In this work, four methods are described and validated for generating in silico ensembles of PROTAC-mediated ternary complexes. Filters based on characteristics of the proposed ternary complexes are ...developed to identify those that resemble known crystal structures. We then show how to use these modeling techniques a priori to discriminate the PROTAC-mediated degradation behavior of a mutant protein vs its wild type, of three closely related targets, and among three different PROTAC molecules.
The intent of this article is to review the numerous factors that affect the mechanical properties of particle- or fiber-filler-containing indirect dental resin composite materials. The focus will be ...on the effects of degradation due to aging in different media, mainly water and water and ethanol, cyclic loading, and mixed-mode loading on flexure strength and fracture toughness. Several selected papers will be examined in detail with respect to mixed and cyclic loading, and 3D tomography with multi-axial compression specimens. The main cause of failure, for most dental resin composites, is the breakdown of the resin matrix and/or the interface between the filler and the resin matrix. In clinical studies, it appears that failure in the first 5 years is a restoration issue (technique or material selection); after that time period, failure most often results from secondary decay.
We propose an extension of Newton's method for unconstrained multiobjective optimization (multicriteria optimization). This method does not use a priori chosen weighting factors or any other form of ...a priori ranking or ordering information for the different objective functions. Newton's direction at each iterate is obtained by minimizing the max-ordering scalarization of the variations on the quadratic approximations of the objective functions. The objective functions are assumed to be twice continuously differentiable and locally strongly convex. Under these hypotheses, the method, as in the classical case, is locally superlinear convergent to optimal points. Again as in the scalar case, if the second derivatives are Lipschitz continuous, the rate of convergence is quadratic. Our convergence analysis uses a Kantorovich-like technique. As a byproduct, existence of optima is obtained under semilocal assumptions. PUBLICATION ABSTRACT
Celotno besedilo
Dostopno za:
CEKLJ, DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Abstract
Three-dimensional, Gross-Pitaevskii equation (GPE) simulations are presented of the interaction between neutron superfluid vortices and proton superconductor flux tubes in a rotating, ...harmonic trap, representing an idealized model of the outer core of a neutron star. Low-energy states of the neutron condensate are calculated by evolving the GPE in imaginary time in the presence of a prescribed, static, rectilinear flux tube array. The calculations are carried out as a function of the angle between the global magnetic and rotation axes, and the amplitude and sign of the current–current and density couplings between the neutron and proton condensates. It is found that the system is frustrated by the competition between vortex–vortex repulsion and vortex-flux-tube attraction (pinning), leading to the formation of vortex tangles and ‘glassy’ behaviour characterized by multiple metastable states spaced closely in energy. The dimensionless parameters in the simulations are ordered as one expects in a neutron star, but the dynamic range is many orders of magnitude smaller than in reality, so caution must be exercised when assessing the astrophysical implications. Nevertheless, the results suggest that tangled vorticity may be endemic in neutron star outer cores.
Extending upon our previous publication Drummond, M. ; J. Chem. Inf. Model. 2019, 59, 1634−1644 , two additional computational methods are presented to model PROTAC-mediated ternary complex ...structures, which are then used to predict the efficacy of any accompanying protein degradation. Method 4B, an extension to one of our previous approaches, incorporates a clustering procedure uniquely suited for considering ternary complexes. Method 4B yields the highest proportion to date of crystal-like poses in modeled ternary complex ensembles, nearing 100% in two cases and always giving a hit rate of at least 10%. Techniques to further improve this performance for particularly troublesome cases are suggested and validated. This demonstrated ability to reliably reproduce known crystallographic ternary complex structures is further established through modeling of a newly released crystal structure. Moreover, for the far more common scenario where the structure of the ternary complex intermediate is unknown, the methods detailed in this work nonetheless consistently yield results that reliably follow experimental protein degradation trends, as established through seven retrospective case studies. These various case studies cover challenging yet common modeling situations, such as when the precise orientation of the PROTAC binding moiety in one (or both) of the protein pockets has not been experimentally established. Successful results are presented for one PROTAC targeting many proteins, for different PROTACs targeting the same protein, and even for degradation effected by an E3 ligase that has not been structurally characterized in a ternary complex. Overall, the computational modeling approaches detailed in this work should greatly facilitate PROTAC screening and design efforts, so that the many advantages of a PROTAC-based degradation approach can be effectively utilized both rapidly and at reduced cost.
ABSTRACT
The coupled, time-dependent Gross–Pitaevskii and Ginzburg–Landau equations are solved simultaneously in three dimensions to investigate the equilibrium state and far-from-equilibrium, ...spin-down dynamics of an interpenetrating neutron superfluid and proton type-II superconductor, as an idealized description of the outer core of a neutron star. The simulations generalize previous calculations without the time-dependent Ginzburg–Landau equation, where proton feedback is absent. If the angle θ between the rotation and magnetic axes does not equal zero, the equilibrium state consists of geometrically complicated neutron vortex and proton flux-tube tangles, as the topological defects pin to one another locally but align with different axes globally. During spin-down, new types of motion are observed. For θ = 0, entire vortices pair rectilinearly with flux tubes and move together while pinned. For θ ≠ 0, vortex segments pair with segments from one or more flux tubes, and the paired segments move together while pinned. The degree to which proton feedback impedes the deceleration of the crust is evaluated as a function of θ and the pinning strength, η. Key geometric properties of vortex-flux-tube tangles, such as filament length, mean curvature, and polarity are analysed. It is found that proton feedback smooths the deceleration of the crust, reduces the rotational glitch sizes, and stabilizes the vortex tangle dynamics. The dimensionless control parameters in the simulations are mutually ordered to match what is expected in a real neutron star, but their central values and dynamic ranges differ from reality by many orders of magnitude due to computational limitations.
Abstract
The equilibrium configurations of neutron superfluid vortices interacting with proton superconductor flux tubes in a rotating, harmonic trap are non-trivial in general, when the ...magnetorotational symmetry is broken. A non-zero angle θ between the magnetic and rotation axes leads to tangled vorticity due to competition between vortex-vortex repulsion and vortex-flux-tube pinning. Here, we investigate the far-from-equilibrium behaviour of the vortices, as the trap decelerates, by solving the time-dependent, stochastic, Gross-Pitaevskii equation numerically in three dimensions. The numerical simulations reveal new vortex behaviours. Key geometrical attributes of the evolving vortex tangle are characterized, as is the degree to which pinning impedes the deceleration of the neutron condensate as a function of η, the pinning strength, and θ. The simulated system is a partial analogue of the outer core of a decelerating neutron star, albeit in a very different parameter regime.
Rotational glitches in some rotation-powered pulsars display power-law size and exponential waiting-time distributions. These statistics are consistent with a state-dependent Poisson process, where ...the glitch rate is an increasing function of a global stress variable (e.g., crust-superfluid angular velocity lag), diverges at a threshold stress, increases smoothly while the star spins down, and decreases step-wise at each glitch. A minimal, seven-parameter, maximum likelihood model is calculated for PSR J1740−3015, PSR J0534+2200, and PSR J0631+1036, the three objects with the largest samples whose glitch activity is Poisson-like. The estimated parameters have theoretically reasonable values and contain useful information about the glitch microphysics. It is shown that the maximum likelihood, state-dependent Poisson model is a marginally (23%-27%) better post factum "predictor" of historical glitch epochs than a homogeneous Poisson process for PSR J1740−3015 and PSR J0631+1036 and a comparable predictor for PSR J0534+2200. Monte Carlo simulations imply that 50 glitches are needed to test reliably whether one model outperforms the other. It is predicted that the next glitch will occur at Modified Julian Date (MJD) 57,784 256.8, 60,713 1935, and 57,406 1444 for the above three objects, respectively. The analysis does not apply to quasiperiodic glitchers like PSR J0537−6910 and PSR J0835−4510, which are not described accurately by the state-dependent Poisson model in its original form.
This paper presents a parallel approach for solving the Vehicle Routing Problem with Simultaneous Pickup and Delivery (VRPSPD). The parallel algorithm is embedded with a multi-start heuristic which ...consists of a variable neighborhood descent procedure, with a random neighborhood ordering (RVND), integrated in an iterated local search (ILS) framework. The experiments were performed in a cluster with a multi-core architecture using up to 256 cores. The results obtained on the benchmark problems, available in the literature, show that the proposed algorithm not only improved several of the known solutions, but also presented a very satisfying scalability.
In response to the emerging crisis and growing calls from patients and clinicians for guidance 5, a working group of clinical experts from the International College of Obsessive Compulsive Spectrum ...Disorders (ICOCS) and the Obsessive-Compulsive and Related Disorders Research Network of the European College of Neuropsychopharmacology (OCRN) have produced this consensus statement with the aim of delivering pragmatic guidance at the earliest opportunity to clinicians for managing this complex challenge. Based on the risks associated with exposure and response prevention (ERP) in the pandemic (see below), and uncertainty as to which of the two evidence-based treatments, pharmacotherapy or cognitive behaviour therapy (CBT), represents the most efficacious first line treatment modality 11, pharmacotherapy should be the first option for adults and children with OCD with contamination, washing or cleaning symptoms during the COVID-19 pandemic. Consider A) type of medication; most patients should receive an SSRI, or if not responsive, another SSRI and as a third choice clomipramine (for which an ECG may be required in certain patient groups); Note US Food and Drug Administration "black box" warnings or advice from equivalent national regulatory authorities regarding increased risk in young people and other vulnerable patient groups. Check for adverse effects and be available for any concerns related to "activation" or newly emergent or increased suicidal ideation, which in the young can be mitigated by starting treatment at a low dose and titrating more gradually; B) dosage; if the patient is on a suboptimal dose, consider increasing it, paying attention to any contraindications; C) SSRI-resistance; consider a low dose of adjunctive antipsychotic (aripiprazole, risperidone, quetiapine, olanzapine), especially if a tic is present; D) adherence; ensure the patient is able to obtain an adequate supply and is taking the treatment regularly.
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