Candidiasis is considered an emerging public health concern because of the occurrence of drug-resistant Candida strains and the lack of available structurally diverse antifungal drug armamentariums. The indole alkaloid globospiramine from the anticandidal Philippine medicinal plant Voacanga globosa exhibits a variety of biological activities; however, its antifungal properties remain to be explored. In this study, we report the in vitro antifungal activities of globospiramine against Candida albicans and Candida tropicalis and explore its possible target proteins using in silico methods. The colony-forming unit (CFU) viability assay revealed time- and concentration-dependent anticandidal effects of the alkaloid by decreasing almost 50% of the viable CFUs 60 min after treatment. Results of the MIC and MFC assays indicated inhibitory and fungicidal effects of globospiramine against C. albicans (MIC = 8 µg/mL; MFC = 4 µg/mL) and potential fungistatic effects against C. tropicalis at lower concentrations (MIC = 4 µg/mL; MFC > 64 µg/mL). The FAM-FLICA poly-caspase assay showed metacaspase activation in C. albicans cells at concentrations of 16 and 8 µg/mL, which agreed with the MIC and MFC values. Molecular docking and molecular dynamics simulation experiments indicated stable, strong binding of globospiramine with the target proteins 1,3-β-glucan synthase and Als3 adhesin enzymes, which are indirectly involved in apoptotic-driven candidal inhibition.

The broad emission bump in the electromagnetic spectra observed following the detection of gravitational waves created during the kilonova event of merger of two neutron stars in August 2017, GW170817, has been linked to the heavy elements of lanthanides (Z=57-71), and a new understanding of creation of heavy elements in the r-process. The initial spectral emission bump has a wavelength range of 3000 - 7000 \AA, thus covering the region of ultraviolet (UV) to optical (O) wavelengths, and is similar to those seen for lanthanides. Most lanthanides have large number of closely lying energy levels which introduce extensive sets of radiative transitions which often form broad region of lines of significant strength. The current study explores these broad features through photoabsorption spectroscopy of 25 lanthanides ions, Ho I-III, Er I-IV, Tm I-V, Yb I-VI and Lu I-VII. With excitations only to a few orbitals up beyond the ground configurations, we find most of these ions cover large number of bound levels with open $4f$ orbital and produce tens to about hundred thousands lines that may form one or multiple broad features in X-ray to UV, O, and infrared (IR) regions. Spectrum of each of 25 ions is presented indicating presence, shape and wavelength region of the features. Accuracy of atomic data to interpret the merger spectra has been a outstanding problem. The present study aims at providing improved atomic data for energies and transition parameters obtained using relativistic Breit-Pauli approximation implemented in the atomic structure code SUPERSTRUCTURE. The present data have been benchmarked with available experimental data for energies and transition parameters. The study finds that number of ions under the present study are possible contributors of the emission bump of GW170817. All atomic data will be made available online at NORAD-Atomic-Data database.

Invasive fungal infections by Candida albicans frequently cause mortality in immunocompromised patients. Neutrophils are particularly important for fungal clearance at the early phase of infections, yet little has been known regarding which surface receptor controls neutrophil phagocytic activities during systemic C. albicans infection. CD137, which is encoded by Tnfrsf9, belongs to the tumor necrosis receptor superfamily and has been shown to regulate neutrophils in Gram-positive bacterial infection. Here, we used genetic and immunological tools to probe the involvement of CD137 signaling in innate defense mechanisms against systemic C. albicans infection. We first found that Tnfrsf9-/- mice were susceptible to C. albicans infection, whereas injection of anti-CD137 agonistic antibody protected the host from infection, suggesting that CD137 signaling is indispensable for innate immunity against C. albicans infection. Priming of isolated neutrophils with anti-CD137 antibody promoted their phagocytic and fungicidal activities through phospholipase C. In addition, injection of anti-CD137 antibody significantly augmented restriction of fungal growth in Tnfrsf9-/- mice that received WT neutrophils. In conclusion, our results demonstrate that CD137 signaling contributes to defense mechanisms against systemic C. albicans infection by promoting rapid fungal clearance whereby harmful immunopathology-induced tissue injuries are minimalized.

It is estimated that almost 4% of all neonatal intensive care unit admissions are attributed to Candida spp. infections. Clinical diagnosis of invasive fungal infection (IFI) is not easy as signs and symptoms are commonly vague. Mannan antigen (MA) in neonates is not well studied and the aim of this study was to evaluate the use of MA (Platelia™ Candida Ag Plus kit, Bio-Rad) in a neonatal unit. This is a prospective case-control study, which compared the performance of MA between neonates who had rectal Candida colonization with non-colonized controls. We cultured 340 rectal swabs of neonates and 39 of them were positive for Candida albicans colonization. MA was checked in 25 C. albicans colonized and in 30 non-colonized neonates with similar postnatal age and gender distribution. During the hospitalization period there was not any IFI in the neonatal population. MA was negative in all non-colonized neonates (30/30, 100% specificity) and in 24 out of 25 colonized neonates (96% specificity). However, the one infant with positive rectal colonization and MA had recent Candida mucositis. The results indicate a high specificity of the assay even in neonates colonized with Candida. Further investigation in neonates with IFI is required in order to determine the sensitivity of the method.

Antifungal agents are not always efficient in resolving vulvovaginal candidiasis (VVC), a common genital infection caused by overgrowth of Candida spp., including Candida albicans, or preventing recurrent infections. Although lactobacilli (which are dominant microorganisms constituting healthy human vaginal microbiota) are important barriers against VVC, the Lactobacillus metabolite concentration needed to suppress VVC is unknown. Therefore, we quantitatively evaluated Lactobacillus metabolite concentrations to determine their effect on Candida spp., including 27 vaginal strains of Lactobacillus crispatus, Lactobacillus jensenii, Lactobacillus gasseri, Lacticaseibacillus rhamnosus, and Limosilactobacillus vaginalis, with inhibitory abilities against biofilms of Candida clinical isolates. Lactobacillus culture supernatants suppressed viable bacteria by approximately 24%-92% relative to preformed Candida biofilms, but their suppression differed between strains, not species. Lactate production was necessary to suppress preformed biofilms and hyphal elongation of C. albicans, whereas hydrogen peroxide was not always essential. Both lactic acid and hydrogen peroxide were required to suppress Candida planktonic cell growth. Lactobacillus strains that significantly inhibited biofilm formation in culture supernatant also inhibited Candida adhesion to epithelial cells in an actual live bacterial adhesion competition test. Healthy human microflora and their metabolites may play important roles in the development of new antifungal agent against VVC caused by C. albicans.

Candida albicans as an opportunistic pathogen exploits the host immune system and causes a variety of life-threatening infections. The polymorphic nature of this fungus gives it tremendous advantage to breach mucosal barriers and cause a variety of oral and disseminated infections. Enterococcus faecalis, another opportunistic pathogen co-exists with C. albicans in several niches in the human body, including the oral cavity and gastrointestinal tract. However, interactions between E. faecalis and C. albicans on oral mucosal surfaces remain unknown. Here, for the first time, we comprehensively characterized the interactive profiles between laboratory and clinical isolates of C. albicans (SC5314 and BF1) and E. faecalis (OG1RF and 846) on an organotypic oral mucosal model. Our results demonstrated that the two species formed robust biofilms on the mucosal tissue surface with profound surface erosion and fungal invasion. Specifically, this effect was more pronounced in the laboratory isolates than in the clinical isolates. Notably, several genes of C. albicans involved in tissue adhesion, hyphal formation, fungal invasion, and biofilm formation were significantly upregulated in the presence of E. faecalis. This study highlights the strain-dependent cross-kingdom interactions between E. faecalis and C. albicans on oral mucosa, demonstrating the requisite to study more substrate-dependent polymicrobial interactions.

Biofilms play a crucial role in the development of Candida-associated denture stomatitis. Inhibition of microbial adhesion to PMMA and phosphate containing PMMA has been examined in this work. C. albicans and mixed salivary microbial biofilms were compared on naked and salivary pre-conditioned PMMA surfaces in the presence or absence of antimicrobials (cetyl pyridinium chloride [CPC], KSL-W, histatin 5 [his 5]). Polymers with varying amounts of phosphate (0-25%) were tested using four C. albicans oral isolates as well as mixed salivary bacteria and 24 h biofilms were assessed for metabolic activity and confirmed using Live/Dead staining and confocal microscopy. Biofilm metabolism was reduced as phosphate density increased (15%: P=0.004; 25%: P=0.001). Loading of CPC on 15% phosphated disks showed a substantial decrease (P=0.001) in biofilm metabolism in the presence or absence of a salivary pellicle. Salivary pellicle on uncharged PMMA enhanced the antimicrobial activity of CPC only. CPC also demonstrated remarkable antimicrobial activity on mixed salivary bacterial biofilms under different conditions displaying the potent efficacy of CPC (350 µg/ml) when combined with an artificial protein pellicle (Biotene half strength).

Introduction: Oral candidiasis is an opportunistic fungal infection, often caused by Candida albicans. One of the virulence factors of C. albicans is sterol 14a-demethylase or CYP51. Compounds of anthocyanins (ternatin, cyanin) and flavonoids (rutin, isoquercetin, kaempferol, myricetin, limocitrin) from the extract of the Clitoria ternatea (butterfly pea) plant are believed to have potential to inhibit the CYP51 virulence factor of C. albicans to suppress oral candidiasis. The purpose of this research was to investigate the interaction between the ligands of anthocyanins and flavonoids from C. ternatea (butterfly pea) with CYP51. Methods: The in silico study applied molecular docking to examine the molecular interactions (binding affinity) between the anthocyanin and flavonoid ligands of interest from C. ternatea and the CYP51 receptor of C. albicans. Results: Predicted interactions exist between the ligands of anthocyanins (ternatin, cyanin) and flavonoids (rutin, isoquercetin, kaempferol, myricetin, limocitrin) from C. ternatea and the CYP51 receptor of C. albicans. Conclusion: C. ternatea has the potential to provide anti-fungal agents that can inhibit or slow down the occurrence of oral candidiasis, as indicated by in silico studies. However, it is important to conduct additional research regarding the properties of the plant to determine the unknown aspects of its effects to the human body.

The aim of this study is to have an idea on the molecular mechanisms of C. albicans resistance to fluconazole in Burkina Faso, by studying the polymorphism of the ERG11 gene, and its implication in the C. albicans virulence and resistance in vivo according to the Galleria mellonella model; (2) Methods: Ten (10) clinical strains including, 5 resistant and 5 susceptible and 1 virulent and susceptible reference strain SC5314 are used. For the estimation of virulence, the larvae were inoculated with 10 μL of C. albicans cell suspension at variable concentrations: 2,5.105, 5.105, 1.106, and 5.106 CFU/larva of each strain. For the in vivo efficacy study, fluconazole was administered at 1, 4 and 16 mg/kg respectively to G. mellonella larvae, after infection by inoculum 5.106 CFU / larvae of each strain; (3) Results: Six (6) non-silent mutations in the ERG11 gene (K143R, F145L, G307S, S405F, G448E, V456I on ERG11p) were found in 4 resistant isolates. Larval mortality depended on fungal burden and strain. The inoculum 5.106 CFU caused 100% mortality in 2 days for the 2 CAAL-1 and CAAL-2 strains carrying the F145L mutation, in 3 days for the reference strain SC5314, in 4 days for the ensemble of resistant strains, and in 5 days for the ensemble of susceptible strains. The comparison of the mortality due to the reference strain SC5314 CFU / larva and the average mortality due to the two mutant F145L strains, shows a significant difference (P <0.05).Fluconazole significantly protected (P> 0.05) the larvae from infection by susceptible strains and the reference strain. However, 100% mortality in 6 days after injection of the resistant strains, was observed (4) Conclusions: Certain mutations in the ERG11 gene such as the F145L mutation are thought to be a source of increased virulence in Candida albicans. Fluconazole effectively protected larvae from infection by susceptible strains in vivo, unlike resistant strain

Meiosis is a specialized cell division that produces haploid gametes from diploid germ cells, and the phosphorylation activity of cyclin-CDK complexes and Polo-like kinase is required for synaptonemal complex (SC) disassembly and metaphase I exit. Here, we identified a novel protein MSCDK (meiotic substrate of cyclin dependent kinase) that functions as a substrate of CDK1 in initiating SC disassembly and metaphase I transition during meiosis prophase I in mice. Deletion of MSCDK caused germ cell death and infertility in males but not females. Mechanistically, we show that MSCDK is sparsely localized as discrete foci along synaptic homologous chromosomes from the early zygotene to the early diplotene, and we confirm that MSCDK can be phosphorylated by CDK1 and dephosphorylated by the cell cycle exit regulator phosphatase PP1α. We also provide evidence that MSCDK is essential for SC disassembly based on its dephosphorylation-related function, which apparently promotes HSPA2 nuclear recruitment.

Despite well-documented health benefits of probiotics Saccharomyces, its application in oral health has not been comprehensively assessed. Dental caries is a transmissible disease initiated by acid production of cariogenic bacteria and yeast, such as Streptococcus mutans and Candida albicans, on tooth enamel and followed by subsequent enamel demineralization. Here, we investigated the effect of two Saccharomyces strains (Saccharomyces boulardii, Saccharomyces cerevisiae) on S. mutans-C. albicans cross-kingdom interactions using a cariogenic planktonic model. Viable cells, pH changes and gene expression were measured. S. cerevisiae and S. boulardii inhibited the growth of C. albicans either in dual-, or multi-species conditions. Saccharomyces also inhibited C. albicans hyphal formation. Furthermore, Saccharomyces reduced the acidity of the culture medium which usually plummeted below pH 5 when S. mutans and C. albicans were present in the model. The presence of Saccharomyces maintained the culture medium above 6 even after overnight incubation, demonstrating a protective potential against dental enamel demineralization. S. boulardii significantly downregulated S. mutans atpD and eno genes expression. Overall, our results shed light on a new promising candidate, Saccharomyces, for dental caries prevention due to its potential to create a less cariogenic environment marked by a neutral pH and reduced growth of C. albicans.

Protein synthesis has been a very rich target for developing classes of drugs to control prokaryotic and eukaryotic pathogens. Despite the development of new drug formulations, treating human cutaneous and visceral Leishmaniasis still needs significant improvement due to considerable side effects and low adherence to the usual treatment regimen. In this work, we show that the di-substituted urea-derived compound I-17 is effective in inhibiting the promastigote forms and intracellular amastigotes of the Leishmania (L.) amazonensis and L. infantum species, in addition to exhibiting low macrophage cytotoxicity. We also show a potential immunomodulatory effect of I-17 in infected macrophages, which exhibited increased expression of inducible Nitric Oxide Synthase (NOS2) and Nitric Oxide (NO) production. Our data suggest that I-17 and new derivatives of this compound may be helpful in developing new drugs for treating leishmaniasis.

Invasive candidiasis (IC) is associated with high morbidity and mortality in hospitalized patients if not diagnosed early. Long-term use of central venous catheters is a predisposing factor for IC. Hyphal forms of Candida albicans (the major etiological agent of IC) are related to invasion of host tissues. The secreted proteins of hyphae are involved in virulence, host interaction, immune response, and immune evasion. To identify IC diagnostic biomarker candidates, we characterized the C. albicans hyphal secretome by gel-free proteomic analysis, and further assessed the antibody-reactivity patterns to this subproteome in serum pools from 12 patients with non-catheter-associated IC (ncIC), 11 patients with catheter-associated IC (cIC), and 11 non-IC patients. We identified 301 secreted hyphal proteins stratified to stem from the extracellular region, cell wall, cell surface, or intracellular compartments. ncIC and cIC patients had higher antibody levels to the hyphal secretome than non-IC patients. Seven secreted hyphal proteins were identified to be immunogenic (Bgl2, Eno1, Pgk1, Glx3, Sap5, Pra1 and Tdh3). Antibody-reactivity patterns to Bgl2, Eno1, Pgk1 and Glx3 discriminated IC patients from non-IC patients, while those to Sap5, Pra1 and Tdh3 differentiated between cIC and non-IC patients. These proteins may be useful for development of future IC diagnostic tests.

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.

Abstract: The effect of collagen type 1 (Col I) oxidation on Adipose Tissue-Derived Mesenchymal Stem Cells (ADMSCs) remodeling is described as a model for acute oxidative stress. Morphologically, remodeling was presented by a mechanical rearrangement of adsorbed FITC-Col I and a trend for its organization in a fibril-like pattern - a process strongly abrogated in oxidized samples, but without visible changes in cell morphology. The cellular proteolytic activity was quantified in multiple samples utilizing fluorescence de-quenching (FRET effect). In the presence of ADMSCs a significant increase of native FITC-Col I fluorescence was observed, almost absent in the oxidized samples. Parallel studies in cell-free systems confirmed the enzymatic de-quenching of native FITC-Col I by Clostridial collagenase, again showing significant inhibition in oxidized samples. The structural changes in the oxidized Col I was further studied by Differential Scanning Calorimetry: an additional endotherm at 33.6°C along with the typical for native Col I at 40.5°C with sustained enthalpy (∆H) was observed in oxidized samples. Collectively, it has been evidenced that remodeling of Col I by ADMSCs is altered upon oxidation due to the intrinsic changes in the protein structure, thus presenting a novel mechanism for the control of stem cells' behavior toward collagen.

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.

Objective: Type I interferon receptor (IFNAR) signaling contributes to several autoimmune and vascular diseases such as atherosclerosis and stroke. The purpose of this study was to assess the influence of IFNAR1 deficiency on the formation and progression of experimental abdominal aortic aneurysms (AAAs). Methods: AAAs were induced in type I interferon receptor subunit 1 (IFNAR1) deficient and wild type control male mice via intra-infrarenal aortic infusion of porcine pancreatic elastase. Immunostaining for IFNAR1 was evaluated in experimental and clinical aneurysms. The initiation and progression of experimental AAAs was assessed via ultrasound imaging prior to (day 0) and 3-, 7-, and 14-days following elastase infusion. Aneurysmal histopathology was analyzed at sacrifice. Results: Increased aortic medial and adventitial IFNAR1 expression was present in both clinical AAAs harvested at surgery and experimental AAAs. Following AAA initiation, wild type mice experienced progressive, time-dependent infrarenal aortic enlargement. This progression was substantially attenuated in IFNAR1 deficient mice. On histological analyses, medial elastin degradation, smooth muscle cell depletion, leukocyte accumulation and neoangiogenesis were markedly diminished in IFNAR1 deficient as compared to wild type mice. Conclusion: IFNAR1 deficiency limited experimental AAA progression in response to intra-aortic elastase infusion. Combined with clinical observations, these results suggest a regulatory role for IFNAR1 activity in AAA pathogenesis.

Type 2 diabetes has been linked to the expression of Human Leukocyte Antigens, principally to the major Histocompatibility Complex Class II and only scarce reports to Major Histocompatibility Complex class I in specific populations. The objective of the present work was to explore the presence of polymorphisms in the MHC class I related to Type 2 diabetes in the Mexican population using the GWAS SIGMA database. This database contains information of 3,848 Mexican individuals with type 2 diabetes and 4,366 control individuals from the same population without clinical or hereditary history of the disease. The searching criteria considered a P value < 0.005 and odds ratio, OR > 1.0. Ten novel statistically significant nucleotide variants were identified: four polymorphisms associated with HLA-A (A*03:01:01:01), and six with HLA-C (C*01:02:01:01). These alleles have a high prevalence in Latin American populations and could potentially be associated with autoimmunity mechanisms related with the development of Type 2 diabetes complications.

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.

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.

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.

Abstract: Targeted ubiquitination and proteasomal degradation regulates various cellular pathways, and the discovery that CPT induced rapid proteasomal degradation of topoI is the primary mechanism of CPT resistance was novel and compelling. CPTs are used extensively to treat various solid tumors like colorectal, gastric, pancreatic, ovarian and small cell lung cancer. The response rate is low and the classical mechanisms of drug resistance are yet to be validated. Remarkably, CPT resistant cells degrade topoI rapidly by UPP and recently we’ve published the molecular determinants of this pathway. To further understand the UPP mediated CPT resistance mechanism we used targeted proteasome prohibition by ixazomib (MLN9708) to stabilize topoI and determine its impact on CPT resistance. CPT resistant and sensitive cancer lines were both treated with ixazomib in combination with CPT. The CPT induced rate of topoI degradation, and its stabilization by ixazomib, was visualized and estimated by immunohistochemistry, immunofluorescence and immunoblotting assays, MTT and subG1 assays provided the drug sensitivity. Our results demonstrate that cells that degrade topoI rapidly are very resistant to CPT, and ixazomib significantly inhibits CPT induced topoI degradation. Notably, inhibition of proteasomal degradation by ixazomib overcomes the drug resistance and sensitizes the cells for CPTs.

ND1 subunit possesses the majority of the inhibitor binding domain of the human MRC-I. This is an attractive target for the search for new inhibitors that seek mitochondrial dysfunction. It is known, from in vitro experiments, some metabolites from Annona muricata called acetogenins have important biological activities such as anticancer, antiparasitic, and insecticide. Previous studies propose an inhibitory activity of bovine MRC-I by bis-THF acetogenins such as annocatacin B, however, there are few studies on its inhibitory effect on human MRC-I. In this work, we evaluate the molecular and energetic affinity of the annocatacin B molecule with the human ND1 subunit in order to elucidate its potential capacity to be a good inhibitor of this subunit. For this purpose, QM optimizations, MD simulations and MM/PBSA analysis were performed. As a control to compare our outcomes, the molecule rotenone, which is a known MRC-I inhibitor, was chosen. Our results show that annocatacin B has a greater affinity for the ND1 structure, its size and folding were probably the main characteristics that contributed to stabilize the molecular complex. Furthermore, the MM/PBSA calculations showed a 35% stronger BFE compared to the rotenone complex. Detailed analysis of the BFE shows that the aliphatic chains of annocatacin B play a key role in molecular coupling by distributing favorable interactions throughout the major part of the ND1 structure. These results are consistent with experimental studies that mention that acetogenins may be good inhibitors of MRC-I.

Background and objectives: The correlation of cardiac troponin I with early in-hospital outcomes in acute myocardial infarction is not well established. This study aims to assess the role of troponin I in predicting in-hospital outcomes and early left ventricular systolic dysfunction in patients with ST-segment elevation myocardial infarction (STEMI). Patients and methods: In a prospective study, 116 patients (74males and 42 females), with STEMI who had been admitted to the Coronary CareUnit from March 2015 to September 2015 were enrolled. Patients were divided according to the level of troponin I on admission into 3 groups (low, medium and high elevation). Results: The mean age (+ SD) of the patients was 60+11.4 years. The troponin level of 66.2% of males was high compared with 52.4% of females (p=0.002). The incidence of acute pulmonary edema (21.1%), cardiogenic shock (7%) and early left ventricular systolic dysfunction (49.3%) was significantly higher among patients with high troponin level compared with (0%, 0% and 16%, respectively) among patients with low troponin level. All deaths and cardiac arrest were of high troponin level. Conclusions: High admission troponin I in STEMI permits early identification of patients at increased risk of major cardiac complications and death.

Based on the geochemical analysis of the volcanic material from the sediment core AMK-340, central zone of the Reykjanes Ridge, we could detect two ash-bearing sediment units accumulated during the Termination I. They correlate to the Ash Zone I in the North Atlantic Late Quaternary sediments having an age of 12170-12840, within the Younger Dryas cold chronozone, and 13600-14540 years, within and Bølling-Allerød warm chronozone. The ash of the Younger Dryas unit is presented mostly by the mafic and persilicic material originated from the Icelandic volcanoes; Vedde Ash is presented in one sediment sample from this unit. The ash of the Bølling-Allerød unit is presented mostly by the mafic shards which are related to the basalts of the rift zone on the Reykjanes Ridge, having presumably the local origin. A detection of Vedde Ash helped to specify the timing of the previously reconstructed paleoceanographic changes for the Termination I in the point of study: a significant warming in the area could occur as early as 300 years prior to the end of the conventional Younger Dryas cold chronozone.

Group-B enteroviruses (EV-B) are ubiquitous naked single-stranded positive RNA viral pathogens that are responsible for common acute or persistent human infections. Their genome is composed in the 5'end by a non-coding region, which is crucial for the initiation of the viral replication and translation processes. RNA domain-I secondary structures can interact with viral or cellular proteins to form viral ribonucleoprotein (RNP) complexes regulating viral genomic replication, whereas RNA domains-II to -VII (IRES) are known to interact with cellular ribosomal subunits to initiate the viral translation process. Natural 5’ terminally deleted viral forms lacking some genomic RNA domain-I secondary structures have been described in EV-B induced murine or human infections. Recent in vitro studies have evidenced that the loss of some viral RNP complexes in the RNA domain-I can modulate the viral replication and infectivity levels in EV-B infections. Moreover, the disruption of secondary structures of RNA domain-I could impair viral RNA sensing by RIG-I or MDA5 receptors, a way to overcome antiviral innate immune response. Overall, natural 5′ terminally deleted viral genomes resulting in the loss of various structures in the RNA domain-I could be major key players of host-cell interactions driving the development of acute or persistent EV-B infections.

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.

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.

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.

This study aimed to evaluate the impact of Candida albicans on subgingival biofilm formation on dental implant surfaces. Scanning electron microscopy (SEM) and confocal laser scanning microscopy (CLSM) were used to compare biofilm structure and microbial biomass in the presence and absence of the fungus after periods of 24, 48, and 72 h. Quantitative polymerase chain reaction (qPCR) was used to quantify the number of viable and total micro-organisms for each of the biofilm-forming strains. A general linear model was applied to compare CLSM and qPCR results between control and test conditions. The biofilm developed with C. albicans at 72 h had a higher bacterial biomass, with a significantly higher cell viability (p &lt; 0.05). After both 48 and 72 h of incubation, in the presence of C. albicans, there was a significant increase in counts of Fusobacterium nucleatum and Porphyromonas gingivalis and in the cell viability of Streptococcus oralis, Aggregatibacter actinomycetemcomitans, F. nucleatum, and P. gingivalis. Using a dynamic in vitro multispecies biofilm model, C. albicans exacerbated the development of the biofilm grown on dental implant surfaces, significantly increasing the number and cell viability of periodontal bacteria.

PCSK9 is implicated in familial hypercholesterolemia via targeting the cell surface PCSK9-LDLR complex toward lysosomal degradation. The M2 repeat in the PCSK9's C-terminal domain is essential for its extracellular function, potentially through its interaction with an unidentified “protein X”. The M2 repeat was recently shown to bind an R-x-E motif in MHC-class-I proteins (implicated in the immune system), like HLA-C, and causing their lysosomal degradation. These findings suggested a new role of PCSK9 in the immune system and that HLA-like proteins could be “protein X” candidates. However, the participation of each member of the MHC-I protein family in this process and their regulation of PCSK9's function have yet to be determined. Herein, we compared the implication of MHC-I-like proteins such as HFE (involved in iron homeostasis) and HLA-C on the extracellular function of PCSK9. Our data revealed that the M2 domain regulates the intracellular sorting of the PCSK9-LDLR complex to lysosomes, and that HFE is a new target of PCSK9 that inhibits its activity on the LDLR, whereas HLA-C enhances its function. This work suggests the potential modulation of the PCSK9 functions through interactions of HFE and HLA-C.

The treatment of benzylidenemalononitriles 3a-c with phenylhydrazines 4a-n in refluxing ethanol did not provide pyrazole derivatives but furnished hydrazones 1a-o. The structure of hydrazones was secured by X-Ray analysis. Newly synthesized hydrazones 1a-o were tested against 8 Candida spp. strains in a dose response assay to determine the minimum inhibitory concentration (MIC99). Five compounds 1c, 1d, 1i, 1k and 1l were identified as promising antifungal agents against Candida spp. (C. albicans SC5314, C. glabrata, C. tropicalis, C. parapsilosis and C. glabrata (R azoles)) with MIC99 values ranging from 16 to 32 µg/mL. To further evaluate the antifungal potential of the active compounds, they have been assayed against a mammalian cell line HEK293 to determine general cell toxicity and on NCI-60 cancer cell lines panel, demonstrating selectivity antifungal activity over cytotoxicity.

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.

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 aim of this work is to introduce new ways to model the I-V characteristic of a PV cell or PV module using straight lines and Bézier curves. This is a complete novel approach, Bézier curves being previously used mainly for computer graphics. The I-V characteristic is divided in three sections, modeled with lines and a quadratic Bézier curve in the first case and with three cubic Bézier curves in the second case. The result proves to be accurate and relies on the fundamental points usually present in the PV cell datasheets: Voc (the open circuit voltage), Isc (the short circuit current), Vmp (the maximum power corresponding voltage) and Imp (the maximum power corresponding current) and the parasitic resistances Rsh0 (shunt resistance at Isc) and Rs0 (series resistance at Voc). The proposed algorithm completely defines all the implied control points and the error is analyzed. The temperature and irradiance influence is also analyzed. The model is also compared using the least squares fitting method. The final validation shows how to use Bézier cubic curves to accurately represent the I-V curves of an extensive range of PV cells and arrays.

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.

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).

A study of Bianchi Type I cosmological model is undertaken in the framework of creation of particles. To accommodate the creation of new particles, the universe is regarded as an Open thermodynamical system. The energy conservation equation is modified with the incorporation of a creation pressure in the energy momentum tensor. Exact solutions of the field equations are obtained (i) for a particular choice of the particle creation function and (ii) by considering the deceleration parameter to be constant. In the first model the behavior of the solution at late times is investigated. The physical aspects of the model have also been discussed. In the case of the second model we have restricted our analysis to the power law behaviour for the average scale factor. This leads to a particular form for the particle creation function. The behavior of the solution is investigated and the physical aspects of the model have also been discussed for the matter dominated era.

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.

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 victims and Ayatollah Khamenei’s criticisms concerning its stated duration and toll valid. 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

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.

The molecular entity that catalyzes ferredoxin (Fd)-dependent cyclic electron flow around photosystem I (PSI) (Fd-CEF) remains unknown. To elucidate the in vivo molecular mechanism of Fd-CEF, the evaluation of Fd reduction‒oxidation kinetics is a good indicator of Fd-CEF activity. Recent research showed that the expression of Fd-CEF activity requires the oxidation of plastoquinone, and furthermore, chloroplast NAD(P)H dehydrogenase does not catalyze Fd-CEF in Arabidopsis thaliana. In the present research, the effect of reduced Fd on Fd-CEF activity was analyzed by comparing wild-type and pgr5-deficient mutants (pgr5hope1). PGR5 has been proposed to be the mediator of Fd-CEF, and pgr5hope1 showed the same CO2 assimilation rate and the same reduction‒oxidation level of PQ as WT, but P700 oxidation with Fd was highly reduced, unlike WT. As expected, the activity of Fd-CEF was enhanced in pgr5hope1 compared to the wild type, and its activity was also enhanced with the oxidation of PQ by the increase in the CO2 assimilation rate. The present in vivo research clearly shows that the expression of Fd-CEF activity requires reduced Fd in addition to oxidized PQ, and PGR5 does not catalyze Fd-CEF.

HLA class-I (HLA-I) polyreactive monoclonal antibodies (mAbs) reacting to all HLA-I alleles were developed by immunizing HLA-E monomeric heavy chain (HC) (Open Conformers, OCs). Two of the mAbs (TFL-006 and TFL-007) bound to the HC’s coated on a solid matrix. The binding was inhibited by a peptide 117AYDGKDY123, present in all alleles of the six HLA-I isoforms but masked by 2-microglobulin -m) in intact HLA-I trimers (Closed Conformers, CCs). Identical HLA-I polyreactivity is observed in IVIg administered to lower anti-HLA antibodies (Abs) in HLA-sensitized patients, but the mechanism is unknown. We hypothesized that the mAbs that mimic IVIg HLA-I polyreactivity might mimic the immunomodulatory functions of IVIg. We tested the relative binding affinity of the mAbs and IVIg for both OCs- and CCs and compared their effects on (a) the phytohemagglutinin (PHA)-activation T-cells, (b) the production of anti-HLA-II antibody (Ab) by B-memory cells, and anti-HLA-I Ab by immortalized B-cells, and (c) the upregulation of CD4+, CD25+, and Fox P3+ T-regs. The mAbs bound only to OCs, whereas IVIg is bound to both CCs and OCs. The mAbs suppressed blastogenesis and proliferation of PHA-activated T-cells, anti-HLA Ab production by B-cells and expanded the T-regs, better than IVIg. We conclude that a humanized version of the TFL-mAbs could be an ideal therapeutic IVIg-mimetic.

The micropaleontological study (radiolarians and foraminifera) of the sediment core AMK-340, Reykjanes Ridge, North Atlantic, combined with the radiocarbon dating and Oxygen/Carbon isotopic record, provided data for the reconstruction of the summer paleotemperature on the water depth of 100 m, and paleoenvironments during the Termination I in the age interval of 14.5–8 ka. The response of the main microfossil species on the paleoceanographic changes within the Bølling-Allerød (BA) warming, the Younger Dryas (YD) cold event, and final transition to the warm Holocene was different. The BA warming was well reflected in the radiolarian and benthic but not planktic foraminiferal record. The high abundances of the cold-water radiolarian species Amphimelissa setosa as the Greenland/Iceland Sea indicator marked a cooling at the end of the BA and within the start of the YD at 13.2–12.3 ka. The micropaleontological and isotopic data together with the paleotemperature estimates for the Reykjanes Ridge at 60° N document that, after the warm BA, the middle YD ca. 12.5–12.2 ka was the next significant step toward the Holocene warming. Start of the Holocene interglacial conditions was reflected in abundant occurrence of the microfossils being indicators of the open boreal North Atlantic environments and lower oxygen isotope values indicating increasing warmth.

(1) Background: In orthognathic surgery, segmental Le Fort I osteotomies are a valuable method to correct maxillary deformities or transversal discrepancies. However, these procedures are technically challenging, and osteosynthesis can be prone to error. (2) Methods: In this retrospective, monocentric cohort study, patients were enrolled who underwent a virtually planned segmental maxillary osteotomy during their combined treatment. Positioning and osteosynthesis were achieved by either a 3D-printed splint and conventional mini plates or Patient-Specific Implants (PSI). The preoperative CT data, virtual planning data, and postoperative CBCT data were segmented. The deviation of all segments from the desired virtually planned position was measured using the analysis function of the IPS Case Designer. (3) Results: 28 Patients in the PSI Group and 22 in the conventional groups could be included. The PSI group showed significantly lower deviation from the planned position anteroposteriorly (-0.63±1.62mm vs. -1.3±2.54mm) and craniocaudally (-1.39±1.59mm vs. -2.7±3.1mm). For rotational deviations, the Pitch (0.64±2.59° vs. 2.91±4.08°) as well as the inward rotation of the lateral segments was positively influenced by PSI. (4). Conclusions: The presented data show that patient-specific osteosynthesis significantly reduces deviations from the preoperative plan in virtually planned cases. Especially transversal expansions and vertical positioning can be addressed better.

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.

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.

Cardiac vascular diseases, especially acute myocardial infarction (AMI), are one of the leading causes of death worldwide. Therefore cardio-specific biomarkers such as cardiac Troponin I (cTnI) play an essential role in diagnostics. In order to enable rapid and accurate measurement of cTnI with the potential of online measurements, a proof of concept of a chemiluminescence-based biosensor is presented. A flow cell was designed and combined with a sensitive CMOS camera allowing an optical readout. In addition, a microfluidic setup was established, and cTnI was determined selectively. The biomarker cTnI was expressed in E. coli, and its characterization and correct folding were investigated by different analytical methods. This recombinant cTnI was used for enzyme-linked immunosorbent assays (ELISA), calibrated against commercially available recombinant cTnI, and applied for the biosensor measurements. Based on chemiluminescence detection, the biosensor was successfully tested, and the cTnI biomarker could be reproducibly determined in buffer, spiked blood serum, and plasma.

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.

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.

Progression of oral squamous cell carcinoma (OSCC) has been associated with an escape of tumor cells from the host immune surveillance due to an increased knowledge of its underlying molecular mechanisms and its modulation by the tumor microenvironment and immune cell repertoire. In this study the expression of HLA class I (HLA-I) antigens and of components of the antigen processing machinery (APM) was analyzed in 160 pathologically classified human papilloma virus (HPV)-negative OSCC lesions and correlated to the intra-tumoral immune cell response, IFN- signaling and to the patients outcome. A heterogeneous, but predominantly lower constitutive protein expression of HLA-I APM components was found in OSCC sections when compared to non-neoplastic cells. Tumoral HLA-I APM component expression was further categorized into the three major phenotypes HLA-Ihigh/APMhigh, HLA-Ilow/APMlow and HLA-Idiscordant high/low/APMhigh. In the HLA-Ihigh/APMhigh group, the highest frequency of intra-tumoral CD8+ T cells and lowest number of CD8+ T cells close to FoxP3+ cells was found. Patients within this group presented the most unfavorable survival, which was significantly evident in stage T2 tumors. Despite a correlation with the number of intra-tumoral CD8+ T cells, tumoral JAK1 expression as a surrogate marker for IFN- signaling was not associated with HLA-I/APM expression. Thus, the presented findings strongly indicate the presence of additional factors involved in the immunomodulatory process of HPV-negative OSCC with a possible tumor-burden-dependent complex network of immune escape mechanisms beyond HLA-I/APM components and T cell infiltration in this tumor entity.

A literature review was conducted to summarize the frequency of the D-allele of the angiotensin-converting enzyme-1 in all countries with available data. Using an ecological study design limited to high income countries, we found that the country-level frequency of the D-allele was associated with increased COVID-19 incidence and mortality.

We propose the Hamiltonian formalism of Bianchi type 1 cosmological model for perfect fluid. We have considered both the equation of state parameter ω and the cosmological constant Λ as the function of volume V(t) which is defined by the product of three scale factors of the Bianchi type 1 line element. We propose a Lagrangian for the anisotropic Bianchi type-1 model in view of a variable mass moving in a variable potential . We can decompose the anisotropic expansion in terms of expansion and shearing motion by Lagrangian mechanism. We have considered a canonical transformation from expanding scale factor to scalar field ø which helps us to give the proper classical definition of that scalar field in terms of scale factors of the mentioned model. This definition helps us to explain the cosmological inflation. We have used large anisotropy(as in the cases of Bianchi models) and proved that cosmic inflation is not possible in such large anisotropy. Therefore we can conclude that the extent of anisotropy is less in case of our universe. Otherwise the inflation theory which explained the limitations of Big Bang cannot be resolved.Part II is contained with some analysis of the lagrangian ; derived in Part I ; on the quintessence model.

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.

A new copper(I) complex, [Cu2(L)2dppm](PF6)2 (1) [L = 3-(2-Pyridyl)-5,6-diphenyl-1,2,4-triazine and dppm: Bis(diphenylphosphino)methane] was prepared and characterized by IR, 1H-NMR, 31P-NMR spectroscopy, elemental and thermogravimetric analysis, and single-crystal X-ray diffraction technique. Complex 1 is a dinuclear compound, showing that L and dppm act as tridentate and bidentate chelating ligands, respectively. The two Cu(I) atoms exhibit a distorted tetrahedral coordination sphere embedded in N3P environments. The supramolecular interactions in the solid-state structure are characterized by C−H···N, C−H···F, C-H···π and π···π intermolecular interactions that were analyzed by inspection of the Hirshfeld surface and fingerprint plots. Additionally, the complex was studied experimentally in solution by UV–Vis spectroscopy and cyclic voltammetry; also, theoretical studies with Time-Dependent Density Functional Theory (TD-DFT) were performed. Moreover, the optical and electrochemical properties have been studied, focusing on the band gap. Compound 1 has been used as a co-sensitizer in a dye-sensitized solar cell, showing good activity.

Understanding surface water evaporation in tropical catchments is pivotal for effective water management, but limited research exists on stable isotopic (δ2H and δ18O) assessment of water evaporation losses. Our study bridges that gap, examining stable isotopes in meteoric water and surface waters across tropical regions, both humid and semi-arid. Using the Craig-Gordon model, we calibrated evaporation-to-inflow (E/I) ratios, identifying distinct E/I variations between seasons and regions. Notably, the semi-arid region consistently exhibited higher E/I ratios due to climatic characteristics. By integrating the Hamiltonian Monte Carlo and the No-U-Turn Sampler, we were able to quantify uncertainties in isotopic and meteorological parameters, resulting in E/I estimates within 68% and 95% confidence intervals. Our Bayesian model insights are critical for freshwater resource optimization and hydrological modeling in tropical regions.

Despite recent improvements in the methods used to eradicate and minimize mosquito populations, they still pose severe threats to human health. This study aimed to investigate the Larvicidal potentials of silver nanoparticles of Ocimum gratissimum on wild Anopheles larvae from Lagos. The plant used in this study was collected from the southeastern part of Nigeria, Ibite-Olo in Ezeagu Local Government Area of Enugu State. Wild Anopheles mosquito larvae were collected from a field at Kosofe Local Government Area of Lagos State, Nigeria where resistant Anopheline populations have been reported in and around Lagos State were brought to the laboratory and kept under standard insectary conditions (25–29 °C;78–82% relative humidity). Aqueous extract of Ocimum gratissimum was made and subsequently into the silver nanoparticles. A bioassay test was performed according to WHO guidelines, with six different concentrations to assess the larvicidal activity and values obtained were subjected to log prohibit regression analysis to obtain LC₅₀ and values with 95% confidence limit. The results of the larvicidal activities of the silver nanoparticles of Ocimum gratissimum showed that the mortality rate was dose-dependent with the percentage mortality increasing at a direct proportional rate as with dose and time of exposure. Ocimum gratissimum gave LC₅₀ at 0.5 ppm and LC₉₅ at 2.5 ppm respectively. The biosynthesized silver nanoparticles augmented the larvicidal activity of the silver nanoparticles of Ocimum gratissimum on wild Anopheles larvae from Lagos. Therefore, this study showed that the silver nanoparticles of Ocimum gratissimum have the potency to be used against an insecticide-resistant mosquito vector and are a suitable candidate for the development of novel natural insecticides.

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.

Candida auris is an emerging multidrug resistant yeast causing nosocomial infections and associated with high mortality in immunocompromised patients. Rapid identification and characterisation is necessary for its diagnosis and containing spread. In this study, we present a selective culture medium for all C. auris clades. This medium is sensitive with a limit of detection of 102 CFU/ml. The 100% specificity of SCA (Specific C. auris) medium is confirmed on a set of 134 Candida strains, 50 bacterial species and 200 human stool samples. Thus, this medium specifically selects for C. auris isolation from clinical samples, and allows studying its phenotypic profile.

The regulation of intracellular pH in yeast (Saccharomyces cerevisiae) cells is critical for cell function and viability. In yeast, protons (H+) can be excreted from cell by the plasma membrane ATPase Pma1 and pumped into vacuoles by the vacuolar H+-ATPase. Because Pma1 is critical to the survival of yeast cells, it is unknown whether other compensatory components are involved in the pH homeostasis in the absence of Pma1. To elucidate how intracellular pH is regulated independently of Pma1, we employed a screening approach by exposing the yeast haploid deletion mutant library (ver 4.0) to the selective plant plasma membrane H+-ATPase inhibitor PS-1, which we previously reported. After repeated screenings and verification, we identified two proteins, ALY1 and ALY2, that play a role in the regulation of intracellular pH when Pma1 is deficient. Our research uncovers a new perspective on the regulation of intracellular pH related to Pma1 and also preliminarily reveals a role for ALY1 and ALY2 in the regulation of intracellular pH.

Autoantibodies against type 1 interferons (IFN-I) are highly specific marker for type 1 autoimmune polyglandular syndrome (APS-1). Moreover, determination of antibodies to IFN-ω and IFN-α2 allows a short-term diagnosis in patients with isolated and atypical forms of APS-1. In this study, a comparison of three different methods, namely, multiplex microarray-based, cell-based and enzyme-linked immunosorbent assays for detection of antibodies against omega-interferon and alpha2-interferon was carried out. A total of 206 serum samples from adult patients with APS-1, APS-2, isolated autoimmune endocrine pathologies, non-autoimmune endocrine disorders and healthy individuals were analyzed. In the APS-1 patient cohort (n=18), there was good agreement between the results of anti- IFN-I antibody tests performed by three methods, with 100% specificity and sensitivity for microarray-based assay. Although only the cell-based assay can determine the neutralizing activity of autoantibodies, the microarray-based assay can serve as a highly specific and sensitive screening test to identify anti- IFN-I antibody positive patients.

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

Metal complexes feature a wide range of available geometries, diversified lability, controllable hydrolytic stability, and easily available rich redox activity. These characteristics combined with the specific properties of the coordinated organic molecules result in many different mechanisms of biological action, making each of the myriads of the classes of metal coordination compounds unique. This focused review presents combined and systematized results of the studies of a group of copper(I) (pseudo)halide complexes with aromatic diimines and tris(aminomethyl)phosphines of a general formula [CuX(NN)PR₃], where X = I^- or NCS^-, NN = 2,2’-bipyridyl, 1,10-phenanthroline, 2,9-dimethyl-1,10-phenanthroline or 2,2’-biquinoline, and PR₃ = Air-stable tris(aminomethyl)phosphines. The structural and electronic properties of the phosphine ligands and luminescent complexes are discussed. The complexes with 2,9-dimethyl-1,10-phenanthroline, apart from being air- and water-stable, exhibit a very high in vitro antimicriobial activity against the Staphylococcus aureus and Candida albicans. Moreover, some of the complexes also show a strong in vitro antitumor activity against human ovarian carcinoma cell lines: MDAH 2774 and SCOV 3, CT26 (mouse colon carcinoma), and A549 (human lung adenocarcinoma) cell lines. The tested complexes are moderately able to induce DNA lesions through free radical processes, however the trends do not reflect observed differences in biological activity.

The newly emerging nosocomial pathogen Candida auris is linked with persistent hospital-acquired infections and abrupt outbreaks across six continents. Genotypic analysis is indicative of the appearance of independent distinct clades of this particular fungus in different geographic locations simultaneously. Intrusive deep seated infections in addition to colonization have been diagnosed primarily in hospitalized patients and have drawn a lot of attention because of different antifungal susceptibility profiles and transmission despite strict preventive measures. Problems with the accurate identification of C. auris using phenotypic and molecular approaches has raised concerns about the detection of relevant levels of the problem. Candida family associated infections are a serious causative agent of mortality and morbidity in immune-compromised individuals. Candida auris are also known as superbug fungus that spreads rapidly all over the world. In 2009, shortly after the first case, various strains across the six continents have been recognized as nosocomial pathogens. Simultaneous and independent C. auris outbreaks appear to be of great concern for the healthcare settings as well as scientific community. Additionally, microbiological misidentification and multidrug resistance, rarely noticed for other non-albicans Candida species, lead to problems in obliteration and frequent treatment failures for C. auris infections. This review article aims to provide a comprehensive and up to date report on the global C. auris outbreaks, considering clinical along with microbiological characteristics, virulence mechanisms and susceptibility to antifungals, as well as the effectiveness of available preventive and therapeutic implementations.

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.

This study examines the practicality and limitations of using a FANUC CRX-10 iA/l collaborative robot to assemble a product component, highlighting the trade-offs between increased roboisation and reduced manual intervention. Through a detailed case study in the i-Labs laboratory, critical factors affecting precision assembly such as station layout, tooling design and robot programming are discussed. The findings highlight the benefits of robots for non-stop operation, freeing up human operators for higher value tasks despite longer cycle times. In addition, the paper advocates further research into reliable gripping of small components, a current challenge for robotics. The work contributes to open science by sharing partial results and methods that could inform future problem solving in robotic assembly.

Invasive fungal infections, notably candidemia, have been associated with COVID-19. The epidemiology of candidemia has significantly changed during the COVID-19 pandemic. We aim to identify the microbiological profile, resistance rates, and outcomes of COVID-19 associated candidemia (CAC) compared to patients with candidemia not associated with COVID-19. We retrospectively collected data on patients with candidemia admitted to the American University of Beirut Medical Center between 2004 and 2022. We compared the epidemiology of candidemia during and prior to the COVID-19 pandemic. Additionally, we compared the outcomes of critically ill patients with CAC to those with candidemia without COVID-19 from March 2020 till March 2022. Among 245 candidemia episodes, 156 occurred prior to the pandemic and 89 during the pandemic. Of the latter, 39 (43.8%) were CAC, most of which (82%) were reported from intensive care units (ICU). Non-albicans Candida (NAC) spp. were predominant throughout the study period (67.7%). Candida auris infection was the most common cause of NAC spp. in CAC. C. glabrata had decreased susceptibility rates to fluconazole and caspofungin during the pandemic period (46.1% and 38.4% respectively). Mortality rate in the overall ICU population during the pandemic was 76.6%, much higher than the previously reported mortality of candidemia from previous studies at our center. There was no significant difference in 30-day mortality between CAC and non-CAC (75.0% vs 78.1%; P =0.76). Performing ophthalmic examination (P = 0.002), CVC removal during the 48 hours following the candidemia (P = 0.008) and identifying the Candida spp. (P = 0.028) were significantly associated with a lower case-fatality rate. The epidemiology of candidemia has been significantly affected by the COVID-19 pandemic at our center. Rigorous infection control measures and proper antifungal stewardship are essential to combat highly resistant species like C. auris.

Abstract: Comorbidities of patients may be related to the duration of mechanical ventilation, survival, and Candida isolation during intensive care unit (ICU) stay. To examine the frequency of Candida isolation and significant comorbidities in the surgical intensive care unit (ICU) in Osijek University Hospital, Croatia, the data from the electronic database from May 2016 to June 30, 2023, were analyzed. In a cross-sectional study examining 15,790 microbiological samples, different strains of Candida were observed in 581 samples from 236 patients. The control group was 160 consecutive patients from March-May 2019, and 161 in the same months of 2020 (pre- and post-COVID-19). Comorbidities, duration of mechanical ventilation and survival were compared. Patients with isolated Candida were more often non-elective, had significantly more heart, kidney, liver diseases and sepsis (P<0.001). The duration of mechanical ventilation was 9.2 [2.2-9.24], 96 [24-146], 160 [19.5-343] and 224 [73.5-510] hours in controls, and patients with Candida albicans, non-albicans, and in patients with ³2 Candidas isolated. The mortality was significantly higher and reached 42% in patients with Candida isolated, while in the control group, it was 19% (P<0.001). In a multivariate analysis adjusted for patient’s age, SAPS II score, days of ICU, and type of admission, only sepsis was independent predictor of mortality (OR = 2.27).

The extended finite element method (XFEM) is now widely used in crack simulations and the direction of propagation of the XFEM crack in SS-304 has been quite interesting. This paper discusses the direction,θ(+ve in anti-clockwise direction), of the XFEM crack (under mode-I) propagation based on the von Mises stress-field around the crack-tip for static loading under the light water reactors (LWRs) conditions. The Mises core region from the crack-tip is chosen for β=〖90〗^o, the angle between the load and the initial crack. Experimental data for LWRs’environment is obtained and the simulations have been carried out applying three different static loads and results for the direction of the crack are calculated by measuring the stress-field around the crack-tip. It has been found that the direction of the XFEM varies inversely as the stress-field around the crack tip is increased. The computational results have been compared with the numerical results based on the minimum strain energy density criterion[S-criterion].

Progression of oral squamous cell carcinoma (OSCC) has been associated with an escape of tumor cells from the host immune surveillance with growing evidence of its underlying molecular mechanisms and its interaction with the immune cell control. In this study the expression of HLA class I (HLA-I) antigens and of components of the antigen processing machinery (APM) was analyzed in 160 consecutive human papilloma virus (HPV)-negative OSCC lesions and correlated to tumor specific parameters, the intratumoral immune cell response and to the patients outcome. A heterogeneous, but predominantly lower constitutive protein expression of HLA-I APM components was seen in OSCC sections when compared to non-neoplastic cells. Based on the expression levels of HLA-I APM components three main OSCC subgroups were detected and categorized into HLA-Ihigh/APMhigh, HLA-Ilow/APMlow and HLA-Idiscordant high/low/APMhigh phenotypes. In the HLA-Ihigh/APMhigh group, the highest frequency of intratumoral CD8+ T cells and lowest number of CD8+ T cells close to FoxP3 cells was found. Despite being associated with the highest T cell infiltration, patients within this group presented the most unfavorable survival, which was most evident in stage T2 tumors. Thus, the presented findings strongly indicate the presence of additional factors involved in the immunomodulatory process of HPV-negative OSCC with a possible tumor-burden-dependent complex network of immune escape mechanisms beyond HLA-I/APM components and T cell infiltration in this tumor entity.

Candida spondylodiscitis (CS) is a rare disease, for which therapeutic option are limited to fluconazole or echinocandins and the treatment should be administered up to 12 months. In case of reduced azole susceptibility, there is a scarcity of therapeutic options with adequate bone penetration and limited toxicity. We report the first case of successful use of rezafungin for a spondylodiscitis due to Candida parapsilosis with reduced susceptibility to azoles. The patient, affected by paraplegia and short bowel syndrome, was diagnosed with CS with culture on vertebral biopsy guided by a 18-FDG-PET/CT scan. He received rezafungin 200 mg weekly for 26 weeks, after 10 weeks of previous antifungal treatment. He had a full clinical, radiologic and biochemical response to the therapy with rezafungin, with no adverse effects. Rezafungin is a promising therapy for Candida osteomyelitis, especially when first line therapies are ineffective or contraindicated.

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.

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.

The II law of thermodynamics is most often given in three supposedly equivalent formulations: two Clausius (I and II) and one Kelvin. The most general and indisputable entropy formulation belong to Clausius (II). The earlier Clausius I principle determines the natural direction heat flow between bodies at different temperatures. On the other hand, the Kelvin principle states that it is impossible to completely convert heat into work. The author argues that the Kelvin principle is a weaker statement (or more strictly non-equivalent) than Clausius I principle, and the latter is a weaker statement than Carnot principle, which is equivalent to Clausius II principle. As a result, the Kelvin principle and the Clausius I principle are not exhaustive formulations of the II law of thermodynamics. At the same time, it turns out that the Carnot principle becomes such a formulation. Apart from providing a complete set of proof and disproof, the author, indicates where the methodological errors were made in the alleged proof of the equivalence of the Kelvin principle and both Clausius principles.

Background: Given the increasing request for natural pharmacological molecules, this study assessed the antimicrobial capacity of Pistacia lentiscus L. essential oil (PLL-EO) obtained from the leaves of wild plants growing in North Sardinia (Italy), toward a wide range of periodontal bacteria and Candida including laboratory and clinical isolates sp., together with its anti-inflammatory activity and safety; Methods: PLL-EO was screened by gas chromatography / mass spectrometry. The minimal inhibitory concentration (MIC) was determined. The anti-inflammatory activity was measured by cyclooxygenase (COX 1/2) and lipoxygenase (LOX) inhibition while the antioxidant capacity was determined electro-chemically and by the MTT assay. The WST-1 assay was used to ascertain cytotoxicity toward four line of oral cells; Results: According to the concentrations of terpens, PLL-EO is a pharmacologically active phytocomplex. MICs against periodontal bacteria ranged between 3.13 and 12.5 µg/ml, while against Candida sp. were between 6.25 and 12.5 µg/ml. Oxidation by COX 1/2 and LOX was inhibited by 80% and 20% µg/mL of the oil respectively. Antioxidant activity seemed negligible, and no cytotoxicity arose; Conclusions: PLL-EO exhibits a broad-spectrum activity against periodontal bacteria and Candida, with an interesting dual inhibitory capacity toward COX2 and LOX inflammatory enzymes and without side effects against oral cells.

It is known that complexes based on natural polysaccharides are able to eliminate bone defects. Prolonged hyperglycemia means low bone regeneration and a chronic inflammatory response. The purpose of the study was to increase the efficiency of early bone formation in a cavity of critical size in diabetes mellitus in the experiment. The polyelectrolyte complex contains high molecular ascorbate of chitosan, chondroitin sulfate, sodium hyaluronate, heparin, adgelon serum growth factor, sodium alginate and amorphous nanohydroxyapatite (CH-SA-HA). Studies were conducted on 5 groups of white female Wistar rats: group 1 - regeneration of a bone defect in healthy animals under a blood clot; group 2 - regeneration of a bone defect under a blood clot in animals with diabetes mellitus; group 3 - bone regeneration in animals with diabetes mellitus after filling the bone cavity with a collagen sponge; group 4 - filling of a bone defect with a CH-SA-HA construct in healthy animals; Group 5 - filling of a bone defect CH-SA-HA in animals with diabetes mellitus. Implantation of the CH-SA-HA construct into bone cavities in type I diabetic rats can accelerate the rate of bone tissue repair. The inclusion of modifying polysaccharides and apatite agents in the construction may be a prospect for further improvement of the properties of implants.

Human Perrault syndrome (PRLTS) is defined by autosomal recessive inheritance with primary ovarian insufficiency and early hearing loss. Most PRLTS disease proteins modulate mitochondrial transcription or translation. Among the genetic causes are ClpP mutations, which trigger also complete azoospermia, whose cellular and molecular underpinnings are unknown. Here, the ClpP-null mouse model was studied by global transcriptomics, proteomics, RT-qPCR, immunoblots, tissue fractionation, testis histology, and was crossed with STING/IFNAR mutants. Spermatogenesis showed accumulated early spermatocytes, versus deficits of desynapsis and kinetochore factors; excess Dazl/Stra8 and acetylSMC3, versus deficient SHCBP1L, were molecular correlates. Spermiogenesis showed few round spermatids, tsHMG/TFAM in elongated spermatids was absent; transcripts for tail/acrosome factors were downregulated from start. Nuclear anomalies included a failed Rec8 induction, early BRDT deficiency, histone H3 cleavage, and cGAMP increase, among antiviral responses typical of ClpP-mutants. However, deletion of downstream innate immune signals STING/IFNAR failed to reestablish fertility. As mitochondrial triggers, we observed accumulation of ClpX, with PTCD1, POLDIP2, GRSF1, ALKBH7, DNAJA3, AURKAIP1, VWA8, and Perrault proteins ERAL1, PEO1, HARS2, partially showing nuclear redistribution. ClpP-depletion is known to cause extra-mitochondrial release of mispacked mtDNA/mtRNA/protein complexes. Now we define nuclear inflammatory responses and meiotic arrest as consequences, similar to observations in mito-mice and mutator-mice.

Human Perrault syndrome (PRLTS) is defined by autosomal recessive inheritance with primary ovarian insufficiency and early hearing loss. Most PRLTS disease proteins modulate mitochondrial transcription or translation. Among the genetic causes are ClpP mutations, which trigger also complete azoospermia, whose cellular and molecular underpinnings are unknown. Here, the ClpP-null mouse model was studied by global transcriptomics, proteomics, RT-qPCR, immunoblots, tissue fractionation, testis histology, and was crossed with STING/IFNAR mutants. Spermatogenesis showed accumulated early spermatocytes, versus deficits of desynapsis and kinetochore factors; excess Dazl/Stra8 and acetylSMC3, versus deficient SHCBP1L, were molecular correlates. Spermiogenesis showed few round spermatids, tsHMG/TFAM in elongated spermatids was absent; transcripts for tail/acrosome factors were downregulated from start. Nuclear anomalies included a failed Rec8 induction, early BRDT deficiency, histone H3 cleavage, and cGAMP increase, among antiviral responses typical of ClpP-mutants. However, deletion of downstream innate immune signals STING/IFNAR failed to reestablish fertility. As mitochondrial triggers, we observed accumulation of ClpX, with PTCD1, POLDIP2, GRSF1, ALKBH7, DNAJA3, AURKAIP1, VWA8, and Perrault proteins ERAL1, PEO1, HARS2, partially showing nuclear redistribution. ClpP-depletion is known to cause extra-mitochondrial release of mispacked mtDNA/mtRNA/protein complexes. Now we define nuclear inflammatory responses and meiotic arrest as consequences, similar to observations in mito-mice and mutator-mice.

Electrical remodelling as a result of the homeodomain transcription factor 2 (Pitx2)‐dependent gene regulation was linked to atrial fibrillation (AF) and AF patients with single nucleotide polymorphisms at chromosome 4q25 responded favorably to Class I antiarrhythmic drugs (AADs). The possible reasons behind this remain elusive. The purpose of this study was to assess the efficacy of AADs disopyramide, quinidine, and propafenone on human atrial arrhythmias mediated by Pitx2-induced remodelling, from a single cell to the tissue level, using drug binding models with multi-channel pharmacology. Experimentally calibrated populations of human atrial action potential (AP) models in both sinus rhythm (SR) and Pitx2-induced AF conditions were constructed by using two distinct models to represent morphological subtypes of AP. Multi-channel pharmacological effects of disopyramide, quinidine, and propafenone on ionic currents were considered. Simulated results showed that Pitx2-induced remodelling increased maximum upstroke velocity (dVdtmax) and conduction velocity (CV), and decreased AP duration (APD) and wavelength (WL). At the concentrations tested in this study, these AADs decreased dVdtmax and CV and prolonged APD in the setting of Pitx2-induced AF. Our findings of alterations in WL indicated that quinidine and disopyramide may be more effective against Pitx2-induced AF than propafenone by prolonging WL.

Background Candida auris is an emerging multidrug-resistant fungal pathogen that represents a serious threat to healthcare settings currently. Objective: Its objective was to determine the prevalence of C. auris in the hospital since its initial detection in late 2019. Methods: Using an adapted risk assessment tool, we reviewed the charts. and medical files of all suspected? and confirmed cases of C. auris cases reported at King Khalid University Hospital, Riyadh between November 2019 and December 2022. Anonymized data were retrieved in a pre-established datasheet and analyzed to determine the epidemiological characteristics of C. auris infection in our facility. We established our initial prevalence by age, gender, risk factors, and according to sampling source. Results: Of the 53 confirmed cases positive for C. auris during the study period, 33 (62%) were males. Their ages ranged between 15 and 98; most positive cases occurred in 50 and above. Only one of the confirmed cases was hospital-acquired. All patients had at least one risk factor, and Urine samples yielded the greatest number of positive cases while admission to healthcare facilities constituted the highest risk in our study. Conclusion: Establishing a local prevalence could serve as our baseline/benchmark to compare with regional and international benchmarks.

Microarray patches (MAPs) have the potential to be a safer, more acceptable, easier to use, and more cost-effective means for the administration of vaccines than injection by needle and syringe. Here, we report findings from a randomized, partially double-blind, placebo-controlled Phase I trial using the Vaxxas high-density MAP (HD-MAP) to deliver a measles rubella (MR) vaccine. Healthy adults (N = 63, age 18–50 years) were randomly assigned 1:1:1:1 to four groups: uncoated (placebo) HD-MAPs, low-dose MR HD-MAPs (~3,100 median cell-culture infectious dose [CCID50] measles, ~4,300 CCID50 rubella); high dose MR-HD-MAPs (~9,300 CCID50 measles, ~12,900 CCID50 rubella); or a sub-cutaneous (SC) injection of an approved MR vaccine, MR-Vac (≥1,000 CCID50 per virus). The MR vaccines were stable and remained viable on HD-MAPs when stored at 2–8°C for at least 24 months. When MR HD-MAPs stored at 2–8°C for 24 months were transferred to 40°C for 3 days in a controlled temperature excursion, loss of potency was minimal, and MR HD-MAPs still met World Health Organisation (WHO) specifications. MR HD-MAP vaccination was safe and well-tolerated; any systemic or local adverse events (AEs) were mild or moderate. Similar levels of binding and neutralizing antibodies to measles and rubella were induced by low-dose and high-dose MR HD-MAPs and MR-Vac. The neutralizing antibody seroconversion rates at day 28 after vaccination for the low-dose HD-MAP, high-dose HD-MAP and MR-Vac groups were 37.5%, 18.8% and 35.7% respectively for measles and 37.5%, 25.0% and 35.7% respectively for rubella. Most participants were seropositive for measles and rubella antibodies at baseline, which appeared to negatively impact the number of participants that seroconverted to vaccines delivered by either route. The data reported here suggest HD-MAPs could be a valuable means for delivering MR-vaccine to hard-to-reach populations and support further development. Clinical trial registry number: ACTRN12621000820808.

Background. Candida bloodstream infections (CBSIs) have decreased among pediatric populations in the United States, but remain an important cause of morbidity and mortality. Species distributions and susceptibility patterns of CBSI isolates diverge widely between children and adults. Awareness of these patterns can inform clinical decision-making for empiric or pre-emptive therapy of children at risk for candidemia. Methods. CBSIs occurring from 2006-2016 among patients in a large children’s hospital were analyzed for age specific trends in incidence rate, risk factors for breakthrough-CBSI and death, as well as underlying conditions. Candida species distributions and susceptibility patterns were evaluated in addition to antifungal agent use. Results. The overall incidence rate of CBSI among this complex patient population was 1.97/1,000 patient-days. About half of CBSI episodes occurred in immunocompetent children and 14% in Neonatal Intensive Care Unit (NICU) patients. Antifungal resistance was minimal: 96.7% of isolates were fluconazole-, 99% were micafungin-, and all were amphotericin susceptible. Liposomal amphotericin was the most commonly prescribed antifungal agent including for NICU patients. Overall CBSI-associated mortality was 13.7%; there were no deaths associated with CBSI among NICU patients after 2011. Conclusions. Pediatric CBSI characteristics differ substantially from those in adults. Improved management of underlying diseases and antimicrobial stewardship may further decrease morbidity and mortality from CBSI while continuing to maintain low resistance rates among Candida isolates.

The aim of our work was to check if one of the products of natural origin, namely honey bee propolis may be an alternative or supplement to currently used antifungal agents. The activity of 50 ethanolic extracts of propolis (EEPs), harvested in Polish apiaries, was tested on a group of 69 clinical isolates of C. albicans. Most of the EEPs showed satisfactory activity, with minimum fungicidal concentrations (MFC) mainly in the range of 0.08-1.25% (v/v). Eradication of biofilm from polystyrene microtitration plates in 50% (MBEC50) required concentrations in the range of 0.04% (v/v) to more than 1.25% (v/v). High activity was also observed in eradication of biofilm formed by C. glabrata and C. krusei on the surfaces of PVC and silicone catheters. EEPs at subinhibitory concentrations inhibited yeast-to-mycelia morphological transformation of C. albicans in liquid medium and mycelial growth on solid medium. A synergistic effect was observed for the action of EEPs in combination with fluconazole (FLU) and voriconazole (VOR) against C. albicans. In the presence of EEP at concentration as low as 0.02%, the MICs of FLU and VOR were 256 to 32 times lower in comparison to those of the drug alone. Evidences for the fungal cell membrane as the most probable target of EEPs are presented.

Soft-Core architecture for Analogue to Digital Converter (ADC) sampling is useful for mixed signal applications. Soft-core architecture for cutting edge odd or even ADC sampling with interface to block RAM memory has not been found. Soft-core architecture as a concept has become popular due to the advantage of customization for different applications as compared to general-core architecture suited for single application. The latest generation of piece wise sampling is odd sampling and was introduced in the second decade of the 20th century. Odd and even order sampling techniques are analogue in nature driven by a tuned (tuned for odd or even) mixer. This paper proposes a third-generation piece wise sampling with soft-core architecture that enables an option to select both odd and even while interfacing to memory mapping. The proposed odd/even has superior SNR performance of 6 dB as compared to existing architecture such as Mod-∆ which recorded worst performance of 18 dB. Advances in soft-core technology have allowed a niche odd/even switching field to be identified and studied, the study has also been extended to include memory architecture.

The growing increase in infections caused by C. tropicalis, associated with its drug resistance and consequent high mortality, especially in immunosuppressed people, today generates a serious global public health problem. In the search for new potential drug candidates that can be used as treatments or adjuvants in the control of infections by these pathogenic yeasts, the objective of this research was to evaluate the action of isoespintanol (ISO) against the formation of biofilms fungal, the mitochondrial membrane potential (∆Ψm) and its effect on the integrity of the cell wall. We report the ability of ISO to inhibit the formation of biofilms by up to 89.35%, in all cases higher than the values expressed by amphotericin B (AFB). Flow cytometric experiments using rhodamine 123 (Rh123) showed the ability of ISO to cause mitochondrial dysfunction in these cells. Likewise, experiments using calcofluor white (CFW) and analyzed by flow cytometry, showed the ability of ISO to affect the integrity of the cell wall by stimulating chitin synthesis; these changes in the integrity of the wall were also observed through transmission electron microscopy (TEM). These mechanisms are involved in the antifungal action of this monoterpene.

Considerable attention has been given to the research field of bioorganometallic chemistry, which is a hybrid chemistry field between biology and organometallic chemistry. The introduction of biomolecules, which have hydrogen bonding sites and chiral centers, into organometallic compounds is considered to be a promising strategy to construct chirality-organized bioorganometallic conjugates. This feature paper sketches an outline of induction of helical chirality into bioorganometallic conjugates. Topics covered include control of the helical chirality of 1,n’-disubstituted ferrocene moieties in ferrocene-dipeptide conjugates and the chirality induction of the Au(I)–Au(I) axis in the dinuclear organogold(I)-uracil conjugates.

The aim of current study is adjusted and synthesized liposomal compound of N. sativa and evaluation its antifungal properties against C. parapsilosis isolates. Fifteen clinical isolates of C. parapsilosis complex isolates were obtained from hospitalized patients affected by candidemia in Mashhad city, Iran, along with a reference strain of C. parapsilosis (ATCC 22019) were assessed by flight mass spectrometry (MALDI-TOF) method, as described previously. N. sativa is encapsulated in liposomal Nanocariers by using thin film hydration technique. At the beginning liposomal nanoparticles was characterized and confirmed with the dynamic light scattering technique (DLS) and Transmission electron microscopy. Then minimum inhibitory concentration of liposomal N. sativa oil was conducted with the CLSI M27 A3 protocol and finally Cytotoxicity function of N. sativa oil liposomal nanocarriers on PBMCs was investigated and confirmed with MTT assay by the results of this research N. sativa oil-Lip-NP didn’t show any toxic effect on PBMCs and The minimum inhibitory concentration (MIC) range of free N. sativa oil and liposomal formulation with inhibitory effects on candida isolates was between 128 - 8, 250 - 31.25 µg ml also MIC50 and MIC90 were 125,187 and 32,96, µg ml respectively. Due to the hydrophobicity and hydrophilicity, biocompatibility, particle size, non-toxic effect, and higher cell viability of N. sativa oil -Lip-NP, it could be considered a more effective approach to treating fungal infections.

The seeds of red clover are heteromorphic and two color morphs can be visually recognized, light purple and yellow, resulting from heterozygosity and recessive homozygosity at two loci. Here, we report the responses of seed imbibition, seed germination, and early seedling growth of the two morphs to distilled water, sodium chloride, and complete nutrient solution. The sensitivity of red clover seeds to treatments increased with the stage of development in what seems to be a cumulative process. No differences were found in seed imbibition between morphs or between treatments. In seedling growth, on the contrary, treatments were always effective, but differences between morphs were only observed in seeds that were treated with nutrient solution, whereas in the intermediate stage of seed germination, the effects by treatments were observed together with the appearance of differences between morphs in distilled water and in the treatment by sodium chloride solution. Simultaneously, the superior performance of the yellow morph that was found in germination, which appears to be a trait stable across cultivars of red clover seeds, turned into a superior performance of the light purple morph in seedling growth.

Sublingual vaccines offer the benefits of inducing mucosal immunity to protect against respiratory viruses, including Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) and influenza, while also enabling needle-free self-administration. Previously, we developed a sublingual vaccine formulated with the SARS-CoV-2 receptor binding domain antigen and Poly(I:C) adjuvant in nonhuman primates, cynomolgus macaques. This study examined the immune and inflammatory responses elicited by the sublingual influenza vaccine containing hemagglutinin (HA) antigen and Poly(I:C) adjuvant and assessed the safety of this vaccine in nonhuman primates. The Poly(I:C)-adjuvanted sublingual vaccine induced both mucosal and systemic immunities. Specifically, the sublingual vaccineproduced HA-specific secretory IgA antibodies in saliva and nasal washings, and HA-specific IgA and IgG were detected in the blood. This vaccine appeared to be safe, as judged from the results of blood tests and plasma C-reactive protein levels. Notably, sublingual vaccination neither increased the production of inflammation-associated cytokines—IFN-alpha, IFN-gamma, and IL-17—in the blood, nor upregulated the gene expression of proinflammatory cytokines—IL12A, IL12B, IFNA1, IFNB1, CD69, and granzyme B—in white blood cells. Moreover, DNA microarray analyses revealed that sublingual vaccination evoked both enhancing and suppressing expression changes in genes associated with immune-related responses in cynomolgus monkeys. Therefore, the sublingual vaccine with Poly(I:C) adjuvant is safe and creates a balanced state of enhancing and suppressing the immune-related response.

The Jakarta LARP community, established in March 2020 and primarily active in Gelora Bung Karno, fosters inclusivity, diversity, and physical role-playing activities. It adheres to a policy of excluding ultra-nationalist ideologies and integrates new members despite language barriers. Bruhn (2011) defines this kind of community sharing the same goals, values, and lifestyles, while McMillan & Chavis (1986) outline four aspects of the sense of community.The research discovered that communities endure by utilizing solidarity built on the basis of their peculiarities. This study employed ethnographic methods alongside grounded research to identify the community's culture and their efforts to sustain and utilize it as community solidarity.

Fungal infections caused by Candida spp. are responsible for high hospital morbidity and mortality rates. Therefore, there is a continuous search for new antifungal medicines, particularly ones with anti-Candida activity. This review analyzed articles published between 2002 and 2023 considering the anti-Candida activity of chemical compounds identified or isolated in plants of the Anacardiaceae family. In addition, the in-silico prediction of the isolated compounds described was performed. The analysis of 35 studies showed that extracts, essential oils, and compounds from the anti-Candida activity were frequently determined in vitro using the minimum inhibitory concentration (MIC). The most commonly tested species were Candida albicans, C. tropicalis, C. parapsilosis, C. glabrata, C. krusei, and C. guilliermondii, respectively. Essential oils were the most used form (37% of the studies). The isolated compounds with antifungal effects include cardanol, estragole, trans-anethole, β-caryophyllene, myrcene, catechin-3-o-rhamnoside, β-sitosterol-3-O-glucoside, 24Z-isomasticadienolic acid, oleanolic acid, and oleanolic aldehyde. The in-silico evaluation of those isolated compounds revealed the compounds' drug-likeness and possible antifungal activity. However, some of them showed high toxicity. In conclusion, compounds from the Anacardiaceae family show promise for developing new therapeutic antifungal drugs, especially in combination with conventional antifungals.

Candida tropicalis, an opportunistic pathogen, ranks among the primary culprits of invasive candidiasis, a condition notorious for its resistance to conventional antifungal drugs. The urgency to combat these drug-resistant infections has spurred the quest for novel therapeutic compounds, with a particular focus on those of natural origin. In this study, we set out to evaluate the impact of Isoespintanol (ISO), a monoterpene derived from Oxandra xylopioides, on the transcriptome of C. tropicalis. Leveraging transcriptomics, our research aimed to unravel the intricate transcriptional changes induced by ISO within this pathogen. Our differential gene expression analysis unveiled 186 differentially expressed genes (DEGs) in response to ISO, with a striking 85% of these genes experiencing upregulation. These findings shed light on the multifaceted nature of ISO's influence on C. tropicalis, spanning a spectrum of physiological, structural, and metabolic adaptations. The upregulated DEGs predominantly pertained to crucial processes, including ergosterol biosynthesis, protein folding, response to DNA damage, cell wall integrity, mitochondrial activity modulation, and cellular responses to organic compounds. Simultaneously, 27 genes were observed to be repressed, affecting functions such as cytoplasmic translation, DNA damage checkpoints, membrane proteins, as well as metabolic pathways like trans-methylation, trans-sulfuration, and trans-propylamine. These results underscore the complexity of ISO's antifungal mechanism, suggesting that it targets multiple vital pathways within C. tropicalis. Such complexity potentially reduces the likelihood of the pathogen developing rapid resistance to ISO, making it an attractive candidate for further exploration as a therapeutic agent. In conclusion, our study provides a comprehensive overview of the transcriptional responses of C. tropicalis to ISO exposure. The identified molecular targets and pathways offer promising avenues for future research and the development of innovative antifungal therapies to combat infections caused by this pathogenic yeast.

Background: Fungi are ubiquitous microorganisms that are easily dispersed through the air. In healthcare environments, indoor air can favor the spread of healthcare-associated fungal infections, compromising mainly immunocompromised hospitalized individuals. Thus, this study aimed to evaluate the indoor air contamination in healthcare environments, investigating mainly the presence of potentially pathogenic yeasts. Methods: Indoor air samples were collected from twelve healthcare environments (hospital and medical clinics). After the growth, isolation, and purification of the yeast colonies, the isolates were identified by polymerase chain reaction using species-specific primers for yeasts of the genus Candida and sequencing of D1/D2 domains of the large ribosomal subunit (LSU rRNA). Results: Fourteen yeast species were identified, including emerging pathogens. Species of clinical importance such as Candida parapsilosis, Candida orthopsilosis, Candida glabrata, Rhodotorula mucilaginosa, and Trichosporon mucoides were present. C. Parapsilosis was the most prevalent species, followed by Rodothorula mucilaginosa. Conclusions: The present study shows that potentially fungal pathogens were present in air samples from healthcare environments, proving the role of indoor air in spreading infections. Thus, monitoring air quality in healthcare environments is a fundamental approach in developing infection control measures, especially those related to invasive fungal infections.

Central metabolic pathways may play a major role in the virulence of pathogenic fungi. Here, we have investigated the susceptibility of a Candida parapsilosis mutant deficient in trehalase activity (atc1Δ/ntc1Δ strain) to the azolic compounds Fluconazole and Itraconazole. A time-course exposure to Itraconazole but not Fluconazole induced a significant degree of cell-killing in mutant cells compared to the parental strain. Flow cytometry determinations indicated that Itraconazole was able to induce a marked production of endogenous ROS together with a simultaneous increase in membrane potential, these effects being irrelevant after Fluconazole addition. Furthermore, only Itraconazole induced a significant synthesis of endogenous trehalose. The recorded impaired capacity of mutant cells to produce structured biofilms was further increased in the presence of both azoles, with Itraconazole being more effective than Fluconazole. Our results in the opportunistic pathogen yeast C. parapsilosis reinforce the study of trehalose metabolism as an attractive therapeutic target and allow extending the hypothesis that the generation of internal oxidative stress may be a component of the antifungal action exerted by the compounds currently available in medical practice.

Candida glabrata is a yeast of increasing medical relevance, particularly in critically ill patients. It is the second most isolated Candida species associated with invasive candidiasis (IC) behind C. albicans. The attributed higher incidence is primarily due to an increase in the acquired immunodeficiency syndrome (AIDS) population, cancer, and diabetes patients. The elderly population and the frequent use of indwelling medical devices are also predisposing factors. The work aimed to review various virulence factors that facilitate the survival of pathogenic C. glabrata in IC. The available published research articles related to the pathogenicity of C. glabrata were retrieved and reviewed from four credible databases, mainly Google Scholar, ScienceDirect, PubMed, and Scopus. The articles highlighted many virulence factors associated with pathogenicity in C. glabrata, including adherence to a susceptible host surface, evading host defences, and producing hydrolytic enzymes (e.g., phospholipases, proteases, and haemolysins). The factors facilitate infection initiation. Other virulent factors include iron regulation and genetic mutations. Accordingly, biofilm production, tolerance to high-stress environments, and development of resistance to the antifungal drug, notably to fluconazole and other azole derivatives, were reported. The review provided evident pathogenic mechanisms and antifungal resistance associated with C. glabrata in ensuring its sustenance and survival.

To assess the clinical efficacy of a novel organic olive oil-based denture adhesive and its effect on Candida Albicans growth in maxillary edentulous individuals wearing complete dentures. Individuals were selected from two Dental Schools in Portugal and Spain. Twenty-eight complete dentures were relined, following a standardized protocol. The novel product (Test) was compared with a commercialized adhesive (Control) and Vaseline (Placebo) randomly assigned in a cross-study design. The retention resistance was measured with a Gnathometer and a dynamometer, the patient related outcome evaluations with a 5-points questionnaire and the Candida albicans growth in a Sabouraud dextrose agar (SDA) medium in order to evaluate differences between the placebo and experimental product. Twenty-three participants were included. Dynamometer evaluation showed significant differences between not using a denture adhesive and using either (experimental, p = .03; control, p = .04), no significant differences between the two adhesives (p &gt; .05). In the subjective analysis, the experimental adhesive showed a significantly longer effectiveness (p = .001); the control reported better results at taste (p = .03) in chewing (p = .001). The test adhesive showed better (p &lt; .001) Candida albicans growth inhibition. The experimental adhesive showed longer effectiveness than the control and placebo with a better inhibition capacity for the growth of Candida albicans, patients reported better abilities for speech, chewing, taste and retirement in the control adhesive.

Candida species are one of the most important causes of human infections, especially in hospitals and among immunocompromised patients. The correct and rapid etiological identification of yeast infections is important to provide adequate therapy, reduce mortality and control outbreaks. In this study, Candida species were identified in patients with suspected fungal infection, and phenotypic and genotypic identification methods were compared. A total of 167 axenic fungal cultures and 46 clinical samples were analyzed by HardyCHROM®, MicroScan®, and PCR-RFLP. The species of the C. albicans complex were the most frequent, followed by C. tropicalis and C. glabrata. Less common but clinically relevant species of Candida were also isolated. The comparison between the three methods was concordant, especially for the most common Candida species. Fungal DNA amplification was successful in all clinical samples.

Candida glabrata has thoroughly adapted to successfully colonize human mucosal membranes and survive in vivo pressures prior to and during antifungal treatment. Out of all the medically relevant Candida species, C. glabrata has emerged as a leading cause of azole, echinocandin, and multidrug (MDR: azole + echinocandin) adaptive resistance. Neither mechanism of resistance is intrinsic to C. glabrata, since stable genetic resistance depends on mutation of drug target genes, FKS1 and FKS2 (echinocandin resistance), and a transcription factor, PDR1, which controls expression of major drug transporters, such as CDR1 (azole resistance). However, another hallmark of C. glabrata is the ability to withstand drug pressure both in vitro and in vivo prior to stable ‘genetic escape’. Additionally, these resistance events can arise within individual patients, which underscores the importance of understanding how this fungus is adapting to its environment and to drug exposure in vivo. Here, we explore the evolution of echinocandin resistance as a multistep model that includes general cell stress, drug adaptation (tolerance), and genetic escape. The extensive genetic diversity reported in C. glabrata will be highlighted.

IMPORTANCE: On December 10, 2021, the FDA published a Determination Letter, along with a Statistical Review and Evaluation Report, and concluded that under the non-informative prior, the local Bayesian optimal interval design (BOIN) design, in its revised form, can be designated fit-for-purpose for identifying the maximum tolerated dose of a new drug, assuming that dose-toxicity relationship is monotonically increasing. Although setting the BOIN design parameter p.tox = 1.4 * target.DLT.rate is recommended in almost all BOIN methodology articles and is the default value in the R package BOIN, it's unclear if the choice of p.tox should only depend on the target DLT rate and if certain range of p.tox could produce the same BOIN boundary table. DESIGN: In this simulation study, following parameters were varied one at a time, using R package BOIN, to explore their effects on the equivalence intervals of p.saf and p.tox: 1) target DLT rate, 2) n.earlystop, 3) cutoff.eli, 4) cohortsize, and 5) ncohort. And a simple 3+3 design was used as an example to explore equivalent sets of BOIN design parameters that can generate the same boundary table. RESULTS: When the early stopping parameter n.earlystop is relatively small or the cohortsize value is not optimized via simulation, it might be better to use p.tox < 1.4 * target.DLT.rate, or try out different cohort sizes, or increase n.earlystop, whichever is both feasible and provides better operating characteristics. This is because if the cohortsize was not optimized via simulation, even when n.earlystop = 12 and cohortsize > 3, the BOIN escalation/de-escalation rules generated using p.tox = 1.4 * target.DLT.rate could be exactly the same as those calculated using p.tox > 3 * target.DLT.rate, which might not be acceptable for some pediatric trials targeting 10% DLT rate. The traditional 3+3 design stops the dose finding process when 3 patients have been treated at the current dose level, 0 DLT has been observed, and the next higher dose has already been eliminated. If additional 3 patients were required to be treated at the current dose in the situation described above, the decision rules of this commonly used 3+3 design could be generated using BOIN design with target DLT rates ranging from 18% to 29%, p.saf ranging from 8% to 26%, and different p.tox values ranging from 39% to 99%. These BOIN parameters also need to satisfy a set of conditions. Meaning: This study demonstrates the importance of interpreting BOIN design parameter p.tox as an interval of toxicity rates that are considered too toxic, rather than one prespecified value that corresponds to the lowest toxicity probability that is deemed overly toxic. When designing a dose-finding trial using BOIN, it is important to perform simulation studies to identify equivalent sets of BOIN design parameters that can generate the same boundary table so that we can better compare the safety properties of different boundary tables.

The presence of the mite, Varroa destructor, requires the use of acaricide treatments in most honeybee colonies. Amitraz is one of the most common acaricide substances used by beekeepers. Some Varroa mite populations have developed resistance to amitraz leading to a loss of efficacy of amitraz-based treatments. Two products, Apivar and Supatraz were applied in the same apiary. Both treatments are amitraz-based but have a different galenics. Thanks to field data, a dynamic model was used to simulate the action of Apivar and Supatraz on the mite population. We consider two parameters to compare the products: daily mortality rate and treatment duration. In the field, the percentage of efficacy between the two products was not significantly different but Supatraz kills mite faster and decreases 90% of the mite infestation in 28.4 days compared to 50.9 days for Apivar. Thanks to modelling, we showed the daily impact of the two different products on mite population. Supatraz has a higher daily mortality rate during the first two weeks than Apivar. Supatraz requires a lower efficacy to stabilize the varroa mite population due to its faster release of active ingredient than Apivar, needing a shorter period to achieve the same result. Depending on the model, Supatraz conserve a good efficacy for low resistant mites but not for high resistant mites. These results show that the comparison of the efficacy of two products with different characteristics (duration of treatment and daily mortality rate) should be analyzed with caution.