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Presents a response to a commentary on endovascular technique for dealing with chronic total occlusions (CTO). Avoidance of pressurization of the false lumen; Issue of cost of true lumen reentry device; Expansion of the types of lesion treated with a primary endovascular procedure; Way to succeed in treating CTO.

Machine learning (ML) has been an important arsenal in computational biology used to elucidate protein function for decades. With the recent burgeoning of novel ML methods and applications, new ML approaches have been incorporated into many areas of computational biology dealing with protein function. We examine how ML has been integrated into a wide range of computational models to improve prediction accuracy and gain a better understanding of protein function. The applications discussed are protein structure prediction, protein engineering using sequence modifications to achieve stability and druggability characteristics, molecular docking in terms of protein–ligand binding, including allosteric effects, protein–protein interactions and protein-centric drug discovery. To quantify the mechanisms underlying protein function, a holistic approach that takes structure, flexibility, stability, and dynamics into account is required, as these aspects become inseparable through their interdependence. Another key component of protein function is conformational dynamics, which often manifest as protein kinetics. Computational methods that use ML to generate representative conformational ensembles and quantify differences in conformational ensembles important for function are included in this review. Future opportunities are highlighted for each of these topics. [ABSTRACT FROM AUTHOR]

Background: Iliac artery anatomy can have a dramatic impact on the success of endovascular complex aortic aneurysm (CAA) procedures as endograft delivery systems need to be advanced and manipulated through these access vessels. The aim of this study was to evaluate the outcomes of iliac artery conduits with emphasizes on open vs endovascular conduits performed to facilitate CAA endovascular repair. Methods: All patients who had open or endovascular iliac conduits prior to endovascular CAA repair to treat thoracoabdominal, juxtarenal, or suprarenal aneurysms at the University of Colorado Hospital from January 2009 through January 2019 were included. Patients who presented with symptomatic or ruptured aortic aneurysms were excluded. Outcomes of interest included postoperative complications and mortality in patients undergoing iliac conduits. Results: Twenty-seven patients with a total of 42 conduits were included in the study. The majority of patients (N = 15, 56%) were female and the average age was 72 ± 9 years. The calculated VQI cardiac index was.6% (range,.3%–.8%). Eighteen (43%) endovascular and 24 (57%) open iliac conduits were performed during the study period. Thirty (71%) conduits were performed in a staged fashion, while 12 (29%) were performed at the same time as endovascular CAA repair. The mean time between conduit and definitive aneurysm repair surgery was 130 ± 68 days in the endovascular and 107 ± 79 days in the open groups (P =.87). No aneurysm rupture occurred during the staging period in either group. The median follow-up for the entire cohort was 18 ± 22 months. The median length of hospital stay for patients undergoing endovascular and open ICs was 6 (ranging, 1–28 days) and 7 days (ranging, 3–18 days), respectively. Patients undergoing open conduits had significantly more complications than those undergoing endovascular conduit (endoconduit) creation. A total of 4 (15%) patients died within 30 days after aneurysm repair. Out of 23 survivors, 18 (78%) patients were discharged home, 4 (18%) patients were discharged to a skilled nursing facility, and 1 (4%) patient was discharged to an acute rehabilitation facility. No mortality difference based on type of conduit was found. Conclusions: Overall complication rate associated with creation of open iliac artery conduits is not negligible. Endoconduits, which carry less morbidity than open conduits, are preferred as a first-line adjunctive access procedure to facilitate complex endovascular aortic aneurysm repair. [ABSTRACT FROM AUTHOR]

Abstract: In this paper, we propose a novel method to extend the fast multipole method (FMM) to calculate the electrostatic potential due to charges inside or outside a dielectric sphere. The key result which allows such an extension is the construction of a small number (two for a 10−2 relative error in reaction potentials inside the sphere) of image point charges for source point charges inside or outside the dielectric sphere. Numerical results validate the accuracy and high efficiency of the resulting algorithm. [Copyright &y& Elsevier]

Provides information on a study regarding risks and benefits of primary wound closure after appendectomy in the presence of perforation. Effects of appendiceal histology on clinical infection; Wound management of open and close appendiceal incision; Comparison on the wound management.

Identifying mechanisms that control molecular function is a significant challenge in pharmaceutical science and molecular engineering. Here, we present a novel projection pursuit recurrent neural network to identify functional mechanisms in the context of iterative supervised machine learning for discovery-based design optimization. Molecular function recognition is achieved by pairing experiments that categorize systems with digital twin molecular dynamics simulations to generate working hypotheses. Feature extraction decomposes emergent properties of a system into a complete set of basis vectors. Feature selection requires signal-to-noise, statistical significance, and clustering quality to concurrently surpass acceptance levels. Formulated as a multivariate description of differences and similarities between systems, the data-driven working hypothesis is refined by analyzing new systems prioritized by a discovery-likelihood. Utility and generality are demonstrated on several benchmarks, including the elucidation of antibiotic resistance in TEM-52 beta-lactamase. The software is freely available, enabling turnkey analysis of massive data streams found in computational biology and material science. [ABSTRACT FROM AUTHOR]

In a preceding paper [J. Chem. Phys. 131, 154103 (2009)], we introduced a new, hybrid explicit/implicit method to treat electrostatic interactions in computer simulations, and tested its performance for liquid water. In this paper, we report further tests of this method, termed the image-charge solvation model (ICSM), in simulations of ions solvated in water. We find that our model can faithfully reproduce known solvation properties of sodium and chloride ions. The charging free energy of a single sodium ion is in excellent agreement with the estimates by other electrostatics methods, while offering much lower finite-size errors. Similarly, the potentials of mean force computed for Na-Cl, Na-Na, and Cl-Cl pairs closely reproduce those reported previously. Collectively, our results demonstrate the superior accuracy of the proposed ICSM method for simulations of mixed media. [ABSTRACT FROM AUTHOR]

In this paper, a new solvation model is proposed for simulations of biomolecules in aqueous solutions that combines the strengths of explicit and implicit solvent representations. Solute molecules are placed in a spherical cavity filled with explicit water, thus providing microscopic detail where it is most needed. Solvent outside of the cavity is modeled as a dielectric continuum whose effect on the solute is treated through the reaction field corrections. With this explicit/implicit model, the electrostatic potential represents a solute molecule in an infinite bath of solvent, thus avoiding unphysical interactions between periodic images of the solute commonly used in the lattice-sum explicit solvent simulations. For improved computational efficiency, our model employs an accurate and efficient multiple-image charge method to compute reaction fields together with the fast multipole method for the direct Coulomb interactions. To minimize the surface effects, periodic boundary conditions are employed for nonelectrostatic interactions. The proposed model is applied to study liquid water. The effect of model parameters, which include the size of the cavity, the number of image charges used to compute reaction field, and the thickness of the buffer layer, is investigated in comparison with the particle-mesh Ewald simulations as a reference. An optimal set of parameters is obtained that allows for a faithful representation of many structural, dielectric, and dynamic properties of the simulated water, while maintaining manageable computational cost. With controlled and adjustable accuracy of the multiple-image charge representation of the reaction field, it is concluded that the employed model achieves convergence with only one image charge in the case of pure water. Future applications to pKa calculations, conformational sampling of solvated biomolecules and electrolyte solutions are briefly discussed. [ABSTRACT FROM AUTHOR]

• The technique bypasses technically challenging derivation of stochastic representative solutions underlying Monte Carlo solution of initial boundary value problems. • In contrast to MC solutions, the technique estimates non-problem-specific impulse-response functions, i.e., Green's functions, which can be used to solve IBVP's subject to an infinite array of boundary and internal forcing conditions. • A random walker swarm is launched from a chosen response (or impulse) point, well-developed RWboundary interaction models can be implemented, and a simple estimator is used to estimate the transition density - and corresponding Green's function - between the response/impulse point and the impulse/response point. • Deleterious depletion of RW's at absorbing Dirichlet boundaries is solved using a RW respawning algorithm, while spatial variance in estimated GF's, produced by our naĩve transition density estimator, is minimized using a simple area-averaging technique. • The proposed technique is tested against three problems having known Green's functions. • The paper is presented in recipe fashion, and is aimed at non-specialists. A stochastic method is described for estimating Green's functions (GF's), appropriate to linear advection-diffusion-reaction transport problems, evolving in arbitrary geometries. By allowing straightforward construction of approximate, though high-accuracy GF's, within any geometry, the technique solves the central challenge in obtaining Green's function solutions. In contrast to Monte Carlo solutions of individual transport problems, subject to specific sets of conditions and forcing, the proposed technique produces approximate GF's that can be used: a) to obtain (infinite) sets of solutions, subject to any combination of (random and deterministic) boundary, initial, and internal forcing, b) as high fidelity direct models in inverse problems, and c) as high quality process models in thermal and mass transport design, optimization, and process control problems. The technique exploits an equivalence between the adjoint problem governing the transport problem Green's function, G (x , t | x ′ , t ′) , and the backward Kolmogorov problem governing the transition density, p (x , t | x ′ , t ′) , of the stochastic process used in Green's function construction. We address nonspecialists and report four contributions. First, a recipe is outlined for diagnosing when stochastic Green's function estimation can be used, and for subsequently estimating the transition density and associated Green's function. Second, a naive estimator for the transition density is proposed and tested. Third, Green's function estimation error produced by random walker absorption at Dirichlet boundaries is suppressed using a simple random walker splitting technique. Last, spatial discontinuity in estimated GF's, produced by the naive estimator, is suppressed using a simple area averaging method. The paper provides guidance on choosing key numerical parameters, and the technique is tested against two simple unsteady, linear heat conduction problems, and an unsteady groundwater dispersion problem, each having known, exact GF's. [ABSTRACT FROM AUTHOR]

Conformational fluctuations within scFv antibodies are characterized by a novel perturbation-response decomposition of molecular dynamics trajectories. Both perturbation and response profiles are stratified into stabilizing and destabilizing conditions. The linker between the VH and VL domains exhibits the dominant dynamical response by being coupled to nearly the entire protein, responding to both stabilizing and destabilizing perturbations. Perturbations within complementarity-determining regions (CDR) induce rich behavior in dynamic response. Among many effects, stabilizing any CDR loop in the VH domain triggers a destabilizing response in all CDR loops in the VL domain and vice versa. Destabilizing residues within the VL domain are likely to stabilize all CDR loops in the VH domain, and, when these residues are not buried, the CDR loops in the VL domain are also likely to be stabilized. These effects, described by shifts in normal mode characteristics, initiate a propensity for dynamic allostery with possible functional implications in bispecific antibodies. [ABSTRACT FROM AUTHOR]

Molecular dynamics simulation is commonly employed to explore protein dynamics. Despite the disparate timescales between functional mechanisms and molecular dynamics (MD) trajectories, functional differences are often inferred from differences in conformational ensembles between two proteins in structure-function studies that investigate the effect of mutations. A common measure to quantify differences in dynamics is the root mean square fluctuation (RMSF) about the average position of residues defined by Cα-atoms. Using six MD trajectories describing three native/mutant pairs of beta-lactamase, we make comparisons with additional measures that include Jensen-Shannon, modifications of Kullback-Leibler divergence, and local p-values from 1-sample Kolmogorov-Smirnov tests. These additional measures require knowing a probability density function, which we estimate by using a nonparametric maximum entropy method that quantifies rare events well. The same measures are applied to distance fluctuations between Cα-atom pairs. Results from several implementations for quantitative comparison of a pair of MD trajectories are made based on fluctuations for on-residue and residue-residue local dynamics. We conclude that there is almost always a statistically significant difference between pairs of 100 ns all-atom simulations on moderate-sized proteins as evident from extraordinarily low p-values. [ABSTRACT FROM AUTHOR]

RiVax is a candidate ricin toxin subunit vaccine antigen that has proven to be safe in human phase I clinical trials. In this study, we introduced double and triple cavity-filling point mutations into the RiVax antigen with the expectation that stability-enhancing modifications would have a beneficial effect on overall immunogenicity of the recombinant proteins. We demonstrate that 2 RiVax triple mutant derivatives, RB (V81L/C171L/V204I) and RC (V81I/C171L/V204I), when adsorbed to aluminum salts adjuvant and tested in a mouse prime-boost-boost regimen were 5- to 10-fold more effective than RiVax at eliciting toxin-neutralizing serum IgG antibody titers. Increased toxin neutralizing antibody values and seroconversion rates were evident at different antigen dosages and within 7 days after the first booster. Quantitative stability/flexibility relationships analysis revealed that the RB and RC mutations affect rigidification of regions spanning residues 98-103, which constitutes a known immunodominant neutralizing B-cell epitope. A more detailed understanding of the immunogenic nature of RB and RC may provide insight into the fundamental relationship between local protein stability and antibody reactivity. [ABSTRACT FROM AUTHOR]

The effects of somatic mutations that transform polyspecific germline (GL) antibodies to affinity mature (AM) antibodies with monospecificity are compared among three GL-AM Fab pairs. In particular, changes in conformational flexibility are assessed using a Distance Constraint Model (DCM). We have previously established that the DCM can be robustly applied across a series of antibody fragments (VL to Fab), and subsequently, the DCM was combined with molecular dynamics (MD) simulations to similarly characterize five thermostabilizing scFv mutants. The DCM is an ensemble based statistical mechanical approach that accounts for enthalpy/entropy compensation due to network rigidity, which has been quite successful in elucidating conformational flexibility and Quantitative Stability/Flexibility Relationships (QSFR) in proteins. Applied to three disparate antibody systems changes in QSFR quantities indicate that the VH domain is typically rigidified, whereas the VL domain and CDR L2 loop become more flexible during affinity maturation. The increase in CDR H3 loop rigidity is consistent with other studies in the literature. The redistribution of conformational flexibility is largely controlled by nonspecific changes in the H-bond network, although certain Arg to Asp salt bridges create highly localized rigidity increases. Taken together, these results reveal an intricate flexibility/rigidity response that accompanies affinity maturation. [ABSTRACT FROM AUTHOR]

Background: The body-bar Pebble Game (PG) algorithm is commonly used to calculate network rigidity properties in proteins and polymeric materials. To account for fluctuating interactions such as hydrogen bonds, an ensemble of constraint topologies are sampled, and average network properties are obtained by averaging PG characterizations. At a simpler level of sophistication, Maxwell constraint counting (MCC) provides a rigorous lower bound for the number of internal degrees of freedom (DOF) within a body-bar network, and it is commonly employed to test if a molecular structure is globally under-constrained or over-constrained. MCC is a mean field approximation (MFA) that ignores spatial fluctuations of distance constraints by replacing the actual molecular structure by an effective medium that has distance constraints globally distributed with perfect uniform density. Results: The Virtual Pebble Game (VPG) algorithm is a MFA that retains spatial inhomogeneity in the density of constraints on all length scales. Network fluctuations due to distance constraints that may be present or absent based on binary random dynamic variables are suppressed by replacing all possible constraint topology realizations with the probabilities that distance constraints are present. The VPG algorithm is isomorphic to the PG algorithm, where integers for counting "pebbles" placed on vertices or edges in the PG map to real numbers representing the probability to find a pebble. In the VPG, edges are assigned pebble capacities, and pebble movements become a continuous flow of probability within the network. Comparisons between the VPG and average PG results over a test set of proteins and disordered lattices demonstrate the VPG quantitatively estimates the ensemble average PG results well. Conclusions: The VPG performs about 20% faster than one PG, and it provides a pragmatic alternative to averaging PG rigidity characteristics over an ensemble of constraint topologies. The utility of the VPG falls in between the most accurate but slowest method of ensemble averaging over hundreds to thousands of independent PG runs, and the fastest but least accurate MCC. [ABSTRACT FROM AUTHOR]

Le Châtelier’s principle is the cornerstone of our understanding of chemical equilibria. When a system at equilibrium undergoes a change in concentration or thermodynamic state (i.e., temperature, pressure, etc.), La Châtelier’s principle states that an equilibrium shift will occur to offset the perturbation and a new equilibrium is established. We demonstrate that the effects of stabilizing mutations on the rigidity ⇔ flexibility equilibrium within the native state ensemble manifest themselves through enthalpy-entropy compensation as the protein structure adjusts to restore the global balance between the two. Specifically, we characterize the effects of mutation to single chain fragments of the anti-lymphotoxin-β receptor antibody using a computational Distance Constraint Model. Statistically significant changes in the distribution of both rigidity and flexibility within the molecular structure is typically observed, where the local perturbations often lead to distal shifts in flexibility and rigidity profiles. Nevertheless, the net gain or loss in flexibility of individual mutants can be skewed. Despite all mutants being exclusively stabilizing in this dataset, increased flexibility is slightly more common than increased rigidity. Mechanistically the redistribution of flexibility is largely controlled by changes in the H-bond network. For example, a stabilizing mutation can induce an increase in rigidity locally due to the formation of new H-bonds, and simultaneously break H-bonds elsewhere leading to increased flexibility distant from the mutation site via Le Châtelier. Increased flexibility within the VH β4/β5 loop is a noteworthy illustration of this long-range effect. [ABSTRACT FROM AUTHOR]

Abstract: This paper extends the image charge solvation model (ICSM) [Y. Lin, A. Baumketner, S. Deng, Z. Xu, D. Jacobs, W. Cai, An image-based reaction field method for electrostatic interactions in molecular dynamics simulations of aqueous solutions, J. Chem. Phys. 131 (2009) 154103], a hybrid explicit/implicit method to treat electrostatic interactions in computer simulations of biomolecules formulated for spherical cavities, to prolate spheroidal and triaxial ellipsoidal cavities, designed to better accommodate non-spherical solutes in molecular dynamics (MD) simulations. In addition to the utilization of a general truncated octahedron as the MD simulation box, central to the proposed extension is an image approximation method to compute the reaction field for a point charge placed inside such a non-spherical cavity by using a single image charge located outside the cavity. The resulting generalized image charge solvation model (GICSM) is tested in simulations of liquid water, and the results are analyzed in comparison with those obtained from the ICSM simulations as a reference. We find that, for improved computational efficiency due to smaller simulation cells and consequently a less number of explicit solvent molecules, the generalized model can still faithfully reproduce known static and dynamic properties of liquid water at least for systems considered in the present paper, indicating its great potential to become an accurate but more efficient alternative to the ICSM when bio-macromolecules of irregular shapes are to be simulated. [Copyright &y& Elsevier]

Previous works have demonstrated that protein rigidity is related to thermodynamic stability, especially under conditions that favor formation of native structure. Mechanical network rigidity properties of a single conformation are efficiently calculated using the integer body-bar Pebble Game (PG) algorithm. However, thermodynamic properties require averaging over many samples from the ensemble of accessible conformations to accurately account for fluctuations in network topology. We have developed a mean field Virtual Pebble Game (VPG) that represents the ensemble of networks by a single effective network. That is, all possible number of distance constraints (or bars) that can form between a pair of rigid bodies is replaced by the average number. The resulting effective network is viewed as having weighted edges, where the weight of an edge quantifies its capacity to absorb degrees of freedom. The VPG is interpreted as a flow problem on this effective network, which eliminates the need to sample. Across a nonredundant dataset of 272 protein structures, we apply the VPG to proteins for the first time. Our results show numerically and visually that the rigidity characterizations of the VPG accurately reflect the ensemble averaged PG properties. This result positions the VPG as an efficient alternative to understand the mechanical role that chemical interactions play in maintaining protein stability. [ABSTRACT FROM AUTHOR]

The knowledge gained from biology datasets can streamline and speed-up pharmaceutical development. However, computational models generate so much information regarding protein behavior that large-scale analysis by traditional methods is almost impossible. The volume of data produced makes the transition from data to knowledge difficult and hinders biomedical advances. In this work, we present a novel visual analytics approach named WaveMap for exploring data generated by a protein flexibility model. WaveMap integrates wavelet analysis, visualizations, and interactions to facilitate the browsing, feature identification, and comparison of protein attributes represented by two-dimensional plots. We have implemented a fully working prototype of WaveMap and illustrate its usefulness through expert evaluation and an example scenario. [ABSTRACT FROM AUTHOR]

A survey of 4,032 youth in grades 5 through 12 was conducted to determine the impact youth's use of the Internet was having on their use of the public library. Results indicated that 100% of the youth had access to the Internet from one or more locations, and that although one quarter of the youth accessed the Internet at the public library, the public library was the least frequently used source of Internet access. For youth without Internet access at home, the public library was also the least used alternate source of access. Approximately 69% of the youth reported that they had visited a public library during the school year. Having Internet access at home did not affect whether or not youth visited the library however, Internet access at home appears to have affected the frequency with which youth visit the library. Youth without Internet access at home visited the library more frequently, whereas youth with Internet access at home visited the library less frequently. Use of the Internet also appeared to have diminished youth's need to use the public library as a source of personal information however, use of the Internet appeared not to have affected their use of the public library for school work or for recreation. Among youth, use of both the Internet and the public library appear to be complementary activities. [ABSTRACT FROM AUTHOR]

Background: Although women make up nearly half of medical school classes in the United States, just over 20% of residents in surgery are women (excluding obstetrics/gynecology). The objective of this study was to identify whether the proportion of women surgeons on the faculty who have frequent encounters with medical students during their surgery rotation influences the student’s perceptions about women surgeons or their career choice.Methods: Seven US medical schools with proportions of women surgeons on the fulltime faculty varying from 10% to 40% were selected to participate in this survey. Women medical students graduating in the spring of 2000 were asked to complete an anonymous 29 question survey designed to assess their perceptions of women surgeons’ career satisfaction. Demographic information about the students such as career choice, age, and marital status was also collected. The differences in responses between those schools with 40% women faculty and those with less than 15% were analyzed.Results: The overall response rate was 74% (305 of 413). Forty-five percent of students had daily or weekly contact with a woman surgery attending. There were no differences in perceptions of women surgeons’ career satisfaction for those students at schools with 40% women surgeons versus those with less than 15%. However, 21 of 24 (88%) students choosing surgery as a career were from the three schools with a greater number of women surgical role models (P <0.0001). Students who chose a career in surgery perceived the women faculty’s career satisfaction to be higher than did those students not choosing a surgical career (P <0.01).Conclusions: Women medical students perception of women surgeons’ career satisfaction did not appear to be affected by the proportion of women surgeons on the faculty at their medical school. However, their choice of surgery as a career was strongly associated with a higher proportion of women on the surgical faculty. [Copyright &y& Elsevier]