bluuebunny/crossref_metadata_2025 huggingface dataset:
The Bradykinin System Contributes to the Regulation of Prostaglandin-Endoperoxide Synthase 2 Expression in Human Amnion Fibroblasts: Implications for Term and Preterm Birth
Authors: Ni Xiao-tian , Wang Wang-sheng , Liu Yun , Lin Yi-kai , Zhang Fan , Lei Wen-jia , Ling Li-jun , Pan Fan , Zhu Ya-nan , Li Meng-die , Duan Tao , Liu Ming , Sun Kang
Published: May 2022

Background

Bradykinin (BK) and its biologically active metabolite des-Arg9 bradykinin (DABK) play a pivotal role in inflammation. Since chorioamnionitis is the leading cause of preterm birth and prostaglandin E2 (PGE2) derived from the amnion is key to labor initiation, we investigated if bradykinin peptides are part of the regulatory network of PGE2 synthesis in human amnion at parturition.

Methods

Human amnion tissue was obtained from term and preterm birth for the study of the changes of the bradykinin system at parturition. Cultured primary human amnion fibroblasts, the major source of PGE2, were used to study the effects of bradykinin peptides on PTGS2 expression and PGE2 production as well as the effects of infection mediators on bradykinin receptors.

Results

Bradykinin peptides and their receptors BDKRB1 and BDKRB2 were present in human amnion, and their abundance increased in term and preterm labor. However, transcripts of the genes encoding the bradykinin precursor and its proteolytic cleavage enzymes were hardly detectable in human amnion despite the increased abundance of bradykinin peptides in term and preterm labor, suggesting that there is an alternative source of bradykinin peptides for human amnion and their actions are enhanced in human amnion at parturition. In-vitro studies in cultured human amnion fibroblasts showed that both BK and DABK increased the expression of prostaglandin-endoperoxide synthase 2 (PTGS2), the rate-limiting enzyme in prostaglandin synthesis, and subsequent PGE2 production. These effects of BK and DABK were mediated through BDKRB2 and BDKRB1 receptors, respectively, with subsequent activation of the p38 and ERK1/2 pathways. Moreover, lipopolysaccharide (LPS) and serum amyloid A1 (SAA1), the important mediators of infectious inflammation, induced the expression of both BDKRB1 and BDKRB2 through toll-like receptor 4 (TLR4). Induction of BDKRB1 and BDKRB2 expression by LPS and SAA1 enhanced BK- or DABK-induced PTGS2 expression and PGE2 production in human amnion fibroblasts.

Conclusions

This study demonstrated for the first time that the human amnion is a target tissue of bradykinin peptides and the bradykinin system may be part of the regulatory network of PTGS2 expression and PGE2 production in human amnion fibroblasts at both term and preterm birth, which may be enhanced by infection.
Sexual Dimorphism in the Association of Serum Retinol-Binding Protein-4 With Long-Term Dynamic Metabolic Profiles in Non-Diabetes
Authors: Xiang Jiali , Dai Huajie , Hou Yanan , Wang Qi , Wang Tiange , Li Mian , Zhao Zhiyun , Lu Jieli , Dai Meng , Zhang Di , Xu Yu , Ning Guang , Wang Weiqing , Wang Jiqiu , Bi Yufang , Xu Min
Published: May 2022

Objectives

We aimed to investigate the association of circulating retinol-binding protein-4 (RBP4) levels with long-term cardiometabolic risk profiles and whether sex disparity mattered.

Methods

We included 784 non-diabetic participants aged 40 years and above from a well-defined community-based cohort at baseline in 2005 and they were invited to attend the on-site follow-up examination for two consecutive times with 3-year intervals in 2008 and 2011, respectively. Serum RBP4 was measured at baseline, and the anthropometry and biochemical measurements were performed at each visit. Generalized estimating equation models were used to assess the association of serum RBP4 levels with the dynamic changes in adiposity and glucolipid profile.

Results

Based on all the baseline and the 3- and 6-year follow-up data, baseline serum RBP4 levels (each 1-unit of log10RBP4) were significantly associated with waist circumference [β=3.12, 95% confidence interval (CI) (0.77, 5.47), P=0.01], fasting, and 2-h post-loading glucose [β=0.26 (0.05, 0.47), P=0.02, and 1.70 (1.29, 2.12), P< 0.0001], serum triglycerides [β=0.75, 95% CI (0.54, 0.96), P< 0.0001], total cholesterol [β=0.47, 95% CI [0.23 0.70], P<0.0001), and marginally with body mass index (β=0.97, 95% CI (0.02, 1.93), P=0.046], in total participants, after adjusting potential confounders. The association of RBP4 with 2-h post-loading glucose was stronger in women than that in men [β=1.99, 95% CI (1.49, 2.50) vs. 0.61 (-0.14, 1.36), P for interaction=0.001]. The analysis of change in Z-score of cardiometabolic profiles corresponding to each 1-unit increment in log10RBP4 showed consistent results.

Conclusions

Higher RBP4 levels are associated with longitudinal increase in adiposity and deteriorated glucolipid profile defined by repeated measurements. The associations differ in sex regarding to the 2-h post-loading glucose.
Reliability Evaluation Method of AC/DC Hybrid Distribution Network Considering Voltage Source Converter Restoration Capability and Network Reconfiguration
Authors: Zhang Lu , Yu Shunjiang , Cai Yongxiang , Tang Wei , Cheng Hongkai
Published: May 2022

In the AC/DC hybrid distribution network, non-faulty areas can maintain uninterrupted power supply by adjusting the control mode of the voltage source converter (VSC) after a fault. In addition, the non-faulty areas can also be restored through network reconfiguration. To account for the impact of these two restoration methods on reliability accurately, this article proposed a reliability evaluation method for the AC/DC hybrid distribution network considering VSC restoration capability and network reconfiguration. First, a restoration optimization model of the AC/DC hybrid distribution network considering network reconfiguration and control modes of VSC is established, which can give full play to these two restoration methods while ensuring the radial constraints of the network. Then, the failure mode and effects analysis (FMEA) method is introduced and combined with the restoration optimization model to analyze the impact caused by faults on the network. Among them, the FMEA method is utilized to determine the network topology after fault isolation, and on this basis, the restoration optimization model is solved to obtain the outage time of loads in the network. Finally, the aforementioned work is combined with the sequential Monte Carlo method to evaluate the reliability of the AC/DC hybrid distribution network to adequately simulate the fluctuation characteristics of distributed generation (DG) and load. The case study shows that the proposed method can accurately evaluate the reliability of the AC/DC hybrid distribution network.
Identification of Seasonal and Annual Groundwater Level Trends in Temperate Climatic Conditions
Authors: Minea Ionuț , Boicu Daniel , Amihăiesei Vlad , Iosub Marina
Published: May 2022

The management of groundwater resources must take into account their variation trends. In this sense, 3 statistical methods were used to identify seasonal and annual groundwater level trends: Mann-Kendall test (MK), Innovative Analysis Method (ITA) and Spearman’s Rho test (SR). Each method was applied for 5 time series (one annual and four seasonal) from 148 hydrological wells from Eastern Romania. The wells were classified in 8 cluster groups based on water depth, using the cluster analysis, covering the full range of depths from under 1.4 to over 15.5 m. Coupling statistical methods (MK and SR test) with one based on graphical analysis (ITA method) offers the possibility of obtaining statistically significant results (between 53% and 69% for spring season, 68% and 96% for autumn season and 68% and 81% from annual values). The decreasing trend of water depth is more obvious for summer and autumn season, for 72%–74% from analyzed wells (based on SR and ITA method) and 68% for annual series (based on MK test). The spatial distribution of seasonal and annual trends highlights that in the northern and central parts of the region, the groundwater depth suffers depletion induced by the effects of prolonged meteorological and hydrological drought manifested in this area in the last decades.
Analysis of Gray Water Footprint Changes and Driving Forces Caused by Sectoral Trade in Southeast China
Authors: Yu Fan , Zhang Chen , Wang Yuan , Zhu Lin , Jin Jianhui , Deng Haijun , Ling Hongbo , Shi Rui , He Yanmin , Yu Jinru , Jiang Peipei
Published: May 2022

Evaluation of gray water footprint (GWF) flow and its driving mechanism is imperative to trace the source of pollution and formulate the pollution responsibility-sharing strategies to reduce the shortage of water. We quantify the GWF of 22 sectors in Fujian Province in 2002, 2007, 2012, and 2017, using an economic input–output life cycle assessment (EIO-LCA) model, and establish a five-factor structural decomposition analysis (SDA) model to track the driving forces of the GWF. The results show that the animal husbandry sector of the primary industry is the largest outsourcing sector, outsourcing an average of 7 Bm3 GWF by other regions annually. The construction sector is an industry with more pollution outsourcing at the production end, and it should take additional pollution responsibility for its upstream sector. The changes of the GWF in Fujian Province are mainly driven by the final demand per capita and GWF outsourcing. The sector most affected by force drivers is construction, followed by machinery and equipment manufacturing, and other services. This study better reflects the sectoral pollution outsourcing situation by assessing sectoral GWF flow and net inflow GWF caused by sector trading. We aim at identifying new sectors of water pollution and sharing the pollution responsibility between upstream and downstream, providing a new perspective to analyze water quality problems in water-rich regions. Moreover, our findings imply an urgent need to develop policies related to water pollution transfer for various sectors from a whole supply chain perspective.
Tourism Demand Forecasting Considering Environmental Factors: A Case Study for Chengdu Research Base of Giant Panda Breeding
Authors: He Jianhong , Liu Dong , Guo Yulei , Zhou Daohua
Published: May 2022

Effectively prediction of the tourism demand is of great significance to rationally allocate resources, improve service quality, and maintain the sustainable development of scenic spots. Since tourism demand is affected by the factors of climate, holidays, and weekdays, it is a challenge to design an accurate forecasting model obtaining complex features in tourism demand data. To overcome these problems, we specially consider the influence of environmental factors and devise a forecasting model based on ensemble learning. The model first generates several sub-models, and each sub-model learns the features of time series by selecting informative sequences for reconstructing the forecasting input. A novel technique is devised to aggregate the outputs of these sub-models to make the forecasting more robust to the non-linear and seasonal features. Tourism demand data of Chengdu Research Base of Giant Panda Breeding in recent 5 years is used as a case to validate the effectiveness of our scheme. Experimental results show that the proposed scheme can accurately forecasting tourism demand, which can help Chengdu Research Base of Giant Panda Breeding to improve the quality of tourism management and achieve sustainable development. Therefore, the proposed scheme has good potential to be applied to accurately forecast time series with non-linear and seasonal features.
The Adaptive Significance of Flash Behavior: A Bayesian Model
Authors: Sherratt Thomas N. , Loeffler-Henry Karl
Published: May 2022

Some cryptic animals have conspicuous color patches that are displayed when they move. This “flash behavior” may serve several functions, but perhaps the most widely invoked explanation is that the display makes it harder for the signaler to be found by predators once it has settled. There is now some experimental evidence that flash behavior while fleeing can enhance the survivorship of prey in the manner proposed. However, to date there has been no explicit mathematical model to help understand the way in which flash displays might interfere with the search process of predators. Here we apply Bayesian search theory to show that the higher the conspicuousness of a prey item, the sooner a predator should give up searching for it in an area where it appears to have settled, although the relationship is not always monotonically decreasing. Thus, fleeing prey that give the impression of being conspicuous will tend to survive at a higher rate than prey seen to flee in their cryptic state, since predators search for flashing prey for an inappropriately short period of time. The model is readily parameterized and makes several intuitive predictions including: (1) the more confident a predator is that a prey item has settled in a given area, the longer it will search there, (2) the more conspicuous the flash display, the greater its effect in reducing predation, (3) flash behavior will especially benefit those prey with an intermediate level of crypsis when at rest, and (4) the success of flash displays depends on the predator being uncertain of the prey’s resting appearance. We evaluate the empirical evidence for these predictions and discuss how the model might be further developed, including the incorporation of mimicry which would maintain the deception indefinitely.
Diversity and Vertical Distribution of Epiphytic Angiosperms, in Natural and Disturbed Forest on the Northern Coast of Jalisco, Mexico
Authors: Flores-Argüelles Alejandra , Espejo-Serna Adolfo , López-Ferrari Ana Rosa , Krömer Thorsten
Published: May 2022

Background and Aims

Epiphytes are an important component of tropical forests, also they are sensitive to disturbance and deforestation caused by humans, since they depend on their host trees and the micro environmental conditions that these provide. The aim of this study was to analyze the differences in species richness, composition, and vertical distribution of epiphytic angiosperms between areas with natural and disturbed forest at the Northern Coast of Jalisco state, Mexico.

Methods

The presence/absence of epiphytic angiosperms was evaluated in each vertical zone of a selected tree, as well as those present in the understory, both in natural and disturbed sites in three types of vegetation (gallery forest, oak forest, tropical semideciduous forest) with a total of 30 plots of 20 m × 20 m in six sites. Alpha diversity was calculated for each site, as well as species turnover (beta diversity) between habitats. An analysis of variance was performed to determine if there was a significant difference in species richness between sites and, also to compare the height and diameter at breast height (DBH) of the host trees. Multivariate analyzes were used to group the sites according to their floristic composition. Furthermore, a linear regression was performed to detect any relationship between the number of species and the phorophyte structure.

Results

We recorded 45 species, 29 genera and nine families of epiphytic angiosperms. The most diverse families were Bromeliaceae and Orchidaceae and the richest genus was Tillandsia. Although the disturbed sites had more species, a significant difference in richness was not found, except for the disturbed gallery forest. Epiphytic angiosperms presented a high beta diversity, since the sites shared only between 2 and 18% of the recorded species. The inner portion of the canopy (Z3 and Z4) hosted most of the species in all sites and the understory had a high representation of epiphytes except for the disturbed oak forest, where these were absent. A relationship between the DBH and the number of species was found only at the disturbed sites, however, it was highly influenced by the high number of taxa registered in disturbed gallery forest. Therefore, the size of the trees could not be considered a factor in determining the diversity of epiphyte species.

Conclusion

The diversity of epiphytic angiosperm species from the North Coast of Jalisco has not been severely affected by the human disturbance. Most of the species have morphological and physiological adaptations that allow their establishment and survival in adverse climatic conditions. Our results suggest that epiphytic angiosperms cannot be considered as a good indicator for natural or disturbed environments in this region but should be considered in environmental conservation, as they present a high beta diversity.
Identification of a Cancer Stem Cells Signature of Head and Neck Squamous Cell Carcinoma
Authors: Wu Zeng-Hong , Li Cheng , Zhang You-Jing , Zhou Wen
Published: May 2022

Background: Head and neck squamous cell carcinoma (HNSCC) ranks as the sixth most widespread and deadly cancer. In recent times, it has been determined that undifferentiated cell populations with stem cell-like properties in HNSCC are major factors influencing recurrence and progression.

Method: In this study, we determine key genes related to stemness by merging WGCNA with HNSCC mRNAsi based on the online database.

Results: We first download the mRNA expression-based stemness index (mRNAsi) data and contrast the expression levels of mRNAsi in cancers and control samples; we found significantly elevated mRNAsi expressions in HNSCC tissues (p = 0.002). Moreover, the brown module showed a relatively high negative correlation with mRNAsi (cor = -0.8). Thus, we selected the brown module as the interesting module and used it for following analysis. We screened 20 key genes (PDGFRB, PLPP4, CALU, ADAMTS14, COL5A3, KCNE4, LOXL1, CLEC11A, PODN,BGN, AEBP1, COL1A2, LAMA4, LOXL2, LRRC15, THY1, SPON2, COL1A1, NID2, and AC134312.5) including and as to decide the neighbor genes biological interaction network of these 20 stemness-related genes in HNSCC. The top 10 frequent alterations were PIK3CA, FGF3, FGF19, FGF4, DVL3, P3H2, GNB4, COL22A1, COL14A1, and PLOD2.

Conclusion: This study showed the critical role of stemness-related genes in HNSCC. However, more related studies are needed to confirm these results.
Upregulation of Ferroptosis-Related Fanconi Anemia Group D2 is a Poor Prognostic Factor and an Indicator of Tumor Immune Cell Infiltration in Lung Adenocarcinoma
Authors: Zhang Jingtao , Wang Dongli , Chen Xiubao , Ji Lingyun , Yu Minmin , Guo Minghao , Zhang Dexin , Chen Weida , Xu Fei
Published: May 2022

Fanconi anemia (FA) group D2 (FANCD2) is a ferroptosis-related gene crucial for DNA damage repair and negative ferroptosis regulation. Our study aimed to evaluate its prognostic value as well as its association with ferroptosis and immune infiltration in lung adenocarcinoma (LUAD). Transcriptome sequencing data, clinical information, and immunohistochemistry data were collected from the TCGA, GEO, and HPA databases, respectively, for three independent cohorts. Univariate and multivariate analyses were used to assess the correlations between FANCD2 expression and overall survival or clinicopathological parameters. cBioPortal was utilized to investigate the FANCD2 alteration status. Gene and protein networks based on FANCD2 interactions were generated using GeneMANIA and STRING, respectively. Based on the CancerSEA database, the function of FANCD2 was explored at the single-cell level. The relationships between FANCD2 expression levels and tumor-infiltrating immune cells and their equivalent gene signatures were analyzed using TIMER, GEPIA, TISIDB, and ssGSEA databases. CIBERSORT was used to analyze the relevance of the infiltration of 24 types of immune cells. The results revealed that FANCD2 expression was significantly upregulated in LUAD and lung squamous cell carcinoma (LUSC) tissues than that in normal tissues. Further, the overexpression of FANCD2 was closely associated with poor survival for Patients with LUAD but not for patients with LUSC. FANCD2 expression levels were related to tumor-infiltrating immune cells and their matching gene signatures, including CD8+ T cells, natural killer (NK) cells, dendritic cells (DC), and Th2 cells in cases of LUAD. Therefore, FANCD2 was identified as a crucial molecule underlying the synergistic effects of ferroptosis and immunotherapy for Patients with LUAD.
Shared and Cell-Type-Specific Gene Expression Patterns Associated With Autism Revealed by Integrative Regularized Non-Negative Matrix Factorization
Authors: Guan Jinting , Zhuang Yan , Kang Yue , Ji Guoli
Published: May 2022

Human brain-related disorders, such as autism spectrum disorder (ASD), are often characterized by cell heterogeneity, as the cell atlas of brains consists of diverse cell types. There are commonality and specificity in gene expression among different cell types of brains; hence, there may also be commonality and specificity in dysregulated gene expression affected by ASD among brain cells. Moreover, as genes interact together, it is important to identify shared and cell-type-specific ASD-related gene modules for studying the cell heterogeneity of ASD. To this end, we propose integrative regularized non-negative matrix factorization (iRNMF) by imposing a new regularization based on integrative non-negative matrix factorization. Using iRNMF, we analyze gene expression data of multiple cell types of the human brain to obtain shared and cell-type-specific gene modules. Based on ASD risk genes, we identify shared and cell-type-specific ASD-associated gene modules. By analyzing these gene modules, we study the commonality and specificity among different cell types in dysregulated gene expression affected by ASD. The shared ASD-associated gene modules are mostly relevant to the functioning of synapses, while in different cell types, different kinds of gene functions may be specifically dysregulated in ASD, such as inhibitory extracellular ligand-gated ion channel activity in GABAergic interneurons and excitatory postsynaptic potential and ionotropic glutamate receptor signaling pathway in glutamatergic neurons. Our results provide new insights into the molecular mechanism and pathogenesis of ASD. The identification of shared and cell-type-specific ASD-related gene modules can facilitate the development of more targeted biomarkers and treatments for ASD.
Immune Landscape and Classification in Lung Adenocarcinoma Based on a Novel Cell Cycle Checkpoints Related Signature for Predicting Prognosis and Therapeutic Response
Authors: Yang Jian , Chen Zhike , Gong Zetian , Li Qifan , Ding Hao , Cui Yuan , Tang Lijuan , Li Shiqin , Wan Li , Li Yu , Ju Sheng , Ding Cheng , Zhao Jun
Published: May 2022

Lung adenocarcinoma (LUAD) is one of the most common malignancies with the highest mortality globally, and it has a poor prognosis. Cell cycle checkpoints play a central role in the entire system of monitoring cell cycle processes, by regulating the signalling pathway of the cell cycle. Cell cycle checkpoints related genes (CCCRGs) have potential utility in predicting survival, and response to immunotherapies and chemotherapies. To examine this, based on CCCRGs, we identified two lung adenocarcinoma subtypes, called cluster1 and cluster2, by consensus clustering. Enrichment analysis revealed significant discrepancies between the two subtypes in gene sets associated with cell cycle activation and tumor progression. In addition, based on Least Absolute Shrinkage and Selection Operator (LASSO) Cox regression, we have developed and validated a cell cycle checkpoints-related risk signature to predict prognosis, tumour immune microenvironment: (TIME), immunotherapy and chemotherapy responses for lung adenocarcinoma patients. Results from calibration plot, decision curve analysis (DCA), and time-dependent receiver operating characteristic curve (ROC) revealed that combining age, gender, pathological stages, and risk score in lung adenocarcinoma patients allowed for a more accurate and predictive nomogram. The area under curve for lung adenocarcinoma patients with 1-, 3-, 5-, and 10-year overall survival was: 0.74, 0.73, 0.75, and 0.81, respectively. Taken together, our proposed 4-CCCRG signature can serve as a clinically useful indicator to help predict patients outcomes, and could provide important guidance for immunotherapies and chemotherapies decision for lung adenocarcinoma patients.
Recent Advances in Solid Tumor CAR-T Cell Therapy: Driving Tumor Cells From Hero to Zero?
Authors: Safarzadeh Kozani Pouya , Safarzadeh Kozani Pooria , Ahmadi Najafabadi Milad , Yousefi Fatemeh , Mirarefin Seyed Mohamad Javad , Rahbarizadeh Fatemeh
Published: May 2022

Chimeric antigen receptor T-cells (CAR-Ts) are known as revolutionary living drugs that have turned the tables of conventional cancer treatments in certain hematologic malignancies such as B-cell acute lymphoblastic leukemia (B-ALL) and diffuse large B-cell lymphoma (DLBCL) by achieving US Food and Drug Administration (FDA) approval based on their successful clinical outcomes. However, this type of therapy has not seen the light of victory in the fight against solid tumors because of various restricting caveats including heterogeneous tumor antigen expression and the immunosuppressive tumor microenvironments (TME) that negatively affect the tumor-site accessibility, infiltration, stimulation, activation, and persistence of CAR-Ts. In this review, we explore strategic twists including boosting vaccines and designing implementations that can support CAR-T expansion, proliferation, and tumoricidal capacity. We also step further by underscoring novel strategies for triggering endogenous antitumor responses and overcoming the limitation of poor CAR-T tumor-tissue infiltration and the lack of definitive tumor-specific antigens. Ultimately, we highlight how these approaches can address the mentioned arduous hurdles.
Humoral Immune Response Diversity to Different COVID-19 Vaccines: Implications for the “Green Pass” Policy
Authors: Polvere Immacolata , Parrella Alfredina , Zerillo Lucrezia , Voccola Serena , Cardinale Gaetano , D’Andrea Silvia , Madera Jessica Raffaella , Stilo Romania , Vito Pasquale , Zotti Tiziana
Published: May 2022

In the COVID-19 pandemic year 2021, several countries have implemented a vaccine certificate policy, the “Green Pass Policy” (GPP), to reduce virus spread and to allow safe relaxation of COVID-19 restrictions and reopening of social and economic activities. The rationale for the GPP is based on the assumption that vaccinated people should maintain a certain degree of immunity to SARS-CoV-2. Here we describe and compare, for the first time, the humoral immune response to mRNA-1273, BNT162b2, Ad26.COV2.S, and ChAdOx1 nCoV-19 vaccines in terms of antibody titer elicited, neutralizing activity, and epitope reactogenicity among 369 individuals aged 19 to 94 years. In parallel, we also considered the use of a rapid test for the determination of neutralizing antibodies as a tool to guide policymakers in defining booster vaccination strategies and eligibility for Green Pass. Our analysis demonstrates that the titer of antibodies directed towards the receptor-binding domain (RBD) of SARS-CoV-2 Spike is significantly associated with age and vaccine type. Moreover, natural COVID-19 infection combined with vaccination results, on average, in higher antibody titer and higher neutralizing activity as compared to fully vaccinated individuals without prior COVID-19. We also found that levels of anti-Spike RBD antibodies are not always strictly associated with the extent of inhibition of RBD-ACE2 binding, as we could observe different neutralizing activities in sera with similar anti-RBD concentrations. Finally, we evaluated the reactivity to four synthetic peptides derived from Spike protein on a randomly selected serum sample and observed that similar to SARS-CoV-2 infection, vaccination elicits a heterogeneous antibody response with qualitative individual features. On the basis of our results, the use of rapid devices to detect the presence of neutralizing antibodies, even on a large scale and repeatedly over time, appears helpful in determining the duration of the humoral protection elicited by vaccination. These aspects and their implications for the GPP are discussed.
Macrophage Differentiation and Polarization Regulate the Release of the Immune Checkpoint Protein V-Domain Ig Suppressor of T Cell Activation
Authors: Noubissi Nzeteu Gaetan Aime , Schlichtner Stephanie , David Sulamith , Ruppenstein Aylin , Fasler-Kan Elizaveta , Raap Ulrike , Sumbayev Vadim V. , Gibbs Bernhard F. , Meyer N. Helge
Published: May 2022

Recently, the V-domain immunoglobulin suppressor of T-cell activation (VISTA) was identified as a negative immune checkpoint regulator (NCR) that is mainly expressed in hematopoietic cells. Preclinical studies have shown that VISTA blockade results in impeded tumor growth and improved survival. Nevertheless, little is known about the physiological role of VISTA expression in macrophages. This study focused on the differential expression of VISTA in human monocytes and macrophages in order to elucidate a putative role of VISTA regulation upon macrophage polarization and activation. We observed that human peripheral monocytes constitutively release soluble VISTA, which was regulated via matrix metalloproteinases. However, monocyte stimulation with cytokines that induce macrophage differentiation, such as granulocyte-macrophage colony–stimulating (GM-CSF) and macrophage colony-stimulating factor (M-CSF), substantially reduced soluble VISTA release. VISTA release was further affected by various pro- and anti-inflammatory stimuli that led to macrophage polarization, where activated M1 macrophages generally released more VISTA than M2 macrophages. Additionally, we observed that stimulation of activated macrophages with the toll-like receptor 4 ligand lipopolysaccharide (LPS) led to a further decrease of soluble VISTA release. Moreover, we found that soluble VISTA impairs T cell cytotoxic activity but did not induce their programmed death. Our results suggest that VISTA is constantly produced and released in the peripheral blood where it may contribute to peripheral tolerance.
Comprehensive Testing of Chemotherapy and Immune Checkpoint Blockade in Preclinical Cancer Models Identifies Additive Combinations
Authors: Principe Nicola , Aston Wayne J. , Hope Danika E. , Tilsed Caitlin M. , Fisher Scott A. , Boon Louis , Dick Ian M. , Chin Wee Loong , McDonnell Alison M. , Nowak Anna K. , Lake Richard A. , Chee Jonathan , Lesterhuis Willem Joost
Published: May 2022

Antibodies that target immune checkpoints such as cytotoxic T lymphocyte antigen 4 (CTLA‐4) and the programmed cell death protein 1/ligand 1 (PD-1/PD-L1) are now a treatment option for multiple cancer types. However, as a monotherapy, objective responses only occur in a minority of patients. Chemotherapy is widely used in combination with immune checkpoint blockade (ICB). Although a variety of isolated immunostimulatory effects have been reported for several classes of chemotherapeutics, it is unclear which chemotherapeutics provide the most benefit when combined with ICB. We investigated 10 chemotherapies from the main canonical classes dosed at the clinically relevant maximum tolerated dose in combination with anti‐CTLA-4/anti-PD-L1 ICB. We screened these chemo-immunotherapy combinations in two murine mesothelioma models from two different genetic backgrounds, and identified chemotherapies that produced additive, neutral or antagonistic effects when combined with ICB. Using flow cytometry and bulk RNAseq, we characterized the tumor immune milieu in additive chemo-immunotherapy combinations. 5-fluorouracil (5-FU) or cisplatin were additive when combined with ICB while vinorelbine and etoposide provided no additional benefit when combined with ICB. The combination of 5-FU with ICB augmented an inflammatory tumor microenvironment with markedly increased CD8+ T cell activation and upregulation of IFNγ, TNFα and IL-1β signaling. The effective anti‐tumor immune response of 5-FU chemo-immunotherapy was dependent on CD8+ T cells but was unaffected when TNFα or IL-1β cytokine signaling pathways were blocked. Our study identified additive and non-additive chemotherapy/ICB combinations and suggests a possible role for increased inflammation in the tumor microenvironment as a basis for effective combination therapy.
Comprehensive Analysis of the Relationships Between the Gut Microbiota and Fecal Metabolome in Individuals With Primary Sjogren’s Syndrome by 16S rRNA Sequencing and LC–MS-Based Metabolomics
Authors: Yang Li , Xiang Zhao , Zou Jinmei , Zhang Yu , Ni Yuanpiao , Yang Jing
Published: May 2022

The gut microbiota has been associated with primary Sjogren’s syndrome (pSS), yet the biological implications of these associations are often elusive. We analyzed the fecal microbiota through 16S rRNA gene amplification and sequencing in 30 patients with pSS and 20 healthy controls (HCs); At the same time, the fecal metabolome was characterized by ultrahigh-performance liquid chromatography–mass spectrometry. In addition, correlation analyses of microbiota and metabolome data were performed to identify meaningful associations. We found that the microbiota composition of pSS patients was significantly different from that of HCs. The pSS gut microbiota is characterized by increased abundances of proinflammatory microbes, especially Escherichia-Shigella, and decreased abundances of anti-inflammatory microbes. Concerning the metabolome, a multivariate model with 33 metabolites efficiently distinguished cases from controls. Through KEGG enrichment analysis, we found that these metabolites were mainly involved in amino acid metabolism and lipid metabolism. The correlation analysis indicated that there were certain correlations between the microbiota and metabolism in pSS patients. In addition, an abundance of Escherichia-Shigella was found to be correlated with high levels of four metabolites (aflatoxin M1, glycocholic acid, L-histidine and phenylglyoxylic acid). Our research suggests that in pSS patients, the gut microbiota is characterized by a specific combination of proinflammatory changes and metabolic states. Escherichia-Shigella is a factor related to gut dysbiosis, which may promote intestinal damage and affect amino acid metabolism.
Interaction Between microRNAs and Myeloid-Derived Suppressor Cells in Tumor Microenvironment
Authors: Liang Lifei , Xu Xiaoqing , Li Jiawei , Yang Cheng
Published: May 2022

Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of cells generated during a series of pathologic conditions including cancer. MicroRNA (miRNA) has been considered as a regulator in different tumor microenvironments. Recent studies have begun to unravel the crosstalk between miRNAs and MDSCs. The knowledge of the effect of both miRNAs and MDSCs in tumor may improve our understanding of the tumor immune escape and metastasis. The miRNAs target cellular signal pathways to promote or inhibit the function of MDSCs. On the other hand, MDSCs transfer bioinformation through exosomes containing miRNAs. In this review, we summarized and discussed the bidirectional regulation between miRNAs and MDSCs in the tumor microenvironment.
Role of Early Life Cytotoxic T Lymphocyte and Natural Killer Cell Immunity in Paediatric HIV Cure/Remission in the Anti-Retroviral Therapy Era
Authors: Vieira Vinicius A. , Herbert Nicholas , Cromhout Gabriela , Adland Emily , Goulder Philip
Published: May 2022

Only three well-characterised cases of functional cure have been described in paediatric HIV infection over the past decade. This underlines the fact that early initiation of combination antiretroviral therapy (cART), whilst minimising the size of the viral reservoir, is insufficient to achieve cure, unless other factors contribute. In this review, we consider these additional factors that may facilitate functional cure in paediatric infection. Among the early life immune activity, these include HIV-specific cytotoxic T-lymphocyte (CTL) and natural killer (NK) cell responses. The former have less potent antiviral efficacy in paediatric compared with adult infection, and indeed, in early life, NK responses have greater impact in suppressing viral replication than CTL. This fact may contribute to a greater potential for functional cure to be achieved in paediatric versus adult infection, since post-treatment control in adults is associated less with highly potent CTL activity, and more with effective antiviral NK cell responses. Nonetheless, antiviral CTL responses can play an increasingly effective role through childhood, especially in individuals expressing then ‘protective’ HLA-I molecules HLA-B*27/57/58:01/8101. The role of the innate system on preventing infection, in shaping the particular viruses transmitted, and influencing outcome is discussed. The susceptibility of female fetuses to in utero mother-to-child transmission, especially in the setting of recent maternal infection, is a curiosity that also provides clues to mechanisms by which cure may be achieved, since initial findings are that viral rebound is less frequent among males who interrupt cART. The potential of broadly neutralising antibody therapy to facilitate cure in children who have received early cART is discussed. Finally, we draw attention to the impact of the changing face of the paediatric HIV epidemic on cure potential. The effect of cART is not limited to preventing AIDS and reducing the risk of transmission. cART also affects which mothers transmit. No longer are mothers who transmit those who carry genes associated with poor immune control of HIV. In the cART era, a high proportion (>70% in our South African study) of transmitting mothers are those who seroconvert in pregnancy or who for social reasons are diagnosed late in pregnancy. As a result, now, genes associated with poor immune control of HIV are not enriched in mothers who transmit HIV to their child. These changes will likely influence the effectiveness of HLA-associated immune responses and therefore cure potential among children.
The Potential Role of Gut Microbial-Derived Exosomes in Metabolic-Associated Fatty Liver Disease: Implications for Treatment
Authors: Zhang Binbin , Zhao Jianan , Jiang Minjie , Peng Dandan , Dou Xiaobing , Song Yu , Shi Junping
Published: May 2022

The prevalence and incidence of metabolic-associated fatty liver disease (MAFLD), a clinically heterogeneous disease whose primary clinical therapies include dietary control and exercise therapy, is increasing worldwide and constitutes a significant medical burden. Gut microbes influence the physiopathological processes of the liver through different mechanisms based on the gut-liver axis. Exosomes are essential carriers of intercellular communication. Most previous studies have focused on adipocyte- and hepatocyte-derived exosomes, while the critical role of microbial-derived exosomes and the molecular mechanisms behind them in MAFLD have received little attention. Therefore, we searched and screened the latest relevant studies in the PubMeb database to elucidate the link between microbial-derived exosomes and the pathogenesis of MAFLD, mainly in terms of insulin resistance, intestinal barrier, inflammatory response, lipid metabolism, and liver fibrosis. The aim was to provide a theoretical framework and support for clinical protocols and innovative drug development.
Collection Time, Location, and Mosquito Species Have Distinct Impacts on the Mosquito Microbiota
Authors: Pérez-Ramos Daniel W. , Ramos Martina M. , Payne Kyle C. , Giordano Bryan V. , Caragata Eric P.
Published: May 2022

The mosquito microbiota affects many aspects of mosquito biology including development and reproduction. It also strongly impacts interactions between the mosquito host and pathogens that cause important disease in humans, such as dengue and malaria. Critically, the mosquito microbiota is highly diverse and can vary in composition in response to multiple environmental variables, but these effects are not always consistent. Understanding how the environment shapes mosquito microbial diversity is a critical step in elucidating the ubiquity of key host-microbe-pathogen interactions in nature. To that end, we examined the role of time of collection, collection location and host species on mosquito microbial diversity by repeating collections at two-month intervals on a trapping grid spanning three distinct biomes. We then used 16S rRNA sequencing to compare the microbiomes ofAedes taeniorhynchus,Anopheles crucians, andCulex nigripalpusmosquitoes from those collections. We saw that mosquito diversity was strongly affected by both time and collection location. We also observed that microbial richness and diversity increased from March to May, and thatAn. cruciansandCx. nigripalpushad greater microbial diversity thanAe. taeniorhynchus. However, we also observed that collection location had no impact on microbial diversity except for significantly lower bacterial richness observed in mosquitoes collected from the mangrove wetlands. Our results highlight that collection time, collection location, and mosquito species each affect aspects of mosquito microbial diversity, but their importance is context dependent. We also demonstrate that these variables have differing impacts on mosquito diversity and mosquito microbial diversity. Our findings suggest that the environment likely plays an important but variable role in influencing the composition of the mosquito microbiota.
Interfacial and Interlaminar Shear Strength of Unidirectional Viscose Fibre-Reinforced Epoxy Composites—an Overview of the Comparability of Results Obtained by Different Test Methods
Authors: Graupner Nina , Müssig Jörg
Published: May 2022

In this study, the apparent interfacial and interlaminar shear strength (IFSS and ILSS) of single fibres and unidirectional (UD) viscose fibre-reinforced epoxy composites were characterised using different test methods. Microbond and pull-out tests were used to analyse the IFSS of single fibres embedded in epoxy and the transverse tensile test was applied to measure the IFSS of UD fibre-reinforced composites. The short beam shear test, single edge notched bending test (SENB), double-notched tensile test and double-notched compression test were applied to characterise the ILSS. The composites were produced from continuous tows with fibre mass fractions of 20%, 30% and 40% and fibres of different fineness (1.7, 3.3 and 28.0 dtex). The results showed that the different test procedures led to different trends of ILSS depending on the fibre mass fraction and fibre fineness used. The transverse tensile test revealed that the IFSS decreased with increasing fibre mass fraction and fibre diameter. A different trend was found with the short beam shear test and the SENB test for the ILSS. Here, higher values were detected with increasing fibre mass content, and the influence of the fineness was less noticeable. The double-notched shear tests (tensile and compression) showed a different trend: the ILSS increased with increasing fibre mass fraction from 20% to 30%. With a further increase to 40%, the ILSS tend to decrease slightly. An influence of the fibre fineness on the ILSS could not be statistically proven. The different trends of the test methods are attributed to the constitution of the composite and the different load application caused by the test procedures.
Obesity and Impaired Metabolic Health Increase Risk of COVID-19-Related Mortality in Young and Middle-Aged Adults to the Level Observed in Older People: The LEOSS Registry
Authors: Stefan Norbert , Sippel Katrin , Heni Martin , Fritsche Andreas , Wagner Robert , Jakob Carolin E. M. , Preißl Hubert , von Werder Alexander , Khodamoradi Yascha , Borgmann Stefan , Rüthrich Maria Madeleine , Hanses Frank , Haselberger Martina , Piepel Christiane , Hower Martin , vom Dahl Jürgen , Wille Kai , Römmele Christoph , Vehreschild Janne , Stecher Melanie , Solimena Michele , Roden Michael , Schürmann Annette , Gallwitz Baptist , Hrabe de Angelis Martin , Ludwig David S. , Schulze Matthias B. , Jensen Bjoern Erik Ole , Birkenfeld Andreas L.
Published: May 2022

Advanced age, followed by male sex, by far poses the greatest risk for severe COVID-19. An unresolved question is the extent to which modifiable comorbidities increase the risk of COVID-19-related mortality among younger patients, in whom COVID-19-related hospitalization strongly increased in 2021. A total of 3,163 patients with SARS-COV-2 diagnosis in the Lean European Open Survey on SARS-CoV-2-Infected Patients (LEOSS) cohort were studied. LEOSS is a European non-interventional multi-center cohort study established in March 2020 to investigate the epidemiology and clinical course of SARS-CoV-2 infection. Data from hospitalized patients and those who received ambulatory care, with a positive SARS-CoV-2 test, were included in the study. An additive effect of obesity, diabetes and hypertension on the risk of mortality was observed, which was particularly strong in young and middle-aged patients. Compared to young and middle-aged (18–55 years) patients without obesity, diabetes and hypertension (non-obese and metabolically healthy; n = 593), young and middle-aged adult patients with all three risk parameters (obese and metabolically unhealthy; n = 31) had a similar adjusted increased risk of mortality [OR 7.42 (95% CI 1.55–27.3)] as older (56–75 years) non-obese and metabolically healthy patients [n = 339; OR 8.21 (95% CI 4.10–18.3)]. Furthermore, increased CRP levels explained part of the elevated risk of COVID-19-related mortality with age, specifically in the absence of obesity and impaired metabolic health. In conclusion, the modifiable risk factors obesity, diabetes and hypertension increase the risk of COVID-19-related mortality in young and middle-aged patients to the level of risk observed in advanced age.
Alterations of Fungal Microbiota in Patients With Cholecystectomy
Authors: Xu Jun , Ren Xinhua , Liu Yun , Zhang Yuanyuan , Zhang Yiwen , Chen Guodong , Huang Qing , Liu Qing , Zhou Jianhua , Liu Yulan
Published: May 2022

Increasing evidence suggests a high risk of gastrointestinal postoperative comorbidities (such as colorectal cancer) in patients with postcholecystectomy (PC). Although previous studies implicated the role of fungi in colon carcinogenesis, few reports focused on the fungal profile in patients with PC. We enrolled 104 subjects, including 52 patients with PC and 52 non-PC controls (CON), for fecal collection to detect the fungal composition by an internal transcribed spacer (ITS) 1 rDNA sequencing. Data showed that Candida (C.) glabrata and Aspergillus (A.) Unassigned were enriched, and Candida albicans was depleted in patients with PC. In addition, postoperative duration was the main factor to affect the fungal composition. Machine learning identified that C. glabrata, A. Unassigned, and C. albicans were three biomarkers to discriminate patients with PC from CON subjects. To investigate the fungal role in colon carcinogenesis, the subjects of the PC group were divided into two subgroups, namely, patients with PC without (non-CA) and with precancerous lesions or colorectal cancer (preCA_CRC), by histopathological studies. C. glabrata was found to be gradually accumulated in different statuses of patients with PC. In conclusion, we found fungal dysbiosis in patients with cholecystectomy, and the postoperative duration was a potent factor to influence the fungal composition. The accumulation of C. glabrata might be connected with carcinogenesis after cholecystectomy.