Multistate Method to Efficiently Account for Tautomerism and Protonation in Alchemical Free-Energy Calculations.

The majority of drug-like molecules contain at least one ionizable group, and many common drug scaffolds are subject to tautomeric equilibria. Thus, these compounds are found in a mixture of protonation and/or tautomeric states at physiological pH. Intrinsically, standard classical molecular dynamics (MD) simulations cannot describe such equilibria between states, which negatively impacts the prediction of key molecular properties in silico. Following the formalism described by de Oliveira and co-workers (J. Chem. Theory Comput. 2019, 15, 424-435) to consider the influence of all states on the binding process based on alchemical free-energy calculations, we demonstrate in this work that the multistate method replica-exchange enveloping distribution sampling (RE-EDS) is well suited to describe molecules with multiple protonation and/or tautomeric states in a single simulation. We apply our methodology to a series of eight inhibitors of factor Xa with two protonation states and a series of eight inhibitors of glycogen synthase kinase 3ß (GSK3ß) with two tautomeric states. In particular, we show that given a sufficient phase-space overlap between the states, RE-EDS is computationally more efficient than standard pairwise free-energy methods.

Rational design of an artificial tethered enzyme for non-templated post-transcriptional mRNA polyadenylation by the second generation of the C3P3 system.

We have previously introduced the first generation of C3P3, an artificial system that allows the autonomous in-vivo production of mRNA with m7GpppN-cap. While C3P3-G1 synthesized much larger amounts of capped mRNA in human cells than conventional nuclear expression systems, it produced a proportionately much smaller amount of the corresponding proteins, indicating a clear defect of mRNA translatability. A possible mechanism for this poor translatability could be the rudimentary polyadenylation of the mRNA produced by the C3P3-G1 system. We therefore sought to develop the C3P3-G2 system using an artificial enzyme to post-transcriptionally lengthen the poly(A) tail. This system is based on the mutant mouse poly(A) polymerase alpha fused at its N terminus with an N peptide from the λ virus, which binds to BoxBr sequences placed in the 3'UTR region of the mRNA of interest. The resulting system selectively brings mPAPαm7 to the target mRNA to elongate its poly(A)-tail to a length of few hundred adenosine. Such elongation of the poly(A) tail leads to an increase in protein expression levels of about 2.5-3 times in cultured human cells compared to the C3P3-G1 system. Finally, the coding sequence of the tethered mutant poly(A) polymerase can be efficiently fused to that of the C3P3-G1 enzyme via an F2A sequence, thus constituting the single-ORF C3P3-G2 enzyme. These technical developments constitute an important milestone in improving the performance of the C3P3 system, paving the way for its applications in bioproduction and non-viral human gene therapy.

Adaptive Data-Driven Deep-Learning Surrogate Model for Frontal Polymerization in Dicyclopentadiene.

Frontal polymerization (FP) is a self-sustaining curing process that enables rapid and energy-efficient manufacturing of thermoset polymers and composites. Computational methods conventionally used to simulate the FP process are time-consuming, and repeating simulations are required for sensitivity analysis, uncertainty quantification, or optimization of the manufacturing process. In this work, we develop an adaptive surrogate deep-learning model for FP of dicyclopentadiene (DCPD), which predicts the evolution of temperature and degree of cure orders of magnitude faster than the finite-element method (FEM). The adaptive algorithm provides a strategy to select training samples efficiently and save computational costs by reducing the redundancy of FEM-based training samples. The adaptive algorithm calculates the residual error of the FP governing equations using automatic differentiation of the deep neural network. A probability density function expressed in terms of the residual error is used to select training samples from the Sobol sequence space. The temperature and degree of cure evolution of each training sample are obtained by a 2D FEM simulation. The adaptive method is more efficient and has a better prediction accuracy than the random sampling method. With the well-trained surrogate neural network, the FP characteristics (front speed, shape, and temperature) can be extracted quickly from the predicted temperature and degree-of-cure fields.

Simulation of aqueous solutes using the adaptive solvent-scaling (AdSoS) scheme.

The Adaptive Solvent-Scaling (AdSoS) scheme [J. Chem. Phys. 155 (2021) 094107] is an adaptive-resolution approach for performing simulations of a solute embedded in a fine-grained (FG) solvent region surrounded by a coarse-grained (CG) solvent region, with a continuous FG ↔ CG switching of the solvent resolution across a buffer layer. Instead of relying on a distinct CG solvent model, AdSoS is based on CG models defined by a dimensional scaling of the FG solvent by a factor s, accompanied by the s-dependent modulation of its mass and interaction parameters. The latter changes are designed to achieve an isomorphism between the dynamics of the FG and CG models, and to preserve the dispersive and dielectric solvation properties of the solvent with respect to a solute at FG resolution. As a result, the AdSoS scheme minimizes the thermodynamic mismatch between different regions of the adaptive-resolution system. The present article generalizes the scheme initially introduced for a pure atomic liquid in slab geometry to more practically relevant situations involving (i) a molecular dipolar solvent (e.g., water); (ii) a radial geometry (i.e., spherical rather than planar layers); and (iii) the inclusion of a solute (e.g., water molecule, dipeptide, ion, or ion pair).

How I manage differential gas exchange in peripheral venoarterial extracorporeal membrane oxygenation.

Dual circulation is a common but underrecognized physiological occurrence associated with peripheral venoarterial extracorporeal membrane oxygenation (ECMO). Competitive flow will develop between blood ejected from the heart and blood travelling retrograde within the aorta from the ECMO reinfusion cannula. The intersection of these two competitive flows is referred to as the "mixing point". The location of this mixing point, which depends upon the relative strengths of the native and extracorporeal pumps, will determine which regions of the body are perfused with blood ejected from the left ventricle and which regions are perfused by reinfused blood from the ECMO circuit, effectively establishing dual circulations. Because gas exchange within these circulations is dictated by the native lungs and membrane lung, respectively, oxygenation and carbon dioxide removal may differ between regions-depending on how well gas exchange is preserved within each circulation-potentially leading to differential oxygenation or differential carbon dioxide, each of which may have important clinical implications. In this perspective, we address the identification and management of dual circulation and differential gas exchange through various clinical scenarios of venoarterial ECMO. Recognition of dual circulation, proper monitoring for differential gas exchange, and understanding the various strategies to resolve differential oxygenation and carbon dioxide may allow for more optimal patient management and improved clinical outcomes.

Geophysical evidence for an enriched molten silicate layer above Mars's core.

The detection of deep reflected S waves on Mars inferred a core size of 1,830 ± 40 km (ref. 1), requiring light-element contents that are incompatible with experimental petrological constraints. This estimate assumes a compositionally homogeneous Martian mantle, at odds with recent measurements of anomalously slow propagating P waves diffracted along the core-mantle boundary2. An alternative hypothesis is that Mars's mantle is heterogeneous as a consequence of an early magma ocean that solidified to form a basal layer enriched in iron and heat-producing elements. Such enrichment results in the formation of a molten silicate layer above the core, overlain by a partially molten layer3. Here we show that this structure is compatible with all geophysical data, notably (1) deep reflected and diffracted mantle seismic phases, (2) weak shear attenuation at seismic frequency and (3) Mars's dissipative nature at Phobos tides. The core size in this scenario is 1,650 ± 20 km, implying a density of 6.5 g cm-3, 5-8% larger than previous seismic estimates, and can be explained by fewer, and less abundant, alloying light elements than previously required, in amounts compatible with experimental and cosmochemical constraints. Finally, the layered mantle structure requires external sources to generate the magnetic signatures recorded in Mars's crust.

Poor success rates with double pelvic osteotomy for craniodorsal luxation of total hip prosthesis in 11 dogs.

OBJECTIVE: To report the outcome of double pelvic osteotomy (DPO) for craniodorsal luxation of total hip replacement (THR). STUDY DESIGN: Retrospective case series. ANIMALS: Eleven client-owned animals. METHODS: Dogs with craniodorsal luxation of THR and high angle of lateral opening (ALO) were considered candidates for DPO. The ALO and the version angle (VA) were measured on pre- and post-DPO radiographs. Pre- and post-DPO ALO and VA were compared using a Wilcoxon signed-rank test. Clinical and radiographic outcomes were assessed at 2 and 6 months post-DPO. RESULTS: Eleven DPOs were performed on 11 dogs after THR luxation. The ALO was reduced from a median of 66.2° (range 37.3-73.1°) to 55.9° (range 13.2-60.0°) (p ≤ .001), and VA increased from a median of 25.6° (range 6.8-51.9°) to 35.3° (range 15.1-51.7°) (p ≤ .03). Craniodorsal luxation recurred in five dogs and was managed with closed reduction (one dog), capsulorrhaphy (one dog), or repositioning of the acetabular cup (three dogs). The median clinical follow-up duration was 19.7 months (range 3.4-73.0). In the long term, seven dogs required explantation (five aseptic loosenings, two infections) (median 8.2 months, range 2.6-50.6). CONCLUSION: Reluxation was frequent after DPO, 5/11 dogs requiring additional procedures, including three cup revisions. The long-term outcome was considered to be poor due to frequent explantation. CLINICAL SIGNIFICANCE: Double pelvic osteotomy may be considered to avoid cup replacement when managing craniodorsal THR luxations in dogs but is not recommended due to high complication rates.

Influence of the Lennard-Jones Combination Rules on the Simulated Properties of Organic Liquids at Optimal Force-Field Parametrization.

We recently introduced the CombiFF scheme [Oliveira et al., J. Chem. Theory Comput. 2020, 16, 7525], an approach for the automated refinement of force-field parameters against experimental condensed-phase data for large compound families. Using this scheme, once the time-consuming task of target-data selection and curation has been performed, the force-field optimization itself is both straightforward and fast. As a result, CombiFF provides an ideal framework for evaluating the influence of functional-form decisions on the accuracy of a force field at an optimal level of parametrization. We already used this approach to assess the effect of using an all-atom representation compared to united-atom representations in the force field [Oliveira et al., J. Chem. Theory Comput. 2022, 18, 6757]. Here, CombiFF is applied to assess the effect of three Lennard-Jones combination rules, geometric-mean (GM), Lorentz-Berthelot (LB), or Waldman-Hagler (WH), on the simulated properties of organic liquids. The comparison is performed in terms of the experimental liquid density ρliq, vaporization enthalpy ΔHvap, surface-tension coefficient γ, static relative dielectric permittivity ϵ, and self-diffusion coefficient D. The calibrations of the three force-field variants are carried out independently against 2044 experimental values for ρliq, and ΔHvap concerning 1516 compounds. The resulting root-mean-square deviations from experiment are 30.0, 26.9, and 36.7 kg m-3 for ρliq and 2.8, 2.8, and 2.9 kJ mol-1 for ΔHvap, when applying the GM, LB, and WH combination rules, respectively. In terms of these (and the other) properties, the three combination rules perform comparatively well, with the GM and LB results being more similar to each other and slightly more accurate compared to experiment. In contrast, the use of distinct combination rules for the parameter calibration and property calculation leads to much larger errors.

Frontal Polymerizations: From Chemical Perspectives to Macroscopic Properties and Applications.

The synthesis and processing of most thermoplastics and thermoset polymeric materials rely on energy-inefficient and environmentally burdensome manufacturing methods. Frontal polymerization is an attractive, scalable alternative due to its exploitation of polymerization heat that is generally wasted and unutilized. The only external energy needed for frontal polymerization is an initial thermal (or photo) stimulus that locally ignites the reaction. The subsequent reaction exothermicity provides local heating; the transport of this thermal energy to neighboring monomers in either a liquid or gel-like state results in a self-perpetuating reaction zone that provides fully cured thermosets and thermoplastics. Propagation of this polymerization front continues through the unreacted monomer media until either all reactants are consumed or sufficient heat loss stalls further reaction. Several different polymerization mechanisms support frontal processes, including free-radical, cat- or anionic, amine-cure epoxides, and ring-opening metathesis polymerization. The choice of monomer, initiator/catalyst, and additives dictates how fast the polymer front traverses the reactant medium, as well as the maximum temperature achievable. Numerous applications of frontally generated materials exist, ranging from porous substrate reinforcement to fabrication of patterned composites. In this review, we examine in detail the physical and chemical phenomena that govern frontal polymerization, as well as outline the existing applications.

Development of an open-source software for isomer enumeration.

This article documents enu, a freely-downloadable, open-source and stand-alone program written in C++ for the enumeration of the constitutional isomers and stereoisomers of a molecular formula. The program relies on graph theory to enumerate all the constitutional isomers of a given formula on the basis of their canonical adjacency matrix. The stereoisomers of a given constitutional isomer are enumerated as well, on the basis of the automorphism group of this matrix. The isomer list is then reported in the form of canonical SMILES strings within files in XML format. The specification of the molecule family of interest is very flexible and the code is optimized for computational efficiency. The algorithms and implementations underlying enu are described, and simple illustrative applications are presented. The enu code is freely available on GitHub at https://github.com/csms-ethz/CombiFF .

Knowledge of surgeons and practical stances of healthcare institutions in the Ile-de-France region toward sustainable development: A cross-sectional study.

PURPOSE OF THE STUDY: Climate change represents one of the gravest threats to health. Surgical activities mobilize a large number of resources which contribute to increased emission of CO2 and anesthetic gases in the environment. The objective of this study was to assess the level of knowledge of surgeons and the practical stances of healthcare establishments toward sustainable development. METHODS: This was a descriptive cross-sectional study, lasting 2 months. From 1 May 2021 to 30 June 2021, surgeons were asked via an online questionnaire to participate. RESULTS: A total of 131 out of the 457 contacted surgeons responded. A majority practiced in the private sector, 48.9% knew little about the rules of sustainable development in operating theaters, and 43.5% had an average level. The sustainable development charter was available in only 23% of establishments, while 19% had a sustainable development committee, and specific sustainable development actions were carried out in 27%. CONCLUSION: The level of knowledge of surgeons in Île-de-France on sustainable development was low. In general, surgical units were not complying with the rules of good practice on CO2 reduction. It is necessary to find strategies to reduce the impact of operating theaters on the environment.

Force fields optimized against experimental data for large compound families using CombiFF: Validation considering non-target properties and polyfunctional compounds.

The CombiFF scheme is a workflow for the automated calibration of force-field parameters against condensed-phase experimental data considering simultaneously entire classes of organic molecules. The main steps of this scheme are: (i) selection of a molecule family; (ii) enumeration of all isomers; (iii) query for experimental data; (iv) automatic construction of the molecular topologies; (v) iterative refinement of the force-field parameters considering the entire family. In two recent articles, CombiFF was applied to the design of GROMOS-compatible united-atom force fields for the saturated acyclic haloalkanes and for saturated acyclic compounds involving eight common chemical functional groups of oxygen and nitrogen. This calibration and the subsequent initial validation involved two limitations: (i) the experimental data considered was restricted to values for the pure-liquid density ρliq and the vaporization enthalpy ΔHvap of the compounds; (ii) beyond monofunctional compounds, the training set only involved homo-polyhaloalkanes (possibly mixing halogen types) in the first study, and homo-polyfunctional compounds of the considered oxygen or nitrogen functional groups (no mixing of different group types) in the second one. The goal of this article is to further test the accuracy of CombiFF-generated force fields by extending the validation to: (i) nine additional properties that were not used as optimization targets (pure-liquid thermodynamic, dielectric and transport properties, as well as solvation properties); (ii) hetero-polyfunctional molecules that were not included in the calibration and initial validation sets. The results for the nine additional properties show good agreement with experiment, except for the shear viscosity and the dielectric permittivity. There, larger discrepancies are observed, likely due to the united-atom representation adopted for the aliphatic groups and to the implicit treatment of electronic polarization effects. The results for the hetero-polyfunctional molecules also show reasonable agreement with experiment in terms of the monitored properties.

Comparison of the United- and All-Atom Representations of (Halo)alkanes Based on Two Condensed-Phase Force Fields Optimized against the Same Experimental Data Set.

The level of accuracy that can be achieved by a force field is influenced by choices made in the interaction-function representation and in the relevant simulation parameters. These choices, referred to here as functional-form variants (FFVs), include for example the model resolution, the charge-derivation procedure, the van der Waals combination rules, the cutoff distance, and the treatment of the long-range interactions. Ideally, assessing the effect of a given FFV on the intrinsic accuracy of the force-field representation requires that only the specific FFV is changed and that this change is performed at an optimal level of parametrization, a requirement that may prove extremely challenging to achieve in practice. Here, we present a first attempt at such a comparison for one specific FFV, namely the choice of a united-atom (UA) versus an all-atom (AA) resolution in a force field for saturated acyclic (halo)alkanes. Two force-field versions (UA vs AA) are optimized in an automated way using the CombiFF approach against 961 experimental values for the pure-liquid densities ρliq and vaporization enthalpies ΔHvap of 591 compounds. For the AA force field, the torsional and third-neighbor Lennard-Jones parameters are also refined based on quantum-mechanical rotational-energy profiles. The comparison between the UA and AA resolutions is also extended to properties that have not been included as parameterization targets, namely the surface-tension coefficient γ, the isothermal compressibility κT, the isobaric thermal-expansion coefficient αP, the isobaric heat capacity cP, the static relative dielectric permittivity ϵ, the self-diffusion coefficient D, the shear viscosity η, the hydration free energy ΔGwat, and the free energy of solvation ΔGche in cyclohexane. For the target properties ρliq and ΔHvap, the UA and AA resolutions reach very similar levels of accuracy after optimization. For the nine other properties, the AA representation leads to more accurate results in terms of η; comparably accurate results in terms of γ, κT, αP, ϵ, D, and ΔGche; and less accurate results in terms of cP and ΔGwat. This work also represents a first step toward the calibration of a GROMOS-compatible force field at the AA resolution.

Leveraging the sampling efficiency of RE-EDS in OpenMM using a shifted reaction-field with an atom-based cutoff.

Replica-exchange enveloping distribution sampling (RE-EDS) is a pathway-independent multistate free-energy method currently implemented in the GROMOS software package for molecular dynamics (MD) simulations. It has a high intrinsic sampling efficiency as the interactions between the unperturbed particles have to be calculated only once for multiple end-states. As a result, RE-EDS is an attractive method for the calculation of relative solvation and binding free energies. An essential requirement for reaching this high efficiency is the separability of the nonbonded interactions into solute-solute, solute-environment, and environment-environment contributions. Such a partitioning is trivial when using a Coulomb term with a reaction-field (RF) correction to model the electrostatic interactions but not when using lattice-sum schemes. To avoid cutoff artifacts, the RF correction is typically used in combination with a charge-group-based cutoff, which is not supported by most small-molecule force fields as well as other MD engines. To address this issue, we investigate the combination of RE-EDS simulations with a recently introduced RF scheme including a shifting function that enables the rigorous calculation of RF electrostatics with atom-based cutoffs. The resulting approach is validated by calculating solvation free energies with the generalized AMBER force field in water and chloroform using both the GROMOS software package and a proof-of-concept implementation in OpenMM.

2021: Perioperative and critical care year in review for the cardiothoracic surgery team.

For yet another year, our lives have been dominated by a pandemic. This year in review, we feature an expert panel opinion regarding extracorporeal support in the context of COVID-19, challenging previously held standards. We also feature survey results assessing the impact of the pandemic on cardiac surgical volume. Furthermore, we focus on a single center experience that evaluated the use of pulmonary artery catheters and the comparison of transfusion strategies in the Restrictive and Liberal Transfusion Strategies in Patients With Acute Myocardial Infarction (REALITY) trial. Additionally, we address the impact of acute kidney injury on cardiac surgery and highlight the controversy regarding the choice of fluid resuscitation. We close with an evaluation of dysphagia in cardiac surgery and the impact of prehabilitation to optimize surgical outcomes.

Targeting the Major Groove of the Palindromic d(GGCGCC)2 Sequence by Oligopeptide Derivatives of Anthraquinone Intercalators.

GC-rich sequences are recurring motifs in oncogenes and retroviruses and could be targeted by noncovalent major-groove therapeutic ligands. We considered the palindromic sequence d(G1G2C3G4C5C6)2, and designed several oligopeptide derivatives of the anticancer intercalator mitoxantrone. The stability of their complexes with an 18-mer oligonucleotide encompassing this sequence in its center was validated using polarizable molecular dynamics. We report the most salient structural features of two novel compounds, having a dialkylammonium group as a side chain on both arms. The anthraquinone ring is intercalated in the central d(CpG)2 sequence with its long axis perpendicular to that of the two base pairs. On each strand, this enables each ammonium group to bind in-register to O6/N7 of the two facing G bases upstream. We subsequently designed tris-intercalating derivatives, each dialkylammonium substituted with a connector to an N9-aminoacridine intercalator extending our target range from a six- to a ten-base-pair palindromic sequence, d(C1G2G3G4C5G6C7C8C9G10)2. The structural features of the complex of the most promising derivative are reported. The present design strategy paves the way for designing intercalator-oligopeptide derivatives with even higher selectivity, targeting an increased number of DNA bases, going beyond ten.

Replica-Exchange Enveloping Distribution Sampling Using Generalized AMBER Force-Field Topologies: Application to Relative Hydration Free-Energy Calculations for Large Sets of Molecules.

Free-energy differences between pairs of end-states can be estimated based on molecular dynamics (MD) simulations using standard pathway-dependent methods such as thermodynamic integration (TI), free-energy perturbation, or Bennett's acceptance ratio. Replica-exchange enveloping distribution sampling (RE-EDS), on the other hand, allows for the sampling of multiple end-states in a single simulation without the specification of any pathways. In this work, we use the RE-EDS method as implemented in GROMOS together with generalized AMBER force-field (GAFF) topologies, converted to a GROMOS-compatible format with a newly developed GROMOS++ program amber2gromos, to compute relative hydration free energies for a series of benzene derivatives. The results obtained with RE-EDS are compared to the experimental data as well as calculated values from the literature. In addition, the estimated free-energy differences in water and in vacuum are compared to values from TI calculations carried out with GROMACS. The hydration free energies obtained using RE-EDS for multiple molecules are found to be in good agreement with both the experimental data and the results calculated using other free-energy methods. While all considered free-energy methods delivered accurate results, the RE-EDS calculations required the least amount of total simulation time. This work serves as a validation for the use of GAFF topologies with the GROMOS simulation package and the RE-EDS approach. Furthermore, the performance of RE-EDS for a large set of 28 end-states is assessed with promising results.

The Role of Surface Chemistry in the Orientational Behavior of Water at an Interface.

Molecular dynamics studies have demonstrated that molecular water at an interface, with either a gas or a solid, displays anisotropic orientational behavior in contrast to its bulk counterpart. This effect has been recently implicated in the like-charge attraction problem for colloidal particles in solution. Here, negatively charged particles in solution display a long-ranged attraction where continuum electrostatic theory predicts monotonically repulsive interactions, particularly in solutions with monovalent salt ions at low ionic strength. Anisotropic orientational behavior of solvent molecules at an interface gives rise to an excess interfacial electrical potential which we suggest generates an additional solvation contribution to the total free energy that is traditionally overlooked in continuum descriptions of interparticle interactions in solution. In the present investigation we perform molecular dynamics simulation based calculations of the interfacial potential using realistic surface models representing various chemistries as well as different solvents. Similar to previous work that focused on simple model surfaces constructed by using oxygen atoms, we find that solvents at more realistic model surfaces exhibit substantial anisotropic orientational behavior. We explore the dependence of the interfacial solvation potential on surface properties such as surface group chemistry and group density at silica and carboxylated polystyrene interfaces. For water, we note surprisingly good agreement between results obtained for a simple O-atom wall and more complex surface models, suggesting a general qualitative consistency of the interfacial solvation effect for surfaces in contact with water. In contrast, for an aprotic solvent such as DMSO, surface chemistry appears to exert a stronger influence on the sign and magnitude of the interfacial solvation potential. The study carries broad implications for molecular-scale interactions and may find relevance in explaining a range of phenomena in soft-matter physics and cell biology.

Review of the current antibiotic guidelines used in dermatologic surgery.

Antibiotics have been used as a prophylaxis for dermatologic procedures. We will review the various procedures that specific antibiotics with dosages are used for, depending on the procedure, diagnosis, and circumstance of the patient. We will examine the current and updated guidelines used in dermatologic surgery and the overlapping guidelines across other fields. Physicians must consider the side effects of antibiotics and the resistance that may occur as a result before using the class or level of prophylaxis. Initial evaluation for alcohol, chlorhexidine, or iodine should be measured as well. Updated guidelines aim to address the contraindications of antibiotics, yet further research is needed to avoid antibiotic resistance and to explore alternative methods of antibiotic application, such as intranasal and intravenous.