Online Model-Based Testing under Uncertainty

Modern software systems are required to operate in a highly uncertain and changing environment. They have to control the satisfaction of their requirements at run-time, and possibly adapt and cope with situations that have not been completely addressed at design-time. Software engineering methods and techniques are, more than ever, forced to deal with change and uncertainty (lack of knowledge) explicitly. For tackling the challenge posed by uncertainty in delivering more reliable systems, this paper proposes a novel online Model-based Testing technique that complements classic test case generation based on pseudo-random sampling strategies with an uncertainty-aware sampling strategy. To deal with system uncertainty during testing, the proposed strategy builds on an Inverse Uncertainty Quantification approach that is related to the discrepancy between the measured data at run-time (while the system executes) and a Markov Decision Process model describing the behavior of the system under test. To this purpose, a conformance game approach is adopted in which tests feed a Bayesian inference calibrator that continuously learns from test data to tune the system model and the system itself. A comparative evaluation between the proposed uncertainty-aware sampling policy and classical pseudo-random sampling policies is also presented using the Tele Assistance System running example, showing the differences in achieved accuracy and efficiency

Reserves forecasting for open market operations

Bank reserves ; Open market operations

The value function of an asymptotic exit-time optimal control problem

We consider a class of exit--time control problems for nonlinear systems with a nonnegative vanishing Lagrangian. In general, the associated PDE may have multiple solutions, and known regularity and stability properties do not hold. In this paper we obtain such properties and a uniqueness result under some explicit sufficient conditions. We briefly investigate also the infinite horizon problem

Leucine-rich alpha-2-glycoprotein 1 (LRG1) as a novel ADC target

Leucine-rich alpha-2-glycoprotein 1 (LRG1) is present abundantly in the microenvironment of many tumours where it contributes to vascular dysfunction, which impedes the delivery of therapeutics. In this work we demonstrate that LRG1 is predominantly a non-internalising protein. We report the development of a novel antibody–drug conjugate (ADC) comprising the anti-LRG1 hinge-stabilised IgG4 monoclonal antibody Magacizumab coupled to the anti-mitotic payload monomethyl auristatin E (MMAE) via a cleavable dipeptide linker using the site-selective disulfide rebridging dibromopyridazinedione (diBrPD) scaffold. It is demonstrated that this ADC retains binding post-modification, is stable in serum and effective in in vitro cell studies. We show that the extracellular LRG1-targeting ADC provides an increase in survival in vivo when compared against antibody alone and similar anti-tumour activity when compared against standard chemotherapy, but without undesired side-effects. LRG1 targeting through this ADC presents a novel and effective proof-of-concept en route to improving the efficacy of cancer therapeutics

PENGARUH DESENTRALISASI FISKAL TERHADAP PERTUMBUHAN EKONOMI DI KABUPATEN/KOTA DI WILAYAH PROVINSI JAWA TIMUR

Penelitian ini bertujuan untuk mengetahui pengaruh DAU, DAK, PAD, dan DBH terhadap pertumbuhan ekonomi. Pertumbuhan ekonomi diukur dengan menggunakan data laju pertumbuhan ekonomi Kabupaten/Kota di Jawa Timur pada Tahun 2011-2015 Atas Dasar Harga Konstan Tahun 2010. Populasi dalam penelitian ini adalah kabupaten/kota di Provinsi Jawa Timur periode 2011-2015. Pengambilan sampel dalam penelitian ini menggunakan metode puposive sampling dan jumlah sampel yang memenuhi kriteria sebanyak 190 sampel. Data yang digunakan dalam penelitian ini merupakan data sekunder yang diperoleh dari Direktorat Jenderal Perimbangan Keuangan Kementerian Keuangan dan Badan Pusat Statistik. Pengujian hipotesis penelitian ini menggunakan analisis regresi berganda. Hasil uji dari regresi berganda menunjukkan bahwa DAU tidak berpengaruh terhadap pertumbuhan ekonomi. DAK dan PAD berpengaruh negatif terhadap pertumbuhan ekonomi. Sebaliknya, DBH berpengaruh positif terhadap pertumbuhan ekonomi

New discoveries at Woolsey Mound, MC118, northern Gulf of Mexico

Woolsey Mound, a 1km-diameter carbonate-gas hydrate complex in the northern Gulf of Mexico, is the site of the Gulf’s only seafloor monitoring station-observatory in its only research reserve, Mississippi Canyon 118. Active venting, outcropping hydrate, and a thriving chemosynthetic community recommend the site for study. Since 2005, the Gulf of Mexico Hydrates Research Consortium has been conducting multidisciplinary studies to 1. Characterize the site, 2. Establish a facility for real-time monitoring-observing of gas hydrates in a natural setting, 3. Study the effects of gas hydrates on seafloor stability, 4. Establish fluid migration routes and estimates of fluid-flux at the site, 5. Establish the interrelationships between the organisms at the vent site and the association-dissociation of hydrates. A variety of novel geological, geophysical, geochemical and biological studies has been designed and conducted, some in survey mode, others in monitoring mode. Geophysical studies involving merging multiple seismic data acquisition systems accompanied by the application of custom processing techniques verify communication of surface features with deep structures. Supporting geological data derive from innovative recovery techniques. Geochemical sensors, used experimentally in survey mode, including aboard an AUV, double as monitoring devices. A suite of pore-fluid sampling devices has returned data that capture change at the site in daily increments; using only noise as an energy source, hydrophones have returned daily fluctuations in physical properties. Ever-expanding capabilities of a custom-ROV have been determined by research needs. Processing of new as well as conventional data via unconventional means has resulted in the discovery of new features…..vents, faults, benthic fauna…..and modification of others including pockmarks, hydrate outcrops, vent activity, and water-column chemical plumes. Though real-time monitoring awaits communications and power link to land, periodic data-collection reveals a carbonate-hydrate mound, part of an immensely complex hydrocarbon system

Regulation of the interaction between PIPKIγ and talin by proline-directed protein kinases

The interaction of talin with phosphatidylinositol(4) phosphate 5 kinase type Iγ (PIPKIγ) regulates PI(4,5)P2 synthesis at synapses and at focal adhesions. Here, we show that phosphorylation of serine 650 (S650) within the talin-binding sequence of human PIPKIγ blocks this interaction. At synapses, S650 is phosphorylated by p35/Cdk5 and mitogen-activated protein kinase at rest, and dephosphorylated by calcineurin upon stimulation. S650 is also a substrate for cyclin B1/Cdk1 and its phosphorylation in mitosis correlates with focal adhesion disassembly. Phosphorylation by Src of the tyrosine adjacent to S650 (Y649 in human PIPKIγ) was shown to enhance PIPKIγ targeting to focal adhesions (Ling, K., R.L. Doughman, V.V. Iyer, A.J. Firestone, S.F. Bairstow, D.F. Mosher, M.D. Schaller, and R.A. Anderson. 2003. J. Cell Biol. 163:1339–1349). We find that Y649 phosphorylation does not stimulate directly PIPKIγ binding to talin, but may do so indirectly by inhibiting S650 phosphorylation. Conversely, S650 phosphorylation inhibits Y649 phosphorylation by Src. The opposite effects of the phosphorylation of Y649 and S650 likely play a critical role in regulating synaptic function as well as the balance between cell adhesion and cell motility

Contacts between the endoplasmic reticulum and other membranes in neurons

The cytoplasm of eukaryotic cells is compartmentalized by intracellular membranes that define subcellular organelles. One of these organelles, the endoplasmic reticulum, forms a continuous network of tubules and cisternae that extends throughout all cell compartments, including neuronal dendrites and axons. This network communicates with most other organelles by vesicular transport, and also by contacts that do not lead to fusion but allow cross-talk between adjacent bilayers. Though these membrane contacts have previously been observed in neurons, their distribution and abundance has not been systematically analyzed. Here, we have carried out such analysis. Our studies reveal new aspects of the internal structure of neurons and provide a critical complement to information about interorganelle communication emerging from functional and biochemical studies

Endophilins interact with Moloney murine leukemia virus Gag and modulate virion production

BACKGROUND: The retroviral Gag protein is the central player in the process of virion assembly at the plasma membrane, and is sufficient to induce the formation and release of virus-like particles. Recent evidence suggests that Gag may co-opt the host cell's endocytic machinery to facilitate retroviral assembly and release. RESULTS: A search for novel partners interacting with the Gag protein of the Moloney murine leukemia virus (Mo-MuLV) via the yeast two-hybrid protein-protein interaction assay resulted in the identification of endophilin 2, a component of the machinery involved in clathrin-mediated endocytosis. We demonstrate that endophilin interacts with the matrix or MA domain of the Gag protein of Mo-MuLV, but not of human immunodeficiency virus, HIV. Both exogenously expressed and endogenous endophilin are incorporated into Mo-MuLV viral particles. Titration experiments suggest that the binding sites for inclusion of endophilin into viral particles are limited and saturable. Knock-down of endophilin with small interfering RNA (siRNA) had no effect on virion production, but overexpression of endophilin and, to a lesser extent, of several fragments of the protein, result in inhibition of Mo-MuLV virion production, but not of HIV virion production. CONCLUSIONS: This study shows that endophilins interact with Mo-MuLV Gag and affect virion production. The findings imply that endophilin is another component of the large complex that is hijacked by retroviruses to promote virion production

Evolutionary consequences of intra-patient phage predation on microbial populations

The impact of phage predation on bacterial pathogens in the context of human disease is not currently appreciated. Here, we show that predatory interactions of a phage with an important environmentally transmitted pathogen, Vibrio cholerae, can modulate the evolutionary trajectory of this pathogen during the natural course of infection within individual patients. We analyzed geographically and temporally disparate cholera patient stool samples from Haiti and Bangladesh and found that phage predation can drive the genomic diversity of intra-patient V. cholerae populations. Intra-patient phage-sensitive and phage-resistant isolates were isogenic except for mutations conferring phage resistance, and moreover, phage-resistant V. cholerae populations were composed of a heterogeneous mix of many unique mutants. We also observed that phage predation can significantly alter the virulence potential of V. cholerae shed from cholera patients. We provide the first molecular evidence for predatory phage shaping microbial community structure during the natural course of infection in humans. DOI: http://dx.doi.org/10.7554/eLife.03497.00