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Abstract Unicystic ameloblastoma (UAM) of the jaw can be effectively reduced in volume through decompression, which promotes bone regeneration and restores jaw symmetry. This study quantitatively evaluated changes in mandible volume and symmetry following decompression of mandibular UAM. This study included 17 patients who underwent surgical decompression followed by second-stage curettage for mandibular UAM. Preoperative and postoperative three-dimensional computed tomography (CT) images were collected. Bone volume and the area of cortical perforation were measured to assess bone growth during decompression. Mandibular volumetric symmetry was analyzed by calculating the volumetric ratio of the two sides of the mandible. Twelve pairs of landmarks were identified on the surface of the lesion regions, and their coordinates were used to calculate the mean asymmetry index (AI) of the mandible. Paired t-tests and the Mann–Whitney U test were used for statistical analysis, with p

Abstract Glioma, with its heterogeneous microenvironments and genetic subtypes, presents substantial challenges for treatment prediction and development. We integrated 3D bioprinting and multi-algorithm machine learning as a novel approach to enhance the assessment and understanding of glioma treatment responses and microenvironment characteristics. The bioprinted patient-derived glioma tissues successfully recapitulated molecular properties and drug responses of native tumors. We then developed GlioML, a machine learning workflow incorporating nine distinct algorithms and a weighted ensemble model that generated robust gene expression-based predictors, each reflecting the diverse action mechanisms of various compounds and drugs. The ensemble model superseded the performance of all individual algorithms across diverse in vitro systems, including sphere cultures, complex 3D bioprinted multicellular models, and 3D patient-derived tissues. By integrating bioprinting, the evaluative scope of the treatment expanded to T cell-related therapy and anti-angiogenesis targeted therapy. We identified promising compounds and drugs for glioma treatment and revealed distinct immunosuppressive or angiogenic myeloid-infiltrated tumor microenvironments. These insights pave the way for enhanced therapeutic development for glioma and potentially for other cancers, highlighting the broad application potential of this integrative and translational approach.

The pursuit of high-performance is worth considerable effort in catalysis for energy efficiency and environmental sustainability. To develop redox catalysts with superior performance for soot combustion, a series of MnxCoy oxides were synthesized using MgO template substitution. This method greatly improves the preparation and catalytic efficiency and is more in line with the current theme of green catalysts and sustainable development. The resulting Mn1Co2.3 has a strong activation capability of gaseous oxygen due to a high concentration of Co3+ and Mn3+. The Mn doping enhanced the intrinsic activity by prompting oxygen vacancy formation and gaseous oxygen adsorption. The nanosheet morphology with abundant mesoporous significantly increased the solid–solid contact efficiency and improved the adsorption capability of gaseous reactants. The novel design of Mn1Co2.3 oxide enhanced its catalytic performance through a synergistic effect of Mn doping and the porous nanosheet morphology, showing significant potential for the preparation of high-performance soot combustion catalysts.

An important factor for investigating climate change in the Sanjiangyuan is the evolution of the spatio-temporal pattern of lakes in this region. The present study used the Google Earth Engine (GEE) platform to extract lakes from 2000 to 2020. The present approach created a lake distribution dataset yearly and analyzed spatial and temporal patterns over 20 years. The analysis of lakes focused on the reaction of the Sanjiangyuan Lakes area to changes in climate, glaciers, and permafrost. The findings indicated that the Sanjiangyuan region contains 143 lakes, the majority of which are predominantly small, measuring 1–10 km2. The small lakes account for 60.14 % of the total and are primarily located in the source regions of the Yangtze River and Yellow River. The findings demonstrated that the Sanjiangyuan lakes experienced a significant expansion over the past two decades, particularly from 2011 to 2020. These lakes are divided into expanded, atrophic, and stable categories. Expanded lakes showed significant inter-annual trends in expansion, while atrophic lakes showed smaller fluctuations. The area of stable lakes experienced a consistent decline after 2010, despite a consistent expansion tendency from 2001 to 2010. Moreover, the results indicated that alterations in the size of glaciers and ice reserves in the Sanjiangyuan region have had the greatest influence on the fluctuation in lake area. Among the factors that affect the climate, temperature had the most significant effect on the change in lake area, followed by precipitation.

The Bohai Sea, known for being the lowest latitude seasonally frozen sea area in the world, experienced severe ice conditions with a 30-year recurrence period during the winter of 2009-2010. Water-sediment flux is a crucial parameter for water quality management in marine environment. Using a highly accurate three-dimensional hydrodynamic and sediment transport numerical model, the significant wave height (Hs), current velocity, suspended sediment concentration (SSC) and water-sediment flux in the Bohai Sea during ice-covered and ice-free conditions are compared. Our findings indicate that the current velocity and sediment resuspension decrease under the ice coverage, but increase at the edge of the ice. The net outflow tidal flux (TF) in winter under ice-free conditions accounts for 24.5% of the whole year. The net outflow TF increases by 32.7% during ice-covered conditions, primarily due to the pressure difference between high air pressure superimposing heavy sea ice in the northwest Bohai Sea and the low air pressure in Bohai Strait, resulting in increased ebb velocity and decreased flood velocity. The net outflow suspended sediment flux (SSF) during ice-free conditions in the winter is 2.32×109 kg, while SSF increases by 1.24 times during ice-covered conditions, leading to worse water quality in the outer sea. The decrease of TF in the southern part of the Bohai Strait and the reduction of suspended sediment concentration by nearly 15 mg/l lead to the significant decrease in SSF. This study has significance guiding value for understanding the source-sink sedimentation system and water quality research in East China Sea.

Introduction2-Amino-1-methyl-6-phenylimidazole [4,5-b] pyridine (PhIP), a heterocyclic amine (HAA), is found in meat products heated at high temperatures. However, PhIP is a mutagenic and potential carcinogenic compound. Cassiae semen, a type of medicine and food homology plant, is abundant in China and has been less applied for inhibiting heterocyclic amines.MethodsTo investigate the inhibitory effect of cassiae semen extract on PhIP formation within a model system and elucidate the inhibitory mechanism, an ultrasonic-assisted method with 70% ethanol was used to obtain cassiae semen extract, which was added to a model system (0.6 mmol of phenylalanine: creatinine, 1:1). PhIP was analyzed by LC–MS to determine inhibitory effect. The byproducts of the system and the mechanism of PhIP inhibition were verified by adding the extract to a model mixture of phenylacetaldehyde, phenylacetaldehyde and creatinine.ResultsThe results indicated that PhIP production decreased as the concentration of cassiae semen extract increased, and the highest inhibition rate was 91.9%. Byproduct (E), with a mass–charge ratio of m/z 199.9, was detected in the phenylalanine and creatinine model system but was not detected in the other systems. The cassiae semen extract may have reacted with phenylalanine to produce byproduct (E), which prevented the degradation of phenylalanine by the Strecker reaction to produce phenylacetaldehyde.DiscussionCassiae semen extract consumed phenylalanine, which is the precursor for PhIP, thus inhibiting the formation of phenylacetaldehyde and ultimately inhibiting PhIP formation. The main objective of this study was to elucidate the mechanism by which cassiae semen inhibit PhIP formation and establish a theoretical and scientific foundation for practical control measures.

Glioblastoma (GBM) presents a significant therapeutic challenge due to the limited efficacy of existing treatments. Chimeric antigen receptor (CAR) T-cell therapy offers promise, but its potential in solid tumors like GBM is undermined by the physical barrier posed by the extracellular matrix (ECM). To address the inadequacies of traditional 2D cell culture, animal models, and Matrigel-based 3D culture in mimicking the mechanical characteristics of tumor tissues, we employed biomaterials and digital light processing-based 3D bioprinting to fabricate biomimetic tumor models with finely tunable ECM stiffness independent of ECM composition. Our results demonstrated that increased material stiffness markedly impeded CAR-T cell penetration and tumor cell cytotoxicity in GBM models. The 3D bioprinted models enabled us to examine the influence of ECM stiffness on CAR-T cell therapy effectiveness, providing a clinically pertinent evaluation tool for CAR-T cell development in stiff solid tumors. Furthermore, we developed an innovative heat-inducible CAR-T cell therapy, effectively overcoming the challenges posed by the stiff tumor microenvironment.

Joining of dissimilar superalloys is indispensable in the field of advanced manufacture, achieving a high-quality joint while minimizing thermal damage to substrates during diffusion bonding is a critical but challenging pursuit. A low-temperature and rapid diffusion bonding strategy enabled by pulsed current was proposed to resolve this challenge. Attributed to the enhanced interfacial plastic-deformation and carbide-precipitation, pulsed current rapidly achieved a nanovoid-free and tight joint of GH3536 and GH5188 superalloys at a low temperature of 850 °C for 5 min. Meanwhile, the rapid joining process prevented the interfacial carbides from coarsening and allowed their elimination in a short-term heat-treatment. The carbide dissolution, recrystallization of highly-deformed grain and cross-interface grain growth during heat-treatment significantly enhanced the joint performance, the heat-treated joint exhibited a high ultimate strain of 25.5 % and a tensile strength comparable to the raw GH3536.

We present an analysis of the enhanced spin Hall effect of light (SHEL) resulting from a reflected Airy beam off the interface of an air-topological insulator (TI). Our study suggests that the surface conductivity of TI film and the decay factors of Airy beams are crucial in increasing the spin-splitting distance and the spatial shifts of the left-handed circularly polarized (LCP) and right-handed circularly polarized (RCP) components. An apparent spatial shift asymmetry depending on the decay factors can be observed between the LCP and RCP components, where the coupling of intrinsic and extrinsic angular momentum will play a significant impact. The connection among the thickness of TI film, chemical potential and the incident frequency at the fixed decay factors is thoroughly examined to achieve the maximum of spatial shifts. We find that the coupling between the upper and lower surfaces’ conductivity could be responsible for the pronounced SHEL. These conclusions can be extended to other interfaces of comparable structures, such as insulators coated with a layer of two-dimensional Dirac material. Our work provides novel insights into the use of innovative beams incident on the surface of TI film and their potential applications in optical detection.

Objectives The objective of this study was to evaluate the early predictors of bacterial pneumonia infection in children with congenital heart disease (CHD) after cardiopulmonary bypass (CPB).Design Retrospective study.Setting A freestanding tertiary paediatric hospital in China.Participants Patients admitted to the hospital due to CHD who underwent open-heart surgery.Outcome measures We retrospectively reviewed and analysed data from 1622 patients with CHD after CPB from June 2018 to December 2020 at the Children’s Hospital of Nanjing Medical University. Enrolled patients were assigned to an infection group or a non-infection group according to the presence of postoperative bacterial pneumonia infection, and the differences in clinical indicators were compared. Potential predictors were analysed by multivariate logistic regression analysis and area under the curve (AUC) analysis.Results Among the 376 patients (23.2%) in the infection group, the three most common bacteria were Streptococcus pneumoniae in 67 patients (17.8%), Escherichia coli in 63 patients (16.8%) and Haemophilus influenzae in 53 patients (14.1%). The infection group exhibited a lower weight (8.0 (6.0–11.5) kg vs 11.0 (7.5–14.5) kg, p

Abstract Background Neutralizing antibody plays a key role in protecting hosts from invasive pathogens and their virulent components. Current high-throughput assays for antibody screening are based on binding activities. However, those antibodies with high affinity may not have neutralizing activities. Subsequent functionality assays are necessary to identify neutralizing antibodies from binders with high affinity to their target antigens, which is laborious and time-consuming. Therefore, a versatile platform that can rapidly identify antibodies with both high binding affinity and neutralizing activity is desired to curb future pandemics like COVID-19. Results In this proof-of-concept study, we adapted Saccharomyces cerevisiae to either display human antibodies on the yeast surface or secrete soluble antibodies into the cultivation supernatant under a controllable ‘switch’ through different carbon source induced promoters. Initially, an engineered chimeric-bispecific Fab antibody, derived from humanized nanobodies against both Clostridioides difficile toxin A and B (TcdA and TcdB), was successfully expressed either on the yeast cell surface or in the culture medium with intact bioactivity, suggesting the applicability of our system in antibody display and secretion. Next, a combinatorial Fab library was constructed from B cells isolated from a convalescent patient with a high serological neutralizing titer against TcdB. Following three rounds of magnetic bead enrichment and one round of flow cytometry sorting, antibodies against TcdB were enriched efficiently. We then sorted out single binders with high binding affinity and induced them to express soluble antibodies in culture medium. The neutralizing activity of culture supernatant was analyzed using cell-based assay immediately. This way, we rapidly identified two unique neutralizers (out of seven binders) that can neutralize the cytotoxicity of TcdB. Conclusion The antibody screening platform described here simplifies the neutralizing antibody discovery procedure and will be an attractive alternative for screening functional antibodies against infectious diseases.

Recycled asphalt pavement (RAP) mixtures are widely adopted due to their significant economic and social benefits from utilizing pavement recycling materials. This study incorporates basalt fibers (BF) and polyester fibers (PF) into plant-mixed hot recycled asphalt mixtures to analyze their enhancement effects on the high-temperature, low-temperature, and fatigue performance at different RAP content levels. Additionally, the study investigates the impact of fiber and RAP additions on the compaction characteristics of the mixtures using gyratory compaction tests, aiming to increase the RAP content of plant-mixed hot recycled asphalt mixtures. Experimental results demonstrate that at 30% and 50% RAP content levels, basalt fibers exhibit more pronounced enhancement effects on the performance of recycled asphalt mixtures compared to polyester fibers. Incorporating basalt fibers increases the fracture energy of recycled asphalt mixtures by 8.63% and 13.9%, and improves fatigue life by 154% and 135%, respectively. Moreover, the addition of both types of fibers increases compaction difficulty, with polyester fibers showing a more significant influence on the compaction energy index (CEI).

The world’s transportation system is overburdened by ever-growing travel demand, which brings mobility, safety, and pollution problems. To combat these issues and make better use of existing road capacity on urban arterials, public transit buses are designed to carry more people in fewer vehicles. However, transit buses travel slowly and make frequent intermittent stops, resulting in unreliable travel times and inconvenient riding experiences; this hinders people from choosing to travel on public transit buses. However, a research gap exists in using connected and automated vehicle (CAV) technologies specifically for transit bus operation optimization. To bridge this gap, the present study extended CAV applications to transit bus operation and developed a transit bus control method based on cooperative adaptive cruise control (CACC). The proposed model first optimized bus segment speeds to minimize schedule deviations and fuel consumption. Then, a CACC algorithm was integrated with optimal segment speed. The proposed control method was implemented through micro-simulations of an actual corridor in Jinan, Shandong, China. The evaluation results indicate that the proposed control method reduced the total arrival deviation up to 65.1% and total fuel consumption up to 6.8%. The study adapts CAV technologies to transit bus operation. The findings in this study validate CAV applications in transit bus operation.

Taking into account the impact of time factors on emission reductions and brand reputation, the reference carbon emission effect and dual-channel supply chain are incorporated into a unified analysis framework. We applied differential game theory to build models under centralized decision-making and decentralized decision-making. The aim of the research is to explore the strategies of a single manufacturer and a single retailer on product pricing, low-carbon production, and advertising. The research analyses the impact of reference carbon emission effects, cost coefficients, and interchannel substitutable coefficients on profits. In order to alleviate the double marginal effect brought about by decentralized decision-making, a cost-compensation coordination mechanism is proposed. The conclusions are as follows. First, centralized decision-making is the optimal decision-making mode, but further consultation is required to implement it voluntarily by both parties. Second, a cost-recovery contract occurs when the fixed fee that the retailer gives the manufacturer meets certain conditions. The contract can make the retailer’s advertising investment reach the level of centralized decision-making and improve the member’s profit under the decentralized decision-making. The coordination mechanism is effective. Third, the reference carbon emission effect can bring about an increase in the manufacturer’s low-carbon production input and profits. The retailer’s advertising investment is not affected by the reference carbon emission effect. Fourth, wholesale prices and online or offline retail prices are all positively correlated with the market share of the channel. The price-substitution coefficient between channels is positively correlated with both low-carbon inputs and profits.

Dipeptides have been shown to be an important taste substance in alcoholic beverages. However, the characterization of dipeptides in Chinese liquors was poor. Here, dansylation combined with liquid chromatography – mass spectrometry was employed to analyze dipeptides in eight liquors of two flavors. Consequently, 35 dipeptides were identified from liquors and 32 of them were quantified. Dipeptide quantification showed LODs smaller than 2.5 ng/mL. The calibration curves showed concentration spans from two to three orders of magnitude with satisfactory linearity. The matrix effects in low and high concentrations were from −25.71 % to 24.19 % and −14.82 % to 20.73 %, respectively. Intra- and inter-day precision is lower than 15 % for both low and high concentrations. The dipeptide contents in sauce flavor liquors were higher than those in strong flavor liquors. Ala- and -Phe dipeptides showed their unique trends between sauce and strong flavor liquors. This study provides new clues to evaluate taste of liquors.

Abstract Chimeric antigen receptor (CAR)-T cell therapy is rapidly advancing as cancer treatment, however, designing an optimal CAR remains challenging. A single-chain variable fragment (scFv) is generally used as CAR targeting moiety, wherein the complementarity-determining regions (CDRs) define its specificity. We report here that the CDR loops can cause CAR clustering, leading to antigen-independent tonic signalling and subsequent CAR-T cell dysfunction. We show via CARs incorporating scFvs with identical framework and varying CDR sequences that CARs may cluster on the T cell surface, which leads to antigen-independent CAR-T cell activation, characterized by increased cell size and interferon (IFN)-γ secretion. This results in CAR-T cell exhaustion, activation-induced cell death and reduced responsiveness to target-antigen-expressing tumour cells. CDR mutagenesis confirms that the CAR-clustering is mediated by CDR-loops. In summary, antigen-independent tonic signalling can be induced by CDR-mediated CAR clustering, which could not be predicted from the scFv sequences, but could be tested for by evaluating the activity of unstimulated CAR-T cells.

An ultrahigh strain-independent damping in Mg–1Mn alloy was prepared by cold rolling process. Combined with microstructure characterization, the mechanical properties and damping capacities of Mg–1Mn alloy with different reduction were systematically investigated. By the appropriate cold rolling process, numerous parallel dislocations, stacking faults (SFs) and a few non-basal dislocations are introduced into Mg matrix. Due to the non-basal dislocations and stacking faults coexists with basal dislocations, their reaction with each other leads to the activation of more non-basal slips and increase of strain hardening rate, which simultaneously improves the strength and plasticity of Mg–1Mn alloy. On the other hand, the increase of number of moveable dislocations and SFs, acting as dissipated source, effectively improves the damping capacity. Especially, the Mg–1Mn alloy shows an ultrahigh strain-independent damping capacity, which outperforms the high-damping Mg-0.6Zr alloy. When the reduction is 20%, the alloys show a good comprehensive mechanical properties: the ultimate tensile strength (UTS), the yield strength (YS) and plasticity is 206 MPa, 156 MPa and 49.8%. This work provides a new strategy for preparing high-strength, high-plasticity and high-damping magnesium alloy.

Different solution treatments were carried out on the semi-continuously cast Mg-9.55Gd-2.27Y-1.28Zn-0.55Zr-0.11Nd (wt.%) alloy at temperatures of 480 °C, 500 °C, and 520 °C. It was found that the different solution treatment temperatures led to different phase constitutions of the alloy. The Mg3RE-type eutectic phases transform into long period stacking order (LPSO) phases with various morphologies after solution treatment. Increasing the solution temperature resulted in larger grain size, greater number of lamellar LPSO phases, and segregation of Zr element. Block LPSO phases also shifted to rod LPSO phase. After ageing treatment, the special spatial structure consisting of prismatic β′ precipitates, basal γ′ precipitates, and lamellar LPSO phases hindered dislocation movement effectively, leading to high strength.However, the accumulation of massive dislocations promoted the premature formation of cracks at the grain boundary and LPSO/Mg matrix interface, resulting in a rapid decrease in ductility of the alloy. After solution treatment at 480 °C for 12 h and aged at 200 °C for 48 h, the Mg-9.55Gd-2.27Y-1.28Zn-0.55Zr-0.11Nd alloy exhibited favorable comprehensive mechanical properties at room temperature: ultimate tensile strength (UTS) of 383 MPa, tensile yield strength (TYS) of 269 MPa, and fracture elongation (EL) of 5.1%.

The paper proposes a three-scale binary medium-based constitutive model on the basis of the meso structures and micro components to describe the elasto-plastic mechanical behavior of mudstone samples. Based on the breakage mechanism of geomaterials, mudstone samples are considered as two different materials (bonded and frictional elements) at mesoscales. From micro to meso scales, given the similar but different mineralogy composition and porosity of the bonded and frictional elements at microscale, as well as their separate mechanical characteristics, different homogenization methods are adopted to obtain their respective meso mechanical properties. At the mesoscale, in view of the unique meso structures and the continuous material transformation, the extended self-consistent scheme (SCS) is improved to be adaptable to elasto-plastic composites with varying meso components. With the consideration of the evolution form of the breakage ratio under the external loading being given based on the assumed strength distribution of the meso bonded elements, the mechanical relations between meso and macro scales are established. Finally, on the basis of the mean-field method and combined with the critical mechanical connections between different scales, the micro-meso-macro constitutive model for mudstone samples are proposed. The model validation shows that, with a few model parameters, the proposed model can well reflect the stress and deformation features of mudstone samples with complex micro-components.

BRD4-NUT’s bipartite binding and activation of p300 in NUT carcinoma nucleates a feed-forward spread of histone hyperacetylation and chromatin condensation that sustains aberrant pro-proliferation gene transcription and perpetual tumor cell growth.

The effect of the lamellar long period stacking order (LPSO) phase on both mechanical properties and damping capacity of magnesium alloys is still vague. After heat treatment at 540 °C for 4 h and 450 °C for 10 h, the Mg-10Gd-2Y–1Zn-0.5Zr-0.2Nd (wt%) alloy with the lamellar LPSO phase is prepared to study the influence of lamellar LPSO phase on damping capacity and mechanical properties. Combined transmission electron microscopy (TEM) and scanning electron microscopy (SEM) equipped with electron back-scattering patterns (EBSD) system, it is surprisingly found that the growth direction of the lamellar LPSO phase on basal plane is nearly parallel to the slip direction of basal dislocations, which is benefit from dislocations movement on basal plane. The dislocations move on basal plane easily, lead to a relative high damping capacity. The alloy with LPSO phases shows higher ultimate tensile strength (UTS) and elongation (EL), increased from 234 MPa to 2.6% to 254 MPa and 4.6%, respectively. The lamellar LPSO phase has an attribution to UTS and EL due to its kink deformation mechanism. Therefore, the lamellar LPSO phase can be used as a functional phase to enhance the damping capacity and mechanical properties at the same time, and providing new ideas about preparing high-strength and high-damping magnesium alloy.

With increasing environmental awareness, the issue of atmospheric pollution has gained significant attention. Specifically, three types of atmospheric pollutants, namely, nitrogen oxides, volatile organic compounds, and carbon monoxide, have become the focus of widespread concern. In addressing these pollutants, mesoporous zeolites have emerged as promising materials due to their large specific surface area, which enables effective dispersion of active sites, and their large pore volume, which facilitates efficient diffusion. This article provides a comprehensive overview of the preparation methods of mesoporous zeolites and their applications in removing nitrogen oxides, volatile organic compounds, and carbon monoxide. It also highlights the challenges and limitations faced by the application of mesoporous zeolites in pollutant removal and emphasizes their potential as efficient catalysts.

As an immune adjuvant, proinflammatory allogeneic dendritic cells (AlloDCs) have demonstrated promising immune-priming effects in several preclinical and clinical studies. The effector cells, including NK cells and T cells are widely acknowledged as pivotal factors in the effectiveness of cancer immunotherapy due to their ability to selectively identify and eradicate malignant cells. 4-1BB, as a costimulatory receptor, plays a significant role in the stimulation of effector cell activation. This study evaluated the anti-tumor effects when combining intratumoral administration of the immune-adjuvant AlloDCs with systemic α4-1BB treatment directly acting on effector cells. In both the CT-26 murine colon carcinoma model and B16 murine melanoma model, AlloDCs demonstrated a significant enhancement in the therapeutic efficacy of α4-1BB antibody. This enhancement was observed through the delayed growth of tumors and prolonged survival. Analysis of the tumor microenvironment (TME) in the combined-treatment group revealed an immune-inflamed TME characterized by increased infiltration of activated endogenous DCs and IFNγ+ CD8+ T cells, showing reduced signs of exhaustion. Furthermore, there was an augmented presence of tissue-resident memory (TRM) CD8+ T cells (CD103+CD49a+CD69+). The combination treatment also led to increased infiltration of CD39+CD103+ tumor-specific CD8+ T cells and neoantigen-specific T cells into the tumor. Additionally, the combined treatment resulted in a less immunosuppressive TME, indicated by decreased infiltration of myeloid-derived suppressor cells and Tregs. These findings suggest that the combination of intratumoral AlloDCs administration with systemic agonistic α4-1BB treatment can generate a synergistic anti-tumor response, thereby warranting further investigation through clinical studies.

Abstract Background Dysregulation of inhibitor of differentiation/DNA binding (ID) genes is linked to cancer growth, angiogenesis, invasiveness, metastasis and patient survival. Nevertheless, few investigations have systematically determined the expression and prognostic value of ID genes in acute myeloid leukemia (AML). Methods The expression and clinical prognostic value of ID genes in AML were first identified by public databases and further validated by our research cohort. Results Using public data, the expression of ID1/ID3 was markedly downregulated in AML, and the expression of ID2 was greatly upregulated in AML, whereas ID4 showed no significant difference. Among the ID genes, only ID3 expression may be the most valuable prognostic biomarker in both total AML and cytogenetically normal AML (CN-AML) and especially in CN-AML. Clinically, reduced ID3 expression was greatly associated with higher white blood cell counts, peripheral blood/bone marrow blasts, normal karyotypes and intermediate cytogenetic risk. In addition, low ID3 expression was markedly related to FLT3 and NPM1 mutations as well as wild-type TP53. Despite these associations, multivariate Cox regression analysis revealed that ID3 expression was an independent risk factor affecting overall survival (OS) and disease free survival (DFS) in CN-AML patients. Biologically, a total of 839 mRNAs/lncRNAs and 72 microRNAs were found to be associated with ID3 expression in AML. Importantly, the expression of ID3 with discriminative value in AML was further confirmed in our research cohort. Conclusion The bioinformatics analysis and experimental verification demonstrate that low ID3 expression independently affects OS and DFS in patients with CN-AML, which might be seen as a potential prognostic indicator in CN-AML.

Abstract Interleukin 27 (IL-27), a heterodimeric cytokine composed of Epstein-Barr virus-induced 3 and p28, is a pleiotropic cytokine with both pro-and anti-inflammatory properties. However, the precise role of IL-27 in acute graft-versus-host disease is not yet fully understood. In this study, utilizing mice with IL-27 p28 deficiency in dendritic cells (DCs), we demonstrated that IL-27 p28 deficiency resulted in impaired Treg cell function and enhanced effector T cell responses, corresponding to aggravated aGVHD in mice. In addition, using single-cell RNA sequencing, we found that loss of IL-27 p28 impaired Treg cell generation and promoted IL-1R2+TIGIT+ pathogenic CD4+ T cells in the thymus at a steady state. Mechanistically, IL-27 p28 deficiency promoted STAT1 phosphorylation and Th1 cell responses, leading to the inhibition of Treg cell differentiation and function. Finally, patients with high levels of IL-27 p28 in serum showed a substantially decreased occurrence of grade II-IV aGVHD and more favorable overall survival than those with low levels of IL-27 p28. Thus, our results suggest a protective role of DC-derived IL-27 p28 in the pathogenesis of aGVHD through modulation of the Treg/Teff cell balance during thymic development. IL-27 p28 may be a valuable marker for predicting aGVHD development after transplantation in humans.

The metabolic environment of tumours has wide-ranging effects on the anti-tumour immune response and the outcome of immune therapy. Authors show here that the purine metabolite inosine enhances tumour immunogenicity and thus immune checkpoint blockade therapy response by inhibiting the ubiquitin-activating enzyme UBA6 in tumour cells.

AgCu+TiH2+Nb filler was newly-designed to braze Ti2AlNb and SiBCN. The Ag–Cu melt firstly filled the interfacial gaps and then solidified into refractory Ag(s,s) via Ti–Cu interaction, while Nb refined the brittle compounds and relieved the residual stresses well. The obtained joint exhibited a shear strength of 73 ± 10.2 MPa and 81.7 ± 9.5 MPa at room temperature and 600 °C respectively, which is 3.1 and 1.7 times of that with AgCu. No softening occurred at 600 °C and the strength remained 24 ± 1.4 MPa at 800 °C. The proposed method provides a new strategy for preparing high-temperature joint at low temperature, to address the issues of poor thermal resistance as well as huge residual stresses and excessive formation of brittle phases.

Cyclocarya paliurus (C. paliurus), a nutritional and nutraceutical resource for human and animal diets, has been constantly explored. The available biological components of C. paliurus were triterpenoids, polysaccharides, and flavonoids. Recent studies in phytochemical-phytochemistry; pharmacological-pharmacology has shown that C. paliurus performed medicinal value, such as antihypertensive, antioxidant, anticancer, antimicrobial, anti-inflammatory and immunological activities. Furthermore, C. paliurus and its extracts added to drinks would help to prevent and mitigate chronic diseases. This review provides an overview of the nutritional composition and functional applications of C. paliurus, summarizing the research progress on the extraction methods, structural characteristics, and biological activities. Therefore, it may be a promising candidate for developing functional ingredients in traditional Chinese medicine. However, a more profound understanding of its active compounds and active mechanisms through which they perform biological activities is required. As a result, the plant needs further investigation in vitro and in vivo.

Due to extreme operating conditions such as high-speed and heavy loads, ball screws are prone to damages, that affect the accuracy and operational safety of the mechanical equipment. As strong background noise and weak fault characteristics, it is difficult to capture the inherent fault state only depending on the time-domain or frequency-domain information from the vibration signal. In this paper, a fault diagnosis method for the ball screw based on continuous wavelet transform (CWT) and two-dimensional convolutional neural network (2DCNN) is proposed. The noise-reducing vibration signal is obtained via CWT. The time-frequency graph of the noise reduction signal can more comprehensively reflect the fault information of the ball screw. The time-frequency graph is used as the input to train and test the 2DCNN. Finally, diagnosis results of different types of faults reveal that the proposed CWT-2DCNN fault diagnosis method can achieve an average recognition rate of 99.67%. Compared with one-dimensional convolutional neural network (1DCNN) and traditional BP neural network, the proposed method has fast network convergence and high recognition accuracy. Time-frequency graphs of the noise-reduced signal used as fault features for classification can effectively avoid the problem of uncertainty due to the manual extraction of features. The proposed method has high application potential in the field of ball screw pair fault diagnosis.

The rare earth conversion film has attracted more and more attention in recent years because of its good corrosion resistance and non - toxicity. The concept and film forming mechanism of rare earth conversion film were briefly introduced, and the application of rare earth in corrosion prevention for ferrous metals as well as the nonferrous metals of aluminum, magnesium, zinc and their alloys was summarized. This study found that the corrosion resistance of composite rare earth conversion film was better than that of the single rare earth conversion film. Moreover, it also explained the reason why cerium conversion film had better corrosion resistance than other rare earth conversion films. Finally, it pointed out that the composite rare earth conversion film, rare earth composite alloy coating and densification of rare earth conversion film would be the development direction.

Abstract Objectives Non‐infectious uveitis is often secondary to systemic autoimmune diseases, with Behçet's disease (BD) and Vogt‐Koyanagi‐Harada disease (VKHD) as the two most common causes. Uveitis in BD and VKHD can show similar clinical manifestations, but the underlying immunopathogenesis remains unclear. Methods To understand immune landscapes in inflammatory eye tissues, we performed single‐cell RNA paired with T cell receptor (TCR) sequencing of immune cell infiltrates in aqueous humour from six patients with BD (N = 3) and VKHD (N = 3) uveitis patients. Results Although T cells strongly infiltrated in both types of autoimmune uveitis, myeloid cells only significantly presented in BD uveitis but not in VKHD uveitis. Conversely, VKHD uveitis but not BD uveitis showed an overwhelming dominance by CD4+ T cells (> 80%) within the T cell population due to expansion of CD4+ T cell clusters with effector memory (Tem) phenotypes. Correspondingly, VKHD uveitis demonstrated a selective expansion of CD4+ T cell clones which were enriched in pro‐inflammatory Granzyme H+ CD4+ Tem cluster and showed TCR and Th1 pathway activation. In contrast, BD uveitis showed a preferential expansion of CD8+ T cell clones in pro‐inflammatory Granzyme H+ CD8+ Tem cluster, and pathway activation for cytoskeleton remodelling, cellular adhesion and cytotoxicity. Conclusion Single‐cell analyses of ocular tissues reveal distinct landscapes of immune cell infiltration and T‐cell clonal expansions between VKHD and BD uveitis. Preferential involvements of pro‐inflammatory CD4+ Th1 cells in VKHD and cytotoxic CD8+ T cells in BD suggest a difference in disease immunopathogenesis and can guide precision disease management.

A defining feature of successful vaccination is the ability to induce long-lived antigen-specific memory cells. T follicular helper (Tfh) cells specialize in providing help to B cells in mounting protective humoral immunity in infection and after vaccination. Memory Tfh cells that retain the CXCR5 expression can confer protection through enhancing humoral response upon antigen re-exposure but how they are maintained is poorly understood. CXCR5+ memory Tfh cells in human blood are divided into Tfh1, Tfh2, and Tfh17 cells by the expression of chemokine receptors CXCR3 and CCR6 associated with Th1 and Th17, respectively. Here, we developed a new method to induce Tfh1, Tfh2, and Tfh17-like (iTfh1, iTfh2, and iTfh17) mouse cells in vitro. Although all three iTfh subsets efficiently support antibody responses in recipient mice with immediate immunization, iTfh17 cells are superior to iTfh1 and iTfh2 cells in supporting antibody response to a later immunization after extended resting in vivo to mimic memory maintenance. Notably, the counterpart human Tfh17 cells are selectively enriched in CCR7+ central memory Tfh cells with survival and proliferative advantages. Furthermore, the analysis of multiple human cohorts that received different vaccines for HBV, influenza virus, tetanus toxin or measles revealed that vaccine-specific Tfh17 cells outcompete Tfh1 or Tfh2 cells for the persistence in memory phase. Therefore, the complementary mouse and human results showing the advantage of Tfh17 cells in maintenance and memory function supports the notion that Tfh17-induced immunization might be preferable in vaccine development to confer long-term protection.

Mesoscale eddies (MEs) affect the transport and redistribution of oceanic matter and energy. The long-lived and long-distance propagation of individual eddies has garnered extensive attention; however, short-lived MEs (< 7 days) have been widely overlooked. In this study, the basic features of short-lived MEs and their spatial-temporal variations in a tropical eddy-rich region were extracted and analyzed for the first time. Short-lived cyclonic and anticyclonic eddies (CEs/AEs) were found to be widespread in two eddy belts in the tropical region of the western Pacific warm pool (WPWP). The CEs and AEs were formed by the shear instability between large-scale circulations and were distributed on both sides of the North Equatorial Countercurrent, with significant differences in spatial distribution. The variations in sea surface temperature, mixed layer depth, and surface chlorophyll-a concentration in the core of the WPWP were spatially and temporally related to the development of the two eddy belts. This new insight into short-lived MEs in the tropical region contributes to our current understanding of ocean eddies. The potential impacts of short-lived MEs on climate change, global air–sea interactions, and tropical cyclone formation should receive adequate attention and further assessment in future research.

The growing economic uncertainty makes consumers realize the importance of financial preparedness and management ability. Based on the U.S. National Financial Capability Study dataset from 2009, 2012, 2015, and 2018, this study explores the nexus between consumer financial knowledge and financial behaviors of credit card use. The results indicate that financial knowledge positively affects consumer credit card ownership and desirable financial behaviors of credit card use, and is negatively related to undesirable credit card behaviors. The results are robust to different regression methods and after removing income outliers. The heterogeneity test shows that financial knowledge cannot enhance desirable credit card behaviors because of the income limitations in the low-income group. Therefore, there are implications for policymakers, financial sectors, and consumers to improve consumers' usage of credit cards and cultivate proper consumption habits by enhancing consumer financial knowledge.

BackgroundChildren and adolescents increasingly commonly suffer from obesity and headache. It has been confirmed that there is an association between obesity and headache in adults; however, evidence of such an association in paediatric populations is still controversial. Therefore, this study examined the relationship between obesity and headache among children and adolescents in the US.MethodsThe cross-sectional data of 3948 participants were obtained from the National Health and Nutrition Examination Survey 1999–2004. Weighted logistic regression models were applied to investigate the association between obesity and headache. Subgroup analysis stratified by sex and age was performed to explore the potential difference in the association of paediatric obesity with headache. The performance of paediatric obesity on headache was assessed by receiver operating characteristic (ROC) curve.ResultsThe present study involved 3948 participants, of whom 713 (18.1%) had headache. Compared to those without headache, participants with headache tended to be girls and adolescents, have less calcium intake, and have higher levels of body mass index (BMI), C-reactive protein (CRP), serum ferritin and triglycerides (TGs) (all P < 0.05). After fully adjusting for potential confounders, the ORs with 95% CIs for headache were 1.03 (0.58–1.54) and 1.25 (0.68–2.30) for overweight and obese participants in comparison with normal-weight controls, respectively, implying no association of paediatric obesity with headache independent of other potential confounding factors. In addition, although higher odds of headache were noted in girls and adolescents (aged 10–17 years), no statistically significant difference was found across any subgroups. The area under the ROC (AUC) of paediatric obesity on headache was 0.634.ConclusionsIn summary, our study indicated that obesity is not associated with headache among US children and adolescents. Further prospective studies with larger sample size are needed to validate our findings.

Background Cerebral small vessel disease is associated with higher ratios of soluble‐epoxide hydrolase derived linoleic acid diols (12,13‐dihydroxyoctadecenoic acid [DiHOME] and 9,10‐DiHOME) to their parent epoxides (12(13)‐epoxyoctadecenoic acid [EpOME] and 9(10)‐EpOME); however, the relationship has not yet been examined in stroke. Methods and Results Participants with mild to moderate small vessel stroke or large vessel stroke were selected based on clinical and imaging criteria. Metabolites were quantified by ultra‐high‐performance liquid chromatography–mass spectrometry. Volumes of stroke, lacunes, white matter hyperintensities, magnetic resonance imaging visible perivascular spaces, and free water diffusion were quantified from structural and diffusion magnetic resonance imaging (3 Tesla). Adjusted linear regression models were used for analysis. Compared with participants with large vessel stroke (n=30), participants with small vessel stroke (n=50) had a higher 12,13‐DiHOME/12(13)‐EpOME ratio (β=0.251, P=0.023). The 12,13‐DiHOME/12(13)‐EpOME ratio was associated with more lacunes (β=0.266, P=0.028) but not with large vessel stroke volumes. Ratios of 12,13‐DiHOME/12(13)‐EpOME and 9,10‐DiHOME/9(10)‐EpOME were associated with greater volumes of white matter hyperintensities (β=0.364, P

Abstract Background The aberrant differentiation of T follicular helper (Tfh) cells plays an important role in the pathogenesis of systemic lupus erythematosus (SLE). However, the mechanism of regulating Tfh cells differentiation remains unclear. Long noncoding RNAs (lncRNAs) act as important regulators in the processes of innate and adaptive immune response. Whether lncRNAs are involved in regulating Tfh cell differentiation and autoimmune responses need to be further identified. Methods The characters and functions of human IL21‐AS1 and its mouse homologous lncRNA (mIl21‐AS) were investigated by a series of biochemical assays and cell transfection assay. mIl21‐AS1 regulating humoral immune response in vivo was explored by keyhole limpet haemocyanin (KLH) and chronic graft versus host disease (cGVHD) model. Results Human IL21‐AS1 and its mouse homologous lncRNA (mIl21‐AS) were identified and cloned. We uncovered that IL21‐AS1 was highly expressed in CD4+ T cells of SLE patients and Tfh cells, which promoted differentiation of Tfh cells. Mechanistically, IL21‐AS1 bound heterogeneous nuclear ribonucleoprotein U and recruited acetyltransferases CREB‐binding protein to the promoter of IL21, leading to the transcriptional activation of IL21 and Tfh cells differentiation through increasing Histone H3 acetylation level on IL21 promoter. Moreover, Tfh proportion and antibodies production were significantly increased in mIl21‐AS knock‐in mice immunized with KLH. mIl21‐AS1 overexpression also exacerbated the lupus‐like phenotype in cGVHD mice model. Conclusions Our results demonstrate that IL21‐AS1 activates IL21 transcription via epigenetic mechanism to promote germinal centre response, adding insight into the molecular regulation of autoimmune pathogenesis and providing a novel target for SLE treatment.

Immune checkpoint inhibitors (ICIs) have revolutionized the oncology field. However, a significant number of patients do not respond, at least partly due to the lack of preexisting anti-tumor T-cell immunity. Therefore, it is emergent to add an immune-priming step to improve efficacy. Here, we report a combined approach consisting of intratumoral administration of pro-inflammatory allogeneic dendritic cells (AlloDCs) and systemic treatment with αCTLA-4 that can drastically improve the anti-tumor efficacy compared to αCTLA-4 monotherapy. When evaluated in mice with large established CT-26 tumors, monotherapy with αCTLA-4 neither delayed tumor progression nor improved mice survival. However, combination treatment of AlloDCs and αCTLA-4 drastically improved the effectiveness, with 70% of mice being cured. This effect was T cell-dependent, and all survived mice rejected a subsequent tumor re-challenge. Further investigation revealed an immune-inflamed tumor microenvironment (TME) in the combination treatment group characterized by enhanced infiltration of activated antigen-presenting endogenous DCs and CD8+ T cells with a tissue-resident memory (TRM) phenotype (CD49a+CD103+). This correlated with elevated levels of tumor-specific CD39+CD103+CD8+ T cells in the tumor and “tumor-matching” NKG2D+CD39+CX3CR1+CD8+ T cells in peripheral blood. Moreover, splenocytes from mice in the combination treatment group secreted significantly higher IFN-γ upon stimulation with the peptide from the endogenous CT-26 retroviral gp70 (model neoantigen), confirming the induction of a tumor-specific CD8+ T-cell response. Taken together, these data indicate a strong anti-tumor synergy between AlloDCs and αCTLA-4 that warrant further clinical investigation with the corresponding human AlloDC product (ilixadencel) for patients receiving αCTLA-4 therapy.

The common γ chain family of cytokines and their receptors play fundamental roles in the immune system. Evolutionary studies of γ chain cytokines have elegantly illustrated how the immune system adapts to ever-changing environmental conditions. Indeed, these studies have revealed the uniqueness of cytokine evolution, which exhibits strong positive selection pressure needed to adapt to rapidly evolving threats whilst still conserving their receptor binding capabilities. In this review, we summarise the evolutionary mechanisms that gave rise to the characteristically diverse family of γ chain cytokines. We also speculate on the benefits of studying cytokine evolution, which may provide alternative ways to design novel cytokine therapeutic strategies. Additionally, we discuss current evolutionary models that elucidate the emergence of distinct cytokines (IL-4 and IL-13) and cytokine receptors (IL-2Rα and IL-15Rα). Finally, we address and reflect on the difficulties associated with evolutionary studies of rapidly evolving genes and describe a variety of computational methods that have revealed numerous aspects of cytokine evolution.

Abstract Background Leaf senescence is a highly complex and meticulous regulatory process, and the disruption of any factor involved in leaf senescence might lead to premature or delayed leaf senescence and thus result in reduced or increased crop yields. Despite sincere efforts by scientists, there remain many unsolved problems related to the regulatory factors and molecular mechanisms of leaf senescence. Results This study successfully revealed that OsHXK1 was highly expressed in senescent leaves of rice. The upregulation of OsHXK1 led to premature senescence of rice leaves, a decreased level of chlorophyll, and damage to the chloroplast structure. The overexpression of OsHXK1 resulted in increases in glucose and ROS levels and produced programmed cell death (PCD) signals earlier at the booting stage. Further analysis showed that expression level of the respiratory burst oxidase homolog (RBOH) genes and OsGLO1 were increased in OsHXK1-overexpressing plants at the booting stage. Conclusions Overall, the outcomes of this study suggested that OsHXK1 could act as a positive regulator of rice leaf senescence by mediating glucose accumulation and inducing an increase in ROS.

Nitrogen oxides emitted from diesel vehicle exhaust seriously endanger the atmospheric environment and human health, which have attracted people’s attention. Among numerous nitrogen oxide (NOx) removal technologies, photocatalytic removal of NOx and SCR have received widespread attention. The photocatalytic treatment of NOx technology is a good choice due to its mild reaction conditions and low costs. Moreover, NH3-SCR has been widely used in denitration technology and plays an important role in controlling NOx emissions. In NH3-SCR technology, the development of high-efficiency catalysts is an important part. This paper summarizes the research progress of metal oxide catalysts for NH3-SCR reactions, including V-based catalysts, Mn-based catalysts, Fe-based catalysts, Ce-based catalysts, and Cu-based catalysts. Meanwhile, the detailed process of the NH3-SCR reaction was also introduced. In addition, this paper also describes a possible SO2 poisoning mechanism and the stability of the catalysts. Finally, the problems and prospects of metal oxide catalysts for NOx removal were also proposed.

Artificial intelligence(AI)is the frontier of computer science. In recent years, AI has developed rapidly in many fields, and its research in ophthalmology is also increasing. The research of AI in corneal related diseases mainly includes the early diagnosis and grading of keratoconus, preoperative evaluation of corneal refractive surgery, prediction of surgical parameters, judgment of the classification and degree of infectious keratitis, evaluation of reintervention after corneal transplantation, auxiliary detection of corneal nerve endings in diabetic peripheral neuropathy, and screening of pterygium. Through the neural network, the support vector machine, and the decision tree, the sensitivity and specificity of the model can reach more than 90%. AI can provide objective clinical decision-making for clinicians and precise clinical treatments for patients. This article reviews the research of AI in corneal diseases in recent years.

Abstract Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by extraordinary heterogeneity, due to the complex pathogenesis and diverse manifestations. Stratification of patients for therapy and prognosis represents a major challenge to manage SLE. Conventional biomarkers for disease diagnosis and activity assessment provide very limited insight into immunological pathogenesis and therapeutic response rates. The advancement of “omics” technologies including genomics, transcriptomics, proteomics, and metabolomics has constituted an unprecedented opportunity to characterize the immunopathological landscape in individual patients with SLE. Indeed, genomic studies reveal a subset of SLE patients carrying one or more functional single nucleotide polymorphisms (SNPs) underlying immune dysregulation while transcriptomic studies have revealed subgroups in SLE patients showing distinct signatures for Type I interferon (TI‐IFN) pathway activation or aberrant differentiation of B cells into plasma cells. This review will summarize results from the latest studies using omics technology to understand SLE heterogeneity. In addition, we propose that the application of artificial intelligence, such as by machine learning‐based nonlinear dimensionality reduction method uniform manifold approximation and projection (UMAP) can further strengthen the analysis of omics big data. The combination of new technology and novel analysis pipeline can lead to breakthroughs in stratifying SLE patients for a better monitoring of disease activity and more precise design of treatment regime, not only for conventional immunosuppression but also novel immunotherapies targeting B‐cell activating factor (BAFF), TI‐IFN, and interleukin 2 (IL‐2).

The basidiomycetous yeast Rhodosporidium toruloides (R. toruloides) is an excellent producer for neutral lipids, including triacylglycerols (TAG). Partially because genetic tools for this yeast were less developed, limited efforts were shown to explore its capacity for the production of higher-value lipids such as diacylglycerols (DAG). Here, four genes linked to the interconversion between DAG and TAG were manipulated to promote the production of DAG and free fatty acids (FFA). Among them, three TAG synthesis-related genes, DGA1, LRO1, and ARE1, were down-regulated successively via the RNA interference technology, and an endogenous TAG lipase encoded by TGL5 was fused with LDP1 and over-expressed to convert TAG into DAG and FFA. Results showed that those engineered R. toruloides strains grew normally under nutrient-rich conditions but notably slower than the parental strain NP11 in the lipid production stage. When cultivated in nitrogen-limited media, engineered strains were able to produce total lipids with improved contents of DAG and FFA by up to two-fold and three-fold, respectively. Further correlation analysis between lipid composition and cell density indicated that the formation of TAG correlated positively with cell growth; however, other lipids including DAG did negatively. This study offered valuable information and strains to engineer R. toruloides for advanced production of fatty acid derivatives.

Carboxyl compounds have a significant influence on the flavor of Chinese Baijiu. However, because of the structural diversity and low concentration, the deep profiling of carboxyl compounds in Chinese Baijiu is still challenging. In this work, a systematic method for comprehensive analysis of carboxyl compounds in Chinese Baijiu was established. After derivatized under optimized conditions, 197 p-dimethylaminophenacyl bromide-derived carboxylic compounds were annotated by multidimensional information including accurate mass, predicted tR, in-silico MS/MS, and diagnostic ions for the first time. In addition, 48 of the 197 carboxyl compounds were positively identified, and three of them were newly identified in Chinese Baijiu. Moreover, we found the number and the concentration of carboxyl compounds in sauce-flavor Baijiu were more abundant than in strong-flavor Baijiu. This work provides a novel method for the analysis of carboxyl compounds in Baijiu and other complex samples.

Oncolytic virotherapy holds promise of effective immunotherapy against otherwise nonresponsive cancers such as glioblastoma. Our previous findings have shown that although oncolytic Semliki Forest virus (SFV) is effective against various mouse glioblastoma models, its therapeutic potency is hampered by type I interferon (IFN-I)-mediated antiviral signaling. In this study, we constructed a novel IFN-I-resistant SFV construct, SFV-AM6, and evaluated its therapeutic potency in vitro, ex vivo, and in vivo in the IFN-I competent mouse GL261 glioma model. In vitro analysis shows that SFV-AM6 causes immunogenic apoptosis in GL261 cells despite high IFN-I signaling. MicroRNA-124 de-targeted SFV-AM6-124T selectively replicates in glioma cells, and it can infect orthotopic GL261 gliomas when administered intraperitoneally. The combination of SFV-AM6-124T and anti-programmed death 1 (PD1) immunotherapy resulted in increased immune cell infiltration in GL261 gliomas, including an increased tumor-reactive CD8+ fraction. Our results show that SFV-AM6-124T can overcome hurdles of innate anti-viral signaling. Combination therapy with SFV-AM6-124T and anti-PD1 promotes the inflammatory response and improves the immune microenvironment in the GL261 glioma model.

Oncolytic viruses (OVs) represent promising therapeutic agents for cancer therapy by selective oncolysis and induction of anti-tumor immunity. OVs can be engineered to express tumor-associated antigens and immune-modulating agents to provoke stronger antitumor immunity. Here, we engineered vaccinia virus (VV) and Semliki Forest virus (SFV) to express neuroblastoma-associated antigen disialoganglioside (GD2) and the immune modulator Helicobacter pylori neutrophil-activating protein (NAP) and compared their therapeutic potency. Oncolytic VV did not exhibit any antitumor benefits, whereas SFV was able to delay subcutaneous neuroblastoma (NXS2) tumor growth. Additional expression of the GD2 mimotope (GD2m) by VV-GD2m or SFV-GD2m did not improve their anti-tumor capacity compared to the parent viruses. Further arming these OVs with NAP resulted in contrasting anti-tumor efficacy. VV (VV-GD2m-NAP) significantly improved therapeutic efficacy compared to VV-GD2m, which was also associated with a significantly elevated anti-GD2 antibody, whereas there was no additive antitumor efficacy for SFV-GD2m-NAP compared to SFV-GD2m, nor was the anti-GD2 antibody response improved. Instead, NAP induced higher neutralizing antibodies against SFV. These observations suggest that distinct immune stimulation profiles are elicited when the same immunostimulatory factor is expressed by different OVs. Therefore, careful consideration and detailed characterization are needed when engineering OVs with immune-modulators.

In recent years, the US society has witnessed a sharp growth in political divide, particularly between those holding conservative and liberal views (Pew Research Center, 2014, 2017). Among the multitude of issues that the American people find divisive, the issue on gun regulation has been one of the most controversial ones (Pew Research Center, 2021) wherein attitudes towards guns vary drastically and are divided along partisan lines. Citizens take to platforms of civic participation such as town hall meetings to express concerns about such divisive issues and seek accountability from politicians. This analysis focuses on one such instance and documents how, with the focal issue of high-capacity firearms, both the citizen and politician adjust their next actions in this gun regulation discussion. Specifically, we observe how the citizen reformulates the notion of gun rights while the politician shifts the perspectives of his responses.

Pyrolysis is an emerging and effective means for sludge disposal. Biochar derived from sludge has broad application prospects, however, is limited by heavy metals. In this study, the fate of heavy metals (HMs) in pyrolysis coupling with acid washing treatment for sewage sludge was comprehensively investigated for the first time. Most of the HMs redistributed in the pyrolyzed residues (biochar) after pyrolysis, and the enrichment order of the HMs was: Zn > Cu > Ni > Cr. Compared with various washing agents, phosphoric acid presented a superior washing effect on most heavy metals (Cu, Zn, and Cr) in biochars derived at low pyrolysis temperature and Ni in biochars derived at high pyrolysis temperature. The optimal washing conditions for heavy metals (including Cu, Zn, Cr, and Ni) removal by H3PO4 were obtained by batch washing experiments and the response surface methodology (RSM). The total maximum HM removal efficiency was 95.05% under the optimal washing specifications by H3PO4 (acid concentration of 2.47 mol/L, L/S of 9.85 mL/g, and a washing temperature of 71.18 °C). Kinetic results indicated that the washing process of heavy metals in sludge and biochars was controlled by a mixture of diffusion and surface chemical reactions. After phosphoric acid washing, the leaching concentrations of HMs in the solid residue were further reduced compared with that of biochar, which were below the USEPA limit value (5 mg/L). The solid residue after pyrolysis coupling with acid washing resulted in a low environmental risk for resource utilization (the values of the potential ecological risk index were lower than 20). This work provides an environmentally friendly alternative of pyrolysis coupling with acid washing treatment for sewage sludge from the viewpoint of the utilization of solid waste.