Protective anti-gB neutralizing antibodies targeting two vulnerable sites for EBV-cell membrane fusion.

Epstein-Barr virus (EBV) infects more than 90% of the world's adult population and accounts for a significant cancer burden of epithelial and B cell origins. Glycoprotein B (gB) is the primary fusogen essential for EBV entry into host cells. Here, we isolated two EBV gB-specific neutralizing antibodies, 3A3 and 3A5; both effectively neutralized the dual-tropic EBV infection of B and epithelial cells. In humanized mice, both antibodies showed effective protection from EBV-induced lymphoproliferative disorders. Cryoelectron microscopy analyses identified that 3A3 and 3A5 bind to nonoverlapping sites on domains D-II and D-IV, respectively. Structure-based mutagenesis revealed that 3A3 and 3A5 inhibit membrane fusion through different mechanisms involving the interference with gB-cell interaction and gB activation. Importantly, the 3A3 and 3A5 epitopes are major targets of protective gB-specific neutralizing antibodies elicited by natural EBV infection in humans, providing potential targets for antiviral therapies and vaccines.

Evaluation of serum Epstein-Barr virus envelope glycoproteins antibodies and their association with systemic autoimmune diseases.

Systemic autoimmune diseases (SADs) are a growing spectrum of autoimmune disorders that commonly affect multiple organs. The role of Epstein-Barr virus (EBV) infection or reactivation as a trigger for the initiation and progression of SADs has been established, while the relationship between EBV envelope glycoproteins and SADs remains unclear. Here, we assessed the levels of IgG, IgA, and IgM against EBV glycoproteins (including gp350, gp42, gHgL, and gB) in serum samples obtained from patients with rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE), and found that RA and SLE patients exhibited a statistically significant increase in the levels of 8 and 11 glycoprotein antibodies, respectively, compared to healthy controls (p < 0.05). The LASSO model identified four factors as significant diagnostic markers for RA: gp350 IgG, gp350 IgA, gHgL IgM, and gp42 IgA; whereas for SLE it included gp350 IgG, gp350 IgA, gHgL IgA, and gp42 IgM. Combining these selected biomarkers yielded an area under the curve (AUC) of 0.749 for RA and 0.843 for SLE. We subsequently quantified the levels of autoantibodies associated with SADs in mouse sera following immunization with gp350. Remarkably, none of the tested autoantibody levels exhibited statistically significant alterations. Elevation of glycoprotein antibody concentration suggests that Epstein-Barr virus reactivation and replication occurred in SADs patients, potentially serving as a promising biomarker for diagnosing SADs. Moreover, the absence of cross-reactivity between gp350 antibodies and SADs-associated autoantigens indicates the safety profile of a vaccine based on gp350 antigen.

Gender differences in plasma S100B levels of patients with major depressive disorder.

BACKGROUND: Low concentrations of S100B have neurotrophic effects and can promote nerve growth and repair, which plays an essential role in the pathophysiological and histopathological alterations of major depressive disorder (MDD) during disease development. Studies have shown that plasma S100B levels are altered in patients with MDD. In this study, we investigated whether the plasma S100B levels in MDD differ between genders. METHODS: We studied 235 healthy controls (HCs) (90 males and 145 females) and 185 MDD patients (65 males and 120 females). Plasma S100B levels were detected via multifactor assay. The Mahalanobis distance method was used to detect the outliers of plasma S100B levels in the HC and MDD groups. The Kolmogorov-Smirnov test was used to test the normality of six groups of S100B samples. The Mann-Whitney test and Scheirer-Ray-Hare test were used for the comparison of S100B between diagnoses and genders, and the presence of a relationship between plasma S100B levels and demographic details or clinical traits was assessed using Spearman correlation analysis. RESULTS: All individuals in the HC group had plasma S100B levels that were significantly greater than those in the MDD group. In the MDD group, males presented significantly higher plasma S100B levels than females. In the male group, the plasma S100B levels in the HC group were significantly higher than those in the MDD group, while in the female group, no significant difference was found between the HC and MDD groups. In the male MDD subgroup, there was a positive correlation between plasma S100B levels and years of education. In the female MDD subgroup, there were negative correlations between plasma S100B levels and age and suicidal ideation. CONCLUSIONS: In summary, plasma S100B levels vary with gender and are decreased in MDD patients, which may be related to pathological alterations in glial cells.

Vesicular Stomatitis Virus-Based Epstein-Barr Virus Vaccines Elicit Strong Protective Immune Responses.

Epstein-Barr virus (EBV), the first identified human tumor virus, is etiologically associated with various kinds of malignant and benign diseases, accounting for 265,000 cancer incident cases and 164,000 cancer deaths in 2017. EBV prophylactic vaccine development has been gp350 centered for several decades. However, clinical studies show that gp350-centered vaccines fail to prevent EBV infection. Advances in the EBV infection mechanisms shed light on gB and gHgL, the two key components of the infection apparatus. In this study, for the first time, we utilized recombinant vesicular stomatitis virus (VSV) to display EBV gB (VSV-ΔG-gB/gB-G) or gHgL (VSV-ΔG-gHgL). In vitro studies confirmed successful virion production and glycoprotein presentation on the virion surface. In mouse models, VSV-ΔG-gB/gB-G or VSV-ΔG-gHgL elicited potent humoral responses. Neutralizing antibodies elicited by VSV-ΔG-gB/gB-G were prone to prevent B cell infection, while those elicited by VSV-ΔG-gHgL were prone to prevent epithelial cell infection. Combinatorial vaccination yields an additive effect. The ratio of endpoint neutralizing antibody titers to the endpoint total IgG titers immunized with VSV-ΔG-gHgL was approximately 1. The ratio of IgG1/IgG2a after VSV-ΔG-gB/gB-G immunization was approximately 1 in a dose-dependent, adjuvant-independent manner. Taken together, VSV-based EBV vaccines can elicit a high ratio of epithelial and B lymphocyte neutralizing antibodies, implying their unique potential as EBV prophylactic vaccine candidates. IMPORTANCE Epstein-Barr virus (EBV), one of the most common human viruses and the first identified human oncogenic virus, accounted for 265,000 cancer incident cases and 164,000 cancer deaths in 2017 as well as millions of nonmalignant disease cases. So far, no prophylactic vaccine is available to prevent EBV infection. In this study, for the first time, we reported the VSV-based EBV vaccines presenting two key components of the EBV infection apparatus, gB and gHgL. We confirmed potent antigen-specific antibody generation; these antibodies prevented EBV from infecting epithelial cells and B cells, and the IgG1/IgG2a ratio indicated balanced humoral-cellular responses. Taken together, we suggest VSV-based EBV vaccines are potent prophylactic candidates for clinical studies and help eradicate numerous EBV-associated malignant and benign diseases.

N(6)-methyladenosine-binding protein YTHDF1 suppresses EBV replication and promotes EBV RNA decay.

N6 -methyladenosine (m6 A) modification of mRNA mediates diverse cellular and viral functions. Infection with Epstein-Barr virus (EBV) is causally associated with nasopharyngeal carcinoma (NPC), 10% of gastric carcinoma, and various B-cell lymphomas, in which the viral latent and lytic phases both play vital roles. Here, we show that EBV transcripts exhibit differential m6 A modification in human NPC biopsies, patient-derived xenograft tissues, and cells at different EBV infection stages. m6 A-modified EBV transcripts are recognized and destabilized by the YTHDF1 protein, which leads to the m6 A-dependent suppression of EBV infection and replication. Mechanistically, YTHDF1 hastens viral RNA decapping and mediates RNA decay by recruiting RNA degradation complexes, including ZAP, DDX17, and DCP2, thereby post-transcriptionally downregulating the expression of EBV genes. Taken together, our results reveal the critical roles of m6 A modifications and their reader YTHDF1 in EBV replication. These findings contribute novel targets for the treatment of EBV-associated cancers.

In-depth analysis reveals complex molecular aetiology in a cohort of idiopathic cerebral palsy.

Cerebral palsy is the most prevalent physical disability in children; however, its inherent molecular mechanisms remain unclear. In the present study, we performed in-depth clinical and molecular analysis on 120 idiopathic cerebral palsy families, and identified underlying detrimental genetic variants in 45% of these patients. In addition to germline variants, we found disease-related postzygotic mutations in ∼6.7% of cerebral palsy patients. We found that patients with more severe motor impairments or a comorbidity of intellectual disability had a significantly higher chance of harbouring disease-related variants. By a compilation of 114 known cerebral-palsy-related genes, we identified characteristic features in terms of inheritance and function, from which we proposed a dichotomous classification system according to the expression patterns of these genes and associated cognitive impairments. In two patients with both cerebral palsy and intellectual disability, we revealed that the defective TYW1, a tRNA hypermodification enzyme, caused primary microcephaly and problems in motion and cognition by hindering neuronal proliferation and migration. Furthermore, we developed an algorithm and demonstrated in mouse brains that this malfunctioning hypermodification specifically perturbed the translation of a subset of proteins involved in cell cycling. This finding provided a novel and interesting mechanism for congenital microcephaly. In another cerebral palsy patient with normal intelligence, we identified a mitochondrial enzyme GPAM, the hypomorphic form of which led to hypomyelination of the corticospinal tract in both human and mouse models. In addition, we confirmed that the aberrant Gpam in mice perturbed the lipid metabolism in astrocytes, resulting in suppressed astrocytic proliferation and a shortage of lipid contents supplied for oligodendrocytic myelination. Taken together, our findings elucidate novel aspects of the aetiology of cerebral palsy and provide insights for future therapeutic strategies.

Immunization with a Self-Assembled Nanoparticle Vaccine Elicits Potent Neutralizing Antibody Responses against EBV Infection.

Epstein-Barr virus (EBV) infection is a global health concern infecting over 90% of the population. However, there is no currently available vaccine. EBV primarily infects B cells, where the major glycoprotein 350 (gp350) is the main target of neutralizing antibodies. Given the advancement of nanoparticle vaccines, we describe rationally designed vaccine modalities presenting 60 copies of gp350 on self-assembled nanoparticles in a repetitive array. In a mouse model, gp350s on lumazine synthase (LS) and I3-01 adjuvanted with MF59 or aluminum hydroxide (Alhydrogel) elicited over 65- to 133-fold higher neutralizing antibody titers than the corresponding gp350 monomer to EBV. Furthermore, immunization with gp350D123-LS and gp350D123-I3-01 vaccine induced a Th2-biased response. For the nonhuman primate model, gp350D123-LS in MF59 elicited higher titers of total IgG and neutralizing antibodies than the monomeric gp350D123. Overall, these results support gp350D123-based nanoparticle vaccine design as a promising vaccine candidate for potent protection against EBV infection.

Compound heterozygous ZP1 mutations cause empty follicle syndrome in infertile sisters.

Empty follicle syndrome (EFS) is a condition in which no oocyte is retrieved from mature follicles after proper ovarian stimulation in an in vitro fertilization procedure. Genetic evidence accumulates for the etiology of recurrent EFS without pharmacological or iatrogenic problems. In this study, we present two infertile sisters in a family with EFS after three cycles of standard ovarian stimulation with human chorionic gonadotrophin and/or gonadotropin-releasing hormone agonist therapy. Via whole-exome sequencing and cosegregation test, we identified compound heterozygous mutations in the gene of ZP1 in both of the infertile sisters. Coimmunoprecipitation tests and homology modeling analysis confirmed that both mutated ZP1 disrupt the formation of oocyte zona pellucida by interrupting the interaction among ZP1, ZP2, and ZP3. We thus propose that the specific mutations in ZP1 gene render a causality for the intractable EFS.

A novel human lncRNA SANT1 cis-regulates the expression of SLC47A2 by altering SFPQ/E2F1/HDAC1 binding to the promoter region in renal cell carcinoma.

SLC47A2 encodes MATE 2-K in the kidney, which mediates the secretion of certain endogenous and exogenous compounds. SLC47A2 was dramatically repressed in patients with renal cell carcinoma (RCC), and a lower level of SLC47A2 might act as a negative prognostic marker, although the mechanism is not well understood. In this study, we aimed to investigate the mechanism via which SLC47A2 is downregulated in RCC. Based on the annotation information of the SLC47A2 locus available in the UCSC genome browser database, we identified a novel lncRNA, which is transcribed from the SLC47A2 locus and named it SANT1. Overexpression and knock-down assays were performed to investigate the effects of SANT1 on cis-regulation of SLC47A2. We verified the direct binding between SANT1 and SFPQ/E2F1/HDAC1 using the cross-linking and immunoprecipitation (CLIP) assay. Chromatin immunoprecipitation was performed to confirm the molecular mechanism via which SANT1 activates the transcription of the SLC47A2 coding region. We observed that SANT1 can cis-regulate its own genetic locus. In tumour-adjacent tissues, the SLC47A2 locus highly expresses SANT1, which can remove the regulatory SFPQ/E2F1/HDAC1 suppressor complex from the promoter region, thereby significantly increasing the levels of the H3K27ac modification and RNAPII binding. Owing to a low SANT1 level, the binding of this inhibitory complex in the promoter region is upregulated in RCC, which results in silencing of the SLC47A2 coding region. In conclusion, we identified a novel lncRNA and elucidated the mechanism via which it regulates SLC47A2 expression in RCC.

[Clinical and genotypic analysis of two Chinese pedigrees affected with hereditary coagulable factor VII deficiency].

OBJECTIVE: To explore molecular etiology and clinical characteristics of two pedigrees affected with hereditary factor VII(FVII) deficiency. METHODS: The nine exons and flanking sequences of the F7 gene of the probands were amplified by PCR. The amplicons were analyzed by direct sequencing. Suspected mutations were subjected to SWISS-MODEL modeling and analysis of protein structure change by Pymol software and conservation of amino acids across various species. RESULTS: For proband of pedigree 1, the prothrombin time (PT), FVII activity (FVII:C) and FVII antigen (FVII:Ag) were 36.3 s, 3%, 53.56%, respectively. Sequencing revealed a compound heterozygous variants of c.80_81delCT and c.1371G>T(p.Arg439Ser). His son carried a heterozygous c.1371G>T (p.Arg439Ser) variant. For proband of pedigree 2, the PT, FVII:C and FVII:Ag were 22.3 s, 4%, 1.58%, respectively. Sequencing has revealed a compound heterozygous c.278G>T(p.Arg75Met) missense variant in exon 3 and c.1278T>G (p.His408Gln) in exon 9 of the F7 gene. His mother and son both carried a heterozygous c.278G>T(p.Arg75Met) variant. Three-dimensional simulation and homology analysis revealed that the p.Arg439Ser and p.Arg75Met can respectively alter part of hydrogen bonds and two highly conserved amino acids. CONCLUSION: Two novel heterozygous missense variants of the F7 gene [c.1371G>T(p.Arg439Ser) and c.278G>T(p.Arg75Met)] probably account for the decrease of factor VII in the two pedigrees.

Histone H3 Lysine 4 Trimethylation, Lysine 27 Trimethylation, and Lysine 27 Acetylation Contribute to the Transcriptional Repression of Solute Carrier Family 47 Member 2 in Renal Cell Carcinoma.

In recent years, finding effective biomarkers for identifying early stage cancer and predicating prognosis is crucial for renal cell carcinoma (RCC) diagnosis and treatment. In this study, a dramatic decrease of the solute carrier family 47 member 2 (SLC47A2) mRNA in RCC comparing with the paired adjacent nontumor tissues from patients at low Tumor Node Metastasis stage was observed. Thus, patients with SLC47A2 transcriptional repression are susceptible to RCC. Little is known about the regulation mechanism of SLC47A2 We found that it was a bivalent gene that was enriched with both histone H3 lysine 4 trimethylation (H3K4me3) and lysine 27 trimethylation (H3K27me3). Loss of mixed lineage leukemia 1 binding at the gene promoter caused decreased H3K4me3 enrichment and H3K4me3/H3K27me3 ratio, and subsequently repressed the expression of SLC47A2 These two epigenetic markers modulated the expression of SLC47A2 simultaneously, suggesting the regulation pattern for bivalent genes. Histone H3 lysine 27 acetylation also contributed to the expression of SLC47A2 An E2F1-histone deacetylase 10 complex catalyzed deacetylation of H3K27, then prevented the enrichment of H3K4me3, and finally reduced SLC47A2 expression. Consequently, the combined effect of all these factors determined SLC47A2 transcriptional repression in RCC tissues.

[Determination of enantiomeric impurity of timolol maleate in bulk substances and eye drops].

OBJECTIVE: To determine the enantiomeric impurity contents of domestic timolol maleate in bulk drugs and eye drops. METHODS: Enantiomer impurity of timolol was assayed by chiral high performance liquid chromatography. The chromatographic conditions were as follows:chiralcel OD chiral column (4.6 mm ×150 mm, 5µm), detection wavelength:297 nm, mobile phase:hexane-isopropanol-diethylamine (480:20:1), column temperature:25 ℃, flow rate:1.0 ml/min, sample injection volume:5 µl. RESULTS: The resolution between R- and S-timolol was more than 4. The enantiomeric impurity contents were less than 0.67% on average in two batches of timolol maleate bulk drugs, and 0.31% on average in three batches of timolol maleate eye drops. CONCLUSION: Enantiomeric impurity contents in each batch of products all meet European Pharmacopoeia criteria, which can be used as references in Chinese Pharmacopoeia criteria.

[Enantiomeric separation and impurity determination of valaciclovir hydrochloride].

OBJECTIVE: To determine the contents of L-enantiomer impurity in valaciclovir hydrochloride. METHODS: Valaciclovir enantiomers were separated and determined by using chiral high performance liquid chromatography. Chromatographic conditions were as follows:CROWNPAK(®) CR(+) chiral column (4 mm×150 mm, 5 µm), detection wavelength:254 nm, mobile phase:water-methanol-perchloric acid (19:1:0.1), flow rate:0.75 ml/min, sample injection volume:10 µl. RESULTS: D-valaciclovir was completely separated from L-enantiomer impurity. The contents of L-enantiomer impurity were 0.65%-2.62% on average in 8 batches of valaciclovir hydrochloride. CONCLUSION: Enantiomeric impurity contents in each batch of products were all meet criteria of United States Pharmacopeia, which can be used in criteria of Chinese Pharmacopeia as references.

Research on provincial water resources carrying capacity and coordinated development in China based on combined weighting TOPSIS model.

With the continuous development of the economy and society, along with the sustained population growth, the issue of water resources carrying capacity in China has attracted increasing attention. This paper constructs a model for evaluating the provincial water resources carrying capacity in China from four dimensions: water, economy, society, and ecology. Utilizing this model, we analyze the spatiotemporal variations in water resources carrying capacity among 31 provinces in China from 2005 to 2021. Additionally, we delve into the coupling coordination and influencing factors of water resources carrying capacity. The study reveals an overall increasing trend in China's water resources carrying capacity index, with the ecological indicator exhibiting the most significant growth while the water resources sub-indicator lags behind. There are notable regional differences, with higher water resources carrying capacity observed in the eastern coastal areas and relatively lower capacity in the western regions. The ecological criterion becomes a core factor constraining water resources carrying capacity from 2005 to 2015, gradually giving way to the prominence of the social criterion since 2015. The coordination degree is relatively higher in the eastern regions, more scattered in the western regions, and relatively stable in the central regions. Based on the research findings, a series of recommendations are proposed, including strengthening environmental protection policies, optimizing water resources management mechanisms, improving water use efficiency, and promoting economic structural diversification. These suggestions aim to facilitate the sustainable development of water resources carrying capacity in China.

Evaluation of dried blood spots for Epstein-Barr virus nucleic acid testing.

Epstein-Barr virus (EBV) is a ubiquitous and oncogenic virus that is associated with various malignancies and non-malignant diseases and EBV DNA detection is widely used for the diagnosis and prognosis prediction for these diseases. The dried blood spots (DBS) sampling method holds great potential as an alternative to venous blood samples in geographically remote areas, for individuals with disabilities, or for newborn blood collection. Therefore, the objective of this study was to assess the viability of detecting EBV DNA load from DBS. Matched whole blood and DBS samples were collected for EBV DNA extraction and quantification detection. EBV DNA detection in DBS presented a specificity of 100 %. At different EBV DNA viral load in whole blood, the sensitivity of EBV DNA detection in DBS was 38.78 % (≥1 copies/mL), 43.18 % (≥500 copies/mL), 58.63 % (≥1000 copies/mL), 71.43 % (≥2000 copies/mL), 82.35 % (≥4000 copies/mL), and 92.86 % (≥5000 copies/mL), respectively. These results indicated that the sensitivity of EBV DNA detection in DBS increased with elevating viral load. Moreover, there was good correlation between EBV DNA levels measured in whole blood and DBS, and on average, the viral load measured in whole blood was about 6-fold higher than in DBS. Our research firstly demonstrated the feasibility of using DBS for qualitative and semi-quantitative detection of EBV DNA for diagnosis and surveillance of EBV-related diseases.

[Role of COX-2/PGE2/EP4 Axis-induced Macrophage Functional Activation 
in NSCLC Development].

BACKGROUND: Tumor microenvironment (TME) is one of the important factors in tumorigenesis and progression, in which tumor-associated macrophages (TAMs) play an important role in non-small cell lung cancer (NSCLC) progression. However, the mechanism of TAMs in NSCLC progression remains unclear, so this study aimed to investigate the role of TAMs in NSCLC progression and to find potential therapeutic targets. METHODS: Gene Expression Profiling Interactive Analysis (GEPIA) database was used to analyze the expression of prostaglandin E2 receptor 4 (EP4) mRNA in NSCLC and normal lung tissues; the protein expression levels of cyclooxygenase-2 (COX-2), EP4, cluster of differentiation 86 (CD86), CD163 and CD31 were detected by immunohistochemistry (IHC) in 120 NSCLC tissues and 24 paracancerous tissues specimens. The nude mouse lung adenocarcinoma cell A549 and macrophage RAW264.7 co-transplanted tumor model was established. And the samples were collected by gavage with EP4 inhibitor E7046, and then stained with hematoxylin-eosin (HE), IHC, and immunofluorescence (IF), and then detected by Western blot for the epithelial mesenchymal transformation (EMT) of the tumor tissues of the nude mice in each group. Western blot was used to detect the expressions of EMT related protiens in each group of nude mice; full-length transcriptome sequencing was used to screen the key genes causing liver metastasis and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis was performed. RESULTS: EP4 mRNA expression level in NSCLC tissues was generally lower than that in normal lung tissues (P<0.05); COX-2, EP4, CD163, CD31 proteins were differentially expressed in NSCLC tissues and adjacent tissues, and differences were observed in many clinicopathological parameters of NSCLC patients; RAW264.7 shortened the latency period of tumorigenesis of A549 and promoted the proliferation of tumors and liver metastasis of tumors, and E7046 could reduce tumor cell proliferation activity, tumor tissue vascular density and M2-type macrophage infiltration in nude mice; IF staining showed that macrophages were mainly distributed around the metastatic foci of tumors; Western blot results showed that compared with A549 alone transplantation group, the relative expression of E-cadherin protein in tumor tissues of mice in A549 and RAW264.7 co-transplantation group was significantly decreased, and the difference was statistically significant (P<0.05), while the relative expression of N-cadherin protein was up-regulated, but the difference was not statistically significant (P>0.05); the main pathways enriched in the differential genes of the full-length transcriptome were the PI3K-AKT and MAPK signaling pathways. CONCLUSIONS: During NSCLC development, the COX-2/PGE2/EP4 axis may promote tumor progression by inducing macrophage functional activation, and EP4 may be a potential new target for tumor immunotherapy. This study provides new perspectives and ideas for in-depth exploration of the mechanisms of NSCLC development, as well as a theoretical basis for the development of new therapeutic strategies for NSCLC.

Occurrence and distribution of atrazine in groundwater from agricultural areas in China.

There has been heavy application of chemical pesticides to farmland worldwide. As a state with a heavy emphasis on farming, China has extensively applied chemical pesticides to farmlands. Atrazine (ATZ), one of the most widely used herbicide in the world, has been used in large quantities in weed control in many crops, which poses a relatively large threat to groundwater utilization and agricultural safety. A nationwide sampling and analysis of ATZ in 8146 groundwater monitoring wells from 10 main grain producing areas were conducted during 2019. The results showed that the detection rate of ATZ in groundwater was 40.79 %, with detected concentrations up to 2.86 µg/L. ATZ detection rate was significantly higher in phreatic aquifers than confined aquifer. The concentration of ATZ decreased significantly with the depth increasing, the detected depth of ATZ in groundwater was varied from 5 to 1100 m, and 70.27 % of the detected ATZ was distributed in the depth of 0-51.8 m. The detection rate of ATZ in most north regions lower than south regions in China, and ATZ with high concentration was mainly occurred in southern regions. ATZ is more likely to migrate into the groundwater in the water resource rich areas. The concentration of ATZ decreased with TDS increasing, 74.39 % of the ATZ was detected in groundwater with TDS concentration <1 g/L. The hydrochemical type of groundwater in ATZ-enrichment environment were mainly Ca-HCO3 and Mixed type. According to classification and regression tree analysis, the high ATZ detection rate were closely related with groundwater depth (<51.8 m) and high organic matter content.

Epidermal stem cells manipulated by pDNA-VEGF165/CYD-PEI nanoparticles loaded gelatin/ß-TCP matrix as a therapeutic agent and gene delivery vehicle for wound healing.

The success of gene therapy largely relies on a safe and effective gene delivery system. The objective of this study is to design a highly efficient system for the transfection of epidermal stem cells (ESCs) and investigate the transfected ESCs (TESCs) as a therapeutic agent and gene delivery reservoir for wound treatment. As a nonviral vector, ß-cyclodextrin-linked polyethylenimines (CYD-PEI) was synthesized by linking ß-cyclodextrin with polyethylenimines (600 Da). Gelatin scaffold incorporating ß-tricalcium phosphate (ß-TCP) was utilized as a substrate for the culture and transfection of ESCs. With the CYD-PEI/pDNA-VEGF165 polyplexes incorporated gelatin/ß-TCP scaffold based 3D transfection system, prolonged VEGF expression with a higher level was obtained at day 7 in ESCs than those in two-dimensional plates. Topical application of the TESCs significantly accelerated the skin re-epithelization, dermal collagen synthesis, and hair follicle regeneration. It also exhibited a potential in scar inhibition by regulating the distribution of different types of collagen. In contrast to ESCs, an additive capacity in stimulating angiogenesis at the wound site was observed in the TESCs. The present study provides a basis for the TESCs as a promising therapeutic agent and gene delivery reservoir for wound therapy.

Bioinformatics analysis of the pathogenic link between Epstein-Barr virus infection, systemic lupus erythematosus and diffuse large B cell lymphoma.

Epstein-Barr virus (EBV) is a risk factor for diffuse large B-cell lymphoma (DLBCL) and systemic lupus erythematosus (SLE). While prior research has suggested a potential correlation between SLE and DLBCL, the molecular mechanisms remain unclear. The present study aimed to explore the contribution of EBV infection to the pathogenesis of DLBCL in the individuals with SLE using bioinformatics approaches. The Gene Expression Omnibus database was used to compile the gene expression profiles of EBV-infected B cells (GSE49628), SLE (GSE61635), and DLBCL (GSE32018). Altogether, 72 shared common differentially expressed genes (DEGs) were extracted and enrichment analysis of the shared genes showed that p53 signaling pathway was a common feature of the pathophysiology. Six hub genes were selected using protein-protein interaction (PPI) network analysis, including CDK1, KIF23, NEK2, TOP2A, NEIL3 and DEPDC1, which showed preferable diagnostic values for SLE and DLBCL and involved in immune cell infiltration and immune responses regulation. Finally, TF-gene and miRNA-gene regulatory networks and 10 potential drugs molecule were predicted. Our study revealed the potential molecular mechanisms by which EBV infection contribute to the susceptibility of DLBCL in SLE patients for the first time and identified future biomarkers and therapeutic targets for SLE and DLBCL.

A gB nanoparticle vaccine elicits a protective neutralizing antibody response against EBV.

Epstein-Barr virus (EBV) is a global public health concern, as it is known to cause multiple diseases while also being etiologically associated with a wide range of epithelial and lymphoid malignancies. Currently, there is no available prophylactic vaccine against EBV. gB is the EBV fusion protein that mediates viral membrane fusion and participates in host recognition, making it critical for EBV infection in both B cells and epithelial cells. Here, we present a gB nanoparticle, gB-I53-50 NP, that displays multiple copies of gB. Compared with the gB trimer, gB-I53-50 NP shows improved structural integrity and stability, as well as enhanced immunogenicity in mice and non-human primate (NHP) preclinical models. Immunization and passive transfer demonstrate a robust and durable protective antibody response that protects humanized mice against lethal EBV challenge. This vaccine candidate demonstrates significant potential in preventing EBV infection, providing a possible platform for developing prophylactic vaccines for EBV.