Interleukin-33 (IL-33), a member of the IL-1 cytokine family has been recently associated with the development of autoimmune diseases, including SLE. IL-33 is an alarmin and a pleiotropic cytokine that affects various types of immune cells via binding to its receptor, ST2. In this study, we determine the impact of intraperitoneal IL-33 treatments in young lupus, NZB/W F1 mice. Mice were treated from the age of 6 to 11 weeks. We then assessed the proteinuria level, renal damage, survival rate, and anti-dsDNA antibodies. The induction of regulatory B (Breg) cells and changes in gene expression were also examined. In comparison to the control group, young NZB/W F1 mice administered with IL-33 had a better survival rate as well as reduced proteinuria level and lupus nephritis. IL-33 treatments significantly induced IgM anti-dsDNA antibody, IL-10 expressing Breg cells, and alternatively induced M2 macrophage gene signatures. These results imply that IL-33 exhibit regulatory roles during lupus onset via the expansion of protective IgM anti-dsDNA as well as regulatory cells such as Bregs and M2 macrophages.

Hepatitis B virus (HBV) infection remains a global public problem despite the availability of effective vaccine. In the past decades, nonalcoholic fatty liver disease (NAFLD) has surpassed HBV as the most common cause of chronic liver disease worldwide. The prevalence of concomitant chronic hepatitis B (CHB) and NAFLD, thus, reaches endemic in geographic regions where both conditions are common. Patients with CHB and NAFLD are at increased risk of liver disease progression to cirrhosis and hepatocellular carcinoma. Due to complexity of the pathogenesis, accurate diagnosis of NAFLD in CHB patients can be challenging. Liver biopsy is considered the gold standard for diagnosing and determining the disease severity, but it is an invasive procedure with potential complications. There is a growing body of literatures on the application of novel noninvasive serum biomarkers and advanced radiological modalities to diagnose and evaluate NAFLD, but most have not been adequately validated especially for patients with CHB. Currently, there is no approved therapy for NAFLD though many new agents are in different phases of development. This review provides a summary of the epidemiology, clinical features, diagnosis and management of the NAFLD and highlights the unmet needs in the areas of CHB and NAFLD coexistence.

Among many other themes, Leonardo da Vinci’s Manuscript B contains several drawings of centrally planned churches, some of which are represented using a plan view paired with a bird’s-eye view. The use of a bird’s-eye instead of an elevation represents an innovative depiction technique, which allows to combine the immediacy of the perspective view with the measurability of the façades, and therefore to describe the three-dimensionality of the buildings. To understand the reasons behind the use of this original technique, the edifices’ shape and classify them we decided to use 3D digital reconstruction techniques, for their ability to avoid misunderstandings in the reconstruction process and in the results. This article describes the method to create the digital models of sixteen churches. A Visual programming language (VPL) script was used as 3D base for modelling the churches achieved from a classification code expressing the aggregative rules of the churches. Then, the geometric process for the construction of the plan and its relationship with the elevation measures was studied for each church. Finally, this information was used for the completion of the 3D models, distinguishing more output variants each time there was an inconsistency between plan and perspective view, a variability of one architectural element or an uncertainty.

Non-homologous end joining (NHEJ) is the main DNA repair mechanism for the repair of double strand breaks (DSBs) throughout the course of the cell cycle. DSBs are generated in developing B and T lymphocytes during V(D)J recombination to increase the repertoire of B and T cell receptors. DSBs are also generated during the class switch recombination (CSR) process in mature B lymphocytes, providing distinct effector functions of antibody heavy chain constant regions. Thus, NHEJ is important for both V(D)J recombination and CSR. NHEJ comprises core Ku70 and Ku80 subunits that form the Ku heterodimer, which binds DSBs and promotes the recruitment of accessory factors (e.g., DNA-PKcs, Artemis, PAXX, Mri) and downstream core factors (XLF, Lig4 and XRCC4). In recent decades, new NHEJ proteins have been reported, increasing complexity of this molecular pathway. Numerous in vivo mouse models have been generated and characterized to identify the interplay of NHEJ factors and their role in development of adaptive immune system. This review summarizes the currently available mouse models lacking one or several NHEJ factors, with a particular focus on early B cell development. We also underline genetic interactions and redundancy in the NHEJ pathway in mice.

Infection with the hepatitis B virus (HBV) is a public health problem in many parts of the world, due to its frequency, complications and socio-economic consequences. This study aimed to assess the seroprevalence of hepatitis B virus infection in rural areas and in urban areas. This cross-sectional study assessed the prevalence of HBV infection from 2015-2018 at CHR-Sokodé and USP of Ogaro. Biological data of 3000 participants (500 per year in each zone) enrolled and results of HBsAg were assessed during the study period. Female are represented 60% with average age comprised between [20, 29] years old. The high rate of participants enrolled (45.10%) are come for the monitoring of pregnancy. The prevalence of VHB during the study are 20.33% (610/3000), high prevalence (6.27%) and the means of VHB prevalence are shown in the age range between [30; 39] with 12.17% (365/3000) of female and 8.17% (235/3000) of male are positive after diagnostic detection of HBsAg (antigen of Hepatitis B virus). The prevalence of HBV in rural zone (Ogaro) are 5.23% and 15.07% in urban zone (Sokodé) and the high prevalence (17.50%) are shown in urban zone. The high prevalence of young suggests that some effort will be due to sensibilized young for HBV sexual transmission and the way of prevention. In addition, some research would be done in research of alternative therapy against this infection.

Based on the key molecule of humoral adaptive immunity, the antibody, evolution of the system comprises molecular genetic, cell biologic and immunologic mechanisms, and as a network the system is likely governed and can be characterized by physical rules as well. While deep sequencing can provide vast amounts of data related primarily to clonal relationships, functional interpretation of such data is hampered by the inherent limitations of converting sequence to structure to function. In this paper a novel model of structural interaction space, termed radial adjustment of system resolution, or RADARS, is proposed. The model is based on the radial growth of resolution of structural recognition, corresponding to increasing affinity of immune reactivity, and the virtual infinity of directions of growth, corresponding to the ability to respond to almost any molecular structure. Levels of interaction strength appear as shells of the sphere representing the system. B-cell development and immune responses can be readily interpreted in the model and quantitative properties of the antibody network can be inferred from the physical properties of a quasi-spherical system growing multi-radially. The system is described by double-Pareto distribution, sampling the lognormally distributed equilibrium constants at a rate of phi square. Finally, general strategies for merging antibody sequence space into structural space are outlined.

A highly crystallized monoclinic-scheelite type BiVO4 powders were successfully synthesized by solvothermal method. The as-synthesized BiVO4 powders were characterized by XRD, FE-SEM, Raman spectroscopy, UV-vis DRS spectroscopy and TA-PL. From the XRD data and Raman spectra, the monoclinic-scheelite phase BiVO4 sample can be obtained at higher solvothermal synthesis temperature more than 140 oC. The preparation conditions such as, the Bi/V molar ratio and synthesis temperature, have significantly effects on the morphologies of the BiVO4 samples. BVO2 sample shows the highest PL peak, which has the highest formation rate of OH radicals and the highest photocatalytic activity. This result suggests that the formation rate of OH radicals shows a good correlation with the photocatalytic activity.

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

Metastasis in oncological diseases remains one of the main reasons for negative prognosis regarding treatment. Any new data on the biophysical and biochemical characteristics of circulating metastatic cells will help to develop the concept of antimetastatic therapy. In this study we found a number of differences in spectroscopic and morphological features of circulating metastatic cells. FTIR and Raman spectra of cultivated by adhesive and de-adhesive methods (last as a model for metastatic cells) have showed spectroscopic features, namely in FTIR in the region of CH - stretching vibrations associated with structural rearrangements in the cell membrane, as well as changes in the intensity and position of the PO2- group vibrations bands correlated with a proliferative activity. The spectral features in the regions of OH stretching and Amid I vibrations and other spectral markers of the metastatic cells under different cultivation conditions were derived. Raman spectra showed redistribution of amino acid Tyr/Trp ratio and in Tyr duplet intensity in the region of 500-900 cm-1 , as well different glycogen level in different cells. The spectroscopic markers are in the accordance with biochemical data. CARS and confocal optical microscopy were applied for determination a state of the cells and F-actin expression level that turned out to be higher for adhesive cells in comparison with de-adhesive cells. Shape and morphological property of the cells drastically differs. The correlation of vibrational markers with biochemical data and cytofluorometric method were discussed.

The instability of double-diffusive convection of an Oldroyd-B fluid in a vertical porous layer caused by temperature and solute concentration differences with the Soret effect is studied using a modified Darcy–Brinkman–Oldroyd model. Under the Oberbeck-Boussinesq approximation, the validity of Squire's theorem is demonstrated, allowing for considering only the two-dimensional linear instability. Based upon perturbation theory, an Orr-Sommerfeld eigenvalue problem is derived and numerically simulated using the Chebyshev collocation method. We examine the effects of the relevant dimensionless parameters on the neutral stability curves. It is discovered that PrD and λ1 have dual effects on the instability, respectively. When PrDc1 < PrD < PrDc2, PrD boosts flow stability. The impact of λ1 on fluid stability is influenced by PrD. Furthermore, Le and η have dual effects on the instability. When η< 0.8, it promotes flow instability. Le enhances the flow in-stability when Le < 0.7 and inhibits the instability when Le > 0.7. In addition, the magnitude of Le influences the role of Sr. There exists a critical value for Le. When Le < Lec2, Sr strengthens the in-stability of the flow, and when Le> Lec2, Sr plays an inhibiting role. Finally, the relaxation pa-rameter λ2 promotes flow stability.

This study evaluated the neuroprotective potential of peptain-1 conjugated to a cell-penetrating peptide (CPP-P1) in an ocular hypertension model of glaucoma. Brown Norway (BN) rats were subjected to intraocular pressure (IOP) elevation via intracameral injection of silicone oil (SO), with concurrent intravitreal injections of either CPP-P1 or a vehicle. Retinal cross-sections were analyzed for markers of neuroprotection, including cAMP Response Element-Binding Protein (CREB), phosphorylated CREB (p-CREB), growth-associated protein-43 (GAP43), synapsin-1 (SYN1), and superoxide dismutase 2 (SOD2). Hematoxylin and eosin staining was used to assess retinal layer thickness. SO-treated rats exhibited significant reductions in the thickness of the inner nuclear layer (INL, 41%, p=0.016), inner plexiform layer (IPL, 52%, p=0.0002), and ganglion cell layer (GCL, 57%, p=0.001). CPP-P1 treatment mitigated these reductions, preserving INL thickness by 32% (p=0.059), IPL by 19% (p=0.119), and GCL by 31% (p=0.057). Increased levels of CREB and p-CREB were observed in IOP-elevated, CPP-P1-treated retinas compared to IOP-elevated vehicle-treated retinas. Although overall GAP43 levels were low, there was a modest increase in expression within the IPL and GCL in SO- and CPP-P1-treated retinas (p=0.15 and p=0.09, respectively) compared to SO- and vehicle-treated retinas. SO injection reduced SYN1 expression in both IPL and GCL (p=0.01), whereas CPP-P1 treatment significantly increased SYN1 levels in the IPL (p=0.03) and GCL (p=0.002). While SOD2 expression in the GCL was minimal across all groups, a trend toward increased expression was observed in CPP-P1-treated animals (p=0.16). The SO model was replicated with SO removal after 7 days and monitored for 21 days followed by retinal flat-mount preparation to assess retinal ganglion cell (RGC) survival. A 42% loss in RGCs (p=0.009) was observed in SO-injected eyes, which was reduced by approximately 37% (p=0.03) with CPP-P1 treatment. These findings suggest that CPP-P1 is a promising neuroprotective agent that promotes retinal ganglion cell survival and the preservation of other retinal neurons, potentially through enhanced CREB signaling in a rat model of SO-induced ocular hypertension.

Wastewater-based epidemiology (WBE) is a promising approach that has been used to monitoring the exposure to pathogens and understanding the status of disease outbreaks in defined population groups. Viral RNAs of SARS-Cov-2 and influenza A and B were detected and quantified by two commercial kits in three wastewater treatment plants (WWTP) selected in different regions of Canton Ticino (Switzerland). We have monitored the presence of SARS-CoV-2 during two big waves of pandemic, from March 2021 until June 2023, when number of confirmed cases and tests decreased. The presence of influenza A and B viruses was investigated from October 2022 to June 2023. We confirmed the presence of SARS-CoV-2 and influenza A and B in all the WWTP monitored; RNA concentration in wastewater could be correlated with clinical cases confirming that WBE is a powerful tool to monitor diseases dissemination supporting the management of an epidemic.

(1) Background: Hepatitis B virus (HBV) sequencing data are important for monitoring HBV evolution. We aimed to molecularly characterize HBV sequences from participants with HBV surface antigen (HBsAg+) positive serology and occult hepatitis B infection (OBI+). (2) Methods: We utilized archived plasma samples from a cohort of people living with (PLWH) in Botswana. HBV DNA was sequenced, genotyped and analyzed for mutations. We compared mutations from study sequences to those from previously generated HBV sequences in Botswana. The impact of OBI-associated mutations on protein function was assessed using the Protein Variation Effect Analyzer. (3) Results: Sequencing success was higher in HBsAg+ than OBI+ samples [86/128 (67.2%) vs 21/71 (29.2%)]. Overall, 93.5% (100/107) sequences were genotype A1, 2.8% (3/107) were D3 and 3.7% (4/107) were E. We identified 13 escape mutations in 18/90 (20%) sequences with HBsAg coverage, with K122R having the highest frequency. The mutational profile of current sequences differed from previous Botswana HBV sequences, suggesting possible mutational changes over-time. Mutations deemed to have an impact on protein function were tpQ6H, surfaceV194A and preCW28L. (4) Conclusions: We characterized HBV sequences from PLWH in Botswana. Escape mutations were prevalent and were not associated with OBI. Longitudinal HBV studies are needed to investigate HBV natural evolution.

Connexins (Cxs) are transmembrane proteins that assemble into gap junction channels (GJCs) and hemichannels (HCs). Previous research supports the involvement of Rho GTPases and actin microfilaments in the trafficking of Cxs, formation of GJCs plaques, and regulation of channel activity. Nonetheless, it remains uncertain whether distinct types of Cxs HCs and GJCs respond differently to Rho GTPases or changes in actin polymerization/depolymerization dynamics. Our investigation revealed that inhibiting RhoA, a small GTPase that controls actin polymerization, or disrupting actin microfilaments with cytochalasin B (Cyto-B), resulted in reduced GJCs plaque size at appositional membranes and increased transport of HCs to non-appositional plasma membrane regions. Notably, these effects were consistent across different Cx types, since Cx26 and Cx43 exhibited similar responses despite having distinct trafficking routes to the plasma membrane. Functional assessments showed that RhoA inhibition and actin depolymerization decreased the activity of Cx43 GJCs while significantly increasing HCs activity. However, the functional status of GJCs and HCs composed of Cx26 remained unaffected. This study supports the hypothesis that RhoA, through its control of the actin cytoskeleton, facilitates the transport of HCs to appositional cell membranes for GJCs formation while simultaneously limiting the positioning of free HCs at non-appositional cell membranes, independently of Cx type. This dynamic regulation promotes intercellular communication and reduces non-selective plasma membrane permeability through a Cx-type dependent mechanism, whereby Cx43 HCs and GJCs are affected, but Cx26 channels are not.

Monoclonal antibodies (mAbs) have become an increasingly important therapeutic modality in recent years, with applications in oncology, hematology, and immunology. This review discusses the production of therapeutic mAbs, including the various types of mAbs (murine, chimeric, humanized, and fully human), their key applications, and the techniques used for their production, including hybridoma technology, single B cell antibody technology, and phage display technology. The review then proposes advanced techniques to overcome them. These include microfluidic sorting, alternative expression systems (including plants, bacteria, and yeast, and cell-free production systems), and the development of complex antibody formats like bi-specific monoclonal antibodies, antibody fragments, antibody-drug conjugates, and nanobody development. These advanced techniques promise to enhance the efficiency, cost-effectiveness, and scalability of mAb production, paving the way for more effective therapeutic applications. This review highlights the theoretical significance of integrating innovative technologies to overcome existing challenges in mAb production, ultimately advancing the field of precision medicine.

Background: Targeting Hepatitis B virus (HBV) infection in human is crucial due to its adverse. Herbal medicine has long been significant in this regard, with flavonoids demonstrating promising results. Hence, establishing a way of identifying flavonoids with anti-HBV activities is the aim of the present study. Methods: Flavonoid structures with anti-HBV activities were retrieved. A flavonol-based pharmacophore model was established using LigandScout v4.4. Screening was performed using the PharmIt server. A QSAR equation was developed and validated with independent sets of compounds. Applicability domain (AD) was defined using Euclidean distance calculations for model validation. Results: The best model, consisting of 57 features was generated. HTS using the flavonol-based model resulted in 509 unique hits. The model's sensitivity and specificity were 71% and 100%, respectively. The QSAR model with two predictors, x4a and qed, exhibited strong predictive performance with an adjusted-R² value of 0.85 and 0.90 of Q2. Conclusion: The QSAR model has been validated with two separate chemical sets, guaranteeing the model's reproducibility and usefulness for other flavonols by utilizing the predictive characteristics of X4A and qed. These results provide new possibilities for discovering future anti-HBV drugs by integrating modeling and experimental research.

Cystatin F (CstF) is a protease inhibitor of cysteine cathepsins, including those involved in acti-vating the perforin/granzyme cytotoxic pathways. It is targeted to the endolysosomal pathway but can also be secreted to the extracellular milieu or endocytosed by bystander cells. CtsF was shown to be significantly increased in tuberculous pleurisy, and during HIV coinfection, pleural fluids display high viral loads. In human macrophages, we revealed a strong upregulation of CstF during infection with Mycobacterium tuberculosis (Mtb). CstF manipulation using RNA si-lencing led to increased proteolytic activity of lysosomal cathepsins, improving Mtb intracellular killing. Here, we investigate the impact of CstF depletion during coinfection of Mtb-infected mac-rophages with lymphocytes infected with HIV. Our results indicate that decreasing CstF released by phagocytes impacts the major pro-granzyme convertase cathepsin C of cytotoxic immune cells. Consequently, an observed increase of the granzyme B apoptotic effects leads to a significant re-duction in viral replication in HIV-infected lymphocytes. Overall, our results indicate a mecha-nism of Mtb/HIV evasion of the cytotoxic mediated pathogen killing driven by the ax-is CstF/ catC/granzymes contributing to this syndemic interaction. Ultimately, this knowledge can be crucial for developing new therapeutic approaches to control both pathogens based on manipulating CstF.

Heart failure (HF) affects about 60 million people worldwide, making it one of the chronic conditions with the greatest health and economic impact. The primary objective was to assess the efficacy of lung ultrasound (LUS) in the management of HF in order to intervene early and reduce the rate of hospital readmissions. A systematic search was conducted on PubMed, Embase, Google Scholar, Web of Science, and Scopus, including clinical trials, meta-analysis, systematic reviews, and original articles from 2019/1/1-2023/12/31, about LUS for the assessment of HF, on an outpatient basis, for HF diagnosis or/and decompensation. There may be risk of bias because the effects are dependent on the persons delivering the intervention. The results were synthetized by PRISMA method. A total of 873 articles were identified of which 33 articles were selected: [n=19] focused on prognostic assessment of HF, [n=11] centred on multimodal diagnostic assessments, and [n=2] addressing therapeutic guidance for HF diagnosis. LUS exhibits advantages in the detection of sub-clinical congestion linked to prognostic significance in re-admission and mortality during out-patient follow-up, after hospital discharge, and in complex scenarios as the patients' homes or institutional long-term care facilities. However, there are considerable uncertainties in their interpretation and monitoring changes due to its lack of standardization. The need for an updated international consensus on the use of LUS seems obvious.

B-1 cells, a subtype of B lymphocytes, are found in lymphoid tissues and peritoneal and pleural cavities. They play diverse roles, releasing cytokines, generating antibodies, regulating the immune response, engaging in phagocytosis, and moving to inflammatory sites. However, their physiology remains partially understood, especially in stressful conditions like sleep restriction. This study aimed to investigate murine B-1 cell activation and differentiation under sleep restriction. Male C57BL/6J mice underwent an 18-hour sleep restriction for 21 days, followed by Candida albicans or Paracoccidioides brasiliensis infection. Purified peritoneal B-1 cells were evaluated for activation markers, microbicidal molecules, cytokine gene expression, Toll-like receptors, and commitment factors. Results showed that sleep restriction minimally influenced activation marker expression in B-1 cells across infection models. However, under sleep restriction, microbicidal molecule production increased in P. brasiliensis (NO) and C. albicans (ROS) infections. Gene expression revealed elevated TLR-2 and cytokines (IL-12, IL-6, TNF-α) in sleep-restricted animals. Lineage commitment analysis indicated myeloid polarization in sleep-restricted B-1 cells for all infection models. These findings underscore the impact of sleep restriction on B-1 cell activation and differentiation, with outcomes varying based on infection type. This study highlights the importance of investigating immunological changes resulting from sleep restriction.

Chromosomal instability (CIN), defined by variations in the number or structure of chromosomes from cell to cell, is recognized as a distinctive characteristic of cancer, associated with the ability of tumors to adapt to challenging environments. CIN has been recognized as a source of genetic variation that leads to clonal heterogeneity (CH). Recent findings suggest a potential association between CIN and CH with the prognosis of BC patients, particularly in tumors expressing the epidermal growth factor receptor 2 (HER2+). In fact, information on the role of CIN in other BC subtypes, including luminal B BC, is limited. Additionally, it remains unknown whether CIN in luminal B BC tumors, above a specific threshold, could have a detrimental effect on the growth of human tumors, or if low or intermediate CIN levels could be linked to a more favorable BC patient prognosis when contrasted with elevated levels. Clarifying these relationships could have a substantial impact on risk stratification and the development of future therapeutic strategies aimed at targeting CIN in BC. This study aimed to assess CIN and CH in tumor tissue samples from ten patients with luminal B BC, and compared them with established clinicopathological parameters. The results of our study show that luminal B BC patients exhibit intermediate CIN and stable aneuploidy, both of which correlated with lymphovascular invasion. These findings suggest that evaluating CIN, CH and aneuploidy could improve risk stratification, the prediction of clinical outcomes and future therapeutic approaches in luminal B BC patients.

The three-component reaction of enaminones, benzaldehyde and hydrazine-HCl or four-component reaction of enaminones, benzaldehyde, hydrazine–HCl and ethyl cyanoacetate in water in the presence of catalytic amount of ammonium acetate has been devised as a straightforward , sustainable approach for the synthesis of 1-H-pyrazole, N-aminopyridine and pyrazol[3,4-b]pyridine derivatives . The key benefits of this approach is simple experimental procedure associated with cost effective and environmentally friendly techniques.

Chronic hepatitis B virus (HBV) infection is the largest global cause of hepatocellular carcinoma (HCC). Current HBV treatment options include pegylated interferon-alpha and nucleos(t)ide analogues (NAs), which have been shown to be effective in reducing HBV DNA levels to become undetectable. However, literature has shown that some patients have persistent risk of developing HCC. The mechanism in which this occurs is not fully elucidated, however it has been discovered that HBV covalently closed circular DNA (cccDNA) integrates into critical HCC driver genes in hepatocytes upon initial infection and are not targets of current NA therapy. Some studies suggest that HBV undergoes compartmentalization in peripheral blood mononuclear cells that serve as a sanctuary for replication during antiviral therapy. The aim of this review is to expand on how patients with HBV may develop HCC despite years of HBV viral suppression and carry worse prognosis than treatment-naive HBV patients who develop HCC. Furthermore, HCC recurrence after initial surgical or locoregional treatment in this setting may cause carcinogenic cells to be-have more aggressively in the treatment experienced. Curative novel therapies targeting the life cycle of HBV, modulating the host immune response, and inhibiting HBV RNA translation are being investigated.

In this paper, a swarm trajectory planning method is proposed for multiple autonomous surface vehicles (ASVs) in an unknown and obstacle-rich environment. Specifically, based on the point cloud information of the surrounding environment obtained from local sensors, a kinodynamic path searching method is used to generate a series of waypoints in the discretized control space at first. Next, after fitting B-spline curves to the obtained waypoints, a nonlinear optimization problem is formulated to optimize the B-spline curves based on gradient-based local planning. Finally, a numerical optimization method is used to solve the optimization problems in real-time to obtain collision-free, smooth and dynamically feasible trajectories relying on a shared network. Simulation results demonstrate the effectiveness and efficiency of the proposed swarm trajectory planning method for a network of ASVs.

Heterosis plays a significant role in enhancing variety, boosting yield, and raising economic value, but the molecular mechanism is still unclear. We analyzed the transcriptomes and 3D genomes of hybrid (F1) and its parents (w30 and 082). Analysis of the expression revealed a total of 485 specially expressed genes (SEGs), 173 differentially expressed genes (DEGs) above parental expression level, more actively expressed genes and up-regulated DEGs in F1. Further study revealed that the DEGs detected in F1 and its parents were mainly involved in response to auxin, plant hormone signal transduction, DNA metabolic process, Purine metabolism, starch and sucrose metabolism, which suggested that these biological processes may play a crucial role in the heterosis of B. rapa. The analysis of 3D genome data revealed that hybrid F1 tend to contain more transcriptionally active A compartments after hybridization. Additionally, F1 had a smaller TAD (topologically associated domain) genome length, but the number was the highest, and the expression change of activated TAD was higher than repressed TAD. More specific TAD boundaries were detected between parents and F1. Subsequently, 140 DEGs with genomic structural variants were selected as potential candidate genes. Among them, we found two DEGs with consistent expression changes in A/B compartments and TADs. Our findings suggest that genomic structural variants, such as TADs and A/B compartments, may affect gene expression and contribute to heterosis in B. rapa. This study provides further insight into the molecular mechanism of heterosis in B. rapa.

Background: Chronic Hepatitis B Virus (HBV) infection is a global health concern, associated with severe liver diseases, necessitating ongoing research on novel drug candidates. This study aims to identify potential drug candidates targeting HBV core protein (HBcAg) and disrupting capsid assembly, a critical step in the virus's life cycle. Methods: HBcAg in complex with HBV inhibitors were obtained from the Protein Data Bank (PDB). CavityPlus server was used for analysis of druggable cavity. Structure-based pharmacophores were extracted from identified cavities, and potential allosteric ligand binding sites were assessed using CavPharmer, CorrSite, and CovCys. LigandScout was employed for ligand-based pharmacophore screening against an FDA-approved library. The ZINC database was screened with features extracted from CavPharmer. Molecular docking studies were conducted using Autodock Vina. Lead compounds were selected based on docking scores, binding modes, and interactions within the druggable cavity. Results: Strong druggable pockets were found for Ciclopirox, while Compound 24, NVR10-001E2, and others showed medium to weak pockets. Ligand-based pharmacophores varied in size and complexity. Screening revealed potential hits matching these pharmacophores, including Ciclopirox olamine, Voriconazole, Enasidenib, and Statins. A large compound database search yielded additional hits like ZINC86859997 and ZINC63280172. Docking analyses confirmed these hits' potential, highlighting their interactions with critical HBc protein residues, offering promising leads for hepatitis B drug development. Conclusions: Voriconazole, Enasidenib, and Lovastatin have shown promises. These hits displayed favorable interactions with crucial HBc protein residues, indicating their potential as lead compounds The mechanism of action of statins with anti-HBV activities also highlighted. This comprehensive approach offers valuable insights into targeting HBc protein for antiviral drug discovery.

The persistent burden of chronic hepatitis B among ≤5-year-old children in Africa suggests missed opportunities for controlling mother-to-child transmission (MTCT) of the hepatitis B virus (HBV). This scoping review maps the evidence base on the risk of HBV MTCT, the status of HBV MTCT mitigation strategies including hepatitis B birth-dose vaccination, and the role of systems complexity on the suboptimal adoption and performance of hepatitis B birth-dose vaccination programs in Africa. Overall, 88 peer-reviewed and grey literature sources published between 2000–2022 were included in this review. The evidence base consistently argues for a growing risk of HBV MTCT amidst the HIV co-epidemic in the region. Without universal HBV screening programs integrated within broader antenatal care services, current selective hepatitis B birth-dose vaccination is unlikely to effectively interrupt HBV MTCT. We underscore critical health systems-related barriers to universal adoption and optimal performance of hepatitis B birth-dose vaccination programs in the region. To better conceptualize the role of complexity and system-wide effects on the observed performance of the program, we propose an adapted systems-based logic model. Ultimately, exploring contextualized complex systems approaches to scaling-up universal hepatitis B birth-dose vaccination programs should form an integral part of the regional research agenda.

Avenanthramides (Avns) and its derivatives, a group of polyphenolic compounds found abundantly in Oats (Avena sativa Linn.) have emerged as a promising candidate for neuroprotection due to their immense anti-oxidant, anti-inflammatory, and anti-apoptotic properties. Neurodegenerative diseases (NDDs), characterized by progressive degeneration of neurons, present a significant global health burden with limited therapeutic options. The phosphoinositide 3-kinase (PI3K) signalling pathway plays a crucial role in cell survival, growth, and metabolism, making it an attractive target for therapeutic intervention. Dysregulation of PI3K signalling has been implicated in the pathogenesis of various NDDs including Alzheimer's and Parkinson's disease. Avns has been shown to modulate PI3K/AKT signalling, leading to increased neuronal survival, reduced oxidative stress, and improved cognitive function. This review explores the potential of Avns polyphenols, as modulators of the PI3K signalling pathway focusing on their beneficial effects against NDDs. Further, we outlined the need for clinical exploration to elucidate the specific mechanisms of Avns action on the PI3K/AKT pathway and its potential interactions with other signalling cascades involved in neurodegeneration. Based on the available literature using relevant keywords from Google Scholar, PubMed, Scopus, Science Direct, and Web of Science, our review emphasizes the potential of Avns as a therapeutic strategy for NDDs and warrants further investigation and clinical exploration.

Atherosclerotic cardiovascular disease (ASCVD) remains the leading cause of death worldwide and the risk of a major cardiovascular event is highest among those with established disease. Ongoing management of these patients relies on the accurate assessment of their response to any prescribed therapy, and their residual risk, in order to optimize treatment. Recent international guidelines and position statements concur that the plasma concentration of apolipoprotein B (apoB) is the most accurate measure of lipoprotein associated ASCVD risk. This is especially true for the growing number of individuals with diabetes, obesity or the metabolic syndrome, and those on statin therapy. Most guidelines, however, continue to promote LDL-C as the primary risk marker due to uncertainty as to whether the greater accuracy of apoB is sufficient to warrant a paradigm shift. Recommendations regarding apoB measurement vary, and the information provided on how to interpret apoB results is sometimes insufficient, particularly for the non-lipid specialist. Misinformation regarding the reliability of the assays is also frequently repeated despite its equivalent or better standardization than many other diagnostic assays. Thus, demand for apoB testing is relatively low, which means there is little incentive to increase its availability or reduce its cost. In this review, we examine the results of recent clinical outcomes studies and meta-analyses on the relative values of apoB, LDL-C and non-HDL-C as markers of ASCVD risk. Although there is seemingly minimal difference among these markers when only population-based metrics are considered, it is evident from our analysis that, from a personalized or precision medicine standpoint, a great many individuals would benefit, at a negligible total cost, if apoB measurement were better integrated into the diagnosis and treatment of ASCVD.

Immune surveillance by natural killer (NK) cells and their recruitment to sites of inflammation renders them susceptible to viral infection, potentially modulating their effector function. Here, we analyzed innate RNA receptor signaling in NK cells downstream of direct Influenza A virus (IAV) infection and its impact on NK cell effector function. Infection of NK cells with IAV resulted in the activation of TBK1, NF-κB and subsequent type-I IFN secretion. CRISPR- generated knockouts in primary human NK cells revealed that this effect depended on the antiviral cytosolic RNA receptor RIG-I. Transfection of NK cells with synthetic 3p-dsRNA, a strong RIG-I agonist that mimics viral RNA, resulted in a similar phenotype and rendered NK cells resistant to subsequent IAV infection. Strikingly, both IAV infection and 3p-dsRNA transfection enhanced degranulation and cytokine production by NK cells when exposed to target cells. Thus, RIG-I activation in NK cells both supports their cell intrinsic viral defense and enhances their cytotoxic effector function against target cells.

The mRNA vaccines for SARS-CoV-2 have demonstrated efficacy and immunogenicity in the re-al-world setting. However, most of the research on vaccine immunogenicity has been centered on characterizing the antibody response, with limited exploration into the persistence of spike-specific memory B cell response. Here we monitored the durability of the memory B cell response and characterize the trajectory of spike-specific B cell phenotypes in healthy individuals who have received two doses of the BNT162b2 vaccine up to 9 months post-vaccination. To profile the spike-specific B cell response we applied the tSNE and Cytotree automated approaches. Our data showed the induction of spike-specific IgA+ and IgG+ plasmablasts and IgA+ activated cells 7 days after the second dose which disappeared 3 months later, while subsets of spike-specific IgG+ resting memory B cells became predominant 9 months after vaccination, and they were capable to differentiate into spike-specific IgG secreting cells when in vitro restimulated. Other subsets of spike-specific B cells, such as IgM+ or unswitched IgM+IgD+ or IgG+ double negative/atypical cells, were also elicited by the BNT162b2 vaccine and persisted up to month 9. The analysis of circulating spike-specific IgG, IgA and IgM was in line with the plasmablasts observed. The longitudinal analysis of the antigen-specific B cell response elicited by mRNA-based vaccines provides valuable insights into our understanding of the immunogenicity of this novel vaccine platform destined to a future widespread use, and it is crucial in guiding future decisions and vaccination schedules.

Accumulating reports have suggested that an inability to clear dead cells is a cause of inflammation and cancer and that the fascia is associated with cancer metastasis. Novel corpuscle-connected filiform structures (CCFSs) entangled on the fascia of the internal organs of rats were selectively visualized with high repeatability (93%) under vital staining with Janus Green B (JGB). Serial sections of CCFSs stained with haematoxylin and eosin and with Mattson Trichrome were microscopically examined. In parallel, the immunohistochemistry with CD31, Lyve 1, scanning electron microscopy, and transmission electron microscopy (TEM) were also used to investigate the novel properties of the CCFSs. All of the CCFSs enclosed JGB-stained granules, which was verified by the impromptu coupling of stereo and light microscopes and fluorescence-activated cell sorting. The functions of the CCFSs were discovered under fluorescence microscopy and confocal laser scanning microscopy to be implicated in cell death: fragmented DNAs and f-actins with extracellular DNAs. The dead cells in the CCFSs were verified by using terminal deoxynucleotidyl transferase dUTP nick end labelling and TEM. Moreover, the CCFS had a relatively-high concentration of calcium, a main element for cell death in tissue, which was measured in 2-dimensionally images using time-of-flight secondary ion mass spectrometry. Taken these results, we report for the first time that novel reticular CCFSs are widely entangled on the fascia of the internal organs of rats with the implication for cell death.

The calculation of moments of area is one of the most fundamental aspects of engineering mechanics for calculating the properties of beams or for the determination of invariants in different kind of geometries. While a variety of shapes such as circles, rectangles, ellipses or their combinations can be described symbolically, such symbolic expressions are missing for freeform cross-sections. In particular, periodic B-spline cross-sections are suitable for an alternative beam cross-section, e.g. for the representation of topology optimization results. In this work, therefore, a symbolic description of the moments of area of various parametric representations of such B-splines is computed. The expressions found are then compared with alternative computational methods and checked for validity. The resulting equations show a simple way for fast conceptual computation of such moments of area of periodic B-splines.

Mature B cells notably diversify immunoglobulin (Ig) production through class switch recombination (CSR), allowing the junction of distant “switch” (S) regions. CSR is initiated by activation-induced deaminase (AID) which targets cytosines adequately exposed within single-stranded DNA of transcribed targeted S regions, with a specific affinity for WRCY motifs. In mammals, G-rich sequences are additionally present in S regions, forming canonical G-quadruplexes (G4s) DNA structures which favor CSR. Small molecules interacting with G4-DNA (G4 ligands), proved able to regulate CSR in B lymphocytes, either positively (such as for nucleoside diphosphate kinase isoforms) or negatively (such as for RHPS4). G4-DNA is also implicated in the control of transcription, and due to their impact on both CSR and transcriptional regulation, G4-rich sequences likely play a role in the natural history of B cell malignancies. Since G4-DNA stands at multiple locations in the genome, and notably within oncogene promoters, it remains to be clarified how it can more specifically promote legitimate CSR in physiology, rather than pathogenic translocation. The specific regulatory role of G4 structures in transcribed DNA and/or in corresponding transcripts and recombination hereby appears as a major issue for understanding immune responses and lymphomagenesis.

Diffuse large B-cell lymphoma (DLBCL) is the most common haematological malignancy in humans and dogs. Several studies disclosed some similarities between the two species, including the constitutive activation of NF- κB pathway as a fundamental underlying pathogenetic mecha-nism. In humans, downregulation of IL-1R8 is implicated in DLBCL development, but its role in dogs has not been explored so far. To gain insight into the pathogenesis of this tumor in dogs, we evaluated the mRNA and protein expression of IL-1R8 in 12 hyperplastic lymph nodes ob-tained from dogs not bearing tumors and from 50 dogs with DLBCL. Moreover, we analysed through qRT-PCR the expression of TLR7, TLR9, MYC, and p52 genes that are known to be in-volved in the IL-1R8 regulatory network. IL-1R8 and p52 were downregulated in DLBCLs com-pared to control lymph nodes (p<0.001), while a higher expression of TLR7, TLR9 and MYC was observed in tumors (p<0.01). Immunohistochemistry confirmed gene expression results, reveal-ing a significantly lower IL-1R8 staining score in DLBCLs compared to control lymph nodes (p<0.0001). Taken together, these results suggest that IL-1R8 downregulation may represent one of the mechanisms driving DLBCL pathogenesis in dogs, mainly through dysregulation of the Toll-like/Interleukin receptors signalling cascade and the aberrant activation of classical NF-κB pathway.

Neurological / neurovascular disorders constitute the leading cause of disability and second leading cause of deaths in the world. Some of the major neurological / neurovascular disorders or diseases include stroke, Alzheimer’s disease, spinal cord injury, neonatal hypoxic-ischemic encephalopathy, etc. Their pathophysiology is considered as highly complex and has been blamed as the main obstacle in the development of any drugs for these diseases. In this review, we have described the endothelin system, their involvement in neurovascular disorders, importance of endothelin B receptors (ETBRs) as a novel potential drug target, and its agonism by IRL-1620 (INN - sovateltide), which we are developing as a drug candidate for treating the above-mentioned neurological disorders / diseases. We have highlighted the results of our pre-clinical and clinical studies related to these diseases. The phase I, safety and tolerability study of sovateltide has shown it as a highly safe and well tolerable compound at tested dosages, while pre-clinical and clinical phase II studies have demonstrated its efficacy in treating acute ischemic stroke, where it is currently being developed as a “First in Class” drug. Its testing in Alzheimer’s disease (AD), acute spinal cord injury and neonatal hypoxic-ischemic encephalopathy (HIE) is currently being carried out and are at different stages of drug development. Successful completion of these studies will prove the involvement of ETBRs signaling in neurological / neurovascular diseases and help in development of novel neurological drugs in future.

(1) Background: The diphtheria toxoid antigen is a major component in pediatric and booster combination vaccines and is known to raise a protective humoral immune response upon vaccination. Although antibodies are considered critical for diphtheria protection, little is known about the antigenic determinants that maintain humoral immunity. (2) Methods: One hundred twelve 15-mer peptides covering the entire sequence of DTx protein were prepared by Spot-synthesis. Membrane-bound peptides immunoreactivity with sera from mice immunized with triple DTP vaccine allowed mapping of continuous B-cell epitopes, topological studies, MAPs synthesis, and ELISA development. (3) Results: Twenty epitopes were identified, being 2 in the signal peptide, 5 in the CD, 7 in the HBFT domain, and 5 in the RBD. Two 17-mer (CB/Tx-2/12 and CB/DTx-4-13) derived bi-epitope peptides linked by a Gly-Gly spacer were chemically synthesized. The peptides were used as antigens to coat ELISA plates and assayed with human (huVS) and mice vaccined sera (miVS) for in vitro diagnosis of diphtheria. The assay proved to be highly sensitive (99.96%) and specific (100%) either for huVS and miVS and when compared with a commercial ELISA test, demonstrate high performance. (4) Conclusions: Our work displayed the complete picture of the linear B cell IgG response epitope of the DTx responsible for the protective effect and demonstrated the specificity and eligibility to enter phase IIB studies of some epitopes to develop new and fast diagnostic assays.

This paper contributes to the current debate about Benefit Corporations, presenting the development of this organisational model in Italy, the first country to introduce this hybrid form after the US. Grounded on an institutional logic perspective, it provides a picture of the institutional dynamics that have characterised the rise of this new entrepreneurial form outside the US. The analysis provides an in-depth foundational study of the Italian case and highlights the relevant influence of different institutional pressures in explaining the rise of and constraints in the diffusion of Benefit Corporations. Empirically, it combines secondary data, available from different public sources, and primary data collected through interviews with a series of knowledgeable informants. Based upon the analysis, two aspects appear peculiar for the development of Benefit Corporations in Italy: the interplay between the Benefit Corporation legal form and the certified B Corp model, and the rise of tensions between social entrepreneurship and the third sector ecosystem. This paper concludes that the peculiar institutional pressures leading to the birth of Benefit Corporations in Italy may be source of permanent tensions and of concern for the diffusion of the model.

This study uses a recently developed theory and technique to examine post-acquisition evidence as to the motives for mergers and acquisitions(M&As), and decomposed the M/B ratio into three components: firm-specific error, time-series sector error, and long-run value-to-book. We make a multidimensional grouping according to the frequency of M&As , payment method, proportion of shares acquired, M/B ratio before the merger and total assets of the acquirers before the merge. The results confirm that M&As involve multiple motives, such as market timing, industry and economic shocks, agency and hubris. Using a sample of 2,035 M&As in China, we find that 59% are related to market timing, 68% are related to agency and hubris, 21% are related to industry and economic shocks, 51% are related to multiple motives. Our empirical research finds that the main motives for M&As of listed companies in China are value-decreasing, which have negative impact on the acquirers‘ sustainable development.

DNA double-strand breaks (DSBs) trigger the Ataxia telangiectasia mutated (ATM)-dependent DNA damage response (DDR), which consists of histone H2AX, MDC1, RNF168, 53BP1, PTIP, RIF1, Rev7, and Shieldin. Early stages of B and T lymphocyte development are dependent on recombination activating gene (RAG)-induced DSBs that form the basis for further V(D)J recombination. Non-homologous end joining (NHEJ) pathway factors recognize, process, and ligate DSBs. Based on numerous loss-of-function studies, DDR factors were thought to be dispensable for the V(D)J recombination. In particular, mice lacking Mediator of DNA Damage Checkpoint Protein 1(MDC1) possessed nearly wild-type levels of mature B and T lymphocytes in the spleen, thymus, and bone marrow. NHEJ factor XRCC4-like factor (XLF)/Cernunnos is functionally redundant with ATM, histone H2AX, and p53-binding protein 1 (53BP1) during the lymphocyte development in mice. Here, we genetically inactivated MDC1, XLF, or both MDC1 and XLF in murine vAbl pro-B cell lines and, using chromosomally integrated substrates, demonstrated that MDC1 stimulates the V(D)J recombination in cells lacking XLF. Moreover, combined inactivation of MDC1 and XLF in mice resulted in synthetic lethality. Together, these findings suggest that MDC1 and XLF are functionally redundant during the mouse development, in general, and the V(D)J recombination, in particular.

Gonorrhea is a major global public health problem with emergence of multiple drug-resistant strains with no effective vaccine. This retrospective cohort study aimed to estimate the effectiveness of the New Zealand meningococcal B vaccine against gonorrhea associated hospitalization. The cohort consisted of individuals born 1984-1999 residing in New Zealand, therefore eligible for meningococcal B vaccination during 2004-2008. Administrative datasets of demographics, customs, hospitalization, education, income tax and immunization, were linked using the national Integrated Data Infrastructure. The primary outcome was hospitalization with a primary diagnosis of gonorrhea. Cox’s proportional hazards models were applied with a Firth correction for rare outcomes to generate estimates of hazard ratios. Vaccine effectiveness estimates were calculated as 1-Hazard Ratio expressed as percent. There were 1,143,897 eligible cohort members, with 135 missing information on gender, 16,245 missing ethnicity and/or 197,502 missing deprivation hence 935,496 were included in the analysis. After adjustment for gender, ethnicity and deprivation, vaccine effectiveness (MeNZB™) against hospitalization caused by gonorrhea was estimated to be 24% (95% CI 1-42%). In conclusion, vaccination with MeNZB™ significantly reduced the rate of hospitalization from gonorrhea. This supports prior research indicating possible cross protection of this vaccine against gonorrhea acquisition and disease in the outpatient setting.

High concentrations of Na⁺ or [Co(NH₃)₆]³⁺ can induce the B to Z conformational transition in alternating (dC-dG) oligo and polynucleotides. The use of short DNA oligomers (dC-dG)₄ and (dm⁵C-dG)₄ as models can allow a thermodynamic characterization of the transition. Both form right handed double helical structures (B-DNA) in standard phosphate buffer with 115 mM Na⁺ at 25 ^oC. However, at 2.0 M Na⁺ or 200 mM [Co(NH₃)₆]³⁺, (dm⁵C-dG)₄ assumes a left handed double helical structure (Z-DNA) while the unmethylated (dC-dG)₄ analogue remains right handed under those conditions. We have previously demonstrated that the enthalpy of the transition at 25 ^oC for either inducer can be determined using isothermal titration calorimetry (ITC) [Ferreira, J. M. & Sheardy, R. D., Biophys. J. 2006, 91, 1–7]. Here, ITC is used to investigate the linkages between temperature, water activity and DNA conformation. We found that the determined enthalpy for each titration varied linearly with temperature allowing determination of the heat capacity change (DC_p) between the initial and final states. As expected, the DC_p values were dependent upon the cation (i.e. Na⁺ vs [Co(NH₃)₆]³⁺) as well as the sequence of the DNA oligomer (i. e., methylated vs unmethylated). Osmotic stress experiments were carried out to determine the gain or loss of water by the oligomer induced by the titration. The results are discussed in terms of solvent accessible surface areas, electrostatic interactions and the role of water.

Lambertianic acid (LA) is a biologically active compound from the leaves of Pinus koraiensis. In the present study, apoptotic mechanisms of LA plus TNF-related apoptosis-inducing ligand (TRAIL) were elucidated in non-small cell lung cancer cells (NSCLCs). Cytotoxicity assay, flow cytometry, immunoprecipitation and Western blotting were performed. Here, combined treatment of LA and TRAIL increased cytotoxicity, sub-G1 population and cleaved poly (ADP-ribose) polymerase (PARP) and caspase3/8/9 in A549 and H1299 cells compared to LA or TRAIL alone. Furthermore, combined treatment of LA and TRAIL significantly decreased anti-apoptotic proteins such as B-cell lymphoma 2 (Bcl-2), Fas-like inhibitor protein (FLIP) and X-linked inhibitor of apoptosis protein (XIAP) and enhanced the activation of pro-apoptotic proteins Bid compared to LA or TRAIL alone. In addition, combined treatment of LA and TRAIL upregulated the expression of Death receptor 4 (DR4) and downregulated phosphorylation of nuclear factor kappa-light-chain-enhancer of activated B cells (p-NF-B), inhibitory protein of kB family (p-IB) and FLIP in A549 and H1299 cells along with disrupted binding of XIAP with caspase3 or NF-B. Overall, these findings suggest that lambertianic acid enhances TRAIL-induced apoptosis via inhibition of XIAP/NF-B in TRAIL resistant NSCLCs.

Osteoporosis is an abnormal bone remodeling condition characterized by decreased bone density, which leads to high risks of broken bones. Previous studies have demonstrated that Lycii Radicis Cortex (LRC) extract inhibits bone loss in ovariectomized (OVX) mice by enhancing the osteoblast differentiation. A bioactive compound, Kukoamine B (KB), was identified from a fractionation of LRC extract as a candidate component responsible for an anti-osteoporotic effect. This study investigated the anti-osteoporotic effects of KB using in vitro and in vivo osteoporosis models. KB treatment significantly increased the osteoblastic differentiation and mineralized nodule formation of osteoblastic MC3T3-E1 cells, while it significantly decreased the osteoclast differentiation of primary-cultured monocytes derived from mouse bone marrow. The effects of KB on osteoblastic and osteoclastic differentiations under more physiological conditions were also examined. In the co-culture of MC3T3-E1 cells and monocytes, KB promoted osteoblast differentiation but did not affect osteoclast differentiation. For the in vivo experiments, KB significantly inhibited OVX-induced bone mineral density loss and restored the impaired bone structural properties in osteoporosis model mice. These results suggest that KB may be a potential therapeutic candidate for the treatment of osteoporosis.

Abstract: Presence in a recipient of antibodies directed against donor specific antigens represent a major obstacle in transplanting such patients. Removal of these antibodies represents a challenge for physicians dealing with kidney transplantation. Several strategies, techniques and old and new drugs are to date used to desensitize these patients. Desensitization may occur before transplantation or at the time of transplantation or after transplantation according whether physicians deal with living or deceased donors. Different techniques may be used to reveal the presence of antibodies in the recipients; each technique has different sensitivity and specificity, different advantages and disadvantages. The target of the drugs used to desensitize are B cells, Plasma cells, the antibodies themselves and finally, the complement that is the final actor causing tissue disruption. If B cells are relatively easy to be targeted, more difficult are the plasma cell. Indeed, several new drugs are used in randomized trials also to defeat plasma cells. Antibodies may be removed rather easily, but often their removal is followed by a rebound. Complement is not easy to be defeated and new drugs are to date used to be successful in this action. However is to date possible to desensitize many patients and to obtain successful transplantation.

The current SARS-CoV-2 pandemic is still threatening humankind. Despite first successes in vaccine development and approval, no antiviral treatment is available for COVID-19 patients. The success is further tarnished by the emergence and spreading of mutation variants of SARS-CoV-2, for which some vaccines are not effective anymore. This highlights the urgent need for antiviral therapies even more. This article describes how the Genome-Scale Metabolic Model (GEM) of the host-virus interaction of human alveolar macrophages and SARS-CoV-2 was refined by incorporating the latest information about the virus’s structural proteins and the mutant variants B.1.1.7 and B.1.351. We confirmed the initially identified guanylate kinase as a potential antiviral target with this refined model and identified further potential targets from the purine and pyrimidine metabolism. The model was further extended by incorporating the virus’ lipid requirements. This opened new perspectives for potential antiviral targets in the altered lipid metabolism. Especially the phosphatidylcholine biosynthesis seems to play a pivotal role in viral replication. The guanylate kinase is even a robust target in all investigated mutation variants currently spreading worldwide. These new insights can guide laboratory experiments for the validation of identified potential antiviral targets. Only the combination of vaccines and antiviral therapies will effectively defeat this ongoing pandemic.

Teucrium polium L. is a plant with various claims of ethnobotanical use, primarily for in-flammatory diseases. Chemical studies have already isolated different types of terpenes from the species, and studies have established the pharmacological potential. The present study evaluated the components of T. polium essential oil cultivated in Algerian Saharan Atlas. GC-MS identified the major components as Fenchone (31.25%), 3-Carene (15.77%), cis-Limonene oxide (9.77%), and Myrcene (9.15%). In the in silico prediction, molecules with more than 1% abundance were selected. Regarding Lipinski’s rule, all molecules fol-lowed the rule. All molecules were found to be toxic in at least one model, with some mol-ecules being non-genotoxic (6, 8, 10, 11, 12, 13), others being non-mutagenic (5, 7, 9, 14). Three molecules were selected that showed the best results in pharmacokinetic and toxici-ty studies: the molecules that did not present carcinogenic potential (7 - Myrtenal; 9 - Myr-tenol; 14 – Verbenol). The molecular target was established and it seems that all three bind to the Nuclear Factor NF-kappa-B. Based on the docking and molecular dynamics results. These molecules have potential as anti-inflammatory agents, with further in vitro and in vivo studies needed to evaluate their activities and toxicity.

Often, in biology, we are faced with the problem of exploring relevant unknown biological hypotheses in the form of myriads of combinations of factors/genes/proteins that might be affecting the pathway under certain conditions. In colorectal cancer (CRC) cells treated with ETC-1922159, many genes were found up and down regulated, individually. A recently developed search engine ranked combinations of Nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB)-X (X, a particular gene/protein) at 2^nd order level after drug administration. These rankings reveal which NFκB-X combinations might be working synergistically in CRC. If found true, oncologists can further test the combination of interest in wet lab and determine the mechanism of functioning between the NFκB and X. In this research work, we cover combinations of caspase (CASP) with receptor interacting serine/threonine kinase (RIPK) family, mucin (MUC) family with RIPK, tumor necrosis factor (TNF) with NF-κB family and NF-κB-Inhibitor (NF-κB-I), NFκB-2/I with STAT family, IκB kinase ε (IKBKE) with STAT family, IKBKE with conjugal transfer protein (TRAF), ATP-binding cassette (ABC) domain transporters with NFκB, IKBKE with ubiquitination modifier enzyme and ubiquitination conjugating enzymes (UBA/UBE) and REL-A/B with NFκB .

Hepatitis B Virus (HBV) infection carries a significant health burden worldwide. It is a leading cause of acute and chronic liver disease resulting in cirrhosis and hepatocellular carcinoma (HCC). This virus affects millions globally, and despite several medical advancements, research, and efforts to develop curative treatment, the persistence of HBV in infected individuals by cccDNA and integration pose formidable challenges. This review aims to provide a broad-based overview of HBV persistence, integration and the implications for chronic infection and tumorigenesis. By considering these points, we bring forth insights into the advancement of therapies that aim to disrupt the chronicity of HBV infection and improve clinical outcomes.

Background: Inflammatory Bowel disease (IBD) is one of the worldwide health issues with increasing incidence. Recent data point out that those patients can have a defective immune system, rendering response to vaccinations suboptimal. Since 1990, Hepatitis B Virus (HBV) vaccination has been introduced among the compulsory childhood vaccinations in Oman. Given the questionable immunogenicity of vaccinations in IBD patients, we designed this study to quantify the immune response to scheduled HBV vaccine in IBD patients and compare it with that in a matching control cohort of healthy blood donors at Sultan Qaboos University Hospital (SQUH). Methods: This is a retrospective case-control study that was conducted between the 1st of July 2023 and the 31st of May 2024 at SQUH. Using the hospital information System (HIS), a total of 252 participants were enrolled in our study and divided into two groups. Group (1) included 126 IBD patients and group (2) included 126 healthy controls. Baseline demographics, medical comorbidities and viral serologies before and after vaccination were collected. The primary outcome of the study was to compare the long term immune response to HBV vaccine between the two groups. The secondary outcomes included identifying possible risk factors for suboptimal vaccine response. Results: One hundred and twenty-six participants were included in each group. Durable protective immune response to HBV vaccine was attained in 29 patients (23%) of the IBD group compared to 109 participants (86.5%) of the control group. There was a statistically significant association (p = 0.0156) between prednisolone treatment and low immune response to HBV vaccine. Moreover, esomeprazole usage exhibited a statistically significant association (p < 0.0001) with suboptimal response to HBV vaccine. Meanwhile, there was no statistically significant correlation between low immunogenicity to HBV vaccine and age, sex, type of IBD, comorbidities, and BMI. Conclusions: IBD patients are less immunogenic to HBV vaccination compared to healthy controls. Factors like esomeprazole and/or corticosteroid therapy might be associated with poor immune response. These findings highlight the importance of reassessing the immunogenicity of HBV vaccination and probably other protective vaccinations in all IBD patients as part of their standard of care.

Traumatic brain injury (TBI) affects millions of people each year. Previous studies using the central fluid percussion injury (CFPI) model in adult male rats indicated that elevated intracranial pressure (ICP) was associated with long-term effects, including neuronal cell loss and increased sensory sensitivity post-injury and secondary ICP elevation, that were not seen following injury alone. Investigations also indicated that Cathepsin B (Cath B), a lysosomal cysteine protease, may play a role in the pathological progression of neuronal membrane disruption; however, the specific impact of Cath B inhibition following CFPI remains unknown. Thus, the focus of this study was to evaluate the effects of Cath B inhibition via intracerebroventricular infusion of CA-074Me 2w following injury with or without secondary elevation of ICP. This was accomplished using adult male rats continuously infused with CA-074Me or 10% DMSO as a vehicle control for 2w following either sham injury, a CFPI only, or a CFPI with subsequent ICP elevation to 20mmHg. We assessed Cath B activity in the lateral neocortices and liver, evaluated protein levels of Cath B and Cath B binding partners AIF, Bcl-XL, and Bak. We also conducted histological analyses of total cell counts to assess for cell loss, membrane disruption, and Cath B localization. Finally, we investigated somatosensory changes with the whisker nuisance task. Overall, this study demonstrated that Cath B is not a direct driver of membrane disruption, however, administration of CA-074Me alters Cath B localization and reduced hypersensitivity, emphasizing Cath B being an important component in late secondary pathologies.

Abstract: Background: Viral hepatitis B and C (HBV and HCV) pose significant public health challenges globally, particularly in Nigeria, where access to healthcare and treatment affordability are major concerns. This study aims to identify sociodemographic and clinical predictors of health insurance coverage among patients with HBV and HCV in Nigeria. Methods: A cross-sectional facility-based study was conducted at two secondary hospitals in Nasarawa State, Nigeria. Par-ticipants included patients diagnosed with HBV, HCV, or both and are > 18 years old. Data were collected using a structured questionnaire covering sociodemographic and clinical information, health insurance details, and economic impact. Logistic multivariate regression analysis was used to analyze the relationship between sociodemographic/clinical variables and health insurance status. Results: Out of 295 participants included in the final analysis, 67.1% had health insur-ance, primarily covering hepatitis screening and vaccination. Being aged 31-45 years (adjusted Odds Ratio [aOR]: 5.72, 95% Confidence Interval [CI]: 1.4 - 23.28, p = 0.02), having post-secondary education (aOR: 11.73, CI: 4.09 - 33.66, p < 0.001), and being HIV-positive (aOR: 2.86, CI: 1.02 - 8.02, p = 0.046) were significant predictors of health insurance coverage. Being unemployed significantly reduced the likelihood of having health insurance (aOR: 0.04, CI: 0.01 - 0.11, p < 0.001).Conclusions: This study reveals high insurance coverage among patients seeking viral hepatitis services in Nasarawa state, Nigeria and provides critical insights into the sociodemo-graphic predictors of health insurance coverage. It also highlights the need for the expansion health insurance benefit package that covers for viral hepatitis diagnosis and treatment, espe-cially for the younger adults, unemployed and less educated populations. This should be followed with adequate budgeting and policy implementation monitoring efforts, which are crucial for Nigeria's journey towards universal health coverage and elimination of viral hepatitis.

Current research suggests that polycystic ovary syndrome (PCOS) might originate in utero and implicates the placenta in its pathogenesis. Kisspeptin (KISS1) and neurokinin B (NKB) are produced by the placenta in high amounts, and they have been implicated in several pregnancy complications associated with placental dysfunction. However, their placental expression has not been studied in PCOS. We isolated mRNA after delivery from the placentae of 31 PCOS and 37 control women with term, uncomplicated, singleton pregnancies. The expression of KISS1, NKB, and neurokinin receptors 1, 2, and 3 was analyzed with real-time polymerase chain reaction, using β-actin as the reference gene. Maternal serum and umbilical cord levels of total testosterone, sex hormone binding globulin (SHBG), free androgen index (FAI), androstenedione, dehydroepiandrosterone sulfate (DHEAS), Anti-Mullerian hormone (AMH), and estradiol were also assessed. NKB placental mRNA expression was higher in PCOS versus controls in pregnancies with female offspring. NKB expression depended on fetal gender, being higher in pregnancies with male fetuses. NKB was positively correlated with umbilical cord FAI and AMH, and KISS1 with cord testosterone and FAI; there was also a strong positive correlation between NKB and KISS1 expression. Women with PCOS had higher serum AMH and FAI and lower SHBG than controls. Our findings indicate that NKB might be involved in PCOS-related placental dysfunction, and warrant further investigation. Studies assessing the placental expression of NKB should take fetal gender into consideration.

Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma and a heterogeneous disease characterized by mature B-cell neoplasms. The standard immunochemotherapy for DLBCL is R-CHOP, which includes rituximab, cyclophosphamide, doxoru-bicin, vincristine, and prednisone. Up to 30-40% of patients with DLBCL either exhibit primary refractory disease to standard treatment or experience relapse after the initial response. A 72-year-old man diagnosed with DLBCL involving chromosomal translocations t(1;22)(q21;q11.2) and t(6;18)(p25;q21) showed primary refractory disease after the fourth cycle of R-CHOP. The patient ultimately experienced cardiac involvement by the lymphoma and received salvage chemotherapy. He passed away about 15 months away after the diagnosis of DLBCL. We conducted fluorescence in situ hybridization (FISH) for further analysis of the chromosomal translocations. The breakpoint of chromosome 1q21 was located at a distance of around 151 Mb from the telomeric end of chromosome 1p. The breakpoint in chromosome 22q11 contains the immunoglobulin lambda locus. Furthermore, the breakpoint of chromosome 6p was in the telomeric region of chromosome 6p21. The breakpoint of chromosome 18q21 contains BCL2. This case report presents the first documented co-occurrence of chromosomal translocations t(1;22)(q21;q11.2) and t(6;18)(p25;q21) in a patient with DLBCL. These chromosomal translocations may indicate a worse clinical outcome.

Febrile neutropenia (FN) is a major concern in patients undergoing chemotherapy for diffuse large B-cell lymphoma (DLBCL); however, the overall risk of FN is difficult to assess. This study aimed to develop a model for predicting the occurrence of FN in patients with DLBCL. In this multicenter, retrospective, observational analysis, a multivariate logistic regression model was used to analyze the association between FN incidence and pretreatment clinical factors. We included adult inpatients and outpatients (aged ≥ 18 years) diagnosed with DLBCL who were treated with chemotherapy. The study examined 246 patients. Considering FN occurring during the first cycle of chemotherapy as the primary outcome, a predictive model with a total score of 5 points was constructed as follows: 1 point each for viral hepatitis, extranodal involvement, and a high level of soluble interleukin-2 receptor and 2 points for lymphopenia. The area under the receiver operating characteristic curve of this model was 0.844 (95% confidence interval: 0.777–0.911). Our predictive model can assess the risk of FN before patients with DLBCL start chemotherapy, leading to better outcomes.

The cyclin-dependent kinase (Cdk) 1–cyclin B (CycB) complex plays critical roles in cell cycle regulation. Before Drosophila male meiosis, CycB is exported from the nucleus to the cytoplasm via the nuclear porin 62kD (Nup62) subcomplex in the nuclear pore complex. When this is inhibited, Cdk1 is not activated, and meiosis does not initiate. We investigated the mechanism that controls cellular localization and activation of Cdk1. Cdk1–CycB continuously shuttled into and out of the nucleus in the prolonged G2 phase before meiosis. Overexpression of CycB, but not that with nuclear localization signal sequences, rescued reduced cytoplasmic CycB and inhibition of meiosis in Nup62-silenced cells. Full-scale Cdk1 activation occurred in the nucleus shortly after its rapid nuclear entry. Cdk1-dependent centrosome separation did not occur in Nup62-silenced cells, while Cdk1 interacted with Cdk-activating kinase and Twine/Cdc25C in the nucleus of Nup62-silenced cells, suggesting the involvement of another suppression mechanism. Silencing of roughex rescued Cdk1 inhibition and initiated meiosis. Nuclear exports of Cdk1 ensured its escape from inhibition by cyclin-dependent kinase inhibitor. The complex reentered the nucleus via importin β at the onset of meiosis. We propose a model regarding the dynamics and activation mechanism of Cdk1–CycB to initiate male meiosis.

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.

Background and Aim: Spontaneous bacterial peritonitis is a common infection in liver cirrhosis. This systematic review and meta-analysis provides detailed information on the prevalence of SBP among HBV and HCV-related liver cirrhosis globally. Methods: A systematic search for articles describing the prevalence of SBP in HBV, and HCV related cirrhosis was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) guidelines. Our search returned ten (10) eligible articles involving 1,713 viral cirrhosis cases representing eight (8) countries. A meta-analysis was performed on our eligible studies using the random effect model. A protocol was registered with PROSPERO (CRD42022321790). Results: The pooled prevalence of SBP in HBV associated cirrhosis had the highest estimate [8.0% (95% CI, 2.7 – 21.0%; I2= 96.13%; p < 0.001)], followed by SBP in HCV associated liver cirrhosis [4.0% (95% CI, 1.3% – 11.5%; I2 = 88.99%; p < 0.001)]. China (61.8%, CI: 57.1 – 66.3%), the USA (50.0%, CI: 34.6 – 65.4%), and Holland (31.1%, CI: 21.6 – 42.5%) had the highest estimate for SBP in HBV associated liver cirrhosis, SBP in HCV associated liver cirrhosis and SBP in HBV+HCV associated liver cirrhosis respectively. There was a significant difference in the prevalence of SBP in viral hepatitis-associated liver cirrhosis with the year of sampling and method of SBP detection at P<0.001. There was an increase in SBP incidence at the beginning of 2016 across the liver cirrhosis in this study. Conclusion: The findings of this review revealed an increase in the incidence of SBP in viral hepatitis over the last decade, the latter could be due to the global increase in Bacterial resistance. This indicates a possible future rise in the global prevalence of SBP among HBV, and HCV-related liver cirrhosis.

Antimicrobial resistance is on the rise, and there aren't enough new treatments to combat it. This might send the modern world back to the pre-antibiotic age. The molecular hybrids of pyrazolo[3,4-b]pyridine and triazole have been designed, synthesized, and analyzed for their drug-like molecule nature and in vitro analyses for their inhibition potentials against S. Aureus and K. Pneumoniae. The compounds CY-R2-25 and CY-R2-28 have been identified as the high potential molecules in this series based on in vitro experiments. CY-R2-25 has zone of inhibition values of 15 0.82 and 14 0.7, whilst CY-R2-28 has the zone of inhibition values of 18 0.95 and 16 0.82 against S. Aureus and K. Pneumoniae, respectively. MIC and MIB values for CY-R2-25 and CY-R2-28 against S. Aureus and K. Pneumoniae are 0.25 and 0.5, respectively.

(1) Background: Investigating the characteristics of photosynthetic physiological changes of leaves in Mangifera indica L. cv. 'GuIfei' under enhanced UV-B radiation, natural light exposed trees were regarded as control, and 96 kJ·m-2·d-1enhanced UV-B radiation was artificially simulated in the field; (2) Methods: The changes of fruit maturity and fruit quality, leaf net photosynthetic rate (Pn), photosynthetic pigments contents, photochemical reaction, activities of photosynthetic enzymes and their genes expressions were determined; (3) Results: Compared with CK, the percentage of mature fruits of the treatment was significantly increased, and fruit quality was better. The net photosynthetic rate (Pn), the contents of photosynthetic pigment, Hill reaction activity and photochemical quenching coefficient (qP) of the treatment leaves showed a significantly higher trend than CK. The activities of Rubisco and RCA, and the expression of Rubisco genes rbcL and rbcS were significantly increased; (4) Conclusions: 96 kJ·m-2·d-1 enhanced UV-B radiation treatment improved Rubisco activity through increasing the expression of Rubisco genes rbcL and rbcS, thereby enhancing the CO2-fixing capacity and dark reaction capacity of leaves. Based on this, it raised the net photosynthetic rate of leaves, which promoted the early maturity of 'Guifei' mango by the fast accumulating photosynthetic products.

The Oldroyd–B model for a linear viscoelastic fluid is employed to investigate the buoyant flow in a vertical porous layer with permeable boundaries kept at different uniform temperatures. Seepage flow in the viscoelastic fluid saturated porous layer is modelled through an extended version of Darcy’s law taking into account the Oldroyd–B rheology. The basic stationary flow is parallel to the vertical axis and describes a single–cell vertical pattern where the cell has an infinite vertical height. A linear stability analysis of such a basic flow is carried out to determine the onset conditions for a multicellular pattern. The neutral stability curves and the values of the critical Rayleigh number are evaluated numerically for different retardation time and relaxation time characteristics of the fluid.

Central adiposity is one of the significant determinants of obesity-related hypertension risk, which may arise due to the abdominal fat depot's pathogenic inflammatory nature. Pro-inflammatory cytokines and adipokines up-regulation through nuclear factor-kappa B (NF-κB) activation in adipose tissue has been considered an essential function in the pathogenesis of obesity-related hypertension. This study aimed to ascertain the NF-κB inhibitor (SN50) effect on TNF-α and angiotensinogen (AGT) secretion and expression in mediating the anti-inflammatory effect through its impact on NF-κB activity in humans adipose tissue. Primary human adipocytes were isolated from 20 subjects among 10 overweight and 10 obese with and without hypertension and treated with 10ng/ml LPS in the presence and absence of NF-κB inhibitor, SN50 (50μg/ml). TNF-α secretion and NF-κB p65 activity were detected in supernatants extracted from cultured cells treated and untreated with LPS (10ng/ml) and SN50 (50μg/ml) using enzyme-linked immunosorbent assay (ELISA). The western blot technique detected the protein of NF-κB p65 and AGT. Gene expression of TNF-α and AGT was detected in cells and performed using quantitative real-time polymerase chain reaction (RT-PCR). Treatment of AbdSc adipocytes with LPS (10ng/ml) caused a significant increase in NF-κB p65 among overweight and obese subjects with and without hypertension (P= 0.001) at 24 hours incubation. In contrast, SN50-NF-κB inhibitor causes a reduction of NF-κB p65 in overweight (P= <0.001) and obese subjects with and without hypertension (P= 0.001) at 24 hours incubation. Treatment of AbdSc adipocytes with 10ng/ml LPS caused a significant increase in TNF-α secretion in overweight and obese subjects at all-time points (P= <0.001), whereas SN50 leads to a decrease in TNF-α secretion at 3 and 12 hours incubation. Treatment of AbdSc adipocytes with LPS (10ng/ml) caused increased TNF-α and AGT gene expression twofold compared with untreated cells, whereas, in the presence of SN50, it reduces mRNA AGT levels in both groups. Taken together, these adipokines with NF-κB activation may represent essential biomarkers to evaluate hypertension risk and to provide insight into the pathogenesis of obesity-related hypertension.

The most common type of non-Hodgkin lymphoma in adults is diffuse large B-cell (DLBCL). There is a historical unmet need for more effective therapies in the 2nd and 3rd line setting. Emerging immunochemotherapies have shown activity in small studies of heavily pre-treated patients with prolonged remissions achieved in some patients. Anti-CD19 CAR (chimeric antigen receptor) T cells are potentially curative in the 3rd line and beyond setting and are under investigation in earlier lines of therapy.1 Antibody-drug conjugates (ADC’s) such as polatuzumab vedotin targeting the pan-B-cell marker CD79b has proven effectiveness in multiply-relapsed DLBCL patients. Tafasitamab (MOR208) is an anti-CD19 monoclonal antibody producing prolonged remissions when combined with Lenalidomide in patients who were not candidates for salvage chemotherapy or autologous stem cell transplant. Selinexor, an oral, small-molecule selective inhibitor of XPO1-mediated nuclear export (SINE), demonstrated prolonged activity against heavily-pretreated DLBCL without cumulative toxicity and is being investigated as part of an oral, chemotherapy-free regimen for relapsed aggressive lymphoma. This article reviews current strategies and novel therapies for relapsed/refractory DLBCL.

Indonesia is one of the largest banana producing countries in the world remaining abundance solid waste of banana fruit bunch. The banana fruit bunch contains high natural fibers which were obtained by an impregnation process using potassium hydroxide (KOH) and followed by a carbonization process under steam at 250°C for 5 h. The nanomaterial of TiO₂/fibre was prepared by a hydrothermal process at 200°C for 4 h. Surface morphology proved that the TiO₂ was loaded into the fibre by an increasing roughness of the surface and irregular size of porosity. The development of amorphous to crystalline phase of TiO₂/fibre was clearly observed. The effectiveness of TiO₂/fibre for removal of rhodamine B was investigated from different parameters of adsorptions in aqueous solution. The equilibrium adsorptions show that the Langmuir and Freundlich isotherm exhibited the best correlation coefficient (R² > 0.94) relating to the chemisorption and physisorption interaction in the adsorption process. Kinetic models were well described by the pseudo-first and second-order with the best correlation coefficient (R² > 0.99). These results indicate that nanomaterial TiO₂/fibre can be used as an effective adsorbent for removal of rhodamine B in aqueous solution.

This study aimed to assess the ecotoxicological effects of the interaction of fullerene (C₆₀) and benzo[a]pyrene (B[a]P) on the marine mussel, Mytilus galloprovincialis. The uptake of nC₆₀, B[a]P and mixtures of nC₆₀ and B[a]P into tissues was confirmed by GC-MS, LC-HRMS and ICP-MS. Biomarkers of DNA damage as well as proteomics analysis were applied to unravel the toxic effect of B[a]P and C₆₀. Antagonistic responses were observed at the genotoxic and proteomic level. Differentially expressed proteins (DEPs) were only identified in the B[a]P single exposure and the B[a]P mixture exposure groups containing 1 mg/L of C₆₀, the majority of which were down-regulated (~52%). No DEPs were identified at any of the concentrations of nC₆₀ (p < 0.05, 1% FDR). Using DEPs identified at a threshold of (p < 0.05; B[a]P and B[a]P mixture with nC₆₀), gene ontology (GO) and Kyoto encyclopedia of genes and genomes (KEGG) pathway analysis indicated that these proteins were enriched with a broad spectrum of biological processes and pathways, including those broadly associated with protein processing, cellular processes and environmental information processing. Among those significantly enriched pathways, the ribosome was consistently the top enriched term irrespective of treatment or concentration and plays an important role as the site of biological protein synthesis and translation. Our results demonstrate the complex multi-modal response to environmental stressors in M. galloprovincialis.

Botulinum neurotoxin (BoNT) intoxication can lead to the disease botulism, characterized by flaccid muscle paralysis that can cause respiratory failure and death. Due to the significant morbidity and mortality costs associated with BoNTs high toxicity, developing highly sensitive, rapid, and field-deployable assays are critically important to protect the nation’s food supply against either accidental or intentional contamination. We report here that the B-cell based biosensor assay (CANARY^® Zephyr) detects BoNT/A in buffer and various food matrices rapidly in ≤ 40 min, in small volumes ≈ 50 μL, with minimal processing of samples, and is extremely portable (suitcase-sized equipment). BoNT/A was detected at limits of detection (LOD) < 0.075 ng ± 0.02 in assay buffer while milk matrices (non-fat, 2 %, whole milk) increased the LOD to < 0.175 – 0.314 ng. Limits of detection for the assay in complex foods were < 1 ng ± 0.0 (neutralized acidic juices-carrot, orange and apple); < 16.7 ng ± 7.7 (liquid egg); and varied from < 0. 39 – 3.125 ng for solid complex foods (ground beef, green bean baby puree, smoked salmon). These results show that the CANARY^® Zephyr assay can be a highly useful tool in clinical, environmental, and food safety surveillance programs.

In the present study, we derive a new B-spline technique namely trigonometric B-spline collocation algorithm to solve some initial boundary value problems for the nonlinear Klein-Gordon equation. In order to carry out the time integration with Crank-Nicolson implicit method, the order of the equation is reduced to give a coupled system of nonlinear partial differential equations. The collocation approximation based on trigonometric cubic B-splines for spatial discretization is followed by the linearization of the nonlinear term. The efficiency and accuracy of the present method are validated by measuring the error between the numerical and analytical solutions when exist. The conservation laws representing momentum and energy are also computed for all problems.

The enormous diversity of hair fibers found in human population is striking, while the basic structure of human fibers is often the same! But why do some fibers curl? Curling is related to the machinery and processes that produce different keratin filament orientation in relation to the axis of hair growth, influenced by developmental and molecular control. It is established that a curly hair shaft is produced by a curved hair follicle that have an angulated dermal implantation, with a bulb bent in the shape of golf club, while the outer root sheath is dissymmetrical; have an outer side that is convex bulging and thin and a concave side in which the cells express alpha-smooth muscle protein reflecting internal mechanical force. Yet, the exact cause of hair curling is not known. All the previous studies were short of impacting curly hair treatment. My hypothesis is that the curling mechanical force is generated by a hypersensitive contracted Arrector Pili muscle (APM) of the hair follicle. In curly hair, each APM fiber is shortened; pulling its attachment spot upward towards the epidermis and obliquely or laterally; curling the outer root sheath to produce the curved follicle described above. This contraction has the influence at a time when the young hair root is being formed and keratin microfibrils are being oriented and packed. APM is a multi-unit muscle wherein each fiber contracts independently to create the enormous diversity of curly hair types. APM contraction can be modulated by oral administration of selective smooth muscle relaxing treatment that relax the curved follicle from within. Further studies are needed to confirm the role of APM in shaping curly hair follicle including AI studies, i.e., computer-aided target identification to demonstrate APM active site that can interact with herbal small molecules.

Recently, Gohar et al. introduced a novel, local, and well-behaved fractional calculus. It possesses all the classical properties, and Its locality imposes simplicity and accuracy in modeling fractional order systems. In this article, we further develop the definitions and extend the classical properties of Gohar fractional calculus to address some of the open problems in Calculus. The fractional Gronwall's integral inequality, Taylor power series expansion, and Laplace transform are defined and applied to overcome some of the limitations in the classical integer-order calculus. The fractional Laplace transform is applied to solve Bernoulli-type logistic and Bertalanffy nonlinear fractional differential equations, and the criteria under which it can be applied to solve linear differential equations are investigated.

Liposomal amphotericin B (L-AmB) has become the cornerstone for the treatment of severe invasive fungal infections. However, renal toxicity may be an associated risk. Our aim was to evaluate the incidence of acute kidney injury (AKI) in critically ill patients receiving L-AmB for more than 48 hours. Clinical, demographic and laboratory variables were obtained retrospectively from electronic health record. Follow-up of the patients was for 7 days after L-AmB infusion. Patients were analyzed globally and differentiated between patients with "low" and "high" risk of developing AKI with machine learning techniques. Sixty-seven patients were included: 61 years, 67% male, with mean SOFA score of 4 (3-6.5) and a crude intensive care unit mortality of 34.3%. No significant variations in serum creatinine were observed during the observation period, except for the decrease in the high-risk subgroup. Overall, 26.8% of patients developed AKI-I, while 25% and 13% of patients at low and high risk of AKI developed AKI-I, respectively. The random forest models performed in overall and low-risk subgroup identified several major contributor’s factors to the development of AKI other than L-AmB administration. The development of AKI is multifactorial and the administration of L-AmB appears to be safe in this group of patients.

Disinfection by-products to obtain drinking water, such as CH2Cl2, CHCl3, and BrCHCl2, elicit cytotoxicity and hyperproliferation in human lung fibroblasts (MRC-5). Enzymes of their biotransformation modulate these damages and can generate toxic metabolites. However, it is unknown that the response to oxidative stress is involved in cellular hyperproliferation modulated by nuclear factor-kappa B (NF-κB). Hence, MRC-5 cells were treated with these compounds to evaluate ROS, lipid peroxidation, phospho-NF-κB/p65 (Ser536) levels, CAT, SOD, and GPx activities. Further, the interactions of halomethanes and ROS with IκBα/NF-κB/p65 complex were analyzed by molecular docking. The correlation among biomarkers showed positive relationships between the prooxidant damage with the antioxidant response, particularly in cells treated with CH2Cl2, and BrCHCl2. Furthermore, negative relationships among ROS with levels of NF-κB/p65 in cells treated with CH2Cl2, and CHCl3 were detected. The estimated relative free energy of binding using thermodynamic integration with the p65 subunit of NF-κB was -3.3 kcal/mol for BrCHCl2; -3.5 kcal/mol for both CHCl3 and O2•, and -3.6 kcal/mol for H2O2. The chloride and bromide are in close contact with the IPT domain residues, particularly in the RHD region involved in DNA binding. Ser281 is located in the same domain, allowing this protein's phosphorylation. Similarly, both ROS are in contact with IPT domain into region RHD and H2O2 as side-chain oxygen with Leu280, adjacent to the phosphorylation site of p65. However, a negative correlation among ROS with phospho- NF-κB/p65 suggests ROS's steric hindrance on the C-terminal domain of NF-κB/p65 is involved in antioxidant response.

Primary bone lymphoma of the spine (PBL) is a rare entity and the most shared type of non-Hodgkin lymphoma (LNH) appearing in bone lesions deprived of nodal or extra-nodal in-volvement and accounting for approximately 2% of all lymphomas. Most PBL are diffuse large B-cell lymphomas (DLBCL) and commonly involve the appendicular skeleton. Due to its atypical location and non-specific clinical imaging features mimicking certain neoplastic or infectious processes, this pathology may be misdiagnosed, thus complicating and delaying diagnosis. Our case reports a patient in her sixties who had been suffering from chronic low back pain for a year, and had gradually started to develop cruralgia and fever. She underwent a blood sample, magnetic resonance imaging (MRI), and positron emission tomography (18F-FDG-PET/CT) which revealed significant inflammatory syndrome, a pattern of spondylodiscitis at the L3-L4 level associated with morphological and metabolic invasion extending posteriorly, raising suspicion of epiduritis. No other lesions were found on the rest of the body. Neurosurgical management was performed and a biopsy was made. Histological results showed aggressive and diffuse large B-cell lymphoma, suggesting a diagnosis of PBL. This case highlights the first case of spondylodiscitis mimicking PBL in the lumbar spine, the intricacies of the diagnostic work-up, and the complexity of discriminating with an infectious process in the spine, as both have a similar, non-specific clinical presentation with different prognosis and therapeutic management.

Accurate geometric modeling of blood vessels lumen given their 3D images is a basis for vessel quantification in support of cardiovascular diseases diagnosis, treatment and monitoring. Unlike other approaches, which assume circular or elliptical vessel cross-section, the proposed method employs parametric B-splines combined with the image formation system equations to accurately localize the highly curved lumen boundaries. No image segmentation is involved which might reduce the localization accuracy in effect of spatial discretization. It is shown that the model parameters can be reliably identified by a feedforward neural network which, driven by the cross-section images, predicts the parameter values many times faster than a reference least-squares (LS) model fitting algorithm. Two example applications: modeling the lower extremities artery-vein complexes visualized in steady-state contrast-enhanced magnetic resonance images (MRI) and the coronary arteries pictured in computed tomography angiograms (CTA), are presented and discussed to demonstrate the method potential. Besides application to medical diagnosis, blood-flow simulation and vessel-phantom design, it can serve as a tool for automated annotation of image datasets required to train machine-learning algorithms.

The narrow parking space will result in difficulties in path planning and spot turning caused by sudden changes and discontinuities in path curvature. To address the problem, this paper investigates the performance of three path planning algorithms and proposes a path optimization algorithm. First, the narrow parking space is defined based on single-step parking of the arc-line combination parking algorithm. Second, to compare the arc-line combination algorithm, Hybrid A* algorithm, and particle swarm optimization parking algorithm under different narrow parking spaces, a multi-objective evaluation function is proposed, including three evaluation indicators, namely, the path length, the number of positive and negative conversions of vehicle speed, and the smoothness of the path. Their performance is compared by simulation conducted in MATLAB, the results show that the Hybrid A* algorithm is the better than others for narrow parking spaces. Third, to smooth the planning path, a path optimization algorithm based on the cubic B-spline curve and gradient descent is proposed. Finally, the simulation is conducted between the proposed algorithm and Hybrid A* algorithm, the result shows that the proposal can effectively eliminate the curvature mutation point and constrain the path curvature to meet the requirements of a smooth path.

Hepatitis B Virus (HBV) is a challenge for global health services, affecting millions and leading hundreds to end-stage liver disease each year. This comprehensive review explores the interactions between HBV and the host, examining their impact on clinical outcomes. HBV infection encompasses a spectrum of severity, ranging from acute hepatitis B to chronic hepatitis B, which can potentially progress to cirrhosis and hepatocellular carcinoma (HCC). Occult hepatitis B infection (OBI), characterized by low HBV DNA levels in hepatitis B surface antigen-negative individuals, can reactivate and cause acute hepatitis B. The identification of diverse HBV genotypes reveals distinct geographical distributions and associations with clinical outcomes. Moreover, single nucleotide polymorphisms (SNPs) within the host genome have been linked to several clinical outcomes, including cirrhosis, HCC, OBI, hepatitis B reactivation, and spontaneous clearance. The immune response plays a key role in controlling HBV infection by eliminating infected cells and neutralizing HBV in the bloodstream. Furthermore, HBV can modulate host metabolic pathways involved in glucose and lipid metabolism and bile acid absorption, further influencing disease progression. HBV clinical outcomes correlate with three levels of viral adaptation. In conclusion, the clinical outcomes of HBV infection could result from complex immune and metabolic interactions between the host and HBV. These outcomes can vary among populations and are influenced by HBV genotypes, host genetics, environmental factors, and lifestyle. Understanding the degrees of HBV adaptation is essential for developing region-specific control and prevention measures.

Since the first description of SARS-CoV-2 in China in 2019, thousands of variants have emerged worldwide. For some of them, the constellation of mutations caused changes in virus biology, pathogenicity, infectivityity and transmissibility resulting in dissemination throughout the world. Gamma variant (P.1) differs from SARS-CoV-2 Wuhan strain (B.1) by 12 amino acids in the Spike (S) protein, and presented mutations related to greater affinity for the receptor angioten-sin-converting enzyme 2 (ACE-2) and/or immune escape. The Gamma variant and subvariants were responsible for the second wave of COVID-19 in the Brazilian city of Manaus, characterized by high mortality and rapid transmission. The ability of variants to induce cytokine production may be closely related to their pathogenicity. Herein we observed that there was no significant difference in the quantity of cytokines among macrophages or neutrophils infected with P.1 and B.1 strains. Also, no significant difference was observed in the absolute number of macrophages and neutrophils infected with these variants. Furthermore, no evidence of SARS-CoV-2 replication was observed in macrophages when infected by the two analyzed variants. Our findings suggest that the difference in the epidemiological outcome observed during the P.1 variant spread when compared to B.1, it is not explained by differences in the quantity of cytokines and absolute number of macrophages or neutrophils. Through bioinformatics analysis of the S protein, we observed that the physicochemical differences between the variants and subvariants of P.1, probably refer to the degree of infectivity, due to the impact caused in the recognition of antibodies and receptor af-finity

This paper focuses on a joint model to analyse longitudinal proportion and survival data. After transforming the longitudinal proportional data by a logit function, we adopt a partially linear mixed-effect model for it, in which nonlinear function of time is fitted via using B-splines technique and a centered Dirichlet Process Mixture Model (CDPMM) is specified for a general distribution of random effects. The survival data is assumed to a Cox proportional hazard model, the sharing random effects joint model is developed for the two types of data. Combining the Gibbs sampler and the Metropolis-Hastings algorithm, we propose a Bayesian Lasso (BLasso) method to simultaneously estimate unknown parameters and select important covariates. Simulation studies are conducted to investigate the finite sample performance of the proposed methods. An example from the MA.5 research experiment is used to illustrate the proposed methodologies.

Infectious bursal disease (IBD) is a viral poultry disease known worldwide for impacting the economy and food security. The disease is endemic in Nigeria, with reported outbreaks in vaccinated poultry flocks. To gain insight into the dynamics of infectious bursal disease virus (IBDV) evolution in Nigeria, near-complete genomes of four IBDVs were evaluated. Amino acid sequences in the hypervariable region of the VP2 revealed conserved markers (222A, 242I, 256I, 294I and 299S), associated with very virulent (vv) IBDV, including the serine-rich heptapeptide motif (SWSASGS). Based on the newly proposed classification for segments A and B, the IBDVs clustered in the A3B5 group (where A3 are IBDVs with vvIBDV-like segment A and B5 are from non-vvIBDV-like segment B) forming a monophyletic subcluster. Unique amino acid mutations with yet-to-be-determined biological functions have been observed in both segments. Amino acid sequences of the Nigerian IBDVs showed that they are reassortant viruses. Circulation of reassortant IBDVs may be responsible for the vaccination failures observed in the Nigerian poultry population. Close monitoring of changes in the IBDV genome is recommended to nip deleterious changes in the bud, through the identification and introduction of the most appropriate vaccine candidates and advocacy/extension programs for properly implementing disease control.

Chronic hepatitis B infection remains a significant worldwide health burden, placing persons at risk for hepatocellular cancer and hepatic fibrosis. Chronic hepatitis B virus (CHB) infection is characterized by elevated levels of immunosuppressive regulatory T cells (Tregs), which can inhibit the function of effector T cells and lead to an insufficient immune clearance response against HBV in the host. Theoretically, suppression of Treg functionality and percentage could increase anti-HBV reactivity in CHB-infected patients, although this has not yet been explored. We attempted to enhance our previously established anti-CHB protocol utilizing the GM-CSF+IFN-α+rHBVvac regimen (GMI-HBVac) by incorporating Mafosfamide (MAF), which has been utilized in anticancer therapy in the past. Intravenous administration of MAF to rAAV8-1.3HBV-infected mice resulted in a dose-dependent reduction of Tregs in the blood, rebounding to pretreatment levels 10 days later. To determine the efficacy of anti-CHB, 2ug/ml MAF was combined with the GMI-HBVac in an HBV-infected animal model as an anti-Treg treatment. When rAAV8-1.3HBV-infected mice were immunized with MAF+GMI-HBVac, peripheral blood Tregs decreased significantly, leading to dendritic cell activation, HBV-specific T cell proliferation, and upregulation of IFN-gamma producing CD8+T cells. In addition, MAF+GMI-HBVac vaccination stimulates T cell infiltration in HBV-infected liver. These conditions may contribute to an enhanced immune response and the clearance of HBV-associated antigens, including serum HBsAg, serum HBcAg, and HBcAg+ hepatocytes. Overall, this is the first indication that MAF was utilized as an adjuvant to deplete Tregs and paired with GMI-HBVac as a unique therapeutic vaccine regimen against established CHB mice to produce a functional cure, as seen by the remarkable clearance of HBsAg.

A total of 381 hepatitis B virus (HBV) DNA sequences collected from 9 groups of Siberian native populations were phylogenetically analyzed along with 179 HBV strains sampled in different urban populations of former western USSR republics and 50 strain from Central Asian republics and Mongolia. Different HBV subgenotypes predominated in various native Siberian populations. Subgenotype D1 was dominant in Altaian Kazakhs (100%), Tuvans (100%), and Teleuts (100%) of southern Siberia as well as in Dolgans and Nganasans (69%), who inhabit the polar Taimyr Peninsula. D2 was the most prevalent subgenotype in the combined group of Nenets, Komi, and Khants of the northern Yamalo-Nenets Autonomous Region (71%), and in Yakuts (36%) from northeastern Siberia. D3 was the main subgenotype in South Altaians (76%) and Buryats (40%) of southeastern Siberia, and in Chukchi (51%) of the Russian Far East. Subgenotype C2 was found in Taimyr (19%) and Chukchi (27%), while subgenotype A2 was common in Yakuts (33%). In contrast, D2 was dominant (56%) in urban populations of the former western USSR, and D1 (62%) in Central Asian republics and Mongolia. Statistical analysis demonstrated that the studied groups are epidemiologically isolated from each other and might have contracted HBV from different sources during the settlement of Siberia.

Mutations within the hepatitis B virus (HBV) genome have been associated with rapid progres-sion to hepatocellular carcinoma (HCC); however, there is limited information regarding the prevalence and impact of these mutations in most of sub-Saharan Africa, including Botswana. We aimed to determine the prevalence of HBV mutations known to be associated with progression to HCC using a retrospective, cross-sectional analysis of 48 previously generated HBV sequences from adults with concomitant HBV/HIV initiating HIV antiretroviral therapy in Botswana. The sequences were aligned with reference sequences, and HCC-associated mutations were manually identified using BioEdit. Sixteen (33.3 %) of 48 participant samples had 20 HCC-associated mu-tations. Seven HCC mutations were present in the core region, 4 in the preCore region, 7 in the X region, and one mutation in the surface region, as well as deletions within the preSurface 1 region. Seven of the 16 participants (43.8%) had multiple HCC-associated mutations. There were also previously uncharacterized mutations at positions with known HCC-associated mutations. HCC-associated mutations were common in this cohort; hence, some participants may require close clinical monitoring as they might be more prone to rapid disease progression. Other functionally uncharacterized polymorphisms were also detected and require characterization in future studies.

Dengue is a viral mosquito-borne disease that rapidly spreads in tropical and subtropical countries, including the Philippines. One of its most distinguishing characteristics is the ability of the Dengue Virus (DENV) to easily surpass the innate responses of the body, thus activating B cells of the adaptive immunity to produce virus-specific antibodies. Moreover, Dengvaxia® is the only licensed vaccine for DENV, but recent studies showed that seronegative individuals become prone to increased disease severity and hospitalization. Owing to this limitation of the dengue vaccine, this study determined and compared consensus and unique B cell epitopes among each DENV (1-4) Philippine isolate to identify potential areas of interest for future vaccine studies and therapeutic developments. An in silico-based epitope prediction of forty (40) DENV 1-4 strains, each serotype represented by ten (10) sequences from The National Center for Biotechnology Information (NCBI), was conducted using Kolaskar and Tongaonkar antigenicity, Emini surface accessibility, and Parker hydrophilicity prediction in Immune Epitope Database (IEDB). Results showed that five (5) epitopes were consensus for DENV-1 with no detected unique epitope, one (1) consensus epitope for DENV-2 with two (2) unique epitopes, one (1) consensus epitope for DENV-3 plus two (2) unique epitopes, and two (2) consensus epitopes and one (1) unique epitope for DENV-4. The findings of this study would contribute to determining potential vaccine and diagnostic marker candidates for further research studies and immunological applications against DENV (1-4) Philippine isolates.

Background: Single nucleotide polymorphisms (SNPs) in the SLC10A1 gene, coding for a functional receptor of hepatitis B virus (HBV), sodium taurocholate co-transporting polypeptide (NTCP), may influence the susceptibility, the outcome, and disease course of HBV infection in some populations. Aim: to determine the prevalence of SNPs of NTCP gene, rs2296651 and rs943277, and their relationship with chronic HBV infection in a group of Egyptian patients. Methods: 137 patients with HBV and 65 healthy controls were enrolled, and the patients were divided into two groups; group I chronic HBV infection (68 patients with normal ALT and minimal or no liver necroinflammation or fibrosis) and group II chronic hepatitis B (69 patients with elevated ALT and moderate or severe liver necroinflammation). They were subjected to full history taking, clinical examination, laboratory investigations, abdominal ultrasound, and liver stiffness measurement using both Echosens® Fibroscan and acoustic radiation force impulse (ARFI). Real time PCR TaqMan 5’ allelic discrimination assay was applied to detect the SNPs in NTCP gene, rs2296651 and rs943277. Results: On studying the rs2296651 variant, all controls and patients had genotype GG without any significant association with HBV infection or disease progression. However, the rs943277 variant in all controls and 98% of patients had genotype GA, except for two chronic HBV infection patients who had genotype AA, but no significant difference between patients and controls was found. The non-invasive methods for liver fibrosis assessment ARFI, AST/platelet's ratio (APRI), and fibrosis-4 score (FIB-4) could predict the stages of fibrosis in agreement with Fibroscan with AUCOR 0.8, 0.79, and 0.76, respectively. Conclusion: These findings may suggest that there is no relation between these SNPs of the NTCP gene and susceptibility or chronicity of HBV infection in the Egyptian population. We also suggest that the use of the non-invasive methods for liver fibrosis assessment, ARFI, FIB-4, and APRI may decrease the need for liver biopsies in prediction of significant hepatic fibrosis in chronic HBV patients.

In this note, I analyze the data generated by M. Fodje's (2013) simulation programs "epr-simple" and "epr-clocked". They were written in Python and published on Github. Inspection of the program descriptions shows that they make use of the detection-loophole and the coincidence-loophole respectively. I evaluate them with appropriate modified Bell-CHSH type inequalities: the Larsson detection-loophole adjusted CHSH, and the Larsson-Gill coincidence-loophole adjusted CHSH (NB: its correctness is conjecture, we do not have proof). The experimental efficiencies turn out to be approximately eta = 81% (close to optimal) and gamma = 55% (far from optimal). The observed values of CHSH are, as they should be, within the appropriately adjusted bounds. Fodjes' detection-loophole model turns out to be very, very close to Pearle's famous 1970 model, so the efficiency is close to optimal. The model has the same defect as Pearle's: the joint detection rates exhibit signaling. Fodje's coincidence-loophole model is actually a clever modification of his detection-loophole model. Because of this, however, it cannot lead to optimal efficiency.

Prothrombotic thrombocytopathy mimicking heparin-induced thrombocytopenia has been observed in patients with severe COVID-19 and after immunisation with the Vaxzevria vaccine. Herein, we discuss the possible pathogenesis of this disorder focusing on the possible involvement of anti-platelet factor 4 (PFA) autoantibodies.

We aimed to investigate whether the sequence length of HIV-1 increases over time. A longitudinal analysis of full-length coding region sequences (FLs) during an HIV-1 outbreak among pa-tients with hemophilia and local controls infected with the Korean subclade B of HIV-1 (KSB) was performed. Genes were amplified by overlapping RT-PCR or nested PCR and subjected to direct sequencing. Overall, 141 FLs were sequentially determined over 30 years in 62 KSB-infected patients. Phylogenetic analysis indicated that within KSB, two FLs from plasma donors O and P comprised two clusters together with 8 and 12 patients with hemophilia, respectively. Signature pattern analysis for the KSB of HIV-1 revealed 91 signature nucleotide residues (1.05%). In total, 48 and 43 signature nucleotides originated from clusters O and P, respectively. Only six positions contained 100% specific nucleotide(s) in clusters O and P. Additionally, in-depth FL analysis over 30 years indicates that the KSB FL significantly increased over time before combined antiretroviral therapy (cART) and decreased with cART. The increase occurred due to a significant increase in env and nef genes, originating in the variable regions of both genes. The increase in the sequence length of HIV-1 over time suggests that it has an evolutionary direction.

The objective of this study is to investigate whether the sequence length of HIV-1 increases over time. A longitudinal analysis of full-length coding region sequences (FLs) in an outbreak of HIV-1 infection among patients with hemophilia and local controls identified as infected with the Korean subclade B of HIV-1 (KSB). Genes amplified by overlapping RT-PCR or nested PCR were subjected to direct sequencing. In total, 141 FLs were sequentially determined over 30 years in 62 KSB-infected patients. Non-KSB sequences were retrieved from the Los Alamos National Laboratory HIV Database. Phylogenetic analysis indicated that within KSB, 2 FLs from plasma donors O and P comprised two clusters together with 8 and 12 patients with hemophilia, respectively. Signature pattern analysis for the KSB of HIV-1 revealed signature nucleotide residues at 1.05%, compared with local controls. Additionally, in-depth FLs sequence analysis over 30 years in KSB indicates that the KSB FL significantly increases over time before combined antiretroviral therapy (cART) and decreases on cART. Furthermore, the increase in FLs over time significantly occurred in the subtypes B, C and G, but, there was no increase in the subtypes D, A, and F1. Consequently, subtypes F1 and D had the shortest sequence length. Our analysis was extended to compare HIV-1 with HIV-2 and SIVs. Essentially, the longer the sequence length (SIVsm > HIV-2 > SIVcpz > HIV-1), the longer the survival period. The increase in the length of the HIV-1 sequence over time suggests that it might be an evolutionary direction toward attenuated pathogenicity.

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

The increase in pandemics caused by RNA viruses of zoonotic origin highlights the urgent need for broad-spectrum antivirals against novel and re-emerging RNA viruses. Broad-spectrum antivirals could be deployed as first-line interventions during an outbreak while virus-specific drugs and vaccines are developed and rolled out. Viruses depend on the host’s protein synthesis machinery for replication. Several natural compounds that target the cellular DEAD-box RNA helicase eIF4A, a key component of the eukaryotic translation initiation complex eIF4F, have emerged as potential broad-spectrum antivirals. Rocaglates, a group of flavaglines of plant origin that clamp mRNAs with highly structured 5’UTRs onto the surface of eIF4A through specific stacking interactions, exhibit the largest selectivity and potential therapeutic indices among all known eIF4A inhibitors. Their unique mechanism of action limits the inhibitory effect of rocaglates to the translation of eIF4A-dependent viral mRNAs and a minor fraction of host mRNAs exhibiting stable RNA secondary structures and/or polypurine sequence stretches in their 5´UTRs, resulting in minimal potential toxic side effects. Maintaining a favorable safety profile while inducing efficient inhibition of a broad-spectrum of RNA viruses makes rocaglates into primary candidates for further development as pan-antiviral therapeutics.

Intermetallic alloys like e.g. Iron-Aluminides, Titanium-Aluminides or Molybdenum- Silizides are prospective materials for high-temperature applications. For additive manufacturing (AM) intermetallic structural materials are particularly challenging due to their high melting points, oxygen susceptibility and low temperature brittleness. The feasibility of manufacturing intermetallic Mo-Si-B alloys with the laser additive manufacturing process of direct energy deposition (DED) is demonstrated and recent results in characterizing rapidly solidified material with respect to correlations between process, composition and microstructures are presented. The possibility to dope the material with Yttrium oxide (Y2O3) for dispersion is successfully demonstrated. Current challenges, e.g. homogenous distribution of alloying elements and applicability are addressed.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes an outbreak of COVID-19 disease in humans with the aid of spike protein. It consists of a receptor-binding domain (RBD) that recognizes and binds to the host receptor angiotensin-converting enzyme 2 (ACE2). The aim of this study was to examine the mutational effect of spike protein on the sequence through an interaction study of the mutant spike protein and the human ACE2 protein at the structural level. A total of 17,227 spike proteins from Asia, Africa, Europe, Oceania, South America, and North America were compared to the Wuhan spike protein reference sequence (Wuhan-Hu-1). The structural and stability implications of D614G, N501Y, and S477N mutations were evaluated. The binding affinity between mutated RBD and human ACE2 protein was also studied. The D614G mutation may have originated in Germany, Europe based on the date of the first sample collection report. It is now widely circulated all over the world with most occurrences in North America. The mutations N501Y and S477N may have originated from Oceania based on the date of the first sample collection report and also have the highest occurrences in Oceania. Based on the computational analysis of mutational effects, the D614G, N501Y, and S477N mutations decreased stability and were tolerated. For disease propensity prediction, N501Y was more prone to disease compared to D614G, while S477N was not prone to disease. The mutation of D to G at position 614 and S to N at position 477 for secondary structure prediction shows no changes in secondary structure while remaining in the coil region, whereas the mutation of N to Y at position 501 changes from coil structure to extended strand. N501Y mutation has a higher affinity to human ACE2 protein compared to D614G and S477N based on a docking study. D614G spike mutation was identified to exist between the two hosts based on a comparison of SARS-CoV-2 derived between the mink and human. Further research is needed on the link between the mink mutation N501T and the mutation N501Y in humans, which has evolved as a separate variant.

A quite energetic seismic excitation consisting of one main and additional three distinctive earthquake clusters that occurred in the transition area between the Kefalonia Transform Fault Zone (KTFZ) and the continental collision between Adriatic and Aegean microplates, is thoroughly studied after high–precision aftershocks’ relocation. The activated fault segments are in an area where historical and instrumental data have never claimed the occurrence of a catastrophic (M>6.0) earthquake. The relocated seismicity initially defines an activated structure extending from the northern segment of the Lefkada branch of KTFZ with the same NNE–SSW orientation and dextral strike-slip faulting and then keeping the same sense of motion its strike becomes NE–SW and its dip direction NW. This provides unprecedented information on the link between the KTFZ and the Collision front and sheds more light on the regional geodynamics. The earthquake catalog, which is specially compiled for this study, starts one year before the occurrence of the Mw5.4 mainshock and adequately provides the proper data source for investigating the temporal variation of the b–value, which might be used for discriminating foreshock and aftershock behavior.

Hepatitis B virus (HBV) infection is a major factor in development of various liver diseases such as hepatocellular carcinoma (HCC). Among HBV encoded proteins, HBV X protein (HBx) is known to play key role in development of HCC. Hepatocyte nuclear factor 4α (HNF4α) is a nuclear transcription factor which is critical for hepatocyte differentiation. However, the expression level as well as its regulatory mechanism in HBV infection have yet to be clarified. Here, we observed the suppression of HNF4α in cells which stably express HBV whole genome or HBx protein alone, while transient transfection of HBV replicon or HBx plasmid had no effect on the HNF4α level. Importantly, in the stable HBV- or HBx-expressing hepatocytes, the downregulated level of HNF4α was restored by inhibiting ERK signaling pathway. Our data showed that HNF4α was suppressed during long-term HBV infection in cultured HepG2-NTCP cells as well as in mouse model following hydrodynamic injection of pAAV-HBV or in mice intravenously infected with rAAV-HBV. Importantly, HNF4α downregulation increased cell proliferation which contributed to the formation and development of tumor in xenograft nude mice. The data presented here provided several proofs for the effect of HBV infection in manipulating HNF4α regulatory pathway in HCC development.

It is well known that the event of hepatitis B virus reactivation can occur among patients undergoing treatment for hematological malignancies. In this paper we will present the available data regarding the risk of hepatitis B virus reactivation in this special population of immunosuppressed patients and explore the relevance of an accurate prevention and management of this condition. A computerized literature search was performed using appropriate terms arrangement, including English-written literature only or additional relevant articles. The evaluation of hepatitis B reactivation risk is a multidimensional process, which includes conducting an accurate clinical and physical history, considering the virological categories, the knowledge of the medication chosen to treat these hematological malignancies and the induced grade of immunosuppression. Adopting adequate preventive strategies and surveillance according to the current international recommendations is crucial to prevent HBVr and its dire clinical consequences (hepatitis, liver failure, interruption of lifesaving anti-neoplastic treatments). Universal HBV screening of patients scheduled to undergo treatment for hematological malignancies should be the chosen policy, and clinicians should be aware of the inherent risk of viral reactivation among the different virological categories and the classes of immunosuppressive drugs.

Background: Cytokines and chemokines are critical regulators of innate and adaptive immunities during viral infection. We examined innate and adaptive immune responses to hepatitis C virus (HCV) and hepatitis B virus (HBV) at baseline and against controls. Methods: Twenty-seven cytokines were evaluated before treatment in 27 patients with chronic hepatitis C(CHC) [genotype1 (n=20), genotype2 (n=7), HCVRNA 5.72IU/ml] and 12 chronic hepatitis B(CHB) [e-antigen (Ag) (+) (n=5), e-Ag (-) (n=7), HBVDNA 6.191.31Logcopies/ml] and against controls(n=5). Results: Th1 and Th2 cytokines were significantly higher (p<0.05) in CHB than in CHC. The levels of IL-IL10 in CHC and CHB, and IL15 in CHC(genotype2) and CHB were significantly lower (p<0.05) than in controls. The levels of CXCL8 in CHC and CHB, IL12 in CHC and CHB [e-Ag (-)] and CXCL10 in CHC and CHB were significantly higher (p<0.05) than in controls. IFN-γwas higher in CHB than in controls. Conclusion: Cytokines levels differed between CHB and CHC before treatment. Innate immune responses were impaired in CHB with HBeAg(-) and CHC, but not in CHB with HBeAg(+) with high viral loads. Adaptive immune responses were impaired in CHB and CHC and appear to reflect the distinct state of virus-host immune interactions between CHB and CHC.

The class of A-stable symmetric one-step Hermite-Obrechkoff (HO) methods introduced in [1] for dealing with Initial Value Problems is analyzed. Such schemes have the peculiarity of admitting a multiple knot spline extension collocating the differential equation at the mesh points. As a new result, it is shown that these maximal order schemes are conjugate symplectic which is a benefit when the methods have to be applied to Hamiltonian problems. Furthermore a new efficient approach for the computation of the spline extension is introduced, adopting the same strategy developed in [2] for the BS linear multistep methods. The performances of the schemes are tested in particular on some Hamiltonian benchmarks and compared with those of the Gauss Runge-Kutta schemes and Euler-Maclaurin formulas of the same order.

This study aimed to explore the factors that influence parental involvement in supporting 7 the education of children with disabilities in Malawi, thereby generating insights into the barriers 8 and facilitators they face. We conducted focus groups and in-depth interviews with 25 participants 9 from the Nkhata Bay District: teachers, parents, and children with disabilities. We used the COM-B 10 model to analyse how parents' capabilities, opportunities, and behaviours influence their involve- 11 ment in their children's education. The study revealed that parents of children with disabilities 12 showed willingness, optimism about their children's future, and a strong sense of responsibility for 13 their education. However, factors such as the limited knowledge of children's learning needs, time, 14 low confidence, and financial challenges have constrained their involvement. Schools and commu- 15 nities frequently limit participation opportunities by not consistently practicing or championing pa- 16 rental involvement in policies or actions. The study sheds light on the complex interplay between 17 knowledge, practical constraints, and external support systems that shape parental involvement in 18 the education of children with disabilities. Further research aimed at creating tailored and context- 19 relevant interventions to improve parental involvement in the education of children with disabilities 20 in low-income settings is required.

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

We introduce a novel algebraic structure, termed algebra B, which generalizes Lie algebras through the definition of a non-associative and unital algebra. We demonstrate that algebra B retains essential properties such as bilinearity and antisymmetry, and satisfies both the Jacobi and Malcev identities; this occurs when the product operations of Lie and Malcev algebras are derived from the product operation defined in our algebra. By examining the connections between algebra B, Malcev algebras, and Lie algebras, we establish that algebra B effectively generalizes these structures. Furthermore, we show that algebra B can generate complex entities with a novel structure distinct from those currently known. Our findings lay the groundwork for future investigations into the practical applications and further theoretical development of this new algebraic framework.

Ovarian cancer is among the most common causes of female mortality. Despite improvements in diagnostic methods, non-specific symptoms and delayed gynecological exams can lead to late-stage ovarian tumor discovery. In this study, the effect of an anti-cancer compound, 3-amino-N-(3-chloro-2-methylphenyl)-5-oxo-5,6,7,8-tetrahydrothieno[2,3-b]quinoline-2-carboxamide (Compound 1) was examined. Cytotoxicity, apoptosis, and metabolomic changes in ovarian cancer cell lines SK-OV-3 and OVCAR-3, as well as glycosphingolipid (GSL) expression, both on cancer stem cells (CSCs), marked as CD49f+ and non-CSCs (CD49f-) were explored. Treatment with Compound 1 reduced the percentage of CSCs compared to non-treated cells (P &lt; 0.001). The expression of eight GSLs on CSCs and non-CSCs was examined using flow cytometry. Both cell lines showed a change in the glycophenotype of the cells, either up or down of its expression, after the treatment. These findings raise the possibility of specifically targeting CSCs in ovarian cancer therapy. Additionally, treatment of Compound 1 resulted in a statistically significant increase in both early and late apoptosis (P&lt;0.001) suggesting a pivotal role in initiating programmed cell death by the apoptotic pathway. The metabolic analysis revealed that the treated cancer cells showed reduced metabolic activity compared to the control group (P &lt; 0.001)

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