Application of the method of multiple scales to unravel energy exchange in nonlinear locally resonant metamaterials

In this paper, the effect of weak nonlinearities in 1D locally resonant metamaterials is investigated via the method of multiple scales. Commonly employed to the investigate the effect of weakly nonlinear interactions on the free wave propagation through a phononic structure or on the dynamic response of a Duffing oscillator, the method of multiple scales is here used to investigate the forced wave propagation through locally resonant metamaterials. The perturbation approach reveals that energy exchange may occur between propagative and evanescent waves induced by quadratic nonlinear local interaction

Mutations in the 'DRY' motif of the CB1 cannabinoid receptor result in biased receptor variants.

The role of the highly-conserved 'DRY' motif in the signaling of the CB1 cannabinoid receptor (CB1R) was investigated by introducing single, double and triple alanine mutations into this site of the receptor. We found that the CB1R-R3.50A mutant displays a partial decrease in its ability to activate heterotrimeric Go proteins (~85% of wild-type CB1R (CB1R-WT)). Moreover, this mutant showed impaired beta-arrestin binding in response to agonist stimulus, although its basal beta-arrestin binding was enhanced. More strikingly, the double mutant CB1R-D3.49A/R3.50A was biased toward beta-arrestins, as it gained a robustly increased beta-arrestin1 and beta-arrestin2 binding ability compared to the wild-type receptor, while its G protein activation was decreased. In contrast, the double mutant CB1R-R3.50A/Y3.51A proved to be G protein-biased, as it was practically unable to recruit beta-arrestin2 in response to agonist stimulus, while still activating G proteins, although at a reduced level (~75% of CB1R-WT). Agonist-induced ERK1/2 activation of the CB1R mutants showed good correlation with their beta-arrestin binding ability but not with their G protein activation or inhibition of cAMP accumulation. Our results suggest that G protein-activation and beta-arrestin-binding of the CB1R are mediated by distinct receptor conformations and the conserved 'DRY' motif plays different roles in the stabilization of these conformations, thus mediating both G protein- and beta-arrestin2-mediated functions of CB1R

Model reduction in computational homogenization for transient heat conduction

International audienceThis paper presents a computationally efficient homogenization method for transient heat conduction problems. The notion of relaxed separation of scales is introduced and the homogenization framework is derived. Under the assumptions of linearity and relaxed separation of scales, the microscopic solution is decomposed into a steady-state and a transient part. Static condensation is performed to obtain the global basis for the steady-state response and an eigenvalue problem is solved to obtain a global basis for the transient response. The macroscopic quantities are then extracted by averaging and expressed in terms of the coefficients of the reduced basis. Proof-of-principle simulations are conducted with materials exhibiting high contrast material properties. The proposed homogenization method is compared with the conventional steady-state homogenization and transient computational homogenization methods. Within its applicability limits, the proposed homogenization method is able to accurately capture the microscopic thermal inertial effects with significant computational efficiency

Introductory programming: a systematic literature review

As computing becomes a mainstream discipline embedded in the school curriculum and acts as an enabler for an increasing range of academic disciplines in higher education, the literature on introductory programming is growing. Although there have been several reviews that focus on specific aspects of introductory programming, there has been no broad overview of the literature exploring recent trends across the breadth of introductory programming. This paper is the report of an ITiCSE working group that conducted a systematic review in order to gain an overview of the introductory programming literature. Partitioning the literature into papers addressing the student, teaching, the curriculum, and assessment, we explore trends, highlight advances in knowledge over the past 15 years, and indicate possible directions for future research

SPO11-Independent DNA Repair Foci and Their Role in Meiotic Silencing

In mammalian meiotic prophase, the initial steps in repair of SPO11-induced DNA double-strand breaks (DSBs) are required to obtain stable homologous chromosome pairing and synapsis. The X and Y chromosomes pair and synapse only in the short pseudo-autosomal regions. The rest of the chromatin of the sex chromosomes remain unsynapsed, contains persistent meiotic DSBs, and the whole so-called XY body undergoes meiotic sex chromosome inactivation (MSCI). A more general mechanism, named meiotic silencing of unsynapsed chromatin (MSUC), is activated when autosomes fail to synapse. In the absence of SPO11, many chromosomal regions remain unsynapsed, but MSUC takes place only on part of the unsynapsed chromatin. We asked if spontaneous DSBs occur in meiocytes that lack a functional SPO11 protein, and if these might be involved in targeting the MSUC response to part of the unsynapsed chromatin. We generated mice carrying a point mutation that disrupts the predicted catalytic site of SPO11 (Spo11YF/YF), and blocks its DSB-inducing activity. Interestingly, we observed foci of proteins involved in the processing of DNA damage, such as RAD51, DMC1, and RPA, both in Spo11YF/YFand Spo11 knockout meiocytes. These foci preferentially localized to the areas that undergo MSUC and form the so-called pseudo XY body. In SPO11-deficient oocytes, the number

Antiviral therapies against Ebola and other emerging viral diseases using existing medicines that block virus entry

Emerging viral diseases pose a threat to the global population as intervention strategies are mainly limited to basic containment due to the lack of efficacious and approved vaccines and antiviral drugs. The former was the only available intervention when the current unprecedented Ebolavirus (EBOV) outbreak in West Africa began. Prior to this, the development of EBOV vaccines and anti-viral therapies required time and resources that were not available. Therefore, focus has turned to re-purposing of existing, licenced medicines that may limit the morbidity and mortality rates of EBOV and could be used immediately. Here we test three such medicines and measure their ability to inhibit pseudotype viruses (PVs) of two EBOV species, Marburg virus (MARV) and avian influenza H5 (FLU-H5). We confirm the ability of chloroquine (CQ) to inhibit viral entry in a pH specific manner. The commonly used proton pump inhibitors, Omeprazole and Esomeprazole were also able to inhibit entry of all PVs tested but at higher drug concentrations than may be achieved in vivo. We propose CQ as a priority candidate to consider for treatment of EBOV

Revisiting the martensite/ferrite interface damage initiation mechanism:The key role of substructure boundary sliding

Martensite/ferrite (M/F) interface damage plays a critical role in controlling failure of dual-phase (DP) steels and is commonly understood to originate from the large phase contrast between martensite and ferrite. This however conflicts with a few, recent observations, showing that considerable M/F interface damage initiation is often accompanied by apparent martensite island plasticity and weak M/F strain partitioning. In fact, martensite has a complex hierarchical structure which induces a strongly heterogeneous and orientation-dependent plastic response. Depending on the local stress state, (lath) martensite is presumed to be hard to deform based on common understanding. However, when favourably oriented, substructure boundary sliding can be triggered at a resolved shear stress which is comparable to that of ferrite. Moreover, careful measurements of the M/F interface structure indicate the occurrence of sharp martensite wedges protruding into the ferrite and clear steps in correspondence with lath boundaries, constituting a jagged M/F interfacial morphology that may have a large effect on the M/F interface behaviour. By taking into account the substructure and morphology features, which are usually overlooked in the literature, this contribution re-examines the M/F interface damage initiation mechanism. A systematic study is performed, which accounts for different loading conditions, phase contrasts, residual stresses/strains resulting from the preceding martensitic phase transformation, as well as the possible M/F interfacial morphologies. Crystal plasticity simulations are conducted to include inter-lath retained austenite (RA) films enabling the substructure boundary sliding. The results show that the substructure boundary sliding, which is the most favourable plastic deformation mode of lath martensite, can trigger M/F interface damage and hence control the failure behaviour of DP steels. The present finding may change the way in which M/F interface damage initiation is understood as a critical failure mechanism in DP steels

Enriched Computational Homogenization Schemes Applied to Pattern-Transforming Elastomeric Mechanical Metamaterials

Elastomeric mechanical metamaterials exhibit unconventional mechanical behaviour owing to their complex microstructures. A clear transition in the effective properties emerges under compressive loading, which is triggered by local instabilities and pattern transformations of the underlying cellular microstructure. Such transformations trigger a non-local mechanical response resulting in strong size effects. For predictive modelling of engineering applications, the effective homogenized material properties are generally of interest. For mechanical metamaterials, these can be obtained in an expensive manner by ensemble averaging of the direct numerical simulations for a series of translated microstructures, applicable especially in the regime of small separation of scales. To circumvent this expensive step, computational homogenization methods are of benefit, employing volume averaging instead. Classical first-order computational homogenization, which relies on the standard separation of scales principle, is unable to capture any size and boundary effects. Second-order computational homogenization has the ability to capture strain gradient effects at the macro-scale, thus accounting for the presence of non-localities. Another alternative is micromorphic computational homogenization scheme, which is tailored to pattern-transforming metamaterials by incorporating prior kinematic knowledge. In this contribution, a systematic study is performed, assessing the predictive ability of computational homogenization schemes in the realm of elastomeric metamaterials. Three representative examples with distinct mechanical loading are employed for this purpose: uniform compression and bending of an infinite specimen, and compression of a finite specimen. Qualitative and quantitative analyses are performed for each of the load cases where the ensemble average solution is set as a reference.Comment: 32 pages, 19 figures, 1 table, abstract shortened to fulfil 1920 character limi

Variational Foundations and Generalized Unified Theory of RVE-Based Multiscale Models

A unified variational theory is proposed for a general class of multiscale models based on the concept of Representative Volume Element. The entire theory lies on three fundamental principles: (1) kinematical admissibility, whereby the macro- and micro-scale kinematics are defined and linked in a physically meaningful way; (2) duality, through which the natures of the force- and stress-like quantities are uniquely identified as the duals (power-conjugates) of the adopted kinematical variables; and (3) the Principle of Multiscale Virtual Power, a generalization of the well-known Hill-Mandel Principle of Macrohomogeneity, from which equilibrium equations and homogenization relations for the force- and stress-like quantities are unequivocally obtained by straightforward variational arguments. The proposed theory provides a clear, logically-structured framework within which existing formulations can be rationally justified and new, more general multiscale models can be rigorously derived in well-defined steps. Its generality allows the treatment of problems involving phenomena as diverse as dynamics, higher order strain effects, material failure with kinematical discontinuities, fluid mechanics and coupled multi-physics. This is illustrated in a number of examples where a range of models is systematically derived by following the same steps. Due to the variational basis of the theory, the format in which derived models are presented is naturally well suited for discretization by finite element-based or related methods of numerical approximation. Numerical examples illustrate the use of resulting models, including a non-conventional failure-oriented model with discontinuous kinematics, in practical computations

Increased Rate of Hospitalization for Diabetes and Residential Proximity of Hazardous Waste Sites

BACKGROUND: Epidemiologic studies suggest that there may be an association between environmental exposure to persistent organic pollutants (POPs) and diabetes. OBJECTIVE: The aim of this study was to test the hypothesis that residential proximity to POP-contaminated waste sites result in increased rates of hospitalization for diabetes. METHODS: We determined the number of hospitalized patients 25–74 years of age diagnosed with diabetes in New York State exclusive of New York City for the years 1993–2000. Descriptive statistics and negative binomial regression were used to compare diabetes hospitalization rates in individuals who resided in ZIP codes containing or abutting hazardous waste sites containing POPs (“POP” sites); ZIP codes containing hazardous waste sites but with wastes other than POPs (“other” sites); and ZIP codes without any identified hazardous waste sites (“clean” sites). RESULTS: Compared with the hospitalization rates for diabetes in clean sites, the rate ratios for diabetes discharges for people residing in POP sites and “other” sites, after adjustment for potential confounders were 1.23 [95% confidence interval (CI), 1.15–1.32] and 1.25 (95% CI, 1.16–1.34), respectively. In a subset of POP sites along the Hudson River, where there is higher income, less smoking, better diet, and more exercise, the rate ratio was 1.36 (95% CI, 1.26–1.47) compared to clean sites. CONCLUSIONS: After controlling for major confounders, we found a statistically significant increase in the rate of hospitalization for diabetes among the population residing in the ZIP codes containing toxic waste sites