A Variational Formulation of Dissipative Quasicontinuum Methods

Lattice systems and discrete networks with dissipative interactions are successfully employed as meso-scale models of heterogeneous solids. As the application scale generally is much larger than that of the discrete links, physically relevant simulations are computationally expensive. The QuasiContinuum (QC) method is a multiscale approach that reduces the computational cost of direct numerical simulations by fully resolving complex phenomena only in regions of interest while coarsening elsewhere. In previous work (Beex et al., J. Mech. Phys. Solids 64, 154-169, 2014), the originally conservative QC methodology was generalized to a virtual-power-based QC approach that includes local dissipative mechanisms. In this contribution, the virtual-power-based QC method is reformulated from a variational point of view, by employing the energy-based variational framework for rate-independent processes (Mielke and Roub\'i\v{c}ek, Rate-Independent Systems: Theory and Application, Springer-Verlag, 2015). By construction it is shown that the QC method with dissipative interactions can be expressed as a minimization problem of a properly built energy potential, providing solutions equivalent to those of the virtual-power-based QC formulation. The theoretical considerations are demonstrated on three simple examples. For them we verify energy consistency, quantify relative errors in energies, and discuss errors in internal variables obtained for different meshes and two summation rules.Comment: 38 pages, 21 figures, 4 tables; moderate revision after review, one example in Section 5.3 adde

Novel anisotropic continuum-discrete damage model capable of representing localized failure of massive structures. Part II: identification from tests under heterogeneous stress field

In Part I of this paper we have presented a simple model capable of describing the localized failure of a massive structure. In this part, we discuss the identification of the model parameters from two kinds of experiments: a uniaxial tensile test and a three-point bending test. The former is used only for illustration of material parameter response dependence, and we focus mostly upon the latter, discussing the inverse optimization problem for which the specimen is subjected to a heterogeneous stress field.Comment: 18 pages, 12 figures, 6 table

Dyspraxia in a patient with corticobasal degeneration: the role of visual and tactile inputs to action

Objectives-To investigate the roles of visual and tactile information in a dyspraxic patient with corticobasal degeneration (CBD) who showed dramatic facilitation in miming the use of a tool or object when he was given a tool to manipulate; and to study the nature of the praxic and neuropsychological deficits in CBD. Methods-The subject had clinically diagnosed CBD, and exhibited alien limb behaviour and striking ideomotor dyspraxia. General neuropsychological evaluation focused on constructional and visuospatial abilities, calculation, verbal fluency, episodic and semantic memory, plus spelling and writing because impairments in this domain were presenting complaints. Four experiments assessed the roles of visual and tactile information in the facilitation of motor performance by tools. Experiment I evaluated the patient's performance of six limb transitive actions under six conditions: (1) after he described the relevant tool from memory, (2) after he was shown a Line drawing of the tool, (3) after he was shown a real exemplar of the tool, (4) after he watched the experimenter perform the action, (5) while he was holding the tool, and (6) immediately after he had performed the action with the tool but with the tool removed from his grasp. Experiment 2 evaluated the use of the same six tools when the patient had tactile but no visual information (while he was blindfolded). Experiments 3 and 4 assessed performance of actions appropriate to the same six tools when the patient had either neutral or inappropriate tactile feedback-that is, while he was holding a non-tool object or a different tool. Results-Miming of tool use was not facilitated by visual input; moreover, lack of visual information in the blindfolded condition did not reduce performance. The principal positive finding was a dramatic facilitation of the patient's ability to demonstrate object use when he was holding either the appropriate tool or a neutral object. Tools inappropriate to the requested action produced involuntary performance of the stimulus relevant action. Conclusions-Tactile stimulation was paramount in the facilitation of motor performance in tool use by this patient with CBD. This outcome suggests that tactile information should be included in models which hypothesise modality specific inputs to the action production system. Significant impairments in spelling and letter production that have not previously been reported in CBD have also been documented

Prescribing sodium oxybate for narcolepsy: Demanding that a patient's need is "exceptional" is irrational and should be abandoned

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Mutant p53 establishes targetable tumor dependency by promoting unscheduled replication

Gain-of-function (GOF) p53 mutations are observed frequently in most intractable human cancers and establish dependency for tumor maintenance and progression. While some of the genes induced by GOF p53 have been implicated in more rapid cell proliferation compared with p53-null cancer cells, the mechanism for dependency of tumor growth on mutant p53 is unknown. This report reveals a therapeutically targetable mechanism for GOF p53 dependency. We have shown that GOF p53 increases DNA replication origin firing, stabilizes replication forks, and promotes micronuclei formation, thus facilitating the proliferation of cells with genomic abnormalities. In contrast, absence or depletion of GOF p53 leads to decreased origin firing and a higher frequency of fork collapse in isogenic cells, explaining their poorer proliferation rate. Following genome-wide analyses utilizing ChIP-Seq and RNA-Seq, GOF p53–induced origin firing, micronuclei formation, and fork protection were traced to the ability of GOF p53 to transactivate cyclin A and CHK1. Highlighting the therapeutic potential of CHK1’s role in GOF p53 dependency, experiments in cell culture and mouse xenografts demonstrated that inhibition of CHK1 selectively blocked proliferation of cells and tumors expressing GOF p53. Our data suggest the possibility that checkpoint inhibitors could efficiently and selectively target cancers expressing GOF p53 alleles

Entanglement and Timing-Based Mechanisms in the Coherent Control of Scattering Processes

The coherent control of scattering processes is considered, with electron impact dissociation of H$_2^+$ used as an example. The physical mechanism underlying coherently controlled stationary state scattering is exposed by analyzing a control scenario that relies on previously established entanglement requirements between the scattering partners. Specifically, initial state entanglement assures that all collisions in the scattering volume yield the desirable scattering configuration. Scattering is controlled by preparing the particular internal state wave function that leads to the favored collisional configuration in the collision volume. This insight allows coherent control to be extended to the case of time-dependent scattering. Specifically, we identify reactive scattering scenarios using incident wave packets of translational motion where coherent control is operational and initial state entanglement is unnecessary. Both the stationary and time-dependent scenarios incorporate extended coherence features, making them physically distinct. From a theoretical point of view, this work represents a large step forward in the qualitative understanding of coherently controlled reactive scattering. From an experimental viewpoint, it offers an alternative to entanglement-based control schemes. However, both methods present significant challenges to existing experimental technologies