Trace amine-associated receptor 5 (TAAR5) is a G protein-coupled receptor that belongs to the TAARs family (TAAR1-TAAR9). TAAR5 is expressed in the olfactory epithelium and is responsible for sensing 3-methylamine (TMA). However, recent studies showed that TAAR5 is also expressed in the limbic brain regions and is involved in the regulation of emotional behaviour and adult neurogenesis, suggesting that TAAR5 antagonism may represent a novel therapeutic strategy for anxiety and depression. We used the AtomNet® model, the first deep learning neural network for structure-based drug discovery, to identify putative TAAR5 ligands and tested them in an in vitro BRET assay. We found two mTAAR5 antagonists with low to submicromolar activity that are able to inhibit the cAMP production induced by TMA. Moreover, these two compounds also inhibited the mTAAR5 downstream signalling, such as the phosphorylation of CREB and ERK. These two hits exhibit drug-like properties and could be used to develop further more potent TAAR5 ligands with putative anxiolytic and antidepressant activity.

Enhanced permeation retention (EPR) was a significant milestone discovery by Maeda et al. paving the road for the emerging nanomedicine as a powerful tool in the fight against cancer. Sildenafil is a potent inhibitor of phosphodiesterase 5 (PDE-5) used for treatment of erectile dysfunction (ED) through the relaxation of smooth muscles and the modulation of vascular endothelial permeability. Overexpression of PDE-5 was reported in lung, colon, metastatic breast cancers and bladder squamous carcinoma. Accordingly, there has been a growing interest in using sildenafil as monotherapy or chemoadjuvant in EPR augmentation and management of different types of cancer. Sildenafil had been reported to increase the sensitivity of tumor cells of different origins to the cytotoxic effect of chemotherapeutic agents with augmented apoptosis mediated through inducing the expression of Bad and Bax proapoptotic proteins. It was also reported that the use of sildenafil prior to the administration of Doxorubicin (DOX) increased its EPR-related concentration in breast cancer tissues by 2 folds. Further, a substantial reason of anticancer chemotherapeutic failure is due to multidrug resistance (MDR), exacerbated by the overexpression of ATP-binding cassette (ABC) transporters such as ABCB1 and ABCCs. Sildenafil has demonstrated inhibitory effects on the efflux activity of ABCC4, ABCC5, ABCB1, and ABCG2, ultimately reversing MDR caused by these transporters. In this review, we critically examine the overall potential of sildenafil in enhancing EPR-based anticancer drug delivery pointing up the outcome of the most important related preclinical and clinical studies.

In this article we report the first investigation over time of the atmospheric conditions around TGFs occurrence, using GPS sensors in combination with geostationary satellite observations and ERA5 reanalyses data. The goal is to understand which characteristics are favourable to the development of these events and to investigate if any precursor signals can be expected. A total of 9 TGFs, occurred at a distance lower than 45 km from a GPS sensor, were analysed and two of them are shown here as an example analysis. Moreover, the lightning activity, collected by the World Wide Lightning Location Network (WWLLN) was used in order to identify any links and correlations with TGF occurrence and PWV trends. The combined use of GPS and the stroke rate trends identified, for all cases, a recurred pattern in which an increase of PWV is observed on a timescale of about two hours before the TGF occurrence that can be placed within the lightning peak. The temporal relation between the PWV trend and TGF occurrence is strictly related to the position of GPS sensors in relation to TGF coordinates. The life cycle of these storms observed by geostationary sensors, described TGFs producing clouds as intense with a wide range of extensions and, in all cases, the TGF is located at the edge of the convective cell. Furthermore, the satellite data give an added value in associating the GPS water vapor trend to the convective cell generating the TGF. The investigation with ERA5 reanalyses data showed that TGFs mainly occur in convective environment with not exceptional values with respect to the monthly average value of parameters measured in the same location. Moreover the analysis showed the strong potential of the use of GPS data for the troposphere characterization in areas with complex territorial morphology. This study provided indications on the dynamics of convective systems linked to TGFs and will certainly help refine our understanding on their production highlights a potential approach through the use of GPS data to explore the lightning activity trend and the TGFs occurrence.

Ten-eleven translocation (TET) enzymes are implicated in DNA demethylation through dioxygenase activity, which converts 5-methylcytosine to 5-hydroxymethylcytosine (5-hmC). However, the specific roles of TET enzymes and 5-hmC levels in head and neck squamous cell carcinoma (HNSCC) have not yet been evaluated. In this study, we analyzed 5-hmC levels and TET mRNA expression in a well-characterized dataset of 117 matched pairs of HNSCC tissues and normal tissues. 5-hmC levels and TET mRNA expression were examined via enzyme-linked immunosorbent assay and quantitative real-time PCR, respectively. 5-hmC levels were evaluated according to various clinical characteristics and prognostic implications. Notably, we found that 5-hmC levels were significantly correlated with tumor stage (P = 0.032) and recurrence (P = 0.018). Univariate analysis revealed that low levels of 5-hmC were correlated with poor disease-free survival (DFS; log-rank test, P = 0.038). The expression of TET family genes was not associated with outcomes. In multivariate analysis, low levels of 5-hmC were evaluated as a significant independent prognostic factor of DFS (hazard ratio: 2.352, 95% confidence interval: 1.136–4.896; P = 0.021). Taken together, our findings showed that reduction of TET family gene expression and subsequent low levels of 5-hmC may affect the development of HNSCC.

The three heat-induced coffee contaminants acrylamide, furfuryl alcohol (FA) and 5-hydroxymethylfurfural (HMF) were analyzed in a collective of commercial samples as well as in Coffea arabica seeds roasted under controlled conditions from very light Scandinavian style to very dark Neapolitan style profiles. Regarding acrylamide, average contents in commercial samples were lower than in a previous study in 2002 (196 compared to 303 µg/kg). The roasting experiment confirmed the inverse relationship between roasting degree and acrylamide content, i.e. the lighter the coffee the higher the acrylamide content. However, FA and HMF were inversely related to acrylamide and found in higher contents in darker roasts. Therefore, mitigation measures must consider all contaminants and not be focused isolatedly on acrylamide, specifically since FA and HMF are contained in much higher contents with lower margins of exposure compared to acrylamide.

Enzymes reliant on pyridoxal 5'-phosphate (PLP), the metabolically active form of vitamin B6, hold significant importance in both biology and medicine. They facilitate various biochemical reactions, particularly in amino acid and neurotransmitter metabolisms. Vitamin B6 is absorbed by organisms in its non-phosphorylated form and phosphorylated within cells by pyridoxal kinase (PLK) and pyridox-(am)-ine 5'-phosphate oxidase (PNPOx). The flavin mononucleotide dependent PNPOx enzyme converts pyridoxine 5'-phosphate and pyridoxamine 5'-phosphate into PLP. PNPOx is vital for both biosynthesis and salvage pathways in organisms producing B6 vitamers. However, for those depending on vitamin B6 as nutrient, PNPOx participates only in the salvage pathway. Transferring PLP produced by PNPOx to client apo-enzymes is indispensable for their catalytic function, proper folding and targeting to specific organelles. PNPOx activity deficiencies due to inborn errors lead to severe neurological pathologies, particularly neonatal epileptic encephalopathy. PNPOx enzymes from different organisms maintain PLP homeostasis through highly regulated mechanisms, including structural alterations throughout the catalytic cycle and allosteric PLP binding influencing substrate transformation at the active site. Despite shared features, species-specific regulations are evident among PNPOx enzymes.

Background: Classical Hodgkin's lymphoma (cHL) is a lymph node disease, however, extranodal involvement is present in about 10% of affected individuals. Various forms of direct central nervous system (CNS) involvement have been reported, including intracranial, epidural, leptomeningeal, and intramedullary spinal cord cHL (Table 1). We hereby describe the clinical presentation, work up, and outcomes of two distinctive cases of cHL with intracranial extra-axial spread in patients receiving novel combination and traditional chemotherapy. Methods: This case series (n=2) was conducted following the CARE guidelines. Institutional review board (IRB) approved protocol #24-015 for HIPPA waiver of subjects in our retrospective study. Results: Patients with cHL exhibiting CNS symptoms or relapse refractory cases benefit from neuroimaging and excluding infectious etiologies. Suspicious lesions include iso- to hypointensity on T1 weighted and iso- to hyperintensity on T2 MR scans. Diagnosis is confirmed with biopsy. Treatment with A-AVD has shown more benefit than traditional ABVD chemotherapy. There has been shown progression free survival with nivolumab-AVD (N-AVD) over brentuximab-AVD (B-AVD). Conclusion: cHL with CNS involvement is rare and requires comprehensive workup to exclude infectious and other malignancies. Diagnosis relies on neuroimaging and subsequent brain biopsy. Treatment with novel N-AVD has shown greater PFS in patients with advanced cHL.

Manganese porphyrins reportedly exhibit synergic effects when combined with irradiation. However, an in-depth understanding of intratumoral heterogeneity and immune pathways, as affected by Mn porphyrins, remains limited. Here, we explored the mechanisms underlying immunomodulation of a clinical candidate, MnTnBuOE-2-PyP5+ (BMX-001, MnBuOE), using single-cell analysis in murine carcinoma model. Mice bearing 4T1 tumors were divided into 4 groups: control, MnBuOE, radiotherapy (RT), combined MnBuOE and radiotherapy (MnBuOE/RT). In epithelial cells, epithelial-mesenchymal transition, TNF-α signaling via NF-кB, angiogenesis, and hypoxia-related genes were significantly downregulated in the MnBuOE/RT compared to the RT. All subtypes of cancer-associated fibroblasts (CAFs) were clearly reduced in MnBuOE and MnBuOE/RT. Inhibitory receptor-ligand interactions, in which epithelial cells and CAFs interacted with CD8+ T cells, were significantly lower in the MnBuOE/RT than in the RT. Trajectory analysis showed that DC maturation-associated markers were increased in MnBuOE/RT. M1 macrophages were significantly increased in the MnBuOE/RT compared to the RT, whereas myeloid-derived suppressor cells were decreased. CellChat analysis showed that the number of cell-cell communications was the lowest in the MnBuOE/RT. Our study is the first to provide evidence for the combined radiotherapy with a novel Mn porphyrin clinical candidate, BMX-001 from the perspective of each cell-type within the tumor microenvironment.

Footprints are powerful indicators for evaluating the impact of the bioeconomy of a country on environmental goods, domestically and abroad. In this study, we apply a hybrid approach combining a Multi-Regional Input-Output model and land use modelling to compute the agricultural land footprint (aLF). Furthermore, we added information on land-use change to the analysis and allocated land conversion to specific commodities. The German case study shows that the aLF abroad is larger by a factor of 2.5 to 3 than the aLF in Germany. In 2005 and 2010, conversion of natural and semi-natural land-cover types abroad allocated to Germany due to import increases was 2.5 times higher than the global average. Import increases to Germany slowed down in 2015 and 2020, reducing land conversion attributed to the German bioeconomy to the global average. The case study shows that the applied land footprint provides clear and meaningful information for policymakers and other stakeholders. The presented methodological approach can be applied to other countries and regions covered in the underlying database EXIOBASE. It can be adapted, also for an assessment of other ecosystem functions, such as water or soil fertility.

Abstract: Malnutrition in children aged 0-5 years is a significant public health concern in many societies and is influenced by various sociodemographic factors that, when understood, may improve intervention planning and results. Background. This study aimed to identify the sociodemographic determinants of malnutrition in rural and urban areas of Abia State, Nigeria. Methods. A cross-sectional observational study involving 842 children (aged 6-59 months) and their caregivers was conducted across selected rural and urban areas in Abia State, Nigeria. Data collected through semistructured questionnaires focused on sociodemographic information as well as anthropometric measurements such as weight, height, and mid-upper arm circumference (MUAC). The dietary diversity score (DDS) was also calculated for each child via a questionnaire that recorded the consumption of various food groups over a 7-day period. Chi-square tests were adopted for categorical variables, whereas binomial logistic regression was used to identify determinants of malnutrition and weight classification. Results. Marked sociodemographic differences were found between rural and urban caregivers, with urban caregivers being more likely to have higher knowledge of nutrition (p < 0.01) and education (p < 0.01). Malnutrition, indicated by global acute malnutrition (GAM), was significantly higher in rural areas (53.5%) than in urban areas (46.5%) (χ2 = 5.353, p = 0.021). Logistic regression revealed that children of caregivers in rural areas were more likely to have an abnormal BMI-for-age (AOR: 1.407, 95% CI: 1.001–1.978, p = 0.049), whereas children of caregivers in urban areas were less likely to be malnourished (COR: 0.565, 95% CI: 0.347–0.921, p = 0.022). Conclusion. Implementation scientists should focus on enhancing caregiver education, particularly in rural areas, to promote awareness of diets, thereby reducing malnutrition.

Cholangiocarcinoma is an aggressive cancer with limited treatment options. Current therapies, such as cisplatin and 5-fluorouracil (5-FU), often cause side effects and drug resistance. This study investigated a potential new approach by combining a peanut skin extract (KK4-PSE) with these drugs. The extract effectively inhibited the growth of cholangiocarcinoma cells in laboratory studies and showed even greater selectivity for cancer cells compared to healthy cells. When combined with cisplatin or 5-FU, KK4-PSE enhanced the drugs' effects, leading to cell cycle arrest and increased cell death. These combined treatments also reduced levels of proteins that promote cancer cell survival. In animal models, KK4-PSE combined with 5-FU showed superior tumor suppression compared to the combination with cisplatin. Overall, these findings suggest that KK4-PSE may be a promising synergistic agent to improve the effectiveness of chemotherapy for cholangiocarcinoma, warranting further clinical investigation.

This survey of research literature is an overview of the current state of science addressing DSM-5 diagnostic criteria as it relates to identifying Autism Spectrum Disorder (ASD) in young children. Selected sources are of high quality and have been published since 2020 in peer-reviewed journals relevant to children’s health. The narrative is organized from the earliest to the most recent publications and is divided into sections around categories and themes that highlight the main arguments, findings, and controversies identified by researchers. There are indications in the literature that while ASD can be identified and differentiated from other developmental disorders in young children, doing so requires that clinicians who have relied on the DSM-5 should also use multiple measures, including other formalized screening tools as assessments that gather observational input from parents and caregivers, as well as findings from physical examinations, laboratory investigations, and magnetic resonance imagining (MRI). This high level of corroboration points to an emerging diagnosis paradigm through which transdiagnostic approaches to early diagnosis and intervention may exist.

The construction industry has a notable negative impact on the environment; thus, the promotion of the use of timber structures is an alternative to mitigate its effects. The research develops an artificial intelligence-based decision approach in the calculation of timber structures focused on the enhancement of the sustainability of roof structures. Based on the optimization carried out through genetic algorithms and the framework established in Eurocode 5, a general set of equations has been proposed for a laminated timber roof structure. The tool, which determines the most suitable roof structure for each strength class of laminated timber, allows for the determination of the dimensions of beams and purlins and their respective separations in order to minimize wood consumption. The ultimate goal is to offer multiple solutions regarding strength classes and structural designs in order to foster informed sustainable choices that promote efficient use of resources in construction.

Wood is poised to become a material of choice for future construction. When appropriately managed, it is a renewable material with unique mechanical properties. Beyond its inherent sustainability, the use of wood has a crucial role in addressing climate change concerns due a significantly lower energy consumption and emissions during manufacturing and transportation, while simultaneously acting as a carbon sink. Thus, there has been a growing demand for hardwoods for structural applications, including Castanea sativa Mill., the focal point of this investigation. Albeit in a limited capacity, Eurocode 5-2 offers friction coefficients for softwoods, but it falls short for hardwoods which it is a gap to bridge with this research. These coefficients play a critical role in numerical simulations involving friction, enabling the optimization of joints and, by extension, the overall structural integrity. Test samples were evaluated at 18% moisture content, which is typical of Service Class 2, for various orientations of timber-to-timber and timber-to-steel friction. Considering previous friction coefficients at 12% moisture content, the linear variation was evaluated at an intermediate value of 15%. The results provide an experimental database for numerical simulations and highlight the influence of moisture content on the coefficients, which increase linearly along moisture percentages.

Cancer being a multi-factorial disease, a multi-target approach is needed to treat it with minimal side-effects. Therefore, combined use of a proven herbal formula with chemo-therapy could be the better therapeutic. It may maintain homeostasis by synergistically targeting multiple signaling pathways involved in tumorigenesis, thus circumventing recurrence, resistance, and immunosuppression. Here we aim to determine the effectiveness and safety of an FDA-approved herbal formula, SR033 in combination with 5-fluorouracil (5FU) and paclitaxel (PTX). We report chemo-sensitization and chemo-synergy in HeLa and MCF-7 cell lines, immunomodulation of COX-2, PD-L1, VEGF and TGFβ and overall survival in-vitro and in-vivo via oral and topical delivery of SR033. In-vitro, SR033/5FU significantly reverses 5FU and PTX-resistance, lower COX-2, and PD-L1, resulting in TGFβ/ VEGF axis modulation. Furthermore, the study suggests that due to anti-oxidative potential of SR033, oral administration exerts chemo-preventive activity and restores cellular compartment in solid tumor and ascites-bearing mice models. Furthermore, the topical application, SR033L with low-dose 5FU increases survival rate, reduces tumor growth, and completely restores local and peripheral neutrophil-lymphocyte ratio in solid tumor mice model. The study indicates that SR033 could be a strong candidate in combination with low-dose 5FU and PTX for a holistic approach to cancer management.

The described data set contains features from the machine control of a five-axis milling machine. The features were recorded during thirteen series productions. Each series production includes a changeover process in which the machine was set up for the production of a different product. In addition to the timestamps and the twenty recorded features derived from Numerical Control (NC) control variables, the data set also contains labels for the different production phases. For this purpose, up to 23 phases were assigned, which are based on a generalized milling process. The data set consists of thirteen .csv files, each representing a series production. The data set was recorded in a production company in the contract manufacturing sector for components with real series orders in ongoing industrial production.

The 5-hydroxymethylfurfural (HMF) is a six-carbon heterocyclic organic compound with two substituents an aldehyde group and an alcohol group. It is formed from saccharides as a result of two reactions: the Maillard reaction and the caramelization of saccharides. It has both a negative and a positive effect on the human body, which makes it, even more, an attractive research object. The objective of the study was to determine HMF content in honey samples available on the Polish market using three varied methods and compare the results obtained. The methodology used included: two spectrophotometric methods (by White and Winkler) and the HMF determination method based on the LC-MS/MS technique developed uniquely for this study. The determined HMF content in all tested honey samples did not exceed the applicable standard. All results are within the scope of the European Council Directive 2001/110/EC of 20 December 2001, i.e. they do not exceed HMF content in honey, which is 40 mg/kg.

Toxoplasma gondii is a widespread protozoan parasite that infects most warm-blooded animals, and felids can serve as intermediate and definitive hosts. Pathological diagnosis and serological and etiological investigations were conducted on a captive caracal (Caracal caracal) carcass collected from China in 2022. Pathological diagnosis revealed that cardiac insufficiency, pulmonary edema, hepatic failure, and renal insufficiency were the causes of the caracal’s death. A modified agglutination test (cut-off: 1:25) revealed that IgG antibodies against T. gondii were present in the myocardium juice, hydroperitoneum, and hydropericardium (≥1:800). A viable T. gondii (TgCaracalCHn2) strain was isolated from the tissue samples (heart, brain, spleen, and skeletal muscle) of this caracal using a mouse bioassay. The genotype of TgCaracalCHn2 was ToxoDB#5 (Type II variant), as determined by RFLP-PCR. The strain was avirulent in Swiss mice and matched the prediction of ROP18 and ROP5 gene alleles of TgCaracalCHn2 (2/2). Many tissue cysts (203 ± 265) were observed in mice brains after inoculation with TgCaracalCHn2 tachyzoites. ToxoDB#5 is the dominant genotype in North American wildlife, and this is the first documented isolation of T. gondii ToxoDB#5 from China. This indicates that caracals can accelerate the transmission of T. gondii genotypes.

Inosine 5'-monophoaphate (IMP) allows animals to sense umami. Intake of IMP in C57/KsJ-db/db (db/db) mice induced lipohyperplasia causing the liver cirrhosis, however, how to that of in normal mammals injure health is still unclear. Thus, we had investigated that intake of IMP in C57BL/6J mice effected its metabolic functions. We found that intake of 255 M/d IMP in C57BL/6J mice for 4 months induced hyperlipidemia and body fat rate raised. In mechanism, the expressions of ACC1 and phosphorylated ACC2 in hepatocytes were increased though IMP promoting phosphorylation of AMPK. The increased ACC1 promoted the conversion of acetyl-CoA into TG. These TG were transported out of hepatocytes to avoid NAFLD, causing a deficiency of acetyl-CoA in liver, and then the increased phosphorylated ACC2 promoted cytoplasm fatty acids into mitochondria to convert into acetyl-CoA though the fatty acids β-oxidation pathway, causing a deficiency of fatty acids. Therefore, liver enhanced the absorption of exogenous fatty acids, which were converted into TG caused lipohyperplasia. Moreover, intake of IMP in normal mice induced complement system weaken in liver causing mild inflammation. Our data not only alerted that humans avoid excessive intake of IMP, but also provided novel insights into the adipose of metabolic dysfunctions.

Dehydroaromatization of methane (MDA) is of great interest as a promising process for processing natural and associated petroleum gases, the main component of which is methane. The rapid loss of catalyst activity because of coke formation hinders the introduction of the DHA methane process into industry. Therefore, the aim of the research was to find ways to improve Mo/ZSM-5 catalysts for MDA. The paper presents the results of the synthesis of high-silica zeolites of the ZSM-5 type with a microporous and micro-mesoporous structure, the preparation of Mo/ZSM-5 catalysts based on them, and the study of the physicochemical and catalytic properties of the obtained samples during the non-oxidative conversion of methane into aromatic hydrocarbons. Zeolite catalysts were investigated by IR spectroscopy, X-ray diffraction, TPD-NH3, SEM, HR-TEM, N2-adsorption. It was found that the addition of carbon black at the stage of synthesis of zeolite type ZSM-5 does not lead to structural changes, the obtained samples have a crystallinity equal to 100%. The creation of the micro-mesoporous structure in Mo/ZSM-5 catalysts lead to an increase in their activity and stability in the process of methane dehydroaromatization. The highest conversion of methane is observed on a 4.0%Mo/ZSM-5 catalyst prepared based on of zeolite synthesized using 1.0% carbon black, and is 13.0% in 20 minutes of reaction, while the benzene yield reaches 7.0%. It has been shown by HR-TEM that a more uniform distribution of the active metal component is observed in a zeolite catalyst with a micro-mesoporous structure than in a microporous zeolite.

Pancreatic cancer exhibits a poor prognosis due to the lack of early diagnostic biomarkers and the resistance to conventional chemotherapy. CD44 has been known as a cancer stem cell marker, and plays tumor promotion and drug resistance in various cancers. Especially, the splicing variants are overexpressed in many carcinomas, and play essential roles in the cancer stemness, invasiveness or metastasis, and resistance to treatments. Therefore, the understanding of each CD44 variant (CD44v) function and distribution in carcinomas is essential for the establishment of CD44-targeting tumor therapy. In this study, we immunized mice with CD44v3–10-overexpressed Chinese hamster ovary-K1 (CHO) cells, and established various anti-CD44 monoclonal antibodies (mAbs). One of the established clones (C44Mab-3; IgG1, kappa) recognized peptides of the variant 5-encoded region, indicating that C44Mab-3 is a specific mAb for CD44v5. Moreover, C44Mab-3 reacted with CHO/CD44v3–10 cells or pancreatic cancer cell lines (PK-1 and PK-8) by flow cytometry. The apparent KD of C44Mab-3 for CHO/CD44v3–10 and PK-1 was 7.1 × 10−10 M and 1.9 × 10−9 M, respectively. C44Mab-3 could detect the exogenous CD44v3–10 and endogenous CD44v5 in western blotting, and stained the formalin-fixed paraffin-embedded pancreatic cancer cells, but not normal pancreatic epithelial cells in immunohistochemistry. These results indicate that C44Mab-3 is useful for detecting CD44v5 in various applications, and expected for the application of pancreatic cancer diagnosis and therapy.

Pancreatic cancer is projected to be the second leading cause of cancer-related death by 2030 in the US. The benefits of the most common systemic therapy for various pancreatic cancer have been masked by high drug toxicities, adverse reactions, and resistance. Using nanocarriers like liposomes to overcome these unwanted effects has become very popular. This study aimed to formulate 1,3-bis tetrahydrofuran-2yl-5FU (MFU)-loaded liposomal nanoparticles (Zhubech) and evaluate the stability, MFU release kinetics, in vitro and in vivo anticancer activities, and biodistribution. Particle size and zeta potential were determined using a particle size analyzer, while cellular uptake of rhodamine-entrapped liposomal nanoparticle (Rh0-LnP) was determined by confocal microscopy. Gadolinium hexanoate (Gd-Hex) was synthesized and entrapped into the liposomal nanoparticle (LnP) (Gd-Hex-LnP) as a model contrast agent, to evaluate gadolinium biodistribution and accumulation by LnP in vivo using inductively coupled plasma mass spec-trometry (ICP-MS). The mean hydrodynamic diameters of the blank LnP and Zhubech were 90.0 ± 0.65 nm and 124.9 ± 3.2 nm, respectively. The hydrodynamic diameter of Zhubech was found to be highly stable at 4o C and 25oC for 30 days in solution. In vitro drug release of MFU from Zhubech formulation exhibited the Higuchi model (R2 value = 0.95). Both Miapaca-2 and Panc-1 treated with Zhubech showed reduced viability, two- or four-fold lower than that of MFU-treated cells in 3D spheroids (IC50Zhubech = 3.4 ± 1.0μM vs IC50MFU = 6.8 ± 1.1μM) and organoids (IC50Zhubech = 9.8 ± 1.4μM vs IC50MFU = 42.3 ± 1.0μM) culture models. Confocal imaging confirmed high uptake of rhodamine-entrapped LnP by Panc-1 cells in a time-dependent manner. Tumor efficacy studies in PDX bearing mouse model revealed more than 9-fold decrease in mean tumor volumes in Zhu-bech treated (108 ± 13.5 mm3) compared to 5-FU treated (1,107 ± 116.2 mm3) animals respectively. This study demonstrates that Zhubech may be a potential candidate for delivering drugs for pancreatic cancer treatment.

Single-stand selective monofunctional uracil DNA glycosylase 1 (SMUG1) works to remove uracil and certain oxidized bases from DNA during base excision repair (BER). This review provides a historical characterization of SMUG1 and 5-hydroxymethyl-2'-deoxyuridine (5-hmdU) one important substrate of this enzyme. Biochemical and structural analyses provide remarkable insight into the mechanism of this glycosylase revealing SMUG1 has a unique helical wedge which influences damage recognition during repair. Rodent studies suggest that, while SMUG1 shares substrate specificity with another uracil glycosylase UNG2, loss of SMUG1 can have unique cellular phenotypes. This review highlights the multiple roles SMUG1 may play in preserving genome stability, and how the loss of SMUG1 activity may promote cancer. Finally, we discuss recent studies indicating SMUG1 has moonlighting functions beyond BER, playing a critical role in RNA processing including the RNA component of telomerase.

Multiple studies have shown that hospital settings are poorly cleaned during terminal cleaning. The adequacy of these cleaning methods has been undermined by presence of multi drug resistant bacteria on hospital surfaces. This case is even more serious in developing countries leading to health care- associated infections that pose a great threat to patients, visitors and health care providers in hospital settings.This study used various microbiological techniques to test for antibiotic susceptibility profiles of bacteria present at Thika Level 5 Hospital surfaces, Kenya. A simple random cross sectional study was performed, with a total of 85 samples being collected from five different sites. The sites included male and female wards, health care personnel offices, latrine, and kitchen surfaces. Samples were collected using sterile swabs, dipped in normal saline, and transported to the laboratory within 2Hours for processing.Of the 85 plates cultured, 47 plates showed bacterial growth (55%) on selective media with a significant P value of 0.0357. Seven different species of bacteria were identified biochemically from all sites, Escherichia coli was the most abundant species (28%), and the least was Salmonella typhii (5%). Multiple drug resistance was common in the different bacteria identified. All isolates were resistant to chloramphenical and susceptible to gentamycin. The most resistant microorganism was Staphylococcus aureus (50%), and the least resistant microorganism was Klebsiella pneumoniae (12.5%). The antimicrobial resistant bacterial species identified in this study have been documented to cause serious health care associated infections. These results present a significant public health concern because there is a possibility of patients, staff and visitors contacting nosocomial infections when they come into contact with surfaces at Thika Level 5 Hospital surfaces, Kenya.

Anxiety disorders manifest in women more than in men by almost twofold. This narrative review aims to summarize the sex-related biological factors, which underpin anxiety, focusing on the interactions of sex and tryptophan/serotonin with anxiety.A literature search was conducted using Google Scholar, PubMed/MEDLINE, Scopus, and EMBASE databases from inception until December 31, 2017. This review shows that sex may interact with many serotonin functions thereby modulating anxiety, including 5-HT1A and 5-HT2C receptors, 5-HT transporter and central 5-HT concentrations and metabolism. Sex-steroids modulate the expression of serotonin transporter genes, creating a difference in serotonin availability. Sex and estrous cycle phases lead to varying anxiety responses to tryptophan depletion. Testosterone, progesterone and estrogen are important factors in mediating sex differences in serotonin responses to anxiety-generating behavioral tests. At prenatal levels, there are sex-related differences in the reciprocal relationships between serotonin and the HPA-axis, which modulate anxiety-like behaviors. Activated immune-inflammatory pathways induce indoleamine-2,3-dioxynease (IDO) and the tryptophan catabolite (TRYCAT) pathway thereby increasing tryptophan degradation and increasing the production of TRYCATs including kynurenine and quinolinic acid, which may create an overall anxiogenic effect. The effects of immune activation on IDO are significantly more pronounced in women than men and therefore females may show increased levels of anxiogenic TRYCAT following immune challenge. Aberrations in the IDO-activated TRYCAT pathway are found in pregnant females and parturients and are associated with increased anxiety levels in the postnatal period. The results of this review underscore the necessity of studying the associations between serotonin and anxiety in both sexes taking into account the effects of immune activation on IDO and production of anxiogenic TRYCATs. Future anxiety research should focus on the interactions between serotonin/tryptophan and sex, sex hormones, the menstrual cycle, pregnancy, the HPA axis and the immune system through production of anxiogenic TRYCATs.

A single Cancer immunotherapy has ushered in a transformative era in oncology, bringing forth unprecedented promise and opportunities. However, even with its significant breakthroughs, the domain faces the continual issue of treatment resistance. Such resistance not only restricts the broad effectiveness of these pioneering treatments but also highlights the imperative need for further research. Delving into the complex world of cancer immunotherapy resistance, we identify a range of mechanisms, from primary and secondary resistance to the notable effects of genetic and epigenetic variables, and the pivotal importance of the tumor microenvironment (TME). Additionally, we emphasize the need for innovative strategies to mitigate this resistance, including combination treatments, customized immune checkpoints, and instantaneous monitoring. By advocating for these cutting-edge methods, we foresee a direction that incorporates personalized healthcare, enhanced treatment options, and a steadfast dedication to the welfare of patients. Through a comprehensive and diverse approach, we aim to address the hurdles posed by resistance, elevating cancer immunotherapy as a symbol of hope for patients worldwide.

The field of mitochondrial genomics has advanced rapidly and revolutionized disciplines from molecular anthropology, population genetics, to medical/oncogenetics. However, mtDNA next-generation sequencing (NGS) analysis for matrilineal haplotyping and phylogeographic inference remains hindered by the lack of a consolidated, mitogenome database and efficient bioinformatics pipeline. To address this, we developed a customized human mitogenome database (hMITO DB) embedded in a CLC Genomics workflow for read mapping, variant analysis, haplotyping, and geo-mapping. The database was constructed from 4,286 mitogenomes. The macro-haplogroup (A to Z) distribution and representative phylogenetic tree were found consistent with published literature. The hMITO DB automated workflow was tested using mtDNA-NGS sequences derived from Pap smears and cervical cancer cell lines. The auto-generated read mapping, variants track, and table of haplotypes and geo-origins were completed in 15 min for 47 samples. The mtDNA workflow proved to be a rapid, efficient and accurate means of sequence analysis for translational mitogenomics.

Rett syndrome (RTT), a neurodevelopmental disorder, is mainly caused by mutations in methyl CpG-binding protein 2 (MECP2), which alter the functions of domains to either bind to methylated DNA or interact with a transcriptional co-repressor complex. It has been established that alterations in cyclin-dependent kinase-like 5 (CDKL5) or forkhead box protein G1 (FOXG1) correspond to distinct neurodevelopmental disorders, given that a series of studies have indicated that RTT is also caused by alterations in either one of these genes. We tried to elucidate RTT through evolution and structure assessment of MeCP2, CDKL5, and FOXG1, by focusing on their binding partners and disordered structures. Here, we provide insight into the similarities of the FOXG1 and MECP2 binding partners evolution and function. On the other hand, we suggest that CDKL5 could be a potential candidate for a classical RTT treatment, particularly based on its disordered structure that spans after the catalytic domain to the C-terminus, which shows abundant linear motifs that can bind to molecules with divergent structures of similar affinity. Additionally, we provide insight into the relationship between disordered structure and disease.

Rett syndrome (RTT) is mainly caused by mutations in methyl CpG-binding protein 2, cyclin-dependent kinase-like 5, or forkhead box protein G1. These RTT-causing proteins harbor an intrinsically disordered region (IDR) whose conformation exhibits spatiotemporal heterogeneity, which not only confer versatility to the protein, but also implicates them in diseases. The IDR generally evolves more rapidly than an ordered structure. In this study, we examined the relationship between pathogenic RTT-associated point mutations in RTT-causing proteins and the evolutionary dynamics of sequence features including structural order–disorder, phosphorylation sites, and evolutionary rates. We also analyzed the molecular properties and evolution of proteins that interact with RTT-causing proteins in terms of phylogenetic profiles, tissue specificity, subcellular localization, expression level, and functions. The results indicate that constrained IDRs may function by forming contacts with other regions in the protein sequence causing pathogenic missense mutations likely to arise in the rapidly evolving IDR and affect molecular networks, leading to disease. The results also provide novel insights into the genetic basis for RTT and the evolution of the neocortex in higher vertebrates.

Abstract5′,8-Cyclo-2′-deoxyadenosine (cdA), in the 5′R and 5′Sdiastereomeric forms, are typical non strand-break oxidative DNA lesions, induced by hydroxyl radicals, with emerging importance as a molecular marker. These lesions are exclusively repaired by nucleotide excision repair (NER) mechanism with a low efficiency, thus readily accumulating in the genome. Poly(ADP-ribose) polymerase1 (PARP1) acts as an early responder to DNA damage and plays a key role as a nick sensor in the maintenance of the integrity of the genome by recognizing nicked DNA. So far, it was unknown whether the diastereomeric cdA lesions could induce specific PARP1 binding. Here we provide the first evidence of PARP1 to selectively recognize the diastereomeric lesions 5′S-cdA and 5′R-cdA in vitro as compared to deoxyadenosine in model DNA substrates (23-mers) by using circular dichroism,fluorescence spectroscopy, immunoblotting analysis and gel mobility shift assay. Several features of the recognition of the damaged and undamaged oligonucleotides by PARP1were characterized. Remarkably, PARP1 efficiently binds to both cdA lesions in the double stranded (ds)-oligonucleotides. In particular, PARP1 proved to bind 5′S-cdAwith a higher affinity constant for the 5'S lesion in a model of ds DNA than 5′R-cdA, showing different recognition patterns, also compared with undamaged dA. This new finding highlights the ability of PARP1 to recognize and differentiate the distorted DNA backbone in a biomimetic system caused by different diastereomeric forms of a cdA lesion.

L-17 is a thiadiazine derivative with putative anti-inflammatory, neuroprotective, and antidepressant-like properties. In this study, we applied combined in silico and in vivo electrophysiology techniques to reveal the potential mechanism of action of L-17. PASS 10.4 Professional Extended software suggested that L-17 might have pro-cognitive, antidepressant, and antipsychotic effects. Docking energy assessment with AutoDockVina predicted that the binding affinities of L-17 to the serotonin transporter (SERT) and serotonin receptors 3 and 1A (5-HT3 and 5-HT1A) are compatible to the selective serotonin reuptake inhibitor (SSRI) fluoxetine and selective antagonists of 5-HT3 and 5-HT1A receptors, granisetron and WAY100135, respectively. However, while the binding mechanisms of L-17 to the SERT and 5-HT1A receptor were similar to fluoxetine and WAY100135, its interacting with 5-HT3 receptor might be substantially different from this of granisetron. Acute administration of L-17 led to dose-dependent inhibition of firing activity of 5-HT neurons of the dorsal raphe nucleus. This inhibition was partially reversed by subsequent administration of WAY100135. Based on both in silico and in vivo electrophysiology assessments, we suggest that L-17 is a potent 5-HT reuptake inhibitor and a putative partial agonist of 5-HT1A receptors. As such, L-17 in particular and thiadiazine derivatives, in general, might be a representative of a new class of antidepressant drugs. Since L-17 also possesses neuro- and cardioprotective properties, it can be useful in affective illness developing due to the general medical condition, such as post-stroke and post-myocardial infarction (MI) depression.

In this paper, we present the interaction results of 1,2-dibromo-3-isothiocyanatopropane with some pyrazoles and cytisine and salsoline alkaloids. It has been shown that the reaction results in the one-step and rather mild method for the preparation of the corresponding 1,3-thiazoline bromomethyl derivatives. The yield of this reaction is affected by the presence of a base and the order in which the reagents are added. Molecular docking of the synthesized 1,3-thiazoline derivatives for putative antibacterial activity has been carried out using the penicillin-binding target protein (PBP4) of the bacteria E. coli “Homo sapiens” and S. aureus “Homo sapiens” as an example. Molecular docking shows that the compounds have insignificant binding energies at the level of selected reference drugs (Cephalotin and Chloramphenicol). The presence of natural alkaloids in the structure of thiazoline derivatives somewhat increases the affinity of these substrates for target proteins selected.

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

Although most cases of COVID-19 are paucisymptomatic, severe disease is characterized by immune dysregulation, with a decreased type I interferon response, increased inflammatory indicators, surging IL-6, IL-10 and TNFα suggestive of cytokine storm, progressive lymphopenia, and abnormal blood clotting. Factors determining susceptibility to severe disease are poorly understood, although mortality correlates with increasing age and co-morbidities including diabetes and cardiovascular disease (CVD). Pyridoxal 5'-phosphate (PLP) tends to be insufficient in populations particularly vulnerable to COVID-19, including the elderly, the institutionalized, and people with diabetes and CVD, and PLP becomes further depleted during infection and inflammation. In turn, low PLP results in immune imbalance, as PLP is an essential cofactor in pathways regulating cytokine production, in particular type I interferons and IL-6, and in lymphocyte trafficking and endothelial integrity. Furthermore, normalizing PLP levels attenuates abnormalities in platelet aggregation and clot formation. Finally, PLP insufficiency induces excess secretion of renin and angiotensin, and hypertension. In inflammatory disease, pharmacological doses of PLP decrease circulating TNFα, IL-6 and D-dimer, and animal studies demonstrate that supplemental PLP shortens the duration and severity of viral pneumonia. Severe COVID-19 manifests as an imbalance in the immune response and the clotting system. Pharmacological PLP supplementation may therefore mitigate COVID-19 symptoms by alleviating both the immune suppression underlying viral spread and the pathological hypersecretion of inflammatory cytokines, as well as directly bolstering endothelial integrity and preventing hypercoagulability.

Cowpea (Vigna unguiculata (L.) Walp.) is an important legume cultivated mainly in regions with limited water availability across the African and American continents. Its productivity is significantly affected by environmental stresses. Thaumatin-like proteins (TLPs), which belong to the PR-5 (Pathogenesis-Related 5) protein family, are known to be responsive to both biotic and abiotic stresses. However, their role remains controversial, with some TLPs associated with plant defense (particularly against fungal infections) and others associated with drought response. In this study, we evaluated the structural diversity and gene expression of TLPs in cowpea (VuTLPs) under different stress conditions, including biotic [mechanical injury followed by inoculation with Cowpea Aphid-borne Mosaic Virus (CABMV) or Cowpea Severe Mosaic Virus (CPSMV)] and abiotic (root dehydration). Genomic anchoring of VuTLPs revealed 34 loci encoding these proteins. Neighbor-joining analysis clustered the VuTLPs into three distinct groups. We identified 15 segmental duplication and six tandem duplication gene pairs, with the majority of VuTLP genes found to be under purifying selection. Promoter analysis associated VuTLPs with bHLH, Dof-type, and MYB-related transcription factors, supporting their diverse roles. Diversity in VuTLP function was also observed in their expression profiles under various stress conditions. Gene expression data showed that most VuTLPs are recruited within the first minutes after stress imposition, except in the root dehydration assay, where most transcripts were induced 150 minutes post-stress, a finding also validated by qPCR. Moreover, the data suggest that VuTLPs exhibit functional specialization depending on the stress condition, highlighting their diverse roles and biotechnological potential.

Undernutrition is a significant public health issue in Colombia and globally, influenced by multiple factors. The relationship between food insecurity and acute undernutrition in children has been insufficiently explored. To address this, a descriptive, observational, cross-sectional study was conducted involving 70 children under the age of 5, who presented with moderate to severe acute malnutrition. The study assessed family and child food security using the Latin American and Caribbean Food Security Scale (ELCSA). Analysis of the data revealed that when households face challenges in meeting their basic needs, children are generally the least affected. Caregivers tend to prioritize children's diets, opting to reduce food intake among adults over 18 years of age instead. The causes of malnutrition were explored through the perceptions of guardians, who reported that in 30.2% of cases, malnutrition is linked to inadequate feeding and parenting practices. Specific issues noted by parents included children being too lazy to chew, preferring ultra-processed foods, or refusing to eat altogether. The study found that not all children with acute malnutrition experience food insecurity; in fact, the proportion of children suffering from hunger was very low. The findings suggest that malnutrition in children under 5 years of age is not solely determined by food insecurity but also by other factors such as parenting practices and poor feeding habits. Further research is needed to evaluate food access and quality, particularly in terms of dietary diversity, to better understand the needs of each population. Such studies will be essential in guiding public health interventions aimed at preventing, managing, and addressing malnutrition in children.

Even with 100% certainty of a complete cure for breast cancer (BC), there is still a long way to go toward more efficient treatment. This requires sensitive and timely detection and accurate pre/post-clinical characterizations. Despite the availability of advanced diagnostic tools, many cancer patients lack access to efficient diagnostics that are both highly reliable and affordable. The fluorescence-based optical technique aims to make another significant leap forward in improving patient safety. It offers a convenient operation that reduces healthcare costs compared to visual examination tools (VETs). The primary and metastatic stages of BC consider different cancerous cell lines (MDAs), meaning the highest number of cells in this research (up to 300,000) represents the metastatic stages of BC, and 50,000 represents the primary level of BC developments have been studied based on fluorescence-enhanced photodynamic characterizations. The ability to characterize the fluorescence caused by MDA with 50,000 cells compared to the dominant radiation of MDA with 300,000 cells is emphatic proof of the high potential of fluorescence technique in timely BC detections, specifically before it spreads to the axillary lymph nodes. The specific cell numbers of 50,000 and 300,000 were chosen arbitrarily based on the cultivation of common biological limitations. Comparing the outcomes between 50,000 and 300,000 cells allows for evaluating the fluorescence technique’s diagnostic capability across various stages of breast cancer. This assessment provides valuable insights into the effectiveness of the fluorescence-based characterizing approach in detecting cancerous cells at different stages of the disease. Here, we have assessed fluorescence’s spectral shift and intensity difference as a diagnostic approach to distinguish between cancerous and normal breast cells. This study also presents a two-way structure of the 5-aminolevulinic acid (5-ALA) prodrug and Fluorescein Sodium (FS) effect in BC cell characterization from the perspective of photodynamical procedures and the detection side. 5-ALA induces an accumulation of protoporphyrin IX (PpIX) photosensitizer through a biosynthetic pathway, leading to red radiation of fluorescence measurements depending on different factors, such as temperature, incubation time, added glucose of the culturing medium, as well as photosynthesis processes. The presence and progression of breast cancer can be indicated by elevated levels of Reactive Oxygen Species (ROS), which are associated with the production of PpIX in cells following the administration of 5-ALA. Also, nicotinamide adenine dinucleotide (NADH) and flavin adenine dinucleotide (FAD) fluorophores are recognized as the main factors for fluorescence emissions at around 420-580 nm emission intervals. Considering the MDA’s high metastatic potential, the impact of 5-ALA on MDA’s cellular morphology and viability has been investigated. The molecular fluorophores are the primary probes to MDA’s cellular photodynamic considerations, allowing this widespread pre/post-clinical approach. The fluorescence signal reduction due to decreased cell viability and increased MDA’s cellular death rate after 24 hours of the 5-ALA-induced staining corresponds to the changes in lipid metabolism enzymes of MDAs cultured at different doses, which could be known as a cell death inducer function. Furthermore, statistical concerns have been studied using PCA multivariate component analysis to differentiate MDA cell lines administrated by 5-ALA.

Methylation is a biochemical process involving the addition of a methyl group (-CH3) to various chemical compounds. It plays a crucial role in maintaining the homeostasis of the endothelium, which lines the interior surface of blood vessels and has been linked, among other conditions, to coronary artery disease (CAD). Despite significant progress in CAD diagnosis and treatment, intensive research continues into genotypic and phenotypic CAD biomarkers. This review explores the significance of the methylation pathway and folate metabolism in CAD pathogenesis, with a focus on endothelial dysfunction resulting from deficiency in the active form of folate (5-MTHF). We discuss emerging areas of research into CAD biomarkers and factors influencing the methylation process. By highlighting genetically determined methylation disorders, particularly the MTHFR polymorphism, we propose the potential use of the active form of folic acid (5-MTHF) as a novel CAD biomarker and personalized pharmaceutical for selected patient groups. Our aim is to improve the identification of individuals at high risk of CAD and enhance their prognosis.

Although migraine belongs to the main causes of disability worldwide the mechanisms of its pathogenesis are poorly known, which is among the reasons that this disease is underdiagnosed and undertreated. As migraine diagnosis is based on the subjective assessment of symptoms, there is a need to establish objective markers of its occurrence and severity. Tryptophan (TRP) metabolism has been associated with the pathogenesis of neurological and psychiatric disorders. In the present work, we investigated an association between migraine and the urine concentration of TRP and its metabolites 5-hydroxyindoleacetic acid (5-HIAA), kynurenine (KYN), kynurenic acid (KYNA) and quinolinic acid (QA) in 21 low-frequency episodic migraine patients and 32 controls. Migraine patients displayed lower urinary levels of 5-HIAA and KYNA, but KYN and QA were enhanced as compared with the controls. Consequently, the patients were characterized by different values of the 5-HIAA/TRP, KYN/TRP, KYNA/KYN, and KYNA/QA ratios. Furthermore, urinary concentration of 5-HIAA was negatively correlated with Migraine Disability Assessment score, monthly migraine, and monthly headache days. A negative correlation between Patient Health Questionnaire 9 scores assessing depression. In conclusion, the urinary 5-HIAA level may be an easy-to-determine marker of migraine occurrence and severity and may contribute to the identification of migraine patients with depression.

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.

In May 2022, WHO reported an outbreak of Mpox in several European countries which were previously Mpox free. Mpox (formerly known as monkeypox) is a zoonotic viral disease endemic in Central and West Africa. The sudden emergence of Mpox outside Africa and its subsequent rapid spread lead the WHO to declare the outbreak as Public Health Emergency of International Concern. As of May 15, 2023, a total of 87,704 confirmed cases and 140 deaths had been reported from 111 countries and territories worldwide. Looking back on this outbreak one year later, several important questions have arisen. Here, we address these questions using the classic five Ws: What, When, Where, Who and Why? We discuss these questions and outline what needs to be done to prevent, or at least minimize, outbreaks from emerging and re-emerging viral infection.

In this work, polyacrylic acid-functionalized MCM-41 was synthesized, which was further interacted with calcium ions, to realize enhanced pH-responsive nanocarrier for sustained drug release. First, mesoporous silica nanoparticles (MSNs) were prepared by the sol-gel method. Afterward, (3-trimethoxysilyl)propyl methacrylate (TMSPM) modified surface was prepared by using the post-grafting method, then polymerization of acrylic acid was proceeded. After adding calcium chloride solution, polyacrylic acid-functionalized MSNs with calcium-carboxyl ionic bonds in the polymeric layer, which can prevent the cargo from leaking out of the mesopore, were prepared. The structure and morphology of the modified nanoparticles (PAA-MSNs) were characterized by X-ray diffraction (XRD), Fourier-transform infrared (FT-IR) spectroscopy, transmission electron microscopy (TEM), and N2 adsorption-desorption analysis, etc. The controlled release of guest molecules was studied by using 5-fluorouracil (5-FU). The drug molecules-incorporated nanoparticles showed different releasing rates under different pH conditions. It is considered that our current materials have the potential as pH-responsive targeted nanocarriers in the field of medical treatment.

Trace amine-associated receptors (TAARs) are a family of G protein-coupled receptors present in mammals in the brain and in several peripheral organs. Apart from its olfactory role, TAAR5 is expressed in the major limbic brain areas and regulates brain serotonin functions and emotional behaviors. However, most of its functions remain undiscovered. Given the role of serotonin and limbic regions in some aspects of cognition, we used a temporal decision-making task to unveil a possible role of TAAR5 in cognitive processes. We found that TAAR5 knock-out (KO) mice showed a generally better performance due to a reduced number of errors and displayed a greater rate of improvement at the task than WT littermates. However, task-related parameters, such as time accuracy and uncertainty have not changed significantly. Overall, we show that TAAR5 modulates specific domains of cognition, highlighting a new role in brain physiology.

To characterize the mechanisms by which the highly-conserved exocyst trafficking complex regulates eye physiology in zebrafish and mice, we focused on exoc5 (aka sec10), a central exocyst component. We analyzed both exoc5 zebrafish mutants and retinal pigmented epithelium (RPE)-specific Exoc5 knockout mice. Exoc5 is present in both the non-pigmented epithelium of the ciliary body and in the RPE. In this study we set out to establish an animal model to study the mechanisms underlying the ocular phenotype and to establish if loss of visual function is induced by postnatal RPE Exoc5-deficiency. Exoc5-/- zebrafish showed smaller eyes, with decreased number of melanocytes in the RPE and shorter photoreceptor outer segments. At 3.5 days post fertilization, loss of rod and cone opsins were observed in zebrafish Tg:exoc5 mutants. Mice with postnatal RPE-specific loss of Exoc5 showed retinal thinning associated with compromised visual function, and loss of visual photoreceptor pigments. This retinal phenotype in Exoc5-/- mice was present at 20-weeks, and the phenotype was more severe at 27-weeks, indicating progressive disease phenotype. We previously showed that the exocyst is necessary for photoreceptor ciliogenesis and retinal development. Here, we report that exoc5 mutant zebrafish and mice with RPE-specific genetic ablation of Exoc5 develop abnormal RPE pigmentation, resulting in retinal cell dystrophy and loss of visual pigments associated with compromised vision. As RPE cells are “downstream” of photoreceptor cells in the visual process, these data suggest exocyst-mediated retrograde communication and dependence between the RPE and photoreceptors.

Erectile dysfunction (ED) due to diabetes mellitus remains difficult to treat despite advances in pharmacotherapeutic approaches in the field. Therefore, this study investigated the erectogenic effect of the methanolic extract of Maytenus procumbens roots on type 2 diabetes in rats. The fructose-streptozotocin model was used to induce type 2 diabetes-linked ED in male rats. The sexually active male Sprague Dawley rats were randomly divided into two major groups; normal group and high fructose fed group for 120 days. After 120 days, the high fructose fed group rats were given a single intraperitoneal injection of a freshly prepared streptozotocin solution (30 mg/kg). The diabetic ED rats were orally administered with the extract at 250 mg/kg, daily for 28 days. The serum, brain and penile tissues were removed for biochemical analysis and protein expression. Increased testosterone level, mounting frequency, reduced blood glucose level and serum fructosamine content was observed after 28 days of treatment in diabetic rats. Methanolic extract also exhibited an inhibitory effect on arginase, AChE, and ACE activities. The crude extract further downregulated proteins PDE-5, RhoA and increased expression of eNOS in the diabetic ED treated rats. The results obtained indicate that the methanolic extract of Maytenus procumbens roots ameliorates erectile dysfunction in type 2 diabetes-induced erectile dysfunction in rats.

Liver receptor homolog-1 (LRH-1) has emerged as a regulator of hepatic glucose, bile acid, and mitochondrial metabolism. However, the functional mechanism underlying the effect of LRH-1 on lipid mobilization has not been addressed. This study investigated the regulatory function of LRH-1 in lipid metabolism during fasting. The wild-type (WT) and LRH-1 liver-specific knockout (LKO) mice were either fed or fasted for 24 h, and the liver and serum were isolated. During fasting, the LRH-1 LKO mice showed greater accumulation of triglycerides in the liver compared to that in WT mice. Interestingly, LRH-1 LKO liver decreased the perilipin 5 (PLIN5) expression and genes involved in β-oxidation. Additionally, the LRH-1 agonist dialauroylphosphatidylcholine also enhanced PLIN5 expression in human cultured HepG2 cells. To identify new target genes of LRH-1, these findings directed to analyze the PLIN5 promoter sequence, which revealed −1620/−1614 to be a putative binding site for LRH-1. This was confirmed by promoter activity and chromatin immuno-precipitation assays. Moreover, fasted WT primary hepatocytes showed increased co-localization of PLIN5 in lipid droplets (LDs) compared to that in fasted LRH-1 LKO primary hepatocytes. Overall, these findings suggest that PLIN5 might be a novel target of LRH-1 to mobilize LDs and manage the cellular needs.

A single dose of psilocybin, a psychedelic and serotonin 2A receptor (5-HT2AR) agonist, may be associated with antidepressant effects. The mechanism behind its antidepressive action is unknown but could be linked to increased synaptogenesis and down-regulation of cerebral 5-HT2AR. Here, we investigate if a single psychedelic dose of psilocybin changes synaptic vesicle protein 2A (SV2A) and 5-HT2AR density in the pig brain. Twenty-four awake pigs received either 0.08 mg/kg psilocybin or saline intravenously. Twelve pigs (n=6/intervention) were euthanized one day post-injection, while the remaining twelve pigs were euthanized seven days post-injection (n=6/intervention). We performed autoradiography on hippocampus and prefrontal cortex (PFC) sections with [3H]UCB-J (SV2A), [3H]MDL100907 (5-HT2AR antagonist) and [3H]Cimbi-36 (5-HT2AR agonist). One day post psilocybin injection, we observed 4.4% higher hippocampal SV2A density and lowered hippocampal and PFC 5-HT2AR density (-15.21% to -50.19%). These differences were statistically significant in the hippocampus for all radioligands and in PFC for [3H]Cimbi-36 only. Seven days post-intervention, there was still significantly higher SV2A density in hippocampus (+9.24%) and PFC (+6.1%) whereas there were no longer any differences in 5-HT2AR density. Our findings suggest that psilocybin’s antidepressive actions are linked to increased persistent synaptogenesis and possibly also to an acute decrease in 5-HT2AR density.

CrHZSM-5 was placed in an electric field with appropriate strength in a quartz packed bed reactor with CO2 as oxidant to analyze its catalytic activity. Olefin yield increases with decrease in band gap since lattice oxygen mobility increases by reducing band gap. Fermi level change at the catalyst surface affects the catalytic activity. One way to change Fermi level is use electric field. In high voltage electric field, energy band was curved, bending of the energy band promoted the activity and Fermi level position is increasing. The CCD experiments were carried out with Design-Expert 7.3 software to determine the interaction between four operating variables, namely: temperature, electrical current, gap distance and metal loading. The levels of the independent variables were: temperature (550-700 °C), electrical current (0-12 mA), gap distance (6-14 mm), metal loading (0.5-7.5 %wt.). The conversion of LPG (Liquefied petroleum gas) was greatly increased by weak and effective application of an electric field to the catalyst bed. The obtained results indicated that the maximum yield value (46.94%) can be achieved under 673.66 °C, input electrical current of 11.01 mA, gap distance of 6.55 mm and metal loading of 3.98 wt.%.

Lung cancer is almost the most common cause of cancer death in the world. Clinically, the conventional therapy to eradicate the cancer cells is chemotherapy but a better drug remains required. In this study, the effects of three bufadienolides, kalantuboside B, kalantuboside A and bryotoxin C, isolated from Kalanchoe tubiflora (Harvey) were evaluated and characterized in CL1-5 highly metastatic human lung cancer cells. Contrary to the apoptosis-promoting activity in other cancer cells, these three bufadienolides did not induce apoptosis in CL1-5 cancer cells. Instead, they activated an autophagy pathway, as indicated by the increase of autophagosomes formation. The induction of autophagy by these three bufadienolides was demonstrated to link to down-regulation of p-mTOR as well as up-regulation of LC3-II, ATG5, ATG7, Beclin-1. Moreover, among these three compounds, kalantuboside B in which a monosaccharide is attached at the bufadienolide aglycon, exhibited a better autophagy induction. Our findings revealed an alternative mechanism of drug action by bufadienolides in lung cancer cells and provided evidence for the possibility of treating highly metastatic human lung cancer through an autophagy pathway.

In this contribution, the propylamine-functionalized cellulose (Cell-Pr-NH2) was employed as the catalyst in the three-component reaction between hydroxylamine hydrochloride, various type of aryl/heteroaryl aldehydes, ethyl acetoacetate/ethyl 4-chloroacetoacetate/ or ethyl 3-oxohexanoate. The results of these experiments were the formation of 3,4-disubstituted isoxazol-5(4H)-one heterocycles. The desired five-membered heterocyclic compounds were obtained in good to high yields at room temperature. The investigation of different solvents led us to the conclusion that water is the best solvent to perform the current one-pot, three-component reactions. Attempts to find the optimum catalyst loading clearly showed that 14 mg of Cell-Pr-NH2 seems to be sufficient to carry out the reactions. This method has highlighted some principles of green chemistry including less waste generation, atom economy, use of water as an environmentally friendly solvent, and energy saving. Purification without chromatographic methods, mild reaction conditions, simple work-up, low-cost reaction medium, saving time, and obtainable precursors are other notable features of this one-pot fashion.

RNA-seq faces persistent challenges due to the ongoing expanding array of data processing workflows, none of which have yet achieved standardization to date. It is imperative to determine which method most effectively preserves biological facts. Shannon entropy serves as a tool for depicting the biological status of a system. Thus, we assessed the measurement of Shannon entropy by several RNA-seq workflow approaches, employing RPKM and median normalization on paired samples of 475 TCGA RNA-seq datasets spanning eight different cancer types with 5-year overall survival rates ranging from 30% to 98%. Our analysis revealed that the RPKM normalization coupled with a threshold of log2 fold change ≥1 for indentifying differentially expressed genes, yielded the best results with a correlation coefficient of 0.91. We propose that Shannon entropy can serve as an objective metric for refining the optimization of RNA-seq workflows.

The occurrence of ovarian dysfunction is often due to the imbalance between the formation of reactive oxygen species (ROS) and the (in)effectiveness of the antioxidative defense mechanisms. Primary sources of ROS are the respiratory electron transfer and the activity of NADPH oxidases (NOX), while Superoxide dismutases (SOD) are the main key reg-ulators that control the levels of ROS and reactive nitrogen species intra- and extracel-lularly. Because of their central role, SODs are the subject of research on human ovarian dysfunction, but the sample acquisition is low. The high degree of cellular and molecular similarity between Drosophila melanogaster ovaries and human ovaries provides this model organism with the best conditions for analyzing the role of ROS during ovarian function. In this study, we clarify the localization of the ROS producing enzyme dNox within ovaries of Drosophila melanogaster and by a tissue specific knockdown, we show that dNox derived ROS are involved in the chorion hardening process. Furthermore, we analyze the dSod3 localization and show that reduced activity of dSod3 impacts egg laying behavior, but not the chorion hardening process.

The blood–brain barrier (BBB) plays pivotal roles in synaptic and neuronal functioning by sealing the space between adjacent microvascular endothelial cells. BBB breakdown is present in patients with mild cognitive impairment (MCI) or Alzheimer disease (AD). Claudin-5 (CLDN-5) is a tetra-spanning protein essential for sealing the intercellular space between adjacent endothelial cells in the BBB. In this study, we developed a blood-based assay for CLDN-5 and investigated its diagnostic utility by using 100 cognitively normal (control) subjects, 100 patients with MCI, and 100 patients with AD. Plasma CLDN-5 levels were increased in patients with AD (3.08 ng/mL) compared with controls (2.77 ng/mL). Plasma levels of phosphorylated tau (pTau181), a biomarker of pathological tau, were elevated in patients with MCI or AD (2.86 and 4.20 pg/mL, respectively) compared with control subjects (1.81 pg/mL). In patients with MCI or AD, plasma levels of CLDN-5—but not pTau181—decreased with age, suggesting some age-dependent BBB changes in MCI and AD. These findings suggest that plasma CLDN-5 may a potential biochemical marker for the diagnosis of MCI and AD.

In the realm of the five-category classification endeavor, there has been limited exploration into applied techniques for classifying Arabic text. These methods have primarily leaned on singletask learning, incorporating manually crafted features that lack robust sentence representations. Recently, the Transformer paradigm has emerged as a highly promising alternative. However, when these models are trained using single-task learning, they often face challenges in achieving outstanding performance and generating robust latent feature representations, especially when dealing with small datasets. This issue is particularly pronounced in the context of the Arabic dialect, which has a scarcity of available resources. Given these constraints, this study introduces an innovative approach to dissecting sentiment in Arabic text. This approach combines Inductive Transfer (INT) with the Transformer paradigm to augment the adaptability of the model and refine the representation of sentences. By employing self-attention SE-A and feed-forward sub-layers as a shared Transformer encoder for both the five-category and three-category Arabic text classification tasks, this proposed model adeptly discerns sentiment in Arabic dialect sentences. The empirical findings underscore the commendable performance of the proposed model, as demonstrated in assessments of the Hotel Arabic-Reviews Dataset, the Book Reviews Arabic Dataset, and the LARB dataset.

Transketolase (TKT) is an essential thiamine diphosphate (ThDP)-dependent enzyme of the non-oxidative branch of pentose phosphate pathway, with the glucose-6P flux through the pathway regulated in various medically important conditions. Here, we characterize the brain TKT regulation by acylation in rats with perturbed thiamine-dependent metabolism, known to occur in neurodegenerative diseases. The perturbations are modelled by administration of oxythiamine inhibiting ThDP-dependent enzymes in vivo, or by reduced thiamine availability in the presence of metformin and amprolium, inhibiting intracellular thiamine transporters. Compared to control rats, chronic administration of oxythiamine does not significantly change the modification level of the two detected TKT acetylation sites (K6 and K102), but doubles malonylation of TKT K499, concomitantly decreasing 1.7-fold the level of demalonylase sirtuin 5. The inhibitors of thiamine transporters do not change average levels of TKT acylation or sirtuin 5. TKT structures indicate that the acylated residues are distant from the active sites. The acylations-perturbed electrostatic interactions may be involved in conformational shifts and/or formation of TKT complexes with other proteins or nucleic acids. Acetylation of K102 may affect the active site entrance/exit and subunit interactions. Correlation analysis reveals that the action of oxythiamine is characterized by significant negative correlations of K499 malonylation or K6 acetylation with TKT activity, not observed upon the action of the inhibitors of thiamine transport. However, the transport inhibitors induce significant negative correlations between the TKT activity and K102 acetylation or TKT expression, absent in the oxythiamine group. Thus, perturbations in the ThDP-dependent catalysis or thiamine transport manifest in the insult-specific patterns of the brain TKT malonylation and acetylations.

Cannabidiol, is the first cannabis-derived drug approved for the treatment of Lennox-Gastaut syndrome (LGS), Dravet syndrome (DS), and Tuberous Sclerosis Complex (TSC). The current study performed a descriptive analysis followed by a disproportionality analysis of potential adverse events caused by CBD extracted from the database VigiBase®. Further, biological plausibility of the association between CBD and the serotonin 5-HT1A receptor, as possible cause of adverse events was analyzed and discussed. Data were extracted from VigiBase® database using VigiLyze® signal detection and signal management tool. Adverse events in VigiBase® reports were coded using MedDRA, version 19 of Preferred Terms (PTs). Data were uploaded into SPSS software and analyzed via disproportionality analysis. Statistically significant disproportionality signals for CBD were found for “weight decreased” 5.19 (95% CI: 4.54 - 5.70), “hypophagia” 3.68 (95% CI: 3.22 - 5.27), and “insomnia” 1.6 (95% CI: 1.40 - 1.83). Positive IC025 values were found for “weight decreased” (2.2), “hypophagia” (1.3), and “insomnia” (0.5), indicating a surplus of reported cases. CBD’s interactions with 5-HT1A serotonin receptors may offer a potential biological explanation for the occurrence of insomnia in patients. It is noteworthy that the risk profiles mentioned in the prescribing information for CBD as antiepileptic agent by regulatory agencies showed disparities specifically related to the adverse event “insomnia”.

Background: The presence of single nucleotide polymorphisms in the gene encoding key en-zyme in the folate pathway methyltetrahydrofolate reductase (MTHFR), causes methylation disorders associated with CAD development. Methods: Study group: 42 patients with CAD con-firmed by coronary angiography. Controls: 16 patients without CAD symptoms or significant coronary artery stenosis, based on invasive coronary angiography or multislice computed to-mography with coronary artery calcification scoring. Real-time PCR genotyping was assessed using TaqMan™ probes. Folic acid and 5-MTHF concentrations in blood serum were determined by LC-MS. Results: c.[1286A>C];[1286A>C] MTHFR polymorphism occurred significantly more often in (CAD+) patients compared to (CAD-) cohort and to the European population. The con-centration of 5-MTHF and folic acid in the subgroups of patients with methylation disorders di-vided by genotypes and (CAD+) was lower compared to (CAD-). Conclusions: The homozygous c.1286 A>C MTHFR variant can be considered as CAD genetic marker. In the subjects with the c.1286 A>C heterozygous and homozygous genotypes, lower concentrations of methyltetrahy-drofolate (5-MTHF) were observed. 5-MTHF can be considered as a biomarker of CAD. Identifi-cation of people at high risk of CAD using genetic tests can contribute to personalized therapy using active (methylated) form of folic acid (5-MTHF) in CAD patients with MTHFR polymor-phisms.

In the face of the current energy and environment problems, the full use of biomass resources instead of fossil energy to produce a series of high-value chemicals has great application prospects. 5-hydroxymethylfurfural (HMF), which can be synthesized from lignocellulose as raw material, is an important biological platform molecule. Its preparation and catalytic oxidation of subsequent products have important research significance and practical value. In the actual production process, porous organic polymer (POPs) catalysts are highly suitable for biomass catalytic conversion due to its high efficiency, low cost, good designability, and environmentally friendly features. Here, we briefly described the application of various types of POPs (including COFs、PAFs、HCPs、CMPs) in the preparation and catalytic conversion of HMF from lignocellulosic biomass, and analyzed the influence of the structural properties of catalysts for the catalytic performance. Finally, we summarized some challenges that POPs catalysts will face in biomass catalytic conversion, and prospected the important research directions in future. This review would provide valuable references for the efficient conversion of biomass resources into high-value chemicals in practical applications.

Synthesis of ZSM-5 zeolite from OSDA-free systems has been a very interesting alternative method because it can avoid the usage of organic templates and consequent calcination step. However, in opened reports, organic substance such as alcohol is more or less involved. In the present work, a calcined commercial ZSM-5 zeolite was used as a seed, sodium aluminate as an aluminum source, silica sol as a silicon source, which ensures that there is no any organics (template) in the synthesis system, and polycrystalline ZSM-5 aggregates consisting of rod-like nanocrystals are successfully prepared in a completely OSDA-free system. The effects of seed (chemical component, dosage) and crystallization conditions on the synthesis of ZSM-5 were systematically investigated. The results show that highly crystallinity ZSM-5 aggregate consisting of primary nano-sized crystals with a size of less than 100 nm can be yielded from a gel precursor with 5.6 wt.% seed after hydrothermal treatment for 48 h. The results also shows that the chemical composition of the seeds had little effect on the topological structure and pore structure of the synthesized samples, but the seed with a low Si/Al ratio is more conducive to the rapid crystallization of zeolite and to the improvement of the acid, especially the strong acid centers of the catalyst.

Viruses can induce the fusion of infected and neighboring cells, leading to the formation of syncytia. Cell-cell fusion is mediated by viral fusion proteins on the plasma membrane of infected cells that interact with cellular receptors on neighboring cells. Viruses use this mechanism to spread rapidly to adjacent cells or escape host immunity. For some viruses, syncytium formation is a hallmark of infection and a known pathogenicity factor. For others, the role of syncytium formation in viral dissemination and pathogenicity remains poorly understood. Human cytomegalovirus (HCMV) is an important cause of morbidity and mortality in transplant patients and the leading cause of congenital infections. Clinical HCMV isolates have broad cell tropism but differ in their ability to induce cell-cell fusions, and little is known about the molecular determinants. We developed a system to analyze HCMV glycoprotein B (gB) variants in a defined genetic background. HCMV strains TB40/E and TR were used as vectors to compare the fusogenicity of six gB variants from congenitally infected fetuses with those from three laboratory strains. Five of them conferred the ability to induce fusion of MRC-5 human embryonic lung fibroblasts to one or both backbone strains, as determined by a split GFP-luciferase reporter system. The same gB variants were not sufficient to induce syncytia in infected ARPE-19 epithelial cells, suggesting that additional factors are involved. The system described here allows a systematic comparison of the fusogenicity of viral envelope glycoproteins and may help to clarify whether fusion-promoting variants are associated with increased pathogenicity.

CRISPR-Cas allows us to introduce desired genome editing, including mutations, epitopes, and deletions with unprecedented efficiency. The development of CRISPR-Cas has progressed to such an extent that it is now applicable in various fields with the help of model organisms. C. elegans is one of the pioneering animals in which numerous CRISPR-Cas strategies have been rapidly es-tablished over the past decade. Ironically, the emergence of numerous methods makes the right choice of method difficult. Choosing an appropriate selection or screening approach is the first step in planning a genome modification. This report summarizes the key features and applications of CRISPR-Cas methods using C. elegans and illustrates key strategies. Our overview of significant advances in CRISPR-Cas will help readers to understand current advances in genome editing and navigate various methods of CRISPR-Cas genome editing.

This study focused on the impact of the treatment with the hypomethylating agent 5-Azacitidine on the redox status and inflammation in 24 MDS patients. Clinical and genetic features of MDS patients were recorded and peripheral blood samples were used to determine the activity of the endogenous antioxidant defense system (superoxide dismutase, SOD, catalase, CAT, glutathion peroxidase, GPx, and reductase, GRd, activities), markers of oxidative damage (lipid peroxidation, LPO, and advanced oxidation protein products, AOPP). Moreover, pro-inflammatory cytokines and plasma nitrite plus nitrate levels as markers of inflammation, and CoQ10 plasma levels, were also measured. Globally, MDS patients showed less redox status in terms of a reduction in the GSSG/GSH ratio and in the LPO levels, and increased CAT activity compared with healthy subjects, with not changes in SOD, GPx and GRd activities, and AOPP levels. When analyzed the evolution from early- to advanced stages of the disease, the GPx activity, GSSG/GSH ratio, LPO and AOPP increased, with a reduction in CAT. GPx changes were related with the presence of risk factors such as high-risk IPSS-R or mutational score. Besides, there was an increase in IL-2, IL-6, IL-8 and TNF-α plasma levels, with further increase of IL-2 and IL-10 from early to advanced stage of the disease. However, we did not observe any association between inflammation and oxidative stress. Finally, 5-azacitidine treatment generates oxidative stress in MDS patients, without affecting inflammation levels, suggesting that oxidative status and inflammation are two independent processes.

The COVID-19 pandemic and associated restrictive measures implemented may considerably affect people’s lives. This study aimed to assess the well-being of Vietnamese people after COVID-19 lockdown measures were lifted and life gradually returned to normal. An online survey was organized from 21st to 25th April 2020 among Vietnamese residents aged 18 and over. Besides collecting socio-demographic and COVID-19-related data, the WHO-5 Well-Being Index (scored 0–25) was used to score participants’ well-being. A multivariate logistic regression model was used to determine the predictors of well-being. A total of 1922 responses were analyzed (mean age: 31 years; 30.5% male). Mean well-being score was 17.35±4.97. Determinants of high well-being score (≥13) included older age, eating healthy food, practising physical exercise, working from home, and adhering to the COVID-19 preventive measures. Female participants, persons worried about their relatives’ health, and smokers were more likely to have a low well-being score. In conclusion, after the lockdown measures were lifted, the Vietnamese people continued to follow COVID-19 preventive measures and most of them scored high on the well-being scale. Waiting to achieve large scale COVID-19 vaccine coverage, promoting preventive COVID-19 measures remains important, together with strategies to guarantee the well-being of the Vietnamese people.

Skeletal myopathy encompasses both atrophy and dysfunction and is a prominent event in cancer and chemotherapy-induced cachexia. Here, we investigate the effects of chemotherapeutic agent, 5-fluorouracil (5FU), on skeletal muscle mass and function, and whether small molecule therapeutic candidate, BGP-15, could be protective against the chemotoxic challenge exerted by 5FU. Additionally, we explore the molecular signature of 5FU treatment. Male Balb/c mice received metronomic tri-weekly intraperitoneal delivery of 5FU (23 mg/kg), with and without BGP-15 (15 mg/kg), 6 times in total over a 15-day treatment period. We demonstrated that neither 5FU, nor 5FU combined with BGP-15, affected body composition indices, skeletal muscle mass or function. Adjuvant BGP-15 treatment did, however, prevent the 5FU-induced phosphorylation of p38 MAPK and p65 NF-κB subunit, signalling pathways involved in cell stress and inflammatory signalling, respectively. This as associated with mitoprotection. 5FU reduced the expression of the key cytoskeletal proteins, desmin and dystrophin, which was not prevented by BGP-15. Combined, these data show that metronomic delivery of 5FU does not elicit physiological consequences to skeletal muscle mass and function but is implicit in priming skeletal muscle with a molecular signature for myopathy. BGP-15 has modest protective efficacy against the molecular changes induced by 5FU.

Characterised by the growth of benign tumours, fibropapillomatosis (FP) is a debilitating disease that predominantly afflicts the endangered green turtle (Chelonia mydas). A growing body of histological and molecular evidence has consistently associated FP tumours with Chelonid alphaherpesvirus 5 (ChHV5), leading this virus to be considered the most likely aetiological agent of FP. However, a recent study which detected both ChHV5 and Chelonia mydas papillomavirus 1 (CmPV1) DNA in FP tumour tissues has challenged this hypothesis. The present study aimed to establish the wider prevalence of CmPV1 and co-occurrence with ChHV5 in marine turtles in waters adjacent to the east coast of Queensland, Australia. This comprehensive molecular survey screened a total of 353 samples from 275 foraging turtles using probe-based qPCR. Three sample categories were used in this study: Group A (FP tumours), Group B (non-tumoured skin from turtles with FP tumours) and Group C (non-tumoured skin from turtles without FP tumours). Concurrent detection of ChHV5 and CmPV1 DNA is reported for all three categories, with the highest rate of concurrent detection reported for Group A samples (43.5%). Collectively, these results pivot the way we think about FP; as an infectious disease where two separate viruses may be at play.

A supramolecular host-guest interaction and sensing between cationic pillar[5]arenes (CP5) and L-carnitine were developed by the competitive host-guest recognition for the first time. The fluorescence sensing platform was constructed by CP5 functionalized Au nanoparticles (PP5@Au-NPs) as receptor and probe (rhodamine 123, R123), which shown a high sensitivity and selectivity to L-carnitine detection. Due to the property of the negative charge and molecular size of L-carnitine, it can be highly captured by the CP5 via electrostatic interactions and hydrophobic interactions. The mechanism of host-guest between PP5 and L-carnitine was studied by ¹H NMR and molecular docking, which indicated more affinity binding force of PP5 with L-carnitine. Therefore, a selective and sensitive fluorescent method was developed. It has a linear response of 0.1–2.0 and 2.0–25.0 μM and a detection limit of 0.067 μM (S/N = 3) for L-carnitine. The fluorescent sensing platform was also used to detect L-carnitine in human serum and milk samples, which provided potential applications of detection drugs of abuse, and had path for guarding a serious food safety issues.

Today, non-expensive remote sensing (RS) data from different sensors and platforms can be obtained at short intervals and be used for assessing several kinds of forest characteristics at the level of plots, stands and landscapes. Methods such as composite estimation and data assimilation can be used for combining the different sources of information to obtain up-to-date and precise estimates of the characteristics of interest. In composite estimation a standard procedure is to assign weights to the different individual estimates inversely proportional to their variance. However, in case the estimates are correlated, the correlations must be considered in assigning weights or otherwise a composite estimator may be inefficient and its variance be underestimated. In this study we assessed the correlation of plot level estimates of forest characteristics from different RS datasets, between assessments using the same type of sensor as well as across different sensors. The RS data evaluated were SPOT-5 multispectral data, 3D airborne laser scanning data, and TanDEM-X interferometric radar data. Studies were made for plot level mean diameter, mean height, and growing stock volume. All data were acquired from a test site dominated by coniferous forest in southern Sweden. We found that the correlation between plot level estimates based on the same type of RS data were positive and strong, whereas the correlations between estimates using different sources of RS data were not as strong, and weaker for mean height than for mean diameter and volume. The implications of such correlations in composite estimation are demonstrated and it is discussed how correlations may affect results from data assimilation procedures.

The novel phosphor Eu3+ doped Na5Zn2Gd(MoO4)6 triple molybdate were prepared by the sol-gel method. The structure, morphology, and luminescent properties have been characterized by X-ray diffraction, thermogravimetry-differential thermal analysis, scanning electron microscopy, FTIR spectroscopy and Luminescence spectroscopy. The results indicated that the synthesized Na5Zn2Gd1-x(MoO4)6: xEu3+phosphor consisted of a pure phase with monoclinic structure. Under excitation at 465 nm, the Na5Zn2Gd1-x(MoO4)6: xEu3+ phosphor exhibits intensive red emission band around 610 nm corresponding to the transition of 5D0→7F2 is much higher than that 5D0→7F1 at 594 nm, which was appropriate for blue LED. According to the influence of the synthesis conditions, the phosphors show the highest emission intensity as the doping concentration of Eu3+ was 25 mol.% and the molar ratio of citric acid to metal ions was 2:1. Na5Zn2Gd0.75(MoO4)6: 0.25 Eu3+ with the color coordinates (x= 0.658, y= 0.341) is a stable red phosphor for blue-based white LEDs due to it is closer to the NTSC standard values (0.670, 0.330) comparing with the color coordinates (0.48, 0.50) of the commercial Y2O2S: Eu3+ red phosphor.

In this study, unlike conventional methods for producing vanadium (3.5+) electrolyte by VOSO4 and V2O5, a batch-type hydrothermal reactor was used to produce a vanadium (3.5+) electrolyte for vanadium redox flow batteries through a reduction reaction. The starting material, V2O5, was mixed with different concentrations of citric acid (0.8M, 1.2M, 1.6M, 2.0M) as reducing agent and stirred using a hot plate at 90°C for 60 minutes to achieve complete dispersion in the solution. The resulting solution was then subjected to a hydrothermal reduction reaction in a furnace at 150°C for 24 hours to produce vanadium (3.5+). The mixed state of the produced vanadium (3+) and vanadium (4+) was confirmed using UV-vis spectroscopy. Electrochemical properties were investigated through CV analysis, confirming that the optimal concentration was 1.6M. Charge and discharge experiments were conducted to compare the current efficiency, energy efficiency, and voltage efficiency of the electrolyte prepared by the hydrothermal reduction process and the electrolyte prepared by VOSO4. As a result, the electrolyte produced through the hydrothermal reduction process showed improved performance in all efficiencies. The results shows that vanadium (3.5+) electrolyte could be easily produced through a reaction process using citric acid.

Overhydration (OH) is a common medical problem found in patients with kidney or heart failure, but still a specific marker has not been found. Clinicians today use bioimpedance spectroscopy (BIS), ultrasound (US) markers of fluid overload or markers of heart and kidney function like NT-pro-BNP, GFR or creatinine levels. New serum markers such as Ca-125, Galectin-3 (Gal-3), Adrenomedullin (AMD) and Urocortin-2 (UCN-2), are being researched with promising results. The need to discover a more precise marker of overhydration is dire mainly because physical examination is extremely imprecise. Signs and symptoms of fluid overload like edema or gradual increase of body mass are not always present, especially in patients with chronic kidney disease. This review paper summarizes actual knowledge of a patient's hydration status estimation focusing especially on kidney diseases.

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

The rapidly evolving field of artificial intelligence (AI) continues to witness the introduction of innovative open-source pre-trained models, fostering advancements in various applications. One such model is Llama 2, an open-source pre-trained model released by Meta, which has garnered significant attention among early adopters. In addition to exploring the foundational elements of the Llama v2 model, this paper investigates how these early adopters leverage the capabilities of Llama 2 in their AI projects. Through a qualitative study, we delve into the perspectives, experiences, and strategies employed by early adopters to leverage Llama 2's capabilities. For the purpose of data analysis, the capabilities inherent in the Llama 2 model were employed to conduct keyword extraction from the context of the early adopters' case studies. The findings shed light on the model's strengths, weaknesses, and areas of improvement, offering valuable insights for the AI community and Meta to enhance future model iterations. Additionally, we discuss the implications of Llama 2's adoption on the broader open-source AI landscape, addressing challenges and opportunities for developers and researchers in the pursuit of cutting-edge AI solutions. The present study constitutes an early exploration of the Llama 2 pre-trained model, holding promise as a foundational basis for forthcoming research investigations.

Background Small intestinal neuroendocrine tumors (SI-NETs) are characterized by carcinoid syndrome and carcinoid heart disease (CHD). The aim of study was to identify early risk markers for carcinoid heart disease and survival in a prospective median-term follow-up setting. Methods We measured 5-HIAA, cumulative 5-HIAA exposure (Cum-5-HIAA) based on repeat measurements, proBNP, vascular function, hepatic tumor load and transthoracic echocardiography (TTE) were assessed at baseline and during median 5-year follow-up. Of 65 patients with SI-NETs; 54 patients underwent prospective follow-up. In addition, survival was evaluated during median follow-up of 6 years. Results At baseline three patients had CHD. During median follow-up of 5 years, two patients (4%) developed CHD. Cum-5-HIAA and proBNP correlated with CHD (Westberg Score, Spearman’s ρ = 0.32 and 0.31, respectively). Cum-5-HIAA had a superior diagnostic capability, predicting CHD in receiver operator characteristics analysis with AUC of 0.98 (95% CI: 0.94–1.00) and outperformed proBNP, chromogranin A (CgA), as well as individual serum 5-HIAA measurements (AUC = 0.75, 0.85, and 0.91, respectively). Minor changes in valve regurgitation were frequently detected but did not correlate with vascular function. In 29% of tricuspid and 30% of pulmonic valves regurgitation increased or decreased. CHD, hepatic tumor load, serum 5-HIAA, and elevated aortic pulse wave velocity (PWV) associated with increased mortality in SI-NET patients. Conclusions Cum-5-HIAA is a promising biomarker for CHD risk and outperformed other biomarkers. CHD and hepatic tumor load are strongest predictors of mortality. PWV is a novel predictor of survival. The incidence of CHD was small among the SI-NET patients, probably reflecting successful treatment regimens.

Background P53 gene mutation is a very common event in human neoplasia, and genetic mutations in the P53 gene in a single allele are responsible for a hereditary cancer susceptibility syndrome (Li Fraumeni). These variants encode distinct isoforms of the p53 protein, which may disrupt its transcriptional activity. These point mutant proteins are more stable than the normal protein and the mutant product accumulates at a high level that allows obtaining important information about p53 gene expression in malignant cells, especially in Chronic Lymphocytic Leukemia, (CLL). By Enzyme Linked Immune-Absorbent Assay method, (ELISA), was analyzed the frequency of p53 protein expression to 20 eligible patients diagnosed with CLL for to investigate the relationship of this protein in the stages of the disease and the impact on treatment response and survival. In ELISA technique was used the specific antibodies for isoform p53 protein, PAb 240 antibodies. These antibodies bind specifically to denatured p-53 protein. Species reactivity is for human in conformity with the prospect from Manual, Catalog No. LS-F174, Bio-Rad. Results The average concentrations of p53 proteins in 17 of 20 cases were found 16.76 μg / dl, with CV = 0.5% and the probability index p = 0.034. Very high pathological values in the 3 cases of isoform p53 protein were calculated in 2 men, (PM) in the value of 60 µg / dL, respectively at 40 µg / dL and in the case of females, (PW), in 40 µg / dL value, with the transformation into Diffuse Large Lymphoma, (DLL). Conclusion This ELISA method has proven to be a useful prognostic tool for the application of personalized treatment of on-immune therapy, in cases diagnosed with the type B-CLL.

Transient receptor potential canonical (TRPC) channels are calcium channels with diverse expression profiles and physiological implications in the retina. Neurons and glial cells of rat retinas with photoreceptor degeneration caused by retinitis pigmentosa (RP) exhibit basal calcium levels that are above those detected in healthy retinas. Inner retinal cells are the last to degenerate and are responsible for maintaining the activity of the visual cortex even after complete loss of photoreceptors. We considered the possibility that TRPC1 and TRPC5 channels might be associated with both the high calcium levels and the delay in inner retinal degeneration. TRPC1 is known to mediate protective effects in neurodegenerative processes, while TRPC5 promotes cell death. In order to comprehend the implications of these channels in RP, the co-localization and subsequent physical interaction between TRPC1 and TRPC5 in healthy retina (Sprague-Dawley rats) and degenerating (P23H-1, a model of RP) retina were detected by immunofluorescence and proximity ligation assays. There was an overlapping signal in the innermost retina of all animals where TRPC1 and TRPC5 physically interacted. This interaction increased significantly as photoreceptor loss progressed. Both channels function as TRPC1/5 heteromers in the healthy and damaged retina, with a marked function of TRPC1 in response to retinal degenerative mechanisms. Furthermore, our findings support that TRPC5 channels also function in partnership with STIM1 in Müller and retinal ganglion cells. These results suggest that increase in TRPC1/5 heteromers may contribute to slowing of the degeneration of the inner retina during the outer retinal degeneration.

Colorectal cancer is one of the most common causes of cancer mortality worldwide, and innovative drugs for the treatment of colorectal cancer are continually being revealed. 5-Fluorouracil (5-FU) is a common clinical chemotherapeutic drug. Acquired resistance to 5-FU is a clinical challenge in colorectal cancer. Parecoxib is a selective COX-2-specific inhibitor, which has been demonstrated to inhibit metastasis in colorectal cancers in our previous study. This study aimed to investigate the synergistic antimetastatic activities of parecoxib to 5-FU in human colorectal cancer cells and determine the underlying mechanism. parecoxib and 5-FU synergistically suppressed metastasis in colorectal cancer cells. Treatment with the parecoxib /5-FU combination induced an increase in E-cadherin and decrease in β-catenin. The parecoxib/5-FU combination could inhibit MMP-9 and MMP-2 expression and MMP-9 activity, and the NF-κB pathway might be suppressed as well. Mechanistic analysis denoted that the parecoxib/5-FU combination hindered the essential molecules of the PI3K/Akt route to obstruct metastatic colorectal cancer. Furthermore, the parecoxib/5-FU combination could inhibit reactive oxygen species. Our work showed the antimetastatic capacity of the parecoxib/5-FU combination for colorectal cancers via targeting the PI3K/Akt /NF-κB pathway.

Despite substantial evidence supporting the efficacy of prebiotics for promoting host health and stress resilience, few experiments present evidence documenting the dynamic changes in microbial ecology and fecal microbial-modified metabolites across time. Furthermore, the literature reports a lack of reproducible effects of prebiotics on specific bacteria and bacterial-modified metabolites. The current experiments examined whether consumption of diets enriched in prebiotics (galactooligosaccharides, GOS and polydextrose, PDX) compared to control diet, would consistently impact the gut microbiome and microbial-modified bile acids across time and between two research sites. Male Sprague Dawley rats were fed control or prebiotic diets for several weeks, and their gut microbiome and metabolome were examined using 16S rRNA gene sequencing and untargeted LC-MS/MS analysis. Dietary prebiotics altered beta diversity, relative abundances of bacterial genera, and microbially modified bile acids across time. PICRUSt2 analyses identified four inferred functional metabolic pathways modified by prebiotic diet. Correlational network analyses between inferred metabolic pathways and microbial-modified bile acids revealed deoxycholic acid as a potential network hub. All these reported effects were consistent between the two research sites supporting the conclusion that dietary prebiotics robustly changed the gut microbial ecosystem. Consistent with our previous work demonstrating that GOS/PDX reduces the negative impacts of stressor exposure, we propose that ingesting a diet enriched in prebiotics facilitates the development of a health-promoting gut microbial ecosystem.

The reaction between 5-acetylbarbituric acid and 4-dimethylthiosemicarbazide or 4-hexamethyleneiminyl thiosemicarbazide produces 5-acetylbarbituric-4-dimethylthiosemicarbazone (H2AcbDM) and 5-acetylbarbituric-4N-hexamethyleneiminyl thiosemicarbazone (H2Acbhexim). Eight new complexes with different cooper (II) salts have been prepared and characterized using elemental analysis, molar conductance, UV–vis, ESI-HRMS, FT-IR, magnetic moment, EPR and cyclic voltammetry. In addition, three-dimensional molecular structures of [Cu(HAcbDM)(H2O)2](NO3)·H2O (3a), [Cu(HAcbDM)(H2O)2]ClO4 (4), and [Cu(HAcbHexim)Cl] (6) were determined by single crystal X-ray crystallography, and was carried out an analysis of their supramolecular structure. The H-bonded assemblies were further studied energetically using DFT calculations, MEP surface and QTAIM analyses. In these complexes, the thiosemicarbazone coordinates to the metal ion in an ONS-tridentate manner, in the O-enolate/S-thione form. The electrochemical behavior of the thiosemicarbazones and their copper(II) complexes has been investigated at room temperature using the cyclic voltammetry technique in DMFA. The Cu(II)/Cu(I) redox system was found to be consistent with the quasi-reversible diffusion-controlled process.

With the inclusion of Internet Gaming Disorder (IGD) in both the DSM-5 and ICD-11, understanding the prevalence and diagnostic discrepancies is crucial for developing appropriate interventions. This study presents a meta-analysis of the prevalence of IGD based on two diagnostic criteria. We systematically searched PubMed, Web of Science databases. 17 studies were included in the final analysis, The analysis incorporated studies employing the DSM-5 and ICD-11 criteria and focused on the impact of various factors, including study location, sample size, and quality score, on the reported prevalence rates using a random-effects model. Heterogeneity and publication bias were analyzed using an I2 test and Galbraith plots , The prevalence of IGD varied among the selected studies, with a general pooled prevalence of 5% (95% CI: 3%–7%). Subgroup analysis indicated that the prevalence rates of IGD (DSM-5 criteria) and GD (ICD-11 criteria) do not show significant differences. DSM-5-based scales yielded varied results, while heterogeneity among the studies was high (I2 = 98.50). In contrast, ICD-11-based scales produced more consistent and less variable findings. Our findings highlight that assessment scales, not diagnostic criteria, impact IGD prevalence. This underscores the importance of adopting standardized methodologies to guide public health interventions. However, given the limited research based on ICD-11 diagnostic criteria, further investigation is necessary to determine the variations in prevalence rates of IGD under different diagnostic standards.

Recent events concerning jet fuel contamination of drinking water have shown that we need a better understanding of the effects of ingested jet fuel. To this end, a reproductive study with in-gested jet fuel in rats was undertaken with relatively high concentrations of Jet Propellant (JP)-5 along with a human estrogen receptor activation in vitro assay using JP-5, JP-8, and an alternative jet fuel derived from the camelina plant to help evaluate potential effects of ingested jet fuel. Results of the in vivo study provided evidence that JP-5 can act as an endocrine disruptor, with specific observations including altered hormone levels with JP-5 exposure (significantly lower estradiol levels in male rats and significantly increased Dehydroepiandrosterone levels in females), indi-cations of abnormal estrous cycles, and a decreased male/female offspring ratio. The in vitro hormone receptor activation assay indicated JP-5 and JP-8 are capable of upregulating human estrogen receptor (ER) activity, while the alternative jet fuel derived from the camelina plant was not active in the ER assay. The jet fuels were not able to activate androgen or glucocorticoid re-ceptors in further in vitro assays. These results infer potential endocrine disruption associated with JP-5, with activation of the estrogen receptor as one potential mechanism of action.

Cirrhosis is a chronic disease with multiple etiologies, multiple manifestations, and multi-organ involvement. Affects about 200 million people worldwide. Its main complication is Portal hypertension (PHT). Cirrhotic cardiomyopathy is a consequence of PHT, with heart failure (HF) being the main manifestation. On the other hand, for people with cardiopathy due to other reasons beyond cirrhosis, the presence of the last could act as a trigger to acute HF. Finally, when HF and cirrhosis coexist, the renal system suffers the most, originating from type-5 cardio-renal syndrome, a complex entity with many challenges in diagnosis and treatment. This entity was recently defined and there is a lack of data on the epidemiology of this syndrome. A 77-year-old woman, with cardiovascular risk factors; heart failure with reduced ejection fraction (HFrEF), secondary ischemic and valvular cardiopathy, chronic Kidney disease (CKD), and stable decompensated cirrhosis, went to the emergency department after progressive abdominal perimeter augmentation, legs’ edema and hematochezia. It was assumed acute decompensated cirrhosis and acute decompensated chronic kidney disease, had triggered digestive bleeding and the patient stayed hospitalized. Intravenous diuretic therapy was started but, the ascites and kidney function got worse, the Nt pro-BNP grew until 1125000 pg/ml, and a transthoracic echocardiography showed important signs of congestion, isolated right ventricular dysfunction, with normal cardiac output. After teamwork’s discussion, a type-5 cardio-renal syndrome was assumed deciding not to act on tricuspid regurgitation due to the maladaptive RV remodeling. Hepatorenal syndrome treatment was begun (oral terlipressin and intravenous albumin), followed by decongestion therapy, resulting in a marked improvement in clinical presentation. The kidney, heart, and liver recovered to these basal states. With this clinical case, the authors want to show how multidisciplinary management is important to face tricuspid regurgitation and right ventricular dysfunction.

The intricacies of translational strategies make this stage of the implementation of genetic information one of the most difficult to understand and, at the same time, perhaps the most interesting. It also becomes clear that all this variety of strategies is not just a consequence of a long evolutionary history but is of paramount importance for fine-tuning gene expression and metabolic modulation. This is especially true for those organisms that demonstrate predominantly biochemical and physiological reactions with a lack of behavioural ones. Plants are just such a group of organisms. Overcoming unfavourable environmental conditions occupies a key place in plant physiology. This is especially true with the changing conditions of global warming and the irretrievable loss or depletion of natural ecosystems. Conceptually, the response of plants to abiotic stress is a set of complex and intricate strategies. This is dictated both by a variety of abiotic factors that provoke stressful conditions and by a variety of molecular genetic mechanisms that make it possible to fine-tune the metabolic pathways through which the plant organism overcomes non-standard and non-optimal conditions. In the presented review, we tried to focus on the state-of-the-art in the field of translational regulation in plants under abiotic stress conditions. Various regulatory elements and patterns are considered in relative chronological order. We also considered it necessary to pay attention to key high-performance methods for studying the dynamics of genetic information at the stage of translation.

Jacobian theta function identities are related to the Addition formula for the Weierstrass 1 Sigma function. In this paper, from the Addition formula for Weierstrass Sigma function, new and 2 simple proofs of four square sums theorem are given. Using the addition formula of the theta func- 3 tions, we also give simple proofs of two square sums and eight square sums theorem.

Purpose The COVID-19 pandemic, triggered by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has resulted in over 160 million infections and 3.5 million fatalities worldwide. Evidence of SARS-CoV-2 presence in the highly vascularized penile tissue and the established correlation between COVID-19 and subsequent erectile dysfunction (ED) has emerged. Robot-assisted radical prostatectomy (RARP) is a popular procedure for prostate cancer because of its reliability and swift recovery rate. However, the ED prevalence post-surgery is believed to be comparable to open surgery, and postoperative ED significantly affects the patient's quality of life. Our study aimed to explore the effect of COVID-19 on ED recovery in patients undergoing bilateral nerve preservation during RARP. Materials and Methods We conducted a retrospective study on 85 patients who underwent bilateral nerve-sparing RARP (nsRARP) at our institution between December 2017 and May 2021. Chart reviews and the International Index of Erectile Function-5 (IIEF-5) questionnaire facilitated the analysis. Our objective was to contrast ED recovery after surgery between SARS-CoV-2–infected and non-infected patients using preoperative IIEF-5 scores and scores at 6, 12, and 24 months post-surgery. We defined successful ED recovery as an IIEF-5 score of 17 or higher and successful sexual intercourse. We also compared ED recovery rates between the two groups, regardless of the timing of COVID-19 diagnosis. IBM's SPSS version 18.0 assisted in the statistical analysis, with Fisher's exact test and chi-square test used for comparing categorical variables. Independent t-tests determined mean differences between baseline and postoperative IIEF-5 scores. A p-value less than 0.05 was considered statistically significant. Results From December 2017 to May 2021, our institution executed 213 RARP cases, with 185 of these involving nerve preservation. Among these patients, 133 had an IIEF-5 score of 17 or higher during preoperative EF assessment. We included 85 patients with consistent IIEF-5 records before surgery and at 6, 12, and 24 months post-surgery in this study. Of these, 44 and 41 patients comprised the COVID-19–positive and COVID-19–negative groups, respectively. The COVID-19–positive group had a higher proportion of diabetes mellitus (DM) patients (24 (54.55%) vs. 7 (17.07%), p<0.001). There was no significant difference in preoperative IIEF-5 scores or scores up to 6 months after surgery between the two groups. However, the IIEF-5 scores of the COVID-19–positive group were statistically lower after 12 and 24 months post-surgery. Additionally, the COVID-19–negative group showed a more considerable score increase between 6 and 12 months post-surgery, and the EF recovery rate was lower in the COVID-19–positive group starting from the 12th month after surgery. Within the COVID-19–positive group, no statistically significant difference in IIEF-5 scores was found between single infection and multiple reinfection groups. Conclusions Principal component analysis revealed the impact of COVID-19 on ED recovery in patients who underwent nsRARP. The most substantial changes in IIEF-5 scores occurred between 6 and 12 months. From 12 months onwards, the COVID-19–positive group had significantly lower scores, and fewer patients had IIEF-5 scores above 17. However, the number of COVID-19 diagnoses did not significantly affect the IIEF-5 scores.

Depressive disorder is a disease that causes a decrease in daily function, and the prevalence of depressive disorder in Korea is the highest among OECD countries. However, due to lack of manpower and negative social awareness, timely treatment is not being performed properly. As a solution to this, AI counseling chatbots are emerging, and it is essential to use labeled datasets to create chatbots. Currently, many countries around the world, including Korea, use the Diagnostic and Statistical Manual of Mental Disorders Fifth Edition, DSM-5, but there are no nine labeled datasets according to the DSM-5 depression disorder diagnosis criteria. This study collects sympathetic datasets, analyzes morphemes using Kind Korean Morpheme Analyzer and augments and builds a word dictionary using Word2Vec. As a result, we have labeled the dataset with nine criteria for diagnosing DSM-5 depressive disorder, which will enhance the performance of the counseling chatbot.

The presence of azo dyes in textile effluents is an issue of major concern due to their potential impact on the environment and human health. In this study we investigate the photocatalytic degradation under visible light of Reactive Violet 5 (RV5), an azo dye widely used in the textile industry. A preliminary screening of different titania-based catalysts was carried out to identify the best candidate for RV5 removal. The selected catalyst was then tested in a stirred and aerated lab-scale reactor illuminated with a light LED source (λmax = 460 nm). The effects of pH, catalyst load and hydrogen peroxide additions on the efficiency of dye removal were evaluated. Under the best conditions (pH 10, 3 g/L of catalyst and 60 mM hydrogen peroxide), the dye solution was completely decolorized in about 2 h. Overall, the results obtained suggest that the proposed process may represent a suitable method for the removal of RV5 from textile effluents.

E-commerce businesses employ recommender models to assist in identifying a personalized set of products for each visitor. To accurately assess the recommendations’ influence on customer clicks and buys, three target areas—customer behavior, data collection, user-interface —will be explored for possible sources of erroneous data. Varied customer behavior misrepresents the recommendations’ true influence on a customer due to the presence of B2B interactions and outlier customers. Non-parametric statistical procedures for outlier removal are delineated and other strategies are investigated to account for the effect of a large percentage of new customers or high bounce rates. Subsequently, in data collection we identify probable misleading interactions in the raw data, propose a robust method of tracking unique visitors, and accurately attributing the buy influence for combo products. Lastly, user-interface issues discuss the possible problems caused due to the recommendation widget’s positioning on the e-commerce website and the stringent conditions that should be imposed when utilizing data from the product listing page. This collective methodology results in an exact and valid estimation of the customer’s interactions influenced by the recommendation model in the context of standard industry metrics such as Click-through rates, Buy-through rates, and Conversion revenue.

In this paper, we used meteorological data to simulate vertical profiles of optical turbulence at the Special Astrophysical Observatory (Russia, 43°40′19 ′′ N 41°26′23′′E, 2100 m a.s.l.), site of the 6-m Big Telescope Alt-azimuthal. The vertical profiles of optical turbulence are calculated using ERA-5 reanalysis data. These profiles are corrected using DIMM measurements as well as estimations of atmospheric boundary layer heights. We may note that the method basically reconstructs the most important features of the shape of the measured profile under clear sky. Atmospheric turbulent layers were identified, and the strength of optical turbulence in these layers was estimated. The model hourly values of seeing corresponding to the obtained vertical profiles range from 0.85 to 2.10 arcsec, values of the isoplanatic angle vary in the range from 1 to 3.0 arcsec (at λ = 500 nm). These estimations are close to the measured median of seeing (1.21 arcsec).

Phosphodiesterase type 5 (PDE5) inhibitors are widely used in the treatment of various conditions, including erectile dysfunction and pulmonary hypertension. Despite their clinical efficacy, these drugs quite often cause visual disturbances due to off-target effects on Phosphodiesterase type 5 (PDE6) in the retina. This review explores the application of a general intermolecular binding affinity calculator (GIBAC)-based binding selectivity strategy in the design of PDE5 inhibitors, aiming to enhance binding selectivity and minimize visual side effects. This GIBAC strategy integrates computational structural biological approaches to iteratively refine drug-target binding affinities, thereby improving target specificity and the structural biophysical limit for the efficacy-safety balance of PDE5 inhibitors. Through detailed analysis of PDE5’s and PDE6’s biological role and the molecular mechanisms underlying visual disturbances, this article underscores the necessity of target binding selectivity in PDE5 inhibitor design in future. Additionally, this article discusses the practical applications of GIBAC in computational drug discovery and design, along with the future directions and the potential for GIBAC to transform PDE5 inhibitor development, ultimately enhancing therapeutic outcomes and patient safety. Finally, this article calls for a GIBAC-based paradigm shift in computational drug discovery and design towards the continued development of the pharmaceutical industry.

This paper explores the ethical considerations surrounding the research on echinoderms, a group of invertebrates that has recently garnered attention in the scientific community. We emphasize the importance of responsible animal handling and the need for an ethical framework that encompasses echinoderms. The 3R's principle, advocating for the replacement of conscious living vertebrates with non-sentient material in research, is discussed as a guiding tool in current animal research practices. As invertebrates are generally classified as non-sentient animals, the Replacement dimension tends to favor them as prevalent models in experimental research. While we currently lack the means to assess the mental states of invertebrates, there is undeniable evidence of social behavior in many species, suggesting that a lack of interactions with these organisms could potentially adversely affect their well-being. In the last few years, considerable progress has been made in developing an ethical framework that takes invertebrates into account, particularly cephalopods, crustaceans, and echinoderms. In this context, we discuss the development of a broader conceptual framework of 5R’s that includes Responsibility and Respect, which may guide practices ensuring welfare in echinoderms, even in the absence of any particular normative.

The vascular endothelium is key target for immune, and thrombotic responses that has to be controlled in successful xenotransplantation. Several genes were identified that if induced or overexpressed help to regulate the inflammatory response and preserve the transplanted organ function and metabolism. However, few studies addressed combined expression of such genes. The aim of this work was to evaluate in vivo the effects of the simultaneous expression of a three human genes in a mouse generated using the multi-cistronic F2A technology. Male 3-month-old mice that express human heme oxygenase 1 (hHO-1), ecto-5’-nucleotidase (hE5NT), and ecto-nucleoside triphosphate diphosphohydrolase 1 (hENTPD1) (Transgenic) were compared to wild-type FVB mice (Control). Background analysis include extracellular nucleotide catabolism enzymes profile on the aortic surface, blood nucleotide concentration and serum L-arginine metabolites. Furthermore, inflammatory stress induced by LPS in transgenic and control mice was used to characterize interleukin 6 (IL-6) and adhesion molecules endothelium permeabil-ity responses. Transgenic mice had significantly higher rates of extracellular adenosine triphosphate and adenosine monophosphate hydrolysis on the aortic surface in comparison to control. Increased levels of blood AMP and adenosine were also noticed in transgenics. Moreover, transgenic ani-mals demonstrated the decrease in serum monomethyl-L-arginine level and a higher L-arginine/ monomethyl-L-arginine ratio. Importantly, significantly decreased serum IL-6, and adhesion mol-ecule levels were observed in transgenic mice in comparison to control after LPS treatment. Fur-thermore, reduced endothelial permeability in the LPS-treated transgenic mice was noted as com-pared to LPS-treated control. The human enzymes (hHO-1, hE5NT, hENTPD1) simultaneously encoded in transgenic mice demonstrated benefits in sev-eral biochemical and functional aspects of endothelium. This is consistent in use of this approach in the context of xenotransplantation.

Genome-wide epigenetic changes in plants are being reported during the development and environmental stresses, which are often correlated with gene expression at the transcriptional level. Sum total of the biochemical changes in nuclear DNA, post-translational modifications in histone proteins and variations in the biogenesis of non-coding RNAs in a cell is known as epigenome. These changes are often responsible for variation in expression of the gene without any change in the underlying nucleotide sequence. The changes might also cause variation in chromatin structure resulting into the changes in function/activity of the genome. The epigenomic changes are dynamic with respect to the endogenous and/or environmental stimuli which affect phenotypic plasticity of the organism. Both, the epigenetic changes and variation in gene expression might return to the pre-stress state soon after withdrawal of the stress. However, a part of the epigenetic changes may be retained which is reported to play role in acclimatization, adaptation as well as in the evolutionary processes. Understanding epigenome-engineering for improved stress tolerance in plants has become essential for better utilization of the genetic factors. This review delineates the importance of epigenomics towards possible improvement of plant’s responses to environmental stresses for climate resilient agriculture.

Borneol and menthol were two terpenes wildly used as penetrate enhancer in transdermal drug delivery. To explore their penetration enhancement effect towards hydrophilic drug, 5-FU was selected as model drug. A method combined vitro permeation studies and coarse grain molecular dynamics was used to investigate their penetration enhancement effect towards 5-FU. As a result, although both borneol and menthol showed a penetration enhancement effect towards 5-FU, they differed a lot in the penetration enhancement mechanism, which was also thought to account for their different penetration enhancement effect. As for menthol, SC bilayer disrupting effect seemed to be its main mechanism. While for borneol, its mechanism seemed to be more complicated. Except for disrupting the SC bilayer, it could also increase the permeation of 5-FU by enhancing the diffusion rate of 5-FU or inducing the formation of transient pore. All of this enable us a molecular understanding of borneol and menthol’s penetration enhancement effect towards hydrophilic drug, which might provide some guidance in the latter research and application.

Several studies suggests that ghrelin (GHRL) has neurobiological effects that extend beyond control of food intake. Our previous results confirmed that GHRL modulates the secretory activity of the pineal gland (PG) through nocturnal melatonin (MEL) secretion in sheep, the seasonally reproductive animals. Here we investigated the effects of GHRL (10 ng/ml) on the expression of enzymes limiting synthesis of MEL, including tryptophan 5-hydroxylase 1 (TPH1), serotonin N-acetyltransferase (AA-NAT) and its phosphorylated form p31T-AA-NAT in sheep PG explants (n = 72) during the 4-hour incubation in a gas-liquid interface, at a short (SD) and long (LD) photoperiods. After each hour of incubation selected explants were frozen in liquid nitrogen and stored at -80°C for subsequent analysis (real-time PCR, western-blotting, ELISA). Results show that GHRL regulates nightly MEL secretion in a TPH1-independent manner. The factor modulating GHRL activity was photoperiod. During SD photoperiod GHRL significantly reduced the expression of p31T-AA-NAT, AA-NAT and inhibited MEL secretion from PG explants. Whereas, during LD photoperiod no effect of GHRL on MEL secretion and expression of examined enzymes was noted. Studies indicate that GHRL directly affects PG under in vitro conditions and causes MEL secretion in animals which exhibit seasonality in reproductive and metabolic processes.

The world is currently going through a serious pandemic of viral infection with SARS-CoV-2, a new isolate of coronavirus, resembling and surpassing the crisis that occurred in 2002 and 2013 with SARS and MERS, respectively. SARS-CoV-2 has currently infected more than 142,000 people, causing 5,000 deaths and reaching more than 130 countries worldwide. The very large spreading capacity of the virus clearly demonstrates the potential threat of respiratory viruses to human health, alarming governments around the world that preventive health policies and scientific research are pivotal to overcoming the crisis. Coronavirus disease 2019 (COVID-19) causes flu-like symptoms in most cases. However, approximately 15% of patients will need hospitalization, and 5% require assisted ventilation, depending on the cohorts studied. What is intriguing, however, is the higher susceptibility of elderly individuals, especially those who are more than 60 years old and have comorbidities, including hypertension, diabetes and heart disease. In fact, the death rate in this group may be up to 10-12%. Interestingly, children are somehow protected and not included as a risk group.Thus, here, we discuss some possibilities of molecular and cellular mechanisms by which elderly subjects may be more susceptible to severe COVID-19. In this sense, we raise two main points: i) increased ACE-2 expression in pulmonary and heart tissue of chronic angiotensin 1 receptor (AT1R) blocker users and hypertensive individuals and ii) antibody-dependent enhancement (ADE) after previous exposure to other circulating coronaviruses. We believe these are pivotal points for a better understanding of the pathogenesis of severe COVID-19 and must be addressed with attention by physicians and scientists in the field.

Build a special identical equation, use its calculation characters to prove and search for solution of any odd converging to 1 equation through (*3+1)/2^k operation, change the operation to (*3+2^m-1)/2^k, and get a solution for this equation, give a specific example to verify. Thus prove the Collatz Conjecture is true. Furthermore, analysis the sequences produced by iteration calculation during the procedure of searching for solution, build a weight function model, prove it decrease progressively to 0, build a complement weight function model, prove it increase to its convergence state. Build a (*3+2^m-1)/2^k odd tree, prove if odd in (*3+2^m-1)/2^k long huge odd sequence can not converge, the sequence must outstep the boundary of the tree after infinite steps of (*3+2^m-1)/2^k operation.

Newly characterising 245 Italian and Albanian HCV-2 NS5B sequences collected between 2001 and 2016 was used to reconstruct the origin and dispersion pathways of HCV-2c. The tree of a subset of these sequences aligned with 247 publicly available sequences was reconstructed in spatio-temporal scale using the Bayesian approach, and the effective replication number (Re) was estimated using the birth-death model. Our findings show that HCV-2c was the most prevalent subtype in Italy and Albania, and that GT2 originated in Guinea Bissau in the XVI century and spread to Europe in the XX century. The HCV-2c subtype had two internal nodes respectively dating back to the 1930s and 1950s having as most probable locations Ghana and Italy, respectively. Phylodynamic analysis revealed an exponential increase in the effective number of infections and Re in both Italy between the 1950s and 1980s, and Albania between the 1990s and the early 2000s. It seems very likely that HCV-2c reached Italy from Africa at the time of the second Italian colonisation (1936-1941), but did not reach Albania until the period of dramatic migration to Italy in the 1990s.

The development of a rapid, sensitive, specific method for detecting foodborne pathogens is paramount in supplying safe food to enhance public health safety. Despite the significant improvement in pathogen detection methods, key issues are still associated with rapid methods, such as distinguishing living cells from dead, pathogenic potential or health risk of the analyte at the time of consumption, detection limit, and sample-to-result. The mammalian cell-based assays analyze pathogens' interaction with the host cells and are responsive to only live pathogens or active toxins. In this study, a human embryonic kidney (HEK293) cell line expressing Toll-Like Receptor 5 (TLR-5) and chromogenic reporter system (HEK dual hTLR5) was used for the detection of viable Salmonella in a 96-well tissue culture plate. This cell line responds to low concentrations of TLR5 agonist flagellin. Stimulation of TLR5 ligand activates nuclear factor-kB (NF-κB) - linked alkaline phosphatase (AP-1) signaling cascade inducing the production of secreted embryonic alkaline phosphatase (SEAP). With the addition of a ρ-nitrophenyl phosphate as a substrate, a colored end product representing a positive signal is quantified. The assay's specificity was validated with the top 20 Salmonella enterica serovars and 19 non-Salmonella spp. The performance of the assay was also validated with spiked food samples. The total detection time (sample-to-result), including shortened pre-enrichment (4 h) and selective enrichment (4 h) steps with artificially inoculated outbreak-implicated food samples (chicken, peanut kernel, peanut butter, black pepper, mayonnaise, and peach) was 15 h when inoculated at 1–100 CFU/25 g sample. These results show the potential of HEK-DualTM hTLR5 cell-based functional biosensors for rapid screening of Salmonella.

Introduction: Carcinoid heart disease is a rare cause of right-sided valvular dysfunction, an important complication in patients with carcinoid syndrome. Objectives: We aim to present our own experience regarding early myocardial dysfunction in patients with carcinoid syndrome. Methods: 64 patients (35-90 year old, 62,5% female, 37,5% male patients) with carcinoid syndrome were evaluated be-tween October 2017 and June 2021. All patients underwent two-dimensional echocardiography with additional tissue Doppler and speckle-tracking techniques. For all patients there were measured urinary level of 5- hydroxyindolacetic acid, serotonin and NT-proBNP values. Results: The following echocardiographic features: global longitudinal strain of both ventricles, mean systolic velocity of the left ventricle, systolic velocity of the free wall of right ventricle, correlated with high values of specific biomarkers: serotonin, and urinary 5-hydroxyindolacetic acid, and also with the presence of hepatic metastases and poorly differentiated tumors. Discussion: In this study we identified several patients with early myocardial dysfunction due to carcinoid syndrome, representing a predictive model of poor prognosis, requiring further investigations. Conclusion: Echocardiographic assessment based on the measurement of systolic velocities, as well as the global longitudinal strain of both ventricles, together with specific biomarkers may contribute to better recognition of carcinoid heart disease in clinical practice, but this needs validation through further studies enrolling larger number of patients.

children is challenging. An important advance is the 15-questions Pictorial Personality Traits Questionnaire for Children. A study on students from 10 to 13 years old in Poland validated the questionnaire but with some observations. Thus, there is a need for replication and stronger evi-dence in this age group. In Chile, we replicated the study with 3,423 4th-graders (9 to 12 years old). Teachers, in regular sessions, applied the questionnaire to their entire classes. We found similar results, including that asexual pictograms worked well in both genders. We also found positive relationships between conscientiousness, openness, and extraversion with mathematical performance. Furthermore, a combination of these three traits has a relationship with math performance twice as big as each trait alone. Moreover, students with the lowest scores in this combination of personality traits (6.6% of students) have 0.27 standard deviations less in mathematical performance than those with the highest score, which is 74.3% of students. To the best of our knowledge, this is the first time that a study finds a strong relationship between a combination of personality traits gathered with a 15-question questionnaire and fourth-graders´ math perfor-mances.