Abstract: Breast cancer is one of the leading causes of death in the female population due to the re-sistance of cancer cells to many anticancer drugs used. Curcumin has cytotoxic activities against breast cancer cells, although it has limited use due to its poor bioavailability and rapid metabolic elimination. The synthesis of metal complexes of curcumin and curcuminoids is a relevant topic in the search for more active and selective derivatives of these molecular scaffolds. However, solubil-ity and bioavailability are concomitant disadvantages of these types of molecules. To overcome such drawbacks, the preparation of inclusion complexes offers a chemical and pharmacologically safe option for improving the aqueous solubility of organic molecules. Herein, we describe the preparation of the inclusion complex of dimethoxy curcumin magnesium complex with cyclodex-trin (DiMeOC-Mg-BCD, 5) in the stoichiometric relationship 1:1. This new inclusion complex's solubility in aqueous media (PBS) was improved by a factor of 6x over the free metal complex (DiMeOC-Mg). Furthermore, 5 affects cell metabolic rate, cell morphology, cell migration, induced apoptosis, and downregulation of the MMP-2 and MMP-9, IL-6, and STAT3 expression levels on MDA MB 231 cell lines. Results of an antitumor assay in an in-ovo model showed up to 30% inhi-bition of tumour growth for breast cancer (MDA-MB-231) when using 5 (0.650 mg/Kg dose), and 17.29 % inhibition with the free homoleptic metal complex (1.5 mg/Kg dose, DiMeOC-Mg). While the formulation of inclusion complexes from metal complexes of curcuminoids demonstrates its usefulness in improving the solubility and bioavailability of these metallodrugs, the new DiMeOC-Mg-BCD exhibits excellent potential for use as a therapeutic agent in the battle against breast cancer.

: Intracellular tripeptide glutathione is an important agent of cell survival in hypoxia. Glutathione covalently binds to SH-groups of hemoglobin cysteine residues, protecting them from irreversible oxidation and changes its affinity to oxygen. Reduced glutathione (GSH) can also form a non-covalent complex with hemoglobin. Previously, we showed that hemoglobin tetramer has four noncovalent binding sites of glutathione GSH molecules inside, two of which are released during hemoglobin transition to deoxy form. In this study, we characterized the conserved cysteine residues and residues of non-covalent glutathione binding sites in the sequences of a number of hypoxia tolerant and hypoxia-sensitive mammals. The alpha subunit of all species considered was found to have no conserved cysteines, whereas the beta subunit contains Cys94 residue, which is conserved across species and whose glutathionylation changes the affinity of hemoglobin for oxygen 5-6-fold. In addition, the key residues of noncovalent glutathione binding sites in both alpha and beta subunits are absolutely conserved in all species considered, suggesting a common mechanism of hemoglobin redox regulation for both hypoxia-sensitive and hypoxia-tolerant mammals. The solvent accessibility of all HbA and HbB residues in oxy- and deoxy- forms was analyzed. The key residue betaCys94 is solvent accessible only in the deoxy form.

In diabetic foot infections (DFI), the clinically virulence of skin commensals are generally pre-sumed to be of low virulence. In this single-center study, we divided the wound isolates into two groups: skin commensals (coagulase-negative staphylococci, micrococci, corynebacteria, cutibacteria); and, pyogenicpathogenic pathogens, and followed the patients for ≥ 6 months. In this retrospective study among 1,018 DFI episodes (392 [39%] with osteomyelitis), we identified skin commensals as the sole culture isolates (without accompanying pyogenicpathogenic patho-gens) in 54 cases (5%). After treatment (antibiotic therapy [median of 20 days], hyperbaric oxy-gen in 98 cases [10%]), 251 episodes (25%) were clinical failures. Group comparisons between those growing only skin commensals and controls found no difference in clinical failure (17% vs 24 %, p=0.23) or microbiological recurrence (11% vs 17 %, p=0.23). The skin commensals were mostly treated with non-beta-lactam oral antibiotics. In multivariate logistic regression analysis, isolation of only skin commensals was not associated with failure (odds ratio 0.4, 95% confi-dence interval 0.1-3.8). Clinicians might wish to consider these isolates as potential pathogens when selecting a targeted antibiotic regimen, which may equally base on oral non-beta-lactam antibiotic agents susceptible to the corresponding skin pathogens.

Plasmodium species that cause malaria, a disease responsible for about half a million deaths per annum despite concerted efforts to combat it. The causative agent depends on type III beta phosphatidylinositol 4-kinase (PPI4K) during the development of merozoite. PPI4K is the only clinically validated Plasmodium kinase so far and its inhibitors are effective both in vitro and in vivo. In this work, a small library of ~22 000 fragments was virtually screened using PPI4K homology model to discover potential ligands of the enzyme. 16 virtual hits were selected based on ≤ -9.0 kcal/mol binding energy cut off and were subjected to similarity and substructure searching after they had passed PAINS screening. The derivatives obtained showed improved binding energies, which ranged from -10.00 to -13.80 kcal/mol. Moreover, the topmost ranking compound 31, with interesting drug-like quality was stable within the protein’s binding cavity during the 10 ns molecular dynamics simulation period. In addition, analysis of its binding pose revealed some unique binding interactions with PPI4K active site residues as the basis for the observed improved binding affinity. Overall, compound 31 appears to be a viable starting point for the development of PPI4K inhibitors with antimalarial activity.

Medicinal plants possess a surplus of novel and biologically active secondary metabolites that are responsible for counteracting diseases. Traditionally, Gomphandra tetrandra (Wall.) Sleumer is used to treat mental disorders. The present research was designed to explore phytochemicals from the ethanol leaf extract of Gomphandra tetrandra (Wall.) Sleumer to identify the potential pharmacophore(s) in the treatment of neurological disorders. The chemical compounds of the experimental plant were identified through GC-MS analysis. Besides, in-vitro antioxidant activity was assessed using different methods. Furthermore, in-vivo neurological activity was assessed in Swiss-albino mice. Computer aided analysis was appraised to determine the best-fit phytoconstituent of a total of fifteen identified compounds in the experimental plant extract against beta-amyloid precursor protein. The experimental extract revealed fifteen compounds in GC-MS analysis and the highest content was 9, 12, 15-octadecatrienoic acid (Z, Z, Z). Also, the extract showed potent anti-oxidant activity in in-vitro assays. Furthermore, in in-vivo neurological assays, the extract disclosed significant (p<0.05) neurological activity. The most favorable phytochemicals as neurological agents were selected via ADMET profiling and molecular docking was studied with beta-amyloid precursor protein. Moreover, in the computer aided study, 1, 5-Diphenyl-2H-1, 2, 4-triazoline-3-thione (Pub Chem CID: 2802516) was more active than other identified compounds with strong binding affinity to beta-amyloid precursor protein. The present in vivo and in silico studies revealed neuropharmacological features of G. tetrandra leaves extract as a natural agent against neurological disorders, especially Alzheimer’s disease.

During type 1 diabetes mellitus (T1DM) development, beta-cells undergo intense endoplasmic reticulum (ER) stress that could result in apoptosis through the failure of adaptation to the unfolded protein response (UPR). Islet transplantation is considered an attractive alternative among beta-cell replacement therapies for T1DM. To avoid the loss of beta-cells that will jeopardize the transplant´s outcome, several strategies are being studied. We have previously shown that prolactin induces protection against pro-inflammatory cytokines and redox imbalance-induced beta-cell death by increasing heat shock protein B1 (HSPB1) levels. Since the role of HSPB1 in beta cells has not been deeply studied, we investigated the mechanisms involved in unbalanced protein homeostasis caused by intense ER stress and overload of the proteasomal protein degradation pathway. We tested whether HSPB1-mediated cytoprotective effects involved UPR modulation and improvement of protein degradation via the ubiquitin-proteasome system. We demonstrated that increased levels of HSPB1: attenuated levels of pro-apoptotic proteins like CHOP and BIM, increased protein ubiquitination and the speed of proteasomal protein degradation. Our data showed that HSPB1 induced resistance to proteotoxic stress and thus enhanced cell survival via an increase in beta-cell proteolytic capacity. These results could contribute to generate strategies aiming at optimization of beta-cell replacement therapies.

Study of gross alpha (GA) and gross beta (GB) activity in road and surface deposited sediments were performed in various geographical areas in three Russian cities. To perform radiation measurements, new methods were applied which allow dealing with low mass and low volume dust size (2-100μm) samples obtained after the size fractionation procedure. The 2-10 μm fraction size has the highest gross beta activity concentration (GB)– 1.32Bq/g in Nizhny Novgorod (NN) and Rostov-On-Don (RND) while the 50-100 μm fraction size in Ekaterinburg. This is maybe associated with the subsistence of radionuclides that conveyed through natural processes and anthropogenic applications. The highest gross alpha activity concentration (GA) in fraction sizes was found in Rostov-on-Don city within the 50-100 μm– 0.22Bq/g. The fraction size 50-100 μmhas a higher gross alpha activity concentration than 2-10 and 10-50 μmfraction sizes due to natural partitioning of the main minerals constituting the urban surface deposited sediment (USDS). The geochemical processes that occur during the formation and transportation of USDS are reflected in the observed dependencies.Developed experimental methods of radiation measurements allowed to the extent the methodological base of urban geochemical studies.

The astacin protease Meprin β represents an emerging target for drug development due to its potential involvement in disorders such as acute and chronic kidney injury and fibrosis. Here, we elaborate on the structural basis of inhibition by a specific Meprin β inhibitor. Our analysis of the crystal structure suggests different binding modes of the inhibitor to the active site. This flexibility is caused, at least in part, by movement of the C-terminal region of the protease domain (CTD). The CTD movement narrows the active site cleft upon inhibitor binding. Compared with other astacin proteases, among those the highly homologous isoenzyme Meprin α, differences in the subsites account for the unique selectivity of the inhibitor. Although the inhibitor shows substantial flexibility in the orientation within the active site, the structural data as well as binding analyses including molecular dynamics simulations support a contribution of electrostatic interactions, presumably by arginine residues, to binding and specificity. Collectively, the results presented here and previously support an induced fit and substantial movement of the CTD upon ligand binding and, possibly, during catalysis. To the best of our knowledge, we here present the first structure of a Meprin β holoenzyme containing a zinc ion and a specific inhibitor bound to the active site. The structural data will guide rational drug design and the discovery of highly potent Meprin inhibitors.

Cancer immunotherapy reaches a remarkable achievement in various cancer types and brings new possibilities to improve cancer patients’ long-term survival. However, outcomes vary from case to case, and the present protocol benefits a small fraction of patients. One notable factor is the tumor microenvironment, especially the immune cell components, that may reflect the immune response's status quo on site. Thus, understanding the content of infiltrating immune cells in tumors is not only for research interesting but also a crucial subject toward precision medicine. We implement an algorithm for resolving relative proportions of twenty-one immune cell subclasses from a human tissue profiled transcriptome by microarray technology to reach the goal above. By selecting gene features and then adopting ?-Support Vector Regression, we can construct a deconvolution model and resolve the immune cell context. The excellent consistency between the estimated values and the correct immune-cell composition further demonstrates this approach provides a more natural alternative to revealing samples' immune cell content and reliable results like recent single-cell technologies. Based on this algorithm, the web-based deconvolution tool implemented named mySORT provides a user-friendly interface for estimating the immune cell content by uploading gene expression profiling. We also present comprehensive visualization 2D/3D plots in mySORT so that users can easily make a comparison between different samples. Finally, we synthesized pseudo-bulk expression data from single-cell transcriptomic datasets of 17 melanoma and 16 head and neck cancer patients. The deconvolution results of microarray-based data in the previous study and synthetic pseudo-bulk data all proved the excellent performance of mySORT. We believe that mySORT can help researchers in all fields easily understand complex immune microenvironment. The website of mySORT is freely accessible on https://symbiosis.iis.sinica.edu.tw/mySORT/.

In this brief communication, we propose the concept that capillary regression may represent a primary pathogenic process underlying COVID-19 infection, particularly in the serious and life-threatening manifestations of the disease. We suggest that the marked elevations of pro-inflammatory mediators that are observed in these seriously ill patients may directly induce capillary regression and endothelial cell (EC) loss. Recent autopsy studies are demonstrating EC loss leading to widespread microthrombi and associated tissue damage. Recent work has indicated that interleukin-1 beta (IL-1β), tumor necrosis factor-alpha (TNFα), and thrombin, individually and in combination, can potently cause capillary tube regression in experimental models in vitro and in vivo. Other pro-inflammatory mediators including interferon gamma (IFNγ), interleukin-4 (IL-4), and interleukin-13 (IL-13) were also shown to be pro-regressive and could be relevant mediators in COVID-19 patients. Interestingly, combinations of pharmacologic agents were identified that reduced capillary regression and protected capillary tube networks against these pro-inflammatory mediators. Such an approach might be an important therapeutic option going forward to treat key disease states where capillary regression plays a major underlying pathogenic role. Finally, if capillary regression is occurring in response to these pro-inflammatory mediators during COVID-19 infection, we suggest that combinations of blocking agents directed to these key pro-regressive mediators might be necessary to appropriately treat patients.

The novel coronavirus pneumonia (COVID-19) is a contagious acute respiratory infectious disease whose causative agent has been demonstrated to be a novel virus of the coronavirus family, SARSCoV-2. A recent pre-print study has showed a heme attack on the 1-beta chain of hemoglobin by COVID19. Beta-thalassemia results of a default in the hemoglobin beta- chain synthesis. 1,5% global population are heterozygotes for this disease. In this study, by a multiple linear regression, we have analyzed the evolution of COVID-19 infection in three Italian regions (Puglia, Sardinia, Sicilia) with different beta-thalassemic prevalences, in order to search a link. The results have showed that betathalassemic heterozygote population prevalence is correlated to immunity against COVID-19, by a regression. This paper is only for academic discussion, the hypotheses and conclusions needs to be confirmed by further research .

Given the high prevalence of cutaneous genus beta human papillomavirus (β-HPV) infections, it is important to understand how they are manipulating their host cells. This is particularly true for cellular responses to UV damage, since our skin is continually exposed to UV. The E6 protein from β-HPV (β-HPV E6) decreases the abundance of two essential UV-repair kinases (ATM and ATR). Since β-HPV E6 reduces their availability, the impact on downstream signaling events has been uncertain. We demonstrate that β-HPV E6 decreases ATM and ATR activation. This inhibition extended to XPA, an ATR target necessary for UV repair, lowering both its phosphorylation and accumulation. β-HPV E6 hinders POLη phosphorylation and foci formation, critical steps in translesion synthesis. ATM’s phosphorylation of BRCA1 is also attenuated by β-HPV E6. However, β-HPV E6’s hindrance of ATM/ATR signaling during UV-associated cell cycle arrest was incomplete. While there was less phosphorylation of immediate downstream targets (CHK1), events further down the cascade were not decreased. These observations are consistent with β-HPV infections making UV radiation more deleterious and support the proposed role of β-HPV in early stages of non-melanoma skin cancer development.

In the paper, the author presents explicit and unified expressions for a sequence of improper integrals in terms of the beta functions and the Wallis ratios. Hereafter, the author derives integral representations for the Catalan numbers originating from combinatorics.

Looking for effective synthetic methods for 1H-pyrazolo[3,4-b]quinolines preparation, we came across a procedure where in a three component reaction catalyzed by L-proline, 4-aryl-4,9-dihydro-1H-pyrazolo[3,4-b]quinolines are formed. These compounds can be easily oxidized to a fully aromatic system, which gave hope for a synthetic method that could replace e.g. Friedländer condensation, often used for this purpose, although severely limited by the availability of suitable substrates. However, after careful repetition of the procedures described in the publication, it turned out that the compounds described therein do not form at all. The actual compounds turned out to be 4,4-(phenylmethylene)-bis-(3-methyl-1-phenylpyrazol-5-oles). 4-Aryl-4,9-dihydro-1H-pyrazolo[3,4-b]quinolines were prepared by another method and used as standards to compare the products formed in the original procedure.

Thermal sterilization is generally avoided for 3-D printed components because of the relatively low deformation temperatures for common thermoplastics used for material extrusion-based additive manufacturing. 3-D printing materials required for high-temperature heat sterilizable components for COVID-19 and other applications demands 3-D printers with heated beds, hot ends that can reach higher temperatures than polytetrafluoroethylene (PTFE) hot ends and heated chambers to avoid part warping and delamination. There are several high temperature printers on the market, but their high costs make them inaccessible for full home-based distributed manufacturing required during pandemic lockdowns. To allow for all these requirements to be met for under $1,000, the Cerberus – an open source three-headed self-replicating rapid prototyper (RepRap) was designed and tested with the following capabilities: i) 200^oC-capable heated bed, ii) 500^oC-capabel hot end, iii) isolated heated chamber with 1kW space heater core and iv) mains voltage chamber and bed heating for rapid start. The Cereberus successfully prints polyetherketoneketone (PEKK) and polyetherimide (PEI, ULTEM) with tensile strengths of 77.5 and 80.5 MPa, respectively. As a case study, open source face masks were 3-D printed in PEKK and shown not to warp upon widely home-accessible oven-based sterilization.

This study presents an optimized design for a Segmented Sinusoidal Parameter Winding with Magnetic Wedge Variable Reluctance Resolver (SSPWMW-VRR), addressing challenges like winding asymmetry and harmonic distortion in conventional designs. By integrating Particle Swarm Optimization (PSO) for winding design, Magnetic Equivalent Circuit (MEC) analysis for leakage flux, and machine learning techniques (XGBoost and Multi-Layer Perceptron), the stator slot shape was fine-tuned for improved accuracy. XGBoost outperformed MLP in prediction accuracy with a Mean Absolute Error (MAE) of 0.1172. Finite Element Analysis (FEA) simulations and experimental validation demonstrated a reduction in position errors from ±30’ in conventional VRRs to ±5’ in the optimized design, along with significant harmonic reduction.

The dietary supplement industry is a growing market with a variety of suppliers, producers, and distributors in terms of size and quality. Because of the little amount of regulation placed on the dietary supplement industry compared to the pharmaceutical industry in the United States, there is less pressure on supplement companies ensure that their labels accurately reflect the actual product’s content. There are few studies on the quality of fish oil sold in the U.S., particularly about quantitation of ω-3 fatty acids, specifically eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). The aim of this study was to compare the amount of ω-3 fatty acids found in fish oil capsules and liquids bought from local stores to their label claim. Of the 16 fish oil products tested, 6 were ± 20% outside of the label claim for EPA and 10 of 15 were ± 20% outside of the label claim for DHA. One product did not have a label claim for DHA. The large variance in the amount of omega-3s from the product label could mislead consumers to ingesting significantly more or less than expected.

In previous papers we have derived equations of motion with radiation terms and proved the existence-uniqueness of periodic solution of the 3-body problem of classical electrodynamics. The number of equations of motion – 12 is more than the number of unknown functions – 9. It turns out that 9 equations are independent and the rest 3 ones are consequences of them. These three equations have a solution and they give the expressions for the energy of the moving particles. The main goal of the present paper is to estimate the energy of rounding about the nuclei particles and compare it with the values given by quantum mechanics.

Obesity is associated with chronic low-grade inflammation. Polyunsaturated fatty ac-ids such as omega-3 (n-3), are essential in the pro-resolution of inflammation. An 8-week double-blind randomized clinical trial was conducted with a n-6:n-3, 5:1 ratio, along with daily 1.8 g of n-3 supplementation vs. placebo. A total of 40 subjects were included, 21 in omega 3 group and 19 in placebo group. The n-3 supplementation had a superior effect compared to placebo increasing levels of Resolvin D1 [129.3 (-90.1 - 193.5) vs. -16.8 (-237.8 - 92.5) pg/mL, p=0.041], IL-10 [1.4 (-0.7 - 4.6) vs. -2.0 (-5 - 0.05) pg/mL, p=0.001], and decreasing IL-6 [-0.67 (2.72 - -0.59) vs. 0.03 (-0.59 - 1.84) pg/mL p=0.015], and MCP-1 [-29.6 (-94.9 - 5.50) vs. 18.3 (-97.3 - 66.35) pg/mL, p=0.040]. In con-clusion, n-3 supplementation promoted resolution of inflammation by increasing sys-temic levels of Resolvin D1, IL-10, and decreasing IL-6 and MCP-1.

This paper, from the perspective of Mode 3 of knowledge production, takes the important carrier of knowledge, scientific research papers, as the research object. The mainstream databases (SCIE and SSCI) are chosen as the data sources. Firstly, bibliometric methods are applied to analyze the cooperation status among the main bodies of paper production, including authors and their affiliated institutions, countries, and disciplines; secondly, the Analytic Hierarchy Process (AHP) is used to construct a comprehensive evaluation model for the state of research cooperation in carbon neutrality. Based on the evaluation model, the cooperation characteristics of different disciplinary fields and the relationship between paper cooperation status and high-impact research papers are comparatively analyzed. At the same time, an analysis is conducted on the support from the government, the sponsorship from enterprises, and the participation of the public in the process of paper production. Finally, some suggestions are put forward on how to build an innovative ecosystem for carbon neutrality research from the perspective of Mode 3 of knowledge production.

International law faces numerous challenges in the 21st century, ranging from the traditional issues of sovereignty to emerging threats like cyber warfare and climate change. This article explores the evolving landscape of international law, discussing both the challenges it faces and the prospects for its future. By examining the role of international organizations, the impact of technological advancements, and the growing influence of non-state actors, this article provides a comprehensive overview of the current state of international law and offers insights into how it can adapt to meet the demands of an increasingly interconnected world.

Businesses now formally enter the phase of "think power differentiation and gap" in response to the new economic climate. While AI, big data, empowerment via the internet, and other aspects of the digital economy help to improve technical capabilities and save operating costs, they also push businesses to innovate their strategies at a faster rate. Enterprises are strategically choosing to de-enterprise, moving from focusing on a single business functioning benefit to building an ecosystem of platform services that will give them a competitive edge. Additionally, the organization's structure is evolving continually from a vertical model to a curved working style, in order to achieve this, businesses must recognize the importance of data analysis in day-to-day management and operations, encourage the development of an organizational atmosphere that is driven by data, fully utilize digital technology, modularize areas or production links that perform related tasks, and encourage the reform of organizational structures. By streamlining the output of the product or service to the external community while also enhancing the company's financial performance model, switching from process-to result-oriented evaluation, and putting in place a customized authority and accountability framework. Replace outcome-focused evaluation with process-focused evaluation, and create a customized incentive scheme that balances power, accountability, and rewards.

Abstract: Effectiveness of a Single Fixed Dose 3 mg Rasburicase for Prevention and Management of Hyperuricemia of Tumor Lysis Syndrome in adult Cancer Patients Background: Tumor lysis syndrome (TLS) is a potentially life-threatening complication associated with certain types of cancer. Rasburicase is an essential medicine required to prevent and treat the hyperuricemia associated with TLS. Due to a shortage of rasburicase during the COVID-19 pandemic, a fixed dose strategy of 3 mg rasburicase had been used in many adult cancer patients in our center. Objective: The objective of this study was to assess the effectiveness of a 3 mg fixed dose of rasburicase in preventing and managing hyperuricemia associated with TLS in adult cancer patients. Methods: We conducted a retrospective, observational cohort study between March 2020 and November 2022. The study included adult patients who received a fixed dose of 3 mg rasburicase. The primary outcome measure was the reduction in serum UA levels of

Mechanical ventilation (MV), used in patients with acute lung injury (ALI), induces diaphragmatic myofiber atrophy and contractile inactivity, termed ventilator-induced diaphragm dysfunction. Phosphoinositide 3-kinase- (PI3K-) is crucial in modulating fibrogenesis during the reparative phase of ALI; however, the mechanisms regulating the interactions among MV, myofiber fibrosis, and PI3K- remain unclear. We hypothesized MV with or without bleomycin treatment would increase diaphragm muscle fibrosis through the PI3K- pathway. Five days after receiving a single bolus of 0.075 units bleomycin intratracheally, C57BL/6 mice were exposed to 6 or 10 mL/kg MV for 8 h after receiving 5 mg/kg of AS605240 intraperitoneally. In wild-type mice, bleomycin exposure followed by MV 10 mL/kg prompted significant increases in disruptions of diaphragmatic myofibrillar organization, transforming growth factor-1, oxidative loads, Masson’s trichrome staining, extracellular collagen levels, positive staining of -smooth muscle actin, PI3K- expression, and myonuclear apoptosis (P &lt; 0.05). Decreased diaphragm contractility and peroxisome proliferator activated receptor- coactivator-1 levels were also observed (P &lt; 0.05). MV-augmented bleomycin-induced diaphragm fibrosis and myonuclear apoptosis were attenuated in PI3K-γ-deficient mice and through AS605240-induced inhibition of PI3K- activity (P &lt; 0.05). MV-augmented diaphragm fibrosis after bleomycin-induced ALI is partially mediated through PI3K-γ. Therapy targeting PI3K-γ may ameliorate MV-associated diaphragm fibrosis.

Lysophosphatidic acid (LPA) type 3 (LPA3) receptor mutants were generated in which the sites detected phosphorylated were substituted by non-phosphorylatable amino acids. Substitutions were made in the intracellular loop 3 (IL3 mutant), the carboxyl terminus (Ctail), and both domains (IL3/Ctail). The wild-type (WT) receptor and the mutants were expressed in T-REx HEK293 cells, and the consequences of the substitutions were analyzed employing different functional parameters. Agonist- and LPA-mediated receptor phosphorylation was diminished in the IL3 and Ctail mutants and essentially abolished in the IL3/Ctail mutant, indicating that the main sites were substituted and distributed in both domains. The WT and mutant receptors increased intracellular calcium and ERK 1/2 phosphorylation in response to LPA and PMA. An increase in baseline ERK phosphorylation was detected in the IL3/Ctail mutant. LPA and PMA-induced receptor interaction with β-arrestin 2 and LPA3 internalization were severely diminished in the mutants. Mutant-expressing cells also exhibit increased baseline proliferation and response to different stimuli, which were inhibited by the antagonist Ki16425, suggesting a role of LPA receptors in this process. Migration in response to different attractants was markedly increased in the Ctail mutant, which the Ki16425 antagonist also attenuated.

The main purpose of this article is to consider the smoothness control of a weak solution after some moment if there is known solution regularity until this moment. The necessary tools can be varied. It is possible to control kinetic energy dissipation to fix moment or changing of velocity square or summability of acceleration square to fix at point time.

Abstract: Cervical cancer, which is the fourth most common malignancy and the fourth greatest cause of cancer-related deaths in women globally, continues to be a serious issue for global health. Despite advancements in treatment techniques, particularly the implementation of concomitant chemoradiation therapy, predicting the prognosis of locally advanced cervical cancer, especially for stage III, remains challenging. In recent years, neoadjuvant chemotherapy (NACT) has gained interest as a viable treatment strategy. The objective of this review paper is to scrutinize the clinical data and outcomes associated with NACT in the management of stage 3 cervical cancer. Electronic databases were used to perform a comprehensive literature search, and research up to 2023 were included. The findings suggest that NACT followed by irradiation may have advantages such as lowering tumor size, pelvic architectural distortion, and subclinical distant metastases, therefore enhancing radiation delivery. However, several studies have produced conflicting findings, raising questions regarding toxicity and finding no appreciable survival benefit over radiation alone. NACT followed by radical surgery has demonstrated more promising outcomes compared to surgery alone in terms of increasing rates of overall survival (OS) and progression-free survival (PFS). Additionally, NACT has been associated with decreased tumor growth, parametrial infiltration, nodal, metastases, and vascular space invasion. These findings suggest adjuvant radiation treatment. Although the overall survival rate has been markedly increased by concomitant chemoradiation treatment, metastatic disease continues to be a major factor in the death rate from cervical cancer. Therefore, improving outcomes in locally advanced cervical cancer requires investigating novel systemic treatments, such as NACT. The study also emphasizes how crucial it is to research factors like cisplatin dose-intensity and cycle lengths in order to maximize NACT's efficacy. To prevent the need for subsequent treatments and cumulative toxicity, more study should concentrate on patient selection for NACT followed by surgery.

A new approach is presented for dynamic modeling of chemical and isotopic evolution of C1-3 during the hydrocarbon generation process. Based on systematic data obtained from published papers for pyrolysis of various hydrocarbon sources(type I kerogen/source rock, type II kerogen/source rock, type III kerogen/source rock, crude oil, asphalt, etc), the empirical evolution framework of chemical and isotopic composition of C1-3 during the hydrocarbon generation process was built. Although the empirical framework was built only by fitting large amount of pyrolysis data, the chemical and isotopic composition of C1-3 derived from the pyrolysis experiments all follow the evolution laws, convincing us that it is applicable to the thermal evolution process of various hydrocarbon sources. Based on the simplified formula of the isotopic composition of mixed natural gas at different maturities (δ13Cmixed) δ13Cmixed=(X〖*n〗_iA 〖*δ〗^13 C_iA+Y〖*n〗_iB 〖*δ〗^13 C_iB)/(X〖*n〗_iA+Y〖*n〗_iB ), it can be derived that the cumulative isotopic composition of alkane generated in certain maturity interval can be expressed by the integral of the product of instantaneous isotopic composition and instantaneous yield at certain maturity point, and then divided by the cumulative yield of alkane generated in corresponding maturity interval. Thus, the cumulative isotopic composition(A(X)), cumulative yield(B(X)), instantaneous isotope(C(X)),and instantaneous yield(D(x)) in the dynamic model comply with the following formula during the maturity interval of (X0-X) A(X)=(∫_(X_0)^X▒〖C(X)*D(X)dx〗)/(B(X)), where A(X) and B(X) can be obtained by fitting of pyrolysis data, and D(x) can also be obtained from the derivation of B(X). The dynamic model was applied on the pyrolysis data of Pingliang Shale to illustrate the quantitative evolution of cumulative yield ,instantaneous yield, cumulative isotope and instantaneous isotope of C1-3 with increasing maturity.The dynamic model can quantify the yield of methane, ethane and propane as well as δ13C1, δ13C2 and δ13C3 respectively during the hydrocarbon generation process, which is of great significance to evaluate the natural gas resources of hydrocarbon source rock with different maturity and to identify the origin and evolutionary process of hydrocarbons by chemical and isotopic data. Moreover, this model provides an approach to study the dynamic evolution of isotope series of C1-3 (including reversed isotopic series), which is hopeful to reveal the mechanism responsible for isotopic reversal when combined with post-generation studies.

Introduction. This retrospective study aimed to compare the risk factors for vascular calcification (VC) between pre-hemodialysis (HD) and prevalent HD adult patients while investigating associations with calcification biomarkers. Methods. Baseline data from 30 pre-HD and 85 HD patients were analyzed, including iPTH, vitamin D, FGF23, fetuinA, sclerostin, and VC scores (Adragao method). Multivariable linear regression identified VC predictors. Results: The prevalence of VC was similar in both groups, but HD patients had more pronounced VC scores ≥6. Pre-HD patients were older, with higher prevalence of Balkan endemic nephropathy, hypertension, and less frequent use of calcium phosphate binders. Both groups exhibited similar patterns of hyperphosphatemia, low vitamin D, and iPTH levels. In HD group normal phosphate was significantly common in patients with VC, whereas hyperphosphatemia was significantly common in patients without VC. Fetuin-A levels were higher in pre-HD patients, while FGF23 was elevated in HD patients. In pre-HD patients, male gender was associated with reduced VC risk, while in HD patients, malignancies and serum phosphate levels were negative VC predictors. Conclusion: Effective monitoring and tailored treatment of VC in CKD are still focused on phosphate regulation. Besides, mineral disturbances, hormones and biomarkers regulation, and patient-specific variables need to be considered.

In the context of evaluating physical function in individuals with stroke, the 3-meter backward walk test (3MBWT) emerges as a potential tool of interest. The purpose of this study was to assess the test-retest reliability and construct validity of the 3MBWT and its correlation with falling incidents. Conducted in a neurological rehabilitation center, 35 ambulatory individuals with stroke were enrolled within a month post-stroke onset. These participants, with a Functional Ambulation Category score of ≥4, underwent the 3MBWT, Functional Gait Assessment (FGA), 10-Meter Walk Test (10MWT), and 6-Minute Walk Test (6MWT) three times by different physiotherapists. Results indicated the 3MBWT displayed high reliability (r=0.97-0.98) and showed significant construct validity with other established walking tests like the 6MWT (r=-0.78) and 10MWT (r=0.71), with a moderate correlation to the FGA (r=-0.54). No marked differences in test outcomes were observed between participants based on their fall history. Conclusively, the 3MBWT proves to be highly reliable and validates well with existing walking function assessments for stroke patients, suggesting its potential as a time-efficient alternative.

Breast cancer (BCa) is the most frequently diagnosed malignant tumor in women and is also one of the leading causes of cancer-related death. Most breast tumors are hormone-dependent and estrogen signaling plays a critical role in promoting the survival and malignant behaviors of these cells. Estrogen signaling involves ligand-activated cytoplasmic estrogen receptors that translocate to the nucleus with various co-regulators such as steroid receptor co-activator (SRC) family members, and bind to the promoters of target genes and regulate their expression. SRC-3 is a member of this family that interacts with, and enhances the transcriptional activity of the ligand activated estrogen receptor. Although SRC-3 has important roles in normal homeostasis and developmental processes, it has been shown to be amplified and overexpressed in breast cancer and to promote malignancy. The malignancy-promoting potential of SRC-3 is diverse and involves both promoting malignant behavior of tumor cells and creating a tumor microenvironment that has an immunosuppressive phenotype. SRC-3 also inhibits the recruitment of tumor-infiltrating lymphocytes with effector function and promotes stemness. Furthermore, SRC-3 is also involved in the development of resistance to hormone therapy and immunotherapy during breast cancer treatment. The versatility of SRC-3 in promoting breast cancer malignancy in this way makes it a good target, and methodical targeting of SRC-3 probably will be important for the success of breast cancer treatment.

Powdery mildew disease, caused by Sphaerotheca fusca, is a major disease affecting cucumbers cultivated in greenhouses. This study was conducted to find defense genes induced by DL-3-amino-butyric acid (BABA) and powdery mildew in cucumber. The 2000 and 5000 mg/L BABA treated cucumber exhibited disease severity of 25% and 5%, respectively, whereas the water treated cucumber leaves were severely infected, with a disease severity of 90%. BABA did not effect spore germination of the powdery mildew pathogen,. showing BABA is not antifungal agent against the pathogen. In quantitative real-time PCR analysis, BABA treated cucumber upregulated transcriptional level of the defense genes CsPAL, CsPR3,CsPR1, CsLOX1, CsLOX23, Cs LecRK6.1, CsWRKY20, and Cupi4 in cucumber to maximum levels at 48 h, whereas CsLecRK6.1 reached maximum expression after 24 h and futher salicylic acid (SA) levels were significantly increased in BABA-treated cucumber plants. In addition, the infected cucumber with powdery mildew enhanced the expression levels from1.6 to 47.3 fold of the defense genes PAL, PR3, PR1, Lox1, Lox 23, LecRK6.1, WRKY20, and Cupi4 compared to heathy cucumber. The results suggests the BABA induced defense response is associated with SA signal pathway-dependent systemic acquired resistance (SAR) in cucumber, which is involved in plant resistance mechanisms.

In urban Vehicular Ad Hoc Network (VANET) environments, buildings play a crucial role as they can act as obstacles that attenuate the transmission signal between vehicles. Quantifying the impact of buildings on the transmission quality is essential, especially in critical scenarios involving emergency vehicles, where reliable communication is of utmost importance. In this research, we propose a supervised learning approach based on artificial neural networks (ANNs) to develop a predictive model capable of estimating the level of signal degradation, represented by the bit error rate (BER), based on the obstacles perceived by moving emergency vehicles. By establishing a relationship between the level of signal degradation and the encountered obstacles, our proposed mechanism enables efficient routing decisions to be made prior to the transmission process. Consequently, data packets are routed through paths that exhibit the lowest BER. To gather the necessary training data, we employed SUMO and NS-3 simulations. The simulation results demonstrate that our developed model successfully learns and accurately estimates the BER for new data instances. Overall, our research contributes to enhancing the performance and reliability of communication in urban VANET environments, especially in critical scenarios involving emergency vehicles, by leveraging supervised learning and artificial neural networks to predict signal degradation levels and optimize routing decisions accordingly.

Indole-3-acetic acid (IAA) is a key vegetative hormone that plays crucial roles in plant growth and development. In this study, the effect of the exogenous application of IAA as a biostimulant in the cultivation of onions (Allium cepa) was investigated. Different IAA concentrations were evaluated to determine their effects on onion growth and chemical parameters. Various physical and chemical parameters such as total fresh weight, plant height, chlorophyll content, nitrates, total phenols, and antioxidant capacity (DPPH) were analyzed. The results revealed that exogenous application of IAA had a significant impact on onion growth and quality. Specifically, it was found that certain concentrations of IAA fostered a greater fresh weight of the bulb, an increase in the levels of phenolic compounds and a greater DPPH. However, the onion response to IAA was dependent on the concentration. In conclusion, the present study provides evidence that the exogenous application of IAA as a biostimulant can improve onion growth and quality. These results are relevant for the development of sustainable agricultural practices and could be oriented towards crop improvement.

The altimeter-derived ocean currents have been sparsely evaluated against in situ measurements in the Arctic, particularly for extended time periods. This study uses the extensive mooring array situated in the Fram Strait, representing one of the longest ocean current records, to investigate the relationship between in situ and satellite-derived currents in the region. The primary objective of this research is to analyze the vertical structure of the West Spitsbergen Current (WSC), its spatio-temporal coherence, and its association with surface geostrophic currents during the period of 1997-2012. To assess the vertical structure of the WSC, we utilized the Empirical Orthogonal Functions (EOF) and cross-correlation analysis between neighboring moorings. Remarkably, both velocity components exhibited robust vertical coherence, particularly within the waters of the North Atlantic Inflow, at depths exceeding 800 m. These findings underscore the potential for surface measurements to effectively complement data gaps and facilitate the reconstruction of deeper currents with a monthly temporal resolution. Notably, the surface measurements explain approximately 67% of the variance in the top 800 m of the water column.This comprehensive investigation advances our understanding of the West Spitsbergen Current and its vertical characteristics in the Arctic. Moreover, our findings highlight the valuable synergy between in situ and satellite-derived data, providing critical insights for future ocean current studies in this ecologically sensitive region.

Mutations in the Neuroligin-3 (Nlgn3) gene are implicated in autism spectrum disorder (ASD) and gastrointestinal (GI) dysfunction but cellular Nlgn3 expression in the enteric nervous system remains to be characterised. We combined RNAScope in situ hybridization for Nlgn3 mRNA and immunofluorescence for cholinergic and VIP-expressing submucosal neurons, nitrergic and calretinin-containing myenteric neurons and glial cells. We measured Nlgn3 mRNA neuronal and glial expression via quantitative 3-dimensional image analysis. To validate dual RNAScope/immunofluorescence data, we interrogated available single cell RNA sequencing (scRNASeq) data to assess for Nlgn3, Nlgn1, Nlgn2 and their binding partners, Nrxn1-3, MGDA1 and MGDA2, in enteric neural subsets. Most submucosal and myenteric neurons expressed Nlgn3 mRNA. In contrast to other Nlgns and binding partners, Nlgn3 was strongly expressed in enteric glia, suggesting a role for Neuroligin-3 in mediating enteric neuron-glia interactions. The autism-associated R451C mutation reduces Nlgn3 mRNA expression in cholinergic but not VIPergic submucosal neurons. In the myenteric plexus, Nlgn3 mRNA levels are reduced in calretinin and NOS labelled neurons and S100ß labelled glia. We provide a comprehensive cellular profile for neuroligin-3 expression in ileal neuronal subpopulations of mice expressing the R451C autism-associated mutation in Nlgn3, which may contribute to the understanding of the pathophysiology of GI dysfunction in ASD.

Chronic kidney disease (CKD) is actually considered a public health priority according to the increasing number of patients affected by this condition: this casuistry is not only related to specific glomerular, tubular or autoimmune diseases or a consequence of acute kidney injury (AKI) episodes leading to organ failure, but it is tied to the progression of life expectancy and the impact of comorbidities such as cardiovascular disease, diabetes and cancer. CKD and its comorbidities promote low grade inflammatory status with an impact on patients’ clinical conditions, reducing their possibility for kidney transplantation or graft survival and their survival when receiving renal replacement therapies such as hemodialysis (HD) or peritoneal dialysis (PD). CKD is often referred to as an ageing accelerator: innate immune system dysregulation, in the uraemic proinflammatory milieu, is involved in this accelerated senescence phenomena and pentraxins, particularly Pentraxin-3 (PTX-3), are of particular interest in the development of kidney disease. A complete understanding of the mechanism of CKD progression, innate immune system involvement and a proper definition of PTX-3 role in kidney disease, could redefine the approach for diagnosis and a more centered patients’ management to slow down CKD progression over time and reduce its clinical and social impact.

Porcine parvovirus (PPV) 1 is a major causative pathogen of reproductive failure, and porcine circovirus (PCV) 2 is an etiological pathogen causing PCV-associated and PCV diseases worldwide. PPV2–6 and PCV3 were recently identified as newly emerging viruses with unknown pathogeneses. However, little is known of PPV1–6 and PCV3 effects or their co-infections with PCV2. In this study, we examined 926 samples (272 aborted pig fetuses and 654 pig lung tissues) from domestic pig farms for the presence of PPV1–6 or PCV3 and for PCV2 co-infection with these seven viruses. The prevalence of PPV and PCV was significantly greater in lung tissue samples than aborted pig fetus samples. PPV3–6 were detected for the first time in Korean domestic pigs. Co-infection rates with PCV2 and other viruses were significantly higher in abattoir samples than that in aborted pig fetus samples. Concurrent infections are more common than single infection in pig population and nu-merous infectious pathogens such as PPV and PCV2 can impact the respiratory diseases. Fur-thermore, Korean PPV1 strain (PPV1-82) was identical to the virulent PPV-27a strain in this respect. Our results describe, for the first time the prevalence of PPV1–6 and PCV3 infections and their co-infection rates with PCV2 in Korean domestic pigs.

Crataegus Oxyacantha is used in the treatment of cardiovascular diseases. In related to your biosafety, only in vitro and in vivo genotoxicity of the fruit and the leaf is described, however, the teratogenic potential is unknown. The aim this study was evaluating the transplacental genotoxicity effect of aqueous and hydroalcoholic extract of leaves C. oxyacantha in a rat model and the quantification of malondialdehyde (MDA) in liver. Three different doses of the aqueous and hydroalcoholic extracts of the C. oxyacantha leaf were administered orally (500, 1000 and 2000 mg/kg) to Wistar rats during 5 days through the pregnancy term (16-21 days), sampling in rats were every 24 h during the last 6 days of gestation and only one sample was taken in neonates at birth. A sample of the mother's and neonate's liver was taken for the determination of MDA. The results show that, at the hepatic level, the evaluated doses of extracts C. oxyacantha in pregnant rats and their pups did not show cytotoxicity. However, the aqueous and hydroalcoholic extract generated cytotoxic and genotoxic damage in the short term. On the other hand, only the aqueous extract showed a teratogenic effect. Based on these results, the aqueous and hydroalcoholic extracts of the C. oxyacantha leaf should not be administered during pregnancy.

In spite of its incidence on pistachio trees, the chemical ecology of Labidostomis lusitanica (Germar) (Coleoptera: Chrysomelidae) has been neglected so far. In this work we provide the first evidence of a biologically active male-specific compound that may be promoting field aggregation. Headspace collections by solid-phase microextraction from feral males and females reported the presence of 2-isobutyl-3-methoxypyrazine exclusively on males. Electroantennographic recordings revealed that males and females responded in a dose-dependent manner to increasing stimuli of 2-isobutyl-3-methoxypyrazine, with females overall displaying a higher response than males. In dual-choice tests, both males and females showed a significant preference for the compound in comparison to a pure air stimulus. In the light of these results, the possible role of 2-isobutyl-3-methoxypyrazine as an aggregation cue in L. lusitanica is discussed.

G‐quadruplexes (G4) are structures formed at the ends of the telomere, these are rich in guanines and were stabilized by molecules that bind to specific sites. TMPyP4 and Thymoquinone (TQ) are small molecules that bind to the G4, they have drawn attention because of their role as telomerase inhibitors. The aim of this study was to evaluate the effects of telomerase inhibitors on cellular proliferation, senescence, and death. Two cell lines LC‐HK2 (NSCLC) and RPE‐1 were treated with TMPyP4 (5μM) and TQ (10μM). Both inhibitors were effective in decreasing telomerase activity. TMPyP4 increased the percentage of cells with membrane damage associated with cell death and decreased the frequency of cells in the S‐phase. TMPyP4 changed the cell adhesion ability and modified the pattern of focal adhesion. TQ acted in a dose‐dependent manner, increasing the frequency of senescent cells, and inducing cell cycle arrest in the G1. In conclusion, the effects of both drugs on LC-HK2 and RPE-1 cell lines were different although both are telomerase inhibitors, because TMPyP4 decreased proteins of cell adhesion and TQ induces a decrease in cell viability.

Numerous proteomic and transcriptomic studies have been carried out to better understand the current multi-variant SARS-CoV-2 virus mechanisms of action and effects. However, they are mostly centered on mRNAs and proteins. The effect of the virus on human post-transcriptional regulatory agents such as microRNAs (miRNAs) involved in the regulation of 60% of human gene activity remains poorly explored. Similar to what we have previously done with other viruses such as Ebola and HIV, in this study we investigated the miRNA profile of lung epithelial cells following infection with SARS-CoV-2. At the 24 and 72 hours post-infection, SARS-CoV-2 did not drastically alter the miRNome. About 90% of the miRNAs remained non-differentially expressed. The results revealed that miR-1246, miR-1290 and miR-4728-5p were the most upregulated over time. miR-196b-5p and miR-196a-5p were the most downregulated at 24 h while at 72 h, miR-3924, miR-30e-5p and miR-145-3p showed the highest level of downregulation. In the top significantly enriched KEGG pathways of genes targeted by differentially expressed miRNAs we found, among others, MAPK, RAS, P13K-Akt and renin secretion signaling pathways. By RT-qPCR, we also showed that SARS-CoV-2 may regulate several predicted host mRNA targets involved in the entry of the virus into host cells (ACE2, TMPRSS2, ADAM17 and FURIN), in renin–angiotensin system (RAS) (Renin, Angiotensinogen, ACE), innate immune response (IL-6, IFN1β, CXCL10, SOCS4) and fundamental cellular processes (AKT, NOTCH, WNT). Finally, we demonstrated by dual luciferase assay a direct interaction between miR-1246 and ACE-2 mRNA. This study highlights the modulatory role of miRNAs in the pathogenesis of SARS-CoV-2.

The KRAS mutant population has been undruggable for 40 years. G12C inhibitors and immunotherapy are the beginning of success. It is necessary to summarize the successful experience of the existing treatment model and explore the direction of the next treatment. In this review, we discuss the latest developments in targeted therapy and immunotherapy for KRAS-mutation NSCLC, aiming to provide direction or enlightenment for future treatment strategies.

Carthamin potassium salt isolated from Carthamus tinctorius L. was purified by an improved traditional Japanese method, without using column chromatography. The 1H and 13C nuclear magnetic resonance (NMR) signals of the pure product were fully assigned using one- and two-dimensional NMR spectroscopy, while the high purity of the potassium salt and deprotonation at the 3’ position of carthamin were confirmed by atomic adsorption spectroscopy and nano-electrospray ionization mass spectrometry.

Bone marrow derived adult human mesenchymal stem cells (hMSCs) possess therapeutic qualities that enable them to enhance wound repair. However, the mechanisms by which this occurs remains poorly understood. Basic mechanisms may include the directed migration of delivered cells to target sites and/or the production and release of soluble factors that act at a distance. Allogeneic and even xenogeneic cells may effectively participate in wound repair. Labeled hMSCs were delivered to full-thickness skin wounds that were created in immunologically competent mice. The delivery occurred on day 3 post-wounding using two different carriers; one which released cells and one which retained cells. The fates of the delivered cells were tracked for up to 25 days. During this period, released cells migrated as a tight cohort deep into the wound to reach the subdermal vascular plexus. Simultaneously, enhanced formation of granulation tissue was evident. This migration of hMSCs was not essential in that enhanced granulation tissue formation and wound contraction occurred when cells were retained in the carrier matrix. This provided further evidence for the release of therapeutic factors by hMSCs to sites of injury.

The theories of quantum mechanics and relativity dramatically altered our understanding of the universe ushering in the era of modern physics. Quantum theory deals with objects probabilistically at small scales, whereas relativity deals classically with motion in space and time. We show here that the mathematical structures of quantum theory and of relativity follow together from pure thought, defined and uniquely constrained by the same elementary ``combining and sequencing'' symmetries that underlie standard arithmetic and probability. The key is uncertainty, which inevitably accompanies observation of quantity and imposes the use of pairs of numbers. The symmetries then lead directly to the use of complex \sqrt{-1} arithmetic, the standard calculus of quantum mechanics, and the Lorentz transformations of relativistic spacetime. One dimension of time and three dimensions of space are thus derived as the profound and inevitable framework of physics.

Hepatic encephalopathy (HE) is a form of brain dysfunction that is specifically caused by liver insufficiency and/or portal-systemic shunt. The exact nature of HE is debated, so that conflicting uses of the term HE may cause inconsistencies in its detection and, in turn, issues with its management. This review highlights the meaning of the term HE on the basis of both its historical origins and current consensus. It also provides criteria for the diagnosis of the condition, on the basis of its phenotypes and the risk factors for its occurrence. The procedure for differential diagnosis from other conditions which result in similar phenotypes is considered, together with precipitants and confounders. Finally, the current multidimensional approach for the correct clinical recording of HE episodes is discussed.

The main goal of our work is the revealing of problematic issues related to estimates of the absorption coefficient of colored organic matter in the northern seas from data of the Ocean and Land Color Instrument (OLCI) on the Sentinel-3 satellites. In particular, a comparison of the OLCI standard error estimates ADG443_NN_err., relating to the measurement and retrieval of the geophysical products, with the uncertainties in the real situation of the northern seas, where the natural conditions are extremely unfavorable (first of all, frequent cloudiness, low Sun heights). We conducted a comprehensive multi-sensor study of the uncertainties using various approaches, first at all, directly comparing the data from satellite (OLCI Sentinel-3 and four other ocean color sensors) and field measurements in five sea expeditions 2016-2019, by using the different processing algorithms. Our analysis has shown that the real uncertainties of the final product are significantly higher than the calculated errors of the ADG443_NN_err., which is 100% and ~10%. The main reason for that is the unsatisfactory atmospheric correction. We present the results of the analysis of the different effecting factors (satellite sensors, processing algorithms, use of the other parameters), and formulate the tasks of future work.

Cerebral blood flow (CBF) decreases across the lifespan, and chronic conditions such as dementia and stroke accelerate this decline. Impaired CBF results in reduced delivery of oxygen and nutrients, which can damage the brain over time. Thus, there is a need to identify lifestyle interventions including diet and exercise to maintain CBF with aging and in the presence of chronic disease. In the present study, we used transcranial Doppler ultrasound to record middle cerebral artery velocity (MCAv), a surrogate measure of CBF, during moderate-intensity exercise in sedentary, cognitively-normal older adults (N = 90). A multiple linear regression model (F(4, 85) = 3.21, p = 0.02) showed self-reported omega-3 supplement use significantly moderated the association between age and mean exercising MCAv in these individuals (p = 0.01). Older age was associated with lower exercising MCAv in the group not taking omega-3 supplements, while exercising MCAv showed no decline with increasing age in the group who reported omega-3 supplement use. These findings suggest omega-3 supplementation may have an important role in the preservation of CBF with aging.

Detailed kinetics for a 3-wavelength photopolymerization confinement (PC) system is presented for both numerical solutions and analytic formulas. The dynamic profiles are simulated for oxygen, free radical, and conversion for various situations of: blue-light only, 2-light (red and UV), and 3-light (red, blue, UV). An effective PC requires two conditions: (i) a strong N-inhibition for uncured regime with a low conversion (triggered by the UV-light); and (ii) a weak S-inhibition (oxygen-induced) for high conversion under the blue-light or blue and red-light initiation. Good PC candidates are governed by collective factors of: (i) the double ratio of light-intensity and initiator-concentration, (ii) monomers rate-constant; and (iii) effective absorption constants at specific wavelength and initiators. A new reverse feature for the role of N-inhibition on the blue-conversion is found. Higher oxygen concentration leads to a lower conversion, which could be enhanced by reducing the S-inhibition via a red or blue-light pre-irradiation, having a pre-irradiation time TP=200 s for red-light only, and reduced to 150 s, when both red and blue-light. System under UV-only leads a conversion lower than that of blue-only. However, conversion could be improved by the dual-light (blue and UV), and further enhanced by the pre-irradiation of red-light. The two competing factors, N-inhibition and S-inhibition, could be independently and selectively tailored to achieve: (a) high conversion of blue-light (without UV-light), enhanced by red-light pre-irradiation for minimal S-inhibition; and (b) efficient PC initiated by UV-light produced N-inhibition for reduced confinement thickness and for high print speed.

Epigallocatechin-3-gallate (EGCG) is the most abundant polyphenol in green tea. In this study, the effects of dietary EGCG on oxidative stress and the metabolism and toxicity of acetaminophen in liver were investigated. Rats were fed the diets with (0.54 %) or without EGCG supplementation for four weeks and were then intraperitoneally injected with acetaminophen (1g/kg). Results showed EGCG lowered hepatic oxidative stress and cytochrome P450 (CYP) 1A2, 2E1, and 3A, and UDP-glucurosyltransferase activities prior to acetaminophen injection. After acetaminophen challenge, the elevations in plasma alanine aminotransferase activity and histological changes in liver were ameliorated by EGCG treatment. EGCG reduced acetaminophen-induced apoptosis by increasing the Bax/Bcl2 ratio in liver. EGCG mildly increased autophagy by increasing the LC3B II/I ratio. Lower hepatic acetaminophen-glutathione and acetaminophen-protein adducts contents were observed after EGCG treatment. EGCG increased glutathione peroxidase and NAD(P)H quinone 1 oxidoreductase activities and reduced organic anion-transporting polypeptides 1a1 expression in liver after acetaminophen treatment. Our results indicate that EGCG may lower oxidative stress and reduce the metabolism and toxicity of acetaminophen. The reductions in CYP-mediated acetaminophen bioactivation and uptake transporter, as well as enhanced antioxidant enzyme activity, may limit the accumulation of toxic products in liver and thus lower hepatotoxicity

A nutritional approach could be a promising strategy to prevent or slow the progression of neurodegenerative diseases such as Parkinson’s and Alzheimer’s disease, since there is no effective therapy for these diseases so far. The beneficial effects of omega-3 fatty acids are now well established by a plethora of studies through their involvement in multiple biochemical functions, including synthesis of antinflammatory mediators, cell membrane fluidity, intracellular signalling and gene expression. This systematic review will consider epidemiological studies and clinical trials that assessed the impact of supplementation or dietary intake of omega-3 polyunsaturated fatty acids on neurodegenerative diseases such as Parkinson’s and Alzheimer’s diseases. Indeed, treatment with omega-3 fatty acids, being safe and well tolerated, represent a valuable and biologically plausible tool in the management of neurodegenerative diseases in their early stages.

Genetic activation of the class I PI3K pathway is very common in cancer. This mostly results from oncogenic mutations in PIK3CA, the gene encoding the ubiquitously expressed PI3Kα catalytic subunit, or from inactivation of the PTEN tumour suppressor, a lipid phosphatase which opposes class I PI3K signalling. The clinical impact of PI3K inhibitors in solid tumours, aimed at dampening cancer-cell-intrinsic PI3K activity, has thus far been limited. Challenges include poor drug tolerance, incomplete pathway inhibition and pre-existing or inhibitor-induced resistance. The principle of pharmacologically targeting cancer-cell-intrinsic PI3K activity also assumes that all cancer-promoting effects of PI3K activation are reversible, which might not be the case. Emerging evidence suggests that genetic PI3K pathway activation can induce and/or allow cells to tolerate chromosomal instability, which – even if occurring in a low fraction of the cell population – might help to facilitate and/or drive tumour evolution. While it is clear that such genomic events cannot be reverted pharmacologically, a role for PI3K in the regulation of chromosomal instability could be exploited by using PI3K pathway inhibitors to prevent those genomic events from happening and/or reduce the pace at which they are occurring, thereby dampening cancer development or progression. Such an impact might be most effective in tumours with clonal PI3K activation and achievable at lower drug doses than the maximum-tolerated doses of PI3K inhibitors currently used in the clinic.

Environmental isolates, genetically manipulated organisms, plants, animals and their products and economical methods are being expertly explored to biosynthesize poly-3-hydroxybutyrate plastics of comparable properties to petroplastics. This study assessed a hypothesized feasibility of utilizing a proliferative pleustophytic greenery, water hyacinth (Eichhornia crassipes (Mart.) Solms-Laubach) in Lake Victoria, Uganda as a potential carbon source for poly-3-hydroxybutyrate biosynthesis. The poly-3-hydroxybutyrate biosynthesizing bacteria (Bacillus megaterium) was isolated from municipal sewage sludge and harnessed for batch fermentation of acid-catalysed water hyacinth biomass. Poly-3-hydroxybutyrate formed in the cytoplasm of the bacterial cells was extracted by chloroform extraction method, and thereof confirmed and quantified by UV spectroscopy. Batch fermentation was carried out in 100ml of the culture media in a 250ml fermenter for different times (48, 96, 144 and 192 hours) to determine the best incubation time for maximum yield. An all-out net yield of 61.3% was realized after 96 hours of fermentation. Utilization of this ecological plague for poly-3-hydroxybutyrate biosynthesis is a promising strategy for regulating the weed population along the length of Nile River and the Victorian basin.

The co-circulation of duck hepatitis A virus subtypes 1 (DHAV-1) and 3 (DHAV-3) in ducklings has resulted in significant economic losses. Because ducklings infected with DHAV-1 or DHAV-3 show similar clinical signs and gross lesions, it is important to discriminate these subtypes as early as possible for better clinical management. On the basis of multiple alignments of the 5′-noncoding region sequences of strains DHAV-1 and DHAV-3, universal and type-specific primers were designed and synthesized. Using the primers in a one-tube reverse transcription-PCR (RT-PCR) assay, reference strains of DHAV-1 and DHAV-3 (isolated over a span of 60 years and covering many different countries) were successfully amplified, indicating that the primer sequences were completely conserved. The amplicon sequences results and the sizes of amplicons from reference DHAV-1 and DHAV-3 isolates correlated completely with their genotypes. Moreover, with this one-tube RT-PCR system, the amplicon sizes of liver samples of reference DHAV-1- or DHAV-3-infected birds matched perfectly with their respective genotypes, as determined by virus isolation and neutralization tests. No other RNA viruses of duck origin were detected with the synthesized primers. The sensitivity of viral RNA detection was 10 pg. With this system, 20% genotype 1, 45% genotype 3, and 9% co-infection of the two genotypes were detected in 55 clinical samples. This novel approach could be used for the rapid genotyping DHAV-1 and/or DHAV-3 infection in routine clinical surveillance or epidemiologic screening.

A series of penta-1,4-dien-3-one containing a H-phosphonate scaffold were designed and synthesized. The structures of all title compounds were determined by 1H-NMR, 13C-NMR, 31P-NMR, and HRMS. Bioassay results showed that several of the title compounds exhibited remarkable antibacterial and antiviral activities. Among these, compounds 3c and 3o exhibited substantial antibacterial activities against Xanthomonas oryzae pv. Oryzae (Xoo) and Xanthomonas axonopodis pv. citri (Xac). In addition, compounds 3c, 3f, and 3r showed remarkable curative activities against tobacco mosaic virus (TMV), with 50% effective concentration (EC50) values of 290.0, 234.0, and 373.6 μg/mL, respectively. These were superior to that of ningnanmycin (386.2 μg/mL). Compound 3r exhibited comparative protective activity against TMV, with an EC50 value of 291.1 μg/mL, which was better than that of ningnanmycin (297.1 μg/mL). Notably, the solubility of all title compounds improved relative to the lead compound curcumin. These results suggest that penta-1,4-dien-3-one containing a H-phosphonate scaffold may be considered as an activator for antibacterial and antiviral agents.

Caspase-3, onto which there is a convergence of the intrinsic and extrinsic apoptotic pathways, is the main executioner of apoptosis. We here review the current literature on the intervention of the protease in the execution of naturally occurring neuronal death (NOND) during cerebellar development. We will consider data on the most common altricial species (rat, mouse and rabbit), as well as humans. Among the different types of neurons and glia in cerebellum, there is ample evidence for an intervention of caspase-3 in the regulation of NOND of the post-mitotic cerebellar granule cells (CGCs) and Purkinje neurons as a consequence of failure to establish proper synaptic contacts with target (secondary cell death). It seems possible that also the GABAergic interneurons undergo a similar type of secondary cell death, but the intervention of caspase-3 in this case still remains to be clarified in full. Remarkably, CGCs also undergo primary cell death at the precursor/pre-migratory stage of differentiation, in this case without the intervention of caspase-3. Glial cells as well undergo a process of regulated cell death, but it seems possible that expression of caspase-3, at least in the Bergmann glia, is related to differentiation rather than death.

The peripheral lymphatic system plays a crucial role in the recovery mechanisms after many pathological changes, such as infection, trauma, vascular, or metabolic diseases. The lymphatic clearance of different tissues from waste products, viruses, bacteria and toxic proteins significantly contributes to the correspondent recovery processes. However, understanding of the meningeal lymphatics functions is a challenging problem. The exploration of mechanisms of lymphatic communication with brain fluids as well as the role of the lymphatic system in the brain drainage, clearance and recovery are still in its infancy. Here we review novel concepts on the anatomy and physiology of the lymphatics in the brain, which warrant a substantial revision of our knowledge about the role of lymphatics in the rehabilitation of the brain functions after neural pathologies. We discuss a new vision on how to recruit the meningeal lymphatics by the opening of blood-brain barrier as a trigger mechanism of activation of the meningeal lymphatic drainage. This leads to innovative strategies in neurorehabilitation therapy.

Ziyuan-3 (ZY-3) satellite is the first civilian stereo mapping satellite in China and was designed to achieve the 1: 50000 scale mapping for land and ocean. Rigorous sensor model (RSM) is required to build the relationship between the three-dimensional (3D) object space and two-dimensional (2D) image space of ZY-3 satellite imagery. However, each satellite sensor has its own imaging system with different physical sensor models, which increase the difficulty of geometric integration of multi-source images with different sensor models. Therefore, it is critical to generate generic model， especially rational polynomial coefficients (RPCs) of optical imagery. Recently, relatively a few researches have been conducted on RPCs generation to ZY-3 satellite. This paper proposes an approach to evaluate the performance of RPCs generation from RSM of ZY-3 imagery. Three scenarios experiments with different terrain features (such as ocean, city and grassland) are designed and conducted to comprehensively evaluate the replacement accuracies of this approach and analyze the RPCs fitting error. All the experimental results demonstrate that the proposed method achieved the encouraging accuracy of better than 1.946E-04 pixel in both x-axis direction and y-axis direction, and it indicates that the RPCs is suitable for ZY-3 imagery and can be used as a replacement for the RSM of ZY-3 imagery.

The paper presents an innovative hexapod walking robot built with 3-UPU parallel mechanism. In the robot, the parallel mechanism is used as both an actuator to generate walking and also a connecting body to connect two groups of three legs, thus enables the robot to walk with simple gait by very few motors. In the paper, the forward and inverse kinematics solutions are obtained. The workspace of the parallel mechanism is analyzed using limit boundary search method. The walking stability of the robot is analyzed, which yields the robot’s maximum step length. The gait planning of the hexapod walking robot is studied for walking on both flat and uneven terrains. The new robot, combining the advantages of parallel robot and walking robot, has a large carrying capacity, strong passing ability, flexible turning ability, and simple gait control for its deployment for uneven terrain.

An efficient, eco-compatible and very cheap method for the construction of triazoles via eliminative azide–olefin cycloaddition (EAOC) reaction has been developed by a catalytic system IL/FeCl3, offering an highly regioselective approach to structurally diverse 1,5-disubstituted 1,2,3-triazoles in up to 95% yield. This strategy features the reuse of catalytic system through simple operations. Mechanistic studies indicated that an asynchronous concerted dipolar cycloaddition-elimination process might be involved.

Corona loss generated from conductors is one of the important design factors on ac transmission lines. Based on helical charge simulation method, the 3-D corona loss calculation model considering the conductors’ outer strands in the corona cage is established. With regard to 2-D corona-loss calculation method, the calculation model proposed in this paper can take the electric field strength’s nonuniformity along the axial direction of stranded conductor into consideration, furthermore, it can also calculate the corona loss when the conductor has sag. The calculation results of the LGJ-300/40 and LGJ-400/35 in the small corona cage well coincide with the measurement results, which indicates that the corona-loss calculation model is appropriate. In addition, the corona loss of the bundle conductors 4 × LGJ720 with sag in UHV corona cage is also analyzed.

Aiming at the damage detection and continuous monitoring of high efficiency composite structure, the method of carbon nano sensor embeded in the 3-D braided composite material specimen was put forward and the method of damage location for 3-D braided composite material was described. In this paper, the mechanical and electrical characteristics of carbon nano-fiber were analyzed. Considering the massive data of the health monitoring of composite processing, to ensure that the system has good real-time performance, quaternary matrix Singular Value Decomposition algorithm is proposed to simplify data and improve the efficiency of the algorithm. The existence of injury is determined and the damage location is calculated by comparing with key features of healthy specimen. Experimental results prove the method is feasible and effective.

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.

We investigate entropy generation in unsteady three-dimensional axisymmetric MHD nanofluid flow over a non-linearly stretching sheet. The flow is subject to thermal radiation and a chemical reaction. The conservation equations were solved using the spectral quasi-linearization method. The novelty of the work is in the study of entropy generation in three-dimensional axisymmetric MHD nanofluid and the choice of the spectral quasilinearization method as the solution method. The effects of Brownian motion and thermophoresis are also taken into account when the nanofluid particle volume fraction on the boundary in passively controlled. The results show that as the Hartman number increases, both the Nusselt number and the Sherwood number decrease whereas the skin friction increases. It is further shown that an increase in the thermal radiation parameter corresponds to a decrease in the Nusselt number. Moreover, entropy generation increases with the physical parameters.

This study investigates the preparation of KNN-ZnO composites through optimized sintering conditions under both inert and oxygen atmospheres. Initial experiments employing inert hot pressing were hindered by the necessity for annealing, which resulted in cracks due to the differing thermal expansion coefficients of KNN and ZnO, rendering this method unsuitable for composite fabrication. Consequently, sintering under an oxygen atmosphere was adopted, yielding a uniform distribution of ZnO particles within the KNN matrix. The resultant microstructure demonstrated significant densification, enhanced homogeneity, and minimal porosity. Electrical performance evaluations revealed that while the incorporation of ZnO led to a slight reduction in the ferroelectric properties (d₃₃ and polarization) of the KNN matrix, it concurrently improved the electromechanical quality factor (Q_m) by 40%. However, the overall enhancements were less pronounced when compared to analogous BNT-BT systems, underscoring the necessity for further optimization of processing conditions to boost electromechanical efficiency and piezoelectric response in KNN-based ceramics.

Background: Human β-defensin 2 (HBD2) is a protein important in immune system activation, produced by epithelial cells, mainly as a result of contact with microorganisms or the action of various pro-inflammatory cytokines. According to previous research, it has proven to be important in chronic urticaria, leading us to research on the HBD2 in isolated chronic angioedema. Methods: This cross-sectional study involved 102 participants (three groups): 33 patients with isolated chronic non-hereditary angioedema (AE); 33 patients with angioedema associated with chronic urticaria (CU+AE); and 35 healthy controls (CTRL). They provided saliva and serum samples to determine HBD2 levels using the Enzyme-Linked Immunosorbent Assay-ELISA. Results: Salivary HBD2 levels were significantly higher in those with CU+AE than in the CTRL (p=0.019). While salivary HBD2 values differed between those with angioedema and CTRL, the serum HBD2 values did not. Also, no correlation between the levels of HBD2 in saliva and serum was found. Conclusions: Since we found that salivary HBD2 values were significantly higher in those with CU+AE than in CTRL, this points to a possible role of the HBD2 molecule in pathogenesis of AE. Therefore, more research is needed to determine how reliabile salivary HBD2 measurement is and its significance.

Developing recombinant Saccharomyces cerevisiae strains capable of transporting and fermenting cellobiose directly is a promising strategy for second-generation ethanol production from lignocellulosic biomass. In this study we cloned and expressed in the CEN.PK2-1C strain an intracellular βglucosidase (SpBGL7) from Spathaspora passalidarum, and co-expressed the cellobiose transporter SiHXT2.4 from Scheffersomyces illinoinensis, and two putative transporters from Candida tropicalis (CtCBT1) and Meyerozyma guilliermondii (MgCBT2). While all three transporters allowed cell growth on cellobiose, only the MgCBT2 permease allowed cellobiose fermentation, although cellobiose consumption was stuck (incomplete). The analysis of the βglucosidase and transport activities revealed that the cells stopped to consume cellobiose due to a drop in the transport activity. Since ubiquitinylation of lysine residues at the N- or C-terminal domains of the permease are involved in the endocytosis and degradation of sugar transporters, we constructed truncated versions of the permease lacking lysine residues at the C-terminal domain (MgCBT2ΔC), and at both the C- and N-terminal domain (MgCBT2ΔNΔC), and co-expressed these permeases with the SpBGL7 βglucosidase in an industrial strain. While the strain harboring the MgCBT2ΔC transporter continued to produce stuck cellobiose fermentations as the wild-type MgCBT2 permease, the strain with the MgCBT2ΔNΔC permease was able to consume and ferment all the cellobiose present in the medium. Thus, our results highlight the importance of expressing cellobiose transporters lacking lysine at the N- and C-terminal domains for efficient cellobiose fermentation by recombinant S. cerevisiae.

Oral lichen planus (OLP) is a chronic inflammatory mucosal disease, and an apparent cause has not been identified. OLP is refractory to treatment, and malignant transformation has been reported. Therefore, discovering effective drugs with few adverse effects over long-term administration is crucial. In this study, we established an in vitro OLP model to investigate the effects of Cepharanthin®, an alkaloid mixture derived from Stephania cephalantha Hayata. Four alkaloids from Cepharanthin® suppressed the expression of cytokine genes at various degrees in activated T cells. However, the effect of Cepharanthin® was limited. On the other hand, Cepharanthin® and four alkaloids suppressed the expression of various cytokine genes in human oral epithelial cells when stimulated with IL-β. In the OLP model, activated T cells increased the inflammatory gene expression in the epithelial cells, while Cepharanthin® suppressed their gene expression. Anti-inflammatory effect of Cepharanthin® was observed by protein dot blot. The effects of Cepharanthin®️ might be expressed through two aspects: its effect of mildly suppressing the activation of T lymphocytes and strongly suppressing the response of epithelial cells to inflammatory stimuli. The in vitro model established in this study could be a tool for elucidating the mechanisms of OLP pathogenesis and disease persistence.

Pulmonary arteriovenous malformations (PAVMs) are vascular anomalies resulting in abnormal connection between pulmonary arteries and veins. In 80% of cases, PAVMs are present from birth, but clinical manifestations are rarely seen in childhood. These congenital malformations are typically associated with Hereditary Hemorrhagic Telangiectasia (HHT), a rare disease that affects 1 in 5,000/8,000 individuals. HHT disease is frequently caused by mutations in genes involved in the TGF-β pathway. However, approximately 15% of patients do not have a genetic diagnosis and, among the genetically diagnosed, more than 33% do not meet the Curaçao Criteria. This makes clinical diagnosis even more challenging in the pediatric age group. Here, we introduce an 8 years old patient bearing a severe phenotype of multiple diffuse PAVMs caused by an unknown mutation which ended in lung transplantation. Phenotypically, the case of study follows a molecular pattern HHT-like. Therefore, molecular biology and cellular functional analysis has been performed in primary endothelial cells (ECs) isolated from the explanted lung. The findings revealed a loss of functionality in lung endothelial tissue and a stimulation of endothelial to mesenchymal transition. Understanding the molecular basis of this transition could potentially offer new therapeutic strategies to delay lung transplantation in severe cases.

Immunology and microbiology research in the West Indies has witnessed remarkable growth and innovation, playing a pivotal role in advancing our understanding of immune mechanisms, disease pathogenesis, and therapeutic interventions. This manuscript presents a comprehensive exploration of key areas in West Indian immunology research, spanning from the utilization of bacterial proteins as antibody reagents to the intricate realms of clinical immunology and disease management. The utilization of bacterial immunoglobulin-binding proteins (IBPs), including protein A (SpA), protein G (SpG), and protein L (SpL), has revolutionised serological diagnostics in the region. promise in early disease detection and precision medicine. Microbiological studies in the Caribbean region have shed light on antimicrobial resistance patterns, particularly the emergence of extended-spectrum beta-lactamases (ESBLs), guiding antimicrobial stewardship programs and informing therapeutic strategies. Clinical immunology research has elucidated the molecular pathways underlying immune-mediated disorders, leading to tailored management strategies for conditions such as severe combined immunodeficiency (SCID), neuropsychiatric lupus erythematosus (NPLE), and others. In summary, West Indian immunology and microbiology research has made significant contributions to global healthcare, fostering collaboration, innovation, and improved patient outcomes.

The rates of obesity and obesity-related diseases continue to increase worldwide, classifying obesity as a global epidemic. Endogenous opioids have been implicated in influencing feeding behavior; however, the role of each opioid peptide is still only partially characterized. Therefore, we assessed the role of the proopiomelanocortin (POMC)-derived peptide beta-endorphin (β-END) in long-term high-fat diet (HFD) feeding and glucose homeostasis and assessed if sex-related differences exist in these processes. Male and female mice lacking the ability to produce β-END and their respective controls were subjected to a 12-week HFD consumption to determine the role of the opioid peptide in food intake and glucose homeostasis. Body weight and food intake were measured weekly for twelve weeks. At weeks 6 and 12, plasma glucose levels were measured using an oral glucose tolerance test. Here, we report that male β-END deficient mice gained more weight and consumed more calories than their wildtype controls; however, this difference was not observed in the female mice. Regardless of genotype, female mice consumed more calories per body weight when compared to male mice despite their smaller body weights. Moreover, our findings suggest differences in glucose homeostasis between the wildtype and knockout mice and that these were only observed at week six but not at week 12. Overall, our study suggests that endogenous β-END may play a role in controlling body weight, feeding behavior, and glucose homeostasis and that sex-related differences may exist in this regard.

This study aimed to elucidate the similarities and differences between amyloid-forming corpora amylacea (CA) in the prostate and lung, examine the nature of CAs in cystic tumors of the atrioventricular node (CTAVN), and clarify the distinctions between amyloid-forming CA and spheroid-type amyloid deposition. We conducted proteomics analyses using liquid chromatography–tandem mass spectrometry with laser microdissection and immunohistochemistry to validate the characteristics of CAs in the lung and prostate. Our findings revealed that CAs in these organs primarily consist of common proteins (β2-microglobulin and lysozyme) and locally produced proteins. Moreover, we observed a discrepancy between the histopathological and proteomic analysis results in CTAVN-associated CAs. In addition, while the histopathological appearance of amyloid-forming CAs and spheroid-type amyloid deposits were nearly identical, the latter deposition lacked β2-microglobulin and lysozyme, and exhibited evident destruction of surrounding tissue. A literature review further supported these findings. These results suggest that amyloid-forming CAs in the lung and prostate are formed through a shared mechanism, serving as waste containers (wasteosomes) and/or storage for excess proteins (functional amyloids). In contrast, we hypothesize that while amyloid-forming CA and spheroid-type amyloid deposits are formed, in part, through common mechanisms, the latter are pathological.

Background and Objectives: Gastric cancer (GC) is one of the most commonly diagnosed cancer and the fourth cause of cancer death worldwide. Personalised treatment improves GC outcomes. A molecular classification is needed to choose the appropriate therapy. A classification that uses on-slide biomarkers and formalin-fixed and paraffin-embedded (FFPE) tissue is preferable to comprehensive genomic analysis. In 2016, Setia et al. proposed an on-slide classification, however this is not in widespread use. We propose a modification of this classification that has six subgroups: GC associated with Epstein-Barr virus (GC EBV+), GC with mismatch repair deficiency (GC dMMR), GC with epithelial-mesenchymal transformation (GC EMT), GC with functional loss of p53 due to mutation (GC p53m), CG with intact p53 (GC p53wt) and GC not otherwise specified (GC NOS). This classification also has provision for biomarkers for current or emerging targeted therapies (Her2, PD-L1 and Claudin18.2). Here we assess the implementation and feasibility of this inclusive working classification. Materials and Methods: We constructed a tissue microarray library from a cohort of 79 resection cases from FFPE tissue archives. We used a restricted panel of on-slide markers (EBER, MMR, E-cadherin, beta-catenin and p53), defined their interpretation algorithms, and assigned each case to a specific molecular subtype. Results: GC EBV(+) cases were 6%, GC dMMR cases were 20%, GC EMT cases were 14%, GC p53m cases were 23%, GC p53wt cases were 29% and GC NOS cases were 8%. Conclusions: This working classification uses markers that are widely available in Histopathology and are easy to interpret. A diagnostic subgroup is obtained for 92% of the cases. The proportion of cases in each subgroup is in keeping with other published series. Widescale implementation appears feasible. A study using endoscopic biopsies is warranted.

Abstract: Pasteurella spp. is a gram-negative bacterium that is part of the oral and upper respira-tory tract microbiota of many animals such as canids and felines. In humans it can produce pa-thology primarily associated with animal bites or scratches. In addition, members of this genus, and especially Pasteurella multocida, may also be involved in systemic infections, mainly in im-munocompromised patients in close contact with pets. The aim of this study is to analyse the prevalence and clinical characteristics of infections caused by Pasteurella spp. as well as the sensitivity profile of these isolates obtained in the Microbiology laboratory of the Hospital Can Misses (Ibiza, Ibiza and Formentera Health Area, ASEF) in the period from January 2013 to December 2018. The group of islands of Ibiza and Formentera is known as the Pitiusas Islands. Retrospective descriptive study in which all Pasteurella spp. isolates were analysed in the Microbiology Laboratory of Hospital Can Misses from 1 January 2013 to 31 De-cember 2018. Bacterial identification was performed by Vitek 2 automated biochemical test panel (bioMérieux, Spain) and antimicrobial susceptibility by E-test or antibiotic discs in Mueller-Hinton blood agar, interpreted based on European Committee on An-timicrobial Susceptibility Testing (EUCAST) standards, 2022 version. Medical records were systematically reviewed by collecting demographic data of infected patients, comorbidities, epidemiological data and clinical features of the infection. A total of 22 isolates of Pasterurella spp. were obtained from 22 different patients, 62.8% female, from three different species: 18 P. multocida, 2 P. canis and 2 P. pneumo-tropica. Most isolates came from soft tissue infection samples: 7 wound exudates and 5 abscess material. The antibiotics tested with the highest sensitivity profile were gen-tamicin and cefepime (100% sensitivity). The species most commonly isolated in our environment is P. multocida. Close contact with companion animals, especially cats and dogs, is the main risk factor for Pasteurella spp. infections, although in many cases such contact cannot be established. So Pasteurella spp. infection should be considered a zoonosis in possible emergency, especially in rural areas such as Pitiusas Islands.

Starting from acid chlorides, alkynes, tryptamines, and acroyl chloride, 21 densely substituted tetrahydro-beta-carbolines are prepared in a four-component one-pot reaction. In this study, the aza-Michael addition step to generate intermediate enaminones is optimized in the presence of ytterbium triflate. Moreover, apart from acroyl chloride, all reactants can be deployed in almost equimolar ratios, which increases the atom economy of the sequence. For mechanistic rationali-zation, the concluding aza-anellation was investigated by DFT calculations on potential inter-mediates and corresponding activation energies, revealing that the aza-anellation rather pro-ceeds via ene-reaction than via electrocyclization.

In this manuscript, we reassess the data on beta-amyloid-induced changes of intracellular ions concentrations published previously by Abramov et al. (2003, 2004). Their observations made using high-resolution confocal microscopy with fast temporal resolution of images formed by fluorescent ion-sensitive fluorescent probes in living cells represent an unequivocal support for the amyloid channel theory. However, closer look reveals multiple facts which cannot be explained by channel formation in plasma membrane. Recently proposed amyloid degradation toxicity hypothesis provides the interpretation to these facts by considering that channels are formed in the lysosomal membranes.

Achievement of solid fusion of the lumbosacral junction (L5-S1 level) is an important factor in adult spinal deformity (ASD) surgery. The purpose of this study is to explore the effectiveness and feasibility of injectable rhBMP-2 (a combination of Eschericia coli-derived rhBMP-2 and hydrogel type β-TCP carrier; NOVOSIS Inject) as a bone substitute for the fusion of lumbosacral junction. 20 patients (average age 69.1 years) diagnosed with ASD with sagittal imbalance who underwent surgical treatment including anterior lumbar interbody fusion (ALIF) in the L5-S1 level were evaluated. Injectable rhBMP-2 was applied in L5-S1 ALIF and followed-up for 1-year. Solid fusion rates and changes of clinical outcomes (Oswestry Disability Index [ODI], Visual Analog Scale [VAS] of back and leg) were measured and analyzed at 6 and 12 months after surgery. All postoperative adverse events were evaluated about the association with injectable rhBMP-2. Fusion rates were 68.4% and 100% at 6 and 12 months after surgery. Compared to baseline, ODI were improved to 45.8% and 63.7%, VAS(back) were improved to 69.2% and 72.8%, and VAS(leg) were improved to 49.2% and 64.8% at 6 and 12 months after surgery (p&lt;0.001, respectively). There were no adverse events associated with injectable rhBMP-2. Thus, injectable rhBMP-2 may be a suitable choice of a bone graft substitute when achieving solid interbody fusion in the lumbosacral junction.

Immune checkpoint receptors play a crucial role in steering tumor progression, prompting a focused investigation into the role of TIM3 in breast cancer. Analysis of TCGA BRCA data unveiled diverse correlations between TIM-3 expression and immune cell infiltration across subtypes. In our in-house cohort studied through IHC, significant changes in TIM3 expression with tumor grades were observed. Higher TIM3 expression correlated with increased disease-free survival in pan breast cancer, marking the first revelation of TIM3's positive role in pan BC prognosis. The study indicates that alluring TIM3 response, rather than suppression, may enhance breast cancer prognosis.

Bean is a remarkable crop widely used as food worldwide, underscoring the significance of scientific research conducted on this plant. Developing a strong root system in the early stages of growth, which can spread wider and deeper, along with the consequent development of the shoot system crucial for photosynthesis, enhances the plant's productivity and resistance to diseases and pests. In the current study, the reactions of cultivars Önceler-98 and Topçu beans to different concentrations of IBA (indole-3-butyric acid) during the seedling stage were investigated. Three different concentrations, namely 0 (Control), 50, 100, and 150 µM IBA, were applied, and their effects on root length (RL), root fresh weight (RFW), root dry weight (RDW), number of nodules on roots (RNN), shoot length (SL), shoot fresh weight (SFW), and shoot dry weight (SDW) parameters were measured. The pattern of the experiment was a randomized complete block factorial design with four replications and, statistically significant (p≤0.05) and highly significant (p≤0.01) differences were observed among the means of root and shoot traits. As a result, it was found that the cultivar Önceler-98 generally exhibited better responses to IBA solutions, and the optimal concentration range for both varieties was between 50-100 µM, decreasing at 150 µM and higher concentrations, yet still yielding superior means compared to the control.

Background/Objectives: Patients with chronic kidney disease (CKD) have an increased risk of cardiovascular disease (CVD). Carotid intima-media thickness (C-IMT) is a non-invasive marker of atherosclerosis. Low omega-3 polyunsaturated fatty acids (PUFA) intake and vitamin D deficiency are potential cardiometabolic risk factors in patients with CKD. The aim of this study was to evaluate dietary intake and status of omega-3 PUFA and vitamin D in pre-dialysis and hemodialysis patients and to examine the link of dietary α-linolenic acid (ALA) and fish consumption with blood pressure and C-IMT in CKD patients. Methods: All 77 selected patients (36 pre-dialysis, 41 on hemodialysis) underwent standardized clinical, nutritional, and laboratory assessments. Repeated 24-hour recalls were performed to assess dietary intake. The fatty acid profile was determined by gas-liquid chromatography. Results: Inadequate vitamin D intake and vitamin D status were found in 95% of patients. PUFAs profiles did not differ between hemodialysis and pre-dialysis participants. Dietary intake of ALA was negatively correlated with systolic blood pressure (SBP) (p=0.007), C-IMT (p=0.002), serum CRP (p=0.044), iPTH (p=0.01) and 25(OH)D3 (p=0.006). ALA intake of more than 0.23 g/daily was associated with lower SBP (p=0.001), serum 25(OH)D3 (p=0.004), and C-IMT (p=0.002). Conclusions: This study contributes to a better understanding of the relationship between dietary ALA intake and C-IMT in CKD. The results of this study could emphasize the significant role of the high prevalence of vitamin D deficiency and inadequate omega-3 PUFA intake and status considering CVD health in CKD patients.

Solution-based inorganic-organic halide perovskites are of great interest to researchers because of their unique optoelectronic properties and easy processing. However, polycrystalline perovskite films often show inhomogeneity due to residual strain induced during the film’s post-processing phase. In turn, these strains can impact both their stability and performances. An exhaustive study of residual strains can provide a better understanding and control of how they affect the performance and stability of perovskite films. In this work, we explore this complex interrelationship between residual strains and electrical properties for methylammonium \chemform{CH_3NH_3PbI_{3-x}Cl_x} films using grazing incident X-ray diffraction (GIXRD). We correlate with their resistiviy and carrier mobility using Hall effect. The sin^2($\psi$) technique is used to optimize the annealing parameters for the perovskite films. We also establish that temperature-induced relaxation can yield significant enhancement of the charge carrier transports in perovskite films. Finally, we also use Raman micro-spectroscopy to assess the degradation of perovskite films as a function of their residual strains.

Appropriate animal models of human diseases are a cornerstone in the advancement of science and medicine. To create animal models of neuropsychiatric and neurobehavioral diseases such as ASD necessitates the development of sufficient neurobehavioral measuring tools to translate human behavior to expected measurable behavioral features in animals. Indeed, at least in rodents, adequate neurobehavioral and neurological tests have been developed. Since ASD is characterized by a number of specific behavioral trends with significant severity, animal models of autistic-like behavior have to demonstrate the specific characteristic features, namely impaired social interactions, and communication, restricted, repetitive behavioral patterns with association to several additional impairments such as somatosensory, motor and memory impairments. Thus, an appropriate model must show behavioral impairment of a minimal number of neurobehavioral characteristics using an adequate number of behavioral tests. The proper animal models enable the study of ASD like-behavior from the etiologic, pathogenetic and therapeutic aspects. From the etiologic aspects, models have been developed by the use of immunogenic substances like polyinosinic-polycytidylic acid (PolyIC), Lipopolysaccharide (LPS) and propionic acid or other well-documented immunogens or pathogens, like mycobacterium tuberculosis. Another approach is the use of chemicals like valproic acid, Polychlorinated biphenyls (PCBs), organophosphate pesticides - chlorpyrifos (CPF) and others. These substances were administered either prenatally, generally after the period of major organogenesis, or, especially in rodents, during the early postnatal life. In addition, using modern genetic manipulation methods, genetic models have been created of almost all human genetic diseases that are manifested by autistic like behavior (i.e. fragile X, Rett syndrome, SHANK gene mutation Neuroligin genes and others). Ideally, we should not only evaluate the different behavioral modes affected by the ASD-like behavior but also assess the severity of the behavioral deviations by an appropriate scoring system, as applied to humans.

In this research, the primary goal was to investigate the relationship between strategic planning and organizational performance in Iraq's manufacturing context. The study's primary data sources were 360 manager respondents. The structured questionnaire was used to collect primary data from manufacturing firms located throughout Iraq. To analyze the result, the researcher used descriptive statistics, correlation, and multiple regression analysis. SPSS version 16 software was used to conduct data analysis. The result reveals that the process of strategic planning has a beneficial effect on financial performance. Environmental scanning has a statistically significant positive effect on a company's non-financial performance. Management participation and planning formality positively and statistically significantly affect a business's non-financial performance at the 10 percent level. The domain of strategy and technique has not impacted the company's non-financial performance.

LPA3 receptors were expressed in TREx HEK 293 cells, and their signaling and phosphorylation were studied. The agonist, lysophosphatidic acid (LPA), increased intracellular calcium and ERK phosphorylation through pertussis toxin-insensitive processes. Phorbol myristate acetate, but not LPA, desensitizes LPA3-mediated calcium signaling. The agonists and the phorbol ester-induced LPA3 internalization. Pitstop 2 (clathrin heavy chain inhibitor) markedly reduced LPA-induced receptor internalization; in contrast, phorbol ester-induced internalization was only delayed. LPA induced rapid β-arrestin-LPA3 receptor association. The agonist and the phorbol ester induced marked LPA3 receptor phosphorylation, and phosphorylation sites were detected using mass spectrometry. Phosphorylated residues were detected in the intracellular loop 3 (S221, T224, S225, and S229) and in the carboxyl terminus (S321, S325, S331, T333, S335, Y337, and S343). Interestingly, phosphorylation sites are within sequences predicted to constitute β-arrestin binding sites. These data provide insight into LPA3 receptor signaling and regulation.

It is essential to have a thorough knowledge of the genetic variation among different strains of Xanthomonas citri pv. citri (Xcc), which is responsible for causing citrus bacterial canker. This understanding is important for studying the disease’s characteristics, population structure, and evolution, and ultimately for developing sustainable methods of control. A total of 48 strains, obtained from citrus production areas in Burkina Faso in 2012, 2020, and 2021, were subjected to polymerase chain reaction (PCR) tests using specific primers. The aim was to examine the distribution of type 3 effectors (T3E) and determine the geographical origins of the strains. The examination of the distribution of type 3 non-transcription activate like effectors (TALE) indicates a broader range in strains obtained in 2020 and 2021 compared to those obtained in 2012. However, all strains possess a shared set of three genes, specifically XopE2, XopN, and AvrBs2. Furthermore, all examined effectors were observed in the Bobo-Dioulasso region. Regarding the characterization of TALEs, two profiles containing two to three TALEs were discovered. Profile 1, consisting of two TALEs, was found in 37 Xcc strains, whereas Profile 2, comprising three TALEs, was detected in 11 strains. Out of the three TALEs (A, B, and C) that were identified, TALEs B and C were present in all strains. The correlation matrix indicated a positive association between the T3E content of strains and the duration of their isolation. Principal component analysis revealed a limited organization of the strains under investigation

A comprehensive understanding of the genetic diversity among strains of Xanthomonas citri pv. citri (Xcc), the causative agent of citrus bacterial canker, is crucial for unraveling the pathological nature, structure, and evolution of populations, thereby facilitating the adoption of sustainable control measures. In a collection of 48 strains isolated in 2012, 2020, and 2021 from citrus production areas in Burkina Faso, polymerase chain reaction (PCR) tests utilizing specific primers were conducted to investigate the distribution of type 3 effectors (T3E) and the structuring of strains based on their geographical origins. The analysis of the distribution of type 3 non-transcription activate like effectors (TALE) reveals a more extensive repertoire in strains isolated in 2020 and 2021 compared to those isolated in 2012. Nevertheless, all strains share a common repertoire of three genes, namely XopE2, XopN, and AvrBs2. Additionally, all screened effectors were observed in the Bobo-Dioulasso locality. Concerning the characterization of TALEs, two profiles consisting of two to three TALEs were identified. Profile 1, with two TALEs, was present in 37 Xcc strains, while Profile 2, with three TALEs, was identified in 11 strains. Among the three TALEs (A, B, and C) identified, TALEs B and C were common to all strains. The correlation matrix revealed a positive correlation between the T3E content of strains and the years of their isolation. Multiple component analysis indicated a weak structuring of the tested strains.

This report provides a comprehensive overview of occupational asthma and respiratory hypersensitivity, focusing on some chemicals used in the workplace Includes numerous case studies and research papers related to occupational exposure methacrylates, such as HEMA-HPMA, and respiratory hypersensitivity are discussed And the relationship is explored The book also examines asthma pathophysiology, emerging drug delivery systems used to treat asthma, and the potential of nanoparticles , dendrimers and micellar systems have to improve pulmonary drug delivery in detail The worldwide prevalence of asthma is highlighted, with higher rates in high-GDP countries. The book highlights the need to improve asthma diagnosis, treatment and biomarkers, particularly in rural and low-income countries where the disease is often underdiagnosed and inadequately treated, and discusses the role of inflammation in asthma, in particular secondary inflammation characterized by specific cytokines and inflammation cells In addition, the paper explores various drug delivery methods, such as parenteral and parenteral drugs, pressurized inhalers (pMDIs), dry powder inhalers ( DPIs), nebulizers, nanoparticles, liposomes, micellar systems, microparticles , dendrimers, and gene therapy . These systems aim to increase pulmonary delivery of drugs and improve clinical outcomes. The potential of dendrimer bilirubin-based nanoparticles and micellar systems in the treatment of asthma and lung inflammatory diseases, including asthma, has been discussed in summary, this paper provides an overview of occupational asthma and respiratory hypersensitivity, and this discussion highlights the association between methacrylate exposure and respiratory hypersensitivity.

To accurately and non-destructively monitor the growth of spring wheat in the Hetao Irrigation Area, UAV remote sensing was employed during various fertility stages. Digital image indices from diverse fertilization treatments were calculated and compared with physiological indices to identify the most sensitive digital image indices corresponding to these indices. The study underscored the critical importance of the flowering stage in the growth of spring wheat, thus highlighting the necessity of focusing on this stage. This finding reiterated that the flowering stage was pivotal for spring wheat development in the Hetao Irrigation Area. Several digital image indices, such as GLA, R, G, INT, g, GRVI, MGRVI, RGBVI, EXG, and GRRI, exhibited a high frequency of significant correlations with physiological indices during the four primary reproductive stages of wheat. Consequently, these sensitive digital image indices during the flowering stage can more effectively characterize the physiological indices of spring wheat.

Nucleic acid delivery through extracellular vesicles (EVs) is a well-preserved evolutionary mechanism in all life kingdoms including eukaryotes, prokaryotes, and plants. EVs naturally allow horizontal transfer of native as well as exogenous functional mRNA, that once incorporated in EVs is protected from enzymatic degradation. The possible use of EVs as carriers for vaccine has been investigated showing that EVs expressing recombinant SARS-CoV-2 S protein induced an immune response. Moreover, EV-based vaccines presenting the natural configuration of viral antigens have advantages in conferring long lasting immunization and lower toxicity than synthetic nanoparticles. To overcome the manufacturing limitations of EVs derived from eukaryotic cells, edible plant-derived EVs have been studied as an attractive alternative for vaccine delivery, especially for mucosal administration. We recently showed that EVs obtained from orange juice (oEVs) loaded with SARS-CoV-2 mRNAs protected their cargo from enzymatic degradation and were stable at room temperature for one year. Lyophilized oEVs containing the S1 mRNA were administered to rats by gavage and they induced a specific humoral immune response with generation of blocking antibodies, including IgA, that are the first mucosal barrier in the adaptive immune response. Moreover, a Th1 cytokine secretion occurred, suggesting a specific lymphocyte activation. In conclusion, mRNA-containing oEVs could be used for developing new oral vaccines due to optimal mucosal absorption, resistance to stress conditions, and the ability to stimulate a humoral and cellular immune response.

Inflammation is a conserved process that involve the activation of immune and non-immune cells aiming at protecting the host from bacteria, viruses, toxins and injury. However, unresolved inflammation and permanent release of pro-inflammatory mediators are responsible for the promotion of a condition called “low-grade systemic chronic inflammation”, characterized by tissue and organ damages, metabolic changes and increased susceptibility to non-communicable diseases. Several studies have demonstrated that different dietary components may influence modifiable risk factors for diverse chronic human pathologies. Marine n-3 polyunsaturated fatty acids (n-3 PUFAs), mainly eicosapentaenoic (EPA) and docosahexaenoic acid (DHA), are well recognized anti-inflammatory and immunomodulatory agents able to influence many aspects of the inflammatory process. The aim of this article is to review the recent literature that relates to the modulation of human disease, such as rheumatoid arthritis, by n-3 PUFAs.

This study presents the design and implementation of a PLC microprocessor adhering to the IEC-61131-3 standard, executed on a Cyclone-V FPGA using a DE10-NANO development board. Our microprocessor optimizes the central processing unit by streamlining the data path, achieving a remarkable simulated response time of approximately 60 ns, equivalent to three clock cycles at a 50MHz frequency for Boolean operations. To substantiate our approach, we conducted practical experiments utilizing a FESTO conveyor station, employing relays as actuators, and incorporating optical and inductive sensors. The results underscore the feasibility of our proposed approach and serve as practical validation of its efficacy. This work introduces a promising avenue for the development of cost-effective PLCs employing SoC FPGA variants. Additionally, a thorough comparison of execution times with other early reported architectures. Our microprocessor outperforms even well-established PLCs like the S7-312, with substantial reductions in execution times of 94.54% for floating-point operations, 71.42% to 93.33% for word operations, and up to 78.57% for bit operations.

Rapid analysis and characterization of compounds by mass spectrometry may overlook trace compounds, although targeted analysis methods can significantly improve detection sensitivity, it is difficult to discover novel scaffold compounds. This study developed a strategy for discovering trace compounds in the aging process of traditional Chinese medicine based on MS fragmentation and known metabolic pathway. Specifically, we found that the characteristic component of C. reticulata 'Chachi', methyl N-methylanthranilate (MMA), fragmented in ESI-CID to produce rearrangement ion 3-hydroxyindole, which has been proven to exist in trace amounts in C. reticulata 'Chachi' comparing with the reference substance by LC-MS/MS. By combining the known metabolic pathways of 3-hydroxyindole and the possible methylation reactions that may occur during aging, 10 possible indole derivatives were untargeted predicted. These compounds were confirmed to originate from MMA by purchasing or synthesizing reference substances and all of them were detected in C. reticulata 'Chachi' through LC-MS/MS analysis, achieving trace compound analysis from untargeted to targeted. It may contribute to explain the aging mechanism of C. reticulata 'Chachi' and the strategy of CID-induced special rearrangement ion binding metabolic pathway has potential application value in discovering trace compounds.

Chronic lymphocytic leukemia (CLL) is a hematologic malignancy characterized by progressive accumulation of a rare population of CD5+ B lymphocytes in peripheral blood, bone marrow and lymphoid tissues. CLL exhibits remarkable clinical heterogeneity, with some patients presenting with indolent disease and others progressing rapidly to aggressive CLL. The significant heterogeneity of CLL underscores the importance of identifying novel prognostic markers. Recently, the RAS-related gene RRAS2 has emerged as both a driver oncogene and a potential marker for CLL progression, with higher RRAS2 expression associated with poorer disease prognosis. Although missense somatic mutations in the coding sequence of RRAS2 have not been described in CLL, this study reports the frequent detection of three somatic mutations in the 3' untranslated region (3'UTR) affecting positions +26, +53, and +180 downstream of the stop codon in the mRNA. An inverse relationship was observed between these three somatic mutations and RRAS2 mRNA expression, which correlated with lower blood lymphocytosis and better prognosis. These findings highlight the importance of RRAS2 overexpression in CLL development and prognosis and point to somatic mutations in its 3'UTR as novel mechanistic clues. Our results may contribute to the development of targeted therapeutic strategies and improved risk stratification for CLL patients.

Background: Galectin-3 (Gal-3) overexpression is associated with fibroblastic proliferation and the production of collagen, resulting in increased cardiac fibrosis and remodelling. Aim of the study was to investigate on the expression of Gal-3 in hypertrophic hearts. We examined 19 surgical specimens taken from interventricular septum of 8 patients with Tetralogy of Fallot, 4 patients with aortic valve stenosis, 1 cardiac explant affected from dilated cardiomyopathy, and 6 myocardial biopsies of patients submitted to heart transplantation. Methods: All the samples were routinely processed, stained with Hematoxylin-Eosin, Trichromic stain and elastic fiber stain and selected by having the morphological features of myocardial hy-pertrophy: myocytolysis, nuclear pleomorphism, interstitial fibrosis. Results: At immunohistochemistry, myocardial fibers showed cytoplasmic expression of Gal-3 in the 4 patients with aortic valve stenosis (diffuse in 3 and mild in 1), in the 1 patient with cardiac explant (mild) and in the 4/6 transplanted hearts (mild and focal in 3 and diffuse in 1). The 8 patients affected from Tetralogy of Fallot and 2 patients with transplanted hearts resulted negative. Conclusions: The results agreed with the hypothesis that Gal-3 may play a role in cardiac hyper-trophy; its expression in myocardial fibers is not related with the morphological aspects as suggested by the absence in pediatric cases. The presence in myocardial biopsies taken from transplanted hearts would suggest a possible role in predicting clinical outcome of such patients.

The reaction of 2-bromo-1-(5-methyl-1-(4-nitrophenyl)-1H-1,2,3-triazol-4-yl)ethan-1-one (1) with 4-amino-5-((2,4-dichlorophenoxy)methyl)-4H-1,2,4-triazole-3-thiol (2) in absolute ethanol in the presence of triethyl amine as catalyst gave 2-((4-amino-5-((2,4-dichlorophenoxy)methyl)-4H-1,2,4-triazol-3-yl)thio)-1-(5-methyl-1-(4-nitrophenyl)-1H-1,2,3-triazol-4-yl)ethan-1-one (3) in 73% yield. The structure of the title heterocycle (3) was confirmed by X-ray single crystal diffraction and spectral analyses (NMR and IR).

Autism Spectrum Disorder (ASD) is characterized by varying degrees of difficulty in social interaction and communication. These deficits are often associated with gastrointestinal symptoms, indicating alterations in both intestinal microbiota composition and metabolic activities. The intestinal microbiota influences the function and development of the nervous system. In individuals with ASD, there is an increase in bacterial genera such as Clostridium, as well as species involved in the synthesis of branched-chain amino acids (BCAA) like Prevotella copri. Conversely, decreased amounts of Akkermansia muciniphila, and Bifidobacterium spp. are observed. Epigallocatechin gallate (EGCG) is one of the polyphenols with the greatest beneficial activity on microbial growth and its consumption is associated with reduced psychological distress. Therefore, the objective of this review is to analyze how EGCG and its metabolites can improve the microbial dysbiosis present in ASD and its impact on the pathology. The analysis reveals that EGCG inhibits the growth of pathogenic bacteria like Clostridium perfringens and Clostridium difficile. Moreover, it increases the abundance of Bifidobacterium spp. and Akkermansia spp. As a result, EGCG demonstrates efficacy in increasing the production of metabolites involved in maintaining epithelial integrity and improving brain function. This identifies EGCG as highly promising for complementary treatment in ASD.

Systemic sclerosis (SSc) is a multisystem connective tissue disease characterized by pathological processes involving autoimmunity, vasculopathy, and resultant extensive skin and organ fibrosis. Recent studies have demonstrated activation and aberrant wound healing responses in the epithelial layer of the skin in this disease, implicating the epithelial keratinocytes as a source of pro-fibrotic and inflammatory mediators. In this paper we investigated the role of Immunoglobulin G (IgG) autoantibodies directed against epithelial cells, as potential initiators and propagators of pathological keratocyte activation and the ensuing SSc fibrotic cascade. A keratinocyte cell-based ELISA is used to evaluation binding of SSc IgG. SSc skin biopsies were stained by immunofluorescence for the presence of IgG in the keratinocyte layer. Moreover, IgG purified from SSc sera is evaluated for the potential to activate keratinocytes in tissue culture and to induce signaling in TLR2 &amp; 3 reporter cell lines. We demonstrate enhanced binding of SSc IgG to keratinocytes, and activation of these cells leading to release of IL-1α, representing a potential initiating pathway in this disease.

Galectins have been shown to have roles in cancer progression via contributions to angiogenesis, metastasis, cell division, and evasion of immune destruction. This study analyses galectin-1, -3, and -9 serum concentrations in breast cancer patients by enzyme-linked immunosorbent assay (ELISA) against the characteristics of the patient and tumor such as stage, molecular subtype, and receptor expression. Galectin-9 was found to be statistically significantly increased in HER2 enriched tumors as well as being reduced in patients with hormone receptor positive tumors and increased in patients with HER2 amplified tissues. Galectin-1 was found to be statistically significantly increased in the serum of patients who had undergone hormonal, immunotherapy, or chemotherapy. These findings provide insight as to the changes in galectin levels during cancer progress, response to treatment and molecular phenotype. These findings are valuable in the further understanding of the relationships of galectin and tumor biology and can inform future research on therapeutic targets for galectin inhibitors and the utility of galectin biomarkers.

Erectile dysfunction (ED) is a common and feared complication of radical prostatectomy (RP) for prostate cancer. Recently, tissue engineering is being attempted for post-prostatectomy ED, with controlled interactions between cells, growth factors, and extracellular matrix (ECM) being important for nerve regeneration's structural integrity. In this study, we evaluated the effects of biomechanical ECM patch on human bone marrow-derived mesenchymal stem cells (hBMSCs) morphology and behavior in bilateral cavernous nerve injury (BCNI) rat model. The ECM patch, made of decellularized human fibroblast-derived ECM (hFDM) and a biocompatible polyvinyl alcohol (PVA) hydrogel, was tested with human bone marrow-derived mesenchymal stem cells (hBMSCs) on a bilateral cavernous nerve injury (BCNI) rat model. In vitro analysis showed that the hFDM/PVA + hBMSCs patches significantly increased neural development markers. In vivo experiments demonstrated that the rats treated with the hFDM/PVA patch had higher ICP/MAP ratio, a higher ratio of smooth muscle to collagen, increased content of nNOS, higher levels of eNOS protein expression, and a higher cGMP level compared to the BCNI group. These results indicate that the hFDM/PVA patch is effective in promoting angiogenesis, smooth muscle regeneration, and nitrergic nerve regeneration, which could contribute to improved erectile function in post-prostatectomy ED.