bluuebunny/crossref_metadata_2025 huggingface dataset:
Optimal Dispatch of Multiple Photovoltaic Integrated 5G Base Stations for Active Distribution Network Demand Response
Authors: Zhang Xiang , Wang Zhao , Zhou Zhenyu , Liao Haijun , Ma Xiufan , Yin Xiyang , Lv Guoyuan , Wang Zhongyu , Lu Zhixin , Liu Yizhao
Published: July 2022

Multiple 5G base stations (BSs) equipped with distributed photovoltaic (PV) generation devices and energy storage (ES) units participate in active distribution network (ADN) demand response (DR), which is expected to be the best way to reduce the energy cost of 5G BSs and provide flexibility resources for the ADN. However, the standalone PV-integrated 5G BS has the characteristics of wide distribution, small volume, and large load fluctuations, which will bring strong uncertainty to the ADN by directly participating in the DR. Therefore, a system architecture for multiple PV-integrated 5G BSs to participate in the DR is proposed, where an energy aggregator is introduced to effectively aggregate the PV energy and ES resources of 5G BSs. Then, a two-stage optimal dispatch method is proposed. Specifically, in the large-timescale DR planning stage, an incentive mechanism for multiple PV-integrated 5G BSs to participate in the DR is constructed based on the contract theory, which ensures that multiple 5G BSs respond to and satisfy the peak-shaving demand of the ADN. In the small-timescale online energy optimization stage, based on the energy sharing mode among 5G BSs, a Lyapunov-based online energy optimization algorithm is proposed to optimize the shared energy flow between the internal layer and the interactive layer of 5G BSs, which further improves PV absorption and ensures operation stability of ES in the 5G BS. Simulation results show that the proposed two-stage optimal dispatch method can effectively encourage multiple 5G BSs to participate in DR and achieve the win–win effect of assisting the ADN peak-shaving and low-carbon economic operation of 5G BSs.
Numerical Investigation of Hot Helium Flow Homogenizer on Inter-Unit Flow Rate Uniformity of HTGR Once Through Steam Generator
Authors: Qin Haiqi , Luo Xiaowei , Li Xiaowei , Wu Xinxin
Published: July 2022

High working temperature is a major feature of the high temperature gas-cooled reactor (HTGR). The helical tube once through steam generator (OTSG) should maintain appropriate temperature uniformity. The temperature non-uniformity of the HTGR OTSG includes the in-unit and inter-unit temperature non-uniformity, while the latter is mainly induced by the inter-unit flow rate non-uniformity of primary-side hot helium, which is significantly affected by the inlet structure. In this work, a new inlet structure with a hot helium flow homogenizer is designed, and its flow distribution characteristics are numerically investigated. Accordingly, the optimal geometrical parameters are determined, such as the circular hole diameter on the end wall, the square hole size, and arrangement on the cylinder wall. Increasing the resistance of the flow homogenizer with non-uniformly arranged square holes (NUASHs) can improve inter-unit flow rate uniformity because it decreases the effect of static pressure difference caused by dynamic pressure. Two design parameters (resistance coefficient and flow area ratio of the square hole on both sides) are introduced to evaluate the structure effect of the hot helium flow homogenizer on inter-unit flow rate distribution. They are recommended within the ranges of (7.81–22.42) and (0.53–1.64), respectively. In these recommended ranges, the suction phenomenon near the hot helium inlet can be effectively suppressed, with the critical resistance coefficient of 7.63. By coupling with 19 heat exchange units, the overall performance of the hot helium flow homogenizer is better than that of the current inlet structure with a baffle, with the maximum inter-unit flow rate deviation decreased from 2.97% to 0.30%. This one-magnitude enhancement indicates that the hot helium flow homogenizer with NUASHs is a promising solution to improve inter-unit flow rate uniformity of the HTGR OTSG.
Understanding Growth-Induced Trends in Local Climate Zones, Land Surface Temperature, and Extreme Temperature Events in a Rapidly Growing City: A Case of Bulawayo Metropolitan City in Zimbabwe
Authors: Mushore Terence Darlington , Mutanga Onisimo , Odindi John
Published: July 2022

Assessment of the responses of the urban thermal environment to climate is important, especially because of their possible influence on low- and high-temperature extreme events. This study assessed the combination of remotely sensed land surface temperature (LST) and local climate zones (LCZs) with in situ air temperature-retrieved extreme temperature indices. It aimed to assess the effect of urban growth on the three-dimensional thermal environment in the Bulawayo metropolitan area, Zimbabwe. LST and LCZ were derived from the Landsat data for 1990, 2005, and 2020, while extreme temperature indices and trends were derived from daily minimum and maximum temperature data from a local weather station. Results showed that the built LCZ expanded at the expense of vegetation-based LCZ. Average LST for each LCZ increased from 1990 to 2020, which was attributed to background warming, while the expansion of high LST areas was associated with LCZ transitions. Although average minimum temperature decreased, cool nights increased, warmest nights remained unchanged, and the lowest minimum increased, the highest minimum temperatures decreased, but the trends were not statistically significant (p > 0.05). Indices of daytime warming showed significant changes, which includes an increase in average maximum temperature (p = 0.002), increase in lowest maximum temperature (p = 0), increase in the number of very warm days (p = 0.004), and decrease in the number of cool days (p = 0). The significant increase in daytime extremes was attributed to an increase in highly absorbing LCZ and daytime pollution due to industrial activities. The study also concluded that development in water areas or siltation of water bodies has a greater warming effect than other LCZ changes. The findings show that development needs to consider potential effects on the thermal environment and temperature extremes.
The Impact of Renewable Energy on Carbon Neutrality for the Sustainable Environment: Role of Green Finance and Technology Innovations
Authors: Feng Haiyan
Published: July 2022

Over time environmental degradation has become a severe concern globally, especially in China. Therefore, to solve this serious issue, environmental economists have tried their best to explain the crux of environmental degradation. Besides such efforts, they have not reached a single opinion. Nowadays, economic progress has been considered a primary target to compete with other nations at any cost of environmental degradation. But, there may be some alternative solutions to reduce such costs, and the existing literature has not considered such core indicators. Thus, the present study assesses the eco-friendly variables for a sustainable environment in which green finance, green energy, and research and development expenditures. Moreover, this study also focuses on socio-economic factors like economic growth, urbanization, and openness. Time series estimators such as fully modified ordinary least square and Markov switching regression model are employed to investigate selected variables’ long-run impact on carbon emissions. The estimated outcomes show the significant contribution of green finance, green energy, openness, and R&D expenditures to environmental quality. Likewise, China’s urbanization and economic progress are harmful to environmental quality. Moreover, this study investigates the causal association between the selected variables and shows the two-way causal association between openness and emissions, RE and openness, and green finance and R&D expenditures. The results of the uni-directional association are also interesting. The current study develops some interesting policy implications for a sustainable environment on behalf of empirical outcomes.
Utilization of Straw Resources May Affect the Speciation of Cd and Its Solubility in Cd-Contaminated Paddy Soil
Authors: Zuo Wengang , Yi Siqiang , Chen Yasi , Huang Gulin , Zhu Xiaowen , Li Yunlong , Gu Chuanhui , Bai Yanchao , Shan Yuhua
Published: July 2022

Rice-wheat rotation has long been the most typical cropping system along the mid-lower reaches of the Yangtse River in China, and the full amount returning of wheat straw before rice season is widely practiced in the rotation system. However, massive incorporation of fresh wheat straw may activate Cd in the soil solid phase and cause more labile Cd entering soil solution in Cd-contaminated soil during the flooded rice season. An incubation experiment was conducted under flooded conditions to investigate the solubility and speciation of Cd and its variation and driving factors with an ongoing decomposition phase in simulated Cd-contaminated paddy soil treated with wheat straw addition. The results indicated that wheat straw addition enhanced Cd solubility, and soluble Cd concentration increased with the ongoing decomposition phase. The observed significant positive correlation (r = 0.648, p < 0.01, n = 77) between soluble Cd concentration and DOC content in soil leachate was gradually strengthened with ongoing decomposition. Wheat straw addition decreased the exchangeable fraction of Cd and increased the residual fraction during the first 5 days of decomposition, while the exchangeable Cd increased and the residual Cd decreased after 10 days of decomposition. The exchangeable Cd increased and the residual Cd decreased gradually with ongoing decomposition. Correlation analysis showed that the exchangeable and residual fractions were sensitive to DOC content. Nitrogen fertilizer input further activated Cd by promoting wheat straw decomposition. In summary, wheat straw addition would activate Cd by increasing Cd solubility and promoting the translation from immobile fraction to labile fraction in Cd-contaminated paddy soil under flooded conditions.
Associational Effects and Indirect Interactions-The Dynamical Effects of Consumer and Resource Traits on Generalist-Resource Interactions
Authors: Klapwijk Maartje J. , Bonsall Michael B.
Published: July 2022

Trophic interaction modifications occur in food webs when the direct or indirect interaction between two species is affected by a third species. These behavioral modification effects are often referred to as associational effects. Changes in focal resource availability and consumption by a generalist herbivore can affect a range of outcomes from resource exclusion to multiple resources coexisting with the focal plant species. Here, we investigate the indirect interaction between a focal and alternative resource mediated by a generalist consumer. Using theoretical approaches we analyse the conceptual link between associational effects (both resistance and susceptibility) and the theory of apparent competition and resource switching. We find that changes in focal resource traits have the potential to affect the long-term outcome of indirect interactions. Inclusion of density-dependence expands generalist life-histories and broadens the range where, through associational effects, the availability of alternative resources positively influence a focal resource. We conclude that different forms of associational effects could, in the long-term, lead to a range of indirect interaction dynamics, including apparent competition and apparent mutualism. Our work aims to connects the theoretical body of work on indirect interactions to the concepts of associational effects. The indirect interactions between multiple resources need more thorough investigation to appreciate the range of associational effects that could result from the dynamical interaction between a generalist consumers and its focal and alternative resources.
Comparing Methods of Defining Priority Areas for Greater Sage-Grouse
Authors: Parsons Lindsey , Jenks Jonathan , Runia Travis , Gregory Andrew
Published: July 2022

Wildlife managers delineate priority areas for species to define critical habitat and to prioritize management efforts. Each method used to identify priority areas involves data that can be unavailable or expensive to obtain. Therefore, it is of interest to compare spatial efficiency between methods used for defining priority areas. We compared priority areas created using different methods and data types. We used resource selection function (RSF) models to predict areas of high use and generated a map depicting ≥ 90% predicted use in three seasons; it was 1,143 km2, encompassed 91% of nests, 68% of summer locations, and 71% of winter locations. We compared the RSF priority area to priority areas developed using two alternative methods: (1) modified conservation buffer, and (2) utilization distribution (UD) models. The modified conservation buffer method was used by South Dakota Game, Fish and Parks in 2014 to delineate a priority area by buffering active lek sites by 6.4 km, including connectivity corridors defined via expert opinion, and known high use areas. The priority area generated by the modified conservation buffer method was 3,977 km2, encompassed 95% of nest locations, 92% of spring/summer locations, and 99% of winter locations. Lastly, we developed a priority area using combined UDs from radio-tracking data gathered during spring/summer, and winter and included a lek buffer encompassing 90% of known nest-sites. This priority area was 3,498 km2, encompassed 99% of nests, 98% of spring/summer locations, and 97% of winter locations. The priority area generated by RSF models was the smallest and encompassed the least number of nests and spring/summer and winter locations but was considered the most spatially efficient; it had the most nests, spring/summer locations, and winter locations per 100 km2. The UD and modified conservation buffer methods created priority areas that were similar in size and spatial efficiency. The modified conservation buffer method encompassed >90% of known sage-grouse locations and nests, indicating that in the absence of detailed movement data and more sophisticated modeling, the method can be sufficient in developing an adequate priority area.
Precipitation, Not Land Use, Primarily Determines the Composition of Both Plant and Phyllosphere Fungal Communities
Authors: Dea Hannah I. , Urban Abigail , Kazarina Anna , Houseman Gregory R. , Thomas Samantha G. , Loecke Terry , Greer Mitchell J. , Platt Thomas G. , Lee Sonny , Jumpponen Ari
Published: July 2022

Plant communities and fungi inhabiting their phyllospheres change along precipitation gradients and often respond to changes in land use. Many studies have focused on the changes in foliar fungal communities on specific plant species, however, few have addressed the association between whole plant communities and their phyllosphere fungi. We sampled plant communities and associated phyllosphere fungal communities in native prairie remnants and post-agricultural sites across the steep precipitation gradient in the central plains in Kansas, USA. Plant community cover data and MiSeq ITS2 metabarcode data of the phyllosphere fungal communities indicated that both plant and fungal community composition respond strongly to mean annual precipitation (MAP), but less so to land use (native prairie remnants vs. post-agricultural sites). However, plant and fungal diversity were greater in the native remnant prairies than in post-agricultural sites. Overall, both plant and fungal diversity increased with MAP and the communities in the arid and mesic parts of the gradient were distinct. Analyses of the linkages between plant and fungal communities (Mantel and Procrustes tests) identified strong correlations between the composition of the two. However, despite the strong correlations, regression models with plant richness, diversity, or composition (ordination axis scores) and land use as explanatory variables for fungal diversity and evenness did not improve the models compared to those with precipitation and land use (ΔAIC < 2), even though the explanatory power of some plant variables was greater than that of MAP as measured by R2. Indicator taxon analyses suggest that grass species are the primary taxa that differ in the plant communities. Similar analyses of the phyllosphere fungi indicated that many plant pathogens are disproportionately abundant either in the arid or mesic environments. Although decoupling the drivers of fungal communities and their composition – whether abiotic or host-dependent – remains a challenge, our study highlights the distinct community responses to precipitation and the tight tracking of the plant communities by their associated fungal symbionts.
A Secondary Metabolite Secreted by Penicillium citrinum Is Able to Enhance Parastagonospora nodorum Sensitivity to Tebuconazole and Azoxystrobin
Authors: Kartashov Maksim , Voinova Tatiana , Shcherbakova Larisa , Arslanova Lenara , Chudakova Kseniya , Dzhavakhiya Vitaly
Published: July 2022

Parastagonospora nodorum causes glume and leaf blotch of wheat, a harmful disease resulting in serious losses in grain yield. In many countries including Russia, fungicidal formulations based on triazoles and on triazoles combined with strobilurins are used to control this fungus. However, their prolonged application may promote the selection of fungicide-resistant strains of P. nodorum leading to significant attenuation or even loss of fungicidal effect. Chemosensitization of plant pathogenic fungi with natural compounds represents a promising strategy for mitigating fungicide resistance and other negative impacts of fungicides. In this work, we applied a chemosensitization approach towards P. nodorum strains non-resistant or resistant to tebuconazole or azoxystrobin using 6-demethylmevinolin (6-DMM), a metabolite of Penicillium citrinum. The resistant strains were obtained by the mutagenesis and subsequent culturing on agar media incorporated with increasing doses of Folicur® EC 250 (i.e., tebuconazole) or Quadris® SC 250 (i.e., azoxystrobin). Test strains m8-4 and kd-18, most resistant to tebuconazole and azoxystrobin, respectively, were selected for sensitization experiments. These experiments demonstrated that combining 6-DMM with Folicur® enhanced fungicidal effectiveness in vitro and in vivo in addition to attenuating the resistance of P. nodorum to tebuconazole in vitro. 6-DMM was also found to augment Quadris® efficacy towards kd-18 when applied on detached wheat leaves inoculated with this strain. Experiments on P. nodorum sensitization under greenhouse conditions included preventive (applying test compounds simultaneously with inoculation) or post-inoculation spraying of wheat seedlings with 6-DMM together with Folicur® at dose rates (DR) amounting to 10% and 20% of DR recommended for field application (RDR). Combined treatments were run in parallel with using the same DR of the fungicide and sensitizer, alone. A synergistic effect was observed in both preventive and post-inoculation treatments, when the sensitizer was co-applied with the fungicide at 10% of the RDR. In this case, disease reduction significantly exceeded the protective effect of Folicur® at 10% or 20% of the RDR, alone, and also a calculated additive effect. Collectively, our findings suggest that 6-DMM is promising as a putative component for formulations with triazole and strobilurin fungicides. Such new formulations would improve fungicide efficacy and, potentially, lower rates of fungicides needed for plant pathogen control.
Deletion of microRNA-183-96-182 Cluster in Lymphocytes Suppresses Anti-DsDNA Autoantibody Production and IgG Deposition in the Kidneys in C57BL/6-Faslpr/lpr Mice
Authors: Wang Zhuang , Heid Bettina , Lu Ran , Sachdeva Mohit , Edwards Michael R. , Ren JingJing , Cecere Thomas E. , Khan Deena , Jeboda Taschua , Kirsch David G. , Reilly Christopher M. , Dai Rujuan , Ahmed S. Ansar
Published: July 2022

Dysregulated miRNAs have been implicated in the pathogenesis of systemic lupus erythematosus (SLE). Our previous study reported a substantial increase in three miRNAs located at the miR-183-96-182 cluster (miR-183C) in several autoimmune lupus-prone mice, including MRL/lpr and C57BL/6-lpr (B6/lpr). This study reports thatin vitroinhibition of miR-182 alone or miR-183C by specific antagomirs in activated splenocytes from autoimmune-prone MRL/lpr and control MRL mice significantly reduced lupus-related inflammatory cytokines, interferon-gamma (IFNγ), and IL-6 production. To further characterize the role of miR-182 and miR-183C clusterin vivoin lupus-like disease and lymphocyte phenotypes, we used hCD2-iCre to generate B6/lpr mice with conditional deletion of miR-182 or miR-183C in CD2+lymphocytes (miR-182−/−B6/lpr and miR-183C−/-B6/lpr). The miR-182−/−B6/lpr and miR-183C−/−B6/lpr mice had significantly reduced deposition of IgG immunocomplexes in the kidney when compared to their respective littermate controls, although there appeared to be no remarkable changes in renal pathology. Importantly, we observed a significant reduction of serum anti-dsDNA autoantibodies in miR-183C−/−B6/lpr mice after reaching 24 weeks-of age compared to age-matched miR-183Cfl/flB6/lpr controls.In vitroactivated splenocytes from miR-182−/−B6/lpr mice and miR-183C−/−B6/lpr mice showed reduced ability to produce lupus-associated IFNγ. Forkhead box O1(Foxo1), a previously validated miR-183C miRNAs target, was increased in the splenic CD4+cells of miR-182−/−B6/lpr and miR-183C−/−B6/lpr mice. Furthermore,in vitroinhibition of Foxo1 with siRNA in splenocytes from miR-182−/−B6/lpr and miR-183C−/-B6/lpr mice significantly increased IFNγ expression following anti-CD3/CD28 stimulation, suggesting that miR-182 and miR-183C miRNAs regulate the inflammatory IFNγ in splenocytes via targeting Foxo1. The deletion of either miR-182 alone or the whole miR-183C cluster, however, had no marked effect on the composition of T and B cell subsets in the spleens of B6/lpr mice. There were similar percentages of CD4+, CD8+, CD19+, as well as Tregs, follicular helper T (TFH), germinal center B (GCB), and plasma cells in the miR-183C−/−B6/lpr and miR-182−/−B6/lpr mice and their respective littermate controls, miR-183Cfl/flB6/lpr and miR-182fl/flB6/lpr mice. Together, our data demonstrate a role of miR-183C in the regulation of anti-dsDNA autoantibody productionin vivoin B6/lpr mice and the induction of IFNγ inin vitroactivated splenocytes from B6/lpr mice.
Oncogenetic Function and Prognostic Value of DNA Topoisomerase II Alpha in Human Malignances: A Pan-Cancer Analysis
Authors: Zhao Fulai , Chang Junli , Zhao Peng , Wang Wenyi , Sun Xingyuan , Ma Xiaoping , Yin Mengchen , Wang Yongjun , Yang Yanping
Published: July 2022

Increasing studies have revealed significant associations between TOP2A with oncogenesis and prognosis of human cancers; however, pan-cancer analysis has not been reported. Here, we explored the potential carcinogenic function and the association with clinical outcomes of TOP2A in 33 different human cancers. The results showed that TOP2A was amplified in 31 investigated cancers; TOP2A expression was significantly associated with metastasis of six different cancers and significantly associated with the survival of patients in ten different cancers; TOP2A-encoded protein was obviously upregulated in five available cancers; phosphorylated TOP2A protein at S1106 was significantly upregulated in all six available cancers. Moreover, TOP2A expression was found to be associated with the cancer-associated immune cell infiltration, including fibroblasts, Tregs, and macrophages. In addition, the Kyoto encyclopedia of genes and genomes (KEGG) pathway and Gene Ontology (GO) enrichment analyses revealed a most significant association between TOP2A with the Wnt signaling pathway and DNA conformation change. This work provides a comprehensive knowledge of TOP2A in different cancers, including carcinogenic function, prognostic values for metastasis, and clinical outcomes.
Orthotopic and Heterotopic Murine Models of Pancreatic Cancer Exhibit Different Immunological Microenvironments and Different Responses to Immunotherapy
Authors: Wang Jin , Liu Xingchen , Ji Junsong , Luo Jianhua , Zhao Yuanyu , Zhou Xiaonan , Zheng Jianming , Guo Meng , Liu Yanfang
Published: July 2022

For decades, tumor-bearing murine models established using tumor cell lines have been the most commonly used models to study human cancers. Even though there are several studies reported that implant sites caused disparities in tumor behaviors, few of them illuminated the positional effect on immunotherapy. Herein, we describe surgical techniques for a novel orthotopic implantation of syngeneic pancreatic ductal adenocarcinoma (PDAC) tissue slices. This method has a high success modeling rate and stable growth kinetics, which makes it useful for testing novel therapeutics. Pathological examination indicated that the orthotopic tumor displayed poor vascularization, desmoplastic stromal reaction, and a highly immunosuppressive tumor microenvironment. This unique microenvironment resulted in limited response to PD1/CTLA4 blockade therapy and anti-MUC1 (αMUC1) CAR-T transfer treatment. To reverse the suppressive tumor microenvironment, we developed gene modified T-cells bearing a chimeric receptor in which activating receptor NKG2D fused to intracellular domains of 4-1BB and CD3ζ (NKG2D CAR). The NKG2D CAR-T cells target myeloid-derived suppressor cells (MDSCs), which overexpress Rae1 (NKG2D ligands) within the TME. Results indicated that NKG2D CAR-T cells eliminated MDSCs and improved antitumor activity of subsequently infused CAR-T cells. Moreover, we generated a bicistronic CAR-T, including αMUC1 CAR and NKG2D CAR separated by a P2A element. Treatment with the dual targeted bicistronic CAR-T cells also resulted in prolonged survival of orthotopic model mice. In summary, this study describes construction of a novel orthotopic PDAC model through implantation of tissue slices and discusses resistance to immunotherapy from the perspective of a PDAC microenvironment. Based on the obtained results, it is evident that elimination MDSCs by NKG2D CAR could rescue the impaired CAR-T cell activity.
Increased Expression of Multiple Co-Inhibitory Molecules on Malaria-Induced CD8+ T Cells Are Associated With Increased Function Instead of Exhaustion
Authors: Brandi Johannes , Riehn Mathias , Hadjilaou Alexandros , Jacobs Thomas
Published: July 2022

Activated cytotoxic CD8+ T cells can selectively kill target cells in an antigen-specific manner. However, their prolonged activation often has detrimental effects on tissue homeostasis and function. Indeed, overwhelming cytotoxic activity of CD8+ T cells can drive immunopathology, and therefore, the extent and duration of CD8+ T cell effector function needs to be tightly regulated. One way to regulate CD8+ T cell function is their suppression through engagement of co-inhibitory molecules to their cognate ligands (e.g., LAG-3, PD-1, TIM-3, TIGIT and CTLA-4). During chronic antigen exposure, the expression of co-inhibitory molecules is associated with a loss of T cell function, termed T cell exhaustion and blockade of co-inhibitory pathways often restores T cell function. We addressed the effect of co-inhibitory molecule expression on CD8+ T cell function during acute antigen exposure using experimental malaria. To this end, we infected OT-I mice with a transgenic P. berghei ANKA strain that expresses ovalbumin (PbTG), which enables the characterization of antigen-specific CD8+ T cell responses. We then compared antigen-specific CD8+ T cell populations expressing different levels of the co-inhibitory molecules. High expression of LAG-3 correlated with high expression of PD-1, TIGIT, TIM-3 and CTLA-4. Contrary to what has been described during chronic antigen exposure, antigen-specific CD8+ T cells with the highest expression of LAG-3 appeared to be fully functional during acute malaria. We evaluated this by measuring IFN-γ, Granzyme B and Perforin production and confirmed the results by employing a newly developed T cell cytotoxicity assay. We found that LAG-3high CD8+ T cells are more cytotoxic than LAG-3low or activated but LAG-3neg CD8+ T cells. In conclusion, our data imply that expression of co-inhibitory molecules in acute malaria is not necessarily associated with functional exhaustion but may be associated with an overwhelming T cell activation. Taken together, our findings shed new light on the induction of co-inhibitory molecules during acute T cell activation with ramifications for immunomodulatory therapies targeting these molecules in acute infectious diseases.
SIRPα Mismatch Is Associated With Relapse Protection and Chronic Graft-Versus-Host Disease After Related Hematopoietic Stem Cell Transplantation for Lymphoid Malignancies
Authors: Saliba Rima M. , Srour Samer A. , Greenbaum Uri , Ma Qing , Carmazzi Yudith , Moller Michael , Wood Janet , Ciurea Stefan O. , Kongtim Piyanuch , Rondon Gabriela , Li Dan , Saengboon Supawee , Alousi Amin M. , Rezvani Katayoun , Shpall Elizabeth J. , Cao Kai , Champlin Richard E. , Zou Jun
Published: July 2022

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potentially curative therapy for hematologic malignancies. Alloreactivity after HSCT is known to be mediated by adaptive immune cells expressing rearranging receptors. Recent studies demonstrated that the innate immune system could likewise sense the non-self signals and subsequently enhance the alloimmune response. We recently demonstrated that the donor/recipient mismatch of signal regulatory protein α (SIRPα), an immunoglobulin receptor exclusively expressed on innate cells, is associated with a higher risk of cGVHD and relapse protection in a cohort of acute myeloid leukemia patients who underwent allo-HSCT. Whether these effects also occur in other hematologic malignancies remains unclear. In the present study, we compared outcomes by SIRPα match status in a cohort of 310 patients who received allo-HSCT from an HLA matched-related donor for the treatment of lymphoid malignancies. Multivariable analysis showed that SIRPα mismatch was associated with a significantly higher rate of cGVHD (hazard ratio [HR] 1.8, P= .002), cGVHD requiring systemic immunosuppressive therapy (HR 1.9, P= .005), a lower rate of disease progression (HR 0.5, P= .003) and improved progression-free survival (HR 0.5, P= .001). Notably, the effects of SIRPα mismatch were observed only in the patients who achieved >95% of donor T-cell chimerism. The mismatch in SIRPα is associated with favorable relapse protection and concurrently increased risk of cGVHD in patients who undergo allo-HSCT for lymphoid malignancies, and the optimal donor could be selected based on the finding of the study to mitigate the risk of GVHD and relapse.
Finding Gene Regulatory Networks in Psoriasis: Application of a Tree-Based Machine Learning Approach
Authors: Deng Jingwen , Schieler Carlotta , Borghans José A. M. , Lu Chuanjian , Pandit Aridaman
Published: July 2022

Psoriasis is a chronic inflammatory skin disorder. Although it has been studied extensively, the molecular mechanisms driving the disease remain unclear. In this study, we utilized a tree-based machine learning approach to explore the gene regulatory networks underlying psoriasis. We then validated the regulators and their networks in an independent cohort. We identified some key regulators of psoriasis, which are candidates to serve as potential drug targets and disease severity biomarkers. According to the gene regulatory network that we identified, we suggest that interferon signaling represents a key pathway of psoriatic inflammation.
IL-7 Promotes the Expansion of Circulating CD28- Cytotoxic T Lymphocytes in Patients With IgG4-Related Disease via the JAK Signaling
Authors: Xia Chang-sheng , Long Yan , Liu Yanying , Alifu Aikede , Zeng Xingyue , Liu Chen
Published: July 2022

Objectives

This study aimed to elucidate the changes and associated mechanisms of circulating CD28- cytotoxic T lymphocytes (CTLs) in patients with IgG4-related disease (IgG4-RD).

Methods

Fifty IgG4-RD patients and 15 healthy controls (HCs) were recruited. Peripheral blood mononuclear cells (PBMCs) were isolated, the levels of circulating CD28- CTLs were detected by flow cytometry, and the proportions of CD127lo or GZMB+CD28- CTL subsets were analyzed in the meantime. Mechanistically, PBMCs isolated from IgG4-RD patients were stimulated with IL-7 in the presence or absence of the JAK inhibitor tofacitinib. Flow cytometry was used to analyze the proliferation of CD28- CTLs and the changes in related subpopulations.

Results

Circulating CD4+CD28- CTLs and CD8+CD28- CTLs were significantly increased in IgG4-RD patients compared with HCs, accompanied by an elevation of CD127lo or GZMB+ CTL subsets. Theex vivoculture of PBMCs showed that IL-7 could induce the amplification of CD4+CD28- CTLs and CD8+CD28- CTLs in IgG4-RD. Furthermore, IL-7 promotes the proliferation and functional subset changes of these CD28- CTLs in this disease. The selective JAK inhibitor tofacitinib significantly inhibited the effects of IL-7 on CD4+CD28- CTLs and CD8+CD28- CTLs.

Conclusion

IL-7 can affect the immune balance of IgG4-RD patients by promoting the expansion and function of CD4+CD28- and CD8+CD28- CTLs in IgG4-RD through the JAK pathway. Blockade of the IL-7 signaling pathway may be a new therapeutic strategy for IgG4-RD.
Cell Membrane-Derived Vesicle: A Novel Vehicle for Cancer Immunotherapy
Authors: Xu Caili , Ju Dianwen , Zhang Xuyao
Published: July 2022

As nano-sized materials prepared by isolating, disrupting and extruding cell membranes, cellular vesicles are emerging as a novel vehicle for immunotherapeutic drugs to activate antitumor immunity. Cell membrane-derived vesicles inherit the surface characteristics and functional properties of parental cells, thus having superior biocompatibility, low immunogenicity and long circulation. Moreover, the potent antitumor effect of cellular vesicles can be achieved through surface modification, genetic engineering, hybridization, drug encapsulation, and exogenous stimulation. The capacity of cellular vesicles to combine drugs of different compositions and functions in physical space provides a promising vehicle for combinational immunotherapy of cancer. In this review, the latest advances in cellular vesicles as vehicles for combinational cancer immunotherapy are systematically summarized with focuses on manufacturing processes, cell sources, therapeutic strategies and applications, providing an insight into the potential and existing challenges of using cellular vesicles for cancer immunotherapy.
PRaG Therapy of Refractory Metastatic Gastric Cancer: A Case Report
Authors: Xu Hong , Hong Zhihui , Xu Meiling , Kong Yuehong , Ma Yifu , Shan Chanchan , Xing Pengfei , Zhang Liyuan
Published: July 2022

Patients with metastatic gastric cancer had limited treatments and often had a somber prognosis, especially when patients were unable to tolerate high-intensity cytotoxic treatment due to poor physical condition or organ dysfunction after the failure of standard therapy. Here, we reported a metastatic and proficient mismatch repair (pMMR) gastric adenocarcinoma patient with the Eastern Cooperative Oncology Group (ECOG) performance status score of 2 associated with hypoproteinemia and fatigue, and poor appetite that was unable to tolerate high-intensity therapy after several chemotherapy regimens and anti-angiogenic therapy. After receiving novel triple-combination therapy, which consists of PD-1 inhibitor, Radiotherapy and Granulocyte-macrophage colony-stimulating factor (GM-CSF) therapy (PRaG for short), the patient achieved a complete response (CR) with a progression-free survival time of 14 months, and ECOG performance status score improved from 2 to 0. A significant systemic effect was observed in this case and the PRaG triple-combination therapy might provide a novel treatment strategy for metastatic pMMR gastric cancer patients.
Challenges in the Treatment of Glioblastoma by Chimeric Antigen Receptor T-Cell Immunotherapy and Possible Solutions
Authors: Zhang Peng , Zhang Yang , Ji Nan
Published: July 2022

Glioblastoma (GBM), one of the most lethal brain cancers in adults, accounts for 48.6% of all malignant primary CNS tumors diagnosed each year. The 5-year survival rate of GBM patients remains less than 10% even after they receive the standard-of-care treatment, including maximal safe resection, adjuvant radiation, and chemotherapy with temozolomide. Therefore, new therapeutic modalities are urgently needed for this deadly cancer. The last decade has witnessed great advances in chimeric antigen receptor T (CAR-T) cell immunotherapy for the treatment of hematological malignancies. Up to now, the US FDA has approved six CAR-T cell products in treating hematopoietic cancers including B-cell acute lymphoblastic leukemia, lymphoma, and multiple myeloma. Meanwhile, the number of clinical trials on CAR-T cell has increased significantly, with more than 80% from China and the United States. With its achievements in liquid cancers, the clinical efficacy of CAR-T cell therapy has also been explored in a variety of solid malignancies that include GBMs. However, attempts to expand CAR-T cell immunotherapy in GBMs have not yet presented promising results in hematopoietic malignancies. Like other solid tumors, CAR-T cell therapies against GBM still face several challenges, such as tumor heterogeneity, tumor immunosuppressive microenvironment, and CAR-T cell persistence. Hence, developing strategies to overcome these challenges will be necessary to accelerate the transition of CAR-T cell immunotherapy against GBMs from bench to bedside.
Neoantigens and NK Cells: “Trick or Treat” the Cancers?
Authors: Lv Dan , Khawar Muhammad Babar , Liang Zhengyan , Gao Yu , Sun Haibo
Published: July 2022

Immunotherapy has become an important treatment strategy for cancer patients nowadays. Targeting cancer neoantigens presented by major histocompatibility complex (MHC) molecules, which emerge as a result of non-synonymous somatic mutations with high immunogenicity, is one of the most promising cancer immunotherapy strategies. Currently, several therapeutic options based on the personalized or shared neoantigens have been developed, including neoantigen vaccine and adoptive T-cell therapy, both of which are now being tested in clinical trials for various malignancies. The goal of this review is to outline the use of neoantigens as cancer therapy targets, with an emphasis on neoantigen identification, clinical usage of personalized neoantigen-based cancer therapy agents, and the development of off-the-shelf products based on shared neoantigens. In addition, we introduce and discuss the potential impact of the neoantigen–MHC complex on natural killer (NK) cell antitumor function, which could be a novel way to boost immune response-induced cytotoxicity against malignancies.
An Integrated Transcriptomics and Lipidomics Analysis Reveals That Ergosterol Is Required for Host Defense Against Bacterial Infection in Drosophila
Authors: Deng Zihao , Yang Yanyang , Luo Jiazhen , Zhang Biling , Liu Jiyong , Shui Guanghou , Jiao Renjie , Wei Chuanxian
Published: July 2022

Animals adjust their lipid metabolism states in response to pathogens infection. However, the underlying molecular mechanisms for how lipid metabolism responds to infection remain to be elusive. In this study, we assessed the temporal changes of lipid metabolism profiles during infection by an integrated transcriptomics and lipidomics analysis. Ergosterol is identified to be required for proper host defense to pathogens. Notably, ergosterol level is increased in the hemolymph upon bacterial infection. We show that the increase of ergosterol level by food supplement or genetic depletion of Acsl, a long-chain fatty acid-CoA synthetase, promotes host survival against bacterial challenges. Together, our results suggest a critical role of lipid metabolism adaption in the process of host defense against invading pathogens.
The Alternative Pathway Is Necessary and Sufficient for Complement Activation by Anti-THSD7A Autoantibodies, Which Are Predominantly IgG4 in Membranous Nephropathy
Authors: Manral Pallavi , Caza Tiffany N. , Storey Aaron J. , Beck Laurence H. , Borza Dorin-Bogdan
Published: July 2022

Membranous nephropathy (MN) is an immune kidney disease characterized by glomerular subepithelial immune complexes (ICs) containing antigen, IgG, and products of complement activation. Whereas proteinuria is caused by complement-mediated podocyte injury, the pathways of complement activation remain controversial due to the predominance of IgG4 in ICs, an IgG subclass considered unable to activate complement. THSD7A, a transmembrane protein expressed on podocytes, is the target autoantigen in ~3% of cases of primary MN. In this study, we analyzed sera from 16 patients with THSD7A-associated MN with regard to the anti-THSD7A IgG subclasses and their ability to fix complement in vitro. The serum concentration of anti-THSD7A IgG varied over two orders of magnitude (1.3-243 μg/mL). As a relative proportion of all IgG anti-THSD7A, IgG4 was by far the most abundant subclass (median 79%), followed by IgG1 (median 11%). IgG4 was the dominant subclass of anti-THSD7A antibodies in 14 sera, while IgG1 was dominant in one and co-dominant in another. One quarter of MN sera additionally contained low levels of anti-THSD7A IgA1. ICs formed by predominantly IgG4 anti-THSD7A autoantibodies with immobilized THSD7A were relatively weak activators of complement in vitro, compared to human IgG1 and IgG3 mAbs used as positive control. Complement deposition on THSD7A ICs was dose-dependent and occurred to a significant extent only at relatively high concentration of anti-THSD7A IgG. C3b fixation by THSD7A ICs was completely abolished in factor B-depleted sera, partially inhibited in C4-depleted sera, unchanged in C1q-depleted sera, and also occurred in Mg-EGTA buffer. These results imply that THSD7A ICs predominantly containing IgG4 activate complement at high IgG4 density, which strictly requires a functional alternative pathway, whereas the classical and lectin pathways are dispensable. These findings advance our understanding of how IgG4 antibodies activate complement.
T-Cell Progenitors As A New Immunotherapy to Bypass Hurdles of Allogeneic Hematopoietic Stem Cell Transplantation
Authors: Gaudeaux Pierre , Moirangthem Ranjita Devi , Bauquet Aurélie , Simons Laura , Joshi Akshay , Cavazzana Marina , Nègre Olivier , Soheili Shabi , André Isabelle
Published: July 2022

Allogeneic hematopoietic stem cell transplantation (HSCT) is the treatment of preference for numerous malignant and non-malignant hemopathies. The outcome of this approach is significantly hampered by not only graft-versus-host disease (GvHD), but also infections and relapses that may occur because of persistent T-cell immunodeficiency following transplantation. Reconstitution of a functional T-cell repertoire can take more than 1 year. Thus, the major challenge in the management of allogeneic HSCT relies on the possibility of shortening the window of immune deficiency through the acceleration of T-cell recovery, with diverse, self-tolerant, and naïve T cells resulting from de novo thymopoiesis from the donor cells. In this context, adoptive transfer of cell populations that can give rise to mature T cells faster than HSCs while maintaining a safety profile compatible with clinical use is of major interest. In this review, we summarize current advances in the characterization of thymus seeding progenitors, and their ex vivo generated counterparts, T-cell progenitors. Transplantation of the latter has been identified as a worthwhile approach to shorten the period of immune deficiency in patients following allogeneic HSCT, and to fulfill the clinical objective of reducing morbimortality due to infections and relapses. We further discuss current opportunities for T-cell progenitor-based therapy manufacturing, including iPSC cell sources and off-the-shelf strategies. These opportunities will be analyzed in the light of results from ongoing clinical studies involving T-cell progenitors.
A Persistent Sea-Going Platform for Robotic Fish Telemetry Using a Wave-Propelled USV: Technical Solution and Proof-of-Concept
Authors: Dallolio Alberto , Bjerck Helge B. , Urke Henning A. , Alfredsen Jo A.
Published: July 2022

Over the last few decades, acoustic fish telemetry has developed into a viable approach for remote monitoring of fish behaviour in the marine environment. Simultaneously, unmanned surface and underwater vehicles have found extensive use as scalable, persistent and cost-effective platforms for ocean observation. Equipping such robotic vehicles with fish telemetry receivers constitutes an emerging approach with the potential to significantly push the current operational limits of fish movement studies at sea. Here, we present an energy-autonomous robotic fish telemetry platform realised through the integration of a real-time acoustic receiver into an ocean-going wave- and solar-powered unmanned surface vehicle. The vehicle frame and energy harvesting solutions are based on the commercially available AutoNaut USV, while the vehicle’s control and communication systems were developed using open-source software and standard hardware components. The open architecture permitted deep integration of the acoustic receiver as a system-level payload making fish detections and other sensor data available in real-time to the vehicle’s onboard control system. The vehicle is thus prepared with local situational awareness to support autonomous control during vehicle-fish encounters, as well as conventional interfaces for remote piloting and data management through long-range wireless communication links and the Internet. The vehicle concept was investigated theoretically and experimentally in an acoustic range test and a full-scale sea trial. When driven passively by waves, tag detection performance was comparable to that of traditional moored receivers, while activation of the auxiliary electric thruster caused a reduction in detection radius of more than 50%, confirming wave-power as the ideal mode of propulsion. Finally, by deploying the AutoNaut over a period of several days at the outskirts of a Norwegian fjord during the seaward migration of Atlantic salmon post-smolts, we demonstrated that the vehicle was able to detect an acoustically tagged post-smolt into the open ocean beyond the reach of the fjord’s stationary receiver grid, while using only wave- and solar energy harvesting to power its operation. The ability to observe small individual fish in the ocean environment using an energy-autonomous robotic vehicle creates novel and unprecedented opportunities for scientific inquiry in fish behaviour and movement ecology studies at sea.