Addiction to Runx1 is partially attenuated by loss of p53 in the Eµ-Myc lymphoma model

The Runx genes function as dominant oncogenes that collaborate potently with Myc or loss of p53 to induce lymphoma when over-expressed. Here we examined the requirement for basal Runx1 activity for tumor maintenance in the Eµ-Myc model of Burkitt's lymphoma. While normal Runx1fl/fl lymphoid cells permit mono-allelic deletion, primary Eµ-Myc lymphomas showed selection for retention of both alleles and attempts to enforce deletion in vivo led to compensatory expansion of p53null blasts retaining Runx1. Surprisingly, Runx1 could be excised completely from established Eµ-Myc lymphoma cell lines in vitro without obvious effects on cell phenotype. Established lines lacked functional p53, and were sensitive to death induced by introduction of a temperature-sensitive p53 (Val135) allele. Transcriptome analysis of Runx1-deleted cells revealed a gene signature associated with lymphoid proliferation, survival and differentiation, and included strong de-repression of recombination-activating (Rag) genes, an observation that was mirrored in a panel of human acute leukemias where RUNX1 and RAG1,2 mRNA expression were negatively correlated. Notably, despite their continued growth and tumorigenic potential, Runx1null lymphoma cells displayed impaired proliferation and markedly increased sensitivity to DNA damage and dexamethasone-induced apoptosis, validating Runx1 function as a potential therapeutic target in Myc-driven lymphomas regardless of their p53 status.

Capture and loss of electron by MeV ions penetrating through liquid spray:Formation of negative ion and neutral atom beams

Charge changing processes of MeV ions penetrating through liquid spray is confirmed to be abundant source of various energetic negative ion and neutral atom beams its generic nature is demonstrated.

Gene mapping and expression analysis of 16q loss of heterozygosity identifies WWOX and CYLD as being important in determining clinical outcome in multiple myeloma.

We performed fluorescent in situ hybridization (FISH) for 16q23 abnormalities in 861 patients with newly diagnosed multiple myeloma and identified deletion of 16q [del(16q)] in 19.5%. In 467 cases in which demographic and survival data were available, del(16q) was associated with a worse overall survival (OS). It was an independent prognostic marker and conferred additional adverse survival impact in cases with the known poor-risk cytogenetic factors t(4;14) and del(17p). Gene expression profiling and gene mapping using 500K single-nucleotide polymorphism (SNP) mapping arrays revealed loss of heterozygosity (LOH) involving 3 regions: the whole of 16q, a region centered on 16q12 (the location of CYLD), and a region centered on 16q23 (the location of the WW domain-containing oxidoreductase gene WWOX). CYLD is a negative regulator of the NF-kappaB pathway, and cases with low expression of CYLD were used to define a "low-CYLD signature." Cases with 16q LOH or t(14;16) had significantly reduced WWOX expression. WWOX, the site of the translocation breakpoint in t(14;16) cases, is a known tumor suppressor gene involved in apoptosis, and we were able to generate a "low-WWOX signature" defined by WWOX expression. These 2 genes and their corresponding pathways provide an important insight into the potential mechanisms by which 16q LOH confers poor prognosis.

A Rare Loss-of-Function Variant in Scavenger Receptor Class B Type I (SCARB1) Raises HDL Cholesterol and Increases Risk of Coronary Disease

Scavenger receptor BI (SR-BI) is the major receptor for high-density lipoprotein (HDL)
cholesterol (HDL-C). In humans, high amounts of HDL-C in plasma are associated with a
lower risk of coronary heart disease (CHD). Mice that have depleted Scarb1 (SR-BI
knockout mice) have markedly elevated HDL-C levels but, paradoxically, increased
atherosclerosis. The impact of SR-BI on HDL metabolism and CHD risk in humans remains
unclear. Through targeted sequencing of coding regions of lipid-modifying genes in 328
individuals with extremely high plasma HDL-C levels, we identified a homozygote for a lossof-function
variant, in which leucine replaces proline 376 (P376L), in SCARB1, the gene
encoding SR-BI. The P376L variant impairs posttranslational processing of SR-BI and
abrogates selective HDL cholesterol uptake in transfected cells, in hepatocyte-like cells
derived from induced pluripotent stem cells from the homozygous subject, and in mice.
Large population-based studies revealed that subjects who are heterozygous carriers of
the P376L variant have significantly increased levels of plasma HDL-C. P376L carriers have
a profound HDL-related phenotype and an increased risk of CHD (odds ratio = 1.79, which is
statistically significant).

Cognitive biases and addiction: an evolution in theory and method

An evolution in theoretical models and methodological paradigms for investigating cognitive biases in the addictions is discussed. Anomalies in traditional cognitive perspectives, and problems with the self-report methods which underpin them, are highlighted. An emergent body of cognitive research, contextualized within the principles and paradigms of cognitive neuropsychology rather than social learning theory, is presented which, it is argued, addresses these anomalies and problems. Evidence is presented that biases in the processing of addiction-related stimuli, and in the network of propositions which motivate addictive behaviours, occur at automatic, implicit and pre-conscious levels of awareness. It is suggested that methods which assess such implicit cognitive biases (e.g. Stroop, memory, priming and reaction-time paradigms) yield findings which have better predictive utility for ongoing behaviour than those biases determined by self-report methods of introspection. The potential utility of these findings for understanding "loss of control" phenomena, and the desynchrony between reported beliefs and intentions and ongoing addictive behaviours, is discussed. Applications to the practice of cognitive therapy are considered.

Seeking help from everyone and no-one: Conceptualising the online help-seeking process among adolescent males

Online help-seeking is an emerging trend within the 21st century. Yet despite some movement towards developing online services, little is known about how young people locate, access and receive support online. This study aims to conceptualise the process of online help-seeking among adolescent males. Modified photo-elicitation techniques were employed within eight semi-structured focus group sessions with adolescent males aged 14 – 15 years (n= 56) across seven schools in Northern Ireland. Thematic analyses was conducted within an ontological framework of critical realism and an epistemological framework of contextualism. Informal online help-seeking pathways increased opportunity for social support and reduced stigma but also included loss of control and reduced anonymity. Formal pathways offered increased anonymity but concerns were raised regarding participants’ ability to locate and appraise the quality of information online. A conceptual model of online help-seeking has been developed to highlight the key help seeking pathways taken by adolescent males.

Activation of Akt/PKB, increased phosphorylation of Akt substrates and loss and altered distribution of Akt and PTEN are features of Alzheimer's disease pathology

Studies suggest that activation of phosphoinositide 3-kinase-Akt may protect against neuronal cell death in Alzheimer's disease (AD). Here, however, we provide evidence of increased Akt activation, and hyperphosphorylation of critical Akt substrates in AD brain, which link to AD pathogenesis, suggesting that treatments aiming to activate the pathway in AD need to be considered carefully. A different distribution of Akt and phospho-Akt was detected in AD temporal cortex neurons compared with control neurons, with increased levels of active phosphorylated-Akt in particulate fractions, and significant decreases in Akt levels in AD cytosolic fractions, causing increased activation of Akt (phosphorylated-Akt/total Akt ratio) in AD. In concordance, significant increases in the levels of phosphorylation of total Akt substrates, including: GSK3ßSer9, tauSer214, mTORSer2448, and decreased levels of the Akt target, p27kip1, were found in AD temporal cortex compared with controls. A significant loss and altered distribution of the major negative regulator of Akt, PTEN (phosphatase and tensin homologue deleted on chromosome 10), was also detected in AD neurons. Loss of phosphorylated-Akt and PTEN-containing neurons were found in hippocampal CA1 at end stages of AD. Taken together, these results support a potential role for aberrant control of Akt and PTEN signalling in AD.

Persistent negative effects of pesticides on biodiversity and biological control potential on European farmland

During the last 50 years, agricultural intensification has caused many wild plant and animal species to go extinct regionally or nationally and has profoundly changed the functioning of agro-ecosystems. Agricultural intensification has many components, such as loss of landscape elements, enlarged farm and field sizes and larger inputs of fertilizer and pesticides. However, very little is known about the relative contribution of these variables to the large-scale negative effects on biodiversity. In this study, we disentangled the impacts of various components of agricultural intensification on species diversity of wild plants, carabids and ground-nesting farmland birds and on the biological control of aphids.