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Introduction: Growth arrest-specific 6 (Gas6) protein signaling plays a critical role in maintaining immune homeostasis and regulating inflammation. However, novel mechanisms for modulating macrophage activity through the Gas6 axis are being identified. Gas6 enhances the production of apoptosis inhibitor of macrophages (AIM), a protein with potent anti-inflammatory properties. This study investigates whether Gas6-induced AIM suppresses acute lung injury (ALI) in mice by modulating key inflammatory pathways, including inflammasome activation, autophagy, reactive oxygen species (ROS) generation, and efferocytosis. Methods: ALI was induced in wild-type (WT) and AIM−/− mice via intratracheal administration of LPS. To evaluate the effects of the Gas6-AIM axis on lung inflammation, recombinant Gas6 (rGas6) was treated intraperitoneally. Inflammatory responses were evaluated using enzyme-linked immunosorbent assay, a cell-sizing analyzer, and Bicinchoninic acid assays. Lung pathology was assessed using hematoxylin-eosin staining. NLRP3 inflammasome activation and autophagy were evaluated using western blot, quantitative real-time PCR, and immunofluorescence. Reactive oxygen species (ROS) levels in alveolar macrophages were measured via fluorescence microscopy, while efferocytosis was assessed in cytospin-stained BAL cells and cultured alveolar macrophages co-cultured with apoptotic Jurkat cells. Additionally, rGas6-mediated effects on NLRP3 inflammasome activation and autophagy were validated in mouse bone marrow-derived macrophages (BMDMs) using siRNAs targeting AIM, Axl, LXRα, or LXRβ. Results: Proinflammatory cytokine production, neutrophil infiltration, and protein levels in BALF were significantly reduced by rGas6 administration in WT mice but not in AIM−/− mice. Specifically, rGas6 reduced IL-1β and IL-18 levels, caspase-1 activity, and the production of apoptosis-associated speck-like protein containing a caspase activation and recruitment domain (ASC) in alveolar macrophages. Additionally, rGas6 promoted autophagy and efferocytosis in alveolar macrophages while reducing ROS levels through AIM production. These protective effects were absent in AIM−/− mice. Furthermore, siRNA-mediated silencing of Axl, LXRα, LXRβ, or AIM reversed the inhibitory effects of rGas6 on NLRP3 inflammasome activation in BMDMs, and AIM was essential for rGas6-induced autophagy. Conclusion: Gas6-induced AIM production protects against LPS-induced ALI by inhibiting NLRP3 inflammasome activation, enhancing autophagy and efferocytosis, and reducing oxidative stress. These findings highlight the Gas6–AIM axis as a potential therapeutic target for mitigating inflammatory lung diseases. [ABSTRACT FROM AUTHOR]

The [3 + 2] cycloaddition (32CA) reactions involving 6-butoxy-5,6-dihydro-4H-1,2-oxazine 2-oxide and dimethyl maleate are examined in this study. Molecular electron density theory (MEDT) is applied at the M06-2X/6-311G(d,p) level, coupled with the D3 dispersion correction. The nitronate 1 species are identified as zwitterionic entities through an analysis of the electron localization function (ELF). This 32CA reaction follows an asynchronous one-step mechanism. Conceptual DFT indices are utilized to classify dimethyl maleate as the electrophilic component and the nitronate as the nucleophilic counterpart. The [3 + 2] cycloaddition processes are predominantly governed by kinetic control, as indicated by activation free energies of − 23.6 and − 11.4 kcal.mol−1 for the exo and endo pathways, respectively, aligning with experimental findings. Despite the nucleophilic and electrophilic character of the reagents, the global electron density transfer at the TSs indicates rather polar 32CA reactions. The formation of a pseudoradical center initiates at carbon atoms C3 and C4. A subsequent docking analysis is conducted on cycloadducts 3 and 4 in relation to the main protease of SARS-CoV-2 (6LU7), alongside the co-crystal ligand. The results of this analysis reveal that cycloadducts 3 exhibit higher binding energy, while cycloadducts 4 display lower binding energy compared to the co-crystal ligand. The results confirm that the presence of isoxazolidine ring increases the affinity of the product 3. [ABSTRACT FROM AUTHOR]

Abstract\nHIGHLIGHTSThis paper describes the synthesis, spectroscopic characterization, in-vitro activity on A549 cell line, density functional theory, structure-activity relationship, molecular docking and ADMET evaluation of 2H-pyrido[1,2-a] pyrimidine-2,4(3H)-dione (PY) and 4-hydroxy-1,8-naphthyridin-2(1H)-one (NI). It was discovered that PY and NI showed moderate cytotoxicity against A549 cell line. Both the compounds PY and NI shows a remarkable decrease in the % cell viability of approx. 23% and 22% respectively. The ADMET analysis predicted a stronger effect for the P-glycoprotein activity. The first hyperpolarizabilities (β0) were found to be 2.21*10−30 esu (PY) and 5.79*10−30 esu (NI) respectively and compared with the standard reference urea. It was observed that the chemical reactivity of NI was better as compared to PY and ultimately it may be regarded as a good synthetic intermediate for the synthesis of a number of bioactive heterocycles like Vosaroxin, Gemifloxacin, quinazolines and many more.The two isomeric pyridine derivatives (PY and NI) were synthesized.In-silico studies of PY and NI include DFT, Molecular dynamics, ADMET, etc.The experimental values of PY and NI were in agreement with the theoretical results.PY and NI were investigated on the basis of ADMET and docking score and compared with Gilotrif.Compound NI was found most potent against the cancer cell line (A549).The two isomeric pyridine derivatives (PY and NI) were synthesized.In-silico studies of PY and NI include DFT, Molecular dynamics, ADMET, etc.The experimental values of PY and NI were in agreement with the theoretical results.PY and NI were investigated on the basis of ADMET and docking score and compared with Gilotrif.Compound NI was found most potent against the cancer cell line (A549). [ABSTRACT FROM AUTHOR]

Background: Mosquitoes, as vectors of various pathogens, have been a public health risk for centuries. Human activities such as international travel and trade, along with climate change, have facilitated the spread of invasive mosquitoes and novel pathogens across Europe, increasing the risk of mosquito-borne disease introduction and their spread. Despite this threat, mosquito control in Hungary still relies predominantly on chemical treatments, which poses the risk of developing insecticide resistance in local populations. While pyrethroid resistance has been documented in several countries, there is no information on this issue from Hungary. This study aims to investigate the presence of resistance in Hungarian mosquito populations by analyzing a native, already known disease vector and a recently established invasive species with public health significance. Methods: We assessed the presence of knockdown resistance (kdr) mutations L1014F in Culex pipiens and V1016G and F1534C in Aedes albopictus mosquitoes, which are responsible for pyrethroid resistance. Mosquito specimens were investigated retrospectively, collected from previous years within the framework of local monitoring programs run in urban areas representing five regions of Hungary. The mutations in mosquitoes were detected individually by allele-specific polymerase chain reaction (PCR) and gel electrophoresis, following generally used protocols. Results: In Cx. pipiens, the kdr mutation was detected across all five collection sites, with resistance allele frequencies ranging from 18.1% to 36.3%. Resistance alleles were identified in homozygosity and heterozygosity with the susceptible allele, resulting in 53% of the investigated mosquitoes showing resistance to pyrethroids in the Hungarian populations. In contrast, for Ae. albopictus, the analyzed individuals were found to carry only the susceptible alleles, indicating a homozygous susceptible genotype across the investigated populations on the basis of V1016G and F1534C genes. Conclusions: Our work highlights the consequences of the unilateral and long-term use of chemical treatments on mosquitoes. This indicates an urgent need for a change of concept in mosquito control strategy in Hungary, as well as in countries where mosquito control still relies dominantly on insecticides. The restricted use of chemical treatment is highly recommended to prevent the development of pyrethroid resistance in recently established populations of the invasive Ae. albopictus, and to decrease the public health risk of vector-borne diseases. [ABSTRACT FROM AUTHOR]

This study uses quantum chemical calculations to examine how cation-π interactions impact the structural and electronic properties of the 2,4-dioxo-4-phenylbutanoic acid complex in different solvents. The evaluation of the interaction's nature is accomplished by applying topological analysis of the atoms in molecules. Using natural bond orbital analysis, it is also possible to obtain electron populations that reflect the electron characteristics of the investigated system. Calculations indicate that the strongest/weakest interactions are observed in the selected complex when it is placed in non-polar/polar solvents. Furthermore, the studied complex displays two intramolecular hydrogen bonds in the form of O–H···O. Our findings suggest that the HBs of complex fall within the category of weak and medium HBs. Additionally, the O–H···O HBs are enhanced/diminished in the presence of cation–π interactions when exposed to polar/non-polar solvents. Finally, chemical reactivity descriptors are identified through the analysis of frontier molecular orbitals. [ABSTRACT FROM AUTHOR]

tating an aim is a vital skill for planning effective teaching Nonetheless, it is a skill one has to develop consciously Teacher trainees learn how to formulate aims during their teacher training and validate their aim design in their teaching practice Yet, they face several problems when stating an aim The thematic analysis of aims written by English language teaching (ELT) bachelor and master teacher trainees at the Technical University of Liberec is used to define clusters of aspects that their aim designs consist of The thematic analysis is followed by subsequent Spearman’s correlation coefficients’ statistics and Excel computations to analyse the frequency of those aspects in order to compare ELT bachelor and master teacher trainees’ aim designs and the potential impact of teaching experience on the ability to design an aim These results are contrasted to a preferable aim design description according to the theory The study results show that the aspects the respondents struggle with most are concreteness and student-orientedness, i.e. their aims are stated in vague language and are teacher-centred.

We study the quasinormal modes (QNMs) for scalar and electromagnetic perturbations in the Schwarzschild black hole with a deficit solid angle and quintessence-like matter. Using the sixth-order WKB approximation and the improved asymptotic iteration method, we can determine the dependence of the QNMs on the parameters of the black hole and the parameters on the test fields. The values of the real part and imaginary parts of the QNMs increase with the decrease of the values of the deficit solid angle and density of quintessence-like matter. The QNMs gotten by these two methods are in good agreement. Using the finite difference method, we obtain the time evolution profile of such perturbations in this black hole. [ABSTRACT FROM AUTHOR]

Context: In this paper, we present a theoretical study on the complexation of Co(II), Ni(II), and Cu(II) with a pyrazinamide ligand (PZA), which plays an important role in the treatment of tuberculosis and has biological and pharmacological benefits. It is a hybrid organic/inorganic material involving coordination between a metal ion and PZA ligand containing different coordination sites. This allows it to have different binding modes with metal ions and, therefore, provides a versatile ability to coordinate with metals. This study aimed to optimize the structures of the [M(PZA)2Cl2] complexes using density functional theory (DFT) at the B3LYP/6-311G + (d,p) level and the M06-2X functional is a high-nonlocality functional of double the amount of nonlocal exchange 2X. Various properties, including geometrical parameters, natural bonding orbital (NBO) to determine atomic charges, HOMO–LUMO energies, electronic properties, reactivity (ELF, LOL), NCI-RDG, and molecular electrostatic potential (MEP) on the surfaces of key metal-PZA complexes were determined and described. The AIM method has also been used to examine the chemical bonds. Furthermore, an in silico analysis aiming to explore the ADMET profiles of the compounds under investigation revealed promising aqueous solubility, oral bioavailability and gastrointestinal absorption, in addition to favorable druglikeness non-toxic and non-carcinogenic characteristics. Methods: The DFT method was carried out using Gaussian 09 software and GaussView 5.0. Avogadro software was used to define the geometry of the complexes. The Multiwfn program was used to produce scatter plots of the reduced density gradient (RDG), non-covalent interactions (NCI), ELF, LOL, and to define the parameters selected for the topological analysis of the BCPs using Bader's AIM. [ABSTRACT FROM AUTHOR]

The article is devoted to the problems of the categorical apparatus of the civil service in Ukraine. The civil service in our country is recognized as one of the most important institutions in the formation and development of Ukrainian statehood. It is from this institute that the quality of functioning of the social and political system as a whole and the solution of multifaceted tasks and functions of the modern state depend. Civil service has the greatest influence on the development of constitutional and legal formations and is the basis of state construction. It is argued that the civil service is a complex and multifunctional, legal and political institution, the essence of which is the performance by officials who are endowed with high professionalism, act in a complex relationship and in close interaction both among themselves and with other systemic entities, political forces, by public organizations and citizens, tasks and functions of the state within the legal field and in accordance with the authority granted to them to create social benefits, further development of social well-being and stability in the state. The most important features of the civil service are highlighted: the content of the civil service is an activity aimed at the practical implementation of tasks and functions of the state (analysis, development and implementation of state policy, ensuring the provision of affordable and high-quality administrative services, etc.); the public nature of this activity; professionalism; politically impartial character. It has been established that the priority of human rights and interests over the interests of the state should be the main feature of modern civil service. The goal of the civil service is disclosed, which consists in streamlining and increasing the efficiency of the processes of formation and implementation of state power and state administration, provided that responsibility for the performance of the powers of the position and social and economic guarantees of the civil service are combined. The main goals and tasks of the civil service have been defined in terms of ensuring the fair, effective and stable activity of state authorities in accordance with their powers and competence, aimed at protecting the rights and freedoms of people and citizens, as well as creating conditions for the development of civil society. [ABSTRACT FROM AUTHOR]

This study investigated the effect of using the Accelerative Integrated Method (AIM), with or without additional revision and video-guided practice, on junior primary students' spoken recall accuracy in French. The same beginner AIM French activities were taught by a language specialist to 12 classes in four junior primary levels. Three different conditions of instruction were used each week: (1) one session of AIM instruction, (2) one session of AIM instruction plus one session of revision, and (3) one session of AIM instruction, plus one session of revision, and three sessions of video input. The instruction and revision sessions were facilitated by a language teacher, whereas the video sessions were played by the main class teacher. A two-way ANOVA revealed that Year 1 students benefited from a revision session with the language teacher, but Prep and Year 1 did not benefit from further video exposure. Conversely, the Years 2 and 3 students did not benefit from extra revision with the language teacher, but they did benefit from additional video exposure. Direct observation of the student response to the AIM suggested that the pace of the program needed to be slower for the younger learners. [ABSTRACT FROM AUTHOR]

The current research work incorporates the synthesis, spectroscopic analysis, and in silico studies to evaluate anti-ovarian cancer potential and theoretical studies of 3-β-(2-(6 methoxynaphthalene-2yl)propionoxy)-stigmast-5-en (2). Synthesis of compound 2 was carried out by conjugating β-sitosterol (1) with Naproxen through highly efficient Steglich esterification. The structure elucidation of the synthesised compound has been done using 1H NMR, IR and UV as well as mass spectrometry. Anti-ovarian cancer potential of the compound 2 has been evaluated using its interaction with the ovarian cancer protein 2UZR (binding energy (ΔG) of -6.0 Kcal/mole) with the help of molecular docking studies. Topological parameters have been analyzed by "Atom in molecule" AIM theory. High value of first hyper polarizability (βo =6.071 × 10-30esu) of compound 2 indicates that it can be utilized as an ideal material for NLO applications. [ABSTRACT FROM AUTHOR]

Context: The 2,4-dioxo-4-phenylbutanoic acid (DPBA) is a subject of interest in pharmaceutical research, particularly in developing new drugs targeting viral and bacterial infections. Complexation with metal ions can improve the stability and solubility of organic compounds. The present study uses quantum chemical calculations to explore the structural and electronic results arising from the interaction between the metal cation (Fe2+) and the π-system of DPBA in different solvents. For this purpose, the analyses of atoms in molecules (AIM) and natural bond orbital (NBO) are employed to comprehend the interaction features and the charge delocalization during the process of complexation. The results demonstrate that the strongest/weakest interactions are evident when the complex is situated in non-polar/polar solvents, respectively. In addition, the investigated complex exhibits two intramolecular hydrogen bonds (IMHBs) characterized by the O–H···O motif. The results indicate that the HBs present in the complex fall within the category of weak to medium HBs. Moreover, the O–H···O HBs are influenced by cation–π interactions, which can increase/decrease their strength in polar/non-polar solvents. To enhance understanding of the interactions above, an examination is conducted on various physical properties including the energy gap, electronic chemical potential, chemical hardness, softness, and electrophilicity power. Method: All calculations are conducted within the density functional theory (DFT) using the ωB97XD functional and 6–311 + + G(d,p) basis set. The computations are performed using the quantum chemistry package GAMESS, and the obtained results are visualized by employing the GaussView program. [ABSTRACT FROM AUTHOR]

IntroductionGrowth arrest-specific 6 (Gas6) protein signaling plays a critical role in maintaining immune homeostasis and regulating inflammation. However, novel mechanisms for modulating macrophage activity through the Gas6 axis are being identified. Gas6 enhances the production of apoptosis inhibitor of macrophages (AIM), a protein with potent anti-inflammatory properties. This study investigates whether Gas6-induced AIM suppresses acute lung injury (ALI) in mice by modulating key inflammatory pathways, including inflammasome activation, autophagy, reactive oxygen species (ROS) generation, and efferocytosis.MethodsALI was induced in wild-type (WT) and AIM−/− mice via intratracheal administration of LPS. To evaluate the effects of the Gas6-AIM axis on lung inflammation, recombinant Gas6 (rGas6) was treated intraperitoneally. Inflammatory responses were evaluated using enzyme-linked immunosorbent assay, a cell-sizing analyzer, and Bicinchoninic acid assays. Lung pathology was assessed using hematoxylin-eosin staining. NLRP3 inflammasome activation and autophagy were evaluated using western blot, quantitative real-time PCR, and immunofluorescence. Reactive oxygen species (ROS) levels in alveolar macrophages were measured via fluorescence microscopy, while efferocytosis was assessed in cytospin-stained BAL cells and cultured alveolar macrophages co-cultured with apoptotic Jurkat cells. Additionally, rGas6-mediated effects on NLRP3 inflammasome activation and autophagy were validated in mouse bone marrow-derived macrophages (BMDMs) using siRNAs targeting AIM, Axl, LXRα, or LXRβ.ResultsProinflammatory cytokine production, neutrophil infiltration, and protein levels in BALF were significantly reduced by rGas6 administration in WT mice but not in AIM−/− mice. Specifically, rGas6 reduced IL-1β and IL-18 levels, caspase-1 activity, and the production of apoptosis-associated speck-like protein containing a caspase activation and recruitment domain (ASC) in alveolar macrophages. Additionally, rGas6 promoted autophagy and efferocytosis in alveolar macrophages while reducing ROS levels through AIM production. These protective effects were absent in AIM−/− mice. Furthermore, siRNA-mediated silencing of Axl, LXRα, LXRβ, or AIM reversed the inhibitory effects of rGas6 on NLRP3 inflammasome activation in BMDMs, and AIM was essential for rGas6-induced autophagy.ConclusionGas6-induced AIM production protects against LPS-induced ALI by inhibiting NLRP3 inflammasome activation, enhancing autophagy and efferocytosis, and reducing oxidative stress. These findings highlight the Gas6–AIM axis as a potential therapeutic target for mitigating inflammatory lung diseases.

The excited‐state double proton transfer (ESDPT) reaction in the intermolecular hydrogen‐bonded complex 7‐azaindole:piperidin‐2‐one is investigated by quantum chemical calculations with particular emphasis on the H‐bonding interactions within the system. The natural bond orbital (NBO) calculations show that the X─H···Y H‐bonds in the studied complexes, namely, 7‐azaindole:piperidin‐2‐one (N‐form) and 7H‐pyrrolo[2,3‐b]pyridine:3,4,5,6‐tetrahydropyridin‐2‐ol (T‐form, proton transferred tautomer) are aptly described by nY→σ∗(X−H)${n}_{\mathrm{Y}} \to {\sigma }^*({{\mathrm{X}} - {\mathrm{H}}})$ hyperconjugative charge transfer effect (nY${n}_{\mathrm{Y}}$ is non‐bonded lone‐pair on Y‐atom). That the hyperconjugation effect outplays the rehybridization effect is invoked to account for the observed red‐shifting H‐bonds in harmony with the Bent's rule. The differential nature of interactions underlying the origin of X─H···Y H‐bonds in the complexes (N‐form and T‐form) is explored from atoms‐in‐molecules (AIM) calculations. The H‐bonds in the N‐form are found to have a primarily electrostatic origin (closed‐shell interaction) whereas the relatively stronger H‐bonds in the T‐form are assisted by contribution from shared‐shell (covalent) interaction. The nonoccurrence of the double‐proton transfer reaction in the S0 state is argued from the large barrier for the transformation N‐form → T‐form (N‐form constitutes the global minimum on the S0‐PEC), whereas the stability order is reversed together with a marked reduction of the energy barrier in the S1‐PEC accounting for the ESDPT process. [ABSTRACT FROM AUTHOR]

Using a 1:1 cocrystal of (E)‐N‐(3,4‐difluorophenyl)‐1‐(pyridin‐4‐yl)methanimine with acetic acid, C12H8F2N2·C2H4O2, we investigate the influence of F atoms introduced to the aromatic ring on promoting π–π interactions. The cocrystal crystallizes in the triclinic space group P1. Through crystallographic analysis and computational studies, we reveal the molecular arrangement within this cocrystal, demonstrating the presence of hydrogen bonding between the acetic acid molecule and the pyridyl group, along with π–π interactions between the aromatic rings. Our findings highlight the importance of F atoms in promoting π–π interactions without necessitating full halogenation of the aromatic ring. [ABSTRACT FROM AUTHOR]

The theoretical and experimental analysis of 2-phenyl sulfanyl aniline was detailed in the present study. The B3LYP method with a 6-311++G (d, p) basis set was used to obtain the optimal structure. The 2PSA compound was characterized by FT-IR, FT-Raman and UV-Vis spectral studies. The intermolecular contact of 2PSA was studied by Hirshfeld surface analysis whereas an intra-molecular hydrogen bonding interaction was examined through atoms in molecule analysis. MESP recognizes the nucleophilic and electrophilic regions of inter and intra-non-covalent interaction. Natural bond orbital analysis reveals the interactions between the donor and acceptor. The nonlinear optical (NLO) behavior of the 2PSA compound was investigated by the computed value of the first-order hyperpolarizability. The good NLO quality of the compound has been confirmed through optical analysis, Urbach energy, extinction coefficient, and other parameters. [ABSTRACT FROM AUTHOR]

This study comprehensively analyzes molecular properties for neutral and protonated forms of adenine, caffeine, guanine, paraxanthine, theobromine, and theophylline. It highlights their shared bicyclic structures and biological relevance. Hirshfeld surface analysis reveals intricate interactions within the molecules, with color-coded regions indicating levels of proximity and potential hydrogen bonding. Noncovalent interactions and reduced density gradient analysis further elucidate the nature of interactions, encompassing van der Waals, steric, and hydrogen bonding. Topological parameters, examined through atom in molecule (AIM) analysis, emphasize the strength of hydrogen bonding within the molecules. Drug-likeness assessment underscores the compounds' alignment with drug-like attributes, driven by hydrogen bond donors, acceptors, and molecular weight. Natural bond order (NBO) analysis uncovers electron delocalization, bond order, and hybridization, elucidating interactions and stabilization energies. Nonlinear optical properties (NLO) analysis explores the potential for nonlinear optical phenomena, encompassing static dipole moment, polarizability, and hyper polarizability. The study delves into molecular orbitals and quantum chemical parameters, revealing insights into reactivity, electronegativity, ionization potential, and more. Protonation consistently influences these parameters, leading to shifts in energy levels, electronegativity, and reactivity. Collectively, this study provides a comprehensive understanding of molecular properties and interactions, offering valuable insights for potential applications and further research endeavors. [ABSTRACT FROM AUTHOR]

In this study, the interaction of graphene (G), BC3 nanoflake (B), and NC3 nanoflake (N) with Busulfan (BN) drugs under the influence of electrical fields and solvents is investigated. Density functional theory (DFT) and time-dependent density functional theory (TD-DFT) with 6-31G (d, p) basis set at ωB97XD level are employed to analyze the optimized geometrical structures, and various electronic and thermodynamic parameters of the BN&G, BN&BC3, and BN&NC3 complexes are calculated. The calculated results indicate that the interaction of BN with NC3 nanoflake exhibits higher adsorption energy and enthalpy than BC3 and G nanoflakes. The static electric field (SEF) enhances the dipole moment of BN&BC3 and BN&NC3 complexes, potentially facilitating drug binding to target cells and enhancing therapeutic effects. Furthermore, BC3 nanoflake shows promise in designing sensitive and selective sensors for BN drugs. Nonlinear optics (NLO) results, UV–visible spectra, and infrared (IR) spectra serve as effective methods for drug detection. The bonding nature between BN drug and studied nanoflakes is identified as van der Waals and electrostatic type. Overall, the calculated results indicate that BC3 and NC3 nanoflakes can emerge as promising candidates for the sensitive sensor of BN drugs and targeted drug delivery to cancer cells, respectively. [ABSTRACT FROM AUTHOR]

Bacteriophage therapy is the use of viruses to kill bacteria for the treatment of antibiotic-resistant infections. Little is known about the human immune response following phage therapy. We report the development of phage-specific CD4 T cells alongside rising phage-specific immunoglobulin G and neutralizing antibodies in response to adjunctive bacteriophage therapy used to treat a multidrug-resistant Pseudomonas aeruginosa pneumonia in a lung transplant recipient. Clinically, treatment was considered a success despite the development phage-specific immune responses.

Admixture estimation plays a crucial role in ancestry inference and genome-wide association studies (GWASs). Computer programs such as ADMIXTURE and STRUCTURE are commonly employed to estimate the admixture proportions of sample individuals. However, these programs can be overwhelmed by the computational burdens imposed by the 105 to 106 samples and millions of markers commonly found in modern biobanks. An attractive strategy is to run these programs on a set of ancestry-informative SNP markers (AIMs) that exhibit substantially different frequencies across populations. Unfortunately, existing methods for identifying AIMs require knowing ancestry labels for a subset of the sample. This supervised learning approach creates a chicken and the egg scenario. In this paper, we present an unsupervised, scalable framework that seamlessly carries out AIM selection and likelihood-based estimation of admixture proportions. Our simulated and real data examples show that this approach is scalable to modern biobank datasets. OpenADMIXTURE, our Julia implementation of the method, is open source and available for free.

Abstract The study investigates the molecular structure of 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO) and its derivatives in the gas phase using B3LYP and M06-2X functional methods. Intermolecular interactions are analyzed using natural bond orbital (NBO) and atoms in molecules (AIM) techniques. NO2-substituted TEMPO displays high reactivity, less stability, and softer properties. The study reveals that the stability of TEMPO derivatives is mainly influenced by LP(e) → σ ∗ electronic delocalization effects, with the highest stabilization observed on the oxygen atom of the nitroxide moiety. This work also considers electron density, atomic charges, and energetic and thermodynamic properties of the studied NO radicals, and their relative stability. The proton affinity and gas-phase basicity of the studied compounds were computed at T = 298 K for O-protonation and N-protonation, respectively. The studied DFT method calculations show that O-protonation is more stable than N-protonation, with an energy difference of 16.64–20.77 kcal/mol (22.80–25.68 kcal/mol) at the B3LYP (M06-2X) method. The AIM analysis reveals that the N–O…H interaction in H2O complexes has the most favorable hydrogen bond energy computed at bond critical points (3, − 1), and the planar configurations of TEMPO derivatives exhibit the highest EHB values. This indicates stronger hydrogen bonding interactions between the N–O group and water molecules.

Favipiravir, a medication, has drawn a lot of interest recently as a possible therapeutic option for viral illnesses such as the COVID-19 pandemic. In the current work, Favipiravir + Guanine combination is being spectroscopically characterized using Fourier Transformed Infrared Spectroscopy, Raman, and Surface-Enhanced Raman Spectroscopy tools. Density functional theory along with the Becke 3-Parameter, Lee-Yang-Parr method and the basis set 6-311++ G(d,p) is used to explore the molecular interactions between the monomers of Guanine and Favipiravir. The stability of the complex resulting from the charge delocalization is thoroughly examined by natural bond orbital analysis that demonstrates the C=O∙∙∙H intermolecular hydrogen bond formation. The nature of the intermolecular hydrogen bond is described using atoms in molecules analysis. Molecular electrostatic potential mapping depicts various regions of electrostatic potential for the molecules, characterizing their reactive nature. The complex's frontier molecular orbital gap of 2.39 eV indicates a higher possibility of electronic charge transfer, which in turn enhances the chemical reactivity of the complex. An analysis of the complex's hyperpolarizability reveals a good non-linear optical response. The antiviral activity of the Favipiravir + Guanine complex is demonstrated by its molecular docking against the 6LU7 receptor (−5.61 kcal/mol). [ABSTRACT FROM AUTHOR]

The effects of monosubstitution on the aromaticity of benzene are assessed using a number of different quantitative schemes. The ability of the mobile π-electrons to respond to an external magnetic field is evaluated using several variants of the NICS scheme which calculate the shielding of points along the axis perpendicular to the molecule. Another class of measures is related to the drive toward the uniformity of C-C bond lengths and strengths. Several energetic quantities are devised to approximate an aromatic stabilization energy and the tendency of the molecule to maintain planarity. There is a lack of consistency in that the various measures of aromaticity lead to differing conclusions as to the effects of substituents on the aromaticity of the ring. [ABSTRACT FROM AUTHOR]

In this research, the potential applicability of fullerene (C60), boron nitride cage (B12N12), and (Al/Si)-doped fullerene as an efficient sensing substance for the detection of dacarbazine (DAC) has been explored using density functional theory. The adsorption of DAC on nanocages surface was evaluated by using adsorption energy, quantum theory of atoms in molecule, natural bond orbital (NBO), and frontier molecular orbital (FMOs) analysis. The Al-doped BNNCs exhibit the greatest adsorption energy, while the C60 clusters have the least. B12N11Si and C60 cannot be suitable adsorbents for potential sensor due to the positive free energy. The DAC drug molecule prefers to be adsorbed on boron nitride cage with the aid of its carbonyl group and nitrogen head with an adsorption energy of about − 27.4171 and − 14.3520 kcal/mol, respectively. The large reduction of the HOMO–LUMO gaps of the B12N12 and AlB11N12 after the adsorption of drug reflects not only good selectivity but also easy recovery of the sensor, which suggests them as suitable sensors for DAC detection. [ABSTRACT FROM AUTHOR]

The 2016 reform eliminated the term cause from the French Civil Code. According to authors of the reform, it was intended to make the law simpler and more attractive, yet the functions of cause were to be retained. Concepts such as motive, aim, contrepartie convenue or contenu are even more ambiguous and obscure than the removed term. The aim of the article is to analyse the newly introduced regulations, including previous attempts to reform the French Civil Code and former regulation of the French Civil Code. As a result, the conducted research indicates that the reform did not eliminate the term cause from French civil law, because the content of new terms makes reference to the concept of cause still necessary. The manner in which the reform was carried out raises concerns that the reform contains loopholes. Additionally, the article discusses the differences and similarities between the Polish and French legal systems in the context of cause and its functions. Should the concept of cause in Polish law be abandoned? [ABSTRACT FROM AUTHOR]

The study investigates the molecular structure of 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO) and its derivatives in the gas phase using B3LYP and M06-2X functional methods. Intermolecular interactions are analyzed using natural bond orbital (NBO) and atoms in molecules (AIM) techniques. NO2-substituted TEMPO displays high reactivity, less stability, and softer properties. The study reveals that the stability of TEMPO derivatives is mainly influenced by LP(e) → σ∗ electronic delocalization effects, with the highest stabilization observed on the oxygen atom of the nitroxide moiety. This work also considers electron density, atomic charges, and energetic and thermodynamic properties of the studied NO radicals, and their relative stability. The proton affinity and gas-phase basicity of the studied compounds were computed at T = 298 K for O-protonation and N-protonation, respectively. The studied DFT method calculations show that O-protonation is more stable than N-protonation, with an energy difference of 16.64–20.77 kcal/mol (22.80–25.68 kcal/mol) at the B3LYP (M06-2X) method. The AIM analysis reveals that the N–O...H interaction in H2O complexes has the most favorable hydrogen bond energy computed at bond critical points (3, − 1), and the planar configurations of TEMPO derivatives exhibit the highest EHB values. This indicates stronger hydrogen bonding interactions between the N–O group and water molecules. [ABSTRACT FROM AUTHOR]

The structure of sulfathiazole-4-nitrobenzoic acid (STZBA) was characterized by X-ray diffraction (XRD). The crystal was stabilized by C–H...O, N–H...O, and S–O...S intermolecular interaction along with C–H...π and π...π interactions. The experimental FT-IR, FT-Raman, and UV-Vis spectra of STZBA were recorded and the results were compared with quantum chemical computation using the DFT method. Molecular electron density, topology, and natural bond orbital (NBO) analysis were used to explain the strength of the interaction. The molecular electrostatic potential and Fukui function of STZBA was determined to give a visual representation of charge distribution and provide information about the electrophilic and nucleophilic site of the molecule. Hirshfeld surface analysis was carried out to analyze the stability of the crystal structure. The antimicrobial activity of STZBA was determined against anticancer, bacterial strain E. coli and fungal stain Candida albicans and Sars-cov. Molecular docking analysis was performed with antimicrobial proteins to confirm the bioactivity of the molecule and drug likeness factors were calculated to comprehend the biological assets of STZBA. The molecular dynamic (MD) simulation result explains the protein stability, ligand properties, and protein-ligand interactions. The compounds were assessed for their structural, physic-chemical, pharmacokinetic, and toxicological properties. [ABSTRACT FROM AUTHOR]

Piperazin-1-ium 4-aminobenzoate monohydrate (PPAB) single crystals were grown by slow evaporation method. The grown crystal PPAB has been characterized by single-crystal X-ray diffraction, FTIR, FT-Raman, and UV-visible analysis. The B3LYP method and 6-311G (d, p) basis set were used to optimize the structure. The title compound was investigated theoretically and experimentally by FT-IR, FT-Raman, and UV-Vis spectral analysis. The presence of various functional groups in the structure was elucidated by FTIR and FT-Raman spectral studies. The intermolecular interactions within the crystal structure were investigated using Hirshfeld surface analysis. The crystal packing diagram reveals interesting non-covalent interactions involving C–H···O, N–H···O, and N–H···N hydrogen bonds, leading to the generation of 3D supramolecular architecture. The charge transfer within the molecule was deeply analyzed by using the NBO approach. The molecular electrostatic potential (MEP) and the local reactivity descriptors, such as Fukui function (fk+, fk−) analyses were performed to determine the reactive sites within the molecule. The HOMO and LUMO analysis was used to determine the chemical reactivity and bioactivity of the molecule. Hole-electron analysis was performed to analyze the charge transfer in an excited state. Based on the hole-electron analysis, the inter-fragment charge transfer (IFCT) analysis establishes the amount of charge transfer among different fragments. Topological analyses, such as AIM, RDG, and ELF were carried out to identify the non-covalent interaction within the molecule. The molecular docking studies of the molecule are performed to investigate the binding affinity of the ligand with the protein receptor. Drug-likeness properties, such as Lipinski's rule of five, adsorption, distribution, metabolism, excretion, and toxicity (ADMET) have been investigated by in silico web-based tools like SwissADME and ADMETlab. [ABSTRACT FROM AUTHOR]

FT-Raman, UV-visible, infrared Fourier transform, and DFT approaches, were used on molecule 3-amino-2,5-dichloropyridine. An extensive analysis of the vibrational distribution energy has been undertaken for the complete assignments for all the vibrations. Also carried out atoms in molecules theory of topological analysis, reduced density gradient and electron localization function. The contacts among the giver and acceptor were studied through natural bond orbital. The estimated values for the orbital of the highest and orbital of the lowest for various solvents reflect the electron stimulation properties. The electronic transition was obtained by ultraviolet-visible spectroscopy and time dependent-density function theory method with several solvents. The molecule's reactive regions are obtained by Fukui function and MEP exploration. The compound was subjected to non-linear optical investigations to determine its dipole moment, first-order polarizability, and hyperpolarizability. [ABSTRACT FROM AUTHOR]

Security vulnerabilities in the symmetric-key primitives of a cipher can undermine the overall security claims of the cipher. With the rapid advancement of quantum computing in recent years, there is an increasing effort to evaluate the security of symmetric-key cryptography against potential quantum attacks. This paper focuses on analyzing the quantum attack resistance of AIM, a symmetric-key primitive used in the AIMer digital signature scheme. We present the first quantum circuit implementation of AIM and estimate its complexity (such as qubit count, gate count, and circuit depth) with respect to Grover's search algorithm. For Grover's key search, the most important optimization metric is depth, especially when considering parallel search. Our implementation gathers multiple methods for a low-depth quantum circuit of AIM in order to reduce the Toffoli depth and full depth (such as the Karatsuba multiplication and optimization of inner modules;  Mer ,  LinearLayer). [ABSTRACT FROM AUTHOR]

In this study, the optimal geometry and vibrational assignments of 2-methyl-4-hydro-1,3,4-triazol-thione-5, one of the triazole derivatives, were analysed by the DFT approach and vibrational spectroscopy. PED values were calculated, and vibrational assignments were determined. Experimental results showed that interactions between 2-methyl-4-hydro-1,3,4-triazol-thione-5 and solvent (acetone, acetonitrile, dioxane, and DMF) molecules lead to a red shift of the N-H stretching vibrational band. The computations were performed at the B3LYP/6-311++G(d,p) functional set. The molecular electrostatic potential surface was used to distinguish between electrophilic and nucleophilic regions. The reactivity of the molecular complexes was determined by examining their frontier molecular orbitals. Topological investigations revealed the existence of N-H…N and N-H…O-type hydrogen bonds between 2-methyl-4-hydro-1,3,4-triazole-thiol-5 and solvent molecules. The red-shift of the N-H stretching band and H-bond strength between solute–solvent molecules are in the order of acetonitrile, acetone, dioxane, and DMF.

The Osme bond is defined as pairing a Group 8 metal atom as an electron acceptor in a noncovalent interaction with a nucleophile. DFT calculations with the ωB97XD functional consider MO4 (M = Ru, Os) as the Lewis acid, paired with a series of π electron donors C2H2, C2H4, C6H6, C4H5N, C4H4O, and C4H4S. The calculations establish interaction energies in the range between 9.5 and 26.4 kJ/mol. Os engages in stronger interactions than does Ru, and those involving more extensive π-systems within the aromatic rings form stronger bonds than do the smaller ethylene and acetylene. Extensive analysis questions the existence of a true Osme bond, as the bonding chiefly involves interactions with the three O atoms of MO4 that lie closest to the π-system, via π(C-C)→σ*(M-O) transfers. These interactions are supplemented by back donation from M-O bonds to the π*(CC) antibonding orbitals of the π-systems. Dispersion makes a large contribution to these interactions, higher than electrostatics and much greater than induction. [ABSTRACT FROM AUTHOR]

The structural, vibrational, electronic, and nonlinear optical properties of 4-amino benzoic acid pyrazinoic acid were obtained using spectral methods and density functional theory calculation. The title compound was characterized by Fourier transform infrared, Fourier transform-Raman, UV-Vis spectral studies and single crystal x-ray diffraction technique. By using density functional theory (DFT) using B3LYP method with 6-31 G(d,p) basis sets. The molecular geometry and vibrational frequencies were calculated and compared with the experimental data. The intermolecular contact of title compound was studied by Hirshfeld surface analysis whereas an intra-molecular hydrogen bonding interaction was examined through reduced density gradient plot. Molecular electrostatic potential and Fukui functions were also performed. Wave functional study like electron localization functions were analyzed. Bader's theory of atoms-in-molecule conjointly with natural bond orbital have been analyzed. The natural bond orbital (NBO) analysis enabled in comprehending the stability and charge delocalization in the title molecule. The first hyperpolarizability which is an important parameter for future studies of nonlinear optics (NLO) was calculated to check the potential of the molecule to be an NLO material. [ABSTRACT FROM AUTHOR]

Using density functional theory, polyols were used as model ligands for Cu+/Cu2+ complexes to study the role of the hydrogen bond network on the metal binding affinity. In addition to the gas phase studies, the calculations were performed in 1‐decanol and DMSO solvents. The Cu2+ complexes were the most stable complexes with the highest bond dissociation energies (BDE). The presence of three H‐bonds in the first shell increased BDE values up to 17.99 and 57.07 kcal/mol for Cu+ and Cu2+ complexes in the gas phase, respectively, whereas the presence of another three H‐bonds in the second shell increased BDE values up to 7.27 and 24.35 kcal/mol for Cu+ and Cu2+ complexes in the gas phase, respectively. Therefore, this H‐bond network caused, for example, a more stable Cu+ complex with a formation constant of 1.4 × 1017 times. The natural bond orbital (NBO), atoms in molecules (AIM), and reduced density gradient (RDG) analyses showed that the intramolecular hydrogen bond network led to the enhancement of metal‐binding affinity. [ABSTRACT FROM AUTHOR]

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The motivation of this study is to investigate the interaction of Si12C12, BSi11C12, NSi11C12, BSi12C11 and NSi12C11 nanocages with Glycine amino acid (Gly). The density functional theory (DFT) and time-dependent density functional theory (TD-DFT) at the cam-B3LYP/6-31G (p, d) level of theory by using Gaussian 09 software are utilized for this aim. The calculated results illuminate that the interaction of Gly with Si12C12, BSi11C12, NSi11C12, BSi12C11 and NSi12C11 nanocages is exothermic, and favorable in thermodynamic view. The adsorption of Gly from oxygen site (C=O) with NSi11C12 and BSi12C11 nanocage is more favorable than other complexes. The natural bonding orbital (NBO) results depicted that the electron charge transfer occur from Gly molecule toward SiC nanocage. The atom in molecule (AIM) and reduced density gradient (RDG) results confirm that the bonding between Gly and SiC nanocage is partially covalent or electrostatic type. The gap energy and global hardness of all studied complexes are lower than pure state, so the conductivity and reactivity of these complexes are more. The results of this study demonstrate that the Gly strong interact with BSi11C12, NSi11C12, BSi12C11 and NSi12C11 nanocages and the electrical structures of Gly alter significantly from pure state. These results can be considered in biological systems to investigate the effect of SiC nanocage in drug carriers and also provide information about the interaction of this nanocage with proteins in the body. [ABSTRACT FROM AUTHOR]

Since T cells are key mediators in the adaptive immune system, evaluating antigen-specific T cell immune responses is pivotal to understanding immune function. Commonly used methods for measuring T cell responses include Activation-Induced Marker (AIM) assays and Intracellular Cytokine Staining (ICS). However, combining these approaches has rarely been reported. This study describes a combined AIM + ICS assay and the effect of collecting the supernatant. Peripheral blood mononuclear cells (PBMCs) from seven healthy donors were stimulated with DMSO (negative control), Epstein-Barr virus (EBV) peptide pools, and PHA (positive control). The AIM markers OX40 + CD137+ were used for CD4+ T cells and CD69 + CD137+ and CD107a + CD137+ for CD8+ T cells. Cytokine-secreting cells were identified as CD40L+ cytokine+ for CD4+ and CD69+ or CD107 + cytokine+ for CD8+ T cells. Half of the supernatant was collected before adding the BFA/Monensin/CD137 antibody solution to assess the impact on T cell responses. The CD107a + CD137+ AIM markers combination had a lower background than CD69 + CD137+, making CD107a+ a more sensitive marker for CD8+ AIM markers. Collecting half of the supernatant did not significantly affect the immune responses. Our AIM + ICS combined protocol enables the simultaneous assessment of activation and cytokine release reducing the sample volume for testing T cell responses. We also show that collecting half of the supernatant does not significantly interfere with immune responses detection. [ABSTRACT FROM AUTHOR]

Rheumatoid arthritis (RA) is an autoimmune disease mainly characterized by joint inflammation. It presents extra-articular manifestations, with the lungs being one of the affected areas. Among these, damage to the pulmonary interstitium (Interstitial Lung Disease—ILD) has been linked to proteins involved in the inflammatory process and related to extracellular matrix deposition and lung fibrosis establishment. Peptidyl arginine deiminase enzymes (PAD), which carry out protein citrullination, play a role in this context. A genetic association analysis was conducted on genes encoding two PAD isoforms: PAD2 and PAD4. This analysis also included ancestry informative markers and protein level determination in samples from patients with RA, RA-associated ILD, and clinically healthy controls. Significant single nucleotide variants (SNV) and one haplotype were identified as susceptibility factors for RA-ILD development. Elevated levels of PAD4 were found in RA-ILD cases, while PADI2 showed an association with RA susceptibility. This work presents data obtained from previously published research. Population variability has been noticed in genetic association studies. We present data for 14 SNVs that show geographical and genetic variation across the Mexican population, which provides highly informative content and greater intrapopulation genetic diversity. Further investigations in the field should be considered in addition to AIMs. The data presented in this study were analyzed in association with SNV genotypes in PADI2 and PADI4 to assess susceptibility to ILD in RA, as well as with changes in PAD2 and PAD4 protein levels according to carrier genotype, in addition to the use of covariates such as ancestry markers. Dataset: DOI 10.3390/cells12182235 (published manuscript.). The datasets generated for this study can be found in ClinVar accessions SCV001422427–SCV001422434. Dataset License: Attribution 4.0 International (CC BY 4.0) [ABSTRACT FROM AUTHOR]