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Emerging evidence underscores the importance of CD8 + T cells in the pathogenesis of multiple sclerosis (MS), but the precise mechanisms remain ambiguous. This study intends to elucidate the involvement of a novel subset of follicular CD8 + T cells (CD8 + CXCR5 + T) in MS and an experimental autoimmune encephalomyelitis (EAE) murine model. The expansion of CD8 + CXCR5 + T cells was observed in both MS patients and EAE mice during the acute phase. In relapsing MS patients, higher frequencies of circulating CD8 + CXCR5 + T cells were positively correlated with new gadolinium-enhancement lesions in the central nervous system (CNS). In EAE mice, frequencies of CD8 + CXCR5 + T cells were also positively correlated with clinical scores. These cells were found to infiltrate into ectopic lymphoid-like structures in the spinal cords during the peak of the disease. Furthermore, CD8 + CXCR5 + T cells, exhibiting high expression levels of ICOS, CD40L, IL-21, and IL-6, were shown to facilitate B cell activation and differentiation through a synergistic interaction between CD40L and IL-21. Transferring CD8 + CXCR5 + T cells into naïve mice confirmed their ability to enhance the production of anti-MOG 35-55 antibodies and contribute to the disease progression. Consequently, CD8 + CXCR5 + T cells may play a role in CNS demyelination through heightening humoral immune responses., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Background: Colorectal cancer (CRC) is one of the most common malignant tumors of the digestive system, ranking third for morbidity and mortality worldwide. At present, no effective control method is available for this cancer type. In tumor cells, especially iron metabolization, is necessary for its growth and proliferation. High levels of iron are an important feature to maintain tumor growth; however, the overall mechanism remains unclear., Methods: We used western blotting, immunohistochemistry (IHC) and real-time quantitative PCR to analyze the expression of IGF2BP2 in cell lines and tissues. Further, RNA-sequencing, RNA immunoprecipitation and methylated RNA immunoprecipitation experiments explored the specific binding of target genes. Moreover, the RNA stability assay was performed to determine the half-life of genes downstream of IGF2BP2. In addition, the Cell Counting Kit-8, colony formation assay, 5-ethynyl-2'-deoxyuridine assay and flow cytometry were used to evaluate the effects of IGF2BP2 on proliferation and iron metabolism. Lastly, the role of IGF2BP2 in promoting CRC growth was demonstrated in animal models., Results: We observed that IGF2BP2 is associated with iron homeostasis and that TFRC is a downstream target of IGF2BP2. Further, overexpression of TFRC can rescue the growth of IGF2BP2-knockdown CRC cells. Mechanistically, we determined that IGF2BP2 regulates TFRC methylation via METTL4, thereby regulating iron metabolism and promoting CRC growth. Furthermore, using animal models, we observed that IGF2BP2 promotes CRC growth., Conclusion: IGF2BP2 regulates TFRC mRNA methylation via METTL4, thereby regulating iron metabolism and promoting CRC growth. Our study highlights the key roles of IGF2BP2 in CRC carcinogenesis and the iron transport pathways., (© 2023. The Author(s).)

We have successfully modified a series of pyrrolo[2,1- a ]isoquinolines via direct nitration under mild reaction conditions. Easily accessible nitrates including CAN, Cu(NO 3 ) 2 ·H 2 O, and Fe(NO 3 ) 3 ·9H 2 O all can serve as effective nitrating reagents for functionalizing pyrrolo[2,1- a ]isoquinolines. Various nitro-bearing pyrrolo[2,1- a ]isoquinolines have been efficiently prepared in acceptable to good yields.

Crimean-Congo hemorrhagic fever virus (CCHFV) can cause severe hemorrhagic fever in humans and is mainly transmitted by ticks. There is no effective vaccine for Crimean-Congo hemorrhagic fever (CCHF) at present. We developed three DNA vaccines encoding CCHFV nucleocapsid protein (NP), glycoprotein N-terminal (Gn) and C-terminal (Gc) fused with lysosome-associated membrane protein 1 (LAMP1) and assessed their immunogenicity and protective efficacy in a human MHC (HLA-A11/DR1) transgenic mouse model. The mice that were vaccinated three times with pVAX-LAMP1-CCHFV-NP induced balanced Th1 and Th2 responses and could most effectively protect mice from CCHFV transcription and entry-competent virus-like particles (tecVLPs) infection. The mice vaccinated with pVAX-LAMP1-CCHFV-Gc mainly elicited specific anti-Gc and neutralizing antibodies and provided a certain protection from CCHFV tecVLPs infection, but the protective efficacy was less than that of pVAX-LAMP1-CCHFV-NP. The mice vaccinated with pVAX-LAMP1-CCHFV-Gn only elicited specific anti-Gn antibodies and could not provide sufficient protection from CCHFV tecVLPs infection. These results suggest that pVAX-LAMP1-CCHFV-NP would be a potential and powerful candidate vaccine for CCHFV., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Hu, Zhang, Liu, Ye, Zhao, Zhang, Qiang, Zhang, Lei, Jiang, Cheng and Zhang.)

Oxidative bromination has been serving as a powerful tool for the synthesis of bromo-containing molecules, as this bromination strategy features environmental friendliness, high flexibility in reaction system design and wide abundance of bromide sources and oxidants. The past decade has witnessed a large number of efficient oxidative bromination reaction systems and novel brominated aromatics. This review summarizes recent developments in the field of oxidative preparation of bromoarenes and bromoheteroarenes covering from 2012 to 2022.

Background: Minimal research has been performed regarding total arch replacement through partial upper sternotomy in patients with acute type A aortic dissection who are obese, and the safety and feasibility of this procedure need to be further investigated. The present study investigated the potential clinical advantages of using a partial upper sternotomy versus a conventional full sternotomy for total arch replacement in patients who were obese., Methods: This was a retrospective study. From January 2017 to January 2020, a total of 65 acute type A aortic dissection patients who were obese underwent total arch replacement with triple-branched stent graft. Among them, 35 patients underwent traditional full sternotomy, and 30 patients underwent partial upper sternotomy. The perioperative clinical data and postoperative follow-up results of the two groups were collected, and the feasibility and clinical effect of partial upper sternotomy in total arch replacement were summarized., Results: The in-hospital mortality rates of the two groups were similar. The total operative time, cardiopulmonary bypass, aortic cross-clamp, cerebral perfusion, and deep hypothermic circulatory arrest times were also similar in both groups. The thoracic drainage and postoperative red blood cell transfusion volumes in the partial upper sternotomy group were significantly lower than those in the full sternotomy group. Mechanical ventilation time was shorter in the partial upper sternotomy group than that in the full sternotomy group. Additionally, the incidences of pulmonary infection, hypoxemia, and sternal diaphoresis were lower in the partial upper sternotomy group than those in the full sternotomy group., Conclusion: This study showed that total arch replacement surgery through a partial upper sternotomy in patients with acute type A aortic dissection who are obese is safe, effective, and superior to full sternotomy in terms of blood loss, postoperative blood transfusion, and respiratory complications., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Xie, He, Wu, Qiu, Jiang, Gao and Chen.)

Background: Partial upper sternotomy (mini-ER) can be used in some adult cardiac surgeries but is seldom performed in the treatment of acute type A aortic dissection (AAAD). This study aimed to assess the feasibility and short-term outcomes of complete stent-graft replacement of the arch with triple-branched stent graft for AAAD through a mini-ER., Methods: From 2015 to 2018, 254 patients with AAAD underwent complete stent-graft replacement of the arch with a triple-branched stent graft. Replacement was performed with conventional full sternotomy (con-ER) in 142 patients and with mini-ER in the other 112 patients. Using propensity score matching, the clinical data were compared between 100 patients in the mini-ER group and 100 patients in the con-ER group., Results: After propensity score matching, there were no significant between-group differences in aortic cross-clamp time, cardiopulmonary bypass time, or total operative time. The amount of mediastinal drainage and number of red blood cell units were significantly lower in the mini-ER group compared with the con-ER group (P < .001). The intubation time was significantly shorter in the mini-ER group (P < .001). The treatment costs were also lower in the mini-ER group (P < .001). There were no significant between-group differences in 30-day mortality (9% vs 8%; P > .99) or postoperative complications., Conclusions: This study shows that extensive repair of AAAD through a mini-ER is feasible. It was superior to con-ER in terms of blood loss, postoperative ventilation time, and treatment costs., (Copyright © 2020 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)

Objective: Controversial opinions exist for aortic valve replacement (AVR) through partial upper sternotomy in obese patients. Moreover, this study sought to investigate the potential clinical advantage of partial upper sternotomy aortic valve replacement (mini-AVR) over conventional full sternotomy aortic valve replacement (con-AVR) in obese patients., Methods: This was a retrospective and observational study. From January 2015 to December 2020, a total of 184 obese [body mass index (BMI) ≥ 30 kg  m 2 ] patients undergoing isolated primary AVR were included: 98 patients underwent conventional full sternotomy, and 86 patients underwent partial upper sternotomy. Propensity score (PS) matching was applied to eliminate the bassline imbalances in the mini-AVR and the con-AVR groups., Results: After one-to-one propensity score matching, two groups of 60 patients were obtained. No in-hospital death occurred in the two groups. In addition, cardiopulmonary bypass time and total operative time were similar across the 2 groups, but the aortic cross-clamp time was significantly shorter in the con-AVR group (P = .0.022). The amount of mediastinal drainage at 48 h after surgery (P =  0.018) and postoperative blood transfusions (P =  0.014) were significantly lower in the mini-AVR group. There was no difference in ventilation time (P = .0.145), but a shorter intensive care unit stay time (P =  0.021) in the mini-AVR group., Conclusion: This study demonstrates that aortic valve replacement through a mini-AVR in obese patients is a safe and effective procedure. It outperformed con-AVR in terms of blood loss, blood product transfusion, and ICU stay., (© 2022. The Author(s).)

Malignancies of alimentary tract include esophageal carcinoma (ESCA), stomach adenocarcinoma (STAD), colon adenocarcinoma (COAD), and rectum adenocarcinoma (READ). Despite of their similarities in cancer development and progression, there are numerous researches concentrating on single tumor but relatively little on their common mechanisms. Our study explored the transcriptomic data of digestive tract cancers from The Cancer Genome Atlas database, yielding their common differentially expressed genes including 1,700 mRNAs, 29 miRNAs, and 362 long non-coding RNAs (lncRNAs). There were 12 mRNAs, 5 miRNAs, and 16 lncRNAs in the core competitive endogenous RNAs network by RNA-RNA interactions, highlighting the prognostic nodes of SERPINE1, hsa-mir-145, and SNHG1. In addition, the weighted gene co-expression network analysis (WGCNA) illustrated 20 gene modules associated with clinical traits. By taking intersections of modules related to the same trait, we got 67 common genes shared by ESCA and READ and screened 5 hub genes, including ADCY6, CXCL3, NPBWR1, TAS2R38, and PTGDR2. In conclusion, the present study found that SERPINE1/has-mir-145/SNHG1 axis acted as promising targets and the hub genes reasoned the similarity between ESCA and READ, which revealed the homogeneous tumorigenicity of digestive tract cancers at the transcriptome level and led to further comprehension and therapeutics for digestive tract cancers., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Lu, Shi, Zhang, Zhou, Zhou, Feng, Lu, Yang, Zhang, Liu, Li, Sun, Zheng, Jiang and Yang.)

Hemorrhagic fever with renal syndrome (HFRS) occurs widely throughout Eurasia. Unfortunately, there is no effective treatment, and prophylaxis remains the best option against the major pathogenic agent, hantaan virus (HTNV), which is an Old World hantavirus. However, the absence of cellular immune responses and immunological memory hampers acceptance of the current inactivated HFRS vaccine. Previous studies revealed that a lysosome-associated membrane protein 1 (LAMP1)-targeting strategy involving a DNA vaccine based on the HTNV glycoprotein Gn successfully conferred long-term immunity, and indicated that further research on Gc, another HTNV antigen, was warranted. Plasmids encoding Gc and lysosome-targeted Gc, designated pVAX-Gc and pVAX-LAMP/Gc, respectively, were constructed. Proteins of interest were identified by fluorescence microscopy following cell line transfection. Five groups of 20 female BALB/c mice were subjected to the following inoculations: inactivated HTNV vaccine, pVAX-LAMP/Gc, pVAX-Gc, and, as the negative controls, pVAX-LAMP or the blank vector pVAX1. Humoral and cellular immunity were assessed by enzyme-linked immunosorbent assays (ELISAs) and 15-mer peptide enzyme-linked immunospot (ELISpot) epitope mapping assays. Repeated immunization with pVAX-LAMP/Gc enhanced adaptive immune responses, as demonstrated by the specific and neutralizing antibody titers and increased IFN-γ production. The inactivated vaccine induced a comparable humoral reaction, but the negative controls only elicited insignificant responses. Using a mouse model of HTNV challenge, the in vivo protection conferred by the inactivated vaccine and Gc-based constructs (with/without LAMP recombination) was confirmed. Evidence of pan-epitope reactions highlighted the long-term cellular response to the LAMP-targeting strategy, and histological observations indicated the safety of the LAMP-targeting vaccines. The long-term protective immune responses induced by pVAX-LAMP/Gc may be due to the advantage afforded by lysosomal targeting after exogenous antigen processing initiation and major histocompatibility complex (MHC) class II antigen presentation trafficking. MHC II-restricted antigen recognition effectively primes HTNV-specific CD4 + T-cells, leading to the promotion of significant immune responses and immunological memory. An epitope-spreading phenomenon was observed, which mirrors the previous result from the Gn study, in which the dominant IFN-γ-responsive hot-spot epitopes were shared between HLA-II and H2 d . Importantly, the pan-epitope reaction to Gc indicated that Gc should be with potential for use in further hantavirus DNA vaccine investigations., (Copyright © 2017 Elsevier B.V. All rights reserved.)

BACKGROUND To observe and demonstrate therapeutic effects and side effects of two selective COX-2 inhibitors, imrecoxib and celecoxib, on patients with axial spondyloarthritis (axSpA) and observe the correlation between imaging scores and serum DKK-1 levels. MATERIAL AND METHODS Sixty patients with axSpA were randomly assigned to receive 200 mg imrecoxib or 200 mg celecoxib twice daily. Fifty-one patients who completed follow-up were included in the study. At baseline, week 4, and week 12, the clinical parameters, inflammatory markers (ESR, CRP), and adverse reactions were recorded. Serum DKK-1 levels were investigated by enzyme-linked immunosorbent assay. Radiographic scores were calculated by sacroiliac joint SPARCC (Spondyloarthritis Research Consortium of Canada) score method at baseline serum DKK-1 levels and week 12. RESULTS Patients in the imrecoxib group (n=25) and patients in the celecoxib group (n=26) were improved at week 4. At week 12, all clinical parameters and inflammatory markers were improved in the two groups and the differences was not statistically significant. Serum DKK-1 levels were decreased and the differences were not statistically significant. Serum DKK-1 levels in patients in the imrecoxib group at baseline were negatively correlated with all study parameters, while those in the celecoxib group had correlations with BASFI (r=-0.048, p=0.027) and Schober test (r=0.437, p=0.048), without any correlation with other clinical parameters or inflammatory markers. CONCLUSIONS Patients experienced significant improvement in disease activity, functional parameters, and inflammatory markers when treated with selective COX-2 inhibitors for 12 weeks, and the efficacy of imrecoxib was not inferior to celecoxib. Selective COX-2 inhibitors imrecoxib and celecoxib had no obvious effects on serum DKK-1 levels.

Background: Prophylaxis is widely adopted the best choice against Hemorrhagic fever with renal syndrome (HFRS) caused by Hantavirus. However, loss of memory immune response maintenance remains as major shortcoming in current HFRS vaccine. A recombinant DNA vaccine, pVAX-LAMP/Gn was previously proved efficient, requiring long-term evaluations., Methods & Results: Immune responses of Balb/c mice were assessed by specific and neutralizing antibodies, interferon-γ ELISpot assay, and cytotoxic T-lymphocyte cytotoxicity assay. HTNV-challenge assay identified long-term protection. Safety was confirmed by histological and behavioral analysis. Epitope-spreading phenomenon was noted, revealing two sets of dominant T-cell epitopes cross-species., Conclusion: pVAX-LAMP/Gn established memory responses within a long-term protection. Lysosome-targeted strategy showed promise on Gn-based DNA vaccine and further investigations are warranted in other immunogenic Hantaviral antigens., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Background: Hantaviral diseases can have a high case fatality rate within the absence of broadly effective antiviral treatments or vaccines. We developed a DNA vaccine targeting the Hantavirus glycoprotein N-terminal (Gn) to major histocompatibility complex class II compartment by fusing the antigen with lysosome-associated membrane protein 1 (LAMP1), which altered antigen presenting pathway and activated the CD4+ T cells., Methods: The segments of Gn and LAMP1 were cloned into vector pVAX1, and recombinant plasmid was constructed by inserting Gn sequence into LAMP1, between luminal and the transmembrane/cytoplasmic domains. Subsequently, the protein expression was identified through immunoprecipitation, western blot and Immunofluorescent assay. Adaptive immune responses were assessed by the presence of specific and neutralizing antibodies, interferon (ELISpot results, and cytotoxic T-lymphocyte (CTL) cytotoxicity. Epitope mapping was performed to study the T-cell epitopes. Protective immunity in vivo was evaluated using a novel HTNV-challenging model, and safety evaluation was based on histological and behavioral observations., Results: Native or LAMP1 targeting HTNV Gn was successfully identified. Humoral immune responses were enhanced, featuring with satisfying titers of specific and neutralizing antibody production. The boosted activities of IFN-γ and CTL cytotoxicity witnessed enhanced cellular immune responses. Effective protection against HTNV in vivo was conferred in all three vaccine groups by the challenge model. Safety was confirmed and one dominant T-cell epitope screened from immunized mice overlapped the specific T-cell hot spot in HFRS patients., Conclusion: LAMP1 targeting strategy successfully enhanced the efficacy of HTNV Gn-based vaccine, which is highly immunogenic and safe, showing promise for immunoprophylaxis against HFRS. Further investigations are warranted in the future., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

The intestinal permeability of forskolin was investigated using a single pass intestinal perfusion (SPIP) technique in rats. SPIP was performed in different intestinal segments (duodenum, jejunum, ileum, and colon) with three concentrations of forskolin (11.90, 29.75, and 59.90 µg/mL). The investigations of adsorption and stability were performed to ensure that the disappearance of forskolin from the perfusate was due to intestinal absorption. The results of the SPIP study indicated that forskolin could be absorbed in all segments of the intestine. The effective permeability (P (eff)) of forskolin was in the range of drugs with high intestinal permeability. The P (eff) was highest in the duodenum as compared to other intestinal segments. The decreases of P (eff) in the duodenum and ileum at the highest forskolin concentration suggested a saturable transport process. The addition of verapamil, a P-glycoprotein inhibitor, significantly enhanced the permeability of forskolin across the rat jejunum. The absorbed fraction of dissolved forskolin after oral administration in humans was estimated to be 100 % calculated from rat P (eff). In conclusion, dissolved forskolin can be absorbed readily in the intestine. The low aqueous solubility of forskolin might be a crucial factor for its poor oral bioavailability., (© Georg Thieme Verlag KG Stuttgart · New York.)

Aim: To evaluate the efficacies of six derivatives of Compound 2, a novel YycG histidine kinase inhibitor with the thiazolidione core structure in the treatment of medical device-related biofilm infections., Methods: The minimal inhibitory concentration (MIC) of the derivatives was determined using the macrodilution broth method, and the minimal bactericidal concentration (MBC) was obtained via sub-culturing 100 μL from each negative tube from the MIC assay onto drug-free Mueller-Hinton agar plates. Biofilm-killing effect for immature (6 h-old) biofilms was examined using a semiquantitative plate assay, and the effect on mature (24 h-old) biofilms was observed under a confocal laser scanning microscope (CLSM)., Results: The derivatives potently suppressed the growth of Staphylococcus epidermidis. The MIC values of the derivatives H2-10, H2-12, H2-20, H2-29, H2-27, and H2-28 on S epidermidis ATCC 35984 were 24.3, 6.5, 6.2, 3.3, 3.1, and 1.5 μg/mL, respectively. The MBC values of these derivatives were 48.6, 52.2, 12.4, 52.6, 12.4, and 6.2 μg/mL, respectively. The derivatives killed all bacteria in immature (6 h-old) biofilms and eliminated the biofilm proliferation. The derivatives also displayed strong bactericidal activities toward cells in mature (24 h-old) biofilms, whereas they showed low cytotoxicity and hemolytic activity toward Vero cells and human erythrocytes., Conclusion: The bactericidal and biofilm-killing activities of the new anti-YycG compounds were significantly better than the parent Compound 2.

Unlabelled: Dendritic cells (DC) are very potent antigen-presenting cells (APC) with a unique ability to activate naive T cells to induce the differentiation of TH1/TH2. Monocytes can develop into DC in the presence of different cytokines such as granulocyte-macrophage colony-stimulating factor (GM-CSF) and IL-4. DCs are thought to play a key role in the initiation and maintenance of T cell immunity to inhaled antigens. While the density of DC within the bronchial mucosa is increased in asthma, there is little information currently available concerning the effects of DC in asthmatic children., Objective: To investigate the role of dendritic cells in the pathogenesis of acute attack of asthma in children., Methods: Thomas' method was adopted. The adherent precursors of DC were isolated from peripheral blood of asthmatic children in acute attack stage and healthy controls. The adherent cells were induced with granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-4 (IL-4) and tumor necrosis factor-alpha (TNF-alpha) to DC in vitro. The expression of the surface molecules CD80, CD86, HLA-DR etc. on the DC was examined by fluorescent activated cell sorter (FACS). And the ability to secret IL-10, IL-12 and their potentials to stimulate the proliferative reaction of DC inductive self T- lymphocyte were observed., Results: The results showed that in asthmatic children's acute attack stage, self T- lymphocyte proliferative reaction induced by DC was remarkably increased compared with normal control subjects (P < 0.01). At the same time, the asthmatic children in acute attack stage had remarkably decreased the ability to secret IL-10 compared with normal control subjects (P < 0.01), while the ability to secret IL-12 remarkably decreased compared with normal control subjects (P < 0.01); meanwhile, the HLA-DR and co-stimulating factor CD86(B(7-2)) expressed by DCs remarkably increased in the asthmatic children in acute attack stage compared with normal control subjects (P < 0.01)., Conclusion: DC possibly plays a vital role in the immunological mechanism of asthma by means of inducing the differentiation of TH1/TH2, that is DC may be the key factor in initiating the airway allergic reaction and the possible mechanism may involve interleukins (especially IL-10 and IL-12, etc.) secreted by DCs.