Protein Kinase C delta (PKCδ) has emerged as a key protective molecule against systemic lupus erythematosus (SLE or lupus), an autoimmune disease characterized by anti-double stranded (ds) DNA IgGs. Although PKCδ deficient mice and lupus patients with mutated PRKCD genes clearly demonstrate the requirement of PKCδ for preventing lupus autoimmunity, this critical tolerance mechanism remains poorly understood. We recently reported that PKCδ selectively deletes anti-dsDNA B cells in the germinal center (GC), disclosing a key B cell tolerance mechanism that prevents lupus autoimmunity. PKCδ’s tolerance function is activated by sphingomyelin synthase 2 (SMS2), a lipid enzyme whose expression is generally reduced in B cells from lupus patients. Moreover, pharmacologic strengthening of the SMS2/PKCδ tolerance pathway alleviated lupus pathogenesis in mice. Here, we review relevant publications in order to provide mechanistic insights into PKCδ’s tolerance activity, and discuss the potential significance of therapeutically targeting PKCδ’s tolerance activity in the GC for selectively inhibiting lupus autoimmunity.

Anti-inflammatory agents are widely used for the treatment of inflammatory diseases. Nevertheless, the associated side effects of available drugs make necessary the search for new anti-inflammatory conditions. Here, we investigated the anti-inflammatory activity of solidagenone. Initially, we observed that a single dose of 30, 60 or 90 mg/Kg of solidagenone did not result in mortality or elicit any discernible signs of toxicity in the animals. At the same doses, solidagenone promoted a significative reduction in the migration of neutrophils in an acute peritonitis model and decreased mortality in a lipopolysaccharide-induced endotoxic shock model. Interestingly, treatment with solidagenone conferred a protective effect against leukopenia and thrombocytopenia, hematological disorders commonly observed in sepsis conditions. In addition, treatment with all the doses of solidagenone promoted a significative reduction in nitric oxide, TNF-α, and IL-1β relative to the LPS-stimulated vehicle-treated cultures. Furthermore, gene expression and in silico analyses also supported the modulation of NF-κB pathway by solidagenone. Finally, in silico pharmacokinetics prediction indicated a favorable drugability profile for solidagenone. Taken together, the findings of the present investigation show that solidagenone exhibits significant anti-inflammatory properties in acute experimental models, potentially through the modulation of NF-κB signaling pathway.

The production of bio-chemicals requires the use of microbial strains with efficient substrate conversion and excellent environmental robustness, such as Bacillus coagulans spp. So far the genomes of about 50 strains have been sequenced. Herein, we report a comparative genomic analysis of nine strains on the full repertoire of CAZymes, secretion systems, and resistance mechanisms to environmental challenges. Moreover, B. coagulans Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) immune system along with CRISPR-associated Cas) genes, was also analysed. Overall, this study expands our understanding of the strains genomic diversity of B. coagulans to fully exploit its potential in biotechnological applications.

HepG2 cells reconstituted with Hepatitis B virus (HBV) entry receptor sodium taurocholate co-transporting polypeptide (NTCP) are widely used as a convenient in vitro cell culture infection model for HBV replication studies. As such, it is pertinent that HBV infectivity is maintained at steady-state levels for accurate interpretation of in vitro data. However, variations in HBV infection efficiency due to imbalanced NTCP expression levels in the HepG2 cell line may affect experimental results. In this study, we performed single cell cloning of HepG2-NTCP-A3 parental cells via limiting dilution and obtained multiple subclones with increased permissiveness to HBV. Specifically, one subclone (HepG2-NTCP-A3/C2) yielded more than 4-fold higher HBV infection compared to the HepG2-NTCP-A3 parental clone. In addition, though HBV infectivity was universally reduced in the absence of polyethylene glycol (PEG), subclone C2 maintained relatively greater permissiveness under PEG-free conditions, suggesting the functional heterogeneity within parental HepG2-NTCP-A3 may be exploitable in developing a PEG-free HBV infection model. The increased viral production correlated with increased intracellular viral antigen expression as evidenced through HBcAg immunofluorescence staining. Further, these subclones were found to express different levels of NTCP, albeit with no remarkable morphology or cell growth differences. In conclusion, we isolated subclones of HepG2-NTCP-A3 which support efficient HBV production and thus provide an improved in vitro HBV infection model.

Duke University was founded in 1930 primarily due to funds generated from James B. Duke’s tobacco business. Duke achieved great financial wealth primarily due to the early application of machine rolled cigarettes, as opposed to hand rolled. This early adoption of technology allowed Duke Tobacco to out-produce other companies still selling hand rolled cigarettes. By making smoking more inexpensive and easier than pipe smoking, the cigarette formed the foundation for nicotine addiction in the 1900s, generating huge profits for the tobacco industry. At the time Duke University was founded, little was known about the connection between nicotine, cigarettes, and respiratory diseases such as emphysema and lung cancer. Through James Duke’s philanthropy, the devastating harm from cigarettes has been mitigated in part through the founding of one of the world’s most prominent medical centers and research universities.

This paper investigates the photocatalytic characteristics of Ag Nanowire (AgNW)/TiO2 and AgNW/TiO2/Graphene oxide (GO) nanocomposites. Samples were synthesized by the direct coating of TiO2 particles on the surface of silver nanowires. As-prepared AgNW/TiO2 and AgNW/TiO2/GO nanocomposites were characterized by electron microscopy, X-ray diffraction, UV/visible absorption spectroscopy, and infrared spectroscopy. Transmission electron microscope (TEM) images confirmed the successful deposition of TiO2 nanoparticles on the surface of AgNWs. The photocatalytic activity of synthesized nanocomposites was evaluated using Rhodamine B (RhB) in an aqueous solution as the model organic dye. Results showed that synthesized AgNW/TiO2/GO nanocomposite has superior photocatalytic activities when it comes to the decomposition of RhB.

The aim of the present work was to evaluate the effects of Thalassia testudinum hydroethanolic extract, its polyphenolic fraction, and thalassiolin B on the activity of phase I metabolizing enzymes as well as their antimutagenic effects. Spectrofluorometric techniques were used to evaluate the effect of tested products on rat and human CYP1A and CYP2B activity. The antimutagenic effect of tested products was evaluated in benzo[a]pyrene (BP)-induced mutagenicity assay by Ames test. Finally, the antimutagenic effect of Thalassia testudinum (100 mg/kg) was assessed in a BP-induced mutagenesis in mice. The tested products significantly (p<0.05) inhibit rat CYP1A1 activity, acting as mixed-type inhibitors of rat CYP1A1 (Ki = 54.16±9.09 μg/mL, 5.96±1.55 μg/mL and 3.05±0.89 μg/mL, respectively). Inhibition of human CYP1A1 was also observed (Ki = 197.1±63.40 μg/mL and 203.10±17.29 μg/mL for the polyphenolic fraction and for thalassiolin B, respectively). In addition, the evaluated products significantly inhibit (p<0.05) benzo[a]pyrene (BP)-induced mutagenicity in vitro. Furthermore, oral doses of Thalassia testudinum (100 mg/kg) significantly reduced (p<0.05) the BP-induced micronuclei and oxidative damage, together with an increase of glutathione, in mice. In summary, Thalassia testudinum metabolites exhibit antigenotoxic activity mediated, at least, by the inhibition of CYP1A1-mediated BP biotransformation. Thus, the metabolites of T. testudinum may represent a potential source of chemopreventive compounds for adjuvant therapy of cancer.

The objective of the this study was to reduce the benzo[a]pyrene-induced hepatotoxicity method in herbal medicine products and to give proof that neferine, daidzein, genistein possess antihepa-totoxic effects. B[a]P which classified as a group 1 carcinogen and metabolized to B[a]P-7,8-dihydrodiol-9,10-epoxide (BPDE) causes mutagenic DNA addition products. The reduc-tion of BPDE-DNA adduct formation by B[a]P-7,8-dihydrodiol-9,10-epoxide (BPDE) was derived by benzo[a]pyrene (B[a]P). In HepG2 cells, B[a]P exhibited toxicity and substance treatment of the cells with B[a]P with neferine in lotus and daidzein, genistein in soybean reduced the BPDE-DNA ad-ducts level. The level of B[a]P-metabolites in the substance treatment of the cells was presented that BPDE levels were reduced by neferine in lotus and daidzein, genisten in soybean. These results suggest that neferine in lotus and daidzein, genistein in soybean prevent B[a]P-induced hepato-toxicity for BPDE-DNA adduct formation.

Mucormycosis is an opportunistic fungal infection that is increasingly affecting patients with Coronavirus Disease (COVID-19). This connection is particularly pronounced in specific populations, including individuals with diabetes or those who have recently undergone corticosteroid therapy. Additionally, Cytomegalovirus (CMV) infection is a frequent complication among COVID-19 patients who have previously received corticosteroid or other immune-modulatory treatments. In this case report, we present the clinical details of a 56-year-old male who developed post-COVID pneumonia complicated by both cutaneous mucormycosis and CMV infection.

Introduction: Dental health care workers, particularly dental medicine students (DMS), are at an increased risk of hepatitis B virus (HBV) and hepatitis C virus (HCV) infection. The aim of our study was to assess the level of knowledge on HBV and HCV, estimate needlestick injury (NSI) prevalence and reporting practice in DMS at the University of Zagreb and analyze how enrolment in obligatory and supplemental courses affects knowledge and needlestick injury reporting practice. Materials and methods: The knowledge was assessed by our questionnaires based on Centers for Disease Control general handouts. Additional information was collected to examine the prevalence and reporting practice of NSI. Data was analyzed by descriptive statistical analysis, independent-samples t-tests, proportion analyses and combined factor analyses of categorical and quantitative variables in SPSS and R. Results: In total, 206 students participated. The overall level of HBV and HCV-related knowledge was poor with average scores being 61.90% and 51.35% respectively. Moreover, students enrolled in the first year demonstrated significantly lower levels of knowledge in comparison with their older peers. Of all participants 18.2% sustained a needlestick injury, and majority of them (78.95%) never reported the injury. Conclusion: In conclusion, DMS have low levels of knowledge on important occupational pathogens and poor NSI reporting practice. Moreover, formal education in the current form failed to significantly improve competence of students and theoretical knowledge translates poorly into more conscientious injury reporting practice. We should look for a better way to increase student awareness and level of knowledge on this topic.

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.

Prolonged fatigue is associated with non-pathological causes, and lacks an established therapeutic approach. The current study is aimed at assessing the efficacy of a new food supplement (Improve® Response) based on a chemically characterized pomegranate extract and hydro-soluble vitamins (B complex and C). UHPLC-HRMS analysis of pomegranate extract showed the presence of 59 compounds, with gallotannins and ellagitannins being the most abundant phytochemicals. For the clinical study, 58 subjects were randomized into two groups, 1 and 2 (n = 29, each), which received either the food supplement or placebo. The effects of the food supplement against fatigue were assessed via validated questionnaires, recorded at time intervals t0 (at baseline), t1 (after 28 days), t2 (56 days), and t3 (after follow-up) in combination with the analysis of biochemical markers at t0 and t2. Fatigue Severity Scale (FSS) questionnaire scores were significantly decreased at the t2 and t3 time intervals in subjects treated with the food supplements, while the effect of the food supplement on a 12-Item Short Form Survey (SF-12) was not considerable. Moreover, the food supplement did not significantly affect biochemical parameters associated with fatigue and stressed conditions. This study shows that the food supplement tested reduces prolonged fatigue following two months supplementation in healthy subjects with mild prolonged fatigue.

Influenza is an acute respiratory illness caused by influenza virus infection, which is managed using vaccines and antiviral drugs. Recently, the antiviral effects of plants and foods have gained attention. This review summarizes the therapeutic properties of Euglena against influenza from a functional food viewpoint. While it has been reported that Euglena contributes to suppressing blood sugar levels and ameliorates symptoms caused by stress by acting on the autonomic nervous system, the immunostimulatory and antiviral activities of Euglena have also been reported. In this review, I focused on the immunostimulation of antiviral activity via the intestinal environment and the suppression of viral replication in infected cells. The functions of specific components of Euglena, which also serve as a source of a wide range of nutrients such as vitamins, minerals, amino acids, unsaturated fatty acids, and β-1,3-glucan (paramylon), are also reviewed. Euglena has animal and plant properties and natural compounds with a wide range of functions, providing crucial information for improved antiviral strategies.

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.

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.

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.

The chitin synthase B gene is a key enzyme in the chitin synthesis of insect peritrophic matrix (PM), affecting insects' feeding behavior. The chitin synthase B gene has been cloned from the transcription library of Heortia vitessoides Moore. RT-qPCR showed that HvChsb was highly expressed in the larval stage of H. vitessoides, especially on the first day of the prepupal stage, and in the midgut of larvae and the abdomen of adults. After starvation treatment, HvChsb was found to be significantly inhibited with time. After 48 h of starvation, the feeding experiment showed that HvChsb increased with the prolongation of the refeeding time. The experimental data showed that feeding affected the expression of HvChsb. HvChsb was effectively silenced by RNA interference, so its function was lost, significantly decreasing the survival rate of H. vitessoides. The survival rate from larval-to-pupal stages was only 43.33%, accompanied by abnormal phenotypes. It can be seen that HvChsb plays a key role in the average growth and development of H. vitessoides.

The emergence of multidrug-resistant pathogens such as Listeria monocytogenes and Shiga toxin-producing Escherichia coli (STEC) poses public health challenges, and this has led to a continuous search for effective novel antimicrobial agents. This study aimed to isolate marine actinomycetes from South Africa, evaluate their in vitro antimicrobial activity against Listeria and STEC, and characterize their mechanisms of action. Marine actinoymcetes were isolated and identified by 16S rRNA sequencing. Gas chromatography-mass spectrometry (GC-MS) was used to identify the chemical constituents of bioactive actinomycetes secondary metabolites. Antibacterial activity of the secondary metabolites was assessed by the broth microdilution method and their mode of actions were predicted using computational docking. While five strains showed antibacterial activity during primary screening, only Nocardiopsis dassonvillei strain SOD(B)ST2SA2 exhibited activity during secondary screening for antibacterial activity. GC-MS identified five major bioactive compounds: 1-octadecene, diethyl phthalate, pentadecanoic acid, 6-octadecenoic acid, and tri-fluoroacetoxy hexadecane. SOD(B)ST2SA2`s extract demonstrated the minimum inhibitory con-centration and minimum bactericidal concentration ranging from 0.78–25 mg/ml and 3.13 to > 25 mg/ml, respectively. Diethyl phthalate displayed the lowest bacterial protein binding energies (kcal/mol): −7.2, dihydrofolate reductase; −6.0, DNA gyrase B, and −5.8, D-alanine:D-alanine lig-ase. Thus, marine N. dassonvillei SOD(B)ST2SA2 is a potentially good source of antibacterial compounds that can be used to control STEC and Listeria monocytogenes.

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.

The loss of vitamin D3 upregulated protein 1 (VDUP1) has been implicated in the pathogenesis of various inflammation-related diseases. Notably, reduced expression of VDUP1 has been observed in clinical specimens of ulcerative colitis (UC). However, the role of VDUP1 deficiency in colitis remains unclear. In this study, we investigated the role of VDUP1 in dextran sulfate sodium (DSS)-induced experimental colitis in mice. VDUP1-deficient mice were more susceptible to DSS-induced colitis than their wild-type (WT) littermates after 2% DSS administration. VDUP1-deficient mice exhibited an increased disease activity index (DAI) and histological scores, as well as significant colonic goblet cell loss and an increase in apoptotic cells. These changes were accompanied by a significant decrease in MUC2 mRNA expression and a marked increase in proinflammatory cytokines and chemokines within damaged tissues. Furthermore, phosphorylated NF-B p65 expression was significantly upregulated in damaged tissues in the context of VDUP1 deficiency. VDUP1 deficiency also led to significant infiltration of macrophages into the site of ulceration. An in vitro chemotaxis assay confirmed that VDUP1 deficiency enhanced bone marrow-derived macrophage (BMDM) chemotaxis induced by CCL2. Overall, the loss of VDUP1 plays a critical role in the pathogenesis of UC, and blocking VDUP1 dissociation may represent a promising therapeutic strategy for the treatment of UC.

Canine lymphoma (CL) is one of the most common malignant tumors in dogs. The cause of CL remains unclear. Genetic mutations that have been suggested as possible causes of CL are not fully understood. Whole-exome sequencing (WES) is a time- and cost-effective method for detecting genetic variants targeting only protein-coding regions (exons) that are part of the entire genome region. A total of eight patients with B-cell lymphomas were recruited, and WES analysis was performed on whole blood and lymph node aspirate samples from each patient. A total of 17 somatic variants (GOLIM4, ITM2B, STN1, UNC79, PLEKHG4, BRF1, ENSCAFG00845007156, SEMA6B, DSC1, TNFAIP1, MYLK3, WAPL, ADORA2B, LOXHD1, GP6, AZIN1, and NCSTN) with moderate to high impact were identified by WES analysis. Through a Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis of 17 genes with somatic mutations, a total of 16 pathways were identified. Overall, the somatic mutations identified in this study suggest novel candidate mutations for CL, and further studies are needed to confirm the role of these mutations.

Splenic micronodular T-cell/histiocyte-rich large B-cell lymphoma is possibly derived from nodal T-cell/histiocyte-rich large B-cell lymphoma; however, a transition between the nodal and splenic micronodular forms has not been described to date. Of note, the only lymph nodes to be involved in association with the splenic micronodular pattern of the disease are the splenic hilar lymph nodes, and that, with partial involvement only. Kan et al, in their series of articles, have raised the possibility that corticosteroids, when prescribed prior to splenectomy, cause histopathological and functional modulations (apoptosis, necrosis, tissue shrinkage), which modify or even obscure the diagnostic morphological features. The indications for glucocorticoid therapy are either related to the suspected lymphoma, or else to other comorbidities, like asthma and autoimmune disorders. We propose that patients with the splenic, rather than nodal subset of the disease are likely to have been prescribed corticosteroids prior to histopathologic examination of the involved tissue, causing disparate morphologies in the spleen. Apoptosis, as induced by corticosteroids, is hypothesized as the major mechanism initiating the histopa-thological and functional changes in the splenic micronodular variant of our patients.

In this study, we introduce a new type curve in 3-dimensional space which called B-lift curve and we obtain the Frenet operators of the B-lift curve. Moreover, we consider the correpondence of Frenet operators between the Blift curve and the natural lift curve. Finally, we investigate the B-lift curve according to the main curve is slant helix or darboux helix.

Background: The central channel of the nuclear pore complex (NPC) plays an important role in the selective transport of proteins between the nucleus and cytoplasm. Previous studies have demonstrated that depletion of the Nup62 complex, constructing the nuclear pore channel in premeiotic Drosophila cells, resulted in absence of meiotic cells. We attempted understanding the mechanism underlying the cell cycle arrest before meiosis. Methods: We induced dsRNAs against the nucleoporin mRNAs using the Gal4/UAS system in Drosophila. Results: The cell cycle of the Nup62-depleted cells was arrested before meiosis without CDK1 activation. Ectopic over-expression of CycB, but not constitutively active CDK1, resulted in partial rescue from the arrest. CycB accumulated precociously in the nuclei of Nup62-depleted cells and cells depleted of exportin (encoded by emb). Protein complexes containing CycB, Emb, and Nup62 complex components were observed in premeiotic spermatocytes. CycB, which had precociously migrated into the nucleus, was associated with Emb, and the complex was transported back to the cytoplasm through the central channel, interacting with the Nup62 complex. Conclusion: We proposed that CycB is exported with Emb through the channel interacting with the Nup62 complex before initiation of meiosis. The nuclear export ensures production of active CycB-CDK1 in the cytoplasm.

Immune checkpoints are a set of molecules dysregulated in several human and canine cancers and aberrations of the PD-1/PD-L1 axis are often correlated with a worse prognosis. To gain insight into the role of immune checkpoints in canine diffuse large B-cell lymphoma (cDLBCL), we investigated PD-L1, PD-1 and CD8A expression by RNAscope. Results were correlated with several clinico-pathological features, including treatment, Ki67 index and outcome. A total of 33 dogs treated with CHOP (n=12) or CHOP plus APAVAC (n= 21) were included. PD-L1 signal was diffusely distributed among neoplastic cells, whereas PD-1 and CD8A were localized in tumor infiltrating lymphocytes. However, PD-1 mRNA was also retrieved in tumor cells. An association between PD-L1 and PD-1 scores was identified and a higher risk of relapse and lymphoma-related death was found in dogs treated with chemotherapy alone and dogs with higher PD-L1 and PD-1 scores. The correlation between PD-L1 and PD-1 is in line with the mechanism of immune checkpoints in cancers, where neoplastic cells overexpress PD-L1 that, in turn, binds PD-1 receptors in activated TIL. We also found that Ki67 index was significantly increased in dogs with the highest PD-L1 and PD-1 scores, indirectly suggesting a role in promoting tumor proliferation. Finally, even if the biological consequence of PD-1+ tumor cells is unknown, our findings suggest that PD-1 intrinsic expression in cDLBCL might contribute to tumor growth escaping adaptive immunity.

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.

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.

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.

Diffuse large B-cell lymphoma (DLBCL) requires a complete staging at diagnosis that may have prognostic and therapeutic implications. The role of bone marrow (BM) biopsy (BMB) is contro-versial in the era of nuclear-imaging techniques. We performed a comparative review of 25 studies focused on BM evaluation at DLBCL diagnosis, including at least two of the following techniques: BMB, flow cytometry, and positron emission tomography (PET-FDG). The report about BM involvement (BMi), diagnostic accuracy and prognostic significance was collected and compared among techniques. A concordance analysis between BMB, FCM and PET was also per-formed, and we deeply evaluated the implications of the different types of BMi: concordant by LBCL or discordant by low-grade B-cell lymphoma for both BMB and FCM, and focal or diffuse uptake pattern for PET. As main conclusion, BMB, FCM and PET are complementary tools which provide different and clinically relevant information in the assessment of BMi in newly DLBCL.

Cattle occasionally develop brassica-associated liver disease (BALD) and photosensitisation when grazing turnip or swede (Brassica spp.) forage crops. The liver toxin in these brassica varieties has yet to be discovered. Progoitrin is the dominant glucosinolate in incriminated crops. Apart from goitrin, progoitrin hydrolysis yields the nitrile, 1-cyano-2-hydroxy-3-butene (CHB), and the epithionitrile, 1-cyano-2-hydroxy-3,4-epithiobutane (CHEB). The two compounds were custom-synthesised. In a small pilot trial, New Zealand White rabbits were given either CHB or CHEB by gavage. Single doses of 0.75 mmol/kg of CHB or 0.25 mmol/kg of CHEB were subtoxic and elicited subclinical effects. Higher doses were severely hepatotoxic causing periportal to massive hepatic necrosis associated with markedly elevated serum liver biomarkers often resulting in severe illness or death within 24 h. The possibility that one or both of these hepatotoxic nitriles causes BALD in cattle requires further investigation.

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.

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.

(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.

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.

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.

(1) Background: We aimed to determine the prevalence of hepatitis B virus (HBV) resistance-associated mutations (RAMs) in people with HBV and human immunodeficiency virus (HBV/HIV) in Botswana. (2) Methods: We sequenced HBV from participants with HBV/HIV from the Botswana Combination Prevention Project study (2013-2018) using the Oxford Nanopore GridION platform. Consensus sequences were analyzed for genotypic and mutational profiles. (3) Results: Overall, 98 HBV sequences had evaluable reverse transcriptase region coverage. The median participant age was 43 years (IQR: 37, 49) and 66/98 (67.4%) were female. Most participants, 85/97 (87.6%) had suppressed HIV viral load (VL). HBV RAMs were identified in 61/98 (62.2%) participants. Most RAMs were in positions 204 (60.3%), 180 (50.5%) and 173 (33.3%), mostly associated with lamivudine resistance. The triple mutations, rtM204V/L180M/V173L and was the most predominant (17/61 [27.9%]). Most participants (96.7%) with RAMs were on antiretroviral therapy for a median duration of 7.5 years (IQR: 4.8, 10.5). Approximately 27.9% (17/61) of participants with RAMs had undetectable HBV VL, 50.8% (31/61) had VL &lt;2000IU/mL and 13/61 (21.3%) had VL ≥2000 IU/mL. (4) Conclusions: The high prevalence of lamivudine RAMs discourages the use of ART regimens with 3TC as the only HBV-active drug in people with HIV/HBV.

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.

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.

(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.

The concept of gray-zone lymphoma (GZL) has been progressively refined since its in-troduction in the literature in 1998. For several years, it was applied to a rather broad spectrum of conditions, posing the problem of the differential diagnosis between any type of Hodgkin lymphoma (HL) and diffuse large B-cell lymphoma, with special reference to primary mediasti-nal forms (PMBL). Officially recognized as a provisional entity in the 4th and revised 4th editions of the WHO Classification of Tumour of Haematopoietic and Lymphoid Tissues with the term “B-cell lymphoma unclassifiable with features intermediate between diffuse large B-cell lym-phoma and classical Hodgkin lymphoma”, it was limited to tumours, which showed either morphologic features reminiscent of classical HL (CHL) but carrying a complete B-cell pheno-type or conversely provided with a PMBL morphology but revealing CHL phenotypic charac-teristics. The definition of GZL has been further revised in the recently published International Lymphoma Classification and 5th Edition of the WHO Classification of Haemato-lymphoid Tu-mours, which have limited it to mediastinal neoplasms based on emerging molecular evidences. The aim of this review is to critically discuss the issue of GZL, also in the light of the suboptimal response to current therapies.

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.

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.

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.

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.

Respiratory infections constitute a major reason for infants and children seeking medical advice and visiting health facilities, thus remaining a significant public threat with high morbidity and mortality. The predominant viruses causing viral respiratory infections are influenza A and B viruses (Flu-A, Flu-B), Respiratory Syncytial Virus (RSV), Adenovirus and Coronaviruses. We aimed to record the incidence of RSV, SARS-CoV-2, Influenza A/B and Adenovirus cases with rapid antigen tests and validate the results with RT-PCR assay of upper respiratory specimens with a wide range of viral loads and (co)-infection patterns in children. Clinical samples were collected from early symptomatic children (presenting with fever and/or cough and/or headache within 5–7 days). The surveillance program was conducted in five private pediatrician dispensaries and one Pediatric care unit, from 10 January 2023 to 30 March 2023 in central Greece. The total sample of specimens collected was 784 young children and infants, of which 383 (48.8%) ware female and 401 were male (51.2%). The mean age of participants was 7.3 + 5.5 years. The sensitivity of FLU A &amp; B test was 91.15% (95% CI: 84.33% -95.67%), and the specificity was 98.96% (95% CI: 97.86% - 99.58%). The sensitivity and specificity of the adenovirus and RSV test was {92.45% (95% CI: 81.79% - 97.91%), 99.32% (95% CI: 98.41% -99.78%)} and {92.59% (95% CI: 75.71% -99.09%), 99.47% (95% CI: 98.65% - 99.86%)} respectively. Lastly, the sensitivity of the SARS-CoV-2 test was 100.00% (95% CI: 79.41%-100.00%) and the specificity was 99.74% (95% CI: 99.06% - 99.97%). We recorded proportion of incidence for the Influenza-A and B, (14.3%), - (3.44%) correspondingly, followed by the adenovirus with a proportion (6.9%) and the RSV with (3.7%) incidence proportion and finally, the SARS-CoV-2 (2.3%). The combination of a new multiple rapid test with multiple antigens, will be probably a useful tool with financial impact for health systems targeting the early detection and right treatment of respiratory infections in the emergency departments in primary health care facilities.

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

The 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.

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.

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.

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.

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.

(1) Background: Hepatitis B virus (HBV) viral load (VL) is useful in determining treatment eligibility, however, due to high costs associated with the test, hepatitis B e antigen (HBeAg) is recommended as a proxy for HBV VL in resource-limited settings. (2) Methods: We used 299 archived plasma samples with hepatitis B surface antigen (HBsAg), HBeAg, and HBV VL (cut-off of 20,000 IU/mL and 200,000 IU/mL) results from people living with human immunodeficiency virus (PLWH). HBeAg and HBV VL results were analyzed to evaluate the use of HBeAg to determine CHB treatment eligibility and qualification of HBV prevention of mother-to-child transmission (PMTCT) prophylaxis for the first time in Botswana. (3) Results: Approximately 70.8% and 87.5% of participants with HBeAg-positive serology had HBV viral loads ≥20,000 IU/mL and 200,000 IU/mL respectively. Using logistic regression, the odds of having a qualifying HBV VL for CHB treatment and PMTCT prophylaxis were respectively 55.5 and 110.4 times higher in participants with positive HBeAg serology indicating a statistically significant association between HBeAg status and HBV VL. (4) Conclusions: HBeAg detection may not always correlate with high HBV VL, warranting further research focusing on this association, and other biomarkers that correlate better with HBV VL.

Effects of the enzyme N-acetylgalactosamine-4-sulfatase (Arylsulfatase B, ARSB), which removes the 4-sulfate group at the non-reducing end of chondroitin 4-sulfate, on the expression of PD-L1 were determined and the underlying mechanism of PD-L1 expression elucidated. Initial experiments in human melanoma cells (A375) showed PD-L1 expression increased from 357 ± 31 to 796 ± 50 pg/mg protein (p

Infant hepatitis B vaccine coverage in China is high, with over 95% of infants immunized; however, high vaccine coverage can often mask low timeliness. The vaccination interval between the second and third dose is not clearly defined by immunization guidelines in China. This retrospective cohort study assessed the time interval distribution of hepatitis B vaccination among a cohort of randomly selected live births from Centers for Disease Control and Prevention across four provinces or municipalities in China between January 2017 and December 2021. Among the infants analyzed, 163,224 received the first dose of hepatitis B vaccine with 146,905 (90.0%) and 135,757 (83.2%) infants receiving the second and third doses, respectively. A total of 132,577 (90.2%) infants received the second dose between 28–61 days after the first dose. Of the 119,437 (88.0%) infants that completed the hepatitis B series between 61–214 days after the second dose, 87,067 (64.1%) infants were vaccinated with the third dose between 151–180 days after the second dose. The time interval distribution for the three doses of hepatitis B vaccine varied across the four provinces or municipalities (P&lt;0.001). Of the 58,077 infants who completed the hepatitis B vaccine series, 36,377 (62.6%) infants used the same type of hepatitis B vaccine for all three doses. Overall, the timeliness of hepatitis B vaccination for infants was lower than expected, with regional disparities observed. This highlights the need for improved timeliness through the introduction of a defined timeframe for the last two doses of vaccine, and training for obstetricians and related personnel.

Cathepsins (Caths) are lysosomal proteases that participate in various physiological and pathological processes. Accumulating evidence suggests that cathepsins play a multifaceted role in radiotherapy response. Firstly, cathepsins contribute to the remodelling of the tumor microenvironment by degrading extracellular matrix components, promoting angiogenesis, and facilitating tumor invasion and metastasis. Their proteolytic activity influences the tumor's response to radiation by affecting oxygenation, nutrient availability, and immune cell infiltration within the tumor microenvironment. Furthermore, cathepsins have been implicated in DNA damage repair processes, including non-homologous end joining and homologous recombination. Cathepsin-mediated DNA repair mechanisms can promote radioresistance in cancer cells, limiting the efficacy of radiotherapy. Additionally, cathepsins have been associated with the activation of prosurvival signalling pathways, such as PI3K/Akt and NF-κB, which can confer resistance to radiation-induced cell death. Radiotherapy plays a crucial role in the treatment of various malignancies. However, the effectiveness of radiotherapy can be limited by intrinsic or acquired resistance mechanisms in cancer cells. In recent years, there has been growing interest in understanding the role of cathepsins, a family of proteases, in modulating the response of tumor cells to radiotherapy. In this study, we shed light on the regulation and expression of cathepsin B in colon carcinoma cell line (Caco-2) before and after exposure to radiation were investigated. Radiation-induced upregulation of cathepsin B in dose-independent manner. Proteolytic inhibition of cathepsin B by cathepsin B specific inhibitor CA074 has increased the cytotoxic effect of ionizing irradiation in caco-2 cells. Similar results were also obtained after cathepsin B knockout by CRISPR CAS9. These results showed that cathepsin B could contribute to ionizing radiation resistance and abolishing of cathepsin B either by inhibition its proteolytic activity or expression has increased in caco-2 cells susceptibility to ionizing irradiation.

Our concern was to obtain a biocomposite material with improved properties of the constituent materials (poly(lactic- co-glycolic acid) (PLGA) and zinc–boron (Zn–B) complex) in accordance with the novelties in the field of delivery systems for therapeutic agents which lately redefine the importance of biopolymer nanocomposites with PLGA (biodegradable composites). The advantages of such a biomaterial target the health system, being easy to obtain, through a cost-effective method. The water/oil/water double emulsion method also allows the adjustment of the synthesis parameters, to maximize the degree of Zn–B complex encapsulation. The morphological aspects of the samples (size, shape, porosity) were established by scanning electron microscopy (SEM). Particle size distribution (by volume and by number) was determined by direct light scattering (DLS). For all the synthesized materials, the observed morphology was typical for PLGA, spherical one. The particle size distribution showed that depending on the synthesis conditions, the particles can be obtained with diameters between 10–450 nm range and the value of the zeta potential (ZP) shows that the particles have electronegative surface charge, which offers a favorable perspective on the phenomena of aggregation, flocculation, dispersion. It was observed, applying the design of experiments (DoE), that the size of the particles increased with increasing amounts of PLGA and polyvinyl alcohol (PVA) in the formulation, while ZP increased with higher PLGA and smaller PVA. The encapsulation efficiency was determined by ultra-high performance liquid chromatography/mass spectrometry (UHPLC/MS).

Hepatitis B e antigen (HBeAg) is a marker of wild-type hepatitis B virus replication. In resource-limited countries where access to enzyme-linked immunosorbent assay (ELISA) remains a challenge, rapid diagnostic tests (RDT) constitute a good alternative. The HBeAg status is employed to evaluate eligibility for antiviral therapy and to prevent the transmission of hepatitis B from mother to child (PMTCT). The objective of this study was to assess the diagnostic performance of the SD-Bioline®HBeAg RDT commonly used for detecting HBeAg in laboratories in Burkina Faso. The sample panel used was collected from HBsAg positive patients received in the laboratory for the detection of HBeAg with the rapid test. The samples were retested for HBeAg using the VIDAS HBe/Anti-HBe enzyme-linked fluorescent assay (ELFA) (Gold standard). Then, the viral load (VL) of HBV DNA was determined using the GENERIC HBV CHARGE VIRLAE kit (GHBV-CV). The diagnostic performances of the SD-Bioline®HBeAg and its agreement with the gold standard were calculated with their 95% confidence intervals. 340 sera obtained from HBsAg positive patients were included in this evaluation Compared to the VIDAS HBe/Anti-HBe ELFA test, the sensitivity (Se) and specificity (Sp) of the SD-Bioline®HBeAg test were 33.3% and 97.9% respectively. The concordance between the two tests was 0.42. Depending on the viral load, the Se and Sp varied from 8.8% and 98.3% for a VL &lt; 2,000 IU/mL to 35.5% and 98.4% for a VL &gt; 2,000,000 IU/mL. The results showed a low Sensibility of the SD-Bioline®HBeAg RDT test, indicating that its use is inappropriate for the clinical management of HBV-infected patients. They also highlight the urgent need to develop HBeAg rapid tests with better sensitivities.

The supramolecular based macrocyclic amphiphiles have attracted great attention in the field of drug delivery due to their unique self-assembling nature. Therefore, these macrocycles are used as nanocarriers for the delivery of poor water soluble drugs, and also for those which have lower permeability, and cannot cross the barrier to reach the desired site. Herein, we design and synthesized a new supramolecular amphiphilic macrocycle to overcome these problems. The macrocycle was synthesized in two steps. In first step 4-hydroxybenzaldehyde was treated with 1-bromotetradecane to obtain a derivatized product which was then treated with resorcinol to cyclize and get calix(4)resorcinarene based supramolecular amphiphilic macrocycle. The synthesized macrocycle and intermediate products were characterized by Mass spectrometry, IR and 1H-NMR spectroscopic techniques. The amphiphile was screened for biocompatibility studies, vesicles formation, and then Amphotericin-B was loaded in the supramolecular amphiphile based vesicles and was characterized for shape, size, homogeneity, surface charge, drug entrapment, in-vitro release profile and stability through atomic force microscopy (AFM), Zetasizer, HPLC and FT-IR. Amp-B loaded macrocycle based vesicles were investigated for in-vivo bioavailability in rabbits. The synthesized macrocycle was nontoxic in cancer cells, hemo-compatible and safe in mice. The drug-loaded macrocycle based vesicles appeared spherical, nano-ranged, and homogeneous in size with negative surface charge and were able to load an increased amount of drug. The vesicles are stable upon storage and when incubated with gastric simulated fluid. Amp-B increased oral bioavailability was achieved when delivered in synthesized macrocycle based vesicles. These results point out that the synthesized supramolecular amphiphile is an efficient nanocarrier to enhance the oral bioavailability of lipophilic drugs

Marine seaweeds are nature’s largesse resource in human well-being. Seaweed’s contribution to the food industry is being widened for its rich source of essential vitamins, minerals, and PUFA. ‘Nori’ is a dried sheet of red seaweed Porphyra sp. used to make ‘sushi’ a renowned cuisine in Japan, and other Southeast Asian countries. In this present study, commercial-grade ‘Nori’ was extracted and fractionated with different solvents, and subjected to evaluate the cytotoxic activity on human ovarian tetracarcinoma cells (PA1). As a result, the ethyl acetate fraction was found effective in inhibiting the proliferation of human ovarian cancer cells with an IC50 value of 41.1 µg/mL. The main component responsible for anticancer activity was determined as a sesquiterpene lactone Tatridin B (3h-cyclodeca[b]furan-2-one, 4,9-dihydroxy-6-methyl-3,10-dimethylene-). Moreover, it was found effective in inhibiting NSD2, an important and recently proposed biomarker for several types of cancer. This is a hitherto report on the presence of this compound in ‘Nori’ showing potent anticancer activity on human ovarian tetracarcinoma (PA1).

To investigate the photosynthetic change characteristics of mango leaves under enhanced UV-B radiation, adult ‘Tainong No. 1’ mango (Mangifera indica) trees were treated (N=nine individuals) with simulated enhanced UV-B radiation [24 and 96 kJ/(m2·d)] in the field, and the photochemical reactions, activities of key enzymes in carbon assimilation, and the expression of genes were observed. The results showed that compared with the control, there was a decrease in tree yield and nutritional flavor quality of the fruits under the 96 kJ/(m2·d) treatment, while no significant changes were observed under 24 kJ/(m2·d). After 20 or 40 days, leaves’ net photosynthetic rate (Pn), stomatal conductance (Sc), transpiration rate (Tr), intercellular CO2 concentration (Ci), and chlorophyll a/b under exposure to 96 kJ/(m2·d) of UV-B were significantly lower than in the control, whereas chlorophyll a, chlorophyll b, carotenoids, Hill reaction activity, photochemical quenching coefficient (qP), and Rubisco activities were significantly higher. By contrast, the Hill activity and Rubisco activity under 24 kJ/(m2·d) were significantly higher than the control, while Pn, Sc, Tr, Ci, and the content of photosynthetic pigments were similar to the control. The expression of gene coding the Rubisco big subunit (rbcL) was inhibited by the 96 kJ/(m2·d) treatment. We conclude that stomatal limitation was directly induced by 96 kJ/(m2·d), resulting in the inhibition of photosynthesis and the reduction in yield and deterioration of the quality of mango.

Background: Hepatocellular carcinoma (HCC) is one of most common cancers with a high mortality rate. HBV/HCV infection is an important risk factor to trigger HCC. Therefore, developing serum biomarkers for early diagnosis is crucial to prolong survival in HCC patients. Methods: An antibody array technology was utilized to detect serum from 20 HBV-related HCC patients, 20 chronic hepatitis B patients and 20 normal population, whose results were further validated by ELISA. Results: Both antibody array and ELISA showed that ten growth factors (SCF R, GDF-15, HGF, FGF-4, IGFBP-1, PIGF, GH, GDNF, BDNF and IGF-1) were significantly differential in HCC patients when compared to the non-HCC population. Among these growth factors, the levels of SCF R, GDF-15, HGF, GH and IGF-1 showed significant correlation with hepatitis B and its severity, indicating that these growth factors may promote HCC progression by an HBV-specific mechanism. A therapy targeting these growth factors in hepatitis B patients may help to prevent the development of HCC. FGF4 and GH were found, for the first time, to be upregulated in HCC, suggesting that these two growth factors may serve as novel serum biomarkers for the early diagnosis of HCC. Conclusion: The combined detection of all the differential growth factors may improve the diagnostic accuracy of HCC.

The outbreak of the 2019 Novel Coronavirus (2019-nCoV) has rapidly spread from Wuhan, China to multiple countries, causing staggering number of infections and deaths. A systematic profiling of the immune vulnerability landscape of 2019-nCoV is lacking, which can bring critical insights into the immune clearance mechanism, peptide vaccine development, and antiviral antibody development. In this study, we predicted the potential of all the 2019-nCoV viral proteins to induce class I and II MHC presentation and form linear antibody epitopes. We showed that the enrichment for T cell and B cell epitopes is not uniform on the viral genome, with several focused regions that generate abundant epitopes and may be more targetable. We showed that genetic variations in 2019-nCoV, though fewer for the moment, already follow the pattern of mutations in related coronaviruses, and could alter the immune vulnerability landscape of this virus, which should be considered in the development of therapies. We create an online database to broadly share our research outcome. Overall, we present an immunological resource for 2019-nCoV that could significantly promote both therapeutic development and mechanistic research.

Background: Dual function tail tubular proteins (TTP) belonging to the lytic bacteriophages are the interesting group of biologically active enzymes. Surprisingly, apart from their structural function, they are also polysaccharide hydrolyzes destroying bacterial extracellular components. One of the representatives of this group is TTPB from Klebsiella pneumoniae phage – KP32. TTPB hydrolyzes exopolysaccharide (EPS) of Klebsiella pneumoniae and Enterococcus faecalis strain. This depolymerizing feature was associated with the activity to prevent bacterial biofilm formation. TTPB can inhibit biofilm formation by K. pneumoniae, Enterobacter cloacae, Staphylococcus aureus, Enterococcus faecalis and Pseudomonas aeruginosa strains. Moreover, synergistic activity with antibiotic action has been observed, most likely due to depolymerases’ facilitation of contact of antibiotic with bacterial cells. Methods: TTPB was overexpressed in E coli system, purified and tested towards the bacterial strains using agar overlay method. The hydrolytic activity of TTPB was performed using EPSs of K. pneumoniae PCM2713 and E. cloacae ATCC 13047 as the substrates. Next, we determined the reducing sugar (RS) levels in the TTPB/EPS mixtures, regarding the RS amount obtained after acidic hydrolysis. The antibiofilm activity of TTPB has been set down on bacterial biofilm using a biochemical method. Finally, we have demonstrated the synergistic activity of TTPB with kanamycin. Results: For the first time, the hydrolytic activity of TTPB towards bacterial EPSs has been shown. TTPB releases about a half of the whole RS amount of EPSs belonging to K. pneumoniae PCM 2713 and E. cloacae ATCC 13047 strains. 1.12 µM of the phage protein reduces biofilm of both strains by over 60%. Destroying the bacterial biofilm the phage protein improves the antibiotic action increasing kanamycin effectiveness up to four times.

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.

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.

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.

The -blocker (S)-practolol ((S)-N-(4-(2-hydroxy (isopropylamino)propoxy)phenyl)acetamide) was synthesized with 96% enantiomeric excess (ee) from the chlorohydrin (R)-N-(4-(3-chloro-2 hydroxypropoxy)phenyl)acetamide, which was produced in 97% ee and with 27% yield. Racemic building block 1-((1H-indol-4-yl)oxy)-3-chloropropan-2-ol for the -blocker pindolol was produced in 53% yield and (R)-1-((1H-indol-4-yl)oxy)-3-chloropropan-2-ol was produced in 92% ee. The chlorohydrin 7-(3-chloro-2-hydroxypropoxy)-3,4-dihydroquinolin-2(1H)-one, a building block for a derivative of carteolol was produced in 77% yield. (R)-7-(3-chloro-2-hydroxypropoxy)-3,4-dihydroquinolin-2(1H)-one was obtained in 96% ee. The S-enantiomer of this carteolol derivative was produced in 97% ee in 87% yield. Racemic building block 5-(3-chloro-2-hydroxypropoxy)- 3,4-dihydroquinolin-2(1H)-one, building block for the drug carteolol was also produced in 53% yield, with 99% ee of the R-chlorohydrin (R)-5-(3-chloro-2-hydroxypropoxy)-3,4-dihydroquinolin-2(1H)-one. The yield of all four chlorohydrins increased by use of catalytic amounts of base. The reason for this was found to be less formation of the dimeric by-products compared to use of higher concentration of the base. An overall reduction of reagents and reaction time was also obtained compared to our previous reported data of similar compounds. The enantiomers of the chlorohydrin building blocks were obtained by kinetic resolution of the racemate in transesterification reactions catalyzed by Candida antarctica Lipase B (CALB) from SyncoZymes Co, Shanghai, China. Optical rotations confirmed the absolute configuration of the enantiopure drugs.

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.

Immune responses to influenza (flu) antigens reflect memory to prior infections or vaccinations, which might influence immunity to new flu antigens. Memory of past antigens has been termed “original antigenic sin” or more recently “immune imprinting” and “seniority”. We have researched a comparison between the immune response to live flu infections and inactivated flu vaccina-tions. A brief history of antibody generation theories is presented culminating in new findings about the immune-network theory suggesting that a network of clones exists between an-ti-idiotypic antibodies and T cell receptors. Findings regarding the 2009 pandemic flu strain and immune responses to it are presented, including memory B cells and conserved regions within the hemagglutinin protein. The importance of CD4+ memory T cells and cytotoxic CD8+ T cells responding to both infections and vaccinations are discussed and compared. Innate immune cells like natural killer (NK) cells and macrophages are discussed regarding their roles in adaptive immune responses. Antigen presentation via macroautophagy processes are described. New vaccines in development are mentioned along with the results of some clinical trials. The manu-script concludes with how repeated vaccinations are impacting the immune system and a sketch of what might be behind the imprinting phenomenon, including future research directions.

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.

Introduction: The objectives of this study were to (1) investigate the association between human blood type and COVID-19 infection in both inpatient and longitudinal populations at our institution in South Florida and (2) identify the association between blood type and severity of COVID-19 infection via presence of cellular biomarkers of severe infection in hospitalized individuals. Methods: This study consists of (1) a single-center retrospective analysis of 669 of 2,741 COVID-19 positive screened patients seen from January 1, 2020 until March 31, 2021 at the University of Miami Emergency Department (ED) who tested positive for COVID-19 infection and had a documented ABO blood type and (2) a longitudinal SARS-CoV-2 immunity study (“CITY”) at the University of Miami Miller School of Medicine consisting of 185 survey participants. COVID-19 outcome rates and 95% confidence intervals were calculated for each ABO blood type and Rh group using Chi-squared tests for categorical and ANOVA for continuous variables in the inpatient cohort and Chi-squared tests for the longitudinal cohort, all executed in R studio. Results: Our inpatient cohort had a mean age of 53.6 (± 17.9) years with 48% males and 52% females. When compared to patients with other blood types, those with O- demonstrated less risk of developing COVID-19 pneumonia (26.7% for O- vs. 69.2% for type A-, 56.5% for A+, 71.4% for AB+, 53.7% for B+, 51.5% for O+, p-value= 0.003 via Chi-squared test) and decreased mortality due to COVID-19 infection (17.0% mortality for O vs. 26.3% for A, 29.2% for B, p-value= 0.012 via Chi-squared test). Blood type O- demonstrated less elevated levels of LDH than did other blood types (p-value= 0.001, ANOVA) and a higher frequency of clinically accepted baseline levels of troponin (0.04 ng/mL) (p-value= 0.026, ANOVA) (Figure 1). Most of the longitudinal cohort was ABO blood grouping type O (47% (87/185)), with 33.5% type A, 14.1% B, and 5.4% AB. Most individuals were Rh positive (85.9%). There was no significant association found between COVID status (infection vs. non-infection) and ABO (Chi-squared test (3, N = 185) = 1.8, p = 0.6) or Rh (Chi-squared test (1, N = 185) = 0.16, p = 0.7) blood typing. Nearly all participants had been vaccinated (95.1% (176/185)), with a majority reporting primary vaccination with Pfizer (57.8% (107/185)), followed by Moderna (33% (61/185)), and Johnson & Johnson (4.3% (8/185)). 8 participants (4.3%) were unvaccinated. Conclusions: In an inpatient setting, blood type O sustained less risk of COVID-19 mortality and O- demonstrated less risk of developing COVID-19 pneumonia. In a longitudinal setting, there was no association found between blood type and COVID-19 severity. As the novelty of COVID-19 infection declines with time, further studies on risk-stratification by blood type are encouraged.

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.

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.

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.

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.

This research illustrates modification of multi-walled carbon nanotubes (MWCNT) by ZrO2/Pb to construct nanocomposites (MWCNT/ZrO2/Pb-NCs) by simple precipitation technique and subsequently examine its ability for adsorption of Amido black (AB) and Eosin B (EB) dyes in binary system. The present nanocomposites investigation by FESEM, XRD, FTIR, and EDX analysis, reveal its as-synthesized crystalline nature with cubic morphology and average particle size 30–50 nm. The present nano-adsorbent represent high efficiency for AB and EB adsorption from aqueous solution, while dependency of variables including pH, initial concentration of dyes, contact time and MWCNT/ZrO2/Pb-NCs mass were analyzed by central composite design (CCD). The predicted maximum removal percentage was 95% removal for both dyes is consequence of adjustment of operational conditions at pH of 6.0; 0.05 g MWCNT/ZrO2/Pb-NCs; 15 min stirring at 15 mg L-1 for both dyes. The Langmuir as applicable for representation and description of reveal data of adsorption with adsorption capacity of 15.46 and 16.92 mg g-1 for AB and EB, respectively. Pseudo-first order model owing to its high correlation coefficient and closeness of experimental and theoretical data well represented behavior of corresponding adsorption system. Mechanism examination strongly proof high contribution of external mass transference as the main rate-controlling step. The successful regeneration of MWCNT/ZrO2/Pb-NCs suggested their usefulness in wastewater treatment and its ability of environmental management.

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.

ABO incompatibility is not considered a contraindication for hematopoietic stem cell transplantation (HSCT). Approximately 30% of transplants from related donors and up to 50% of transplants from unrelated donors are ABO-incompatible. The immuno-hematologic investigationsmay evaluate donor/recipient ABO mismatch and anti-A/B isohemoagglutinins (IHAs) titration in pre-HSCT phase. Immediate hemolysis or delayed complications (passenger lymphocyte syndrome and pure red cell aplasia) can appear post-HSCT. Some preventive treatmentstake into consideration the manipulation of the product and decision-making algorithms based on the titration of IHAs in the recipient with clinical protocols for the removal/reduction of IHAs through plasma exchange or immunoadsorption procedures. Currently, the best approach in the managementof ABO-incompatibletransplant is not defined in expert consensus documents or with solid evidence. In addition, the methods for IHAs titration are not standardized. The transfusion strategy must consider both the blood group systems of the recipient and the donor until the RBC engraftment and the confirmed ABO conversion (forward and reverse typing) on two consecutive and independent samples. Therefore, ABO incompatibility in the HSCT is an important immuno-hematologic challenge and request all necessary preventive measures including the appropriate selection of ABO blood components for transfusion.

Chondrocytes maintain the normal morphological structure and physiological function of articular cartilage. However, the increased expression of inflammatory mediators and matrix-degrading enzymes in chondrocytes can promote ECM degradation, consequently disrupting the physiological function of articular cartilage and ultimately leading to the onset of osteoarthritis (OA). Usnic acid (UA), an extract derived from plants, possesses multiple bioactive properties including anti-inflammatory and antioxidant effects. Hence, this study aims to explore the molecular mechanisms underlying its protective effects in an in vitro simulated model of OA in rat chondrocytes. In vivo experiments encompassed three groups: Control, Model, and Usnic acid (50 mg/kg), with sample extraction following 12 weeks of administration. Pathological alterations in articular cartilage were evaluated using Safranin O-fast green staining. Immunohistochemistry (ICH) analysis was employed to assess the expression of matrix degradation-related markers. The levels of serum cytokines were quantified via ELISA assays. In this study, primary rat chondrocytes were employed as the experimental subject. After a 24-hour treatment period, culture supernatants, total RNA, total protein, and nuclear protein were extracted from the different chondrocyte groups. ELISA and qPCR methods were used to measure levels of IL-6, TNF-α, and PGE2. WB and qPCR were employed to assess levels of p65, p-p65, IκBα, p-IκBα, Nrf2, HO-1, NQO1 ADAMTS-4, MMP-1, MMP-3, MMP-13, INOS, COX-2, and COL2A1. IF analysis was performed to examine Nrf2, p-p65 and COL2A1. Results: (1) In vivo, intraperitoneal injection of usnic acid (50mg/kg) can alleviate pathological changes in articular cartilage and the levels of inflammatory and oxidative-related matrix in the serum. (2) UA reduced the level of inflammatory cytokines in IL-1β-induced chondrocytes supernatant. (3) UA can produce anti-inflammatory and antioxidant effects and inhibit chondrocytes matrix degradation through the Nrf2 and NF-κB pathways. (3) The mechanism by which UA exerts a protective role in chondrocytes is mediated by Nrf2 Conclusion: UA inhibits the expression of chondrocyte matrix degradation-related components through Nrf2 mediated Nrf2 pathway and NF-κB pathway, promotes the production of protective substances, and ultimately exerts a protective effect on chondrocytes.

The biological conservation measures factor (B) in the Chinese Soil loss Equation (CSLE) model is one of the main components in evaluating soil erosion, and the accurate calculation of B factor at the regional scale is fundamental in predicting regional soil erosion and the dynamic changes. In this study, we developed an optimal computational procedure for estimating and mapping the B factor in the Google Earth Engine (GEE) cloud computing environment using multiple data sources through data suitability assessment and image fusion. Taking the Yanhe River Basin in the Loess Plateau of China as an example, we evaluated the availability of daily precipitation data (CHIRPS, ERA5, and PERSIANN-CDR data) against the data at national meteorological stations. We estimated the B factor from Sentinel-2 data and proposed a new method, namely trend migration method, to patch the missing values in Sentinel-2 data using three other remote sensing data (MOD09GA, Landsat-7, Landsat-8). We then calculated and mapped the B-factor in Yanhe River Basin based on rainfall erosivity, vegetation coverage, and land use types. The results show that the ERA5 precipitation dataset outperforms the CHIRPS and PERSIANN-CDR data in estimating rainfall erosivity and rainfall, and it can be utilized as an alternative data source for meteorological stations in soil erosion modeling. Compared to the harmonic analysis of time series (HANTS), the trend migration method proposed in this study is more suitable for patching the missing parts of Sentinel-2 data. The restored high-resolution Sentinel-2 data fit nicely with the 10-m resolution land use data, enhancing the B factor calculation accuracy from the region to the spot level. The B factor computation procedure developed in this study is applicable to various river basin and regional scales for regional soil erosion monitoring.

The Hepatitis B virus, chronically infects over 240 million persons worldwide. The Hepatitis B vaccine is 90% effective in preventing perinatal transmission if the first dose is given within the first 24 hours of life followed by a minimum of 2 subsequent doses. In October 2021, Antigua and Barbuda, through it’s only public hospital - the Sir Lester Bird Medical Centre, instituted a hospital based Hepatitis B vaccine birth dose policy. Timely birth dose coverage was 72% and total birth dose coverage 81%. 10.5% of parents refused the hepatitis b – birth dose, of which 76% either felt uncomfortable or preferred to wait. 100% of babies born before arrival received timely vaccine administration, likewise 100% of Hepatitis B exposed babies were vaccinated, with 83% of them receiving the Hepatitis B Immunoglobulin. A maternal Hepatitis B surface antigen result was available for 90.4% of mothers. Barriers to timely birth dose administration included vaccination hesitancy, gaps in healthcare worker knowledge, and the consistent supply of Hepatitis B vaccine. Instituting a quality improvement team, health information system, robust educational efforts, and addressing barriers will make achieving the WHO programmatic targets of eliminating mother to child transmission of hepatitis B by 2030 possible.

Diffuse large B-cell lymphoma (DLBCL) is an aggressive and biologically heterogeneous disease. Approximately 40% of patients with DLBCL will experience disease relapse or will be refractory to first line chemoimmunotherapy. In recent years there have been several new therapeutic agents approved for the treatment of relapsed/refractory (R/R) DLBCL. These agents include anti-CD19 chimeric antigen receptor T-cell therapies (CAR T-cells) and monoclonal antibodies as polatuzumab and tafasitamab. Nevertheless, despite the high efficacy of all these new therapies, there are still patients who do not respond or relapse, representing an unmet clinical need. This review describes new promising therapies that are under investigation to treat R/R DLBCL.

In this work Cu2O nanoparticles (NPs) were created in-situ on graphene functionalized with Thermomyces lanuginosus lipase (G@TLL) where site-oriented supported TLL acted as template and binder in the presence of copper salt by tailorable synthesis under mild conditions, producing a heterogeneous catalyst. Cu2O NPs was confirmed by XRD and XPS. The TEM microscopy showed that the nanoparticles were homogeneously distributed over the G@TLL surface with sizes of 53 nm and 165nm. This G@TLL-Cu2O hybrid was successfully used in the degradation of toxic organic compounds such as trichloroethylene (TCE) and Rhodamine B (RhB). In the case of TCE, the hybrid presented a high catalytic capacity, degrading 60 ppm of product in 60 min in aqueous solution and room temperature without the formation of other toxic subproducts. In addition, a TOF value of 7.5 times higher than the unsupported counterpart (TLL-Cu2O) was obtained, demonstrating the improved catalytic efficiency of the system in the solid-phase. The hybrid also presented an excellent catalytic performance for the degradation of Rhodamine B (RhB) obtaining a complete degradation (48ppm) in 50 min in in aqueous solution and room temperature and with the presence of a green oxidant as H2O2.

The objective of this research is to measure the perception that teachers had about their own performance when they were forced to carry out an Emergency Remote Teaching due to the COVID-19 pandemic. A questionnaire was provided to teachers of every educational stage in the Basque Country (Pre-school, Primary and Secondary Education, Professional Training and Higher Education) obtaining a total of 4,586 responses. The statistical analysis of the data shows that the greatest difficulties reported by educators are shortcomings in their training in digital skills, which has made them perceive more workload during the lockdown and negative emotions. Another finding is the existing digital divide between teachers based on their gender, age and type of school. A further worrying result is the lower technological competence in lower educational levels, which are the most vulnerable in remote teaching. These results invite us to reflect on the measures to be taken to improve equity, social justice and resilience of the educational system, which align with some of the Sustainable Development Goals.

Herewith we report a facile synthesis of zinc oxide doped with (5, 10, 15, and 20 wt%) titanium oxide nanocomposites in gelatin under ultra-sonication. The X-ray diffraction (XRD) data revealed ZnO the formation in addition to a rutile phase TiO2. The ZnO phase size decreased, and the rutile TiO2 phase increased with a TiO2 loading increment. The scanning electron microscopy (SEM) displayed a combination of spherical and hexagonal particles with a 60 – 80 nm size distribution. The prepared nanostructures photocatalytic activity was assisted using Rhodamine B dye, where they showed enhanced photodegradation competence under visible light irradiation. The kinetics of photodegradation followed the first-order kinetics with the 20 % wt sample having the maximum activity. The mechanistic investigation revealed the dominance of h+ and •O2- species during the dye photodegradation. The results indicate the potential application of such gelatin stabilized nanostructures for dye illumination from aqueous solutions under sunlight.

B chromosomes (Bs) were discovered a century ago, and since then most studies have focused on describing their distribution and abundance using traditional cytogenetics. Only recently have attempts been made to understand their structure and evolution at the level of DNA sequence. Many questions regarding the origin, structure, function and evolution of B chromosomes remain unanswered. Here we identify B chromosome sequences from several species of cichlid fish from Lake Malawi by examining the ratios of DNA sequence coverage in individuals with and without B chromosomes. We examine the efficiency of this method, and compare results using both Illumina and PacBio sequence data. The B chromosome sequences detected in 13 individuals from 7 species were compared to assess the rates of sequence replacement. B-specific sequence common to at least 12 of the 13 datasets are identified as the “Core” B chromosome. The location of B sequence homologs throughout the genome provides further support for theories of B chromosome evolution. Finally, we identified candidate genes located on the B chromosome which may regulate the segregation and maintenance of the B chromosome.

B chromosomes are supernumerary chromosomes which are found in addition to the normal standard chromosomes (A chromosomes). B chromosomes are well known to accumulate several types of repeats. Although the evolution of B chromosomes has been subject of numerous studies, the mechanisms of accumulation and evolution of repetitive sequences is not fully understood. Recently, new genomic approaches have shed light on the origin and accumulation of different classes of repetitive sequences in the process of B chromosome formation and evolution. Here we discuss the impact of repetitive sequences accumulation on the evolution of plant B chromosomes.

Myocardium transcriptomes of mouse left and right atria and ventricles were profiled separately to identify the differences that might be responsible for the distinct functional roles of the four heart chambers. In total, 16,886 distinct unigenes have been quantified in all 16 samples collected from four adult male mice from the same litter. 15.76% of the quantified genes on the left and 16.5% on the right exhibited differential expression between the corresponding atrium and ventricle of the same side, while 5.8% in atria and 1.2% in ventricles were differently expressed between the left and the right. Beyond the differentially expressed genes, the study revealed distinct expression control and coordination of ion channels and genes within the cardiac muscle contraction, oxidative phosphorylation, glycolysis/glucogenesis, calcium and adrenergic signaling pathways. Interestingly, while expression of Ank2 (encoding ankyrin-B) oscillates in phase with all its binding partners in the left ventricle, the percentage of synergistically expressed partners of Ank2 is 15% and 37% in the left and right atria and 74% in the right ventricle. The analysis revealed also the high interventricular synchrony of the expression of ion channels.

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.

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.

The presence of premature termination codons (PTCs) in transcripts is dangerous for the cell as they encode potentially deleterious truncated proteins that can act with dominant-negative or gain-of-function effects. To avoid synthesis of these shortened polypeptides, several RNA surveillance systems can be activated to decrease the level of PTC-containing mRNAs. Nonsense-mediated mRNA decay (NMD) ensures an accelerated degradation of mRNAs harboring PTCs by using several key NMD factors such as up-frameshift (UPF) proteins. Another pathway called nonsense-associated altered splicing (NAS) upregulates transcripts that have skipped disturbing PTCs by alternative splicing. Therefore, these RNA quality control processes eliminate abnormal PTC-containing mRNAs from the cells by using positive and negative responses. In this review, we will describe the general mechanisms of NMD and NAS and their respective involvement in the decay of aberrant immunoglobulin and TCR transcripts in lymphoid cells.

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.

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.

Bacterial resistance to antibiotics due to an increased efficiency of the efflux is a serious problem in clinics of infectious diseases. Knowledge of the factors affecting the activity of efflux pumps would help to find the solution. For this, fast and trustful methods for the efflux analysis are needed. Here we analyzed how the assay conditions affect the accumulation of efflux indicators ethidium (Et+) and tetraphenylphosphonium in Salmonella enterica ser. Typhimurium cells. An inhibitor phenyl-alanyl-arginyl-β-naphtylamide was applied to evaluate the input of RND family pumps into the total efflux. In parallel to spectrofluorimetric analysis, we used an electrochemical assessment of Et+ concentration. Results of our experiments indicated that Et+ fluorescence increases immediately after the penetration of this indicator into the cells. However, when cells bind a high amount of Et+, intensity of the fluorescence reaches the saturation level and stops reacting to the accumulated amount of this indicator. For this reason, electrochemical measurements provide more trustful information about the efficiency of efflux when cells accumulate high amounts of Et+. Measure-ments of Et+ interaction with the purified DNA demonstrated that affinity of this lipophilic cation to DNA depends on the medium composition. The capacity of DNA to bind Et+ considerably de-creases in presence of Mg2+, Polymyxin B or when DNA is incubated in high ionic strength media.

Background—In 2011, Miller and Goldman published a study in Human and Experimental Toxicology that found a counterintuitive, positive correlation, r = 0.70 (r² = 0.49, p < .0001), demonstrating that as nations require more vaccine doses for their infants, infant mortality rates (IMRs) tend to increase (worsen). The dataset (n = 30) included the United States, a nation that required the most vaccines for their infants, and all nations with better IMRs than the United States. Dr. E. Bailey, a professor at BYU, and her students, recently read the Miller-Goldman study and found it "troublesome that this manuscript is in the top 5% of all research outputs" and falsely claimed that its findings were due to "inappropriate data exclusion," i.e., failure to analyze the "full dataset" of all 185 nations. The "Bailey reanalysis," titled Infant vaccination does not predict increased infant mortality rate: correcting past misinformation, was posted to the medRxiv preprint server on September 10, 2021 (version 1) and October 5, 2021 (version 3) and Europe PMC preprint server on September 10, 2021. Objective—This present study examines the various claims postulated by the Bailey reanalysis and assesses the robustness of their methodology, analyses, and reported results and conclusions. Methods—Data discussed in this paper are based on the previously mentioned study by Miller and Goldman and the Bailey reanalysis. Results—Linear regression analysis of IMR and the number of vaccine doses for each country yield a statistically significant positive correlation of r = 0.70 (p < .0001) for the top nations (n = 30) chosen by Miller-Goldman and r = 0.16 (p < .04) for the "entire dataset" chosen by Bailey et al (n = 185). Bailey also conducted linear regression analyses (for the year 2019) of IMRs as a function of vaccination rates for each of eight different vaccines and reported statistically significant inverse correlations for 7 of 8 vaccines over the entire range of vaccination rates. However, Miller and Goldman reanalyzed the Bailey analyses for nations with vaccination rates below 60% and found no statistically significant correlation for six vaccines (DPT, Hib, hepatitis B, polio, rotavirus, and measles) and statistically significant positive correlations for tuberculosis (r = 0.8, p < .005) and pneumococcal (r = 0.6 p < .023) vaccines. Conclusions—Bailey’s reanalysis corroborates a statistically significant positive correlation originally reported by Miller and Goldman. However, Bailey’s reported correlation (r = +0.16, p < .04) is small, likely due to poor methodology (failing to account for covariates, i.e., disparities among numerous socioeconomic factors that add uncertainty to their conclusion). The r-value reported by the Bailey reanalysis demonstrates an effect size that is about one-fourth (0.16/0.70) that reported by Miller-Goldman—underscoring how critically important it is for Bailey's reanalysis to eliminate confounding variables. Moreover, Bailey’s linear regression analyses of IMR as a function of vaccination rates for each of eight different vaccines demonstrate that some countries with low vaccination rates have low IMRs, while other countries with high vaccination rates have high IMRs. Rather than supporting a strong inverse correlation, the Bailey reanalysis demonstrates high vaccination rates are neither necessary nor sufficient to cause low IMR.

The paper focuses on the application of a multilevel, integrative and territorial approach to the protection of cultural heritage through planning instruments in Serbia. It points out the problems of the sectoral approach and discusses international recommendations that can be integrated into the planning methodology. The case study is the area of Djerdap National Park, which has an already established international and national importance. The research suggests that the cultural heritage in the area, with the exception of the Roman limes, is still recognized at the level of individual localities. The study emphasizes the importance of aligning all levels of governance to safeguard the whole spatial entity rather than focusing solely on its particular areas. The interna-tional and national importance of the planning area contributes to the strengthening of awareness of heritage and its institutional protection. However, the vitality of the area, which is key to its sustainable development, comes from the local level. Planning documents contribute to the inte-gration of local values and local communities into development programs and projects.

Neuroinflammatory responses are implicated in the pathogenesis of neurodegenerative diseases. In neurodegenerative diseases, neuroinflammatory reactions to neuronal injury are modulated by microglial cells, which are vital innate immune cells in the central nervous system. Activated microglial cells release proinflammatory cytokines, mediators, and neurotoxic factors that induce fatal neuronal injury. The present study investigated the anti-neuroinflammatory effects of cudratricusxanthone L (1), which was isolated from Cudrania tricuspidata. This compound reduced the levels of lipopolysaccharide-stimulated inflammatory mediators and cytokines, including nitric oxide, prostaglandin E2, interleukin (IL)-1β, tumor necrosis factor-α, IL-6, and IL-12. These effects suggested that cudratricusxanthone L (1) suppressed the nuclear factor-kappa B (NF-κB) signaling pathway. Specifically, cudratricusxanthone L (1) also attenuated the phosphorylation of Jun kinase and inhibited p38 mitogen-activated protein kinase (MAPK) signaling in BV2 and rat primary microglial cells. These results indicated that cudratricusxanthone L (1) effectively repressed neuroinflammatory processes in BV2 and rat primary microglial cells by inhibiting NF-κB and the MAPK signaling pathway.

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.

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.

An in vitro medium-throughput screen using M. tuberculosis H37Rv was employed to screen an in-house library of structurally diverse compounds for antimycobacterial activity. From this initial screen, eleven 7-substituted coumarin derivatives with confirmed monoamine oxidase-B and cholinesterase inhibitory activities, demonstrated growth inhibition of more than 50% at a 50 µM concentration. This prompted further exploration of all the 7-substituted coumarins in our library, nineteen in total, as potential antimycobacterial agents. Four derivatives showed promising antimycobacterial activity with MIC₉₉ values of 8.31 – 29.70 µM and 44.15 – 57.17 µM on M. tuberculosis H37Rv in independent assays using Gaste-Fe and 7H9 + OADC media, respectively. These compounds were found to bind to albumin which may explain the variations in MIC between the two assays. Preliminary antimycobacterial evaluation of moxifloxacin resistant M. tuberculosis show that these compounds are able to maintain their activity in fluoroquinolone resistant mycobacteria. Analysis of structure activity relationships for antimycobacterial versus neuronal enzyme inhibitory activity indicate that structural modification on position 4 and/or 7 of the coumarin scaffold may be utilized to improve selectivity towards either inhibition of neuronal enzymes or antimycobacterial effect. Cytotoxicity evaluations of the compounds indicate moderate cytotoxicity with slight selectivity towards mycobacteria. Further neuroprotective assays on SH-SY5Y human neuroblastoma cells indicate significant neuroprotection for selected compounds irrespective of their neuronal enzyme inhibitory properties. These coumarin molecules are thus interesting lead compounds that may provide insight into the design of new antimicrobacterial and/or neuroprotective agents.