A bovine lymphosarcoma cell line infected with theileria annulata exhibits an irreversible reconfiguration of host cell gene expression

Theileria annulata, an intracellular parasite of bovine lymphoid cells, induces substantial phenotypic alterations to its host cell including continuous proliferation, cytoskeletal changes and resistance to apoptosis. While parasite induced modulation of host cell signal transduction pathways and NFκB activation are established, there remains considerable speculation on the complexities of the parasite directed control mechanisms that govern these radical changes to the host cell. Our objectives in this study were to provide a comprehensive analysis of the global changes to host cell gene expression with emphasis on those that result from direct intervention by the parasite. By using comparative microarray analysis of an uninfected bovine cell line and its Theileria infected counterpart, in conjunction with use of the specific parasitacidal agent, buparvaquone, we have identified a large number of host cell gene expression changes that result from parasite infection. Our results indicate that the viable parasite can irreversibly modify the transformed phenotype of a bovine cell line. Fifty percent of genes with altered expression failed to show a reversible response to parasite death, a possible contributing factor to initiation of host cell apoptosis. The genes that did show an early predicted response to loss of parasite viability highlighted a sub-group of genes that are likely to be under direct control by parasite infection. Network and pathway analysis demonstrated that this sub-group is significantly enriched for genes involved in regulation of chromatin modification and gene expression. The results provide evidence that the Theileria parasite has the regulatory capacity to generate widespread change to host cell gene expression in a complex and largely irreversible manner

Survey of motivation for use of voluntary counseling and testing services for HIV in a high risk area of Shenyang, China

<p>Abstract</p> <p>Background</p> <p>HIV voluntary counseling and testing (VCT) is considered an effective prevention method of HIV infection. In order to understand the VCT environment and enhance the effective delivery of VCT services in a country, an accurate assessment of the current status of VCT services is very important.</p> <p>Methods</p> <p>From July 2006 to June 2007, we conducted a cross-sectional survey using a face to face interview among 2676 VCT clients from a high risk area in Shenyang city, China.</p> <p>Results</p> <p>The major demographic characteristics among 2,676 VCT clients were: 41.1% were in the age range 20 to 30 years; 73.1% were males; and 67.1% had attained the level of junior high school education. The primary information source for VCT services was mass media like television (TV) and newspaper in 88.9%. 34.3% were afraid of the result of infection which was the main barrier to accept VCT services among 540 participants answering the question. 75.2% were motivated by recently acquired knowledge about HIV. 47.9% had 3 or more male sex partners, 62.3% had used condoms sometimes, and 14.5% had been infected with a STD. 2.8% of the participants identified themselves as men who have sex with men (MSM). The main demographic characteristics of MSM did not differ from the total group of participants except with respect to age: 63.5% reported having one male sex partner in the preceding 12 months, 44.6% reported never using condoms in the preceding 12 months, and only 2.7% reported a history of sexually transmitted disease.</p> <p>Conclusion</p> <p>Public education offered by health workers in hospitals, private clinics and other medical institutions needs to be strengthened. Given the results from this study, we recommend: (1) making VCT a routine part of health services, especially in areas where many high-risk individuals live; (2) improving the information sources and increasing the understanding of HIV and HIV-infected individuals; (3) enhancing international collaboration in strategic planning, technical assistance, and protocols to translate policy into effective action; (4) supporting Chinese non-government organizations (NGOs) in playing a significant role in the battle against AIDS.</p

Climate change effects on phytoplankton depend on cell size and food web structure

We investigated the effects of warming on a natural phytoplankton community from the Baltic Sea, based on six mesocosm experiments conducted 2005–2009. We focused on differences in the dynamics of three phytoplankton size groups which are grazed to a variable extent by different zooplankton groups. While small-sized algae were mostly grazer-controlled, light and nutrient availability largely determined the growth of medium- and large-sized algae. Thus, the latter groups dominated at increased light levels. Warming increased mesozooplankton grazing on medium-sized algae, reducing their biomass. The biomass of small-sized algae was not affected by temperature, probably due to an interplay between indirect effects spreading through the food web. Thus, under the higher temperature and lower light levels anticipated for the next decades in the southern Baltic Sea, a higher share of smaller phytoplankton is expected. We conclude that considering the size structure of the phytoplankton community strongly improves the reliability of projections of climate change effects

The Probable Cell of Origin of NF1- and PDGF-Driven Glioblastomas

Primary glioblastomas are subdivided into several molecular subtypes. There is an ongoing debate over the cell of origin for these tumor types where some suggest a progenitor while others argue for a stem cell origin. Even within the same molecular subgroup, and using lineage tracing in mouse models, different groups have reached different conclusions. We addressed this problem from a combined mathematical modeling and experimental standpoint. We designed a novel mathematical framework to identify the most likely cells of origin of two glioma subtypes. Our mathematical model of the unperturbed in vivo system predicts that if a genetic event contributing to tumor initiation imparts symmetric self-renewing cell division (such as PDGF overexpression), then the cell of origin is a transit amplifier. Otherwise, the initiating mutations arise in stem cells. The mathematical framework was validated with the RCAS/tv-a system of somatic gene transfer in mice. We demonstrated that PDGF-induced gliomas can be derived from GFAP-expressing cells of the subventricular zone or the cortex (reactive astrocytes), thus validating the predictions of our mathematical model. This interdisciplinary approach allowed us to determine the likelihood that individual cell types serve as the cells of origin of gliomas in an unperturbed system

ARF-BP1 as a potential therapeutic target

In this review, we discuss the recent identification of ARF-BP1 (also known as Mule, UREB1, E3histone, LASU1, and HectH9). ARF-BP1, a HECT domain-containing E3 ubiquitin ligase, interacts with ARF and p53. Its ubiquitin ligase activity is inhibited by ARF. Inactivation of ARF-BP1 stabilised p53 and induced apoptosis. Notably, inactivation of ARF-BP1 also caused cell growth repression in p53-null cells and breast cancer cells with mutant p53. Thus, ARF-BP1 emerges as a novel therapeutic target against cancer regardless of p53 status

A Large Scale shRNA Barcode Screen Identifies the Circadian Clock Component ARNTL as Putative Regulator of the p53 Tumor Suppressor Pathway

BACKGROUND: The p53 tumor suppressor gene is mutated in about half of human cancers, but the p53 pathway is thought to be functionally inactivated in the vast majority of cancer. Understanding how tumor cells can become insensitive to p53 activation is therefore of major importance. Using an RNAi-based genetic screen, we have identified three novel genes that regulate p53 function. RESULTS: We have screened the NKI shRNA library targeting 8,000 human genes to identify modulators of p53 function. Using the shRNA barcode technique we were able to quickly identify active shRNA vectors from a complex mixture. Validation of the screening results indicates that the shRNA barcode technique can reliable identify active shRNA vectors from a complex pool. Using this approach we have identified three genes, ARNTL, RBCK1 and TNIP1, previously unknown to regulate p53 function. Importantly, ARNTL (BMAL1) is an established component of the circadian regulatory network. The latter finding adds to recent observations that link circadian rhythm to the cell cycle and cancer. We show that cells having suppressed ARNTL are unable to arrest upon p53 activation associated with an inability to activate the p53 target gene p21(CIP1). CONCLUSIONS: We identified three new regulators of the p53 pathway through a functional genetic screen. The identification of the circadian core component ARNTL strengthens the link between circadian rhythm and cancer

High-Level Expression of Wild-Type p53 in Melanoma Cells is Frequently Associated with Inactivity in p53 Reporter Gene Assays

Background: Inactivation of the p53 pathway that controls cell cycle progression, apoptosis and senescence, has been proposed to occur in virtually all human tumors and p53 is the protein most frequently mutated in human cancer. However, the mutational status of p53 in melanoma is still controversial; to clarify this notion we analysed the largest series of melanoma samples reported to date. Methodology/Principal Findings: Immunohistochemical analysis of more than 180 melanoma specimens demonstrated that high levels of p53 are expressed in the vast majority of cases. Subsequent sequencing of the p53 exons 5–8, however, revealed only in one case the presence of a mutation. Nevertheless, by means of two different p53 reporter constructs we demonstrate transcriptional inactivity of wild type p53 in 6 out of 10 melanoma cell lines; the 4 other p53 wild type melanoma cell lines exhibit p53 reporter gene activity, which can be blocked by shRNA knock down of p53. Conclusions/Significance: In melanomas expressing high levels of wild type p53 this tumor suppressor is frequently inactivated at transcriptional level

To what extent could performance-based schemes help increase the effectiveness of prevention of mother-to-child transmission of HIV (PMTCT) programs in resource-limited settings? a summary of the published evidence

<p>Abstract</p> <p>Background</p> <p>In resource-limited settings, HIV/AIDS remains a serious threat to the social and physical well-being of women of childbearing age, pregnant women, mothers and infants.</p> <p>Discussion</p> <p>In sub-Saharan African countries with high prevalence rates, pediatric HIV/AIDS acquired through mother-to-child transmission (MTCT) can in largely be prevented by using well-established biomedical interventions. Logistical and socio-cultural barriers continue, however, to undermine the successful prevention of MTCT (PMTCT). In this paper, we review reports on maternal, neonatal and child health, as well as HIV care and treatment services that look at program incentives.</p> <p>Summary</p> <p>These studies suggest that comprehensive PMTCT strategies aiming to maximize health-worker motivation in developing countries must involve a mix of both financial and non-financial incentives. The establishment of robust ethical and regulatory standards in public-sector HIV care centers could reduce barriers to PMTCT service provision in sub-Saharan Africa and help them in achieving universal PMTCT targets.</p