10), but there was no significant difference (P = 1.000).
CONCLUSION: COX-2 mRNA, detected by RT-PCR, is useful in the differential diagnosis of benign and malignant ascites, which also has potential value in the clinical diagnosis of tumors.
Ascites; Cyclooxygensae-2 mRNA; Reverse transcriptase polymerase chain reaction; Malignant tumor
Paenibacillus mucilaginosus is a critical growth-improving silicate bacterium. Here, we report the complete genome sequence of P. mucilaginosus strain KNP414. This information will provide us with the opportunity to understand its molecular mechanisms and develop more effective utilization of the strain.
The structure of a complex of two ribosome synthesis factors and identification of their ribosomal binding sites provides insights into early stages of ribosome biogenesis.
A multitude of proteins and small nucleolar RNAs transiently associate with eukaryotic ribosomal RNAs to direct their modification and processing and the assembly of ribosomal proteins. Utp22 and Rrp7, two interacting proteins with no recognizable domain, are components of the 90S preribosome or the small subunit processome that conducts early processing of 18S rRNA. Here, we determine the cocrystal structure of Utp22 and Rrp7 complex at 1.97 Å resolution and the NMR structure of a C-terminal fragment of Rrp7, which is not visible in the crystal structure. The structure reveals that Utp22 surprisingly resembles a dimeric class I tRNA CCA-adding enzyme yet with degenerate active sites, raising an interesting evolutionary connection between tRNA and rRNA processing machineries. Rrp7 binds extensively to Utp22 using a deviant RNA recognition motif and an extended linker. Functional sites on the two proteins were identified by structure-based mutagenesis in yeast. We show that Rrp7 contains a flexible RNA-binding C-terminal tail that is essential for association with preribosomes. RNA–protein crosslinking shows that Rrp7 binds at the central domain of 18S rRNA and shares a neighborhood with two processing H/ACA snoRNAs snR30 and snR10. Depletion of snR30 prevents the stable assembly of Rrp7 into preribosomes. Our results provide insight into the evolutionary origin and functional context of Utp22 and Rrp7.
Ribosomes are large RNA–protein complexes that manufacture proteins in all living organisms. Synthesis of large and small ribosomal subunits is a fundamental and enormous task that requires activities of approximately 200 assembly factors in eukaryotic cells. These factors transiently associate with the ribosome, forming a series of pre-ribosomal particles. We currently have a poor understanding of the structure and assembly of ribosome precursors. Utp22 and Rrp7 are two interacting proteins present in early precursors of the small ribosomal subunit. In this study, we determined the structure of the Utp22 and Rrp7 complex by X-ray crystallography and NMR and dissected their functional domains by mutagenesis. The structure of Utp22 reveals an unexpected structural similarity to the tRNA CCA-adding enzyme, providing insight into the evolutionary origin of Utp22. Utp22 apparently lacks any enzymatic activity and functions instead as a structural building block. Rrp7 associates extensively with Utp22 and appears to be anchored to pre-ribosomes via a flexible RNA-binding tail. We used RNA–protein crosslinking to identify the binding site and neighboring factor of Rrp7 on pre-ribosomes. Our study provides a detailed insight into the structure of small ribosomal subunit precursors.
Natural product-derived bengamides possess potent antiproliferative activity and target human methionine aminopeptidases (MetAPs) for their cellular effects. Several derivatives were designed, synthesized, and evaluated as MetAP inhibitors. Here, we present four new X-ray structures of human MetAP1 in complex with the inhibitors. Together with the previous structures of bengamide derivatives with human MetAP2 and tubercular MtMetAP1c, analysis of the interactions of these inhibitors at the active site provides structural basis for further modification of these bengamide inhibitors for improved potency and selectivity as anticancer and antibacterial therapeutics.
The fabrication and properties of n-ZnO nanowires/p-CuO coaxial heterojunction (CH) with a photoresist (PR) blocking layer are reported. In our study, c-plane wurtzite ZnO nanowires were grown by aqueous chemical method, and monoclinic CuO (111) was then coated on the ZnO nanowires by electrochemical deposition to form CH. To improve the device performance, a PR layer was inserted between the ZnO buffer layer and the CuO film to serve as a blocking layer to block the leakage current. Structural investigations of the CH indicate that the sample has good crystalline quality. It was found that our refined structure possesses a better rectifying ratio and smaller reverse leakage current. As there is a large on/off ratio between light on and off and the major light response is centered at around 424 nm, the experimental results suggest that the PR-inserted ZnO/CuO CH can be used as a good narrow-band blue light detector.
ZnO nanowires; CuO; Coaxial heterojunction
Chronic unpredictable stress (CUS) can cause behavioral and physiological abnormalities that are important to the prediction of symptoms of depression that may be associated with cerebral glucose metabolic abnormalities. Curcumin showed potential antidepressant effects, but whether or not it can reverse cerebral functional abnormalities and so ameliorate depression remains unknown.
To investigate the effects of curcumin on brain activity in CUS rats, rats were subjected to 3 weeks of CUS and then treated with curcumin orally at a dose of 40 mg/kg/day for one month. 18 F fluorodeoxyglucose (18 F-FDG)-micro positron emission tomography (micro-PET) neuroimaging was used to detect changes in cerebral metabolism. Body weight, sucrose preference, and open field tests were used to record depressive behaviors during CUS and after curcumin treatment.
Three weeks of CUS significantly decreased body weight, sucrose preference, sucrose consumption, total distance travelling, and the number of rearing events. It also induced metabolic alterations in several parts of the brain, showing increased glucose metabolism in the right hemisphere. After curcumin treatment for one month, sucrose preference, sucrose consumption, total distance travelling, and the number of rearing events returned to normal levels. Curcumin treatment also induced strong deactivation of the left primary auditory cortex and activation of amygdalohippocampal cortex.
Curcumin was found to ameliorate the abnormalities in the behavior and brain glucose metabolism caused by CUS, which may account for its antidepressive effects.
The ubiquitous use of dibutyl phthalate (DBP), one of the most widely used plasticizers, results in extensive exposure to humans and the environment. DBP and its major metabolite, monobutyl phthalate (MBP), may alter steroid biosynthesis and their exposure may lead to damage to male reproductive function. Low-doses of DBP/MBP may result in increased steroidogenesis in vitro and in vivo. However, the mechanisms of possible effects of low-dose MBP on steroidogenesis remain unclear. The aim of present study was to elaborate the role of transcription factors and steroidogenic acute regulatory protein in low-dose MBP-induced distruption of steroidogenesis in mouse Leydig tumor cells (MLTC-1 cells).
In the present study, MLTC-1 cells were cultured in RPMI 1640 medium supplemented with 2 g/L sodium bicarbonate. Progesterone level was examined by I125-pregesterone Coat-A-Count radioimmunoassay (RIA) kits. mRNA and protein levels were assessed by reverse transcription-polymerase chain reaction (RT-PCR) and western blot, respectively. DNA-binding of several transcription factors was examined by electrophoretic mobility shift assay (EMSA).
In this study, various doses of MBP (0, 10(−9), 10(−8), 10(−7), or 10(−6) M) were added to the medium followed by stimulation of MLTC-1 cells with human chorionic gonadotrophin (hCG). The results showed that MBP increased progesterone production and steroidogenic acute regulatory protein (StAR) mRNA and protein levels. However, the protein levels of cytochrome P450scc and 3 beta-hydroxy-steroid dehydrogenase (3 beta-HSD) were unchanged after MBP treatment. EMSA assay showed that DNA-binding of steroidogenic factors 1(SF-1), GATA-4 and CCAAT/enhancer binding protein-beta (C/EBP-beta) was increased in a dose-dependent manner after MBP exposure. Western blot tests were next employed and confirmed that the protein levels of SF-1, GATA-4 and C/EBP-beta were also increased. Additionally, western blot tests confirmed the expression of DAX-1, negative factor of SF-1, was dose-dependently down regulated after MBP exposure, which further confirmed the role of SF-1 in MBP-stimulated steroid biosynthesis.
In conclusion, we firstly delineated the regulation of StAR by transcription factors including SF-1, GATA-4 and C/EBP-beta maybe critical mechanism involved in low-dose MBP-stimulated steroidogenesis.
Monobutyl phthalate; Progesterone; Steroidogenic acute regulatory protein; Steroidogenic factors 1; GATA-4; CCAAT/enhancer binding protein-beta; Mouse Leydig tumor cells
Hand, foot and mouth disease (HFMD) is a common pediatric illness. Mainly induced by the Enterovirus 71 and Coxsackievirus A 16 infections, the frequently occurred HFMD outbreaks have become a serious public health problem in Southeast Asia. Currently,only a few studies have investigated the human immunity to HFMD in China. In this study, we conducted a cohort study in Guangdong province, China.
Stored serum samples from children less than 10 years old were analyzed. The levels of EV71 and CA16 specific antibodies before, during and shortly after the 2008 large outbreak of HFMD were evaluated by the microneutralization test. The geometric mean titer (GMT) was calculated and compared. Statistical significance was taken as P < 0.05.
The seroprevalence data showed a continuous circulation of EV71 and CA16 in Guangdong province China in 2007–2009. The low positive rate in 2009 correlated well with the unprecedented outbreak of HFMD in 2010. Age related increase of seroprevalence was identified in 1–3 years old children for EV71 and in 1–5 years old children for CA16 in Guangdong province. High GMT of EV71 and CA16 antibody titers were also found for these age groups.
All of the above findings indicated common infections for these age groups. And they should clearly be at the top of the priority in periodical seroprevalence survey and future vaccination campaign.
Enterovirus 71; Coxsackievirus A 16; Seroprevalence
One popular approach to prepare graphene is to grow them on transition metal substrates via chemical vapor deposition. By using the density functional theory with dispersion correction, we systematically investigate for the first time the interfacial properties of bilayer (BLG) and trilayer graphene (TLG) on metal substrates. Three categories of interfacial structures are revealed. The adsorption of B(T)LG on Al, Ag, Cu, Au, and Pt substrates is a weak physisorption, but a band gap can be opened. The adsorption of B(T)LG on Ti, Ni, and Co substrates is a strong chemisorption, and a stacking-insensitive band gap is opened for the two uncontacted layers of TLG. The adsorption of B(T)LG on Pd substrate is a weaker chemisorption, with a band gap opened for the uncontacted layers. This fundamental study also helps for B(T)LG device study due to inevitable graphene/metal contact.
The aim of this study was to quantify the effects of right ventricular apical pacing (RVAP) on hemodynamics in left anterior descending coronary artery (LAD) and anterior interventricular vein (AIV) contrast to baseline condition in open chest beagles using Doppler ultrasound imaging.
In 6 anesthetized open chest beagles, the spectral Doppler waveforms of the middle segmental LAD and the AIV were acquired with a 5 MHz linear array transducer at baseline condition and during RVAP. The aortic pressure-time curves were recorded synchronously. The Doppler hemodynamic parameters of the LAD and AIV at both states were derived and compared.
The spectral Doppler waveforms of the LAD had a principal diastolic positive wave (Dp), which heelled by a momentary negative wave and a positive wave during early systole at baseline condition. During RVAP, an additional negative wave appeared in the LAD at late systole. The duration of the Dp shortened (227.83±12.16 ms vs 188.50±8.97 ms, P<0.001), and the acceleration of the Dp decreased (11.85±2.22 m/s2 vs 3.54±0.42 m/s2, P<0.001). The spectral Doppler waveforms of the AIV only had a principal positive wave (Sp) at baseline condition, but an additional diastolic negative wave appeared during RVAP. The duration of the Sp shortened (242.99±7.98 ms vs 215.38±15.44 ms, P<0.001), and the acceleration of the Sp decreased (9.61±1.93 m/s2 vs 1.01±0.11 m/s2, P<0.001).
Obvious hemodynamic changes in the LAD and AIV during RVAP were observed, and these abnormal flow patterns in epicardial coronary arteries and vena coronaria may be sensitive and important hints of the disturbed cardiac electrical and mechanical activity sequences.
Recently we have demonstrated that anthocyanins from fruits of Vitis coignetiae Pulliat (AIMs) have anticancer effects. Here, we investigate the effects of AIMs on cell proliferation and invasion as well as epithelial-mesenchymal transition (EMT) which have been linked to cancer metastasis in human uterine cervical cancer HeLa cells. AIMs inhibited the invasion of HeLa cells in a dose-dependent manner. AIMs inhibited MMP-9 expression in a dose-dependent manner. AIMs inhibited the motility of HeLa cells in a wound healing test. AIMs still suppressed NF-κB activation induced by TNF. AIMs also inhibited EMT in HeLa cells. AIMs suppressed vimentin, N-cadherin, and β-catenin expression and induced E-cadherin. AIMs also suppressed expression of β-catenin and Snail, which was regulated by GSK-3. These effects of AIMs were also limited in the HeLa cells treated with TNF. In conclusion, this study indicates that AIMs have anticancer effects by suppressing NF-κB-regulated genes and EMT, which relates to suppression of IκBα phosphorylation and GSK-3 activity, respectively. However, the effects of AIMs were attenuated in the TNF-high condition.
Acquired immune deficiency syndrome (AIDS) is a severe infectious disease that causes a large number of deaths every year. Traditional anti-AIDS drugs directly targeting the HIV-1 encoded enzymes including reverse transcriptase (RT), protease (PR) and integrase (IN) usually suffer from drug resistance after a period of treatment and serious side effects. In recent years, the emergence of numerous useful information of protein-protein interactions (PPI) in the HIV life cycle and related inhibitors makes PPI a new way for antiviral drug intervention. In this study, we identified 26 core human proteins involved in PPI between HIV-1 and host, that have great potential for HIV therapy. In addition, 280 chemicals that interact with three HIV drugs targeting human proteins can also interact with these 26 core proteins. All these indicate that our method as presented in this paper is quite promising. The method may become a useful tool, or at least plays a complementary role to the existing method, for identifying novel anti-HIV drugs.
The Aurora-A kinase gene is frequently amplified and/or over-expressed in a variety of human cancers, leading to major efforts to develop therapeutic agents targeting this pathway. Here we demonstrate that Aurora-A is targeted for ubiquitination and subsequent degradation by the F-box protein FBXW7 in a process that is regulated by GSK3β. Using a series of truncated Aurora-A proteins and site directed mutagenesis, we identified distinct FBXW7 and GSK3β binding sites in Aurora-A. Mutation of critical residues in either site substantially disrupts degradation of Aurora-A. Furthermore, we show that loss of Pten results in the stabilization of Aurora-A by attenuating FBXW7-dependent degradation of Aurora-A through the AKT/GSK3β pathway. Moreover, radiation-induced tumor latency is significantly shortened in Fbxw7+/− Pten+/− mice as compared to either Fbxw7+/− or Pten+/− mice, indicating that Fbxw7 and Pten appear to cooperate in suppressing tumorigenesis. Our results establish a novel posttranslational regulatory network in which the Pten and Fbxw7 pathways appear to converge on the regulation of Aurora-A level.
Aurora-A; Fbxw7; Pten; tumorigenesis; Ubiquitination
The yeast Candida is one of the most frequent pathogens isolated from bloodstream infections and is associated with significant morbidity and mortality. Problems with clinical and microbiological diagnosis of invasive candidiasis (IC) have prompted the development of non-culture-based laboratory methods. Previous reports suggest that serological detection of antibodies might be useful for diagnosing systemic candidiasis.
Diagnosis of IC using antibodies against recombinant Candida albicans enolase (Eno) and fructose-bisphosphate aldolase (Fba1) was evaluated. Using recombinant Eno and Fba1 as coating antigens, enzyme-linked immunosorbent assays (ELISAs) were used to analyze sera from patients with candidemia (n = 101), Candida colonization (n = 50), bacteremia (n = 84), invasive aspergillosis (n = 40); and from healthy controls (n = 200).
The results demonstrated that ELISA detection of anti-Eno and anti-Fba1 IgG distinguished IC from other pathogenic infections in patients and healthy individuals. The sensitivity, specificity, and positive and negative predictive values were 72.3%, 94.7%, 78.5% and 93% for anti-Eno, and 87.1%, 92.8%, 76.5% and 96.4% for anti-Fba1 antibodies, respectively. Combining these two tests improved sensitivity up to 90.1% and negative predictive value up to 97.1%, with specificity and positive predictive values of 90.6% and 72.2%. The tests were specific to the Candida genus and antibody titers were higher for candidemia patients than for controls. Positive antibody tests were obtained before blood culture results for 42.2% of patients for anti-Eno and 51.1% for anti-Fba1.
These data suggest that tests that detect IgG antibodies against Candida enolase and fructose-bisphosphate aldolase, especially when used in combination, could be a powerful tool for diagnosing IC.
Candidemia; Serodiagnosis; Candida enolase; Candida fructose-bisphosphate aldolase; IgG antibody
There is a tunable band gap in ABC-stacked few-layer graphene (FLG) via applying a vertical electric field, but the operation of FLG-based field effect transistor (FET) requires two gates to create a band gap and tune channel's conductance individually. Using first principle calculations, we propose an alternative scheme to open a band gap in ABC-stacked FLG namely via single-side adsorption. The band gap is generally proportional to the charge transfer density. The capability to open a band gap of metal adsorption decreases in this order: K/Al > Cu/Ag/Au > Pt. Moreover, we find that even the band gap of ABA-stacked FLG can be opened if the bond symmetry is broken. Finally, a single-gated FET based on Cu-adsorbed ABC-stacked trilayer graphene is simulated. A clear transmission gap is observed, which is comparable with the band gap. This renders metal-adsorbed FLG a promising channel in a single-gated FET device.
Objective. To investigate neuroprotective effects of scutellarin (Scu) in a rat model of cerebral ischemia with use of 18F-fluorodeoxyglucose (18F-FDG) micro positron emission tomography (microPET). Method. Middle cerebral artery occlusion was used to establish cerebral ischemia. Rats were divided into 5 groups: sham operation, cerebral ischemia-reperfusion untreated (CIRU) group, Scu-25 group (Scu 25 mg/kg/d), Scu-50 group (Scu 50 mg/kg/d), and nimodipine (10 mg/Kg/d). The treatment groups were given for 2 weeks. The therapeutic effects in terms of cerebral infarct volume, neurological deficit scores, and cerebral glucose metabolism were evaluated. Levels of vascular density factor (vWF), glial marker (GFAP), and mature neuronal marker (NeuN) were assessed by immunohistochemistry. Results. The neurological deficit scores were significantly decreased in the Scu-50 group compared to the CIRU group (P < 0.001). 18F-FDG accumulation in the ipsilateral cerebral infarction increased steadily over time in Scu-50 group compared with CIRU group (P < 0.01) and Scu-25 group (P < 0.01). Immunohistochemical analysis demonstrated Scu-50 enhanced neuronal maturation. Conclusion. 18F-FDG microPET imaging demonstrated metabolic recovery after Scu-50 treatment in the rat model of cerebral ischemia. The neuroprotective effects of Scu on cerebral ischemic injury might be associated with increased regional glucose activity and neuronal maturation.
Radio-frequency application of graphene transistors is attracting much recent attention due to the high carrier mobility of graphene. The measured intrinsic cut-off frequency (fT) of graphene transistor generally increases with the reduced gate length (Lgate) till Lgate = 40 nm, and the maximum measured fT has reached 300 GHz. Using ab initio quantum transport simulation, we reveal for the first time that fT of a graphene transistor still increases with the reduced Lgate when Lgate scales down to a few nm and reaches astonishing a few tens of THz. We observe a clear drain current saturation when a band gap is opened in graphene, with the maximum intrinsic voltage gain increased by a factor of 20. Our simulation strongly suggests it is possible to design a graphene transistor with an extraordinary high fT and drain current saturation by continuously shortening Lgate and opening a band gap.
Toxicity is a major contributor to high attrition rates of new chemical entities in drug discoveries. In this study, an order-classifier was built to predict a series of toxic effects based on data concerning chemical-chemical interactions under the assumption that interactive compounds are more likely to share similar toxicity profiles. According to their interaction confidence scores, the order from the most likely toxicity to the least was obtained for each compound. Ten test groups, each of them containing one training dataset and one test dataset, were constructed from a benchmark dataset consisting of 17,233 compounds. By a Jackknife test on each of these test groups, the 1st order prediction accuracies of the training dataset and the test dataset were all approximately 79.50%, substantially higher than the rate of 25.43% achieved by random guesses. Encouraged by the promising results, we expect that our method will become a useful tool in screening out drugs with high toxicity.
Treatment of chronic wounds is becoming increasingly difficult due to antibiotic resistance. Complex natural products with antimicrobial activity, such as honey, are now under the spotlight as alternative treatments to antibiotics. Several studies have shown honey to have broad-spectrum antibacterial activity at concentrations present in honey dressings, and resistance to honey has not been attainable in the laboratory. However not all honeys are the same and few studies have used honey that is well defined both in geographic and chemical terms. Here we have used a range of concentrations of clover honey and a suite of manuka and kanuka honeys from known geographical locations, and for which the floral source and concentration of methylglyoxal and hydrogen peroxide potential were defined, to determine their effect on growth and cellular morphology of four bacteria: Bacillus subtilis, Escherichia coli, Staphylococcus aureus and Pseudomonas aeruginosa. While the general trend in effectiveness of growth inhibition was manuka>manuka-kanuka blend>kanuka>clover, the honeys had varying and diverse effects on the growth and cellular morphology of each bacterium, and each organism had a unique response profile to these honeys. P. aeruginosa showed a markedly different pattern of growth inhibition to the other three organisms when treated with sub-inhibitory concentrations of honey, being equally sensitive to all honeys, including clover, and the least sensitive to honey overall. While hydrogen peroxide potential contributed to the antibacterial activity of the manuka and kanuka honeys, it was never essential for complete growth inhibition. Cell morphology analysis also showed a varied and diverse set of responses to the honeys that included cell length changes, cell lysis, and alterations to DNA appearance. These changes are likely to reflect the different regulatory circuits of the organisms that are activated by the stress of honey treatment.
To study Wnt/beta-catenin in castrate-resistant prostate cancer (CRPC) and understand its function independently of the beta-catenin–androgen receptor (AR) interaction.
We performed beta-catenin immunocytochemical analysis, evaluated TOP-flash reporter activity (a reporter of beta-catenin–mediated transcription), and sequenced the beta-catenin gene in MDA PCa 118a, MDA PCa 118b, MDA PCa 2b, and PC-3 prostate cancer (PCa) cells. We knocked down beta-catenin in AR-negative MDA PCa 118b cells and performed comparative gene-array analysis. We also immunohistochemically analyzed beta-catenin and AR in 27 bone metastases of human CRPCs.
Beta-catenin nuclear accumulation and TOP-flash reporter activity were high in MDA PCa 118b but not in MDA PCa 2b or PC-3 cells. MDA PCa 118a and 118b cells carry a mutated beta-catenin at codon 32 (D32G). Ten genes were expressed differently (false discovery rate, 0.05) in MDA PCa 118b cells with downregulated beta-catenin. One such gene, hyaluronan synthase 2 (HAS2), synthesizes hyaluronan, a core component of the extracellular matrix. We confirmed HAS2 upregulation in PC-3 cells transfected with D32G-mutant beta-catenin. Finally, we found nuclear localization of beta-catenin in 10 of 27 human tissue specimens; this localization was inversely associated with AR expression (P = 0.056, Fisher’s exact test), suggesting that reduced AR expression enables Wnt/beta-catenin signaling.
We identified a previously unknown downstream target of beta-catenin, HAS2, in PCa, and found that high beta-catenin nuclear localization and low or no AR expression may define a subpopulation of men with bone-metastatic PCa. These findings may guide physicians in managing these patients.
beta-catenin; prostate cancer; androgen receptor; hyaluronan synthase