The role of innate immunity in neutralization of viral infections (including COVID-19) and forming long-lasting and specific immune memory is considered. It is assumed that antiviral protection is generated by the mechanism of RNA interference (RNAi) and is based on the presence of specific viral patterns in the DNA library of the host cells.

In this paper, we have used magnetron sputtering to grow the high-quality GeSn layer on Ge (100) with Sn compositin up to 7%. The crystallinity of the GeSn layer is pretty good, and the strain relaxation degree of the GeSn layer is evaluated to be approximately 50%. The root mean square (RMS) value is 0.8 nm, and the averaged TDDs in the GeSn layer is 8.7×109 cm-2, which is obtained from the rocking curve of GeSn layer along (004) plane. PL measurement result shows the significant optical emission from the deposited high-quality GeSn layer, which also means that magnetron sputtering is an optional way to achieve the higher Sn composition GeSn luminescent material. To verify whether our deposited GeSn can used for optoelectronic devices, we fabricate the simple vertical p-i-n diode, and the room temperature current-voltage (I-V) characteristic was obtained. This result paves the way for future sputtered-GeSn optimization, which is critical for the optoelectronic application.

Rapid diagnosis of acute myocardial infarction is critical for intervention and treatment to decrease morbidity and mortality. For this reasons, this study aimed to design a sensitive biosensor for cardiac troponin I (cTnI) for early prediction and intervention. The sensor was designed from golden plate immobilized with anti- cTnI antibody conjugated with horseradish peroxidase (HRP) enzyme. The rate of degradation of H2O2 is directly related to serum cTnI level. Serum cTnI level was quantified from 3 studied groups including; healthy subjects and patients with ischemic heart (IHD) diseases and myocardial infarction (MI) by ELISA and biosensor techniques to achieve the improved sensitivity of the biosensor. It was found that cTnI levels in healthy subjects ranged from 8-13 ng/dl and in patients with IHD ranged from 20 - 41 ng/dl and MI range from 57- 180 ng/dl. The sensitivity of biosensor was ranged from 85-95% compared with ELISA technique. The developed biosensor is promising in ICU hospitals for early diagnosis and prevent complications of the stroke. It is recommended to apply this biosensor in the large scale of patients with different stages of the cardiac disease.

In this paper, we introduce and study the notion of rough I₂-lacunary statistical convergence of double sequences in normed linear spaces. We also introduce the notion of rough I₂-lacunary statistical limit set of a double sequence and discuss about some properties of this set.

The prevalence of multidrug-resistant Gram-negative infections, particularly carbapenem-resistant strains, has become a significant global health concern. Ceftazidime-avibactam (CZA) has emerged as a promising treatment option. However, data on its efficacy and safety in children are scarce, necessitating further investigation. We conducted a retrospective study at a tertiary hospital in Spain from February 2019 to January 2022. Pediatric patients (<16 years) treated with CZA for confirmed or suspected multidrug-resistant Gram-negative infections were included. Clinical and microbiological characteristics, treatment approaches, and outcomes were examined. Eighteen children received CZA treatment. All had complex chronic conditions, with the most frequent underlying main diseases being liver transplantation (n=8) and biliary atresia (n=4). The predominant type of infection for which they received CZA was intra-abdominal infections caused or suspected to be caused by OXA-48-producing Klebsiella pneumoniae. CZA was generally well tolerated. Within the first month of starting CZA therapy, 2 patients died, with one case directly linked to the infection’s fatal outcome. Some patients needed repeated courses of therapy due to recurrent infections, yet no resistance development was noted. In summary, the use of CZA showed effectiveness and safety, while the lack of resistance development highlights CZA’s potential as a primary treatment option against OXA-48-producing infections.

The study assessed the trapping efficacy of locally-modified 1) Gravid Aedes Trap(GAT) lined with insecticide-treated net (ITN) as a killing agent, 2) Autocidal Gravid Ovitrap(AGO) with sticky board in the semi-field system (SFS) and field setting. Fully-balanced Latin square experiments were conducted to compare GAT lined with ITN vs AGO, both with either yeast or grass infusion. Biogents-Sentinel (BGS) with BG-Lure and no CO2 was used as standard trap for Aedes mosquitoes. In the SFS, GAT outperformed AGO in collecting both nulliparous (65% vs 49%,OR=2.22,[95%CI:1.89-2.60],p

Blocking the interaction of the SARS-CoV-2 spike protein with the human angiotensin-converting enzyme II (hACE2) protein serves as a therapeutic strategy for treating COVID-19. Traditional Chinese medicine (TCM) treatments containing bioactive products could alleviate the symptoms of severe COVID-19. However, the emergence of SARS-CoV-2 variants has complicated the process of developing broad-spectrum drugs. As such, the aim in this study was to explore the efficacy of TCM treatments for SARS-CoV-2 variants through targeting the interaction of the viral spike protein with the hACE2 receptor. The antiviral activity was systematically evaluated using a pseudovirus system. Scutellaria baicalensis was found to be effective against SARS-CoV-2 infection through affecting the interaction of viral spike protein with the hACE2 protein. The active molecules of S. baicalensis were identified and analyzed. Baicalein and baicalin, a flavone and a flavone glycoside, respectively, found in S. baicalensis, exhibited strong inhibitory activities, targeting the viral spike protein or hACE2 protein, respectively. Under optimized conditions, virus infection was inhibited by 98% via baicalein-treated pseudovirus and baicalin-treated hACE2. In summary, we identified the potential SARS-CoV-2 inhibitors of the interaction of the Omicron spike protein and hACE2 receptor from S. baicalensis. Future studies on the therapeutic application of baicalein and baicalin against SARS-CoV-2 variants are needed.

A reduction of melatonin function contributes to the acceleration of Alzheimer's disease (AD), and understanding molecular processes of melatonin-related signaling is critical for intervention of AD progression. Recently, we synthesized and tested a series of melatonin derivates with donepezil fragments in silico and in vitro. In this study, one of the most potent compounds, 3c, was studied in an in vivo rat model of pinealectomy (pin) and subsequent icvAβ1-42 infusion. Melatonin was used as a referent drug. The treatment with melatonin and 3c (10 mg/kg, i.p. for 14 days) exerted a beneficial effect on memory decline and concomitant rise of Aβ1-42 and pTAU in the hippocampus in the pin + icvAβ1-42 rats. Melatonin supplementation facilitated the non-amyloidogenic signaling via a non-receptor (histone deacetylase sirtuin 1, SIRT1) and receptor-related signaling (MT/ERK/CREB). The hybrid 3c derivate up-regulated the MT1A and MT2B receptors, pERK and pCREB. Our findings strongly support the hypothesis that melatonin-related derivates may become a promising drug candidate in AD therapy.

To delve into the structure-function relationship of transmembrane proteins (TMPs), robust protocols are needed to produce them in a pure, stable, and functional state. Among all hosts that express heterologous TMPs, E. coli has the lowest cost and fastest turnover. However, many of the expressed in E. coli TMPs are misfolded. Several strategies have been developed to either direct the foreign TMPs to E. coli’s membrane or retain them in a cytosolic soluble form to overcome this deficiency. Here, we summarize protein engineering methods to produce chimera constructs of the desired TMPs fused to either signal peptide or precursor maltose binding protein (pMBP) to direct the entire construct to the periplasm, therefore depositing the fused TMP in the plasma membrane. We further describe strategies to produce TMPs in soluble form by utilizing N-terminally fused MBP without signal peptide. Depending on its N- or C-terminus location, a fusion to apolipoprotein A-I can either direct the TMP to the membrane or shield the hydrophobic regions of the TMP, maintaining the soluble form. Strategies to produce G-protein coupled receptors, TMPs of Mycobacterium tuberculosis, HIV-1 Vpu, and other TMPs are discussed. This knowledge could increase the scope of TMPs’ expression in E. coli.

The spatial and temporal variability in dietary preferences of juvenile three-spined stickleback Gasterosteus aculeatus, was studied across typical coastal habitats of Keret Archipelago, Kandalaksha Bay, the White Sea. Sampling of fish using beach seine was implemented in late July-early August and in late August, and zooplankton samples were collected to make a quantitative evaluation of abundance of potential prey items. Similarity Percentage (SIMPER) analysis implemented over the data obtained from stomach content analysis revealed five planktonic taxa mostly contributing to the diet of juvenile sticklebacks, of which copepod Temora longicornis was the most important prey item at marine sites, while Acartia longiremis prevailed in diet of fishes in marine lagoon. Calculation of selectivity index demonstrated that some taxa (e.g., A. longiremis) were always avoided by juvenile fishes, others (e.g. Microsetella norvegica) were firstly avoided and then selected in late August. Calculation of selectivity index was implemented per sample and per individual fish indicated that taxa like T. longicornis and were selected during the whole period of study, fishes demonstrated pronounced individual variation in prey selectivity. In general, data on selectivity indicated that despite juvenile sticklebacks feed on mostly available prey items, they can demonstrate taxonomic and size-specific prey selectivity.

Kininogens are multidomain glycoproteins found in the blood of most vertebrates. They are important in the blood coagulation cascade pathways - in intrinsic pathway activation leading to thrombin generation partially independently from tissue factor dependent extrinsic pathway, connecting blood coagulation with the kallikrein-kinin system. Nothing is known about the shape on atomic level therefore the endeavor to obtain the good-quality spatial structure of kininogens is important for a better understanding of their role in disease and treatment. Application of cryo-EM is important for solving the spatial structure of kininogens, drawing new frontiers in understanding the function and opening new pathways for drug development.

For gravitational wave (GW) detected neutron star mergers, one of the leading candidates for electromagnetic (EM) counterparts is the afterglow from an ultra-relativistic jet. Where this afterglow is observed, it will likely be viewed off-axis, such as the afterglow following GW170817/GRB 170817A. The temporal behaviour of an off-axis observed GRB afterglow can be used to reveal the lateral jet structure, and statistical model fits can put constraints on the various model free-parameters. Amongst these parameters is the inclination of the system to the line of sight. Along with the GW detection, the afterglow modelling provides the best constraint on the inclination to the line-of-sight and can improve the estimates of cosmological parameters e.g. the Hubble constant, from GW-EM events. However, modelling of the afterglow depends on the assumed jet structure and, often overlooked, the effects of lateral spreading. Here we show how the inclusion of lateral spreading in the afterglow models can affect the estimated inclination of GW-EM events.

Negative corona discharges occur widely in high voltage transmission lines and charged aircraft, which can cause strong electromagnetic interference. Negative corona discharge is typically performed simultaneously at multiple discharge points. In this study, the current and its EM radiation characteristics of single-needle and multi-needle negative corona discharge in different conditions were tested. The current and electromagnetic radiation characteristics of the two discharge structures were compared. The dipole radiation model was established to analyze the EM radiation characteristics of the negative corona discharge.The results show that, It is only when the voltage reaches a certain threshold that the current and electromagnetic radiation fields of the multi-needle discharge structure will be superimposed and their amplitudes will increase significantly. The frequency of electromagnetic radiation signal does not change with the number of needles, cathode geometry and applied voltage, but only depends on ambient pressure. It provides a basis for detecting corona discharge sources under different conditions.

Abstract Octreotide is the first synthetic peptide hormone, consisted of eight amino acids, that mimics the activity of somatostatin, a natural hormone in the body. During the past decades, advanced instrumentation and crystallographic software established X-ray Powder Diffraction (XRPD) as a valuable tool for extracting structural information of biological macromolecules. The latter was demonstrated by the successful structural determination of octreotide at a remarkably high d-spacing resolution (1.87 Å) (PDB code: 6vc1). This study focuses on the response of octreotide to different humidity levels and temperatures, with a particular focus on the stability of the polycrystalline sample. XRPD measurements were accomplished employing an Anton Paar MHC-trans humidity-temperature chamber installed within a laboratory X’Pert Pro diffractometer (Malvern Panalytical). The chamber is employed to control and maintain precise humidity and temperature levels of samples during XRPD data collection. Pawley analysis of the collected data sets revealed that the octreotide polycrystalline sample is remarkably stable and no structural transitions were observed. The compound retains its orthorhombic symmetry (space group: P212121, a = 18.57744(4) Å, b = 30.17338(6) Å, c = 39.70590(9) Å, d~ 2.35 Å). However, a characteristic structural evolution in terms of lattice parameters and volume of the unit-cell is reported mainly upon controlled relative humidity variation. In addition, an improvement of signal-to-noise ratio in the XRPD data under a cycle of dehydration/rehydration is reported. These results underline the importance of considering the impact of environmental factors, as humidity and temperature, in the context of structure-based drug design, thereby contributing to the development of more effective and stable pharmaceutical products.

The Dph1•Dph2 heterodimer from yeast is a radical SAM (RS) enzyme that generates the 3-amino-3-carboxy-propyl (ACP) precursor for diphthamide, a clinically relevant modification on eukaryotic elongation factor 2 (eEF2). ACP formation requires SAM cleavage and atypical Cys-bound Fe-S clusters in each Dph1 and Dph2 subunit. Intriguingly, the first Cys residue in each motif locates next to another, ill-defined cysteine that we show in-here is conserved across eukaryotes. As judged from structural modeling, the orientation of these tandem cysteine motifs (TCM) suggests a candidate Fe-S cluster ligand role. Hence, we generated by site-directed DPH1 and DPH2 mutagenesis, Dph1•Dph2 variants with cysteines from each TCM replaced individually or in combination by serines. Assays diagnostic for diphthamide formation in vivo reveal that while single substitutions in the TCM of Dph2 cause mild defects, double mutations almost entirely inactivate the RS enzyme. Based on enhanced Dph1 and Dph2 subunit instability in response to cycloheximide chases, the variants with Cys substitutions in their cofactor motifs are particularly prone to protein degradation. In sum, we identify a fourth functionally cooperative Cys residue within the Fe-S motif of Dph2 and show that the Cys-based cofactor binding motifs in Dph1 and Dph2 are critical for the structural integrity of the dimeric RS enzyme in vivo.

Bamboo is considered a sustainable construction material due to its ability to grow quickly and its mechanical properties that are comparable to timber. Contributing to the current effort to establish the structural bamboo standards in the National Structural Code of the Philippines (NSCP), this study establishes the characteristic compressive strength of four bamboo species: Bambusa vulgaris (36 samples), Dendrocalamus asper (36 samples), Bambusa blumeana (94 samples), and Guadua angustifolia Kunth (30 samples). The samples were subjected to compressive loading following ISO 22157-1 (2017). The characteristic compressive strength values obtained, according to ISO 12122-1 (2014), were 40.35 MPa for B. vulgaris, 40.21 MPa for D. asper, 46.63 MPa for B. blumeana, and 36.99 MPa for G. angustifolia Kunth. Simple linear analysis, One-way ANOVA, and Welch’s t-Test were used to analyze the correlation models and establish a comparative analysis of the effect of nodes, and geometric and physical properties on the compressive strength of bamboos. Comparing the characteristic compressive strength obtained from this study to the strength of unseasoned structural timber of Philippine woods, all bamboo species showed higher strength values, and thus have great potential as an alternative construction material to timber.

Pseudomonas aeruginosa is an opportunistic pathogen that poses a significant threat to individuals with chronic respiratory ailments, such as cystic fibrosis (CF). The pathogen is highly prevalent in CF individuals and is responsible for chronic infection, resulting in severe tissue damage and poor patient outcome. However, early detection and immediate treatment are critical to prevent bacterial persistence and establishment of chronic infection. Presently, antibiotics including aminoglycosides, beta-lactams, polymyxins, and fluoroquinolones along with anti-inflammatory medications are being used to treat P. aeruginosa infections in CF patients. However, prolonged antibiotic administration has led to the emergence of widespread multidrug resistance in P. aeruginosa (CF isolates), contributing to antimicrobial resistance (AMR) and failure of antimicrobial therapies. Thus, exploring viable alternatives such as antivirulence therapeutics can be vital towards managing pseudomonal infections in CF patients and mitigating the risk of AMR. In this direction, antivirulence strategies achieving targeted inhibition of bacterial virulence pathways/factors, including quorum sensing, efflux pumps, lectins, and iron chelators, have been widely explored against CF isolates of P. aeruginosa. Simultaneously, there have been discussions about the sufficiency of in vitro findings and their successful translation in pulmonary infection models (in vivo) for the clinical implementation of antivirulence therapies hence, this review article presents a bird’s eye view on the pulmonary infections involving P. aeruginosa in CF patients by laying emphasis on factors contributing to bacterial colonization, persistence, and disease progression along with the current line of therapeutics against P. aeruginosa in CF while underscoring the limitation of antimicrobial approaches. We further collate scientific literature and comprehensively discuss the various antivirulence strategies that have been successfully tested against P. aeruginosa isolates from CF patients. This could pave the way towards a paradigm shift towards clinical therapy of pseudomonal infections in CF and can potentially override conventional antimicrobial treatments.

The infections caused by various bacterial pathogens both in clinical and community settings represent a significant threat to public healthcare worldwide. The growing resistance to antimicrobial drugs acquired by bacterial species causing healthcare-associated infections has already become a life-threatening danger noticed by the World Health Organization. Several groups or lineages of bacterial isolates usually called ‘the clones of high risk’ often drive the spread of resistance within particular species. Thus, it is vitally important to reveal and track the spread of such clones and the mechanisms by which they acquire antibiotic resistance and enhance their survival skills. Currently, the analysis of whole genome sequences for bacterial isolates of interest is increasingly used for these purposes, including epidemiological surveillance and developing of spread prevention measures. However, the availability and uniformity of the data derived from the genomic sequences often represents a bottleneck for such investigations. In this dataset, we present the results of a comprehensive genomic epidemiology analysis of 17,546 genomes of a dangerous bacterial pathogen Acinetobacter baumannii. Important typing information including multilocus sequence typing (MLST)-based sequence types (STs), intrinsic blaOXA-51-like gene variants, capsular (KL) and oligosaccharide (OCL) types, CRISPR-Cas systems, and cgMLST profiles are presented, as well as the assignment of particular isolates to nine known international clones of high risk. The presence of antimicrobial resistance genes within the genomes is also reported. These data will be useful for researchers in the field of A. baumannii genomic epidemiology, resistance analysis and prevention measure development.

Alzheimer´s disease (AD) is characterized by the brain deposition of senile plaques composed by amyloid-β peptides (Aβ) that increase inflammation. An endogenous peptide derived from the insulin-like growth factor (IGF)-I, glycine-proline-glutamate (GPE) has IGF-I-sensitizing and neuroprotective actions. Here, we examined the effects of GPE on Aβ levels and hippocampal inflammation generated by the intracerebroventricular infusion of Aβ25-35 during 2 weeks (300 pmol/day) in ovariectomized rats and the signaling-related pathways and levels of Aβ-degrading enzymes associated with these GPE-related effects. GPE prevented the Aβ-induced increase in the phosphorylation of p38 mitogen-activated protein kinase and the reduction in activation of signal transducer and activator of transcription 3, insulin receptor substrate-1 and Akt, as well as on interleukin (IL)-2 and IL-13 levels in the hippocampus. The functionality of somatostatin, measured as the percentage of inhibition of adenylate cyclase activity and the levels of insulin-degrading enzyme were also preserved by GPE co-treatment. These findings indicate that GPE co-administration may protect from Aβ insult by changing hippocampal cytokine content and somatostatin functionality through regulation of leptin- and IGF-I-signaling pathways that could influence the reduction in Aβ levels through modulation of levels and/or activity of Aβ proteases.

Polymerase I (Pol I) is at the epicenter of ribosomal RNA (rRNA) synthesis. Pol I is a target for treatment of cancer. Given the many cellular commonalities between cancer and neurodegeneration (i.e., different faces of the same coin) it seems rational to consider targeting of Pol I or, more generally, rRNA synthesis for treatment of disorders associated with the death of terminally differentiated neurons. Principally, ribosomes synthesize proteins and, accordingly, Pol I can be considered the starting point for protein synthesis. Given that cellular accumulation of abnormal proteins such as α-synuclein and tau is an essential feature of neurodegenerative disorders such as Parkinson disease and fronto-temporal dementia, reduction of protein production is now considered as a viable target for treatment of these and closely related neurodegenerative disorders. Abnormalities in polymerase I activity and rRNA production may also be associated with nuclear and nucleolar stress, DNA damage, and childhood onset neuronal death as is the case for the UBTF E210K neuroregression syndrome. Moreover, restraining the activity of Pol I may be a viable strategy to slow aging. Before starting down the road of Pol I inhibition for treating non-cancerous disorders of the nervous system, many questions must be answered. First, how much Pol I inhibition can neurons tolerate and for how long? Should inhibition of Pol I be continuous or pulsed? Will cells compensate for Pol I inhibition by upregulating the number of active rDNAs? At present, we have no effective and safe disease modulatory treatments for Alzheimer disease, α-synucleinopathies, or tauopathies, and novel therapeutic targets and approaches must be explored.

DNA polymerases replicate cell genomes and/or participate in the maintenance of genome integrity. DNA polymerases sharing high sequence homology with E. coli DNA polymerase I (pol I), have been grouped in Family A. Pol I participates in Okazaki fragment maturation and in bacterial genome repair. Since its discovery in 1956, pol I has been extensively studied, primarily to get deeper insights into the mechanism of DNA replication. As research on DNA polymerases advances, many novel functions of this group of polymerases are uncovered. For example, human DNA polymerase θ (a Family A DNA pol) has been shown to synthesize DNA using RNA as a template, a function typically attributed to retroviral reverse transcriptase. A heightened interest in drug discovery against pol θ has emerged due to its roles in cancer. Likewise, Pol I family enzymes also appear attractive drug-development targets against microbial infections. Development of antimalarial compounds targeting apicoplast apPOL, an ortholog of Pol I, further extends the druggability of this family of enzymes. Here, we summarize reported drug-development efforts against Family A polymerases, and future perspective regarding these enzymes as antibiotic targets. Current techniques such artificial intelligence can be used to facilitate the goal of new drugs.

The field of nephrology has recently directed a considerable amount of attention towards the stimulator of interferon genes (STING) molecule since it appears to be a potent driver of chronic kidney disease (CKD). STING and its activator, the cyclic GMP-AMP synthase (cGAS) are among the most relevant inducers that promote the expression of type I interferons (IFN-Is). These cytokines have been long recognized as part of the mechanism used by the innate immune system to battle viral infections; however, their involvement in sterile inflammation remains unclear. Mounting evidence pointing to the involvement of the IFN-I pathway in sterile kidney inflammation provides potential insights into the complex interplay between the innate immune system and damage to the most sensitive segment of the nephron, the glomerulus. The STING pathway is often cited as the cause of renal disease originating from non-infection related caused by the induction of IFN-I expression. However, other receptors have been implicated in this process, mainly by recognizing host-derived nucleic acids. This review explores the main endogenous inducers of IFN-I in glomerular cells, discusses what exposure to the main autocrine and paracrine cytokines has on these cells, and identifies the pathways that are implicated in the development of glomerular damage.

It has been reported that prostaglandin I2, such as epoprostenol, develops Grave's disease. A 34-year-old woman was diagnosed with idiopathic pulmonary arterial hypertension and started receiving continuous intravenous epoprostenol. Three years after starting epoprostenol, she started complaining of neck swelling and was diagnosed with Grave’s disease. Thyroid function was controlled by thiamazole and levothyroxine. Nevertheless, her thyroid gland enlargement worsened as epoprostenol dose was titrated. After 23 years of treatment with epoprostenol, she suddenly experienced respiratory failure with a giant goiter leading to airway stenosis and passed away. The autopsy confirmed a giant goiter associated with hyperthyroidism and airway stenosis. We experienced a case of idiopathic pulmonary hypertension with a giant goiter and airway stenosis after long-term intravenous epoprostenol therapy.

Infection with Ebola virus (EBOV) is responsible for haemorrhagic fever in humans with a high mortality rate. Combined efforts of prevention and therapeutic intervention are required to tackle highly variable RNA viruses, whose infections often lead to outbreaks. Here, we have screened the 2P2I3D chemical library using a nanoluc-based protein complementation assay (NPCA) and isolated two compounds disrupting the interaction of the EBOV protein fragment VP35IID with the N terminus of the dsRNA-binding proteins PKR and PACT, involved in IFN response and/or intrinsic immunity, respectively. The two compounds inhibited EBOV infection in cell culture as well as infection by measles virus (MV) independently of IFN induction. Consequently, we propose the compounds are antiviral by restoring intrinsic immunity driven by PACT. Given that PACT is highly conserved across mammals, we support further testing of the compounds in other species, as well as against further negative sense RNA viruses.

Copper(I) sulfide (Cu2S) is a low-cost, earth-abundant, and non-toxic thermoelectric material for applications in the middle-high temperature range (&gt;650 K). Although 3D printing these materials can simplify their manufacturing, elevated temperatures observed during sintering impair their crystal structure and energy conversion efficiency. In this study, we demonstrated a novel post-processing methodology to revert the thermoelectric properties of the 3D printed Cu2-xS materials back to the unimpaired state via sulfur infusion. After printing and sintering, sulfur was infused into the specimens under vacuum to optimize their crystal structure and achieve high thermoelectric efficiency. Chemical analysis and X-ray Diffraction (XRD) tests showed that after the sulfur infusion process, the Cu/S ratio was reverted close to the stoichiometric level. 3D printed Cu2-xS showed p-type thermoelectric behavior with electrical conductivity peaking at 143 S-cm-1 at 750 K and Seebeck coefficient of 175 µV-K-1 at 627 K. Figure of merit (ZT) value of 1.0 at 780 K was achieved which is the highest value ever reported for a 3D printed Cu2-xS thermoelectrics at this temperature. Fabrication of environmentally friendly thermoelectric materials with extended dimensional freedom and conversion efficiency has the potential to impact the thermoelectric industry with new energy conversion applications and lowered manufacturing costs.

This research investigated the antihypertensive effects of tamarind products and compared their potentials based on their animal model’s data verified by molecular docking, multitarget interactions in network pharmacology, and dynamic simulation assays. The GC-MS characterized tamarind products were administered to the cholesterol-induced hypertensive Wistar albino rat models. Two-week-intervened animals were dissected to collect serum and organs which were respectively subjected to the analyses of hypertension-linked markers and tissue architectures. Lead biometabolites of tamarinds interacted with eight target receptors in molecular docking and dynamic simulation studies and they were tested for multitarget interactions using network pharmacological analyses. Results showed that serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), C-reactive protein (CRP), Troponin I, and lipid profiles were maximally reinstated by the phenolic-enriched ripened sour over the sweet tamarind flesh extracts, but seed extracts had a smaller influence. Among the tamarind’s biometabolites, Gamma-sitosterol (ϒ-sitosterol) was found to be the best ligand in managing hypertension via the possible ligand-receptor interactions with the guanylate cyclase which displayed the best drug-likeliness through the highest binding energy -9.3 Kcal. Multitargeted interactions-based degree algorithm and phylogenetic tree of pathways showed 14 targeted genes, of which NR3C1, REN, PPARG, and CYP11B1 hub genes, were consistently modulated by the ϒ-sitosterol to reduce hypertension and related risk factors. The dynamic simulation study showed that the P-RMSD values of ϒ-sitosterol-guanylate cyclase were stable between 75.00 to 100.00 ns at the binding pocket. The findings demonstrate that ripened sour tamarind extract may be supplemented to be a more prospective antihypertensive target or nutraceuticals affirming through advanced preclinical and clinical studies.

Manufacturers of photovoltaic modules do not provide all the information necessary to predict their performance under different climatic conditions. This forces the development of mathematical models of behavior and the application of mathematical methods for the calculation of their associated parameters. A toolbox called PVMSim implemented in MATLAB/GUI is proposed in this paper. PVMSIm provides models allowing the simulation of photovoltaic modules. A two-diode model is used to represent the effect of irradiance and temperature on the V-I and V-P characteristic curves. The accuracy of PVMSim has been vaildated by applying the models to two mono-crystalline and multi-crystalline solar modules of different power ratings and manufacturers. The model PVMSim model accuracy was verified against the manufacturer’s datasheet. This paper shows that this tool is useful for designers and professionals who require an intuitive graphical interface for fast and accurate modeling, simulation and sizing of photovoltaic systems.

Soybean is a highly nutritious legume grown globally as a food and feed crop. An examination of a collection of 10 cultivated and 6 wild Korean soybean varieties showed that there is phenotypic variability notable in different soybeans. Therefore, to develop a list of biomarker candidates useful for growing soybeans of better quality and quantity, the genes of 16 Korean soybean varieties were compared with those of the reference Glycine max var. Williams 82. The comparison was made through gene sequencing to facilitate selection of nsSNPs. The objective of the study was to find out the structural and functional variations caused by nsSNPs and discuss whether the collection of Korean soybean varieties qualifies as biomarkers based on their phenotypic traits. Analysis of the data collected was done using four software: SIFT, Polyphen, PANTHER, and I-mutant 2.0, which are designed to detect the rate of functional and structural variations caused by the nsSNPs in cultivated and wild soybean varieties. Genotypic information obtained in the analysis was used to develop a core collection of biomarkers based on whether nsSNP content was found in more than half of the 16 samples. Therefore, the list of biomarker candidates developed from this study showed that Korean soybean could provide valuable information needed in both future crop genetic research and identification of biomarkers.

Dysregulation of the angiotensin-II Type-I receptor (AT1R) and its pathway was reported to associate with poor-prognosis in several malignancies, including colorectal-cancer (CRC). We have explored the therapeutic-potential of targeting AT1R using valsartan, and its pharmacological-interaction with Fluorouracil (5-FU) in CRC. Anti-proliferative function was evaluated in 2-/3-dimensional cells and in vivo models. Anti-proliferative, anti-migratory, apoptotic function and effect on cell-cycle was assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), wound-healing test, and Fluorescence-activated cell sorting (FACS), respectively, while gene-expression was determined at mRNA/protein levels. By histogical analysis and measuring of oxidative/antioxidant markers, we evaluated the anti-inflammatory properties of valsartan. Valsartan suppressed cell-growth and impacted the anti-tumor-activities of 5-FU by apoptosis-induction. Valsartan inhibited the cells migration by perturbation of Matrix metalloproteinase (MMP1). Furthermore, valsartan inhibited tumor-growth and metastasis, and this was more notable in valsartan/5-FU combination-treated-group. The mechanism was plausible to be via the induction of Reactive-oxygen-species (ROS) and down-regulation of Superoxide-dismutase (SOD), thiol/catalase (CAT) as well as Vascular endothelial growth factor (VEGF) and Transforming growth factor beta (TGF-β). Valsartan may protect cells against intestinal fibrosis by modulation of pro-fibrotic and pro-inflammatory components include fibronectin, Interleukin) IL-1β (, Tumor necrosis factor alpha) TNF-α (, Interferon gamma) INF-γ (, and Monocyte Chemotactic Protein 1 (MCP-1). Our findings demonstrated that targeting the AT1R receptor may inhibit tumor-growth and ameliorate fibrosis and inflammation associated with CRC via modulation of AT1 and TGF-β pathways.

A series of dinuclear copper(I) N,C,N- and P,C,P-carbodiphosphorane (CDP) complexes using multidentate ligands CDP(Py)2 (1) and (CDP(CH2PPh2)2 (13) have been isolated and characterized. Detailed structural information was gained by single crystal XRD analyses of nine representative examples. The common structural motive is the central double ylidic carbon atom with its characteristic two lone-pairs involved into binding of two geminal L-Cu(I) fragments at Cu-Cu distances in the range 2.55 – 2.67 Å. In order to enhance conformational rigidity within the characteristic Cu-C-Cu triangle, two types of chelating side arms were symmetrically attached to each phosphorus atom: two 2-pyridyl functions in ligand CDP(Py)2 (1) and its dinuclear copper complexes 2-9 and 11, as well as two diphenylphosphinomethylene functions in ligand CDP(CH2PPh2)2 (13) and its di- and mononuclear complexes 14-18. Neutral complexes were typically obtained via reaction of 1 with Cu(I) species CuCl, CuI, and CuSPh or via salt elimination reaction of [(CuCl)2(CDP(Py)2] (2) with sodium carbazolate. Cationic Cu(I) complexes were prepared upon treating 1 with two equivalents of [Cu(NCMe)4]PF6, followed by the addition of either two equivalent of an aryl phosphine (PPh3, P(C6H4OMe)3) or one equivalent of a bisphosphine ligands DPEPhos, XantPhos or dppf. For the first time carbodiphosphorane CDP(CH2PPh2)2 (13) could be isolated upon treating its precursor [CH(dppm)2]Cl (12) with NaNH2 in liquid NH3. A protonated and a deprotonated derivative of ligand 13 were prepared and their coordination was compared to neutral CDP ligand 13. NMR analysis and DFT calculations reveal, that the most stable tautomer of 13 does not show a CDP (or carbone) structure in its uncoordinated base form. For most of the prepared complexes, photoluminescence upon irradiation with UV light at room temperature was observed. Quantum yields (PL) were determined to 36% for dicationic [(CuPPh3)2(CDP(Py)2)](PF6)2 (4) and to 60% for neutral [(CuSPh)2(CDP(CH2PPh2)2] (16).

The evidential value of an mtDNA match between biological remains and its potential donor is determined by the random match probability of the haplotype. This probability is based on the haplotype’s population frequency estimate. Consequently, implementing a population study representative of the population relevant to the forensic case is vital to correctly evaluating the evidence. The emerging number of poaching cases and the limited availability of such data emphasizes the need for improved fallow deer mtDNA population databank for forensic purposes, including targeting the entire mitochondrial control region. By sequencing the whole mitochondrial control region in 138 animals from five populations in Hungary we found four different haplotypes, including one which has not yet been described. Our results, supplemented with data already available from previous research do not support the possibility of determining the population of origin, although some patterns of geographical separation can be distinguished. Estimates of molecular diversity indicate approximately similarly low mtDNA diversity (Hd=0.565 and π = 0.002), compared with data from other countries. The calculated random match probability of 0.547 shows a high probability of coincidence and, therefore, a limited capacity for exclusion. Consequently, it may be necessary to search for polymorphic sites on other mitochondrial gene sections or to sequence the entire mitogenome of fallow deer.

Plant hormones regulate the adaptive responses to various biotic and abiotic stress factors. Applied exogenously they trigger the natural plant defense mechanisms, a feature that could be implemented in strategies for supporting crop resilience. The potential of exogenous cytokinin-like acting compound (kinetin), the auxin analogue 1-naphtyl acetic acid (NAA), abscisic acid (ABA) and the ethylene-precursor 1-aminocyclopropane-1-carboxylic acid (ACC) to mitigate dehydration was tested on Lactuca sativa (lettuce) grown on 12% polyethylene glycol (PEG). Priming with different blends containing these plant growth regulators applied in bioequivalent concentrations was evaluated through biometric measurements and biochemical analyses. The combined treatment with the four plant hormones exhibited the best dehydration protective effect. The antioxidative enzyme profiling of the PGR-primed individuals revealed increased SOD, catalase and peroxidase activity in the leaves. Immunodetection of higher levels of the rate-limiting enzyme for proline biosynthesis (delta-pyroline-5-carboxylate synthase) in the primed plants coincided with a significantly higher content of the amino acid measured in the leaves. These plants also accumulated particular dehydrin types, which may have contributed to the observed stress-relieving effect. The four-component hormonal mix applied by spraying or through the roots exerted similar stress-mitigating properties on soil-grown lettuce subjected to moderate drought.

Fragile X syndrome (FXS), the most common monogenic cause of inherited intellectual disability and autism spectrum disorder, is caused by a full mutation (&gt;200 CGG repeats) in the Fragile X Messenger Ribonucleoprotein 1 (FMR1) gene. Individuals with FXS experience a wide range of challenges related to social interaction (SI). Animal models, such as Drosophila melanogaster model for FXS where the only ortholog of human FMR1 (dFMR1) is mutated, have played a crucial role in understanding of FXS. The aim of this study was to investigate SI in the dFMR1B55 mutants using the novel Drosophila Shallow Chamber and a Python data processing pipeline based on social network analysis (SNA). In comparison with wild-type flies (w1118), SNA analysis in dFMR1B55 mutants revealed hypoactivity, fewer connections in their networks, a lower ability to efficiently transmit information, fewer alternative pathways for information transmission, a higher variability in the number of interactions they achieved, and tended to stay near the boundaries of the testing chamber. These observed alterations indicate the presence of characteristic strain-dependent social networks in dFMR1B55 flies, commonly referred to as the group phenotype. Finally, a combination of novel research tools is a valuable method for SI research in fruit flies.

Utilizing bioinformatics tools, this study expands our understanding of secondary metabolism in Botrytis cinerea, identifying novel genes within polyketide synthase (PKS), non-ribosomal peptide synthetase (NRPS), sesquiterpene cyclase (STC), diterpene cyclase (DTC), and dimethylal-lyltryptophan synthase (DMATS) families. These findings enrich the genetic framework associ-ated with B. cinerea's pathogenicity and ecological adaptation, offering insights into uncharted metabolic pathways. Significantly, the discovery of previously unannotated genes provides new molecular targets for developing targeted antifungal strategies, promising to enhance crop pro-tection and advance our understanding of fungal biochemistry. This research not only broadens the scope of known secondary metabolites but also opens avenues for future exploration into B. cinerea's biosynthetic capabilities, potentially leading to novel antifungal compounds. Our work underscores the importance of integrating bioinformatics and genomics for fungal research, paving the way for sustainable agricultural practices by pinpointing precise molecular interven-tions against B. cinerea. This study sets a foundation for further investigations into the fungus's secondary metabolism, with implications for biotechnology and crop disease management.

The continuous flowing spacetime forms a spacetime group G, one of its fundamental groups is the Poincare group PO(1,3), and the matter and interaction fields are representations of its intrinsic spacetime group. As a kind of quantized space-time unit, space-time group elements generate both space-time manifolds and matter. Matter and fields are aggregates of the quantum space-time within them and determine their type: the Lorentz group SO(1,3) represents a rotating spacetime corresponding to visible matter and the translation group P^1,3 represents a translational spacetime corresponding to dark matter and dark energy. The aggregation mode of space-time degrees of freedom in matter reveals that charge conjugation symmetry is the inverse symmetry of internal time of charged particles, and the external parity breaking of neutrinos is also due to their internal spatial aggregation mode.

BACKGROUND: Is pharmacovigilance at a moment of prominence for science and in relation to government responsibilities towards their nations, as the new coronavirus pandemic has surprised everyone in a negative and lethal way. OBJECTIVE: Evaluate pharmacovigilance as a resource for controlling and understanding the adverse effects caused by vaccines in use. DESIGN AND SETTING: Narrative review developed by a research group at Faculty of Medicine of the University of Porto. METHODS: This is a narrative review of the literature available in electronic media, government bulletins and similar bodies. The search was carried out using the descriptors: "Pharmacovigilance AND COVID-19 in Brazil", "Vaccine Development AND COVID-19 in Brazil", "Vaccination Hesitancy AND COVID-19 in Brazil", "Pharmacovigilance AND COVID-19", "Vaccine Development AND COVID-19", "Vaccination Hesitancy AND COVID-19", Pharmacovigilance AND COVID-19, Vaccine Development AND COVID-19, Vaccination Hesitancy AND COVID-19, "Public Health Surveillance AND COVID-19". In the period from May 2021 to June 2022. RESULTS: From the database search, 3 journal articles, 4 government bulletins and 535 scientific articles were identified. Of the total of 542 bibliographic materials, 36 were selected according to the selection criteria and objectives of the study. CONCLUSIONS: The vaccines in use have proven efficacy, despite adverse reactions that cannot be attributed solely and exclusively to their use, since the medical history of each patient should be considered in the investigation of each case, especially when there is death. The Brazilian data for adverse events, although the country is continental in its size, are acceptable given the number of deaths recorded.

The inherited ‘EIA’ process at Brexit is based on a ‘Project’ period from Inception tothe start of construction works. The ‘Incompleteness’ of the process covers andidentifies stages that will impact on the environmental cycle: construction period,operational life, de-commissioning and a return to acceptable environmental footprint.A master environment structure-plan framework is required to commence with theupgrading of the complete ‘EIA’ process, embracing separate limbs for the UK’spriority environmental targets for climate change, and other major adverse effectswhich result in serious ‘harm’ to the UK environment. The identification of the processfor ‘incompleteness’ requires effective sustainability, and inclusion of effectivemanagement tools, for the essential ‘monitoring/control/recording’ proceduresthroughout the project life and the natural environmental cycle. This will allow theopportunity for a new approach to a structured ‘Suite of EIAR Directives’, to enable a‘EIAR’ regime that ‘will remain fit and proper for UK purpose’.

Despite available global efforts and funding, Tuberculosis (TB) continues to affect a considerable number of patients worldwide. Policy makers and stakeholders set clear goals to reduce TB incidence and mortality, but the emergence of multidrug-resistant TB (MDR-TB) and extensively drug-resistant TB (XDR-TB) complicate the reach of these goals. Drug-resistance TB needs to be diagnosed rapidly and accurately to effectively treat patients, prevent the transmission of MDR-TB, minimise mortality, reduce treatment costs and avoid unnecessary hospitalisations. In this narrative review, we provide a comprehensive overview of laboratory methods for detecting drug resistance in MTB, focusing on phenotypic, molecular and other drug susceptibility testing (DST) techniques. We found a large variety of methods used, with the BACTEC MGIT 960 being the most common phenotypic DST and the Xpert MTB/RIF being the most common molecular DST. We emphasise the importance of integrating phenotypic and molecular DST to address issues like resistance to new drugs, heteroresistance, mixed infections and low-level resistance mutations. Notably, most of the analysed studies adhered to the outdated definition of XDR-TB and did not consider the pre-XDR definition, thus posing challenges in aligning diagnostic methods with the current landscape of TB resistance.

In recent decades, there have been numerous endeavors to develop a novel category of survival distributions possessing enhanced flexibility through the extension of existing distributions. This article constructs and validates the statistical properties of a novel survival distribution in order to obtain an alternative distribution that is suitable for analyzing survival data by presenting the novel mixture of the Fréchet distribution along with statistical properties such as the probability density function (PDF), cumulative distribution function (CDF), rth ordinary moment, skewness, kurtosis, moment-generating function, mean, variance, mode, survival function, hazard function, and asymptotic behavior, as well as constructing the estimators of the unknown parameter by employing the expectation-maximization (EM) algorithm, and simulated annealing. Additionally, the performance of the proposed estimators was compared with bias, mean squared errors (MSE), and simulated variances, and given an illustrative example of the proposed distribution to the survival data set in order to show that the proposed distribution is appropriate for the right-skewed data. This will be extremely advantageous in survival analysis.

In the era of big data with increasingly complex data structures and ever-larger data scales, matrix-type data are becoming highly valued and their applications in the fields of medicine, industry, education, geography, and astronomy are growing in extent. In recent years, significant progress has been made in the practical use of matrix variable t-distribution finite mixture models for handling data in order to address the issues of multi-subgroup structures and long data tails. In this paper, the expectation-maximization (EM) algorithm with penalized maximum likelihood is proposed to resolve the problem of the unbounded nature of the likelihood function applied to the model by considering the degeneracy of the variance-covariance matrix of this model. Our data were analyzed through simulations and real data, and the results demonstrate that our model is effective in both preventing the likelihood function from being unbounded and in ensuring the accuracy of the estimated parameters of the EM algorithm.

Recently Candida auris has emerged as a multi-resistant fungal pathogen, with a significant clinical impact, and has become a critical issue in WHO fungal priority list, due to its unique ability to persist for long time on human skin and hospital environments. It is therefore fundamental to reinforce hospital surveillance protocols to limit nosocomial outbreaks. The study purpose was the Fourier-Transform Infrared Spectroscopy (FT-IR) application to investigate the phylogenetic relationships between isolated strains within the C. auris outbreak at the university Intensive Care Unit of a Tertiary University hospital in Turin (Italy). In order to calculate a clustering cut-off, intra- and inter-isolates distance values were analysed. Data showed the presence of a major cluster Alfa and a minor cluster Beta with a defined C. auris clustering cut-off. The results were validated by an external C. auris strain and Principal Component and Linear Discriminant Analysis. The application of FT-IR technology had allowed to obtain important information about the phylogenetic relationships between the analysed strains, defining for the first time a “not WGS-based” clustering cut-off with a statistical-mathematical approach. FT-IR could represent a valid alternative to molecular methods for rapid and cost saving typing of C. auris strains with important clinical implications.

The AREB/ABF (ABA response element binding) proteins in plants are vital for plant stress responses, but the understanding of AREB/ABFs in orchid species, an important traditional medicinal and ornamental plants, is limited. Here, twelve AREB/ABF genes were identified within three orchids’ complete genome and classified into three groups (groups I, II, and III) via a phylogenetic analysis, which was further supported by the analysis of their conserved motifs and gene structures. The cis-elements analysis showed that hormone response elements followed by light and stress responses were widely rich in AREB/ABFs. A prediction analysis of orchid ABRE/ABF-mediated regulatory network was further constructed through cis-regulatory elements (CREs) analysis of their promoter regions and revealed that several transcriptional factor (TF) gene family were abundant as the potential regulators for orchid AREB/ABFs. Expression profile analysis based on public transcriptomic data showed that most AREB/ABF genes have distinct tissue-specific expression patterns in orchid plants. Additionally, DcaABI5 as the homolog of ABA INSENSITIVE 5 (ABI5) from Arabidopsis was selected for further analysis. The results showed that Arabidopsis transgenic overexpressing DcaABI5 could rescue the ABA insensitive phenotype in the mutant abi5. Collectively, these findings will provide valuable information on AREB/ABF genes in orchids.

An analysis of 1300+ existing ACE mutations revealed that 400+ are damaging and led us to hy-pothesize that carriers of heterozygous loss-of-function (LoF) ACE mutations (which result in low ACE levels) could be at risk for the development of late-onset Alzheimer’s disease (AD) [Danilov, 2024]. Here we quantified blood ACE levels in EDTA-plasma from 41patients with 10 different heterozygous ACE mutations, as well as 33 controls, and estimated the effect of these mutations on ACE phenotype using a set of mAbs to ACE and two ACE substrates. We found that relatively frequent (~1%) AD-associated ACE mutations in the N domain of ACE, Y215C and G325R are truly damaging and, likely, transport-deficient, with ACE levels in plasma only ~50% of controls. Another AD-associated ACE mutation, R1250Q, in the cytoplasmic tail, did not cause a decrease in ACE and, likely, did not affect surface ACE expression. We have also developed a method to identify patients with anti-catalytic mutations in the N domain. These mutations may result in reduced degradation of amyloid beta peptide Aβ42, an important component for amyloid deposition. Consequently, these could pose a risk factor for the development of AD. Therefore, a systematic analysis of blood ACE levels in patients with all ACE mutations has potential to identify individuals at an increased risk of late-onset AD. These individuals may benefit from future preventive or therapeutic interventions involving a combination of chemical and pharmacological chaperones, as well as proteasome inhibitors, aiming to enhance ACE protein traffic. This approach has been previously demonstrated in a cell model of the transport-deficient ACE mutation, Q1069R [Danilov, 2010].

Milroy's disease (MD), also known as hereditary lymphedema type I, is a rare autosomal dominantly inherited primary lymphedema. It accounts for approximately twenty percent of all primary lymphedemas. MD typically presents clinically with bilateral lower extremity lymphedema. Our case report is about a rare case of MD presenting with unilateral lymphedema in both upper and lower extremities in a patient admitted to our clinic. A 24-year-old woman who had been under observation for lymphedema since she was 8 years old was diagnosed with MD by physical examination, venous Doppler ultrasound, whole body lymphoscintigraphy, and molecular genetic testing in our clinic, and partial improvement was achieved with Complete Decongestive Therapy, the gold standard treatment for lymphedema. Genetic counseling services may be especially useful for the patient and family. Although MD is rarely seen in the literature, many more studies are needed to identify carrier variants in the community.

Obesity and overweight are associated with many metabolic diseases, such as hypertension, diabetes, and dyslipidemia, which are closely related to a sedentary lifestyle and lack of exercise. Aerobic exercise effectively increases the high-density lipoproteins-cholesterol (HDL-C) levels and decreases the triglyceride (TG) levels. The consumption of Cuban policosanol (Raydel®) is also effective in enhancing the HDL-C quantity and HDL functionality to treat dyslipidemia and hypertension. On the other hand, no study has examined the effects of a combination of high-intensity exercise and policosanol consumption in obese subjects to improve metabolic disorders. In the current study, 17 obese subjects (average BMI 30.0±1.1 kg/m2, eight male and nine female) were recruited to participate in a program combining exercise and policosanol (20 mg) consumption for 12 weeks. After completion, their BMI, waist circumference, total fat mass, systolic blood pressure (SBP), and diastolic blood pressure (DBP) decreased by approximately 15% (p=0.022), 12.7% (p=0.008), 33% (p=0.006), 11% (p<0.046), and 13% (p=0.007), respectively. In the serum lipid profile, at week 12, they showed a remarkable decrease in the total cholesterol (TC) and triglyceride (TG) levels, up to 17% (p<0.019) and 54% (p<0.002) from the baseline, respectively. Although the serum HDL-C was increased by approximately +12% from the baseline, the percentage of HDL-C in TC, HDL-C/TC (%), was increased by up to +32% (p=0.007) at week 12. The serum coenzyme Q10 (CoQ10) level was increased 1.2-fold in all participants at week 12 from the baseline. In particular, the male participants showed a 1.4-fold increase (p=0.027) from the baseline. The larger increase in serum CoQ10 was correlated with the larger increase in the serum HDL-C during 12 weeks. The hepatic function parameters were improved; the serum -glutamyl transferase decreased at week 12 by up to 55% (p<0.007), while the aspartate aminotransferase and alanine transaminase levels decreased within the normal range. In the lipoprotein level, the extent of oxidation and glycation were reduced significantly in VLDL and LDL, with a remarkable decrease in the TG content in particles. The antioxidant abilities of HDL2 and HDL3, such as paraoxonase (PON) and ferric ion reduction ability (FRA), were enhanced significantly by up to 1.8-fold (p<0.001) and 1.6-fold (p<0.001) at week 12. The particle size and number of HDL2 were increased up to +10% during the 12 weeks with a remarkable decrease in the TG content, glycation extent, oxidation up to 32% (p=0.032), 18% (p=0.043), and 11% (p=0.023), respectively. The particle number and diameter of HDL3 were increased by up to +9% with a remarkable increase in the PON activity, FRA activity, and TC content of +82% (p<0.001), +56% (p<0.001), and +32% (p=0.009), respectively. Expression of apolipoproteinA-I in HDL2 and HDL3 were significantly elevated more in both gender around 30~48% with more distinct band intensity and less glycation at week 12. These improvements in HDL quality and functionality were linked to the higher survivability of adult zebrafish and their embryos. Under the co-presence of carboxymethyllysine (CML), a microinjection of HDL2 to zebrafish embryo from week 0 resulted in approximately 47% survivability with developmental defects and attenuated speed. On the other hand, the HDL2 microinjection from week 12 resulted in remarkably higher survivability (~ 70%). In conclusion, 12 weeks of Cuban policosanol (Raydel®, 20 mg) consumption with high-intensity exercise showed significant improvement in blood pressure, body fat mass, blood lipid profile without liver damage, CoQ10 metabolism, and renal impairment. At week 12, all participants showed a remarkable decrease in oxidation and glycation extent in the VLDL and LDL with a decrease in the TC and TG content. Significant enhancement of the qualities and functionalities in HDL2 and HDL3 by the policosanol consumption were also detected: increase in apoA-I content, TC content, particle size, and particle numbers along with antioxidant abilities, such as PON and FRA.

The intensive care unit is characterized by the critical care of the infants and children who access it, as well as the high complexity of care. This implies and requires optimal integration among the various professionals working there and their ability to work as a team. The purpose of the study was to describe how nurses perceive clinical risk and how they relate to it and to identify adverse events and related risk factors. Nine nurses, two moderators and one external observer partici-pated in the focus group. In the qualitative analysis, 9 themes describing the perception of clinical risk in PICU were identified, including teamwork, specific training, time management, team communication, management, individual errors, structural criticality, patient fac-tors/characteristics, and standardization. Safety culture can be fostered by hospital management to involve PICU nurses in promoting patient safety, which could improve breaking down barriers that prevent nurses from fulfilling their roles.

Immune surveillance by natural killer (NK) cells and their recruitment to sites of inflammation renders them susceptible to viral infection, potentially modulating their effector function. Here, we analyzed innate RNA receptor signaling in NK cells downstream of direct Influenza A virus (IAV) infection and its impact on NK cell effector function. Infection of NK cells with IAV resulted in the activation of TBK1, NF-κB and subsequent type-I IFN secretion. CRISPR- generated knockouts in primary human NK cells revealed that this effect depended on the antiviral cytosolic RNA receptor RIG-I. Transfection of NK cells with synthetic 3p-dsRNA, a strong RIG-I agonist that mimics viral RNA, resulted in a similar phenotype and rendered NK cells resistant to subsequent IAV infection. Strikingly, both IAV infection and 3p-dsRNA transfection enhanced degranulation and cytokine production by NK cells when exposed to target cells. Thus, RIG-I activation in NK cells both supports their cell intrinsic viral defense and enhances their cytotoxic effector function against target cells.

Apoptosis under severe hypoxia is induced through p53 phosphorylation and HIF-1α-dependent p53 accumulation via ATR activation by DNA damage response (DDR) activation through replication stress. We previously demonstrated that the topoisomerase I catalytic inhibitor, 3EZ, 20Ac-ingenol, specifically induced apoptosis in Jeko-1 and Panc-1 cells, both of which are cell lines that show cyclin D1 overexpression. After progression to the S phase facilitated by nuclear cyclin D1, in the presence of 3EZ, 20Ac-ingenol, an intra S phase checkpoint was induced in ATR activation as part of replication stress-induced DDR. In this study, we examined whether 3EE, 20Ac-ingenol induces a higher degree of p53 phosphorylation and additional HIF-1α and p53 accumulation in response to replication stress-induced DDR activation under the hypoxic condition than under the normoxic condition by controlling ATR activation. 3EE, 20Ac-ingenol induced p53 activation and HIF-1α-dependent p53 accumulation through cooperative ATR activation via induced DDR with the hypoxia in Panc-1 cells. The Jeko-1 cells showed slight HIF-1α accumulation under hypoxia, but this was not decreased by 3EE, 20Ac-ingenol, so that the cells remained resistant to hypoxia. 3EE, 20Ac-ingenol induces an intricate interplay between p53 and HIF-1α accumulation via ATR activations that results in high p53 accumulation, which advanced transient expression and early disappearance of HIF-1?. The strong p53 accumulation and consequent PTEN activation also decreased HIF-1α accumulation and PD-L1 expression, which resulted in intense apoptosis.

Hydraulic fracturing for oil-gas and geothermal reservoir stimulation is closely related to the generation and propagation of Mode I crack. Nonlinear deformation due to rock heterogeneity occurs at such crack tip, which causes the fracture process zone (FPZ) to form before the crack propagates unsteadily. However, the relationship between the FPZ characteristics and rock heterogeneity still remain elusive. We used three rock types common in reservoir for experimental investigation, and each of them includes two subtypes with different heterogeneity due to grain size or microstructural characteristics. Drawing on the experiment results, we calculated the FPZ size in each cracked chevron notched Brazilian disk, and we reproduced the formation process of the FPZ in marble by discrete element method. We showed that strong heterogeneity is favorable to large FPZ size, can enhance the ability of crack generation and complicate crack morphology. Coupling the Weibull distribution with fracture mechanics, the dependence of the FPZ size on heterogeneity degree can be theoretically explained, which suggests that inherent heterogeneity of rocks set physical foundation for formation of FPZ. These findings can improve our recognition to formation mechanism of the Mode I crack and provide useful guidelines for evaluating reservoir fracability.

Electronic structure calculations have been carried out to examine the effect of protonation and water molecules on the heme group of peroxidases in different redox (ferric, ferrous, compounds I and II) and spin states. Shared geometries, spectroscopic properties at Soret region, and thermodynamics of peroxidases are discussed. B3LYP and M06-2X density functionals with different basis sets were employed on a common molecular model of the active site (Fe-centred porphine and proximal imidazole). Computed Gibbs free energies indicate that the corresponding aquo complexes are not thermodynamically stable, supporting the five-coordinate Fe(III) centre in native ferric peroxidases, with a water molecule located at a non-bonding distance. Protonation of the ferryl oxygen of compound II is discussed in terms of thermodynamics, Fe–O bond distances, and redox properties. It is demonstrated that this protonation is necessary to account for the experimental data and computed Gibbs free energies that reveal pKa values of compound II about 8.5 – 9.0. Computation suggests that the origin of the general oxidative properties of peroxidase species, as well as their reactivity towards water and protons and Soret spectral properties, mostly resides on the iron porphyrin and its proximal ligand histidine.

Mesenchymal stem cells (MSCs) are involved in the process of extracellular matrix (ECM) remodeling where collagens play a pivotal role. We recently demonstrated that the remodeling of adsorbed collagen type I might be disordered upon oxidation following its fate in the presence of human adipose-derived MSC (ADMSCs). With the present study, we intended to learn more about the effect of polyphenolic antioxidant Epigallocatechin gallate (EGCG) attempting to mimic the conditions of oxidative stress in vivo and its putative prevention by antioxidants. Collagen Type I was isolated from mouse tail tendon (MTC) and labeled with FITC before oxidizing according to Fe2+/H2O2 protocol. FITC-collagen remodeling by ADMSC was assessed morphologically before and after EGCG pretreatment and confirmed via detailed morphometry analysis measuring the anisotropy index (AI) and fluorescence intensity (FI) in selected regions of interest (ROI), namely: outside the cells; over the cells and central (nuclear perinuclear) region, whereas the pericellular proteolytic activity was measured by de-quenching of fluorescent collagen probes (FRET effect). Here we provide morphological evidence that MTC undergoes significant reorganization by the adhering ADMSC along with the substantial activation of pericellular proteolysis, and further confirm that both processes are suppressed upon collagen oxidation. An important observation was that this abrogated remodeling cannot be prevented by the EGCG pretreatment. Conversely, the detailed morphometry analysis showed that oxidized FITC-collagen rather tends to accumulate beneath the cells and around the cell’s nuclei suggesting the activation of alternative routes for its removal, such as internalization and/or transcytosis. Morphometry analysis also revealed that both processes are supported by EGCG pretreatment.

We obtain exact solutions to the field equations for 5 dimensional LRS Bianchi type-I spacetime in $f(R,T)$ theory of gravity where specifically the following three cases are considered: (i) $f(R,T)=\mu(R+T)$, (ii) $f(R,T)=R \mu + R T \mu^2$ and (iii) $f(R,T)=R+\mu R^2+\mu T$ where $R$ and $T$ respectively the Ricci scalar and trace of the energy-momentum tensor. It is found that the equation of state (EOS) parameter $w$ is governed by the parameter $\mu$ involved in the $f(R,T)$ expressions. We fine-tune the parameter $\mu$ to obtain effect of phantom energy in the model, however we also restrict this parameter to obtain a stable model of the universe. It is noted that the model isotropizes at finite cosmic time.

Mitochondria play key roles in cellular energy metabolism in eukaryotes. Mitochondria of most organisms contain their own genome and specific transcription and translation machineries. The expression of angiosperm mtDNA involves extensive RNA-processing steps, such as RNA trimming, editing, and the splicing of numerous group II-type introns. Pentatricopeptide repeat (PPR) proteins are key players of plant organelle gene expression and RNA metabolism. In the present analysis, we reveal the function of the MITOCHONDRIAL SPLICING FACTOR 2 gene (MISF2, AT3G22670) and show that it encodes a mitochondria-localized PPR protein that is crucial for early embryo-development in Arabidopsis. Molecular characterization of embryo-rescued misf2 plantlets indicates that the splicing of nad2 intron 1 and thus respiratory complex I biogenesis are strongly compromised. Moreover, the molecular function seems conserved between MISF2 protein in Arabidopsis and its orthologous gene (EMP10) in maize, suggesting that the ancestor of MISF2/EMP10 was recruited to function in nad2 processing before the monocot-dicot divergence, ~200 million years ago. These data provide new insights into the function of nuclear-encoded factors in mitochondrial gene expression and respiratory chain biogenesis during plant embryo development.

In the last two decades, variably doped strontium barium niobate (SBN) has attracted a lot of scientific interest mainly due to its specific non-linear optical response. Comparably, the parental compound, i.e., undoped SBN, appears to be less studied so far. Here, two different cuts of single-crystalline nominally pure strontium barium niobate in the composition Sr0.61Ba0.39Nb2O6 (SBN61) are comprehensively studied and analyzed with regard to their photoconductive responses. We present conductivity measurements under systematically varied illumination conditions along either the polar z-axis or perpendicular to it (x-cut). Apart from a pronounced photoconductivity (PC) already under daylight and a large effect upon super-bandgap illumination in general, we observe (i) distinct spectral features when sweeping the excitation wavelength over the sub-bandgap region as then discussed in the context of deep and shallow trap states, (ii) extremely slow long-term relaxation for both light-on and light-off transients in the range of hours and days, (iii) a critical dependence of the photoresponse on the pre-illumination history of the sample, and (iv) a current-voltage hysteresis depending on both the illumination and the electrical-measurement conditions in a complex manner.

A good management of diabetes requires at the same time self-regulation behaviour and a balanced involvement of family components. This study’s aims were: understanding fear of injections and perceptions of family conflicts in preadolescents and adolescents with type 1 diabetes mellitus and their mothers, comparing their perceptions, and identifying the risk factors impacting patients’ quality of life. Participants were one hundred and two patients (Mean age = 14.63, SD = 2.43; age range = 10-19 years; Females = 52) and their mothers (Mean age = 46.94, SD = 6.2, age range = 27-63 years), who filled in self and proxy-report questionnaires. Twenty % of patients and 14.7% of their mothers reported clinical score for fear of self-injection and blood testing. Mothers reported higher fear of injecting and family conflicts compared with the patients. Age, fear of injecting and family conflicts impacted significantly on patients’ quality of life perceptions. Clinical consideration and recommendations are given basing on the empirical results.

Japanese encephalitis (JE) is a vaccine preventable disease caused by the Japanese encephalitis virus (JEV), which is primarily prevalent in Asia. JEV is a Flavivirus, classified into a single serotype with five genetically distinct genotypes (I, II, III, IV, and V). JEV genotype III (GIII) had been the most dominant strain and caused numerous out breaks in the JEV endemic countries until 1990. However, recent data shows the emergence of genotype I (GI) as a dominant genotype and it is gradually displacing GIII. The exact mechanism of this genotype displacement is still unclear. The virus can replicate in mosquito vectors and vertebrate hosts to maintain its zoonotic life cycle; pigs and aquatic wading birds act as an amplifying/reservoir hosts, and humans and equines are the dead end hosts. The important role of pigs as an amplifying host for JEV is well known. However, the influence of other domestic animals especially birds that live in high abundance and close proximity to human is not well studied. Here, we strive to briefly highlight the role of birds in JEV zoonotic transmission, discovery of birds as a natural reservoirs and amplifying host for JEV, species of birds susceptible to JEV infection, and the proposed effect of JEV on poultry industry in future perspective which have been neglected for a long times. We also discussed the recent in vitro and in vivo studies which show that the newly emerged GI viruses replicated more efficiently in bird-derived cells and ducklings/chicks than GIII, and an important role of birds in the JEV genotype shift from GIII to GI.

Indoor dusts are collectively formed from anthropogenic and atmospheric activities. Particle matter 10 (PM10) is inhalable and causes significant inflammation by interaction with the pulmonary epithelial barrier. The mediators involved in bronchial epithelial cells response to dust are remined unknown. The air-liquid interface of our lung on chip model was exposed to indoor dust collected from highly polluted houses in Delhi, India. The media were collected after 4 days and cytokine levels were measured. We found that the concentration of IFN, IFNγ, Interleukin-6 (IL-6), IL1b, TNFa, and Granulocyte monocyte colony stimulating factor (GM-CSF) were significantly increased after exposure to indoor dust. IFN type I pathways were a major response from dust exposure. Further investigation is needed to determine the mechanism of action and targets of dust in bronchial epithelial cells.

The cardioprotective effects of volatile anesthetics versus total intravenous anesthesia (TIVA) are controversial, especially in patients undergoing non-cardiac surgery. Using current generation high-sensitivity cardiac troponin (hs-cTn), we aimed to evaluate the effect of anesthetics on the occurrence of myocardial injury after non-cardiac surgery (MINS). From February 2010 to December 2016, 3555 patients without preoperative hs-cTn elevation underwent non-cardiac surgery under general anesthesia. Patients were grouped according to anesthetic agent; 659 patients were classified into a propofol-remifentanil total intravenous anesthesia (TIVA) group, and 2896 patients were classified into into a volatile group. To balance the use of remifentanil between groups, a balanced group (n=1622) was generated with patients who received remifentanil infusion in the volatile group, and two separate comparisons were performed (TIVA vs. volatile and TIVA vs. balanced). The primary outcome was occurrence of MINS, defined as rise of hs-cTn I ≥ 0.04 ng/mL within postoperative 48 hours. The secondary outcomes were 30-day mortality, postoperative acute kidney injury (AKI), and adverse events during hospital stay (mortality, type I myocardial infarction (MI), and new-onset arrhythmia). In propensity-matched analyses, the occurrence of MINS was lower in the TIVA group compared to the volatile group (OR 0.642; 95% CI 0.450-0.914; p = 0.014). However, after balancing the use of remifentanil, there was no difference between groups in the risk of MINS (OR 0.832; 95% CI 0.554-1.251; p-value = 0.377). There were no significant associations between the two groups in type 1 MI, new-onset atrial fibrillation, in-hospital and 30-day mortality before and after balancing the use of remifentanil. However, the incidence of postoperative AKI was lower in the TIVA group (OR 0.362; 95% CI 0.194-0.675; p-value = 0.001). After balancing the use of remifentanil, volatile anesthesia and TIVA showed comparable effects on MINS in patients undergoing non-cardiac surgery without preoperative myocardial injury. Further studies are needed on the benefit of remifentanil infusion.

Nucleoli are emerging as key sensors of cellular stress and regulators of the downstream consequences on proliferation, metabolism, senescence and apoptosis. NF-kB signalling is activated in response to a similar plethora of stresses, which leads to modulation of cell growth and death programs. Although these pathways are distinct, it is increasingly apparent that they converge at multiple levels. Exposure of cells to certain insults causes a specific type of nucleolar stress that is characterised by degradation of the PolI complex component, TIF-IA, and increased nucleolar size. Recent studies have shown that this atypical nucleolar stress lies upstream of cytosolic IkB degradation and NF-kB nuclear translocation. Under these stress conditions, the RelA component of NF-kB accumulates within functionally altered nucleoli to trigger a nucleophosmin dependent, apoptotic pathway. In this review, we will discuss these points of crosstalk and their relevance to the anti-tumour mechanism of aspirin and small molecule CDK4 inhibitors. We will also briefly discuss how NF-kB-nucleoli crosstalk may be more broadly relevant to the regulation of cellular homeostasis and how it may be exploited for therapeutic purpose.

Looking at different operating climatic conditions, the electrical behavior predicting photovoltaic modules gets very important. For the estimation of output power from photovoltaic (PV) plants this is a very essential and basic aspect. In this paper, the relationship between the I-V curve and the irradiation spectrum is discussed by combining the single diode model. An explicit elementary analytical model with two defined shape parameters is discussed and improved with three approximations and second order Taylor expansion. Then, the explicit elementary analytical model is investigated under varying conditions leveraging the four parameters I_ph, I₀, R_s and R_sh from the single diode model. The relationship between the physical parameters and the condition parameters are discussed and applied to extract the shape parameters at different scenarios. Considering the aging effect, the process of calculation to predict the I-V curve under different splitting spectra is simplified as follow: (1) two shape parameters are gotten from the I-V data at measurement reference conditions (MRC); (2) the short circuit current, open circuit voltage and shape parameters under any splitting spectrum can be calculated based on the relationship provided in article; (3) the performance of PV panel can be predicted with parameters. The validation of this model was experimentally proven leveraging monocrystalline silicon photovoltaic module with different splitting films. Results showed that the model accurately predicts the I-V characteristics for the examined PV modules at different irradiance spectra and cell temperatures. Moreover, the presented model performs superior compared to other investigated models when looking at accuracy and simplicity.

The activity of prioritizing software requirements should be done as efficiently as possible. Selecting the most stable requirements for the most important customers for the development company can be a positive factor when we consider that the available resource does not always encompass the implementation of all requirements. Quantitative methods for reaching software prioritization in releases are many in the field of Search-Based Software Engineering (SBSE). However, we show that it is possible to use qualitative Verbal Decision Analysis (VDA) methods to solve this same type of problem. Moreover, we will use the ZAPROS III-i methods to prioritize requirements considering the opinion of the decision-maker, who will participate in this process. Finally, the results obtained in the VDA structured methods were quite satisfactory when compared to the methods using SBSE. A comparison of results between quantitative and qualitative methods will be made and discussed later.

My innovative entropy measure, Ismail entropy, namely, (IE) is an ultimate generalization to numerous generalized entropies within the literature. The fractal dimension of IE is identified in this paper. On another applicative note, this paper offers some potential applications of fractal dimension to smart cities. The paper ends with closing remarks combined with some challenging open problems and the next phase of research.

The fine structure of Apricot pectin polysaccharides is discussed from both literature and recent work we have performed. Structural characterization utilized 1D and 2D homo- and hetero-nuclear NMR spectroscopy including results from High Performance Size Exclusion Chromatography (HP-SEC), HP Anion-Exchange Chromatography with Pulsed Amperometric Detection (HPAEC-PAD) and FTIR spectroscopy. The purified pectin fraction (F1AP) was found to be composed of D-galacturonic acid, L-rhamnose, D-arabinose and D-galactose in a 1.0 : 0.1 : 0.36 : 0.12 molar ratio, respectively, which is consistent with a pectin RG-1 branched with arabinogalactan side chain polysaccharides, and has a weight-average molecular weight of approximately 1588.2 kDa. The slope of the hydrodynamic radius versus the molar mass was 0.57, indicating the presence of coil conformations. The results from HPAEC-PAD, HPSEC and NMR spectroscopy (1H, 13C, zTOCSY, HSQC, HSQCTOXY and HMBC) demonstrated that F1AP fine fraction F1AP1, derived from original F1AP, has a backbone of (1→4)-linked -D-galacturonic acid and -L-rhamnopyranosyl residues branched with arabinogalactan of multiply glycosidic linkages of T- α-Araf, 3-α-Araf, 5-α-Araf, T- α -Arap, 2- α-Arap side chains, having methyl and acetylated groups, and has high molecular weights (1945 kDa). While the other F1A6 fraction consists predominately of an HG region of pectin polysaccharides with low molecular weights (117.5 kDa), less aggregated. The F1AP1 polysaccharide was highly viscous and its hydrodynamic radius was 64,3 nm. The exponent b of Rh-Mw (conformation plot) was determined to be 0.48, indicating a compact flexible coil conformation of the macromolecule in solution. However, the F1AP6 fraction of apricot fruits belong to backbone of repeats units of [-(1→4)-α-D-GalpA-1]n – both HG and partly contents RG-II polysaccharides, bearing heterosugar sidechains, including α-Ara, α -Rha and β-Gal residues and adopt more stiffness rod like conformation.

Numerous studies were published suggesting that troponin level is related to adverse outcomes in chronic cardiac and non-cardiac conditions. Our study investigated whether troponin levels gathered from an unselected blood sample taken during outpatient care are associated with adverse outcomes in a population with stable coronary artery disease. In a cohort of 949 patients with stable coronary artery disease, average age of 67.5 ± 9.5 years, 69.5% male, 52.1% diabetics, 51.6% with previous myocardial infarction, 57.9% with triple-vessel disease, 21.7% of patients encountered new events during an average period of monitoring of 2.07 ± 0.81 years. Troponin I/99th percentile categorized into tertiles emerged as an independent predictor of death and combined events risk (hazard ratio: 2.02 (1.13-3.60), p=0.017; 2.30 (1.37-3.88, p=0.002, respectively). A troponin ratio > 0.24 was able to identify 53.3% of patients at risk of death and heart failure hospitalization. In patients with stable coronary artery disease and adherent to treatment, troponin level is independently associated with death and heart failure hospitalization in a medium-term follow up.

The growth of plant and process of yield formation in crops are moderated by surrounding conditions as well as interaction of genetic background of plants and environment. In the last two decades significant changes in climate can be observed generating unfavorable and harmful impact on plant development. Drought stress can be considered as one of the most dangerous environmental factor influencing plant life cycle and decreasing production of biomass and finally the yield. Plants can react to water deficit in a wide degree what is dependent on the species, the genetic variability within the species, the phase of the plant ontogenesis, the intensity of stress, and other potential stress factors. In plants there can be observed hybrids between distinct taxa which exhibit certain traits adopted to tolerate stress conditions better than parental plants. Oat × maize addition (OMA) plants are good example of fertile hybrids with retained maize chromosomes as addition to complete oat genome. Hybrids generated via wide crossing can exhibit morphological, physiological and biochemical variations implemented by the occurrence of extra chromosomes of maize, as well as interaction of maize and oat chromatin. The molecular analysis indicated 12.5% OMA lines among all tested descendants of wide oat-maize crossing. On the fourteenth day of the drought, a significant effect of stress on the content of soluble sugars and phenolic compounds was observed, soil drought significantly reduced plant biomass above ground and several yield components. Less water lost revealed by results of the excised leaf water loss test was correlated with high yield of OMA lines. Phenolic compounds content might be used as biochemical indicator of plant drought tolerance since there were significant correlation with high kernel yields of plants subjected to drought stress.

RNA editing involves the insertion, deletion or substitution of single nucleotides within a RNA molecule, without altering the DNA sequence. Adenosine to inosine (A-to-I) editing consists of an RNA modification where single adenosines along the RNA sequence are converted into inosines. Such a biochemical transformation is catalyzed by enzymes belonging to the family of adenosine deaminases acting on RNA (ADARs) and occurs either co- or post-transcriptionally. Initially, the A-to-I RNA editing phenomenon was discovered and studied in messenger RNAs (mRNAs), where it can influence RNA splicing and cause the recoding of codon sequences. The employment of more powerful, high-throughput detection methods has recently revealed that A-to-I editing widely occurs in non-coding RNAs, including microRNAs (miRNAs). MiRNAs are a class of small regulatory non-coding RNAs (ncRNAs) acting as translation inhibitors, known to exert relevant roles in controlling cell cycle, proliferation, and cancer development. Indeed, a growing number of recent researches have evidenced the importance of miRNA editing in cancer biology by exploiting various detection and validation methods. Herein, we briefly overview early and currently available A-to-I miRNA editing detection and validation methods and discuss the significance of A-to-I miRNA editing in human cancer.

Systemic lupus erythematosus (SLE) is a heterogenous autoimmune disease. While its etiology remains elusive, current understanding suggests a multifactorial process with contributions by genetic, immunologic, hormonal, and environmental factors. A hypothesis that combines several of these factors proposes that genomic elements, the L1 retrotransposons, are instrumental in SLE pathogenesis. L1 retroelements are transcriptionally activated in SLE and produce two proteins, ORF1p and ORF2p, which are immunogenic and can drive type I interferon (IFN) production by producing DNA species that activate cytosolic DNA sensors. In addition, these two proteins reside in RNA-rich macromolecular assemblies that also contain well-known SLE autoantigens like Ro60. We surmise that cells expressing L1 will exhibit all the hallmarks of cells infected by a virus, resulting in a cellular and humoral immune response similar to those in chronic viral infections. However, unlike exogenous viruses, L1 retroelements cannot be eliminated from the host genome. Hence, dysregulated L1 will cause a chronic, but perhaps episodic, challenge for the immune system. The clinical and immunological features of SLE can be largely explained by this model. Here we review the support for, and the gaps in, this hypothesis of SLE and its potential for new diagnostic, prognostic, and therapeutic options in SLE.

Streptococcus mutans is well known for having virulence factors associated with its cariogenic role, such as glucosyltransferases, which have been used as targets for the virtual screening of molecules with inhibitory capacity. The Antigen I/II of S. mutans is involved in the adhesion to the surface of the tooth and the bacterial co-aggregation in the biofilm formation, despite that, this protein has not been used as a target in a virtual strategy search for inhibitors. In this study we identified in silico and evaluated in vitro molecules with adhesion inhibitory potential on S. mutans Ag I/II. A virtual screening of 883,551 molecules was conducted, cytotoxicity analysis on fibroblast cells, S. mutans adhesion studies, scanning electron microscopy analysis for bacterial integrity, and molecular dynamics simulation were also performed. We have found three molecules (ZI-187, ZI-939, ZI-906) that were not cytotoxic and inhibited the adhesion of S. mutans to polystyrene microplates. Molecular dynamic simulation by 300 nanoseconds showed stability of the interaction between ZI-187 and Ag I/II (PDB: 3IPK). This work provides three new molecules that targets Ag I/II and have the capacity to inhibit in vitro the S. mutans adhesion on polystyrene microplates and provides a new computational line for the search and selection of safe inhibitory molecules against different pathogens.

Gastrointestinal tumors including pancreatic and colorectal cancers represent one of the greatest public health issues worldwide, leading to million global deaths. Recent research demonstrated that the human heavy chain ferritin (HFt) can encapsulate different type of drugs in its cavity and can bind to its receptor, CD71, in several solid and hematological tumors, thus highlighting the potential use of ferritin for tumor-targeting therapies. Here, we describe the development and characterization of a novel nanomedicine based on the HFt that is named The-0504. In particular, this novel system is a nano-assembly comprising an engineered version of HFt that entraps about 80 molecules of a potent, wide-spectrum, non-camptothecin topoisomerase I inhibitor (Genz-644282). The-0504 can be produced by a standardized pre-industrial process as a pure and homogeneously formulated product with favourable lyophilization properties. The preliminary anticancer activity was evaluated in cultured cancer cells and in a mouse model of pancreatic cancer. Overall results reported here make The-0504 a candidate for further preclinical development against CD-71 expressing deadly tumors

Aberrant neutrophil extracellular trap (NET) formation and the loss of barrier integrity in inflamed intestinal tissues have long been associated with inflammatory bowel disease (IBD). However, whether NETs alter intestinal epithelium permeability during colitis remains elusive. Here, we demonstrated that NETs promote the breakdown in intestinal barrier function for the pathogenesis of intestinal inflammation in mouse models of colitis. NETs were abundant in the colon of mice with colitis experimentally induced by dextran sulfate sodium (DSS) or 2,4,6-trinitrobenzene sulfonic acid (TNBS). Analysis of the intestinal barrier integrity revealed that NETs impaired gut permeability, enabling the initiation of luminal bacterial translocation and inflammation. Furthermore, NETs induced the apoptosis of epithelial cells and disrupted the integrity of tight junctions and adherens junctions. Intravenous administration of DNase I, an enzyme that dissolves the web-like DNA filaments of NETs, during colitis restored the mucosal barrier integrity which reduced the dissemination of luminal bacteria, and attenuated intestinal inflammation in both DSS and TNBS models. We conclude that NETs serve a detrimental factor in the gut epithelial barrier function leading to the pathogenesis of mucosal inflammation during acute colitis.

Curcumin, a natural polyphenolic compound isolated from the plant Curcuma longa, is known to induce autophagy in various cancer cells, including lung cancer. In the present study, we also confirmed by LC3 immunofluorescence and immunoblotting analyses that curcumin triggers autophagy in human lung adenocarcinoma A549 cell line. In parallel with autophagy induction, gene expression of human GD3 synthase (hST8Sia I) responsible for ganglioside GD3 synthesis was markedly elevated in response to curcumin in A549 cells. To investigate transcriptional activation of hST8Sia I associated with autophagy formation in curcumin-treated A549 cells, functional characterization of the 5’-flanking region of the hST8Sia I gene was carried out using luciferase reporter assay system. Deletion analysis demonstrated that the -1146 to -646 region, which includes putative c-Ets-1, CREB, AP-1 and NF-κB binding sites, functions as the curcumin-responsive promoter of hST8Sia I in A549 cells. Site-directed mutagenesis and chromatin immunoprecipitation assay demonstrated that the NF-κB binding site at -731 to -722 was indispensable for the curcumin-induced hST8Sia I gene expression in A549 cells. Moreover, the transcriptional activation of hST8Sia I by curcumin A549 cells was strongly inhibited by compound C, an inhibitor of AMP-activated protein kinase (AMPK). These results suggest that curcumin controls hST8Sia I gene expression via AMPK signal pathway in A549 cells.

Background. Azithromycin (AZM) is widely used in cystic fibrosis (CF) treatment following clinical trials demonstrating improved lung function and fewer pulmonary exacerbations. While the precise mechanisms remain elusive, immunomodulatory actions are thought to be involved. We previously reported impaired phagocytosis and defective anti-inflammatory M2 macrophage polarization in CF macrophages. This study systematically analyzed the effect of AZM on the functions of unpolarized and M1/M2 polarized macrophages in CF. Methods: Monocytes, isolated from the venous blood of patients with CF (pwCF) and healthy controls (HCs) were differentiated into monocyte-derived macrophages (MDMs) and infected with P. aeruginosa. P. aeruginosa uptake and killing by MDMs in the presence or absence of AZM was studied. M1 and M2 macrophage polarizations were induced and their functions and cytokine release were analyzed. Results: Following AZM treatment, both HC and CF MDMs exhibited a significant increase in P. aeruginosa uptake and killing, however, lysosomal acidification remained unchanged. AZM treatment led to higher activation of ERK1/2 in both HC and CF MDMs. Pharmacological inhibition of ERK1/2 using U0126 significantly reduced P. aeruginosa uptake in HC MDMs. M1 macrophage polarization remained unaffected, however, AZM treatment led to increased IL-6 and IL-10 release in both HC and CF M1 macrophages. AZM also significantly increased the phagocytic index for both pHrodo E. coli and S. aureus in CF M1 macrophages. In CF, AZM treatment promoted anti-inflammatory M2 macrophage polarization, with an increased percentage of CD209+ M2 macrophages, induction of the M2 gene CCL18, along with its secretion in the culture supernatant. However, AZM did not restore endocytosis in CF, another essential feature of M2 macrophages. Conclusions: This study highlights the cellular functions and molecular targets of AZM which may involve improved uptake of both gram-positive and gram-negative bacteria, restored anti-inflammatory macrophage polarization in CF. This may in turn shape the reduced lung inflammation observed in clinical trials. In addition, we confirmed the role of ERK1/2 activation for bacterial uptake.

Abstract. The remarks by the Supreme Leader of the Islamic Revolution on the toll of the famines that afflicted occupied Iran in World War I and World War II indicate a desire to incorporate these calamities in Iran’s national narrative and collective memory. His criticism of famine historiography and stated toll numbers, and the unfolding catastrophic famine in Gaza, justify and necessitate a fresh look at each famine’s historiography and toll. This article re-estimates the toll of each famine by including many overlooked and neglected primary sources and in ways not previously done. It builds a trajectory of Iran’s demographic development from 1810 to 1944, and derives the toll of each famine. The World War II famine and typhus epidemics had claimed 5.5 million. World War I famine was also more deadly, though the 1869-73 famine was not far behind. At least 15.5 million Iranians died in the two world wars, a fact nowhere reflected in the history of the conflicts. Iran’s 1944 population of 12 million was unchanged from that of 1850 and a century of population growth obliterated

Introduction: maxillary hypoplasia and mandibular asymmetry may be corrected with orthognathic surgery at the completion of growth. Many patients require segmental Le Fort I osteotomies to obtain the most stable results. Unfortunately, if Invisalign is chosen for pre-surgical preparation, ClinCheck © software does not allow for prediction when these complex surgeries are planned. The objective of this paper was to show the potential of aligners beyond its software in most complex cases like multiple-piece maxillary osteotomies in cleft and non-cleft patients. Method: Thirteen patients who underwent pre-surgical treatment with clear aligners-Invisalign (study group) were matched in terms of diagnosis, surgical procedure, and orthodontic complexity with thirteen patients treated using fixed appliances (control group). A technique based on simple superimposition was devised to enhance the software for creating a suitable occlusion for segmental pre-surgical treatments. Virtual curves following the lower arch were employed to guide the correct pre-surgical positions of the upper teeth. The amount of impressions required in both groups to achieve satisfactory pre-surgical alignment of the segmented arches was compared. Results: one or no refinement phase were needed in the Invisalign group to reach an acceptable pre-surgical occlusion while the amount of pre-surgical impressions taken in order to reach adequate coordination with fixed appliance treatment was slightly higher. The average overall treatment duration did not show a statistically significant variation between the groups. Conclusions: it appears that clear aligner could serve as an effective treatment for individuals with skeletal discrepancies, including cleft and craniofacial anomalies, necessitating segmental Le Fort I osteotomies when aided by the suggested superimposition approach during digital pre-surgical movement simulations. More sophisticated softwares will certainly be implemented in the future.

High incidence of epithelial malignancies in HIV-1 infection is associated with co-infection with oncogenic viruses, such as high-risk human papillomaviruses (HR HPVs), most often HPV16. A collaboration between HIV-1 and HR HPVs in the malignant transformation of epithelial cells exposed to both viruses have long been anticipated. Here, we delineated the effects on in vitro and in vivo properties of HPV16-infected cervical cancer cells of HIV-1 reverse transcriptase. Epidermoid carcinoma Ca Ski cells were made to express RT of HIV-1 clade A (RT_A) or Green Fluorescence Protein (GFP) by lentiviral transduction, subclones with one or six copies of RT_A and six copies of GFP DNA were generated. Expression by subclones of GFP was assessed by flow cytometry, and of RT_A, by Western blotting. Cells were assessed for the levels of mRNA of the RT_A, E6 and its isoforms, and cellular factors characterizing oxidative stress, and EMT by the real-time PCR. Parameters of glycolysis and mitochondrial respiration were assessed by Seahorse technology. Subclones were surveyed for the changes in cell cycle, doubling time, migration capacity, clonogenic activity and for the capacity to form tumors in nude mice. Ca Ski RT_A produced 20-55 fg of RT_A per cell. Expression of RT_A caused a proportional increase in the expression of E6*I isoform. In Ca Ski, RT_A suppressed mitochondrial respiration and oxygen consumption, and increased glycolysis. Compared to parental cells and GFP control, transcription in Ca Ski RT_A of epithelial (E-CADHERIN) state marker was increased, and of mesenchymal (VIMENTIN) decreased, indicating acquisition by cells of the hybrid epithelial/mesenchymal (E/M) phenotype. While Ca Ski GFP and Ca Ski RT_A with one gene insert had reduced migration rate, decreased clonogenic activity in vitro, and diminished capacity to form tumors in nude mice, increase in RT_A copicity/expression mitigated these effects. Altogether, expression of HIV-1 RT_A gave Ca Ski cells the plasticity required to overcome negative effects of lentiviral transduction and potentially increased their tumorigenicity.

This study aimed to detect picobirnavirus (PBV) in the fecal samples of wild and domestic animals from 2014 to 2016 in the Amazon biome. Fecal samples from different animals, including birds (n=41) and mammals (n=217) were used. The PAGE test showed negativity for PBV. However, 32 samples (12.4%, 32/258) showed positive results in RT-PCR analyses. Among the positive sam-ples, pigs and cats, both with 28.12% (9/32), registered the highest frequencies. In phylogenetic analysis, eight sequences from positive samples grouped in the Genogroup 1 of PBV (PBV GI). PBV occurrence was significantly related to cats and pigs, but not other mammals or birds, in-dependently of their geographical origin. Nucleotide analysis demonstrated similarity among the feline group, but the absence of a defined structure between the clades. PBVs are highly wide-spread viruses that can affect the most diverse types of hosts in the Amazon biome, including humans.

The selectin of a demand forecasting method is critical for companies aiming to avoid manufacturing overproduction or shortages in pursuit of sustainable development. Various qualitative and quantitative criteria with different weights must be considered during the evaluation of a forecasting method. The qualitative criteria and criteria weights are usually assessed in linguistic terms. Aggregating these various criteria and linguistic weights for evaluating and selecting demand forecasting methods in sustainable manufacturing is a major challenge. This paper proposes an extension of fuzzy Elimination and Choice Translating Reality (ELECTRE) I to resolve this problem. In the proposed method, fuzzy weighted ratings are defuzzified with the signed distance to develop a crisp ELECTRE I model. Moreover, an extension to ELECTRE I is developed by suggesting an extended modified discordance matrix and a closeness coefficient for ranking alternatives. The proposed extension can overcome the problem of information loss which can lead to incorrect ranking result when using the Hadamard product to combine concordance and modified discordance matrices. A comparison is conducted to show the advantage of the proposed extension. Finally, a numerical example is used to demonstrate the feasibility of the proposed method; furthermore, a numerical comparison is made to display the advantage of the proposed method.

To evaluate the relative importance of IGF-I expression in various cell types for endochon-dral ossification, we quantified the trabecular bone at the secondary spongiosa and epiphysis of the distal femur in 8-12-week-old male mice with a global knockout of the Igf-I gene as well as conditional deletion of the Igf-I gene in osteoblasts, chondrocytes, osteo-blasts/chondrocytes, and their corresponding control wild type littermates. The osteoblast-, chondrocyte- and osteoblast/chondrocyte-specific Igf-I conditional knockout mice were generated by crossing Igf-I floxed mice with Cre transgenic mice in which Cre expression is under the control of Col1α2 or Col2α1 promoter. We found that global disruption of Igf-I resulted in 80% and 70% reduction in bone size, which is defined as total volume, at the secondary spongiosa and epiphysis of the distal femur, respectively. Abrogation of Igf-I in Col1α2-producing osteoblasts, but not Col2α1-producing chondrocytes, decreased bone size by 25% at both the secondary spongiosa and epiphysis while deletion of the Igf-I globally or specifically in osteoblasts or chondrocytes reduced trabecular bone mass by 25%. By contrast, global Igf-I knockout but not conditional knockout of Igf-I in osteoblasts and/or chondrocytes reduced trabecular bone mass in the epiphysis. The reduced trabecu-lar bone mass at the secondary spongiosa in osteoblast- and/or chondrocyte-specific Igf-I conditional knockout mice is caused by reduced trabecular number and increased trabec-ular separation. Immunohistochemistry studies revealed that expression levels of chon-drocyte (COL10, MMP13) and osteoblast (BSP) markers were reduced in the secondary spongiosa and the epiphyses in the global Igf-I knockout mice. Our data indicate that local and endocrine IGF-I actions in bone are pleiotropic and dependent on cell type as well as the bone compartment where IGF-I acts.

Myocardial infarction (MI) is a serious cardiovascular disease that can lead to death. Cardiac troponin I (cTnI) is a biomarker of MI in the circulation system. For detection cTnI protein, many method suffer the same problem, time-consuming. Main drawbacks are time consuming, have tedious operation, require an expensive reader for translating signals, and require non-accessible reagents. Our goal is to create a kit for cTnI protein testing, that the result can easily be read by color difference. The main breakthrough is, the resolution between different concentration can be told by eyes. The result will be future used to create a commercial, potable, convenient, daily-used rapid-test kit. In this study, a cTnI biosensor is proposed that can be read by the naked eye, performs diagnosis based on the pattern color, does not require a reader machine, is easy to operate, and is portable. Our work proposed a device that shortens the diagnosis time, has a quantitative analysis range of 0.32 –200 ng/mL in the human serum matrix, has a 0.32 ng/mL limit of detection (LOD), and shows many advantages comparing to traditional cTnI ELISA plate.

A locally-rotationally-symmetric Bianchi-I model filled with strange quark matter (SQM) is explored in f(R, T) gravity. We take f(R, T) = R + 2 f(T) = R + 2λT, where R is the Ricci scalar, T is the trace of energy-momentum tensor and λ is an arbitrary constant. Exact solutions are obtained by assuming that the expansion scalar is proportional to the shear scalar. This yields a constant value for the deceleration parameter, q = 2, which corresponds to the decelerated phase of the universe. The model is found to be physically viable for λ < −1. SQM during early evolution mimics ultra-relativistic radiation whereas at late times, it behaves as dust, quintessence or even the cosmological constant depending on the value of λ. The effective matter acts as a stiff fluid irrespective of the matter content and of the f(R, T) terms. The model is shear free at late times but remains anisotropic throughout the evolution. In the absence of the f(R, T) terms, SQM accelerates the universe. In the specific case when SQM vanishes at late times, the effect of f(R, T) is to accelerate the universe. The model admits the possibility that SQM could be an alternative to dark energy.

Chorioamnionitis (CA) at term of pregnancy can have infectious and/or inflammatory origin and is associated with adverse outcomes. Triple I (Intrauterine Inflammation, Infection or both, TI) has been proposed to reduce the overdiagnosis of infection and the neonatal overtreatment. The aim of the study is to identify clinical and histological variables predicting adverse outcomes when TI has been suspected and/or confirmed. This retrospective cohort study included 404 pregnancies ≥37 g.a. that were divided into 5 all-inclusive and mutually exclusive groups. TI was defined according to NICHD definition of 2015 and it could be confirmed (TI+) or not (TI-) by histological examination. Signs of infection/inflammation not respecting the definition of TI were classified as “Clinical suspicion”, supported (CS+) or not (CS-) by histology. Histological chorioamnionitis (HCA) without clinical manifestation represented fifth group. Whole Placental Involvement (WPLI), was defined as a histological inflammation involving maternal and fetal side. There were 113 TI+, 30 TI-, 186 CS+, 35 CS- and 40 isolated HCA. WPLI was diagnosed in 133 cases (39.2%). Composite neonatal outcome (CNO) occurred in 114 cases (28.2%) while composite maternal outcome (CMO) occurred in 192 cases (47.5%). TI+ compared to CS+ was more predictive of CNO (p=0.001), CMO (p<0.001) and WPLI (p=0.005). WPLI was related both to CNO (p<0.001) and CMO (p=0.046). TI+ and WPLI showed similar sensitivity but different specificity in predicting CNO. At logistic regression, CNO was independently predicted by TI+ (OR 2.21; p=0.001) and by WPLI (OR 2.23; p=0.001). TI, compared to CS, is a better predictor of CNO and can be useful for the identification of newborns at risk.

Bacterial nitroreductase enzymes that convert prodrugs to cytotoxins are valuable tools for creating transgenic targeted ablation models to study cellular function and cell-specific regeneration paradigms. We recently engineered a nitroreductase (“NTR 2.0”) for substantially enhanced reduction of the prodrug metronidazole, which permits faster cell ablation kinetics, cleaner interrogations of cell function, ablation of previously recalcitrant cell types, and extended ablation paradigms useful for modelling chronic diseases. To provide insight into the enhanced enzymatic mechanism of NTR 2.0, we have solved the X-ray crystal structure at 1.85 Angstroms resolution and compared it to the parental enzyme, NfsB from Vibrio vulnificus. We additionally present a survey of reductive activity with eight alternative nitroaromatic substrates, to provide access to alternative ablation prodrugs, and explore applications such as remediation of dinitrotoluene pollutants. The predicted binding modes of four key substrates were investigated using molecular modelling.

Glutamate excitotoxicity is implicated in the pathogenesis of many disorders, including stroke, traumatic brain injury, and Alzheimer’s disease, for which central insulin resistance is a comorbid condition. Massive glutamate release primarily through ionotropic N-methyl-D-aspartate receptors (NMDARs) causes a sustained rise in [Ca2+]i, followed by mitochondrial depolarization and an increase in intracellular O2• (superoxide) production. Recently, we found that insulin protected neurons against excitotoxicity by diminishing the delayed calcium deregulation (DCD), However, a role of insulin in superoxide production in excitotoxicity still needs to be clarified. The present study is aimed to investigate the effects of insulin on glutamate-evoked superoxide generation and DCD using the fluorescent indicators dihydroethidium, MitoSOX Red, and Fura-FF in rats cultured cortical neurons. We found that insulin significantly diminished both the intracellular and mitochondrial superoxide production in neurons exposed to glutamate and there was a strong linear correlation between [Ca2+]i and intracellular superoxide. MK 801, an inhibitor of NMDAR-gated Ca2+ influx, completely abrogated the glutamate effects in both the presence and absence of insulin. In experiments on sister cultures, insulin diminishes neuronal death. Thus, collectively, data obtained suggest that insulin diminishes glutamate-induced superoxide production in neurons via fall of [Ca2+]i increased and thereby improves viability of neurons

There is high confidence that climate change has increased the probability of concurrent temperature-precipitation extremes, changed their spatial-temporal variations, and affected the relationships between drivers of such natural hazards. However, the extent of such changes has been less investigated in Australia. Daily weather data (131 years, 1889-2019) at 700 grid cells (1◦ × 1◦) across Australia was obtained to calculate annual and seasonal mean daily maximum temperature (MMT) and total precipitation (TPR). A nonparametric multivariate copula framework was adopted to estimate the return period of compound hot-dry (CHD) events based on an ‘And’ hazard scenario (hotter than a threshold ‘And’ drier than a threshold). CHD extremes were defined as years with joint return periods of larger than 25 years. Mann-Kendall nonparametric tests was used to analyse trends in MMT and TPR as well as in the frequency of univariate and CHD extremes. A general cooling-wetting trend was observed over 1889-1989. Significant increasing trends were detected over 1990-2019 in the frequency and severity of hot extremes across the country while trends in dry extremes were mostly insignificant (and decreasing). Results showed a significant increase in the association between temperature and precipitation at various temporal scales. The frequency of CHD extremes was mostly stable over 1889-1989, but significantly increased between 1990 and 2019 at 44% of studied grid cells, mostly located in the north, south-east and south-west. Spatial homogeneity (i.e. connectedness) and propagation of extreme events from one grid cell to its neighbouring cells was investigated across Australia. It can be concluded that this connectedness has not significantly changed since 1889.

Geopolymer cement has been popularly studied nowadays compared to ordinary Portland cement because it demonstrated superior environmental advantages due to its lower carbon emissions and waste material utilization. This paper focuses on the formulation of geopolymer cement from nickel-laterite mine waste (NMW) and coal fly ash (CFA) as geopolymer precursors, and sodium hydroxide (SH) and sodium silicate (SS) as alkali activators. Different mix formulations of raw materials are synthesized to produce a geopolymer based from an I-optimal design and obtained different compressive strengths. A mixed formulation of 50% NMW and 50% CFA, SH-to-SS ratio of 0.5, and an activator-to-precursor ratio of 0.429 yielded the highest 28-day unconfined compressive strength (UCS) of 22.10 ± 5.40 MPa. Furthermore, using an optimized formulation of 50.12% NMW, SH-to-SS ratio of 0.516, and an activator-to-precursor ratio of 0.428, a UCS value of 36.30 ± 3.60 MPa was obtained. The result implies that the synthesized geopolymer material can be potentially used for concrete structures and pavers, pedestrian pavers, light traffic pavers, and plain concrete.

Dyadic data which is also called co-occurrence data (COD) contains co-occurrences of objects. Searching for statistical models to represent dyadic data is necessary. Fortunately, finite mixture model is a solid statistical model to learn and make inference on dyadic data because mixture model is built smoothly and reliably by expectation maximization (EM) algorithm which is suitable to inherent spareness of dyadic data. This research summarizes mixture models for dyadic data. When each co-occurrence in dyadic data is associated with a value, there are many unaccomplished values because a lot of co-occurrences are inexistent. In this research, these unaccomplished values are estimated as mean (expectation) of random variable given partial probabilistic distributions inside dyadic mixture model.

As the rapid development of communication industry, especially the 5G communication and IOT, there will be plenty of electromagnetic (EM) waves in the free space, which carry lots of energies. However, some of these energies are wasted in free space. To reuse these wasted energies, significantly growing interests are towards to the energy harvesting antennas. This paper is aimed to investigate a wearable antenna which can transfer RF energy from ambient sources to direct current by a soft and portable textile antenna. Among the numerous signals in mobile network, the GSM 1800, 3G, WiFi and 4G/5G will be chosen due to the city signal intensity distribution. Hence, a corresponding triple bands antenna has been designed to cover those frequency bands. The CST STUDIO SUITE is used in whole process of antenna design and simulation. The proposed antenna is a hooked dipole antenna with tuning bar (HATB) whose ends have small folded part in each side for better bandwidth performance. The presented antenna provides a wide operating band from 1.8 GHz to 2.5 GHz below -10 dB in return loss. And methods to overcome interference between antennas is found. Furthermore, using the corresponding rectifier to achieve the RF/DC conversion. The overall efficiency of whole rectifier is about 56.8 %, and output power level of the antenna system is 45.92nW. The experimental results could indicate that my textile hooked antenna harvester is a good choice for the charging system of personal wearable attachment, which could achieve low power absorbing for long distance anytime and anywhere.

The gold(I) N-heterocyclic carbene (NHC) complexes, containing a combination of 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene (iPr) and the corresponding 7-azaindole derivative (HL1-4), were prepared and structurally characterized. The complexes of the composition of [Au(iPr)(HLn)], where n = 1–4 for 5-fluoro-7-azaindole (1), 5-bromo-7-azaindole (2), 3-chloro-7-azaindole (3) and 3-iodo-7-azaindole (4), were further evaluated for their in vitro anti-cancer and anti-inflammatory activities. The results showed that complexes (1–4) behave as considerably cytotoxic against human ovarian cancer cell line A2780 (with IC50 = 4–9 mircoM) and cisplatin-resistant cell line A2780R (with IC50 = 5–8 microM, except for 2 with IC50 > 25 microM), providing significantly higher cytotoxicity than anticancer drug cisplatin. Moreover, they also revealed a relatively good selectivity over normal cells (MRC-5), with the values of selectivity index, SI > 2.5. The complex 4 was further studied for its cellular effects in A2780 cells by cell cycle analysis, induction of apoptosis, intracellular ROS production, activation of caspases 3/7 and disruption of mitochondrial membrane potential. The ability of complexes (1–4) to influence the activity of pro-inflammatory transcription factor NF-κB and secretion of TNF-α were evaluated, showing that complex 4 reveals comparable effects as the inflammatory drug Auranofin.

Chinese divination of I Ching has a history of thousands of years. The six lines changes in 64 hexagrams have exceeded one billion scenarios, and the inherent laws among them have not been well revealed to this day. By using big data's technology and coin toss method, this paper simulates the change of 64 hexagrams, and explores the probability and proportion of each hexagram during the change from the perspective of quantification, as well as the maximum and minimum conversion rate of hexagram change. This paper summarizes the basic characteristics and the basic law of hexagram change, and accordingly constructs the spatial form of hexagram change, and reveals the hidden secrets of the ancient Book of changes (I Ching). To achieve this goal, we randomly toss three coins 600 million times to generate 100 million hexagrams. According to the basic rules of hexagram divination, we calculate the hexagram changes. The results showed that: (1) Changes of things are mostly simple changes. The probability of 1 billion randomly generated hexagrams from one to three dynamic lines is close to 80%. (2) About 17% of the 64 hexagrams have no dynamic lines, which means that a significant proportion of the 64 hexagrams are invariant. (3) Small probability changing hexagram certainty and large probability changing hexagram uncertainty. (4) After generating one billion hexagrams at random, the topographic map with the probability of changing hexagrams has axial symmetry and fractal geometric characteristics, and the fractal characteristics are mainly manifested in that the changes on both sides of the symmetry are presented based on the triangle background. These results reflect the obvious characteristics and internal regularity of the changes in the 64 hexagrams of the I Ching. This article provides new ideas for scientific exploration of the internal laws of the 64 hexagrams in the I Ching.

Although many policosanols from different sources, such as sugar cane, rice bran, and insects, have been marketed worldwide, there has been no comparative study of the in vivo efficacy using a hyperlipidemic animal model. This study compared the efficacy of treating dyslipidemia with four different policosanols, including one sugar cane wax alcohol from Cuba (Raydel®) and three policosanols from China (Xi’an Natural sugar cane, Xi’an Realin sugar cane, and Shaanxi rice bran) in hyperlipidemic zebrafish. After 12 weeks of consumption of each policosanol (final 0.1% in diet, wt/wt) and high cholesterol diet (HCD, final 4%, wt/wt) in a tetrabit, the Raydel policosanol group and Xi’an Natural policosanol group showed the highest survivability of approximately 81%, whereas the Xi’an Realin policosanol group and Shaanxi policosanol group showed 57% and 67% survivability, respectively. Among five HCD groups, the Raydel policosanol group showed the lowest serum total cholesterol (TC, p<0.001 versus HCD control) and triglyceride (TG, p<0.001 versus HCD control) with the highest percentage of high-density lipoproteins (HDL)-C in TC. The Raydel policosanol group also showed the lowest serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels with the least infiltration of inflammatory cells and interleukin-6 production in hepatocytes. In the ovary, the Raydel policosanol group also showed the highest contents of mature vitellogenic oocytes with the lowest production of reactive oxygen species and cellular apoptosis in ovarian cells. In the testis, the Raydel policosanol group also showed the healthiest morphology for spermatogenesis with the least interstitial area and reactive oxygen species (ROS) production in testicular cells. In conclusion, 12 weeks of Raydel policosanol consumption resulted in remarkable improvement of the blood lipid profile, amelioration of inflammation in the liver, and enhancement of the cell morphology in the ovary and testis with the highest survivability under the HCD.

The inositol triphosphate associated proteins IRAG1 and IRAG2 are cGMP kinase substrate proteins, which regulate intracellular Ca2+. Previously, IRAG1 was discovered as a 125 kDa membrane protein at the endoplasmic reticulum, that is associated with the intracellular Ca2+ channel IP3R-I and the PKGIβ and inhibits IP3R-I upon PKGIβ-mediated phosphorylation. IRAG2 is a 75 kDa membrane protein homologue of IRAG1 and was recently also determined as a PKGI substrate protein. Several (patho-)physiological functions of IRAG1 and IRAG2 were meanwhile and recently elucidated in a variety of human and murine tissues, e.g. of IRAG1 in various smooth muscles, heart, platelets and other blood cells, of IRAG2 in pancreas, heart, platelets and taste cells. Hence, lack of IRAG1 or IRAG2 leads to diverse phenotypes in these organs, e.g. smooth muscle and platelet disorders or secretory deficiency, respectively. This review aims to highlight the recent research regarding these both regulatory proteins to envision its molecular and (patho-)physiological tasks and to unravel its functional interplay as possible (patho-)physiological counterparts.

Should our planet be visited by an extraterrestrial civilization, the prevailing assumption would undoubtedly be that the extraterrestrial civilization is Type I i.e. its capacity for interstellar travel results from its technological development. This assumption is dangerous for it unnecessarily leads to the Extraterrestrial Tandem Hypothesis (ETH): the belief than an extraterrestrial civilization technologically capable of interstellar travel must also be technologically compatible with the inexorably rapid annihilation of life on Earth. Such a state of things would compromise the planet’s capacity to stage a confident defense should the extraterrestrials prove belligerent. The presumption of Type I extraterrestrials (on the premise of the capacity for interstellar travel alone) is unfounded as extraterrestrials may be Type II i.e. capable of interstellar travel by virtue of natural intrinsic or extrinsic factors. This paper advances, most importantly, that the fundamental policy of first contact should be the employment of various strategies toward the evaluation of the technological capacity of visiting extraterrestrials. This evaluation must be particularly devoted to the detection of Type II extraterrestrials masquerading as Type I (using concealment and Wizard of Oz strategies). Integral to this detection are the concepts of the precedence relation and The Extraterrestrial Exclusion Principle (EEP). A precedence relation is a qualitative relation expressing the relative difficulty of producing a technological action. The Extraterrestrial Exclusion Principle states that a Type I extraterrestrial life form is excluded from certain actions. Such actions are lower in precedence than interstellar travel and may be described as in violation of the EEP or EEP forbidden. EEP actions reveal extraterrestrials to be Type II. As an example, the value of the Hawking Warning is subjected to EEP analysis. Furthermore, a hypothetical conundrum in linguistics termed the Kryptonian Linguistic Paradox (KLP) is discussed as a case of an EEP forbidden act. Finally, the paper explores the limitations of the stated fundamental policy of first contact.

A gold(I) complex with a triphenylphosphine and a monodentate N,N-dimethyldithiocarbamate ligand was synthesized and characterized by Raman spectroscopy and single crystal X-ray diffraction. DFT calculations (Gaussian 09, PBE1PBE/Lanl2dz) were undertaken for a single complex in the gas-phase. The DFT-optimized structure is in good agreement with the crystal structure and the DFT-calculated Raman spectrum also is in excellent agreement with the experimental spectrum. Assignments of the Raman peaks are based on these DFT calculations. Frontier molecular orbitals were calculated and their nature is discussed.

Very disparate types of cell populations exhibit similar transcription specificity for certain genes. We identified 20 genes that were expressed preferentially in myoblasts and cerebellum (Myob/Cbl genes) and examined their cell/tissue-specific epigenetics using a combined approach of comparing DNA methylation, chromatin accessibility, and RNA expression in many different cell populations. Some Myob/Cbl genes shared DNA hypo- or hypermethylated regions in myoblasts and cerebellum. Particularly striking was ZNF556, whose promoter is hypomethylated in expressing cells but highly methylated in the many cell populations that do not express the gene. In reporter gene assays, we demonstrated that its promoter’s activity is methylation-sensitive. The atypical epigenetics of ZNF556 may have originated from its promoter’s hypomethylation and selective activation in sperm progenitors and oocytes. Five of the Myob/Cbl genes (KCNJ12, ST8SIA5, ZIC1, VAX2, and EN2) have much higher RNA levels in cerebellum than in myoblasts and displayed myoblast-specific hypermethylation upstream and/or downstream of their promoters that may downmodulate expression. Differential DNA methylation was associated with alternative promoter usage for Myob/Cbl genes MCF2L, DOK7, CNPY1, and ANK1. Myob/Cbl genes PAX3, LBX1, ZNF556, ZIC1, EN2, and VAX2 encode sequence-specific transcription factors, which likely help drive the myoblast and cerebellum specificity of other Myob/Cbl genes. Our study extends our understanding of epigenetic/transcription associations related to differentiation and may help elucidate relationships between epigenetic signatures and muscular dystrophies or cerebellar-linked neuropathologies.

Tick-borne encephalitis virus (TBEV) is a RNA-containing enveloped virus, a member of the Flaviviridae family. Here we describe a detailed analysis of the size and structure of inactivated TBEV (the Sofyin-Chumakov TBEV strain, used in vaccines). Four analytical methods were used to analyze individual TBEV particles—negative staining TEM, cryo-EM, AFM, and NTA. All methods confirmed that the particles were monodisperse, and their mean size was ~50 nm. Cryo-EM data were used to obtain a 3D electron density model of the virus with clearly distinguishable E-proteins. STEM-EELS analysis detected phosphorous in the particles, which was interpreted as the RNA signal. Altogether, the described analytical procedures can be valuable for the further analysis of vaccine inactivated virus samples.

The presence of potentially pathogenic bacteria on veterinary clinic surfaces may be problematic. In this study we collected swab samples (Fisherbrand, double transport swabs with Stuart’s liquid medium) and water samples from five veterinary rehabilitation clinics. Swabs and water samples were transported to a microbiology lab for processing. At the lab swabs were used to inoculated Hardy’s Cdiff Banana broth (for Clostridium difficile [Cdiff]), and five different types of bacterial growth media, including: Hardy CHROM MRSA agar (methicillin resistant Staphylococcus aureus [MRSA], and S. pseudintermedius [SIM]), Mannitol Salt Agar (S. aureus), Eosin Methylene Blue agar (enterics [ENT]), Pseudomonas Isolation agar (Pseudomonas sp.), and Tryptic Soy Agar [TSA] (non-specific). The most prominent species cultured was Cdiff (on nearly 55% of swabs). Bacillus sp. and Enterics were encountered on nearly 35% of swabs, with MRSA and SIM on just over 10% of swabs. The most contaminated sample site was harnesses/life jackets used with the underwater treadmill (33% of swabs). Underwater treadmill water had total bacterial counts from 1.6 to 2.7 e3 cfu/ml. Of all bacterial species detected SIM tends to be more pathogenic for dogs. Targeted cleaning/disinfecting in these clinics could help reduce risks for both animals and caregivers utilizing these clinics.

Escherichia coli is an indicator microorganism in One Health antibiotic resistance surveillance programmes. The purpose of the study was to describe and compare E. coli isolates obtained from pigs and human contacts from a commercial farm in South Africa using conventional methods and whole genome sequencing (WGS). Porcine E. coli isolates were proportionally more resistant phenotypically and harboured a richer diversity of antibiotic resistance genes, as compared to human E. coli isolates. Different pathovars, namely ExPEC (12.43%, 21/169), ETEC (4.14%; 7/169), EPEC (2.96%, 5/169), EAEC (2.96%, 5/169) and STEC (1.18%, 2/169) were detected at low frequencies. Sequence type complex (STc) 10 were the most prevalent (85.51%, 59/169) among human and porcine isolates. Six STcs (STc10, STc86, STc168, STc206, STc278 and STc469) were shared at the human-livestock interface according to multilocus sequence typing (MLST). Core genome MLST and hierarchical clustering (HC) showed that human and porcine isolates were overall genetically diverse, but some clustering at HC2 to HC200 were observed. In conclusion, even though the isolates shared a spatio-temporal relationship, there were still differences in the virulence potential, antibiotic resistance profiles, and cgMLST and HC according to the source of isolation.

The identification of a new virus Kiparis-144 (KiparisV) in a half-fed tick I persulcatus, removed from a person in the south of the Russian Far East, determined the goal of further research - to study its role in human pathology and the characteristics of its behavior in the tick microbiome. An ELISA study of 439 blood samples from people affected by tick bites indicated a fairly frequent (up to 16.4±1.7%) encounter of people with the KiparisV virus in the territory of natural foci of the Primorsky Territory. It has been shown that this virus, when mono-infected, can cause clinical symptoms characteristic of acute respiratory diseases. During co-infection under the influence of the KiparisV, there was an increase in the activity of Borrelia spp. with the constant production of antibodies to them only of the IgM class and clinical symptoms of Lyme disease for one year (observation period). Electron microscopy of the KiparisV found in a tick removed from a patient showed a picture of the relationship of the KiparisV (up to 100 nm in size) with unknown representatives of the tick microbiome - pathogens of a viral or bacterial nature. In a comparative aspect, a similar electron microscopic picture of the interaction of the KiparisV virus with a known pathogen of viral nature, the ectromelia virus (ECTV), is presented. The importance of the electron microscopy method in describing the tick microbiome is shown. Thus, it has been established that when co-cultivated in the system the helper-virus KiparisV probably tends to use another pathogen of the tick microbiome for its reproduction, influencing its pathogenicity.

a Special Issue of Microorganisms devoted to ‘Microbial Biocatalysis and Biodegradation’ would be incomplete without some form of acknowledgement of the many important roles that dioxygen-dependent enzymes (principally mono- and dioxygenases) play in relevant aspects of biooxygenation. This is reflected by the multiple strategic roles that dioxygen -dependent microbial enzymes play both in generating valuable synthons for chemoenzymatic synthesis, and in facilitating key reactions that drive the global geochemical Carbon Cycle. A useful insight into this relationship can be gained by reviewing the evolution of the current status of 2,5-diketocamphane 1,2-monooxygenase (EC 1.14.14.108) from camphor-grown Pseudomonas putida ATCC 17453. Over the last sixty years, the perceived nature of this monooxygenase has transmogrified significantly. Commencing in the 1960s, extensive initial studies consistently reported that the enzyme was a monomeric true flavoprotein dependent on both FMNH₂ and nonheme iron as bound cofactors. However, over the last decade all those criteria have changed absolutely, and the enzyme is currently acknowledged to be a metal ion-independent homodimeric flavin-dependent two-component monooxygenase deploying FMNH₂ as a cosubstrate. That transition is a paradigm of the ever evolving nature of scientific knowledge.

Background: Increase of collagen I (COL I)/COL III ratio enhances vessel wall stiffness and renders vessels less resistant to blood flow and pressure changes. We hypothesized that COL I/COL III ratio is increased in the brain arteriovenous malformations (bAVMs), which is associated with bAVM hemorrhage. Method: Surgically resected human bAVM samples and mouse bAVMs induced in three transgenic mouse lines with activin receptor-like kinase 1 or endoglin deletion in the endothelial cells or in the brain focally. Colony-stimulating factor receptor inhibitor was used to transiently deplete microglia. COL I and COL III levels, hemorrhage, and gene expression in bAVMs were analyzed. Results: The COL I and COL III levels and the COL I/COL III ratio were higher on human and mouse bAVMs than controls, which was associated with bAVM hemorrhage. Col I and Col III mRNAs were also increased in mouse bAVMs. The degree of microhemorrhage in mouse bAVMs was positively correlated with Col I/Col III ratios. Transient depletion of microglia reduced Col I/Col III ratio and microhemorrhage in mouse bAVMs. Conclusion: COL I/COL III ratio are increased in bAVM vessels, which is associated with bAVM hemorrhage. Depletion of microglia reduces Col I/Col III ratio and hemorrhage in mice bAVMs.