bluuebunny/crossref_metadata_2025 huggingface dataset:
Unraveling the Importance of the Yangtze River and Local Catchment on Water Level Variations of Poyang Lake (China) After the Three Gorges Dam Operation: Insights From Random Forest Modeling
Authors: Li Bing , Yang Guishan , Wan Rongrong , Wang Yanan , Xu Chen , Wang Dianchang , Mi Chuang
Published: July 2022

Investigating the contributions of the factors influencing lake water level and their related changes with regard to hydraulic facilities is vital for understanding the driving mechanism of water level variations under the manifold pressures from anthropogenic activities and climate change. In this study, a random forest (RF) model was used to investigate the changes of the relationship between water level and discharge of the Yangtze River and local tributaries in Poyang Lake, China, based on daily hydrological data from 1980 to 2018. The results indicated that RF exhibited robust capability for water level prediction in Poyang Lake, with average R2 of 0.95, 0.88, 0.92, and 0.94 for the dry, rising, wet, and recession seasons, respectively. Predictor importance analysis showed that the discharge of the Yangtze River had greater influence on the water level than the discharge of local tributaries except for the dry season in Poyang Lake, where the influence on the water level was evident with discharge less than 5,000 m3/s. The influence of the Yangtze River also showed a clear attenuation pattern as the distance from the outlet of the lake increased, where the water level was constantly regulated by the Yangtze River. In addition, the partial dependence plots also indicated that the Yangtze River discharge changes after the TGD operation have resulted in remarkable water level decreases in the wet and recession seasons, especially for the recession period. Meanwhile, a slight increase in water level was predicted under identical discharge of local catchment in the dry season, which was only concentrated in the outlet of the lake. This study indicated the RF model as a robust technique for water level predictions and attribution analysis under multiple temporal and spatial scales. Moreover, this study confirmed the uneven influences of the Yangtze River and local tributaries on water level across different seasons, gauging stations, and phases.
Polyunsaturated Fatty Acids Level and Bone Mineral Density: A Two-Sample Mendelian Randomization Study
Authors: Wang Lin , Zhang Chao , Liang Hao , Zhou Nian , Huang Tianji , Zhao Zenghui , Luo Xiaoji
Published: July 2022

Background

This Mendelian randomization (MR) study aimed to explore the causal relationship between polyunsaturated fatty acids (PUFAs) and bone mineral density (BMD).

Methods

We conducted a two-sample MR analysis to figure out if there is any causal effect of PUFAs on BMD through the summary data from the genome-wide association study (GWAS). Relationships were evaluated through inverse variance weighted (IVW), MR-Egger, weighted median, and maximum likelihood methods. The MR Pleiotropy RESidual Sum and Outlier (MR-PRESSO) test was performed to detect the horizontal pleiotropy.

Results

Our findings revealed that omega-6 fatty acids were negatively related to the TB-BMD (beta-estimate: −0.0515; 95% confidence interval [CI]: −0.0911 to −0.0119; standard error [SE]: 0.0201; p-value: 0.0106). The reverse direction MR analysis showed that TB-BMD was linked to the omega-6 FAs (beta-estimate: −0.0699; 95% CI: −0.1304 to −0.0095; SE: 0.0308; p-value: 0.0265). No statistically significant correlations between PUFAs and BMD were observed after adjusting the interactions between metabolites.

Conclusion

This two-sample MR analyses produced strong and new genomic evidence that there was a causal relationship between omega-6 FAs and BMD. Further investigations are still required to elucidate the potential mechanism.
Association Between Globulin and Diabetic Nephropathy in Type2 Diabetes Mellitus Patients: A Cross-Sectional Study
Authors: Wang Jian , Liu Fang , Kong Rongzhen , Han Xiuxia
Published: July 2022

Background

With the development of economy, the living standard of people all over the world has been greatly improved, and the incidence of diabetes is also increasing. Many people with diabetes also develop other complications that reduce their quality of life. Diabetic nephropathy is a common complication of type2 diabetes. Understanding the related factors of diabetic nephropathy is greatly significant to control the occurrence of diabetic nephropathy and improve patient’s life quality.

Data and Methods

Data were collected from 2009 to 2018 in NHANES. Curve fitting graph was performed to investigate the association between globulin (GLB) and diabetic nephropathy(DN). Four logistic regression models were conducted to control the potential confounding factors. Subgroup analysis was carried out to assess the stability of results.

Results

GLB was positively correlated with the occurrence of DN after controlling for potential confounders. Higher GLB was associated with an increased risk of diabetic nephropathy [odds ratio(OR), 1.10; 95% confidence interval (CI), 1.07-1.13, P < 0.001].

Conclusions

In this cross-sectional study, GLB was significant positively correlated with the occurrence of DN in patients with type2 diabetes mellitus.
Hounsfield Unit for Assessing Bone Mineral Density Distribution Within Cervical Vertebrae and Its Correlation With the Intervertebral Disc Degeneration
Authors: Liang Xiao , Liu Qingtao , Xu Jiaxin , Ding Wenyuan , Wang Hui
Published: July 2022

Study Design

Retrospective radiological analysis.

Objective

To assess bone mineral mass distribution within cervical vertebrae based on Hounsfield unit (HU) measurement, and explore its correlation with intervertebral disc degeneration.

Method

Three hundred and twenty-four patients with degenerative cervical spine disease were retrospectively reviewed and divided into six groups according to age. HU measurement of the whole vertebrae from C3 through C7 was obtained, then HU measurement within upper and lower part of the vertebrae on sagittal plane were obtained from C3 through C7. Disc degeneration on MRI was graded from I to V using the Pfirrmann classification.

Results

There was a significant difference in the HU value from C3 to C7 among Group II to Group VI, the HU value presented consistently decreasing trend from young patients to old patients. In C6 and C7 vertebrae, there were significant differences in HU values between upper and lower parts of the vertebrae. More importantly. In all groups, HU values were highest in the upper part of the C4 vertebrae and then gradually decreased towards C3 and C7. HU value of both upper and lower vertebrae presented decreasing trend along with the aggravation of the disc degeneration.

Conclusion

HU values are not typically consistent throughout all levels of the cervical spine and the distribution within the vertebrae is not homogeneous. Decreased vertebral BMD and vertebral osteoporosis may trigger or exacerbate the adjacent intervertebral disc degeneration.
Construction and Application of a Carbon Emission Model for China’s Coal Production Enterprises and Result Analysis
Authors: Li Yang , Jin Xiangyang , Wang Guoliang , Ren Yuqi , Tan Huiqi , Li Na
Published: July 2022

To achieve the national goal of “peak carbon emissions and carbon neutrality,” a specific action plan is needed. Therefore, it is particularly important to scientifically calculate the total carbon emissions of enterprises in various industries. According to the related enterprises’ characteristics, this study adopts different-source methods to construct the carbon emission calculation model. Carbon dioxide emissions are calculated based on the gas grade, and the results are as follows: 1) Carbon emissions of enterprises are significantly different with various gas grades; 2) gas dissipation accounts for more than 80% of carbon emissions of relevant enterprises, so the gas content in the coal seam increases the effect of carbon emissions; and 3) with the increase in mining depth, carbon emissions are increasing. This innovation of study is, first, comprehensively analyzing the carbon emission sources of relevant enterprises from six aspects, including fuel combustion, torch burning, CH4 and CO2 dissipation, net purchased electricity and heat implication, coal gangue storage and utilization, and coal transportation. Moreover, the source–sink relationship method is proposed when the CH4 and CO2 dissipation is calculated, which avoids human errors such as inaccurate measurement of the actual statistical method and the difficulty of obtaining calculation parameters, thus more accurately calculating the total carbon emissions. The source–sink relationship method can be applied in open coal pits to solve the carbon emission calculation. Implementing green and low-carbon development and achieving the goal of peak carbon emissions and carbon neutrality is significant.
Decoupling Re-Analysis of CO2 Emissions and Economic Growth From Two Dimensions
Authors: Han Yuling , Liu Yiping , Liu Xiao
Published: July 2022

The 21st Conference of the Parties (COP 21) was a significant attempt by governments to make and monitor commitments to limit global warming. However, COP 23 “sought to continue the global momentum to decouple output from greenhouse gas (GHG) emissions.” Among the GHGs, carbon dioxide (CO2) is the major one most countries worry about. This paper examines the decoupling situations of China’s CO2 emissions and economic growth, considering the country’s progress situation from the year 2000 to 2019. For this, we employed two models: the environmental Kuznets curve (EKC) model for exploring the long-run decoupling status and the influence factors of CO2 emissions and the Tapio model for the short-run decoupling status. Later, the Tapio model was extended to analyze the influence of industrial structure, energy structure, and population structure. The long-term results suggest that China’s CO2 emissions have not decoupled yet, but the emission’s intensity has decoupled in mid-2006. The short-term decoupling results revealed that the degree of decoupling changed to weak from strong in the last five years. According to the influencing structure’s results, the industrial and energy structures inhibited CO2 emissions, but their influence was not strong enough to offset the impact of economic growth; however, the population structure indorsed CO2 emissions. Lastly, we found an unusual verdict that is the change of EKC into a U-shape from an inverted U-shape, and the observed reason is the control variable introduction. We also observed that the turning point became greater after introducing the industrial structure separately. Overall, from the perspective of the observed decoupling trends, it is suggested that China should strengthen and further optimize its energy structure to match the industrial structure.
Green Finance Strategies for the Zero-Carbon Mechanism: Public Spending as New Determinants of Sustainable Development
Authors: Xing Lining , Li Jun , Yu Zhang
Published: July 2022

A green economy is one that mainstreams nature and people’s concerns and provides well-paying jobs for the economy. In the past, researchers examined the relationship between financial growth and carbon emissions, and very limited studies examined the role of green finance in carbon extenuation. Based on these four indicators, which are sustainable credit, sustainable safety, sustainable insurance, and sustainable asset, a green finance index was developed in this study. In this study, a vector error correction model (VECM) is used to examine associations between the growth level of green finance, public spending, and the zero-carbon mechanism using data from 2005 to 2018. The results of this study indicate that China’s green finance industry had grown quickly, with enhancements in green finance and increased public spending, all contributing to reducing the country’s environmental degradation. The simultaneous increase in carbon intensity slowed the expansion of non-fossil energy usage, reduced the flow of investing in green projects, and finally deteriorated the development of green finance. Furthermore, renewable energy usage in China is chiefly influenced by carbon intensity and green finance, both of which had clear policy-driven consequences. The effects of green finance strategies have consistently fallen short of expectations and lacked consistency. This study makes recommendations for improving the effectiveness of green finance policy implementation and increasing renewable energy to reduce or erode the economic gains of the zero-carbon mechanism.
Sex Differences Dictate the Movement Patterns of Striped Hyenas, Hyaena hyaena, in a Human-Dominated Landscape
Authors: Bar-Ziv Einat , Picardi Simona , Kaplan Asaf , Avgar Tal , Berger-Tal Oded
Published: July 2022

Large-carnivore populations have experienced significant declines in the past centuries in extended parts of the world. Habitat loss, fragmentation, and depletion of natural resources are some of the main causes of this decline. Consequently, behavioral flexibility, enabling the exploitation of anthropogenic food resources in highly disturbed human-dominated landscapes, is becoming critical for the survival of large carnivores. These behavioral changes increase the potential for human-large carnivore conflict and can further intensify carnivore persecution. Here, we examine how land cover types (representing a gradient of anthropogenic disturbance) alter the behavior of striped hyenas (Hyaena hyaena) in a human-dominated landscape in Israel, and whether differences in life history between males and females affect their reaction to such disturbances and consequently their level of exposure to humans. We used a Hidden Markov Model on GPS-tracking data for seven striped hyenas to segment individual-night trajectories into behavioral states (resting, searching, and traveling). We then used multinomial logistic regression to model hyenas’ behavioral state as a function of the interaction between land cover and sex. Females traveled less than males both in terms of average distance traveled per hour, per night, and nightly net displacement. Most steps were classified as “searching” for females and as “traveling” for males. Female hyenas spent a higher proportion of time in human-dominated areas and a lower proportion in natural areas compared to males, and they were also more likely to be found close to settlements than males. Females changed their time allocation between natural and human-dominated areas, spending more time resting than traveling in natural areas but not in human-dominated ones; males spent more time searching than resting in human-dominated areas but were equally likely to rest or search in natural ones. The differences in life history between male and female hyenas may reflect different motivations for space use as a means to optimize fitness, which affects their exposure to humans and therefore their potential involvement in human-hyenas conflict. Understanding the mechanisms that lead to behavioral change in response to human disturbance is important for adaptive management and promoting human large-carnivores co-existence in general.
Targeted Next-Generation Sequencing Identified Novel Compound Heterozygous Variants in the PTPRQ Gene Causing Autosomal Recessive Hearing Loss in a Chinese Family
Authors: Jin Yuan , Liu Xiao-Zhou , Xie Le , Xie Wen , Chen Sen , Sun Yu
Published: July 2022

Hearing loss is among the most common congenital sensory impairments. Genetic causes account for more than 50% of the cases of congenital hearing loss. The PTPRQ gene, encoding protein tyrosine phosphatase receptor Q, plays an important role in maintaining the stereocilia structure and function of hair cells. Mutations in the PTPRQ gene have been reported to cause hereditary sensorineural hearing loss. By using next-generation sequencing and Sanger sequencing, we identified a novel compound heterozygous mutation (c.997 G > A and c.6603-3 T > G) of the PTPRQ gene in a Chinese consanguineous family. This is the first report linking these two mutations to recessive hereditary sensorineural hearing loss. These findings contribute to the understanding of the relationship between genotype and hearing phenotype of PTPRQ-related hearing loss, which may be helpful to clinical management and genetic counseling.
Comparison of Methods Utilizing Sex-Specific PRSs Derived From GWAS Summary Statistics
Authors: Zhang Chi , Ye Yixuan , Zhao Hongyu
Published: July 2022

The polygenic risk score (PRS) is calculated as the weighted sum of an individual’s genotypes and their estimated effect sizes, which is often used to estimate an individual’s genetic susceptibility to complex traits and disorders. It is well known that some complex human traits or disorders have sex differences in trait distributions, disease onset, progression, and treatment response, although the underlying mechanisms causing these sex differences remain largely unknown. PRSs for these traits are often based on Genome-Wide Association Studies (GWAS) data with both male and female samples included, ignoring sex differences. In this study, we present a benchmark study using both simulations with various combinations of genetic correlation and sample size ratios between sexes and real data to investigate whether combining sex-specific PRSs can outperform sex-agnostic PRSs on traits showing sex differences. We consider two types of PRS models in our study: single-population PRS models (PRScs, LDpred2) and multiple-population PRS models (PRScsx). For each trait or disorder, the candidate PRSs were calculated based on sex-specific GWAS data and sex-agnostic GWAS data. The simulation results show that applying LDpred2 or PRScsx to sex-specific GWAS data and then combining sex-specific PRSs leads to the highest prediction accuracy when the genetic correlation between sexes is low and the sample sizes for both sexes are balanced and large. Otherwise, the PRS generated by applying LDpred2 or PRScs to sex-agnostic GWAS data is more appropriate. If the sample sizes between sexes are not too small and very unbalanced, combining LDpred2-based sex-specific PRSs to predict on the sex with a larger sample size and combining PRScsx-based sex-specific PRSs to predict on the sex with a smaller size are the preferred strategies. For real data, we considered 19 traits from Genetic Investigation of ANthropometric Traits (GIANT) consortium studies and UK Biobank with both sex-specific GWAS data and sex-agnostic GWAS data. We found that for waist-to-hip ratio (WHR) related traits, accounting for sex differences and incorporating information from the opposite sex could help improve PRS prediction accuracy. Taken together, our findings in this study provide guidance on how to calculate the best PRS for sex-differentiated traits or disorders, especially as the sample size of GWASs grows in the future.
Unique Molecular Identifier-Based High-Resolution HLA Typing and Transcript Quantitation Using Long-Read Sequencing
Authors: Cornaby Caleb , Montgomery Maureen C. , Liu Chang , Weimer Eric T.
Published: July 2022

HLA typing provides essential results for stem cell and solid organ transplants, as well as providing diagnostic benefits for various rheumatology, gastroenterology, neurology, and infectious diseases. It is becoming increasingly clear that understanding the expression of patient HLA transcripts can provide additional benefits for many of these same patient groups. Our study cohort was evaluated using a long-read RNA sequencing methodology to provide rapid HLA genotyping results and normalized HLA transcript expression. Our assay used NGSEngine to determine the HLA genotyping result and normalized mRNA transcript expression using Athlon2. The assay demonstrated an excellent concordance rate of 99.7%. Similar to previous studies, for the class I loci, patients demonstrated significantly lower expression of HLA-C than HLA-A and -B (Mann–Whitney U, p value = 0.0065 and p value = 0.0154, respectively). In general, the expression of class II transcripts was lower than that of class I transcripts. This study demonstrates a rapid high-resolution HLA typing assay using RNA-Seq that can provide accurate HLA genotyping and HLA allele-specific transcript expression in 7–8 h, a timeline short enough to perform the assay for deceased donors.
Ethical Implications of e-Health Applications in Early Preventive Healthcare
Authors: Stake Mandy , Heinrichs Bert
Published: July 2022

As a means of preventive medicine early detection and prevention examinations can identify and treat possible health disorders or abnormalities from an early age onwards. However, pediatric examinations are often widely spaced, and thus only snapshots of the children’s and adolescents’ developments are obtained. With e-health applications parents and adolescents could record developmental parameters much more frequently and regularly and transmit data directly for ongoing evaluation. AI technologies could be used to search for new and previously unknown patterns. Although e-health applications could improve preventive healthcare, there are serious concerns about the unlimited use of big data in medicine. Such concerns range from general skepticism about big data in medicine to specific challenges and risks in certain medical areas. In this paper, we will focus on preventive health care in pediatrics and explore ethical implications of e-health applications. Specifically, we will address opportunities and risks of app-based data collection and AI-based data evaluation for complementing established early detection and prevention examinations. To this end, we will explore the principle of the best interest of the child. Furthermore, we shall argue that difficult trade-offs need to be made between group benefit on the one hand and individual autonomy and privacy on the other.
The Classification and Prediction of Ferroptosis-Related Genes in ALS: A Pilot Study
Authors: Zhang Qianqian , Zhao Huihui , Luo Maotao , Cheng Xi , Li Yanan , Li Qingyang , Wang Zheng , Niu Qi
Published: July 2022

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive muscle paralysis, which is followed by degeneration of motor neurons in the motor cortex of the brainstem and spinal cord. The etiology of sporadic ALS (sALS) is still unknown, limiting the exploration of potential treatments. Ferroptosis is a new form of cell death and is reported to be closely associated with Alzheimer’s disease (AD), Parkinson’s disease (PD), and ALS. In this study, we used datasets (autopsy data and blood data) from Gene Expression Omnibus (GEO) to explore the role of ferroptosis and ferroptosis-related gene (FRG) alterations in ALS. Gene set enrichment analysis (GSEA) found that the activated ferroptosis pathway displayed a higher enrichment score, and the expression of 26 ferroptosis genes showed obvious group differences between ALS and controls. Using weighted gene correlation network analysis (WGCNA), we identified FRGs associated with ALS, of which the Gene Ontology (GO) analysis displayed that the biological process of oxidative stress was the most to be involved in. KEGG pathway analysis revealed that the FRGs were enriched not only in ferroptosis pathways but also in autophagy, FoxO, and mTOR signaling pathways. Twenty-one FRGs (NR4A1, CYBB, DRD4, SETD1B, LAMP2, ACSL4, MYB, PROM2, CHMP5, ULK1, AKR1C2, TGFBR1, TMBIM4, MLLT1, PSAT1, HIF1A, LINC00336, AMN, SLC38A1, CISD1, and GABARAPL2) in the autopsy data and 16 FRGs (NR4A1, DRD4, SETD1B, MYB, PROM2, CHMP5, ULK1, AKR1C2, TGFBR1, TMBIM4, MLLT1, HIF1A, LINC00336, IL33, SLC38A1, and CISD1) in the blood data were identified as target genes by least absolute shrinkage and selection operator analysis (LASSO), in which gene signature could differentiate ALS patients from controls. Finally, the higher the expression of CHMP5 and SLC38A1 in whole blood, the shorter the lifespan of ALS patients will be. In summary, our study presents potential biomarkers for the diagnosis and prognosis of ALS.
Partial Least Squares Enhances Genomic Prediction of New Environments
Authors: Montesinos-López Osval A. , Montesinos-López Abelardo , Kismiantini  , Roman-Gallardo Armando , Gardner Keith , Lillemo Morten , Fritsche-Neto Roberto , Crossa José
Published: July 2022

In plant breeding, the need to improve the prediction of future seasons or new locations and/or environments, also denoted as “leave one environment out,” is of paramount importance to increase the genetic gain in breeding programs and contribute to food and nutrition security worldwide. Genomic selection (GS) has the potential to increase the accuracy of future seasons or new locations because it is a predictive methodology. However, most statistical machine learning methods used for the task of predicting a new environment or season struggle to produce moderate or high prediction accuracies. For this reason, in this study we explore the use of the partial least squares (PLS) regression methodology for this specific task, and we benchmark its performance with the Bayesian Genomic Best Linear Unbiased Predictor (GBLUP) method. The benchmarking process was done with 14 real datasets. We found that in all datasets the PLS method outperformed the popular GBLUP method by margins between 0% (in the Indica data) and 228.28% (in the Disease data) across traits, environments, and types of predictors. Our results show great empirical evidence of the power of the PLS methodology for the prediction of future seasons or new environments.
Perthes Disease in a Child With Osteogenesis Imperfecta From a Rare Genetic Variant: A Case Report
Authors: Hong Pan , Zhao Xiaolong , Liu Ruikang , Rai Saroj , Song Yingying , Xu Ruijing , Li Jin
Published: July 2022

Background: Although certain genetic components have been reported as contributing factors for Perthes disease, its etiology remains unclear. We present a rare case of Perthes disease in a child with osteogenesis imperfecta (OI) caused by a mutation in the COL1A1 gene (NM_000088):exon25:c.1726C>T, (p.Gln576X).

Case presentations: A 7-year-old boy was initially treated at our medical facility in March 2016 with a history of chronic pain in right hip joint and limping for a year. He was diagnosed as Perthes disease in the right hip joint. He underwent acetabular osteotomy and ipsilateral proximal femoral varus osteotomy for better containment. During the follow-ups, the right hip demonstrated a normal range of motion without pain, and the pelvic X-ray demonstrated Stulberg Type II hip joint with a round femoral head. In the latest admission in 2022, he suffered from a right femoral shaft fracture after petty violence. After reviewing his medical history, he was suspected of having OI. The whole exome sequencing demonstrated a gene mutation in COL1A1 (OMIM 166200) and confirmed the diagnosis of OI. Telescopic nailing was used to treat the femoral shaft fracture. After the nailing of the right femur, the appearance of the lower extremity seemed normal and symmetrical.

Conclusion: This study revealed that there might be an association between OI and Perthes disease. Our case report enriches the phenotypes of osteogenesis imperfecta and provides insight into the pathogenesis of LCPD.
Complement Inhibition in ANCA-Associated Vasculitis
Authors: Tesar Vladimir , Hruskova Zdenka
Published: July 2022

Efficacy of immunosuppressive treatment of Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is complicated by its toxicity. With the replacement of cyclophosphamide with rituximab, serious adverse events seem to be associated especially with high-dose corticosteroids. Activation of alternative complement pathway plays an important role in the pathogenesis of AAV. Avacopan (C5a receptor inhibitor) was demonstrated to have at least similar efficacy and better safety (in terms of corticosteroid-related adverse events) compared with high-dose corticosteroids in the induction treatment of AAV. Other modes of the inhibition of alternative complement pathway are currently tested in AAV or could be considered on the basis of the experience in other glomerular diseases.
iPSCs in NK Cell Manufacturing and NKEV Development
Authors: Boyd-Gibbins Nicholas , Karagiannis Peter , Hwang Do Won , Kim Shin-Il
Published: July 2022

Natural killer (NK) cell immunotherapies for cancer can complement existing T cell therapies while benefiting from advancements already made in the immunotherapy field. For NK cell manufacturing, induced pluripotent stem cells (iPSCs) offer advantages including eliminating donor variation and providing an ideal platform for genome engineering. At the same time, extracellular vesicles (EVs) have become a major research interest, and purified NK cell extracellular vesicles (NKEVs) have been shown to reproduce the key functions of their parent NK cells. NKEVs have the potential to be developed into a standalone therapeutic with reduced complexity and immunogenicity compared to cell therapies. This review explores the role iPSC technology can play in both NK cell manufacturing and NKEV development.
Microbial Metabolites in the Maturation and Activation of Dendritic Cells and Their Relevance for Respiratory Immunity
Authors: Wilson Kayla R. , Gressier Elise , McConville Malcolm J. , Bedoui Sammy
Published: July 2022

The respiratory tract is a gateway for viruses and bacteria from the external environment to invade the human body. Critical to the protection against these invaders are dendritic cells (DCs) - a group of highly specialized myeloid cells that monitors the lung microenvironment and relays contextual and antigenic information to T cells. Following the recognition of danger signals and/or pathogen molecular associated patterns in the lungs, DCs undergo activation. This process arms DCs with the unique ability to induce the proliferation and differentiation of T cells responding to matching antigen in complex with MHC molecules. Depending on how DCs interact with T cells, the ensuing T cell response can be tolerogenic or immunogenic and as such, the susceptibility and severity of respiratory infections is influenced by the signals DCs receive, integrate, and then convey to T cells. It is becoming increasingly clear that these facets of DC biology are heavily influenced by the cellular components and metabolites produced by the lung and gut microbiota. In this review, we discuss the roles of different DC subsets in respiratory infections and outline how microbial metabolites impact the development, propensity for activation and subsequent activation of DCs. In particular, we highlight these concepts in the context of respiratory immunity.
Small Peptide Derivatives Within the Carbohydrate Recognition Domain of SP-A2 Modulate Asthma Outcomes in Mouse Models and Human Cells
Authors: Francisco Dave , Wang Ying , Marshall Craig , Conway Michelle , Addison Kenneth J. , Billheimer Dean , Kimura Hiroki , Numata Mari , Chu Hong W. , Voelker Dennis R. , Kraft Monica , Ledford Julie G.
Published: July 2022

Surfactant Protein-A (SP-A) is an innate immune modulator that regulates a variety of pulmonary host defense functions. We have shown that SP-A is dysfunctional in asthma, which could be partly due to genetic heterogeneity. In mouse models and primary bronchial epithelial cells from asthmatic participants, we evaluated the functional significance of a particular single nucleotide polymorphism of SP-A2, which results in an amino acid substitution at position 223 from glutamine (Q) to lysine (K) within the carbohydrate recognition domain (CRD). We found that SP-A 223Q humanized mice had greater protection from inflammation and mucin production after IL-13 exposure as compared to SP-A-2 223K mice. Likewise, asthmatic participants with two copies the major 223Q allele demonstrated better lung function and asthma control as compared to asthmatic participants with two copies of the minor SP-A 223K allele. In primary bronchial epithelial cells from asthmatic participants, full-length recombinant SP-A 223Q was more effective at reducing IL-13-induced MUC5AC gene expression compared to SP-A 223K. Given this activity, we developed 10 and 20 amino acid peptides of SP-A2 spanning position 223Q. We show that the SP-A 223Q peptides reduce eosinophilic inflammation, mucin production and airways hyperresponsiveness in a house dust mite model of asthma, protect from lung function decline during an IL-13 challenge model in mice, and decrease IL-13-induced MUC5AC gene expression in primary airway epithelial cells from asthmatic participants. These results suggest that position 223 within the CRD of SP-A2 may modulate several outcomes relevant to asthma, and that short peptides of SP-A2 retain anti-inflammatory properties similar to that of the endogenous protein.
Hepatocyte-Conditional Knockout of Phosphatidylethanolamine Binding Protein 4 Aggravated LPS/D-GalN-Induced Acute Liver Injury via the TLR4/NF-κB Pathway
Authors: Qu Xiao-qin , Chen Qiong-feng , Shi Qiao-qing , Luo Qian-qian , Zheng Shuang-yan , Li Yan-hong , Bai Liang-yu , Gan Shuai , Zhou Xiao-yan
Published: July 2022

Acute liver injury (ALI) is a disease that seriously threatens human health and life, and a dysregulated inflammation response is one of the main mechanisms of ALI induced by various factors. Phosphatidylethanolamine binding protein 4 (PEBP4) is a secreted protein with multiple biological functions. At present, studies on PEBP4 exist mainly in the field of tumors and rarely in inflammation. This study aimed to explore the potential roles and mechanisms of PEBP4 on lipopolysaccharide (LPS)/D-galactosamine (D-GalN)-induced ALI. PEBP4 was downregulated after treatment with LPS/D-GalN in wild-type mice. PEBP4 hepatocyte-conditional knockout (CKO) aggravated liver damage and repressed liver functions, including hepatocellular edema, red blood cell infiltration, and increased aspartate aminotransferase (AST)/alanine aminotrans-ferase (ALT) activities. The inflammatory response was promoted through increased neutrophil infiltration, myeloperoxidase (MPO) activities, and cytokine secretions (interleukin-1β, IL-1β; tumor necrosis factor alpha, TNF-α; and cyclooxygenase-2, COX-2) in PEBP4 CKO mice. PEBP4 CKO also induced an apoptotic effect, including increasing the degree of apoptotic hepatocytes, the expressions and activities of caspases, and pro-apoptotic factor Bax while decreasing anti-apoptotic factor Bcl-2. Furthermore, the data demonstrated the levels of Toll-like receptor 4 (TLR4), phosphorylation-inhibitor of nuclear factor kappaB Alpha (p-IκB-α), and nuclear factor kappaB (NF-κB) p65 were upregulated, while the expressions of cytoplasmic IκB-α and NF-κB p65 were downregulated after PEBP4 CKO. More importantly, both the NF-κB inhibitor (Ammonium pyrrolidinedithiocarbamate, PDTC) and a small-molecule inhibitor of TLR4 (TAK-242) could inhibit TLR4/NF-κB signaling activation and reverse the effects of PEBP4 CKO. In summary, the data suggested that hepatocyte-conditional knockout of PEBP4 aggravated LPS/D-GalN-induced ALI, and the effect is partly mediated by activation of the TLR4/NF-κB signaling pathway.
Vascular Endothelial Growth Factor Receptor, fms-Like Tyrosine Kinase-1 (Flt-1), as a Novel Binding Partner for SARS-CoV-2 Spike Receptor-Binding Domain
Authors: Mutahar Adel Zaid I. , Devaramani Manjunath , Dayal Renu , Saini Dinesh Kumar , Salimath Paramahans V. , Salimath Bharathi P.
Published: July 2022

Angiotensin-converting enzyme 2 (ACE2) and neuropilin 1, a vascular endothelial growth factor (VEGF) receptor, were identified to bind to the SARS-CoV-2 spike receptor-binding domain (spike RBD). In silico analysis based on 3D structure, multiple sequence alignment, and molecular docking of second domain of soluble Flt-1 (sFlt-1) and spike RBD revealed structural similarities, sequence homology, and protein-protein interaction. Interaction and binding of recombinant spike RBD (rspike RBD) and recombinant sFlt-1 (rsFlt-1) in vitro induced a conformational change, as revealed by spectrofluorimetric data, with increased fluorescence intensity in emission spectra as compared to either of the proteins alone. Results on ELISA confirmed the binding and cross-reactivity of rspike-RBD and rsFlt-1 as determined by using either specific antibodies towards each protein or immunized human serum. We found that polyclonal or monoclonal anti-spike RBD antibodies can recognize either rsFlt-1 or rspike RBD, showing cross-reactivity for the two proteins in a dose-dependent binding response. Recognition of bound rspike RBD or rsFlt-1 by anti-Flt-1 or anti-spike RBD antibodies, respectively, as observed by immunoblotting, further confirmed interaction between the two proteins. Immunoprecipitation and immunoblot analysis demonstrated the identification of rspike RBD binding to the Flt-1 receptor on A549 cells. Further, the binding of rspike RBD to Flt-1 receptor was shown using immunofluorescence on 2D-culture or 3D-spheroid of MDA-MB-231 cells, which over-express Flt-1 receptor. Together, our study concludes that the Flt-1 receptor is a novel binding partner for SARS-CoV-2 spike RBD.
Microbiota-Derived Propionate Modulates Megakaryopoiesis and Platelet Function
Authors: Dürholz Kerstin , Schmid Eva , Frech Michael , Azizov Vugar , Otterbein Nadine , Lucas Sébastien , Rauh Manfred , Schett Georg , Bruns Heiko , Zaiss Mario M.
Published: July 2022

Rheumatoid arthritis (RA) is associated with an increased risk for cardiovascular events driven by abnormal platelet clotting effects. Platelets are produced by megakaryocytes, deriving from megakaryocyte erythrocyte progenitors (MEP) in the bone marrow. Increased megakaryocyte expansion across common autoimmune diseases was shown for RA, systemic lupus erythematosus (SLE) and primary Sjögren’s syndrome (pSS). In this context, we evaluated the role of the microbial-derived short chain fatty acid (SCFA) propionate on hematopoietic progenitors in the collagen induced inflammatory arthritis model (CIA) as we recently showed attenuating effects of preventive propionate treatment on CIA severity. In vivo, propionate treatment starting 21 days post immunization (dpi) reduced the frequency of MEPs in the bone marrow of CIA and naïve mice. Megakaryocytes numbers were reduced but increased the expression of the maturation marker CD61. Consistent with this, functional analysis of platelets showed an upregulated reactivity state following propionate-treatment. This was confirmed by elevated histone 3 acetylation and propionylation as well as by RNAseq analysis in Meg-01 cells. Taken together, we identified a novel nutritional axis that skews platelet formation and function.
IL22RA1/JAK/STAT Signaling Acts As a Cancer Target Through Pan-Cancer Analysis
Authors: Zhang Shuai , Yang Guiyan
Published: July 2022

Cytokines and cytokine receptors are important mediators in immunity and cancer development. Interleukin 22 (IL22) is one of the most important cytokines which has protumor effect. Given that common and specific roles of cytokines/receptors in multiple cancers, we conducted a pan-cancer study to investigate the role of IL22RA1 in cancer using The Cancer Genome Atlas (TCGA) database. Notably, we found IL22RA1 transcript was upregulated in 11 cancer types compared with their corresponding control. The mRNA expression level of IL22RA1 was highest in the pancreas among tumor tissues. The higher expression of IL22RA1 was associated with worse overall survival rate in patients. A total of 30 IL22RA1-correlated genes (e.g. IL17D, IL22RA2, IL20RB, IL10RA, IL10RB, TSLP and TYK2) are involved in the JAK/STAT pathway which promotes tumor progression. The upregulation of IL22RA1 in tumors was correlated with immune cell infiltration level. Higher expression of IL22RA2, IL20RB, IL10RA, IL10RB, TSLP, TYK2, STAT1 and STAT3 was associated with decreased overall survival rate in patients. IL22RA1 mutation was observed more in uterine cancer and melanoma compared with the other cancer types. Deactivation of IL22RA1 induced a lot of changes in gene expression. IL22RA1 mutants had upregulated DNA damage/repair genes in uterine cancer, whereas downregulated genes in the FoxO signaling pathway. In melanoma, mutation of IL22RA1 can upregulate the HIF signaling pathway but downregulate metabolic pathways. Our study suggests that IL22RA1/JAK/STAT signaling can be an important target for cancer treatment.
Exploring the Potential of Exosome-Related LncRNA Pairs as Predictors for Immune Microenvironment, Survival Outcome, and Microbiotain Landscape in Esophageal Squamous Cell Carcinoma
Authors: Zhao Fangchao , Li Zhirong , Dong Zefang , Wang Zengying , Guo Pengfei , Zhang Dengfeng , Li Shujun
Published: July 2022

Accumulating studies have demonstrated the indispensable roles of exosomes and long non-coding RNAs (lncRNAs) in cancer progression and the tumor microenvironment (TME). However, the clinical relevance of exosome-related lncRNAs (ER-lncRNAs) in esophageal squamous cell carcinoma (ESCC) remains unclear. Three subtypes were identified by consensus clustering of 3459 valid ER-lncRNA pairs, of which subtype A is preferentially related to favorable prognosis, lower stromal and immune scores, and higher tumor purity scores. Higher immune cell infiltration, higher mRNA levels of immune checkpoints, higher stromal and immune scores, and lower tumor purity were found in subtype C, which presented a poor prognosis. We developed a prognostic risk score model based on 8 ER-lncRNA pairs in the GEO cohort using univariate Cox regression analysis and LASSO Cox regression analysis. Patients were divided into a high risk-score group and low risk-score group by the cut-off values of the 1-year ROC curves in the training set (GEO cohort) and the validation set (TCGA cohort). Receiver operating characteristic (ROC) curves, Decision curve analysis (DCA), clinical correlation analysis, and univariate and multivariate Cox regression all confirmed that the prognostic model has good predictive power and that the risk score can be used as an independent prognostic factor in different cohorts. By further analyzing the TME based on the risk model, higher immune cell infiltration and more active TME were found in the high-risk group, which presented a poor prognosis. Patients with high risk scores also exhibited higher mRNA levels of immune checkpoints and lower IC50 values, indicating that these patients may be more prone to profit from chemotherapy and immunotherapy. The top five most abundant microbial phyla in ESCC was also identified. The best ER-lncRNAs (AC082651.3, AP000487.1, PLA2G4E-AS1, C8orf49 and AL356056.2) were identified based on machine learning algorithms. Subsequently, the expression levels of the above ER-lncRNAs were analyzed by combining the GTEx and TCGA databases. In addition, qRT-PCR analysis based on clinical samples from our hospital showed a high degree of consistency. This study fills the gap of ER-lncRNA model in predicting the prognosis of patients with ESCC and the risk score-based risk stratification could facilitate the determination of therapeutic option to improve prognoses.
Angiotensin AT2 Receptor Stimulation Alleviates Collagen-Induced Arthritis by Upregulation of Regulatory T Cell Numbers
Authors: Sehnert Bettina , Valero-Esquitino Veronica , Schett Georg , Unger Thomas , Steckelings Ulrike Muscha , Voll Reinhard Edmund
Published: July 2022

The angiotensin AT2receptor (AT2R) is a main receptor of the protective arm of the renin-angiotensin system and exerts for instance anti-inflammatory effects. The impact of AT2R stimulation on autoimmune diseases such as rheumatoid arthritis (RA) is not yet known. We investigated the therapeutic potential of AT2R-stimulation with the selective non-peptide AT2R agonist Compound 21 (C21) in collagen-induced arthritis (CIA), an animal model for inflammatory arthritis. Arthritis was induced by immunization of DBA/1J mice with collagen type II (CII). Prophylactic and therapeutic C21 treatment alleviates arthritis severity and incidence in CIA. Joint histology revealed significantly less infiltrates of IL-1 beta and IL-17A expressing cells and a well-preserved articular cartilage in C21- treated mice. In CIA, the number of CD4+CD25+FoxP3+regulatory T (Treg) cells significantly increased upon C21 treatment compared to vehicle. T cell differentiation experiments demonstrated increased expression of FoxP3 mRNA, whereas IL-17A, STAT3 and IFN-gamma mRNA expression were reduced upon C21 treatment. In accordance with the mRNA data, C21 upregulated the percentage of CD4+FoxP3+cells in Treg polarizing cultures compared to medium-treated controls, whereas the percentage of CD4+IL-17A+and CD4+IFN-gamma+T cells was suppressed. To conclude, C21 exerts beneficial effects on T cell-mediated experimental arthritis. We found that C21-induced AT2R-stimulation promotes the expansion of CD4+regulatory T cells and suppresses IL-17A production. Thus, AT2R-stimulation may represent an attractive treatment strategy for arthritis.
IL-18/IL-18R Signaling Is Dispensable for ILC Development But Constrains the Growth of ILCP/ILCs
Authors: Xie Mengying , Zhang Mingying , Dai Mengyuan , Yue Shan , Li Zhao , Qiu Ju , Lu Chenqi , Xu Wei
Published: July 2022

Innate lymphoid cells (ILCs) develop from ILC progenitors in the bone marrow. Various ILC precursors (ILCPs) with different ILC subset lineage potentials have been identified based on the expression of cell surface markers and ILC-associated key transcription factor reporter genes. This study characterized an interleukin (IL)-7Rα+IL-18Rα+ ILC progenitor population in the mouse bone marrow with multi-ILC lineage potential on the clonal level. Single-cell gene expression analysis revealed the heterogeneity of this population and identified several subpopulations with specific ILC subset-biased gene expression profiles. The role of IL-18 signaling in the regulation of IL-18Rα+ ILC progenitors and ILC development was further investigated using Il18- and Il18r1-deficient mice, in vitro differentiation assay, and adoptive transfer model. IL-18/IL-18R-mediated signal was found to not be required for early stages of ILC development. While Il18r1-/- lymphoid progenitors were able to generate all ILC subsets in vitro and in vivo like the wild-type counterpart, increased IL-18 level, as often occurred during infection or under stress, suppressed the growth of ILCP/ILC in an IL-18Ra-dependent manner via inhibiting proliferation and inducing apoptosis.
Development and Verification of a Combined Immune- and Metabolism-Related Prognostic Signature for Hepatocellular Carcinoma
Authors: Guo Yuanyuan , Yang Jing , Gao Hua , Tian Xin , Zhang Xiaojian , Kan Quancheng
Published: July 2022

Immune escape and metabolic reprogramming are becoming important characteristics of tumor biology, which play critical roles in tumor initiation and progression. However, the integrative analysis of immune and metabolic characteristics for the tumor microenvironment in hepatocellular carcinoma (HCC) remains unclear. Herein, by univariate and least absolute shrinkage and selection operator (LASSO) Cox regression analyses, a prognostic signature associated with tumor microenvironment was established based on five immune- and metabolism-related genes (IMRGs), which was fully verified and evaluated in both internal and external cohorts. The C-index was superior to previously published HCC signatures, indicating the robustness and reliability of IMRGs prognostic signature. A nomogram was built based on IMRGs prognostic signature and various clinical parameters, such as age and T stage. The AUCs of nomogram at 1-, 3-, and 5-year (AUC = 0.829, 0.749, 0.749) were slightly better than that of IMRGs signature (AUC = 0.809, 0.734, 0.711). The relationship of risk score (RS) with immune checkpoint expressions, immunophenoscore (IPS), as well as microsatellite instability (MSI) together accurately predicted the treatment efficacy. Collectively, the IMRGs signature might have the potential to better predict prognostic risk, evaluate immunotherapy efficacy, and help personalize immunotherapy for HCC patients.