Fusion with extracellular domain of cytotoxic T-lymphocyte-associated-antigen 4 leads to enhancement of immunogenicity of Hantaan virus DNA vaccines in C57BL/6 mice

<p>Abstract</p> <p>Background</p> <p>Hantaan virus (HTNV) is the causative agent of the most severe form of a rodent-borne disease known as hemorrhagic fever with renal syndrome (HFRS). A safe and effective HTNV vaccine is needed. Vaccination with DNA constructs expressing fused antigen with bioactive factors, has shown promising improvement of immunogenicity for viral agents in animal models, but the effect of fusion strategy on HTNV DNA vaccine has not been investigated.</p> <p>Results</p> <p>DNA plasmids encoding the HTNV nucleocapsid protein (N) and glycoprotein (Gn and Gc) in fusion to the extracellular domain of cytotoxic T-lymphocyte-associated-antigen 4 (eCTLA-4) targeting to antigen presenting cells (APCs) were constructed. Intramuscular immunization of mice with plasmids expressing eCTLA-4-HTNV-N/GP fusion proteins leads to a significant enhancement of the specific antibody response as well as cytotoxic T-lymphocyte (CTL) response in C57BL/6 mice. Moreover, this effect could be further augmented when co-administered with CpG motifs.</p> <p>Conclusions</p> <p>Modification of viral antigen in fusion to bioactive factor will be promising to confer efficient antigen presentation and improve the potency of DNA vaccine in mice.</p

Methylprednisolone as Adjunct to Endovascular Thrombectomy for Large-Vessel Occlusion Stroke

Importance It is uncertain whether intravenous methylprednisolone improves outcomes for patients with acute ischemic stroke due to large-vessel occlusion (LVO) undergoing endovascular thrombectomy. Objective To assess the efficacy and adverse events of adjunctive intravenous low-dose methylprednisolone to endovascular thrombectomy for acute ischemic stroke secondary to LVO. Design, Setting, and Participants This investigator-initiated, randomized, double-blind, placebo-controlled trial was implemented at 82 hospitals in China, enrolling 1680 patients with stroke and proximal intracranial LVO presenting within 24 hours of time last known to be well. Recruitment took place between February 9, 2022, and June 30, 2023, with a final follow-up on September 30, 2023.InterventionsEligible patients were randomly assigned to intravenous methylprednisolone (n = 839) at 2 mg/kg/d or placebo (n = 841) for 3 days adjunctive to endovascular thrombectomy. Main Outcomes and Measures The primary efficacy outcome was disability level at 90 days as measured by the overall distribution of the modified Rankin Scale scores (range, 0 [no symptoms] to 6 [death]). The primary safety outcomes included mortality at 90 days and the incidence of symptomatic intracranial hemorrhage within 48 hours. Results Among 1680 patients randomized (median age, 69 years; 727 female [43.3%]), 1673 (99.6%) completed the trial. The median 90-day modified Rankin Scale score was 3 (IQR, 1-5) in the methylprednisolone group vs 3 (IQR, 1-6) in the placebo group (adjusted generalized odds ratio for a lower level of disability, 1.10 [95% CI, 0.96-1.25]; P = .17). In the methylprednisolone group, there was a lower mortality rate (23.2% vs 28.5%; adjusted risk ratio, 0.84 [95% CI, 0.71-0.98]; P = .03) and a lower rate of symptomatic intracranial hemorrhage (8.6% vs 11.7%; adjusted risk ratio, 0.74 [95% CI, 0.55-0.99]; P = .04) compared with placebo. Conclusions and Relevance Among patients with acute ischemic stroke due to LVO undergoing endovascular thrombectomy, adjunctive methylprednisolone added to endovascular thrombectomy did not significantly improve the degree of overall disability.Trial RegistrationChiCTR.org.cn Identifier: ChiCTR210005172

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Hydrocarbon formation and accumulation of the deep Paleogene of the Jiyang Depression, Shengli Oilfield

Using geochemistry, sedimentary and petroleum geology methods, and based on the analysis of spatial distribution of deep source rocks and sedimentary organic facies, the favorable exploration prospects in the Jiyang Depression, Shengli Oilfield are studieded. There are 4 types of sedimentary organic facies (including anoxic organic facies, anaerobic organic facies, dysaerobic organic facies and aerobic organic facies) in deep source rocks of Kongdian Formation - Sha-4 Member, Paleogene. The source rocks of Anoxic facies and anaerobic facies are discovered in the Sha-4 Member and are proved as excellent source rocks, while the Kongdian Formation source rocks compose mainly of the dysaerobic facies and aerobic facies and served as common source rocks. The whole hydrocarbon expulsion process is divided into 3 stages, including free water expulsion, hydrocarbon generation and energy accumulation, and hydrocarbon expulsion from microfractures. The hydrocarbon expulsion from deep source rocks mainly occurs in the stage of hydrocarbon expulsion from microfractures, during which there are three oil and gas migration modes with different geologic conditions, including vertical migration, lateral migration and downward migration. The studies indicated that the hydrocarbons in shallow and medium formations from the Sha-4 Member excellent source rocks of anoxic and anaerobic facies are mainly accumulated through vertical migration along the faults, while the reservoirs formed by lateral migration and downward migration are still waiting to be revealed. So there is great exporation potential for the deep Paleogene of the Jiyang Depression. Key words: Jiyang Depression, Paleogene, organic facies, hydrocarbon generation and expulsion mechanism, hydrocarbon migration, accumulatio

Control of pressure system development on reservoir formation in the Dongying Sag, Shengli Oilfield, East China

The zonality of abnormal pressure is closely correspondent to the breakthrough pressure (or pressure preservative ability) of mudstones in the Dongying Sag. The breakthrough pressures and formation fluid pressure coefficients rise with increasing depth. The preservation of isolated mudstone intervals is also important to the abnormal pressure formation. Based on the episodic difference of pressure buildup mechanism, source dynamic (fluid pressure in source rocks) fields of critical geologic times were analyzed in lateral plane and vertical profiles in the Dongying Sag. Source dynamic of major source rocks occurs in disequilibrium with time and space, which affects oil-gas sources and reservoir formation and controls the direction of oil-gas migration as a whole. The present reservoirs are distributed along the pressure decreasing directions. The distribution of the reservoirs is successional to the evolution of source dynamic. On the other hand, oil-gas migration and accumulation affect the distribution of formation pressure fields. The isolated mudstone intervals preserve the fluid pressures to different extents. Due to the equilibrium between pressure buildup and pressure relief, source dynamic creates different conditions in various pressure systems during its transference, which cause the differences in types and features of oil-gas reservoirs. Based on the evolutionary history of source dynamic, the reservoir forming process in the Dongying Sag was analyzed. The deep layers of the Shahejie Formation are important targets for us to discover light hydrocarbon and natural gas reservoirs with high pressures. 摘 要: 东营凹陷异常压力的分带性与泥岩的突破压力（或保存能力）具有明显的对应关系，随着深度增加，泥岩突破压力及地层流体压力系数均增大，泥岩封隔层对流体压力的保存也是形成异常压力的重要条件。基于增压机制的阶段性差异，对东营凹陷平面上及典型剖面中重要地质历史时期源动力（烃源岩流体压力）场进行了分析，主力烃源岩的源动力在时间和空间上发育不均衡，从整体上影响了储集层油气来源及油藏的形成，控制了油气运移的方向。现今油藏总体沿地质历史时期源动力场降低的方向分布，表现出油藏的分布与源动力的演化具有一定的继承性；油气运移和成藏也影响了地层压力场的分布，高压油气运移到储集层后，其泥岩封隔层不同程度地保存了流体压力。由于增压-卸压的平衡关系，源动力传递过程中在不同压力系统中构成了不同的动力条件，造成了各压力系统中油气成藏类型和特征具有一定的差异性。根据源动力的演化史，指出沙河街组深层是寻找高压轻质油藏及天然气藏的重要目标。 Key words: Dongying Sag, palaeopressure, petroleum accumulation, controlling, fillin

The Relation between Immunological Features and the Positive SARS-CoV-2 Nucleic Acid in Patients with Nonsevere COVID⁃19

Objective. The novel coronavirus nucleic acid results are the core indicators of illness monitoring. This study aimed to evaluate the relationship between immunological features and positive SARS-CoV-2 nucleic acid by analyzing the clinical and immunological features in nonsevere COVID-19 cases. Methods. Data from nonsevere COVID-19 patients admitted to Haihe Hospital from May 2020 to June 2021 were retrospectively reviewed and analyzed. Results. (1) A total of 122 cases were reviewed in the present study, including 38 mild and 84 moderate cases. The average age of mild cases was significantly different from moderate cases (P<0.001). Eight patients complained of hyposmia and it was more frequent in mild cases (P<0.001). The nucleic acid positive duration (NPD) of nonsevere novel coronavirus was 20.49 (confidence interval (CI) 17.50–3.49) days. (2) The levels of specific IgM and IgG for COVID-19 were higher in mild cases than in moderate cases (P=0.023 and P=0.047, respectively). (3) The correlation analysis with antibodies and T-cell subtypes showed that the lymphocyte (LYM) count, T cells, CD4+T cells, and CD8+T cells had a linear correlation with NPD. (4) Among the 93 patients monitored, 62 COVID-19 cases presented a progressive rise of specific IgM and IgG. The daily increase rates of IgM and IgG were 38.42% (CI 28.22–48.61%) and 24.90% (CI 0.23–29.58%), respectively. Conclusion. The levels and daily increase rates of specific IgM and IgG against the virus can vary between cases. The NPD presented a linear correlation with the LYM, T cells, CD4+T cells, and CD8+T cells. Hence, more attention should be paid to these indicators in clinical practice

Architectures and Applications of BODIPY-Based Conjugated Polymers

Conjugated polymers generally contain conjugated backbone structures with benzene, heterocycle, double bond, or triple bond, so that they have properties similar to semiconductors and even conductors. Their energy band gap is very small and can be adjusted via chemical doping, allowing for excellent photoelectric properties. To obtain prominent conjugated materials, numerous well-designed polymer backbones have been reported, such as polyphenylenevinylene, polyphenylene acetylene, polycarbazole, and polyfluorene. 4,4&prime;-Difluoro-4-bora-3a,4a-diaza-s-indacene (BODIPY)-based conjugated polymers have also been prepared owing to its conjugated structure and intriguing optical properties, including high absorption coefficients, excellent thermal/photochemical stability, and high quantum yield. Most importantly, the properties of BODIPYs can be easily tuned by chemical modification on the dipyrromethene core, which endows the conjugated polymers with multiple functionalities. In this paper, BODIPY-based conjugated polymers are reviewed, focusing on their structures and applications. The forms of BODIPY-based conjugated polymers include linear, coiled, and porous structures, and their structure&ndash;property relationship is explored. Also, typical applications in optoelectronic materials, sensors, gas/energy storage, biotherapy, and bioimaging are presented and discussed in detail. Finally, the review provides an insight into the challenges in the development of BODIPY-based conjugated polymers

Synthesis and Properties of Novel Reactive Dyes Comprising Acyl Fluoride Group on Cotton Fabrics

Novel reactive dyes with mono- and bi-acyl fluoride reactive groups have been designed and synthesized, which are obtained by using 2-amino-8-naphthol-6-sulfonic acid or 1-amino-8-naphthol-3,6-disulfonicacid as the coupling component and 4-aminobenzoyl fluoride (PABF) as the diazo component. Their structures have been defined by nuclear magnetic resonance spectroscopy and ultraviolet&ndash;visible spectra (UV&mdash;Vis). The novel reactive dyes were evaluated on cotton by using the exhaust dyeing method. The properties were examined in detail, and the results showed that the dye concentration of 4% (o.w.f), pH = 9, and salt-free was the most effective condition. The fixation of the novel reactive dyes on cotton was 60.27% and 64.13%, respectively. The micro-fluorine-containing reactive dyes have favorable dyeing properties owing to the covalent bond formed between the reactive group of dyes and the functional group of cotton fibers, which can achieve salt-free dyeing of cotton