Generating Secure Service Compositions

Ensuring that the compositions of services that constitute service-based systems satisfy given security properties is a key prerequisite for the adoption of the service oriented computing paradigm. In this paper, we address this issue using a novel approach that guarantees service composition security by virtue of the generation of compositions. Our approach generates service compositions that are guaranteed to satisfy security properties based on secure service orchestration (SESO) patterns. These patterns express primitive (e.g., sequential, parallel) service orchestrations, which are proven to have certain global security properties if the individual services participating in them have themselves other security properties. The paper shows how SESO patterns can be constructed and gives examples of proofs for such patterns. It also presents the process of using SESO patterns to generate secure service compositions and presents the results of an initial experimental evaluation of the approach

Centralized Modularity of N-Linked Glycosylation Pathways in Mammalian Cells

Glycosylation is a highly complex process to produce a diverse repertoire of cellular glycans that are attached to proteins and lipids. Glycans are involved in fundamental biological processes, including protein folding and clearance, cell proliferation and apoptosis, development, immune responses, and pathogenesis. One of the major types of glycans, N-linked glycans, is formed by sequential attachments of monosaccharides to proteins by a limited number of enzymes. Many of these enzymes can accept multiple N-linked glycans as substrates, thereby generating a large number of glycan intermediates and their intermingled pathways. Motivated by the quantitative methods developed in complex network research, we investigated the large-scale organization of such N-linked glycosylation pathways in mammalian cells. The N-linked glycosylation pathways are extremely modular, and are composed of cohesive topological modules that directly branch from a common upstream pathway of glycan synthesis. This unique structural property allows the glycan production between modules to be controlled by the upstream region. Although the enzymes act on multiple glycan substrates, indicating cross-talk between modules, the impact of the cross-talk on the module-specific enhancement of glycan synthesis may be confined within a moderate range by transcription-level control. The findings of the present study provide experimentally-testable predictions for glycosylation processes, and may be applicable to therapeutic glycoprotein engineering

Deep learning to detect optical coherence tomography-derived diabetic macular edema from retinal photographs: a multicenter validation study

PURPOSE: To validate the generalizability of a deep learning system (DLS) that detects diabetic macular edema (DME) from two-dimensional color fundus photography (CFP), where the reference standard for retinal thickness and fluid presence is derived from three-dimensional optical coherence tomography (OCT). DESIGN: Retrospective validation of a DLS across international datasets. PARTICIPANTS: Paired CFP and OCT of patients from diabetic retinopathy (DR) screening programs or retina clinics. The DLS was developed using datasets from Thailand, the United Kingdom (UK) and the United States and validated using 3,060 unique eyes from 1,582 patients across screening populations in Australia, India and Thailand. The DLS was separately validated in 698 eyes from 537 screened patients in the UK with mild DR and suspicion of DME based on CFP. METHODS: The DLS was trained using DME labels from OCT. Presence of DME was based on retinal thickening or intraretinal fluid. The DLS's performance was compared to expert grades of maculopathy and to a previous proof-of-concept version of the DLS. We further simulated integration of the current DLS into an algorithm trained to detect DR from CFPs. MAIN OUTCOME MEASURES: Superiority of specificity and non-inferiority of sensitivity of the DLS for the detection of center-involving DME, using device specific thresholds, compared to experts. RESULTS: Primary analysis in a combined dataset spanning Australia, India, and Thailand showed the DLS had 80% specificity and 81% sensitivity compared to expert graders who had 59% specificity and 70% sensitivity. Relative to human experts, the DLS had significantly higher specificity (p=0.008) and non-inferior sensitivity (p 50%) and a sensitivity of 100% (p=0.02 for sensitivity > 90%). CONCLUSIONS: The DLS can generalize to multiple international populations with an accuracy exceeding experts. The clinical value of this DLS to reduce false positive referrals, thus decreasing the burden on specialist eye care, warrants prospective evaluation

Flavourful Production at Hadron Colliders

We ask what new states may lie at or below the TeV scale, with sizable flavour-dependent couplings to light quarks, putting them within reach of hadron colliders via resonant production, or in association with Standard Model states. In particular, we focus on the compatibility of such states with stringent flavour-changing neutral current and electric-dipole moment constraints. We argue that the broadest and most theoretically plausible flavour structure of the new couplings is that they are hierarchical, as are Standard Model Yukawa couplings, although the hierarchical pattern may well be different. We point out that, without the need for any more elaborate or restrictive structure, new scalars with "diquark" couplings to standard quarks are particularly immune to existing constraints, and that such scalars may arise within a variety of theoretical paradigms. In particular, there can be substantial couplings to a pair of light quarks or to one light and one heavy quark. For example, the latter possibility may provide a flavour-safe interpretation of the asymmetry in top quark production observed at the Tevatron. We thereby motivate searches for diquark scalars at the Tevatron and LHC, and argue that their discovery represents one of our best chances for new insight into the Flavour Puzzle of the Standard Model.Comment: 18 pp., 8 figures, references adde

Determining the neurotransmitter concentration profile at active synapses

Establishing the temporal and concentration profiles of neurotransmitters during synaptic release is an essential step towards understanding the basic properties of inter-neuronal communication in the central nervous system. A variety of ingenious attempts has been made to gain insights into this process, but the general inaccessibility of central synapses, intrinsic limitations of the techniques used, and natural variety of different synaptic environments have hindered a comprehensive description of this fundamental phenomenon. Here, we describe a number of experimental and theoretical findings that has been instrumental for advancing our knowledge of various features of neurotransmitter release, as well as newly developed tools that could overcome some limits of traditional pharmacological approaches and bring new impetus to the description of the complex mechanisms of synaptic transmission

Proliferation and survival molecules implicated in the inhibition of BRAF pathway in thyroid cancer cells harbouring different genetic mutations

<p>Abstract</p> <p>Background</p> <p>Thyroid carcinomas show a high prevalence of mutations in the oncogene BRAF which are inversely associated with RAS or RET/PTC oncogenic activation. The possibility of using inhibitors on the BRAF pathway as became an interesting therapeutic approach. In thyroid cancer cells the target molecules, implicated on the cellular effects, mediated by inhibition of BRAF are not well established. In order to fill this lack of knowledge we studied the proliferation and survival pathways and associated molecules induced by BRAF inhibition in thyroid carcinoma cell lines harbouring distinct genetic backgrounds.</p> <p>Methods</p> <p>Suppression of BRAF pathway in thyroid cancer cell lines (8505C, TPC1 and C643) was achieved using RNA interference (RNAi) for BRAF and the kinase inhibitor, sorafenib. Proliferation analysis was performed by BrdU incorporation and apoptosis was accessed by TUNEL assay. Levels of protein expression were analysed by western-blot.</p> <p>Results</p> <p>Both BRAF RNAi and sorafenib inhibited proliferation in all the cell lines independently of the genetic background, mostly in cells with BRAF^V600Emutation. In BRAF^V600Emutated cells inhibition of BRAF pathway lead to a decrease in ERK1/2 phosphorylation and cyclin D1 levels and an increase in p27^Kip1. Specific inhibition of BRAF by RNAi in cells with BRAF^V600Emutation had no effect on apoptosis. In the case of sorafenib treatment, cells harbouring BRAF^V600Emutation showed increase levels of apoptosis due to a balance of the anti-apoptotic proteins Mcl-1 and Bcl-2.</p> <p>Conclusion</p> <p>Our results in thyroid cancer cells, namely those harbouring BRAF^V600Emutation showed that BRAF signalling pathway provides important proliferation signals. We have shown that in thyroid cancer cells sorafenib induces apoptosis by affecting Mcl-1 and Bcl-2 in BRAF^V600Emutated cells which was independent of BRAF. These results suggest that sorafenib may prove useful in the treatment of thyroid carcinomas, particularly those refractory to conventional treatment and harbouring BRAF mutations.</p

A New Approach for Determining Phase Response Curves Reveals that Purkinje Cells Can Act as Perfect Integrators

Cerebellar Purkinje cells display complex intrinsic dynamics. They fire spontaneously, exhibit bistability, and via mutual network interactions are involved in the generation of high frequency oscillations and travelling waves of activity. To probe the dynamical properties of Purkinje cells we measured their phase response curves (PRCs). PRCs quantify the change in spike phase caused by a stimulus as a function of its temporal position within the interspike interval, and are widely used to predict neuronal responses to more complex stimulus patterns. Significant variability in the interspike interval during spontaneous firing can lead to PRCs with a low signal-to-noise ratio, requiring averaging over thousands of trials. We show using electrophysiological experiments and simulations that the PRC calculated in the traditional way by sampling the interspike interval with brief current pulses is biased. We introduce a corrected approach for calculating PRCs which eliminates this bias. Using our new approach, we show that Purkinje cell PRCs change qualitatively depending on the firing frequency of the cell. At high firing rates, Purkinje cells exhibit single-peaked, or monophasic PRCs. Surprisingly, at low firing rates, Purkinje cell PRCs are largely independent of phase, resembling PRCs of ideal non-leaky integrate-and-fire neurons. These results indicate that Purkinje cells can act as perfect integrators at low firing rates, and that the integration mode of Purkinje cells depends on their firing rate

The evolution of multiple active site configurations in a designed enzyme

Developments in computational chemistry, bioinformatics, and laboratory evolution have facilitated the de novo design and catalytic optimization of enzymes. Besides creating useful catalysts, the generation and iterative improvement of designed enzymes can provide valuable insight into the interplay between the many phenomena that have been suggested to contribute to catalysis. In this work, we follow changes in conformational sampling, electrostatic preorganization, and quantum tunneling along the evolutionary trajectory of a designed Kemp eliminase. We observe that in the Kemp Eliminase KE07, instability of the designed active site leads to the emergence of two additional active site configurations. Evolutionary conformational selection then gradually stabilizes the most efficient configuration, leading to an improved enzyme. This work exemplifies the link between conformational plasticity and evolvability and demonstrates that residues remote from the active sites of enzymes play crucial roles in controlling and shaping the active site for efficient catalysis