Design and synthesis of conformationally constrained cyclophilin inhibitors showing a cyclosporin-A phenotype in C. elegans

Cyclophilin A (CypA) is a member of the immunophilin family of proteins and receptor for the immunosuppressant drug cyclosporin A (CsA). Here we describe the design and synthesis of a new class of small-molecule inhibitors for CypA that are based upon a dimedone template. Electrospray mass spectrometry is utilised as an initial screen to quantify the protein affinity of the ligands. Active inhibitors and fluorescently labelled derivatives are then used as chemical probes for investigating the biological role of cyclophilins in the nematode Caenorhabditis elegans.     

The effects of bilateral lesions of the amygdala on dyadic social interactions in rhesus monkeys (Macaca mulatta).

The role of the amygdala in dyadic social interactions of adult rhesus monkeys (Macaca mulatta) was assessed after bilateral ibotenic acid lesions. Social, nonsocial, and spatial behaviors of amygdalectomized and control monkeys were assessed in 3 dyadic experiments: constrained, unconstrained, and round robin. Lesions produced extensive bilateral damage to the amygdala. Across all experiments, the amygdalectomized monkeys demonstrated increased social affiliation, decreased anxiety, and increased confidence compared with control monkeys, particularly during early encounters. Normal subjects also demonstrated increased social affiliation toward the amygdalectomized subjects. These results indicate that amygdala lesions in adult monkeys lead to a decrease in the species-normal reluctance to immediately engage a novel conspecific in social behavior. The altered behavior of the amygdalectomized monkeys may have induced the increased social interactions from their normal companions. This is contrary to the idea that amygdalectomy produces a decrease in social interaction and increased aggression from conspecifics. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

漂白剂和表面活性剂的混合(英)

烷基二酚醚二磺酸盐表面活性剂可以很好地和漂白剂次氯酸钠混合 ,在含次氯酸钠的配方中 ,稳定性和溶解性均很好 ,不会促使漂白剂分解。     

The effects of vicarious exposure to the recent massacre at Virginia Tech.

The authors examined whether exposure to the April 2007 Virginia Tech school shootings would increase symptoms of acute stress in students at another university who were not personally involved, but who followed the case vicariously through news media. The authors ran a series of regression analyses using multinomial logit (MNL) models, a methodology which can be used for dealing with categorical outcome variables. The authors found that as TV viewing of the Virginia Tech case increased, the probability that a student would respond with moderate or acute stress symptoms also increased. The authors were able to describe the magnitude of the relationship between vicarious exposure to the Virginia Tech case and acute stress symptomatology. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Clustering semantically heterogeneous distributed aggregate databases

Databases developed independently in a common open distributed environment may be heterogeneous with respect to both data schema and the embedded semantics. Managing schema and semantic heterogeneities brings considerable challenges to learning from distributed data and to support applications involving cooperation between different organisations. In this paper, we are concerned mainly with heterogeneous databases that hold aggregates on a set of attributes, which are often the result of materialised views of native large-scale distributed databases. A model-based clustering algorithm is proposed to construct a mixture model where each component corresponds to a cluster which is used to capture the contextual heterogeneity among databases from different populations. Schema heterogeneity, which can be recast as incomplete information, is handled within the clustering process using Expectation-Maximisation estimation and integration is carried out within a clustering iteration. Our proposed algorithm resolves the schema heterogeneity as part of the clustering process, thus avoiding transformation of the data into a unified schema. Results of algorithm evaluation on classification, scalability and reliability, using both real and synthetic data, demonstrate that our algorithm can achieve good performance by incorporating all of the information from available heterogeneous data. Our clustering approach has great potential for scalable knowledge discovery from semantically heterogeneous databases and for applications in an open distributed environment, such as the Semantic Web.     

'Beyond Four Walls'. The Psycho-social Benefits of Home: Evidence from West Central Scotland

This paper reviews the literatures on housing and ontological security and the meaning of the home in order to derive specific examples of the psycho-social benefits of the home which can be assessed through empirical research. A postal survey measuring these psycho-social benefits was distributed to a random sample of adults in eight local authority districts in West Central Scotland. From the responses to the survey, three factors were constructed relating to the home as a haven, as a locus of autonomy and as a source of status for the occupants. Multivariate analysis showed that housing tenure is less important as an influence upon the attainment of psycho-social benefits from the home than the neighbourhood context and the incidence of problems with the home. Further, those factors negatively associated with psycho-social benefits appear to be more important than those factors positively associated with such benefits. This suggests that future research should focus on the fact that what detracts from psycho-social benefits may be more important than what contributes to them. A further important finding is that, after controlling for other influences, people living alone derive more benefits from the home as a haven and as a locus of autonomy than people in multi-person households.     

Preliminary Evidence on the Diagnostic and Molecular Role of Circulating Soluble EGFR in Non-Small Cell Lung Cancer

Assessment of biological diagnostic factors providing clinically-relevant information to guide physician decision-making are still needed for diseases with poor outcomes, such as non-small cell lung cancer (NSCLC). Epidermal growth factor receptor (EGFR) is a promising molecule in the clinical management of NSCLC. While the EGFR transmembrane form has been extensively investigated in large clinical trials, the soluble, circulating EGFR isoform (sEGFR), which may have a potential clinical use, has rarely been considered. This study investigates the use of sEGFR as a potential diagnostic biomarker for NSCLC and also characterizes the biological function of sEGFR to clarify the molecular mechanisms involved in the course of action of this protein. Plasma sEGFR levels from a heterogeneous cohort of 37 non-advanced NSCLC patients and 54 healthy subjects were analyzed by using an enzyme-linked immunosorbent assay. The biological function of sEGFR was analyzed in vitro using NSCLC cell lines, investigating effects on cell proliferation and migration. We found that plasma sEGFR was significantly decreased in the NSCLC patient group as compared to the control group (median value: 48.6 vs. 55.6 ng/mL respectively; p = 0.0002). Moreover, we demonstrated that sEGFR inhibits growth and migration of NSCLC cells in vitro through molecular mechanisms that included perturbation of EGF/EGFR cell signaling and holoreceptor internalization. These data show that sEGFR is a potential circulating biomarker with a physiological protective role, providing a first approach to the functional role of the soluble isoform of EGFR. However, the impact of these data on daily clinical practice needs to be further investigated in larger prospective studies.     

Adapting Memory Hierarchies for Emerging Datacenter Interconnects

E?cient resource utilization requires that emerging datacenter interconnects support both high performance communication and e?cient remote resource sharing. These goals require that the network be mor...     

Dual Inhibition of MEK and PI3K Pathway in KRAS and BRAF Mutated Colorectal Cancers

Colorectal cancer (CRC) is a heterogeneous disease with multiple underlying causative genetic mutations. Genetic mutations in the phosphatidylinositol-3 kinase (PI3K) and the mitogen activated protein kinase (MAPK) pathways are frequently implicated in CRC. Targeting the downstream substrate MEK in these mutated tumors stands out as a potential target in CRC. Several selective inhibitors of MEK have entered clinical trial evaluation; however, clinical activity with single MEK inhibitors has been rarely observed and acquired resistance seems to be inevitable. Amplification of the driving oncogene KRAS(13D), which increases signaling through the ERK1/2 pathway, upregulation of the noncanonical wingless/calcium signaling pathway (Wnt), and coexisting PIK3CA mutations have all been implicated with resistance against MEK inhibitor therapy in KRAS mutated CRC. The Wnt pathway and amplification of the oncogene have also been associated with resistance to MEK inhibitors in CRCs harboring BRAF mutations. Thus, dual targeted inhibition of MEK and PI3K pathway effectors (mTOR, PI3K, AKT, IGF-1R or PI3K/mTOR inhibitors) presents a potential strategy to overcome resistance to MEK inhibitor therapy. Many clinical trials are underway to evaluate multiple combinations of these pathway inhibitors in solid tumors.