The current report contributes to the understanding of the stereoselectivity of the chiral dirhodium(II) carboxylate catalysts derived from N-protected amino acid ligands. Investigating the possible effect of ligand stereo-purity on catalyst structure and enantioselectivity was carried out. This was justified through a new X-ray crystal structure for Rh2(S,S,S,R-PTTL)4 diastereomer.

The core of risk aggregation in the Solvency II Standard Formula is the so-called square root formula. We argue that it should be seen as a means for the aggregation of different risks to an overall risk rather than being associated with variance-covariance based risk analysis. Considering the Solvency II Standard Formula from the viewpoint of linear geometry, we immediately find that it defines a norm and therefore provides a homogeneous and sub-additive tool for risk aggregation. Hence Euler's Principle for the reallocation of risk capital applies and yields explicit formulas for capital allocation in the framework given by the Solvency II Standard Formula. This gives rise to the definition of diversification functions, which we define as monotone, subadditive, and homogeneous functions on a convex cone. Diversification functions constitute a class of models for the study of the aggregation of risk, and diversification. The aggregation of risk measures using a diversification function preserves the respective properties of these risk measures. Examples of diversification functions are given by seminorms, which are monotone on the convex cone of non-negative vectors. Each L^p norm has this property, and any scalar product given by a non-negative positive semidefinite matrix does as well. In particular, the Standard Formula is a diversification function and hence a risk measure that preserves homogeneity, subadditivity, and convexity.

In this preliminary investigation, a concise molecular docking study using the Pyrx program screened thousands of compounds against the active site of HIV-1 reverse transcriptase. The Virtual Screening library was employed to assess binding energetics scores, focusing on identifying candidates with high Vina Scores. Eight compounds, including Tetrophan, Imatinib, Amentoflavone, Alprazolam, Bilobetin, Bafetinib, Nilotinib, and Ginketin, emerged as promising candidates with significant binding energies.Recognizing compounds that strongly bind to HIV-1 reverse transcriptase holds potential for antiretroviral drug development in the fight against HIV infection. Subsequently, the study evaluated the toxicity properties of these candidates using pKCSM. Amentoflavone, a natural biflavonoid found in Ginkgo biloba and Nilotinib, a tyrosine kinase inhibitor, demonstrated lower overall toxicity profiles compared to other candidates. Further toxicity analysis using Pro-Tox-II revealed Amentoflavone's higher predictive LD50, lower toxicity class, and reduced probabilities of hepatotoxicity, carcinogenicity, mutagenicity, and moderate immunotoxicity compared to Nilotinib. While Nilotinib, a pharmaceutical drug, exhibited higher probabilities of adverse effects in these categories. In summary, Amentoflavone and Nilotinib present as promising candidates with lower toxicity concerns. Amentoflavone, as a natural substance, showcases a more favorable toxicity profile than Nilotinib, offering valuable insights for potential therapeutic applications.

Casein Kinase ІІ (CK2) is one of the most versatile kinases. Its involvement in almost all cellular pathways makes it the Master Regulator of biochemical processes in a cell. This kinase is essential in regulating inflammation, cell differentiation, and cell cycle regulation. Often simultaneously. Its emerging role in senescence also indicates its function's centrality in cellular metabolism. The strategy to target this kinase to treat musculoskeletal disorders seems effective. These disorders often include a component of inflammation, dysregulated cell differentiation, and aging. This review focuses on CK2 target discovery and the diversity of its substrate interactions. We then transition toward the implication of CK2 in musculoskeletal disorders. Through a summary of current strategies for CK2 targeting with a new approach, we discuss the potential aspects that could be addressed in future drug research.

Filamentous manganese (Mn) oxide particles, which occur in the suboxic zone of stratified waterbodies, are important drivers of diverse elemental cycles. Although these particles are considered to be bacteriogenic, the environmental factor responsible for their formation has not been identified. Based on this study of laboratory cultures of a model Mn(II)-oxidizing bacterium, the supply of algal extracellular polymeric substances (EPS) was shown to stimulate Mn(II) oxidation and thus the production of filamentous Mn oxide particles. This observation was consistent with results obtained for naturally occurring particles collected from a near-bottom layer (depth of ~90 m) in the northern basin of Lake Biwa, Japan, that is, most Mn particles resembling delta-MnO2 were associated with an EPS-like gelatinous matrix, which contained dead algal cells and was lectin-stainable. In the lake water column, EPS produced by photosynthesis sank to the bottom layer. The analysis of the quality of water samples, which have been collected from the study site for 18 years, reveals that the annual average total phytoplankton biovolume in the surface layer correlates with the density of filamentous Mn particles in the near-bottom layer. Among different phytoplankton species, green algae appeared to be the key species. The results of this study suggest that algal EPS production induces the formation of filamentous Mn oxide particles in the near-bottom layer of the northern basin of Lake Biwa.

Lettuce is a salt-sensitive crop and has a threshold electrical conductivity of 1.3–2.0 mS cm-1 and above that is considered detrimental. As there has been very little information on the physio-logical response of different critical stages of lettuce under different salt stress (SS), the current study is focused on investigating the effects of SS on the critical physiological traits influencing the carbon assimilation in different growth stages of lettuce. The experiment was conducted in deep-water culture hydroponic system in a greenhouse condition. Four levels of sodium chloride salt treatments (EC: 20, 16, 8, and 1.8 mS cm-1) were applied. During both growth stages (day 11 (GS1) and day 19 (GS2) after salt treatment), the leaf transpiration rate, stomatal conductance, and intercellular CO2 were severely decreased. However, the carbon assimilation rate remained unchanged under SS. Similarly, the water use efficiency increased under the SS. It is concluded that the increasing SS increased stomatal and non-stomatal limiting factors during GS1 suggesting the enhanced limitation in photosynthetic activity while no such trend was observed during GS2. The decreased gm with increased SS at GS1 and GS2 suggested that SS induced the irreversible decrease of gm, which in turn can be responsible for the transient reduction in the Vcmax and Jmax during GS2. Taken together, the evidence from this research recommends that varying the SS levels can significantly affect the physiological performance of lettuce at both growth stages.

Coronavirus disease (COVID-19) is a new discovered strain where WHO officially declares the disease as COVID-19 while the virus responsible for it called Severe Acute Respiratory Syndrome Coronavirus 2 or SARS-CoV-2. The incubation period of this disease is between 14 days. Ordinary clinical symptoms that reported around the world include fever, cough, fatigue, diarrhoea and vomiting as well as asymptomatic for certain people. Infection is spread mainly through broad droplets. In early March 2020, WHO again has announced that COVID-19 is a pandemic with currently no specific treatment. The potential use of SARS-COV-2 proteome as a vaccine candidate by analysing through B-cell and T-cell antigenicity by using a immunoinformatics approach as a vaccine development early stage. In this study, we used consensus sequence for SARS-COV-2 proteome that was retrieved from NCBI database. VaxiJen 2.0 was mainly used to identify the antigenic property of SARS-COV-2 proteins. IEDB then used to analyse the B-cell epitope, the presence of T cell immunogenic epitope in SARS-COV-2 proteins was obtained by using compromise method of MHC class I and II tools that accessible respectively using ProPred-1 server and MHC II Binding Prediction in IEDB database. The best epitopes of B and T-cell epitopes were predicted with high antigencity and the information is disseminated through web-based database resource (https://covid-19.omicstutorials.com/epitopes/). This study will be useful to find a new epitope-based candidate for SARS-COV-2. However, further study needs to be done for the next stages of vaccine development.

This papers objective is to describe a method of in-office 3D designing and 3D printing of a tooth-borne molar distalizer and create a library to easily reproduce the needed distalizers in a private orthodontic clinic. Research objectives were to design and 3D print molar distalizers, clinically use in orthodontic treatment settings, assess the strength and frequency of debonding and or breakage. The print resin used was Dental LT Clear V2 (RS-F2-DLCL-02) from formlabs. The 3D printer used was a Formlabs 3B+printer. 16 patients were treated with these 3D printed distalizers. Patients selected were between 11 Years and 49 Years old, Class II occlusion with no skeletal Class II values. The skeletal cephalometric values of the six patients were within the range of SNA = 81± 3º , SNB = 78 ± 3º , ANB = 3 ± 2º. The mean duration of the 3D printed appliance was 14.58 ± 4.31 weeks. The aim reached, was to position molars and canines in a dental Class I position. The combined failure rate was 0.94. A library of distalizers has been made of sizes between 16mm and 29mm, they are easy to print and easy to use in office.

Several strategies promote phyllosphere colonization by soil-born Trichoderma plant-beneficial strains. One of these is foliar spraying with suspensions containing large amounts of chlamydospores – spores with a thick cell wall structure that makes them highly resistant to harsh environmental conditions. Trichoderma biomass was produced by cultivation on cornmeal medium and compared by microscopic and thermogravimetric analysis with the biomass produced in potato dextrose broth. Both analyses revealed higher chlamydospores content and thicker mycelium in the fungal biomass produced on cornmeal medium. The Trichoderma suspension rich in chlamydospores was sprayed on bitter gourd (Momordica charantia) leaves at two concentration levels, 106 and 108 ufc/ml. The effect of these treatments on plant physiological parameters, leaf photosynthetic pigments, polyphenol and flavonoid contents, antioxidant activity of leaves and fruits and yield was compared to the control (plants sprayed with water) and to the experimental treatment sprayed with 108 ufc propagules produced in potato dextrose broth. The effect of chlamydospore-rich suspensions on plant physiological parameters was more pronounced and long-lasting compared with the other treatments. The treatment with chlamydospore-rich suspension enhanced the accumulation of polyphenols and flavonoids in the leaves and fruits and increased the antioxidant activity. The application of the foliar treatment with Trichoderma suspensions did not modify the cytocompatibility of the extracts from fruits determined on L929 cells.

A new method for multi-shot reconstruction of high-energy photon distributions in the context of studying the interaction between a beam and a plasma in plasma wakefield acceleration (PWFA) experiments is presented. The study investigates the effects of beam perturbations on betatron radiation and analyzes how these perturbations can lead to hosing, a transverse instability that can degrade the quality of the beam. The potential of betatron radiation spectroscopy as a non-invasive diagnostic technique for PWFA experiments is also emphasized.

In the present work, we report on a 3D MOF of {[Pb5(3-OH)(3-NO3)3(6-pmdc)3·H2O}n formula (pmdc = pyrimidine-4,6-dicarboxylate) synthesized by an oven-heated solvent-free procedure. The large connectivity afforded by the three ligands in their coordination to lead(II) ions grows cubic building units characterized by a central Pb atom with an unusual coordination index of 12 and six pmdc ligands occupying the faces. These cubic units are linked one another giving rise to a quite condensed structure that represents an unprecedented topology showing the (4.62)6(43)2(45.610)3(45.68.82)6(46.69)6(612.83) point symbol. The crystalline material has been characterized by routine physico-chemical techniques to confirm its purity and its thermal behaviour has been also studied by thermogravimetric and thermodiffractometric analyses. The solid presents greenish blue photoluminescent emission based on pmdc ligands, as revealed time-dependent density-functional theory (TD-DFT) calculations, by that is substantially more intense than in free H2pmdc ligand according to its improved quantum yield. The emissive capacity of the material is further analysed according to decreasing temperature of the polycrystalline sample, finding that sizeable long-lasting phosphorescence is present.

The paper presents the development of cheap and selective Paper-based Analytical Devices (PADs) for Pd(II) determination. The PADs were obtained with an azoic ligand, (2-(tetrazolylazo)-1,8 dihydroxy naphthalene-3,6,-disulphonic acid), termed TazoC, and filter paper as the substrate. The orange TazoC-PADs interact quickly with Pd(II) solutions by forming a complex purple-blue-colored already at a very acidic pH (lower than 2). The dye complexes no other metal ions at such an acidic media, making TazoC-PADs highly selective to Pd(II) detection. Besides, at higher pH values, other cations, for example, Cu(II) and Ni(II), can interact with TazoC through the formation of stable and pink-magenta-colored complexes; however, it is possible to quantify Pd(II) also in the presence of other cations using a multivariate approach. Indeed, by applying Partial Least Square regression (PLS), the spectra of the TazoC-PADs were related to the Pd(II) concentrations both when present alone in solution and also in the presence of Cu(II) and Ni(II). The PLS models correctly predicted Pd(II) concentrations in unknown samples and tap water spiked with the metal cation.

Influenza virus transcription is catalyzed by the viral RNA-polymerase (FluPol) through a cap-snatching activity. The snatching of the cap of cellular mRNA by FluPol is preceded by its binding to the flexible C-terminal domain (CTD) of the RPB1 subunit of RNA-polymerase II (Pol II). To better understand how FluPol brings the 3’-end of the genomic RNAs in close proximity to the host-derived primer, we hypothesized that FluPol may recognize additional Pol II subunits/domains to ensure cap-snatching. Using binary complementation assays between the Pol II and FluPol subunits and their structural domains, we revealed an interaction between the N-third domain of PB2 and RPB4. This interaction was confirmed by a co-immunoprecipitation assay and found to occur with the homologous domains of influenza B and C FluPols. Residues [1-72] of RPB4 were found critical in this interaction. Numerous punctual mutants generated at conserved positions between influenza A, B and C FluPols in the N-third domain of PB2 exhibited strong transcriptional activity defect. These results suggest that FluPol interacts with several domains/subunits of Pol II, the CTD to bind Pol II initiating host transcription and a second on RPB4 to locate FluPol at the proximity of the 5’-end of nascent host mRNA.

Purpose: Acute kidney injury (AKI) is a severe symptom of the 2019 novel coronavirus disease (COVID-19), especially for patients in a critical condition.This study explored the potential mechanism of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on AKI at the single-cell level. Methods: 15 normal human kidney samples were collected and analyzed using single-cell RNA sequencing (scRNA-seq). Subsequently, we analyzed the components and proportions of kidney cells expressing the host cellular receptor ACE2 and the key protease TMPRSSs family, and analyzed the expression differences in Occidental and Asian populations. Results: We drafted the currently available world's largest human kidney cell atlas with 42,589 cells and identified 19 clusters through unsupervised hierarchical clustering analysis. ACE2 and TMPRSSs genes were significantly co-expressed in podocytes and proximal convoluted tubules as potential host cells targeted by SARS-CoV-2. Comparative analysis showed that ACE2 expression in kidney cells was no less than that in the lung, esophagus, small intestine and colon, suggesting that the kidney may be an important target organ for SARS-CoV-2. In addition, given the high expression of ACE2 and kidney disease-related genes in Occidental donors relative to Asian donors, Occidental populations with SARS-CoV-2 infection might be a higher risk of of kidney injury.

This study determines the equivalent stress intensity factor (SIF) model that best fits the experimental behavior of low-carbon steel under mixed mode (I and II). The study assessed Tanaka, Richard, and Pook's equivalent SIF models. The theoretical values used for comparison correspond to experimental results in a modified C(T) geometry by machining a hole ahead of the crack tip subjected to fatigue loads with a load ratio of R = 0.1. The comparison involved the SIF for six experimental points and the values computed through the numerical simulation. The Paris, Klesnil, and modified Forman-Newman crack growth models were used with each equivalent SIF to analyze the prediction in the estimated number of cycles. The Klesnil model showed the closest prediction since the error between the calculated and experimentally recorded number of cycles is the lowest. However, the material behavior reflects a reduced crack propagation rate attributed to plasticity in the crack tip. Results suggest that Asaro equivalent SIF conservatively estimates the element lifespan with increasing errors from 2.3% at the start of growth to 27 % at the end of the calculation.

In this work, Density Functional Theory (DFT) calculations were employed to study the photocatalytic CO2 to CO reduction by a series of Pt(II) square planar complexes with general formula [Pt(5-R-dpb)Cl] (dpb = 1,3-di(2-pyridyl)benzene anion, R = H, N,N-dimethylaniline,T thiophene, diazaborinine). The CO2 to CO conversion process is thought to proceed via two main steps, namely the photocatalytic/reduction step and the main catalytic step. The simulated absorption spectra exhibit strong bands in the 200 – 400 nm UV-Vis region. The calculated excited state reduction potentials are in the range 0.32 — -0.36 V revealing that the reductive quenching of the T1 state of the complexes could be modulated with suitable changes of the N^C^N pincer ligands. The CO2 fixation and activation by the ‘real’ three coordinated Pt(II) catalyst/intermediate is predicted to be favorable with Pt-CO2 bond dissociation energies, D0 in the range -36.9—-10.3 kcal/mol. The nature of the Pt-CO2 bond is complex with covalent, hyperconjugative and H-bonding interactions prevailing the repulsive electrostatic interactions. The main catalytic cycle is estimated to be a favorable exergonic process.

The SARS-CoV-2 pandemic continues to pose a global threat. While its virulence has subsided, it has persisted due to the continual emergence of new mutations. Although many high-risk conditions related to COVID-19 have been identified, the understanding of protective factors remains limited. Intriguingly, epidemiological evidence suggests a low incidence of the COVID-19-infected CD patients. The present study explores whether their genetic background, namely the associated HLA-DQs, offers protection against severe COVID-19 outcomes. We hypothesize that the HLA-DQ 2/8 alleles may shield CD patients from SARS-CoV-2 and its subsequent effects, possibly due to memory CD4 T cells primed by previous exposure to human-associated common cold coronaviruses (CCC) and higher affinity to those allele's groove. In this context, we examined potential cross-reactivity between SARS-CoV-2 epitopes and human-associated CCC and assessed the binding affinity (BA) of these epitopes to HLA-DQ 2/8. Using computational methods, we analyzed sequence similarity between SARS-CoV-2 and four distinct CCC. Of 924 unique immunodominant 15-mer epitopes with at least 67% identity, 37 exhibited significant BA to HLA-DQ 2/8, suggesting a protective effect. We present various mechanisms that might explain the protective role of HLA-DQ2/8 in COVID-19-afflicted CD patients. If substantiated, these insights could enhance our understanding of gene-environment enigma and viral-host relationship, guiding potential therapeutic innovations against the ongoing SARS-CoV-2 pandemic.

Understanding the energy metabolism and its regulation is one of the clues to metabolic engineering of stress-resistant lignocellulose-converting microbial strains, including also the promising ethanologen Zymomonas mobilis. Z. mobilis is an obligately fermentative, facultatively anaerobic bacterium, carrying an active respiratory chain with a low energy-coupling efficiency. Its respiration does not supply energy to aerobically growing culture on sugary media, yet oxidative phosphorylation has been demonstrated in non-growing cells with ethanol. In the present work we show that in respiring, non-growing Z. mobilis cells, receiving regular small amounts of ethanol, oxidative phosphorylation significantly contributes to the maintenance of their viability. Accordingly, no improvement of viability is seen in the NADH dehydrogenase (ndh)-deficient respiratory mutant, unable to oxidize ethanol. The ethanol effect is hampered also by the protonophoric uncoupler CCCP, or the inhibitor of ATP synthase, DCCD. At higher concentrations (6% v/v) ethanol causes stress that slows down culture growth. By monitoring the activity of several respiratory gene promoters in aerobically growing culture under ethanol stress with the green fluorescent protein reporter system, we demonstrate downregulation of these promoters, in particular the ndh promoter. We speculate that the decrease of the respiratory chain activity mitigates the production of reactive oxygen species.

In many practical applications, it is more convenient to characterize the quality of production processes or service operations throughout the count of nonconformities. In the context of SPC, nonconformities are usually assumed to appear according to the binomial probability model. The conventional way for monitoring nonconformities involves Shewhart-type control procedures based on both constant and time-varying sample sizes. In this article, an EWMA scheme is proposed for monitoring the fraction of nonconforming items with time-varying sample sizes. The proposed control chart is referred to as the EWMAG-B and can be easily adapted to work with a constant sample size by fixing it at a needed value. By means of simulation, it was found out that the EWMAG-B chart outperforms the conventional p control chart in Phase II while detecting changes in the process level is wanted.

The present work evaluates the food effect on the absorption of rivaroxaban (Riva), a BCS II drug, from the orally administered commercial immediate-release tablet (Xarelto IR) using physiologically based pharmacokinetic (PBPK) and conventional in vitro- in vivo correlation (IVIVC) models. The bioavailability of Riva upon oral administration of Xarelto IR tablet is reported to exhibit a positive food effect. The PBPK model for Riva was developed and verified using the previously reported in vivo data for oral solution (5 and 10 mg) and Xarelto IR tablet (5 and 10 mg dose strength). Once the PBPK model was established, the in vivo performance of the tablet formulation with the higher dose strength (Xarelto IR tablet 20 mg in fasted and fed state) was predicted using the experimentally obtained data of in vitro permeability, biorelevant solubility and in vitro dynamic dissolution data using United States Pharmacopeia (USP) IV flow-through cell apparatus. In addition, the mathematical IVIVC model was developed using the in vitro dissolution and in vivo profile of 20 mg strength Xarelto IR tablet in fasted condition. Using the developed IVIVC model, the pharmacokinetic (PK) profile of the Xarelto IR tablet in fed condition was predicted and compared with the PK parameters obtained via the PBPK model. A virtual in vivo PK study was designed using a single-dose, 3-treatment cross-over trial in 50 subjects to predict the PK profile of the Xarelto® IR tablet in the fed state. Overall, the results obtained from the IVIVC model were found to be comparable with that from the PBPK model. The outcome from both the model pointed to the positive food effect on the in vivo profile of the Riva. The developed models thus can be effectively extended to establish bioequivalence for the marketed and novel complex formulations of Riva such as amorphous solid dispersions.

1) Background: Climate change may subject forests to climate conditions to which they are not adapted. Elevated temperatures reduce net photosynthesis by increasing respiration rates and increasingly long droughts dramatically increase morbidity. CO₂ enrichment enhances productivity, but it is not clear to what extent CO₂ enrichment can offset the negative effects of elevated temperatures and longer droughts. 2) Methods: We used a mechanistic landscape model to conduct controlled simulation experiments manipulating CO₂ concentration, temperature, drought length and soil water capacity. 3) Results: We found that elevated CO₂ stimulates productivity such that it dwarfs the negative effect caused by elevated temperature. Energy reserves were not as strongly mitigated by elevated CO₂, and mortality of less competitive cohorts increased. Drought length had a surprisingly small effect on productivity measures, but had a marked negative effect on mortality risk. 4) Conclusions: Elevated CO₂ compensated for the negative effect of longer droughts in terms of productivity measures, but not survival measures.

The new diprotic ligand 3,5-di-tert-butylsalicylaldehyde 4-ethyl-3-thiosemicarbazone, abbreviated H2(3,5-t-Bu2)-sal4eT, exists as the thio-keto tautomer and adopts the E-configuration with respect to the imine double bond as evidenced by single-crystal X-ray analysis and corroborated by spectroscopic characterisation. Upon treatment with Cu(OAc)2·H2O in the presence of either 2,9-dimethyl-1,10-phenanthroline (2,9-Me2-phen) or 1,10-phenanthroline (phen) as a co-ligand in MeOH, this thiosemicarbazone undergoes conformational transformation (relative donor-atom orientations: syn,anti → syn,syn) concomitantly with tautomerization and double deprotonation to afford the ternary copper(II) complexes [Cu{(3,5-t-Bu2)-sal4eT}(2,9-Me2-phen)] (1) and [Cu2{3,5-t-Bu2)-sal4eT}2(phen)] (2). Crystallographic elucidation has revealed that complex 1 is a centrosymmetric dimer of mononuclear copper(II) complex molecules brought about by intermolecular H-bonding. The coordination geometry at the copper(II) centre is best described as distorted square pyramidal in accord with the trigonality index (τ = 0.14). The co-ligand adopts an axial-equatorial coordination mode; hence there is a disparity between its two Cu–N coordinate bonds arising from weakening of the apical one as a consequence of the tetragonal distortion. The axial X-band ESR spectrum of complex 1 is consistent with retention of this structure in solution. Complex 2 is a centrosymmetric dimer of dinuclear copper(II) complex molecules exhibiting intermolecular H-bonding and π-π-stacking interactions. The two copper(II) centres, which are 4.8067(18) Å apart and bridged by the thio-enolate nitrogen of the quadridentate thiosemicarbazonate ligand, display two different coordination geometries, one distorted square planar (τ4 = 0.082) and the other distorted square pyramidal (τ5 = 0.33). Such dinuclear copper(II) thiosemicarbazone complexes, which are crystallographically characterised, are extremely rare. In vitro, complexes 1 and 2 outperform cisplatin as antiproliferative agents in terms of potency and selectivity towards HeLa and MCF-7 cancer cell lines.

Diabetes mellitus is a chronic disease that affects millions of people worldwide. Article focuses on detecting the presence of diabetes in patients using microarray gene data obtained from the pancreas. Handle the high-dimensional nature of the data, four different dimensionality reduction techniques, namely Bessel Function, Discrete Cosine Transform (DCT), Least Square Linear Regression (LSLR), and Artificial Algae Algorithm (AAA) are used. After reduced the data, Meta-heuristic algorithms are applied like Dragonfly Optimization Algorithm (DOA) and Elephant Herding Optimization Algorithm (EHO) for feature selection. Ten classification techniques are using to classify the data in both the format like without feature selection method and with feature selection method. The classification techniques are Non-Linear Regression (NLR), Linear Regression (LR), Gaussian Mixture Model (GMM), Expectation Maximum (EM), Bayesian Linear Discriminant Classifier (BLDC), Logistic Regression (LoR), Softmax Discriminant Classifier (SDC), Support Vector Machine (SVM) with linear kernel, Support Vector Machine (SVM) with polynomial kernel, and Support Vector Machine (SVM) with Radial Basis Function (RBF) kernel. Results showed that the AAA with SVM(RBF) achieved an accuracy of 90% without feature selection. However, when feature selection was applied, with EHO of AAA with SVM(RBF) exhibited the highest accuracy of 95.714%, followed closely by with DOA of AAA with SVM (RBF) at 94.28%.

Herein, we report on a versatile system composed of two Ni(II)-based coordination compounds: a 3D metal-organic framework of {[Ni(μ-3isoani)2]·DMF}n (1) formula and a 0D monomeric [Ni(3isoani)2(H2O)4] (2) complex (where 3isoani = 3-aminoisonicotinato and DMF = dimethylformamide) which show mutual solvent-induced reversible transformations into each other. These 1 ↔ 2 transformations are triggered by the exposure of one compound to the solvent present in the other, that is, the MOF (1) in water and the monomer (2) in DMF. The process is easily followed by the naked eye because it involves a colour change from green (1)-to-brownish green (2), making the system potentially interesting to act as a sensor of those solvents. Moreover, these compounds present very different magnetic properties since 1 shows field-induced single-molecule magnet (SMM) behaviour, which corresponds to one of the few Ni(II)-based compounds showing this property, whereas 2 behaves as a regular paramagnet, all of which is explained according to a careful study of the magnetic properties by means of experimental direct-current (dc) and alternating-current (ac) measurements as well as complete active space self-consistent field (CASSCF) calculations.

Organic light-emitting diodes (OLEDs) are energy-efficient; however, the coordinating ligand can affect their stability. Sky-blue phosphorescent Pt(II) complexes with a C^N chelate, fluorinated-dbi (dbi = [1-(2,4-diisopropyldibenzo[b,d]furan-3-yl)-2-phenyl-1H-imidazole]), and acetylactonate (acac)(1)/picolinate (pic)(2) ancillary ligands were synthesized. The molecular structures were characterized using various spectroscopic methods. The Pt(II) coordination sphere in 2 exhibited a distorted square-planar geometry, with several intra- and inter-molecular interactions involving Cπ⋯H/Cπ⋯Cπ stacking. Complex 1 emitted bright sky-blue light (λmax = 485 nm) with a moderate photoluminescent quantum efficiency of 0.37 and short decay time (6.1 µs) compared to those of 2. Time-dependent density functional theory calculations suggested that the electronic transition of 1 arose from ligand(C^N)-centered π–π* transitions combined with metal-to-ligand charge transfer transitions (MLCT), whereas that of 2 arose from MLCT and ligand(C^N)-to-ligand(pic) charge transfer (LLCT), with minimal contribution from the C^N chelate to the lowest unoccupied molecular orbital. Multi-layered phosphorescent OLEDs using 1 as a dopant and a mixed host, 3,3-di(9H-carbazol-9-yl)-1,1-biphenyl:3-di(9H-carbazol-9-yl)-1,1-biphenyl (mCBP)/9-(3’-carbazol-9-yl-5-cyano-biphenyl-3-yl)-9H-carbazole-3-carbonitrile (CNmCBPCN) were successfully fabricated. At a 10% doping of 1, a current efficiency of 13.6 cd A−1 and external quantum efficiency of 8.4 % at 100 cd m−2 were achieved. These results show that the ancillary ligand in phosphorescent Pt(II) complexes must be considered.

Background: Multi-drug resistance organisms (MDRO) often cause increased morbidity, mortality, and length of stays (LOS). However, there is uncertainty whether the infection of MDRO increase the morbidity, mortality, and ICU-LOS. Objective: This study performed to determine the prevalence of MDRO in ICU, site of infection and the association of MDRO or site of infection with mortality. Secondary outcome was determined by ascertaining the association of MDRO or site of infection with (ICU-LOS). Methods: A retrospective cohort study was performed with adult sepsis patients in ICU. Univariate and multivariate (MVA) logistic regression with cox regression modeling were performed to compute the association of MDRO on ICU-mortality. MVA modelling was performed for ICU-LOS predictors. Results: Out of 228 patients, the isolated MDRO was 97 (42.5%) of which 78% were gram-negative bacteria. The mortality rate among those with MDRO was 85 (37.3%). The hospital acquired infection (HAI) was significantly predictor for ICU-LOS in univariate linear regression (R² = 0.034, P=0.005). In MVA linear regression, both Enterococcus faecalis infection and acinetobacter baumannii (AC) -MDRO were predictors for ICU-LOS with (R² = 0.478, P<0.05). In the univariate cox regression, only the infection with AC- MDRO was a risk factor for ICU-mortality with [ HR =1.802 (95% CI: 1.2 – 2.706; P = 0.005)]. Conclusions: Identifying risk factors for MDRO highlight the appropriate administration of empirical antibiotics and effectively control of source of infection which would reduce mortality and ICU-LOS. The usage of broad- spectrum antibiotics should be limited for those having substantial risk factors to acquire MDRO.

Abstract Antibacterial activities can be improved using mixed ligands. Mixed ligands involved in this research are sodium sulfadiazine (Na-sfz) and dithiocarbamate (ai-dtc). One-pot synthesis was used to synthesize ligand of aniline dithiocarbamate (ai-dtc) and the corresponding coordination compounds of [VO(sfz)(ai-dtc)] and [Zn(sfz)(ai-dtc)]. Crystals of ai-dtc, which grew from the solution when refrigerated after five days, were diffracted with technique of single crystal x-ray crystallography to reveal the structure. Other characterization techniques involving physicochemical parameters, FT-IR, UV-Vis and NMR (1H NMR and 13C NMR) were carried out on ligands of ai-dtc, sfz and corresponding coordination compounds. Differences in results of FT-IR, UV-Vis and NMR between ligands and their respective metal ions confirmed the coordination. The in vitro antibacterial studies showed that the ligands (not the metal complexes) had modest activity against Gram negative bacteria: Staphylococcus aureus, whereas, the coordination compounds had modest activities against the Gram negative bacteria: Escherichia coli and Pseudomonas aeruginosa.

We report a novel dual-band barrier infrared detector (DBIRD) design using type-II superlattices (T2SLs). The DBIRD structure consists of back-to-back barrier diodes: a "blue channel" (BC) diode which has an nBp architecture, an n-type layer of larger bandgap for absorbing blue band infrared/barrier/p-type layer, and a "red channel" (RC) diode which has an pBn architecture, a p-type layer of smaller bandgap for absorbing red band infrared/barrier/n-type layer. Each has a unipolar barrier using a T2SL lattice matched to a GaSb substrate to impede the flow of majority carriers from the absorbing layer. Each channel in the DBIRD can be independently accessed with a low bias voltage, as is preferable for high-speed thermal imaging. Device modeling of DBIRDs and simulation results of the current-voltage characteristics under dark and illuminated conditions are also presented. They predict that dual-band operation of the DBIRD will produce low dark currents and 27-33% quantum efficiencies for the in-band photons in the BC with λc=5.58 μm, and a nearly-constant 33% in the RC with λc=8.05 μm. The spectral quantum efficiency of the BC for 500 K blackbody radiation is approximately 20% over the range of λ=3 − 4.2 μm, while that of the RC has a peak of 42% at 5.7 μm. The DBIRD may provide improved high-speed dual-band imaging in comparison with NBn dual-band detectors.

Neurological disorders have been reported in a large number of coronavirus disease 2019 (COVID-19) patients, suggesting that this disease may have long-term adverse neurological consequences. COVID-19 occurs from the infection by a positive-sense single-stranded RNA virus called severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The membrane fusion protein of SARS-CoV-2, the spike protein, binds to its human host receptor, angiotensin-converting enzyme 2 (ACE2), to initiate membrane fusion between the virus and host cell. The spike protein of SARS-CoV-2 contains the furin protease recognition site and its cleavage enhances the infectivity of this virus. The binding of SARS-CoV-2 to the ACE2 receptor has been shown to downregulate ACE2, thereby increasing the levels of pathogenic angiotensin II (Ang II). The furin protease cleaves between the S1 subunit of the spike protein with the binding domain toward ACE2 and the S2 subunit with the transmembrane domain that anchors to the viral membrane, and this activity releases the S1 subunit into the blood circulation. The released S1 subunit of the spike protein also binds to and downregulates ACE2, in turn, increasing the level of Ang II. Considering that a viral particle contains many spike protein molecules, furin-dependent cleavage would release many free S1 protein molecules each of which can downregulate ACE2, while the infection with a viral particle only affects one ACE2 molecule. Therefore, the furin-dependent release of S1 protein would dramatically amplify the ability to downregulate ACE2 and produce Ang II. We hypothesize that this amplification mechanism that the virus possesses, but not the infection per se, is the major driving force behind COVID-19 associated neurological disorders.

The X-ray induced spin crossover transition of an Fe(II) molecular thin film in the presence and absence of a magnetic field has been investigated. The thermal activation energy barrier in the soft X-ray activation of the spin crossover transition for [Fe{H2B(pz)2}2(bipy)] molecular thin films is reduced in the presence of an applied magnetic field, as measured through X-ray absorption spectroscopy at various temperatures. The influence of a 1.8 T magnetic field is sufficient to cause deviations from the expected exponential spin state transition behavior that is measured in the field free case. We find that orbital moment diminishes with increasing temperature, relative to the spin moment in the vicinity of room temperature.

We developed two human induced pluripotent stem cell (hiPSC)/human embryonic stem cell-specific glycan-recognizing mouse antibodies, R-10G and R-17F, using the Tic (JCRB1331) hiPSC line as an antigen. R-10G recognizes a low-sulfate keratan sulfate, and R-17F recognizes lacto-N-fucopentaose-1. To evaluate the general characteristics of stem cell glycans, we used the hiPSC line 201B7 (HPS0063), a prototype iPSC line. Using an R-10G affinity column, an R-10G-binding protein was isolated. The protein yielded a single but very broad band from 480 to 1,236 kDa by blue native gel electrophoresis. After trypsin digestion, the protein was identified as podocalyxin by liquid chromatography/mass spectrometry. According to Western blotting, the protein reacted with R-10G and R-17F. The R-10G positive band was resistant to digestion with glycan-degrading enzymes, including peptide N-glycanase, but the intensity of the band was decreased significantly by digestion with keratanase, keratanase II, and endo-β-galactosidase, suggesting the R-10G epitope to be a keratan sulfate. These results suggest that keratan sulfate-type epitopes are shared by hiPSCs. However, the keratan sulfate from 201B7 cells contained a polylactosamine disaccharide unit (Galβ1-4GlcNAc) at a significant frequency, whereas that from Tic cells consisted mostly of keratan sulfate disaccharide units (Galβ1-4GlcNAc(6S)). In addition, the abundance of the R-10G epitope was significantly lower in 201B7 cells than in Tic cells.

RNA polymerase II (RNAPII) frequently transcribes non-protein coding DNA sequences in eukaryotic genomes into long non-coding RNA (lncRNA). Here, we focus on the impact of the act of lncRNA transcription on nearby functional DNA units. Distinct molecular mechanisms linked to the position of lncRNA relative to the coding gene illustrate how non-coding transcription controls gene expression. We review the biological significance of the act of lncRNA transcription on DNA processing, highlighting common themes, such as mediating cellular responses to environmental changes. This review presents the background in chromatin signaling to appreciate examples in different organisms where we can interpret functions of non-coding DNA through the act of RNAPII transcription.

Ataxin-2 (human gene symbol ATXN2, protein ATXN2) is the disease protein of Spinocerebellar Ataxia type 2 (SCA2). The large expansions of a polyglutamine (polyQ) stretch above a threshold of ~33 glutamines cause the multi-system nervous atrophy SCA2, while intermediate expansions of 29-32 glutamines contribute to the risk of the motor neuron diseases Amyotrophic Lateral Sclerosis (ALS) and Fronto-Temporal Lobar Dementia (FTLD). To elucidate the cellular function of ATXN2, we further characterized its direct interaction with alpha-Actinin-1 (symbol ACTN1), which had been observed in high-throughput yeast-two-hybrid surveys. An endogenous complex of ATXN2 and ACTN1 proteins was detected by co-immunoprecipitation. In vitro GST-tag pull-down experiments showed that the Calponin-Homology-domain at the N-terminus of ACTN1 binds to the N-terminus of ATXN2. Although an impact of the polyQ expansion on the interaction was not evident in pull-down experiments, a recent characterization of aged Atxn2-CAG100-KnockIn mice provides evidence. Both proteins associated in the cytosol and at the plasma membrane, as determined by sedimentation experiments in mouse brain, and by immunofluorescence microscopy of a transfected monkey cell line and of rat primary hippocampal neurons. In view of the roles of ACTN1 for spine plasticity and postsynaptic receptor control via reassembly of cortical actin, our data help to explain the impaired dendrite maintenance in SCA2.

The mixing of terrestrial groundwater and seawater creates dynamic reaction zones in intertidal areas, where land-derived Fe(II) is oxidized to Fe(III) and then precipitates as Fe hydroxides at groundwater-seawater interface. These hydrogeochemical processes contribute to the formation of iron curtains beneath soil surface, which in turn influences the evolution of coastal aquifers. This paper provides a comprehensive review of physical and geochemical processes at field scale in coastal areas, explores the impact of mineral precipitation on pore structure at pore scale, and synthesizes reactive transport modeling (RTM) approaches for illustrating continuum-scale soil physio-chemical parameters during the evolution of porous media. Upon this review, knowledge gaps and research needs are identified. Additionally, challenges and opportunities are presented. Therefore, the incorporation of observational data into a comprehensive physico-mathematical model becomes imperative for capturing the pore-scale processes in porous media and their influence on groundwater flow and solute transport at large scales. Furthermore, a synergistic approach integrating pore-scale modeling and non-invasive imaging can provide detailed insights into intricate fluid-pore-solid interactions for future studies, as well as facilitate the development of regional engineering-scale models and physio-chemical coupled models with diverse applications in submarine science and engineering.

Background: This practice guideline was developed by the Chronic Kidney Disease (CKD) Task Force, which was composed of clinical and methodological experts. The Saudi Arabian Ministry of Health and its Health Holding Company commissioned this guideline project to support the realization of the Vision 2030's healthcare transformation pillar. Methods: The guideline synthesis was guided by the GRADE-ADOLOPMENT methodology. Results: The final adoloped guideline addressed 12 clinical questions on blood pressure management in patients with CKD through a set of recommendations and performance measures. The recommendations included antihypertensive agents in children, non-renin angiotensin system inhibition (Non-RASi) vs RASi in adults, intensive vs standard blood pressure targets, early vs late assessment for kidney replacement therapy (KRT), late vs early preparation strategy for KRT, CKD symptoms during assessment for KRT or conservative management, initiation of KRT in patients with deteriorating CKD, choice of KRT modality or conservative management in certain CKD patient groups, changing or discontinuing KRT modalities, review frequency for KRT or conservative management, and Information, education and support. Conclusions: These conditional recommendations were based on low to very low certainty of evidence that highlights the need for high-quality randomized trials comparing different antihypertensive agents in patients with CKD.

Enzyme replacement therapy (ERT) improves the somatic manifestations in mucopolysaccharidoses (MPS))．However, because intravenously administered enzymes cannot cross the blood brain barrier (BBB), ERT is ineffective against the progressive neurodegeneration and resultant severe central nervous system (CNS) symptoms observed in patients with neuronopathic MPS. Attempts to surmount this problem have been made with intrathecal and intracerebroventricular ERT intend to achieve CNS effects, but the burdens on patients are inimical to long-term multiple administrations. However, after pabinafusp alfa, a human iduronate-2-sulfatase fused with a BBB-crossing anti-transferrin receptor antibody, showed both central and peripheral efficacy in mice model, subsequent clinical trials in a total of 62 patients with MPS-II (Hunter syndrome) in Japan and Brazil substantiated this dual efficacy and provided an acceptable safety profile. To date, pabinafusp alfa is the only approved intravenous ERT effective against both the somatic and CNS symptoms of patients with MPS-II. This article summarizes the hitherto obtained preclinical and clinical evidence associated with this drug, and discusses the preclinical, translational and clinical challenges of evaluating, ameliorating and preventing the neurodegeneration in patients with MPS-II.

In this work, kinetics of the reaction between 5,10,15,20-tetrakis(N-methylpyridium-4-yl)porphyrin and Ni2+ species were investigated in aqueous solution at 25 ±1 ºC in I = 0.10 M (NaNO3). Speciation of Ni2+ was carried out in I = 0.10 M (NaNO3) in order to provide the distribution of the Ni2+ species with different solution pH. The experimental data have been compared with the speciation diagram constructed from the values of hydrolysis constants of Ni2+ ion. Speciation data showed that the hexaaquanickel(II), [Ni(H2O)6]2+, ions take place in hydrolysis reactions through formation of [Ni(OH2)6-n(OH)n]2-n species with solution pH. Based on the speciation of Ni2+ and pH dependent rate constants, rate expression can be written as: d[Ni(TMPyP)4+]/dt = (k1[Ni2+(aq)] + k2[Ni(OH)+(aq)] + k3[Ni(OH)2o(aq)] + k4[Ni(OH)3-(aq)])[H2TMPyP4+], where k1, k2, k3 and k4 were found to be k1 = (0.62 ± 0.22) × 10-2; k2 = (3.60 ± 0.40) × 10-2; k3 = (2.09 ± 0.52) × 10-2, k4 = (0.53 ± 0.04) × 10-2 M-1s-1 at 25 ±1 °C, respectively. Kinetic results showed that monohydroxo, [Ni(H2O)5(OH)]+, is the most reactive among the [Ni(OH2)6-n(OH)n]2-n species. The enhanced reactivity has been ascribed to the formation of hydrogen bonding between oxygen atom of hydroxyl group of the [Ni(H2O)5(OH)]+ species and the pyrrolic hydrogen atom of the [H2TMPyP]4+. The rate of formation of [Ni(II)TMPyP]4+ complex was to be 3.99 × 10-2 M-1s-1 in I = 0.10 M, NaNO3 (25 ± 1 ºC). Ionic strength effect on the reaction rate is suggested that the net charge of the tetracationic porphyrin is to be +3.6 on the basis of Brønsted-Bjerrum equation. The UV-Vis and fluorescence data revealed that [Ni(II)TMPyP]4+ and H2(TMPyP)4+ interact with DNA, and UV-Vis results suggest that Ni(II)-porphyrin and free base porphyrin interact with DNA via outside binding with self-stacking and intercalation, respectively. Mechanism of kinetics of formation of the [Ni(II)TMPyP]4+ complex in aqueous medium is discussed. An investigation of application of the [Ni(II)TMPyP]4+ complex along with other metalloporphyrins such as Zn2+-, Ru2+-, Pt2+-, [Au(III)TMPyP]5+ as anti-COVID-19 agents is now in progress under international collaboration.

Jingmen viruses are newly described segmented flavi-like viruses that have a worldwide distribution in ticks and have been associated with febrile illnesses in humans. Computational analyses were used to predict that Jingmen flavi-like virus glycoproteins have structural features of class II viral fusion proteins, including an ectodomain consisting of beta-sheets and short alpha-helices, a fusion peptide with interfacial hydrophobicity and a three domain architecture. Jingmen flavi-like virus glycoproteins have a sequence enriched in serine, threonine and proline at the amino terminus, which is a feature of mucin-like domains. Several of the serines and threonines are predicted be modified by the addition of O-linked glycans. Some of the glycoproteins are predicted to have an additional mucin-like domain located prior to the transmembrane anchor, whereas others are predicted to have a stem consisting of two alpha-helices. The flavivirus envelope protein and Jingmen flavi-virus glycoproteins may have diverged from a common class II precursor glycoprotein with a mucin-like domain or domains acquired after divergence.

Considering Cu(tda) chelate is a receptor for adenine and related 6-aminopurines, now we report the synthesis, molecular and crystal structures, thermal stability, spectral properties and DFT calculations on the [Cu(tda)(9heade)(H2O)]•2H2O (1). N7 is found to be the preferred donor atom of 9heade, that can favor the cooperation of a Cu-N7(9heade) bond and an (9heade)N6-H•••O(tda) interligand interaction. But unprecedentedly, the Cu(tda)-9heade molecular recognition in 1 is essentially featured the Cu-N1(9heade), without any N6-H•••O(carboxyl tda) interligand interaction. Nevertheless, being N1 the most basic donor for N9-substituted adenines, this Cu-N1 bond is now assisted by an O2-water mediated interaction (N6-H•••O2 and O2•••Cu weak contact). Also in the crystal packing, the O-H(ol) of 9heade interacts with its own adenine moiety by an O3-water mediated interaction (O(ol)-H•••O3 plus O3-H36•••π(adenine moiety). In turn these water-mediated interactions seems to be responsible to serious alterations on the physical properties of crystalline or grounded samples. Density functional theory calculations were used to evaluate the interactions energetically. Moreover, the quantum theory of atoms-in-molecules (QTAIM) in combination with the noncovalent interaction plot (NCIPlot) were used to analyze the interactions and rationalize the existence and relative importance of hydrogen bonding, chalcogen bonding and π-stacking interactions.

In this paper, the problem of predicting future failure times based on a jointly type-II censored sample from k exponential populations is considered. The Bayesian prediction intervals and point predictors were then obtained. Generalized Bayes is a Bayesian study based on a learning-rate parameter. This study investigated the effects of the learning rate parameters on the prediction results. The loss functions of squared error, Linex, and general entropy were used as point predictors. Monte Carlo simulations were performed to show the effectiveness of the learning rate parameter in improving the results of prediction intervals and point predictors.

: Seasonal influenza (a.k.a flu) is responsible for considerable morbidity and mortality across the globe. The three recognized pathogens that cause epidemics during the winter season are influenza A, B and C. The influenza virus is particularly dangerous due to its mutability. Vaccines are an effective tool in preventing seasonal influenza, and their formulas are updated yearly according to WHO recommendations. However, in order to facilitate decision-making in the planning of the intervention, policymakers need information on the projected costs and quantities related to introducing the influenza vaccine, in order to help governments obtain an optimal allocation of the vaccine each year. In this paper, an approach based on a Controlled Elitism Non-Dominated Sorting Genetic Algorithm (CENSGA) model is introduced to optimize the allocation of influenza vaccination. A bi-objective model is formulated to control the infection volume, and reduce the unit cost of the vaccination campaign. An SIR (Susceptible–Infected–Recovered) model is employed for representing a potential epidemic. The model constraints are based on the epidemiological model, time management, and vaccine quantity. A two-phase optimization process is proposed: guardian control followed by contingent controls. The proposed approach is an evolutionary metaheuristic multi-objective optimization algorithm with a local search procedure based on a hash table. Moreover, in order to optimize the scheduling of a set of policies over a predetermined time to form a complete campaign, an extended CENSGA is introduced with a variable-length chromosome (VLC) along with mutation and crossover operations. To validate the applicability of the proposed CENSGA, it is compared with the classical Non-Dominated Sorting Genetic Algorithm (NSGA-II). The results are analyzed using graphical and statistical comparisons in terms of cardinality, convergence, distribution and spread quality metrics, illustrating that the proposed CENSGA is effective and useful for determining the optimal vaccination allocation campaigns.

G-protein-coupled receptors (GPCR) belong to a large family of molecules eliciting different responses to a variety of signaling molecules. These receptors participate in various physiologic pathways such as metabolism, growth, immune responses, inflammation, vision, taste, olfaction, neurotransmission and even and pathologic responses including chronic inflammatory and vascular diseases. Receptors contributing to the biological responses of renin-angiotensin system (RAS) are members of GPCR family. COVID-19-induced inflammatory cascade has been attributed to acute ACE2 downregulation and imbalance of proinflammatory ACE/AngII/AT1R and anti-inflammatory ACE2/angiotensin (1-7)/Mas axes in favor of the former. Some of the receptors contributing to activities of proteins in RAS including AT1R, AT2R and Mas receptors are members of GPCR family. It is notable that these receptors induce their effects both through G protein and β-arrestin pathway; the former exerts temporary and the latter more sustained effects. In addition to the imbalance of GPCR responses contributing to RAS activities, it has been suggested that SARS-CoV2 pathogenesis might be attributed to the activation of GPCRs or modulating G-proteins involved in adenosine-CFTR regulation system and epithelial Na channel function.This article includes a minireview about the physiological functions of GPCRs and their contribution to COVID-19.

Nonalcoholic fatty liver disease (NAFLD) is becoming the leading cause of hepatocellular carcinoma (HCC), liver-related mortality, and liver transplantation. There is reasonable epidemiological cohort data to recommend surveillance of patients with NAFLD based upon the incidence of HCC. The American Gastroenterology Association (AGA) expert review published in 2020 recommend that NAFLD patients with cirrhosis or advanced fibrosis estimated by non-invasive tests (NITs) should consider HCC surveillance. NITs include fibrosis-4 (FIB-4) index, the enhanced liver fibrosis (ELF) test, FibroScan, and MR elastography. The recommended surveillance modality is abdominal ultrasound (US) given that it is cost effective and noninvasive with good sensitivity. However, US is limited in obese patients and those with NAFLD. In NAFLD patients with a high likelihood of having an inadequate US or if US is attempted but inadequate, CT or MRI may be utilized. The GALAD score, consisting of age, gender, AFP, lens culinaris-agglutinin-reactive fraction of AFP (AFP-L3), and protein induced by vitamin K absence or antagonist-II (PIVKA-II), can help to identify high risk of incident HCC in NAFLD patients. Innovative parameters including Mac-2 binding protein glycated isomer , type IV collagen 7S, free apoptosis inhibitor of macrophage, combination of single nucleoside polymorphisms are expected to be established. Considering a large number of NAFLD population, optimal screening tests must meet several criteria including high sensitivity, cost effectiveness and availability.

Plants offer a simpler and cheaper alternative to mammalian animal models for the study of Endoplasmic Reticulum glycoprotein folding Quality Control (ERQC). In particular, the Arabidopsis thaliana (At) innate immune response to bacterial peptides provides an easy means of assaying ERQC function in vivo. A number of mutants that are useful to study ERQC in planta have been described in the literature, but only for a subset of these mutants the innate immune response to bacterial elicitors has been measured beyond monitoring plant weight and some physio-pathological parameters related to the plant immune response. In order to probe deeper into the role of ERQC in the plant immune response, we monitored expression levels of the PHI-1 and RET-OX genes in the At ER α-Glu II rsw3 and the At UGGT uggt1-1 mutant plants, in response to bacterial peptides elf18 and flg22. The elf18 response was impaired in the rsw3 but not completely abrogated in the uggt1-1 mutant plants, raising the possibility that the latter enzyme is partly dispensable for ERF signalling. In the rsw3 mutant, seedling growth was impaired only by concomitant application of the At ER α-Glu II NB-DNJ inhibitor at concentrations above 500 nM, suggesting residual activity in this mutant. The study highlights the need for extending plant innate immune response studies to assays sampling EFR signalling at the molecular level.

Pathogenicity of many bacteria including Bacillus cereus and Staphylococcus aureus depends on pore-forming toxins (PFTs), which cause lysis of host cells by forming pores in membranes of eukaryotic cells. Bioinformatic analysis revealed in over 600 PFTs a region homologous to the Lys171-Gly250 sequence in hemolysin II (HlyII) from B. cereus, which we designated as “homologous peptide”. Three β-barrel PFTs were used for a detailed comparative analysis. Two of them –HlyII and cytotoxin K2 (CytK2), – are synthesized in Bacillus cereus sensu lato; the third – S. aureus α-toxin (Hla) – is the most investigated representative of the family. Protein modeling showed certain amino acids of homologous peptide to be located on the surface of the monomeric forms of these β-barrel PFTs. We obtained monoclonal antibodies against both a cloned homologous peptide and a 14-membered synthetic peptide DSFNTFYGNQLFMK as part of homologous peptide. The HlyII, CytK2 and Hla regions recognized by the obtained antibodies, as well as an antibody capable of suppressing the hemolytic activity of CytK2, were identified in the course of the work. Antibodies capable of recognizing PFTs of various origins can be useful tools for both identification and suppression of the cytolytic activity of PFTs.

The limited information available on the structure of complexes involving transcription factors and cognate DNA response elements represents a major obstacle in the quest to understand their mechanism of action at the molecular level. We implemented a concerted structural proteomics approach, which combined hydrogen-deuterium exchange (HDX), quantitative protein-protein and protein-nucleic acid cross-linking (XL), and homology analysis, to model the structure of the complex between the full-length DNA binding domain (DBD) of FOXO4 and its DNA binding element (DBE). The results confirmed that FOXO4-DBD assumes the characteristic forkhead topology shared by these types of transcription factors, but its binding mode differs significantly from those of other members of the family. The results showed that the binding interaction stabilized regions that were rather flexible and disordered in the unbound form. Surprisingly, the conformational effects were not limited only to the interface between bound components but extended also to distal regions that may be essential to recruiting additional factors to the transcription machinery. In addition to providing valuable new insights into the binding mechanism, this project provided an excellent evaluation of the merits of structural proteomics approaches in the investigation of systems that arematerial not directly amenable to traditional high-resolution techniques.

-529391451442Citation: To be added by editorial staff during production. Academic Editor: Firstname Lastname Received: date Revised: date Accepted: date Published: date Copyright: © 2023 by the authors. Submitted for possible open access publication under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).0Citation: To be added by editorial staff during production. Academic Editor: Firstname Lastname Received: date Revised: date Accepted: date Published: date Copyright: © 2023 by the authors. Submitted for possible open access publication under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).Abstract: SARS-CoV-2 vaccination offered the opportunity to get out of the pandemic and thereby worldwide health, social, and economic disasters. However, in addition to efficacy, safety is an important issue for any vaccine. The mRNA-based vaccine platform is considered to be safe but side effects are being reported more frequently as more and more people around the world become treated. Myo-pericarditis is the major, but not the only cardiovascular complication of this vaccine, hence it is important not to underestimate other side effects. We report a case series of patients affected by cardiac arrhythmias post mRNA vaccine from our clinical practice and the literature. Reviewing the official vigilance database emerged that heart rhythm disorders after Covid vaccination are not uncommon and deserve more clinical and scientific attention. Since Covid vaccine is the only vaccination to have been related to this side effect questions arose about whether these vaccines could affect heart conduction. Although the risk-benefit is clearly in favor of vaccination heart rhythm disorders are not a negligible issue and there are red flags in the literature about the risk of post-vaccination malignant arrhythmias in some predisposed patients. In light of these findings, we investigated the potential mechanism for the Covid vaccine to impact on cardiac electrophysiology and cause heart rhythm disorders.

RLF-100 (Aviptadil), a synthetic form of Vasoactive Intestinal Peptide (VIP) is shown to block replication of the SARS-CoV-2 virus and has been granted Fast Track Designation by the US FDA for the treatment of Critical COVID-19 with Respiratory Failure. We describe the clinical course of the first patient treated with this investigational medication in an open label manner -- a 54 year old patient suffering antibody-mediated rejection of his double lung transplant who contracted COVID-19 with respiratory failure refractory to all currently available therapies. He received three infusions of RLF-100 under an FDA-approved emergency use IND. Within 24 hours of the third infusion, substantial improvement in oxygen saturation and radiographic improvement in characteristic COVID-19 pneumonitis was noted. He was discharged from intensive care at that point and scheduled for discharge to home at 1 week on room air. Despite an intervening hospitalization for trauma, he remains alive and free of respiratory failure at 28 days post treatment.

Among the many Lysosomal Storage Disorders (LSDs) that would benefit from the establish-ment of novel cell models, either patient-derived or genetically engineered, is Mucopolysaccha-ridosis type II (MPS II). In fact, even though a specific therapeutic approach does exist for this disorder (Enzyme Replacement Therapy, ERT, with recombinant human IDS) and haematopoiet-ic stem cell transplantation (HSCT) may also hold promise whenever the disorder is diagnosed soon enough, both approaches have their own drawbacks. Here we present our results on the establishment and characterization of two MPS II pa-tient-derived stem cell line(s) from deciduous baby teeth. To the best of our knowledge, this is the first time a stem cell population is isolated from LSD patient samples obtained from the oral cavity. Taking into account our results on the molecular and biochemical characterization of those cells and our first insights on their subcellular MPS phenotype, we consider these cells will be a valuable tool for both pathophysiological assessments and drugs screenings. Ultimately, we believe patient-derived dental pulp stem cells (DPSC) may represent a feasible alternative to induced pluripotent stem cells (iPSC) in many labs with standard cell culture con-ditions and limited (human and economic) resources.

The aim of this study is to obtain the Bayes estimators and the maximum likelihood estimators (MLEs) for the unknown parameters of the Rayleigh Weibull (RW) distribution based on progres-sive type-II censored samples. The approximate Bayes estimators are calculated using the idea of Lindley and Tierney-Kadane's approximation method under the squared-error loss function when the Bayes estimators are not handed in explicit forms. In this study, the approximate Bayes esti-mates are compared with the maximum likelihood estimates in the aspect of the estimated risks (ERs) using Monte Carlo simulation. In addition, the coverage probabilities of the parametric bootstrap estimates are calculated. Real lifetime data sets belonging to the cancer types as bladder cancer, head and neck cancer, and leukemia are used to illustrate the emprical results belonging to the approximate Bayes estimates, the maximum likelihood estimates, and the parametric bootstrap intervals.

Although congenital sensorineural hearing loss (SHL) in the bilateral cochleae mainly results from genetic abnormalities, chronic SHL progressing in later life is often influenced by systemic immune disturbances, including autoimmunity, chronic inflammation, and immunosenescence. We have investigated the relationship between the inner ear and systemic immunity and reviewed the possibilities to prevent SHL, including autoimmune SHL and age-related SHL. We also demonstrated two lymphocyte populations, interleukin 1 receptor type II (IL-1R2)-positive T cells (T1R2) and naturally occurring regulatory T cells (nTregs) in CD4⁺ T cells, which increase with aging, suppress host immune function and promote organ degeneration. Alterations in systemic immunity by fewer microbial antigen challenges in the living environment, elimination of immune suppressive lymphocytes, or immune rejuvenation with a reconstituted thymus may contribute not only to renew the cochlear function in SHL, but also to extend the healthy life of functional organs in a vigorous and youthful body, one of humanity’s greatest dreams.

There are no theorems (proven theories) in the biological sciences. We propose that the 3 31 nt minihelix tRNA evolution theorem be universally accepted as one. The 3 31 nt minihelix theorem completely describes evolution of type I and type II tRNAs from ordered precursors (RNA repeats and inverted repeats). Despite diversification of tRNAome sequences, statistical tests overwhelmingly support the theorem. Furthermore, the theorem relates the dominant pathway for the origin of life on Earth, specifically, how tRNAomes and the genetic code may have coevolved. Alternate models for tRNA evolution (i.e., 2 minihelix, convergent and accretion models) are falsified. In the context of the pre-life world, tRNA was a molecule that via mutation could modify anticodon sequences and teach itself to code. We relate the clearest history to date of the chemical evolution of life on Earth. From analysis of tRNA evolution, ribozyme-mediated RNA ligation was a primary driving force in evolution of complexity during the pre-life to life transition on Earth.

Since the spread of the deadly virus SARS-CoV2 in late 2019, researchers have restlessly been seeking for unraveling how the virus factually enters the host cells. Some proteins on each side of the interaction between the virus and the host cells are involved as the major contributors to this process: 1- the nano-machine Spike protein on behalf of the virus, 2- angiotensin converting enzyme II, the mono-carboxypeptidase and the key component of renin angiotensin system on behalf of the host cell, 3- some host proteases and proteins exploited by SARS-CoV2, In this review, the complex process of SARS-CoV2 entrance into the host cells with the contribution of the involved host proteins as well as the sequential conformational changes in the Spike protein tending to increase the probability of complexification of the latter with angiotensin converting enzyme II, the receptor of the virus on the host cells, are discussed. Besides, the release of the catalytic ectodomain of angiotensin converting enzyme II as its soluble form in the extracellular space and its positive or negative impact on the infectivity of the virus are considered.