bluuebunny/crossref_metadata_2025 huggingface dataset:
Inhibition of JAK-STAT Signaling Pathway Alleviates Age-Related Phenotypes in Tendon Stem/Progenitor Cells
Authors: Chen Minhao , Xiao Longfei , Dai Guangchun , Lu Panpan , Zhang Yuanwei , Li Yingjuan , Ni Ming , Rui Yunfeng
Published: March 2021

Diminished regeneration or healing capacity of tendon occurs during aging. It has been well demonstrated that tendon stem/progenitor cells (TSPCs) play a vital role in tendon maintenance and repair. Here, we identified an accumulation of senescent TSPCs in tendon tissue with aging. In aged TSPCs, the activity of JAK-STAT signaling pathway was increased. Besides, genetic knockdown of JAK2 or STAT3 significantly attenuated TSPC senescence in aged TSPCs. Pharmacological inhibition of JAK-STAT signaling pathway with AG490 similarly attenuated cellular senescence and senescence-associated secretory phenotype (SASP) of aged TSPCs. In addition, inhibition of JAK-STAT signaling pathway also restored the age-related dysfunctions of TSPCs, including self-renewal, migration, actin dynamics, and stemness. Together, our findings reveal the critical role of JAK-STAT signaling pathway in the regulation of TSPC aging and suggest an ideal therapeutic target for the age-related tendon disorders.
Sirt6 Regulates the Development of Medullary Thymic Epithelial Cells and Contributes to the Establishment of Central Immune Tolerance
Authors: Zhang Qian , Liang Zhanfeng , Zhang Jiayu , Lei Tong , Dong Xue , Su Huiting , Chen Yifang , Zhang Zhaoqi , Tan Liang , Zhao Yong
Published: March 2021

Although some advances have been made in understanding the molecular regulation of mTEC development, the role of epigenetic regulators in the development and maturation of mTEC is poorly understood. Here, using the TEC-specific Sirt6 knockout mice, we found the deacetylase Sirtuin 6 (Sirt6) is essential for the development of functionally competent mTECs. First of all, TEC-specific Sirt6 deletion dramatically reduces the mTEC compartment, which is caused by reduced DNA replication and subsequent impaired proliferation ability of Sirt6-deficient mTECs. Secondly, Sirt6 deficiency specifically accelerates the differentiation of mTECs from CD80–Aire– immature population to CD80+Aire– intermediate mature population by promoting the expression of Spib. Finally, Sirt6 ablation in TECs markedly interferes the proper expression of tissue-restricted antigens (TRAs) and impairs the development of thymocytes and nTreg cells. In addition, TEC conditional knockout of Sirt6 results in severe autoimmune disease manifested by reduced body weight, the infiltration of lymphocytes and the presence of autoantibodies. Collectively, this study reveals that the expression of epigenetic regulator Sirt6 in TECs is crucial for the development and differentiation of mTECs, which highlights the importance of Sirt6 in the establishment of central immune tolerance.
Lysosome (Dys)function in Atherosclerosis—A Big Weight on the Shoulders of a Small Organelle
Authors: Marques André R. A. , Ramos Cristiano , Machado-Oliveira Gisela , Vieira Otília V.
Published: March 2021

Atherosclerosis is a progressive insidious chronic disease that underlies most of the cardiovascular pathologies, including myocardial infarction and ischemic stroke. The malfunctioning of the lysosomal compartment has a central role in the etiology and pathogenesis of atherosclerosis. Lysosomes are the degradative organelles of mammalian cells and process endogenous and exogenous substrates in a very efficient manner. Dysfunction of these organelles and consequent inefficient degradation of modified low-density lipoproteins (LDL) and apoptotic cells in atherosclerotic lesions have, therefore, numerous deleterious consequences for cellular homeostasis and disease progression. Lysosome dysfunction has been mostly studied in the context of the inherited lysosomal storage disorders (LSDs). However, over the last years it has become increasingly evident that the consequences of this phenomenon are more far-reaching, also influencing the progression of multiple acquired human pathologies, such as neurodegenerative diseases, cancer, and cardiovascular diseases (CVDs). During the formation of atherosclerotic plaques, the lysosomal compartment of the various cells constituting the arterial wall is under severe stress, due to the tremendous amounts of lipoproteins being processed by these cells. The uncontrolled uptake of modified lipoproteins by arterial phagocytic cells, namely macrophages and vascular smooth muscle cells (VSMCs), is the initial step that triggers the pathogenic cascade culminating in the formation of atheroma. These cells become pathogenic “foam cells,” which are characterized by dysfunctional lipid-laden lysosomes. Here, we summarize the current knowledge regarding the origin and impact of the malfunctioning of the lysosomal compartment in plaque cells. We further analyze how the field of LSD research may contribute with some insights to the study of CVDs, particularly how therapeutic approaches that target the lysosomes in LSDs could be applied to hamper atherosclerosis progression and associated mortality.
Cinobufagin-Loaded and Folic Acid-Modified Polydopamine Nanomedicine Combined With Photothermal Therapy for the Treatment of Lung Cancer
Authors: Li Jianwen , Zhang Zhanxia , Deng Haibin , Zheng Zhan
Published: March 2021

Cinobufagin is used as a traditional Chinese medicine for cancer therapy. However, it has some disadvantages, such as poor water solubility, short circulating half-life, and low bioavailability. In the present study, a targeted delivery and smart responsive polydopamine (PDA)-based nanomedicine for delivering cinobufagin was rationally designed to improve the anticancer efficacy of the compound for the treatment of lung cancer. The modification of the nanomedicine using folic acid first mediated tumor targeting via the interaction between folic acid and its receptors on tumor cells. After lysosomes escape, the PDA nanomedicine was triggered by the low pH and released its cargo into the tumor microenvironment. The nanomedicine had a better therapeutic effect against lung cancer when used in combination with photothermal therapy. Compared with other nanomedicines used with photothermal therapy, this nanocarrier was not only sensitive to biologically low pH levels for on-demand drug release, but was also biodegradable, breaking down into biocompatible terminal products. Therefore, the proposed drug delivery system with targeted delivery and smart release demonstrated potential as a multifunctional nanoplatform that can enhance the bioavailability and reduce the side effects of chemotherapeutic agents.
Ionic Charge-Transfer Liquid Crystals Formed by Alternating Supramolecular Copolymerization of Liquid π-Donors and TCNQ
Authors: Iguchi Hiroaki , Furutani Hidenori , Kimizuka Nobuo
Published: March 2021

A new family of liquid π-donors, lipophilic dihydrophenazine (DHP) derivatives, show remarkably high π-electron-donor property which exhibit supramolecular alternating copolymerization with 7,7,8,8-tetracyanoquinodimethane (TCNQ), giving ionic charge-transfer (ICT) complexes. The ICT complexes form distinct columnar liquid crystalline (LC) mesophases with well-defined alternating molecular alignment as demonstrated by UV-Vis-NIR spectra, IR spectra, and X-ray diffraction (XRD) patterns. These liquid crystalline ICT complexes display unique phase transitions in response to mechanical stress: the columnar ICT phase is converted to macroscopically oriented smectic-like mesophases upon applying shear force. Although there exist reports on the formation of ICT in the crystalline state, this study provides the first rational identification of ICT mesophases based on the spectroscopic and structural data. The liquid crystalline ICT phases are generated by strong electronic interactions between the liquid π-donors and solid acceptors. It clearly shows the significance of simultaneous fulfillment of strong π-donating ability and ordered self-assembly of the stable ICT pairs. The flexible, stimuli-responsive structural transformation of the ICT complexes offer a new perspective for designing processable CT systems with controlled hierarchical self-assembly and electronic structures.
Priority Intervention Targets Identified Using an In-Depth Sampling HIV Molecular Network in a Non-Subtype B Epidemics Area
Authors: Zhao Bin , Song Wei , An Minghui , Dong Xue , Li Xin , Wang Lu , Liu Jianmin , Tian Wen , Wang Zhen , Ding Haibo , Han Xiaoxu , Shang Hong
Published: March 2021

Molecular network analysis based on the genetic similarity of HIV-1 is increasingly used to guide targeted interventions. Nevertheless, there is a lack of experience regarding molecular network inferences and targeted interventions in combination with epidemiological information in areas with diverse epidemic strains of HIV-1.We collected 2,173 pol sequences covering 84% of the total newly diagnosed HIV-1 infections in Shenyang city, Northeast China, between 2016 and 2018. Molecular networks were constructed using the optimized genetic distance threshold for main subtypes obtained using sensitivity analysis of plausible threshold ranges. The transmission rates (TR) of each large cluster were assessed using Bayesian analyses. Molecular clusters with the characteristics of ≥5 newly diagnosed cases in 2018, high TR, injection drug users (IDUs), and transmitted drug resistance (TDR) were defined as priority clusters. Several HIV-1 subtypes were identified, with a predominance of CRF01_AE (71.0%, 1,542/2,173), followed by CRF07_BC (18.1%, 393/2,173), subtype B (4.5%, 97/2,173), other subtypes (2.6%, 56/2,173), and unique recombinant forms (3.9%, 85/2,173). The overall optimal genetic distance thresholds for CRF01_AE and CRF07_BC were both 0.007 subs/site. For subtype B, it was 0.013 subs/site. 861 (42.4%) sequences of the top three subtypes formed 239 clusters (size: 2-77 sequences), including eight large clusters (size ≥10 sequences). All the eight large clusters had higher TR (median TR = 52.4/100 person-years) than that of the general HIV infections in Shenyang (10.9/100 person-years). A total of ten clusters including 231 individuals were determined as priority clusters for targeted intervention, including eight large clusters (five clusters with≥5 newly diagnosed cases in 2018, one cluster with IDUs, and two clusters with TDR (K103N, Q58E/V179D), one cluster with≥5 newly diagnosed cases in 2018, and one IDUs cluster. In conclusion, a comprehensive analysis combining in-depth sampling HIV-1 molecular networks construction using subtype-specific optimal genetic distance thresholds, and baseline epidemiological information can help to identify the targets of priority intervention in an area epidemic for non-subtype B.
Reduced Number and Activity of Circulating Endothelial Progenitor Cells in Acute Aortic Dissection and Its Relationship With IL-6 and IL-17
Authors: Huang Zhenhua , Liu Zhihao , Wang Keke , Ye Zi , Xiong Yan , Zhang Bin , Liao Jinli , Zeng Lijing , Zeng Haitao , Liu Gexiu , Zhan Hong , Yang Zhen
Published: March 2021

This study investigates the alteration in function and number of circulating endothelial progenitor cells (EPCs) in patients with aortic dissection (AD), compared with hypertensive patients, and its possible mechanism. Thirty-four patients with acute aortic dissection (AAD) and 20 patients with primary hypertension were involved. Flow cytometry analysis was performed to detect the number of CD34+/KDR+ cells, and acetylated low density lipoprotein (ac-LDL) and lectin fluorescent staining method was applied to test the number of cultured EPCs. In addition, EPC migration and proliferation were measured, and plasma interleukin 6 (IL-6) and interleukin 17 (IL-17) levels were investigated. The number of circulating EPCs in the AAD group was lower than that in the non-AD group, and the proliferation and migration of circulating EPCs in the AAD group were lower than that in the non-AD group. In addition, the number, proliferation, and migration of circulating EPCs were significantly inversely correlated with the aortic dissection detection risk score (ADD-RS). More importantly, increased plasma IL-6 and IL-17 level was found in the AAD group, and the two inflammatory factors were inversely associated with the function and number of circulating EPCs in the AAD group. We first demonstrated that the number and function of circulating EPCs are reduced in the AAD group, which may be partly related to upregulated plasma IL-6 and IL-17. Our study provides novel insight on the underlying mechanism and potential therapeutic target of AAD.
Angular Unconformity of the Late Quaternary Strata in the Hetao Basin, North of the Ordos Block (West China): Timing and Its Tectonic Implications
Authors: Bai Luanxi , Xu Xiwei , Luo Hao , Li Kang , Tan Xibin , Zhao Junxiang
Published: March 2021

Following the uplift of the Tibet Plateau and the continuous subduction of the Pacific Plate, graben faulting began to appear around the Ordos Block in the Cenozoic. The Hetao Basin is a Cenozoic rift basin between the Ordos Block and the Yinshan Mountains, and Late Quaternary sedimentary strata, which have lacustrine facies, are widely distributed inside this basin. However, the evolution of the Hetao Basin and its related fault systems has been debated for a long time due to the lack of tectonic evidence. In this study, four sections named Haolaigou, Bianqianghao, Huhesala, and Hazigai are selected along the north margin of the Hetao Basin. With the lithology and structural analysis of the Upper Pleistocene series in these sections, two new angular unconformities are found within the 10 m thick sedimentary sequence of the lacustrine sediments. Based on the dating results, we speculate that these two upper and lower angular unconformities are formed between 33 ka BP and 40 ka BP, and 60 ka BP and 80 ka BP, respectively. The angular unconformities also provide tectonic constraints for the latest and ongoing tectonic activity in the Quaternary. This tectonic movement begins at around 80 ka BP and causes two different unconformities of the lower strata with varying degrees of deformation (tilt) but also leads to the final death of the ancient lake.
Characteristics of Organic Matter and Biomarkers in Core Sediments From the Offshore Area of Leizhou Peninsula, South China Sea
Authors: Gao Yuan , Tan Jingqian , Xia Jia , Wang Yao-Ping , Wang Sibo , Han Yongqiang , He Jiefeng , Song Zhiguang
Published: March 2021

Total organic carbon (TOC), total nitrogen (TN) and multi-biomarker indexes were analyzed for two sediment cores from the eastern coastal area of the Beibu Gulf (core 45, AMS 14C dated) and Qiongzhou Strait (core 29), South China Sea. The results showed that the TOC and TN content of the samples studied were 0.32–0.62% and 0.02–0.07%, respectively. The hydrocarbons in offshore sediments of Leizhou Peninsula were consisted of biogenic hydrocarbons and petrogenic hydrocarbons. The Core 29 sediments contain more terrigenous organic matter than that of sediments in core 45 due to the difference in hydrodynamic conditions. The composition and distribution of various lipid biomarkers indicate the presence of petrogenic hydrocarbons in the sediments of the whole profile of two sediment cores. There are multiple natural sources of hydrocarbons that could potentially contribute to the petroleum background through oil seeps and erosion of carbon-rich rock outcrops or bitumen deposits. Deep sourced hydrocarbon inputs from the submarine hydrocarbon seepage cannot be excluded. Further study is needed to resolve the specific sources for the petrogenic hydrocarbons and may be significant to petroleum exploration in the study area.
Bennettitalean Leaves From the Permian of Equatorial Pangea—The Early Radiation of an Iconic Mesozoic Gymnosperm Group
Authors: Blomenkemper Patrick , Bäumer Robert , Backer Malte , Abu Hamad Abdalla , Wang Jun , Kerp Hans , Bomfleur Benjamin
Published: March 2021

Bennettitaleans are an extinct group of gymnosperms that are among the most iconic plants of Earth’s vegetation during the Mesozoic Era. The sudden appearance and rise to dominance of the Bennettitales during the Triassic remains a mystery. Leaf fossils similar to typical bennettitalean foliage occur in late Paleozoic deposits worldwide, but bennettitalean foliage can be identified with certainty only in case the fossils are sufficiently well-preserved to show epidermal features. So far, the characteristic stomatal architecture of the group has never been systematically documented in these putative Paleozoic remains. Here, we present well-preserved bennettitalean leaves from Permian deposits in two widely separated regions of equatorial Pangea. Two species of cuticle-bearing leaf compressions from the late Permian Umm Irna Formation, Jordan, are here formally described asPterophyllum pottiiBomfleur et Kerp sp. nov. andNilssoniopteris jogianaBlomenkemper et Abu Hamad sp. nov. Moreover, bulk maceration of samples from the Umm Irna Formation yielded six additional types of dispersed bennettitalean cuticles that are here informally described. In addition, the Cisuralian (early Permian) uppermost part of the Upper Shihhotse Formation exposed at the Palougou section in Shanxi Province, China, has yielded the oldest unambiguous bennettitalean fossils known to date; they consist of fragments of entire-margined leaves with well-preserved cuticles that we assign toNilssoniopteris shanxiensisBäumer, Backer et Wang sp. nov. Unlike the characteristic puzzle-patterned cuticles typical of many Jurassic and Cretaceous bennettites, the cuticles of these Permian bennettitalean remains show non-sinuous anticlinal walls, greater variety in stomatal orientation, and rare occurrence of transversely divided subsidiary cells—features that have until now almost exclusively been documented from the hitherto oldest cuticle-bearing Triassic bennettitalean material. Finally, the taxonomic richness, disjunct distribution, and broad variety in macro- and micromorphological features in these Permian bennettitalean remains lead us to suspect that the origin of the group will date back still further in time, and might in fact coincide with very early occurrences of Bennettitales-like foliage from the Pennsylvanian and Cisuralian, such asPterophyllum cottaeanum,P. eratum, orP. grandeuryi.
Antecedents and Relative Importance of Student Motivation for Science and Mathematics Achievement in TIMSS
Authors: Winberg Mikael , Palm Torulf
Published: March 2021

Although motivation has been shown to have substantial influence on learning, the relative significance of Students’ motivational characteristics, compared to other school-related factors, for student learning and performance is still unclear. Furthermore, knowledge about the relative importance of different situational variables for predicting these motivational characteristics is crucial for educational decisions about how to enhance student motivation. This study examined (1) the relative importance of motivational characteristics derived from five different theories on motivation and epistemic beliefs, compared to almost 300 situational factors, for predicting student performance on the TIMSS 2011 achievement tests in science and mathematics, and (2) how student motivational characteristics can be predicted by the background variables in the TIMSS 2011 questionnaires and an additional questionnaire about motivation accompanying TIMSS in Sweden. Up to 52% of the variation in student performance could be predicted by models containing all background variables, and student motivational characteristics were among the most important variables in the model. Models that comprised only student motivational characteristics from several motivation theories predicted up to 27% of student performance on the achievement test, while models using only single motivational characteristics predicted, on average, 7%. Results emphasize teachers’ importance for student motivation. Five teacher features were consistently among the most important variables in predicting Students’ motivational characteristics. These five variables predicted as much of the variation in important student motivational characteristics as the remaining 300 situational variables together.
An Analysis of Glucose Effectiveness in Subjects With or Without Type 2 Diabetes via Hierarchical Modeling
Authors: Hu Shihao , Lu Yuzhi , Tura Andrea , Pacini Giovanni , D’Argenio David Z.
Published: March 2021

Glucose effectiveness, defined as the ability of glucose itself to increase glucose utilization and inhibit hepatic glucose production, is an important mechanism maintaining normoglycemia. We conducted a minimal modeling analysis of glucose effectiveness at zero insulin (GEZI) using intravenous glucose tolerance test data from subjects with type 2 diabetes (T2D, n=154) and non-diabetic (ND) subjects (n=343). A hierarchical statistical analysis was performed, which provided a formal mechanism for pooling the data from all study subjects, to yield a single composite population model that quantifies the role of subject specific characteristics such as weight, height, age, sex, and glucose tolerance. Based on the resulting composite population model, GEZI was reduced from 0.021 min–1 (standard error – 0.00078 min–1) in the ND population to 0.011 min–1 (standard error – 0.00045 min–1) in T2D. The resulting model was also employed to calculate the proportion of the non–insulin-dependent net glucose uptake in each subject receiving an intravenous glucose load. Based on individual parameter estimates, the fraction of total glucose disposal independent of insulin was 72.8% ± 12.0% in the 238 ND subjects over the course of the experiment, indicating the major contribution to the whole-body glucose clearance under non-diabetic conditions. This fraction was significantly reduced to 48.8% ± 16.9% in the 30 T2D subjects, although still accounting for approximately half of the total in the T2D population based on our modeling analysis. Given the potential application of glucose effectiveness as a predictor of glucose intolerance and as a potential therapeutic target for treating diabetes, more investigations of glucose effectiveness in other disease conditions can be conducted using the hierarchical modeling framework reported herein.
Spatiotemporal Changes of the Environmental DNA Concentrations of Amphidromous Fish Plecoglossus altivelis altivelis in the Spawning Grounds in the Takatsu River, Western Japan
Authors: Inui Ryutei , Akamatsu Yoshihisa , Kono Takanori , Saito Minoru , Miyazono Seiji , Nakao Ryohei
Published: March 2021

The Ayu Plecoglossus altivelis altivelis is an amphidromous fish that is not only the most important commercial fishery species in Japanese rivers but also has a high economic value in recreational fishing. However, the degradation of its spawning grounds has caused a decrease in its abundance. In this study, we used environmental DNA (eDNA) to monitor the Ayu in the Takatsu River in Japan to (1) identify the spawning season in three known spawning grounds, (2) clarify changes in the main spawning grounds during the spawning season, and (3) discover unknown spawning grounds. We collected 1 L of the surface river water at three known spawning grounds nine times in 2018 and seven times in 2019 in the lower reaches of the Takatsu River. We also collected samples from seven unknown sites in 2018. The water samples were filtered through glass fiber filters. Total eDNA was extracted from each filtered sample and a Real-time quantitative PCR was performed with the specific primers and probe for Ayu. The results of the eDNA analyses showed that (1) the spawning season was in November in 2018 and in September in 2019. (2) One site was used as a spawning ground in both the early and the late spawning season, depending on the year. At the second site, the frequency of use changed year by year. The third site was the main spawning ground in the middle to late spawning season every year. From these results, we elucidated that some spawning grounds are used regularly every year, while the use of others varies year by year. (3) In five of the seven unknown sites, the nighttime eDNA concentrations were high at least once during the four surveys, suggesting that these sites may have functioned as spawning grounds. In particular, one site could be an important new spawning ground.
Nitrogen Uptake, Not Transfer of Carbon and Nitrogen by CMN, Explains the Effect of AMF on the Competitive Interactions Between Flaveria bidentis and Native Species
Authors: Chen Xue , Li Qiao , Wang Liting , Meng Yanliang , Jiao Shaona , Yin Jilin , Xu Haiyun , Zhang Fengjuan
Published: March 2021

Rhizophagus intraradices, one of the common arbuscular mycorrhizal fungi (AMF) grown in the roots ofFlaveria bidentis, facilitates the invasion of this exotic plant species into China. However, it is still unknown whether nutrient transfer through the common mycorrhizal networks (CMN) between this exotic species and the native species enhances the competitive growth ofF. bidentisover the native species. To elucidate this question and the related mechanism, an isotopic labeling technique was used to test the transfer of carbon (C) and nitrogen (N) by CMN. Native species likeSetaria viridisandEclipta prostratawere selected to compete withF. bidentisin a polyvinyl chloride (PVC) box. Two competitive groups (F. bidentis-S. viridisandF. bidentis-E. prostrata), three treatments (monoculture ofF. bidentis, the mixture ofF. bidentisand the native plant, and the monoculture of the native plant), and two levels of AMF (presence or absence) were assigned. Results showed that the corrected index of relative competition intensity (CRCI) ofF. bidentisin the presence of AMF < 0 suggests that the competition facilitated the growth ofF. bidentiswith eitherS. viridisorE. prostrata. The reason was that the inoculation ofR. intra radicessignificantly increased the C and N contents ofF. bidentisin the mixtures. However, the effects ofR. intra radiceson the two native species were different: negative effect on the growth ofS. viridisand positive effect on the growth ofE. prostrata. The change of N content inS. viridisorE. prostratawas consistent with the variation of the biomass, suggesting that the N uptake explains the effects ofR. intraradiceson the competitive interactions betweenF. bidentisand the two native species. Moreover, the transfer of C and NviaAMF hyphal links did occur betweenF. bidentisand the native species. However, the transfer of C and N by the CMN was not positively related to the competitive growth ofF. bidentis.
Weighted Gene Co-expression Network Analysis Reveals Different Immunity but Shared Renal Pathology Between IgA Nephropathy and Lupus Nephritis
Authors: Jia Ni-Ya , Liu Xing-Zi , Zhang Zhao , Zhang Hong
Published: March 2021

Both IgA nephropathy (IgAN) and lupus nephritis (LN) are immunity-related diseases with a complex, polygenic, and pleiotropic genetic architecture. However, the mechanism by which the genetic variants impart immunity or renal dysfunction remains to be clarified. In this study, using gene expression datasets as a quantitative readout of peripheral blood mononuclear cell (PBMC)- and kidney-based molecular phenotypes, we analyzed the similarities and differences in the patterns of gene expression perturbations associated with the systematic and kidney immunity in IgAN and LN. Original gene expression datasets for PBMC, glomerulus, and tubule from IgAN and systemic lupus erythematosus (SLE) patients as well as corresponding controls were obtained from the Gene Expression Omnibus (GEO) database. The similarities and differences in the expression patterns were detected according to gene differential expression. Weighted gene co-expression network analysis (WGCNA) was used to cluster and screen the co-expressed gene modules. The disease correlations were then identified by cell-specific and functional enrichment analyses. By combining these results with the genotype data, we identified the differentially expressed genes causatively associated with the disease. There was a significant positive correlation with the kidney expression profile, but no significant correlation with PBMC. Three co-expression gene modules were screened by WGCNA and enrichment analysis. Among them, blue module was enriched for glomerulus and podocyte (P < 0.05) and positively correlated with both diseases (P < 0.05), mainly via immune regulatory pathways. Pink module and purple module were enriched for tubular epithelium and correlated with both diseases (P < 0.05) through predominant cell death and extracellular vesicle pathways, respectively. In genome-wide association study (GWAS) enrichment analysis, blue module was identified as the high-risk gene module that distinguishes LN from SLE and contains PSMB8 and PSMB9, the susceptibility genes for IgAN. In conclusion, IgAN and LN showed different systematic immunity but similarly abnormal immunity in kidney. Immunological pathways may be involved in the glomerulopathy and cell death together with the extracellular vesicle pathway, which may be involved in the tubular injury in both diseases. Blue module may cover the causal susceptibility gene for IgAN and LN.
A Fast Multi-Locus Ridge Regression Algorithm for High-Dimensional Genome-Wide Association Studies
Authors: Zhang Jin , Chen Min , Wen Yangjun , Zhang Yin , Lu Yunan , Wang Shengmeng , Chen Juncong
Published: March 2021

The mixed linear model (MLM) has been widely used in genome-wide association study (GWAS) to dissect quantitative traits in human, animal, and plant genetics. Most methodologies consider all single nucleotide polymorphism (SNP) effects as random effects under the MLM framework, which fail to detect the joint minor effect of multiple genetic markers on a trait. Therefore, polygenes with minor effects remain largely unexplored in today’s big data era. In this study, we developed a new algorithm under the MLM framework, which is called the fast multi-locus ridge regression (FastRR) algorithm. The FastRR algorithm first whitens the covariance matrix of the polygenic matrix K and environmental noise, then selects potentially related SNPs among large scale markers, which have a high correlation with the target trait, and finally analyzes the subset variables using a multi-locus deshrinking ridge regression for true quantitative trait nucleotide (QTN) detection. Results from the analyses of both simulated and real data show that the FastRR algorithm is more powerful for both large and small QTN detection, more accurate in QTN effect estimation, and has more stable results under various polygenic backgrounds. Moreover, compared with existing methods, the FastRR algorithm has the advantage of high computing speed. In conclusion, the FastRR algorithm provides an alternative algorithm for multi-locus GWAS in high dimensional genomic datasets.
Adipocyte Oncostatin Receptor Regulates Adipose Tissue Homeostasis and Inflammation
Authors: Sanchez-Infantes David , Stephens Jacqueline M.
Published: March 2021

Adipocytes are the largest cell type in terms of volume, but not number, in adipose tissue. Adipocytes are prominent contributors to systemic metabolic health. Obesity, defined by excess adipose tissue (AT), is recognized as a low-grade chronic inflammatory state. Cytokines are inflammatory mediators that are produced in adipose tissue (AT) and function in both AT homeostatic as well as pathological conditions. AT inflammation is associated with systemic metabolic dysfunction and obesity-associated infiltration and proliferation of immune cells occurs in a variety of fat depots in mice and humans. AT immune cells secrete a variety of chemokines and cytokines that act in a paracrine manner on adjacent adipocytes. TNFα, IL-6, and MCP-1, are well studied mediators of AT inflammation. Oncostatin M (OSM) is another proinflammatory cytokine that is elevated in AT in human obesity, and its specific receptor (OSMRβ) is also induced in conditions of obesity and insulin resistance. OSM production and paracrine signaling in AT regulates adipogenesis and the functions of AT. This review summarizes the roles of the oncostatin M receptor (OSMRβ) as a modulator of adipocyte development and function its contributions to immunological adaptations in AT in metabolic disease states.
cGAS-STING Pathway Does Not Promote Autoimmunity in Murine Models of SLE
Authors: Motwani Mona , McGowan Jason , Antonovitch Jennifer , Gao Kevin MingJie , Jiang Zhaozhao , Sharma Shruti , Baltus Gretchen A. , Nickerson Kevin M. , Marshak-Rothstein Ann , Fitzgerald Katherine A.
Published: March 2021

Detection of DNA is an important determinant of host-defense but also a driver of autoinflammatory and autoimmune diseases. Failure to degrade self-DNA in DNAseII or III(TREX1)-deficient mice results in activation of the cGAS-STING pathway. Deficiency of cGAS or STING in these models ameliorates disease manifestations. However, the contribution of the cGAS-STING pathway, relative to endosomal TLRs, in systemic lupus erythematosus (SLE) is controversial. In fact, STING deficiency failed to rescue, and actually exacerbated, disease manifestations in Fas-deficient SLE-prone mice. We have now extended these observations to a chronic model of SLE induced by the i.p. injection of TMPD (pristane). We found that both cGAS- and STING-deficiency not only failed to rescue mice from TMPD-induced SLE, but resulted in increased autoantibody production and higher proteinuria levels compared to cGAS STING sufficient mice. Further, we generated cGASKOFaslpr mice on a pure MRL/Faslpr background using Crispr/Cas9 and found slightly exacerbated, and not attenuated, disease. We hypothesized that the cGAS-STING pathway constrains TLR activation, and thereby limits autoimmune manifestations in these two models. Consistent with this premise, mice lacking cGAS and Unc93B1 or STING and Unc93B1 developed minimal systemic autoimmunity as compared to cGAS or STING single knock out animals. Nevertheless, TMPD-driven lupus in B6 mice was abrogated upon AAV-delivery of DNAse I, implicating a DNA trigger. Overall, this study demonstrated that the cGAS-STING pathway does not promote systemic autoimmunity in murine models of SLE. These data have important implications for cGAS-STING-directed therapies being developed for the treatment of systemic autoimmunity.
Mechanisms of Peritoneal Fibrosis: Focus on Immune Cells–Peritoneal Stroma Interactions
Authors: Terri Michela , Trionfetti Flavia , Montaldo Claudia , Cordani Marco , Tripodi Marco , Lopez-Cabrera Manuel , Strippoli Raffaele
Published: March 2021

Peritoneal fibrosis is characterized by abnormal production of extracellular matrix proteins leading to progressive thickening of the submesothelial compact zone of the peritoneal membrane. This process may be caused by a number of insults including pathological conditions linked to clinical practice, such as peritoneal dialysis, abdominal surgery, hemoperitoneum, and infectious peritonitis. All these events may cause acute/chronic inflammation and injury to the peritoneal membrane, which undergoes progressive fibrosis, angiogenesis, and vasculopathy. Among the cellular processes implicated in these peritoneal alterations is the generation of myofibroblasts from mesothelial cells and other cellular sources that are central in the induction of fibrosis and in the subsequent functional deterioration of the peritoneal membrane. Myofibroblast generation and activity is actually integrated in a complex network of extracellular signals generated by the various cellular types, including leukocytes, stably residing or recirculating along the peritoneal membrane. Here, the main extracellular factors and the cellular players are described with emphasis on the cross-talk between immune system and cells of the peritoneal stroma. The understanding of cellular and molecular mechanisms underlying fibrosis of the peritoneal membrane has both a basic and a translational relevance, since it may be useful for setup of therapies aimed at counteracting the deterioration as well as restoring the homeostasis of the peritoneal membrane.
Testing Cancer Immunotherapy in a Human Immune System Mouse Model: Correlating Treatment Responses to Human Chimerism, Therapeutic Variables and Immune Cell Phenotypes
Authors: Marín-Jiménez Juan A. , Capasso Anna , Lewis Matthew S. , Bagby Stacey M. , Hartman Sarah J. , Shulman Jeremy , Navarro Natalie M. , Yu Hui , Rivard Chris J. , Wang Xiaoguang , Barkow Jessica C. , Geng Degui , Kar Adwitiya , Yingst Ashley , Tufa Dejene M. , Dolan James T. , Blatchford Patrick J. , Freed Brian M. , Torres Raul M. , Davila Eduardo , Slansky Jill E. , Pelanda Roberta , Eckhardt S. Gail , Messersmith Wells A. , Diamond Jennifer R. , Lieu Christopher H. , Verneris Michael R. , Wang Jing H. , Kiseljak-Vassiliades Katja , Pitts Todd M. , Lang Julie
Published: March 2021

Over the past decade, immunotherapies have revolutionized the treatment of cancer. Although the success of immunotherapy is remarkable, it is still limited to a subset of patients. More than 1500 clinical trials are currently ongoing with a goal of improving the efficacy of immunotherapy through co-administration of other agents. Preclinical, small-animal models are strongly desired to increase the pace of scientific discovery, while reducing the cost of combination drug testing in humans. Human immune system (HIS) mice are highly immune-deficient mouse recipients rtpeconstituted with human hematopoietic stem cells. These HIS-mice are capable of growing human tumor cell lines and patient-derived tumor xenografts. This model allows rapid testing of multiple, immune-related therapeutics for tumors originating from unique clinical samples. Using a cord blood-derived HIS-BALB/c-Rag2nullIl2rγnullSIRPαNOD (BRGS) mouse model, we summarize our experiments testing immune checkpoint blockade combinations in these mice bearing a variety of human tumors, including breast, colorectal, pancreatic, lung, adrenocortical, melanoma and hematological malignancies. We present in-depth characterization of the kinetics and subsets of the HIS in lymph and non-lymph organs and relate these to protocol development and immune-related treatment responses. Furthermore, we compare the phenotype of the HIS in lymph tissues and tumors. We show that the immunotype and amount of tumor infiltrating leukocytes are widely-variable and that this phenotype is tumor-dependent in the HIS-BRGS model. We further present flow cytometric analyses of immune cell subsets, activation state, cytokine production and inhibitory receptor expression in peripheral lymph organs and tumors. We show that responding tumors bear human infiltrating T cells with a more inflammatory signature compared to non-responding tumors, similar to reports of “responding” patients in human immunotherapy clinical trials. Collectively these data support the use of HIS mice as a preclinical model to test combination immunotherapies for human cancers, if careful attention is taken to both protocol details and data analysis.
Innate Immune Memory in Hematopoietic Stem/Progenitor Cells: Myeloid-Biased Differentiation and the Role of Interferon
Authors: Chen Lili , Ozato Keiko
Published: March 2021

Innate immune memory was first described for monocytes and other myeloid cells. This memory is designated Immune Training, in which the host animals that had experienced pathogen infection earlier acquire improved resistance to a second infection. Innate immune memory is mediated by an epigenetic mechanism traced to transcriptional memory that is conserved throughout evolution and has been selected for the ability to mount an adaptive response to shifting environments. Accumulating evidence shows that not only peripheral myeloid cells but hematopoietic stem/progenitor cells (HSCs/HSPCs) can acquire epigenetic memory upon pathogen exposure. Systemic pathogen infection causes HSCs to exit from quiescence and facilitate myeloid-biased differentiation that leads to efficient host defense. This sequence of events is common in HSC memory generation, which is triggered by different stimuli. Recent studies show that not only pathogens but other stimuli such as metabolic stress can generate memory in HSCs. This review summarizes recent publications relevant to HSC memory. We discuss the current understanding of initial sensors, soluble mediators/cytokines involved in memory formation, including Type I and Type II interferons along with future implications.
Spatial Organization of Chromatin: Transcriptional Control of Adaptive Immune Cell Development
Authors: Pongubala Jagan M. R. , Murre Cornelis
Published: March 2021

Higher-order spatial organization of the genome into chromatin compartments (permissive and repressive), self-associating domains (TADs), and regulatory loops provides structural integrity and offers diverse gene regulatory controls. In particular, chromatin regulatory loops, which bring enhancer and associated transcription factors in close spatial proximity to target gene promoters, play essential roles in regulating gene expression. The establishment and maintenance of such chromatin loops are predominantly mediated involving CTCF and the cohesin machinery. In recent years, significant progress has been made in revealing how loops are assembled and how they modulate patterns of gene expression. Here we will discuss the mechanistic principles that underpin the establishment of three-dimensional (3D) chromatin structure and how changes in chromatin structure relate to alterations in gene programs that establish immune cell fate.
Age-Related Dynamics of Lung-Resident Memory CD8+ T Cells in the Age of COVID-19
Authors: Goplen Nick P. , Cheon In Su , Sun Jie
Published: March 2021

Following respiratory viral infections or local immunizations, lung resident-memory T cells (TRM) of the CD8 lineage provide protection against the same pathogen or related pathogens with cross-reactive T cell epitopes. Yet, it is now clear that, if homeostatic controls are lost following viral pneumonia, CD8 TRM cells can mediate pulmonary pathology. We recently showed that the aging process can result in loss of homeostatic controls on CD8 TRM cells in the respiratory tract. This may be germane to treatment modalities in both influenza and coronavirus disease 2019 (COVID-19) patients, particularly, the portion that present with symptoms linked to long-lasting lung dysfunction. Here, we review the developmental cues and functionalities of CD8 TRM cells in viral pneumonia models with a particular focus on their capacity to mediate heterogeneous responses of immunity and pathology depending on immune status.
A Novel Strategy to Study the Invasive Capability of Adherent-Invasive Escherichia coli by Using Human Primary Organoid-Derived Epithelial Monolayers
Authors: Mayorgas Aida , Dotti Isabella , Martínez-Picola Marta , Esteller Miriam , Bonet-Rossinyol Queralt , Ricart Elena , Salas Azucena , Martínez-Medina Margarita
Published: March 2021

Over the last decades, Adherent-InvasiveEscherichia coli(AIEC) has been linked to the pathogenesis of Crohn’s Disease. AIEC’s characteristics, as well as its interaction with the gut immune system and its role in intestinal epithelial barrier dysfunction, have been extensively studied. Nevertheless, the currently available techniques to investigate the cross-talk between this pathogen and intestinal epithelial cells (IECs) are based on the infection of immortalized cell lines. Despite their many advantages, cell lines cannot reproduce the conditions in tissues, nor do they reflect interindividual variability or gut location-specific traits. In that sense, the use of human primary cultures, either healthy or diseased, offers a system that can overcome all of these limitations. Here, we developed a new infection model by using freshly isolated human IECs. For the first time, we generated and infected monolayer cultures derived from human colonic organoids to study the mechanisms and effects of AIEC adherence and invasion on primary human epithelial cells. To establish the optimal conditions for AIEC invasion studies in human primary organoid-derived epithelial monolayers, we designed an infection-kinetics study to assess the infection dynamics at different time points, as well as with two multiplicities of infection (MOI). Overall, this method provides a model for the study of host response to AIEC infections, as well as for the understanding of the molecular mechanisms involved in adhesion, invasion and intracellular replication. Therefore, it represents a promising tool for elucidating the cross-talk between AIEC and the intestinal epithelium in healthy and diseased tissues.
The Transferrin Receptor-Directed CAR for the Therapy of Hematologic Malignancies
Authors: Guo Zilong , Zhang Yirui , Fu Mingpeng , Zhao Liang , Wang Zhen , Xu Zhuoshuo , Zhu Huifen , Lan Xiaoli , Shen Guanxin , He Yong , Lei Ping
Published: March 2021

As many patients ultimately relapse after chimeric antigen receptor (CAR) T-cell therapy, identification of alternative targets is currently being evaluated. Substantial research efforts are underway to develop new targets. The transferrin receptor (TfR) is prevalently expressed on rapidly proliferating tumor cells and holds the potential to be the alternative target. In order to investigate the efficacy and challenges of TfR-targeting on the CAR-based therapy strategy, we generated a TfR-specific CAR and established the TfR-CAR–modified T cells. To take the advantage of TfR being widely shared by multiple tumors, TfR-CAR T cells were assessed against several TfR+ hematological malignant cell lines. Data showed that TfR-CAR T cells were powerfully potent in killing all these types of cells in vitro and in killing T-ALL cells in vivo. These findings suggest that TfR could be a universal target to broaden and improve the therapeutic efficacy of CAR T cells and warrant further efforts to use these cells as an alternative CAR T cell product for the therapy of hematological malignancies.
MicroLet-7b Regulates Neutrophil Function and Dampens Neutrophilic Inflammation by Suppressing the Canonical TLR4/NF-κB Pathway
Authors: Chen Binzhen , Han Jia , Chen Shaoheng , Xie Rufeng , Yang Jie , Zhou Tongming , Zhang Qi , Xia Rong
Published: March 2021

Sepsis is a heterogeneous syndrome caused by a dysregulated host response during the process of infection. Neutrophils are involved in the development of sepsis due to their essential role in host defense. COVID-19 is a viral sepsis. Disfunction of neutrophils in sepsis has been described in previous studies, however, little is known about the role of microRNA-let-7b (miR-let-7b), toll-like receptor 4 (TLR4), and nuclear factor kappa B (NF-κB) activity in neutrophils and how they participate in the development of sepsis. In this study, we investigated the regulatory pathway of miR-let-7b/TLR4/NF-κB in neutrophils. We also explored the downstream cytokines released by neutrophils following miR-let-7b treatment and its therapeutic effects in cecal ligation and puncture (CLP)-induced septic mice. Six-to-eight-week-old male C57BL/6 mice underwent CLP following treatment with miR-let-7b agomir. Survival (n=10), changes in liver and lungs histopathology (n=4), circulating neutrophil counts (n=4), the liver-body weight ratio (n=4–7), and the lung wet-to-dry ratio (n=5–6) were recorded. We found that overexpression of miR-let-7b could significantly down-regulate the expression of human-derived neutrophilic TLR4 at a post-transcriptional level, a decreased level of proinflammatory factors including interleukin-6 (IL-6), IL-8, tumor necrosis factor α (TNF-α), and an upregulation of anti-inflammatory factor IL-10 in vitro. After miR-let-7b agomir treatment in vivo, neutrophil recruitment was inhibited and thus the injuries of liver and lungs in CLP-induced septic mice were alleviated (p=0.01 and p=0.04, respectively), less weight loss was reduced, and survival in septic mice was also significantly improved (p=0.013). Our study suggested that miR-let-7b could be a potential target of sepsis.