Background: Catalase is a vital antioxidant enzyme that dismutates H₂O₂ into water and molecular oxygen. Many protocols have been developed to measure catalase enzyme activity. Spectrophotometric methods are the most common assays that used to assess catalase enzyme activity. Methods: Because the rate-limiting step during catalase enzyme activity depends upon the dissociation of hydrogen peroxide, the developed assay measures the reaction between a hydroquinone/anilinium sulfate/ammonium molybdate reagent and Unreacted Hydrogen Peroxide, which results in the production of a purple, disubstituted quinone compound with a maximum absorbance value at 550 nm. Results: To clarify the precision of the developed method, the coefficients of variation were determined to be 2.6% and 4.7% for within run measurements and between run measurements, respectively. This method returned results that correlated well (r = 0.9982) with the results returned using the peroxovanadate method to assess catalase enzyme activity. Additionally, we examined the use of the newly developed hydroquinone assay to measure catalase enzyme activity in liver and bacterial homogenate samples. Conclusion: These results demonstrated that this assay can be used for scientific research and routine health applications because it is inexpensive, simple, accurate, and rapid. This method is suitable for use in clinical pathology laboratories because it is simple and produces precise and reproducible results.

GPT-4 was released in March 2023 to wide acclaim, marking a very substantial improvement across the board over GPT-3.5 (OpenAI's previously best model, which had powered the initial release of ChatGPT). Despite the genuinely impressive improvement, however, there are good reasons to be highly skeptical of GPT-4's ability to reason. This position paper discusses the nature of reasoning; criticizes the current formulation of reasoning problems in the NLP community and the way in which the reasoning performance of LLMs is currently evaluated; introduces a collection of 21 diverse reasoning problems; and performs a detailed qualitative analysis of GPT-4's performance on these problems. Based on the results of this analysis, the paper argues that, despite the occasional flashes of analytical brilliance, GPT-4 at present is utterly incapable of reasoning.

As the echoes of ChatGPT's remarkable success continue to permeate the AI community, its formidable successor, GPT-4, has emerged, showing off a wealth of novel features. In this concise paper, we elucidate the capabilities of GPT-4 and conduct a comparative analysis with its predecessor, ChatGPT, offering insights into their relative strengths and advancements in the rapidly evolving field of generative AI. We also present a comprehensive summary of the major performance results reported by OpenAI on GPT-4 across various Natural Language Processing (NLP) tasks. We place great emphasis on the innovative advancements offered by GPT-4 in comparison to its predecessors. Our focus is on highlighting its remarkable performance while also mentioning its limitations. The purpose of this paper is to deliver a succinct understanding of the new features and performance benchmarks of GPT-4.

The development and optimization of an effective non-viral gene delivery method for genetic manipulation of primary human T cells is a major challenge in clinical immunotherapy researches. According to the low transfection efficiency of conventional methods in human primary T cells, there is an effort in order to increase the transfection rate in these cells. Protamine is an FDA-approved compound with a documented safety profile that enhances DNA condensation for gene delivery. In this study, the effect of protamine on the transfection efficiency of standard transfection reagents, TurboFect, and Lipofectamine 2000 was evaluated in order to transfect primary human T cells. Results demonstrated that protamine condenses DNA and increases the positive charge of DNA/Cargo complex efficiently without any cytotoxic effect on the primary human T cells. The results also revealed that the DNA/Protamine/Cargo complexes effectively transfect human primary T cells.

In 2019, Chinese government implemented the first round of National Centralized Drug Procurement (NCDP) pilot (so-called "4+7" policy) in mainland China, achieved a prominent price reduction of 52% on average for 25 bidding winning products. Under cross-price elasticity theory, the price behavior of pharmaceutical enterprises for policy-related drugs might change. This study used drug purchasing data from the Centralized Drug Procurement Survey in Shenzhen 2019, and applied single-group Interruption Time Series (ITS) design to examine the impact of "4+7" policy on the drug price index (DPI) of policy-related drugs. The ITS analysis showed that the DPI of winning (-0.183 per month, p<0.0001) and non-winning (-0.034 per month, p=0.046) products significantly decreased after the implementation of "4+7" policy. No significant difference was found for the immediate change of DPI for alternative drugs (p=0.537), while a significant decrease in change trend was detected in the post-"4+7" policy period (-0.003 per month, p=0.014). The DPI of the overall policy-related drugs significantly decreased (-0.261 per month, p<0.0001) after "4+7" policy. These findings indicate that the price behavior of pharmaceutical enterprises changed under NCDP policy, while the price linkage effect is still limited. It is necessary to further expand the scope of centralized purchased drugs and strengthen the monitoring of related drugs regarding price change and consumption structure.

The abundant mechanical vibration energy in bridge road environment can be converted into electric energy by using the piezoelectric energy harvest technology, which could be an efficient way to provide energy required by the wireless sensor network in the bridge condition monitoring system. An autonomous energy harvesting system has been designed based on cantilever beams for sensing and acquiring the bridge vibration energy. After the analysis of the dynamic properties of the piezoelectric cantilever beam in the energy conversion, three kinds of interface circuits were compared through simulation and experimental results. It was shown that the VD interface circuit has less power loss. Furthermore, the proposed closed loop control method based on the VD circuit was simple, adaptive, and self-powered, which is suitable for the road energy harvesting application. Finally, the energy harvesting system based on VD circuit was realized with harvested power of around 0.8mW.

Carcinoembriogenic antigen (CEA) is a routine marker for follow-up of colo-rectal cancers. We aimed to determine whether a CEA increase within the normal range can be linked to a recurrence risk. We included 78 consecutive patients with colo-rectal cancer, who underwent curative surgical treatment with or without chemo- or radiotherapy. As reference, we used the smallest value of the CEA during follow-up. A total of 34/78 patients (43.6%) had fluctuations of CEA of at least 1.1 ng/ml, with or without increases above 5 ng/ml. In 27/34 patients (79.4%) increases of CEA were explained either by recurrence (15/34 patients, 44.1%), adjuvant chemotherapy (7/34 patients, 20.6%) or benign pathology (5/34 patients, 14.7%). In 5 of 22 recurrences (23%) a CEA increase of at least 1.1 ng/ml, but below 5 ng/ml preceded the clinical relapse by a median of 8 months (range 3-22 months). The 4-year disease-free survival was 89% in patients with postoperative CEA <2.5 ng/ml, and 55% in patients with CEA >2.5 ng/ml. CEA increase by at least 1.1 ng/ml within the normal range, after curative treatment of colorectal cancer can be either an early sign of relapse or can be usually explained by other pathological processes.

(1) Background: AI technology has been deeply applied to online shopping platform to provide more accurate and personalized services for consumers. It is of great significance to study the different functional experience of AI for consumers to improve the current application status of AI technology.(2)Method: Based on the "S-O-R" model, this study divided the AI technology expe-rienced by the consumers of online shopping platform into accuracy, insight and interaction experience. Takes the perceived value as the mediating variable from the prospect of perceived utility value and perceived hedonic value. This article use empirical research method to analyze the effect of three dimensions of online shopping AI experience to research the internal influence mechanism of consumers purchase intention. (3) Results:① The accuracy, insight and interaction experience of AI marketing technology have a significant positive impact on consumers' per-ceived utility value and hedonic value respectively; ②Both of the perceived utility value and perceived hedonic value obtained by AI technology experience can promote the formation of consumers' purchase intention; ③ The perceived hedonic value was better than perceived utility value to promote the consumers' purchase intention; ④The results of multi group analysis show that some younger and less experiences consumers groups prefer the pleasure experience such as shopping desire stimulation, shopping process relaxation and pleasure that AI marketing brought. However, utilitarian value cannot promote this kind of consumers' purchase intention. (4) Con-clusions: Perceived utility value and perceived hedonic value can be the intermediary between AI technology and consumers' purchase intention.

Cocrystallizaiton could improve most physicochemical properties of specific active pharmaceutical ingredients, which has great potential in pharmaceutical development. In this study, the cocrystal of nitrofurantoin and 4-aminobenzoic acid was prepared with solid-state (solvent-free or green-chemistry) grinding approach, and the above cocrystal has been characterized by Raman and terahertz vibrational spectroscopic techniques. Spectral results show that the vibrational modes of the cocrystal within the whole spectral region are different from those of the corresponding parent materials. The dynamic process of such pharmaceutical cocrystal formation has also been monitored directly with Raman spectra. These results offer us unique means for characterizing the cocrystal conformation from molecule-level and also provide us rich information about the reaction dynamic of cocrystal formation within pharmaceutical fields.

Tyrosine kinase fibroblast growth factor receptor (FGFR), which is aberrant in various cancer types, is a promising target for cancer therapy. Here we reported the design, synthesis, and biological evaluation of a new series of 6-(2,6-dichloro-3,5-dimethoxyphenyl)-4-substituted-1H-indazoles derivatives as potent FGFR inhibitors. Compound 10a was first identified as a potent FGFR1 inhibitor, with good enzymatic inhibition. Further structure-based optimization revealed that compound 13a is the most potent FGFR1 inhibitor in this series with the enzyme inhibitory activity about 30.2 nM of IC50 value.

Sulfate, the main dissolved contaminant in acid mine drainage (AMD), is ubiquitous in watersheds affected by coal and metal mining operations worldwide. Engineered passive bioremediation systems (PBS) are low-cost technologies that remediate sulfate contamination by promoting (1) precipitation of sulfate-bearing compounds, such as schwertmannite and gypsum; and (2) microbially-mediated sulfate reduction (BSR) to sulfide with subsequent precipitation of sulfide minerals. In this study, chemical and sulfur isotopic data are used to infer multiple pathways for sulfate sequestration in the Tab-Simco PBS. By simultaneously monitoring sulfate concentrations and δ34SSO4 values at four sampling points across the PBS, we (1) identified that the organic layer within the bioreactor was the primary site of BSR processes contributing to sulfate sequestration; (2) observed seasonal variations of BSR processes; (3) estimated that initially the BSR processes contributed up to 30% to sulfate sequestration in the Tab-Simco bioreactor; and (4) determined that BSR contribution to sulfate sequestration continuously declined over the PBS operational lifetime. Together, our results highlight the utility of combining geochemical and microbial fingerprinting techniques to decipher complementary processes involved in sulfur cycling in a PBS as well as the value of adding the sulfur isotope approach as an essential tool to help understand, predict, prevent and mitigate sulfate contamination in AMD-impacted systems.

Curcumin, a hydrophobic polyphenol compound derived from the rhizome of the Curcuma genus, has a wide spectrum of biological and pharmacological applications. Previously, curcumin nanoparticles with different stabilizers had been produced successfully in order to enhance solubility and per oral absorption. In the present study, we tested the anti-inflammatory effect of D-α-Tocopheryl polyethylene glycol 1000 succinate (TPGS)-stabilized curcumin nanoparticles in vivo. Lambda-carrageenan (λ-carrageenan) was used to induce inflammation in rats; it was given by an intraplantar route and intrapelurally through surgery in the pleurisy test. In the λ-carrageenan-induced edema model, TPGS-stabilized curcumin nanoparticles were given orally one hour before induction and at 0.5, 4.5, and 8.5 h after induction with two different doses (1.8 and 0.9 mg/kg body weight (BW)). Sodium diclofenac with a dose of 4.5 mg/kg BW was used as a standard drug. A physical mixture of curcumin-TPGS was also used as a comparison with a higher dose of 60 mg/kg BW. The anti-inflammatory effect was assessed on the edema in the carrageenan-induced paw edema model and by the volume of exudate as well as the number of leukocytes reduced in the pleurisy test. TPGS-stabilized curcumin nanoparticles with lower doses showed better anti-inflammatory effects, indicating the greater absorption capability through the gastrointestinal tract.

IL1RA intron 2 86-bp repeat and IL4 intron 3 70-bp repeat are VNTRs that have been associated with various diseases, but their role in obesity is elusive. The objective of this study was to investigate the association of IL1RA and IL4 VNTRs with obesity and adiposity in 315 Malaysian subjects (128 M/187 F; 23 Malays/251 ethnic Chinese/41 ethnic Indians). The allelic distributions of IL1RA and IL4 were significantly different among ethnicities, and the alleles were associated with total body fat (TBF) classes. Individuals with IL1RA I/II genotype or allele II had greater risk of having higher adiposity - even after controlling for ethnicity [Odds Ratio (OR) of I/II genotype = 12.21 (CI = 2.54, 58.79; p = 0.002); II allele = 5.78 (CI = 1.73, 19.29; p = 0.004)]. However, IL4 VNTR B2 allele was only significantly associated with overall adiposity status before adjusting for ethnicity [OR = 1.53 (CI = 1.04, 2.23; p = 0.03)]. TBF was also significantly higher in those with IL1RA II allele compared with I allele (31.79 ± 2.52 vs. 23.51 ± 0.40; p = 0.005). Taken together, IL1RA intron 3 VNTR seems to be a genetic marker for overall adiposity status in Malaysian subjects.

The Koka gold deposit is located in the Elababu shear zone between the Nakfa terrane and the Adobha Abiy terrane, NW Eritrea. Based on the paragenetic study two main stages of gold mineralization were identified in the Koka gold deposit: 1) an early stage of pyrite-chalcopyrite-sphalerite-galena-gold-quartz vein; and 2) a second stage of pyrite-quartz veins. NaCl-aqueous inclusions, CO2-rich inclusions, and three-phase CO₂-H₂O inclusions occur in the quartz veins at Koka. The ore-bearing quartz veins formed at 268℃, from NaCl-CO₂-H₂O(-CH₄) fluids averaging 5 wt% NaCl eq. The ore-forming mechanisms include fluid immiscibility during stage I, and mixing with meteoric water during stage II. Oxygen, hydrogen and carbon isotopes suggest that the ore-forming fluids originated as mixtures of metamorphic water, meteoric water and magmatic water, whereas sulfur isotope suggest an igneous origin. Features of geology and ore-forming fluid at Koka deposit are similar to those of orogenic gold deposits, suggesting the Koka deposit might be an orogenic gold deposit related to granite.

The activity and cyclability of Cu-MOF-74 as catalyst was studied for the ligand-free C-O cross-coupling reaction of 4-nitrobenzaldehyde (NB) with phenol (Ph) to form 4-formyldiphenyl ether (FDE). Cu-MOF-74 is characterized by unsaturated copper sites in a highly porous metal-organic framework. The influence of solvent, reaction temperature, NB/Ph ratio, catalyst concentration and basic agent (type and concentration) were evaluated. High conversions were achieved at 120°C, 5 mol% of catalyst, NB/Ph ratio of 1:2, DMF as solvent and 1 equivalent of K2CO3 base. The activity of Cu-MOF-74 material was higher than other ligand-free copper catalytic systems tested in this study. This catalyst was easily separated and reused in five successive runs, achieving a remarkable performance without significant porous framework degradation. The leaching of copper species in the reaction medium was negligible. The O-arylation between NB and Ph took place only in the presence of Cu-MOF-74 material, being negligible without the solid catalyst.

A series of novel N-n-butyl-1,8-naphthalimide derivatives were synthesized via a three-step reaction involving nucleophilic substitution and acylation. All of the compounds were characterized by IR, ¹H NMR, ¹³C NMR, MS, and elemental analysis, and the crystal structure of N-n-butyl-4-[N’,N’-bis(2`,4`-dichlorobenzoyl)ethylamino]-1,8-naphthalimide was determined. The π-π stacking interactions and hydrogen bonds between the two molecular core planes (naphthalimide ring) and the van der Waals forces between the flexible n-butyl groups resulted in a 3D long-chain structure. The UV-vis and fluorescence properties of the title compounds were investigated. The results indicated that the monosubstituted 1,8-naphthalimide derivatives bearing an electron-donating group on the benzene ring or a structure with a larger conjugative effect exhibited enhanced fluorescence properties.

Transition-metal-free synthesis of 4-pyrones via TfOH-promoted nucleophilic addition/cyclization of diynones and water has been developed. This transformation is simple, atom economical and environmentally benign, providing rapid and efficient access to substituted 4-pyrones.

Renal cell carcinoma (RCC) is the most common kidney cancer, accounting for approximately 80–90 % of all primary kidney cancer. Treatment for patients with advanced RCC remains unsatisfactory. Rare cancer stem cells (CSCs) are proposed to be responsible for failure of current treatment. Here, we investigate the effects of CBFA2T2 on CSCs regulation in RCC, as well as to elucidate the possible mechanisms. We showed that CBFA2T2 expression can significantly predict the survival of RCC patients. Functional assays showed that knocking-down of CBFA2T2 can inhibit cell migration and invasion in 786-O and A-498 cells in vitro, and reduce ALDH^high CSCs populations. Furthermore, CBFA2T2 expression is necessary for sphere-forming ability and cancer stem cells marker expression in RCC cell lines. Collectively, our data suggest that CBFA2T2 expression correlates with aggressive characteristics of RCC and CBFA2T2 is required for maintenance of “stemness” through regulation of stem cells factors, thereby highlighting CBFA2T2 as a potential therapeutic target for RCC treatment.

Diisocyanates, particularly toluene diisocyanate (TDI) are useful for the preparation of various polyurethanes with specific applications as leather-like materials, adhesives, insoles etc. Blocking agents can be used for the operational simplicity and reducing the hazards of TDI. In this paper we reported the use of 3-(4-bromo-phenyl)-1H-pyrazole to block toluene diisocyanate (TDI). FTIR, NMR, thermogravimetric analysis, contact angle and differential scanning calorimetry (DSC) and were used for characterization. Effectiveness of blocking was confirmed by spectroscopic techniques. DSC thermogram shows that blocked adducts deblock at 240 °C causing the regeneration of TDI and blocking agents to react with polyols of different molecular weights forming polyurethanes. The characterization of polyurethanes has been done by Infrared spectroscopy, Nuclear magnetic resonance spectroscopy, thermogravimetric analysis, differential scanning calorimetry and contact angle study.

Distribution systems can form islands when faults occur. Each island represents a subsection with variable boundaries subject to the location of a fault(s) in the system. A subsection with variable boundaries is referred to as island in this paper. For operation in autonomous mode, it is imperative to detect the island configurations and stabilize these subsections. This paper presents a novel scheme for the detection of islanding boundaries and stabilizing the system during autonomous operation. In the first stage, a boundary detection method is proposed to detect the configuration of the island. In the second stage a dynamic voltage sensitivity factor (DVSF) is proposed to assess the dynamic performance of the system. In the third stage, a wide area load shedding program is adopted based on DVSF to shed the load in weak busbars and stabilize the system. The proposed scheme is validated and tested on a generic 18-bus system using a combination of EMTDC/PSCAD and MATLAB softwares.

Infection with Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2) causes Coronavirus Disease 2019 (COVID-19), which has reached pandemic proportions. A number of effective vaccines have been produced, including mRNA vaccines and viral vector vaccines, which are now being implemented on a large scale in order to control the pandemic. The mRNA vaccines are composed of the Spike S1 protein encoding mRNA, incorporated in a lipid nanoparticle, stabilized by polyethylene glycol (PEG). mRNA vaccines are novel in many respects, including cellular uptake, the intracellular routing, processing, and secretion of the viral protein. Viral vector vaccines have incorporated DNA sequences encoding the SARS-CoV-2 Spike S1 protein into (attenuated) adenoviruses. The antigen presentation routes in MHC class I and class II, in relation to induction of virus neutralizing antibodies and cytotoxic T-lymphocytes will be reviewed. In rare cases, mRNA vaccines induce unwanted immune mediated side effects. mRNA based vaccines may lead to an anaphylactic reaction. This reaction may be triggered by PEG. The intracellular routing of PEG, and potential presentation in the context of CD1 will be discussed. Adenovirus vector based vaccines have been associated with thrombocytopenic thrombosis events. The anti-platelet factor 4 antibodies found in these patients could be generated due to conformational changes of relevant epitopes presented to the immune system.

Heparins, Unfractionated or Low Molecular Weight, are permanently at the spotlight of both clinical indications and laboratory monitoring. An accurate drug dosage is necessary for an effi-cient and safe therapy. The one-stage anti-FXa kinetics’ assays are the most widely and universally used with full automation for large series, without needing exogenous Antithrombin. WHO in-ternational standards are available for UFH and LMWH, but external quality assessment surveys still report a high inter-assay variability. This heterogeneity results from: assay formulation, designed without or with dextran sulfate to measure all heparin in blood circulation; calibrators for testing UFH or LMWH with the same curve; and automation parameters. The various factors which impact heparin measurements are reviewed, and we share our experience to optimize assays for completely testing plasma heparin. Evidence is provided on the usefulness of low molecular weight dextran sulfate to mobilize all drug present in blood circulation. Other key factors concern adjustment of assay conditions to obtain fully superimposable calibration curves for UFH and LMWH, and automation parameters. The study is illustrated by the performances of the various anti-FXa assays used for testing heparin on UFH or LMWH treated patients’ plasmas and obtained using citrate or CTAD anticoagulants. Comparable results are obtained only when CTAD anti-coagulant is used. Using citrate UFH is underestimated in the absence of dextran sulfate. Heparin calibrators, adjustment of automation parameters and data treatment contribute to other smaller differences.

The oxidative stress is one of the main cause for cardiovascular diseases (like Hypertension) also one of the results of these diseases. This study involved 56 subjects matched ages and sex divided into two groups; 28 hypertensive subject and 28 healthy subject as control group. The following analysis was done: 4-Hydroxy-2-nonenal(4HNE) and albumin. The results show that there is a significant increase in (4HNE) between patients group and control group. The increase in 4HNE which is a product of lipid peroxidation is attributed to destruction in body cell caused by due to the increase in stress events. It has been concluded that is important nappy on ideal weight, because obesity considered main factors for heart disease and hardening of the arteries. The aim of this study was to investigate the relationship between of some oxidative stress markers and cardiovascular diseases.

Drug functionalization through formation of hydrophilic groups is the norm in phase I metabolism of drugs for modification of drug action. The reactions involved are mainly oxidative catalyzed mostly by CYP isoenzymes. The benzene ring, as phenyl or fused with other rings, is the most common hydrophobic pharmacophoric moiety in drug molecules. On the other hand the alkoxy group (mainly methoxy) bonded to the benzene ring assumes an important and sometimes essential pharmacophoric status in some drug classes. Upon metabolic oxidation, both moieties, i.e. the benzene ring and the alkoxy group, produce hydroxy groups; the products are arenolic in nature. Through a pharmacokinetic effect, the hydroxy group enhances the water solubility and elimination of the metabolite with the consequent termination of drug action. However, through hydrogen bonding, the hydroxy group may modify the pharmacodynamics of the interaction of the metabolite with the site of parent drug action (i.e. the receptor). Accordingly, the expected pharmacologic outcome will be enhancement, retaining, attenuation, or loss of activity of the metabolite relative to the parent drug. All the above issues have been presented and discussed in this review using selected members of different classes of drugs with inferences regarding mechanisms, drug design and drug development.

Observation of the ambient aerosol surface area concentrations is important to understand the aerosol toxicity because an increased surface area may be able to act as an enhanced reaction interface for certain reactions between aerosol particles and biological cells, as well as an augmented carrier surface for co-pollutants. In this study, the concentration of aerosol surface area was measured from April 2015 to March 2016 in Fukuoka, Japan. We investigated the monthly and diurnal variations in the correlations between the aerosol surface area and black carbon (BC) and sulfate concentrations. Throughout the year, aerosol surface area concentration was strongly correlated with the concentrations of BC, which has relatively large surface area since BC particles are usually submicron agglomerates consisting of much smaller (tens of nanometers) sized primary soot particles. The slopes of the regression between the aerosol surface area and BC concentrations was highest in August and September 2015. This appears to have been the results of an increase in the proportion of the airmass that originated on the main islands of Japan. This may enhance the introduction of the BC from the main islands of Japan that is relatively fresh (or “uncoated”), thereby maintaining its larger surface area.

The aim of this study was to examine oxidative stress and low level of alpha-1-antitrypsin (A1AT) in primary Sjögren's syndrome (pSS), and evaluate the associated autoreactivity against unmodified and their 4-hydroxy-2-nonenal (HNE)-modified peptides with pSS. Two differentially expressed proteins, alpha-1-acid glycoprotein 1 (A1AG1) and A1AT, exhibited 2-fold differences, and their HNE modifications were identified by depleted-albumin and immunoglobulin G (IgG) serum protein, in-solution digestion, in-gel digestion, and nano-LC-MS/MS from pSS patients and age-matched healthy controls (HCs). Furthermore, levels of proteins, confirmation of HNE modifications, HNE-protein adducts and autoreactivity against unmodified and their HNE-modified peptides were further validated. Levels of the HNE-protein adduct and A1AG1 were significantly higher in pSS patients than HCs, but levels of A1AT were significantly lower in pSS patients compared to HCs. Only the HNE modification of A1AT was confirmed. Further, concentrations of anti-A1AT^50-63 IgG and anti-A1AT^50-63 HNE IgA were significantly lower in pSS patients than HCs. Our study suggests that elevated HNE-protein adduct, oxidative stress, level [odds ratio (OR) 4.877, p = 0.003], lowered A1AT level (OR 3.910, p = 0.010) and a decreased level of anti-A1AT^50-63 IgG (OR 3.360, p = 0.010) showed an increased risk in pSS patients compared to HCs, respectively.

The turnover of the RNA molecules is determined by the rates of transcription and RNA degradation. Several methods have been developed to study mRNA turnover since the beginnings of molecular biology. Here we summarize the main methods to measure RNA half-life: transcription inhibition, gene control and metabolic labelling. These methods were used to detect the cellular activity of the mRNAs degradation machinery, including the exo-ribonuclease Xrn1 and the exosome. Less progress has been made in the study of the differential stability of mature RNAs because the different methods have often yielded inconsistent results so that an mRNA considered to be stable can be classified as unstable by another method. Recent advances in the systematic comparison of different method variants in yeast have permitted the identification of the least invasive methodologies that reflect half-lives the most faithfully, which is expected to open the way for a consistent quantitative analysis of the determinants of mRNA stability.

Although RNA modifications were discovered decades ago, the identification of enzymes that write, read, and erase RNA modifications enabled their functional study and spawned the field of epitranscriptomics. Coupling that knowledge to new methods has enabled the precise pinpointing of epitranscriptomic modifications across the transcriptome plus the elucidation of their functional consequences. PCIF1 (Phosphorylated CTD Interacting Factor 1) was shown to add N6, 2’-O-dimethyladenosine (m⁶Am) marks at the first nucleotide after the 5’ N7-methylguanosine (m⁷G) cap. In this review, we discuss the epitranscriptomic regulation of mRNA in general, and focus on m⁷G cap-adjacent m⁶Am in particular. m⁶Am positions can now be distinguished from N6-methyladenosine (m⁶A) using new techniques leveraging PCIF1-knockout cells. Although m⁶Am modification sites can be detected precisely, conflicting data have been published regarding how cap-adjacent m⁶Am marks affect their host mRNA. Discrepancies in the data mean that the effects of cap-adjacent m⁶Am on mRNA stability, decapping, and translation continue to be debated. Finally, while PCIF1 is predominantly nuclear, a subset of results suggest a possible cytoplasmic role as well. Taken together, these contradictory results which employed different methodologies and cell lines means that further experiments are required to determine the ultimate biological function(s) of m⁷G cap-adjacent m⁶Am.

The peroxiredoxin (PRDX) family, a new family of proteins with a pivotal antioxidative function, is ubiquitously synthesized and abundantly identified in various organisms. In contrast to the intracellular localization of other family members (PRDX1/2/3/5/6), PRDX4 is the only known secretory form and protects against oxidative damage by scavenging reactive oxygen species in both the intracellular (especially the endoplasmic reticulum) compartments and the extracellular space. Recently, we generated unique human PRDX4 (hPRDX4) transgenic (Tg) mice on a C57BL/6J background and investigated the critical and diverse protective roles of PRDX4 against diabetes mellitus, atherosclerosis, insulin resistance, and nonalcoholic fatty liver disease (NAFLD) as well as evaluated its role in the intestinal function in various animal models. Our published data have shown that PRDX4 helps prevent the progression of metabolic syndrome by reducing local and systemic oxidative stress and synergistically suppressing steatosis, inflammatory reactions, and/or apoptotic activity. These observations suggest that Tg mice may be a useful animal model for studying the relevance of oxidative stress on inflammation and the dysregulation of lipid/bile acid/glucose metabolism upon the progression of human metabolic syndrome, and that specific accelerators of PRDX4 may be useful as therapeutic agents for ameliorating various chronic inflammatory diseases.

Nine 2-(1,2-benzothiazol-3-yl)-N-(4-oxo-2-phenyl-1,3-thiazolidin-3-yl) propanamides were designed and synthesized, combining benzisothiazole and 4-thiazolidinone in one frame. The aim of the study was to verify their effectiveness to contrast the inflammatory/oxidative process in which free oxygen and nitrite (ROS and RNS) radicals, advanced glycation products (AGEs), inflammatory cytokines and matrix metalloproteinases (MMPs) are involved. Docking studies of all the compounds were performed in order to explore their binding mode at the MMP-9 protein. An appreciable anti-inflammatory/wound healing effects of the tested compounds was highlighted. Derivative 23, bearing a 4-carboxyphenyl substituent at C2 of the 4-thiazolidinone ring, exhibited the highest activity, being able to inhibit MMP-9 at nanomolar level (IC₅₀ = 40 nM).

Liver related diseases are the 3rd leading causes (9.3%) of mortality in type 2 diabetes mellitus (T2DM) in Japan. T2DM is closely associated with nonalcoholic fatty liver disease (NAFLD) which is the most prevalent chronic liver disease worldwide. Nonalcoholic steatohepatitis (NASH), a severe form of NAFLD, can lead to hepatocellular carcinoma (HCC) and hepatic failure. There are no established pharmacotherapies for NASH patients with T2DM. Though vitamin E is established as a 1st line agent in NASH without T2DM, its efficacy was recently denied in NASH with T2DM. The effects of pioglitazone on NASH histology with T2DM have extensively been established, but several concerns exist such as body weight gain, fluid retention, cancer incidence, and bone fracture. Glucagon-like peptide 1 (GLP-1) receptor agonists and sodium/glucose cotransporter 2 (SGLT2) inhibitors are expected to ameliorate NASH　(LEAN study, LEAD trial, and E-LIFT study). Among a variety of SGLT2 inhibitors, dapagliflozin have already entered phase 3 trials (DEAN study). A key clinical question is what kinds of anti-diabetic drugs are the most appropriate for the treatment of NASH to prevent progression of hepatic fibrosis resulting in HCC/liver-related mortality without increasing risk at cardiovascular or renal events. The combination therapies such as glucagon receptor agonist/GLP-1 or gastrointestinal peptide /GLP-1 will be under development. This review focuses on antidiabetic agents and future perspectives on the view of the treatment of NAFLD with T2DM.

Zircon xenocrysts from alkali basalts in Ratanakiri Province, Cambodia, represent a unique low-Hf zircon, within a 12,000 km long Indo-Pacific megacryst zone. Colourless, yellow, brown and red crystals ({100}, {101}, subordinate {211}, {1103}), with hopper growth and corrosion features, range up to 20 cm in size. Zircon chemistry implicates juvenile, Zr-saturated, mantle-derived alkaline melt (Hf 0.6–0.7 wt%, Y <0.2 wt%, U+Th+REE <600 ppm, Zr/Hf 66–92, Eu/Eu*_N ~ 1, positive Ce/Ce*_N, HREE enrichment). Incompatible element depletion with increasing Yb/Sm_N from core to rim at ~ constant Hf suggests single stage growth. Ti-in-zircon temperatures (~570–740 °C) are lower than predicted by crystal morphology (800–900 °C) and decrease from core to rim (D_T = 10–50 °C). The d¹⁸O values (4.88 to 5.01‰ VSMOW) are relatively low for xenocrysts from the zircon Indo-Pacific zone (ZIP). The ¹⁷⁶Hf/¹⁷⁷Hf values (+ εHf 4.5–10.2) give T_{Depleted Mantle} model source ages of 260–462 Ma and T_Crustal ages of 391–754 Ma. The source magmas reflect variably depleted lithospheric mantle with little supracrustal input. Zircon U-Pb (0.88–1.56 Ma) and (U-Th)/He (0.86–1.02 Ma) ages are older than host basalt ages (~0.7 Ma), suggesting limited residence before transport. Zircon genesis suggests Zr-saturated, Al-undersaturated, carbonatitic-influenced, low-degree partial melting (<1%) of peridotitic mantle at ~60 km beneath the Indochina terrane.

We synthesized a small series of five 3-[4-arylmethoxy)phenyl]propanoic acids using an easy and short step synthetic route. All compounds were tested in vitro against a set of four protein targets identified as key elements in diabetes: GPR40, aldose reductase (AKR1B1), PPARγ and GLUT-4. Compound 1 displayed an EC₅₀ value of 0.075 μM against GPR40 and was an AKR1B1 inhibitor, showing IC₅₀ = 7.4 μM. Compounds 2 and 3 behave as AKR1B1 inhibitors, GPR40 agonists and showed an increase of 2 to 4-times in the mRNA expression of PPARγ, as well as the GLUT-4 levels. Docking studies were conducted in order to explain the polypharmacological mode of action and the interaction binding mode of the most active compounds on these targets. Compounds 1-3 were tested in vivo at 100 mg/kg dose, being 2 and 3 orally actives, reducing glucose levels in a non insulin-dependent diabetes mellitus mice model. Compounds 2 and 3 showed robust in vitro and in vivo efficacy, and could be considered as promising multitarget antidiabetic drug candidates. This is the first report of a single molecule with these four polypharmacological target action.

A series of Si-bearing MgAl₂O₄-spinels were synthesized at 1500-1650 °C and 3–6 GPa. These spinels had SiO₂ contents up to ~1.03 wt%, and showed a substitution mechanism of Si⁴⁺ + Mg²⁺ = 2Al³⁺. Unpolarized Raman spectra were collected from polished single grains, and displayed a set of well-defined Raman peaks at ~610, 823, 856 and 968 cm^-1 which had not been observed before. Aided with the Raman features of natural Si-free MgAl₂O₄-spinel, synthetic Si-free MgAl₂O₄-spinel, natural low quartz, synthetic coesite, synthetic stishovite and synthetic forsterite, we infer that these Raman peaks should belong to the SiO₄ groups. The relations between the Raman intensities and SiO₂ contents of the Si-bearing MgAl₂O₄-spinels suggest that at some P-T conditions some Si must adopt the M-site. Unlike the SiO₄ groups with very intense Raman signals, the SiO₆ groups are largely Raman-inactive. We have further found that the Si cations primarily appear on the T-site at P-T conditions ≤ ~3–4 GPa and 1500 °C, but attain a random distribution between the T-site and M-site at P-T conditions ≥ ~5–6 GPa and 1630–1650 °C. This Si-disordering process observed for the Si-bearing MgAl₂O₄-spinels hints that similar Si-disordering might happen to the (Mg,Fe)₂SiO₄-spinels (ringwoodite), the major phase in the lower part of the mantle transition zone of the Earth and the index mineral for the very strong shock stage experienced by extraterrestrial materials. The likely consequences have been explored.

Large population passages of the SARS-CoV-2 in the past two and a half years have allowed the circulating virus to accumulate an increasing number of mutations in its genome. The most recently emerging Omicron subvariants have the highest number of mutations in the Spike (S) protein gene and these mutations mainly occur in the receptor-binding domain (RBD) and the N-terminal domain (NTD) of the S gene. The eCDC and the WHO recommend partial Sanger sequencing of the SARS-CoV-2 S gene RBD and NTD on the PCR-positive samples in diagnostic laboratories as a practical means of determining the variants of concern to monitor a possible increased transmissibility, increased virulence, or reduced effectiveness of vaccines against them. The author’s diagnostic laboratory has implemented the eCDC/WHO recommendation by sequencing a 398-base segment of the N gene for the definitive detection of SARS-CoV-2 in clinical samples, and sequencing a 445-base segment of the RBD and a 490-509-base segment of the NTD for variant determination. This paper presents 5 selective cases to illustrate the challenges of using Sanger sequencing to diagnose Omicron subvariant when the samples harbor a high level of co-existing minor subvariant sequences with multi-allelic single nucleotide polymorphisms (SNPs) or possible recombinant Omicron subvariants containing a BA.1 NTD and a BA.2 RBD, which can only be detected by using specially designed PCR primers. The current large-scale surveillance programs using next-generation sequencing (NGS) do not face similar problems because NGS focuses on deriving consensus sequence.

We consider rotational hypersurface in the four dimensional Euclidean space. We calculate the mean curvature and the Gaussian curvature, and some relations of the rotational hypersurface. Moreover, we define the third Laplace-Beltrami operator and apply it to the rotational hypersurface.

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

Herein, two title compounds, N-Benzoyl-N’-4-cyanophenyl thiourea (I) and N-(4-nitrobenzoyl)-N’-4-cyanophenyl thiourea (II) were synthesized in high yield, via aroyl isocyanate and 4-aminobenzonitrile. The structure of the prepared compounds was characterized by elementary analysis and FT-IR, ¹H, ¹³C NMR spectroscopic methods. Cyclic voltammetric (CV) experiments were performed with glassy carbon electrode. The reduction potential values of different functional group such as nitro, cyano in title compounds were investigated using CV curves.

The novel coronavirus COVID- 19 disease is extremely contagious and has been spread worldwide. First COVID-19 case was identified in December, 2019 and within three months, more than one million affected cases and over 65,000 deaths have been reported. SARS-coronavirus 2 (SARS-CoV-2) also known as 2019-nCoV is a causative agent of COVID-19 disease and belongs to the SARS CoV (Severe Acute Respiratory Syndrome corona virus) family. The SARS-CoV-2 enters the human body by binding its viral surface spike protein with the host angiotensin-converting enzyme 2 (ACE2) receptors and cause infection. To prevent the virus entry and its transmission in the human body, we focused on the two domains of ACE2: i) the N-terminal extracellular binding domain (18-740 residues) reported for coronavirus spike interaction, and ii) the C-terminal cytoplasmic region (762-805 residues) to prevent the virus transmission. Therefore, we proposed: i) inhibition of receptor binding domain (RBD) of SARS-CoV-2 and human ACE2 protein may prevent the virus entry to the host and ii) inhibition of phosphorylation at Ser-787 of ACE2 protein may prevent the transmission of the virus in the COVID-19 patients. In the past, the critical role of Ser 787 in human ACE2 protein has been experimentally verified in SARS-CoV transmission, that upon binding to the receptor, SARS- CoV induces CKII- mediated phosphorylation of ACE2 at Ser-787 that in-turn facilitate virus entry to host cells, followed by replication and activation of ACE2, initiates downstream signaling leading to lung fibrosis. Therefore, in this study, we have suggested post-translational modification (PTM) O-β-GlcNAcylation, and two compounds Chloroquine and 2-hydroxybenzohydrazine might share the common pathways to prevent the COVID-19 infection in human. The addition of O-β-GlcNAcylation at same or neighboring Ser/ Thr residues results in phosphorylation inhibition and a change in protein structural and functional confirmations. Thereby, using neural networking methods, we have identified Ser/ Thr residues in ACE2 that are potential sites for phosphorylation and / or O-β-GlcNAcylation. Molecular docking showed that UDP-GlcNAc has more binding affinity with Ser-787 than the phosphoryl group. Moreover, chloroquine and 2-hydroxybenzohydrazine also showed great potential to bind at Ser-787 that may result in inhibition of Ser-787 phosphorylation and downstream signaling. Furthermore, O-β-GlcNAcylation, chloroquine and 2-hydroxybenzohydrazine showed their high affinity at ACE2-SARS-CoV-2receptor binding domain that may prevent the entry of SARS-CoV-2 into human body. In conclusion, inhibition of human ACE2 phosphorylation at Ser-787 and ACE2-SARS-CoV-2 binding domain could be promising targets against SARS-CoV-2 infection.

Synthesis of poly(o-phenylenediamine) (PoPD) and poly(o-phenylenediamine)-ZnO (PoPD-ZnO) nanocomposites on carbon steel by in-situ polymerization with HCl acid as doping acid Material coating. The composition and structure of PoPD-ZnO nanocomposites were characterized by Fourier transform infrared spectroscopy (FTIR), X-ray diffraction (XRD) and scanning electron microscopy (SEM). The corrosion protection ability of polymer coatings in 3.5% NaCl was studied by potentiodynamic polarization curves and electrochemical impedance spectroscopy. It can be seen from the electrochemical corrosion experimental data that PoPD-WPU coating (PWC) and PoPD-ZnO-WPU coating (PZWC) can effectively improve the corrosion resistance of the carbon steel substrate, and the corrosion rate is reduced by 2-3 orders of magnitude compared with carbon steel. The conclusion demontrates that PoPD can effectively extend the service life of carbon steel substrates. In addition, it is advantageous to form a compact and low-defect coating when added nano-particle ZnO, which is advantageous for the POPD film to develop its good barrier property and corrosion resistance.

Background: Extremely rare progressive diseases like Sedaghatian-type Spondylometaphyseal Dysplasia (SSMD) can be neonatally lethal and therefore go undiagnosed or are difficult to treat. Recent sequencing efforts have linked this disease to mutations in GPX4, with consequences in the resulting enzyme, glutathione peroxidase 4. This offers potential diagnostic and therapeutic avenues for those suffering from this disease, though the steps toward these treatments is often convoluted, expensive, and time-consuming. Main body: The CureGPX4 organization was developed to promote awareness of GPX4-related diseases like SSMD, as well as support research that could lead to essential therapeutics for patients. We provide an overview of the 21 published SSMD cases and have compiled additional sequencing data for four previously unpublished individuals to illustrate the genetic component of SSMD, and the role of sequencing data in diagnosis. We outline in detail the steps CureGPX4 has taken to reach milestones of team creation, disease understanding, drug repurposing, and design of future studies. Conclusion: The primary aim of this review is to provide a roadmap for therapy development for rare, ultra-rare, and difficult to diagnose diseases, as well as increase awareness of the genetic component of SSMD. This work will offer a better understanding of GPx4-related diseases, and help guide researchers, clinicians, and patients interested in other rare diseases find a path towards treatments.

Cutaneous leishmaniasis (CL) is a neglected tropical disease, which causes severe skin lesions. Due to the lack of effective vaccines, and toxicity or reduced effectiveness of available drugs in addition to complex and prolonged treatments, there is an urgent need to develop alternatives for the treatment for CL with different mechanisms of action. In our effort to search for new promising hits against Leishmania parasites we prepared 18 acyl hydrazone derivatives of thiochroman-4-ones. Compounds were evaluated for their in vitro antileishmanial activity against the intracellular amastigote form of Leishmania panamensis and cytotoxic activity against human monocytes (U-937 ATCC CRL-1593.2). Our results show that derivatization of the thiochroman-4-ones with acyl hydrazones significantly enhances the antileishmanial activity. Among the compounds tested semicarbazone and thiosemicarbazone derivatives of thioflavanone 19 and 20 displayed the highest antileishmanial activities, with EC₅₀ values of 5.4 and 5.1 µM and low cytotoxicities (100.2 and 50.1 µM respectively), resulting in higher indexes of selectivity (IS).

A study has been carried out on Ta and Nb recovery by liquid-liquid extraction process using 4-methylacetophenone (4-MAcPh) as organic phase. The 4-MAcPh was compared to methylisobutylketone (MIBK) with respect to extraction efficiencies (kD values) at different concentrations of H2SO4 in the aqueous phase. The results showed a similar extraction of Nb for both solvents. However, for Ta extraction efficiency is increased by a factor of 1.3 for 4-MAcPh. In addition, the MIBK solubilized completely after 6 mol L-1 of H2SO4 against only a loss of 0.14 to 4% for 4-MAcPh between 6 and 9 mol L-1 of H2SO4. The potential of 4-MAcPh has also been studied to selectively recover Ta from a model capacitor waste solution. The results showed a selectivity for Ta in the presence of impurities such as Fe, Ni, Mn. The 4-MAcPh also presents the advantage of having physicochemical properties adapted to its use in liquid-liquid extraction technologies such as mixer-settlers.

Nanotechnology is an emerging field of modern science based on the use of nanoparticles (NPs) with a huge potential in many sectors, including nanomedicine. Their small size confers them unique properties because they are subject to physical laws that are in the middle between classical and quantum physics. In this context, NPs project plays a pivotal role because the composition, size, shape and surface proprieties need to be carefully considered for their optimal design and application. As reported in this review, NPs are classified in inorganic (metallic NPs; quantum dots; carbon-based nanostructures; mesoporous silica nanoparticles) and organic (liposomes and micelles, dendrimers and polymer nanoparticles) ones. Here, we report an accurate description of the potential of each NPs type focusing on their multiple areas of application like theranostics drug delivery, imaging, tissue engineering, antimicrobial techniques and nanovaccines, and therefore they represent a promise to revolutionize the new era of nanomedicine, especially in cancer research.

The rapid emergence and worldwide detection of the SARS-CoV-2 omicron variant underscore the importance of robust genomic surveillance systems and prompt information sharing among global public health partners. The Omicron variant has rapidly replaced the delta variant as a dominating SARS-CoV-2 variant because of natural selection, favoring the variant with higher infectivity and more strong vaccine breakthrough ability. Also known as B.1.1.529, Omicron has four sub-variants, BA.1, BA.2, BA.3, and BA.4. Among them, BA.1 is the currently prevailing sub-variant, BA.2 is found to be able to alarmingly re-infect patients initially infected by omicron BA.1. BA.3 sub-variants is a combination of mutations of BA.1 and BA.2, especially in the spike protein. Today emerging is the BA.4, herein described and first detected in Italy, harboring a new mutation, specifically a deletion in the ORF 1 ab gene, corresponding to KSF141_del in non-structural protein 1 (nsp1), a critical virulence factor able to suppress host translation. The bioinformatics comparison analysis with the other three sub-variants pointed out that the deletion was not present previously and was never reported until now. Therefore, we can speculate that omicron BA.4; will become a new dominating “variant of concern” and might also break vaccine protection . On the other hand, we show that other proteins are mutated in the BA.4 in particular, seven mutations are recognized in the nucleocapsid (N) protein, the capability of five different types of rapid antigenic tests to recognize it.

Oenothera flower petals change color during senescence. When in full bloom, the flowers of O. tetraptera are white and those of O. laciniata and O. stricta are yellow; however, the colors change to pink and orange, respectively, when the petals fade. We analyzed the flavonoid components in these petals as a function of senescence using HPLC-DAD and LC-MS. In all three species, cyanidin 3-glucoside (Cy3G) was found in faded petals, and the content of Cy3G increased in senescence. In full bloom (0 h), no Cy3G was detected in any of the petals, but after 12 h, the content of Cy3G in O. tetraptera was 0.97 μmol/gFW and that in O. laciniata was 1.82 μmol/gFW. Together with anthocyanins, major flavonoid components in petals were identified. Quercitrin was detected in the petals of O. tetraptera, and isosalipurposide was found in the petals of O. laciniata and O. stricta. The content of quercitrin did not change during senescence, but that of isosalipurposide in O. laciniata increased from 3.4 μmol/gFW at 0 h to 4.8 μmol/gFW at 12 h. The color change in all the three Oenothera flowers was confirmed to be due to the de novo biosynthesis of Cy3G.

Beer is a fermented beverage with a history as old as human civilization and its productive process has been spread all around the world becoming unique in every country and iconic of entire populations. Ales and lagers are by far the most common beers; however, the combination of raw materials, manufacture techniques and aroma profiles are almost infinite, so it is not surprising to notice that there is a large amount of different beer styles, each of them with unique characteristics. Nowadays, diversification is becoming increasingly important in the brewing market and the brewers are continuously interested in improving and extending the already wide range of products, especially in craft brewery. One of the major components that can have a deep impact on the final product is yeast, since it is able to convert carbohydrates in wort, especially maltose and maltotriose, into ethanol, carbon dioxide and other minor aroma-active compounds. Saccharomyces cerevisiae (top‐fermenting yeasts used to produce ales) and Saccharomyces pastorianus (cryotolerant bottom‐fermenting hybrids between S. cerevisiae and Saccharomyces eubayanus responsible for the fermentation of lagers) are most used in breweries. However, an increasing number of different yeast starter cultures are commercially available, to improve the production efficiency also at relative low temperatures and to obtain desirable and diversified aroma profiles avoiding undesired compounds. Four main genetic engineering-free trends are becoming popular in craft brewing yeast development: 1) the research for novel reservoirs as source of new performant S. cerevisiae yeasts; 2) the creation of synthetic hybrids between S. cerevisiae and Saccharomyces non-cerevisiae in order to mimic lager yeasts by expanding their genetic background; 3) the exploitation of evolutionary engineering approaches; 4) the usage of non-Saccharomyces yeasts either in co-coculture or in sequential fermentation with S. cerevisiae. In the present work we summarized pro and contra of these approaches and provided an overview on the most recent advances on how brewing yeast genome evolved and domestication took place. Finally, we delineated how the correlations maps between genotypes and relevant brewing phenotypes can assist and further improve the search for novel craft beer starter yeasts.

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

Ataxin-2 (ATXN2) acts during stress-responses, modulating mRNA translation and nutrient metabolism. Atxn2 knockout mice exhibit progressive obesity, dyslipidemia and insulin resistance. Conversely, the progressive ATXN2 gain-of-function due to polyGlutamine (polyQ) expansions leads to a dominantly inherited neurodegenerative process named spinocerebellar ataxia type 2 (SCA2), with early adipose tissue loss and late muscle atrophy. We tried to understand lipid dysregulation in a SCA2 patient brain and in an authentic mouse model. Thin layer chromatography of a patient cerebellum was compared to the lipid metabolome of Atxn2-CAG100-KnockIn (KIN) mouse spinocerebellar tissue. The human pathology caused deficits of sulfatide, galactosylceramide, cholesterol, C22/24-sphingomyelin and gangliosides GM1a/GD1b, despite quite normal levels of C18-sphingomyelin. Cerebellum and spinal cord from the KIN mouse showed a consistent decrease of various ceramides, with a significant elevation of sphingosine in the more severely affected spinal cord. Deficiency of C24/26-sphingomyelins contrasted with excess C18/20-sphingomyelin. Spinocerebellar expression profiling revealed consistent reductions of CERS protein isoforms, of Sptlc2 and Smpd3, but upregulation of Cers2 mRNA, as prominent anomalies in the ceramide-sphingosine metabolism. Reduction of Asah2 mRNA correlated to deficient S1P levels. In addition, downregulations for the elongase Elovl1, Elovl4, Elovl5 mRNAs and ELOVL4 protein explain the deficit of very-long-chain sphingomyelin. Reduced ASMase protein levels correlated to the accumulation of long-chain sphingomyelin. Overall, a deficit of myelin lipids was prominent in SCA2 nervous tissue at prefinal stage, not compensated by transcriptional adaptation of several metabolic enzymes. Myelination is controlled by mTORC1 signals, so our human and murine observations are in agreement with the known role of ATXN2 yeast, nematode and mouse orthologs as mTORC1 inhibitors and autophagy promoters.

The grain size of CVD (Chemical Vapor Deposition) graphene was controlled by changing the precursor gas flow rates, operation temperature, and chamber pressure. Graphene of average grain sizes of 4.1 µm, 2.2 µm, and 0.5 µm were synthesized in high quality and full coverage. The possibility to tailor the thermoelectric conversion characteristics of graphene has been exhibited by examining the grain size effect on the three elementary thermal and electrical properties of σ, S, and k. Electrical conductivity (σ) and Seebeck coefficients (S) were measured in a vacuum for supported graphene on SiO₂/Si FET (Field Effect Transistor) substrates so that the charge carrier density could be changed by applying a gate voltage (V_G). Mobility (µ) values of 529~1042, 459~745, and 314~490 cm²/V·s for the three grain sizes of 4.1 µm, 2.2 µm, and 0.5 µm, respectively, were obtained from the slopes of the measured σ vs. V_G graphs. The power factor (PF), the electrical portion of the thermoelectric figure of merit (ZT), decreased by about one half as the grain size was decreased, while the thermal conductivity (k) decreased by one quarter for the same grain decrease. Finally, the resulting ZT increased more than two times when the grain size was reduced from 4.1 µm to 0.5 µm.

Immune checkpoint inhibitors (ICIs) have obtained durable responses in many cancers, making it possible to foresee their potential in improving the health of cancer patients. However, immunotherapies are limited at the moment to a minority of patients and there is a need for a better understanding of the basic molecular mechanisms and functions of pivotal immune regulatory molecules. Immune checkpoint cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and regulatory T (Treg) cells play pivotal roles in hindering the anticancer immunity. Treg cells suppress antigen-presenting cells (APCs) by depleting immune stimulating cytokines, producing immunosuppressive cytokines and constitutively expressing CTLA-4. CTLA-4 molecules bind with higher affinity to CD80 and CD86 than CD28 and act as competitive inhibitors of CD28 in APCs. The purpose of this review is to summarize state-of-the-art understanding of the molecular mechanisms underlining CTLA-4 immune regulation and the correlation of ICI response with CTLA-4 expression in Treg cells from preclinical and clinical studies for possibly improving CTLA-4-based immunotherapies, while highlighting the knowledge gap.

Red mud is a hazardous waste of alumina industry that contains high amounts of iron, aluminum, titanium and REEs. One of the promising methods for the extraction of iron from red mud is car-bothermic reduction with the addition of sodium salts. This research focuses on the process of hy-drochloric high-pressure acid leaching using 10–20% HCl of two samples of non-magnetic tailings obtained by 60-minute carbothermic roasting of red mud at 1300 °C and the mixture of 84.6 wt. % of red mud and 15.4 wt. % Na2SO4 at 1150 °C, respectively, with subsequent magnetic separation of metallic iron. An influence of temperature, leaching duration, solid-to-liquid-ratio and acid con-centration on dissolution behavior of Al, Ti, Mg, Ca, Si, Fe, Na, La, Ce, Pr, Nd, Sc, Zr were studied. Based on the investigation of the obtained residues, mechanism of passing of valuable elements into the solution was proposed. It has shown that 90% Al, 91% Sc and above 80% of other REEs can be dissolved under optimal conditions; Ti can be extracted into the solution or the residue depending on the leaching temperature and acid concentration. Based on the research results, novel flowsheets for red mud treatment were developed.

Background: Colorectal cancer (CRC) remains a leading cause of cancer-related morbidity and mortality in both sexes globally. This is not unconnected with the heterogeneity and plasticity of CRC stem cells (CRC-SCs) which stealthily exploit niche-related and (epi)genetic factors to facilitate metastasis, chemoresistance, tumor recurrence, and disease progression. Despite accumulating evidence of the role of dysregulated microRNAs in malignancies, the therapeutic efficacy of pharmacological-targeting of CRC-SC-associated microRNAs is relatively under-explored. Experimental approach: In this present study, we employed relatively new bioinformatics approaches, analyses of microarray data, western blot, RT-PCR, and functional assays to show that hsa-miR-324-5p expression is significantly suppressed in CRC cells, and inversely correlates with the aberrant expression of SOD2. Results: This converse hsa-miR-324-5p/SOD2 relationship is associated with enhanced oncogenicity, which is effectively inhibited by 4-AAQB as evidenced by inhibited cell viability and proliferation, as well as, attenuated migration, invasion and clonogenicity in 4-AAQB-treated DLD1 and HCT116 cells. We also showed that 4-AAQB-induced re-expression of hsa-miR-324-5p, akin to short-interfering RNA reduced SOD2 expression, correlates with the concurrent down-regulation of SOD2, N-cadherin, vimentin, c-Myc, and BcL-xL2, with concomitant up-regulation of E-cadherin and BAX2 proteins. Enhanced expression of hsa-miR-324-5p in the CRC cells suppressed their tumorigenicity in vitro and in vivo. Additionally, 4-AAQB synergistically potentiates FOLFOX anticancer effect by eliciting the re-expression of SOD2-suppressed hsa-miR-324 and inhibiting SOD2-mediated tumorigenicity. Conclusion: Our findings highlight the pre-clinical anti-CSC efficacy of 4-AAQB, with or without FOLFOX in CRC, and suggest a potential novel therapeutic strategy for CRC patients.

A new type of gold nanoparticles was synthesized by using benzoyl pyrazolone as a capping agent. The synthesized AuNPs exhibited a spherical shape and a monodisperse and fluorescence emission characteristic peak at 650 nm. The AuNPs –BMPBP was demonstrated as sensitive and selective fluorescent chemosensor for detection of Al ³⁺ ion. In the presence of Al ³⁺ ion, the fluorescent emission of BMPBP-AuNPs at 650 nm, increased with an increasing concentration of Al ³⁺ ion with a low detection limit (2 µM), the proposed method provided to apply determination of Al ³⁺ ion of tap water with satisfactory results.

Miscarriage due to blastocyst implantation failure occurs in up to two-thirds of all miscarriage cases in human. The calcium ion has been shown to be involved in many cellular signal transduction pathways as well as in the regulation of cell adhesion, which is necessary for the embryo implantation process. Exposure to endocrine-disrupting chemicals (EDs) during early gestation results in disruption of intrauterine implantation and uterine reception, leading to implantation failure. In this study, ovarian estrogen (E2), bisphenol A (BPA), or 4-tert-octylphenol (OP), with or without ICI 182,780 (ICI) were injected subcutaneously from gestation day 1 to gestation day 3 post-coitus. The expression levels of the calcium transport genes were assessed in maternal uteri and implantation sites. The number of implantation sites was significantly low in the OP group, and implantation sites were absent in the E2 and EDs+ICI groups. There were different calcium transient transport channel expression levels in uterus and implantation site samples. The levels of TRPV5 and TRPV6 gene expression were significantly increased by EDs with/without ICI treatment in uterus. Whereas, TRPV5 and TRPV6 gene expression were significantly lower in implantation sites samples. NCX1 and PMCA1 mRNA levels were significantly decreased by OP and BPA in the implantation site samples. Compared to vehicle treatment in uterus, both the MUC1 mRNA and protein levels were markedly high in all but the BPA group. Taken together, these results suggest that both BPA and OP can impair embryo implantation through alteration of calcium transport gene expressions and by affecting uterine receptivity.

Toll-like receptors (TLRs) play a key role in the innate immune response to numerous pathogens, including Acanthamoeba sp. The aim of this study was to determine the expression of TLR2 and TLR4 in the eyes of mice following intranasal infection with Acanthamoeba sp. Amoebae used in this study were isolated from the bronchial aspirate of a patient with acute myeloid leukemia (AML) and atypical symptoms of pneumonia. We found statistically significant differences in the expression of TLR2 and TLR4 in the eyes of immunocompetent mice at 8, 16, and 24 days post Acanthamoeba sp. infection (dpi) compared to control. Immunosuppressed mice showed significant differences in the expression of TLR2 at 16 and 24 dpi compared to uninfected animals. Our results indicate that TLR2 and TLR4 are upregulated in the eyes of mice in response to Acanthamoeba sp. We suggest that it is possible for trophozoites to migrate through the optic nerve from the brain to the eyes.

Exposure to psychosocial stress is a risk factor for cardiovascular disease, including vascular aging, angiogenesis, and atherosclerosis-based cardiovascular disease (ACVD). Dipeptidyl peptidase-4 (DPP-4) is a complex enzyme (also called CD26) that acts as a membrane-anchored cell surface exopeptidase. DPP4 is upregulated in metabolic and inflammatory cardiovascular disorders. The widespread expression of DPP4 macrophages and immune cells and the noncatalytic function of DPP4 (also called CD26) as a signaling and binding protein across a wide range of species suggest a teleological role for DPP4 in inflammation and immune response. DPP-4 exhibits many physiological and pharmacological functions by regulating its extremely abundant substrates [e.g., stromal cell-derived factor-1α/ C-X-C chemokine receptor type-4, glucagon-like peptide-1 (GLP-1), etc.]. Over last ten year, emerging data demonstrated unexpected roles for GLP-1 and DPP-4 in extracellular and intracellular signaling, immune activation, inflammation, oxidative stress production, cell apoptosis, insulin resistance, and lipid metabolism,. This mini review has focuses on recent novel findings in this field, highlighting an imbalance between GLP-1 and DPP4 as a potential therapeutic molecular target in treatments of chronic psychological stress-related atherosclerotic cardiovascular disease in humans and animals.

In the present study, we have systematically examined the clinical significance of Nectin-4 (encoded by the PVRL-4 gene), a marker for breast cancer stem cells (CSCs), in cancer metastasis and angiogenesis using a variety of human specimens, including invasive duct carcinoma (IDC) with multiple grades, several types of primary tumors to local and distant relapses, lymph node metastases and circulating tumor cells (CTCs). Nectin-4 was overexpressed in more than 92% of samples with 65.2% Nectin-4 positive cells. The level of expression was increased with increasing tumor grade (GI-III) and size (T1-4) of IDC specimens. More induction of Nectin-4 was noted in relapsed samples from a variety of tumors (colon, tongue, liver, kidney, ovary, buccal mucosa) in comparison to primary tumors, while paired adjacent normal tissues do not express any Nectin-4. A high expression of Nectin-4 along with other representative markers in CTCs and lymph node metastasis was also observed in cancer specimens. An increased level of Nectin-4 along with representative metastatic (CD-44, Sca1, ALDH1, Nanog) and angiogenic (Ang-I, Ang-II, VEGF) markers was noted in metastatic tumors (local and distant) in comparison to primary tumors that were correlated with different grades of tumor progression. In addition, greater expression of Nectin-4 was observed in secondary tumors (distant metastasis, e.g., breast to liver or stomach to gallbladder) in comparison to primary tumors. Nectin-4 was overexpressed at all stages of metastasis and angiogenesis, thus appearing to play a major role in tumor relapse through the PI3K-Akt-NFκβ pathway.

School Feeding Programmes are social safety net interventions providing educational and health benefits to vulnerable children in developing countries. This study assessed the impact of Osun Elementary School Feeding and Health Programme (O-MEALS) on the enrolment and retention of rural primary schools in Osun State. Multi stage sampling technique was used to select 188 respondents while data was collected through interview schedule. Percentages, Chi-square, PPMC and T-test were used for data analysis. Findings revealed that over half (51.6%) of the respondents were male, aged 9.38 ± 1.84 years and majority (83.0%) had a family size of 6-10 people. Food incentives (=1.25), health challenge (=0.69), and peer influence (=0.67) were major factors affecting school attendance. More than half (53.2%) of the respondents had unfavourable perception towards the school feeding programme. Results showed a significant difference between pupils’ enrolment (t = 5.332, p = 0.006) and retention rate (t = 58.386, p = 0.000) before and after the commencement of O-MEALS. Furthermore, pupils’ enrolment and retention (r = 0.993, p = 0.001) after the commencement of O-MEALS was significantly related. Food incentive was a major factor affecting school attendance, which fostered an improvement in the poor enrolment and retention previously experienced. Since a good number of the pupils possessed unfavourably perception towards the school feeding programme, it was recommended that effective monitoring be established to checkmate food vendors’ activities in delivering quality and satisfactory services. Likewise, the Government’s policies on school restructuring and levy, which had proved counterproductive, should be reviewed.

The blue sepal color of hydrangea is due to a metal complex anthocyanin composed of 3-O-glucosyldelphinidin (1) and an aluminum ion with the co-pigments 5-O-caffeoylquinic acid (2) and/or 5-O-p-coumaroylquinic acid (3). The three components, namely, anthocyanin, Al³⁺ and 5-O-acylquinic acids, are essential for blue color development, but the complex is unstable and only exists in aqueous solution. Furthermore, the complex did not give analyzable NMR spectra or crystals. Therefore, many trials to determine the detailed chemical structure of the hydrangea-blue complex have failed to date. Instead, via experiments mixing 1, Al³⁺ and 2 or 3 in a buffered solution at pH 4.0, we obtained the same blue solution derived from the sepals. However, the ratio was not stoichiometric but fluctuated. To determine the composition of the complex, we tried direct observation of the molecular ion of the complex using electrospray-ionization mass spectrometry. In a very low-concentration buffer solution (2.0 mM) at pH 4.0, we reproduced the hydrangea-blue color by mixing 1, 2 and Al³⁺ in ratios of 1:1:1, 1:2:1 and 1:3:1. All solution gave the same molecular ion peak at m/z = 843, indicating that the blue solution has a ratio of 1:1:1 for the complex. By using 3, the observed mass number was m/z = 827 and the ratio of 1, 3 and Al³⁺ was also 1:1:1. A mixture of 1, 3-O-caffeoylquinic acid (4) and Al³⁺ did not give any blue color but instead was purple, and the intensity of the molecular ion peak at m/z = 843 was very low. These results strongly indicate that the hydrangea blue-complex is composed of a ratio of 1:1:1 for 1, Al³⁺ and 2 or 3.

Current neural network models can demonstrate reasonable-looking behavior, considered by some developers and researchers human-like. For example, a large language model GPT-3 is susceptible to human-like cognitive biases. Yet there is no data of such models solving emotional intelligence (EI) tasks. They are connected to the abilities that has been previously considered as specifically human EI is an important aspect of human communication. The ability to understand and respond to emotional cues is essential for effective communication. Therefore, it is crucial to determine the ways AI models such as ChatGPT demonstrate EI. The present research aims to measure the EI of GPT-4, a large language model trained by OpenAI. Russian version of the Mayer–Salovey–Caruzo Emotional Intelligence Test sections B, C, D, F, G and H were used in this research. High points were obtained in Understanding emotions scale and Strategic EI. Mean points are obtained in Managing emotions scale. Low and less reliable values are obtained in Using emotions to facilitate thought scale. Thus, GPT-4 seems already capable of identifying emotions in text and describing techniques for managing them. However, complex cases and irregular situations requiring emotions qualitative analysis would be a hard task for GPT-4.

The use of bacteriophage is reemerging as a tool for combatting multi-drug resistant bacterial infections. In our previous study, we showed that colistin resistant carbapenem-resistant Klebsiella pneumoniae (ColR-CRKP) is more susceptible to killing by lytic tailed phages, including ФNJS1 specific for nonmucoid K. pneumoniae. Although we demonstrated that alteration on surface charges of ColR-CRKP promotes phage adherence and infection, the receptor for ФNJS1 was still unknown. In current study, we identified O-antigen was involved in the reversible adsorption, and outer membrane protein (OMP) FepA may be served as one of the irreversible receptors for ФNJS1. We firstly found accelerated reversible phage adsorption to ColR-CRKP cells, and that periodate treatment of bacteria inhibited the phage binding, indicating LPS may be involved in phage reversible adsorption. ФNJS1-resistant bacterial mutants screening revealed that mutants in ∆wecG(mTn5) and ∆wecA(mTn5), two genes responsible for LPS biosynthesis, affected phage adsorption capacity and phage infectivity. The loss of wzyE encoding O-antigen polymerase showed no significant difference in phage adsorption but increased phage infectivity, suggesting the long chain length of O-antigen may also be a barrier for bacteriophage infection. Among four OMP mutants including ∆fepA, ∆fhuA, ∆ompA and ∆ompC, only ∆fepA slowed phage lysis rate, suggesting FepA may be as one of irreversible receptors for ФNJS1. The results are helpful to better understand why ColR-CRKP sensitizes phage infection and to combat multi-drug resistant K. pneumoniae infections in the future.

Endoplasmic reticulum (ER) stress perturbs cell homeostasis and induces the unfolded protein response (UPR). In breast cancer, this process is activated by oestrogen deprivation and is associated with tamoxifen resistance. We present evidence that the transcription factor SOX2 and the long noncoding RNA SOX2 overlapping transcript (SOX2OT) are up-regulated in oestrogen receptor-positive (ER+) breast cancer and in response to oestrogen deprivation. We examined the effect of the UPR on SOX2 and SOX2OT expression, and the effect of SOX2OT on UPR pathways in breast cancer cell lines. The induction of the UPR by thapsigargin or glucose deprivation up-regulates SOX2OT expression. This up-regulation is also shown with the anti-oestrogen 4OH-tamoxifen and mTOR inhibitor everolimus in ER + breast cancer cells that are sensitive to oestrogen deprivation or everolimus treatment. SOX2OT overexpression decreased BiP and PERK expression. This effect of SOX2OT overexpression was confirmed on BiP and PERK pathway by q-PCR. Our results show that a long noncoding RNA regulates the UPR and evince a new function of SOX2OT as a participant of ER stress reprogramming of breast cancer cells.

Hyperbaric oxygen (HBO) treatment has been proven to attenuate neuroinflammation in rats. This study aimed to determine the potential mechanism underlying the anti-inflammatory effects of HBO treatment on burn-induced neuroinflammation in rats. Thirty-six adult male Sprague–Dawley (SD) rats were randomly assigned to the following six groups (n = 6 per group): (1) sham burn with sham HBO treatment, (2) sham burn with HBO treatment, (3) burn with 1-week sham HBO treatment, (4) burn with 2-week sham HBO treatment, (5) burn with 1-week HBO treatment, and (6) burn with 2-week HBO treatment. SD rats that received third-degree burn injury were used as a full-thickness burn injury model. Subsequently, we analyzed the expression of proteins involved in the galectin-3 (Gal-3)-dependent Toll-like receptor-4 (TLR-4) pathway through enzyme-linked immunosorbent assay (ELISA), immunohistochemistry (IHC) analysis, and Western blotting, and a behavior test was also conducted. The behavior test revealed that HBO treatment significantly suppressed mechanical hypersensitivity in the burn with HBO treatment group compared with the burn with sham HBO treatment group (p < 0.05). ELISA results showed that tumor necrosis factor alpha (TNF-α) and interleukin 1 beta (IL-1β) levels in the dorsal horn of the spinal cord and the skin were significantly decreased in the burn with HBO treatment group compared with the burn with sham HBO treatment group (p < 0.05). Western blotting results demonstrated that HBO treatment significantly reduced the expression of Gal-3 and TLR-4 in the dorsal horn of the spinal cord in the burn with HBO treatment group compared with the burn with sham HBO treatment group (p < 0.05). IHC analysis results showed that the expression of Gal-3, TLR-4, CD68, and CD45 in the dorsal horn of the spinal cord was significantly lower in the burn with HBO treatment group than in the burn with sham HBO treatment group (p < 0.05), and the expression of CD68 and macrophage migration inhibitory factor (MIF) in the right hind paw skin was significantly lower. The expression of vimentin and fibroblast growth factor (FGF) in the right hind paw skin was significantly higher after HBO treatment (p < 0.05). This study proved that early HBO treatment relieves neuropathic pain, inhibits the Gal-3-dependent TLR-4 pathway, and suppresses microglia/macrophage activation in a rat model.

(RADA)4 nanoscaffolds are excellent candidates for use as peptide delivery vehicles: they are relatively easy to synthesize with custom bio-functionality, and assemble in situ to allow a focal point of release. This enables (RADA)4 to be utilized in multiple release strategies by embedding a variety of bioactive molecules in an all-in-one ‘construct’. One novel strategy focuses on the local, on-demand release of peptides triggered via proteolysis of tethered peptide sequences. However, the spatial-temporal morphology of self-assembling nanoscaffolds may greatly influence the ability for enzymes to both diffuse into as well as actively cleave substrates. Fine structure and its impact on overall affect on peptide release is poorly understood. In addition, fractal networks observed in nanoscaffolds are linked to the fractal nature of diffusion in these systems. Therefore, matrix morphology and fractal dimension of virgin (RADA)4 and mixtures of (RADA)4 and matrix metalloproteinase 2 (MMP-2) cleavable substrate modified (RADA)4 were characterized over time. Sites of high (GPQG+IASQ, CP1) and low (GPQG+PAGQ, CP2) cleavage activity were chosen. Fine structure was visualized using established according to established methods. After 2 hrs of incubation, nanofiber networks showed an established fractal nature, however nanofibers continued to bundle in all cases as incubation times increased. It was observed that despite extensive nanofiber bundling after 24 hrs of incubation time, the CP1 and CP2 nanoscaffolds were susceptible to MMP-2 cleavage. The properties of these engineered nanoscaffolds characterized herein illustrate that they are an excellent candidate as an enzymatically initiated peptide delivery platform.

Breast Cancer (BC) is the second most common type of cancer worldwide and displays the highest cancer-related mortality among women worldwide. Targeted therapies have revolutionized the way BC has been treated in the last decades improving life expectancies of millions of women. Among the different molecular pathways that have been of interest for the development of targeted therapies are the Cyclin-Dependent Kinases (CDK). CDK inhibitors are a class of molecules that already exist in nature and those belonging to the INK4 protein family specifically inhibit the CDK4/6 proteins. CDK4/6 inhibitors specifically block the transition from the G1 to the S phase of the cell cycle by dephosphorylation of the retinoblastoma tumor suppressor protein. In the past four years CDK4/6 inhibitors palbociclib, ribociclib, and abemaciclib received their first FDA approval for the treatment of Hormone Receptor (HR)-positive and Human Epidermal growth factor Receptor 2 (HER2)-negative breast cancer after showing significant improvements in progression-free survival in the PALOMA-1, MONALEESA-2 and the MONARCH-2 randomized clinical trials, respectively. After the encouraging results from these clinical trials, CDK4/6 inhibitors have also been investigated in the other BC subtypes. In HER2-positive BC, combination of CDK4/6 inhibitors with HER2-targeted therapies showed promise in preclinical studies and their clinical evaluation is ongoing. Moreover, in triple-negative BC, CDK4/6 inhibitors efficacy has been investigated in combination with other targeted therapies or immunotherapies. This review summarizes the molecular background and clinical efficacy of CDK4/6 inhibitors as single agents or in combination with other targeted therapies for the treatment of BC. Future directions of ongoing clinical trials and predictive biomarkers will be further debated.

The association between human and cat (F. catus) is well known. This domestic animal is also known for its malodorous urine and feces. The complexity of the odorous urine and feces impacts human life by triggering the human sensory organ in a negative way. The objective of this research was to identify the volatile organic chemicals (VOCs) and associated odors in cat urine and feces using gas chromatography-mass spectrometry and simultaneous sensory analysis of fresh and aged samples. The solid-phase microextraction (SPME) technique was used to pre-concentrate the VOCs emitted from urine or feces samples. Twenty-one compounds were identified as emitted from fresh urine, whereas 64 compounds were emitted from fresh feces. A contrasting temporal impact was observed on the emission of VOCs for urine and feces. On aging, the emission increased to 36 detected chemicals for stale urine, whereas only 17 chemicals were detected in stale feces. Not all compounds were malodorous; some compounds had a pleasant hedonic smell to the human nose. Although trimethylamine, low molecular weight organic acids, and ketones were contributors to the odor to some extent, phenolic compounds and aromatic heterocyclic organic N compounds generated the most intense odors and substantially contributed to the overall malodor, as observed by this study. This work might be useful to formulate cat urine and feces odor remediation approaches to reduce odor impacts.

Trigonella foenum is one of the oldest medicinal plants that grow in many parts of Iran with the diverse ecological situation. Employing this plant for treating diabetes and high cholesterol has a long history, because of some metabolites. Due to the habitat of fenugreek is a wide range of climatic conditions, it may have power to cope with climate variation. The main intention of this inquiry was to understand the effect of the environmental variables on this therapeutic plant features. It was also interesting for us to understand which environment variables are more impressive for enhancing of trigonelline and 4-hydroxy isoleucine content as the most important metabolites of this plant. For achieving this goal, environmental information and vegetal data were analyzed to discover the role of nature on the seed part of fenugreek life in 50 different regions of Iran. Canonical correspondence analysis (CCA) displayed that high content of metabolites and some morphological characteristics happened in high temperature and solar irradiation. Partial least squares regression (PLSR) and path analysis used to find the best predictors and direct and indirect effect of all variables on 4-hydroxy isoleucine and trigonelline. Ecological condition were the best predictors and had the highest direct and indirect impact on 4-hydroxy isoleucine. However, for trigonelline, the environment did not play a senior role. It seems that the reaction of components of fenugreek does not follow the same way. Studying on morphological, primary and secondary metabolites, and surrounding environment of fenugreek, helped us to have a more precise judgment about the life of this plant.

In this work, the solar light-induced redox photoactivity of the ZnO semiconductor material was used to prepare at room temperature CuxO-ZnO composite catalysts with a control of the chemical state of the copper oxide phase. The preparation of Cu2(I)O-ZnO and Cu(II)O-ZnO composite catalysts was achieved by using Cu(acac)2 in THF-water and Cu(NO3)2 in water as metallic precursor, respectively. Prior to the implementation of the photo-assisted synthesis method, the most efficient photoactive ZnO material was selected among different ZnO materials prepared by the low temperature polyol method and through the precipitation method with carbonates and carbamates as precipitation agent, by taking the photocatalytic degradation of the 4-chlorophenol compound in water under simulated solar light as model reaction. The ZnO support materials were characterized by XRD, BET, TGA, SEM and TEM, and the synthesis method was strongly influencing their photoactivity in terms of 4-chlorophenol degradation and of total organic carbon removal. The most photoactive ZnO material was prepared by precipitation with carbonates and calcined at 300°C, and was taking advantage of a high specific surface area and a small mean crystallite size for achieving a complete 4-chlorophenol mineralization within 70 min of reaction, with a minimum Zn2+ released to the solution due to surface photocorrosion. Beside thermal catalysis applications, this work opened a new route for the facile synthesis of Cu2O-ZnO heterojunction photocatalysts, that could take advantage under solar light of the heterojunction built between the p-type semi-conductor Cu2O with direct visible light band gap and the ZnO semiconductor phase.

Western Anatolia comprises a vast amount of various volcanic successions spanning from Eocene to Upper Miocene periods. These units mainly display southward younging in broad sense and display large amounts of chemical variation that spanned from basalt to rhyolite. The southward younging of magmatism and chemical variations have been largely attributed to the retreat and roll-back of the Hellenic slab and the western escape of the Anatolian microplate. However, there is still a lack of high precision data to pinpoint the exact nature of the magmatism and lithospheric tectonics. In this contribution we investigated a poorly known region along the Western Anatolia along Manisa district called Karakılıçlı volcanic field. We investigated two different volcanic sections (Kalpakkaya and Çamlık hill) that display the best volcano-sedimentary features in terms of geochronology and geochemistry. Samples acquired from the bottom, middle and upper portions of these sections display Early-Middle Miocene ages of 17.64±0.20, 17.22±0.15, 16.16±0.17 and 16.36±0.13, 15.79±0.71 and 13.61±0.20 Ma respectively. The results indicate that the volcanism in the region generated by the melting of the mantle and/or lithospheric mantle by slab retreat and roll-back of the Hellenic slab and evolved in the shallow magma chambers/mushes by fractional crystallization, magma mixing and crustal assimilation.

It is estimated that pancreatic cancer will be the 2^nd leading cause of cancer-related deaths globally by 2030, highlighting the ongoing lack of effective treatment options in this devastating condition. There is a lack of reliable prognostic or predictive markers in pancreatic cancer to guide management decisions, whether for systemic chemotherapy, molecularly targeted therapies, or immunotherapies. To date, the results for targeted agents and immunotherapies in unselected populations of chemo-refractory pancreatic cancer have not met expectations. The reasons for this lack of efficacy of immunotherapy in pancreatic cancer are incompletely understood. The challenges in pancreatic cancer include the physical barrier created by the dense desmoplastic stroma surrounding the tumor, chemokine-mediated exclusion of T cells, poor antigenicity, paucity of infiltrating T cells within the tumor, ultimately leading to an immunosuppressive microenvironment. A better understanding of the role of inflammation in pancreatic cancer, its tumor microenvironment and individualized patient-related features, be they molecular, clinical or histopathological would enable a more effective tailored approach to the management of pancreatic cancer. In this review, the role of inflammation, the immune tumor microenvironment and potential immune biomarkers in pancreatic cancer are explored.

Inflammatory granulocytes are characterized by oxidative burst, which may promote oxidative stress and lipid modification both in affected tissues and on systemic level. On the other hand, redox signaling involving lipid peroxidation products acting as second messengers of free radicals play important, not yet fully understood, roles in pathophysiology of inflammation and various stress-associated disorders. Therefore, the aim of this study was to evaluate the onset of oxidative stress and alterations of enzyme-dependent lipid metabolism resulting from redox imbalance in granulocytes and plasma obtained from patients with psoriasis vulgaris or psoriatic arthritis, in comparison to the healthy subjects. The results obtained revealed enhanced activity of pro-oxidant enzymes NADPH and xanthine oxidases in granulocytes, with a decrease of enzymatic and non-enzymatic antioxidants in plasma of psoriatic patients. The Nrf2 and its regulators were increased in both forms of psoriasis, while HO-1 levels were increased only in psoriasis vulgaris. Redox imbalance was associated with decreased levels of phospholipids and of free PUFAs, but with enhanced activity of enzymes involved in lipid metabolism (PLA2, PAF-AH COX1/2) and increased lipid peroxidation products 4-hydroxynonenal (4-HNE), isoprostanes and neuroprostanes. Increased endocannabinoids and GPR55 were observed in both forms of the disease, while expression of CB1 was increased only in pateints with psoriatic arthritis, opposite to CB2, which was increased only in psoriasis vulgaris. Protein modifications by ROS and lipid peroxidation product 4-HNE promoted apoptosis of granulocytes by increased caspases in both forms of psoriasis. This study indicates that excessive activation of granulocytes, causing oxidative stress and lipid modifications, is an important pathophysiology of psoriasis. Consequently, lower Nrf2 activity and CB2 expression may promote progression of psoriasis into advanced, arthritic form of the disease.

Ischemic neuron loss contributes to brain dysfunction in patients with cardiac arrest (CA). Histidine–tryptophan–ketoglutarate (HTK) solution is a preservative used during organ transplantation. Can HTK also protect neurons from severe hypoxia (SH) following CA? We isolated rat primary cortical neurons and induced SH with or without HTK. Changes in caspase-3, hypoxia-inducible factor 1-alpha (HIF-1α), and NADPH oxidase-4 (NOX4) expression were evaluated at different time points till 72 h. Using a rat asphyxia model, we induced CA-mediated brain damage and then completed resuscitation. HTK or sterile saline was administered into the left carotid artery. Neurological deficit scoring and mortality were evaluated for 3 days. Then the rats were sacrificed for evaluating NOX4 and H2O2 level in blood and brain. In the in vitro study, HTK attenuated SH- and H2O2-mediated cytotoxicity in a volume- and time-dependent manner, associated with persisted HIF-1α expression, reductions in procaspase-3 activation and NOX4 expression. The inhibition of HIF-1α abrogated HTK’s effect on NOX4. In the in vivo study, neurological scores were significantly improved by HTK. H2O2 level, NOX4 activity and NOX4 gene expression were all decreased in the brain specimen of HTK-treated rats. Our results suggest that HTK acts as an effective neuroprotective solution.

Much evidence has accumulated over the past decade in favor of a significant association between dysbiosis, neuroinflammation and neurodegeneration. Presently, the pathogenetic mechanisms triggered by molecules produced by the altered microbiota, also responsible for the onset and evolution of Alzheimer Disease will be described. Our attention will be focused on the role of astrocytes and microglia. Numerous studies have progressively demonstrated how these glial cells are important to ensure an adequate environment for neuronal activity in healthy conditions. Furthermore, it is becoming evident how both cell types can mediate the onset of neuroinflammation and lead to neurodegeneration when subjected to pathological stimuli. Based on this information, the role of major microbiota products in shifting the activation profiles of astrocytes and microglia from a healthy to a diseased state will be discussed focussing on Alzheimer Disease pathogenesis.

Chronic kidney diseases (CKD) and end stage renal disease (ESRD) are growing threats worldwide. Tissue engineering is a new hope to surpass the current limitations such as the shortage of donor. To do so, the first step would be fabrication of an intact decellularized kidney scaffold. In the current study, an automatic decellularization device was developed to perfuse and decellularize male rats' kidneys using both sodium lauryl ether sulfate (SLES) and sodium dodecyl sulfate (SDS) and to compare their efficacy in kidney decellularization and post-transplantation angiogenesis. After anesthesia, kidneys were perfused with either 1% SDS solution for 4 h or 1% SLES solution for 6 h. The decellularized scaffolds were stained with hematoxylin and eosin (H&E), periodic acid Schiff (PAS), Masson’s trichrome, and alcian blue to determine cell removal and glycogen, collagen and glycosaminoglycans (GAGs) contents, respectively. Moreover, scanning electron microscopy (SEM) was performed to evaluate the cell removal and preservation of microarchitecture of both SDS and SLES scaffolds. Additionally, DNA quantification assay was applied for all groups in order to measure residual DNA in the scaffolds and normal kidney. In order to demonstrate biocompatibility and bioactivity of the decellularized scaffolds, allotransplantation was performed in back muscle and angiogenesis was evaluated. Complete cell removal in both SLES and SDS groups was observed in SEM and DNA quantification assays. Moreover, the extracellular matrix (ECM) architecture of rat kidney in the SLES group was significantly preservation better than the SDS group was shown. The formation of blood capillaries and vessels were observed in the kidney allotransplantations in both SLES and SDS decellularized kidneys. In conclusion, we demonstrated that both SLES and SDS could be promising tools in kidney tissue engineering. The better preservation of ECM than SDS, introduces SLES as the solvent of choice for kidney decellularization. ¬¬

We introduce a new class of Vertex Operator Algebras Y+ and their duals, which generalize the standard W-algebras WN of type sl(N). These algebras can be defined in terms of junctions of boundary conditions and interfaces in the GL-twisted N = 4 Super Yang Mills gauge theory. The aim of these technical calculations is to find the relation of these ortho-symplectic Y-algebras to truncations of even W\infinity.

This research aims to find out whether the synthetic 1, 2, 4-triazine and its derivatives have antifungal effects and can protect humans from infection with Candida albicans. Molecular docking and molecular dynamic simulation are widely used in modern drug design to target a We are interested in using molecular docking and molecular dynamics modelling to investigate the interaction between the derivatives of 1, 2, 4-triazine and the resulting lanosterol 14 - demethylase (CYP51) of Candida albicans The inhibition of Candida albicans CYP51 is the main goal of our research. The 1, 2, 4-triazine and its derivatives have been docked to the CYP51 enzyme, which is involved in Candida albicans Multidrug Drug Resistance (MDR). Autodock tools were used to identifying the binding affinities of molecules against the target proteins. Compared to conventional fluconazole, the molecular docking results indicated that each drug has a high binding affinity for CYP51 proteins and forms unbound interactions and hydrogen bonds with their active residues and surrounding allosteric residues. The docking contacts were made using a 10 ns MD simulation with nine molecules. RMSD, RMSF, hydrogen bonds, and the Rg all confirm these conclusions. In addition, these compounds were expected to have a favorable pharmacological profile and low toxicity. The compounds are being offered as scaffolds for the development of new antifungal drugs and as candidates for future in vitro testing.

(R)-1-(4-Amino-3,5-dichlorophenyl)-2-bromoethan-1-ol has been synthesised in 93% enantiomeric excess (ee) by asymmetric reduction of the corresponding ketone catalysed by a ketoreductase and NADPH as the co-factor in DMSO. (S)-N-(2,6-Dichloro-4-(1-hydroxyethyl)phenyl)acetamide has been synthesised in >98% ee by the same system. Both synthons are potential precursors for clenbuterol enantiomers. Clenbuterol is a β₂-agonist used in veterinary treatment of asthma in several countries. The drug is listed on the World Anti-doping Agency’s Prohibited list due to its effect on increased protein synthesis in the body. However, racemic clenbuterol has recently been shown to reduce the risk of Parkinson’s disease. In order to reveal which one (or both) of the enantiomers that cause this effect, the pure enantiomers need to be studied separately. Our biocatalytic approach in order to obtain enantiopure clenbuterol should be applicable to industrial scale.

Here we present an overview of speleothem δ18O records from South America, which mostly are available in the Speleothem Isotopes Synthesis and Analysis (SISAL_v1) database. South American tropical and subtropical δ18O time series are primarily interpreted as being driven by the amount effect and, consequently show the past history of the convection intensity of convergence zones such as the Intertropical Convergence Zone and the South America Monsoon System. We investigate past hydroclimate scenarios in South America related to the South American Monsoon System in three different time scales: Late Pleistocene, Holocene and the last two millennia. The precession driven insolation is the main driver of convective variability over the continent during the last 250 kyrs, including the Holocene period. However a dipole is observed between the west and east portions of the continent. Records located in the central region of Brazil appear to be weakly affected by insolation driven variability and more susceptible to the South Atlantic Convergence Zone. Cold episodic events in Northern Hemisphere increase the activity of the South American Monsoon System on all time scales, in turn increasing rainfall amounts in South America, as was documented during Heinrich events in the late Pleistocene and Bond events in the Holocene, as well as during the Little Ice Age.

Abstract: The purpose of this study was to understand the role of infection in the origin of chromosomal anomalies linked to neurodevelopmental disorders. In patients with neurodevelopmental disorders, DNA’s from viruses and bacteria including known teratogens were tested against chromosome anomalies known to cause the disorders. Results support a theory that parental infections disrupt elaborate multi-system gene coordination needed for neurodevelopment. Genes essential for neurons, lymphatic drainage, immunity, circulation, angiogenesis, barriers, structure, and chromatin activity were all found close together in polyfunctional clusters that were deleted in neurodevelopmental disorders. These deletions account for immune, circulatory, and structural deficits that accompany neurologic deficits. In deleted clusters, specific and repetitive human DNA matched infections and passed rigorous artifact tests. In some patients, epigenetic driver mutations were found and may be functionally equivalent to deleting a cluster or changing topologic chromatin interactions because they change access to large chromosome segments. In three families, deleted DNA sequences were associated with intellectual deficits and were not included in any database of genomic variants. These sequences were thousands of bp and unequivocally matched foreign DNAs. Analogous homologies were also found in chromosome anomalies of a recurrent neurodevelopmental disorder. Viral and bacterial DNAs that match repetitive or specific human DNA segments are thus proposed to interfere with highly active break repair during meiosis, and sometimes delete polyfunctional clusters, and disable epigenetic drivers. Mis-repaired gametes produce zygotes containing rare chromosome anomalies which cause neurologic disorders and accompanying non-neurologic signs. Neurodevelopmental disorders may be examples of assault on the human genome by foreign DNA with some infections more likely tolerated because they resemble human DNA segments. Further tests of this model await new technology.

To cope the high glycemic variability (GV) is crucial in the management of multiple daily insulin (MDI) in diabetes. We compared the effect of low dose metformin 750mg/d adding vildagliptin 100mg/d (DPP4+LMET) or the high dose metformin 1500mg/d (HMET), in type 2 diabetes (T2D) with MDI, evaluating GV by continuous glucose monitoring (CGM). Single center, open-label, 12 weeks - 2 period crossover design. Twenty T2D with inadequately controlled (7.0% <HbA1c ≦9.0%) with MDI + LMET were enrolled. Primary endpoints were GV and hypoglycemia derived from CGM performed after each 12 weeks treatment periods. There was no significant difference in HbA1c, body weight changes, total daily dose of insulin. DPP4+LMET compared to the HMET, significantly reduced the calculated GV value, mean (7.15±1.3 vs 7.82±1.6, p<0.05), standard deviation (1.78±0.55 vs 2.27±1.11, p=0.03), continuous overlapping net glycemic action (6.44±1.28 vs 7.12±1.69, p<0.05), J-Index (26.7±11.0 vs 34.9±19.8, p<0.05), high blood glucose index (3.01±1.96 vs. 6.73±4.85, p=0.02), and mean amplitude of glycemic excursions (4.53±1.35 vs 5.50±2.34, p=0.03). The GV metrics with hypoglycemia and nocturnal hypoglycemia were not significantly different. DPP4+LMET decreased GV associated with hyperglycemia. Adding DPP4 inhibitor to the lower dose of metformin is an alternative approach to the stable GV in MDI.

Gene or genome editing (GE) revises, removes, or replaces a mutated gene at the DNA level; it is a tool. Gene therapy (GT) offsets mutations by introducing a "normal" version of the gene into the body while the diseased gene remains in the genome; it is a medicine. So far, no in vivo GE product has been approved, as opposed to 22 GT products approved by the FDA. However, several are under development, and the FDA anticipates their fast entry, as evidenced by the FDA's actions of issuing GE-specific guidelines. The potential of GE in treating diseases far supersedes any other modality due to the recognized role of genes in most human diseases. While GT products add missing genes, GE tools can overcome many aberrations. However, GE presents many safety challenges, including off-target impact, delivery consistency, and long-term effects of gene-fixing. However, most of these concerns will be resolved once the FDA begins approving them, leading to hundreds of products capable of treating untreatable diseases.

In this study, the changes in mass, compressive strength and length were analyzed to investigate sulfate resistance according to ground granulated blast furnace slag (GGBFS) blending ratio and type of sulfate solution. All alkali activated mortars showed excellent sulfate resistance when immersed in sodium sulfate (Na₂SO₄) solution. However, when immersed in magnesium sulfate (MgSO₄) solution, different sulfate resistance results were obtained depending on the presence of GGBFS. Alkali activated GGBFS blended mortars showed a tendency to increase mass, increase length and decrease compressive strength when immersed in magnesium sulfate solution, but the alkali activated FA mortars did not show any significant difference depending on the types of sulfate solution. The deterioration of alkali activated GGBFS blended mortars in the immersion of magnesium sulfate solution was confirmed by the decomposition of C-S-H which is the reaction product by magnesium ion and the formation of gypsum (CaSO₄·2H₂O) and brucite (Mg(OH)₂).

Tuberculosis (TB) is a contagious disease, caused by Mycobacterium tuberculosis (MTB) that has infected and killed a lot of people in the past. At present treatments against TB are available at a very low cost. Since these chemical drugs have many adverse effects on health, more attention is now given on the plant-derived phytochemicals as potential agents to fight against TB. In this study, 5 phytochemicals, 4-hydroxybenzaldehyde, benzoic acid, bergapten, psoralen, and p-hydroxybenzoic acid, are selected to test their potentiality, safety, and efficacy against two potential targets, the MTB RNA polymerase and enoyl-acyl carrier protein (ACP) reductase, the InhA protein, using various tools of in silico biology. The molecular docking experiment, drug-likeness property test, ADME/T-test, P450 SOM prediction, pharmacophore mapping, and modeling, solubility testing, DFT calculations, and PASS prediction study had confirmed that all the molecules had the good potentiality to inhibit the two targets. However, two agents, 4-hydroxybenzaldehyde and bergapten were considered as the best agents among the five selected agents and they also showed far better results than the two currently used drugs, that function in these pathways, rifampicin (MTB RNA polymerase) and isoniazid (InhA protein). These two agents can be used effectively to treat tuberculosis.

C-type lectin CD209/DC-SIGN and CD209L/L-SIGN proteins are distinct cell adhesion and pathogen recognition receptors that mediate cellular interactions and recognize a wide range of pathogens including, viruses such as SARS, SARS-CoV-2, bacteria, fungi and parasites. Pathogens exploit CD209L family proteins to promote infection and evade the immune recognition system. CD209L and CD209 are widely expressed in SARS-CoV-2 target organs and can contribute to infection and pathogenesis. CD209L family receptors are highly susceptible to alternative splicing and genomic polymorphism, which may influence virus tropism and transmission in vivo. The carbohydrate-recognition domain (CRD) and the neck/repeat region represent the key features of CD209L family proteins that are also central to facilitating cellular ligand interactions and pathogen recognition. While, the neck/repeat region is involved in oligomeric dimerization, the CRD recognizes the mannose containing structures present on specific glycoproteins such as those found on the SARS-CoV-2 spike protein. Considering the role of CD209L and related proteins in diverse pathogen recognition, this review article discusses the recent advances in the cellular and biochemical characterization of CD209 and CD209L and their roles in viral uptake, which has important implications in understanding the host-pathogen interaction, the viral pathobiology and driving vaccine development of SARS-CoV-2.

Binderless zeolite macrostructures in the form of ZK-4 microspheres were prepared using anion exchange resin beads as shape directing macrotemplates. The particles were synthesized under hydrothermal conditions at different temperatures and treatment times. The influence of the different synthesis parameters was investigated by X-ray diffraction, scanning electron microscopy, fluorescence X, nitrogen adsorption measurements and ²⁹Si solid NMR. Fully crystalline spheres similar in size and shape to the original resin beads were obtained by a hydrothermal treatment at the highest temperatures (150 - 180 °C) for a short treatment time of 24 h. The synthesized microspheres showed to be promising in the molecular decontamination of Volatile Organic Compounds (VOCs).

The increased expression of β4-galactosyltransferase (β4GalT) 4 was closely associated with poor prognosis of colon cancer. Recently, we showed that the expression of the β4GalT4 gene is regulated by the 0.17 kb core promoter region containing one binding site for Specificity protein 1 (Sp1). To develop a novel screening method for anti-colon cancer drugs, two sensor cell lines having the luciferase gene under the control of two β4GalT4 gene promoters that differed in length were established from SW480 human colon cancer cells. The hGT4-0.17-sensor cells possessed the luciferase reporter driven by the 0.17 kb promoter, while the hGT4-0.3-sensor cells possessed the luciferase reporter driven by the 0.3 kb promoter containing one binding site each for colon cancer-related transcription factors including activator protein 2, E2F, caudal-related homeobox transcription factors, and Runt-related transcription factors besides Sp1. Upon treatment with mitogen-activated protein kinase inhibitor U0126, the promoter activities of the hGT4-0.3-sensor cells decreased significantly, while those of the hGT4-0.17-sensor cells unchanged. These results suggest that the responsiveness to U0126 differs between two sensor cell lines due to the different regulation of the luciferase reporters. This study provides the novel screening method for anti-colon cancer drugs by the combination of two sensor cell lines.

In this paper, the active front-end (AFE) converter topology for the total harmonic distortion (THD) reduction in a wind energy system (WES) is used. A higher THD results in serious pulsations in the wind turbine (WT) output power and in several power losses at the WES. The AFE converter topology improves capability, efficiency and reliability in the energy conversion devices; by modifying a conventional back-to-back converter, from using a single voltage source converter (VSC) to use pVSC connected in parallel the AFE converter is generated. The THD reduction is done by applying a different phase shift angle at the carrier of digital sinusoidal pulse width modulation (DSPWM) switching signals of each VSC. To verify the functionality of the proposed methodology, the WES simulation in Matlab-Simulink® is analyzed, and the experimental laboratory tests using the concept of rapid control prototyping and the real-time simulator Opal-RT® Technologies is achieved. The obtained results show a type-4 WT with total output power of 6MVA, generating a THD reduction up to 5.5 times at the WES.

Direct Behavior Rating (DBR) as a behavioral progress monitoring tool can be designed as longitudinal assessment with only short intervals between measurement points. The reliability of these instruments has been evaluated mostly in observational studies with small samples based on generalizability theory. However, for standardized use in the pedagogical field, a larger and broader sample is required in order to assess measurement invariance between different participant groups and over time. Therefore, we constructed a DBR with multiple items to measure the occurrence of specific externalizing and internalizing student classroom behaviors on a Likert scale (1 = never to 7 = always). In a pilot study, two trained raters observed 16 primary school students and rated the student behavior over all items with a satisfactory reliability. In the main study, 108 regular primary school students, 97 regular secondary school students and 14 students in a clinical setting were rated daily over one week (five measurement points). IRT analyses confirmed the instrument’s technical adequacy, and latent growth models demonstrated the instrument’s stability over time. Further development of the instrument and study designs to implement DBRs are discussed.

The selenoprotein glutathione peroxidase 4 (GPX4) is one of the main antioxidant mediators in the human body. Its central function involves the reduction of complex hydroperoxides into their respective alcohols often using reduced Glutathione (GSH) as a reducing agent. GPX4 has become a hotspot therapeutic target in biomedical research following its characterization as a chief regulator of ferroptosis, and its subsequent recognition as a specific pharmacological target for the treatment of an extensive variety of human diseases including cancers and neurodegenerative disorders. Several recent studies have provided insights into how GPX4 is distinguished from the rest of the glutathione peroxidase family, the unique biochemical properties of GPX4, how GPX4 is related to lipid peroxidation and ferroptosis, and how the enzyme may be modulated as a potential therapeutic target. This current report aims to review the literature underlying all these insights and present an up-to-date perspective on the current understanding of GPX4 as a potential therapeutic target.

Microbial populations involved in forming the distinctive precipitates of the S, Fe, Mn, and Ca cycles in the San Diego River watershed reflect an interplay between mineralogy of the rocks in the watershed, sparse rainfall, ground- and surface-water anoxia, and runoff of high sulfate, treated imported water. In the less developed headwaters, Temescal Creek tributary emerges from pyrite-bearing metamorphic rocks, and thus exhibits both an oxidized Fe and reduced S cycle. In the middle reaches, the river moves through developed land where treated, imported high sulfate Colorado River water enters from urban runoff. Mast Park surrounded by caliche-bearing sedimentary rocks is a site where marl is precipitating. Cobbles in riffles in the river are coated black with Mn oxide. When the river encounters deep-seated volcanic bedrock, it wells up to precipitate both Fe and Mn oxides at Old Mission Dam. Then, directly flowing through caliche-laced sedimentary rocks, Birchcreek tributary precipitates tufa. Further downstream, at a site that periodically receives full sunlight, a sulfuretum sets up during the summer when the river is deoxygenated. Such a rich geochemistry results in activity of iron and manganese oxidizing bacteria, sulfur oxidizers and reducers, and cyanobacteria precipitating calcareous marl and tufa.

The toxic effects of 4-octylphenol (4-OP) have been studied in species such as mouse and fish; however, the toxic effects of 4-OP in male specific niche cells has not been researched. In this study, we investigated the molecular mechanism of toxicity of 4-OP in mouse TM4 Sertoli cells. TM4 cells were treated with four concentrations (0, 10, 30, and 50 µM/mL) of 4-OP at time points 24, 48, and 72 h. Cell viability and apoptosis assay was conducted following exposure. 4-OP significantly decreased cell viability in a concentration- and time-dependent manner, and increased apoptosis. Quantitative PCR analysis showed that Bad, Bax, and Bak mRNA expression levels were higher in exposed cells than in the control, but Bcl-2 expression was decreased. Western blotting revealed that 4-OP induced activities of caspase-3 and phosphorylation of Bad in a concentration- and time-dependent manner. Additionally, cytochrome C protein did not colocalize with mitochondria marker dye by 24 h. Cytochrome c protein expression increased in a time-dependent manner with 50 µM/mL. These results suggest that 4-OP induces mitochondria-mediated apoptosis by regulation of Bcl-2 family proteins and caspase-3 activation in male Sertoli cells.

Maintenance of integrity and function of the gastric mucosa (GM) requires a high regeneration rate of epithelial cells during the whole life span. The health of the gastric epithelium highly depends on redox homeostasis, antioxidant defense and activity of detoxifying systems within the cells as well as robustness of blood supply. Bioactive products of lipid peroxidation, in particular second messengers of free radicals, the bellwether of which is 4-hydroxynonenal (HNE), are important mediators in physiological adaptive reactions and signaling but they are also thought to be implicated in the pathogenesis of numerous gastric diseases. Molecular mechanisms and consequences of increased production of HNE and its protein adducts in response to stressors during acute and chronic gastric injury are well studied. However, several important issues related to the role of HNE in gastric carcinogenesis, tumor growth and progression, the condition of GM after eradication of Helicobacter pylori, or the relevance of antioxidants for HNE-related redox homeostasis in GM still need more studies and new comprehensive approaches. In this regard, preclinical studies and clinical intervention trials are required, which should also include the use of state-of-the-art analytical techniques such as HNE determination by immunohistochemistry and ELISA as well as modern mass-spectroscopy methods.

Immunotherapy has been considered for years as a viable and attractive treatment option for patients with cancer. Among immunotherapy arsenal, the targeting of intratumoral immune cells by immune-checkpoint inhibitory agents has recently revolutionized the treatment of several subtypes of tumours. These approaches aimed at restoring an effective anti-tumour immunity, rapidly reached the market thanks to the simultaneous identification of inhibitory signals that dampen an effective antitumor response in a large variety of neoplastic cells, and the clinical development of monoclonal antibodies targeting checkpoint receptors. Leading therapies in solid tumours are mainly focused on the cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4) and programmed-death 1 (PD-1) pathways. These approaches have found a promising testing ground in both Hodgkin lymphoma and non-Hodgkin lymphoma, mainly because in these diseases the malignant cells interact with the immune system and commonly provide signals that regulate immune function. Although several trials have already demonstrated evidence of therapeutic activity with some checkpoint inhibitors in lymphoma, many of the immunologic lessons learned from solid tumours may not directly translate to lymphoid malignancies. In this sense, the mechanisms of effective antitumor responses are different between the different lymphoma subtypes, while the reasons for this substantial difference remain partially unknown. This review will discuss the current advances of immune-checkpoint blockade therapies in B-cell lymphoma and will build a projection of how the field may evolve in the near future. In particular, we will analyze the current strategies being evaluated both preclinically and clinically with the aim to foster the use of immune-checkpoint inhibitors in non-Hodgkin lymphoma, including combination approaches with chemotherapeutics, biological agents and/or different immunologic therapies.

Crimean-Congo hemorrhagic fever virus (CCHFV) is the causative agent of a tick-borne infection with significant mortality rate of up to 40% in the endemic areas, with evidence for geographical expansion. Lacking effective therapeutics and control measures, the development of protective CCHFV vaccine remains a crucial public health task. This manuscript describes, for the first time, a Bovine herpesvirus type 4 (BoHV-4) based viral vector (BoHV4-∆TK-CCHFV-N) and its immunogenicity and protection potential in BALB/c and IFNAR^-/- mice models in comparison with Adenovirus type 5 (Ad5-N) and pCDNA3.1 myc/His A (pCD-N1), two widely used vaccine platforms. All constructs expressing viral nucleocapsid (N) protein successfully elicited cytokine and total/specific antibody responses in BALB/c mice. BoHV4-∆TK-CCHFV-N and Ad5-N constructs further produced 100% protection in IFNAR^-/- mice during CCHFV Ank-2 strain lethal challenge. Despite elevated specific antibody responses in both animal models, the produced antibodies were unable to neutralize the virus in vitro. A comparison of delivery platforms was not possible, due to similar protection rates in IFNAR^-/- mice. In conclusion, vector-based CCHFV N protein expression proved to constitute an effective approach for the vaccine development pipeline and BoHV-4 emerged as a strong alternative to previously-used virus vectors.

Premature ovarian insufficiency (POI) is a highly prevalent disorder, characterized by the development of menopause before age of 40. Most cases are idiopathic; however, in some women the cause of this condition (e.g. anticancer treatment, genetic disorders, and enzymatic defects) may be identified. Although hormone replacement therapy, the principal therapeutic approach for POI, helps to alleviate the related symptoms, this does not effectively solve the issue of fertility. Assisted reproductive techniques also lack efficacy in these women. Thus, the effective approach to manage the patients with POI is highly warranted. Several mechanisms, associated with POI, have been identified, including lack of FSH receptor functioning, alterations in the apoptosis control, mutations in Sal-like 4 genes, thymulin or basonuclin-1 deficiency etc. The above-mentioned may be good targets for gene therapy in order to correct defects, leading to POI. The goal of this review is to summarize the current experience on the POI studies, that employed gene therapy, and to discuss the possible future directions in this field.

We live in the time of profound transformations commonly labelled with the word “globalization”. The rise of one ecological-technological-social system encompassing our whole planet is an important element of these processes. Solving big global problems demands knowledge of two complementary sorts: on the one hand – going “in depth”, on the other – going “in breadth”. The present paper assumes the second (in a sense: philosophical) perspective. It tries to analyze some relations between the development of technology (IT) and the development of democracy. The notion of democracy, its various forms and axiological reasons for it are considered first. In the subsequent chapter different consequences (both positive and negative) the IT development has for contemporary democracy are discussed. In the next chapter the evolutionary nature of the technological development is debated as well as the question of (democratic) control of this process. The development of Artificial General Intelligence is presented as a challenge for democracy

Objective: Diabetes is associated with increased cardiovascular and cerebrovascular disease-related mortality. We investigated the association between carotid intima-media thickness (CIMT) with clusterin (CLU), amylin, secreted frizzled-related protein-4 (SFRP-4), total and active glucagon-like peptide-1 (GLP-1) levels, and dipeptidyl peptidase-4 (DPP-4) in type 2 diabetes mellitus (T2DM) individuals with or without coronary artery disease (CAD). Methods: This study consisted of four groups in Medicine Hospital between April- October, 2017: Control group (mean ages: 50.3 ± 10.7 years, 20 females and 15 males), diabetic group (DM) (mean ages: 53.9 ± 11.1, 14 females and 23 males), CAD group (mean ages: 62.6 ± 11.8, 17 females and 17 males) and CAD+ DM group: (mean ages: 62.6 ± 11.8 years, 18 females and 18 males). Results: Both CAD and CAD+DM groups have higher CIMT levels than controls. CAD+DM group have also significantly higher CIMT levels than DM group. Left external carotid artery (ECA) was only found different in DM group from controls. When compared with controls, DM, CAD groups have low DPP-4 and GLP-1_total concentration. Control group have significantly lower SFRP-4 levels than DM, CAD and CAD+DM (p<0.001) groups. Serum GLP-1_total levels were found to be significantly low in CAD+DM group when compared to control group. Conclusion: DPP-4 and SFRP-4 levels are predictive marker for atherosclerosis in diabetes, correlates well with HOMA-IR particularly in diabetes. CIMT has the potential to be a clinically useful predictor of vascular risk in diabetic patients with CAD. Large cohorts and at-risk populations are needed to confirm the predictive value of these findings.

The glycosaminoglycan, heparan sulphate (HS), orchestrates many developmental processes. Yet its biological role has not yet fully been elucidated. Small molecule chemical inhibitors can be used to perturb HS function and these compounds pro-vide cheap alternatives to genetic manipulation methods. However, existing chemical inhibition methods for HS also interfere with chondroitin sulphate (CS), complicating data interpretation of HS function. Herein, a simple method for the selective inhibition of HS biosynthesis is described. Using endogenous metabolic sugar pathways, Ac4GalNAz produces UDP-GlcNAz, which can target HS synthesis. Cell treatment with Ac4GalNAz resulted in defective chain elongation of the polymer and decreased HS expression. Conversely, no adverse effect on CS production was observed. The inhibition was transient and dose-dependent, affording rescue of HS expression after removal of the unnatural azido sugar. The utility of inhibition is demonstrated in cell culture and in whole or-ganisms, demonstrating that this small molecule can be used as a tool for HS inhibition in biological systems.

The Chang’e-4 (CE-4) lunar rover, equipped with The Visible and Near-IR Imaging Spectrometer(VNIS) which based on acousto-optic tunable filter spectroscopy, was launched to the far side of the moon on December 8, 2018. The detection band of VNIS ranges from 0.45 to 2.4μm. Because of the weak reflection of infrared radiation from the lunar surface, a static electronic phase-locked acquisition method is adopted in the infrared channel for signal amplification. In this paper, full-link simulations and modeling are conducted of the infrared channel information flow of the instrument. The signal/noise characteristics of VNIS are analyzed in depth, and the signal-to-noise(SNR) ratio prediction and laboratory verification are presented. On January 4, 2019, the VNIS started working successfully and acquired high-resolution spectrum data of the far side of the moon for the first time. Through analysis, the SNR ratio is in line with predictions, and the data obtained by VNIS in orbit are consistent with the information model proposed in this paper.