Accelerated Computation of Free Energy Profile at ab Initio Quantum Mechanical/Molecular Mechanics Accuracy via a Semi-Empirical Reference Potential. I. Weighted Thermodynamics Perturbation

Free energy profile (FE Profile) is an essential quantity for the estimation of reaction rate and the validation of reaction mechanism. For chemical reactions in condensed phase or enzymatic reactions, the computation of FE profile at ab initio (ai) quantum mechanical/molecular mechanics (QM/MM) level is still far too expensive. Semiempirical (SE) method can be hundreds or thousands of times faster than the ai methods. However, the accuracy of SE methods is often unsatisfactory, due to the approximations that have been adopted in these methods. In this work, we proposed a new method termed MBAR+wTP, in which the ai QM/MM free energy profile is computed by a weighted thermodynamic perturbation (TP) correction to the SE profile generated by the multistate Bennett acceptance ratio (MBAR) analysis of the trajectories from umbrella samplings (US). The weight factors used in the TP calculations are a byproduct of the MBAR analysis in the post-processing of the US trajectories, which are often discarded after the free energy calculations. The results show that this approach can enhance the efficiency of ai FE profile calculations by several orders of magnitude

Global burden of colistin-resistant bacteria : mobilized colistin resistance genes study (1980-2018)

Colistin is considered to be an antimicrobial of last-resort for the treatment of multidrug-resistant Gram-negative bacterial infections. The recent global dissemination of mobilized colistin resistance (mcr) genes is an urgent public health threat. An accurate estimate of the global prevalence of mcr genes, their reservoirs and the potential pathways for human transmission are required to implement control and prevention strategies, yet such data are lacking. Publications from four English (PubMed, Scopus, the Cochrane Database of Systematic Reviews and Web of Science) and two Chinese (CNKI and WANFANG) databases published between 18 November 2015 and 30 December 2018 were identified. In this systematic review and meta-analysis, the prevalence of mcr genes in bacteria isolated from humans, animals, the environment and food products were investigated. A total of 974 publications were identified. 202 observational studies were included in the systematic review and 71 in the meta-analysis. mcr genes were reported from 47 countries across six continents and the overall average prevalence was 4.7% (0.1-9.3%). China reported the highest number of mcr-positive strains. Pathogenic Escherichia coli (54%), isolated from animals (52%) and harboring an IncI2 plasmid (34%) were the bacteria with highest prevalence of mcr genes. The estimated prevalence of mcr-1 pathogenic E. coli was higher in food-animals than in humans and food products, which suggests a role for foodborne transmission. This study provides a comprehensive assessment of prevalence of the mcr gene by source, organism, genotype and type of plasmid

PRMT2 promotes dextran sulfate sodium-induced colitis by inhibiting SOCS3 via histone H3R8 asymmetric dimethylation

BACKGROUND AND PURPOSE: There is emerging evidence for critical roles of epigenetic modifiers in development of inflammatory bowel disease (IBD). Protein arginine methyltransferase 2 (PRMT2) is responsible for methylation of arginine residues on histones and targets transcription factors critically involved in many cellular processes, including gene transcription, mRNA splicing, cell proliferation and differentiation. However, its role in colitis remains unknown. In this study, the role and underlying mechanisms of PRMT2 in colitis was studied. EXPERIMENTAL APPROACH: A mouse dextran sulfate sodium (DSS)-induced experimental colitis model was applied to study PRMT2 in colitis. Lentivirus induced PRMT2 silencing or overexpression in vivo was applied to address the role of PRMT2 in colitis. Detailed western blot and expression analysis was done to understand epigenetic changes induced by PRMT2 in colitis. KEY RESULTS: PRMT2 is highly expressed in patients with IBD, inflamed colon of mice and TNF-α stimulated mice gut epithelial cells. PRMT2 overexpression aggravates while knockdown alleviates DSS-induced colitis in mice, suggesting that PRMT2 is a pivotal mediator of colitis development. Mechanistically, PRMT2 mediates colitis by increasing repressive histone mark H3R8 asymmetric methylation (H3R8me2a) at the promoter region of the suppressor of cytokine signaling 3 (SOCS3) promoter. Resultant inhibition of SOCS3 expression and SOCS3-mediated degradation of TNF receptor associated factor 5 (TRAF5) via ubiquitination led to elevated TRAF5 expression and TRAF5-mediated downstream NF-κB/MAPK activation. CONCLUSION AND IMPLICATIONS: Our study demonstrates that PRMT2 acts as a transcriptional co-activator for proinflammatory genes during colitis. Hence targeting PRMT2 may provide a novel therapeutic approach for colitis

Antibiotic Resistance in Salmonella Typhimurium Isolates Recovered From the Food Chain Through National Antimicrobial Resistance Monitoring System Between 1996 and 2016

Salmonella is a major foodborne pathogen which causes widespread contamination and infection worldwide. Salmonella Typhimurium is one of the leading serovars responsible for human and animal salmonellosis, globally. The increasing rate of antibiotic resistance in Salmonella Typhimurium poses a significant global concern, and an improved understanding of the distribution of antibiotic resistance patterns in Salmonella Typhimurium is essential for choosing the suitable antibiotic for the treatment of infections. To evaluate the roles of animal and human in antibiotic resistance dissemination, this study aims to categorize 11,447 S. Typhimurium strains obtained across the food-chain, including food animals, retail meats and humans for 21 years in the United States by analyzing minimum inhibitory concentrations (MICs) values for 27 antibiotics. Random Forest Algorithm and Hierarchical Clustering statistics were used to group the strains according to their minimum inhibitory concentration values. Classification and Regression Tree analysis was used to identify the best classifier for human- and animal-populations’ isolates. We found the persistent population or multi-drug resistant strains of S. Typhimurium across the four time periods (1996∼2000, 2001∼2005, 2006∼2010, 2011∼2016). Importantly, we also detected that there was more diversity in the MIC patterns among S. Typhimurium strains isolated between 2011 and 2016, which suggests significant emergence of diversified multi-drug resistant strains. The most frequently observed (43%) antibiotic resistance patterns found in S. Typhimurium were tetra-resistant pattern ASSuT (ampicillin, streptomycin, sulfonamides, and tetracycline) and the penta-resistant pattern ACSSuT (ampicillin, chloramphenicol, streptomycin, sulfonamides, and tetracycline). Animals (mainly swine and bovine) are the major source for these two frequently found antibiotic resistance patterns. The occurrence of antibiotic resistant strains from humans and chicken is alarming. Strains were mostly susceptible to fluoroquinolones. Together, this study helped in understanding the expansion of dynamics of antibiotic resistance of S. Typhimurium and recommended fluoroquinolones as a possible treatment options against S. Typhimurium infection

Spatially Constrained Organic Diquat Anolyte for Stable Aqueous Flow Batteries

Redox-active organic materials (ROMs) are becoming increasingly attractive for use in redox flow batteries as promising alternatives to traditional inorganic counterparts. However, the reported ROMs are often accompanied by challenges, including poor solubility and stability. Herein, we demonstrate that the commonly used diquat herbicides, with solubilities of >2 M in aqueous electrolytes, can be used as stable anolyte materials in organic flow batteries. When coupled with a ferrocene-derived catholyte, the flow cells with the diquat anolyte demonstrate long galvanic cycling with high capacity retention. Notably, the mechanistic underpinnings of this remarkable stability are attributed to the improved π-conjugation that originated from the near-planar molecular conformations of the spatially constrained 2,2′-bipyridyl rings, suggesting a viable structural engineering strategy for designing stable organic materials

Machine-Learning-Assisted Free Energy Simulation of Solution-Phase and Enzyme Reactions

Despite recent advances in the development of machine learning potentials (MLPs) for biomolecular simulations, there has been limited effort on developing stable and accurate MLPs for enzymatic reactions. Here we report a protocol for performing machine-learning-assisted free energy simulation of solution-phase and enzyme reactions at the ab initio quantum-mechanical/molecular-mechanical (ai-QM/MM) level of accuracy. Within our protocol, the MLP is built to reproduce the ai-QM/MM energy and forces on both QM (reactive) and MM (solvent/enzyme) atoms. As an alternative strategy, a delta machine learning potential (ΔMLP) is trained to reproduce the differences between the ai-QM/MM and semiempirical (se) QM/MM energies and forces. To account for the effect of the condensed-phase environment in both MLP and ΔMLP, the DeePMD representation of a molecular system is extended to incorporate the external electrostatic potential and field on each QM atom. Using the Menshutkin and chorismate mutase reactions as examples, we show that the developed MLP and ΔMLP reproduce the ai-QM/MM energy and forces with errors that on average are less than 1.0 kcal/mol and 1.0 kcal mol–1 Å–1, respectively, for representative configurations along the reaction pathway. For both reactions, MLP/ΔMLP-based simulations yielded free energy profiles that differed by less than 1.0 kcal/mol from the reference ai-QM/MM results at only a fraction of the computational cost

The lightest organic radical cation for charge storage in redox flow batteries

In advanced electrical grids of the future, electrochemically rechargeable fluids of high energy density will capture the power generated from intermittent sources like solar and wind. To meet this outstanding technological demand there is a need to understand the fundamental limits and interplay of electrochemical potential, stability, and solubility in low-weight redox-active molecules. By generating a combinatorial set of 1,4-dimethoxybenzene derivatives with different arrangements of substituents, we discovered a minimalistic structure that combines exceptional long-term stability in its oxidized form and a record-breaking intrinsic capacity of 161 mAh/g. The nonaqueous redox flow battery has been demonstrated that uses this molecule as a catholyte material and operated stably for 100 charge/discharge cycles. The observed stability trends are rationalized by mechanistic considerations of the reaction pathways.United States. Dept. of Energy. Office of Basic Energy Sciences. Chemical Sciences, Geosciences, & Biosciences Division (Contract DE-AC02-06CH11357

Annulated Dialkoxybenzenes as Catholyte Materials for Non‐aqueous Redox Flow Batteries: Achieving High Chemical Stability through Bicyclic Substitution

1,4‐Dimethoxybenzene derivatives are materials of choice for use as catholytes in non‐aqueous redox flow batteries, as they exhibit high open‐circuit potentials and excellent electrochemical reversibility. However, chemical stability of these materials in their oxidized form needs to be improved. Disubstitution in the arene ring is used to suppress parasitic reactions of their radical cations, but this does not fully prevent ring‐addition reactions. By incorporating bicyclic substitutions and ether chains into the dialkoxybenzenes, a novel catholyte molecule, 9,10‐bis(2‐methoxyethoxy)‐1,2,3,4,5,6,7,8‐octahydro‐1,4:5,8‐dimethanenoanthracene (BODMA), is obtained and exhibits greater solubility and superior chemical stability in the charged state. A hybrid flow cell containing BODMA is operated for 150 charge–discharge cycles with a minimal loss of capacity.A novel bicyclical substituted dialkoxy‐benzene molecule, 9,10‐bis(2‐methoxy‐ethoxy)‐1,2,3,4,5,6,7,8‐octahydro‐1,4:5,8‐dimethanenoanthracene (BODMA), is developed for use as catholyte materials in non‐aqueous redox flow batteries with greater solubility (in their neutral state) and improved chemical stability (in their charged state). A hybrid flow cell using BODMA demonstrates stable efficiencies and capacity over 150 cycles. The molecular design approach of BODMA can be inspirational for future development of redox active molecules.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/139992/1/aenm201701272.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/139992/2/aenm201701272-sup-0001-S1.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/139992/3/aenm201701272_am.pd