A controlled experiment for the empirical evaluation of safety analysis techniques for safety-critical software

Context: Today's safety critical systems are increasingly reliant on software. Software becomes responsible for most of the critical functions of systems. Many different safety analysis techniques have been developed to identify hazards of systems. FTA and FMEA are most commonly used by safety analysts. Recently, STPA has been proposed with the goal to better cope with complex systems including software. Objective: This research aimed at comparing quantitatively these three safety analysis techniques with regard to their effectiveness, applicability, understandability, ease of use and efficiency in identifying software safety requirements at the system level. Method: We conducted a controlled experiment with 21 master and bachelor students applying these three techniques to three safety-critical systems: train door control, anti-lock braking and traffic collision and avoidance. Results: The results showed that there is no statistically significant difference between these techniques in terms of applicability, understandability and ease of use, but a significant difference in terms of effectiveness and efficiency is obtained. Conclusion: We conclude that STPA seems to be an effective method to identify software safety requirements at the system level. In particular, STPA addresses more different software safety requirements than the traditional techniques FTA and FMEA, but STPA needs more time to carry out by safety analysts with little or no prior experience.Comment: 10 pages, 1 figure in Proceedings of the 19th International Conference on Evaluation and Assessment in Software Engineering (EASE '15). ACM, 201

Maternal age effect and severe germ-line bottleneck in the inheritance of human mitochondrial DNA

The manifestation of mitochondrial DNA (mtDNA) diseases depends on the frequency of heteroplasmy (the presence of several alleles in an individual), yet its transmission across generations cannot be readily predicted owing to a lack of data on the size of the mtDNA bottleneck during oogenesis. For deleterious heteroplasmies, a severe bottleneck may abruptly transform a benign (low) frequency in a mother into a disease-causing (high) frequency in her child. Here we present a high-resolution study of heteroplasmy transmission conducted on blood and buccal mtDNA of 39 healthy mother–child pairs of European ancestry (a total of 156 samples, each sequenced at ∼20,000× per site). On average, each individual carried one heteroplasmy, and one in eight individuals carried a disease-associated heteroplasmy, with minor allele frequency ≥1%. We observed frequent drastic heteroplasmy frequency shifts between generations and estimated the effective size of the germ-line mtDNA bottleneck at only ∼30–35 (interquartile range from 9 to 141). Accounting for heteroplasmies, we estimated the mtDNA germ-line mutation rate at 1.3 × 10−8 (interquartile range from 4.2 × 10−9 to 4.1 × 10−8) mutations per site per year, an order of magnitude higher than for nuclear DNA. Notably, we found a positive association between the number of heteroplasmies in a child and maternal age at fertilization, likely attributable to oocyte aging. This study also took advantage of droplet digital PCR (ddPCR) to validate heteroplasmies and confirm a de novo mutation. Our results can be used to predict the transmission of disease-causing mtDNA variants and illuminate evolutionary dynamics of the mitochondrial genome

A precise HST parallax of the cataclysmic variable EX Hydrae, its system parameters, and accretion rate

Using the HST Fine Guidance Sensor, we have measured a high precision astrometric parallax of the cataclysmic variable EX Hydrae, pi=15.50+-0.29mas. From the wavelength-integrated accretion-induced energy flux, we derive a quiescent accretion luminosity for EX Hya of Lacc = (2.6+-0.6)x10e32 erg. The quiescent accretion rate then is Mdot=(6.2\+-1.5)x10e-11 (M1/0.5Msun)^(-1.61})Msun/yr. The time-averaged accretion rate, which includes a small correction for the rare outbursts, is 6% higher. We discuss the system parameters of EX Hya and deduce M1=0.4-0.7Msun, M2=0.07-0.10Msun, and i=76.0deg-77.6deg, using recent radial velocity measurements of both components and restrictions imposed by other observational and theoretical constraints. We conclude that the secondary is undermassive, overluminous, and expanded over a ZAMS star of the same mass. Near the upper limit to M1, the accretion rate of the white dwarf coincides with that due to near-equilibrium angular momentum loss by gravitational radiation and angular momentum transfer from the orbit into the spin-up of the white dwarf. Near the lower mass limit, the correspondingly higher accretion rate requires that either an additional angular momentum loss process is acting besides gravitational radiation or that accretion occurs on a near-adiabatic time scale. The latter possibility would imply that EX Hya is in a transient phase of high mass transfer and the associated spin-up of the white dwarf.Comment: 7 pages A&A-Latex, 1 Figure, accepted for publication in A&

Surface Roughness of Commercial Composites after Different Polishing Protocols: An Analysis with Atomic Force Microscopy

Polishing may increase the surface roughness of composites, with a possible effect on bacterial growth and material properties. This preliminary in vitro study evaluates the effect of three different polishing systems (PoGo polishers, Enhance, Venus Supra) on six direct resin composites (Gradia Direct, Venus, Venus Diamond, Enamel Plus HFO, Tetric Evoceram, Filtek Supreme XT)

Characterization of anti-drug antibody responses to the T-cell engaging bispecific antibody cibisatamab to understand the impact on exposure

An appropriately designed pharmacokinetic (PK) assay that is sensitive for anti-drug antibody (ADA) impact on relevant exposure is an alternative strategy to understand the neutralizing potential of ADAs. However, guidance on how to develop such PK assays and how to confirm the functional ADA impact on exposure is missing. Here, the PK assay of a T-cell-engaging bispecific antibody, cibisatamab, was developed based on its mechanism of action (MoA). Using critical monoclonal anti-idiotypic (anti-ID) antibody positive controls as ADA surrogates, the impact on exposure was evaluated pre-clinically. In a phase I clinical trial (NCT02324257), initial data suggest that the combination of ADA and PK assays for correlation of the ADA response with cibisatamab exposure. To understand the neutralizing potential of patient-derived ADAs on drug activity, advanced ADA characterization has been performed. Structural binding analysis of ADAs to antibody domains of the drug and its impact on targeting were assessed. For this purpose, relevant patient ADA binding features were identified and compared with the specific monoclonal anti-ID antibody-positive controls. Comparable results of target binding inhibition and similar impacts on exposure suggest that the observed reduction of Cmax and Ctrough levels in patients is caused by the neutralizing potential of ADAs and allows a correlation between ADA response and loss of exposure. Therefore, the described study provides important functional aspects for the development of an appropriately designed PK assay for bispecific antibodies as an alternative option towards understanding the neutralizing ADA impact on exposure

The space density and X-ray luminosity function of non-magnetic cataclysmic variables

We combine two complete, X-ray flux-limited surveys, the ROSAT Bright Survey (RBS) and the ROSAT North Ecliptic Pole (NEP) survey, to measure the space density (\rho) and X-ray luminosity function (\Phi) of non-magnetic CVs. The combined survey has a flux limit of F_X \ga 1.1 \times 10^{-12} erg cm^{-2}s^{-1} over most of its solid angle of just over 2\pi, but is as deep as \simeq 10^{-14} erg cm^{-2}s^{-1} over a small area. The CV sample that we construct from these two surveys contains 20 non-magnetic systems. We carefully include all sources of statistical error in calculating \rho and \Phi by using Monte Carlo simulations; the most important uncertainty proves to be the often large errors in distances estimates. If we assume that the 20 CVs in the combined RBS and NEP survey sample are representative of the intrinsic population, the space density of non-magnetic CVs is 4^{+6}_{-2} \times 10^{-6} pc^{-3}. We discuss the difficulty in measuring \Phi in some detail---in order to account for biases in the measurement, we have to adopt a functional form for \Phi. Assuming that the X-ray luminosity function of non-magnetic CVs is a truncated power law, we constrain the power law index to -0.80 \pm 0.05. It seems likely that the two surveys have failed to detect a large, faint population of short-period CVs, and that the true space density may well be a factor of 2 or 3 larger than what we have measured; this is possible, even if we only allow for undetected CVs to have X-ray luminosities in the narrow range 28.7< log(L_X/erg\,s^{-1})<29.7. However, \rho as high as 2 \times 10^{-4} pc^{-3} would require that the majority of CVs has X-ray luminosities below L_X = 4 \times 10^{28} erg s^{-1} in the 0.5--2.0 keV band.Comment: MNRAS, accepted. 14 pages, 8 figure

Biodegradable Polydepsipeptides

This paper reviews the synthesis, characterization, biodegradation and usage of bioresorbable polymers based on polydepsipeptides. The ring-opening polymerization of morpholine-2,5-dione derivatives using organic Sn and enzyme lipase is discussed. The dependence of the macroscopic properties of the block copolymers on their structure is also presented. Bioresorbable polymers based on polydepsipeptides could be used as biomaterials in drug controlled release, tissue engineering scaffolding and shape-memory materials

Mechanisms of local immunosuppression in cutaneous melanoma

Cutaneous melanoma is highly immunogenic, yet primary melanomas and metastases develop successfully in otherwise immunocompetent patients. To investigate the local immunosuppressive microenvironment, we examined the presence of suppressor T lymphocytes and tolerising dendritic cells (DCs), the expression of immunosuppressive cytokines (IL-10, TGFβ1 and TGFβ2) and the enzyme indoleamine 2,3-dioxygenase (IDO) using qRT–PCR and immunohistochemistry in primary skin melanomas, negative and positive sentinel lymph nodes (SLN), and lymph nodes with advanced metastases. Our results indicate that tolerogenic DCs and suppressor T lymphocytes are present in melanoma at all stages of disease progression. They express transforming growth factor β receptor 1 (TGFβR1), and are therefore susceptible to TGFβ1 and TGFβ2 specifically expressed by primary melanoma. We found that expression of IDO and interleukin 10 (IL-10) increased with melanoma progression, with the highest concentration in positive SLN. We suggest that negative SLN contain immunosuppressive cells and cytokines, due to preconditioning by tolerogenic DCs migrating from the primary melanoma site to the SLN. In primary melanoma, TGFβ2 is likely to render peripheral DCs tolerogenic, while in lymph nodes IDO and TGFβ1 may have a major effect. This mechanism of tumour-associated immunosuppression may inhibit the immune response to the tumour and may explain the discrepancy between the induction of systemic immunity by anti-melanoma vaccines and their poor performance in the clinic

Dectin-1 Positive Dendritic Cells Expand after Infection with Leishmania major Parasites and Represent Promising Targets for Vaccine Development

Acknowledgments This work was supported by the Priority Program of the German Research Foundation (DFG) (RI 1849/2-1 and 4-1) and the Wellcome Trust (102705). We gratefully acknowledge our Ethiopian partners at the Armauer Hansen Research Institute, Addis Ababa. Rawleigh Howe for excellent supervision of flow cytometry analysis performed at the Armauer Hansen Research Institute and Selfu Girma, Birtukan Endale, Genet Amare and Hareg Yetesh for technical support during the field trips and laboratory work. Supplementary Material The Supplementary Material for this article can be found online at http://www.frontiersin.org/articles/10.3389/fimmu.2018.00263/full#supplementary-material.Peer reviewedPublisher PD