Relativistic Mean-Field Theory Equation of State of Neutron Star Matter and a Maxwellian Phase Transition to Strange Quark Matter

The equation of state of neutron star matter is examined in terms of the relativistic mean-field theory, including a scalar-isovector $\delta$-meson effective field. The constants of the theory are determined numerically so that the empirically known characteristics of symmetric nuclear matter are reproduced at the saturation density. The thermodynamic characteristics of both asymmetric nucleonic matter and $\beta$-equilibrium hadron-electron $npe$-plasmas are studied. Assuming that the transition to strange quark matter is an ordinary first-order phase transition described by Maxwell's rule, a detailed study is made of the variations in the parameters of the phase transition owing to the presence of a $\delta$-meson field. The quark phase is described using an improved version of the bag model, in which interactions between quarks are accounted for in a one-gluon exchange approximation. The characteristics of the phase transition are determined for various values of the bag parameter within the range $B\in[60,120]$ $MeV/fm^{3}$ and it is shown that including a $\delta$-meson field leads to a reduction in the phase transition pressure $P_{0}$ and in the concentrations $n_{N}$ and $n_{Q}$ at the phase transition point.Comment: 17 pages, 8 figure

Towards an Entropy-based Analysis of Log Variability

Rules, decisions, and workflows are intertwined components depicting the overall process. So far imperative workflow modelling languages have played the major role for the description and analysis of business processes. Despite their undoubted efficacy in representing sequential executions, they hide circumstantial information leading to the enactment of activities, and obscure the rationale behind the verification of requirements, dependencies, and goals. This workshop aimed at providing a platform for the discussion and introduction of new ideas related to the development of a holistic approach that encompasses all those aspects. The objective was to extend the reach of the business process management audience towards the decisions and rules community and increase the integration between different imperative, declarative and hybrid modelling perspectives. Out of the high-quality submitted manuscripts, three papers were accepted for publication, with an acceptance rate of 50%. They contributed to foster a fruitful discussion among the participants about the respective impact and the interplay of decision perspective and the process perspective

Advances in molecular preclinical therapy mediated by imaging.

Several advances have been made toward understanding the biology of cancer and most of them are due to robust genetic studies that led to the scientific recognition that although many patients have the same type of cancer their tumors may have harbored different molecular alterations. Personalized therapy and the development of advanced techniques of preclinical imaging and new murine models of disease are emerging concepts that are allowing mapping of disease markers in vivo and in some cases also receptor targeted therapy. Aim of this review is to illustrate some emerging models of disease that allow patient tumor implantation in mice for subsequent drug testing and advanced approaches for therapy mediated by preclinical imaging. In particular we discuss targeted therapy mediated by high frequency ultrasound and magnetic resonance, two emerging techniques in molecular preclinical therapy

Search algorithms as a framework for the optimization of drug combinations

Combination therapies are often needed for effective clinical outcomes in the management of complex diseases, but presently they are generally based on empirical clinical experience. Here we suggest a novel application of search algorithms, originally developed for digital communication, modified to optimize combinations of therapeutic interventions. In biological experiments measuring the restoration of the decline with age in heart function and exercise capacity in Drosophila melanogaster, we found that search algorithms correctly identified optimal combinations of four drugs with only one third of the tests performed in a fully factorial search. In experiments identifying combinations of three doses of up to six drugs for selective killing of human cancer cells, search algorithms resulted in a highly significant enrichment of selective combinations compared with random searches. In simulations using a network model of cell death, we found that the search algorithms identified the optimal combinations of 6-9 interventions in 80-90% of tests, compared with 15-30% for an equivalent random search. These findings suggest that modified search algorithms from information theory have the potential to enhance the discovery of novel therapeutic drug combinations. This report also helps to frame a biomedical problem that will benefit from an interdisciplinary effort and suggests a general strategy for its solution.Comment: 36 pages, 10 figures, revised versio

Scalable and privacy-respectful interactive discovery of place semantics from human mobility traces

Mobility diaries of a large number of people are needed for assessing transportation infrastructure and for spatial development planning. Acquisition of personal mobility diaries through population surveys is a costly and error-prone endeavour. We examine an alternative approach to obtaining similar information from episodic digital traces of people’s presence in various locations, which appear when people use their mobile devices for making phone calls, accessing the internet, or posting georeferenced contents (texts, photos, or videos) in social media. Having episodic traces of a person over a long time period, it is possible to detect significant (repeatedly visited) personal places and identify them as home, work, or place of social activities based on temporal patterns of a person’s presence in these places. Such analysis, however, can lead to compromising personal privacy. We have investigated the feasibility of deriving place meanings and reconstructing personal mobility diaries while preserving the privacy of individuals whose data are analysed. We have devised a visual analytics approach and a set of supporting tools making such privacy-preserving analysis possible. The approach was tested in two case studies with publicly available data: simulated tracks from the VAST Challenge 2014 and real traces built from georeferenced Twitter posts

MicroRNA-277 Modulates the Neurodegeneration Caused by Fragile X Premutation rCGG Repeats

Fragile X-associated tremor/ataxia syndrome (FXTAS), a late-onset neurodegenerative disorder, has been recognized in older male fragile X premutation carriers and is uncoupled from fragile X syndrome. Using a Drosophila model of FXTAS, we previously showed that transcribed premutation repeats alone are sufficient to cause neurodegeneration. MiRNAs are sequence-specific regulators of post-transcriptional gene expression. To determine the role of miRNAs in rCGG repeat-mediated neurodegeneration, we profiled miRNA expression and identified selective miRNAs, including miR-277, that are altered specifically in Drosophila brains expressing rCGG repeats. We tested their genetic interactions with rCGG repeats and found that miR-277 can modulate rCGG repeat-mediated neurodegeneration. Furthermore, we identified Drep-2 and Vimar as functional targets of miR-277 that could modulate rCGG repeat-mediated neurodegeneration. Finally, we found that hnRNP A2/B1, an rCGG repeat-binding protein, can directly regulate the expression of miR-277. These results suggest that sequestration of specific rCGG repeat-binding proteins could lead to aberrant expression of selective miRNAs, which may modulate the pathogenesis of FXTAS by post-transcriptionally regulating the expression of specific mRNAs involved in FXTAS

A phase II study of mitomycin C, cisplatin and continuous infusion 5-fluorouracil (MCF) in the treatment of patients with carcinoma of unknown primary site

Carcinoma of unknown primary site remains a common clinical diagnosis, accounting for between 5 and 10% of all cancer patients. Numerous combination chemotherapy regimens have been used in the management of carcinoma of unknown primary site, resulting in response rates of 0–48%. We present the results of a single centre phase II study of the use of the combination of mitomycin C (7 mg m−2 on day 1 of cycles 1, 3 and 5) cisplatin (60 mg m−2 on day 1) and continuous infusion 5-fluorouracil (300 mg m−2 daily), MCF, delivered as a 21-day cycle, in patients with carcinoma of unknown primary site. Thirty-one patients with a diagnosis of carcinoma of unknown primary site were treated in Aberdeen Royal Infirmary between 1997 and 2001 with MCF. In total, 136 cycles of MCF were delivered (median of 5 cycles per patient). Toxicity was acceptable, with 19% grade 3 or 4 neutropenia, 16% grade 3 or 4 thrombocytopenia and 13% grade 3 or 4 nausea and vomiting. No cases of neutropenic sepsis were seen and there were no treatment-related deaths, however, six patients developed thrombotic complications. The overall response rate was 27% (CR 3%; PR 23%). Median time to progression was 3.4 months (95% CI 1.1–5.6 months) and median overall survival was 7.7 months (95% CI 5.7–9.8 months). Survival at 1 year was 28%, and at 2 years, 10%. MCF is a tolerable regimen with comparable toxicity, response rates and survival data to most platinum-based combination chemotherapy regimens in use for this devastating disease

Biological activity of the thyroid TRK-T3 oncogene requires signalling through Shc

The thyroid TRK-T3 oncogene, produced by a chromosomal translocation, is a chimeric, constitutively activated version of the NTRK1/NGF receptor and it is able to transform NIH3T3 cells and differentiate PC12 cells. TRK-T3 oncoprotein triggers multiple signal transduction pathways. Among others, TRK-T3 binds and phosphorylates the Shc and SNT1/FRS2 adaptor proteins both involved in coupling the receptor tyrosine kinase to the mitogen-activated protein kinase pathway by recruiting Grb2/SOS. We were interested in defining the role of Shc in the oncogenesis by TRK-T3. The mutation of TRK-T3 tyrosine 291, docking site for both Shc and FRS2, abrogates the oncogene biological activity. To directly explore the role of Shc we used the ShcY317F mutant, which carries the mutation of a tyrosine residue involved in Grb2 recruitment. We demonstrated that the ShcY317F mutant exerts an inhibitory effect on TRK-T3 transforming activity. Such effect can be modulated by the amount of ShcY317F protein and affects the viability of cells expressing TRK-T3 by means of a mechanism involving apoptosis. Our results indicate a definitive role of the adaptor protein Shc in TRK-T3 transforming activity

Histone deacetylases suppress cgg repeat-induced neurodegeneration via transcriptional silencing in models of Fragile X Tremor Ataxia Syndrome

Fragile X Tremor Ataxia Syndrome (FXTAS) is a common inherited neurodegenerative disorder caused by expansion of a CGG trinucleotide repeat in the 59UTR of the fragile X syndrome (FXS) gene, FMR1. The expanded CGG repeat is thought to induce toxicity as RNA, and in FXTAS patients mRNA levels for FMR1 are markedly increased. Despite the critical role of FMR1 mRNA in disease pathogenesis, the basis for the increase in FMR1 mRNA expression is unknown. Here we show that overexpressing any of three histone deacetylases (HDACs 3, 6, or 11) suppresses CGG repeat-induced neurodegeneration in a Drosophila model of FXTAS. This suppression results from selective transcriptional repression of the CGG repeat-containing transgene. These findings led us to evaluate the acetylation state of histones at the human FMR1 locus. In patient-derived lymphoblasts and fibroblasts, we determined by chromatin immunoprecipitation that there is increased acetylation of histones at the FMR1 locus in pre-mutation carriers compared to control or FXS derived cell lines. These epigenetic changes correlate with elevated FMR1 mRNA expression in pre-mutation cell lines. Consistent with this finding, histone acetyltransferase (HAT) inhibitors repress FMR1 mRNA expression to control levels in pre-mutation carrier cell lines and extend lifespan in CGG repeat-expressing Drosophila. These findings support a disease model whereby the CGG repeat expansion in FXTAS promotes chromatin remodeling in cis, which in turn increases expression of the toxic FMR1 mRNA. Moreover, these results provide proof of principle that HAT inhibitors or HDAC activators might be used to selectively repress transcription at the FMR1 locus.open293