DRAGON-Data: a platform and protocol for integrating genomic and phenotypic data across large psychiatric cohorts.

BACKGROUND: Current psychiatric diagnoses, although heritable, have not been clearly mapped onto distinct underlying pathogenic processes. The same symptoms often occur in multiple disorders, and a substantial proportion of both genetic and environmental risk factors are shared across disorders. However, the relationship between shared symptoms and shared genetic liability is still poorly understood. AIMS: Well-characterised, cross-disorder samples are needed to investigate this matter, but few currently exist. Our aim is to develop procedures to purposely curate and aggregate genotypic and phenotypic data in psychiatric research. METHOD: As part of the Cardiff MRC Mental Health Data Pathfinder initiative, we have curated and harmonised phenotypic and genetic information from 15 studies to create a new data repository, DRAGON-Data. To date, DRAGON-Data includes over 45 000 individuals: adults and children with neurodevelopmental or psychiatric diagnoses, affected probands within collected families and individuals who carry a known neurodevelopmental risk copy number variant. RESULTS: We have processed the available phenotype information to derive core variables that can be reliably analysed across groups. In addition, all data-sets with genotype information have undergone rigorous quality control, imputation, copy number variant calling and polygenic score generation. CONCLUSIONS: DRAGON-Data combines genetic and non-genetic information, and is available as a resource for research across traditional psychiatric diagnostic categories. Algorithms and pipelines used for data harmonisation are currently publicly available for the scientific community, and an appropriate data-sharing protocol will be developed as part of ongoing projects (DATAMIND) in partnership with Health Data Research UK.

Preschool development, temperament and genetic liability as early markers of childhood ADHD: A cohort study.

Background: ADHD is associated with multiple adverse outcomes and early identification is important. The present study sets out to identify early markers and developmental characteristics during the first 30 months of life that are associated with ADHD 6 years later. Methods: 9201 participants from the prospective Avon Longitudinal Study of Parents and Children (ALSPAC) birth cohort were included. Outcome measures were parent-rated ADHD symptom scores (Strengths and Difficulties Questionnaire, SDQ) and ADHD diagnosis (Development and Wellbeing Assessment, DAWBA) at age 7. Seventeen putative markers were identified from previous literature and included: pre- and peri-natal risk factors, genetic liability (ADHD polygenic risk scores, PRS), early development, temperament scores and regulatory problems. Associations were examined using regression analysis. Results: Univariable regression analysis showed that multiple early life factors were associated with future ADHD outcomes, even after controlling for sex and socio-economic status. In a multivariable linear regression model; temperament activity scores (B = 0.107, CI = 0.083-0.132), vocabulary delay (B = 0.605, CI = 0.211-0.988), fine motor delay (B = 0.693, CI = 0.360-1.025) and ADHD PRS (B = 0.184, CI = 0.074-0.294) were associated with future symptoms (R 2 = 10.7%). In a multivariable logistic regression model, ADHD PRS (OR = 1.39, CI = 1.10-1.77) and temperament activity scores (OR = 1.09, CI = 1.04-1.16) showed association with ADHD diagnosis. Conclusion: As well as male sex and lower socio-economic status, high temperament activity levels and motor and speech delays in the first 30 months of life, are associated with childhood ADHD. Intriguingly, given that genetic risk scores are known to explain little of the variance of ADHD outcomes, we found that ADHD PRS added useful predictive information. Future research needs to test whether predictive models incorporating aspects of early development and genetic risk scores are useful for predicting ADHD in clinical practice.

Preventive Hoof Trimming and Animal-Based Welfare Measures Influence the Time to First Lameness Event and Hoof Lesion Prevalence in Dairy Cows.

Background: The objectives of this study were to, (1) investigate the impact of the Dutch five-step hoof trimming (HT) technique on time to lameness and hoof lesion prevalence in grazing (GR) and non-grazing (NGR) dairy cows, and (2) determine the association between potential benefits of HT and animal-based welfare measures during lactation. A total of 520 non-lame cows without hoof lesions from 5 dairy farms (GR = 2, NGR = 3) were enrolled at early (within 30 days in milk; DIM) and late lactation (above 200 DIM), and randomly allocated to either trimmed (HGR or HNGR) or control groups (CON-GR and CON-NGR). Locomotion scores, body condition, hock condition, leg hygiene, and hoof health were assessed at monthly intervals until the following 270 days in milk. The data were analyzed using Kaplan-Meier survival analysis, multivariable Cox, and logistic regression models. The overall incidence rate of lameness was 36.2 cases/100 cows/month, with corresponding rates of 27.4, 31.9, 48.4, and 45.8 cases/100 cows/month in HGR, HNGR, CON-GR, and CON-NGR, respectively. Time to first lameness event was significantly higher in HGR (mean ± S.E; 8.12 ± 0.15) compared to CON-GR (7.36 ± 0.26), and in HNGR (8.05 ± 0.16) compared to CON-NGR (7.39 ± 0.23). The prevalence of hoof lesions in the enrolled cows was 36.9%, with a higher occurrence in CON-GR (48.8%) than HGR (23.2%), and in CON-NGR (52.6%) compared to HNGR (32.2%). The majority of hoof lesions were non-infectious in grazing (HGR vs. CON-GR; 21.3 vs. 33.3%) and non-grazing herds (HNGR vs. CON-NGR; 25.0 vs. 40.4%). The risk of lameness was higher in underconditioned cows (Hazard ratio; HR = 3.1, 95% CI 1.2-7.4), presence of hoof lesion (HR = 33.1, 95% CI 17.6-62.5), and there was variation between farms. Aside HT, lower parity (OR = 0.4, 95% CI 0.2-0.8), normal hock condition (OR = 0.06; 95% 0.01-0.29), and absence of overgrown hoof (OR = 0.4; 95% 0.2-0.7) were protective against non-infectious hoof lesions. Functional HT is beneficial as a lameness preventive strategy during lactation; however, ensuring older cows are in good body condition and free from hock injuries are equally important.

Antiviral activity of betacyanins from red pitahaya (Hylocereus polyrhizus) and red spinach (Amaranthus dubius) against dengue virus type 2 (GenBank accession no. MH488959).

This study investigated the antiviral activity of betacyanins from red pitahaya (Hylocereus polyrhizus) and red spinach (Amaranthus dubius) against dengue virus type 2 (DENV-2). The pulp of red pitahaya and the leaves of red spinach were extracted using methanol followed by sub-fractionation and Amberlite XAD16N column chromatography to obtain betacyanin fractions. The half maximum cytotoxicity concentration for betacyanin fractions from red pitahaya and red spinach on Vero cells were 4.346 and 2.287 mg ml-1, respectively. The half-maximal inhibitory concentration (IC50) of betacyanin fraction from red pitahaya was 125.8 µg ml-1 with selectivity index (SI) of 5.8. For betacyanin fraction from red spinach, the IC50 value was 14.62 µg ml-1 with SI of 28.51. Using the maximum non-toxic betacyanin concentration, direct virucidal effect against DENV-2 was obtained from betacyanin fraction from red pitahaya (IC50 of 126.70 µg ml-1; 95.0 % virus inhibition) and red spinach (IC50 value of 106.80 µg ml-1; 65.9 % of virus inhibition). Betacyanin fractions from red pitahaya and red spinach inhibited DENV-2 in vitro.

Umai Dish Preparation Practices and Food Safety Behaviors in Bintulu Locals on Borneo Island, Malaysia.

ABSTRACT: Umai is a popular, traditional, native dish of the Melanau ethnic group in Sarawak. It is prepared using thin slices of raw marine fish marinated with calamansi juice and seasoned with other ingredients. The local people believe that the acidity of the citrus juice, along with the use of salt and spice, can slightly cook the fish and remove the fishy smell. The aim of this study was to investigate (i) the different umai handling and preparation practices and (ii) the personal experience of umai consumption among respondents. A purposive sample of 100 umai makers, divided into two equal groups, professionals and nonprofessionals, participated in the study. We found that Spanish mackerel and hairfin anchovy were ranked first and second in the list of species chosen for making umai, with the former mostly preferred by the professional group, as opposed to the latter, which was preferred by the nonprofessional group. Black pomfret was ranked third, where it is equally preferred by both groups. About 20% of respondents would freeze the raw fish chunks prior to preparing umai, as opposed to 26% who would sun dry their fish. Other techniques, such as salting and marinating (using calamansi juice), were also used during the preparation of umai. Most of the respondents indicated that they would consider the umai ready to eat soon after marinating (with all ingredients) the raw fish. One-third of both respondent groups indicated that they would chill the umai dish at 4°C for 30 min before serving. The respondents could not provide any rationale behind these food preparation practices. Overall, this study provides evidence of the different preparation methods for umai. These practices can thus be considered important targets for public health education campaigns seeking to improve food safety surrounding this food group.

About Ganoderma boninense in oil palm plantations of Sumatra and peninsular Malaysia: Ancient population expansion, extensive gene flow and large scale dispersion ability.

Wood rot fungi form one of the main classes of phytopathogenic fungus. The group includes many species, but has remained poorly studied. Many species belonging to the Ganoderma genus are well known for causing decay in a wide range of tree species around the world. Ganoderma boninense, causal agent of oil palm basal stem rot, is responsible for considerable yield losses in Southeast Asian oil palm plantations. In a large-scale sampling operation, 357 sporophores were collected from oil palm plantations spread over peninsular Malaysia and Sumatra and genotyped using 11 SSR markers. The genotyping of these samples made it possible to investigate the population structure and demographic history of G. boninense across the oldest known area of interaction between oil palm and G. boninense. Results show that G. boninense possesses a high degree of genetic diversity and no detectable genetic structure at the scale of Sumatra and peninsular Malaysia. The fact that few duplicate genotypes were found in several studies including this one supports the hypothesis of spore dispersal in the spread of G. boninense. Meanwhile, spatial autocorrelation analysis shows that G. boninense is able to disperse across both short and long distances. These results bring new insight into mechanisms by which G. boninense spreads in oil palm plantations. Finally, the use of approximate Bayesian computation (ABC) modelling indicates that G. boninense has undergone a demographic expansion in the past, probably before the oil palm was introduced into Southeast Asia.

Anti-dengue virus serotype 2 activity and mode of action of a novel peptide.

AIM: To identify a novel antiviral peptide against dengue virus serotype 2 (DENV-2) by screening a phage display peptide library and to evaluate its in vitro antiviral activity and mode of action. METHODS AND RESULTS: A phage display peptide library was biopanned against purified DENV-2 and resulted in the identification and selection of a peptide (peptide gg-ww) for further investigation. ELISA was performed, and peptide gg-ww was shown to possess the highest binding affinity against DENV-2. Thus, peptide gg-ww was synthesized for cytotoxicity and antiviral assays. Virus plaque reduction assay, real-time PCR and immunofluorescence assay were used to investigate the inhibitory effect of peptide gg-ww on DENV-2 infection in Vero cells. Three different assays (pre-, simultaneous and post-treatments assays) were performed to investigate the peptide's mode of action. Results indicated that peptide gg-ww possessed strong antiviral activity with a ~96% inhibition rate, which was achieved at 250 µmol l(-1) . Viral replication was inhibited during a simultaneous treatment assay, indicating that the entry of the virus was impeded by this peptide. CONCLUSIONS: Peptide gg-ww displayed antiviral action against DENV-2 by targeting an early stage of viral replication (i.e. during viral entry). SIGNIFICANCE AND IMPACT OF THE STUDY: Peptide gg-ww may represent a new therapeutic candidate for the treatment of DENV infections and is a potential candidate to be developed as a peptide drug.

Activation of EphA receptors mediates the recruitment of the adaptor protein Slap, contributing to the downregulation of N-methyl-D-aspartate receptors.

Regulation of the activity of N-methyl-d-aspartate receptors (NMDARs) at glutamatergic synapses is essential for certain forms of synaptic plasticity underlying learning and memory and is also associated with neurotoxicity and neurodegenerative diseases. In this report, we investigate the role of Src-like adaptor protein (Slap) in NMDA receptor signaling. We present data showing that in dissociated neuronal cultures, activation of ephrin (Eph) receptors by chimeric preclustered eph-Fc ligands leads to recruitment of Slap and NMDA receptors at the sites of Eph receptor activation. Interestingly, our data suggest that prolonged activation of EphA receptors is as efficient in recruiting Slap and NMDA receptors as prolonged activation of EphB receptors. Using established heterologous systems, we examined whether Slap is an integral part of NMDA receptor signaling. Our results showed that Slap does not alter baseline activity of NMDA receptors and does not affect Src-dependent potentiation of NMDA receptor currents in Xenopus oocytes. We also demonstrate that Slap reduces excitotoxic cell death triggered by activation of NMDARs in HEK293 cells. Finally, we present evidence showing reduced levels of NMDA receptors in the presence of Slap occurring in an activity-dependent manner, suggesting that Slap is part of a mechanism that homeostatically modulates the levels of NMDA receptors.

Risk Factors for Nipah virus infection among pteropid bats, Peninsular Malaysia.

We conducted cross-sectional and longitudinal studies to determine the distribution of and risk factors for seropositivity to Nipah virus (NiV) among Pteropus vampyrus and P. hypomelanus bats in Peninsular Malaysia. Neutralizing antibodies against NiV were detected at most locations surveyed. We observed a consistently higher NiV risk (odds ratio 3.9) and seroprevalence (32.8%) for P. vampyrus than P. hypomelanus (11.1%) bats. A 3-year longitudinal study of P. hypomelanus bats indicated nonseasonal temporal variation in seroprevalence, evidence for viral circulation within the study period, and an overall NiV seroprevalence of 9.8%. The seroprevalence fluctuated over the study duration between 1% and 20% and generally decreased during 2004-2006. Adult bats, particularly pregnant, with dependent pup and lactating bats, had a higher prevalence of NiV antibodies than juveniles. Antibodies in juveniles 6 months-2 years of age suggested viral circulation within the study period.

Natural product-derived antitumor compound phenethyl isothiocyanate inhibits mTORC1 activity via TSC2.

Phenethyl isothiocyanate (1) is a natural dietary phytochemical with cytostatic, cytotoxic, and antitumor activity. The effects of 1 were investigated on the activity of mTOR, a kinase that enhances the translation of many RNAs encoding proteins critical for cancer cell growth, including the angiogenesis regulator HIF1α. Compound 1 effectively blocked HIF1α RNA translation in MCF7 breast cancer cells, and this was associated with reduced phosphorylation of 4E-BP1 and p70 S6K, well-characterized downstream substrates of the mTOR-containing mTORC1 complex. Compound 1 also inhibited mTORC1 activity in mouse embryonic fibroblasts (MEFs). The 1-mediated inhibition of mTORC1 activity appeared to be independent of the upstream regulators PTEN, AKT, ERK1/2, and AMPK. By contrast, 1-mediated inhibition of mTORC1 activity was dependent on the presence of TSC2, part of a complex that regulates mTORC1 activity negatively. TSC2-deficient MEFs were resistant to 1-mediated inhibition of p70 S6K phosphorylation. TSC2-deficient MEFs were also partially resistant to 1-mediated growth inhibition. Overall, the present results confirm that 1 inhibits mTORC1 activity. This is dependent on the presence of TSC2, and inhibition of mTORC1 contributes to optimal 1-induced growth inhibition. Inhibition of RNA translation may be an important component of the antitumor effects of phenethyl isothiocyanate.

Cellular transcripts of chicken brain tissues in response to H5N1 and Newcastle disease virus infection.

BACKGROUND: Highly-pathogenic avian influenza (HPAI) H5N1 and Newcastle disease (ND) viruses are the two most important poultry viruses in the world, with the ability to cause classic central nervous system dysfunction in poultry and migratory birds. To elucidate the mechanisms of neurovirulence caused by these viruses, a preliminary study was design to analyze host's cellular responses during infections of these viruses. METHODS: An improved mRNA differential display technique (Gene Fishing™) was undertaken to analyze differentially expressed transcripts regulated during HPAI H5N1 and velogenic neurotropic NDV infections of whole brain of chickens. The identification of differentially expressed genes (DEGs) was made possible as this technique uses annealing control primers that generate reproducible, authentic and long PCR products that are detectable on agarose gels. RESULTS: Twenty-three genes were identified to be significantly regulated during infections with both viruses, where ten of the genes have been selected for validation using a TaqMan® based real time quantitative PCR assay. Some of the identified genes demonstrated to be key factors involving the cytoskeletal system, neural signal transduction and protein folding during stress. Interestingly, Septin 5, one of the genes isolated from HPAI H5N1-infected brain tissues has been reported to participate in the pathogenic process of Parkinson's disease. CONCLUSIONS: In this limited study, the differentially expressed genes of infected brain tissues regulated by the viruses were found not to be identical, thus suggesting that their neurovirulence and neuropathogenesis may not share similar mechanisms and pathways.

Differential induction of apoptosis in human breast cancer cell lines by phenethyl isothiocyanate, a glutathione depleting agent.

Phenethyl isothiocyanate (PEITC) is a naturally occurring electrophile which depletes intracellular glutathione (GSH) levels and triggers accumulation of reactive oxygen species (ROS). PEITC is of considerable interest as a potential chemopreventive/chemotherapeutic agent, and in this work, we have investigated the effects of PEITC on human breast cancer cell lines. Whereas PEITC readily induced apoptosis in MDA-MB-231 cells (associated with rapid activation of caspases 9 and 3, and decreased expression of BAX), MCF7 cells were relatively resistant to the apoptosis promoting effects of PEITC. The relative resistance of MCF7 cells was associated with high basal expression of NRF2, a transcription factor that coordinates cellular protective responses to oxidants and electrophiles and raised intracellular levels of GSH. This raised basal expression of NRF2 appeared to be a response to on-going production of ROS, since treatment with the antioxidant and GSH precursor N-acetylcysteine (NAC) reduced NRF2 expression. Moreover, pre-treatment of MDA-MB-231 cells with NAC rendered these cells relatively resistant to PEITC-induced apoptosis. In summary, our data confirm that PEITC may be an effective chemopreventive/therapeutic agents for breast cancer. However, differences in the basal expression of NRF2 and resultant changes in GSH levels may be an important determinant of sensitivity to PEITC-induced apoptosis.

Cytotoxicity of Southeast Asian snake venoms

Cytotoxicity of venoms from eleven medically important snakes found in Southeast Asia (Naja kaouthia, Naja siamensis, Naja sumatrana, Ophiophagus hannah, Bungarus candidus, Bungarus fasciatus, Enhydrina schistosa, Calloselasma rhodostoma, Trimeresurus purpureomaculatus and Tropidolaemus sumatranus) was determined, based on the MTS cytotoxicity assay, which determines the survival of viable cells in monolayer MDCK and Vero cell cultures upon exposure to the snake venoms. Snake venom toxicity was expressed as the venom dose that killed 50% of the cells (CTC50) under the assay conditions. Venoms of C. rhodostoma (2.6 µg/mL, 1.4 µg/mL) and O. hannah were the most cytotoxic (3.8 µg/mL, 1.7 µg/mL) whereas N. siamensis venom showed the least cytotoxicity (51.9 µg/mL, 45.7 µg/mL) against Vero and MDCK cells, respectively. All the viper venoms showed higher cytotoxic potency towards both Vero and MDCK cell lines, in comparison to krait and cobra venoms. E. schistosa did not cause cytotoxicity towards MDCK or Vero cells at the tested concentrations. The cytotoxicity correlates well with the known differences in the composition of venoms from cobras, kraits, vipers and sea snakes.(AU)

Epidemiology and clinical characteristics of hospitalized patients with pandemic influenza A (H1N1) 2009 infections: the effects of bacterial coinfection.

BACKGROUND: Numerous reports have described the epidemiological and clinical characteristics of influenza A (H1N1) 2009 infected patients. However, data on the effects of bacterial coinfection on these patients are very scarce. Therefore, this study explores the impact of bacterial coinfection on the clinical and laboratory parameters amongst H1N1 hospitalized patients. FINDINGS: This retrospective study involved hospitalized patients with laboratory-confirmed H1N1 infections (September 2009 to May 2010). Relevant clinical data and the detection of bacterial coinfection from respiratory or sterile site samples were obtained. Multiplex PCR was used to determine the co-existence of other respiratory viruses. Comparison was made between patients with and without bacterial coinfection. The occurrence of coinfection was 34%; 14 (28%) bacterial and only 3 (6%) viral. Mycoplasma pneumoniae (n = 5) was the commonest bacteria followed by Staphylococcus aureus (n = 3). In univariate analysis, clinical factors associated with bacterial coinfection were age > 50 years (p = 0.02), presence of comorbidity (p = 0.04), liver impairment (p = 0.02), development of complications (p = 0.004) and supplemental oxygen requirement (p = 0.02). Leukocytosis (p = 0.02) and neutrophilia (p = 0.004) were higher in bacterial coinfected patients. Multivariate logistic regression analysis revealed that age > 50 years and combined complications were predictive of bacterial coinfection. CONCLUSIONS: Bacterial coinfection is not uncommon in H1N1 infected patients and is more frequently noted in the older aged patients and is associated with higher rates of complications. Also, as adjunct to clinical findings, clinicians need to have a higher index of suspicion if neutrophilia was identified at admission as it may denote bacterial coinfection.

Endometrial hyperplasia - the dilemma of management remains: a retrospective observational study of 280 women.

OBJECTIVE: To quantify the rate of inconsistency in histopathological reporting between endometrial biopsy specimens (obtained by Pipelle endometrial sampler or curettage) and hysterectomy specimens using the World Health Organization classification criteria. STUDY DESIGN: A retrospective review of the records of 280 women with a histopathological diagnosis of endometrial hyperplasia treated in Ipswich Hospital NHS Trust, UK from 1 January 1998 to 31 May 2009. RESULTS: Discrepancy was found between the histopathological results of endometrial samples and hysterectomy specimens. The discrepancy was doubled for specimens obtained using a Pipelle endometrial sampler, with false-positive (i.e. overdiagnosis when the hysterectomy specimen showed a better diagnosis) and false-negative (i.e. underdiagnosis when the hysterectomy specimen showed a worse diagnosis) rates of 5.3% and 22.6%, respectively. For curettage specimens, the false-positive and false-negative rates were 1.8% and 13.2%, respectively. All cases of curettage were performed under general or regional anaesthesia, and were preceded by hysteroscopy. Apart from age, no risk factors were associated with a worse diagnosis. The association of age differed between types of endometrial hyperplasia and cancer; the strongest association was seen for cancer and the weakest association was seen for simple hyperplasia. CONCLUSION: Hysteroscopy and curettage may be considered when simple or complex hyperplasia is diagnosed from a specimen obtained with a Pipelle endometrial sampler. When a diagnosis of atypical hyperplasia is made, irrespective of the method of endometrial sampling, the gynaecologist must be concerned that endometrial carcinoma exists concomitantly within the uterus.

Cellular transcripts regulated during infections with Highly Pathogenic H5N1 Avian Influenza virus in 3 host systems.

BACKGROUND: Highly pathogenic Avian Influenza (HPAI) virus is able to infect many hosts and the virus replicates in high levels in the respiratory tract inducing severe lung lesions. The pathogenesis of the disease is actually the outcome of the infection as determined by complex host-virus interactions involving the functional kinetics of large numbers of participating genes. Understanding the genes and proteins involved in host cellular responses are therefore, critical for the elucidation of the mechanisms of infection. METHODS: Differentially expressed transcripts regulated in a H5N1 infections of whole lung organ of chicken, in-vitro chick embryo lung primary cell culture (CeLu) and a continuous Madin Darby Canine Kidney cell line was undertaken. An improved mRNA differential display technique (Gene Fishing™) using annealing control primers that generates reproducible, authentic and long PCR products that are detectable on agarose gels was used for the identification of differentially expressed genes (DEGs). Seven of the genes have been selected for validation using a TaqMan® based real time quantitative PCR assay. RESULTS: Thirty seven known and unique differentially expressed genes from lungs of chickens, CeLu and MDCK cells were isolated. Among the genes isolated and identified include heat shock proteins, Cyclin D2, Prenyl (decaprenyl) diphosphate synthase, IL-8 and many other unknown genes. The quantitative real time RT-PCR assay data showed that the transcription kinetics of the selected genes were clearly altered during infection by the Highly Pathogenic Avian Influenza virus. CONCLUSION: The Gene Fishing™ technique has allowed for the first time, the isolation and identification of sequences of host cellular genes regulated during H5N1 virus infection. In this limited study, the differentially expressed genes in the three host systems were not identical, thus suggesting that their responses to the H5N1 infection may not share similar mechanisms and pathways.

Synthesis and Biological Evaluation of JAHAs: Ferrocene-Based Histone Deacetylase Inhibitors.

N(1)-Hydroxy-N(8)-ferrocenyloctanediamide, JAHA (7), an organometallic analogue of SAHA containing a ferrocenyl group as a phenyl bioisostere, displays nanomolar inhibition of class I HDACs, excellent selectivity over class IIa HDACs, and anticancer action in intact cells (IC(50) = 2.4 µM, MCF7 cell line). Molecular docking studies of 7 in HDAC8 (a,b) suggested that the ferrocenyl moiety in 7 can overlap with the aryl cap of SAHA and should display similar HDAC inhibition, which was borne out in an in vitro assay (IC(50) values against HDAC8 (µM, SD in parentheses): SAHA, 1.41 (0.15); 7, 1.36 (0.16). Thereafter, a small library of related JAHA analogues has been synthesized, and preliminary SAR studies are presented. IC(50) values as low as 90 pM toward HDAC6 (class IIb) have been determined, highlighting the excellent potential of JAHAs as bioinorganic probes.

Evidence for Nipah virus recrudescence and serological patterns of captive Pteropus vampyrus.

This study aimed to describe the transmission dynamics, the serological and virus excretion patterns of Nipah virus (NiV) in Pteropus vampyrus bats. Bats in captivity were sampled every 7-21 days over a 1-year period. The data revealed five NiV serological patterns categorized as high and low positives, waning, decreasing and increasing, and negative in these individuals. The findings strongly suggest that NiV circulates in wild bat populations and that antibody could be maintained for long periods. The study also found that pup and juvenile bats from seropositive dams tested seropositive, indicating that maternal antibodies against NiV are transmitted passively, and in this study population may last up to 14 months. NiV was isolated from the urine of one bat, and within a few weeks, two other seronegative bats seroconverted. Based on the temporal cluster of seroconversion, we strongly believe that the NiV isolated was recrudesced and then transmitted horizontally between bats during the study period.

Anti-angiogenic effects of dietary isothiocyanates: mechanisms of action and implications for human health.

Isothiocyanates (ITCs) are electrophilic compounds derived from plants and are thought to play a major role in the potential chemopreventive effects associated with high intake of cruciferous vegetables. ITCs are also being evaluated for chemotherapeutic activity in early phase clinical trials. In addition to their effects on carcinogen metabolism and cancer cell survival and proliferation, ITCs have been shown to effectively interfere with angiogenesis in vitro and in vivo. Angiogenesis is the development of a new blood supply from existing vasculature and is required for tumours to develop beyond a small size limit determined by the diffusion limit for oxygen. Inhibition of angiogenesis may play a key role in the potential chemopreventive/chemotherapeutic activity of ITCs. In this review we highlight recent data demonstrating that ITCs have anti-angiogenic activity and identify potential molecular targets for these effects, including hypoxia-inducible factor (HIF), nuclear factor κB (NF-κB), activator protein 1 (AP1) and tubulin. We also discuss these findings in light of the potential chemopreventive/chemotherapeutic effects of ITCs.

Characterization of Nipah virus from naturally infected Pteropus vampyrus bats, Malaysia.

We isolated and characterized Nipah virus (NiV) from Pteropus vampyrus bats, the putative reservoir for the 1998 outbreak in Malaysia, and provide evidence of viral recrudescence. This isolate is monophyletic with previous NiVs in combined analysis, and the nucleocapsid gene phylogeny species.