Evidence for Zoonotic Potential of Enterocytozoon bieneusi in Its First Molecular Characterization in Captive Mammals at Bangladesh National Zoo

To determine the occurrence and genotypes of Enterocytozoon bieneusi in captive mammals at Bangladesh National Zoo and to assess their zoonotic significance, 200 fecal samples from 32 mammalian species were examined using a nested PCR and sequencing of internal transcribed spacer (ITS) gene. Enterocytozoon bieneusi was detected in 16.5% (33/200) of the samples. Seven different ITS genotypes were identified, including two known genotypes (D and J) and five new ones (BAN4 to BAN8). Genotype D was the most common genotype being observed in 19 isolates. In phylogenetic analysis, four genotypes (D, BAN4, BAN5, and BAN6), detected in 30 isolates (90.9%), belonged to Group 1 having zoonotic potential. The sequence of genotype J found in a Malayan pangolin was clustered in so‐called ruminant‐specific Group 2. The other two genotypes BAN7 and BAN8 were clustered in primate‐specific Group 5. To our knowledge, this is the first report of molecular characterization of E. bieneusi in Bangladesh, particularly in captive‐bred wildlife in this country. The potentially zoonotic genotypes of E. bieneusi are maintained in zoo mammals that may transmit among these animals and to the humans through environmental contamination or contact.     

Synthesis and biological evaluation of potential modulators of malarial glutathione-S-transferase(s)

Glutathione-S-transferase(s) (E.C.2.5.1.18, GSTs) have been investigated in parasitic protozoans with respect to their biochemistry and they have been identified as potential vaccine candidates in protozoan parasites and as a target in the synthesis of new antiparasitic agents. In a search towards the identification of novel biochemical targets for antimalarial drug design, the area of Plasmodium glutathione metabolism provides a number of promising chemotherapeutic targets. GST activity was determined in various subcellular fractions of malarial parasites Plasmodium yoelii and was found to be localized mainly in the cytosolic fraction (specific activity, c. 0.058 ± 0.016 μmol/min/mg protein). Hemin, a known inhibitor of mammalian GST(s), maximally inhibited this enzyme from P. yoelii to nearly 86%. In a search towards synthetic modulators of malarial GST(s), 575 compounds belonging to various chemical classes were screened for their effect on crude GST from P. yoelii and 92 compounds belonging to various chemical classes were studied on recombinant GST from P. falciparum. Among all the compounds screened, 83 compounds inhibited/stimulated the enzyme from P. yoelii/P. falciparum to the extent of 40% or more.     

Influence of Serum and Albumin on Echinocandin In Vitro Potency and Pharmacodynamics

The echinocandins target fungi by inhibiting the production of (1,3)-β-d-glucan, an essential component of the fungal cell wall. These agents have less toxicity to mammalian cells, as compared to other antifungals; however, they maintain potent activity against many pathogenic fungi, including polyene- and azole-resistant isolates. Members of this class are highly protein-bound, and the addition of serum or albumin to the growth medium has profound effects on their in vitro potency and pharmacodynamics. In addition, studies have demonstrated an association between in vitro activity, in the presence of serum, and outcomes in animal models of invasive fungal infections. Serum and albumin may also be useful to help detect echinocandin-resistant Candida isolates with point mutations in the gene that encodes for glucan synthase. Thus, in vitro studies evaluating echinocandins in the presence of protein can provide valuable insight regarding their potency and pharmacodynamics.     

Looking up in Scotland? Multinationalism,multiculturalism and political elites

At a time when all the political parties of Scotland are trying to establish a persuasive vision of the nation, inquiry into where ethnic and racial minorities fit into these debates provides one understudied means of bridging literatures on multinationalism and multiculturalism. Focusing especially on the lesser known question of how elite political actors are positioning minorities within projects of nation-building, this article draws upon original empirical data in which three predominant clusters emerge. The first centres on an aspirational pluralism, in so far as political elites are less inclined – in contrast to counterparts in some other minority nations – to place ethnically determined barriers on membership of Scottish nationhood. The second concerns the competing ways in which the legacy of Scotland's place in the British Empire is appropriated by actors of different political hues, and so assumes a multiform role. The third cluster points to potential limitations in minority claims-making and recognition, especially in terms of formal multilingualism and corporate multifaithism, something that may partly be explained by the tension between multinationalism and multiculturalism. Taken together, the article illustrates how elite political actors can play a vital role in ensuring that appeals to nationhood in Scotland can be meaningfully calibrated to include minorities too.     

Sociologists,Archbishops, and ‘making a verb of a noun’

ABSTRACT

Contemporary discussion about race has a tendency to set off out without first checking the rear view mirror. In Theories of Race and Ethnicity: Contemporary Debates and Perspectives, in contrast, Murji and Solomos identify what has and has not been covered, and so appeal at the outset for a ‘more sustained’ account of changing research agendas of race and ethnic relations. Taken as a whole, the collection allows the editors to contemplate ‘what factors explain the mobilizing power of ideas about race and ethnicity in the contemporary environment?' and whether indeed ‘it is the “real” rather than race that should be placed in quotation marks’.     

Assessments of 226Ra and 222Rn concentration in well and tap water from Sik,Malaysia, and consequent dose estimates

Abstract

The ingestion of ²²⁶Ra, inhalation, and ingestion of ²²²Rn in water is considered the primary health risk for lungs and stomach. This study presents the concentrations of ²²⁶Ra and ²²²Rn in well and tap water collected from Sik, Malaysia, using HPGe and RAD7 detectors. Maximum average concentrations of ²²⁶Ra and ²²²Rn were found 47.6?±?3.6 mBq/l and 9.3?±?1.4?Bq/l in well water, respectively, and minimum were found 17.1?±?3.6 mBq/l and 1.6?±?1.0?Bq/l in tap water, respectively. A positive correlation (R=.88) was found between ²²⁶Ra and ²²²Rn determined by HPGe and RAD7 detectors, respectively. Infants in the age group of 0–1 y appeared to be at risk with respect to the annual effective doses from ²²⁶Ra and ²²²Rn as compared to the other age groups. However, annual effective doses for all three age groups from intake of ²²⁶Ra and ²²²Rn in well and tap drinking water were found below the World Health Organization (WHO) recommended level of .1 mSv/y_.     

Imaging and therapy of malignant pleural mesothelioma using replication-competent herpes simplex viruses

BACKGROUND: Malignant pleural mesothelioma (MPM) is an aggressive cancer that is refractory to current treatment modalities. Oncolytic herpes simplex viruses (HSV) used for gene therapy are genetically engineered, replication-competent viruses that selectively target tumor cells while sparing normal host tissue. The localized nature, the potential accessibility and the relative lack of distant metastasis make MPM a particularly suitable disease for oncolytic viral therapy. METHODS: The infectivity, selective replication, vector spread and cytotoxic ability of three oncolytic HSV: G207, NV1020 and NV1066, were tested against eleven pathological types of MPM cell lines including those that are resistant to radiation therapy, gemcitabine or cisplatin. The therapeutic efficacy and the effect on survival of NV1066 were confirmed in a murine MPM model. RESULTS: All three oncolytic HSV were highly effective against all the MPM cell lines tested. Even at very low concentrations of MOI 0.01 (MOI: multiplicity of viral infection, ratio of viral particles per cancer cell), HSV were highly effective against MPM cells that are resistant to radiation, gemcitabine and cisplatin. NV1066, an oncolytic HSV that expresses green fluorescent protein (GFP), was able to delineate the extent of the disease in a murine model of MPM due to selective infection and expression of GFP in tumor cells. Furthermore, NV1066 was able to reduce the tumor burden and prolong survival even when treatment was at an advanced stage of the disease. CONCLUSION: These findings support the continued investigation of oncolytic HSV as potential therapy for patients with therapy-resistant MPM.     

Modelling multivariate outcomes in hierarchical data, with application to cluster randomised trials

In the cluster randomised study design, the data collected have a hierarchical structure and often include multivariate outcomes. We present a flexible modelling strategy that permits several normally distributed outcomes to be analysed simultaneously, in which intervention effects as well as individual-level and cluster-level between-outcome correlations are estimated. This is implemented in a Bayesian framework which has several advantages over a classical approach, for example in providing credible intervals for functions of model parameters and in allowing informative priors for the intracluster correlation coefficients. In order to declare such informative prior distributions, and fit models in which the between-outcome covariance matrices are constrained, priors on parameters within the covariance matrices are required. Careful specification is necessary however, in order to maintain non-negative definiteness and symmetry between the different outcomes. We propose a novel solution in the case of three multivariate outcomes, and present a modified existing approach and novel alternative for four or more outcomes. The methods are applied to an example of a cluster randomised trial in the prevention of coronary heart disease. The modelling strategy presented would also be useful in other situations involving hierarchical multivariate outcomes.     

Crystal structure of a Cbf5-Nop10-Gar1 complex and implications in RNA-guided pseudouridylation and dyskeratosis congenita

H/ACA RNA-protein complexes, comprised of four proteins and an H/ACA guide RNA, modify ribosomal and small nuclear RNAs. The H/ACA proteins are also essential components of telomerase in mammals. Cbf5 is the H/ACA protein that catalyzes isomerization of uridine to pseudouridine in target RNAs. Mutations in human Cbf5 (dyskerin) lead to dyskeratosis congenita. Here, we describe the 2.1 A crystal structure of a specific complex of three archaeal H/ACA proteins, Cbf5, Nop10, and Gar1. Cbf5 displays structural properties that are unique among known pseudouridine synthases and are consistent with its distinct function in RNA-guided pseudouridylation. We also describe the previously unknown structures of both Nop10 and Gar1 and the structural basis for their essential roles in pseudouridylation. By using information from related structures, we have modeled the entire ribonucleoprotein complex including both guide and substrate RNAs. We have also identified a dyskeratosis congenita mutation cluster site within a modeled dyskerin structure.     

Attenuation of recombinant vesicular stomatitis virus-human immunodeficiency virus type 1 vaccine vectors by gene translocations and g gene truncation reduces neurovirulence and enhances immunogenicity in mice

Recombinant vesicular stomatitis virus (rVSV) has shown great potential as a new viral vector for vaccination. However, the prototypic rVSV vector described previously was found to be insufficiently attenuated for clinical evaluation when assessed for neurovirulence in nonhuman primates. Here, we describe the attenuation, neurovirulence, and immunogenicity of rVSV vectors expressing human immunodeficiency virus type 1 Gag. These rVSV vectors were attenuated by combinations of the following manipulations: N gene translocations (N4), G gene truncations (CT1 or CT9), noncytopathic M gene mutations (Mncp), and positioning of the gag gene into the first position of the viral genome (gag1). The resulting N4CT1-gag1, N4CT9-gag1, and MncpCT1-gag1 vectors demonstrated dramatically reduced neurovirulence in mice following direct intracranial inoculation. Surprisingly, in spite of a very high level of attenuation, the N4CT1-gag1 and N4CT9-gag1 vectors generated robust Gag-specific immune responses following intramuscular immunization that were equivalent to or greater than immune responses generated by the more virulent prototypic vectors. MncpCT1-gag1 also induced Gag-specific immune responses following intramuscular immunization that were equivalent to immune responses generated by the prototypic rVSV vector. Placement of the gag gene in the first position of the VSV genome was associated with increased in vitro expression of Gag protein, in vivo expression of Gag mRNA, and enhanced immunogenicity of the vector. These findings demonstrate that through directed manipulation of the rVSV genome, vectors that have reduced neurovirulence and enhanced immunogenicity can be made.