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Insights into oncogenesis derived from cancer susceptibility loci (SNP) hold the potential to facilitate better cancer management and treatment through precision oncology. However, therapeutic insights have thus far been limited by our current lack of understanding regarding both interactions of these loci with somatic cancer driver mutations and their influence on tumorigenesis. For example, although both germline and somatic genetic variation to the p53 tumor suppressor pathway are known to promote tumorigenesis, little is known about the extent to which such variants cooperate to alter pathway activity. Here we hypothesize that cancer risk-associated germline variants interact with somatic TP53 mutational status to modify cancer risk, progression, and response to therapy. Focusing on a cancer risk SNP (rs78378222) with a well-documented ability to directly influence p53 activity as well as integration of germline datasets relating to cancer susceptibility with tumor data capturing somatically-acquired genetic variation provided supportive evidence for this hypothesis. Integration of germline and somatic genetic data enabled identification of a novel entry point for therapeutic manipulation of p53 activities. A cluster of cancer risk SNPs resulted in increased expression of prosurvival p53 target gene KITLG and attenuation of p53-mediated responses to genotoxic therapies, which were reversed by pharmacologic inhibition of the prosurvival c-KIT signal. Together, our results offer evidence of how cancer susceptibility SNPs can interact with cancer driver genes to affect cancer progression and identify novel combinatorial therapies. Significance: These results offer evidence of how cancer susceptibility SNPs can interact with cancer driver genes to affect cancer progression and present novel therapeutic targets.

The central east coast of Australia is frequently impacted by large hail and damaging winds associated with severe convective storms, with individual events recording damages exceeding AUD 1 billion. These storms present a significant challenge for forecasting because of their development in seemingly marginal environments. They often have been observed to intensify upon approaching the coast, with case studies and climatological analyses indicating that interactions with the sea breeze are key to this process. The relative importance of the additional lifting and vorticity along the sea-breeze front in comparison with the change to a cooler, moister air mass with stronger low-level shear behind the front has yet to be investigated. Here, the role of the sea-breeze air mass is isolated using idealized numerical simulations of storms developing in a horizontally homogeneous environment. The base-state substitution (BSS) modeling technique is utilized to introduce the sea-breeze air mass following initial storm development. Relative to a simulation without BSS, the storm is longer lived and more intense, ultimately developing supercell characteristics including increased updraft rotation, deviant motion to the left of the mean wind vector, and a strong reflectivity gradient on the inflow edge. Separately simulating the changes in the thermodynamic and wind fields reveals that the enhanced storm longevity and intensity are primarily due to the latter. The change in the low-level environmental winds slows gust-front propagation, allowing the storm to continue to ingest warm, potentially buoyant environmental air. At the same time, increased low-level shear promotes the development of persistent updraft rotation that causes the storm to make a transition from a multicell to a supercell.

Understanding wildfire-atmosphere interactions is key to improved accuracy of predictions of wildfire behavior. This is needed for improved preparedness to mitigate loss of life and property during wildfire events, particularly for situations with strong fire-atmosphere coupling. Here we present observations from the passage of a cold front over the Sir Ivan Dougherty wildfire on February 2017 in eastern Australia. We demonstrate that an increase in near-surface atmosphere moisture associated with the cold front, when combined with changes in fire behavior at that time, led to reduced thermodynamic stability that helped to trigger a thunderstorm. This fire-trigged supercell thunderstorm produced lightning, while radar observations identified a mesocyclonic circulation within the pyrocumulonimbus, similar to a supercell thunderstorm. Results highlight the need to monitor the thermodynamic properties of air masses approaching wildfires and the rapid evolution of pyrocumulonimbus, which may develop mesocyclone characteristics. Weather radar offers the most effective capability to achieve such insights.

In this work an Application Specific Integrated Circuit (ASIC) for an implantable electrochemical biosensor system (SMART implant, Stett et al., 2014) is presented. The ASIC drives the measurement electrodes and performs amperometric measurements for determining the oxygen concentration, potentiometric measurements for evaluating the pH-level as well as temperature measurements. A 10-bit pipeline analog to digital (ADC) is used to digitize the acquired analog samples and is implemented as a single stage to reduce power consumption and chip area. For pH measurements, an offset subtraction technique is employed to raise the resolution to 12-bits. Charge integration is utilized for oxygen and temperature measurements with the capability to cover current ranges between 30 nA and 1 μA. In order to achieve good performance over a wide range of supply and process variations, internal reference voltages are generated from a programmable band-gap regulated circuit and biasing currents are supplied from a wide-range bootstrap current reference. To accommodate the limited available electrical power, all components are designed for low power operation. Also a sequential operation approach is applied, in which essential circuit building blocks are time multiplexed between different measurement types. All measurement sequences and parameters are programmable and can be adjusted for different tissues and media. The chip communicates with external unites through a full duplex two-wire Serial Peripheral Interface (SPI), which receives operational instructions and at the same time outputs the internally stored measurement data. The circuit has been fabricated in a standard 0.5-μm CMOS process and operates on a supply as low as 2.7 V. Measurement results show good performance and agree with circuit simulation. It consumes a maximum of 500 μA DC current and is clocked between 500 kHz and 4 MHz according to the measurement parameters. Measurement results of the on-chip ADC show a Differential Non Linearity (DNL) lower than 0.5 LSB, an Integral Non Linearity (INL) lower than 1 LSB and a Figure of Merit (FOM) of 6 pJ/conversion.

International audience; A variety of diagnostic and therapeutic medical technologies rely on long term implantation of an electronic device to monitor or regulate a patient's condition. One proposed approach to powering these devices is to use a biofuel cell to convert the chemical energy from blood nutrients into electrical current to supply the electronics. We present here an enzymatic microbiofuel cell whose electrodes are directly integrated into a digital electronic circuit. Glucose oxidizing and oxygen reducing enzymes are immobilized on microelectrodes of an application specific integrated circuit (ASIC) using redox hydrogels to produce an enzymatic biofuel cell, capable of harvesting electrical power from just a single droplet of 5 mM glucose solution. Optimisation of the fuel cell voltage and power to match the requirements of the electronics allow self-powered operation of the on-board digital circuitry. This study represents a step towards implantable self-powered electronic devices that gather their energy from physiological fluids.

In this paper test generation methods and appropriate fault models for testing and analysis of embedded systems described as (extended) finite state machines ((E)FSMs) are presented. Compared to simple FSMs, EFSMs specify not only the control flow but also the data flow. Thus, we define a two-level fault model to cover both aspects. The goal of this paper is to reuse well-known FSM-based test generation methods for automation of embedded system testing. These methods have been widely used in testing and validation of protocols and communicating systems. In particular, (E)FSMs-based specification and testing is more advantageous because (E)FSMs support the formal semantic of already standardised formal description techniques (FDTs) despite of their popularity in the design of hardware and software systems., {"references":["Specification and Description Language SDL-92, ITU-T\nRecommendation Z.100, 1992.","Information processing systems - Open Systems Interconnection -\nEstelle: A formal description technique based on an extended state\ntransition model, International Standard ISO 9074, 1989.","R. Buessow, R. Geisler, and M. Klar, \"Specifying safety-critical\nembedded systems with statecharts and Z: A case study\", In Proceedings\nof Fundamental Approaches to Software Engineering (FASE-98),\nLisbon, 1998.","M. Mendler, G. Luettgen. Statecharts, \"From Visual Syntax to Model-\nTheoretic Semantics\", In K. Bauknecht, W. Brauer, and Th. M├╝ck\n(editors), Workshop on Integrating Diagrammatic and Formal\nSpecification Techniques (IDFST 2001), pages 615-621, Vienna, 2001.","B. Potter, J. Sinclair, and D. Till, \"Introduction to Formal Specification\nand Z (2nd Edition)\", Prentice Hall PTR; 1996.","A. V. Aho et al., \"An optimisation technique for protocol conformance\ntest generation based on UIO sequences and Rural Chinese Postman\nTours\", In S. Aggarwal and K. Sabnani, editors, Protocol Specification,\nTesting, and Verification, New Jersey, 1988.","S. Fujiwara, et al., \"Test selection based on finite state models\", IEEE\ntransaction on Software Engineering 17(6): 591-603, 1991.","H. Richter et al., \"A Concept For a Reliable, Cost-Effective, Real-Time\nLocal-Area Network for Automobiles\", In Proceedings of Joint\nconference Embedded in Munich and Embedded Systems, Munich,\n2004.","O. Henniger, A. Ulrich, and H. König, \"Transformation of Estelle\nmodules aiming at test case derivation\", Chapmann & Hall, 1995.\n[10] H. Fouchal, et al., \"Generation of timed automata from Estelle\nspecifications\", In International Workshop on the Formal Technique\nESTELLE, Evry, France, 1998.\n[11] A. Avizienis, J-C. Laprie, and B. Randell, \"Fundamental Concepts of\nComputer System Dependability\", IARP/IEEE-RAS Workshop on\nRobot Dependability: Technological Challenge of Dependable, Robots\nin Human Environments, 2001.\n[12] L. A. Corts, P. Eles, and Z. Peng, \"Verification of embedded systems\nusing a petri net based representation\", In Proceedings of the 13th\ninternational symposium on System synthesis, Madrid, 2000."]}

Feedback-controlled puffing of neon and deuterium has been applied to control the edge-localized-mode behavior and the target plate power deposition during high-power H -mode discharges in ASDEX Upgrade. A regime has been found in which more than 90% of the heating power is lost through radiation and divertor detachment occurs, without deterioration of the energy confinement. The plasma remains in the H mode, exhibiting small-amplitude, high-frequency ELM's, which do not penetrate to the target plates in the strike zone region.

In this paper, a framework for the specification of embedded systems described as ‘predicated’ extended finite state machines (p-EFSMs) is proposed. Compared to simple FSMs, p-EFSMs allow the control flow and the data flow description of hardware modules or software processes. We introduce a new variant of the EFSM model, a so-called ‘predicated’ EFSM that extends the usual EFSM. This extension offers a more convenient mean to specify constraints on the system's transitions. Secondly, it provides an easy mapping onto formal description techniques. Thirdly, it allows the development of an embedded system independently from the implementation, i.e. without favoring a hardware or a software. Crucial tasks in the design of reliable embedded systems are analysis and testing. These allow the system developer to detect bugs that may be very costly to do in subsequent phases of the system development. We identify the different testing issues and demonstrate how the bugs can be detected by means of p-EFSMs. Failure detection and elimination improve the likelihood of the well-functioning and the reliability of the embedded system.

Acoustic waves, capable of transmitting through optically opaque objects, have been widely used in biomedical imaging, industrial sensing and particle manipulation. High-fidelity wave front shaping is essential to further improve performance in these applications. An acoustic analog to the successful spatial light modulator (SLM) in optics would be highly desirable. To date there have been no techniques shown that provide effective and dynamic modulation of a sound wave and which also support scale-up to a high number of individually addressable pixels. In the present study, we introduce a dynamic spatial ultrasound modulator (SUM), which dynamically reshapes incident plane waves into complex acoustic images. Its transmission function is set with a digitally generated pattern of microbubbles controlled by a complementary metal–oxide–semiconductor (CMOS) chip, which results in a binary amplitude acoustic hologram. We employ this device to project sequentially changing acoustic images and demonstrate the first dynamic parallel assembly of microparticles using a SUM., Alexander von Humboldt-Stiftung, European Research Council, Projekt DEAL