Retinoid X receptor (RXR) antagonists are not only useful as chemical tools for biological research, but also are candidate drugs for treatment of various diseases, including diabetes and allergy, although no RXR antagonist has yet been approved for clinical use. In this review, we describe currently available RXR antagonists, their structural classification, and their evaluation, focusing on the latest research.

Cell-penetrating peptides (CPPs), a group of small peptides capable of promoting the transport of molecular cargo across the plasma membrane, have become important tools in promoting the cellular uptake of exogenously delivered macromolecules. GV1001, a peptide derived from a reverse-transcriptase subunit of telomerase (hTERT) and developed as a vaccine against various cancers, reportedly has unexpected CPP properties. Unlike typical CPPs, such as the HIV-1 TAT peptide, GV1001 enabled the cytosolic delivery of macromolecules such as proteins, DNA and siRNA via extracellular heat shock protein 90 (eHSP90) and 70 (eHSP70) complexes. The eHSP-GV1001 interaction may have biological effects in addition to its cytosolic delivery function. GV1001 was originally designed as a MHC class II-binding cancer epitope, but its CPP properties may contribute to its strong anti-cancer immune response relative to other telomerase peptide-based vaccines. Cell signaling via eHSP-GV1001 binding may lead to unexpected biological effects, such as direct anticancer or antiviral effects. In this review, we focus on the CPP effects of GV1001 bound to eHSP90 and ehsp70.

MicroRNAs (miRNAs) are a kind of conserved small non-coding RNAs that participate in regulating gene expression by targeting multiple molecules. Early studies have shown that the expression of miRNAs changes significantly in different tumor tissues and cancer cell lines. It is well acknowledged that such variation is involved in almost all biological processes, including cell proliferation, mobility, survival and differentiation. Increasing experimental data indicate that miRNA dysregulation is a biomarker of several pathological conditions including cancer, and that miRNA can exert a causal role, as oncogenes or tumor suppressor genes, in different steps of the tumorigenic process. Anticancer therapies based on miRNAs are currently being developed with a goal to improve outcomes of cancer treatment. In our present study, we review the function of miRNAs in tumorigenesis and development, and discuss the latest clinical applications and strategies of therapy targeting miRNAs in cancer.

It is known that the class of p-normed spaces (0 < p ≤ 1) is an important generalization of usual normed spaces with rich topological and geometrical structure, but the most of tools and general principles in nature with nonlinearity have not been developed yet, thus the main goal of this paper is to develop tools for nonlinear analysis under the framework of p-vector spaces. In particular, we first develop the general fixed point theorems which provide solutions to answer Schauder conjecture since 1930’s in the affirmative for p-vector spaces when p = 1 (which is just general topological vector spaces); then the one best approximation result for upper semi-continuous mappings is given, which is used as a powerful tool to establish fixed points for non-self set-valued mappings with either inward or outward set conditions; and finally we establish comprehensive existence results of solutions for Birkhoff-Kellogg Problems, and the general principle of nonlinear alternative by including Leray-Schauder alternative and related results. The results given in this paper not only include the corresponding results in the existing literature as special cases, but also expected to be useful tools for the study of nonlinear problems arising from theory to practice.

Observations of the X-ray binary system Her X-1 by the AstroSat Soft X-ray Telescope 1 (SXT) were carried out in 2020 through 2023 with the goals of measuring X-ray spectrum changes with the 35-day disk rotation phase and measuring eclipses at different 35-day phases. The four multi-day long observations were scheduled during: turn-on to Main High (MH) and MH rise; MH state; Short High (SH) state; and Low State (LS). 35-day phase was determined using monitoring observations with the Swift Burst Alert Telescope (BAT). Nine eclipses were observed at a range of 35-day phases, with at least one eclipse during each observation. Data with dips were separated from data without dips. The variation of X-ray spectral parameters vs. 35-day phase shows the following: eclipse parameters are nearly constant, showing that the scattering corona does not change with 35-day phase; dips show an increase in covering fraction but not column density compared to non-dip data; the 1 keV line normalization indicates an origin in a small region near the continuum emission region, likely the magnetospheric accretion flow from the inner disk onto the neutron star; and the change in blackbody normalization (area) shows that the emission region is much larger than the 1 keV emission region, and consistent with the inner edge of the accretion disk.

Heme is located in the active site of proteins and has diverse and important biological functions, such as electron transfer and oxygen transport and/or storage. The distortion of heme porphyrin is considered an important factor for the diverse functions of heme because it correlates with the physical properties of heme, such as oxygen affinity and redox potential. Therefore, clarification of the relationship between heme distortion and the protein environment is crucial in protein science. Here, we analyzed the fluctuation in heme distortion in the protein environment for hemoglobin and myoglobin using molecular dynamics (MD) simulations and quantum mechanical (QM) calculations. We also investigated the protein structures of hemoglobin and myoglobin stored in Protein Data Bank and found that heme is distorted along the doming mode, which correlates with its oxygen affinity, more prominently in the protein environment than in the isolated state, and the magnitude of distortion is different between hemoglobin and myoglobin. This tendency was also observed in the results of MD simulations and QM calculations. These results suggest that heme distortion is affected by its protein environment and fluctuates around its fitted conformation, leading to physical properties that are appropriate for protein functions.

Urban and agricultural runoffs can transport contaminants and pesticides into freshwater ecosystems, particularly in the developing tropics. For instance, organophosphate and pyrethroids pesticides like glyphosate, malathion, and permethrin have been found in tropical streams. The uncontrolled application of these pesticides has become a growing concern due to their adverse effects on various non-targeted organisms. Unfortunately, most studies have focused on a few selected model species, ignoring the effects on other nontarget organisms, which may play an important role in tropical lotic ecosystems. In addition, the biological characteristics of aquatic crustaceans, including their morphology, physiology, and behavior, make them susceptible to toxic chemicals. For this reason, this study used the widely distributed freshwater shrimp Xiphocaris elongata as a model organism to determine the acute toxicity of permethrin, malathion, and glyphosate. Our results show that the proportion of mortality of X. elongata in each concentration group became progressively higher as the concentration of exposure increased. We also found that the synthetic pyrethroid permethrin is the most toxic pesticide tested, followed by organophosphate malathion and glyphosate. Experiments with this freshwater shrimp showed a good control performance and reproducibility for the tested pesticides. This study demonstrated that X. elongata is a suitable test organism that can be a representative bioindicator of pesticide toxicity in tropical streams.

Ultrasound (US) scans of the inferior vena cava (IVC) provide useful information on the volume status of a patient. However, their investigation is user-dependent and prone to measurement errors. An important technical problem is the objective difficulty in studying a very compliant blood vessel like IVC, which makes large respirophasic movements and shows a complicated three dimensional geometry. Using bi-dimensional (2D) B-mode views either in long or short axis has improved the characterization of IVC dynamics compared to a measurement along a single direction (M-mode). However, specific movements of the IVC can challenge also the information provided by these 2D sections. Thus, these two orthogonal views, provided by an US system in X-plane, are here integrated by an innovative method. It is tested on simulated videos of the IVC performing complicated movements, that are compensated by the new method, overcoming the biased measurements provided by 2D scans. The method is then applied on example experimental data.

Drug-induced liver disease represents one of the main problems in the therapeutic field. As with most pathologies, also in this case various risk factors can be recognised, such as age, sex, but also the gut microbiota. Therefore all drugs on the market can, in fact, cause hepatotoxicity of varying degrees. Drugs used in the treatment of IBD can also cause these adverse effects and even lead to DILI. In this review, the various classes of drugs used in the treatment of IBD were taken into consideration and the various adverse effects on the liver were illustrated. In particular, a major role has emerged regarding hepatotoxicity of immunosuppressants. Biological drugs, however, seem to be responsible for these complications to a much lesser extent.

In order to correct attenuated millimeter-wavelength (Ka-band) radar data and address the problem of instability, an attenuation correction methodology (attenuation correction with variation trend constraint; VTC) was developed. Using synchronous observation conditions and multi-band radars, the VTC method adopts the variation trends of reflectivity in X-band radar data captured with wavelet transform as a constraint to adjust reflectivity factors of millimeter-wavelength radar. The correction was evaluated by comparing reflectivities obtained by millimeter-wavelength cloud radar and X-band weather radar. Experiments showed that attenuation was a major contributory factor in the different reflectivities of the two radars when relatively intense echoes exist, and the attenuation correction developed in this study significantly improved data quality for millimeter-wavelength radar. Reflectivity differences between the two radars were reduced and reflectivity correlations were enhanced. Errors caused by attenuation were eliminated, while variation details in the reflectivity factors were retained. The VTC method is superior to the bin-by-bin method in terms of correction amplitude and can be used for attenuation correction of shorter wavelength radar assisted by longer wavelength radar data.

Sometimes a pavement deflects only because of seasonal volume change of expansive soils in the pavement subgrade. Engineering practitioners expect an implementable and straightforward analysis method for a geosynthetic-reinforced pavement subjected to the swelling/shrinkage issue of expansive clayey subgrade, in an effort to find the bending moment, shear force and tension force distributions through the reinforced pavement, which are induced from the volumetric changes of subgrade soils. The virtual load method (VLM) was proposed in the past following the Timoshenko beam theory to analyze geosynthetic-reinforced pavement on expansive soils. In the VLM, the unknown virtual distributed load was obtained in the way by applying the inverse theory for the identification of material parameters of the pavement-foundation system. It was seen that the selection of the number of material parameters to obtain virtual load significantly affects the accuracy of the structural properties of the pavement and tensile properties of the geosynthetics if the linear least square method is used. In this paper, a unique numerical scheme was proposed in the hopes of solving the issue. After a forward problem was solved numerically, the Timoshenko beam deflection was taken as a start-up for the inverse problem to back analyze the load applied to the pavement. Solutions from forward/backward examples have explicitly shown the accuracy achieved related to the bending moment in the pavement and tension in the geosynthetic reinforcements. The proposed methodology can be applied for an in-depth understanding of the geosynthetic function for the mitigation of longitudinal cracks on pavements caused by heave/shrinkage of expansive soils.

Brine-dependent recovery process has seen much global research efforts in the past two decades because of their benefits over other oil recovery methods. The process involves the tweaking of the ionic composition and strength of the injected water to improve oil production. In recent years, several studies ranging from laboratory coreflood experiments by many researchers to field trials by several companies admit to the potential of recovering additional oil in sandstone and carbonate reservoirs. Sandstone and carbonate rocks are composed of completely different minerals, with varying degree of complexity and heterogeneity, but wettability alteration has been widely considered as the consequence rather than the cause of brine-dependent recovery. However, there is no consensus on the cause as several mechanisms have been proposed to relate the wettability changes to the improved recovery. This review paper aims to provide a state-of-the-art development in published research and various efforts of the industry. This review outlines an overview of laboratory and field observations, descriptions of underlying mechanisms and their validity, the complexity of the oil-brine-rock interactions, modelling works, and comparison between sandstone and carbonate rocks. The provided information is intended to provide the reader with up-to-date information, point to relevant studies for those who are new and those implementing either laboratory- or field-scale projects to speed up the process of further investigations in this research area. Overall, the outcome of this review would potentially be of immense benefit to the oil industry.

Background: Several kinds of research say that adjuvant blood glucose and blood pressure are usual, but an efficient solution for medical application count remains. This review analyzes the pandemic blood pressure and blood glucose to identify the publications which tell about the clinical practices and research gaps in systematic research.Methods: A study guides to identify the research of Blood Pressure (BP) and Blood Glucose. In order to analyze the recent innovations and research on BP and Blood glucose, the relevant publications and literature from journals were identified.Results: Co-morbidity of BP and Blood glucose is reported as very high. The commonness of blood pressure is thrice as high in type I diabetes patients and almost two times higher in type II diabetes patients when compared to others without Diabetes. The pervasiveness of getting depression is more in the female when compared with men. A detailed study about the linkage of BP and blood glucose tells that the relationship between them is not exactly clear.Limitations: Nearly all reviews providing the linkage of BP and blood glucose are with some limitations and they are not providing any clear conclusion.Conclusions: Present research tells that people having high blood glucose will have a greater chance of getting high blood pressure. More research is needed to state the linkage between BP, blood glucose, and the growth of diabetes mellitus issues and to provide support for managing Diabetes.

We have investigated the influence of the relative proportions of glass formers in a series of lithium alumino-borosilicate glasses with respect to electrical conductivity () and glass transition temperature (Tg) as functions of glass structure, as determined by Raman spectroscopy. The ternary lithium alumino-borate glass exhibits the highest  and lowest Tg among all the compositions of the glass series, 30Li2O•3Al2O3• (67-x) B2O3•xSiO2. However, as B2O3 is replaced by SiO2, a shallow minimum in  as well as a shallow maximum in Tg are observed near x = 27, where the Raman spectra indicate isolated diborate/tetraborate/orthoborate groups are being progressively replaced by danburite/reedmergnerite-like borosilicate network units. Overall, as the glasses become silica-rich,  is minimized, while Tg is maximized. In general, these findings show correlations among Tg, (sensitive to network polymerization),  (proportional to ionic mobility), and the different borate and silicate glass structural units as determined by Raman spectroscopy. X-ray diffraction analyses demonstrate the absence of appreciable crystallinity in the glasses investigated. However, scanning electron microscopy (SEM) images of HF-etched samples showed that glasses, and especially the borate-rich compositions comprise two distinct glassy phases. The isolated phase is 25-100 nm in diameter, dispersed evenly in a glassy matrix.

Drug-induced liver injury (DILI) stands as a significant cause of drug attrition. To mitigate clinical DILI risks, assessing drugs using human liver models is crucial since animal studies may fall short due to species-specific liver pathway variations. Cell-based preclinical hepatotoxicity testing is often pertinent. In the present study, cells from a human liver cancer line (HepG2, HepaRG) were cultured in both formats of 2D and 3D spheroids to explore their responses to drugs. Liver-specific marker expressions across cell lines and culture formats were also examined to assess disparities in drug-induced liver injury marker expressions. In cytotoxicity assays, HepG2 cells exhibited heightened sensitivity to amiodarone HCl, while HepaRG cells showed greater sensitivity to acetaminophen. Generally, 2D cultures were more responsive to drugs than 3D cultures. Consistency was observed between cytotoxicity assays and liver injury markers AST and ALT. Variations were also noted in liver cell marker secretion, with albumin and urea concentrations declining post-drug treatment, particularly with higher baseline expression in HepaRG cells and 3D cultures. Additionally, mRNA expression levels of CYP enzymes involved in hepatocellular drug metabolism were compared following treatment with enzyme inducers. CYP1A2 and CYP2C9 were not expressed in HepG2 cells. On the other hand, CYP3A4 was expressed higher in 3D culture than in 2D culture. HepaRG cells exhibited significantly increased expression of all three enzymes post-treatment. Notably, enzyme expression was notably higher in 3D cultures than in 2D cultures. Collectively, these findings suggest that HepaRG cells and 3D cultures hold promise for evaluating DILI during early-stage drug development.

The atomic structures of Zn and Na borophosphate glasses were studied by X-ray and neutron diffraction. Peaks assigned to the B−O, P−O, and O−O distances confirm that only BO4 units co-exist with the PO4 tetrahedra. The Zn−O and Na−O coordination numbers are found to be a little larger than four. The narrowest peaks of the Zn−O first-neighbor distances exist for the glasses along a line connecting the Zn(PO3)2 and BPO4 compositions (50 mol% P2O5) which is explained by networks of ZnO4, BO4, and PO4 tetrahedra with twofold coordinated oxygens. Calculated amounts of the available oxygen support this interpretation. Broadened peaks occur for glasses with lower P2O5 contents, consistent with the presence of threefold coordinated oxygens. The two distinct P−O peak components of the Zn and Na borophosphate glasses differ in their relative abundances which is interpreted by Na+ cations that coordinate oxygens in some P−O−B bridges, something not seen for the Zn2+ ions.

Fragile X syndrome (FXS) is a genetic disorder caused by a mutation in the fragile X messenger ribonucleoprotein 1 (FMR1) gene and known to be a leading cause of inherited intellectual disability globally. It results in a range of intellectual, developmental, and behavioral problems. Fragile X premutation associated conditions (FXPAC), also caused by a smaller CGG expansion (55 to 200 CGG repeats) in the FMR1 gene, is linked to other conditions that increase morbidity and mortality for affected persons. Limited research has been conducted on the burden, characteristics, diagnosis, and management of these conditions in Africa. This comprehensive review provides an overview of the current literature on FXS and FXPAC in Africa, epidemiology, clinical features and challenges faced, such as discrimination against affected persons, limited awareness and research, poor access to resources and genetic services and treatment. It further provides an in-depth analysis of the existing worldwide data for the diagnosis and treatment of these disorders. This review will improve understanding of FXS and FXPAC in Africa by incorporating existing knowledge, identifying research gaps, and potential topics for future research to enhance the well-being of individuals and families affected by FXS and FXPAC in the region.

The inclusion of spent hemp biomass (SHB), an extracted byproduct from industrial cannabidiol (CBD) production, in the diets of dairy cows and lambs appear to be safe with minor effects on the metabolism, including a decrease of circulating cholesterol and increase bilirubinemia, both associated with liver metabolism. Those effects could be consequence of the presence of cannabinoids, particularly Δ9-tetrahydrocannabinol (THC) and CBD in the SHB. This study aimed to study the transcriptional profile of the liver of dairy cows and lambs fed SHB. Dairy cows received SHB or alfalfa pellet for four weeks of intervention (IP) and four weeks of withdrawal periods (WP). Finishing lambs were fed a control diet (CON), 10% (LH2) or 20% (HH2) SHB for 2 months or 1 month followed by 1-month SHB withdrawal (LH1 and HH1, respectively). RNA sequencing was performed, and the mRNA was annotated using the latest reference genomes. The RNAseq data were filtered, normalized for library size and composition, and statistically analyzed by DESeq2. The bioinformatic analysis was performed by using DAVID, Gene Set Enrichment (GSE) analysis, and the Dynamic Impact Approach. Using a 0.2 FDR cut-off, we identified only ≤24 differentially expressed genes (DEG) in the liver by feeding SHB in dairy cows and a larger number of DEG in lambs (from 71 in HH1 vs. CON to 552 in LH1 vs. CON). The KEGG analysis demonstrated that feeding SHB in dairy cows and lambs had relatively minor to moderate metabolic alterations in dairy cows and lambs mainly associated with amino acids and lipid metabolism whereas cholesterol synthesis was overall activated in lambs. GSE analysis identified activation of PPAR signaling pathway only in dairy cows. We found an opposite effect on activation of metabolism of drug and xenobiotics by cytochrome P450 enzymes in dairy cows and lambs receiving less SHB but an inhibition in HH2 lambs. Immune system-related pathways were inhibited by feeding SHB in lambs, but the impact was minor. Cumulatively, inclusion of SHB containing cannabinoids in dairy and lambs demonstrate very little effects on the alteration of transcriptomic profile of the liver.

Receptor–ligand interactions at cell interfaces initiate signaling cascades essential for cellular communication and effector functions. Specifically, T cell receptor (TCR) interactions with pathogen-derived peptides presented by the major histocompatibility complex (pMHC) molecules on antigen-presenting cells are crucial for T cell activation. The binding duration, or dwell time, of TCR–pMHC interactions correlates with downstream signaling efficacy, with strong agonists exhibiting longer lifetimes compared to weak agonists. Traditional surface plasmon resonance (SPR) methods quantify 3D affinity but lack cellular context and fail to account for factors like membrane fluctuations. In the recent years, single-molecule Förster resonance energy transfer (smFRET) has been applied to measure 2D binding kinetics of TCR–pMHC interactions in a cellular context. Here, we introduce a rigorous mathematical model based on survival analysis to determine exponentially distributed receptor–ligand interaction lifetimes, verified through simulated data. Additionally, we developed a comprehensive analysis pipeline to extract interaction lifetimes from raw microscopy images, demonstrating the model’s accuracy and robustness across multiple TCR–pMHC pairs. Our new software suite automates data processing to enhance throughput and reduce bias. This methodology provides a refined tool for investigating T cell activation mechanisms, offering insights into immune response modulation.

Transplanted organs experience several episodes of ischemia and Ischemia-reperfusion. The graft injury resulting from ischemia-reperfusion (IRI) remains a significant obstacle to the successful survival of transplanted grafts. Temperature plays an important role in cellular metabolic rates since biochemical reactions are highly temperature dependent. Therefore, ischemia-triggered degradative reactions could be mitigated by lowering temperature. Whether a local hypothermia on liver before blockage of blood flow protects liver grafts against IRI has not been investigated. In this study, we applied local hypothermia to mouse donor livers for a specific duration before stopping blood flow to liver lobes, a procedure called "liver precooling." Mouse donor liver temperature in control groups was controlled at 37ºC. Subsequently, the liver donors were preserved in cold University of Wisconsin solution for various durations followed by orthotopic liver transplantation. Liver graft injury, function and inflammation were assessed at 1- and 2-days post-transplantation. Liver precooling exhibited a significant improvement in graft function, revealing more than a 47% decrease in plasma aspartate transaminase (AST) and alanine aminotransferase (ALT) levels, coupled with a remarkable reduction of approximately 50% in liver graft histological damage compared to the control group. The protective effects of liver precooling were associated with the preservation of mitochondrial function, substantial reduction in hepatocyte cell death, and a significantly attenuated inflammatory response. A retrospective analysis of patient data revealed a close correlation between hypothermia and enhanced liver graft function. Taken together, reduction of the cellular metabolism and enzymatic activity to a minimum level before ischemia protects against IRI during transplantation.

The aim of this review is to provide a survey of the recent advances and the main remaining challenges related to the ultrananocrystalline diamond (UNCD) nanowires and other nanostructures which exhibit excellent capability as the core components for many diverse novel sensing devices, due to the unique material properties and geometry advantages. The doping introduced in the gas phase during deposition promotes p-type or n-type conductivity. With the establishment of the UNCD nanofabrication techniques, more and more nanostructure based devices are being explored in measuring basic physical and chemical parameters via classic and quantum methods, as exemplified by gas sensors, ultraviolet photodetectors, piezoresistance effect based devices, biological applications, and nitrogen-vacancy color center based magnetic field quantum sensors. Highlighted finally are some of the remaining challenges and future outlook in this area.

Analysing the human body by direct observation can lead to misinterpretation of underlying trends, whereas in vitro organ models facilitate their understanding. Likewise, in vitro organ models serve as valuable tools for assessing the toxicity of compounds. However, none of the existing models had the features we considered critical for toxicity assessment, so we developed an in vitro liver model for toxicity assessment. We used four different types of primary liver cells: Hepatic sinusoidal endothelial cells, hepatic stellate cells, Kupffer cells and hepatocytes. We cultured them in different combinations of composition and volume of cell medium, hepatocyte proportion of total cells, and addition of extracellular matrix. We added rifampicin, ibuprofen and 5-fluorouracil to this model and observed the microanatomy and physiology changes for a week with preclinical and clinical instruments. Among the different model configurations, we selected the feature combination of the in vitro model that had similar biomarker values to those measured by the clinical instruments used in clinical diagnostics. When we exposed the selected model configuration to rifampicin, ibuprofen and 5-fluorouracil, the viability of Kupffer cells and liver sinusoidal endothelial cells was significantly lower than in the untreated samples. In contrast, we observed negligible viability of hepatocytes compared to the untreated samples. We have built an in vitro liver model that resembles the liver microenvironment and we have analysed it with clinical instrumentation to facilitate the data translation. In this sense, we have established that Kupffer and LSEC cells are suitable candidates for the search for clinical diagnostic markers of liver function.

BackgroundLiving donor liver transplantation offers comparable long-term results to cadaveric donor transplantation. This study analyzes the selection process of living liver donors at a Western transplant center that utilizes both donation forms. MethodsThis retrospective analysis examined potential living donors, collecting medical data and reasons for refusal, and divided patients by indication and urgency for transplantation. ResultsFrom January 2013 to December 2023, 594 potential living donors were assessed at Jena University Hospital. Of these, 124 living donor transplants were performed. During outpatient evaluation, 357 potential donors were excluded. Subsequently, 238 individuals underwent inpatient assessment, with 100 more being excluded. Main reasons for donor refusal included medical or psychological issues (n=160), disease progression in recipients (n=90), and recipient refusal or donor withdrawal (n=54). The evaluation process showed a trend towards considering more distant relatives and acquaintances as donor candidates with increasing severity of the recipient's disease.

This research focuses on examining the responses of interest groups listed in the European Transparency Register to the ongoing Russia-Ukraine war. Its aim is to investigate the nuanced reactions of 2,579 commercial and business associations and 2,957 companies and groups to the conflict, as expressed through their X (Twitter) activities. Utilizing advanced text mining, NLP and LDA techniques, this study conducts a comprehensive analysis encompassing language dynamics, thematic shifts, sentiment variations, and activity levels exhibited by these entities both before and after the outbreak of the war. The results obtained reflect a progressive decreasing in negative emotions regarding the conflict over time. Likewise, multiple forms of outside lobbying are identified in the communication strategies of interest groups. All in all, this empirical inquiry into how interest groups adapt their messaging in response to complex geopolitical events holds the potential to provide invaluable insights into the multifaceted role of lobbying in shaping public policies.

The spectra and global distributions of the X-ray emissions generated by the solar wind charge-exchange (SWCX) process in the terrestrial magnetosheath are investigated based on a global hybrid model and a global geocoronal hydrogen model. The solar wind O6+ ions which are the primary charge state for oxygen ions in solar wind are considered. The line emissivity of the charge-exchange born O5+ ions are calculated by Spectral Analysis System for Astrophysical and Lab oratory (SASAL). It is found that the emission lines from the O5+ ranges from 105.607 to 118.291 eV with the strong line at 107.047 eV. We then simulated the magnetosheath X-ray emission intensity distributions with a virtual camera at two positions of north pole and dusk at six stages during the passing of a perpendicular interplanetary shock combined with a tangential discontinuity structure through the Earth’s magnetosphere. During this process, the X-ray emission intensity increases with time, and the maximum value is 27.11 keV cm-2 s-1 sr-1 on the dayside, which is 4.5 times that before the solar wind structure reaches the Earth. A clear shock structure can be seen in the magnetosheath and moves earthward. The maximum emission intensity seen at dusk is always higher than that seen at north pole.

Uveal melanoma (UM) poses a significant clinical challenge due to its high metastasis rate and poor prognosis. Melatonin, noted for its anti-cancer properties in various malignancies, including cutaneous melanoma, shows promise in UM treatment. This study aimed to evaluate melatonin receptor expression in primary UM and its association with UM-related mortality and prognostic factors. Immunohistochemical analysis of 47 primary UM tissues showed low expression of MTNR1A and MTNR1B receptors, with MTNR1A significantly higher in patients who succumbed to UM. Analysis of TCGA data from 80 UM patients revealed RNA expression for MTNR1A, RORα, and NQO2, but not MTNR1B or GPR50. Higher MTNR1A RNA levels were observed in patients with a BAP1 mutation, and higher NQO2 RNA levels were noted in patients with the epithelioid tumor cell type. However, Kaplan-Meier analysis did not show distinct survival probabilities based on receptor expression. The study concludes that UM clinical samples express melatonin receptors, suggesting a potential mechanism for melatonin's anti-cancer effects. Despite finding higher MTNR1A expression in patients who died of UM, no survival curve differences were observed. Further research is needed to explore additional mechanisms of melatonin’s oncostatic effects, including its antioxidant properties and immune modulation.

Several studies with kaempferol (KP) and linearolactone (LL) have shown antiparasitic activities. However, the toxicity of treat-ments with both active principles is unknown. Therefore, this study aimed to evaluate the toxicological effects of treatments with KP and LL on the amoebic liver abscess (ALA) model in M. auratus administered intraperitoneally (i.p.). For this, ALA in-duction was carried out in male hamsters with 1.5 x105 E. histolytica trophozoites inoculated in the left hepatic lobe. The lesion evolved for four days and the i.p. of the treatments with KP (5 mg/kg body weight/day) and LL (10 mg/kg body weight/day) was carried out for four consecutive days. For histopathological evaluation, NMR studies, paraclinical analysis, and necropsy were performed. The results revealed that the inhibition of ALA by KP and LL were similar to that metronidazole (MTZ). Biochemical parameters revealed hepatic and renal alterations in all treatment groups, mainly for KP (AST and BUN). The lesions found in the organs were those that are directly linked to the pathology. In conclusion, KP and LL decrease ALA development but have few toxicological effects. Both compounds combined with MTZ could be therapeutic alternatives for amoebiasis caused by E. histolytica.

Kombucha is a popular sparkling sugared tea, fermented by a symbiotic culture of acetic acid bacteria (AAB) and yeast. The demand for Kombucha is increasing worldwide mainly due to its perceived health benefits and appealing sensory properties. This study isolated and characterised the dominant AAB and yeast from starter culture and Kombucha broth after 0, 1, 3, 5, 7, 9, 11, and 14 days of fermentation at ambient temperature (~22°C). Changes in the microbial composition were associated with variations in the physico-chemical characteristics of Kombucha tea, such as pH, titratable acidity, and total soluble solids (TSS). During fermentation, the acidity increased, and TSS decreased. The yield, moisture content and water activity of the cellulosic pellicles which had developed by the end of fermentation were attributed to the presence of AAB. Yeast and AAB were isolated from the Kombucha samples using glucose yeast extract mannitol ethanol acetic acid (GYMEA) and yeast extract glucose chloramphenicol (YGC) media respectively, using serial dilutions. Phenotypic and taxonomic identification of AAB and yeast were determined by morphological and biochemical characterisation, followed by sequence analysis of the ribosomal RNA gene (16S rRNA for AAB and ITS for yeast). The dominant AAB species in the cellulosic pellicle and Kombucha broth was identified as Komagataeibacter rhaeticus. The yeast isolates belonged to Debaryomyces prosopidis and Zygosaccharomyces lentus.

Alcoholic liver disease (ALD) develops when the immunotolerant environment of the liver is compromised due to excessive alcohol consumption. ALD progression involves variations in the expression of multiple genes, resulting in liver inflammation and the development of a leaky gut. Molecular mechanism involved for ALD progression is still unclear, and due to that there are currently no FDA-approved drugs available for its treatment. In this study, the protective effects of Graphene oxide nanoparticles (GO) was investigated against ethanol-induced damage in the gut-liver axis in in vitro. GO was synthesized using a modified Hummer's method and characterization was done. Given the general concerns regarding nanoparticle toxicity, assessment of cell viability, lipid accumulation, DNA damage, cell death, and the generation of reactive oxygen species (ROS) were conducted using various techniques. Furthermore, gene expression of pro- and anti-inflammatory cytokines was done using RT-qPCR. The findings revealed that GOs promoted cell viability even against ethanol treatment. Additionally, lipid accumulation significantly decreased when cells were treated with GO alongside ethanol compared to ethanol treatment alone, with similar trends observed for other assays. Gene expression analysis indicated that GO treatment reduced the expression of proinflammatory cytokines while enhancing the expression of antioxidant genes. Moreover, GO treatment led to improvements in gut permeability and a reduction in proinflammatory cytokines in colon cells damaged by ethanol. These findings suggest that GO holds promise as a drug carrier, exhibiting no observed toxic effects. By shedding light on the protective effects of GO against ethanol-induced damage, this study contributes to the burgeoning field of nanoparticle-mediated therapy for ALD.

The current management of colorectal cancer liver metastasis (CRCLM) patients involves a multidisciplinary approach with surgical resection remaining the primary curative option. The advances in liver surgery have improved outcomes, enabling more patients to undergo surgery successfully. In addition, the development of imaging software has improved the preoperative planning and patient selection for surgery and other interventions. Systemic therapies, such as targeted therapies and immunotherapies have enhanced the chances of complete resection. Targeted agents in combination with chemotherapy, have shown efficacy in downstaging tumors and increasing resectability.

The sexual reproduction of ascomycetes is controlled by the mating-type(MAT) locus. (Pseudo)homothallic reproduction has been hypothesized based on genetic data from Hirsutella sinensis (Genotype #1 of Ophiocordyceps sinensis). In this study, the differential occurrence of the mating-type genes in the MAT1-1 and MAT1-2 idiomorphs, which constitute the genetic control of O. sinensis reproduction, was analyzed in 237 strains and 5 genomes of H. sinensis. The mating-type genes were differentially transcribed in H. sinensis Strain L0106, and the MAT1-2-1 transcript in H. sinensis Strain 1229 was alternatively spliced, with an unspliced intron I containing stop codons; these findings constitute O. sinensis reproduction controls at the transcriptional and coupled transcriptional-translational levels. The occurrence of the mating-type genes and a-/α-pheromone receptor genes differed among the 5 H. sinensis genomes. The differential occurrence and transcription of these genes are inconsistent with self-fertilization under (pseudo)homothallism but suggest self-sterility of H. sinensis, which therefore needs a mating partner to achieve sexual outcrossing under heterothallism or hybridization. Consistent occurrence and transcription of the mating-type genes of both the MAT1-1 and MAT1-2 idiomorphs have been reported in natural and cultivated Cordyceps sinensis, but these findings are insufficient to determine the reproduction mode(s) because of the co-occurrence of >90 fungal species and multiple genomically independent genotypes of O. sinensis. The mutant MAT1-1-1 and α-pheromone receptor transcripts in natural C. sinensis result in the N-terminus or middle-truncated proteins, with changes in hydrophobicity and secondary structures of the proteins, suggesting heterogeneous fungal source(s) of the proteins and hybridization reproduction.

The farnesoid X receptor (FXR)/βKlotho/fibroblast growth factors (FGFs) pathway is crucial for maintaining the intestinal barrier and preventing colorectal cancer (CRC). We used an FXR ago-nist, GW4064, and FXR knockout (KO) mice to investigate the role of FXR/Klothos/FGFs pathways in lipopolysaccharide (LPS)-induced intestinal barrier dysfunction and colon carcinogenesis. The results showed that upregulation of FXR in enterocytes effectively ameliorated intestinal tight junction markers (claudin1, Zonula occludens-1), inflammation, and bile acid levels, thereby protecting mice from intestinal barrier dysfunction and colon carcinogenesis. GW4064 treatment increased FXR, αKlotho, βKlotho, FGF19, FGF21, and FGF23 in wild-type mice exposed to LPS, while FXR KO mice had decreased levels. FXR KO mice exhibited elevated colon cancer markers (β-catenin, LGR5, CD44, CD34, Cyclin D1) under LPS, underscoring the pivotal role of FXR in inhibiting the development of colon tumorigenesis. The varying gut microbiota responses in FXR KO mice versus wild-type mice post-LPS exposure emphasize the pivotal role of FXR in pre-serving intestinal microbial health, involving Bacteroides thetaiotaomicron, Bacteroides acidifaciens, and Helicobacter hepaticus. Our study validates the effectiveness of GW4064 in alleviating LPS-induced disruptions to the intestinal barrier and colon carcinogenesis, emphasizing the importance of the FXR/αKlotho/βKlotho/FGFs pathway and the interplay between bile acids and gut microbiota.

Spinocerebellar ataxia type 3 is a neurodegenerative disease caused by an abnormal expansion of CAG repeats in the disease gene ATXN3, leading to prolonged polyglutamine (polyQ) tracts in the respective protein ataxin-3. The polyQ-expanded protein forms polyQ-containing aggregates in several brain regions which leads to neuronal cell loss. Autophagy is thought to play a significant role in clearing these polyQ-containing protein aggregates. Therefore, the autophagy mechanism was investigated in SCA3 with focus on the autophagic protein p62/sequestosome-1. Human and mouse RNA sequencing data were analyzed to determine RNA expression level of autophagic genes. Additionally, autophagy was studied in the SCA3 304Q knock-in mouse model and through several cell culture experiments using HEK-293T cells transfected with ATXN3 of differ-ent polyQ lengths. For cell culture experiments, autophagy was induced with rapamycin treat-ment, proteasomal degradation was blocked with MG132 and degradation of autophagic pro-teins was investigated using cycloheximide treatment. Here, we report an increased autophagy impairment with SCA3 disease progression seen in HEK-293T cells transfected with ATXN3 plasmid with expanded polyQ tracts, higher aged 304Q-knock-in mice, or human post-mortem brain material. Furthermore, co-localized aggregation of the autophagic protein p62 and the dis-ease protein ATXN3 was observed in the course of SCA3 disease. Therefore, we suggest a signifi-cant role for p62 in aggregate formation seen in the neurodegenerative disease SCA3.

Hydrogen-bond (H-bond) energies in 310-helices of short alanine peptides were systematically examined by precise DFT calculations with the negative fragmentation approach (NFA), a modified method based on the molecular tailoring approach. The contribution of each H-bond was evaluated in detail from the 310-helical conformation of total energies (whole helical model; WH3-10 model), and the results were compared with the property of H-bond in a-helix from our previous study. The H-bond energies of the WH3-10 model exhibited tendencies different from those exhibited by the -helix, in that they depended on the helical position of the relevant H-bond pair. H-bond pairs adjacent to the terminal H-bond pairs were observed to be strongly destabilized. The analysis of electronic structures indicated that structural characteristics cause the destabilization of the H-bond in 310-helices. We also found that the longer the helix length, the more stable the H-bond in the terminal pairs of the WH3-10 model, suggesting the action of H-bond cooperativity.

This paper presents a two-stage ADC based on pseudo-differential operational transconductance amplifier (OTA), which is designed for the readout circuit of X-ray linear array sensor. This hybrid ADC employs an incremental sigma-delta ADC and a cyclic ADC, achieving a good trade-off between accuracy and conversion speed. The two stages share the same hardware to reduce power consumption and die area. A common-mood feedback module is used to suppress the influence of charge injection, and the effectiveness is demonstrated by detailed theoretical analysis. A test chip of 14-bit ADC is fabricated in 0.35μm CMOS technology. The measured root mean square (RMS) value of DNL is 0.254 LSB, and the maximum value of INL is -0.776/+1.56 LSB. The measured effective number of bits (ENOB) is 13.43 bits.

The liver diseases are posing serious threat to human health associated with abusive use of allopathy medicines, especially in developing economies like Pakistan. The strengthening of detoxification system using natural products might be a suitable option to minimize the liver problems. In this current research, Zingiber officinale and Azadirachta indica were evaluated for their hepatoprotective role. For the purpose, 20 Sprague Dawley rats were equally divided into four groups i.e., negative control, paracetamol positive control, 2.5% ginger and 2% neem powder, respectively. During 42 days study, the levels of bilirubin and liver enzymes significantly elevated due to liver damage. Although, the values dropped (20-25%) in treatment group. Serum glucose and serum lipid profile increased in positive control group, but reduced (5-10%) in both ginger and neem groups. The serum protein profile declined in liver damage group, however, improved (~5%) in treatment groups. The hematological parameters slightly declined in liver damage group, but increased in ginger and neem groups. Moreover, the white blood cells differential count and renal parameters showed abnormal values in liver damage group, but improved after treatment. This study is promising and highlighted the hepato-protective role of neem and ginger that may open several avenues of research.

X-ray Fluorescence Computed Tomography (XFCT) is an emerging non-invasive imaging technique providing molecular-level data, gaining attention for high-resolution imaging. However, increased sensitivity with benchtop X-ray sources raises radiation exposure. Artificial Intelligence (AI), particularly deep learning (DL), has revolutionized medical imaging by delivering high-quality images in the presence of noise. In XFCT, traditional methods rely on complex algorithms for noise reduction, but AI holds promise in addressing high-dose concerns. We present an optimized SCUNet model for noise reduction in low-concentration XRF images. Compared to higher-dose images, our method’s effectiveness is evaluated. While various denoising techniques exist for X-ray and CT, few address to XFCT. The DL model is trained and assessed using the augmented data, focusing on background noise reduction. Image quality is measured using PSNR and SSIM, comparing outcomes with 100% X-ray dose images. Results show the proposed algorithm achieves high-quality images from low-dose and low-contrast agents, with a maximum PSNR of 39.05 and SSIM of 0.86. The model outperforms BM3D, NLM, DnCNN, and SCUNet in both visual inspection and quantitative analysis, particularly in high-noise scenarios. This indicates the potential of AI, specifically the SCUNet model, in significantly improving XFCT imaging by mitigating the trade-off between sensitivity and radiation exposure.

It has been demonstrated that cancer cells that have survived cancer treatment may be more malignant than the original cancer cells. These cells are considered to be the main cause of metastasis in prognosis. A Nanog-overexpressing colon-26 (Nanog+colon26) was generated and its metastatic potential was confirmed to be enhanced, indicating higher malignancy. Extracellular vesicles (EVs) secreted from the cell line (Nanog+colon26EVs) were administered to mice at 5 μg nine times (three times per week for three weeks) via the tail vein (PBS was used as a control). Subsequently, Nanog+colon26 cells were administered to mice via the spleen, and the quantity of metastatic colonies in the liver was analyzed two weeks later. The results demonstrated that the administration of EVs suppressed metastasis. The enhanced phagocytic activity of macrophages observed in the group treated with Nanog+colon26EVs indicated the involvement of the immune system in the observed metastasis-suppressing effect. Small RNA sequencing was conducted to identify Nanog-dependent miRNAs that exhibited significant changes (Fc>=1.5 or Fc

The archival Rossi X-ray Timing Explorer (RXTE) Proportional Counter Array (PCA) observations of HZ Her/Her X-1 are analyzed here. The time periods for Anomalous Low States are refined. The 35-day X-ray lightcurve of Her X-1 is produced using 35-day phases determined with RXTE All-Sky Monitor (ASM) and Swift Burst Altert Telescope (BAT) data, with adjustments based on the RXTE/PCA data. The result is the highest sensitivity 35-day lightcurve of Her X-1. The RXTE/PCA data were separated into 8 differents states of the 35-day cycle: Main High (MH) turn-on, MH, MH decline, Low State (LS) 1, Short High (SH) turn-on, SH, SH decline, and LS2. Orbital lightcurves were created for each state, and the different states are compared. Eclipse data was extracted for each state to determine the changes of eclipse shape with 35-day phase. A scattering corona model was fit to the eclipses for the different 35-day states: this shows that the corona is present at all 35-day phases with similar intensity. We carried out a search for previously-reported dips with no absorption, but did not find any.

Inflammation is implicated in the etiology of obesity-related diseases. Thromboxane-prostanoid receptor (TPR) is known to play a role in mediating an inflammatory response in a variety of cells. Gut-derived lipopolysaccharide (LPS), a TLR4 agonist, is elevated in obesity. Moreover, free fatty acids (FFAs) are important mediators of obesity-related inflammation. However, the role and mechanisms by which TPR regulates the inflammatory response in human immune cells remain unclear. We sought to determine the link between TPR and obesity and the role/mechanisms by which TPR alters LPS or stearic acid (SA)-induced inflammatory response in PBMCs. Cells were pre-treated with agents blocking TPR signaling, followed by treatment with LPS or stearic acid (SA). Our findings showed that TPR mRNA levels are higher in PBMCs from individuals with obesity. Blockade of TPR as well as ROCK which acts downstream of TPR, attenuated LPS and/or SA-induced pro-inflammatory response. On the other hand, TPR activation using its agonist enhanced the pro-inflammatory effects of LPS and/or SA. Of note, TPR agonist by itself elicits an inflammatory response which was attenuated by blocking TPR or ROCK. Our data suggest that TPR plays a key role in promoting an inflammatory response in human PBMCs and this effect is mediated via TLR4 and/or ROCK signaling.

Daridorexant, as the first Dual Orexin Receptor Antagonist (DORA) marketed in Europe, offers a novel therapeutic approach to insomnia. However, data regarding its real-world safety are scarce. Thus, the aim of this study was to assess its safety profile using a large-scale pharma-covigilance database. Daridorexant-related Adverse Drug Reaction (ADR) reports from the FDA Adverse Event Reporting System were scrutinized, and ADRs were selected using reporting odds ratio (ROR) as a measure of disproportionality. Frequencies of events related to daridorexant were compared to all other drugs (reference group, RG1) and only to other DORAs (RG2). Only significant disproportionalities to both RGs were evaluated in-depth. A total of 845 dari-dorexant-related reports were selected; nightmares (n = 146; Dari vs. RG1: ROR = 113.74; 95%CI[95.13, 136]; Dari vs. RG2: ROR = 2.35; 95CI%[1.93, 2.85]), depression (n = 22; Dari vs. RG1: 2.13; [1.39, 3.25]; Dari vs. RG2: ROR = 2.31; 95CI%[1.45, 3.67]), and hangover (n = 20; Dari vs. RG1: ROR = 127.92; 95CI%[81.98, 199.62]; Dari vs. RG2: 3.38; [2.04, 5.61]) were considered as safety signals. These data provide valuable insights into the real-world safety profile of dari-dorexant, supporting the existence of safety signals related to nightmares, depression, and hang-over.

Protein tyrosine phosphatase receptor type E (PTPRE) is a member of the “classical” protein tyrosine phosphatase subfamily and regulates a variety of cellular processes in a tissue-specific manner by antagonizing the function of protein tyrosine kinases. PTPRE plays a tumorigenic role in different human cancer cells, but its role in retinoblastoma (RB), the most common malignant eye cancer in children, remains to be elucidated. Etoposide resistant RB cell lines and RB patients display significant higher PTPRE expression levels compared to chemosensitive counterparts and the healthy human retina, respectively. PTPRE promotor methylation analyses revealed that PTPRE expression in RB is not regulated via this mechanism. Lentiviral PTPRE knockdown (KD) induced a significant decrease in growth kinetics, cell viability, and anchorage independent growth of etoposide resistant Y79 and WERI RB cells. Caspase-dependent apoptosis rates were significantly increased and a re-sensitization for etoposide could be observed after PTPRE depletion. In vivo chicken chorioallantoic membrane (CAM) assays revealed decreased tumor formation capacity as well as reduced tumor size and weight following PTPRE KD. Expression levels of miR631 were significantly downregulated in etoposide resistant RB cells and patients. Transient miR631 overexpression resulted in significantly decreased PTPRE levels and concomitantly decreased proliferation and increased apoptosis levels in etoposide resistant RB cells, impacts mirroring PTPRE KD effects and indicating PTPRE regulation via this miR. Additionally, PTPRE KD led to altered phosphorylation of protein kinase SGK3 and - dependent on the cell line - also AKT and ERK1/2, suggesting potential PTPRE downstream signaling pathways. In summary, these results indicate an oncogenic role of PTPRE in chemoresistant retinoblastoma.

Dipeptidyl peptidase 9 (DPP9) is a multifunctional intracellular protease with roles in tumour growth, inflammation and mitochondrial function. We developed a hepatocyte-specific DPP9 knockout mouse (DPP9-KO) to explore DPP9 in a mouse model of hepatocellular carcinoma (HCC). DPP9-KO mice were generated by crossing Albumin-Cre mice (Wt/Wt Cre+/+) with DPP9 floxed mice (Fl/Fl Cre-/-). Mice were treated with Diethylnitrosamine and Thioacetamide then an atherogenic High Fat Diet until 28 weeks of age. DPP9-KO mice had reduced liver and subcuta-neous adipose tissue mass and lower fasting plasma glucose, fewer small macroscopic liver nod-ules compared to DPP9-WT mice. However, there were no differences in the total number of mac-roscopic liver nodules, tumour burden, inflammation score and steatosis score. Consistent with the known ability of DPP9 to suppress NLRP1 activation, activated caspase-1 protein was ele-vated in DPP9-KO mouse liver. Additionally, Nfkbib, Cxcl10 and Ccl5 mRNA and protein levels of autophagy marker beclin1 and tumour suppressor p53 were increased. In conclusion, DPP9 de-pletion in hepatocytes may reduce liver cancer initiation, via mechanisms that may include in-creased autophagy and innate tumour suppression in this experimental model. Finally, the data supports DPP9 having a role in glucose regulation by the liver.

Taste and smell function decline with age, with robust impairment in the very old. Much less is known about taste and smell function in young and middle old. We investigated taste and smell sensitivity via thresholds in a sub-sample of the NutriAct Family Study (NFS), the NFS Examinations cohort (NFSE; N=251, age M=62.5 years). We examined different aspects relating to taste and smell function: the degree to which taste and smell sensitivity relate to another and to taste and smell preferences, the role of gender and age, as well as effects on Quality of Life (QOL). Taste thresholds were highly correlated but no correlation was observed between taste and smell thresholds and between thresholds and preference. Women were more sensitive for both taste and smell than men. We found no effect of age on sensitivity and no effect of sensitivity on QoL. All null-findings were corroborated with Bayesian statistics providing evidence for the null hypotheses. Together our results indicate the independence of taste and smell despite their overlap during sensorial experiences. We found no evidence for age-related sensory decline, which could be due to our sample´s characteristics of non-clinical volunteers with good dental health and 93% non-smokers.

Methylmercury (MeHg) intoxication is a global health concern. Although MeHg neurotoxicity is well-recognized, less is known about MeHg's effects on metabolism. In this study, we evaluated MeHg intoxication (20mg/L in drinking water for 20 days) effects on liver and epididymal white fat (EWF) in young ApoE knockout (ko) and wild-type mice. The former is well-known to show spontaneous dyslipidemia. Hg levels in hair, liver, and EWF were measured to assess the degree of MeHg exposure. We also evaluated body weight gain, plasma triglycerides, total cholesterol levels, and liver injury by assessing steatosis score, AST, ALT, SOD, and TBAR levels. To evaluate EWF, we analyzed mean wet weight and adipocyte diameter, plasma leptin levels and metabolomics. Hg levels were markedly higher among intoxicated mice. ApoE ko mice showed higher Hg in the hair but lower levels in the liver and EWF than wild-type controls. Among wild-type mice, MeHg compromised weight gain and increased liver TBAR levels compared to non-challenged controls. Among non-intoxicated mice, ApoE deficiency significantly increased triglyceride, total cholesterol, and liver transaminases with reduced EWF wet weight, hepatic SOD, and plasma leptin levels. MeHg accumulation together with ApoE deficiency elevated total cholesterol, triglycerides, hepatic transaminases, and TBARS. We found distinct EWF metabolite activity in different scenarios of ApoE deficiency and MeHg intoxication, highlighting increased cardiovascular risk especially when both challenges occur. Further studies are required to elucidate the underlying mechanisms involved in these effects and the target nutritional interventions in most need to ameliorate them.

Alcoholic liver disease (ALD) is a major cause of chronic liver disease. This term covers a broad spectrum of liver lesions, from simple steatosis to alcoholic hepatitis and cirrhosis. The patho-genesis of ALD is multifactorial and not fully elucidated due to complex mechanisms related to direct ethanol toxicity with subsequent hepatic and systemic inflammation. The accumulation of pro-inflammatory cytokines and the reduction of anti-inflammatory cytokines promote the development and progression of ALD. To date, there are no targeted therapies to counteract disease progression and prevent acute liver failure. Corticosteroids reduce mortality by acting on the hepatic-systemic inflammation. On the other hand, several studies analyzed the effect of the inhibition of pro-inflammatory cytokines and the stimulation of anti-inflammatory cytokines as potential therapeutic targets in ALD. This narrative review aims to clarify the role of the cy-tokines in the pathogenesis and treatment of ALD.

Non-Vitamin K Oral Anticoagulants (NOACs) have revolutionized anticoagulant therapy, offering improved safety and efficacy over traditional agents like warfarin. This review comprehensively examines the dual roles of NOACs—Apixaban, Rivaroxaban, Edoxaban, and Dabigatran—not only as anticoagulants but also as modulators of inflammation via Protease-Activated Receptor (PAR) signaling. We highlight the unique pharmacotherapeutic properties of each NOAC, supported by key clinical trials demonstrating their effectiveness in preventing thromboembolic events. Beyond their established anticoagulant roles, emerging research suggests that NOACs influence inflammation through PAR signaling pathways, implicating factors such as FXa and Thrombin in the modulation of inflammatory responses. This review synthesizes current evidence on the anti-inflammatory potential of NOACs, exploring their impact on inflammatory markers and conditions like atherosclerosis and diabetes. By delineating the mechanisms by which NOACs mediate anti-inflammatory effects, this work aims to expand their therapeutic utility, offering new perspectives for managing inflammatory diseases. Our findings underscore the broader clinical implications of NOACs, advocating for their consideration in therapeutic strategies aimed at addressing inflammation-related pathologies. This comprehensive synthesis not only enhances understanding of NOACs' multifaceted roles but also paves the way for future research and clinical applications in inflammation and cardiovascular health

Background. Transferrin receptor 1 (TfR1), glucose transporter 1 (GLUT1), and CD98hc are candidates for targeted therapy at the blood-brain barrier (BBB). Our objective was to challenge the expression of TfR1, GLUT1, and CD98hc in brain capillaries by the histone deacetylase inhibitor (HDACi) valproic acid (VPA). Methods. Primary mouse brain capillary endothelial cells (BCECs) and brain capillaries isolated from mice injected intraperitoneally with VPA were examined using RT-qPCR and ELISA. Targeting to the BBB was performed by injecting monoclonal anti-TfR1 (Ri7217)-conjugated gold nanoparticles measured using ICP-MS. Results. In BCECs co-cultured with glial cells, Tfrc mRNA expression was significantly higher after 6 h VPA returning to baseline after 24 h. In vivo Glut1 mRNA expression was significantly higher in males, but not females', receiving VPA, whereas Cd98hc mRNA expression was unaffected by VPA. TfR1 increased significantly in vivo after VPA, whereas GLUT1 and CD98hc were unchanged. Uptake of anti-TfR1-conjugated nanoparticles was unaltered by VPA in spite upregulated TfR expression. Conclusions. VPA upregulates TfR1 in brain endothelium in vivo and in vitro. VPA does not increase GLUT1 and CD98hc proteins. The increase in TfR1 does not result in higher anti-TfR1 antibody targetability, suggesting targeting sufficiently occurs with available transferrin receptors without further contribution from accessory VPA-induced TfR1.

High-quality and large-size single crystals of lead-free Na0.5Bi0.5TiO3 were grown using the Czo-chralski technique. The crystals had pure perovskite structure with rhombohedral symmetry and were translucent in the visible and near infrared spectral ranges recorded in the interval 350-1050 nm. The energy gaps determined from the X-ray photoelectron spectroscopy (XPS) and optical measurements were approximately 2.92 eV. The current-voltage characteristics, depolarization current, dc (σdc) and ac (σac) electrical conductivity, and Seebeck coefficient of the crystals were investigated. The frequency/temperature-dependent electrical properties were also measured and analyzed through complex impedance spectroscopy. An overlapping reversible insulator-metal transition (resistive switching) on nanoscales, caused by the electric field, was detected. This was the first time that most of these investigations were performed for this material. The following conductivity mechanisms of NBT single crystals were identified: (i) quasi-free electron and hole conduction and hopping-charges mechanism at low temperatures, (ii) small polaron conductivity in the middle temperature range, and (iii) a significant contribution of the oxygen vacancies to conductivity in the high temperature range. The activation energy values determined from the conductivity data, the imaginary part of the electric impedance and the modulus indicate that the relaxation process in the high-temperature range is attributable to both single and double ionized oxygen vacancies, in combination with the hopping of electrons between Ti4+ and Ti3+. P-type electrical conductivity was also found. These discoveries create new possibilities of reducing the electrical conductivity of NBT and improving the process of effectively poling this material. The density of the electronic states was investigated using an ab initio method. The energy gap cal-culated for NBT (R3c) was 2.8 eV, and is well comparable to those determined from XPS and optical measurements. Our results indicate the possibility of tuning material properties by inten-tionally creating non-stoichiometry/structural defects (oxygen vacancies, cation excess and cation deficiency).

Background: Endotheliopathy is common pathologic findings in patients with acute and long COVID-19. It may be associated with disease severity and predispose to long-term complications. Plasma levels of a proteoglycan syndecan-1 are found to be significantly elevated in patients with COVID-19, but its roles in assessing the disease severity and predicting long-term outcome are not fully understood. Methods: 124 consecutive hospitalized patients with SARS-CoV2 infection were prospectively enrolled and blood samples were collected on admission (T1), 3-4 days following treatment (T2), and 1-2 days prior to discharge or death (T3). Plasma levels of syndecan-1 were determined using an immunosorbent assay; various statistical analyses were performed to determine the association between plasma syndecan-1 levels and disease severity or the 60-day mortality rate. Results: Compared with those in the healthy controls, plasma levels of syndecan-1 in patients with critical COVID-19 were significantly higher (p<0.0001). However, there was no statistically significant difference among patients with different disease severity (p>0.05), resulting from large individual variability. Longitudinal analysis demonstrated that while the levels fluctuated during hospitalization in all patients, plasma syndecan-1 levels were persistently elevated from baseline in critical COVID19 patients. Cox proportional hazard regression analyses revealed that elevated plasma levels of syndecan-1 (>260 ng/mL at T1, >1018 ng/mL at T2, and >461 ng/mL at T3) were significantly associated with the 60-day mortality rate. Conclusions: Endotheliopathy, marked by glycocalyx degradation and elevated plasma syndecan-1, occurs in nearly all hospitalized patients with SARS-CoV2 infection; the elevated plasma syndecan-1 is associated with increased mortality in COVID-19 patients.

Terpenoids, including monoterpenoids (C₁₀), norisoprenoids (C₁₃) and sesquiterpenoids (C₁₅), constitute a large group of plant-derived naturally occurring secondary metabolites which chemical structure is highly diverse. A quantitative structure-activity relationship (QSAR) model to predict the terpenoids toxicity and to evaluate the influences of their chemical structure, was developed in this study, by assessing the toxicity of 27 terpenoid standards using Gram-negative bioluminescent Vibrio fischeri, in real time. Under the test conditions, at concentration of 1 µM, the terpenoids showed a toxicity level lower than five %, with exception of geraniol, citral, (S)-citronellal, geranic acid, (±)-α-terpinyl acetate and geranyl acetone. Moreover, the standards tested displayed a toxicity level higher than 30 % at concentration of 50 to 100 µM, with the exception of (+)-valencene, eucalyptol, (+)-borneol, guaiazulene, β-caryophellene and linalool oxide. Regarding the functional group, the terpenoids toxicity was observed in the following order: alcohol > aldehyde ~ ketone > ester > hydrocarbons. CODESSA software was employed to develop the QSAR models based on the correlation of terpenoids toxicity and a pool of descriptors related to each chemical structure. The QSAR models, based on t-test values, showed that terpenoids toxicity was mainly attributed to geometric (e.g., asphericity) and electronic (e.g., max partial charge for a C atom [Zefirov's PC]) descriptors. Statistically, the most significant overall correlation was the four-parameter equation with training and test coefficient correlation higher than 0.810 and 0.535, respectively, and square coefficient of cross-validation (Q²) higher than 0.689. According to the obtained data, the QSAR models are a suitable and a rapid tool to predict the terpenoids toxicity in a diversity of food products.

Commercial buildings are a significant consumer of energy worldwide. Logistics facilities, and specifically warehouses, are a common building type yet under-researched in the demand-side energy forecasting literature. Warehouses have an idiosyncratic profile when compared to other commercial and industrial buildings with a significant reliance on a small number of energy systems. As such, warehouse owners and operators are increasingly entering in to energy performance contracts with energy service companies (ESCOs) to minimise environmental impact, reduce costs, and improve competitiveness. ESCOs and warehouse owners and operators require accurate forecasts of their energy consumption so that precautionary and mitigation measures can be taken. This paper explores the performance of three machine learning models (Support Vector Regression (SVR), Random Forest, and Extreme Gradient Boosting (XGBoost)), three deep learning models (Recurrent Neural Networks (RNN), Long Short-Term Memory (LSTM), and Gated Recurrent Unit (GRU)), and a classical time series model, Autoregressive Integrated Moving Average (ARIMA) for predicting daily energy consumption. The dataset comprises 8,040 records generated over an 11-month period from January to November 2020 from a non-refrigerated logistics facility located in Ireland. The grid search method was used to identify the best configurations for each model. The proposed XGBoost models outperform other models for both very short load forecasting (VSTLF) and short term load forecasting (STLF); the ARIMA model performed the worst.

There are four subtypes of adenosine receptors (ARs), named A1, A2A, A2B and A3, all of which are G protein-coupled receptors. The A2BAR, coupled to both Gαi and Gαq G proteins, is one of the several G-protein-coupled receptors that are expressed in a significantly higher level in some cancer tissues in comparison to adjacent normal tissues. There is growing evidence that the A2BAR plays an important role in tumor cell proliferation, angiogenesis, metastasis, and immune suppression. Thus, A2BAR antagonists are potentially novel attractive anticancer agents. Several antagonists targeting at the A2BAR are currently in clinical trials for various types of cancers. In this review, we first describe the signaling, agonists, and antagonists of the A2BAR. We further discuss the role of the A2BAR in the progression of various types cancers, and the rationale of using A2BAR antagonists in cancer therapy

Uterine leiomyosarcoma (LMS) is a rare and aggressive form of uterine cancer, with a poor prognosis and high number of uterine cancer-related deaths. Chimeric Antigen Receptor (CAR) T-cell therapy is an immunotherapy approach to antigen specific of cancer cell, thereby enhancing the immune system's ability to target and destroy cancer cells. This study aims to investigate the potential of targeting differentially expressed genes (DEGs) as a novel therapeutic strategy using CAR T-cell technology in LMS. Genome datasets were obtained from NCBI-GEO database, Of the five datasets, genes that experienced significant overexpression in at least three datasets were categorized as DEGs, and DEGs were evaluated for protein localization, Gene Ontology, bioactivity, interaction, and overexpression. The results identified 25 DEGs, with ten of them expressed on the plasma membrane; four of them—HMMR, KIF20A, PRC1, and ZWINT—were part of the main protein network derived from the 25 DEGs. The dominant bioactivity of these PMGs involves influencing the cell cycle, particularly processes related to chromosome segregation. In conclusion, HMMR, KIF20A, PRC1, and ZWINT are high-potential DEGs as candidates for tumor-associated antigen CAR T-cell therapy. Further research, both in vitro and in vivo, is needed to enhance the validity of these findings.

The aim of this work is a comprehensive study of the effect of variable atomic composition and structural-phase state of (CoFeZr)x(MgF2)100-x nanocomposites (NCs) on their nonlinear electronic and magnetic/magneto-optical properties. Micrometer-thick nanocomposites layers on the glass substrates were obtained by ion-beam sputtering of a composite target in the argon atmosphere in a wide range of compositions x=9-51at.% The value of the resistive percolation threshold xper=34 at.%, determined from the concentration dependences of the electrical resistance of NCs, coincides with the beginning of nucleation of metallic nanocrystals CoFeZr in MgF2 dielectric matrix. The absolute value of maximum magnetoresistance of NCs is 2.4 % in a magnetic field of 5.5 kOe at x=25 at.%, up to the percolation threshold. Two maxima appear in the concentration dependences of magneto-optical transversal Kerr effect, one of which at x = 34 at.% corresponds to the formation of CoFeZr alloy nanocrystals of a hexagonal structure, and the second one at x=45 at.% corresponds to the phase transition of nanocrystals from a hexagonal to a cubic body-centered structure. The magnetic percolation threshold in (CoFeZr)x(MgF2)100-x system at xfm=34 at.% with the appearance of a hysteresis loop and a coercive force of Hc≈ 8 Oe, coincides with the resistive percolation threshold xper=34 at.%. Concentration dependence of the coercive force showed that at low contents of metallic alloy x<30 at.% NCs are superparamagnetic (Hc=0). With an increase of the alloy content, in the region of magnetic and resistive percolation thresholds NCs exhibit a magnetically soft ferromagnetic character and do not change it far beyond the percolation threshold with the maximum value of the coercive force Hc< 30 Oe. Decrease in magnetic order and soft ferromagnetic are influenced by the diamagnetic phase FeF2 that we discovered at the interface of magnetic nanocrystals CoFeZr with a dielectric matrix MgF2 by the Mössbauer spectroscopy.

Structure from Motion with Multi-View Stereo photogrammetry (SfM) is increasingly utilised in geoscience investigations as a cost-effective method of acquiring high resolution (sub-meter) topographic data, but has not been thoroughly tested in gullied savanna systems. The aim of this study was to test the accuracy of topographic models derived from aerial (via an Unmanned Aerial Vehicle, ‘UAV’) and ground-based (via a handheld digital camera, ‘Ground’) SfM in modelling a hillslope gully system in dry-tropical savanna, and to assess the strengths and limitations of the approach at different scales. A UAV survey covered an entire hillslope gully system (0.715 km²), whereas a Ground survey covered a single gully within the broader system (650 m²). SfM topographic models, including Digital Surface Models (DSM) and dense point clouds, were compared against RTK-GPS point data and a pre-existing airborne LiDAR Digital Elevation Model (DEM). Results indicate UAV SfM can deliver topographic models with a resolution and accuracy suitable to define gully systems at a hillslope scale (e.g., 0.1 m resolution with ~ 0.5 – 1.3 m elevation error), while ground-based SfM is more capable of quantifying gully morphology (e.g., 0.01 m resolution with ~ 0.1 m elevation error). Key strengths of SfM for these applications include: the production of high resolution 3D topographic models and ortho-photo mosaics, low survey instrument costs (< $AUD 3,000); and rapid survey time (4 and 2 hours for UAV and Ground survey respectively). Current limitations of SfM include: difficulties in reconstructing vegetated surfaces; uncertainty as to optimal survey and processing designs; and high computational demands. Overall, this study has demonstrated great potential for SfM to be used as a cost-effective tool to aid in the mapping, modelling and management of hillslope gully systems at different scales, in tropical savanna landscapes and elsewhere.

A Cu₂ZnSnS₄ (CZTS) film with a thickness of approximately 1.5 μm was fabricated on a Mo-coated glass substrate by annealing a CZTS precursor fabricated from nanoparticle ink. The chemical states of the elements in the CZTS thin film in the depth direction were studied to identify the presence of secondary phases, which are detrimental to the performance of solar cells containing CZTS. X-ray diffraction was unable to detect any secondary phases in CZTS because of their small relative amount. Instead, X-ray photoelectron spectroscopy (XPS), which is highly sensitive to chemical state, was conducted at different depths in the CZTS film to further check the presence of secondary phases. XPS analysis revealed peaks shift consistent with the presence of secondary phases. For the CZTS film annealed in a S atmosphere at 575 °C for 3 h, the film surface consisted of a secondary-phase layer composed of CuS, ZnS, and SnSx (x=1 or 2) originating from the decomposition of CZTS. At depths below 80 nm, the film was pure CZTS. Formation of MoS2 at the CZTS–Mo interface was confirmed by XPS analysis of Mo and S.

Lead-based ternary chalcogenide thin films of the (PbTe)1-x(PbS)x system were obtained by plasma-enhanced chemical vapor deposition technique (PECVD) under conditions of a nonequilibrium low-temperature argon plasma of an RF discharge (40.68 MHz) at a reduced pressure (0.01 Torr). High-purity elements were directly used as starting materials – Pb, S and Te. Plasma-chemical synthesis was carried out on the surface of of c-sapphire and silicon substrate. The physicochemical properties of the films were studied by various analytical methods. The dependence of the Seebeck coefficient, resistivity, and power factor on the structural properties and composition has been studied. The thermoelectric characteristics were found to be dependent on the film composition. Upon the selection of optimal sulfur concentration one can increase the power factor as compared to single phase PbS ot PbTe films.

Globally, over the past several months millions of persons contracted the coronavirus disease 2019 (COVID-19) resulting in significant mortality. Health care systems are negatively impacted including the care of individuals with cancers and other chronic diseases such as chronic active hepatitis, cirrhosis and hepatocellular carcinoma. There are various probable pathogenic mechanisms that have been presented to account for liver injury in COVID-19 patients such as hepatotoxicity cause by therapeutic drugs, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection of the bile duct cells and hepatocytes, hypoxia and systemic inflammatory response. Liver biochemistry tests such as AST, ALT, GGT and ALP are deranged in COVID-19 patients with liver injury. Hepatocellular damage results in the elevation of serum AST and ALT levels in early onset disease while a cholestatic pattern that develops as the disease progress causes higher levels of ALP, GGT, direct and total bilirubin. These liver biochemistry tests are prognostic markers of disease severity and should be carefully monitored in COVID-19 patients. We conducted a systematic review of abnormal liver biochemistry tests in COVID-19 and the possible pathogenesis involved. Significant findings regarding the severity, hepatocellular pattern, incidence and related clinical outcomes in COVID-19 patients are highlighted.

Integrated crop-livestock production (ILP) is an interesting alternative for more sustainable soil use. However, more studies are needed to analyze soil pore properties under ILP at the micrometer scale. Thus, this study proposes a detailed analysis of soil pore architecture at the micrometer scale in three dimensions. For this purpose, samples of an Oxisol under ILP subjected to minimum tillage (MT) and no-tillage (NT) with ryegrass as cover crop (C) and silage (S) were investigated. The soil micromorphological properties of the soil were analyzed using X-ray microtomography. The MT(C) system showed the highest values of porosity (c. 20.4%), connectivity (c. 32.8×103), volume (c. 26%), and number of pores (c. 32%) in a rod-like shape. On the other hand, the MT(S), NT(C), and NT(S) systems showed higher tortuosities (c. 2.2, c. 2.0, and c. 2.1) and lower pore connectivities (c. 8.3×103, c. 6.9×103, and c. 6.2×103), especially in S use. Ellipsoidal and rod-shaped pores predominated over spheroidal and disc-shaped pores in all treatments. The results of this study show that the use of ryegrass as a cover crop improves soil physical properties, especially in MT. For S use, the type of soil management (MT or NT) did not show any differences.

We developed an ovarian cancer-targeted drug delivery system based on a follicle-stimulating hormone receptor (FSHR) peptide. The lipophilic chemotherapeutic drug SN38 and the photosensitizer IR820 were loaded into the phospholipid bilayer of liposomes. Near-infrared laser irradiation stimulated the generation of reactive oxygen species, causing short-term reactive molecular species and spatial-temporal restricted photodamage to the biological targets. The reactive molecular species and spatial-temporal restricted photodamage enhanced the release and uptake of chemotherapy drugs and increased the sensitivity to chemotherapy drugs in ovarian cancer cells. FSH liposomes loaded with SN38 and IR820 (SN38/IR820-Lipo@FSH) were prepared using thin-film hydration-sonication. FSH peptide binding was analyzed using 1H NMR spectrum and Maldi-Tof. The average size and zeta potential of SN38/IR820-Lipo@FSH were 105.1 ± 1.15 nm (PDI: 0.204 ± 0.03) and −27.8 ± 0.42 mV, respectively. SN38/IR820-Lipo@FSH exhibited good drug-loading properties and the in vitro release was slow. FSH significantly increased the uptake of liposomes, inhibited cell proliferation, and induced apoptosis in A2780 cells. Moreover, SN38/IR820-Lipo@FSH exhibited good tumor-targeting ability and anti-ovarian cancer activity in vivo. The SN38/IR820-Lipo@FSH exhibited specific targeting to A2780 ovarian cancer cells. The combination of chemotherapy and photodynamic treatment based on an FSH peptide-targeted delivery system may be an effective approach to treating ovarian cancer.

Background: Exposure to chronic low levels of aflatoxin B1 (AFB1) contamination can lead to immune suppression and nutritional consequences that might greatly contributed in the increase of hepatocellular carcinoma (HCC). The toxicity of AFB1 is greatly vary between different population, affected by age, gender, and environmental factors. Material and subjects: Aflatoxin B1 (AFB1) was measured in 50 blood samples collected from non B, C hepatitis viruses and non CMV-Ab liver disease patients from different general hospitals and polyclinic in KSA during period 01-2013 to 06-2014. All Patients demonstrate elevation of ALT and AST with unknown etiology. Serum samples were obtained and kept at −20 °C for AFB1detection. Results: Out of the 50 blood samples, 38 demonstrate a detectable serum level of AFB1 while the remaining 12 patients were AFB1 negative and used as control participants. While AST was non-significantly different in AFB1 exposed patients, ALT was significantly higher in AFB1 positive samples compared to control AFB1-negative. AFB1 was positively correlated with AST and ALT as liver function enzymes and with age as a risk factor of long duration of AFB1 chronic exposure. Multiple linear regression analysis ascertained the association between AFB1 chronic exposure and ALT increase in liver dysfunction Saudi patients. Conclusion: Measurement of elevated ALT as marker of liver injury in AFB1 chronically exposed Saudi patients can help to avoid the future development of HCC. Moreover, early detection of AFB1 exposure, together with early vaccination against HBV and HCV can remove the synergistic effects of these two etiological factors and thus decrease the risk of developing liver cancer.

The vomeronasal system serves as a pivotal element in mammalian sensory biology, allowing the perception of chemical signals essential for social communication via the activation of two main receptor families, V1R and V2R. The expression of V1Rs and V2Rs is linked with that of the G-protein alpha-subunits, Gαi2 and Gαo, respectively. The exploration of the evolutionary pathways of V1Rs and V2Rs across all mammalian species remains a main challenge, juxtaposing available genomic data against emerging immunohistochemical evidence. However, recent investigations, in contrast to what is predicted by the currently annotated genomic sequences, have revealed the expression of Gαo in the vomeronasal neuroepithelium of wild canids, including wolves and foxes. In the present study, the employment of a specific antibody raised against the mouse V2R2, member of the C-family of vomeronasal receptors, V2Rs, has confirmed the expression of this receptor in the fox and wolf, but it has revealed the lack of expression in the dog. This may reflect the impact of domestication on the regression of the VNS in this species, in contrast to their wild counterparts, and underscores the effects of artificial selection on sensory functions. Thus, these findings suggest a more refined chemical detection capability in wild species.

Let β= (((24!)!)!)!, and let {${\mathcal P}_{n^2+1}$} denote the set of all primes of the form {$n^2+1$}. Let ${\mathcal M}$ denote the set of all positive multiples of elements of the set {${\mathcal P}_{n^2+1} \cap (\beta,\infty)$}. The set {${\mathcal X}=\{0,\ldots,\beta\} \cup {\mathcal M}$} satisfies the following conditions: (1) ${\rm card}({\mathcal X})$ is greater than a huge positive integer and it is conjectured that ${\mathcal X}$ is infinite, (2)} we do not know any algorithm deciding the finiteness of ${\mathcal X}$, (3)~a~known and short algorithm for every {$n \in N$} decides whether or not {$n \in {\mathcal X}$}, (4) a known and short algorithm returns an integer~$n$ such that ${\mathcal X}$ is infinite if and only if ${\mathcal X}$ contains an element greater than $n$. The following problem is open: {\em simply define a set {${\mathcal X} \subseteq N$} such that ${\mathcal X}$ satisfies conditions (1)-(4), and \underline{we do not know any representation of~~${\mathcal X}$~~as a finite union of sets whose definitions are simpler than} \underline{the definition of ${\mathcal X}$}} {\tt (5)}. Let {$f(1)=2$}, {$f(2)=4$}, and let {$f(n+1)=f(n)!$} for every integer {$n \geqslant 2$}. For a positive integer $n$, let {$\Psi_n$} denote the following statement: {\em if a system of equations ${\mathcal S} \subseteq \Bigl\{x_i!=x_k: i,k \in \{1,\ldots,n\}\Bigr\} \cup \Bigl\{x_i \cdot x_j=x_k: i,j,k \in \{1,\ldots,n\}\Bigr\}$ has only finitely many solutions in positive integers \mbox{$x_1,\ldots,x_n$}, then each such solution \mbox{$(x_1,\ldots,x_n)$} satisfies {$x_1,\ldots,x_n \leqslant f(n)$}.} We prove that for every statement $\Psi_n$ the bound {$f(n)$} cannot be decreased. The author's guess is that the statements {$\Psi_1,\ldots,\Psi_9$} are true. We prove that the statement $\Psi_9$ implies that the set ${\mathcal X}$ of all {non-negative} integers $k$ whose number of digits belongs to {${\mathcal P}_{n^2+1}$} satisfies conditions {\tt (1)-(5)}.

Fifty years on from the classical fluid-mosaic model of Singer and Nicolson, current views of the plasma membrane portray a much more complex view of this interface region. Compartmentalization, together with transbilayer and lateral asymmetries, provide the structural foundation for functional specializations at the cell surface, including the active role of the lipid microenvironment in the modulation of membrane-bound proteins. The chemical synapse, the site where neurotransmitter-coded signals are decoded by neurotransmitter receptors, adds another layer of complexity to the plasma membrane architectural intricacy, mainly due to the need to accommodate a sizeable number of molecules in a minute subcellular compartment with dimensions barely reaching the micrometer. In this review, we discuss how Nature has developed suitable adjustments to accommodate different types of membrane-bound receptors and scaffolding proteins via membrane microdomains, and how this “efford-sharing” mechanism has evolved to optimize crosstalk or separation or coupling where/when appropriate. To this end, we use a fast ligand-gated neurotransmitter receptor, the nicotinic acetylcholine receptor, and a second-messenger G-protein coupled receptor, the cannabinoid receptor, as paradigmatic example.

Bosentan, an endothelin-receptor antagonist (ERA), has potential anti-atherosclerotic properties. We investigated the complementary effects of bosentan and atorvastatin on the progression and composition of the atherosclerotic lesions in diabetic mice. Forty-eight male apoE-/- mice were fed high-fat diet (HFD) for 14 weeks. At week 8, diabetes was induced with streptozotocin and mice were randomized into 4 groups: 1) Control/COG: no intervention. 2) ΒΟG: bosentan 100 mg/kg/day per os. 3) ATG: atorvastatin 20mg/kg/day per os). 4) BO+ATG: Combined administration of bosentan and atorvastatin. The intra-plaque contents of collagen, elastin, monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor-a (TNF-a), matrix-metalloproteinases (MMP-2,-3,-9), and TIMP-1 concentrations were determined. The percentage of lumen stenosis significantly decreased across all treated groups: BOG: 19.5±2.2%, ATG: 12.8±4.8%, BO+ATG: 9.1±2.7% compared to controls (24.6±4.8%, p&lt;0.001). Both atorvastatin and bosentan significantly increased collagen content and fibrous cap thickness versus COG (p&lt;0.01). All intervention groups reduced the relative intra-plaque concentrations of MCP-1, MMP-3,-9, and increased TIMP-1 compared to COG (p&lt;0.001). Importantly, bosentan showed modest but additive to atorvastatin effects on the latter parameters compared COG (p&lt;0.05). Bosentan treatment in diabetic, atherosclerotic apoE-/- mice delayed the atherosclerosis progression and enhanced plaques’ stability, showing modest but complementary effects with atorvastatin, which are promising in atherosclerotic cardiovascular diseases.

Fragile X syndrome (FXS) is caused by the full mutation in the FMR1 gene on the Xq27.3 chromosome region. It is the most common monogenic cause of Autism Spectrum Disorder (ASD) and inherited intellectual disability (ID). Besides ASD, ID and other issues, individuals with FXS may exhibit sleep problems and impairment of circadian rhythm (CR). The Drosophila melanogaster models of FXS, such as dFMR1B55, present excellent model for research in the FXS field. During this study, sleep pattern and CR in dFMR1B55 mutants were analyzed, using a new platform based on continuous high-resolution videography in integration with a highly-customized version of software. This methodology provides more sensitive results, which could be crucial for all further research in this model of fruit flies. The study revealed that dFMR1 B55 male mutants can be considered weak rhythmic flies rather than totally arrhythmic, and present a good alternative animal model of genetic disorder, which includes impairment of CR and sleep behavior. The combination of videography and software used in the current study should be recommended as a gold-standard methodology for such further research.

Extensive evidence indicates that activation of P2X7 receptor (P2X7R), an ATP-gated ion channel highly expressed in immune and brain cells, is strictly associated with the release of extracellular vesicles. Through this process, P2X7R-expressing cells regulate non-classical protein secretion and transfer bioactive components to other cells, including misfolded proteins, participating in inflammatory and neurodegenerative diseases. In this review, we summarize and discuss the studies addressing the impact of P2X7R activation on extracellular vesicle release and their activities.

Hepatitis B virus (HBV) is the dominant risk factor for hepatocellular carcinoma (HCC). HBV X protein (HBx) plays crucial roles in HCC carcinogenesis. HBx interferes with several signaling pathways including Notch1 pathway in HCC. In our study, we found that Notch1 was highly expressed in HCC especially in large HCC. Notch1 and HBx co-localized in HCC and their levels were positively correlated with each other. Notch1 expression was more elevated in HepG2.2.15 than that in HepG2. HBx activated Notch1 pathway in HepG2.2.15. Repression of HBx and Notch1 pathway attenuated the growth of HepG2.2.15. Notch1, ERK and AKT pathways were inhibited after a γ-secretase inhibitor treatment. Dual-specificity phosphatase 1 (DUSP1) and phosphatase and tensin homolog (PTEN) were up-regulated after the γ-secretase inhibitor treatment and Hes1 inhibition. Luciferase reporter assays showed that Hes1 repressed the promoters of DUSP1 and PTEN and this was reverted by γ-secretase inhibitor treatment. Western blotting demonstrated that DUSP1 dephosphorylated pERK and PTEN dephosphorylated pAKT. Collectively, we reported a link among HBx, Notch1 pathway, DUSP1/PTEN, and ERK/AKT pathways, which influenced HCC cell survival and could be a therapeutic target for HCC.

Stimulation of the alpha 7 nicotinic acetylcholine receptor (α7nAChR) has shown beneficial effects in several acute inflammatory disease models. This study aims to examine whether treatment with the selective α7nAChR agonist PHA 568487 can dampen inflammation and thereby improve cardiac function after myocardial infarction in mice. The possible anti-inflammatory properties of α7nAChR agonist PHA 568487 were tested in vivo using the air pouch model and in a permanent occlusion model of acute myocardial infarction in mice. Hematology parameters and cytokine levels were determined. Infarct size and cardiac function were assessed via echocardiography 24 h and one week after the infarction. Treatment with α7nAChR agonist PHA 568487 decreased 12 (CCL27, CXCL5, IL6, CXCL10, CXCL11, CXCL1, CCL2, MIP1a, MIP2, CXCL16, CXCL12 and CCL25) out of 33 cytokines in the air pouch model of acute inflammation. However, α7nAChR agonist PHA 568487 did not alter infarct size, ejection fraction, cardiac output or stroke volume at 24 h nor at 7 days after the myocardial infarction compared with control mice. In conclusion, despite promising immunomodulatory effects in the acute inflammatory air pouch model, α7nAChR agonist PHA 568487 did not affect infarct size or cardiac function after a permanent occlusion model of acute myocardial infarction in mice. Consequently, this study does not strengthen the hypothesis that stimulation of the α7nAChR is a future treatment strategy for acute myocardial infarction when reperfusion is lacking. However, whether other agonists of the α7nAChR can have different effects remains to be investigated.

The G-protein-coupled estrogen receptor (GPER; G protein-coupled estrogen receptor 30, also known as GPR30) is a novel estrogen receptor and has emerged as a promising target for ovarian cancer. GPER, a seven-transmembrane receptor, suppresses cellular viability and migration in studied ovarian cancer cells. However, its impact on the fallopian tube, which is the potential origin of high-grade serous (HGSC) ovarian cancer, has not been addressed. This study was conducted to evaluate the relationship of GPER, ovarian cancer subtypes, i.e., high-grade serous cell lines (OV90 and OVCAR420), as well as potential HGSC ovarian cancer origin (i.e., the fallopian tube cell line FT190). The selective ligand assessed here is the agonist G-1, which was utilized in an in vitro study to characterize its effects on cellular viability and migration. As a result, this study has addressed the effect of a specific GPER antagonist in combination with an agonist on cell viability, providing a better understanding of the effects of these compounds on our diverse group of studied cell lines. Strikingly, attenuated cell proliferation and migration behaviors were observed in the presence of G-1. Thus, our in vitro study reveals the impact of the origin of HGSC ovarian cancers and highlights the GPER agonist G-1 as a potential therapy for ovarian cancer.

Two X chromosomes of female mammals randomly inactivate one of paternal or maternal X chromosome in early embryonic development and all the daughter cells produced from these cells retain the same feature of X chromosome inactivation, which is called X chromosome inactivation (XCI). Studying the mechanisms of XCI is important for understanding epigenetic that plays an important role in age-associated diseases. The previous studies have demonstrated that binding of RNAs and DNAs may play a role in activating gene expression. In this paper, our study aims to explore whether the mechanisms of XCI involve the RNA binding strength to X chromosome DNAs. The bioinformatics analyses based on big data were used to analyze the simulated binding strength of RNAs (RNA binding strength) to 23 chromosomes (including X chromosome and 22 human autosomes) and the characteristics of repetitive sequences in the X-inactivation centre. The results revealed that RNA binding strength of the long arm of the X chromosome that is almost entirely inactivated in XCI was significantly lower than that of all autosomes and the short arm of X chromosome, meanwhile the RNA binding strengths of inactivation regions in X chromosome were significantly lower than that of regions escaping from XCI. Different repetitive sequence clusters within the center of XCI presented a cross distribution characteristic. To further prove whether the repetitive sequences in human X chromosome involve in XCI, we cloned long interspersed element (LINE-1, L1) and short interspersed element (Alu) from human Xq13, the center of XCI, and constructed expression vectors carrying sense-antisense combination repetitive sequences (L1s or Alus). Effects of combined L1 or combined Alu sequences on expression of EGFP reporter gene were examined in stably transfected HeLa cells, which simulates the effects of repetitive sequences located on chromosomes. The results of experiments revealed transcribed L1 repetitive sequences activated EGFP reporter gene expression, so did the Alus. The experiment results suggested repetitive sequences activated genes by interaction of transcribed RNAs and DNAs. Since the binding of RNAs and DNAs can activate gene, so the low RNA binding strength of human X chromosome may be one of reasons of XCI. The cross distribution characteristics of different repetitive sequence clusters leading to a cascade of gene activation or gene inactivation may be the reason of transcriptional silencing one of the X chromosomes in female mammals.

WNT10B belongs to the family of WNT proteins that are implicated in a range of phenomena that are affected by the Wnt signaling pathway. Recent studies have shown that WNT10B plays a role in colorectal cancer. WNTs have been found to directly affect the stemness of the tumor cells via regulation of ASCL2. Switching off the ASCL2 literally blocks the stemness process of the tumor cells and vice versa. Furthermore, recent findings suggest BVES to be highly suppressed in malignancies and in vitro deletions of BVES show higher Wnt signaling activity to induce stem- ness. WNT10B was found to be highly expressed in such cases. Often, in biology, we are faced with the problem of exploring relevant unknown biological hypotheses in the form of myriads of combination of factors that might be affecting the pathway under certain conditions. For example, WNT10B-ASCL2 is one such 2^nd order combination whose relation needs to be tested under the influence of recently developed porcupine-WNT inhibitor ETC-1922159. The inhibitor is known to suppress PORCN (porcupine) and thus inhibit a range of oncogenes known to be directly or indirectly affected by the Wnts. In a recent unpublished work in bioRxiv, Sinha 1, we had the opportunity to rank these unknown biological hypotheses for down regulated genes at 2^nd order level after the drug was administered. The in silico observations showed that the combination of WNT10B-ASCL2 was assigned a relatively lower rank, thus validating the pipeline’s efficacy with the confirmed wet lab experiment that indicate that both WNT10B and ASCL2 were down regulated after treatment in cancer cells. Here, we take one step further by in silico analysis of the 3rd order combinations of WNT10B-X-X (X can be known or unknown factor), from a range of 100 randomly picked down regulated genes after ETC-1922159 treatment. The pipeline uses the density based HSIC (Hilbert Schmidt Information Criterion) sensitivity index with an rbf (ra- dial basis function) kernel, which is known to be highly effective in sensitivity analysis. Various unknown/unexplored/untested 3^rd order biological hypotheses emerge some of which are con- firmed in wet lab, while others need to be tested. The potential of such ranking is indispensable in the current era of search in a vast combinatorial forest.

Objective: to retrospectively evaluate the incidence rate (IR) of echocardiographic signs suspected for pulmonary hypertension (PH) in Systemic sclerosis (SSc) patients after the introduction of a combination therapy with bosentan and sildenafil for treatment or prevention of digital ulcers. Methods: patients attending the Scleroderma Unit of the Universital Hospital of Careggi from July 2010 to July 2023 were enrolled. Patients older than 18 years old, with an history of digital ulcers, treated with bosentan and sildenafil in combination for at least 12 months were included. Patients with a diagnosis of PH preceding the introduction of the therapy were excluded. Demographical data, disease duration, laboratoristic and instrumental data (pulmonary function tests, echocardiographic estimation of pulmonary artery pressure (PAPs) and ultrasonographic value of renal resistive index) were collected. The IR of echocardiographic signs suspected for pulmonary hypertension and their 95% confidence interval were calculated in events/1000 patients-years.Results: forty-seven patients were enrolled; mean disease duration was 12,14 years (SD 5,87). Mean duration of the combination treatment was 78.33 (SD 41.37) months and total at-risk time was 3525 months. Two patients (4,2%) presented echocardiographic signs of PH (sPAP 50 mmHg and 40 mmHg); the IR was calculated to be 6.8/1000 patients-years (95% CI 6,02-7,7). In one of the 2 patients RHC excluded PAH, while the other patient refused to undergo to RHC and PAH could not be confirmed/excluded. A stability of PFTs and echocardiografic PAPs was observed during the observation time. Conclusions: the results of this retrospective study suggest that combination therapy with endothelin receptor antagonist and Phosphodiesterase-5 (PDE5) inhibitors could help in preventing PAH in SSc; prospective case-control studies on larger population are needed to improve knowledge in this field.

Introduction: Successful R0 resection is crucial for the survival of patients with primary liver cancer (PLC) or liver metastases. Up to date, surgical resection lacks a sensitive, real-time intraoperative imaging modality to determine R0 resection. Real-time intraoperative visualization with near-infrared light fluorescence (NIRF) using indocyanine green (ICG) may have the potential to meet this demand. This study evaluates the value of ICG visualization in PLC and liver metastases surgery regarding R0 resection rates. Materials and Methods Patients with PLC or liver metastases were included in this prospective cohort study. ICG 10mg was administered intravenously 24 hours before surgery. Real-time intraoperative NIRF visualization was made with the SpectrumTM Fluorescence Imaging Camera System. First, all liver segments were inspected with the fluorescence imaging system and intraoperative ultrasound for identification of the known tumor as well as additional lesions, compared to preoperative MRI. PLC, liver metastases, and additional lesions were then resected according to oncological principles. Of all resected specimens the resection margins were analyzed with the fluorescence imaging system for ICG positive spots right after resection. Histology of additional detected lesions as well as ICG fluorescence compared to histological resection margins were assessed. Results Of the 66 included patients median age was 65.5 years (IQR 58.7 - 73.9), 27 (40.9%) were female and 18 (27.3%) were operated laparoscopically. Additional ICG positive lesions were detected in 23 (35.4%) patients of which nine (29%) were malignant. In patients with no fluorescent signal at the resection margin, R0 rate was 93.9%, R1 rate was 6.1%, and R2 rate was 0% compared to a ICG positive resection margin with a R0 rate of 64.3%, R1 rate of 21.4%, and R2 rate of 14.3% (p=0.005). One and two year overall survival were 95.2% and 88.4%, respectively. Conclusion The here presented study provides significant evidence that ICG NIRF guidance helps to identify R0 resection intraoperatively. This offers a true potential to verify radical resection and improve patients´ outcome. Furthermore, implementation of NIRF guided imaging in liver tumor surgery allows to detect a considerable amount of additional malignant lesions.

The present article describes the synthesis of an isonicotinate-derived meso-arylporphyrin, that has been fully characterized by spectroscopic methods (including fluorescence spectroscopy), as well as by elemental analysis and by HR-MS. The structure of a n-hexane monosolvate has been determined by single crystal X-ray diffraction analysis. The radical scavenging activity of this new porphyrin against the 2,2-diphenyl-1-picrylhydrazyl (DDPH) radical has been measured. Its antifungal activity against three yeast strains (C. albicans ATCC 90028, C. glabrata ATCC 64677 and C. tropicalis ATCC 64677) has been tested, using the disk diffusion and the microdilution methods. Whereas the measured antioxidant activity was low, the porphyrin showed moderate but encouraging antifungal activity. Finally, a study of its effect on the germination of lentil seeds revealed interesting allelopathic properties.

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

Traditional photodynamic therapy (PDT), a clinical cancer therapeutic approach using light in killing cancer cells, is often limited by insufficient light penetration, inefficient photosensitizer energy transfer, and inadequate oxygen in hypoxic tumors. Employing X-ray to activate photosensitizer in PDT can potentially overcome these limitations. Here, we compared protocols to synthesize a novel nano-photosensitizer composed of a europium-doped yttrium oxide core with a silica shell (Y₂O₃:Eu@SiO₂) which can be utilized in such therapeutic method, i.e., X-ray activated PDT (XPDT). Transmission electron microscopy (TEM) and dihydroethidium (DHE) were utilized to evaluate the effects of various synthesis conditions on the characteristics of Y₂O₃:Eu@SiO₂ and their ability to generate reactive oxygen species (ROS). The in vivo tumor suppression effects of the Y₂O₃:Eu@SiO₂ were assessed by ¹⁸F-fluorothymidine position emission tomography (¹⁸F-FLT PET) in human ovarian cancer xenografts using radiation sensitive CAOV3 and radiation resistant SKOV3 cell lines. Our data revealed a positive correlation between nanoparticle condensation time and core size as well as a negative correlation between urea concentrations and core size. Addition of cetyltrimethylammonium bromide (CTAB) during core synthesis enhanced particle dispersion. Two silica coating conditions showed the greatest efficiency in the enhancement of ROS generation. Furthermore, our in vivo study revealed suppression of tumor growth by Y₂O₃:Eu@SiO₂ administration when compared to non-treated control. Silica shell provides flexibility to conjugate moieties that specifically target to cancers. This nano-photosensitizer demonstrates the significant promise for overcoming limitations of conventional PDT and combating various cancers in clinical applications.

Heme proteins serve diverse and pivotal biological functions. Therefore, clarifying the mechanisms of these diverse functions of heme is a crucial scientific topic. Distortion of heme porphyrin is one of the key factors regulating the chemical properties of heme. Here, we constructed convolutional neural network models for predicting heme distortion from the tertiary structure of the heme-binding pocket to examine their correlation. For saddling, ruffling, doming, and waving distortions, the experimental structure and predicted values were closely correlated. Furthermore, we assessed the correlation between the cavity shape and molecular structure of heme and demonstrated that hemes in protein pockets with similar structures exhibit near-identical structures, indicating the regulation of heme distortion through the protein environment. These findings indicate that the tertiary structure of the heme-binding pocket regulates the distortion of heme porphyrin, thereby controlling the chemical properties of heme relevant to the protein function; this implies a structure–function correlation in heme proteins.

The aim of this article is to identify the best available evidences analyzing liver samples, normall and pathological. In the study were used liver samples, collected during necropsy, from healthy patients and from patients diagnosed with cirrhosis .This mentioned, are known as routinally practice for hepatitis C diagnosis, which conduct to hepatic cirrhosis. In this study direction, chronic liver diseases stimulate a degree of hepatocyte injury. So previously mentioned modifications, alters thet affect the liver architecture and finally ends in cirrhosis are well analyse on microscopic preparates. Folowing morphological steps, it is possible to analyse normal and alterate liver structure, on colored preparates.

Portal myofibroblasts (PMF) are known to be critical in bile duct injury, but their role in liver fibrogenesis remains underexplored. Thy-1, an adhesion molecule integral to fibroblasts, relevant in fibrogenesis and detectable in serum as soluble Thy-1 (sThy-1), is expressed by PMF but not hepatic stellate cells in vitro. This study aimed to elucidate the correlation between Thy-1 expression in liver histology and sThy-1 levels in serum with the degree of liver fibrosis in patients with primary biliary cholangitis (PBC) and metabolic dysfunction associated steatotic liver disease (MASLD). Liver histology samples were stained for Thy-1 and sThy-1 was measured using an enzyme-linked immunosorbent assay (ELISA). In patients with PBC and MASLD, portal Thy-1 expression significantly correlated with increased fibrosis. The sinusoidal Thy-1 expression also significantly correlated with increased fibrosis in patients with PBC (p

A high intake of carbohydrates, associated with obesity, is one of the major causes of fatty liver disease in humans. This study investigated how high carbohydrate intake induces fatty liver disease in Blunt snout bream (Megalobrama amblycephala). Blunt snout bream were fed a high-carbohydrate diet (HCBD) for 60 days. Their growth indices were evaluated, and the transcriptomes, metabolites, biochemistry, and histology of their blood and livers were analyzed. The final weight, weight gain, specific growth rate, and feed conversion ratio were all higher in the HCBD group than in the control group, but not significantly so (P > 0.05). The hepatosomatic index (HSI) differed significantly in the two groups (P < 0.05), and the metabolomics results showed that a high carbohydrate intake induced significant increases in plasma α/β-glucose, succinate, and tyrosine, which could increase hepatic glycogen and triglyceride. Low levels of betaine were also found in the livers of the HCBD group. The histology and blood biochemistry results suggested abnormal liver, with excessive lipid accumulation and liver damage. A transcriptome analysis and quantitative reverse transcription–PCR (RT–qPCR) indicated that the expression of the factors INSR, IRS, PI3K, PDK, AKT, ACC, IL6, AP1, ChREBP-MLX, PEPCK, and FBP in the insulin signaling pathway was significantly upregulated and that of SOCS3, GSK3β, and AMPK significantly downregulated in the HCBD. This pattern is associated with the nonalcoholic fatty liver disease (NAFLD) pathway. This study extends our understanding of how high carbohydrate causes increased fat deposition in the liver, enhanced glycolysis (α/β-glucose) in the plasma, and reduced betaine in the liver. This leads to activation of hepatocyte insulin resistance and lipogenesis by regulating the expression of genes related to fatty liver disease.

The TanDEM-X mission is acquiring a new dataset to provide a temporally independent DEM, called "TanDEM-X Change DEM". This set of acquisitions taken between 2017 and 2020 has a clear temporal separation to the TanDEM-X global DEM data which were acquired between 2010 and 2015. Therefore, this new DEM aims to enable the characterization of terrain changes. Improvements in the acquisition planning and the data processing were necessary to generate this Change DEM with fewer acquisitions but still very high accuracy. For this, the use of an edited TanDEM-X DEM as a "starting point" for the interferometric processing is mandatory.

Background: Bioelectrical impedance (BIA) and ultrasound (US) have become popular for estimating body fat percentage (BF%) due to their low cost and clinical convenience. However, agreement of these devices with gold standard method still require investigation. The aim was to analyze the agreement between a gold standard %BF assessment method with BIA and US devices. Methods: Twenty-three men (age 30.1 ± 7.7 years, 82.5 ± 14.9 kg, 1.77 ± 0.05 m) underwent Dual Energy X-Ray Absorptiometry (DXA), BIA (tetrapolar) and US (three-site method) %BF assessment. Pearson and concordance correlations were analyzed. T-test compared means between methods, and Bland Altman plots analyzed agreement and proportional bias. Alpha was set at &lt; .05. Results: Pearson coefficients between BIA and US with DXA were high (BIA = 0.94; US = 0.89; both p &lt; .001). Concordance coefficient was high for BIA (0.80) and moderate for US (0.49). BF% measured by BIA (24.5 ± 7.5) and US (19.4 ± 7.0) were on average 4.4% and 9.6% lower than DXA (29.0 + 8.5%), respectively (p &lt; .001). Lower and upper agreement limits between DXA and BIA were -1.45 and 10.31, while between DXA and US were 2.01 and 17.14, respectively. There was a tendency of both BIA (p = .09) and US (p = .057) to present proportional bias and underestimate BF%. Conclusions: Despite the correlation, the mean difference between the methods were significant, and the agreement limits are very wide. This indicate that BIA and US, as measured in this study, have limited potential to accurately measure %BF compared to DXA, especially in individuals with higher body fat.

Boutique hotels emerged in the late 1970s since then the product has become more mainstream. The draw of boutique hotels is more personalized services. When marketing and providing services to a niche market it is smart to be able to differentiate potential guests to best meet their needs. The generational cohort theory states that a population may be divided into segments based on their generation. This research focuses on Generation X to find out what they are seeking in a boutique hotel product. Based upon how they chose their travel destination there were significant differences between culinary experience, attractions/activities, and cost/budget.

Abstract: Kiwifruit, a perennial horticultural crop known for its nutritional value, faces significant challenges due to biotic and abiotic stresses, affecting its yield and quality. Leucine-rich repeat receptor-like proteins (LRR-RLPs), a major group of receptor-like proteins in plants, have diverse functions in plant physiology, including growth, development, signal transduction, and stress responses. Despite their importance, the specific roles of kiwifruit LRR-RLPs in response to biotic and abiotic stresses remain poorly understood. In this study, we investigated the expression patterns of kiwifruit LRR-RLPs under various stress conditions, including pathogen stress, heat stress, waterlogging stress, and copper stress. Through genome and transcriptome analyses, we identified a total of 101, 164, and 105 LRR-RLPs in Actinidia Chinensis 'Hongyang', Actinidia eriantha 'Huate', and Actinidia chinensis 'Red5' kiwifruit, respectively, classified into 9 subgroups based on phylogenetic relationships. Synteny analysis revealed that the expansion of kiwifruit LRR-RLPs was primarily attributed to segmental duplication events. Using RNA-seq data from pathogen-infected kiwifruits, we identified specific LRR-RLP genes potentially involved in different stages of pathogen infection. Additionally, we observed the potential involvement of kiwifruit LRR-RLPs in abiotic stress responses, with upstream transcription factors possibly regulating their expression. Furthermore, protein interaction network analysis unveiled the participation of kiwifruit LRR-RLP genes in the regulatory network of abiotic stress responses. These findings highlight the crucial roles of LRR-RLPs in mediating both biotic and abiotic stress responses in kiwifruit, offering valuable insights for the breeding of stress-resistant kiwifruit varieties.

The increased prevalence of obesity worldwide has been implicated for the alarming rise of the incidence of gestational diabetes and preeclampsia as well, both considered as threatening conditions for both mother and fetus. We studied gene polymorphisms of the proinflammatory cytokine Interleukin 6 (IL-6) and the gene expression levels of VEGF and VEGF-receptor all known to be involved in pregnancy complications aiming to identify possible predisposing risk factors in pregnancies with obesity. G allele of IL-6 was found to correspond with an increased risk for gestational diabetes and preeclampsia occurrence. Furthermore, in obese pregnant mothers with either gestational diabetes or pre-existing type 2 diabetes and to those developed preeclampsia it was confirmed that gene expression levels of VEGF were reduced while they were increased for VEGF receptor. We conclude that the genetic profile of the obese pregnant woman shares a common background with that of a pre-existing type 2 diabetes mellitus and therefore predisposes to complications in pregnancy.

Orthohepadnavirus causes chronic hepatitis in a broad range of mammals, including primates, cats, woodchucks, and bats. Hepatitis B virus (HBV) X protein inhibits type-I interferon (IFN) signaling, promoting HBV escape from the innate immune system to establish persistent infection. However, whether X proteins of Orthohepadnavirus viruses in the other species have similar inhibitory activity remains unknown. Here, we investigated the anti-IFN activity of 17 Orthohepadnavirus X proteins derived from various hosts. We observed conserved activity of Orthohepadnavirus X proteins in inhibiting TIR-domain-containing adaptor protein inducing IFN-β (TRIF)-mediated IFN-β signaling pathway through TRIF degradation. X proteins from domestic cat hepadnavirus (DCH), a novel member of Orthohepadnavirus, inhibited mitochondrial antiviral signaling protein (MAVS)-mediated IFNβ signaling pathway comparable with HBV X. These results indicate that inhibition of IFN signaling is conserved in Orthohepadnavirus X proteins.

Pituitary adenylyl cyclase activating polypeptide (PACAP) belongs to the vasoactive intestinal polypeptide (VIP)/secretin/glucagon superfamily. PACAP is present in two forms, PACAP-38 and PACAP-27, and binds to three guanine-regulatory (G) protein-coupled receptors (PAC1, VPAC1, and VPAC2). PACAP is expressed in the central and peripheral nervous systems with high PACAP levels found in the hypothalamus, a brain region involved in feeding and energy homeostasis. PAC1 receptors are high-affinity and PACAP-selective receptors, while VPAC1 and VPAC2 receptors show a comparable affinity to PACAP and VIP. PACAP and its receptors are expressed in the central and peripheral nervous systems, with moderate to high expression in the hypothalamus, amygdala, and other limbic structures. Consistent with their expression, PACAP is involved in several physiological responses and pathological states. A growing body of literature suggests that PACAP regulates food intake in laboratory animals. However, there is no comprehensive review of the literature on this topic. Thus, the purpose of this article is to review the literature regarding the role of PACAP and its receptors in food intake regulation and to synthesize how PACAP exerts its anorexic effects in different brain regions. To achieve this goal, we searched PubMed and reviewed 68 articles regarding the regulatory action of PACAP on food intake. Here, we present the literature regarding the effect of exogenous PACAP on feeding and the role of endogenous PACAP in this process. We also provide evidence regarding the effect of PACAP on the homeostatic and hedonic aspects of food intake, the neuroanatomical sites where PACAP exerts its regulatory action, which PACAP receptors may be involved, and the role of various signaling pathways and neurotransmitters in hypophagic effects of PACAP.

Background: Plasma levels of von Willebrand factor (VWF) are significantly elevated in patients with COVID-19. However, the dynamic changes and prognostic value of this biomarker in hospitalized patients with COVID-19 are not determined. Methods: 124 patients infected with SARS-CoV2 were prospectively recruited for the study. Serial blood samples were obtained at the time of admission (D1), 3-4 days following standard of care treatments (D2), and 1-2 days prior to discharge or death (D3). Plasma VWF antigen, ADAMTS13 antigen and activity, as well as the ratio of VWF/ADAMTS13 were determined, followed by statistical analyses. Results:While admission plasma levels of VWF in COVID-19 patients were significantly elevated, no statistical significance was detected among patients of different disease severity. Plasma ADAMTS13 activity, but not its antigen levels, were significantly lower in patients with severe or critical COVID-19 compared with other groups. Interestingly, the ratios of plasma VWF antigen to ADAMTS13 antigen were significantly higher in patients with severe or critical COVID-19 than in those with mild to moderate disease. More importantly, plasma levels of VWF and VWF/ADAMTS13 ratios were persistently elevated in patients with COVID-19 during hospitalization. Kaplan-Meier and Cox proportional hazard regression analysis revealed that an increased plasma VWF or ratio of VWF/ADAMTS13 at D2 and D3 associated with an increased mortality rate. Conclusions: Persistent endotheliopathy, marked by an elevated level of plasma VWF or an increased VWF/ADAMTS13 ratio, is present in all hospitalized patients following SARS-CoV2 infection and strongly associated with mortality.

For paramagnetic and elastic materials in the presence of quasi-static magnetic field, there is correspondingly quasi-static magnetic pressure, in contrast to the radiational electromagnetic pressure associated with electromagnetic momentum density. A thermodynamic pressure demagnetization is demonstrated. For the elastic dielectrics in the presence of quasi-static electrical field, its dual effect can be easily obtained by variable transformation.

Abstract: Short-chain fatty acids (SCFAs) are the major microbial metabolites produced in the gut through the fermentation of non-digestible fibers. SCFAs act through free fatty acid receptor 2 and 3 (FFAR2 and 3), which are known to be expressed on glucagon-like peptide-1 (GLP-1)-secreting L-cells. This pathway is suggested to protect the intestinal mucosa. We aimed to investigate how lack of fiber affects the production of SCFAs and the vulnerability of the co-lon. Additionally, the involvement of FFAR2 and 3 in GLP-1 secretion and intestinal protection. SCFA concentrations in luminal contents from chow- or fiber-free diet-fed mice were analysed by LC‒MS. SCFAs were applied to isolated perfused colons from FFAR2/3 double KO and WT mice, and the secretion of GLP-1 was measured. Dextran sulfate sodium (DSS) colitis was induced in chow- or fiber-free diet-fed mice as well as in FFAR2/3 KO and WT mice. The removal of die-tary fiber significantly decreased total colonic SCFA concentrations, with specific decreases in acetate, propionate, and butyrate. SCFAs significantly increased colonic GLP-1 secretion but not in FFAR2/3 KO mice. In the DSS model, the removal of dietary fiber increased the severity and delayed recovery. Colitis severity was independent of FFAR2 and FFAR3 signaling.

This study aimed to investigate the coloring ingredient potential of liver homogenates that form Zn-protoporphyrin (ZnPP), a natural red pigment, after anaerobic incubation. The liver homogenates were used to develop nitrite-free sterile pork liver pâtés. These liver homogenates can be applied in the formulation of pâtés directly or as a centrifuged insoluble fraction that is highly concentrated in ZnPP. Both the whole homogenate and its insoluble fraction were adjusted to pH 7.5 before their use in the formulation of pâtés with and without antioxidant (0.5% ascorbate plus 0.1% tocopherol) addition. Pâtés formulated with the whole homogenate showed color and texture characteristics similar to those of the positive control with nitrite. However, high levels of the insoluble fraction also led to pâtés with improved color characteristics but with a two-fold softened texture. Therefore, the form and amount of ZnPP added played a role in the final appearance of the product. The ZnPP pigment was more stable than heme was in the sterilization treatment, and antioxidant addition proved to be unnecessary. The ZnPP-rich ingredients allowed for the preparation of nitrite-free cooked liver pâtés with a stable red color and could be potentially applied in other uncured cooked meat products.

We conducted a hybrid-design study on a historical cohort of 359 adult recipients of a liver graft who received transplants between 1996 and 2002. The study aimed to identify predictors of survival and investigate the prevalence of co-morbidities among long-term survivors. The actuarial (95% CI) patient survival of the overall study cohort was 96% (94.6%-98.3%), 69% (64.2%-73.6%), 55% (49.8%-59.9%), 42.8% (37.6%-47.8%), and 34% (29.2%-38.9%) at 1, 5, 10, 15, and 20 years, respectively. The actuarial (95% CI) graft survival was 93.8% (91.6%-97.2%), 67.6% (62.2%-71.5%), 54.3% (49.6%-59.3%), 42.1% (37.3%-47.4%), and 33.8% (29.0%-38.4%) at 1, 5, 10, 15, and 20 years, respectively. The leading cause of death was hepatitis C virus recurrence (24.6%), followed by extrahepatic malignancies (16.9%), infection (14.4%), and hepatocellular carcinoma recurrence (14.4%). The Cox proportional hazards analysis revealed that several independent factors were associated with the survival probability. These factors include younger donor and recipient ages (p=0.001 and 0.004, respectively), female recipient sex (p<0.001), absence of HCV (p<0.01), absence of HCC (p=0.001), and absence of diabetes mellitus at one year (p<0.01). At the latest follow-up, the leading comorbidities in the long-term survivors were hypertension (53.6%), obesity (18.7%), diabetes mellitus (17.1%), hyperlipidemia (14.7%), chronic kidney dysfunction (14.7%), and extrahepatic malignancies (13.8%), with 73.9% of patients having more than one complication. The Kaplan-Meier probability (95% CI) of complication-free survival was 65.4% (60.2%-70.3%), 38.4% (33.4%-43.7%), 17.8% (14.1%-22.2%), 7.2% (4.8%-10.5%), and 1.94% (0.85%-4.15%) at 1, 5, 10, 15, and 20 years, respectively. Aging with a liver graft is associated with an increased risk of complications and requires ongoing care to reduce the long-term attrition rate resulting from chronic immunosuppression.

Purpose: To analyze the genetic and molecular profile of liver nodules in the context of Fontan-associated liver disease (FALD) with the aim of identifying possible biomarkers for predictive outcome and personalized therapy. Methods: this retrospective monocentric study included 9 patients who developed FALD in the context of congestive cirrhosis:1 regenerative nodular hyperplasia, 2 hepatic adenomas (HA) and 4 hepatocellular carcinoma (HCC), 1 fibrolamellar carcinoma (FLC) and 1 intrahepatic cholangiocarcinoma (ICC). The lesions were analyzed by histology and immunohistochemistry (b-catenin, glypican 3, glutamine synthetase and SOX9). To study the molecular profile of neoplastic FALD, targeted NGS was performed on DNA and RNA from formalin-fixed paraffin embedded neoplastic liver tissue of 1 HA, 2 HCCs, 1 FLC and 1 ICC. Results: Molecular analysis showed 3 patients with copy number alteration involving FGFR3, and one patient with a hotspot mutation on CTNNB1 and NRAS genes. All 5 patients showed a tumor mutational burden ranging from low to intermediate. Variants of unknown significance in GNAS were present in 2 HCC and 1 ICC. The single FLC had a DNAJB1-PRKACA fusion. Conclusions: The molecular results seem to be consistent with a peculiar molecular profile of the malignant FALD which may be useful for new target therapies for HCC/ICC in FALD.

Duchenne muscular dystrophy (DMD) is caused by genetic mutations in the cytoskeletal-sarcolemmal anchor protein dystrophin. Repeated cycles of sarcolemmal tearing and repair lead to a variety of secondary cellular and physiological stressors that are thought to contribute to weakness, atrophy, and fibrosis. Collectively, these stressors can contribute to a pro-inflammatory milieu in locomotor, cardiac, and respiratory muscles. Given the many unwanted side effects that accompany current anti-inflammatory steroid-based approaches for treating DMD (e.g., glucocorticoids), there is a need to develop new therapies that address inflammation and other cellular dysfunctions. Adiponectin receptor (AdipoR) agonists, which stimulate AdipoR1 and R2 isoforms on various cell types, have emerged as therapeutic candidates for DMD due to their anti-inflammatory, anti-fibrotic, and pro-myogenic properties in pre-clinical human and rodent DMD models. Although these molecules represent a new direction for therapeutic intervention, the mechanisms through which they elicit their beneficial effects are not yet fully understood, and DMD-specific data is limited. The overarching goal of this review is to investigate how adiponectin signaling may ameliorate pathology associated with dystrophin deficiency through inflammatory-dependent and -independent mechanisms, and to determine if current data supports their future progression to clinical trials.

Algorithms for machine learning have found extensive use in numerous fields and applications. One important aspect of effectively utilizing these algorithms is tuning the hyperparameters to match the specific task at hand. The selection and configuration of hyperparameters directly impact the performance of machine learning models. Achieving optimal hyperparameter settings often requires a deep understanding of the underlying models and the appropriate optimization techniques. While there are many automatic optimization techniques available, each with its own advantages and disadvantages, this article focuses on hyperparameter optimization for well-known machine learning models. It explores cutting-edge optimization methods and provides guidance on applying them to different machine learning algorithms. The article also presents real-world applications of hyperparameter optimization by conducting tests on spatial data collections for landslide susceptibility mapping. Based on the experiment's results, both Bayesian optimization and metaheuristic algorithms showed promising performance compared to baseline algorithms. For example, the metaheuristic algorithm improved the overall accuracy of the random forest model. Additionally, Bayesian algorithms, such as Gaussian processes, performed well for models like KNN and SVM. The paper thoroughly discusses the reasons behind the efficiency of these algorithms. By successfully identifying appropriate hyperparameter configurations, this research paper aims to assist researchers, spatial data analysts, and industrial users in developing machine learning models more effectively. The findings and insights provided in this paper can contribute to enhancing the performance and applicability of machine learning algorithms in various domains.

Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related deaths. Classically, liver transplantation (LT) can be curable for HCC tumors within the Milan criteria. Bridging strategies to reduce the dropouts from LT waiting lists or/and to downstage patients who are beyond Milan criteria are widely utilized. We conducted a literature-based review to evaluate the role of systemic therapies as a bridging treatment to liver transplantation (LT) in HCC patients. Tyrosine Kinase Inhibitors (TKIs) can be used as a bridging systemic therapy to LT in patients with contraindication to locoregional liver-directed therapies. Immune Checkpoint Inhibitors (ICIs) treatment can be utilized either as a monotherapy or as a combination therapy with Bevacizumab or TKIs prior to LT. Acute rejection post liver transplantation is a concern in the context of ICIs treatment. Thus, a safe ICI washout period before LT and cautious post-LT immunosuppression strategies are required to reduce post-LT rejections and to optimize clinical outcomes. Nevertheless, prospective clinical trials are needed to establish definitive conclusions about the utility of systemic therapy as a bridging modality prior to LT in HCC patients.

We proposed a so-called Beta Kumaraswamy Burr Type X distribution which gives the extension of the Kumaraswamy-G class of family distribution. Some properties of this proposed model were provided, like: the expansion of densi- ties and quantile function. We considered the Bayes and maximum likelihood methods to estimate the parameters and also simulate the model parameters to validate the methods based on dierent set of true values. Some real data sets were employed to show the usefulness and exibility of the model which serves as generalization to many sub-models in the elds of engineering, medical, survival and reliability analysis.

We proposed a so-called Beta Kumaraswamy Burr Type X distribution which gives the extension of the Kumaraswamy-G class of family distribution. Some properties of this proposed model were provided, like: the expansion of densities and quantile function. We considered the Bayes and maximum likelihood methods to estimate the parameters and also simulate the model parameters to validate the methods based on different set of true values. Some real data sets were employed to show the usefulness and flexibility of the model which serves as generalization to many sub-models in the field of engineering, medical, survival and reliability analysis.