Food allergies are a growing public health concern worldwide, especially in children and young adults. Allergen-specific IgE plays a central role in the pathogenesis of food allergies, but their titers poorly correlate with allergy development. Host immune systems yield allergen-specific immunoglobulin (Ig)A, IgE and IgG subclasses with low or high affinities and differential Fc N-glycosylation patterns that can affect the allergic reaction to food in multiple ways. High affinity IgE is required to induce strong mast cell activation eventually leading to allergic anaphylaxis while low affinity IgE can even inhibit the development of clinically relevant allergic symptoms. IgA and IgG antibodies can inhibit IgE-mediated mast cell activation through various mechanisms, thereby protecting IgE-positive individuals from allergy development. The production of IgE and IgG with differential allergenic potential seems to be affected by the signaling strength of individual B cell receptors, and by cytokines from T cells. This review provides an overview of the diversity of the B cell response and the diverse roles of antibodies in food allergy.

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

Background/methods: For mechanistic studies, in vitro human B cell differentiation and generation of plasma cells are invaluable techniques. However, the heterogeneity of both T cell-dependent (TD) and T cell-independent (TI) stimuli and the disparity of culture conditions used in existing protocols makes interpretation of results challenging. The aim of the present study was to achieve the most optimal B cell differentiation conditions using isolated CD19⁺ B cells and PBMC cultures. We addressed multiple seeding densities, different durations of culturing and various combinations of TD stimuli and TI stimuli including B cell receptor (BCR) triggering. B cell expansion, proliferation and differentiation was analyzed after 6 and 9 days by measuring B cell proliferation and expansion, plasmablast and plasma cell formation and immunoglobulin (Ig) secretion. In addition, these conditions were extrapolated using cryopreserved cells and differentiation potential was compared. Results: This study demonstrates improved differentiation efficiency after 9 days of culturing for both B cell and PBMC cultures using CD40L and IL-21 as TD stimuli and 6 days for CpG and IL-2 as TI stimuli. We arrived at optimized protocols requiring 2500 and 25.000 B cells per culture well for TD and TI assays, respectively. The results of the PBMC cultures were highly comparable to the B cell cultures, which allows dismissal of additional B cell isolation steps prior to culturing. In these optimized TD conditions, the addition of anti-BCR showed little effect on phenotypic B cell differentiation, however it interferes with Ig secretion measurements. Addition of IL-4 to the TD stimuli showed significantly lower Ig secretion. The addition of BAFF to optimized TI conditions showed enhanced B cell differentiation and Ig secretion in B cell but not in PBMC cultures. With this approach, efficient B cell differentiation and Ig secretion was accomplished when starting from fresh or cryopreserved samples. Conclusion: Our methodology demonstrates optimized TD and TI stimulation protocols for more indepth analysis of B cell differentiation in primary human B cell and PBMC cultures while requiring low amounts of B cells, making them ideally suited for future clinical and research studies on B cell differentiation of patient samples from different cohorts of B cell-mediated diseases.

Certain species of Mucorales have been identified as causative agents of mucormycosis, a rare yet often lethal fungal infection. Notably, these fungi exhibit intrinsic resistance to common azole drugs, which target lipids. Given the pivotal role of lipids in drug resistance and their contribution to the innate resistance to azoles, this study provides a comprehensive overview of key lipid classes, including sphingolipids (SLs), glycerophospholipids(GPLs), and sterols, in Rhizopus delemar 99-880, a well-characterized reference strain among Mucorales. Through high-throughput analysis involving the identification and quantification of intermediates, we have elucidated the biosynthetic pathways of SLs, PGLs, and sterols. Notably, the acidic SLs were not found probably because the acidic branch of the SL biosynthesis pathway terminates at α-hydroxy phytoceramides as evident by their high abundance. Intermediates in the neutral SL pathway incorporated higher levels of 16:0 fatty acid compared to other pathogenic fungi. A strikingly high phosphatidylethanolamine (PE)/phosphatidylcholine (PC) ratio was observed among GPLs. Ergosterol remains the major sterol, similar to other fungi, and our analysis confirms the existence of alternate ergosterol biosynthesis pathways. The total lipidomic profile of R. delemar 99-880 offers insights into its lipid metabolism and potential implications for studying pathogenesis and drug resistance mechanisms.

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.

The proliferation and survival signals emanating from the B-cell receptor (BCR) constitute a crucial aspect of mature lymphocyte’s life. Dysregulated BCR signaling is considered a potent contributor to tumor survival in different subtypes of B cell non-Hodgkin lymphomas (B-NHLs). In the last decade, emergence of BCR-associated kinases as rational therapeutic targets has led to the development and approval of several small molecule inhibitors targeting either Bruton's tyrosine kinase (BTK), spleen tyrosine kinase (SYK), or phosphatidylinositol 3 kinase (PI3K), offering alternative treatment options to standard chemoimmunotherapy, and making some of these drugs valuable assets in the anti-lymphoma armamentarium. Despite their initial effectiveness, these precision medicine strategies are limited by primary resistance in aggressive B-cell lymphoma like diffuse large B cell lymphoma (DLBCL) and mantle cell lymphoma (MCL), especially in the case of first generation BTK inhibitors. In these patients, BCR-targeting drugs often fail to produce durable responses, and nearly all cases eventually progress with a dismal outcome, due to secondary resistance. This review will discuss our current understanding of the role of antigen-dependent and antigen-independent BCR signaling in DLBCL and MCL and will cover both approved inhibitors and investigational molecules being evaluated in early preclinical studies. We will discuss how the mechanisms of action of these molecules, and their off/on-target effects can influence their effectiveness and lead to toxicity, and how our actual knowledge supports the development of more specific inhibitors and new, rationally based, combination therapies, for the management of MCL and DLBCL patients.

Background: Diffuse large B-cell lymphoma is the most common type of non-Hodgkin's lymphoma. Due to the variety of clinical manifestations, accurate diagnosis can be challenging. Here, we present a case of DLBCL that was initially misdiagnosed as a hematoma, highlighting the importance of considering malignancy in the setting of non-responsive soft tissue swelling. Methods: A 76-year-old man presented to the emergency department with right periorbital swelling and ecchymosis. The symptoms first appeared after an injury and did not resolve spontaneously. The patient was taking warfarin for atrial fibrillation. A facial bone CT revealed a large irregular homogeneous mass. An extraconal hematoma was suspected based on clinical history and radiologic findings. Incision and drainage were performed, resulting in evacuation of old blood. Despite continued drainage, the patient's symptoms worsened. A comparison with the previous CT revealed an increase in the size of the lesion. As a result, a surgical excisional biopsy was performed. Results: Biopsy of the mass showed a diffuse infiltrate of lymphocytes around the tissue. The diagnosis of diffuse large B-cell lymphoma was confirmed pathologically. The patient was referred to hematology for further management. Conclusions: DLBCL is a rare disease associated with a poor prognosis. Due to the previous injury and the use of anticoagulants, the patient was initially misdiagnosed as having a hematoma. This delayed the prompt diagnosis and affected the timing of treatment initiation. We must be aware that a malignant mass is a potential cause of unresponsive soft tissue swelling.

GeneVac-B® was recently licensed in Burkina Faso and is widely used for population vaccination. This study aimed to evaluate the immune response in people fully vaccinated against hepatitis B with the GeneVac-B® vaccine in Burkina Faso under actual conditions of use. This cross-sectional study included individuals fully vaccinated with GeneVac-B®. For each consenting participant, sociodemographic and clinical data were collected using a structured questionnaire. Approximately 4 mL of whole blood was collected for immunological (anti-HBs, HBsAg, anti-HCV and anti-HIV) and biochemical (blood glucose, total cholesterol, and triglycerides) testing. The anti-HBs titer was used to determine the immune response. A total of 392 participants were included in the study. The mean age was 35.5±15 years. Approximately 56.1% had been previously exposed to HBV. Three hundred eighty (380) participants had an anti-HBs titer ≥ 12 mIU/mL, a seroprotection rate of 96.9%, and 12 had a titer < 12 mIU/mL, a nonresponse rate of 3.1%. Among the nonresponders, 11 (11/12; 91.7%) had high total cholesterol levels (> 240 mg/dL), and 8 (8/12; 66.7%) were older than 40 years of age. The results showed an excellent immune response to GeneVac-B® in our study population. However, age > 40 and high total cholesterol appear to be factors associated with nonresponse.

Accurate computational prediction of B-cell epitopes can greatly enhance biomedical research and rapidly advance efforts to develop therapeutics, monoclonal antibodies, vaccines, and immunodiagnostic reagents. Previous research efforts have primarily focused on the development of computational methods to predict linear epitopes rather than conformational epitopes, although the latter is much more biologically predominant. Several conformational B-cell epitope prediction methods have recently been published, but their predictive performances are weak. Here, we present a review of the latest computational methods and assess their performances on a diverse test set of 29 non-redundant unbound antigen structures. Our results demonstrate that ISPIPab outperformed all other methods. Finally, we suggest new strategies and opportu-nities to improve computational predictions of conformational B-cell epitopes.

Lamin A, B and C, the nuclear intermediate-filament proteins, play a role in epigenetic regulation. While Lamin B is expressed in all nucleated cells studied, Lamin A/C are transcribed in most somatic cell types except mature B lymphocytes. Since Epstein-Barr virus (EBV), a human gammaherpesvirus, is associated with tumorigenic processes and is known to alter the epigenotype of its host cells, we studied the expression of the LMNA gene and its epigenetic marks in EBV-carrying human lymphoid cell lines. We observed a high lamin A/C mRNA and protein expression in EBV-immortalized lymphoblastoid cell lines (LCLs) and in group III Burkitt lymphoma (BL) lines where hypomethylated first exons were observed with activating histone marks. In most cell lines with low promoter activity a highly methylated first exon could be detected. Our data showed that methylation of the first exon of LMNA was associated with the downregulation of LMNA expression whereas euchromatic histone marks were enriched at active LMNA promoters in EBV-immortalized LCLs. These data suggest a role for viral latency products to activate LMNAp in EBV-infected latency type III B cells in vitro. Expression of lamin A/C may contribute to the establishment of activated B cell phenotype that needs further explorations.

Chimeric Antigen Receptor (CAR) T-cell therapy has demonstrated high rates of response in recurrent B-cell Acute Lymphoblastic Leukemia in children and young adults. Despite this success, a fraction of patients experience relapse after treatment. Relapse is often preceded by recovery of healthy B cells, which suggests loss or dysfunction of CAR T cells in bone marrow. This site is harder to access, and thus is not monitored as frequently as peripheral blood. Understanding the interplay between B cells, leukemic cells and CAR T cells in bone marrow is paramount in ascertaining the causes of lack of response. In this paper, we put forward a mathematical model representing the interaction between constantly renewing B cells, CAR T cells and leukemic cells in the bone marrow. Our model accounts for the maturation dynamics of B cells and incorporates effector and memory CAR T cells. The model provides a plausible description of the dynamics of the various cellular compartments in bone marrow after CAR T infusion. After exploration of the parameter space, we found that the dynamics of CAR T product and disease were independent of the dose injected, initial B-cell load and tumor burden. We also show theoretically the importance of CAR T product attributes in determining therapy outcome, and have studied a variety of possible response scenarios, including second dosage schemes. We conclude by setting out ideas for the refinement of the model.

Non-coding RNAs (ncRNAs) comprise a diverse class of non-protein coding transcripts that regulate critical cellular processes associated with cancer. Advances in RNA-sequencing (RNA-Seq) have led to the characterization of non-coding RNA expression across different types of human cancers. Through comprehensive RNA-Seq profiling, a growing number of studies demonstrate that ncRNAs, including long non-coding RNA (lncRNAs) and microRNAs (miRNA), play central roles in progenitor B-cell Acute Lymphoblastic Leukemia (B-ALL) pathogenesis. Furthermore, due to their central roles in cellular homeostasis and their potential as biomarkers, the study of ncRNAs continues to provide new insight into the molecular mechanisms of B-ALL. This article reviews the ncRNA signatures reported for all B-ALL subtypes, focusing on technological developments in transcriptome profiling and recently discovered examples of ncRNAs with biologic and therapeutic relevance in B-ALL.

B-cell lymphomas (BCL) is the most frequent hematological cancer in dogs. Treatment typically consists of chemotherapy, with CHOP-based protocols. However, outcome remains generally poor, urging the exploration of new therapeutic strategies with a targeted approach. Myc tran-scription factor plays a crucial role in regulating cellular processes and its dysregulation is im-plicated in numerous human and canine malignancies, including canine BCL (cBCL). This study aims to evaluate the efficacy of indirectly inhibiting Myc in cBCL using BI2536 and MZ1 com-pounds in two in vitro models (CLBL-1 and KLR-1201). Both BI2536 and MZ1, alone and com-bined, affected cell viability in a significant concentration and time-dependent manner. Western Blot revealed an upregulation of PLK1 expression in both cell lines upon treatment with BI2536, in association with a reduction in c-Myc protein levels. Conversely, MZ1 led to a decrease in its primary target, BRD4, along with a reduction in c-Myc. Furthermore, BI2536, both alone and in combination with MZ1, induced larger transcriptomic changes in cells compared to MZ1 alone, primarily affecting MYC target genes and genes involved in cell cycle regulation. These data un-derscore the potential role of Myc as therapeutic target in cBCL, providing a novel approach to indirectly modulate this molecule.

B lymphocyte development has two DNA recombination processes: V(D)J recombination of the immunoglobulin (Igh) gene variable region and class switching of the Igh constant regions from IgM to IgG, IgA, or IgE. V(D)J recombination is required for successful maturation of B cells from pro-B to pre-B to immature-B and then to mature B cells in the bone marrow. CSR occurs outside of the bone marrow when mature B cells migrate to peripheral lymphoid organs, such as spleen and lymph nodes. Both V(D)J recombination and CSR depend on an “open chromatin” state that makes DNA accessible to specific enzymes, recombination activating gene (RAG), and activation-induced cytidine deaminase (AID). Acetyltransferases GCN5 and PCAF possess redundant functions acetylating histone H3 lysine 9 (H3K9). Here, we generated a mouse model that lacks both GCN5 and PCAF in B cells. We found that double-deficient mice possess low levels of mature B cells in the bone marrow and peripheral organs, an accumulation of pro-B cells in bone marrow, and reduced CSR levels. We conclude that both GCN5 and PCAF are required for B cell development in vivo.

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.

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.

We analyze the humoral and B-cell mediated immunogenic response induced by GP5 lineal epitopes from porcine reproductive and respiratory syndrome virus (PRRSV) to explore the role of this protein in the protective response. For inoculation, pigs aged twenty-one days were allocated into six groups (seven pigs per group): control (PBS), vehicle (carrier), vaccinated (Ingelvac-PRRSV, MLV®), non-vaccinated and naturally infected, GP5-B and GP5-B3. Subsequently blood samples were collected and analyzed. Cytokine were measured by ProcartaPlex kit. Peptide-specific IgGs and cross-reactivity against peptides were analyzed by ELISA and B-cell subpopulations were analyzed by flow cytometry. At 2 days post-immunization (dpi), the GP5-B3 peptide increased the serum concentrations of cytokines associated to activate adaptive cellular immunity (IL-1β and IL-12). The concentration of IgGs anti-GP5-B increased in both cases at 21 and 42 dpi, while IgGs anti-GP5-B3 increased at 21 dpi and remained at the same level until 42 dpi. Also, antibody-forming/Plasma B cells (CD2+/CD21-) and primed B cells (CD2-/CD21+) from immunized pigs showed an increase at 42 dpi. Conversely the naïve B cells from immunized pigs decreased compared with the controls. Importantly, Both GP5-B and GP5-B3 peptides exhibited immunoreactivity against serum antibodies from vaccinated group, as well as non-vaccinated and naturally infected group. In conclusion, GP5-B and GP5-B3 peptides elicited immunogenicity mediated by antigen specific IgG´s and B-cell activation.

Growing evidence has revealed the implication of germline variation in cancer predisposition and prognostication. Here, we describe an analysis of putatively disruptive rare variants across the genomes of 726 patients with B-cell lymphoid neoplasms. We discovered a significant enrichment of 26 genes in germline protein truncating variants (PTVs), affecting cell signaling (MET, JAK2, ANGPT2), energy metabolism (ACO1) and nucleic acid metabolism and repair pathways (NT5E, DCK). Interestingly, some of these variants were restricted to either chronic lymphocytic leukemia (CLL) (i.e., ANGPT2 and AKR1C3) or B-cell lymphoma cases (PNMT, TPT1 and IGHMBP2). Additionally, we detected 1,675 likely disrupting variants in genes associated with cancer, of which 44.75% were novel events and 7.88% were PTVs. Among these, the most frequently affected genes were ATM, BIRC6, CLTCL1A and TSC2. Homozygous or compound heterozygous variants were detected in 28 cases; and coexisting somatic events were observed in 17 patients, some of which affected key lymphoma drivers such as ATM, KMT2D and MYC. Finally, we observed that variants in the helicase gene WRN were independently associated with shorter survival in CLL. Our study results support an important role for rare germline variation in the pathogenesis, clinical presentation and disease outcome of B-cell lymphoid neoplasms.

Background: The intrauterine and early extrauterine development represents a “window of opportunity” in the immunological development. The underlying mechanisms are still poorly understood. The aim of this study was to provide reference values B cell subpopulations in cord blood of term newborns, juveniles and in adults to find the spectrum of their physiological age-related variation. Methods: In this study, we used flow cytometry to evaluate human B lymphocytes and subpopulations in cord blood (n = 10), in peripheral blood from healthy juveniles aged 1 to 17 years (n=20) and from donors aged 24 to 62 years (n = 10). Results: Our findings showed increasing frequencies of IgM memory B cells, class-switched memory B cells, marginal zone B cells and plasmablasts, from cord blood to peripheral blood of juveniles and adults. In con-trast, the percentage of naïve B cells was higher in newborns than in juveniles and adults. The frequencies of were similar in cord blood and peripheral blood of adults. Interestingly, transitional B cells frequencies were similar in cord blood and adults but significantly lower in juveniles. Conclusions: The frequencies of circulating B cell subpopulation are subject to considerable changes during on-togeny, reflecting overlying effects of maturation and of the acquisition of an adaptive immune memory.

The BAFF-APRIL system is crucial for the pathogenesis of systemic lupus erythematosus (SLE) by promoting B cell survival, differentiation and the maintenance of humoral autoimmunity. Here, we investigated the relationship of BCMA expression on B cell subsets with its ligands BAFF and APRIL, together with soluble BCMA, and with clinical and serologic variables in a cohort of 100 SLE patients (86 under conventional and 14 under belimumab therapy) and 30 healthy controls (HC) using multicolor flow cytometry and ELISA. We found that BCMA expression in SLE patients was significantly increased on all B cell subsets compared to HCs, with all examined components of the BAFF-APRIL system being upregulated. BCMA expression was significantly increased on switched and unswitched memory B cells compared to naïve B cells, both in HCs and SLE. BCMA expression on B cells correlated with plasmablast frequencies, serum anti-dsDNA antibodies and complement consumption, while soluble BCMA correlated with plasmablast frequency, highlighting its potential as clinical biomarker. Belimumab treatment significantly reduced BCMA expression on most B cell subsets and soluble TACI, and contributes to the inhibition of almost the entire BAFF-APRIL system and restoration of B cell homeostasis. These results provide insights into the complex dysregulation of the BAFF-APRIL system in SLE and highlight the therapeutic potential of targeting its components, particularly BCMA, in addition to its use as biomarker for disease activity.

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.

Diffuse large B cell lymphoma (DLBCL), the most frequent type of non-Hodgkin lymphoma in adulthood, remains challenging clinical issues. Despite enhanced remission rates can be achieved, there are one-third of patients who will not respond to current treatment or will relapse with resistant disease, necessitating ongoing efforts on effective treatment strategies and agents. The vacuole H+-ATPase inhibitor bafilomycin A1 is broadly used to block late stage of autophagy flux at high concentration. In this study, we show that, to our surprise, bafilomycin A1 effectively inhibited and killed DLBCL cells at nanomolar concentrations (5nM). Bafilomycin A1 targeted cell cycle regulators cyclin D1 and cyclin E2 to induce cell cycle arrest in G0/G1 phase. Meanwhile, it induced caspase-dependent apoptosis with concomitant cleaved caspase-3 and Parp. Furthermore, we found that bafilomycin A1 inhibited autophagy flux at both early and late stages of the autophagy flux through activating ERK and mammalian target of rapamycin signaling, as well as by inhibiting the degradation of autolysosomes. We speculated that bafilomycin A1 as autophagy inhibitor might enhance the effect of DLBCL chemotherapeutic drug rituximab. Accordingly, our results provided evidence that the combination of bafilomycin A1 with rituximab enhanced the inhibition of DLBCL cells notably. Taken together, our data suggest that bafilomycin A1 may be a promising candidate drug in the therapy of diffuse large B cell lymphoma.

Acidic ostreolysin A/pleurotolysin B (OlyA/PlyB, formerly known as ostreolysin (Oly), and basic 20 kDa equinatoxins (EqTs) are cytolytic proteins isolated from the edible mushroom Pleurotus ostreatus and the sea anemone Actinia equina, respectively. Both toxins, although from different sources, share many similar biological activities: (i) colloid-osmotic shock by forming pores in cellular and artificial membranes enriched in cholesterol and sphingomyelin; (ii) increased vascular endothelial wall permeability in vivo and perivascular oedema; (iii) dose-dependent contraction of coronary vessels; (iv) haemolysis with pronounced hyperkalaemia in vivo; (v) bradycardia, myocardial ischemia and ventricular extrasystoles accompanied by progressive fall of arterial blood pressure and respiratory arrest in rodents. Both types of toxins are haemolytic within nanomolar range concentrations, and it seems that hyperkalaemia plays an important role in toxin cardiotoxicity. However, it was observed that the haemolytically more active EqT III is less toxic than EqT I, the most toxic and least haemolytic EqT. In mice, EqT II is more than 30 times more toxic than OlyA/PlyB when applied intravenously. These observations imply that haemolysis with hyperkalaemia is not the sole cause of the lethal activity of both toxins. Additional mechanisms responsible for lethal action of the two toxins are direct effects on heart, coronary vasoconstriction and related myocardial hypoxia. In this review, we appraise the pathophysiological mechanisms related to the chemical structure of OlyA/PlyB and EqTs, as well as their toxicity.

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

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.

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

IQGAP1 is a multi-functional scaffold protein. However, its role in B cell development and function is not known. Here, we demonstrate Iqgap1mice contained significantly increased numbers of B220+ B, B220+IgM pro/pre-B, and B220+IgM+ immature-B cells in the bone marrow. Here, we show IQGAP1 as the essential scaffold that regulates early B cell development and function. Iqgap1mice contained significantly increased numbers of B220+ B, B220+IgM pro/pre-B, and B220+IgM+ immature-B cells in the bone marrow. New-forming and follicular B cell numbers were increased, while the marginal zone B cell numbers were significantly reduced in the spleen of the Iqgap1mice. Lack of IQGAP1 reduced T-dependent and T-independent humoral responses. Mechanistically, the lack of IQGAP1 considerably decreased the phosphorylation of Mek1/2, Erk1/2, and Jnk1/2. B cells from Iqgap1mice failed to suppress IL-7R-mediated activation of Stat5a/b, an essential step for cell-cycle exit and initiate light-chain recombination, leading to a reduction in RS rearrangement frequency. Lack of IQGAP1 resulted in a significant reduction of IRF4 and IRF8 in BM B cells. Our study provides the first evidence that IQGAP1-based signalosome is essential for the development and functions of B cells.

Treating relapsed and refractory diffuse large B-cell lymphoma is still challenging for clinicians, but the available CAR-T and bispecific antibodies revolutionized therapy. Autologous stem cell transplantation was the most effective treatment modality previously. The authors report data from a single center over ten years. The retrospective study included 116 patients. There were 53 relapsed, 39 primary refractory cases, 19 had CNS involvement, and 5 received primary consolidation transplants. The median duration of follow-up was 46 months. The median event-free survival was 75 months, and the median overall survival was 105 months for all cases. Five-year overall survival was 59%, and event-free survival was 54%. Pretreatment prognostic factors at diagnosis had no effect on the outcome of transplantation. The authors found no difference between survival in relapsed or refractory cases, and the number of salvage lines or the germinal center / activated B-cell type also did not influence the results. Complete metabolic response before transplant confirmed by 18FDG PET/CT strongly affected survival. The pretransplant creatinine and CRP levels significantly influenced the long-term outcome. The number of stem cells infused did not affect survival, but engraftment within nine days did result in better survival. These data support the finding that the response to salvage therapy did select a better prognostic group who may still benefit from autologous transplantation.

Dengue virus is a global health problem most prevalent in tropical and subtropical regions. However, after the approval of two vaccines, Dengvaxia, TV003/TV005 of Takeda, for its prevention, problems were reported, like enhanced risks of infection or less efficiency of protection. Since then, more struggles have been in demand for the development of better vaccines. Here, we conducted a new design through an in-silico strategy. Initially, epitopes were chosen based on their antigenicity, immunogenicity, and binding affinity with MHC molecule, while excluded with allergenicity, toxicity and potential risk of antibody dependent enhancement. Subsequently, a core antigen was constructed with selected epitopes and linked with distinct adjuvant proteins to achieve three candidate vaccines, PSDV-1~3. PSDV-2 was chosen for further validation based on their advantage in physicochemical and structural properties. With a panel of simulations, this artificial protein showed tight binding with pattern recognition receptors, good stability, robust immune induction, and ultimately was confirmed as a high quality vaccine candidate. The plasmid for its recombinant expression was then designed accordingly. With our new design, one more choice was obtained for the effective protection from Dengue virus. Further experimental validations are still require to confirm it protection capacity and safety.

Primary cutaneous B-cell lymphomas (PCBCLs) are B-cell lymphomas that can occur in the skin without evidence of extracutaneous involvement. The 2005 WHO/EORTC classification of cutaneous lymphomas and its 2018 update have distinguished three main categories based on clinicopathological, immunohistochemical and genetic characteristics: primary cutaneous marginal zone lymphoma (PCMZL), primary cutaneous follicle centre lymphoma (PCFCL), and primary cutaneous diffuse large B-cell lymphoma, leg type (PCDLBCL-LT). PCMZL and PCFCL are clinically indolent, while PCDLBCL-LT is an aggressive lymphoma. Due to its low incidence and lack of prospective studies, it is difficult to establish a standard treatment for each subgroup. The objective of our study was to describe the clinical and pathological characteristics of 103 patients with cutaneous B-cell lymphoma from 12 centres belonging to the Spanish Lymphoma Oncology Group. The median age was 53 years (40-65). According to skin extension, 62% had single site lymphoma, 17% had regional lymphoma and 20% had multifocal lymphoma. Histology: 66% had PCMZL, 26% had PCFCL, and 8% had PCDLBCL-LT. Twenty-three percent of the patients were treated exclusively with surgery, 26% with radiotherapy only, 21% with surgery plus radiotherapy, 10% with polychemotherapy, and 5% with rituximab monotherapy. Overall, 96% of patients achieved a complete response, and 44% subsequently relapsed, most of them relapsing either locally or regionally. The 10-year OS was 94.5% for the entire cohort, 98% for the PCMZL cohort, 95% for the PCFCL cohort and 85.7% for the PCDLBCL-LT cohort. Our data are comparable to those of other published series, except for the high frequency of PCMZL. The expected heterogeneity in therapeutic management has been observed.

Fluorescent bioprobes are invaluable tools for visualizing live cells and deciphering complex biological processes by targeting intracellular biomarkers without disrupting cellular functions. In addition to protein-binding concepts, fluorescent probes utilize various mechanisms, including membrane, metabolism, and gating-oriented strategies. This study introduces a novel fluorescent mechanism distinct from existing ways. Here, we developed a B-cell selective probe, CDrB, with unique transport mechanisms. Through SLC-CRISPRa screening, we identified two transporters, SLCO1B3 and SLC25A41, by sorting out populations exhibiting higher and lower fluorescence intensities, respectively, demonstrating contrasting activities. We confirmed that SLCO1B3, with comparable expression levels in T and B cells, facilitates the transport of CDrB into cells, while SLC25A41, overexpressed in T lymphocytes, actively exports CDrB. The observation suggests that SLC25A41 plays a crucial role in discriminating between T and B lymphocytes. Furthermore, it reveals the potential for reversible localization of SLC25A41 to demonstrate its distinct activity. This study is the first report to unveil a novel strategy of SLC by exporting the probe. We anticipate that this research will open up new avenues for developing fluorescent probes.

Diffuse large B cell lymphoma (DLBCL) is curable with chemoimmunotherapy in ~65% of patients. One of the hallmarks of the pathogenesis and resistance to therapy in DLBCL is inhibition of apoptosis, which allows malignant cells to survive and acquire further alterations. Inhibition of apoptosis can be the result of genetic events inhibiting the intrinsic or extrinsic apoptotic pathways, as well as their modulators, such as the inhibitor of apoptosis proteins, P53, and components of the NF-kB pathway. Mechanisms of dysregulation include upregulation of anti-apoptotic proteins and downregulation of pro-apoptotic proteins via point mutations, amplifications, deletions, translocations, and influences of other proteins. Understanding the factors contributing to resistance to apoptosis in DLBCL is crucial in order to be able to develop targeted therapies that could improve outcomes by restoring apoptosis in malignant cells. This review describes the genetic events inhibiting apoptosis in DLBCL, provides a perspective of their interactions in lymphomagenesis, and discuss their implication for the future of DLBCL therapy.

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.

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.

Despite successful vaccination efforts, the emergence of new SARS-CoV-2 variants poses ongoing challenges to control COVID-19. Understanding humoral responses concerning SARS-CoV-2 infections and their impact is crucial for developing future vaccines that are effective worldwide. Here, we identified 41 immunodominant linear IgG B-cell epitopes in its Spike glycoprotein with a SPOT synthesis peptide array probed with a pool of serum from hospitalized COVID-19 patients. Bioinformatics showed a restricted set of epitopes unique to SARS-CoV-2 compared to other coronavirus family members. Potential crosstalk was also detected with Dengue virus (DENV), confirmed by screening individuals infected with DENV before the COVID-19 pandemic in a commercial ELISA assay for anti-SARS-CoV-2 antibodies. Higher reactivity indices were often measured in individuals with a pre-pandemic dengue infection than those with COVID-19. A high-resolution evaluation of antibody reactivity against peptides representing epitopes in the spike protein identified ten sequences in the NTD, RBD, and S2 domains. Functionally, antibody-dependent enhancement (ADE) in SARS-CoV-2 infection of monocytes was observed with pre-pandemic dengue-positive sera. A significant increase in viral load was measured compared to controls, with no detectable neutralization or considerable cell death, suggesting its role in viral entry. This study highlights the importance of identifying the epitopes generated during the humoral response to a pathogenic infection to understand the potential interplay of previous and future conditions on disease. Vaccine development and optimization strategies should be mindful of the potential for A.D.E. that could differ geographically due to endemic biological risks.

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.

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

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

Background: Cord blood represents a link between intrauterine and early extrauterine development. Cord blood cells map an important time frame in human immune imprinting processes. It is unknown whether sex of the newborn affects the lymphocyte subpopulations in cord blood. Methods: 9 B and 21 T cell subpopulations were characterized by flow cytometry in human cord blood from 16 male and 21 female newborns, respectively. Results: Except for marginal zone B cells and transitional B cells, B cell count in all subsets was higher in cord blood of male newborns than in female newborns. Frequency of naive thymus negative Th cells was significantly higher in male cord blood whereas the remaining T cell subpopulations showed a higher count in cord blood of female newborns. Conclusion: Our study is the first revealing sex differences in B and T cell subpopulations of human cord blood. These results indicate that sex might have a higher impact for the developing immune system urging the need to expand research in this area.

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

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

Coronavirus disease (COVID-19) is a new discovered strain where WHO officially declares the disease as COVID-19 while the virus responsible for it called Severe Acute Respiratory Syndrome Coronavirus 2 or SARS-CoV-2. The incubation period of this disease is between 14 days. Ordinary clinical symptoms that reported around the world include fever, cough, fatigue, diarrhoea and vomiting as well as asymptomatic for certain people. Infection is spread mainly through broad droplets. In early March 2020, WHO again has announced that COVID-19 is a pandemic with currently no specific treatment. The potential use of SARS-COV-2 proteome as a vaccine candidate by analysing through B-cell and T-cell antigenicity by using a immunoinformatics approach as a vaccine development early stage. In this study, we used consensus sequence for SARS-COV-2 proteome that was retrieved from NCBI database. VaxiJen 2.0 was mainly used to identify the antigenic property of SARS-COV-2 proteins. IEDB then used to analyse the B-cell epitope, the presence of T cell immunogenic epitope in SARS-COV-2 proteins was obtained by using compromise method of MHC class I and II tools that accessible respectively using ProPred-1 server and MHC II Binding Prediction in IEDB database. The best epitopes of B and T-cell epitopes were predicted with high antigencity and the information is disseminated through web-based database resource (https://covid-19.omicstutorials.com/epitopes/). This study will be useful to find a new epitope-based candidate for SARS-COV-2. However, further study needs to be done for the next stages of vaccine development.

Soluble CD163 (sCD163) functions as a scavenger receptor for haptoglobin-hemoglobin complexes, and is mostly expressed by monocytes and macrophages. The level of soluble CD163 has been used to determine macrophage activation. Our goal was to determine whether the loading of M2 CD163 positive tumor-associated macrophages (TAMs) through the secretion of sCD163 affects overall survival in patients with DLBCL and eventually discriminates subgroups of patients with different prognosis. sCD163 levels were measured in 40 frozen serum samples from patients diagnosed with DLBCL and 30 healthy individuals (HI) using an enzyme-linked immunosorbent assay (ELISA). Statistical analyses were performed using SPSS version 28. The results showed that patients who achieved complete response after standard-of-care immuno-chemotherapy and were alive and disease-free after 12 months of follow-up, but had elevated sCD163 levels (above median) at diagnosis, presented a significantly worse overall survival compared to those with initial serum sCD163 levels below median (p=0.03). Consequently, serum sCD163 level in DLBCL patients may constitute a marker of long-term response to chemo-immunotherapy.

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) 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.

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

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

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

During the last few years, the world witnessed one of the worst calamities to humankind- the COVID-19 pandemic. We also witnessed the development of vaccines at an unprecedented pace against the SARS-CoV-2- the causative agent. India was among the hard-hit countries by COVID-19, developed its indigenous vaccine and implemented vaccines developed in other countries as well. Initially, the antibody level and the neutralizing antibody titer against the pathogen were considered as the correlates of immune protection from the disease. However, the long-term protection from the pathogen was provided by the immune memory cells viz. T and B memory cells and their ability to efficiently make recall responses. In this regard, globally the research studies focused mainly on the mRNA-based vaccines. The studies on immune memory response, particularly- the B cell memory response bestowed by the vaccines given to Indians is relatively obscure. We studied the level of RBD specific memory B cells in the peripheral circulation of the study participants and the ability of B cells to secrete antigen-specific antibodies among Indians vaccinated with Covaxin (BBV152), Covishield (AZD1222), Corbevax (BECOV2D) and Sputnik Light (Gam-COVID-Vac) as well as unvaccinated individuals. Our study revealed that Corbevax and Sputnik Light conferred better antibody-secreting cell (ASC) responses.

The past few years have brought substantial progress toward understanding how human cytomegalovirus (HCMV) enters the remarkably wide spectrum of cell types and tissues that the virus is observed to infect. Neuropilin-2 and platelet-derived growth factor receptor alpha (PDGFRα) were identified as receptors, respectively, for the trimeric and pentameric glycoprotein H / glycoprotein L (gH/gL) complexes that in large part govern HCMV cell tropism, while CD90 and CD147 were also found to play roles during entry. X-ray crystal structures for the proximal viral fusogen, glycoprotein B (gB), and for the pentameric gH/gL complex (pentamer) were solved. A novel virion gH complex consisting of gH bound to UL116 instead of gL was described, and findings supporting the existence of a stable complex between gH/gL and gB were reported. Additional work indicates that the pentamer promotes a mode of cell-associated spread that resists antibody neutralization, as opposed to the trimeric gH/gL complex (trimer), which appears to be broadly required for the infectivity of cell-free virions. Finally, viral factors such as UL148 and US16 were identified that can influence the incorporation of the alternative gH/gL complexes into virions. We will review these advances and their implications for understanding HCMV entry and cell tropism.

The adoption of ADS-B in Latin America has been gradual but steady. Some countries, such as Brazil, Chile and Mexico, have made significant progress in the implementation of this system, while others are still in the early stages. It should be noted that the implementation of ADS-B is used in both military and civilian environments. For this reason, this research aims to provide information on the different characteristics that make up the surveillance systems. However, there are fundamental factors to promote the adaptation of ADS-B in Latin America, since they reduce the risk of collisions and air accidents by providing accurate and real-time information on the position and altitude of aircraft. On the other hand, it allows optimizing flight routes and reducing waiting time on the ground, which translates into fuel and cost savings for airlines. ADS-B increases the number of aircraft that can safely operate in the same airspace, which is especially important in regions with growing air traffic. ADS-B adoption in Latin America is expected to continue to grow in the coming years. The drivers for ADS-B adoption remain in place, and governments in the region are taking steps to accelerate its implementation.

We conducted a retrospective analysis of the immunohistochemical (IHC) staining GRP94, an ER stress protein on large B-cell lymphoma (LBCL) cells, intracellular p53, and 15 factors involved in the metabolism of CHOP regimen :AKR1C3 (HO-metabolism), CYP3A4 (CHOP-metabolism) and HO efflux pumps (MDR1, MRP1). The study subjects were 42 patients with LBCL at our hospital. IHC staining using antibodies against the 17 factors. The odds ratios by logistic regression analysis using a dichotomous variable of CR, non-CR/relapse were statistically significant: for MDR1, MRP1, and AKR1C3. The overall survival (OS) after R-CHOP was compared by the log-rank test. The four groups showed that Very good (5-year OS, 100%) consisted of 4 patients showed negative IHC staining for both GRP94 and CYP3A4. Very poor (1-year OS, 0%), consisted of 3 patients who showed positive results of IHC for both GRP94 and CYP3A4. The remaining 35 patients comprised two subgroups: Good (5-year OS 60-80%.): 15 patients who showed negative staining for both MDR1 and AKR1C3, Poor: 5-year OS, 10-20%) :20 patients who showed positive staining for either MDR, AKR1C3,,MRP1 or p53. The Histological Prognostic Index (HPI) (The four groups: Very poor, Poor, Good, and Very pood) is a breakthrough method for stratifying patients based on factors involved in the development of treatment resistance.

Introduction: Known for its persistent blood-feeding behavior from dawn to dusk, Aedes albopictus is recognized as one of the most dangerous mosquito species due to its role as a vector for diseases such as dengue. Studies have demonstrated that Aedes albopictus thrives in micro-breeding sites predominantly located on private properties, including abandoned containers and manholes used for rainwater and irrigation. This study investigates an innovative methodology, the TombiniNet, to mitigate the proliferation of Aedes albopictus by engaging citizens in the active management of micro-breeding sites on their properties. Materials and Methods: The study was conducted in Alessandria, a city with approximately 100,000 inhabitants, focusing on a sample of 200 houses and a population of about 5,000 people. Researchers conducted a comprehensive survey and analysis of micro-breeding sites for Aedes albopictus on both private and communal properties. The larval control measures were conducted from April to October, aligning with the peak mosquito breeding season. The study's sample included 51% of houses that allowed researchers access, and within these, 81% had Aedes albopictus larvae, often found in diverse water Containers holes of which basically manholes on villa garden floors. For monitoring the adult populations were used ovitraps that were not placed in private homes but in public areas to monitor and control the mosquito population. Results: The study identified that up to 70% of micro-breeding sites for Aedes albopictus in northern Alessandria were located on private properties. Citizen participation was critical to the success of the intervention, with a marked decrease in the number of adult tiger mosquitoes observed in areas where residents actively managed breeding sites using the TombiniNet. The TombiniNet was particularly effective in private areas, as it could be regularly maintained by residents, preventing debris accumulation that could hinder drainage. Discussion: The findings highlight the importance of engaging citizens in mosquito control programs to effectively manage Aedes albopictus populations in urban areas. The TombiniNet intervention demonstrated that a simple, cost-effective solution could significantly reduce mosquito breeding sites on private properties. By addressing both communal and private breeding sites, a comprehensive and sustainable approach to mosquito management can be achieved, thereby reducing the risk of disease transmission. Future studies should focus on long-term monitoring and the development of additional innovative solutions to enhance citizen participation and control measures. The study's success also pointed out the limitations of applying such interventions in public areas where debris could impede the net's effectiveness.

We present atomic structures and nonequilbrium synthesis of new class of materials, where the basic structural unit is a diamond tetrahedron. When units of one, two, and three tetrahedra are randomly packed, we create distinct phases of amorphous Q-carbon. Four tetrahedra in two adjacent layers lead to crystalline diamond lattice, which has four missing tetrahedra alternately. When these four missing tetrahedra are filled, we create subunit cell of crystalline Q-diamond. Theoretical calculations show that superconducting transition temperature (Tc) in 50 atomic % B-doped Q-diamond can reach near room temperature at ambient pressures. This is consistent with our earlier results using low-loss EELS measurements in 50 atomic % B-doped Q-carbon, which had mostly amorphous QB3 phase mixed with some crystalline Q-diamond phase. These EELS results showed that the Tc for these samples was in between 90K and 300K. Theoretical calculations of density of states, Eliashberg function, electron-phonon interaction parameter, and root-mean-square and logarithmic average of frequency in crystalline Q-diamond show Tc in the range of 268K to 300K, which is in a complete agreement with our EELS results in QB3.

BACKGROUND: Chronic hepatitis B infected with Hepatitis B virus remains a major health concern worldwide. Despite standard interferon-α and nucleotide analogues have been shown to reduce the deterioration of liver disease among chronic hepatitis B patients, covalently closed circular DNA was still difficult to eradicate. METHODS: A literature search of Pubmed and Web of science was performed with the following key words: ‘CRISPR’, ‘CRISPR/Cas9’, ‘hepatitis B’, ‘HBV’, ‘chronic hepatitis B’ and ‘HBV cccDNA’. The information about CRISPR/Cas9 for the treatment of HBV cccDNA or hepatitis B was reviewed. RESULTS: CRISPR/Cas9 could treat hepatitis B through suppressing or clearing HBV cccDNA with different gRNAs. CONCLUSION: With the emergence of CRISPR/Cas9 (the RNA-guided clustered regulatory interspaced short palindromic repeats, CRISPR) editing technology, clearance of hepatitis B virus and better prevention of liver carcinoma seemed to be possible.

The use of chimeric antigen receptors (CAR-T cells) for the treatment of patients with malignant haematological diseases has become a well-established application, for conditions such as refractory or relapsed B cell acute lymphoblastic leukaemia (B-ALL), B cell lymphomas (BCL), and multiple myeloma (MM). Nearly 35,000 patients have received autologous CAR-T cells for the treatment of these conditions only in the USA. Since their approval by the Food and Drug Administration (FDA) in 2017, over 1200 clinical trials have been initiated globally and there are at least 10 different CAR-T cells with approval by different regulatory agencies around the globe. In the USA the Food and Drug Administration (FDA) has approved 6 commercial CAR-T cells that are widely distributed worldwide. At the time of this writing, several clinical trials have been performed in patients with solid tumours such as glioblastoma, renal and pancreatic cancer, as well as in patients with autoimmune conditions such as systemic lupus erythematosus (SLE), idiopathic inflammatory myositis (IIM), and systemic sclerosis (SS). There are also several studies showing the potential benefit of CAR-T cells for other non-malignant diseases such as asthma and even fungal infections. In this review, without pretending to cover all the current areas of treatments with CAR-T cells, we offer a brief summary of some of the most relevant aspects of the use of CAR-T cells for some of these conditions.

B-cell lymphoid malignancies is a heterogeneous group of hematologic cancers, where Bruton's tyrosine kinase (BTK) inhibitors have received FDA approval for several subtypes. The first-in-class covalent BTK inhibitor, ibrutinib, binds to the C481 amino acid residue to block the BTK enzyme and prevent the downstream signaling. Resistance to covalent BTK inhibitors can occur through mutations at the BTK binding site (C481S) but also other BTK sites and the phospholipase C gamma 2 (PLCγ2) resulting in downstream signaling. To bypass the C481S mutation, non-covalent BTK inhibitors, such as pirtobrutinib, were developed and are active against both wild-type and the C481S mutation. In this review, we discuss the molecular and genetic mechanisms which contribute to acquisition of resistance to covalent and non-covalent BTK inhibitors. In addition, we discuss the new emerging class of BTK degraders, which utilize the evolution of proteolysis-targeting chimeras (PROTACs) to degrade the BTK protein and constitute an important avenue of overcoming resistance. The moving landscape of resistance to BTK inhibitors and the development of new therapeutic strategies highlight the ongoing advances, that are being made towards the pursue of cure of B-cell lymphoid malignancies.

New strategies for enhancing drug delivery to the blood–brain barrier (BBB) represents a major challenge in treating cerebral diseases. Nano-emulsion based nanocarriers represent an ideal candidate to improve drug delivery thanks to their versatility in functionalization and cargo protection. In this work, a paclitaxel loaded nano-emulsion has been firstly functionalized and stabilized with two layers constituted of chitosan and hyaluronic acid, and, secondly, the latter has been conjugated to the CRT peptide. CRT is a bioactive peptide that selectively recognizes bEnd.3 cells, model of the BBB, thanks to its interactions with transferrin (Tf) and its receptor (TfR). Cytotoxic results showed a higher uptake of CRT functionalized nano-emulsion 41.5 % more than the negative control, demonstrating the ability of this novel tool to be accumulated on the brain endothelium tissue. Thanks to these results, our approach can be fully generalizable to the design of multifunctional nanocarriers for delivery of therapeutic agents to the central nervous systems.

Hepatocellular carcinoma (HCC) is the most common primary malignant tumor of the liver and the third leading cause of cancer-related death worldwide. Liver transplantation (LT) is the best therapy for most patients with non-metastatic HCC. In recent years, the management of patients with HCC has changed considerably, thanks to the improvement of molecular biology knowledge and the introduction of immunotherapy. To date, systemic therapy is authorized in the Western world only in patients with advanced HCC. However, this therapy could lead not only to stabilize the tumour disease or improve survival but could display excellent response and lead to downstaging of the tumor that finally permits liver transplantation. There are increasing reports of patients that have performed liver transplantation after pretreatment with immune checkpoint inhibitors (ICIs). However, due to the intrinsic mechanism of ICIs to stimulate the immune response against tumors, they could also cause graft rejection. This review aims to evaluate the readiness and outcomes of liver transplantation in patients with advanced HCC who have previously undergone treatment with ICIs. It seeks to identify the challenges, risks, and benefits associated with this conversion therapy. The integration of ICIs into the treatment paradigm for advanced HCC necessitates a nuanced approach to liver transplantation. While early evidence supports the feasibility of LT following ICI therapy, there is an urgent need for standardized guidelines and more extensive longitudinal studies to optimize patient selection, timing, and post-transplant management.

The normative and safeguarding role of ethics and law in the development of biomedical science and technology, as well as their importance in promoting the progress of the industry, analyzed the key role of ethics and law in the field of biomedical science and technology, by restricting scientific research behavior, protecting the rights and safety of subjects, providing a solid guarantee for scientific research activities, and promoting the healthy development of biomedical science and technology. At the same time, the positive role of ethics and law in promoting international cooperation and exchange of biomedical science and technology is also discussed, which will inject strong impetus into the global development of biomedical science and technology. In addition, through case analysis, the paper demonstrates the key role of ethical review in the field of biomedical science and technology, as well as the importance of law in maintaining market order, protecting subjects' rights and interests, and fairness and justice. The successful practice of ethics and law in the development of biomedical science and technology is emphasized, which proves that following ethical principles and legal framework is the key factor to promote the progress of biomedical science and technology. This paper explores the important role of ethics and law in the development of biomedical science and technology, and provides valuable reference and guidance for practitioners in the industry. By following ethical principles and legal norms, we will jointly promote the prosperity and development of biomedical science and technology, and contribute to the common progress of human health.

Background: Occupational accidents contribute 46-65% of hepatitis B virus (HBV) infections among healthcare workers (HCWs). Vaccine against HBV infection offers protection of more than 90%. Despite availability of the vaccines in Tanzania, it’s uptake among HCWs in primary health facilities remains understudied. This study explored HBV vaccine uptake and associated factors among HCWs in rural and urban settings of north western Tanzania. Methodology: A cross-sectional analytical study was conducted between June and July in 2022 among HCW in Misungwi and Ilemela districts. Data were collected using a self-administered questionnaire and analyzed using IBM SPSS® version 25. Results: A total of 402 HCWs were recruited, their mean age was 34.9±7.77 years. Approximately half (54.7% (220/402) of HCWs had received at least one shot of HBV vaccine with only (18% (76/402) being fully vaccinated. Ilemela showed significantly higher uptake (χ2=23.64, df=1, p=0.00) of HBV vaccine as compared to their counterparts in Misungwi. Being male (aOR=2.38, 95% CI 1.28-4.45, p=0.006), working in urban (aOR=5.75, 95% CI 2.91-11.35, p=0.00) and employment duration of more than two years (aOR=3.58, 95%CI 1.19-10.74, p=0.023) were significantly associated with higher odds of HBV vaccination. Moreover, high perceived susceptibility to HBV infection (aOR=2.20, 95% CI1.02-4.75, p=0.044) and history of needle prick injuries (aOR=6.87, 95%CI 3.55-13.26, p=0.00) were also significantly associated with higher odds of HBV vaccination. Conclusion: There was low uptake of HBV vaccine among HCW in primary health facilities with a noteworthy difference between rural and urban settings.. Therefore, advocacy campaigns as well as resource mobilization towards promotion of HBV vaccination in primary health facilities are pivotal.

ABSTRACT. In this paper, we run for all INDIA mutations and variants a biomathematical numerical method for analysing mRNA nucleotides sequences based on UA/CG Fibonacci numbers proportions (Perez, 2021). In this study, we limit ourselves to the analysis of whole genomes, all coming from the mutations and variants of SARS-CoV2 sequenced in India in 2020 and 2021. We then demonstrate - both on actual genomes of patients and on variants combining the most frequent mutations to the SARS-CoV2 Wuhan genomes and then to the B.1.617 variant - that the numerical Fibonacci AU / CG metastructures increase considerably in all cases analyzed in ratios of up to 8 times. We can affirm that this property contributes to a greater stability and lifespan of messenger RNAs, therefore, possibly also to a greater INFECTUOSITY of these variant genomes. Out of a total of 108 genomes analyzed: - None ("NONE") of them contained a number of metastructures LOWER than those of the reference SARS-CoV2 Wuhan genome. - Eleven (11) among them contained the same number of metastructures as the reference genome. - 97 of them contained a GREATER number of metastructures than the reference genome, ie 89.81% of cases. The average increase in the number of metastructures for the 97 cases studied is 4.35 times the number of SARS-CoV2 UA/CG 17711 Fibonacci metastructures. Finally, we put a focus on B.1.617.2 crucial exponential growth Indian variant. Then, we demonstrate, by analyzing the main worldwide 19 variants, both at the level of spikes and of whole genomes, how and why these UA / CG metastuctures increase overall in the variants compared to the 2 reference strains SARS-CoV2 Wuhan and D614G.

The ongoing SARS-CoV-2 pandemic has raised concerns surrounding immunological protection against the virus, particularly for people with inborn errors of immunity (IEI). While COVID-19 vaccination induces robust antibody, memory B-cell, and T-cell responses in healthy individuals, how well vaccination protects people with IEI against infection and severe disease remains unclear – especially in the context of new viral variants and vaccine formulations – leading to anxiety, ongoing self-isolation, and repeated vaccination with limited evidence of increased efficacy. Whilst most people with IEI generate some level of cellular and/or humoral immunity to COVID-19 vaccination, the level of protection and durability of the response are unclear. Alongside vaccination, antibody-based therapeutics are aimed at limiting infection and severe disease in this cohort. Immunoglobulin replacement therapy (IgRT) provides passive immunity in antibody-deficient individuals. However, to successfully prevent SARS-CoV-2 infection, a sufficient number of neutralizing antibodies must be present in product. While antibodies against circulating variants are eventually present in IgRT products (both from natural infection and vaccination of the donors), evidence of their capacity to recognize new variants is limited. Furthermore, while antibody-based pre- and post-exposure prophylaxis can be effective, they are susceptible to decreased efficacy in the context of variant evolution. This review provides an in-depth overview of current knowledge about COVID-19 vaccine efficacy in IEIs, the efficacy of SARS-CoV-2-specific antibody products, and knowledge and technological advances required for continued protection of people with IEI.

Medical image segmentation is a critical step in various healthcare applications, aiding in diagnosis, treatment planning, and disease monitoring. In this study, we investigate the efficacy of a segmentation approach based on the 2D wavelet transform. Leveraging a dataset comprising 10 diverse medical images, we evaluate the performance of our segmentation method using three key metrics: accuracy, precision, and recall. Our findings demonstrate that the proposed approach enhances segmentation accuracy, offering promising results compared to existing methods. By harnessing the multi-resolution feature extraction capabilities of the 2D wavelet transform, our method achieves improved delineation of medical image structures, paving the way for more accurate and efficient healthcare interventions.

Chronic hepatitis B (CHB) infection and the Hepatitis B virus X protein (HBx) are major risk factors associated with hepatocellular carcinoma (HCC). In CHB infection, HBx induces mitochondrial dysfunction, exhaustion and impaired function in hepatocytes. Restoring hepatocyte health along with reduction in virus replication could be an ideal treatment for CHB. Thiourea derivatives are well known for their antiviral property though their effect on mitochondrial and/ or hepatocyte health remains obscure. This study focus on the repurposing of thiourea derivatives (DSA-00, DSA-02, and DSA-09) on hepatocyte replenishment. HepG2.2.15 cells were treated with thiourea derivatives, alongside Entecavir (ETV). The proteomics analysis showed both DSA-00 and ETV were enriched with proteins associated with antiviral responses. In addition, DSA-00 additionally showed increase in proteins linked to mitochondrial response. Whereas DSA-02 exhibited association with innate immune system and citric acid cycle and DSA-09 displayed pathways similar to DSA-00 and ETV. Treated groups exhibited enhanced bio-energetic and antiviral response as compared to the untreated group. FACS analysis revealed the restoration of exhausted hepatocytes by thiourea derivatives through targeting mitochondria. Our findings suggest that thiourea derivatives hold potential as a novel therapeutic agent that seems to restore mitochondrial health along with anti-viral response in CHB.

Centromeres, the chromosomal loci where spindle fibers attach during cell division to segregate chromosomes, are typically found within satellite arrays in plants and animals. Satellite arrays have been difficult to analyze because they comprise megabases of tandem head-to-tail highly repeated DNA sequences. Much evidence suggests that centromeres are epigenetically defined by the location of nucleosomes containing the centromere-specific histone H3 variant cenH3, independently of the DNA sequences where they are located; however, the reason that cenH3 nucleosomes are generally found on rapidly evolving satellite arrays has remained unclear. Recently, long read sequencing technology has clarified the structures of satellite arrays and sparked rethinking of how they evolve, while new experiments and analyses have helped bring both understanding and further speculation about the role these highly repeated sequences play in centromere identification.

Abstract: DNA fragmentation factors 40 and 45 (DFF40 and DFF45) and B-cell lymphoma 2 (Bcl-2) expression were evaluated in the normal human endometrium and myometrium. DFF40, DFF45, and Bcl-2 expression was assessed via immunohistochemistry in the proliferative, secretory, and atrophic endometrium and myometrium collected postmenopausally and premenopausally during the proliferative and secretory phases of the menstrual cycle. The endometrium showed significantly higher DFF40 and DFF45 expression than that in the uterine myometrium; compared to the stroma, endometrial glands showed the highest expression in pre- and postmenopausal specimens. Glandular expression of DFF45 was dependent on the menstrual cycle, reaching its highest level in the secretory endometrium. The glandular expression of DFF40 and DFF45 was significantly lower in postmenopausal specimens than that in premenopausal tissue. No cycle-dependent changes were reported for stromal or myometrial DFF40 or DFF45 expression. Compared to the endometrial stroma and myometrium, Bcl-2 showed the highest expression in the glandular proliferative endometrium and the lowest expression in the stromal secretory endometrium and myometrium during the secretory phase of the cycle. DFF45 and Bcl-2 showed menstrual cycle-dependent expression, which was limited to the glandular layer of the endometrium.

This study fabricated piezoelectric fibers of polyvinylidene fluoride (PVDF) with graphene using near-field electrospinning (NFES) technology. A uniform experimental design table U*7 (7^4 ) was applied, considering weight percentage (1-13 wt%), distance between needle and disk collector (2.1-3.9 mm), and applied voltage (14.5-17.5 kV). We optimized the parameters using electrical property measurements and the Kriging response surface method. Adding 13 wt% graphene significantly improved electrical conductivity, increasing from 17.7 μS/cm for pure PVDF to 187.5 μS/cm. The fiber diameter decreased from 21.4 μm in PVDF/1% graphene to 9.1 μm in PVDF/13% graphene. Adding 5 wt% graphene increased the β-phase content by 6.9%, reaching 65.4% compared to pure PVDF fibers. Material characteristics were investigated using scanning electron microscopy (SEM), Fourier-transform infrared spectroscopy (FTIR), X-ray diffraction analysis (XRD), contact angle measurements, and tensile testing. Optimal parameters included 3.47 wt% graphene, yielding 15.82 mV voltage at 5 Hz and 5 N force (2.04 times pure PVDF). Force testing showed a sensitivity (S) of 7.67493 log(mV/N). Fibers were attached to electrodes for piezoelectric sensor applications. Results affirmed enhanced electrical conductivity, piezoelectric performance, and mechanical strength. The optimized piezoelectric sensor could be applied to measure physiological signals, such as attaching it to the throat under different conditions to measure the output voltage. The force-to-voltage conversion facilitated subsequent analysis.

This study explores the potential of natural compounds, including Daidzin, Luteolin, and Silibinin, as inhibitors of human monoamine oxidase B (MAO-B) for the treatment of Parkinson's disease. Docking simulations were performed using Autodock Vina with Pyrx program to evaluate the binding affinities of these compounds with MAO-B. Results indicate that Daidzin, Luteolin, and Silibinin exhibit promising binding affinities with MAO-B, with Daidzin demonstrating the highest affinity. Toxicity parameters were further predicted using the PkCSM Server, confirming the low toxicity of these compounds. Overall, the findings suggest that Daidzin, Luteolin, and Silibinin have the potential to be effective and safe treatments for Parkinson's disease through their inhibition of MAO-B. Further experimental validation is warranted to support their therapeutic efficacy in clinical settings.

: (1) Background: Hepatitis B core antibodies (anti-HBc) are a marker of hepatitis B virus (HBV) exposure; hence a normal HBV serology profile is characterized by HBV surface antigen (HBsAg) and anti-HBc positivity. However atypical HBV serologies occur and we aimed to determine the prevalence of an atypical profile (HBsAg+/anti-HBc-) in a cohort of people with HIV-1 (PWH) in Botswana. (2) Methods: Plasma samples from an HIV-1 cohort in Botswana (2013-2018) were used. Samples were screened for HBsAg and anti-HBc. Next generation sequencing was done using the GridION platform. Wilcoxon rank-sum test and Chi-squared tests were used for comparison of continuous and categorical variables respectively. (3) Results: HBsAg+/anti-HBc- prevalence was 13.7% (95% CI 10.1 – 18.4) (36/263). HBsAg+/anti-HBc- participants were significantly younger (p&lt;0.001), female (p=0.02), ART naïve (p=0.04) and had detectable HIV viral load (p=0.02). There were no mutational differences in sequences isolated from participants with HBsAg+/anti-HBc- versus those with HBsAg+/anti-HBc+ serology. (4) Conclusions: We report a high HBsAg+/anti-HBc– atypical serology profile prevalence among PWH in Botswana. We caution against HBV testing algorithms that consider only anti-HBc+ samples for HBsAg testing as they are likely to underestimate HBV prevalence. Studies to elucidate the mechanisms and implications of this profile are warranted.

Background: Antibiotic resistance is an urgent issue everywhere in the globe. It is necessary to look into new sources of antibiotics to address this issue. Aim of the study: studying the purification of Corallopyronin B from various soil conditions in Egypt, as well as the antibacterial effectiveness of Corallopyronin B in preclinical animal testing and randomized human clinical trials phases 1/2. Type of the study: Screening experimental study. Methodology: Several soil conditions in Egypt were examined to create bacterial isolates that generated the antibiotic chemical Corallopyronin B. Using reversed-phase HPLC, Myxopyronin B was purified. The test antibiotic's minimum inhibitory concentration( MIC) and in vitro antibacterial activity were ascertained using the paper disc diffusion assay and the broth microdilution technique. Furthermore, in stages 1/2 of randomized clinical trials including human and animal models, pharmacokinetics, adverse drug reactions, and the in vivo antibacterial spectrum were discovered. Results: The soil bacterial isolate Corallococcus coralloides DSM 2259, grown on a Casein yeast peptone( CYP) plate, produced Corallopyronin B from its culture supernatant. At MICs more than 100 mcg/ml, the test antibiotic inhibited the growth of many Gram -ve bacteria, including Escherichia coli, while preventing the growth of numerous Gram +ve bacteria, with MICs ranging from 1 to 10 mcg/ml. Eukaryotic cells, on the other hand, including those in humans and fungi, were unharmed. The test antibiotic was shown to have a bactericidal effect by inhibiting bacterial DNA-dependent RNA polymerase( RNLP). In phases 1/2 of randomized human clinical trials, when 600 mg of the dose per 70 kg of body weight was administered SC, the Cmax was 8.6 mcg/ml at Tmax 1 hour; T1/2 reached 136 min following first-order kinetics of elimination. It stopped acting around 6-7 hours after SC was administered. In the preclinical and randomized human clinical trial phases 1/2, less than 6 percent of experimental candidates had uncommon toxicity, showing reduced bile flow. Protein binding with plasma albumin was detected which reached about 83%. Conclusion: The current work was noteworthy since it involved the production of the bactericidal antibiotic Corallopyronin B from Corallococcus coralloides DSM 2259 which was isolated from several soil environments in Egypt.

Background: Antibiotic resistance is an urgent issue everywhere in the globe. It is necessary to look into new sources of antibiotics to address this issue. Aim of the study: studying the purification of Corallopyronin B from various soil conditions in Egypt, as well as the antibacterial effectiveness of Corallopyronin B in preclinical animal testing and randomized human clinical trials phases 1/2. Type of the study: Screening experimental study. Methodology: Several soil conditions in Egypt were examined to create bacterial isolates that generated the antibiotic chemical Corallopyronin B. Using reversed-phase HPLC, Myxopyronin B was purified. The test antibiotic's minimum inhibitory concentration( MIC) and in vitro antibacterial activity were ascertained using the paper disc diffusion assay and the broth microdilution technique. Furthermore, in stages 1/2 of randomized clinical trials including human and animal models, pharmacokinetics, adverse drug reactions, and the in vivo antibacterial spectrum were discovered. Results: The soil bacterial isolate Corallococcus coralloides DSM 2259, which was grown on a Casein yeast peptone( CYP) plate, produced Corallopyronin B from its culture supernatant. At MICs more than 100 mcg/ml, the test antibiotic inhibited the growth of many Gram -ve bacteria, including Escherichia coli, while also preventing the growth of numerous Gram +ve bacteria, with MICs ranging from 1 to 10 mcg/ml. Eukaryotic cells, on the other hand, including those in humans and fungi, were unharmed. The test antibiotic was shown to have a bactericidal effect by inhibiting bacterial DNA-dependent RNA polymerase( RNLP). In phases 1/2 of randomized human clinical trials, when 600 mg of the dose per 70 kg of body weight was administered SC, the Cmax was 8.6 mcg/ml at Tmax 1 hour; T1/2 reached 136 min following first-order kinetics of elimination. It stopped acting around 6-7 hours after SC was administered. In the preclinical and randomized human clinical trial phases 1/2, less than 6 percent of experimental candidates had uncommon toxicity, which showed up as reduced bile flow. Protein binding with plasma albumin was detected which reached about 83%. Conclusion: The current work was noteworthy since it involved the production of the bactericidal antibiotic Corallopyronin B from Corallococcus coralloides DSM 2259 which was isolated from several soil environments in Egypt.

The aim this text to present the confined covariant quark model (CCQM) and review its applications to the decays of B mesons. We do so in the context of existing experimental measurements and theoretical results of other authors, which we review also. The physics principles are in detail exposed for the CCQM, the other results (theoretical and experimental) are surveyed in an enumerative way with comments. We proceed by considering successively three categories of decay processes: leptonic, semileptonic and non-leptonic.

Rising raw material prices can have a significant impact on the financial performance of the food and beverage (F&B) business. The purpose of this study was to determine the impact of rising prices of staples onfinancial resilience F&B business in Indonesia. This study uses a quantitative approach with bivariate correlation analysis and secondary data from the financial reports of F&B companies listed on the Indonesia Stock Exchange for the 2020-2022 period. The results showed that the increase in the price of basic commodities had a significant positive impact onfinancial resilience F&B company. This can be seen from the decline in the profitability and liquidity of F&B companies as a result of the increase in the price of basic commodities. Therefore, F&B companies must pay attention to and manage the risk of rising prices of basic commodities to maintainfinancial resilience and sustainable business continuity.

Autoimmune disorders and some types of blood cancer originate when B lymphocytes malfunction. In particular, when B cells produce antibodies recognizing the body’s proteins, it leads to various autoimmune disorders. And when B cells of various developmental stages transform into cancer cells, it results in blood cancers, including multiple myeloma, lymphoma, and leukemia. Thus, new methods of targeting B cells are required for various patient groups. Here, we used protein kinase inhibitors alectinib, brigatinib, ceritinib, crizotinib, entrectinib, and lorlatinib previously approved as drugs treating anaplastic lymphoma kinase (ALK)-positive lung cancer cells. We hypothesized that the same inhibitors will efficiently target leukocyte tyrosine kinase (LTK)-positive, actively protein-secreting mature B lymphocytes, including plasma cells. We isolated CD19-positive human B cells from the blood of healthy donors and used two alternative methods to stimulate cell maturation toward plasma cells. Using cell proliferation and flow cytometry assays, we found that ceritinib and entrectinib eliminate plasma cells from B cell populations. Alectinib, brigatinib, and crizotinib also inhibited B cell proliferation, while lorlatinib had no or limited effect on B cells. More generally, we concluded that several drugs previously developed to treat ALK-positive malignant cells can be also used to treat LTK-positive B cells.

The population of Bifidobacterium spp in faecal samples from breast-fed and formula-fed infants were investigated and developed antibiogram. The common bacterial growth media such as Man Rogos Sharpe (MRS), Brain Heart Infusion (BHI), Luria Bertani (LB) broth and Bifidobacteria agar were evaluated by the enumeration of Bifidobacterium spp. in faecal material. The results demonstrated that the population of Bifidobacterium spp. in the faecal samples of breast-fed infants is numerically high and, low in formula-fed infants. Phylogenetic analysis of the 16S rRNA, (Xylose/Fructose-6-phosphate phosphoketolase) xfp, and RFLP map of Bifidobacteria isolates suggested a presence of possible new and different Bifidobacterium spp. The intensity of the reddish brown colour formed during the f6ppk (Fructose-6-phosphate phosphoketolase) assay confirms the presence of variable Bifidobacteria. The highest recovery and diversity of Bifidobacteria were obtained from Bifidobacteria agar media. Growth in various media resulted in the formation of small (SCV) and big colony variants (BCV). We understand that the various antibiotic minimum inhibitory concentration (MIC) values obtained by applying different media, growth conditions, after bile salt treatment, and at low pH can vary. This study concludes that the variation of microbiological conditions differentiating resistant and susceptible strains is influenced by the test conditions as well.

Influenza B virus (IBV) is a major respiratory pathogen of humans, particularly in the elderly and children and vaccines are the most effective way to control it. In previous work, incorporation of two mutations (E580G, S660A) along with the addition of a HA epitope tag in the PB1 segment of B/Brisbane/60/2008 (B/Bris) resulted in an attenuated strain that was safe and effective as a live attenuated vaccine. A third attempted mutation (K391E) in PB1 was not always stable. Interestingly, viruses that maintained the K391E mutation were associated with the mutation E48K. To explore the contribution of the E48K mutation for stability of the K391E mutation, a vaccine candidate was generated by inserting both mutations along with attenuating mutations E580G and S660A in PB1 of B/Bris (B/Bris PB1att 4M). Serial passage of the B/Bris PB1att 4M vaccine candidate in eggs and MDCK indicated high stability. In silico structural analysis revealed a potential interaction between amino acids at positions 48 and 391. In mice, B/Bris PB1att 4M was safe and provided complete protection against homologous challenge. These results confirm the compensatory effect of mutation E48K to stabilize the K391E mutation, resulting in a safer, yet still protective, IBV LAIV vaccine.

Maternal-derived immunity is a critical component for survival and success of offspring in pigs to protect from circulating pathogens like Type 2 Porcine Reproductive and Respiratory Syndrome Virus (PRRSV-2). The purpose of this study was to investigate the transfer of anti-PRRSV immunity to piglets from gilts that received modified-live virus (MLV) alone (TRT 0), or in combination with one of two autogenous inactivated vaccines (AIVs, TRT 1+2). Piglets from these gilts were challenged with the autogenous PRRSV-2 strain at two weeks of age and their adaptive immune response (IR) was evaluated until 4 weeks post inoculation (wpi). The systemic humoral and cellular IR was analyzed in the pre-farrow gilts, and in piglets, pre-inoculation, and at 2- and 4-wpi. Both AIVs partially protected the piglets with reduced lung pathology and increased weight gain; TRT 1 also lowered piglet viremia best explained by the AIV-induced production of neutralizing antibodies in gilts and their transfer to the piglets. In piglets, pre-inoculation, the main systemic IFN-γ producers were CD21α+ B cells. From 0 to 4 wpi, the role of these B cells declined and CD4 T cells became the primary systemic IFN-γ producers. In lungs, CD8 T cells were the primary and CD4 T cells the secondary IFN-γ producers including a novel subset of porcine CD8α-CCR7- CD4 T cells, potentially terminally differentiated CD4 TEMRA cells. In summary, this study demonstrates that maternal AIV vaccination can improve protection of pre-weaning piglets against PRRSV-2; it shows the importance of transferring neutralizing antibodies to piglets; and it introduces two novel immune cell subsets in pigs – IFN-γ producing CD21α+ B cells and CD8α-CCR7- CD4 T cells.

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.

Presenting a case report on the occurrence of IgA nephropathy with hepatitis B infection in a 32-year-old male patient with main complaints of generalized weakness, easy fatigue, and bilateral swelling of the lower extremities. IgA nephropathy (IgAN), or Berger’s disease, is the most common primary glomerulonephritis worldwide. It is characterized by the formation of IgA1-containing circulating immune complexes and their deposition in the glomerular mesangium. Its etiology remains multifactorial and often idiopathic. IgA nephropathy alone does not have an infectious etiology; instead, it usually develops in conjunction with an infectious condition that triggers a dysregulated immune response. There is no proof that any particular infectious agent is the secondary cause of IgA nephropathy. Hepatitis B virus (HBV) infection is an infectious agent associated with renal complications, including IgA nephropathy. Symptoms include gross haematuria and mild proteinuria indicative of renal involvement. Laboratory investigations and serological tests are followed by imaging studies such as ultrasound and renal biopsy to confirm the diagnosis. The challenges encountered during the diagnostic process included overlapping symptoms and limitations of available diagnostic tests, highlighting the need for comprehensive diagnostic evaluation and multidisciplinary management approaches in similar cases. This case underscores the importance of recognizing and managing both conditions simultaneously to prevent long-term complications such as end-stage renal disease.

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.

Previous studies have shown that immunization within the first hours/days after birth promotes the shift from the intrauterine Th2 immune response toward the Th1 immunity resulting in lower risk of developing allergic diseases. We are currently conducting a prospective cohort study among 307 participants divided into groups based on their TB and hepatitis B vaccination status (vaccinated at birth, within the first 12 months of life or unvaccinated) and also based on whether the participants had factors contributing to the development of allergic diseases. In each group we assessed the fact of primary diagnosis of atopic dermatitis at 12 and 18 months of age. It was demonstrated that atopic dermatitis (AD) was diagnosed from birth to 12 months of age much less frequently in those infants who had received the tuberculosis (TB) vaccine from day 3 to day 7 and hepatitis B vaccine within the first 24 hours of birth, including newborns with a high risk of developing allergic diseases. The probability of onset of AD at 12 and 18 months was also lower in timely vaccinated children, even though a burdened allergic anamnesis starts playing a more central role in development of AD at this age. Our findings testify to the fact that timely BCG-M and hepatitis B vaccination can produce a protective effect against the onset of AD, yet this effect diminishes with aging.

To face the high tolerance of biofilms to antibiotics, it is urgent to develop new strategies to fight against these bacterial consortia. We describe here an innova-tive antibiofilm nano vector, consisting of a Dispersin B-permethylated-β-cyclodextrin/ciprofloxacin adamantly (DspB-β-CD/CIP-Ad). For this purpose, complexation assays between CIP-Ad and (i) unmodified β-CD and (ii) different derivatives of β-CD, that are 2,3-O-dimethyl-β-CD, 2,6-O-dimethyl-β-CD, and 2,3,6-O-trimethyl-β-CD were tested. A stoichiometry of 1/1 was obtained for the β -CD/CIP-Ad complex by NMR analysis. ITC experiments were carried out to determine Ka, ΔH, ΔS thermodynamic parameters of the complex between β-CD or its different derivatives in the presence of CIP-Ad. A stoichiometry 1/1 of β-CD/CIP-Ad complexes was confirmed with variable affinity according to the type of methylation. A phase solubility study showed increased CIP-Ad solubili-ty with CDs concentration, pointing out complex formation. The evaluation of the antibacterial activity of CIP-Ad and the 2,3-O-dimethyl-β-CD/CIP-Ad or 2,3,6-O-trimethyl-β-CD/CIP-Ad complexes was performed on S.epidermidis strains. MIC studies showed that the complex of CIP-Ad and 2,3-O-dimethyl-β-CD exhibited similar antimicrobial activity to CIP-Ad alone, while the interaction with 2,3,6-O-trimethyl-β-CD increased MIC values. Antimicrobial assays on S. epidermidis biofilms demonstrated that the synergistic effect observed with the DspB/CIP association was partly maintained with the 2,3-O-dimethyl-β-CDs/CIP-Ad complex. To obtain this "all in one" nano vector, able to destroy the biofilm matrix and release the antibiotic simultaneously, we covalently grafted DspB on three carboxylic permethylated CD derivatives with different length spacer arms. The strategy was validated by demonstrating that a DspB-permethylated-β-CD/ciprofloxacin-Ad nanovector exhibited efficient antibiofilm activity.

The CYSTM (cysteine-rich transmembrane module) protein family comprises small molecular cysteine-rich tail-anchored membrane proteins found in many eukaryotes. The Saccharomyces cerevisiae strains carrying the CYSTM genes YDRO34W-B and YBR056W-A (MNC1) fused with GFP were used to test expression of these genes under different stresses. The YBR056W-A (MNC1) and YDR034W-B genes are expressed under stress conditions caused by the toxic concentrations of heavy metal ions such as manganese, cobalt, nickel, zinc, cuprum, and 2.4-dinitrophenol uncoupler. YDR034W-B but not YBR056W-A is expressed under alkali and cadmium stresses. YBR056W-A is localized in intracellular membranes, while YDR034W-B is localized in the cytoplasmic membrane. The null-mutants in both genes demonstrated both decreased cell concentration and lytic phenotype when cultivated in the presence of excess manganese. This indicates the involvement of Mnc1 and YDR034W-B proteins in manganese detoxification, probably by complexation of its ion.

The World Health Organization estimated that around 66 thousand HBV are caused by needlestick injuries annually. Healthcare students should be aware of HBV transmission route and preventive measures. This study assessed the knowledge, attitudes, and practices toward HBV among Jordanian healthcare students and its associated factor. A cross-national study conducted from March to August. The participants were asked to complete the questionnaire. It had four sections: participants' sociodemographic, knowledge, attitudes, and practices about HBV. 2322 participants were enrolled, 67.9% were females, 26.4% were medical student, 35.9% were in the 3rd year. 40% of the participants held a high level of knowledge and attitude. 63.9% of participants had good practices toward HBV. Medical students in the last year of study, encountered HBV patients , had better knowledge. Male students from medicine college, encountered HBV patients and had extra HBV courses showed better attitude. High practice level was associated with being dentistry student, at 5th year, encountered HBV patient and extras HBV courses. This study demonstrated insufficient knowledge and attitudes toward HBV, the practices level toward HBV among healthcare students was promising. Subsequently, public health efforts should modify the knowledge and attitude gaps to reinforce awareness and minimizing risks of the infection.

Chronic Hepatitis B (CHB) Virus infection is major etiological factor for liver cirrhosis and/ or liver cancer. The viral protein, major contributor in predisposition of chronicity and Hepatocellular Carcinoma (HCC) is Hepatitis B x (HBx) protein. Its dynamic subcellular distribution to an extent determines its multifactorial role. It is a regulatory protein which modulates viral as well as host machinery in favours to HBV persistence. An insight on HBx stabilising factors is critical for therapeutic purpose. The precise role of HBx in the pathogenesis of Chronicity of HBV is not known. Summary: This review comprehensively summarizing different mechanisms and their regulation by HBx protein with respect to chronicity and HCC emphasising viral persistence. Key Messages 1. HBx is a key protein for viral persistence. 2. Dynamic subcellular distribution of HBx determines its function. 3. HBx modulates cellular machinery to favours HBV survival. 4. HBx affects various intermediary mechanisms contributing to disease progression. 5. HBx may be a potent target to prevent the disease progression towards HCC.

Cardiovascular disease (CVD) places a heavy burden on older patients and the global healthcare system. A large body of evidence suggests that exercise training is essential in preventing and treating cardiovascular disease, but the underlying mechanisms are not well understood. Here, we used the Drosophila melanogaster animal model to study the effects of early-life exercise training (ELET) on the aging heart and lifespan. We found in flies that age-induced arrhythmias are conserved across different genetic backgrounds. The fat body is the primary source of circulating lipoproteins in flies. Inhibition of fat body apoLpp (the flies apoB homolog) demonstrated that low expression of apoLpp reduced the development of arrhythmias in aged flies but did not affect average lifespan. At the same time, ELET can also reduce the expression of apoLpp mRNA in aged flies and have a protective effect on the heart, which is similar to the inhibition of apoLpp mRNA. Although treatment of apoLppRNAi and ELET alone had no significant effect on lifespan, the combination of apoLppRNAi and ELET extended the average lifespan of flies. Therefore, we conclude that apoLppRNAi and ELET are sufficient to resist age-induced arrhythmias, which may be related to the decreased expression of apoLpp mRNA, and that apoLppRNAi and ELET have a combined effect on prolonging the average lifespan.

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.

In this present work, we are reporting a novel route for the synthesis of the tetracyclic ring systems, which is a common core of crinipellin via oxidative dearomatization, cycloaddition and oxa- di-pi-methane rearrangement. We considered to exploring a route to tetracyclic core (1e) of Crinipellin and tricyclic core (1g) of Allicaol B through intermolecular diels alder reaction and photochemically 1,2 acyl shift. Moreover, docking study of compound 13 and 16has been investigated against AcrB multidrug efflux pump of Escherichia coli (PDB ID: 1T9U), main protease of SARS COV-2 (PDB ID: 6W63), DNA gyrase of Streptococcus pneumonia (PDB ID: 4Z2C), human estrogen receptor alpha (PDB ID: 3ERT), human lanosterol 14-alpha-demethylase (CYP51)(PDB ID: 3JUS) and cyclooxygenase-2 (Prostaglandin Synthase-2) (PDB ID: 1CX2). The obtained results herein are important for the exploitation of the therapeutic potential of these derivatives as antimicrobial, antiviral, anticancer, antifungal or anti-inflammatory agents.

Multiple sclerosis is an autoimmune disorder where both T cells and B cells are implicated in pathology. However, it remains unclear how these two distinct populations cooperate to drive disease. There is ample evidence from studies in both MS patients and mouse models that Th17, B cells, and follicular T helper (TFH) cells contribute to disease. This review article describes the literature that identifies mechanisms by which Th17, TFH, and B cells cooperatively drive disease activity in MS and EAE. The curation of this literature has identified that CNS-infiltrating TFH cells act with TH17 cell to contribute to an inflammatory B cell response in neuroinflammation. This demonstrates that TFH cells and their products are promising targets for therapies in MS.

Introduction: Laeverin is an extravillous trophoblast marker playing a significant role in the trophoblast migration. The purpose of this study was to evaluate the association between the amniotic and serum laeverin concentrations at 16-22 weeks of gestation and the fetal and placental ultrasound measurements in healthy, unaffected pregnancies. Materials and methods: This was a prospective cross-sectional study. Pregnant women with singleton pregnancies undergoing amniocentesis were recruited consecutively. Fetal structural malformations and/or aneuploidy were exclusion criteria. Fetal biometric parameters and placental growth/perfusion were measured in 44 high-risk pregnancies who had no pregnancy complication and any other chronic disease. Maternal serum and amniotic levels of laeverin were essayed with sandwich enzyme-linked immunosorbent assay. Results: Serum laeverin levels are decreasing slightly with the maternal age in mid-gestation. Serum laeverin level correlated negatively slightly with head size of the fetus with the gestational length at delivery (β=-0.38, 95% confidence interval (CI) -0.03-0.01), while the amniotic laeverin level correlated strongly with the abdominal circumference of the fetus (β=-0.64, 95% CI: -0.03-0.01). Furthermore, laeverin level in the amnion correlated moderately and positively with the placental volume (β=0.46, 95% CI: 0.01-0.08). Conclusions: Laeverin levels detected in the serum and in the amniotic fluid denotes the fetoplacental growth in uncomplicated high-risk pregnancies.

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.

Although lymphoma is the most frequent malignancy in common variable immunodeficiency (CVID), solid tumors, especially under influence of oncogenic viruses, are not considered. Furthermore, in vitro genetic studies and cell cultures are not adequate for immune system and HBV interaction. We adopted previously introduced clinical model of host-virus interaction (i.e. infectious process in immunodeficiency) for analysis of B cells and specific IgG role (observational study of a CVID patient who received intravenous immunoglobulin (IVIG)) Suddenly, the patient deteriorated with positive result of HBs, HBV-DNA (369x106copies). In spite of lamivudine therapy and IVIG escalation (from 0.3 to 0.4g/kg), CT showed 11cm intrahepatic tumor (hepatocellular carcinoma). Anti-HBs had been positive in time-lapse analysis (range 111-220 IU/ml). Replacement therapy intensification was complicated by immune complex disease with renal failure. The fulminant HCC in CVID and the development of the tumor as the first sign is interesting. Unfortunately, treatment with hepatitis B immune globulins (HBIG) plays a major role in posttransplant maintenance therapy. Anti-HBs substitution has not been proven to be effective, oncoprotective nor safe. Therefore, immunosuppression in HBV-infected recipients should be carefully minimized, patient selection more precise with the exclusion of HBV-positive donors. Our clinical model show HCC pathway with important humoral host factors, contrary to epidemiological/cohort studies highlighting risk factors only (e.g. chronic hepatitis). Lack of cell cooperation, B cell deficiency observed in CVID plays a crucial role in high HBV replication, especially in carcinogenesis.

This paper comprehensively explores the integration of cloud computing and advanced recommendation systems, emphasizing their pivotal roles in enhancing user experiences and operational efficiencies across digital platforms. It reviews the evolution of recommendation algorithms, highlighting their application in diverse domains such as e-commerce and media. The study evaluates the performance of advanced models like UniLLMRec against traditional counterparts using datasets from news and e-commerce domains. Additionally, the paper discusses the infrastructure architecture of cloud computing, demonstrating its capability to support scalable and efficient data processing. Through experimental insights and methodology, the research underscores the transformative impact of cloud technologies on optimizing recommendation system performance, thereby advancing digital engagement and competitiveness.

PET imaging of bacterial infection could potentially provide added benefit for patient care by non-invasive means. [68Ga]Ga-desferrioxamine B – a radiolabelled siderophore – shows specific uptake by human-pathogenic bacteria like Staphylococcus aureus or Pseudomonas aeruginosa as well as sufficient serum stability for clinical application. Here, we provide data for automated production of [68Ga]Ga-desferrioxamine B on two different cassette based synthesis modules (Modular-Lab PharmTracer and GRP 3V) using commercially available cassettes together with an approved 68Ge/68Ga radionuclide generator. Quality control including determination of radiochemical purity as well as a system suitability test was set up via RP-HPLC on a C18 column. The two described production processes, using an acetic acid/acetate buffer system with ascorbic acid as a radiation scavenger for radiolabelling, yield ready-to-use formulations with sufficient activity yield. Batch data showed radiochemical purity of &gt;95 % as determined by RP-HPLC and ITLC as well as excellent stability over 2 hours post production. Specifications for routine production were set up and validated with four master batches for each synthesis module. Based on this study, an academic clinical trial for imaging of bacterial infection was initiated. Both described synthesis methods enable reproducible, automated in-house production of [68Ga]Ga-desferrioxamine B for clinical application.

We conducted a topological analysis of the novel, non-associative, and unital algebraic structure known as Bermejo Algebras, developed by Alejandro Bermejo, which includes the Algebra B and Treon Algebra. This algebras can define Lie and Malcev algebras when their product operations are derived from the Bermejo Algebras product. Central to this study are treons, complex entities that arise as isomorphisms of Algebra B when the field is real. We define the vector spaces associated with Bermejo Algebras to establish equivalence classes and a quotient topology, resulting in Hausdorff spaces that do not depend on traditional norms, inner products, or metrics. Our findings lay the groundwork for constructing new types of differential manifolds, opening new avenues for advanced mathematical research.

We present an exploration of algebra B, a recently published unital and non-associative algebra. Unique complex entities emerged from this algebra, distinct from both quaternion and complex number systems, which we termed treons. We defined the treonic number system and established an isomorphism between this system and the real vector space. Our findings revealed that the treonic representation maintained structural integrity under the defined operations. Based on this foundation, we proceed to determine Euler identity for algebra B within the treonic system. By presenting the fundamental definitions and properties of algebra B, we derived a generalized version of Euler identity applicable within this algebra. This formula revealed the emergence of hyperbolic trigonometric entities, extending the applicability of Euler identity beyond traditional complex numbers. Our results provide a theoretical foundation for a deeper understanding of the properties and behaviors of complex entities within this expanded algebraic framework, thus enabling new theoretical developments and practical applications in the realms of advanced mathematics and theoretical physics.

Gold nanostructures (AuNSs) were used to fabricate surface-enhanced Raman spectroscopy (SERS) substrates. These AuNSs were produced by the solid-state dewetting method from thin films. The fragmentation process was studied at 300 °C, considering the duration of the thermal treatment for 1, 3, 6, and 12 hours. These SERS substrates were then employed to detect Rhodamine B (RhB) as a model analyte, simulating a contaminant in water at a concentration of 5 ppm. The morphology of the AuNSs was examined using SEM, which revealed a spheroidal shape beginning to coalesce after 12 hours. The size of the AuNSs was estimated to range from 22 ± 7 to 24 ± 6 nm, depending on the annealing time. The surface plasmon resonance of the AuNSs was determined using absorption spectroscopy, showing a shift as the annealing time increased. The SERS signals of RhB adsorbed on the AuNS substrates were studied, and a comparative analysis showed no significant differences in the positions of the bands; however, variations in intensity enhancement ranged from 20 to 90 times for 6 and 3 hours, respectively. Three new vibrational modes, observed at 1683, 1720, and 1789 cm–1, have been identified and reported.

Background: Across the world, antibiotic resistance is a grave problem. To address this issue, it is necessary to investigate new antibiotic sources. Aim of the study: Egypt's diverse soil habitats were used to produce bacterial Myxopyronin B, which was then tested for antimicrobial activity in preclinical animal studies and randomized human clinical trials stages 1/2. Type of the study: Screening experimental study. Methodology: Egypt's various soil conditions were examined for the development of bacterial isolates that produced the antibiotic compound Myxopyronin B. Reversed phase HPLC was used to purify Myxopyronin B. To determine the test antibiotic's minimum inhibitory concentration( MIC) and invitro antibacterial activity, the Broth microdilution method and the Paper disc diffusion assay were utilized. Moreover, in vivo antibacterial spectrum, adverse medication responses, and pharmacokinetics were found in preclinical animal testing stages and phases 1/2 of randomized clinical studies involving volunteer humans. Results: Myxopyronin B was generated from the culture supernatant of Myxococcus SDU36, the main soil bacterial isolate cultured on a Casein yeast peptone plate. With MICs less than 100 mcg/ml, the test antibiotic prevented the growth of several Gram +ve bacteria, whereas, at MICs higher than 100 mcg/ml, it inhibited the development of a small number of Gram -ve bacteria, including Escherichia coli. However, eukaryotic cells—such as those found in fungi and humans—were unaffected. The test antibiotic was seen to inhibit prokaryotic DNA-dependent RNA polymerase( RNLP), indicating its bactericidal activity. Mean Cmax was 9-10 mcg/ ml at mean Tmax 1 hour when 600 mg dose was orally administered in randomized human clinical trials phases 1/2, and T1/2 reached 2.25 hours following first-order kinetics of elimination. Duration of its action was nearly 8 hours after oral administration. Rare toxicity was detected during preclinical and randomized human clinical trials phases 1/2 in the form of mild diarrhea and GI upset in less than 7 % of experimental candidates. It exhibited approximately 90% plasma protein binding, especially with albumin which resulted in prolonged therapeutic action. It showed a concentration dependant antibiotic killing effect. With the concentration-dependent killing pattern, the higher the drug concentration relative to the pathogen minimum inhibitory concentration( MIC), the greater the rate and extent of antimicrobial activity. Conclusion: The present study was promising due to the production of the bactericidal antibiotic Myxopyronin B from Myxococcus sp. SDU36 isolated from different soil environments in Egypt.

Annually, more than 1.5 million preventable new hepatitis B (HBV) infections continue to occur, with an estimated global burden of 296 million individuals living with chronic hepatitis B infection. This substantial health challenge results in over 820,000 annual deaths attributed to complications such as liver cirrhosis and hepatocellular carcinoma (HCC). HBV vaccination remains the cornerstone of public health policy to prevent chronic hepatitis B and its related complications. It serves as a crucial element in the global effort to eliminate HBV, as established by the World Health Organization (WHO), with an ambitious 90% vaccination target by 2030. However, reports on global birth dose coverage reveal substantial variability, with an overall coverage rate of only 46%. This comprehensive review thoroughly examines global trends in HBV vaccination coverage, investigating the profound impact of vaccination on HBV prevalence and its consequences across diverse populations, including both high-risk and general demographics. Additionally, the review addresses the formidable challenges and facilitating factors essential for achieving WHO's HBV vaccination coverage objectives and elimination strategies in the coming decade and beyond.