Reparameterization of the chemical-potential equalization model with DFTB3: A practical balance between accuracy and transferability.

To improve the performance of the third-order density-functional tight-binding method (DFTB3) for non-covalent interactions involving organic and biological molecules, a chemical-potential equalization (CPE) approach was introduced [J. Phys. Chem. A, 116, 9131 (2012)] and parameterized for the H, C, N, O, and S chemical elements [J. Chem. Phys., 143, 084123 (2015)]. Based largely on equilibrium structures, the parameterized DFTB3/CPE models were shown to exhibit improvements in molecular polarizabilities and intermolecular interactions. With more extensive analyses, however, we observe here that the available DFTB3/CPE models have two critical limitations: (1) they lead to sharply varying potential energy surfaces, thus causing numerical instability in molecular dynamics (MD) simulations, and (2) they lead to spurious interactions at short distances for some dimer complexes. These shortcomings are attributed to the employed screening functions and the overfitting of CPE parameters. In this work, we introduce a new strategy to simplify the parameterization procedure and significantly reduce free parameters down to four global (i.e., independent of element type) ones. With this strategy, two new models, DFTB3/CPE(r) and DFTB3/CPE(r†) are parameterized. The new models lead to smooth potential energy surfaces, stable MD simulations, and alleviate the spurious interactions at short distances, thus representing consistent improvements for both neutral and ionic hydrogen bonds.

Accelerating the density-functional tight-binding method using graphical processing units.

Acceleration of the density-functional tight-binding (DFTB) method on single and multiple graphical processing units (GPUs) was accomplished using the MAGMA linear algebra library. Two major computational bottlenecks of DFTB ground-state calculations were addressed in our implementation: the Hamiltonian matrix diagonalization and the density matrix construction. The code was implemented and benchmarked on two different computer systems: (1) the SUMMIT IBM Power9 supercomputer at the Oak Ridge National Laboratory Leadership Computing Facility with 1-6 NVIDIA Volta V100 GPUs per computer node and (2) an in-house Intel Xeon computer with 1-2 NVIDIA Tesla P100 GPUs. The performance and parallel scalability were measured for three molecular models of 1-, 2-, and 3-dimensional chemical systems, represented by carbon nanotubes, covalent organic frameworks, and water clusters.

A large chromosomal inversion affects antimicrobial sensitivity of Escherichia coli to sodium deoxycholate.

Resistance to antimicrobials is normally caused by mutations in the drug targets or genes involved in antimicrobial activation or expulsion. Here we show that an Escherichia coli strain, named DOC14, selected for increased resistance to the bile salt sodium deoxycholate, has no mutations in any ORF, but instead has a 2.1 Mb chromosomal inversion. The breakpoints of the inversion are two inverted copies of an IS5 element. Besides lowering deoxycholate susceptibility, the IS5-mediated chromosomal inversion in the DOC14 mutant was found to increase bacterial survival upon exposure to ampicillin and vancomycin, and sensitize the cell to ciprofloxacin and meropenem, but does not affect bacterial growth or cell morphology in a rich medium in the absence of antibacterial molecules. Overall, our findings support the notion that a large chromosomal inversion can benefit bacterial cells under certain conditions, contributing to genetic variability available for selection during evolution. The DOC14 mutant paired with its isogenic parental strain form a useful model as bacterial ancestors in evolution experiments to study how a large chromosomal inversion influences the evolutionary trajectory in response to various environmental stressors.

In vitro synergy between sodium deoxycholate and furazolidone against enterobacteria.

BACKGROUND: Antimicrobial combinations have been proven as a promising approach in the confrontation with multi-drug resistant bacterial pathogens. In the present study, we identify and characterize a synergistic interaction of broad-spectrum nitroreductase-activated prodrugs 5-nitrofurans, with a secondary bile salt, Sodium Deoxycholate (DOC) in growth inhibition and killing of enterobacteria. RESULTS: Using checkerboard assay, we show that combination of nitrofuran furazolidone (FZ) and DOC generates a profound synergistic effect on growth inhibition in several enterobacterial species including Escherichia coli, Salmonella enterica, Citrobacter gillenii and Klebsiella pneumoniae. The Fractional Inhibitory Concentration Index (FICI) for DOC-FZ synergy ranges from 0.125 to 0.35 that remains unchanged in an ampicillin-resistant E. coli strain containing a ß-lactamase-producing plasmid. Findings from the time-kill assay further highlight the synergy with respect to bacterial killing in E. coli and Salmonella. We further characterize the mechanism of synergy in E. coli K12, showing that disruption of the tolC or acrA genes that encode components of multidrug efflux pumps causes, respectively, a complete or partial loss, of the DOC-FZ synergy. This finding indicates the key role of TolC-associated efflux pumps in the DOC-FZ synergy. Overexpression of Nitric Oxide-detoxifying enzyme Hmp results in a three-fold increase in FICI for DOC-FZ interaction, suggesting a role of nitric oxide in the synergy. We further demonstrate that DOC-FZ synergy is largely independent of NfsA and NfsB, the two major activation enzymes of the nitrofuran prodrugs. CONCLUSIONS: This study is to our knowledge the first report of nitrofuran-deoxycholate synergy against Gram-negative bacteria, offering potential applications in antimicrobial therapeutics. The mechanism of DOC-FZ synergy involves FZ-mediated inhibition of TolC-associated efflux pumps that normally remove DOC from bacterial cells. One possible route contributing to that effect is via FZ-mediated nitric oxide production.

Novel 5-Nitrofuran-Activating Reductase in Escherichia coli.

The global spread of multidrug-resistant enterobacteria warrants new strategies to combat these pathogens. One possible approach is the reconsideration of "old" antimicrobials, which remain effective after decades of use. Synthetic 5-nitrofurans such as furazolidone, nitrofurantoin, and nitrofurazone are such a class of antimicrobial drugs. Recent epidemiological data showed a very low prevalence of resistance to this antimicrobial class among clinical Escherichia coli isolates in various parts of the world, forecasting the increasing importance of its uses to battle antibiotic-resistant enterobacteria. However, although they have had a long history of clinical use, a detailed understanding of the 5-nitrofurans' mechanisms of action remains limited. Nitrofurans are known as prodrugs that are activated in E. coli by reduction catalyzed by two redundant nitroreductases, NfsA and NfsB. Furazolidone, nevertheless, retains relatively significant antibacterial activity in the nitroreductase-deficient ΔnfsA ΔnfsBE. coli strain, indicating the presence of additional activating enzymes and/or antibacterial activity of the unreduced form. Using genome sequencing, genetic, biochemical, and bioinformatic approaches, we discovered a novel 5-nitrofuran-activating enzyme, AhpF, in E. coli The discovery of a new nitrofuran-reducing enzyme opens new avenues for overcoming 5-nitrofuran resistance, such as designing nitrofuran analogues with higher affinity for AhpF or screening for adjuvants that enhance AhpF expression.

Charge-induced electromechanical actuation of two-dimensional hexagonal and pentagonal materials.

Using first-principles calculations, we investigate electromechanical properties of two-dimensional (2D) hexagonal and pentagonal materials as a function of electron and hole dopings, in which 2D materials including graphene, chair-like graphane, table-like graphane, penta-graphene (PG), hydrogenated penta-graphene (HPG), and penta-CN2 are considered. We find that the actuation responses such as actuation strain, stress generated, and work area-density per cycle of the 2D materials in the case of hole doping are substantially larger than those of electron doping. Moreover, the electromechanical properties of the 2D materials can be improved by hydrogenation. In particular, the actuation strain and work area-density per cycle of graphane and HPG are much larger than those of graphene and PG for hole doping, respectively. Interestingly, both the 2D hexagonal and pentagonal materials show an asymmetric dependence of theoretical strength (a maximum value of the stress that the materials can achieve by applying the strain) on the electron and hole dopings. These results provide an important insight into the electromechanical properties of the 2D hexagonal and pentagonal materials, which are useful for artificial muscle applications.

Synthesis and anti-proliferative activity of novel azazerumbone conjugates with chalcones.

The conjugation of azazerumbone ((3E,7E,11E)-5,5,8,12-tetramethylazacyclododeca-3,7,11-trien-2-one (7)) and 2,4-dihydroxychalcones was carried out for the preparation of novel target compounds 9a-g with 1-ethylene-4-methylene-1,2,3-triazole linker and 10a-f with propylene linker between amide nitrogen of azazerumbone and 4-hydroxy group of chalcone. The anti-proliferative activity of these compounds against the LU-1, Hep-G2, MCF-7 and SW480 human cancer cell lines were significantly improved compared to those of azazerumbone or zerumbone. The anti-proliferative activities of (3E,7E,11E)-1-((1-(2-(3-hydroxy-4-((E)-3-(3-methoxyphenyl)acryloyl)phenoxy)ethyl)-1H-1,2,3-triazol-4-yl)methyl)-5,5,8,12-tetramethyl azacyclododeca-3,7,11-trien-2-one (9b) and (3E,7E,11E)-1-(3-(4-((E)-3-(3,4,5-trimethoxyphenyl)acryloyl)phenoxy)propyl)-5,5,8,12-tetramethylazacyclododeca-3,7,11-trien-2-one (10d) are nearly comparable to those of ellipticine.

Radiotherapy promotes tumor-specific effector CD8+ T cells via dendritic cell activation.

Radiotherapy is an important treatment for cancer. The main mode of action is thought to be the irreversible damage to tumor cell DNA, but there is evidence that irradiation mobilizes tumor-specific immunity, and recent studies showed that the efficacy of high-dose radiotherapy depends on the presence of CD8(+) T cells. We show in this study that the efficacy of radiotherapy given as a single, high dose (10 Gy) crucially depends on dendritic cells and CD8(+) T cells, whereas CD4(+) T cells or macrophages are dispensable. We show that local high-dose irradiation results in activation of tumor-associated dendritic cells that in turn support tumor-specific effector CD8(+) T cells, thus identifying the mechanism that underlies radiotherapy-induced mobilization of tumor-specific immunity. We propose that in the absence of irradiation, the activation status of dendritic cells rather than the amount of tumor-derived Ag is the bottleneck, which precludes efficient anti-tumor immunity.

Multipole Expansion of Atomic Electron Density Fluctuation Interactions in the Density-Functional Tight-Binding Method.

The accuracy of the density-functional tight-binding (DFTB) method in describing noncovalent interactions is limited due to its reliance on monopole-based spherical charge densities. In this study, we present a multipole-extended second-order DFTB (mDFTB2) method that takes into account atomic dipole and quadrupole interactions. Furthermore, we combine the multipole expansion with the monopole-based third-order contribution, resulting in the mDFTB3 method. To assess the accuracy of mDFTB2 and mDFTB3, we evaluate their performance in describing noncovalent interactions, proton transfer barriers, and dipole moments. Our benchmark results show promising improvements even when using the existing electronic parameters optimized for the original DFTB3 model. Both mDFTB2 and mDFTB3 outperform their monopole-based counterparts, DFTB2 and DFTB3, in terms of accuracy. While mDFTB2 and mDFTB3 perform comparably for neutral and positively charged systems, mDFTB3 exhibits superior performance over mDFTB2 when dealing with negatively charged systems and proton transfers. Overall, the incorporation of the multipole expansion significantly enhances the accuracy of the DFTB method in describing noncovalent interactions and proton transfers.

Toward Quantum Chemical Free Energy Simulations of Platinum Nanoparticles on Titania Support.

Platinum nanoparticles (Pt-NPs) supported on titania surfaces are costly but indispensable heterogeneous catalysts because of their highly effective and selective catalytic properties. Therefore, it is vital to understand their physicochemical processes during catalysis to optimize their use and to further develop better catalysts. However, simulating these dynamic processes is challenging due to the need for a reliable quantum chemical method to describe chemical bond breaking and bond formation during the processes but, at the same time, fast enough to sample a large number of configurations required to compute the corresponding free energy surfaces. Density functional theory (DFT) is often used to explore Pt-NPs; nonetheless, it is usually limited to some minimum-energy reaction pathways on static potential energy surfaces because of its high computational cost. We report here a combination of the density functional tight binding (DFTB) method as a fast but reliable approximation to DFT, the steered molecular dynamics (SMD) technique, and the Jarzynski equality to construct free energy surfaces of the temperature-dependent diffusion and growth of platinum particles on a titania surface. In particular, we present the parametrization for Pt-X (X = Pt, Ti, or O) interactions in the framework of the second-order DFTB method, using a previous parametrization for titania as a basis. The optimized parameter set was used to simulate the surface diffusion of a single platinum atom (Pt1) and the growth of Pt6 from Pt5 and Pt1 on the rutile (110) surface at three different temperatures (T = 400, 600, 800 K). The free energy profile was constructed by using over a hundred SMD trajectories for each process. We found that increasing the temperature has a minimal effect on the formation free energy; nevertheless, it significantly reduces the free energy barrier of Pt atom migration on the TiO2 surface and the transition state (TS) of its deposition. In a concluding remark, the methodology opens the pathway to quantum chemical free energy simulations of Pt-NPs' temperature-dependent growth and other transformation processes on the titania support.

Integrated Sensing Chip for Ultrasensitive Label-Free Detection of the Products of Loop-Mediated Isothermal Amplification.

Loop-mediated isothermal amplification (LAMP) is a nucleic acid amplification technique that has been widely used for the detection of pathogens in many organisms. Current LAMP-based sensors usually require the LAMP products to be labeled in order for them to be detected. Here, we present a novel label-free LAMP chip, which consists of a nanopore thin-film sensor embedded inside a LAMP reaction chamber. A fraction of LAMP primers is immobilized on the sensor surface, allowing the LAMP products to be synthesized and bound to the sensor surface via immobilized primers. After the LAMP reaction components are removed from the reaction chamber, the amplified LAMP products bound to the sensor surface give rise to significantly increased transducing signals, which can be measured by a portable optical spectrometer through an optical fiber probe. As a demonstration, we used the LAMP chip to detect the causal agent of late blight, Phytophthora infestans, which is one of the most devastating plant pathogens and poses a major threat to sustainable crop production worldwide. We show that this chip can detect as low as 1 fg/µL of P. infestans DNA in 30 min, which corresponds to an attomolar level of 1.6 × 10-6 attomole/µL and is at least 10 times more sensitive than the currently available methods. This label-free sensing technology holds great promise to open up a new avenue for ultrasensitive, highly specific, rapid, and cost-effective point-of-care diagnostics of plant, animal, human, and foodborne pathogens.

Efficacy of Lemon Myrtle Essential Oil as a Bio-Fungicide in Inhibiting Citrus Green Mould.

The effectiveness of lemon myrtle (LM) (Backhousia citriodora) essential oil (EO) was investigated to combat Penicillium digitatum by in vitro agar diffusion and vapour assay and in artificially infected oranges. The main constituent of LM EO was revealed as citral when analysed in gas chromatography-mass spectrometry. Pure citral was also included in the experiment for comparison. The in vitro fungal growth was significantly inhibited by LM EO at 1, 2, 3, 4 and 5 µL per disc while complete growth inhibition by both the pure citral and LM EO occurred at 4 and 5 µL per disc. Inoculated fruits treated by dipping in 1000 µL L-1 LM EO solutions for 5, 10, 15, 30 and 120 s showed significantly lower fungal wounds compared to control. While longer dipping times led to some rind injuries, fruits with a 5 and 10 s dip were found free from any injury. The evaluation after dipping and storage confirmed that the fruits maintained the sensory attributes and were not compromised by the incorporation of the essential oil. The results of this study indicate that LM EO can be a promising alternative to synthetic fungicides for preserving the quality of citrus fruits during storage.

When less is more: shortening the Lpp protein leads to increased vancomycin resistance in Escherichia coli.

Vancomycin is a naturally occurring cell-wall-targeting glycopeptide antibiotic. Due to the low potency of this antibiotic against Gram-negative pathogens, such as Escherichia coli, there is a limited knowledge about interactions between vancomycin and this group of bacteria. Here, we show that an in-frame 63 bp deletion of the lpp gene caused a fourfold increase in vancomycin resistance in E. coli. The resulting protein, LppΔ21, is 21 amino acids shorter than the wild-type Lpp, a helical structural lipoprotein that controls the width of the periplasmic space through its length. The mutant remains susceptible to synergistic growth inhibition by combination of furazolidone and vancomycin; with furazolidone decreasing the vancomycin MIC by eightfold. These findings have clinical relevance, given that the vancomycin concentration required to select the lpp mutation is reachable during typical vancomycin oral administration for treating Clostridioides difficile infections. Combination therapy with furazolidone, however, is likely to prevent emergence and outgrowth of the lpp-mutated Gram-negative coliforms, avoiding exacerbation of the patient's condition during the treatment.

An Overview of Polymer Composite Films for Antibacterial Display Coatings and Sensor Applications.

The escalating presence of pathogenic microbes has spurred a heightened interest in antimicrobial polymer composites tailored for hygiene applications. These innovative composites ingeniously incorporate potent antimicrobial agents such as metals, metal oxides, and carbon derivatives. This integration equips them with the unique ability to offer robust and persistent protection against a diverse array of pathogens. By effectively countering the challenges posed by microbial contamination, these pioneering composites hold the potential to create safer environments and contribute to the advancement of public health on a substantial scale. This review discusses the recent progress of antibacterial polymer composite films with the inclusion of metals, metal oxides, and carbon derivatives, highlighting their antimicrobial activity against various pathogenic microorganisms. Furthermore, the review summarizes the recent developments in antibacterial polymer composites for display coatings, sensors, and multifunctional applications. Through a comprehensive examination of various research studies, this review aims to provide valuable insights into the design, performance, and real-time applications of these smart antimicrobial coatings for interactive devices, thus enhancing their overall user experience and safety. It concludes with an outlook on the future perspectives and challenges of antimicrobial polymer composites and their potential applications across diverse fields.

Acetyl-Click Screening Platform Identifies Small-Molecule Inhibitors of Histone Acetyltransferase 1 (HAT1).

HAT1 is a central regulator of chromatin synthesis that acetylates nascent histone H4. To ascertain whether targeting HAT1 is a viable anticancer treatment strategy, we sought to identify small-molecule inhibitors of HAT1 by developing a high-throughput HAT1 acetyl-click assay. Screening of small-molecule libraries led to the discovery of multiple riboflavin analogs that inhibited HAT1 enzymatic activity. Compounds were refined by synthesis and testing of over 70 analogs, which yielded structure-activity relationships. The isoalloxazine core was required for enzymatic inhibition, whereas modifications of the ribityl side chain improved enzymatic potency and cellular growth suppression. One compound (JG-2016 [24a]) showed relative specificity toward HAT1 compared to other acetyltransferases, suppressed the growth of human cancer cell lines, impaired enzymatic activity in cellulo, and interfered with tumor growth. This is the first report of a small-molecule inhibitor of the HAT1 enzyme complex and represents a step toward targeting this pathway for cancer therapy.

Accurate Free Energies for Complex Condensed-Phase Reactions Using an Artificial Neural Network Corrected DFTB/MM Methodology.

Semiempirical methods like density functional tight-binding (DFTB) allow extensive phase space sampling, making it possible to generate free energy surfaces of complex reactions in condensed-phase environments. Such a high efficiency often comes at the cost of reduced accuracy, which may be improved by developing a specific reaction parametrization (SRP) for the particular molecular system. Thiol-disulfide exchange is a nucleophilic substitution reaction that occurs in a large class of proteins. Its proper description requires a high-level ab initio method, while DFT-GAA and hybrid functionals were shown to be inadequate, and so is DFTB due to its DFT-GGA descent. We develop an SRP for thiol-disulfide exchange based on an artificial neural network (ANN) implementation in the DFTB+ software and compare its performance to that of a standard SRP approach applied to DFTB. As an application, we use both new DFTB-SRP as components of a QM/MM scheme to investigate thiol-disulfide exchange in two molecular complexes: a solvated model system and a blood protein. Demonstrating the strengths of the methodology, highly accurate free energy surfaces are generated at a low cost, as the augmentation of DFTB with an ANN only adds a small computational overhead.

Structural and functional characterization of NEMO cleavage by SARS-CoV-2 3CLpro.

In addition to its essential role in viral polyprotein processing, the SARS-CoV-2 3C-like protease (3CLpro) can cleave human immune signaling proteins, like NF-κB Essential Modulator (NEMO) and deregulate the host immune response. Here, in vitro assays show that SARS-CoV-2 3CLpro cleaves NEMO with fine-tuned efficiency. Analysis of the 2.50 Å resolution crystal structure of 3CLpro C145S bound to NEMO226-234 reveals subsites that tolerate a range of viral and host substrates through main chain hydrogen bonds while also enforcing specificity using side chain hydrogen bonds and hydrophobic contacts. Machine learning- and physics-based computational methods predict that variation in key binding residues of 3CLpro-NEMO helps explain the high fitness of SARS-CoV-2 in humans. We posit that cleavage of NEMO is an important piece of information to be accounted for, in the pathology of COVID-19.

Mindfulness-Based Smoking Cessation Delivered Through Telehealth and Text Messaging for Low-Income Smokers: Protocol for a Randomized Controlled Trial.

BACKGROUND: Tobacco use is the leading cause of preventable morbidity and mortality. Adults with low income and members of certain racial and ethnic minority groups are less likely to quit, and therefore, they experience profound tobacco-related health disparities. Mindfulness training can increase the rates of smoking cessation and lapse recovery, and telehealth and SMS text messaging have the potential to provide more accessible treatment. OBJECTIVE: This study aims to test the efficacy of delivering mindfulness-based smoking cessation treatment through text messaging (iQuit Mindfully) and telehealth (group videoconferencing), both as stand-alone interventions and in combination. In addition, it aims to examine the underlying mechanisms of mindfulness treatment. METHODS: In this 2×2 randomized controlled trial, participants are randomized into 1 of 4 groups based on assignment to iQuit Mindfully text messages (yes or no) and mindfulness videoconference groups (yes or no). The primary outcomes are biochemically verified smoking abstinence at 8, 12, and 24 weeks after the start of treatment. Secondary outcomes include the frequency of home mindfulness practice and self-reported levels of mindfulness, emotions, craving, withdrawal, dependence, self-efficacy, and social support. RESULTS: Recruitment, treatment, and assessment began in spring and summer 2021, and data collection is expected to continue through spring 2024. CONCLUSIONS: This project aims to improve smoking cessation outcomes for low-income, racially and ethnically diverse smokers through mindfulness-based telehealth group counseling and text messaging support. We also aim to advance the scientific study of the mechanisms of action of mindfulness treatment, which could inform the development of more efficacious and efficient treatments to reduce tobacco disparities. TRIAL REGISTRATION: Clinicaltrials.gov NCT04965181; https://clinicaltrials.gov/ct2/show/NCT04965181. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/35688.

Unusual hydrogen implanted gold with lattice contraction at increased hydrogen content.

The experimental evidence for the contraction of volume of gold implanted with hydrogen at low doses is presented. The contraction of lattice upon the addition of other elements is very rare and extraordinary in the solid-state, not only for gold but also for many other solids. To explain the underlying physics, the pure kinetic theory of absorption is not adequate and the detailed interaction of hydrogen in the lattice needs to be clarified. Our analysis points to the importance of the formation of hydride bonds in a dynamic manner and explains why these bonds become weak at higher doses, leading to the inverse process of volume expansion frequently seen in metallic hydrogen containers.