Predicting kinase inhibitor resistance: Physics-based and data-driven approaches.

Resistance to small molecule drugs often emerges in cancer cells, viruses, and bacteria as a result of the evolutionary pressure exerted by the therapy. Protein mutations that directly impair drug binding are frequently involved in resistance, and the ability to anticipate these mutations would be beneficial in drug development and clinical practice. Here, we evaluate the ability of three distinct computational methods to predict ligand binding affinity changes upon protein mutation for the cancer target Abl kinase. These structure-based approaches rely on first-principle statistical mechanics, mixed physics- and knowledge-based potentials, and machine learning, and were able to estimate binding affinity changes and identify resistant mutations with remarkable accuracy. We expect that these complementary approaches will enable the routine prediction of resistance-causing mutations in a variety of other target proteins

Inequalities between the lowest eigenvalues of Laplacians with mixed boundary conditions

The eigenvalue problem for the Laplacian on bounded, planar, convex domains with mixed boundary conditions is considered, where a Dirichlet boundary condition is imposed on a part of the boundary and a Neumann boundary condition on its complement. Given two different such choices of boundary conditions for the same domain, we prove inequalities between their lowest eigenvalues. As a special case, we prove parts of a conjecture on the order of mixed eigenvalues of triangles

Bidirectionally pumped optical amplifier

An optical amplifier (200) comprises an active fiber (201), a first pump source (202) and a second pump source (203). The amplifier further comprises a first and a second coupling device (210, 211) having at least two input ports and at least two output ports. Said first and second coupling devices, said first and second pump sources and said active fiber are connected in such a manner as: the first input ports of said first and seconed coupling devices are connected to said first and second pump sources, respectively; the first output ports of said first and second coupling devices are connected to a first and a second end of said active fiber, respectively; the second output port of said first coupling devices is connected to the second input port os said second coupling device; the second output port of said second coupling device is connected to the second input port of said first coupling device

Bidirectionally pumped optical amplifier

An optical amplifier (200) comprises an active fiber (201), a first pump source (202) and a second pump source (203). The amplifier further comprises a first and a second coupling device (210, 211) having at least two input ports and at least two output ports. Said first and second coupling devices, said first and second pump sources and said active fiber are connected in such a manner as: the first input ports of said first and seconed coupling devices are connected to said first and second pump sources, respectively; the first output ports of said first and second coupling devices are connected to a first and a second end of said active fiber, respectively; the second output port of said first coupling devices is connected to the second input port os said second coupling device; the second output port of said second coupling device is connected to the second input port of said first coupling device

Modular nanomagnet design for spin qubits confined in a linear chain

On-chip micromagnets enable electrically controlled quantum gates on electron spin qubits. Extending the concept to a large number of qubits is challenging in terms of providing large enough driving gradients and individual addressability. Here we present a design aimed at driving spin qubits arranged in a linear chain and strongly confined in directions lateral to the chain. Nanomagnets are placed laterally to one side of the qubit chain, one nanomagnet per two qubits. The individual magnets are "U"-shaped, such that the magnetic shape anisotropy orients the magnetization alternately towards and against the qubit chain even if an external magnetic field is applied along the qubit chain. The longitudinal and transversal stray field components serve as addressability and driving fields. Using micromagnetic simulations we calculate driving and dephasing rates and the corresponding qubit quality factor. The concept is validated with spin-polarized scanning electron microscopy of Fe nanomagnets fabricated on silicon substrates, finding excellent agreement with micromagnetic simulations. Several features required for a scalable spin qubit design are met in our approach: strong driving and weak dephasing gradients, reduced crosstalk and operation at low external magnetic field.Comment: 6 pages, 4 figure

Interactions between Social and Topping Up Insurance under ex-post Moral Hazard

As health expenditure and need for corresponding funding rises, resorting to topping up insurance can seem natural. Complementary and supplementary insurances are both topping up contracts and, as such, are treated as one in the theoretical literature on optimal insurance. We argue that distinguishing them is crucial, and should be considered carefully when defining policies impacting the structure of the health insurance system, as these two kinds of insurance can have opposite effects on social insurance coverage. In this model, the optimal social insurance rate is defined endogenously and varies according to redistribution and the ex-post moral hazard characteristics of the insurance. This game has three stages and is solved through backward induction. The optimal social insurance rate is chosen first, by maximising social welfare. Second, individuals choose their private complementary and supplementary contracts. In the third stage they decide on their level of labour and consumption of health and other goods. Results indicate that whereas the presence of complementary insurance decreases the optimal size of social insurance, the offset effects of supplementary insurance can improve welfare

Volcano monitoring from space using high-cadence planet CubeSat images applied to Fuego Volcano, Guatemala

Fuego volcano (Guatemala) is one of the most active and hazardous volcanoes in the world. Its persistent activity generates lava flows, pyroclastic density currents (PDCs), and lahars that threaten the surrounding areas and produce frequent morphological change. Fuego’s eruption deposits are often rapidly eroded or remobilized by heavy rains and its constant activity and inaccessible terrain makes ground-based assessment of recent eruptive deposits very challenging. Earth-orbiting satellites can provide unique observations of volcanoes during eruptive activity, when ground-based techniques may be too hazardous, and also during inter-eruptive phases, but have typically been hindered by relatively low spatial and temporal resolution. Here, we use a new source of Earth observation data for volcano monitoring: high resolution (~3 m pixel size) images acquired from a constellation of over 150 CubeSats (‘Doves’) operated by Planet Labs Inc. The Planet Labs constellation provides high spatial resolution at high cadence (\u3c1–72 h), permitting space-based tracking of volcanic activity with unprecedented detail. We show how PlanetScope images collected before, during, and after an eruption can be applied for mapping ash clouds, PDCs, lava flows, or the analysis of morphological change. We assess the utility of the PlanetScope data as a tool for volcano monitoring and rapid deposit mapping that could assist volcanic hazard mitigation efforts in Guatemala and other active volcanic regions

Interactions between Social and Topping Up Insurance under ex-post Moral Hazard

As health expenditure and need for corresponding funding rises, resorting to topping up insurance can seem natural. Complementary and supplementary insurances are both topping up contracts and, as such, are treated as one in the theoretical literature on optimal insurance. We argue that distinguishing them is crucial, and should be considered carefully when defining policies impacting the structure of the health insurance system, as these two kinds of insurance can have opposite effects on social insurance coverage. \indent In this model, the optimal social insurance rate is defined endogenously and varies according to redistribution and the ex-post moral hazard characteristics of the insurance. This game has three stages and is solved through backward induction. The optimal social insurance rate is chosen first, by maximising social welfare. Second, individuals choose their private complementary and supplementary contracts. In the third stage they decide on their level of labour and consumption of health and other goods. \indent Results indicate that whereas the presence of complementary insurance decreases the optimal size of social insurance, the offset effects of supplementary insurance can improve welfare

Interactions between Social and Topping Up Insurance under ex-post Moral Hazard

As health expenditure and need for corresponding funding rises, resorting to topping up insurance can seem natural. Complementary and supplementary insurances are both topping up contracts and, as such, are treated as one in the theoretical literature on optimal insurance. We argue that distinguishing them is crucial, and should be considered carefully when defining policies impacting the structure of the health insurance system, as these two kinds of insurance can have opposite effects on social insurance coverage. In this model, the optimal social insurance rate is defined endogenously and varies according to redistribution and the ex-post moral hazard characteristics of the insurance. This game has three stages and is solved through backward induction. The optimal social insurance rate is chosen first, by maximising social welfare. Second, individuals choose their private complementary and supplementary contracts. In the third stage they decide on their level of labour and consumption of health and other goods. Results indicate that whereas the presence of complementary insurance decreases the optimal size of social insurance, the offset effects of supplementary insurance can improve welfare