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.

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.

Rapid energy-efficient manufacturing of polymers and composites via frontal polymerization.

Thermoset polymers and composite materials are integral to today's aerospace, automotive, marine and energy industries and will be vital to the next generation of lightweight, energy-efficient structures in these enterprises, owing to their excellent specific stiffness and strength, thermal stability and chemical resistance1-5. The manufacture of high-performance thermoset components requires the monomer to be cured at high temperatures (around 180 °C) for several hours, under a combined external pressure and internal vacuum 6 . Curing is generally accomplished using large autoclaves or ovens that scale in size with the component. Hence this traditional curing approach is slow, requires a large amount of energy and involves substantial capital investment6,7. Frontal polymerization is a promising alternative curing strategy, in which a self-propagating exothermic reaction wave transforms liquid monomers to fully cured polymers. We report here the frontal polymerization of a high-performance thermoset polymer that allows the rapid fabrication of parts with microscale features, three-dimensional printed structures and carbon-fibre-reinforced polymer composites. Precise control of the polymerization kinetics at both ambient and elevated temperatures allows stable monomer solutions to transform into fully cured polymers within seconds, reducing energy requirements and cure times by several orders of magnitude compared with conventional oven or autoclave curing approaches. The resulting polymer and composite parts possess similar mechanical properties to those cured conventionally. This curing strategy greatly improves the efficiency of manufacturing of high-performance polymers and composites, and is widely applicable to many industries.

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.

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).

Rare and Common Variants in KIF15 Contribute to Genetic Risk of Idiopathic Pulmonary Fibrosis.

Rationale: Genetic studies of idiopathic pulmonary fibrosis (IPF) have improved our understanding of this disease, but not all causal loci have been identified. Objectives: To identify genes enriched with rare deleterious variants in IPF and familial pulmonary fibrosis. Methods: We performed gene burden analysis of whole-exome data, tested single variants for disease association, conducted KIF15 (kinesin family member 15) functional studies, and examined human lung single-cell RNA sequencing data. Measurements and Main Results: Gene burden analysis of 1,725 cases and 23,509 control subjects identified heterozygous rare deleterious variants in KIF15, a kinesin involved in spindle separation during mitosis, and three telomere-related genes (TERT [telomerase reverse transcriptase], RTEL1 [regulator of telomere elongation helicase 1], and PARN [poly(A)-specific ribonuclease]). KIF15 was implicated in autosomal-dominant models of rare deleterious variants (odds ratio [OR], 4.9; 95% confidence interval [CI], 2.7-8.8; P = 2.55 × 10-7) and rare protein-truncating variants (OR, 7.6; 95% CI, 3.3-17.1; P = 8.12 × 10-7). Meta-analyses of the discovery and replication cohorts, including 2,966 cases and 29,817 control subjects, confirm the involvement of KIF15 plus the three telomere-related genes. A common variant within a KIF15 intron (rs74341405; OR, 1.6; 95% CI, 1.4-1.9; P = 5.63 × 10-10) is associated with IPF risk, confirming a prior report. Lymphoblastoid cells from individuals heterozygous for the common variant have decreased KIF15 and reduced rates of cell growth. Cell proliferation is dependent on KIF15 in the presence of an inhibitor of Eg5/KIF11, which has partially redundant function. KIF15 is expressed specifically in replicating human lung cells and shows diminished expression in replicating epithelial cells of patients with IPF. Conclusions: Both rare deleterious variants and common variants in KIF15 link a nontelomerase pathway of cell proliferation with IPF susceptibility.

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.

Mammalian acetate-dependent acetyl CoA synthetase 2 contains multiple protein destabilization and masking elements.

Besides contributing to anabolism, cellular metabolites serve as substrates or cofactors for enzymes and may also have signaling functions. Given these roles, multiple control mechanisms likely ensure fidelity of metabolite-generating enzymes. Acetate-dependent acetyl CoA synthetases (ACS) are de novo sources of acetyl CoA, a building block for fatty acids and a substrate for acetyltransferases. Eukaryotic acetate-dependent acetyl CoA synthetase 2 (Acss2) is predominantly cytosolic, but is also found in the nucleus following oxygen or glucose deprivation, or upon acetate exposure. Acss2-generated acetyl CoA is used in acetylation of Hypoxia-Inducible Factor 2 (HIF-2), a stress-responsive transcription factor. Mutation of a putative nuclear localization signal in endogenous Acss2 abrogates HIF-2 acetylation and signaling, but surprisingly also results in reduced Acss2 protein levels due to unmasking of two protein destabilization elements (PDE) in the Acss2 hinge region. In the current study, we identify up to four additional PDE in the Acss2 hinge region and determine that a previously identified PDE, the ABC domain, consists of two functional PDE. We show that the ABC domain and other PDE are likely masked by intramolecular interactions with other domains in the Acss2 hinge region. We also characterize mice with a prematurely truncated Acss2 that exposes a putative ABC domain PDE, which exhibits reduced Acss2 protein stability and impaired HIF-2 signaling. Finally, using primary mouse embryonic fibroblasts, we demonstrate that the reduced stability of select Acss2 mutant proteins is due to a shortened half-life, which is a result of enhanced degradation via a nonproteasome, nonautophagy pathway.

Simultaneous parametrization of torsional and third-neighbor interaction terms in force-field development: The LLS-SC algorithm.

The calibration of torsional interaction terms by fitting relative gas-phase conformational energies against their quantum-mechanical values is a common procedure in force-field development. However, much less attention has been paid to the optimization of third-neighbor nonbonded interaction parameters, despite their strong coupling with the torsions. This article introduces an algorithm termed LLS-SC, aimed at simultaneously parametrizing torsional and third-neighbor interaction terms based on relative conformational energies. It relies on a self-consistent (SC) procedure where each iteration involves a linear least-squares (LLS) regression followed by a geometry optimization of the reference structures. As a proof-of-principle, this method is applied to obtain torsional and third-neighbor interaction parameters for aliphatic chains in the context of the GROMOS 53A6 united-atom force field. The optimized parameter set is compared to the original one, which has been fitted manually against thermodynamic properties for small linear alkanes. The LLS-SC implementation is freely available under http://github.com/mssm-labmmol/profiler.

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.

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.

RestraintMaker: a graph-based approach to select distance restraints in free-energy calculations with dual topology.

The calculation of relative binding free energies (RBFE) involves the choice of the end-state/system representation, of a sampling approach, and of a free-energy estimator. System representations are usually termed "single topology" or "dual topology". As the terminology is often used ambiguously in the literature, a systematic categorization of the system representations is proposed here. In the dual-topology approach, the molecules are simulated as separate molecules. Such an approach is relatively easy to automate for high-throughput RBFE calculations compared to the single-topology approach. Distance restraints are commonly applied to prevent the molecules from drifting apart, thereby improving the sampling efficiency. In this study, we introduce the program RestraintMaker, which relies on a greedy algorithm to find (locally) optimal distance restraints between pairs of atoms based on geometric measures. The algorithm is further extended for multi-state methods such as enveloping distribution sampling (EDS) or multi-site [Formula: see text]-dynamics. The performance of RestraintMaker is demonstrated for toy models and for the calculation of relative hydration free energies. The Python program can be used in script form or through an interactive GUI within PyMol. The selected distance restraints can be written out in GROMOS or GROMACS file formats. Additionally, the program provides a human-readable JSON format that can easily be parsed and processed further. The code of RestraintMaker is freely available on GitHub https://github.com/rinikerlab/restraintmaker.

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.

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.

Anisotropic frontal polymerization in a model resin-copper composite.

This work investigates experimentally and numerically frontal polymerization in a thermally anisotropic system with parallel copper strips embedded in 1,6-hexanediol diacrylate resin. Both experiments and multiphysics finite element analyses reveal that the front propagation in the thermally anisotropic system is orientation-dependent, leading to variations in the front shape and the front velocity due to the different front-metal strip interaction mechanisms along and across the metal strips. The parameters entering the cure kinetics model used in this work are chosen to capture the key characteristics of the polymerization front, i.e., the front temperature and velocity. Numerical parametric analyses demonstrate that the front velocity in the directions parallel and perpendicular to the metal strips increases as the system size decreases and approaches the analytical prediction for homogenized systems. A two-dimensional homogenized model for anisotropic frontal polymerization in the metal-resin system is proposed.

Replica-Exchange Enveloping Distribution Sampling: Calculation of Relative Free Energies in GROMOS.

Molecular dynamics (MD) simulations have become an important tool to investigate biological systems. Free-energy calculations based on MD are playing an increasingly important role for computer-aided drug design and material discovery in recent years. Free-energy differences between pairs of end-states can be estimated using well-established methods such as thermodynamic integration (TI) or Bennett's acceptance ratio (BAR). An attractive alternative is the recently developed replica-exchange enveloping distribution sampling (RE-EDS) method, which enables estimating relative free-energy differences between multiple molecules from a single simulation. Here, we provide an introduction to the principles underlying RE-EDS and give an overview of the RE-EDS pipeline. In addition, we provide a description of the two complementary tools RestraintMaker and amber2gromos. We briefly discuss the findings of three recent applications of RE-EDS to calculate relative binding or hydration free energies. In all three studies, good agreement was found between the results obtained using RE-EDS and experimental values as well as values obtained using other free-energy methods.

Controllable Frontal Polymerization and Spontaneous Patterning Enabled by Phase-Changing Particles.

Frontal polymerization provides a rapid, economic, and environmentally friendly methodology to manufacture thermoset polymers and composites. Despite its efficiency and reduced environmental impact, the manufacturing method is underutilized due to the limited fundamental understanding of its dynamic control. This work reports the control and patterning of the front propagation in a dicyclopentadiene resin by immersion of phase-changing polycaprolactone particles. Predictive and designed patterning is enabled by multiphysical numerical analyses, which reveal that the interplay between endothermic phase transition, exothermic chemical reaction, and heat exchange govern the temperature, velocity, and propagation path of the front via two different interaction regimes. To pattern the front, one can vary the size and spacing between the particles and increase the number of propagating fronts, resulting in tunable physical patterns formed due to front separation and merging near the particles. Both single- and double-frontal polymerization experiments in an open mold are performed. The results confirm the front-particle interaction mechanisms and the shapes of the patterns explored numerically. The present study offers a fundamental understanding of frontal polymerization in the presence of heat-absorbing second-phase materials and proposes a potential one-step manufacturing method for precisely patterned polymeric and composite materials without masks, molds, or printers.

An Optimized Reverse Genetics System Suitable for Efficient Recovery of Simian, Human, and Murine-Like Rotaviruses.

An entirely plasmid-based reverse genetics (RG) system was recently developed for rotavirus (RV), opening new avenues for in-depth molecular dissection of RV biology, immunology, and pathogenesis. Several improvements to further optimize the RG efficiency have now been described. However, only a small number of individual RV strains have been recovered to date. None of the current methods have supported the recovery of murine RV, impeding the study of RV replication and pathogenesis in an in vivo suckling mouse model. Here, we describe useful modifications to the RG system that significantly improve rescue efficiency of multiple RV strains. In addition to the 11 group A RV segment-specific (+)RNAs [(+)ssRNAs], a chimeric plasmid was transfected, from which the capping enzyme NP868R of African swine fever virus (ASFV) and the T7 RNA polymerase were expressed. Second, a genetically modified MA104 cell line was used in which several components of the innate immunity were degraded. Using this RG system, we successfully recovered the simian RV RRV strain, the human RV CDC-9 strain, a reassortant between murine RV D6/2 and simian RV SA11 strains, and several reassortants and reporter RVs. All these recombinant RVs were rescued at a high efficiency (≥80% success rate) and could not be reliably rescued using several recently published RG strategies (<20%). This improved system represents an important tool and great potential for the rescue of other hard-to-recover RV strains such as low-replicating attenuated vaccine candidates or low-cell culture passage clinical isolates from humans or animals.IMPORTANCE Group A rotavirus (RV) remains as the single most important cause of severe acute gastroenteritis among infants and young children worldwide. An entirely plasmid-based reverse genetics (RG) system was recently developed, opening new ways for in-depth molecular study of RV. Despite several improvements to further optimize the RG efficiency, it has been reported that current strategies do not enable the rescue of all cultivatable RV strains. Here, we described a helpful modification to the current strategies and established a tractable RG system for the rescue of the simian RRV strain, the human CDC-9 strain, and a murine-like RV strain, which is suitable for both in vitro and in vivo studies. This improved RV reverse genetics system will facilitate study of RV biology in both in vitro and in vivo systems that will facilitate the improved design of RV vaccines, better antiviral therapies, and expression vectors.

On the Effect of the Various Assumptions and Approximations used in Molecular Simulations on the Properties of Bio-Molecular Systems: Overview and Perspective on Issues.

Computer simulations of molecular systems enable structure-energy-function relationships of molecular processes to be described at the sub-atomic, atomic, supra-atomic or supra-molecular level and plays an increasingly important role in chemistry, biology and physics. To interpret the results of such simulations appropriately, the degree of uncertainty and potential errors affecting the calculated properties must be considered. Uncertainty and errors arise from (1) assumptions underlying the molecular model, force field and simulation algorithms, (2) approximations implicit in the interatomic interaction function (force field), or when integrating the equations of motion, (3) the chosen values of the parameters that determine the accuracy of the approximations used, and (4) the nature of the system and the property of interest. In this overview, advantages and shortcomings of assumptions and approximations commonly used when simulating bio-molecular systems are considered. What the developers of bio-molecular force fields and simulation software can do to facilitate and broaden research involving bio-molecular simulations is also discussed.