Lippia grata Essential Oil Acts Synergistically with Ampicillin Against Staphylococcus aureus and its Biofilm.

Antimicrobial resistance (AMR) presents a global challenge as microorganisms evolve to withstand the effects of antibiotics. In addition, the improper use of antibiotics significantly contributes to the AMR acceleration. Essential oils have garnered attention for their antimicrobial potential. Indeed, essential oils extracted from plants contain compounds that exhibit antibacterial activity, including against resistant microorganisms. Hence, this study aimed to evaluate the antimicrobial and antibiofilm activity of the essential oil (EO) extracted from Lippia grata and its combination with ampicillin against Staphylococcus aureus strains (ATCC 25923, ATCC 700698, and JKD6008). The plant material (leaves) was gathered in Mossoro, RN, and the EO was obtained using the hydrodistillation method with the Clevenger apparatus. The antimicrobial activity of the EO was assessed through minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) assays. Antibiofilm activity was evaluated by measuring biomass using crystal violet (CV) staining, viable cell counting, and analysis of preformed biofilms. In addition, the synergistic effects of the EO in combination with ampicillin were examined by scanning electron and confocal microscopy. The EO displayed a MIC value of 2.5 mg/mL against all tested S. aureus strains and an MBC only against S. aureus JKD6008 at 2.5 mg/mL. L. grata EO caused complete biofilm inhibition at concentrations ranging from 10 to 0.312 mg/mL against S. aureus ATCC 25923 and 10 to 1.25 mg/mL against S. aureus ATCC 700698 and S. aureus JKD6008. In the viable cell quantification assay, there was a reduction in CFU ranging from 1.0 to 8.0 logs. The combination of EO with ampicillin exhibited a synergistic effect against all strains. Moreover, the combination showed a significantly inhibiting biofilm formation and eradicating preformed biofilms. Furthermore, the EO and ampicillin (individually and in combination) altered the cellular morphology of S. aureus cells. Regarding the mechanism, the results revealed that L. grata EO increased membrane permeability and caused significant membrane damage. Concerning the synergy mechanism, the results revealed that the combination of EO and ampicillin increases membrane permeability and causes considerable membrane damage, further inhibiting bacteria synergistically. The findings obtained here suggest that L. grata EO in combination with ampicillin could be a viable treatment option against S. aureus infections, including MRSA strain.

Anion-Responsive Colorimetric and Fluorometric Red-Shift in Triarylborane Derivatives: Dual Role of Phenazaborine as Lewis Acid and Electron Donor.

Photophysical modulation of triarylboranes (TABs) through Lewis acid-base interactions is a fundamental approach for sensing anions. Yet, design principles for anion-responsive TABs displaying significant red-shift in absorption and photoluminescence (PL) have remained elusive. Herein, a new strategy for modulating the photophysical properties of TABs in a red-shift mode has been presented, by using a nitrogen-bridged triarylborane (1,4-phenazaborine: PAzB) with a contradictory dual role as a Lewis acid and an electron donor. Following the strategy, PAzB derivatives connected with an electron-deficient azaaromatic have been developed, and these compounds display a distinct red-shift in their absorption and PL in response to an anion. Spectroscopic analyses and quantum chemical calculations have revealed the formation of a tetracoordinate borate upon the addition of fluoride, narrowing the HOMO-LUMO gap and enhancing the charge-transfer character in the excited state. This approach has also been demonstrated in modulating the photophysical properties of solid-state films.

Photophysics of Solvated Molecules: Computational Protocol Combining Nuclear Ensemble and Nonequilibrium State-Specific Solvation Methods.

Efficient calculations of the photophysical properties of molecules are essential for both understanding experimental results and accelerating materials discovery through computational simulations. However, to achieve accurate results, the effects of the surrounding medium must be taken into account. Here, we present a computational protocol that combines the nuclear ensemble method with a nonequilibrium state-specific polarizable continuum model to simulate absorption, fluorescence, phosphorescence, and intersystem crossing processes. Additionally, we introduced an extrapolation strategy that enables predictions for multiple solvents without incurring additional computational costs. We demonstrate the method's effectiveness by modeling the photophysical properties of a molecule that exhibits thermally activated delayed fluorescence, showcasing how these properties vary with solvent polarity. We also provide insight into the relationship between the solvent and photophysics by using ensemble analysis to rationalize simulation results. Furthermore, we introduce a metric for the intensity of the charge transfer character of electronic states and demonstrate how vibrations can significantly mix the electronic character of excited states. Overall, this work presents a computational approach that offers new insights into the photophysics of molecules and has the potential to advance materials discovery.

Comparative study of thermally activated delayed fluorescent properties of donor-acceptor and donor-acceptor-donor architectures based on phenoxazine and dibenzo[a,j]phenazine.

A new thermally activated delayed fluorescence (TADF) compound based on a donor-acceptor (D-A) architecture (D = phenoxazine; A = dibenzo[a,j]phenazine) has been developed, and its photophysical properties were characterized. The D-A compound is applicable as an emitting material for efficient organic light-emitting diodes (OLEDs), and its external quantum efficiency (EQE) exceeds the theoretical maximum of those with prompt fluorescent emitters. Most importantly, comparative study of the D-A molecule and its D-A-D counterpart from the viewpoints of the experiments and theoretical calculations revealed the effect of the number of the electron donor on the thermally activated delayed fluorescent behavior.

Assessing the effects of increasing conjugation length on exciton diffusion: from small molecules to the polymeric limit.

Organic solar cells (OSC) generally contain long-chain π-conjugated polymers as donor materials, but, more recently, small-molecule donors have also attracted considerable attention. The nature of these compounds is of crucial importance concerning the various processes that determine device performance, among which singlet exciton diffusion is one of the most relevant. The efficiency of the diffusion mechanism depends on several aspects, from system morphology to electronic structure properties, which vary importantly with molecular size. In this work, we investigated the effects of conjugation length on the exciton diffusion length through electronic structure calculations and an exciton diffusion model. By applying extrapolation procedures to thiophene and phenylene vinylene oligomer series, we investigate their electronic and optical properties from the small-molecule point of view to the polymeric limit. Several properties are calculated as a function of oligomer size, including transition energies, absorption and emission spectra, reorganization energies, exciton coupling and Förster radii. Finally, an exciton diffusion model is used to estimate diffusion lengths as a function of oligomer size and for the polymeric limit showing agreement with experimental data. Results also show that longer conjugation lengths correlate with longer exciton diffusion lengths in spite of also being associated with shorter exciton lifetimes.

Dynamical exciton decay in organic materials: the role of bimolecular recombination.

Excitons play a critical role in light emission when it comes to organic semiconductors. In high exciton concentration regimes, monomolecular and bimolecular routes for exciton recombination can yield different products affecting significantly the material's optical properties. Here, the dynamical decay of excitons is theoretically investigated using a kinetic Monte Carlo approach that addresses singlet exciton diffusion. Our numerical protocol includes two distinct exciton-exciton interaction channels: exciton annihilation and biexciton cascade emission. Our findings reveal that these channels produce different consequences concerning diffusion and spectroscopic properties, being able to explain diverging experimental observations. Importantly, we estimate critical exciton densities for which bimolecular recombination becomes dominant and investigate its effect on average exciton lifetimes and diffusion lengths.

Activation Energies and Diffusion Coefficients of Polarons and Bipolarons in Organic Conductors.

Intrachain diffusion of charge carriers in organic conductors is analyzed. Using a tight-binding model Hamiltonian that includes strong electron-phonon coupling combined with a Langevin equation, we simulate both polaron and bipolaron dynamics under quantum-corrected thermal effects. Nonadiabatic molecular time evolution is used to determine how these quasiparticles diffuse through a nondegenerate conjugated polymer. By means of a phenomenological approach, we evaluate the diffusion coefficient and activation energies for the motion of both polarons and bipolarons. The analysis of activation energies, in agreement with available experimental data, suggests that the presence of bipolarons may inhibit the efficiency of organic-based devices. The results presented here point to the importance of taking a closer look at the effects of bipolaron dynamics in organic devices.

Modeling temperature dependent singlet exciton dynamics in multilayered organic nanofibers.

Organic nanofibers have shown potential for application in optoelectronic devices because of the tunability of their optical properties. These properties are influenced by the electronic structure of the molecules that compose the nanofibers and also by the behavior of the excitons generated in the material. Exciton diffusion by means of Förster resonance energy transfer is responsible, for instance, for the change with temperature of colors in the light emitted by systems composed of different types of nanofibers. To study in detail this mechanism, we model temperature dependent singlet exciton dynamics in multilayered organic nanofibers. By simulating absorption and emission spectra, the possible Förster transitions are identified. Then, a kinetic Monte Carlo model is employed in combination with a genetic algorithm to theoretically reproduce time-resolved photoluminescence measurements for several temperatures. This procedure allows for the obtainment of different information regarding exciton diffusion in such a system, including temperature effects on the Förster transfer efficiency and the activation energy of the Förster mechanism. The method is general and may be employed for different systems where exciton diffusion plays a role.

Modeling the Emission Spectra of Organic Molecules: A Competition between Franck-Condon and Nuclear Ensemble Methods.

The emission spectra of flexible and rigid organic molecules are theoretically investigated in the framework of the Franck-Condon (FC) and nuclear ensemble (NE) approaches, both of which rely on results from density functional theory but differ in the way vibrational contributions are taken into account. Our findings show that the emission spectra obtained using the NE approach are in better agreement with experiment than the ones produced by FC calculations considering both rigid and flexible molecules. Surprisingly, the description of a suitable balance between the vibronic progression and the emission spectra envelope shows dependency on the initial sampling for the NE calculations which must be judiciously selected. Our results intend to provide guidance for a better theoretical description of light emission properties of organic molecules with applications in organic electronic devices.

Molecular modeling of multi-target analogs of huperzine A and applications in Alzheimer's disease.

CONTEXT: Given the diverse pathophysiological mechanisms underlying Alzheimer's disease, it is improbable that a single targeted drug will prove successful as a therapeutic strategy. Therefore, exploring various hypotheses in drug design is imperative. The sequestration of Fe(II) and Zn(II) cations stands out as a crucial mechanism based on the mitigation of reactive oxygen species. Moreover, inhibiting acetylcholinesterase represents a pivotal strategy to enhance acetylcholine levels in the synaptic cleft. This research aims to investigate the analogs of Huperzine A, documented in scientific literature, considering of these two hypotheses. Consequently, the speciation chemistry of these structures with Fe(II) and Zn(II) was scrutinized using quantum chemistry calculations, molecular docking simulations, and theoretical predictions of pharmacokinetics properties. From the pharmacokinetic properties, only two analogs, HupA-A1 and HupA-A2, exhibited a theoretical permeability across the blood-brain barrier; on the other hand, from a thermodynamic standpoint, the enantiomers of HupA-A2 showed negligible chelation values. The enantiomers with the most favorable interaction parameters were S'R'HupA-A1 (ΔGBIND = -40.0 kcal mol-1, fitness score = 35.5) and R'R'HupA-A1 (ΔGBIND = -35.5 kcal mol-1, fitness score = 22.61), being compared with HupA (ΔGBIND = -41.75 kcal mol-1, fitness score = 39.95). From this study, some prime candidates for promising drug were S'R'HupA-A1 and R'R'HupA-A1, primarily owing to their favorable thermodynamic chelating capability and potential anticholinesterase mechanism. METHODS: Quantum chemistry calculations were carried out at B3LYP/6-31G(d) level, considering the IEF-PCM(UFF) implicit solvent model for water. The coordination compounds were assessed using the Gibbs free energy variation and hard and soft acid theory. Molecular docking calculations were conducted using the GOLD program, based on the crystal structure of the acetylcholinesterase protein (PDB code = 4EY5), where the ChemScore function was employed with the active site defined as the region within a 15-Å radius around the centroid coordinates (X = -9.557583, Y = -43.910473, Z = 31.466687). Pharmacokinetic properties were predicted using SwissADME, focusing on Lipinski's rule of five.

Quantifying how single dose Ad26.COV2.S vaccine efficacy depends on Spike sequence features.

In the ENSEMBLE randomized, placebo-controlled phase 3 trial (NCT04505722), estimated single-dose Ad26.COV2.S vaccine efficacy (VE) was 56% against moderate to severe-critical COVID-19. SARS-CoV-2 Spike sequences were determined from 484 vaccine and 1,067 placebo recipients who acquired COVID-19. In this set of prespecified analyses, we show that in Latin America, VE was significantly lower against Lambda vs. Reference and against Lambda vs. non-Lambda [family-wise error rate (FWER) p < 0.05]. VE differed by residue match vs. mismatch to the vaccine-insert at 16 amino acid positions (4 FWER p < 0.05; 12 q-value ≤ 0.20); significantly decreased with physicochemical-weighted Hamming distance to the vaccine-strain sequence for Spike, receptor-binding domain, N-terminal domain, and S1 (FWER p < 0.001); differed (FWER ≤ 0.05) by distance to the vaccine strain measured by 9 antibody-epitope escape scores and 4 NTD neutralization-impacting features; and decreased (p = 0.011) with neutralization resistance level to vaccinee sera. VE against severe-critical COVID-19 was stable across most sequence features but lower against the most distant viruses.

[Epidemiology of ophidism in Venezuela (1996-2004)]. / Epidemiologia del ofidismo en Venezuela (1996-2004).

The data of accidents caused by snakebites in Venezuela, registered at the morbidity statistics of the Direction of Epidemiology and Strategic Analysis of the Ministry of Health and Social Development were analyzed. During the years of 1996-2004, 53,792 snakebites were registered in Venezuela (5,976 cases average per year), with a higher incidence during the year 2004 (7,486 incidents). Zulia reported the highest frequency of all the states (5,975 cases); meanwhile the Midwestern region, constituted by Lara, Portuguesa, Falc6n and Yaracuy states, had a higher morbidity for snake bites. The highest incidence, distributed per states was registered in Cojedes, during the year 2001, with 228.72 cases per 100,000 inhabitants. When it was determined by regions, the highest incidence occurred during the year 2004 at los Llanos with 63.81 per 100,000 inhabitants. The median of the incidence rate for Venezuela during the period was of 21.46 accidents per 100,000 inhabitants. The classification of the endemic areas for ophidism, according to the percentiles 23, 50, 75 and 90, organized the country in: (a) states and regions of very high endemicity, (b) high endemicity, (c) middle, (d) low and (e) very low endemicity. These epidemiological data indicated that the accidents caused by snakes constitute a collective health problem in Venezuela.

Modelling the quenching effect of chloroaluminum phthalocyanine and graphene oxide interactions: implications for phototherapeutic applications.

Photodynamic therapy (PDT) and photothermal therapy (PTT) are promising candidates for cancer treatment and their efficiency can be further enhanced by using a combination of both. While chloroaluminum phthalocyanine (AlClPc) has been studied extensively as a photosensitizer in PDT, nanographene oxide (nGO) has shown promise in PTT due to its high absorption of near-infrared radiation. In this work, we investigate the energy transport between AlClPc and nGO for their combined use in phototherapies. We use density functional theory (DFT) and time-dependent DFT to analyze the electronic structure of AlClPc and its interaction with nGO. Based on experimental parameters, we model the system's morphology and implement it in Kinetic Monte Carlo (KMC) simulations to investigate the energy transfer mechanism between the compounds. Our KMC calculations show that the experimentally observed fluorescence quenching requires modeling both the energy transfer from dyes to nGO and a molecular aggregation model. Our results provide insights into the underlying mechanisms responsible for the fluorescence quenching observed in AlClPc/nGO aggregates, which could impact the efficacy of photodynamic therapy.

Infective Endocarditis due to Non-HACEK Gram-Negative Bacilli: Clinical Characteristics and Risk Factors from a Prospective Multicenter Brazilian Cohort.

Background: Non-HACEK Gram-negative bacilli (NGNB) infective endocarditis (IE) has a growing frequency. We aimed to describe cases of NGNB IE and find associated risk factors. Methods: We conducted a prospective observational study of consecutive patients with definitive IE according to the modified Duke criteria in four institutions in Brazil. Results: Of 1154 adult patients enrolled, 38 (3.29%) had IE due to NGNB. Median age was 57 years, males predominated, accounting for 25/38 (65.8%). Most common etiologies were Pseudomonas aeruginosa and Klebsiella spp. (8 episodes, 21% each). Worsening heart failure occurred in 18/38 (47.4%). Higher prevalence of embolic events was found (55,3%), mostly to the central nervous system 7/38 (18.4%). Vegetations were most commonly on aortic valves 17/38 (44.7%). Recent healthcare exposure was found in 52.6% and a central venous catheter (CVC) in 13/38 (34.2%). Overall mortality was 19/38 (50%). Indwelling CVC (OR 5.93; 95% CI, 1.29 to 27.3; p = 0.017), hemodialysis (OR 16.2; 95% CI, 1.78 to 147; p = 0.008) and chronic kidney disease (OR 4.8; 95% IC, 1.2 to 19.1, p = 0.049) were identified as risk factors for mortality. Conclusions: The rate of IE due to NGNB was similar to that in previous studies. Enterobacterales and P. aeruginosa were the most common etiologies. NGNB IE was associated with central venous catheters, prosthetic valves, intracardiac devices and hemodialysis and had a high mortality rate.

Quantifying how single dose Ad26.COV2.S vaccine efficacy depends on Spike sequence features.

It is of interest to pinpoint SARS-CoV-2 sequence features defining vaccine resistance. In the ENSEMBLE randomized, placebo-controlled phase 3 trial, estimated single-dose Ad26.COV2.S vaccine efficacy (VE) was 56% against moderate to severe-critical COVID-19. SARS-CoV-2 Spike sequences were measured from 484 vaccine and 1,067 placebo recipients who acquired COVID-19 during the trial. In Latin America, where Spike diversity was greatest, VE was significantly lower against Lambda than against Reference and against all non-Lambda variants [family-wise error rate (FWER) p < 0.05]. VE also differed by residue match vs. mismatch to the vaccine-strain residue at 16 amino acid positions (4 FWER p < 0.05; 12 q-value ≤ 0.20). VE significantly decreased with physicochemical-weighted Hamming distance to the vaccine-strain sequence for Spike, receptor-binding domain, N-terminal domain, and S1 (FWER p < 0.001); differed (FWER ≤ 0.05) by distance to the vaccine strain measured by 9 different antibody-epitope escape scores and by 4 NTD neutralization-impacting features; and decreased (p = 0.011) with neutralization resistance level to vaccine recipient sera. VE against severe-critical COVID-19 was stable across most sequence features but lower against viruses with greatest distances. These results help map antigenic specificity of in vivo vaccine protection.

Diabatic Decomposition Perspective on the Role of Charge Transfer and Local Excitations in Thermally Activated Delayed Fluorescence.

Thermally activated delayed fluorescence (TADF) is a phenomenon that relies on the upconversion of triplet excitons to singlet excitons by means of reverse intersystem crossing (rISC). It has been shown both experimentally and theoretically that the TADF mechanism depends on the interplay between charge transfer and local excitations. However, the difference between the diabatic and adiabatic character of the involved excited states is rarely discussed in the literature. Here we develop a diabatization procedure to implement a four-state model Hamiltonian to a set of TADF molecules. We provide physical interpretations of the Hamiltonian elements and show their dependence on the electronic state of the equilibrium geometry. We also demonstrate how vibrations affect the TADF efficiency by modifying the diabatic decomposition of the molecule. Finally, we provide a simple model that connects the diabatic Hamiltonian to the electronic properties relevant to TADF and show how this relationship translates into different optimization strategies for rISC, fluorescence, and overall TADF performance.

Dual-photofunctional organogermanium compound based on donor-acceptor-donor architecture.

A dual-photofunctional organogermanium compound based on a donor-acceptor-donor architecture that exhibits thermally activated delayed fluorescence and mechano-responsive luminochromism has been developed. The developed compound was successfully applied as an emitter for efficient organic light-emitting diodes.

Immune Correlates Analysis of a Single Ad26.COV2.S Dose in the ENSEMBLE COVID-19 Vaccine Efficacy Clinical Trial.

Anti-spike IgG binding antibody, anti-receptor binding domain IgG antibody, and pseudovirus neutralizing antibody measurements four weeks post-vaccination were assessed as correlates of risk of moderate to severe-critical COVID-19 outcomes through 83 days post-vaccination and as correlates of protection following a single dose of Ad26.COV2.S COVID-19 vaccine in the placebo-controlled phase of ENSEMBLE, an international, randomized efficacy trial. Each marker had evidence as a correlate of risk and of protection, with strongest evidence for 50% inhibitory dilution (ID50) neutralizing antibody titer. The outcome hazard ratio was 0.49 (95% confidence interval 0.29, 0.81; p=0.006) per 10-fold increase in ID50; vaccine efficacy was 60% (43, 72%) at nonquantifiable ID50 (< 2.7 IU50/ml) and rose to 89% (78, 96%) at ID50 = 96.3 IU50/ml. Comparison of the vaccine efficacy by ID50 titer curves for ENSEMBLE-US, the COVE trial of the mRNA-1273 vaccine, and the COV002-UK trial of the AZD1222 vaccine supported consistency of the ID50 titer correlate of protection across trials and vaccine types.

Immune correlates analysis of the ENSEMBLE single Ad26.COV2.S dose vaccine efficacy clinical trial.

Measuring immune correlates of disease acquisition and protection in the context of a clinical trial is a prerequisite for improved vaccine design. We analysed binding and neutralizing antibody measurements 4 weeks post vaccination as correlates of risk of moderate to severe-critical COVID-19 through 83 d post vaccination in the phase 3, double-blind placebo-controlled phase of ENSEMBLE, an international randomized efficacy trial of a single dose of Ad26.COV2.S. We also evaluated correlates of protection in the trial cohort. Of the three antibody immune markers we measured, we found most support for 50% inhibitory dilution (ID50) neutralizing antibody titre as a correlate of risk and of protection. The outcome hazard ratio was 0.49 (95% confidence interval 0.29, 0.81; P = 0.006) per 10-fold increase in ID50; vaccine efficacy was 60% (43%, 72%) at non-quantifiable ID50 (<2.7 IU50 ml-1) and increased to 89% (78%, 96%) at ID50 = 96.3 IU50 ml-1. Comparison of the vaccine efficacy by ID50 titre curves for ENSEMBLE-US, the COVE trial of the mRNA-1273 vaccine and the COV002-UK trial of the AZD1222 vaccine supported the ID50 titre as a correlate of protection across trials and vaccine types.

Unified Framework for Photophysical Rate Calculations in TADF Molecules.

One of the challenges in organic light-emitting diodes research is finding ways to increase device efficiency by making use of the triplet excitons that are inevitably generated in the process of electroluminescence. One way to do so is by thermally activated delayed fluorescence (TADF), a process in which triplet excitons undergo upconversion to singlet states, allowing them to relax radiatively. The discovery of this phenomenon has ensued a quest for new materials that are able to effectively take advantage of this mechanism. From a theoretical standpoint, this requires the capacity to estimate the rates of the various processes involved in the photophysics of candidate molecules, such as intersystem crossing, reverse intersystem crossing, fluorescence, and phosphorescence. Here, we present a method that is able to, within a single framework, compute all of these rates and predict the photophysics of new molecules. We apply the method to two TADF molecules and show that results compare favorably with other theoretical approaches and experimental results. Finally, we use a kinetic model to show how the calculated rates act in concert to produce different photophysical behavior.