A multiscale polymerization framework towards network structure and fracture of double-network hydrogels

Double-network(DN)hydrogels,consisting of two contrasting and interpenetrating polymer networks,are considered as perhaps the toughest soft-wet materials.Current knowledge of DN gels from synthesis methods to toughening mechanisms almost exclusively comes from chemically-linked DN hydrogels by experiments.Molecular modeling and simulations of inhomogeneous DN structure in hydrogels have proved to be extremely challenging.Herein,we developed a new multiscale simulation platform to computationally investigate the early fracture of physically-chemically linked agar/polyacrylamide(agar/PAM)DN hydrogels at a long timescale.A“random walk reactive polymerization”(RWRP)was developed to mimic a radical polymerization process,which enables to construct a physically-chemically linked agar/PAM DN hydrogel from monomers,while conventional and steered MD simulations were conducted to examine the structural-dependent energy dissipation and fracture behaviors at the relax and deformation states.Collective simulation results revealed that energy dissipation of agar/PAM hydrogels was attributed to a combination of the pulling out of agar chains from the DNs,the disruption of massive hydrogen bonds between and within DN structures,and the strong association of water molecules with both networks,thus explaining a different mechanical enhancement of agar/PAM hydrogels.This computational work provided atomic details of network structure,dynamics,solvation,and interactions of a hybrid DN hydrogel,and a different structural-dependent energy dissipation mode and fracture behavior of a hybrid DN hydrogel,which help to design tough hydrogels with new network structures and efficient energy dissipation modes.Additionally,the RWRP algorithm can be generally applied to construct the radical polymerization-produced hydrogels,elastomers,and polymers.

A new precision medicine initiative at the dawn of exascale computing

Which signaling pathway and protein to selea to mitigate the patient's expected drug resistance?The number of possibilities facing the physician is massive,and the drug combination should fit the patient status.Here,we briefly review current approaches and data and map an innovative patient-specific strategy to forecast drug resistance targets that centers on parallel(or redundant)proliferation pathways in specialized cells.It considers the availability of each protein in each pathway in the specific cell,its activating mutations,and the chromatin accessibility of its encoding gene.The construction of the resulting Proliferation Pathway Network Atlas will harness the emerging exascale computing and advanced artificial intelligence(Al)methods for therapeutic development.Merging the resulting set of targets,pathways,and proteins,with current strategies will augment the choice for the attending physicians to thwart resistance.

Activation mechanisms of clinically distinct B-Raf V600Eand V600K mutants

Dear Editor,B-Raf,the main effector of Ras in the mitogen-activated protein kinase(MAPK)pathway,is among the most highly mutated kinases in human cancer[1].About 40%-60%of melanoma patients harbor B-Raf mutations,of which∼90%involve V600E and V600K.B-RafV600E is more frequent(60%-80%)than B-RafV600K(10%-30%).Substitution of a Val codon by Glu requires a single nucleotide change,whereas Val to Lys requires two[2].This is in line with melanoma patients harboring the V600K mutation,who usually suffer from higher sun exposure that may induce increased DNA damage[3].Since both mutations occur at the same position of the kinase domain and are mutated to charged residues,it was believed that the B-Raf V600E and V600K mutantswould share a similar behavior,and in clinical trials,patients with V600E and V600K mutations have been recruited into the same cohort.