Primary ciliary dyskinesia (PCD) is caused by pathologic variants in over 50 different genes that affect the structure and function of motile cilia. Low nasal NO (nNO) is a biomarker for diagnosis in patients with features of PCD; but the reason why it is low is unclear. At the cellular level, a characteristic feature shared by most PCD patients is that antigens and other particles are not cleared from the epithelial surface. Poor antigen clearance results in pro-oxidant pathway activation and airway epithelial damage and may predispose PCD patients to DUOX1- and IL33- mediated asthma. Secondary ciliary dysfunction, such as that caused by viruses or by smoking, can also contribute to asthma development. Variants in genes underlying the function of cilia, can be associated with poor lung function, even in the absence of PCD. Single nucleotide polymorphisms in PCD – related genes can be associated with increased asthma severity. The role of cilia and antigen stasis is the pathophysiology of asthma is an important area for research, because specific airway clearance techniques and other therapeutic interventions, such as antioxidants, could be of value in preventing the development of asthma and asthma-like symptoms.

Transient receptor potential melastatin-8 (TRPM8) is a cation channel that is activated by cold and “cooling agents” such as menthol and icilin, which induce a cold sensation. Stimulation of TRPM8 activates an intracellular signaling cascade that ultimately leads to a change in the gene expression pattern of the cells. Here, we investigated the TRPM8-induced signaling pathway that links TRPM8 channel activation to gene transcription. Using a pharmacological approach, we show that inhibition of phosphatidylinositol 4-phosphate 5 kinase alpha (PIP5K), an enzyme essential for the biosynthesis of phosphatidylinositol 4,5-bisphosphate, attenuated TRPM8-induced gene transcription. Analyzing the link between TRPM8 and Gq proteins, we show that pharmacological inhibition of the beta gamma subunits impairs TRPM8 signaling. In addition, genetic studies showed that TRPM8 requires an activated Galpha subunit for signaling. In the nucleus, the TRPM8-induced signaling cascade triggers an activation of the transcription factor AP-1, a complex consisting of a dimer of basic region leucine zipper (bZIP) transcription factors. Here, we identified the bZIP protein c-Jun as an essential component of AP-1 within the TRPM8-induced signling cscade. In summary, with PIP5K, Gq subunits and c-Jun we have identified key molecules in the TRPM8-induced signaling from the plasma membrane to the nucleus.

Colorectal cancer (CRC) remains a major global health issue. Although chemotherapy is the first-line treatment, its effectiveness is limited due to drug resistance developed in CRC. To overcome resistance and improve the prognosis of CRC patients, investigation for new therapeutic approaches is necessary. Using human colorectal adenocarcinoma (HT29) and metastatic CRC (SW620) cell lines, the potential anticancer properties of a newly synthesized compound 1-(Isobutyl)-3-(4-methylbenzyl) benzimidazolium chloride (IMBZC) were evaluated by performing MTT cytotoxicity, cell migration, and colony formation assays, as well as by monitoring apoptosis-related protein and gene expression using Western blot and reverse transcription-quantitative polymerase chain reaction technologies. Tested at various concentrations, the half-maximal inhibitory concentrations (IC50) of IMBZC on HT29 and SW620 cell growth were determined to be 6.97 μg/mL and 4.89 μg/mL, respectively. IMBZC did not alter cell growth of normal cells HEK293. In addition, IMBZC inhibited cell migration and significantly decreased colony formation, suggesting its promising role in suppressing cancer metastasis. Mechanistic analyzes revealed that IMBZC treatment increased the expression of pro-apoptotic proteins p53 and Bax, while decreasing the expression of anti-apoptotic proteins Bcl-2 and Bcl-xL, thus indicating the induction of apoptosis in IMBZC-treated CRC cells, compared to untreated cells. Additionally, the addition of IMBZC to conventional chemotherapeutic drugs (i.e., 5-fluorouracil, irinotecan, and oxaliplatin) resulted in an increase in the cytotoxic potential of the drugs. In conclusion, the study suggests that IMBZC has substantial anticancer effects against CRC cells through its ability to induce apoptosis, inhibit cancer cell migration and colony formation, and enhance the cytotoxic effects of conventional chemotherapeutic drugs. These findings indicate that IMBZC could be a promising chemotherapeutic drug for the treatment of CRC. Further research should be conducted using in vivo models to confirm the anti-CRC activities of IMBZC.

The responses of inflammatory cytokines and brain-derived neurotrophic factor (BDNF) to a high-intensity interval training (HIIT) session were compared between 7 postmenopausal (57±2 y) and 8 premenopausal females (44±3 y) during the luteal phase of their menstrual cycle, when estrogen and progesterone are highest, and. HIIT consisted of 10 x 1 min running intervals (90% maximum heart rate) separated by 1 min recovery intervals. Blood samples were collected at baseline (fasted), pre-exercise (postprandial), and 0, 30 and 90 min post-HIIT and analyzed for interleukin (IL-6) and 10 (IL-10), tumour necrosis factor-alpha (TNF-α) and BDNF. IL-6 significantly increased from pre-exercise to 0 min post-HIIT in postmenopausal (+40%, p=0.01) but 30 min post-HIIT in premenopausal females (+60%, p=0.02). IL-6 remained elevated at 90 min post-HIIT in premenopausal (+104%, p=0.05) and to a higher degree in postmenopausal (+385%, p<0.001). IL-10 showed no response. TNF-α increased from pre- to 0 min post-HIIT (+10%, p=0.05), then decreased to below pre-exercise at 30 min (-10%, p=0.02) and 90 min (-5%, p=0.04) in both groups. BDNF increased immediate post-HIIT in premenopausal (+60%, p<0.001) but not postmenopausal females. The differences in IL-6 and BDNF response to HIIT between pre and postmenopausal females provide evidence of the role of female reproductive hormones in the regulation of these exercise-induced responses.

Carbapenemase-producing Enterobacter spp. Serratia marcescens, Citrobacter freundii, Providencia spp. and Morganella morganii (CP-ESCPM) are increasingly identified as causative agents of nosocomial infections but are still not under systematic genomic surveillance. In this study, using a combination of whole genome sequencing and conjugation experiments, we sought to elucidate the genomic characteristics and transferability of resistance genes in clinical CP-ESCPM isolates from Bulgaria. Among the 36 sequenced isolates, NDM-1 (12/36), VIM-4 (11/36), VIM-86 (8/36) and OXA-48 (7/36) carbapenemases were identified; two isolates carried both NDM-1 and VIM-86. The majority of carbapenemase genes were found on self-conjugative plasmids. IncL plasmids were responsible for the spread of OXA-48 among E. hormaechei, C. freundii and S. marcescens. IncM2 plasmids were generally associated with the spread of NDM-1 in C. freundii and S. marcescens, and also of VIM-4 in C. freundii. IncC plasmids were involved in the spread of the recently described VIM-86 in P. stuartii isolates. IncC plasmids carrying blaNDM-1 and blaVIM-86 have been observed too. blaNDM-1 was also detected on IncX3 in S. marcescens and on IncT plasmid in M. morganii. The significant resistance transfer rates highlight the role of the ESCPM group as a reservoir of resistance determinants and stress the need for strengthening the infection control measures.

Thrombosis after severe acute respiratory syndrome coronavirus 2 vaccination is a serious complication in patients who have a thrombophilic predisposition. In this case, a female patient with no family history of thrombophilia who had pediatric antiphospholipid syndrome (APS) developed deep vein thrombosis (DVT) when she was 6 years old; 6 months after receiving a second dose of the BNT162b2 vaccine, DVT reoccurred. The original thrombi were found in the right common iliac vein and the inferior vena cava, with concomitant left pulmonary infarction. The patient was treated with anticoagulants for 6 years after DVT onset, with subsequent treatment cessation for 5 years without recurrence. She received the BNT162b2 vaccine at 17 years of age, 1 week before a routine outpatient visit. Platelet factor 4 elevation was detected 14 days after the first vaccination, persisting for 5 months without thrombotic symptoms. Six months after the second vaccine dose, the DVT recurred and was treated with a direct oral anticoagulant. The vaccine exacerbated the patient’s APS by activating coagulation, causing thrombosis recurrence. Platelet factor 4 levels may indicate coagulation status. When patients predisposed to thrombosis are vaccinated, coagulation status and platelet activation markers should be monitored to prevent DVT development.

.Bacground: Sepsis remains a major health challenge worldwide, characterized by a dysre-gulated host response to infection, leading to high mortality and morbidity in intensive care units (ICUs). The Fibrosis 4 (FIB-4) index, originally developed to assess liver fibrosis in hepatitis C patients, has recently been explored for its potential prognostic value in sepsis patients. Method: This study retrospectively analyzed 309 sepsis patients admitted to the Internal Me-dicine and Anaesthesia ICUs between December 12, 2021, and December 15, 2023, to inves-tigate the relationship between FIB-4 levels, Acute Physiology and Chronic Health Evaluation (APACHE), and Sequential Organ Failure Assessment (SOFA) and clinical outcomes. Results: The study found that higher FIB-4 measurements were statistically significantly asso-ciated with increased 28-day mortality, with a cut-off value of 4.9 providing a sensitivity of 54.92% and specificity of 74.25%. Logistic regression analysis indicated that elevated Conclusion:FIB-4 levels were a significant predictor of early mortality, suggesting that the FIB-4 index could serve as a valuable prognostic tool in assessing the severity and prognosis of sepsis patients.

Background: This study addresses the burgeoning impact of Large Language Models (LLMs) such as ChatGPT on the integrity of online examinations and seeks to demonstrate latent and advanced LLM reasoning capabilities. The research devises an iterative self-reflective strategy for invoking critical thinking and higher-order reasoning in LLMs based on multimodal exam questions using visuals and text. Methods: The proposed strategy was demonstrated and evaluated on real exam questions by subject experts and the performance of ChatGPT (GPT-4) with vision was estimated on an additional dataset of 600 text descriptions of multimodal exam questions, focusing on its response to complex, visual, and textual prompts. Results: The results indicate that latent multi-hop reasoning capabilities can be invoked using the proposed self-reflective strategy, which can effectively steer ChatGPT towards correct answers by integrating critical thinking from each modality into the final response. Meanwhile, ChatGPT demonstrated considerable proficiency in being able to answer multimodal exam questions across 12 subjects. Conclusions: This work challenges findings from recent studies which claim that existing LLMs are unable to reason on complex multimodal tasks, and therefore this study underscores the need for enhanced online exam security measures like proctoring software, that can mitigate the potential misuse of AI technologies in educational settings.

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.

Metabolomics profiling for accurate and reliable quantification of organic acids that carry a carboxylic acid functional group in complex biological samples, remains a major analytical challenge in clinical chemistry research. Several procedural barriers associated with quantification of clinically important carboxylic containing metabolites (CCMs) including spontaneous decarboxylation during ionization, poor chromatographic resolution, and retention on a reverse-phase column, limit the sensitivity, specificity, and reproducibility of multiple-reaction monitoring (MRM) based LC-MS assay development. We report a targeted metabolomics-based analytical method for the quantification of CCMs using phenylenediamine derivatization. Accurate and sensitive quantification of CCMs is successfully demonstrated in an array of biological matrices. Recovery of metabolites from different matrices (plasma, serum, urine, saliva, tissues, and cell extracts), ranged from 90% to 105%, with all the CVs ≤ 10%. The method showed linearity over a broad dynamic range from 0.1 ng/mL to 10 µg/mL with linear regression coefficients of 0.99 for most of the metabolites tested herein, that covers broad-based applicability with the analysis of biological samples. In most cases the LODs were as low as 0.01 ng/mL. The phenylenediamine-based derivatization of carboxyl acid library consisting of more than 70 endogenous metabolites was constructed for metabolite identification, which spanned more than 40 biological pathways. The library included a wide-variety of structurally variant CCMs such as amino acids/conjugates, short to medium chain organic acids, di/tri-carboxylic acids/conjugates, fatty acids and some ring-containing CCMs. We compared the CCMs profiles of pancreatic cancer cells with normal pancreatic epithelial cells to test and validate the biological utility of this method. The comparative profiling between cancerous and normal cells resulted in the identification of potential biomarkers in pancreatic cancer, and their correlation with several key metabolic pathways such as central carbon energy metabolism, protein metabolism, including TCA cycle, glycolysis, Gln-Glu pathway, and biosynthesis of amino acids and unsaturated fatty acids was established. The method, described herein, for the first time enables the sensitive and highly specific quantification of CCMs on small sample size with high reproducibility in a high throughput manner. Given the biological and functional significance of this class of metabolites, this mass spectrometry based targeted quantitative assay, fills an important gap and is likely to support a wide range of applications for basic, clinical, and translational research.

This study proposes an innovative pharmacovigilance approach, VIGI-4, leveraging ChatGPT Teams Pro version. Our method involves aggregating data from all phase 4 studies published in February 2024 to identify adverse reactions. These results are categorized by disease state alphabetically, demonstrating the method's capacity to generate structured and easily navigable outputs. The results section is tailored to exemplify the valuable, actionable insights attainable through our workflow. This research emphasizes the game-changing potential of integrating advanced technologies such as ChatGPT into pharmacovigilance, signaling a new era in safeguarding drug safety.

Background: Open AI developed ChatGPT, a language model based on the GPT architecture, designed for text-based communication. Trained on diverse internet texts, ChatGPT generates contextually appropriate responses using machine learning. It understands input through analysis and context interpretation, generating coherent and contextually relevant responses. Interaction is possible through messaging platforms. Materials and Methods: In November 2023, we utilized ChatGPT 3.5, the default version at that time, to answer questions from the Italian National Residency Program Admission Tests (SSMs) of 2021, 2022, and 2023. The questions cover clinical, diagnostic, analytical, therapeutic, and epidemiological scenarios, sometimes accompanied by images. The study compared ChatGPT's answers to the official corrections on the Italian Ministry of University and Research (MUR) website. The scoring method used for evaluation was 1 point for correct answers, 0 points for unanswered questions, and -0.25 points for incorrect answers, reflecting the SSM test scoring system. Results: In summary, ChatGPT was tested with a total of 420 questions, 140 for each test. It achieved an overall accuracy of 80.48%, providing correct answers for 338 questions and incorrect answers for 82 questions. When faced with questions containing both text and images, it answered 55% correctly and 45% incorrectly. The model's performance varied over time, with an 82.14% accuracy rate in 2021 and 2022 (115 correct out of 140) and a 77.14% accuracy rate in 2023 (108 correct out of 140). Applying thisscoring method to the SSM test, ChatGPT would have scored 105 points in 2021 and 2022, and 100 points in 2023. Conclusions: ChatGPT has exhibited above-average performance in the last three SSM tests, highlighting its robust capability to interpret clinical scenarios and offer precise diagnostic and therapeutic guidance. Despite this, some limitations persist, notably the software's inability to interpret non-textual information.

Additive manufacturing (AM) or 3D printing of metals is gaining popularity due to its flexibility in fabricating parts with highly complex designs, as well as simplifying manufacturing steps and optimizing process times. In this investigation, 17-4 PH stainless steel was additively manufactured using Laser-Powder Bed Fusion (L-PBF), followed by functionalization through a DUPLEX treatment. This treatment involved a plasma-assisted nitriding process, followed by deposition of an arc-PVD c-Al0.7Cr0.3N hard coating. The microstructural modifications resulting from plasma nitriding (such as the formation of Fe2,3N and Fe4N, and the αN or expanded martensite phases), and the surface improvements with the c-Al0.7Cr0.3N coating on the 3D-printed 17-4 PH steel, are evaluated in comparison to conventionally manufactured 17-4 PH steel. These microstructural characteristics are correlated with the mechanical response of the treated surfaces. As a result of the plasma nitriding process, the hardness of the 3D-printed 17-4 PH SS increased by approximately 260%. The wear, measured through dynamic and static scratch-testing, was reduced by approximately 31%. This improvement was attributed to the modification of adhesive failure mechanisms, leading to a reduction in wear volume, improved coating adhesion, and enhanced scratch resistance.

Human Immunodeficiency Virus (HIV) infection and its latent recurrent infection make vaccine development a significant challenge for traditional vaccines; however, the mRNA delivery of multiepitope antigens capable of creating antibodies against the surface proteins of HIV-1 and HIV-2 along with their respective Nef proteins, responsible for the latent infection can bring a most effective, as well as affordable solution to the unresolved epidemics of HIV. In this paper, we present the complete design of a multiepitope vaccine to prevent acute infections and inactivate Nef proteins that block the MHC-1 and MHC-2 pathways to hide the virus for later reinfection.

This paper presents the PEnsemble 4 model, a sophisticated machine learning framework that integrates IoT-based environmental data to accurately forecast maize yield. With the projected significant growth in global maize demand over the next decade, the inherent risks posed by the crop’s dependence on weather conditions necessitate improved prediction capabilities. The PEnsemble 4 model, developed with high accuracy, incorporates comprehensive datasets encompassing soil attributes, nutrient composition, weather conditions, and UAV-captured vegetation imagery. By employing a combination of Huber and M estimates, the PEnsemble 4 model effectively analyzes temporal patterns in vegetation indices, specifically CIre and NDRE, which serve as reliable indicators of canopy density and plant height. In addition, this research significantly contributes to precision agriculture by offering an efficient and sustainable alternative to conventional farming practices through precise yield predictions. Notably, the PEnsemble 4 model enables earlier estimation, advancing the timeline for yield prediction from the conventional day 100 in the R6 stage to day 79 in the R2 stage. This improvement enhances decision-making processes in farming operations. The remarkable accuracy rate of 91% underscores the importance of adopting a multifaceted data approach that harnesses IoT-derived environmental insights. Additionally, the PEnsemble 4 model extends its benefits beyond yield prediction, facilitating the detection of water and crop stress, as well as disease monitoring in broader agricultural contexts. Ultimately, the PEnsemble 4 model establishes a new standard in maize yield prediction, revolutionizing crop management and protection through the synergistic utilization of IoT and machine learning technologies.

The reactivity of 3,5-di-(pyridin-4-yl)-1,2,4-thiadiazole (L1) with 1,4-diiodotetrafluorobenzene (1,4-DITFB) was explored and the halogen-bonded 1:1 co-crystal (1) was successfully isolated and structurally characterized.

This is a brief critique of the functions—particularly olfactory functions—specified for the “Chemosensory Protein” (CSPs) molecule family. On the basis of these proteins’ presence in the sensory antennal lymph of locusts, odor chemosensory ligand binding functions have been hypothesized. According to this hypothesis, the entire protein molecule superfamily is referred to as “CSPs”. However, new information and developments in the field of CSP molecular research, such as the expression of CSP genes in the gut, brain, fat body, wings, epidermis, and pheromone gland, as well as gene expression profiling from most early developmental stages—that is, CSP expression well in advance of the appearance of chemical sense nerve cells—strongly suggest that the protein molecule has other roles that are unrelated to chemosensing. Moreover, CSPs are found in bacterial microbial prokaryote organisms in addition to insects and all other arthropods. Thus, we examine the molecule’s name, definition, RNA editing, protein structure, lipid binding properties, DNA interaction, and evolutionary characteristics in brief before referring to this protein family as “Chemosensory Proteins”. As a means of renaming this protein family, this review article discusses the latest findings (“CSP” is attached to the tail of bigger intracellular proteins) and attempts to compel all the data. Because of its highly conserved molecular distinctive feature (four adjacent cysteines), we propose renaming “CSPs” as “4CSPs” (4 Cysteines Soluble Proteins) and use at least for abbreviations for distinctive animal proteins the common peptide 5-letter code, such as “Bommo-4CSPs”.

Depression is the commonest mental disorder worldwide. Both antidepressants and psychotherapy are effective in treating depression, but response to these treatments is often incomplete. Yoga-based interventions (YBIs) have emerged as a promising adjunctive treatment for depression. Recent research has attempted to identify the biological mechanisms associated with the antidepressant actions of YBIs. In this scoping review, conducted according to the PRISMA-ScR guidelines, the PubMed and Scopus databases were searched to retrieve research on biomarkers of response to YBIs in patients with depression. Eleven studies were included in the review. Based on these studies, YBIs may improve depression through beneficial effects on systemic inflammation, stress axis regulation, cardiac autonomic functioning, and possibly reductions in oxidative stress-related cellular damage. Increases in brain-derived neurotrophic factor (BDNF) may represent a final common pathway upon which these processes converge. Though these results are theoretically plausible, they should be interpreted with caution due to certain methodological limitations in the existing research. Replication of these results and improvements in study methodology, and the evaluation of other biomarkers relevant to the pathophysiology of depression, could further elucidate the mechanism of action of YBIs in this disorder, and identify which patients would benefit most from this treatment approach.

The study aimed to know the direct effect of strategic leadership on the quality of service represented by wireless communications services, in addition to knowing the indirect effect of strategic leadership on the quality of service when using performance as an intermediary variable. This research was conducted in government institutions in the Republic of Yemen. Represented by the offices of the Ministry of Communications and Information Technology in five Yemeni cities, it targeted senior management employees, boards of directors, and middle management concerned with strategic planning and strategic leadership. To measure and evaluate the factors of strategic leadership and service quality in Offices of the Yemeni Ministry of Communications Ministry of Communications and Information Technology of the Republic of Yemen. Moreover, performance. A questionnaire was formulated and distributed to the study sample, and data was collected through questionnaires for 150 individuals in some offices of the Yemeni Ministry of Communications. This study uses structural equation model analysis from the Partial Least Squares program through the Smart Plus 4 programs. The study reached a set of results, including that all models show a direct, positive and significant effect of strategic leadership on the quality of service represented by the quality of services in the offices of the Ministry of Communications. As well as the positive relationship between them, as well as the direct and positive impact of performance on the quality of service, as well as the positive and significant relationship between them. While the results indicated a positive and significant indirect effect of strategic leadership on service quality, there is also a positive and significant indirect relationship between strategic leadership on service quality when using performance as an intermediary variable.

Owing to their extensive biological potential, essential oils (EOs) and their bioactive phytochemicals have gained attention from the scientific community. Within this domain, Terpinen-4-ol (T-4-ol), a bioactive monoterpene alcohol and the major constituent of tea tree oil (TTO), has made its way into translational research. Recent literature on T-4-ol strongly indicates its diverse pharmacological properties, including but not limited to antimicrobial, antivirulent, antioxidant, anti-inflammatory, anti-hypertensive, and anti-cancer effects. Hence, this review provides a comprehensive overview of the multifaceted biological activities exhibited by T-4-ol, emphasizing its medicinal potential for widescale application. The antibacterial and antifungal effectiveness of T-4-ol has been discussed encompassing its role in combating a broad spectrum of bacterial and fungal pathogens, respectively. The review delves into the antivirulent prospects of T-4-ol, shedding light on its ability to attenuate virulence and mitigate bacterial pathogenesis. Scientific literature on the antioxidant and anti-inflammatory activity of T-4-ol highlighting its role in neutralizing reactive oxygen species and modulating inflammatory pathways has also been collated. Furthermore, the review elaborates on the cardioprotective and anti-hypertensive properties of T-4-ol and augments literature on its anti-cancer mechanism against various cancer cell lines. Overall, this review consolidates the existing knowledge on T-4-ol, providing a holistic understanding of its pharmacological abilities. The exploration of these diverse attributes positions T-4-ol as a promising candidate for further research and therapeutic repurposing in various biomedical applications.

Parkinson’s disease (PD) is one of the most common neurodegenerative diseases. Recent data highlight similarities between neurodegenerative diseases including PD and type 2 diabetes mellitus (T2DM) suggesting a crucial interplay between the gut–brain axis. GLP-1R agonists, known for their use in T2DM treatment, are currently extensively studied as novel PD modifying agents. For this narrative review article, we searched PubMed and Scopus databases for peer-reviewed research, review articles and clinical trials regarding GLP-1R agonists and PD, published in the English language with no time restrictions. We also screened the references of the selected articles for possible additional articles in order to include most of the key recent evidence. Our research was conducted between February 2023 and February 2024. We used the terms “GLP-1”, “GLP-1 receptor”, “GLP-1R agonists”, “PD”, “T2DM”, “insulin”, “neurodegenerative disease”, “glucose”, “animal models”, “clinical trials” in different combinations. Many data on animal models and preclinical studies show that GLP1-R agonists can restore dopamine levels, inhibit dopaminergic loss, attenuate neuronal degeneration and alleviate motor and non-motor features of PD. Evidence from clinical studies are also very promising enhancing the possibility of adding GLP1-R agonists in the current armamentarium of drugs available for PD treatment.

Diagnosis of neonatal sepsis is difficult as signs and symptoms are nonspecific. Interleukin-6 (IL-6) is a promising marker for neonatal sepsis. We aimed to test the accuracy of IL-6 in term and preterm infants after 72 hours of life (late-onset sepsis-LOS). We searched for IL-6 diagnostic accuracy studies between 1990 and 2020 using the PubMed database. Study selection was performed. The range of reported IL-6 sensitivities and specificities was 68% to 100% and 28% to 100%, respectively, the median values were 85.7% and 82% from 15 studies including 1306 infants. Subgroup analysis was performed. Sensitivity (87% vs 82%), but not specificity (both 86%), was better in preterm infants than in preterm and term infants. Early sample collection had the highest sensitivity (84%), but the lowest specificity (86%). To assess quality we used a STARD checklist adapted for septic neonates. Limitation of this review include the heterogeneous group of studies on the one side and the small number of studies on the other side that analyzed different combinations of biomarker. We concluded that IL-6 had a good performance especially in the preterm infant population and best results are achieved by measurements at the time of LOS suspicion.

We describe the development and validation of a HPLC-MS/MS method to assess the pharmacokinetics and tumour distribution of fenretinide, a synthetic retinoid chemically related to all-trans-retinoic acid, after administration of a novel oral nanoformulation of fenretinide, called bionanofenretinide (BNF). BNF was developed to overcome the major limitation of fenretinide: its poor aqueous solubility and bioavailability due to its hydrophobic nature. The method proved to be reproducible, precise, and highly accurate for the measurement of the drug and the mains metabolites. The lower limit of quantification resulted 1 ng/mL. The curve range of 1-500 ng/mL and 50-2000 ng/mL, for plasma and tumor homogenate respectively, was appropriate for the analysis, as demonstrated by the accuracy between 96.8% and 102.4% for plasma and 96.6-102.3% for tumor. The inter-days precision and accuracy determined on quality controls at 3 different levels were in ranges of 6.9%-7.5% and 99.3-101.0% and 0.96-1.91% and 102.3-105.8% for plasma and tumour, respectively.

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

The aim of this study was to determine the microbial stability, challenge to L. monocytogenes, and some physicochemical properties of turkey breast meat by alginate-based coating enriched with postbiotics (8% concentration, CFS) of Bifidobacterium bifidum DSM 20456 and Bifidobacterium bifidum BB12 strains. For this purpose, firstly, some antimicrobial and total phenolic matter, flavonoid, and DPPH activity values of postbiotics were determined. In addition, FTIR analysis was performed to see the intermolecular interactions of the biological coating agent. As a result of the study, alginate solution with postbiotic showed significant differences in pH, a*, b*, yeast-mold values of turkey meat during storage (7 days), while L* value, total aerobic mesophilic bacteria count (TMAP), psychrotrophic bacteria (PAB), lactic acid bacteria (LAB) and Listeria monocytogenes count were not effective (p>0.05).

Toxoplasmosis is a zoonosis of warm-blooded animals, affecting also humans, caused by Toxo-plasma gondii, an obligate intracellular parasite with a complex biological cycle. Toxoplasmosis is considered a re-emerging zoonosis and an important public health threat, also for the absence, up to now, of efficient vaccines and preventive measures. Sources of transmission to humans are environmental or food-borne, mainly through the consumption of raw and undercooked meat, predominantly of Sus scrofa, considered highly susceptible to T. gondii. Mainly in the last dec-ades, an effective strategy to counter animal infectious diseases was based on the discovery of resistance immuno-genetic markers, possibly to be used for association studies between geno-typic and phenotypic traits and consequently in Marker Assisted Selection. Until now, this gen-otyping approach has never been adopted for T. gondii infection, so this study aimed, for the first time, to fill this gap. In particular, pigs, reared in different farms of Central Italy, were serologically characterized by an ELISA assay performed on diaphragm meat juice. Out of 179 tested animals, 98 resulted seropositive (54.74%), 57 seronegative (31.84%) and 24 doubtful (10.6%), underlining a possible re-emerging diffusion of this protozoan in the investigated areas. Atten-tion was firstly focused on IL-18 gene, encoding for a pro-inflammatory cytokine that plays a key role starting from the upstream steps of the immunity pathway towards T. gondii. A RT-PCR assay followed by Sanger sequencing of IL-18 cDNA was de novo developed. For this interleukin, at this stage, genetic analysis has not highlighted significant polymorphic variations compared to the reference sequence, except for a seropositive animal. However, the outcomes of this pre-liminary innovative study will be investigated in depth analyzing other relevant genetic re-gions and other target genes.

With the aim to develop novel scaffolds for sustained release of drugs, we initially developed an easy approach for the synthesis of α,ω-homobifunctional mercaptoacyl poly(alkyl oxide)s. This was based on the esterification of the terminal hydroxyl groups of poly(alkyl oxide)s with suitably S-4-methoxytrityl (Mmt) protected mercapto acids, followed by removal of the acid labile S-Mmt group. This method allowed the efficient synthesis of the title compounds in high yield and purity, which were further used in the development a thioether cross-linked liposome scaffold, by thia-Michael reaction of the terminal thiol groups with preformed nano-sized liposomes bearing maleimide groups on their surface. The reaction process was followed by 1H-NMR, using a Carr-Purcell-Meiboom-Gill (CPMG) relaxation dispersion NMR experiment (1H-NMR CPMG), which allowed real-time monitoring and optimization of the reaction process. The thioether cross-linked liposomal scaffold that was synthesized was proven to preserve the nanosized characteristics of the initial liposomes and allowed sustained release of calcein (which was used as a chromophore), providing evidence for the efficient synthesis of a novel drug release scaffold consisted of nanoliposome building blocks.

The ability of recombinant, SARS-CoV-2 Spike (S) protein to modulate the production of two COVID-19 relevant, pro-inflammatory cytokines (IL-6 and IFN-γ) in PBMC cultures of healthy, pre-Covid-19 subjects was investigated. We observed that cytokine production was largely and diversely modulated by the S protein depending on antigen or mitogen stimulation, as well as on the protein source, insect (S-in) or human (S-hu) cells. While both proteins co-stimulated cytokine production by polyclonally CD3-activated T cells, PBMC activation by the mitogenic lectin Concanavalin A (Con A) was up modulated by S-hu protein and down-modulated by S-in protein. These modulatory effects were likely mediated by the S glycans as demonstrated by direct Con A-S binding experiments and use of yeast mannan as Con A binder. While being ineffective in modulating memory antigenic T cell responses, the S proteins and mannan were able to induce IL-6 production in unstimulated PBMC cultures and upregulate the expression of Mannose Receptor (CD206), a marker of anti-inflammatory M2 macrophage. Our data point to a relevant role of N-glycans, particularly N-mannosidic chains, decorating the S protein in the immunomodulatory effects here reported. These novel biological activities of the S glycan ectodomain may add to the comprehension of Covid-19 pathology and immunity to SARS-CoV-2.

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

This study investigates the moderating effect of corporate governance on the associations of internal audit and quality of internal audit with quality of financial reporting among commercial banks in the Republic of Yemen. The final sample includes 210 internal auditors, heads of internal auditors, chairpersons, and members of audit committees. Using a survey-based methodology, the results of the Smart-PL4 analysis showed a positive association between internal audit and quality of internal audit and quality of financial reporting. Interestingly, the results showed an insignificant association between internal audit, quality of internal audit, and quality of financial reporting when considering the moderating effect of corporate governance. The findings of this study contributes valuable insights to the existing literature on the influence of internal audit, quality of internal audit, and corporate governance on quality of financial reporting in developing countries, specifically in Yemen.

The sustainability of Indigenous Socioecological Systems (ISES) faces significant threats from global anthropogenic environmental changes, endangering Indigenous People (IP), who safeguard a substantial portion of the world's natural capital. Indigenous Traditional Food Systems (ITFS) are crucial within ISES, providing not only diverse and nutritious food but also holding cultural, spiritual, and economic significance. Despite embodying sustainable lifestyles, Indigenous voices remain underrepresented in climate and sustainability discussions. Addressing this gap, the research adopts the Political Ecological Theoretical Framework (PETF) to analyze the regulatory impact on the adaptability, resilience, and sustainability of ITFS. Two Indigenous communities, the Karen in Thailand and various groups in the Republic of Sakha (Yakutia) in Russia, serve as case studies. The study aims to establish a theoretical framework integrating Indigenous concerns into policies and regulations, emphasizing self-determination, cultural preservation, and land rights. Findings emphasize the necessity for comprehensive legal frameworks prioritizing Indigenous involvement in climate resilience and sustainability efforts, moving beyond symbolic gestures towards meaningful collaboration and decision-making power. Recognizing Indigenous vulnerability and engaging them as active partners is essential for navigating climate challenges within ISES and ITFS.

(1) Background: The aim of study was to investigate the salt consumption by children and adolescents from the Silesian Province (Poland), taking into account the region’s dietary traditions and number of years of school education. (2) Methods : 300 students aged 10–18 from different types of schools, were enrolled in the study and divided into groups in terms of: school, sex, the state of nutrition. The survey questionnaire about dietary habits, including the frequency and serving size with respect to 12 salty products was used. On the basis of the frequency and the amount of consumed products, as well as the data on salt content, the amount of total daily intake of salt was estimated.; (3) Results: The mean daily intake of salt by children and adolescents was 1.083 g ( 0.433 g of sodium); children aged 10–12 consumed the highest amount of salt (1.296 g/day) compared to pupils aged 13–15 (1.131 g of sodium) and adolescents aged 16–18 (0.863 g/day); (4) Conclusions: With age, as a result of various factors, the consumption of salt declines. The parents impact and the familial socio-environmental factors begin to wane, and other factors start to have influence, e.g. school education of healthy lifestyle, health behavior of peers.

Antipsychotic drug (APD) medication can lead to metabolic dysfunctions and weight gain, which together increase morbidity and mortality. Metabolically active visceral adipose tissue (VAT) in particular plays a crucial role in the etiopathology of these metabolic dysregulations. Here we studied the effect of 12 weeks drug medication by daily oral feeding of clozapine and haloperidol on the perirenal fat tissue as part of VAT of male and female Sprague Dawley rats in the context of complex former investigations on brain, liver, and blood. Adipocyte area values were determined as well as triglycerides, non-esterified fatty acids (NEFAs), glucose, glycogen, lactate, malondialdehyde equivalents, ferric iron and protein levels of Perilipin-A, hormone-sensitive-lipase (HSL), hepcidin, glucose transporter-4 (Glut-4) and insulin receptor-ß (IR-ß). We found increased adipocyte mass in males with slightly higher adipocyte area values in both males and females under clozapine medication. Triglycerides, NEFAs, glucose and oxidative stress in the medicated groups were unchanged or slightly decreased. In contrast to controls and haloperidol medicated rats, perirenal adipocyte mass and serum leptin levels were not correlated under clozapine. Protein expressions of perilipin-A, Glut-4 and HSL were decreased under clozapine medication. IR-ß expression changed sex-specifically in the clozapine medicated groups associated with higher hepcidin levels in the perirenal adipose tissue of clozapine-medicated females. Taken together, clozapine and haloperidol have a smaller effect than expected on perirenal adipose tissue. The perirenal adipose tissue shows only weak changes in lipid and glucose metabolism. The main changes can be seen in the proteins examined and probably in their effect on liver metabolism.

Chronic lymphocytic leukemia (CLL) is characterized by dysfunctional B cells. Immune checkpoint molecules such as cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), and programmed death-1 (PD-1) are upregulated in patients with CLL and may correlate with prognostic markers such as beta-2 microglobulin (B2M). The aim of this study was to evaluate the levels of immune checkpoints on B-cell subsets and to further correlate them with B2M levels in patients with CLL. We recruited 21 patients with CLL and 12 controls. B cell subsets and the levels of immune checkpoint expression were determined using conventional multi-color flowcytometry. Basal levels of B2M in patients with CLL were measured using an Enzyme-linked immunosorbent assay. Patients with CLL had increased levels of activated B cells when compared to the control group, p< 0.001. The expression of PD-1 and CTLA-4 were increased on activated B cells and memory B cells, p< 0.05. There were no associations between B2M levels and the measured immune checkpoints on B cell subsets, after adjusting for sex and age. African patients with CLL express elevated levels of PD-1 and CTLA-4 immune checkpoints on activated and memory B cell subsets. However, there is no correlation between these immune checkpoint expressions and B2M levels.

Objective: The pleiotropic effect of hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) is responsible for potent defense against inflammatory response. This study evaluated the inhibitory effects of HMG-CoA reductase inhibitors on monosodium urate (MSU)-induced inflammatory response through the regulation of interleukin-37 (IL-37) expression. Methods: Serum was collected from patients with gout (n = 40) and from healthy controls (n = 30). The mRNA and protein expression of target molecules IL-1b, IL-37, caspase-1, and Smad3 was measured in THP-1 cells stimulated with MSU, atorvastatin, or rosuvastatin using real-time quantitative polymerase chain reaction and Western blot assay. Transfection with IL-1b or Smad3 siRNA in THP-1 cells was used to verify the pharmaceutical effect of statins in uric acid-induced inflammation. Results: Serum IL-37 level in gout patients was significantly higher than in controls (p < 0.001) and was associated with serum uric acid level (r = 0.382, p = 0.008). THP-1 cells stimulated with MSU markedly induced IL-37 mRNA expression and transition of IL-37 from cytoplasm to nucleus. Recombinant IL-37 treatment dose-dependently inhibited activation of caspase-1 and IL-1b in MSU-induced inflammation. Atorvastatin and rosuvastatin attenuated caspase-1 activation and mature IL-1b expression but augmented translocation of IL-37 from cytoplasm to nucleus. Atorvastatin and rosuvastatin induced phosphorylation of Smad3 in THP-1 cells treated with MSU crystals. Statins potently attenuated translocation of IL-37 from cytoplasm to nucleus in THP-1 cells transfected with Smad3 siRNA compared to cells with negative control siRNA. Conclusion: This study revealed that statins inhibit MSU-induced inflammatory response through augmentation of phosphorylated Smad3-mediated IL-37 expression in THP-1 cells.

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

In ore regions impacted by mining and metal smelting emissions, distinguishing between geogenic anoma-lies and anthropogenic contamination poses a significant challenge. In a study from two areas with different mining histories in the Ore Mountains, Czech Republic, we demonstrate that targeted sampling of topsoils and subsoils respecting local geology and correct soil data treatment respecting soil textural variability effects are indispensable to correctly construct and interpret geochemical maps and identify anthropogenic contam-ination by As, Cu, Pb, and Zn. The list of analysed elements must include both potentially toxic and lithogenic elements, otherwise natural controls of soil composition cannot be deciphered. By using empirical cumulative distribution functions, we found that local backgrounds for As/Fe and Pb/Ti are significantly naturally ele-vated (5.7 to 9.8 times and 2.1 to 2.7 times higher, respectively) compared to the global averages. We con-structed geochemical maps with topsoil minus subsoil concentrations to show the main directions of spreading anthropogenic contamination. The anthropogenic diffuse contamination contribution was calcu-lated (1.12·10-4 and 1.42·10-4 for As/Fe and 16.5·10-4 and 16.2·10-4 for Pb/Ti, respectively), which corresponds to topsoil enrichment by ca. 15 and 14 mg kg-1 for As and ca. 35 and 42 mg kg-1 for Pb in the two study areas. Our study thus provided the first published quantitative estimates of geogenic and anthropogenic contribution to this well-known montane area. The obtained estimates were comparable to the results obtained previously from the local peat archives. The approach we used is efficient in deciphering natural and anthropogenic controls of PTEs in geochemically complicated areas.

Lipopolysaccharides (LPS) have been reported to be important factors in promoting the progression of hepatocellular carcinoma (HCC), but the corresponding molecular mechanisms remain to be elucidated. We hypothesize that epiregulin (EREG), an epidermal growth factor (EGF) family member derived from hepatic stellate cells (HSCs) and activated by LPS stimulation, is a crucial mediator of HCC progression in the tumor microenvironment. we used a mouse xenograft model of Huh7 cells mixed with half the number of LX-2 cells, with/without intraperitoneal LPS injection, to elucidate the role of EREG in LPS-induced HCC. In the mouse model, LPS administration significantly enlarged the size of xenografted tumors and elevated the expression of EREG in tumor tissues compared with those in negative controls. Moreover, CD34 immunostaining and the gene expressions of angiogenic markers by reverse transcription polymerase chain reaction revealed higher vascularization, with increased IL-8 expression in the tumors of the mice group treated with LPS compared to those without LPS. Our data collectively suggested that EREG plays an important role in the cancer microenvironment under the influence of LPS to increase not only tumor cell growth and migration/invasion of HCC cells but also tumor neovascularization via IL-8 signaling.

Human sepsis is one of the leading cause of death worldwide and is known to be a harmful damaging host inflammatory condition, primarily caused by endotoxin released by gram-negative bacteria. Despite antibiotics administration being widely used to treat disease, effective targeted therapeutic strategies for the sepsis are still lacking. Here, we demonstrate that CM1, a derivative of natural polyphenol chrysin, exerts anti-inflammatory activity by inducing the ubiquitin-editing protein TNFAIP3 and NAD-dependent deacetylase sirtuin 1 (SIRT1). We found that CM1 attenuated Toll-like receptor 4 (TLR4)-induced the generation of inflammatory cytokines by inhibiting the extracellular-signal-regulated kinase (ERK)/MAPK and nuclear factor kappa B (NF-κB) signaling pathway. In addition, the treatment of macrophages with CM1 induced the expression of TNFAIP3 and SIRT1 in TLR4-stimulated primary macrophages, however the anti-inflammatory properties of CM1 was disappeared by siRNA silencing of TNFAPI3 or by the genetic and pharmacologic inhibition of SIRT1. Importantly, intravenously administration of CM1 resulted in the decreased susceptibility to endotoxin-induced sepsis, leading to inhibition of the generation of proinflammatory cytokines and neutrophils infiltration into lung than control mice. Collectively, these findings suggest that CM1 has the potential to be a treatment candidate for diverse inflammatory diseases including sepsis.

Oncostatin M (OSM), an inflammatory cytokine belonging to interleukin-6 superfamily, is recognized as an essential factor secreted by osteal macrophages to orchestrate bone remodelling. Osteoprotegerin (OPG) produced by osteoblasts regulates osteoclastogenesis. We previously demonstrated that bone morphogenetic protein-4 (BMP-4) stimulates OPG synthesis in osteoblast-like MC3T3-E1 cells, and that SMAD1/5/8(9), p38 mitogen-activated protein kinase (MAPK), and p70 S6 kinase positively regulates the OPG synthesis. The present study is aimed to investigate the effect of OSM on BMP-4-stimulated OPG synthesis in osteoblasts. OSM suppressed the release and the mRNA expression of OPG upregulated by BMP-4 in MC3T3-E1 cells.  Neither the BMP-4-induced phosphorylation of SMAD1/5/9 nor that of p38 MAPK affected by OSM. On the other hand, the BMP-4-stimulated phosphorylation of p70 S6 kinase was considerably suppressed by OSM. These results strongly suggest that OSM suppresses the BMP-4-stimulated OPG synthesis via inhibition of the p70 S6 kinase-mediated pathway in osteoblasts.

Endothelial function is regulated by a myriad of complex pathways. In our previous study, the expression of miR-378a-3p was shown to inhibit endothelial autophagy and impair endothelial function. However, the mechanism underlying the effect of miR-378a-3p in endothelial cells remains to be elucidated. By employing an in silico approach, Protein Disulfide Isomerase 4 (PDIA-4) was identified as a target of miR-378-3p; however, its’ role in endothelial cells is not known. We here report that endothelial cell-specific loss of PDIA-4 leads to impaired autophagic flux accompanied by loss of endothelial function and apoptosis. Endothelial cell-specific loss of PDIA-4 also induced marked changes in endothelial cells’ architecture, accompanied with the loss of endothelial markers and gain of mesenchymal markers consistent with endothelial-to-mesenchymal transition (EndMT). Loss of PDIA-4 activates TGF-signaling, and inhibition of TGF-signaling inhibits EndMT in PDIA-4 silenced endothelial cells in vitro. Our findings help elucidate the role of PDIA-4 in endothelial autophagy and endothelial function and provide a potential target to modulate and/or limit autophagy and EndMT in (patho-)physiological conditions.

This is a brief critique of the functions—particularly olfactory functions—specified for the “Chemosensory Protein” (CSPs) molecule family. On the basis of these proteins’ presence in the sensory antennal lymph of locusts, odor chemosensory ligand binding functions have been hypothesized. According to this hypothesis, the entire protein molecule superfamily is referred to as “CSPs”. However, new information and developments in the field of CSP molecular research, such as the expression of CSP genes in the gut, brain, fat body, epidermis, and pheromone gland, as well as gene expression profiling from most early developmental stages—that is, CSP expression well in advance of the appearance of chemical sense nerve cells—strongly suggest that the protein molecule has other roles that are unrelated to chemosensing. Moreover, CSPs are found in bacterial microbial prokaryote organisms in addition to insects. Thus, we examine the molecule’s name, definition, RNA editing, protein structure, lipid binding properties, DNA interaction, and evolutionary characteristics in brief before referring to this protein family as “Chemosensory Proteins”. This article tries to compel and discuss the most recent information as a way to rename this protein family. Because of its highly conserved molecular distinctive feature (four adjacent cysteines), we propose renaming “CSPs” as “4CSPs” (4 Cysteines Soluble Proteins).

Cathepsin B (CatB) is thought to be essential for the induction of Porphyromonas gingivalis lipopolysaccharide (Pg LPS)-induced Alzheimer’s disease- like pathologies in mice, including interleukin-1β (IL-1β) production and cognitive decline. However, little is known about the role of CatB in Pg virulence factor-induced IL-1β production by microglia. We first subjected IL-1β-luciferase reporter BV-2 microglia to inhibitors of Toll-like receptors (TLRs), IκB kinase, and the NLRP3 inflammasome following stimulation with Pg LPS and outer membrane vesicles (OMVs). To clarify the involvement of CatB, we used several known CatB inhibitors, including CA-074Me, ZRLR, and human β-defensin 3 (hBD3). IL-1β production in BV-2 microglia induced by Pg LPS and OMVs was significantly inhibited by the TLR2 inhibitor C29 and the IκB kinase inhibitor wedelolactonne, but not by the NLRPs inhibitor MCC950. Both hBD3 and CA-074Me significantly inhibited Pg LPS-induced IL-1β production in BV-2 microglia. Although CA-074Me also suppressed OMV-induced IL-1β production, hBD3 did not inhibit it. Furthermore, both hBD3 and CA-074Me significantly blocked Pg LPS-induced nuclear NF-κB p65 translocation and IκBα degradation. In contrast, hBD3 and CA-074Me did not block OMV-induced nuclear NF-κB p65 translocation or IκBα degradation. Furthermore, neither ZRLR, a specific CatB inhibitor, nor shRNA-mediated knockdown of CatB expression had any effect on Pg virulence factor-induced IL-1β production. Interestingly, phagocytosis of OMVs by BV-2 microglia induced IL-1β production. Finally, the structural models generated by AlphaFold indicated that hBD3 can bind to the substrate-binding pocket of CatB, and possibly CatL as well. These results suggest that Pg LPS induces CatB/CatL-dependent synthesis and processing of pro-IL-1β without activation of the NLRP3 inflammasome. In contrast, OMVs promote the synthesis and processing of pro-IL-1β through CatB/CatL-independent phagocytic mechanisms. Thus, hBD3 can improve the IL-1β-associated vicious inflammatory cycle induced by microglia through inhibition of CatB/CatL.

Results showed that mulberry leaves could significantly reduce backfat thickness (P&lt;0.05) and increase intramuscular fat (IMF) content (P&lt;0.05). Lipidomics analysis showed that mulberry leaves improved lipid profile composition and increased the proportion of triglycerides (TG). Interestingly, IMF content was positively correlated with acyl C18:2 and negatively correlated with C18:1 of differential TGs. In addition, cecal microbiological analysis showed that mulberry leaves could increase the abundance of bacteria such as UCG−005, Muribaculaceae_norank, Prevotellaceae_NK3B31_group, Limosilactobacillus, and so on. At the same time improve the L-tyrosine-baton rouge ester, Oleic acid methyl ester, 21-deoxycortisol, N-acetyldihydrosphingosine, Mulberrin relative abundance. In this study, we found that mulberry leaves could extremely significantly increasing the mRNA relative expression of lipoprotein lipase (LPL), fatty acid-binding protein 4 (FABP4) and peroxisome proliferators-activated receptor γ (PPARγ) in muscle (P＜0.01), significantly increasing mRNA relative expression of diacylglycerol acyltransferase 1 (DGAT1) (P＜0.05) and significantly decreasing the mRNA relative expression of acetyl CoA carboxylase (ACC) (P＜0.05), and aignificantly upregulated hormone-sensitive triglyceride lipase (HSL), peroxisome proliferators-activated receptor α (PPARα) mRNA relative expression (P＜0.05) in backfat. In addition mulberry leaves could increased serum leptin and adiponectin (P＜0.01). Ultimately lead to up-regulation of IMF and down-regulation of backfat.

We analyzed mineralogical characteristics, and major as well as rare earth element concentrations from a cryptotephra layer in sediments of the infilled maar of Auel (Eifel, Germany). The results of detailed geochemical analyses of clinopyroxenes and their glassy rim of the specific layer are most similar to those from the Campanian Ignimbrite (CI) Tephra occurrence in a loess section at Urluia (Romania). Both records show idiomorphic green clinopyroxenes and formation of twisted minerals up to millimeter scale. The cryptotephra in the Auel core has an age of around 39,940 yr b2k in the ELSA-20 chronology, almost identical to the latest Ar/Ar dates for the Campanian Ignimbrite/Y5 eruption. These observations suggest that parts of the CI ash cloud were transported also northwestward into Central Europe, whereas the main branch of the CI ash plume was transported from southern Italy towards the NE, E and SE.

Background: Skin is exposed to ultraviolet radiation (UV) and air pollution and recent works demonstrated these factors have additive effects in the disturbance of skin homeostasis. Nuclear factor erythroid 2-related factor 2 (Nrf2) and aryl hydrocarbon receptor (AHR) appears appropriate targets in the management of combined environmental stressors. The protective effects of Silymarin (SM), an antioxidant and anti-inflammatory complex of flavonoids, were evaluated. Methods: Reactive oxygen species (ROS) and interleukin 1-alpha (IL-1a) were quantified in UV+urban dust stressed reconstructed human epidermis (RHE) treated with SM. Gene expression study was conducted on targets related to AHR and Nrf2. SM agonistic activity on cannabinoid receptor type 2 (CB2R) was evaluated on mast cells. Clinical study quantified the performance of SM and cannabidiol (CBD), in skin exposed to solar radiation and air pollution. Results: SM decreased morphological alterations, ROS and IL-1a in UV+urban dust stressed RHE. AHR and Nrf2 related genes were upregulated that control antioxidant effector and barrier function. Interleukin 8 gene expression was decreased. Clinical study confirmed SM to improve homogeneity and perceived well-being of urban skins exposed to UV, outperforming CBD. SM activated CB2R and release of β-endorphin from mast cells. Conclusions: SM provides protection of skin from oxidative stress and inflammation caused by two major factors of exposome and appears mediated by AHR-Nrf2. SM activation of CB2R opens a new understanding of SM anti-inflammatory properties.

Vaccine-induced immune thrombotic thrombocytopenia (VITT) is a rare but severe adverse event that was first observed during the global vaccination campaign against SARS-CoV-2 infection, specifically in those receiving adenoviral vector-based vaccines for Coronavirus disease 2019 (COVID-19). VITT develops 4 to 42 days post-vaccination and is characterized by the development of platelet-activating anti-platelet factor 4 (PF4) antibodies, leading to thrombocytopenia and thrombosis at unusual sites. The rise in awareness and subsequent prompt recognition of VITT was paramount in reducing mortality. Moreover, as vaccination campaigns around the world continue, a better understanding of VITT not only has important clinical implications but is also crucial for future vaccine development. In this review, we summarize the clinical features, pathophysiology, and incidence rates of VITT as well as highlight other anti-PF4 antibody-mediated disorders of growing clinical significance.

This paper outlines the evolution of a learning technology interface from a Beta version to launch with educators and its alignment to pedagogical theory, designed to maximise collaboration between teacher and student. It explores how the “co-creation” of curricula via textual sources that underpin teaching and learning can be enhanced through interactive e-books and outlines the challenges involved in this praxis. With a number of stakeholders involved in the live use of the platform (including teachers, students, HE educators, course instructors, curriculum designers and software developers), iterative feedback loops informed real-time design improvements to both the interface and the-ory. This collaboration utilised a design-based research (DBR) approach (Wang and Hannafin, 2005), which is outlined here as explanation of how the tool developed and how iterative feedback helped to reconsider the challenges educators face in implementing pedagogical innovation across differing contexts. We propose how speculative design (Lukens and DiSalvo, 2012) and Activity Theory (Engeström, 1987) workshops can methodologically enhance the planning and evaluation phases inherent to DBR approaches, which involve students to prepare for educators’ innovation. Finally, we conclude with how educators can utilise these design principles using stratified approaches to help prepare organisational approaches for innovation.

Alzheimer's disease (AD) is characterized by abnormal amyloid beta (Aβ) plaques and hyperphosphorylated tau in the brain. Aβ plaques precede cognitive impairments and can be detected through amyloid-PET or in cerebrospinal fluid (CSF). Assessing the plasma Aβ42/Aβ40 ratio seems promising for non-invasive and cost-effective detection of brain Aβ accumulation. This approach involves some challenges, including the accuracy of blood-based biomarker measurements and the establishment of clear, standardized thresholds to categorize the risk of developing brain amyloid pathology. Plasma Aβ42/Aβ40 ratio was measured in 277 volunteers without dementia, 70 AD patients and 18 non-AD patients using single-molecule array. Patients (n=88) and some volunteers (n=66) were subject to evaluation of amyloid status by CSF Aβ quantification or PET analysis. Thresholds of plasma Aβ42/Aβ40 ratio were determined based on a Gaussian mixture model, a decision tree, and the Youden index. The 0.0472 threshold, the one with the highest sensitivity, was retained for general population without dementia screening, and the 0.0450 threshold was retained for research and clinical trials recruitment, aiming to minimize the need for CSF or PET analyses to identify amyloid-positive individuals. These findings offer a promising step towards a cost-effective method for identifying individuals at risk of developing AD.

The superficial quality of the strip is a very important issue in steel production; the profile, flat-ness, and geometry of strip are indicators of supreme quality. Considering the dimensions, the thickness is one of the most important variables in the production of strip. In the present study the elastic curve of Back Up Rolls (BUR) is analyzed, considering them as simply supported beams as well as the effect of rolls on the profile of the strip, specifically in the strip edge pro-ducing edge drop. The analysis is simulated with a model in 3D using a Finite Element Method (FEM) considering +0.039mm crown on Back Up Roll and +0.101mm crown on Work Roll (WR). The results showed that there is an instability zone of 76mm in the strip edge, this geometry is symmetrical in both ends of the strip, it was validated with the results of compact X-ray thick-ness gauge from a 4-high cold mill. This study not only provides a theoretical basis for the edge drop, but also provides the basis for the understanding of deformation on rolls used in rolling mill processes and their effect on the thickness, profile, shape, and dimensional quality of strips.

Cinnamate 4-hydroxylase (C4H) is a cytochrome P450-dependent monooxygenase enzyme that catalyzes a key step in phenylpropanoid metabolism in plants. However, there is very limited information on the function of C4H in medicinal plants. In the present study, the C4H gene from the Ferula pseudalliacea genome (named FpC4H) was cloned and characterized. In addition, the expression levels of FpC4H in the roots, stems, leaves, flowers and seeds were investigated via real-time PCR. FpC4H showed the most similarity with C4H proteins from Daucus carota. The results predicted that FpC4H, as well as its orthologs, is an unstable and hydrophilic protein. A high genetic distance was observed between FpC4H and C4H from monocots based on evolutionary analysis. Moreover, a variable region related to the variable function of C4H was detected in conserved domain region of C4H proteins. Protein structure analysis revealed that isoleucine and leucine residues are frequently present in the binding region of FpC4H, and two ion binding regions, cysteine258 and asparagine217, were identified in the 3D structure of FpC4H. Expression analysis revealed that the FpC4H gene is expressed in all organs of F. pseudallicea. A low expression level of FpC4H was recorded in leaves, and a high expression level was observed in flower tissues. Based on the expression profile, FpC4H seems to be linked to a high content of phenolic compounds in flowers.

Febrile infections are a common cause of presentation to the emergency department (ED) in chil-dren. While viral infections are usually self-limiting, sometimes bacterial illnesses may lead to sepsis and severe complications. Inflammatory biomarkers such as C reactive protein (CRP) and procalcitonin are usually the first blood exams performed in the ED to differentiate bacterial and viral infections; the better understanding of immunochemical pathways has nowadays led to the discovery of new and more specific biomarkers that could play a role in the emergency setting. The aim of this narrative review is to provide the most recent evidence on biomarkers and predictor models combining them for serious bacterial infections (SBI) diagnosis in febrile children. Litera-ture analysis showed that inflammatory response is a complex mechanism in which many bio-chemical and immunological factors contribute to host response in SBI. CRP and procalcitonin still represent the most used biomarkers in the pediatric ED for the diagnosis of SBI. Their sensibility and sensitivity increase when combined and for this reason it is reasonable to take them both into consideration in the evaluation of a febrile children. The potential of machine learning tools, who represent a real novelty in medical practice, in conjunction with routine clinical and biological in-formation, may improve accuracy of diagnosis and target therapeutic options in SBI. However, studies on this matter are not yet validated in younger populations, making their relevance in pe-diatric precision medicine still uncertain. More data from further researches are needed to improve clinical practice and decision making using these new technologies.

A Staudinger reaction on solid phase between an electronodeficit organic azide such as sulfonyl azide, and the phosphite triester formed upon phosphoramidite coupling is a convenient method for chemical modification of oligonucleotides at the internucleotidic phosphate position. In this work, 4-carboxybenzenesulfonyl azide either with a free carboxy group or in the form of an activated ester such as pentafluorophenyl, 4-nitrophenyl, or pentafluorobenzyl ester were used to introduce a carboxylic acid function to the terminal or internal internucleotidic phosphate of an oligonucleotide via Staudinger reaction. A subsequent treatment with excess primary alkyl amine followed by usual work-up, after prior activation with a suitable peptide coupling agent such as HBTU/HOBt in the case of a free carboxyl, afforded amide-linked oligonucleotide conjugates in good yields including multiple conjugations of up to the exhaustive modification at each phosphate position for a weakly activated pentafluorobenzyl ester, whereas more strongly activated and, thus, more reactive aryl esters provided only single conjugations at the 5′-end. The conjugates synthesized include those with di- and polyamines that introduce a positively charged side-chain to potentially assist intracellular delivery of the oligonucleotide.

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.

Neuromyelitis Optica Spectrum Disorder (NMOSD) is a rare immune-mediated relapsing-remitting disease of the central nervous system. The usage of rituximab, to prevent NMOSD relapses, is common in Sweden, but the knowledge on long-term efficacy and risk for severe infections are limited. We performed a retrospective cohort study with medical chart review of rituximab-treated NMOSD patients at the Karolinska University Hospital, Sweden, to assess the occurrence of relapses and severe infectious events (SIE). Furthermore, we collected data on CD19+ lymphocyte, and IgG levels during therapy. A total of 42 NMOSD patients; 24 with aquaporin -4 antibodies (AQP4+), eight with myelin oligodendrocyte glycoprotein antibodies (MOG+) and 10 with absence of antibodies (double-seronegative) were included. During a mean treatment time of 4.4 years, 37% AQP4+, 75% MOG+, and 60% double-seronegative patients experienced 1 relapse. SIEs were common with 46% of AQP4+, 25% of MOG+, and 40% of double-seronegative patients affected. Incomplete CD19+ lymphocyte suppression did not predict a relapse and there was no correlation between IgG levels and SIEs. In conclusion, our data demonstrated a high risk for both relapses and SIEs in rituximab-treated NMOSD patients highlighting the need for close clinical vigilance of disease activity and infections during treatment.

Banana is one of the most important fruits in the world due to its status as a major food source for more than 400 million people. Fusarium oxysporum f. sp. cubense tropical race 4 (Foc TR4) causes substantial losses of banana crops every year, and molecular host resistance mechanisms are currently unknown. We here performed a genome-wide analysis of the autophagy related protein 8 (ATG8) family in a wild banana species. The banana genome was found to contain 10 MaATG8 genes. Four MaATG8s formed a gene cluster in the distal part of chromosome 4. Phylogenetic analysis of ATG8 families in banana, Arabidopsis thaliana, Citrus, rice, and ginger revealed five major phylogenetic clades shared by all of these plant species, demonstrating evolutionary conservation of the MaATG8 families. The transcriptomic analysis of plants infected with Foc TR4 showed that almost all of the MaATG8 genes were more highly induced in resistant cultivars than in susceptible cultivars. Finally, MaATG8F was found to interact with MaATG4B in vitro (with yeast two-hybrid assays), and MaATG8F and MaATG4B all positively regulated banana resistance to Foc TR4. Our study provides novel insights into the structure, distribution, evolution, and expression of the MaATG8 family in bananas. Furthermore, the discovery of interactions between MaATG8F and MaATG4 could facilitate future researches of disease resistance genes for genetic improvement of bananas.

Using qRT-PCR analysis, the LcIL-8 expression level indicated broad expression in most detected tissues, with the most predominant expression in whole blood at 6 to 24 h after infection with S. iniae at concentrations of 105 colony-forming unit (CFU)/fish (p &lt; 0.05). After immersion with F. covae, the LcIL-8 transcript was upregulated in the gills, liver and intestine, with the highest expression level found in the gills. However, LcIL-8 was downregulated in all tested tissues at 48 and 96 h after infection with the two pathogenic strains, indicating that Lc-IL8 has a short half-life during the early immune responses to pathogens. MIC analysis of rLcIL-8 protein against S. iniae was 10.42 ± 3.61 µg/mL. Furthermore, the functional analyses clearly demonstrated that 10 and 100 µg of rLcIL-8 protein efficiently enhanced the phagocytic activity of Asian seabass phagocytes in vitro (p &lt; 0.05). Additionally, in vivo injection of S. iniae following the rLcIL-8 protein indicated that 50 and 100 µg of rLc-IL-8 were highly effective in protecting fish from the tested pathogen (p &lt; 0.001). These results indicate that rLcIL-8 plays a crucial role in the defense mechanisms against bacterial infections in the target fish.

Background: Inflammasomes recognize cytosolic danger signals, including pathogens, and subsequently induce the secretion of pro-inflammatory cytokines, such as interleukin (IL)-1β. Studying inflammasomes in the red fox (Vulpes vulpes) is crucial from a wildlife veterinary and public health perspective, as it can be used to help control and prevent the transmission of zoonotic pathogens. The understanding of how diversity in inflammasomes across species affects pathogen carriage in the red fox is still limited. Methods: We investigated the activation and intracellular mechanisms of three inflammasomes (NLRP3, AIM2, and NLRC4) in fox peripheral blood mononuclear cells (PBMCs), using established triggers and inhibitors derived from humans and mice. Results: Fox PBMCs exhibited normal activation and induction of IL-1β secretion in response to representative inflammasome triggers (ATP and nigericin for NLRP3, dsDNA for AIM2, flagellin for NLRC4). However, in inhibitor studies, MCC950, a selective NLRP3 inhibitor, suppressed IL-1β secretion mediated by the fox AIM2 and NLRC4 inflammasomes. Conclusions: These findings suggest that NLRP3 may have a common role in dsDNA- and flagellin-mediated inflammasome activation in the red fox. In conclusion, this fox inflammasome biology can be applied to the control of zoonotic infections and the treatment of inflammasome-mediated diseases in the red fox.

Tocilizumab against interleukin-6 receptor (IL-6R) has been demonstrated to inhibit the progression of diverse cancers in vitro and in vivo. Nonetheless, evidence regarding the anti-tumor effects of Tocilizumab on human colorectal carcinoma (CRC) corresponding to IL-6R expression levels re-mains scarce. To investigate the influence of IL-6R expression, SW480 and HT-29 cells inoculated subcutaneously into NU/NU mice were used as our human CRC xenograft models with anti-IL-6R antibody (Tocilizumab) therapy. IL-6R expression levels, the histology of CRC growth/ invasiveness and tumor growth-related signaling pathway were estimated by H&E and immunohistochemical staining. SW480 tumor cells with higher IL-6R expression levels exerted better responsiveness in Tocilizumab therapy than the treated HT-29 group. Likewise, therapeutic effects of Tocilizumab on the proliferative ability with mitotic index and Ki-67 expressions, the invasiveness with MMP-9 proteinase expressions, ERK 1/2 and STAT3 signaling transduction in SW480 treatment group were superior to HT-29 treatment group. In light of our results, IL-6R is the key indicator for the efficacy of Tocilizumab treatment in CRC xenografts. From the perspective of precision medicine, tumor response to anti-IL-6R antibody therapy could be predicted on the basis of IL-6R expression levels. In this manner, Tocilizumab may serve as a targeted and promising anti-CRC therapy.

Periodontitis is a disease that originates from gingival tissue, and if left untreated, can cause inflammation to spread to deeper tissues, altering bone homeostasis, and even leading to tooth loss. When the bacteria in plaque reach sufficient numbers, the immune system responds by activating immune cells that will produce cytokines, including interleukin-1 (IL-1), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α). These immune signaling molecules will coordinate the inflammatory responses. IL-1 binds to the IL-1 receptor (IL-1R) on the surface of target cells, initiating an inflammatory response by activating intracellular signalling pathways. Inhibition of IL-1R can prevent the interaction of IL-1 with this receptor, thereby halting the activation of the inflammatory pathway. By substituting this connection with active anti-inflammatory substances, it is possible to prevent the contact between IL-1 and IL-1R. The licorice plant, Glycyrrhiza glabra, includes eight types of flavonoids with significant anti-inflammatory potential, namely isoliquiritigenin, glyzaglabrin, prunetin, shinpterocarpin, licochalcone A, glabridin, glisoflavone, and isoangustone A. This study aims to assess the potential of such flavonoids as candidates for periodontitis treatment through molecular docking, using AutoDock Tools v.1.5.6. All tested compounds showed highly stable bonds to IL-1R, with a binding affinity values below -7 kcal/mol. Van der Waals forces, hydrogen bonds, and hydrophobic bonds all contribute to the stability of these interactions. Among the eight tested compounds, glisoflavone, which has a Ki value of 90.89 nM and a ΔG value of -9.61 kcal/mol, has the highest binding stability to IL-1R.

We successfully fabricated Ag@Cu2O core-shell decorated on reduced graphene oxide (rGO) nanocomposites (ACRN) by a simple and convenient in situ substitution method. The properties of these ACRN with heterostructure layers were characterized by scanning and transmission electron microscopies and absorption spectroscopy. We used p-nitrophenol (4-NP) as a probe molecule to determine the chemical catalytic activity of the ACRN. Upon introduction of rGO, a high electron transfer efficiency was achieved; thus, the catalytic activity was improved significantly. Therefore, the ACRN exhibited significantly improved catalytic activity for the reduction of 4-NP and showed the high application value in the removal of toxic and harmful substances from water. In addition, the fabricated ACRN was used for the reduction of organic dyes and explosive pollutants to generate nontoxic products. Furthermore, the high charge redistribution and transfer among Ag, Cu2O and rGO in the ACRN induced the high catalytic reduction of organic pollutants, indicating the excellent potential of these materials for applications in water pollution treatment.

Background: This study retrospective evaluates patients with stage IV melanoma treated with Nivolumab and Ipilimumab combination therapy from two regional oncology centers from Romania between the years of 2019 up to the end of 2022. Methods: The data were analyzed in SAS for Windows, V9.4. The survival curves were estimated using the Kaplan-Meier method, and survival distributions were compared with log-rank test. The effects of the main clinical and pathological variables on OS and PFS were investigated with Cox regression. Results: Kaplan-Meier curve of OS in all evaluable patients enrolled in the study resulted in a median OS of 346 days (95% CI: 150-NA) and a median PFS of 211 days (95% CI: 113-430). 45.3% of the patients experienced adverse events during the Nivolumab + Ipilimumab treatment with some of them having multiple organ systems involved. Discussion: The OS values were lower than that reported in approval clinical trials, but the results show a marked improvement when comparing to results obtained by chemotherapy regimens previously used in these scenarios. Conclusion: This study provides real-world insights into the survival data and safety profiles of combination therapy with anti-PD-1 antibodies and anti-CTLA-4 antibodies.

Post-stroke depressive disorders (PSD) and post-stroke cognitive impairments (PCI) are frequent consequences of ischemic stroke (IS). The study was focused on exploring possible associations between relative volumes of cortical and limbic brain structures during the acute period of IS, and changes in biochemical indices of hypothalamic-pituitary-adrenal, sympathoadrenal medullary and inflammatory systems, with the development of PSD or PCI after mild or moderate IS. Patients developing PSD later on had significantly smaller relative volumes of the hippocampus, entorhinal cortex, and temporal pole versus patients without depressive symptoms. PCI development was associated with significantly smaller volumes of temporal pole and supramarginal gyrus versus patients without cognitive changes. Multiple logistic regression analysis showed higher likelihood of developing PSD in patients with smaller temporal pole volume (β0=10.9; β=-4.27; p=0.04) and increased salivary α-amylase activity (β0=-3.55; β=2.68e-05; p=0.02,). PCI likelihood was higher in patients with smaller supramarginal gyrus volume (β0=3.41; β=-0.99; p=0.047), smaller temporal pole volume (β0=3.41; β=-3.12; p=0. 06), and increased hair cortisol concentration at admission (index of accumulated stress load within a month before IS; β0=3.41; β=-0.05; p=0.08). The data support the hypothesis suggesting predisposition to PSD and PCI and multi hit scenarios of their pathogenesis with IS providing a final hit.

Boeremia exigua var. exigua is a recurrent pathogen causing root rot in industrial chicory. Currently, there is no chemical or varietal control for this disease, and thus management strategies need to be developed. This study determined the biocontrol effect of strains of Pseudomonas protegens bacteria with antimicrobial compounds on the fungus B. exigua var. exigua under in vitro, in vivo and field conditions. In addition, root colonization by these bacteria was estimated by molecular analysis. Eighteen isolates of Pseudomonas spp were evaluated and the strains that showed the greatest in vitro inhibition of fungal mycelial growth (mm), Ca10A and ChB7, were selected. Inoculation with the strain ChB7 showed less severity (necrotic area) under in vivo conditions (root trials) compared to the control inoculated with the pathogen (P≤0.05). The molecular analysis revealed that root colonization of plants grown in pots was equal or greater than 70%. Similar levels were observed in the field trials conducted in Selva Negra and Canteras experimental stations (2015-16 season), with values ranging from 85.7 to 70.5% and from 75.0 to 79.5%, respectively. Regarding yield (ton ha-1), values were higher in the treatments inoculated with strains Ca10A and ChB7 (P≤0.05) in both experimental sites, while a lower incidence and severity of root rot were observed in Selva Negra. These results suggest that the Chilean strains of P. protegens are a promising tool for the control of root diseases in industrial chicory.

Effective therapeutics for Alzheimer's disease (AD) are in great demand worldwide. In our previous work, we responded to this need by synthesizing novel drug candidates consisting of 4-amino-2,3-polymethylenequinolines conjugated with butylated hydroxytoluene via fixed-length alkylimine or alkylamine linkers (spacers) and studying their bioactivities pertaining to AD treatment. Here, we report significant extensions of these studies, including the use of variable-length spacers and more detailed biological characterizations. Conjugates were potent inhibitors of acetylcholinesterase (AChE, minimum IC50 15.1±0.2 nM) and butyrylcholinesterase (BChE, minimum IC50 5.96±0.58 nM), with weak inhibition of off-target carboxylesterase. Conjugates with alkylamine spacers were more effective cholinesterase inhibitors than alkylimine analogs. Optimal inhibition for AChE was exhibited by cyclohexaquinoline and for BChE by cycloheptaquinoline. Increasing spacer length elevated potency against both cholinesterases. Structure-activity relationships agreed with docking results. Mixed-type reversible AChE inhibition, dual docking to catalytic and peripheral anionic sites, and propidium iodide displacement suggested the potential of hybrids to block AChE-induced β-amyloid (Aβ) aggregation. Hybrids also exhibited inhibition of Aβ self-aggregation in the thioflavin test; those with a hexaquinoline ring and C8 spacer were the most active. Conjugates demonstrated high antioxidant activity in ABTS and FRAP assays as well as inhibition of luminol chemiluminescence and lipid peroxidation in mouse brain homogenates. Quantum-chemical calculations explained antioxidant results. Computed ADMET profiles indicated favorable blood-brain barrier permeability suggesting CNS activity potential. Thus, the conjugates could be considered promising multifunctional agents for potential treatment of AD.

Reactions of picolinamides with 1,3-propanesultone in methanol followed by the treatment with ketones led to a series of previously unknown chemical transformations, yielding first pyridinium salts (2a-f) with a protonated endocyclic nitrogen atom and then heterocyclic salts (3a-j) containing a 4-imidazoline ring. The structures of intermediate and final products were determined by IR and 1H, 13C NMR spectroscopy and X-ray study. The effects of the ketone and alcohol structures on the product yield were studied by quantum-chemical calculations. The stability of salts 3a-j towards hydrolysis and alcoholysis makes them excellent candidates for the search of new types of biologically active compounds.

(1) Background: The aim of this study was to analyze the relationship between the serum levels of soluble transferrin receptor (sTfR) and interleukin 4 (IL-4), and disease activity and organ mani-festations in SLE patients. (2) Methods: We studied 200 SLE patients and 50 controls. We analyzed disease activity, organ involvement, serum sTfR, IL-4, and interleukin-6 (IL-6) levels, and antinu-clear and antiphospholipid antibody profiles. (3) Results: The median serum levels of sTfR (p>0.000001) and IL-4 (p<0.00001) were higher in the study group than in the controls. SLE patients, compared to the controls, had significantly lower HGB levels (p<0.0001), a lower iron concentration (p=0.008), a lower value of total iron-binding capacity (TIBC) (p=0.03), and lower counts of RBC (p=0.004), HCT (p=0.0004), PLT (p=0.04), neutrophil (p=0.04), and lymphocyte (p<0.0001). Serum sTfR levels were negatively correlated with lymphocyte (p=0.0005), HGB (p=0.0001) and HCT (p=0.008), and positively correlated with IL-4 (p=0.01). Elevated serum sTfR >2.14 mg/dL was associated with an increased risk of myocardial infarction (OR: 10.6 95 CI 2.71–464.78; p=0.001), ischemic heart disease (OR: 3.25 95 CI 1.02–10.40; p=0.04), lung manifestations (OR: 4.48 95 CI 1.44–13.94; p=0.01), and hematological manifestations (OR: 2.07 95 CI 1.13–3.79; p=0.01), and with a reduced risk of neuropsychiatric manifestations (OR: 0.42 95 CI 0.22–0.80; p=0.008). Serum IL-4 was negatively correlated with CRP (p=0.003), and elevated serum IL-4 levels > 0.17 mg/l were associated with a reduced risk of mucocutaneous manifestations (OR: 0.48 95 CI 0.26–0.90; p=0.02). (4) Conclusions: In SLE patients, elevated serum levels of sTfR were associated with an increased risk of cardiovascular, pulmonary, and hematological manifestations, and with a decreased risk of neuropsychiatric manifestations. In contrast, elevated serum IL-4 levels were associated with a decreased risk of mucocutaneous manifestations.

CD44 is a type I transmembrane glycoprotein, and possesses various isoforms which are largely classified into CD44 standard and CD44 variant (CD44v) isoforms. Some variant-encoded regions play critical roles in tumor progression. However, the function of CD44 variant 4 (CD44v4)-encoded region has not been fully understood. Using peptide immunization, we developed an anti-CD44v4 mAb, C₄₄Mab-108, which is useful for flow cytometry, western blotting, and immunohistochemistry. In this study, we determined the critical epitope of C₄₄Mab-108 by enzyme-linked immunosorbent assay (ELISA). We used the alanine (or glycine)-substituted peptides of the CD44v4-encoded region (amino acids 271-290 of human CD44v3-10), and found that C₄₄Mab-108 did not recognize the alanine-substituted peptides of D280A and W281A. Furthermore, these peptides could not inhibit the recognition of C₄₄Mab-108 in flow cytometry and immunohistochemistry. The results indicate that the critical binding epitope of C₄₄Mab-108 includes Asp280 and Trp281 of CD44v3-10.

Superficial discolored spots on Atlantic salmon (Salmo salar) fillets are a serious quality problem for commercial seafood farming. Previous reports proposed that the black spots (called melanized focal changes (MFC)) may be melanin, but no convincing evidence has been reported. In this study, we performed chemical characterization of MFC, and also of red pigment (called red focal changes (RFC)), of salmon fillets using alkaline hydrogen peroxide oxidation and hydroiodic acid hydrolysis. This revealed that the MFC contain 3,4-dihydroxyphenylalanine (DOPA)-derived eumelanin whereas the RFC only contain trace amounts of eumelanin. Therefore, probably, the black color of MFC can be explained by the presence of eumelanin from accumulated melanomacrophages. For the red pigment, we could not find a significant signature of either eumelanin or pheomelanin, and the red color is probably predominantly hemorrhagic in nature. However, we found that in RFC the level of pigmentation did increase together with some melanogenic metabolites. Comparison with a “mimicking experiment,” in which a mixture of a salmon homogenate + DOPA was oxidized with tyrosinase, suggested that the RFC include conjugations of DOPAquinone and/or DOPAchrome with salmon muscle tissue proteins. In short, the results suggest that melanogenic metabolites in MFC and RFC derive from different chemical pathways, which would agree with the two different colorations deriving from distinct cellular origins, namely melanomacrophages and red blood cells, respectively.

This study investigates the therapeutic potential of new compound, potassium 2-[2-(2-oxo-4-phenylpyrrolidin-1-yl) acetamido]ethanesulfonate (Compound I), in depression. Willner's chronic unpredictable mild stress model of depression in 48 male Wistar rats was used a depression model. The rats were randomized into four groups, including an intact group, a Compound I group, a Fluoxetine group, and a control group receiving saline. Behavioral tests, such as the Porsolt forced swim test, hole-board test, elevated plus maze test, and light-dark box, were used to assess the animals' conditions. Our results demonstrated that Compound I effectively reduced the immobilization time of rats in the forced swim test, increased orientation and exploratory behavior, and decreased the latency period of going into the dark compartment compared to the control group. Hippocampal and striatal serotonin concentrations were increased in the Compound I group, and the compound also reduced the level of corticosterone in the blood plasma of rats compared to intact animals. These results suggest that Compound I has a reliable antidepressant activity, comparable to that of the reference antidepressant Fluoxetine.

The craft guilds have been at the core of important historiographical debates on the economic, social and political history of medieval cities for twenty years. The aim of this article is to examine the seamen’s guilds in the town ports of Northern Peninsula in the late Middle Ages. This study analyzes fundamental aspects of the social assistance, labour organization and social identity of the town ports, located on the maritime border of the Kingdom of Castile. In contrast to the more classical view of the craft guilds as protectionist institutions, which only served the interests of a privileged group of masters, this analysis highlights the contribution of the seamen craft guilds to the organization of labor at sea, the training of sea workers, the ability to negotiate with merchants and avoid labor exploitation, the provision of social assistance to the most vulnerable population, and the ability to lead the social protest for the guilders’ representation in the urban government. In summary, it is concluded that the seafarers’ guilds were constituted as networks of mutual help between individuals in the labor, welfare and political spheres of the population of the town ports of Northern Iberia in the late Middle Ages.

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

Morphine-induced antinociception is partially reduced in interleukin-31 (IL-31) receptor A (IL-31RA)-deficient mice, indicating that IL-31RA is crucial for morphine-induced peripheral antinociception. Herein, we examined the combined effects of IL-31 and morphine on antinociceptive activity and itch-associated scratching behavior (LLS) in mice, and elucidated the regulatory mechanisms. A hot-plate test was used to assess antinociception. LLS was automatically detected and recorded via computer. IL-31RA mRNA expression was assessed using real-time polymerase chain reaction. Repeated pre-treatment with IL-31 resulted in significant antinociceptive activity. Repeated administration of morphine decreased the morphine-induced antinociceptive activity, LLS counts, and regular dose, and inhibited IL-31-induced LLS. These results suggested that repeated administration of morphine depleted inter-neuronal IL-31RA levels, preventing morphine-induced antinociception. Therefore, IL-31 may be helpful as an adjunct analgesic to morphine. To explore the benefits of IL-31, its influence on morphine-induced antinociceptive tolerance in mice was examined. IL-31 and morphine combination increased analgesic action which increased the expression of DRG neuronal IL-31RA, elucidating the site of peripheral antinociception of morphine. This site may induce exocytosis of IL-31RA in the sensory nervous system. Collectively, the suppressive effect of IL-31 on morphine-induced antinociceptive tolerance may result from IL-31RA supplementation in sensory nerves.

End-stage heart failure (ESHF) leads to hypoperfusion and edema formation in the whole body and is accompanied by neurohormonal and immunological alterations. Orthotopic heart transplantation (HTX) has been used as a beneficial option for ESHF. Due to the shortage of donor hearts, the ideal matching and timing of donors and recipients has become more important. Our aim was to explore the relationship between the clinical outcome of HTX and the cytokine and apolipoprotein profiles of the recipient pericardial fluid obtained at transplantation after opening the pericardial sac. The clinical data and the interleukin, adipokine and lipoprotein levels in the pericardial fluid of twenty recipients were investigated. Outcome variables included primer graft dysfunction (PGD), need for posttransplantation mechanical cardiac support (MCS), International Society for Heart and Lung Transplantation grade ≥ 2R rejection and mortality. Recipient risk scores were also investigated. Leptin levels were significantly lower in patients with PGD than in those without PGD (median: 6.36 [IQR: 5.55-6.62]; versus 7.54 [IQR=6.71-10.44]; p = 0.029). Higher ApoCII levels (median: 14.91 [IQR: 11.55-21.30] versus 10.31 [IQR=10.02-13.07]; p = 0.042) and ApoCIII levels (median: 60.32 [IQR: 43.00-81.66] versus 22.84 [IQR=15.84-33.39]; p=0.005) were found in patients (n=5) who died in the first 5 years after HTX. In patients who had rejection (n=4) in the first month after transplantation, the levels of adiponectin (median: 74.48 [IQR: 35.51-131.70] versus 29.96 [IQR: 19.86-42.28]; p=0.039), ApoCII (median: 20.11 [IQR: 13.06-23.54] versus 10.32 [IQR: 10.02-12.84]; p=0.007) and ApoCIII (median: 70.97 [IQR: 34.72-82.22] versus 26.33 [IQR: 17.18-40.17; p=0.029) were higher than those in the nonrejection group. Moreover, the pericardial thyroxine (T4) levels (median: 3.96 [IQR: 3.49-4.46] versus 4.69 [IQR: 4.23-5.77]; p=0.022) were lower in patients with rejection than in patients who did not develop rejection. Our results indicate that apolipoproteins can facilitate the monitoring of rejection and could be a useful tool in the forecast of early and late complications.

Immune checkpoint inhibitors (ICIs), including anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and anti-programmed death-1 (PD-1) antibodies, have initiated a new era in the treatment of malignant melanoma. ICIs can be used in various settings, including as first-line, adjuvant, and neoadjuvant therapy. In the scope of this review, we examined clinical studies utilizing ICIs in the context of treating oral mucosal melanoma, a rare disease albeit with an extremely poor prognosis, with a specific focus on unraveling the intricate web of resistance mechanisms. The absence of a comprehensive review focusing on ICIs in oral mucosal melanoma is notable. Therefore, this review seeks to address this deficiency by offering a novel and thorough analysis of the current status, potential resistance mechanisms, and future prospects of applying ICIs specifically to oral malignant melanoma. Clarifying and thoroughly understanding these mechanisms will facilitate the advancement of effective therapeutic approaches and enhance the prospects for patients suffering from oral mucosal melanoma.

Load shifting is one of the demand side management (DSM) strategies to support the efficiency in the electricity grid during the peak hours demand. Load shifting at the appliance level is interesting to review since the appliance usage is one of the main inputs in the load profile analysis. More review studies in load shifting at the appliance level are required as it is a specific issue of load profile research body, and still limited studies are available at this moment. It is also essential to focus on the appliance usage patterns to better understand the impacts and characteristics of the individual appliance. The existing studies in load shifting have applied common structured literature reviews, and our study addresses the transparency of each stage and sub-stage of the selection of the final list studies. The finding shows that efficiency has been achieved in the installed capacity reduction, cost including emission reductions, and peak consumption reduction. The most applied method in the load shifting at the appliance level is by developing the load shifting optimisation algorithms. This work contributes to provide a transparent process of applying a systematicity literature review, where it becomes a source of knowledge and grounded theory. It contributes to a limited and specific research of load shifting at the appliance level by highlighting and discussing the key findings for the readers. In specific, it contributes to improve energy efficiency by presenting the load shifting methods at the appliance level and identifying the controllable and uncontrollable appliances. This detail review study at the appliance level can make valuable contributions to support decision and policy-making by illuminating new dynamic system in load shifting area in specific, and demand side management in general for energy efficiency.

In this study, a composite film was developed for electrochemical sensing of tryptophan (Trp). Porous reduced graphene oxide (PrGO) was utilized as the electron transfer layer, and a C-undecylcalix[4] resorcinarene Langmuir-Blodgett (CUCR-LB) film served as the molecular recognition layer. Atomic force microscopy (AFM), transmission electron microscopy (TEM), Raman spectroscopy, scanning electron microscopy (SEM), and electrochemical experiments were employed to analyze the characteristics of the CUCR-LB/PrGO composite film. The electrochemical behavior of Trp on the CUCR-LB/PrGO composite film was investigated, revealing a linear response range of Trp was 1.0×10-7 to 3.0×10-5 mol L-1 and a detection limit of 3.0×10-8 mol L-1. Furthermore, the developed electroanalytical method successfully determined Trp content in an amino acid injection samples. This study not only introduces a rapid and reliable electrochemical method for determination of Trp but also presents a new strategy for constructing high-performance electrochemical sensing platforms.

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

We report on recent experimental results on β decay into self-conjugate (N=Z) nuclei with mass number 58≤A≤70. Super-allowed β decays from the Jπ=0+ ground state of a Z=N+2 parent nucleus are to the isobaric analogue state, through so-called Fermi transitions, and to Jπ=1+ states, by way of Gamow–Teller (GT) transitions. The operator of the latter decay is a generator of Wigner’s SU(4) algebra and as a consequence GT transitions obey selection rules associated with this symmetry. Since SU(4) is progressively broken with increasing A, mainly as a consequence of the spin–orbit interaction, this symmetry is not relevant for the nuclei considered here. We argue, however, that the pseudo-spin–orbit splitting can be small in nuclei with 58≤A≤70, in which case nuclear states exhibit an approximate pseudo-SU(4) symmetry. To test this conjecture, GT decay strength is calculated with use of a schematic Hamiltonian with pseudo-SU(4) symmetry. Some generic features of the GT β decay due to pseudo-SU(4) symmetry are pointed out. The experimentally observed GT strength indicates a restoration of pseudo-SU(4) symmetry for A=70.

The prevalent pathogens associated with bovine uterine infections are bacteria that appear to increase the host's susceptibility to secondary infections with other bacteria or viruses, among which BoHV-4 is the most frequently found. In this work, the study of the pathways of apoptosis induction was carried out on an experimental model of primary culture of endometrial cells, in order to know the implication of BoHV-4 and the presence of bacterial LPS in the pathogenesis of the bovine reproductive tract. For this, different staining techniques and molecular analysis by RT-PCR were used. The results obtained allowed us to conclude that the level of cell death observed in the proposed primary culture is directly related to the time of viral infection and the presence of LPS in BoHV-4 infection. The apoptosis indices in cells infected with BoHV-4, BoHV-4 + LPS presented a maximum that correlates with the appearance of the cytopathic effect, and the maximum viral titers in the model studied. However, morphological, biochemical and molecular changes were evident during both early and late stages of apoptosis. These findings provide information on the factors that may influence the pathogenesis of BoHV-4 and help to better understand the mechanisms involved in virus infection.

Norovirus (NoV) is recognised as a major cause of epidemic and sporadic acute gastroenteritis (AGE) in all age groups. Information on the genetic diversity of the NoVs circulating in the 1980s and 1990s, before the development and adoption of dedicated molecular assays, is limited compared to the last decades. In the period 1986-2020, uninterrupted viral surveillance was conducted in symptomatic children hospitalized for AGE in Palermo, Italy, providing a unique time capsule for exploring the epidemiological and evolutionary dynamics of enteric viruses. In this 35-year long time span NoVs of genogroup II (GII) were detected in 15.6% of AGE requiring hospitalization, whilst GI NoVs in 1.4%. Overall, the predominant NoV capsid (Cap) genotype was GII.4 (60.8%), with temporal replacement of the GII.4 Cap variants and associated polymerase (Pol) types. The chronology of emergence and circulation of the different GII.4 variants were consistent with the data available in literature. Also, for GII.3 and GII.2 NoVs the circulation of different lineages/strains, differing in either the Cap or Pol genes or in both, was observed. This long-term study revealed the ability of NoVs to modify continuously and rapidly their genomic makeup and highlights the importance of surveillance activities for vaccine design.

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

Introduction: The objective of the study is to assess the failure of therapies with HFNO (High-Flow Nasal Oxygen), CPAP, Bilevel or combined therapy in patients with hypoxemic acute respiratory failure due to SARS-CoV-2 during their hospitalization. Methods: Retrospective and observational study of SARS-CoV-2 positive patients who required non-invasive respiratory support (NIRS), at the Reina Sofía General University Hospital of Murcia between March 2020 and May 2021. Results: Of 7355 patients, 197 (11,8%) were included. 95 of them failed this therapy (48,3%). We objectivated that during hospitalization in the ward the combined therapy with HFNO and CPAP had a lower failure rate overall and the highest treatment purely with Bilevel (p = 0,005). In the comparison of failure in therapy without two levels of airway pressure, HFNO, CPAP and combined therapy of HFNO with CPAP, (35,6% of patients) presented a 24,2% failure compared to those who did have two levels of pressure with Bilevel and combined therapy of HFNO with Bilevel (64,4% of patients) with 75,8% associated failure (OR: 0, 374; CI 95%: 0,203-0,688. p=0,001).Conclusions: The use of NIRS in conventional hospitalization is safe and effective in patients with respiratory failure secondary to SARS-CoV-2 infection. The therapeutic strategy with Bilevel increases the probability of failure, with the combined therapy strategy with CPAP and HFNO being the most promising option.

Dysfunction and selective loss of retinal ganglion cells (RGCs) is a known cause of vision loss in glaucoma and other neuropathies where ocular hypertension (OHT) is the major risk factor. We investigated the impact of transient non-ischemic OHT spikes (spOHT) on RGC function and viability in vivo to identify cellular pathways linking low-grade repetitive mechanical stress to RGC pathology. We found that repetitive spOHT had an unexpectedly high impact on intraocular homeostasis and RGC viability, while exposure to steady OHT (stOHT) of similar intensity and duration failed to induce pathology. The repetitive spOHT induced a rapid activation of the inflammasome, marked by the upregulation of NLRP1, NLRP3, AIM2, caspases -1, -3/7, -8, gasdermin D (GsdmD) and the release of interleukin-1β (IL-1β) and other cytokines into the vitreous. Similar effects were also detected after 5 weeks of exposure to chronic OHT in an induced glaucoma model. The onset of these immune responses in both spOHT and glaucoma models preceded a 50% deficit in pattern electroretinograms (PERG) amplitude, and significant loss of RGCs at 7 days post-injury. Inactivation of inflammasome complexes in NLRP1-/- , Casp1-/- and GsdmD-/- knockout animals, significantly suppressed the spOHT induced inflammatory response and protected RGCs. Our results demonstrate that mechanical stress produced by acute repetitive spOHT or chronic OHT is mechanistically linked to inflammasome activation, which leads to RGC dysfunction and death.

We define a spinor-Minkowski metric for SL(4,C). It is not a trivial generalization of the SL(2,C) metric and it involves the Minkowskian one. We define 4x4 version of the Pauli matrices and eight 4-component associated generalized eigenvectors that can be regarded as undotted covariant spinors. The 4-component spinors can be grouped into four categories. Each category transforms in its own way. The outer products of pairwise combinations of 4-component spinors can be associated with 4-vectors. Including the dotted covariant, undotted and dotted contravariant forms totally we have sixteen pairs of spinors. Eight of them live in the conjugate space which has no countepart in SL(2,C).

This study continued the analysis of immunization with the receptor binding domain (RBD) associated with the adjuvants Dimethyldioctadecylammonium bromide (DDA) and Saponin (Sap) (RBD+DDA/Sap) or Aluminum hydroxide (AH) and outer membrane vesicles (OMVs) of Neisseria meningitidis (RBD+AH/OMV); from adult to old age and assessed maternal-fetal transference of antibodies. Outbred Swiss mice were immunized with 2 intramuscular (IM) doses with the antigenic preparations RBD+DDA/Sap, RBD+AH/OMV or RBD alone. The humoral immune response was evaluated using ELISA, avidity-ELISA, Immunoblotting and a Omicron-surrogate-neutralization assay (BA.1), while the cellular immune response was analyzed by ELISpot. Our previous work studied the IgG response; here, we verified that IgM levels were higher right after the immunization doses, but, as IgG, it persisted until 368 days after the immunization. The avidity of IgM increased from low to intermediate-to-high after the booster dose. RBD+DDA/Sap presented neutralizing indexes against Omicron at days 47 and 176, while RBD+AH/OMV showed neutralization on days 21, 47 and 176. Cellular response, measured 465 days after immunization, revealed IFN-Y and IL-4 secretion. The offspring of RBD+DDA/Sap had detectable antibodies, which decreased around 45 days after birth, the last point we analyzed. The results suggested that DDA/Sap is a promising adjuvant mixture to enhance humoral and cellular immune response against SARS-CoV-2, improving maternal-fetal transference of antibodies; cross-reactivity with Omicron variant; and the maintenance of antibodies for a long period.

Various 4-aminotetrahydropyridinylidene salts were treated with aldehydes in alkaline medium. Their conversion to 5-substituted -hydroxyketones in a one-step reaction succeeded only with an aliphatic aldehyde. Instead, aromatic aldehydes gave 5-substituted -aminoketones or a single -diketone. The new compounds were characterized by spectroscopic methods and a single crystal structure analysis. Some of them showed anticancer and antibacterial properties.

In mammals, the role of interleukin-18 (IL-18) in the immune response is to drive inflammatory and, normally therefore, anti-viral responses. IL-18 also shows promise as a vaccine adjuvant in mammals. Chicken IL-18 (chIL-18) has been cloned. The aim of this study was to investigate the potential of chIL-18 to act as a vaccine adjuvant in the context of a live recombinant Fowlpox virus vaccine (fpIBD1) against Infectious bursal disease virus (IBDV). fpIBD1 protects against mortality, but not against damage to the bursa of Fabricius caused by IBDV infection. The Fowlpox virus genome itself contains several candidate immunomodulatory genes, including potential IL-18 binding proteins (IL-18bp). We have knocked out (Δ) the potential IL-18bp genes in fpIBD1 and inserted (::) the cDNA encoding chIL-18 into fpIBD1 in the non-essential ORF030, generating five new viral constructs –fpIBD1::chIL-18, fpIBD1ΔORF073, fpIBD1ΔORF073::chIL-18, fpIBD1ΔORF214 and fpIBD1ΔORF214::chIL-18. The subsequent protection from challenge with virulent IBDV, as measured by viral load and bursal damage, given by these altered fpIBD1 strains, was compared to that given by the original fpIBD1. The results show that chIL-18 can act as a vaccine adjuvant, giving complete protection against challenge, with no detectable virus or damage in the bursa of Fabricius.

The rapid progress in artificial intelligence, machine learning, and natural language processing has led to the emergence of increasingly sophisticated large language models (LLMs) enabling their use in healthcare. The study assesses the performance of two LLMs: the GPT-3.5 and GPT-4 models in passing the medical examination for access to medical specialist training in Spain MIR. Our objectives included gauging the model's overall performance, analyzing discrepancies across different medical specialties, discerning between theoretical and practical questions, estimating error proportions, and assessing the hypothetical severity of errors committed by a physician. We studied the 2022 Spanish MIR examination after excluding those questions requiring image evaluations or having acknowledged errors. The remaining 182 questions were presented to the LLM ChatGPT4 and GPT-3.5 in Spanish and English. Logistic regression models analyzed the relationships between question length and question sequence d performance. GPT-4 outperformed GPT -3.5, scoring 86.81% in Spanish (p<0.001). English translations had a slightly enhanced performance. Among medical specialties, GPT-4 achieved a 100% correct response rate in several areas, with specialties like Pharmacology, ICU, and Infectious Diseases showing lower performance. The error analysis revealed that while a 13.2% error rate existed, gravest categories like "error requiring intervention to sustain life" and "error resulting in death" had a 0% rate. Conclusions: GPT-4 performs robustly on the Spanish MIR examination, varying its capability to discriminate knoweldge across specialties. While the model's high success rate is commendable, understanding the error severity is critical, especially when considering AI's potential role in real-world medical practice and its implication on patient safety.

Over the past two decades, a growing body of evidence observations have shown group two innate lymphoid cells (ILC2) to be critical drivers of Type 2 (T2) inflammatory responses associated with allergic inflammatory conditions such as asthma. ILC2 release copious amounts of pro-inflammatory T2 cytokines – interleukin (IL)-4, IL-5, IL-9, and IL-13. This review provides a comprehensive overview of the newly discovered regulatory subtype of ILC2 described in murine and human mucosal tissue and blood. These KLRG1+ILC2 have the capacity to produce the anti-inflammatory cytokine, IL-10. Papers compiled in this review were based on query of PubMed and Google Scholar for articles published from 2000-2023 using keywords “IL-10” and “ILC2”. Studies with topical relevance to IL-10 production by ILC2 were included. ILC2 respond to microenvironmental cues including retinoic acid (RA), IL-2, IL-4, IL-10, IL-33, as well as neuropeptide mediators such as neuromedin-U (NMU), prompting a shift towards IL-10 and away from T2 cytokine production. In contrast, TGF-β attenuates IL-10 production by ILC2. Immune regulation provided by IL-10+ILC2s holds potential significance for management of T2 inflammatory conditions. The observation of context-specific cues which alter phenotype of ILC warrants examining characteristics of ILC subsets to determine the extent of plasticity or whether the current classification of ILCs requires refinement.

Graphyne is a material that has unique mechanical properties, but little is known about how these properties change when the material has holes. In this work, the effect of hole geometry, considering circular, triangle, and rhombus hole configurations, on the mechanical nonlinear response of γ-graphyne structures is studied. Graphyne, graphdiyne, graphyne-3, and graphyne-4 structures are under investigation. An efficient nonlinear finite element analysis (FEA) method is adequately implemented under large deformations for this purpose. The study varied the size and shape of the holes to understand how these changes affect the nanostructure's mechanical response. The results indicate that the hole geometry significantly impacts the mechanical nonlinear response of γ-graphyne structures. The holes' size and shape affect the structures' elastic behavior, deformation, and strength. The findings can be used to optimize the design of γ-graphyne structures for specific mechanical applications. The study highlights the importance of considering the hole geometries in the design and fabrication of these materials.

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.

Preterm birth (PB) is a leading cause of perinatal morbidity and mortality. PB prediction is per-formed by measuring cervical length, with a detection rate of around 70%. Although it is known that a cytokine-mediated inflammatory process is involved in the pathophysiology of PB, no screening method implemented in clinical practice includes cytokine levels as a predictor varia-ble. Here, we quantified cytokines in cervical-vaginal mucus of pregnant women (18-23.6 weeks of gestation) with high- or low-risk for PB determined by cervical length, collecting relevant obstetric information. IL-2, IL-6, IFN-γ, IL-4, and IL-10 were significantly higher in the high-risk group, while IL-1ra was lower. Two different models for PB prediction were created using the Random Forest machine-learning algorithm: the full model with 12 clinical variables and cyto-kine values, and the adjusted model, including the most significant variables -maternal age, IL-2, and cervical length- (detection rate 66 vs 87%, false positive rate 12 vs 3.33%, false negative rate 28 vs 6.66%, and area under the curve 0.722 vs 0.875, respectively). The adjusted model integrat-ing cytokines showed a detection rate 8 points higher than the gold standard calculator, which may allow us to identify PB risk more accurately and implement strategies for preventive in-terventions

SARS-CoV-2 mRNA vaccination can entail chronic fatigue/dis-autonomy tentatively termed post-acute COVID-19 vaccination syndrome (PACVS). We explored receptor autoantibodies and interleukin-6 (IL-6) as somatic correlates of PACVS. Blood markers determined before and six months after first-time SARS-CoV-2-vaccination of healthy controls (N = 89, 71 females, mean/ median age 39/ 49 years) were compared with corresponding values of PACVS-affected persons (N= 191, 159 females, mean/median age: 40/39 years) exhibiting chronic fatigue/dis-autonomy (≥ three symptoms for ≥ five months after last SARS-CoV-2 mRNA vaccination) not due to SARS-CoV-2 infection and/or confounding diseases/medications. Normal vaccination response encompassed decreases of 11 receptor-antibodies (by 25 - 50 %, p < 0.0001), increases in two receptor-antibodies (by 15 - 25 %, p < 0.0001) and normal IL-6. In PACVS, serological vaccination-response appeared significantly (p < 0.0001) altered, allowing discrimination from normal post-vaccination state (sensitivity = 90%, p &lt; 0.0001) by increased angiotensin II type 1 receptor antibodies (cut-off ≤ 10.7 U/ml, ROC-AUC = 0.824 ± 0.027), decreased alpha-2B adrenergic receptor antibodies (cut-off ≥ 25.2 U/ml, ROC-AUC = 0.828 ± 0.025) and increased IL-6 (cut-off ≤ 2.3 pg/ml, ROC-AUC = 0.850 ± 0.022). PACVS is thus indicated as a somatic syndrome delineated/detectable by diagnostic blood markers

Andrographis paniculata leaves have been widely used in traditional medicine due to their rich content of phenolic compounds. In this study, we evaluated the total phenolic and flavonoid content of Andrographis paniculata leaf extracts (ALE), as well as its antioxidant activities against DPPH, ABTS, and hydrogen peroxide radicals. Additionally, we conducted cell viability assays, RT-PCR, and western blot analysis to investigate the biochemical effects of ALE on UVB-induced HaCaT cells. Our results revealed that ALE exhibited a high concentration of polyphenols and flavonoids, which were associated with potent abiotic antioxidant properties. Furthermore, ALE treatment effectively abrogated the damage caused by UVB radiation on key molecules such as hyaluronan synthase 1, Aquaporin 3, and loricrin in HaCaT cells. ALE also demonstrated the ability to reduce the overactivation of mitogen-activated protein kinases (MAPKs) and the expression of pro-inflammatory cytokines, including interleukin-6 and interleukin-1β in UVB-induced HaCaT cells. Additionally, ALE positively influenced the peroxisome proliferator-activated receptor alpha in these cells. Overall, our findings highlight the antioxidant and anti-inflammatory effects of ALE, as well as its significant role in modulating skin barrier functions. These results contribute to the growing body of evidence supporting the therapeutic potential of ALE in skincare and dermatological applications.

Background and Objectives: Stroke is a main leading cause for mortality and morbidity worldwide. Treat-ment of this pathology is still under development and its risk factors remain the main target to be reached. Therefore, we aim to determine the role of interleukin 1 beta in atheromatosis, as risk factor for stroke and the reole of this biomarker in stroke prognosis. Materials and Methods: The study conducted enrolled 56 patients diagnosed with ischemic stroke in the anterior (AVT) and posterior vascular territory (PVT). All patients had venous blood collected at admission and 7 days after the onset of the cerebral ischemia in order to determine plasma concentration for interleukin 1 beta. At the same time an extracranial carotid ultrasound was performed. Results: Interleukin 1 beta collected at admission was positively correlated with NIHSS at admission (Pearson index 0,424) and both measurements were corelated with carotid stenosis (Spearmen correlation index 0,529, respectively 0,653). Conclusion: Interleukin 1 beta could be a reliable biomarker for stroke prognosis and carotid atheromatosis development.

Good hand hygiene has proven to be essential in reducing the uncontrolled spread of human pathogens. Cold atmospheric plasma (CAP) may provide an alternative to disinfecting hands with ethanol-based handrubs when hand washing facilities are unavailable. CAP can be safely applied to the skin if the energy is well controlled. In this study, RF and DC plasma sources was built with a pin-to-mesh electrodes configuration inside a fused silica tube of 5 mm of inner diameter. Microbiological assays based on EN 13697:2015+A1:2019 using Escherichia coli DSM 682 or Staphylococcus epidermidis DSM 20044 were used to examine the antimicrobial effect of various plasma conditions. Metal and silicone disks that model skin were used as inoculation matrices. The prototype air radio frequency (RF) CAP achieved significant disinfection in the MHz range on stainless steel and silicone substrates. This is equivalent to half the performance of direct current CAP, which is only effective on conductive substrates. Using only electricity and air CAP could, with further optimization, replace or complement current hand disinfection methods, and mitigate the economic burden of public health crises in the future.

In this work, optimal consumption and investment strategies are derived for risk-averse investors under the 4/2 stochastic volatility class of models. We work under an expected utility (EUT) framework and consider a Constant Relative Risk Aversion (CRRA) investor, who might also be ambiguity-averse. The corresponding Hamilton-Jacobi-Bellman (HJB) and HJB-Isaacs (HJBI) equations are solved in closed-form for a subset of the parametric space and under some restrictions on the portfolio setting, for complete markets. Conditions for proper changes of measure and well defined solutions are provided. These are the first analytical solutions for the 4/2 stochastic volatility model and the embedded 3/2 model for the type of excess returns established in .

Chat generative pre-trained transformer (ChatGPT) is a developed language model and a subgroup of artificial intelligence (AI) which has demonstrated noticeable innovation in interactions between computer models and human studies. The release of ChatGPT in November 2022 attracted over 100 million users in a short time. It has unlimited applications in different fields of studies such as technology and science. ChatGPT utilizes deep learning and internet text to produce responses that resemble human language, although their accuracy is not always guaranteed. ChatGPT and GPT-4 can make a huge revolution in biology, medical, dental research, and health care. However, it's important to acknowledge the limitations of ChatGPT such as limitation in accessing the latest data. ChatGPT has generated both excitement and concern regarding its potential misuse. Its utilization in scientific publications has sparked debates and prompted the development of policies to govern the use of it. Although ChatGPT has certain limitations, it could impact on many different fields of study. There are challenges associated with using ChatGPT in the field of laboratory medicine and biology, particularly in the interpretation of test results. In this article, we review some of the applications of ChatGPT and GPT-4 in biology, dental and medical studies, and concerns about ChatGPT. Despite ChatGPT's conversational abilities are impressive, there are important considerations regarding its use in different fields of research and academic public.

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