Formalizing (web) standards: an application of test and proof

Most popular technologies are based on informal or semiformal standards that lack a rigid formal semantics. Typical examples include web technologies such as the DOM or HTML, which are defined by the Web Hypertext Application Technology Working Group (WHATWG) and the World Wide Web Consortium (W3C). While there might be API specifications and test cases meant to assert the compliance of a certain implementation, the actual standard is rarely accompanied by a formal model that would lend itself for, e.g., verifying the security or safety properties of real systems. Even when such a formalization of a standard exists, two important questions arise: first, to what extend does the formal model comply to the standard and, second, to what extend does the implementation comply to the formal model and the assumptions made during the verification? In this paper, we present an approach that brings all three involved artifacts - the (semi-)formal standard, the formalization of the standard, and the implementations - closer together by combining verification, symbolic execution, and specification based testing

Activation of SGK1 in endometrial epithelial cells in response to PI3K/AKT inhibition impairs embryo implantation

Background: Serum & Glucocorticoid Regulated Kinase 1 (SGK1) plays a fundamental role in ion and solute transport processes in epithelia. In the endometrium, down-regulation of SGK1 during the window of receptivity facilitates embryo implantation whereas expression of a constitutively active mutant in the murine uterus blocks implantation. Methods/Results: Here, we report that treatment of endometrial epithelial cells with specific inhibitors of the phosphoinositide 3-kinase (PI3K)/AKT activity pathway results in reciprocal activation of SGK1. Flushing of the uterine lumen of mice with a cell permeable, substrate competitive phosphatidylinositol analogue that inhibits AKT activation (AKT inhibitor III) resulted in Sgk1 phosphorylation, down-regulation of the E3 ubiquitin-protein ligase Nedd4-2, and increased expression of epithelial Na+ channels (ENaC). Furthermore, exposure of the uterine lumen to AKT inhibitor III prior to embryo transfer induced a spectrum of early pregnancy defects, ranging from implantation failure to aberrant spacing of implantation sites. Conclusion: Taken together, our data indicate that the balanced activities of two related serine/threonine kinases, AKT and SGK1, critically govern the implantation process

LEFTY2 inhibits endometrial receptivity by downregulating Orai1 expression and store-operated Ca²+ entry

Early embryo development and endometrial differentiation are initially independent processes, and synchronization, imposed by a limited window of implantation, is critical for reproductive success. A putative negative regulator of endometrial receptivity is LEFTY2, a member of the transforming growth factor (TGF)-β family. LEFTY2 is highly expressed in decidualizing human endometrial stromal cells (HESCs) during the late luteal phase of the menstrual cycle, coinciding with the closure of the window of implantation. Here, we show that flushing of the uterine lumen in mice with recombinant LEFTY2 inhibits the expression of key receptivity genes, including Cox2, Bmp2, and Wnt4, and blocks embryo implantation. In Ishikawa cells, a human endometrial epithelial cell line, LEFTY2 downregulated the expression of calcium release-activated calcium channel protein 1, encoded by ORAI1, and inhibited store-operated Ca2+ entry (SOCE). Furthermore, LEFTY2 and the Orai1 blockers 2-APB, MRS-1845, as well as YM-58483, inhibited, whereas the Ca2+ ionophore, ionomycin, strongly upregulated COX2, BMP2 and WNT4 expression in decidualizing HESCs. These findings suggest that LEFTY2 closes the implantation window, at least in part, by downregulating Orai1, which in turn limits SOCE and antagonizes expression of Ca2+-sensitive receptivity genes

Formal Model-Based Assurance Cases in Isabelle/SACM : An Autonomous Underwater Vehicle Case Study

Isabelle/SACM is a tool for automated construction of model-based assurance cases with integrated formal methods, based on the Isabelle proof assistant. Assurance cases show how a system is safe to operate, through a human comprehensible argument demonstrating that the requirements are satisfied, using evidence of various provenances. They are usually required for certification of critical systems, often with evidence that originates from formal methods. Automating assurance cases increases rigour, and helps with maintenance and evolution. In this paper we apply Isabelle/SACM to a fragment of the assurance case for an autonomous underwater vehicle demonstrator. We encode the metric unit system (SI) in Isabelle, to allow modelling requirements and state spaces using physical units. We develop a behavioural model in the graphical RoboChart state machine language, embed the artifacts into Isabelle/SACM, and use it to demonstrate satisfaction of the requirements

Ownership and control in a competitive industry

We study a differentiated product market in which an investor initially owns a controlling stake in one of two competing firms and may acquire a non-controlling or a controlling stake in a competitor, either directly using her own assets, or indirectly via the controlled firm. While industry profits are maximized within a symmetric two product monopoly, the investor attains this only in exceptional cases. Instead, she sometimes acquires a noncontrolling stake. Or she invests asymmetrically rather than pursuing a full takeover if she acquires a controlling one. Generally, she invests indirectly if she only wants to affect the product market outcome, and directly if acquiring shares is profitable per se. --differentiated products,separation of ownership and control,private benefits of control

Certification of breast centres in Germany: proof of concept for a prototypical example of quality assurance in multidisciplinary cancer care

<p>Abstract</p> <p>Background</p> <p>The main study objectives were: to develop a set of requirements of comprehensive breast centres; to establish a nationwide voluntary certification programme for breast centres based on such requirements, a certified quality management system (QMS), and scheduled independent, external audits and periodic recertification; and to demonstrate the general acceptance of such a certification programme with a view to introducing similar certification programmes for other major cancers.</p> <p>Methods</p> <p>Breast centres introduced a QMS and voluntarily participated in an external certification procedure based on guideline-derived Requirements of Breast Centres specifically developed for the application procedure, all subsequent audits and recertification. All data (numbers of pending and successful applications, sites/centre, etc.) were collected by a newly founded, independent organisation for certification of cancer services delivery. Data analysis was descriptive.</p> <p>Results</p> <p>Requirements of Breast Centres were developed by the German Cancer Society (DKG), the German Society of Senology (DGS) and other relevant specialist medical societies in the form of a questionnaire comprising 185 essential items based on evidence-based guidelines and the European Society of Breast Cancer Specialists' (EUSOMA) requirements of specialist breast units. From late 2002 to mid 2008, the number of participating breast centres rose from 1 to 175. As of mid 2008, 77% of an estimated 50,000 new breast cancers in Germany were diagnosed and treated at certified breast centres, 78% of which were single-site centres.</p> <p>Conclusion</p> <p>Nationwide voluntary certification of breast centres is feasible and well accepted in Germany. Dual certification of breast centres that involves certification of breast services to guideline-derived requirements in conjunction with independent certification of a mandatory QMS can serve as a model for other multidisciplinary site-specific cancer centres.</p

Laparoscopic Fertility-Sparing Surgery for Early Ovarian Malignancies

The demand for fertility-sparing surgery (FSS) has increased in the last decade due to increased maternal age, increased incidence of ovarian malignancies in younger patients, and technical advances in surgery. Data on oncological safety and fertility outcomes of patients with ovarian cancer after laparoscopic FSS are sparse, but some retrospective studies have shown that open FSS may be offered to selected patients. We assessed the role of minimally invasive FSS in comparison with radical surgery (RS) in terms of oncological safety and reproductive outcomes after FSS in this multicenter study. Eighty patients with FIGO stage I/II ovarian cancer treated with laparoscopic FSS or RS between 01/2000 and 10/2018 at the participating centers (comprehensive gynecological cancer centers with minimally invasive surgical expertise) were included in this retrospective analysis of prospectively kept data. Case–control (n = 40 each) matching according to the FIGO stage was performed. Progression-free survival [150 (3–150) and 150 (5–150) months; p = 0.61] and overall survival [36 (3–150) and 50 (1–275) months; p = 0.65] did not differ between the FSS and RS groups. Eight (25.8%) women became pregnant after FSS, resulting in seven (22.5%) deliveries; three (37.5%) patients conceived after in vitro fertilization, and five (62.5%) conceived spontaneously. Laparoscopic FSS seems to be applicable and oncologically safe for patients with early-stage ovarian cancer, with adequate fertility outcomes

Using fahp-vikor for operation selection in the flexible job-shop scheduling problem: A case study in textile industry

Scheduling of Flexible Job Shop Systems is a combinatorial problem which has been addressed by several heuristics and meta-heuristics. Nevertheless, the operation selection rules of both methods are limited to an ordered variant wherein priority-dispatching rules are not simultaneously deemed in the reported literature. Therefore, this paper presents the application of dispatching algorithm with operation selection based on Fuzzy Analytic Hierarchy Process (FAHP) and VIKOR methods while considering setup times and transfer batches. Dispatching, FAHP, and VIKOR algorithms are first defined. Second, a multi-criteria decision-making model is designed for operation prioritization. Then, FAHP is applied to calculate the criteria weights and overcome the uncertainty of human judgments. Afterwards, VIKOR is used to select the operation with the highest priority. A case study in the textile industry is shown to validate this approach. The results evidenced, compared to the company solution, a reduction of 61.05% in average delay