bluuebunny/crossref_metadata_2025 huggingface dataset:
Emerging trends and hotspots in metabolic dysfunction-associated fatty liver disease (MAFLD) research from 2012 to 2021: A bibliometric analysis
Authors: Liao Yudi , Wang Liya , Liu Fang , Zhou Yanyu , Lin Xiaoqi , Zhao Zijun , Xu Saihong , Tang Dan , Jiao Yingfu , Yang Liqun , Yu Weifeng , Gao Po
Published: January 2023

Background

Metabolic dysfunction-associated fatty liver disease (MAFLD) has become the most common chronic liver disease. MAFLD is a major risk factor for end-stage liver disease including cirrhosis and primary liver cancer. The pathogenesis of MAFLD is complex and has not yet been clarified. To the best of our knowledge, few studies have conducted quantitative bibliometric analysis to evaluate published MAFLD research. In this study, we conducted a comprehensive analysis of MAFLD publications over the past decade to summarize the current research hotspots and predict future research directions in this field.

Methods

Articles into MAFLD published from 2012 to 2021 were identified from the Science Citation Index-Expanded of Web of Science Core Collection. CiteSpace software, VOSviewer, the “bibliometrix” R package, and the Online Analysis Platform of Literature Metrology were used to analyze the current publication trends and hotspots.

Results

We retrieved 13959 English articles about MAFLD published from 2012 to 2021. Primary sites of publication were dominated by the United States until 2014, when China became the source of most published MAFLD-related research papers. The United States was found to be the most engaged country in international cooperative efforts. Shanghai Jiao Tong University was the most productive institution. Loomba R was the most productive author with 123 articles. The co-cited keyword cluster tag showed ten main clusters: #0 liver fibrosis, #1 hemoglobin, #2 metabolic associated fatty liver disease, #3 egcg, #4 myocardial infarction, #5 heart disease, #6 pnpla3, #7 hepatocellular carcinoma, #8 noninvasive marker, and #9 children. Keyword burst analysis showed that gut microbiota was the highest-intensity research hotspot.

Conclusion

In the past decade, the number of publications on MAFLD increased dramatically, especially in the last three years. Gut microbiota became an important research direction for etiological and therapeutic investigations into MAFLD. Insulin resistance was also a key factor in studying the development of MAFLD in recent years. Liver fibrosis was an important focus of disease development. This study provides systematic information, helps guide future research, and helps to identify mechanisms and new treatment methods for MAFLD.
Epidemiology and the economic burden of traumatic fractures in China: A population-based study
Authors: Huang Bo-xuan , Wang Yan-hua , Wang Hai-bo , Wang Chu , Jin Fei-fei , Li Jing , Gan Lan-xia , Shi Ying , Jiang Bao-guo , Zhang Dian-ying
Published: January 2023

Objectives

National data on the admission rate, distribution, in-hospital mortality, and economic burden of traumatic fractures in China is unclear. We aimed to conduct a cross-sectional population-based study to determine such above data at the national level in China.

Methods

A national administrative database was used to review all traumatic fracture hospitalizations in China during 2020, from which a total of 2,025,169 inpatients with traumatic fractures was retrieved. Admission rates and in-hospital mortality rates stratified by age, sex, and region were calculated. The causes of traumatic fracture and economic burden were described.

Results

The admission rate of traumatic fractures of all China population in 2020 was 1.437‰. The admission rate increased with age and varied with genders and causes of injuries. Falls are the leading cause of traumatic fracture hospitalization, followed by road traffic injuries. The most common diagnoses were femoral neck fractures, with a number of 138,377. The in-hospital mortality was 1.209‰. Road traffic injuries led to the highest in-hospital mortality. The median length of stay was 10 days, with the median hospitalization cost of ¥20,900 (about $3,056).

Conclusion

Traumatic fractures are concerning conditions with a high admission rate and in-hospital mortality in China, which are mainly caused by falls and road traffic injuries. The government should implement more public health policies to enhance the health of the elderly and improve transportation safety to prevent traumatic fractures.
Systematic assessment of streptozotocin-induced diabetic metabolic alterations in rats using metabolomics
Authors: Si Qingying , Guo Jinxiu , Yang Xiumei , Guo Yujin , Wu Linlin , Xie Dadi , Jiang Pei
Published: January 2023

Purpose

Type 1 diabetes is characterized by elevated blood glucose levels, which negatively impacts multiple organs and tissues throughout the body, and its prevalence is on the rise. Prior reports primarily investigated the serum and urine specimen from diabetic patients. However, only a few studies examined the overall metabolic profile of diabetic animals or patients. The current systemic investigation will benefit the knowledge of STZ-based type 1 diabetes pathogenesis.

Methods

Male SD rats were arbitrarily separated into control and streptozotocin (STZ)-treated diabetic rats (n = 7). The experimental rats received 50mg/kg STZ intraperitoneal injection daily for 2 consecutive days. Following 6 weeks, metabolites were assessed via gas chromatography-mass spectrometry (GC-MS), and multivariate analysis was employed to screen for differentially expressed (DE) metabolites between the induced diabetic and normal rats.

Results

We identified 18, 30, 6, 24, 34, 27, 27 and 12 DE metabolites in the serum, heart, liver, kidney, cortex, renal lipid, hippocampus, and brown fat tissues of STZ-treated diabetic rats, compared to control rats. Based on our analysis, the largest differences were observed in the amino acids (AAs), B-group vitamin, and purine profiles. Using the metabolic pathway analysis, we screened 13 metabolic pathways related to the STZ-exposed diabetes pathogenesis. These pathways were primarily AA metabolism, followed by organic acids, sugars, and lipid metabolism.

Conclusion

Based on our GC-MS analysis, we identified potential metabolic alterations within the STZ-exposed diabetic rats, which may aid in the understanding of diabetes pathogenesis.
Role of welding residual stress in stainless steel piping with application of the leak-before-break technology
Authors: Liu Zhenshun , Zhang Sheng , Mao Qing , Zheng Xiang Yuan
Published: January 2023

The predicted leakage rate of piping circumferential through-wall cracks (CTWC) under various loading levels is a critical factor for the application of leak-before-break (LBB) technology. In current engineering approaches, the effect of welding residual stress has not been carefully taken into account. In this paper, both numerical analyses and comparative verification are adopted to examine the influence of typical welding residual stress field on the crack opening displacement for austenitic stainless steel piping with representative geometric dimensions and in situ measured material performance curves. An in-depth investigation is carried out to reveal the effect of the residual stress on morphological parameters of the CTWC flow channel. In the case where the residual internal stress of welding has the greatest effect, the Henry-Fauske model is employed to analyze the flow medium passing through the CTWC and the corresponding leak rate for a typical nuclear power plant. The results indicate that the welding residual stress leads to a substantial change in the crack opening displacement and crack morphology parameters. Both the current GE/EPRI method and the NUREG/CR-6837 modification recommended by the American Electric Power Research Institute underestimate the effect of this phenomenon, resulting in a higher prediction of the medium leakage rate. A similar situation is most likely to occur for the cases of short cracks in thin-walled piping and long cracks in thick-walled piping. Additionally, the obtained results reveal that the welding residual stress causes the whole crack surface to open negatively, and the axial line of the long crack on the thick-walled piping is close to a conic curve under specific conditions.
Research on simplified modeling of large-scale wind farms based on equivalent transfer function and aggregate equivalent
Authors: Ding Ran , Yang Chun , Mei Rui , Yang Hongyu , Ji Jie , Shi Qi
Published: January 2023

Introduction: In grid-connected research of large-scale wind farms, the problem of long simulation time exists in the research based on detailed model. In order to realize the fast simulation and grid-connected transient research of wind farm, this paper presents a simplified equivalent model of wind farm based on equivalent transfer function and improved capacity weighting method.

Methods: This paper analyzes the mathematical model of wind turbine, corresponding to the strategy of design simplification, and the simplified model is built according to the equivalent transfer function. In addition, this paper considers the equivalent line loss model of collector line, classifies and aggregates the simplified wind turbines, and calculates the equivalent value of the converged wind turbines by using the improved capacity weighting method, the grid-connected simplified modeling of large-scale wind farm is realized.

Results: A model of wind farm-MMC-HVDC flexible grid-connected wind power system is built. The simulation results show that the simplified equivalent model improves the simulation speed greatly while guaranteeing the dynamic characteristics.

Discussion: The simplified equivalent strategy of wind farm can keep the same dynamic performance with the detailed model, and improve the simulation speed, and realize the fast simulation and grid-connected transient research of wind farm.
Developing PCC and DCC integral effects test experiments at the High Temperature Test Facility
Authors: Gutowska Izabela , Woods Brian G. , Halsted Joshua
Published: January 2023

Among the Next-Generation Nuclear Plant (NGNP) designs, the High-Temperature Gas-Cooled Reactors (HTGRs) are very attractive, due to their inherent safety features, high power conversion efficiency, and potential of providing high-temperature process heat. To perform a thorough safety study and to license these types of reactors, sufficient information needs to be provided about the phenomena that occur during accident scenarios. While several experimental research efforts have been dedicated in the past to investigate accident scenarios, knowledge gaps still exist in the phenomena characteristic of pressurized and depressurized conduction cooldown (PCC/DCC) transients as well as for normal operation scenarios. This paper summarizes the Oregon State University High Temperature Test Facility (HTTF) test matrix, experimental campaign, and selected tests results. High Temperature Test Facility is a scaled Integral Test Facility (IET) that is capable of mimicking scaled dimensions and operational conditions of the Modular High-Temperature Gas Cooled Reactor (MHTGR). The goal of the High Temperature Test Facility is to provide experimental data on the DCC, PCC and normal operating scenarios of the reference Modular High-Temperature Gas Cooled Reactor design. The DCC, PCC, mixing, heat up and cooldown tests described in this paper were performed at prototypical Modular High-Temperature Gas Cooled Reactor temperatures, scaled initial pressure conditions (∼200 kPa), and thermal power input of less than 70 kW. Presented test data show temperature distributions in the High Temperature Test Facility core, upper plenum, cross duct, or lower plenum. Based on these temperature profiles attempts to investigate stratified flow, natural convection flow, heat up, cooldown and mixing phenomena are made. Furthermore, this paper evaluates the performed test campaign in the light of the Very High Temperature Gas-cooled Reactor Phenomena Identification and Ranking Table (PIRT) and proposes experiments to complement the existing PCC/DCC testing database for the validation of the thermal-hydraulic codes.
Risk assessment framework for cumulative effects (RAFCE)
Authors: Antwi Effah Kwabena , Boakye-Danquah John , Owusu-Banahene Wiafe , Dabros Anna , Eddy Ian MS , Silver Daniel Abraham , Abolina Evisa , Eddy Brian , Winder Richard S.
Published: January 2023

Introduction: Regional environmental risk assessment is a practical approach to understanding and proactively addressing the cumulative effects of resource development in areas of regional importance. However, regional assessment is methodologically complex, and frameworks to identify and prioritize regional risk issues to guide effective management decisions are lacking. This research develops a risk and impacts-based cumulative effects assessment framework for scoping regional cumulative effects issues to guide present and future project and regional assessment. We operationalized the framework dubbed Risk Assessment Framework for Cumulative Effects (RAFCE) to assess the risks and impacts of proposed mining development in the Ring of Fire region of Northern Ontario, Canada.

Methods: Methodologically, we built on existing studies to understand the key valued ecosystem components (VECs) impacted by mining; organized an expert Bowtie Risk Assessment Tool workshop and interviews to identify regional risks and define the VECs impacted by mining; and developed an impact prioritization model that helped quantify and prioritize impacts of mining.

Results and Discussion: RAFCE enabled us to: a) identify drivers and impacts of cumulative effects and potential preventive and mitigation measures for effective cumulative effects management and b) describe, quantify, and rank the major impact and components of regional interest. Using RAFCE, we can identify and prioritize impacts that are cross-cutting, multisector‐driven, synergistic, and relevant to a region, visualize and understand the risk management process, identify policy and management issues to prevent risks or mitigate impacts, and ultimately inform resource allocation for effective regional cumulative effects assessment outcomes. RAFCE is suitable for engaging diverse stakeholders in planning for regional cumulative effects assessment.
RETRACTED: An empirical investigation of the impact of renewable and non-renewable energy consumption and economic growth on climate change, evidence from emerging Asian countries
Authors: Zhao Jingyun , Zhang Taiming , Ali Arshad , Chen Jian , Ji Houqi , Wang Tiantian
Published: January 2023

One of the greatest challenges facing humanity in the current millennium is the need to mitigate climate change, and one of the most viable options to overcome this challenge is to invest in renewable energy. The study dynamically examines the impact of renewable and non-renewable energy consumption and economic growth on climate change, using Augmented Mean Group (AMG) technique in emerging Asian countries during the period 1975–2020. The estimated results show that the consumption of renewable energy sources significantly mitigates climate change, while the consumption of non-renewable energy sources significantly contributes to climate change. Furthermore, economic growth, investment in transport infrastructure, and urbanization significantly accelerate climate change in specific emerging Asian countries. The results further demonstrate the validity of the inverted U-shaped EKC hypothesis in emerging Asian economies. Country-specific analysis results using AMG estimates shows that renewable energy consumption reduces climate change for all specific emerging Asian countries. However, the consumption of non-renewable energy sources and investments in transport infrastructure have significant incremental impacts on climate change in all countries. Urbanization contributes significantly to climate change, with the exception of Japan, which does not have any significant impact on climate change. The significant progressive effect of GDP and the significant adverse impact of GDP2 on climate change confirm the validity of the inverted U-shaped EKC hypothesis in India, China, Japan, and South Korea. Moreover, the Dumitrescu and Hurlin causality test confirmed a pairwise causal relationship between non-renewable energy consumption and GDP, supporting the feedback hypothesis. According to the empirical analysis of this study, the best strategy for climate change mitigation in specific emerging countries in Asia is to transition from non-renewable energy to renewable energy.
The role of institutional quality in assessing the environmental externality of financial inclusion: A DCCE approach
Authors: Latif Nazia , Safdar Noreen , Liaquat Malka , Younas Kanwal , Nazeer Nadia , Rafeeq Rifat
Published: January 2023

Controlling environmental contamination requires the use of environmental regulation. The growth of green finance depends on digital finance. The objectives of the study are threefold: first, to explore the impact of digital financial inclusion in deriving climate change; second, to trace the shape of the financial inclusion-based environmental Kuznets curve; and third, to investigate the intersecting effect of digital financial inclusion and institutional quality on environmental quality. Using panel data from 48 Asian economies between 1996 and 2020, heterogeneity, non-stationarity, and cross-sectional dependence are addressed using an econometric method called “dynamic common correlated effects (DCCE).” The empirical evidence confirms a significant relationship between environmental performance and financial inclusiveness. Furthermore, the findings also validated the inverted U-shape environmental Kuznets curve based on financial inclusiveness. Our research suggests that a strong institutional framework has the potential to mitigate the long-term negative consequences of financial inclusion on the environment. To establish coordinated control of environmental quality, the government fully utilizes the environmental regulation and digital inclusive finance environmental governance. Consequently, to achieve environmental sustainability, policymakers in Asian countries should develop policies that enhance financial inclusion and institutional quality.
Genetic and epigenetic effects on couple adjustment in context of romantic relationship: A scoping systematic review
Authors: Khani Pouria , Ansari Dezfouli Mitra , Nasri Farzad , Rahemi Maryam , Ahmadloo Salma , Afkhami Hamed , Saeidi Farzane , Tereshchenko Sergey , Bigdeli Mohammad Reza , Modarressi Mohammad Hossein
Published: January 2023

Introduction: Couples’ relationships defined by a complex interaction between the two partners and their intrapersonal traits. Romantic; relationships and love are associated with marital satisfaction and stability, as well as couples’ happiness and health. Personality traits influence romantic relationships and, personality influenced by genetical and non-genetically factors. The roles of non-genetically factors such as socioeconomic position and external appearance have revealed in determining the quality of romantic relationships.

Methods: We; performed a scoping systematic review to assess the association between genetics and epigenetic factors and romantic relationship. Relevant articles were identified by PubMed, EMBASE, Web of Science, Scopus, and the APA PsycInfo searching between inception and 4 June 2022.

Results: Different studies evaluated the associated polymorphisms in 15 different genes or chromosomal regions. In the first step; we classified them into four groups: (1) Oxytocin-related signaling pathway (OXTR, CD38, and AVPR1A); (2) Serotonin-related signaling pathway (SLC6A4, HTR1A, and HTR2A); (3) Dopamine and catecholamine-related signaling pathway (DRD1, DRD2, DRD4, ANKK1, and COMT); and (4) other genes (HLA, GABRA2, OPRM1, and Y-DNA haplogroup D-M55). Then, we evaluated and extracted significant polymorphisms that affect couple adjustment and romantic relationships.

Discussion: Overall, the findings suggest that genetic and epigenetics variants play a key role in marital adjustment and romantic relationships over time.
Identification of functional gene modules by integrating multi-omics data and known molecular interactions
Authors: Chen Xiaoqing , Han Mingfei , Li Yingxing , Li Xiao , Zhang Jiaqi , Zhu Yunping
Published: January 2023

Multi-omics data integration has emerged as a promising approach to identify patient subgroups. However, in terms of grouping genes (or gene products) into co-expression modules, data integration methods suffer from two main drawbacks. First, most existing methods only consider genes or samples measured in all different datasets. Second, known molecular interactions (e.g., transcriptional regulatory interactions, protein–protein interactions and biological pathways) cannot be utilized to assist in module detection. Herein, we present a novel data integration framework, Correlation-based Local Approximation of Membership (CLAM), which provides two methodological innovations to address these limitations: 1) constructing a trans-omics neighborhood matrix by integrating multi-omics datasets and known molecular interactions, and 2) using a local approximation procedure to define gene modules from the matrix. Applying Correlation-based Local Approximation of Membership to human colorectal cancer (CRC) and mouse B-cell differentiation multi-omics data obtained from The Cancer Genome Atlas (TCGA), Clinical Proteomics Tumor Analysis Consortium (CPTAC), Gene Expression Omnibus (GEO) and ProteomeXchange database, we demonstrated its superior ability to recover biologically relevant modules and gene ontology (GO) terms. Further investigation of the colorectal cancer modules revealed numerous transcription factors and KEGG pathways that played crucial roles in colorectal cancer progression. Module-based survival analysis constructed four survival-related networks in which pairwise gene correlations were significantly correlated with colorectal cancer patient survival. Overall, the series of evaluations demonstrated the great potential of Correlation-based Local Approximation of Membership for identifying modular biomarkers for complex diseases. We implemented Correlation-based Local Approximation of Membership as a user-friendly application available at https://github.com/free1234hm/CLAM.
Osteoimmune regulation underlies oral implant osseointegration and its perturbation
Authors: Albrektsson T. , Tengvall P. , Amengual L. , Coli P. , Kotsakis G. A. , Cochran D.
Published: January 2023

In the field of biomaterials, an endosseous implant is now recognized as an osteoimmunomodulatory but not bioinert biomaterial. Scientific advances in bone cell biology and in immunology have revealed a close relationship between the bone and immune systems resulting in a field of science called osteoimmunology. These discoveries have allowed for a novel interpretation of osseointegration as representing an osteoimmune reaction rather than a classic bone healing response, in which the activation state of macrophages ((M1–M2 polarization) appears to play a critical role. Through this viewpoint, the immune system is responsible for isolating the implant biomaterial foreign body by forming bone around the oral implant effectively shielding off the implant from the host bone system, i.e. osseointegration becomes a continuous and dynamic host defense reaction. At the same time, this has led to the proposal of a new model of osseointegration, the foreign body equilibrium (FBE). In addition, as an oral wound, the soft tissues are involved with all their innate immune characteristics. When implant integration is viewed as an osteoimmune reaction, this has implications for how marginal bone is regulated. For example, while bacteria are constitutive components of the soft tissue sulcus, if the inflammatory front and immune reaction is at some distance from the marginal bone, an equilibrium is established. If however, this inflammation approaches the marginal bone, an immune osteoclastic reaction occurs and marginal bone is removed. A number of clinical scenarios can be envisioned whereby the osteoimmune equilibrium is disturbed and marginal bone loss occurs, such as complications of aseptic nature and the synergistic activation of pro-inflammatory pathways (implant/wear debris, DAMPs, and PAMPs). Understanding that an implant is a foreign body and that the host reacts osteoimmunologically to shield off the implant allows for a distinction to be drawn between osteoimmunological conditions and peri-implant bone loss. This review will examine dental implant placement as an osteoimmune reaction and its implications for marginal bone loss.
An integrative systems biology view of host-pathogen interactions: The regulation of immunity and homeostasis is concomitant, flexible, and smart
Authors: Grossman Zvi , Meyerhans Andreas , Bocharov Gennady
Published: January 2023

The systemic bio-organization of humans and other mammals is essentially “preprogrammed”, and the basic interacting units, the cells, can be crudely mapped into discrete sets of developmental lineages and maturation states. Over several decades, however, and focusing on the immune system, we and others invoked evidence – now overwhelming – suggesting dynamic acquisition of cellular properties and functions, through tuning, re-networking, chromatin remodeling, and adaptive differentiation. The genetically encoded “algorithms” that govern the integration of signals and the computation of new states are not fully understood but are believed to be “smart”, designed to enable the cells and the system to discriminate meaningful perturbations from each other and from “noise”. Cellular sensory and response properties are shaped in part by recurring temporal patterns, or features, of the signaling environment. We compared this phenomenon to associative brain learning. We proposed that interactive cell learning is subject to selective pressures geared to performance, allowing the response of immune cells to injury or infection to be progressively coordinated with that of other cell types across tissues and organs. This in turn is comparable to supervised brain learning. Guided by feedback from both the tissue itself and the neural system, resident or recruited antigen-specific and innate immune cells can eradicate a pathogen while simultaneously sustaining functional homeostasis. As informative memories of immune responses are imprinted both systemically and within the targeted tissues, it is desirable to enhance tissue preparedness by incorporating attenuated-pathogen vaccines and informed choice of tissue-centered immunomodulators in vaccination schemes. Fortunately, much of the “training” that a living system requires to survive and function in the face of disturbances from outside or within is already incorporated into its design, so it does not need to deep-learn how to face a new challenge each time from scratch. Instead, the system learns from experience how to efficiently select a built-in strategy, or a combination of those, and can then use tuning to refine its organization and responses. Efforts to identify and therapeutically augment such strategies can take advantage of existing integrative modeling approaches. One recently explored strategy is boosting the flux of uninfected cells into and throughout an infected tissue to rinse and replace the infected cells.
Novel pre-clinical mouse models for chronic Graft-versus-Host Disease
Authors: Verlaat Lydia , Riesner Katarina , Kalupa Martina , Jung Beate , Mertlitz Sarah , Schwarz Constanze , Mengwasser Jörg , Fricke Claudine , Penack Olaf
Published: January 2023

Despite considerable progress in allogeneic hematopoietic cell transplantation (allo-HCT) has been achieved over the past years, chronic Graft-versus-Host Disease (cGvHD) still contributes to high morbidity rates, thus remaining a major hurdle in allo-HCT patients. To understand the complex pathophysiology of cGvHD and to develop refined prophylaxis and treatment strategies, improved pre-clinical models are needed. In this study, we developed two murine cGvHD models, which display high long-term morbidity but low mortality and depict the heterogeneous clinical manifestations of cGvHD seen in patients. We established a haploidentical C57BL/6→B6D2F1 allo-HCT model that uses myeloablative radiation and G-CSF-mobilized splenocytes as stem cell source and a sub-lethally irradiated Xenograft model, which utilizes the transfer of human peripheral blood mononuclear cells (PBMCs) into NOD scid gamma (NSG)-recipients. We characterized both mouse models to exhibit diverse clinical and histopathological signs of human cGvHD as extensive tissue damage, fibrosis/sclerosis, inflammation and B cell infiltration in cGvHD target organs skin, liver, lung and colon and found a decelerated immune cell reconstitution in the late phase after HCT. Our pre-clinical models can help to gain a deeper understanding of the target structures and mechanisms of cGvHD pathology and may enable a more reliable translation of experimental findings into the human setting of allo-HCT.
Selective CD28 blockade impacts T cell differentiation during homeostatic reconstitution following lymphodepletion
Authors: Habib Jakob G. , Liu Danya , Crepeau Rebecca M. , Wagener Maylene E. , Ford Mandy L.
Published: January 2023

Introduction

Costimulation blockade targeting the CD28 pathway provides improved long-term renal allograft survival compared to calcineurin inhibitors but may be limited as CTLA-4-Ig (abatacept, belatacept) blocks both CD28 costimulation and CTLA-4 coinhibition. Directly targeting CD28 while leaving CTLA-4 intact may provide a mechanistic advantage. Fc-silent non-crosslinking CD28 antagonizing domain antibodies (dAb) are currently in clinical trials for renal transplantation. Given the current standard of care in renal transplantation at most US centers, it is likely that lymphodepletion via thymoglobulin induction therapy could be used in patients treated with CD28 antagonists. Thus, we investigated the impact of T cell depletion (TCD) on T cell phenotype following homeostatic reconstitution in a murine model of skin transplantation treated with anti-CD28dAb.

Methods

Skin from BALB/cJ donors was grafted onto C56BL/6 recipients which were treated with or without 0.2mg anti-CD4 and 10μg anti-CD8 one day prior to transplant and with or without 100μg anti-CD28dAb on days 0, 2, 4, 6, and weekly thereafter. Mice were euthanized six weeks post-transplant and lymphoid cells were analyzed by flow cytometry.

Results

Anti-CD28dAb reversed lymphopenia-induced differentiation of memory CD4+ T cells in the spleen and lymph node compared to TCD alone. Mice treated with TCD+anti-CD28dAb exhibited significantly improved skin graft survival compared to anti-CD28dAb alone, which was also improved compared to no treatment. In addition, the expression of CD69 was reduced on CD4+ and CD8+ T cells in the spleen and lymph node from mice that received TCD+anti-CD28dAb compared to TCD alone. While a reduced frequency of CD4+FoxP3+ T cells was observed in anti-CD28dAb treated mice relative to untreated controls, this was balanced by an increased frequency of CD8+Foxp3+ T cells that was observed in the blood and kidney of mice given TCD+anti-CD28dAb compared to TCD alone.

Discussion

These data demonstrate that CD28 signaling impacts the differentiation of both CD4+ and CD8+ T cells during homeostatic reconstitution following lymphodepletion, resulting in a shift towards fewer activated memory T cells and more CD8+FoxP3+ T cells, a profile that may underpin the observed prolongation in allograft survival.
Integrative analysis of single-cell transcriptomics reveals age-associated immune landscape of glioblastoma
Authors: Wu Songang , Li Xuewen , Hong Fan , Chen Qiang , Yu Yingying , Guo Shuanghui , Xie Yuanyuan , Xiao Naian , Kong Xuwen , Mo Wei , Wang Zhanxiang , Chen Shaoxuan , Zeng Feng
Published: January 2023

Glioblastoma (GBM) is the most malignant tumor in center nervous system. Clinical statistics revealed that senior GBM patients had a worse overall survival (OS) comparing with that of patients in other ages, which is mainly related with tumor microenvironment including tumor-associated immune cells in particular. However, the immune heterogeneity and age-related prognosis in GBM are under studied. Here we developed a machine learning-based method to integrate public large-scale single-cell RNA sequencing (scRNA-seq) datasets to establish a comprehensive atlas of immune cells infiltrating in cross-age GBM. We found that the compositions of the immune cells are remarkably different across ages. Brain-resident microglia constitute the majority of glioblastoma-associated macrophages (GAMs) in patients, whereas dramatic elevation of extracranial monocyte-derived macrophages (MDMs) is observed in GAMs of senior patients, which contributes to the worse prognosis of aged patients. Further analysis suggests that the increased MDMs arisen from excessive recruitment and proliferation of peripheral monocytes not only lead to the T cell function inhibition in GBM, but also stimulate tumor cells proliferation via VEGFA secretion. In summary, our work provides new cues for the correlational relationship between the immune microenvironment of GBM and aging, which might be insightful for precise and effective therapeutic interventions for senior GBM patients.
Phosphoinositol 3-kinase-driven NET formation involves different isoforms and signaling partners depending on the stimulus
Authors: de Carvalho Oliveira Vanessa , Tatsiy Olga , McDonald Patrick P.
Published: January 2023

Neutrophil extracellular traps (NETs) serve to immobilize and kill pathogens, but also can contribute to the progression of several inflammatory and auto-immune diseases, as well as cancer. Whence the importance of elucidating the mechanisms underlying NET formation. In this regard, the PI3K signaling pathway has been shown to be crucial; yet little is known about which of its components are involved. Here, we identified the PI3K isoforms and associated signaling partners that are mobilized in response to different classes of physiological NET inducers (inflammatory cytokines, growth factors, chemoattractants). NET generation was assessed by microscopy and signalling molecule activation by immunoblot using phospho-antibodies. Across the various stimuli, PI3Kα and PI3Kγ isoforms clearly contributed to NET induction, while the participation of other isoforms was stimulus-dependent. Some PI3K isoforms were also found to signal through Akt, the canonical downstream effector of PI3K, while others did not. Downstream of PI3K, mTOR and PLCγ2 were used by all stimuli to control NET generation. Conversely, the involvement of other kinases depended on the stimulus – both TNFα and GM-CSF relied on PDK1 and Akt; and both TNFα and fMLP additionally used S6K. We further established that all PI3K isoforms and downstream effectors act belatedly in NET generation, as reported previously for PI3K. Finally, we revisited the PI3K-PDK1-Akt signaling hierarchy in human neutrophils and again found stimulus-dependent differences. Our data uncover unsuspected complexity and redundancy in the signaling machinery controlling NET formation through the all-important PI3K pathway. Conserved signaling molecules represent therapeutic targets for pathologies involving NETs and in this regard, the existence of drugs currently used in the clinic or undergoing clinical trials (which target PI3K isoforms, mTOR or Akt), underscores the translational potential of our findings.
Adenovirus vector-mediated single chain variable fragments target the nucleocapsid protein of porcine epidemic diarrhea virus and protect against viral infection in piglets
Authors: Wang Fengqing , Zhang Qing , Zhang Fanqing , Zhang En , Li Mei , Ma Shiwei , Guo Jianming , Yang Zhibiao , Zhu Jianguo
Published: January 2023

Porcine epidemic diarrhea virus (PEDV) mainly infects the intestinal epithelial cells of pigs, causing porcine epidemic diarrhea (PED). In particular, the virus causes severe diarrhea, dehydration, and death in neonatal piglets. Maternal immunity effectively protects neonatal piglets from PEDV infection; however, maternal antibodies can only prevent PEDV attachment and entry into target cells, but have no effects on intracellular viruses. Intracellular antibodies targeting virus-encoded proteins are effective in preventing viral infection. We previously identified four single chain variable fragments (scFvs), ZW1-16, ZW3-21, ZW1-41, and ZW4-16, which specifically targeted the PEDV N protein and significantly inhibited PEDV replication and up-regulated interferon-λ1 (IFN-λ1) expression in host cells. In our current study, the four scFvs were subcloned into replication-defective adenovirus vectors to generate recombinant adenoviruses rAdV-ZW1-16, rAdV-ZW3-21, rAdV-ZW1-41, and rAdV-ZW4-16. ScFvs were successfully expressed in Human Embryonic Kidney 293 (HEK293) cells and intestinal porcine epithelial cell line J2 (IPEC-J2) and were biosafe for piglets as indicated by body temperature and weight, scFv excretion in feces, IFN-γ and interleukin-4 (IL-4) expression in jejunum, and pathological changes in porcine tissue after oral administration. Western blotting, immunofluorescence, and immunohistochemical analyses showed that scFvs were expressed in porcine jejunum. The prophylactic effects of rAdV-ZW, a cocktail of the four rAdV-scFvs, on piglet diarrhea caused by PEDV was investigated. Clinical symptoms in piglets orally challenged with PEDV, following a two-time treatment with rAdV-ZW, were significantly reduced when compared with PEDV-infected piglets treated with phosphate buffered saline (PBS) or rAdV-wild-type. Also, no death and jejunal lesions were observed. ScFv co-localization with the PEDV N protein in vivo was also observed. Next, the expression of pro-inflammatory serum cytokines such as tumor necrosis factor-α (TNF-α), IL-6, IL-8, IL-12, and IFN-λ was assessed by enzyme-linked immunosorbent assay (ELISA), which showed that scFvs significantly suppressed PEDV-induced pro-inflammatory cytokine expression and restored PEDV-inhibited IFN-λ expression. Therefore, our study supported a promising role for intracellular scFvs targeting the PEDV N protein to prevent and treat diarrhea in PEDV-infected piglets.
The neutrophil elastase inhibitor, sivelestat, attenuates acute lung injury in patients with cardiopulmonary bypass
Authors: Pan Tuo , Tuoerxun Tayierjiang , Chen Xi , Yang Cheng-Jin , Jiang Chen-Yu , Zhu Yi-Fan , Li Ze-Shi , Jiang Xin-Yi , Zhang Hai-Tao , Zhang He , Wang Ya-Peng , Chen Wei , Lu Li-Chong , Ge Min , Cheng Yong-Qing , Wang Dong-Jin , Zhou Qing
Published: January 2023

Background

The sivelestat is a neutrophil elastase inhibitor thought to have an effect against acute lung injury (ALI) in patients after scheduled cardiac surgery. However, the beneficial effect of sivelestat in patients undergoing emergent cardiovascular surgery remains unclear. We aim to evaluate the effect of sivelestat on pulmonary protection in patients with ALI after emergent cardiovascular surgery.

Methods

Firstly, a case-control study in 665 patients undergoing emergent cardiovascular surgery from January 1st, 2020 to October 26th, 2022 was performed. 52 patients who received sivelestat (0.2mg/kg/h for 3 days) and 613 age- and sex-matched controls. Secondly, a propensity-score matched cohort (sivelestat vs control: 50 vs 50) was performed in these 665 patients. The primary outcome was a composite of adverse outcomes, including 30-day mortality, ECMO, continuous renal replacement therapy (CRRT) and IABP, etc. The secondary outcome included pneumonia, ventricular arrhythmias and mechanical ventilation time, etc.

Results

In propensity-matched patients, the 30-day mortality (16% vs 24%, P=0.32), stroke (2% vs 8%, P=0.17), ECMO(6% vs 10%, P=0.46), IABP(4% vs 8%, P=0.40) and CRRT(8% vs 20%, P=0.08) had no differences between sivelestat and control group; sivelestat could significantly decrease pneumonia (40% vs 62%, P=0.03), mechanical ventilation time (median: 96hours, IQR:72-120hours vs median:148hours, IQR:110-186hours, P<0.01), bilateral pulmonary infiltrates (P<0.01), oxygen index (P<0.01), interleukin-6(P=0.02), procalcitonin(P<0.01) and C-reactive protein(P<0.01).

Conclusion

Administration of sivelestat might improve postoperative outcomes in patients with ALI after emergent cardiovascular surgery. Our results show that sivelestat may be considered to protect pulmonary function against inflammatory injury by CPB.

Registration

http://www.chictr.org.cn/showproj.aspx?proj=166643, identifier ChiCTR2200059102.
T cell immunity ameliorates COVID-19 disease severity and provides post-exposure prophylaxis after peptide-vaccination, in Syrian hamsters
Authors: Somogyi Eszter , Kremlitzka Mariann , Csiszovszki Zsolt , Molnár Levente , Lőrincz Orsolya , Tóth József , de Waal Leon , Pattijn Sofie , Reineking Wencke , Beineke Andreas , Tőke Enikő R.
Published: January 2023

Background

The emergence of novel SARS-CoV-2 variants that resist neutralizing antibodies drew the attention to cellular immunity and calls for the development of alternative vaccination strategies to combat the pandemic. Here, we have assessed the kinetics of T cell responses and protective efficacy against severe COVID-19 in pre- and post-exposure settings, elicited by PolyPEPI-SCoV-2, a peptide based T cell vaccine.

Methods

75 Syrian hamsters were immunized subcutaneously with PolyPEPI-SCoV-2 on D0 and D14. On D42, hamsters were intranasally challenged with 102 TCID50 of the virus. To analyze immunogenicity by IFN-γ ELISPOT and antibody secretion, lymphoid tissues were collected both before (D0, D14, D28, D42) and after challenge (D44, D46, D49). To measure vaccine efficacy, lung tissue, throat swabs and nasal turbinate samples were assessed for viral load and histopathological changes. Further, body weight was monitored on D0, D28, D42 and every day after challenge.

Results

The vaccine induced robust activation of T cells against all SARS-CoV-2 structural proteins that were rapidly boosted after virus challenge compared to control animals (~4-fold, p<0.05). A single dose of PolyPEPI-SCoV-2 administered one day after challenge also resulted in elevated T cell response (p<0.01). The vaccination did not induce virus-specific antibodies and viral load reduction. Still, peptide vaccination significantly reduced body weight loss (p<0.001), relative lung weight (p<0.05) and lung lesions (p<0.05), in both settings.

Conclusion

Our study provides first proof of concept data on the contribution of T cell immunity on disease course and provide rationale for the use of T cell-based peptide vaccines against both novel SARS-CoV-2 variants and supports post-exposure prophylaxis as alternative vaccination strategy against COVID-19.
Vascular inflammation on a chip: A scalable platform for trans-endothelial electrical resistance and immune cell migration
Authors: Ehlers Haley , Nicolas Arnaud , Schavemaker Frederik , Heijmans Jeroen P. M. , Bulst Martin , Trietsch Sebastiaan J. , van den Broek Lenie J.
Published: January 2023

The vasculature system plays a critical role in inflammation processes in the body. Vascular inflammatory mechanisms are characterized by disruption of blood vessel wall permeability together with increased immune cell recruitment and migration. There is a critical need to develop models that fully recapitulate changes in vascular barrier permeability in response to inflammatory conditions. We developed a scalable platform for parallel measurements of trans epithelial electrical resistance (TEER) in 64 perfused microfluidic HUVEC tubules under inflammatory conditions. Over 250 tubules where exposed to Tumor necrosis factor alpha (TNFα) and interferon gamma (INF-γ) or human peripheral blood mononuclear cells. The inflammatory response was quantified based on changes TEER and expression of ICAM and VE-cadherin. We observed changes in barrier function in the presence of both inflammatory cytokines and human peripheral blood mononuclear cells, characterized by decreased TEER values, increase in ICAM expression as well changes in endothelial morphology. OrganoPlate 3-lane64 based HUVEC tubules provide a valuable tool for inflammatory studies in an automation compatible manner. Continuous TEER measurements enable long term, sensitive assays for barrier studies. We propose the use of our platform as a powerful tool for modelling endothelial inflammation in combination with immune cell interaction that can be used to screen targets and drugs to treat chronic vascular inflammation.
Stem cell- derived extracellular vesicles as new tools in regenerative medicine - Immunomodulatory role and future perspectives
Authors: Karnas Elżbieta , Dudek Patrycja , Zuba-Surma Ewa K.
Published: January 2023

In the last few decades, the practical use of stem cells (SCs) in the clinic has attracted significant attention in the regenerative medicine due to the ability of these cells to proliferate and differentiate into other cell types. However, recent findings have demonstrated that the therapeutic capacity of SCs may also be mediated by their ability to secrete biologically active factors, including extracellular vesicles (EVs). Such submicron circular membrane-enveloped vesicles may be released from the cell surface and harbour bioactive cargo in the form of proteins, lipids, mRNA, miRNA, and other regulatory factors. Notably, growing evidence has indicated that EVs may transfer their bioactive content into recipient cells and greatly modulate their functional fate. Thus, they have been recently envisioned as a new class of paracrine factors in cell-to-cell communication. Importantly, EVs may modulate the activity of immune system, playing an important role in the regulation of inflammation, exhibiting broad spectrum of the immunomodulatory activity that promotes the transition from pro-inflammatory to pro-regenerative environment in the site of tissue injury. Consequently, growing interest is placed on attempts to utilize EVs in clinical applications of inflammatory-related dysfunctions as potential next-generation therapeutic factors, alternative to cell-based approaches. In this review we will discuss the current knowledge on the biological properties of SC-derived EVs, with special focus on their role in the regulation of inflammatory response. We will also address recent findings on the immunomodulatory and pro-regenerative activity of EVs in several disease models, including in vitro and in vivo preclinical, as well as clinical studies. Finally, we will highlight the current perspectives and future challenges of emerging EV-based therapeutic strategies of inflammation-related diseases treatment.