Distributed resource discovery using a context sensitive infrastructure

Distributed Resource Discovery in a World Wide Web environment using full-text indices will never scale. The distinct properties of WWW information (volume, rate of change, topical diversity) limits the scaleability of traditional approaches to distributed Resource Discovery. An approach combining metadata clustering and query routing can, on the other hand, be proven to scale much better. This paper presents the Content-Sensitive Infrastructure, which is a design building on these results. We also present an analytical framework for comparing scaleability of different distribution strategies

An architecture for using commodity devices and smart phones in health systems

The potential of patient-centred care and a connected eHealth ecosystem can be developed through socially responsible innovative architectures. The purpose of this paper is to define key innovation needs. This is achieved through conceptual development of an architecture for common information spaces with emergent end-user applications by supporting intelligent processing of measurements, data and services at the Internet of Things (IoT) integration level. The scope is conceptual definition, and results include descriptions of social, legal and ethical requirements, an architecture, services and connectivity infrastructures for consumer-oriented healthcare systems linking co-existing healthcare systems and consumer devices. We conclude with recommendations based on an analysis of research challenges related to how to process the data securely and anonymously and how to interconnect participants and services with different standards and interaction protocols, and devices with heterogeneous hardware and software configurations

Weight change and ovarian steroid profiles in young women

Objective: To investigate possible short-term effects of voluntary weight loss on ovarian steroid profiles in young women, in light of better established long-term effects in older women. Design: We tested for an association of voluntary weight change over the course of a menstrual cycle with salivary E2 and P profiles in the same menstrual cycle. Setting: Students were recruited in a college residence hall, and they provided daily saliva samples to a researcher living nearby. Patient(s): The 65 women who participated were all college students and ranged in age between 18 and 23 years. Intervention(s): None. Main Outcome Measure(s): Weight was assessed in the first week of the menstrual cycle and first week of the following menstrual cycle. Estradiol and P were measured by radioimmunoassay in daily saliva samples. Result(s): We did not detect a suppressive effect of weight loss on the overall level of either hormone. However, we did find evidence for more distinct follicular and luteal E2 peaks in women who gained weight. Peak luteal P also arrived about 2 days earlier in women who gained weight. Conclusion(s): This finding adds to evidence that short-term response of ovarian function to weight loss in young women is less pronounced than long-term response in older women.AnthropologyHuman Evolutionary Biolog

β-Amyloid precursor protein-b is essential for Mauthner cell development in the zebrafish in a Notch-dependent manner

Amyloid precursor protein (APP) is a transmembrane glycoprotein that has been the subject of intense research because of its implication in Alzheimer's disease. However, the physiological function of APP in the development and maintenance of the central nervous system remains largely unknown. We have previously shown that the APP homologue in zebrafish (Danio rerio), Appb, is required for motor neuron patterning and formation. Here we study the function of Appb during neurogenesis in the zebrafish hindbrain. Partial knockdown of Appb using antisense morpholino oligonucleotides blocked the formation of the Mauthner neurons, uni- or bilaterally, with an aberrant behavior as a consequence of this cellular change. The Appb morphants had decreased neurogenesis, increased notch signaling and notch1a expression at the expense of deltaA/D expression. The Mauthner cell development could be restored either by a general decrease in Notch signaling through γ-secretase inhibition or by a partial knock down of Notch1a. Together, this demonstrates the importance of Appb in neurogenesis and for the first time shows the essential requirement of Appb in the formation of a specific cell type, the Mauthner cell, in the hindbrain during development. Our results suggest that Appb-regulated neurogenesis is mediated through balancing the Notch1a signaling pathway and provide new insights into the development of the Mauthner cell

Background risk of breast cancer and the association between physical activity and mammographic density

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The anticancer activity of lytic peptides is inhibited by heparan sulfate on the surface of the tumor cells

<p>Abstract</p> <p>Background</p> <p>Cationic antimicrobial peptides (CAPs) with antitumor activity constitute a promising group of novel anticancer agents. These peptides induce lysis of cancer cells through interactions with the plasma membrane. It is not known which cancer cell membrane components influence their susceptibility to CAPs. We have previously shown that CAPs interact with the two glycosaminoglycans (GAGs), heparan sulfate (HS) and chondroitin sulfate (CS), which are present on the surface of most cells. The purpose of this study was to investigate the role of the two GAGs in the cytotoxic activity of CAPs.</p> <p>Methods</p> <p>Various cell lines, expressing different levels of cell surface GAGs, were exposed to bovine lactoferricin (LfcinB) and the designer peptide, KW5. The cytotoxic effect of the peptides was investigated by use of the colorimetric MTT viability assay. The cytotoxic effect on wild type CHO cells, expressing normal amounts of GAGs on the cell surface, and the mutant pgsA-745, that has no expression of GAGs on the cell surface, was also investigated.</p> <p>Results</p> <p>We show that cells not expressing HS were more susceptible to CAPs than cells expressing HS at the cell surface. Further, exogenously added heparin inhibited the cytotoxic effect of the peptides. Chondroitin sulfate had no effect on the cytotoxic activity of KW5 and only minor effects on LfcinB cytotoxicity.</p> <p>Conclusion</p> <p>Our results show for the first time that negatively charged molecules at the surface of cancer cells inhibit the cytotoxic activity of CAPs. Our results indicate that HS at the surface of cancer cells sequesters CAPs away from the phospholipid bilayer and thereby impede their ability to induce cytolysis.</p

Vitamin D supplementation and breast cancer prevention : a systematic review and meta-analysis of randomized clinical trials

In recent years, the scientific evidence linking vitamin D status or supplementation to breast cancer has grown notably. To investigate the role of vitamin D supplementation on breast cancer incidence, we conducted a systematic review and meta-analysis of randomized controlled trials comparing vitamin D with placebo or no treatment. We used OVID to search MEDLINE (R), EMBASE and CENTRAL until April 2012. We screened the reference lists of included studies and used the “Related Article” feature in PubMed to identify additional articles. No language restrictions were applied. Two reviewers independently extracted data on methodological quality, participants, intervention, comparison and outcomes. Risk Ratios and 95% Confident Intervals for breast cancer were pooled using a random-effects model. Heterogeneity was assessed using the I2 test. In sensitivity analysis, we assessed the impact of vitamin D dosage and mode of administration on treatment effects. Only two randomized controlled trials fulfilled the pre-set inclusion criteria. The pooled analysis included 5372 postmenopausal women. Overall, Risk Ratios and 95% Confident Intervals were 1.11 and 0.74–1.68. We found no evidence of heterogeneity. Neither vitamin D dosage nor mode of administration significantly affected breast cancer risk. However, treatment efficacy was somewhat greater when vitamin D was administered at the highest dosage and in combination with calcium (Risk Ratio 0.58, 95% Confident Interval 0.23–1.47 and Risk Ratio 0.93, 95% Confident Interval 0.54–1.60, respectively). In conclusions, vitamin D use seems not to be associated with a reduced risk of breast cancer development in postmenopausal women. However, the available evidence is still limited and inadequate to draw firm conclusions. Study protocol code: FARM8L2B5L

The FANCM:p.Arg658* truncating variant is associated with risk of triple-negative breast cancer.

Breast cancer is a common disease partially caused by genetic risk factors. Germline pathogenic variants in DNA repair genes BRCA1, BRCA2, PALB2, ATM, and CHEK2 are associated with breast cancer risk. FANCM, which encodes for a DNA translocase, has been proposed as a breast cancer predisposition gene, with greater effects for the ER-negative and triple-negative breast cancer (TNBC) subtypes. We tested the three recurrent protein-truncating variants FANCM:p.Arg658*, p.Gln1701*, and p.Arg1931* for association with breast cancer risk in 67,112 cases, 53,766 controls, and 26,662 carriers of pathogenic variants of BRCA1 or BRCA2. These three variants were also studied functionally by measuring survival and chromosome fragility in FANCM -/- patient-derived immortalized fibroblasts treated with diepoxybutane or olaparib. We observed that FANCM:p.Arg658* was associated with increased risk of ER-negative disease and TNBC (OR = 2.44, P = 0.034 and OR = 3.79; P = 0.009, respectively). In a country-restricted analysis, we confirmed the associations detected for FANCM:p.Arg658* and found that also FANCM:p.Arg1931* was associated with ER-negative breast cancer risk (OR = 1.96; P = 0.006). The functional results indicated that all three variants were deleterious affecting cell survival and chromosome stability with FANCM:p.Arg658* causing more severe phenotypes. In conclusion, we confirmed that the two rare FANCM deleterious variants p.Arg658* and p.Arg1931* are risk factors for ER-negative and TNBC subtypes. Overall our data suggest that the effect of truncating variants on breast cancer risk may depend on their position in the gene. Cell sensitivity to olaparib exposure, identifies a possible therapeutic option to treat FANCM-associated tumors