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Global warming intensifies extreme precipitation events, impacting society significantly, and drought is one of the most important stress factors for the ecological security of the Yellow River Basin (YRB). Understanding the time-domain abrupt changes and evolutionary mechanisms of drought events is crucial for comprehending the water resource dynamics in the basin. Taking the YRB as an example, we analyzed spatiotemporal variations in precipitation, identified abrupt changes, and calculated the 12-month standardized precipitation index (SPI12) to investigate drought evolution in the YRB. We identified four key drought attributes (number, duration, peak, and severity) utilizing the run theory. The spatial distribution of drought factors and typical drought events were identified, as well as the response of SPI12 to teleconnection and driving forces. The results indicate: Precipitation changed markedly around 2000, decreasing by 17.1 mm/10 yr before 2000, and increasing by 43.8 mm/10 yr thereafter. The maximum precipitation was also 1.95 times the minimum. Summer precipitation accounted for 53 % of the annual average. Downstream precipitation was 83.9 % and 25.3 % higher than that upstream and midstream, respectively. Spatial variation in precipitation was most notable upstream, with decreases concentrated in the north, impacting 24.9 %, and increases mainly in the south, covering 24.3 %. Short-term spatial changes were minimal, indicating gradual external influences. Abrupt changes in precipitation occurred in spring (1992), summer (1996), and winter (1970). Short-term cyclical fluctuations of 6–15 years were observed across distinct watersheds, with seasonal variations of 61 years for summer, 14 years for autumn, and 23 years for winter. The driest year was 2000, with an SPI12 of –1,35 in July. The center of drought activity is concentrated in the midstream, where it underwent two significant shifts: from the 1960 s to the 1980 s, the drought center moved northeastward, then shifted westward until the 2000 s, with longest displacement of 414.41 km to the east-northeast. This region had the highest drought frequency (15 events), total duration (225 months), and intensity (237) over the past 63 years. The SPI12 was influenced by the El Niño-Southern Oscillation (ENSO), Pacific Decadal Oscillation (PDO), and Arctic Oscillation (AO) before 2000, showing significant positive correlations with ENSO and AO, and a negative correlation with PDO. From 2000 to 2020, climate (q-value mean: 0.18) and DEM (q-value mean: 0.22) were the primary factors influencing drought variations, with climate interactions weakening and elevation interactions strengthening. This research provides crucial insights for effective water resource management and drought mitigation strategies in the Yellow River Basin.

Lupus nephritis (LN), a complex complication of systemic lupus erythematosus, requires in-depth cellular and molecular analysis for advanced treatment strategies, including mRNA vaccine development. In this study, we analyzed single-cell RNA sequencing data from 24 LN patients and 10 healthy controls, supplemented by bulk RNA-seq data from additional LN patients and controls. By applying non-negative matrix factorization (NMF), we identified four distinct leukocyte meta-programs in LN, highlighting diverse immune functions and potential mRNA vaccine targets. Utilizing 12 machine learning algorithms, we developed 417 predictive models incorporating gene sets linked to key biological pathways, such as MTOR signaling, autophagy, Toll-like receptor, and adaptive immunity pathways. These models were instrumental in identifying potential targets for mRNA vaccine development. Our functional network analysis further revealed intricate gene interactions, providing novel insights into the molecular basis of LN. Additionally, we validated the mRNA expression levels of potential vaccine targets across multiple cohorts and correlated them with clinical parameters such as the glomerular filtration rate (GFR) and pathological stage. This study represents a significant advance in LN research by merging single-cell genomics with the precision of NMF and machine learning, broadening our understanding of LN at the cellular and molecular levels. More importantly, our findings shed light on the development of targeted mRNA vaccines, offering new possibilities for diagnostics and therapeutics for this complex autoimmune disease.

Lupus nephritis (LN) is a challenging condition with limited diagnostic and treatment options. In this study, we applied 12 distinct machine learning algorithms along with Non-negative Matrix Factorization (NMF) to analyze single-cell datasets from kidney biopsies, aiming to provide a comprehensive profile of LN. Through this analysis, we identified various immune cell populations and their roles in LN progression and constructed 102 machine learning-based immune-related gene (IRG) predictive models. The most effective models demonstrated high predictive accuracy, evidenced by Area Under the Curve (AUC) values, and were further validated in external cohorts. These models highlight six hub IRGs (CD14, CYBB, IFNGR1, IL1B, MSR1, and PLAUR) as key diagnostic markers for LN, showing remarkable diagnostic performance in both renal and peripheral blood cohorts, thus offering a novel approach for noninvasive LN diagnosis. Further clinical correlation analysis revealed that expressions of IFNGR1, PLAUR, and CYBB were negatively correlated with the glomerular filtration rate (GFR), while CYBB also positively correlated with proteinuria and serum creatinine levels, highlighting their roles in LN pathophysiology. Additionally, protein-protein interaction (PPI) analysis revealed significant networks involving hub IRGs, emphasizing the importance of the interleukin family and chemokines in LN pathogenesis. This study highlights the potential of integrating advanced genomic tools and machine learning algorithms to improve diagnosis and personalize management of complex autoimmune diseases like LN.

Land use and cover change (LUCC) is directly linked to the sustainability of ecosystems and the long-term well-being of human society. The Helong Region in the Loess Plateau has become one of the areas most severely affected by soil and water erosion in China due to its unique geographical location and ecological environment. The long-term construction of terraces and orchards is one of the important measures for this region to combat soil erosion. Despite the important role that terraces and orchards play in this region, current studies on their extraction and understanding remain limited. For this reason, this study designed a land use classification system, including terraces and orchards, to reveal the patterns of LUCC and the effectiveness of ecological restoration projects in the area. Based on this system, this study utilized the Random Forest classification algorithm to create an annual land use and cover (LUC) dataset for the Helong Region that covers eight periods from 1986 to 2020, with a spatial resolution of 30 m. The validation results showed that the maps achieved an average overall accuracy of 87.54% and an average Kappa coefficient of 76.94%. This demonstrates the feasibility of the proposed design and land coverage mapping method in the study area. This study found that, from 1986 to 2020, there was a continuous increase in forest and grassland areas, a significant reduction in cropland and bare land areas, and a notable rise in impervious surface areas. We emphasized that the continuous growth of terraces and orchards was an important LUCC trend in the region. This growth was primarily attributed to the conversion of grasslands, croplands, and forests. This transformation not only reduced soil erosion but also enhanced economic efficiency. The products and insights provided in this study help us better understand the complexities of ecological recovery and land management.

IntroductionLupus nephritis (LN), a severe complication of systemic lupus erythematosus (SLE), presents significant challenges in patient management and treatment outcomes. The identification of novel LN-related biomarkers and therapeutic targets is critical to enhancing treatment outcomes and prognosis for patients.MethodsIn this study, we analyzed single-cell expression data from LN (n=21) and healthy controls (n=3). A total of 143 differentially expressed genes were identified between the LN and control groups. Then, proteomics analysis of LN patients (n=9) and control (SLE patients without LN, n=11) revealed 55 differentially expressed genes among patients with LN and control group. We further utilizes protein-protein interaction network and functional enrichment analyses to elucidate the pivotal role of COL6A3 in key signaling pathways. Its diagnostic value is evaluate through its correlation with disease progression and renal function metrics, as well as Receiver Operating Characteristic Curve (ROC) analysis. Additionally, immunohistochemistry and qPCR experiments were performed to validate the expression of COL6A3 in LN.ResultsBy comparison of single-cell and proteomics data, we discovered that COL6A3 is significantly upregulated, highlighting it as a critical biomarker of LN. Our findings emphasize the substantial involvement of COL6A3 in the pathogenesis of LN, particularly noting its expression in mesangial cells. Through comprehensive protein-protein interaction network and functional enrichment analyses, we uncovered the pivotal role of COL6A3 in key signaling pathways including integrin-mediated signaling pathways, collagen-activated signaling pathways, and ECM-receptor interaction, suggesting potential therapeutic targets. The diagnostic utility is confirmed by its correlation with disease progression and renal function metrics of the glomerular filtration rate. ROC analysis further validates the diagnostic value of COL6A3, with the area under the ROC values of 0.879 in the in-house cohort, and 0.802 and 0.915 in tubular and glomerular external cohort samples, respectively. Furthermore, immunohistochemistry and qPCR experiments were consistent with those obtained from the single-cell RNA sequencing and proteomics studies. DiscussionThese results proved that COL6A3 is a promising biomarker and therapeutic target, advancing personalized medicine strategies for LN.

ObjectivePrevious research has partially revealed distinct gut microbiota in ankylosing spondylitis (AS). In this study, we performed non-targeted fecal metabolomics in AS in order to discover the microbiome–metabolome interface in AS. Based on prospective cohort studies, we further explored the impact of the tumor necrosis factor inhibitor (TNFi) on the gut microbiota and metabolites in AS.MethodsTo further understand the gut microbiota and metabolites in AS, along with the influence of TNFi, we initiated a prospective cohort study. Fecal samples were collected from 29 patients with AS before and after TNFi therapy and 31 healthy controls. Metagenomic and metabolomic experiments were performed on the fecal samples; moreover, validation experiments were conducted based on the association between the microbiota and metabolites.ResultsA total of 7,703 species were annotated using the metagenomic sequencing system and by profiling the microbial community taxonomic composition, while 50,046 metabolites were identified using metabolite profiling. Differential microbials and metabolites were discovered between patients with AS and healthy controls. Moreover, TNFi was confirmed to partially restore the gut microbiota and the metabolites. Multi-omics analysis of the microbiota and metabolites was performed to determine the associations between the differential microbes and metabolites, identifying compounds such as oxypurinol and biotin, which were correlated with the inhibition of the pathogenic bacteria Ruminococcus gnavus and the promotion of the probiotic bacteria Bacteroides uniformis. Through experimental studies, the relationship between microbes and metabolites was further confirmed, and the impact of these two types of microbes on the enterocytes and the inflammatory cytokine interleukin-18 (IL-18) was explored.ConclusionIn summary, multi-omics exploration elucidated the impact of TNFi on the gut microbiota and metabolites and proposed a novel therapeutic perspective: supplementation of compounds to inhibit potential pathogenic bacteria and to promote potential probiotics, therefore controlling inflammation in AS.

Abstract Background Prenatal invasive genetic testing is commonly recommended to pregnancies of early-onset FGR or FGR combined with a structural defect. Our study aimed to explore the genetic findings for FGR without structural malformations according to cytogenetic karyotyping and single nucleotide polymorphism array (SNP array) technology over a 10-year period. Methods A total of 488 pregnancies diagnosed with FGR without structural malformation were retrospectively reviewed. Cytogenetic karyotyping was performed on all the subjects, and SNP array was available from 272 of them. Based on the gestational age at onset, the cohort was classified into four groups: ≤ 24, 25–28, 29–32, and > 32 weeks of gestation. According to the ultrasound findings, they were grouped into isolated FGR, FGR with soft markers, and FGR with non-structural anomalies. In pregnancies of young maternal age, based on the results of maternal serum screening (MSS), they were categorized into high-risk and low-risk MSS groups. Results Nineteen (3.9%) cases of chromosomal abnormalities were detected by cytogenetic karyotyping, including 11 cases of numerical abnormalities, 5 cases of structural abnormalities, and 3 cases of mosaicism. Trisomy 21 was the most frequent abnormality. Abnormal karyotypes were more frequently observed in cases diagnosed at ≤ 24 weeks (7.2%) than those in any other group. Among pregnancies with normal karyotype, an incremental yield of 4.2% were revealed by SNP array technology regarding clinically relevant aberrations. The additional detection rates by SNP array in cases diagnosed at ≤ 24 weeks (6.5%), cases with soft markers (9.5%), and cases with high-risk MSS (12.0%) were higher than those in other groups within each classification. All the cases with abnormal karyotypes and 7 out of 11 pregnancies with clinically relevant anomalies revealed by SNP array alone resulted in pregnancy terminations. Conclusion Chromosome abnormality is an important etiology for FGR with no associated structural malformations, and plays a crucial role in pregnancies decision-making. SNP array improves the detection of genetic anomalies especially in FGR diagnosed at ≤ 24 weeks, FGR combined with soft makers, and FGR combined with high-risk MSS.

In response to inflammatory stimuli in conditions such as autoimmune disorders, infections and cancers, immune cells organize in nonlymphoid tissues, which resemble secondary lymphoid organs. Such immune cell clusters are called tertiary lymphoid structures (TLS). Here, we describe the potential role of TLS in the pathogenesis of autoimmune disease, focusing on lupus nephritis, a condition that incurs major morbidity and mortality. In the kidneys of patients and animals with lupus nephritis, the presence of immune cell aggregates with similar cell composition, structure, and gene signature as lymph nodes and of lymphoid tissue-inducer and -organizer cells, along with evidence of communication between stromal and immune cells are indicative of the formation of TLS. TLS formation in kidneys affected by lupus may be instigated by local increases in lymphorganogenic chemokines such as CXCL13, and in molecules associated with leukocyte migration and vascularization. Importantly, the presence of TLS in kidneys is associated with severe tubulointerstitial inflammation, higher disease activity and chronicity indices, and poor response to treatment in patients with lupus nephritis. TLS may contribute to the pathogenesis of lupus nephritis by increasing local IFN-I production, facilitating the recruitment and supporting survival of autoreactive B cells, maintaining local production of systemic autoantibodies such as anti-dsDNA and anti-Sm/RNP autoantibodies, and initiating epitope spreading to local autoantigens. Resolution of TLS, along with improvement in lupus, by treating animals with soluble BAFF receptor, docosahexaenoic acid, complement inhibitor C4BP(β-), S1P1 receptor modulator Cenerimod, dexamethasone, and anti-CXCL13 further emphasizes a role of TLS in the pathogenesis of lupus. However, the mechanisms underlying TLS formation and their roles in the pathogenesis of lupus nephritis are not fully comprehended. Furthermore, the lack of non-invasive methods to visualize/quantify TLS in kidneys is also a major hurdle; however, recent success in visualizing TLS in lupus-prone mice by photon emission computed tomography provides hope for early detection and manipulation of TLS.

Bastian et al. (2012) argued that the meat paradox—caring for animals yet eating them—creates a tension between people’s moral standards (caring for animals) and their behavior (eating them) that can be resolved via mechanisms of motivated moral disengagement. One disengagement mechanism that is thought to play a central role is the denial of food-animal minds and therefore their status as moral patients. This idea has garnered substantial interest and has framed much of the psychological approach to meat consumption. We subjected Studies 1 and 2 of Bastian et al. (2012) to high-powered direct replications and found support for the target article’s hypotheses, concluding a successful replication. Perceptions of animals’ minds were negatively related to their perceived edibility (original: r = –.42 [–.67, –.08]; replication: r = –.45 [–.69, –.12]), positively related to moral concern for them (original: r = .77 [.58, .88]); replication: r = .83 [.68, .91]) and positively related to negative affect related to eating them (original: r = .80 [.63, .90]; replication: r = .80 [.62, .90]). Learning that an animal will be used for food led people to deny its mental capabilities (original: d = 0.40 [0.15, 0.65]; replication: d = 0.30, 95% CI [0.24, 0.37]), with the affect slightly weaker than the original. Our findings support the idea that the meat paradox is resolved through people’s motivated denial of food animals’ minds. Materials, data, and code are available on the OSF: https://osf.io/h2pqu/. This Registered Report has been officially endorsed by Peer Community in Registered Reports: https://doi.org/10.24072/pci.rr.100545.

In this paper, a new self-adaptive algorithm with the inertial technique is proposed for solving the split equality problem in p-uniformly convex and uniformly smooth Banach spaces. Under some mild control conditions, a strong convergence theorem for the proposed algorithm is established. Furthermore, the results are applied to split equality fixed point problem and split equality variational inclusion problem. Finally, numerical examples are provided to illustrate the convergence behaviour of the algorithm. The main results in this paper improve and generalize some existing results in the literature.

In this paper, the split feasibility problem is studied in real Banach spaces. Through the W-mapping, a new iterative algorithm with the inertial technique for solving the split feasibility problem is proposed, which the step size is self-adaptive and no prior estimation of operator norm is required. We prove that the proposed algorithm converges weakly to a solution of the split feasibility problem under some mild conditions. Finally, the effectiveness of the proposed algorithm is indicated by numerical experiments. Our results are innovative and can enrich recently announced related results in the literature.

Abstract To explore the aging assessment method of the oil–paper insulation in power transformers, the polarization and depolarization current (PDC) characteristics of oil–paper composite insulation samples are investigated under high applied voltage. Based on the asymmetry of polarization absorption current and depolarization current and the polarity effect of insulation pressboard, the repeated polarization current test method is proposed. A novel aging characteristic parameter, which is the ratio of the normalized charge for the first polarization and the normalized charge for the second polarization, is extracted. The difference between the decay rates of the first polarization current and the second polarization current increases at first and then decreases with the polarization time, and decreases with increasing aging degree of the pressboard. The more serious the insulation aging is, the smaller the variation range of aging characteristic parameter with polarization time is, and the closer the value is to 1. With decrease in the DP, the maximum of aging characteristic parameter changes in a decreasing trend. The aging condition of the oil–paper composite insulation can be assessed by the repeated polarization current method and the relationship between the aging characteristic parameter and the polarization time.

Osteoarthritis (OA) causes joint pain, stiffness, and dysfunction in middle-aged and older adults; however, its pathogenesis remains unclear. Circular RNAs (circRNAs) are differentially expressed in patients with OA and participate in a multigene, multitarget regulatory network. CircRNAs are involved in the development of OA through inflammatory responses, including proliferation, apoptosis, autophagy, differentiation, oxidative stress, and mechanical stress. Most circRNAs are used as intracellular miRNA sponges in chondrocytes, endplate chondrocytes, mesenchymal stem cells, synoviocytes, and macrophages to promote the progression of OA. However, a small portion of circRNAs participates in the pathogenesis of OA by intracellular mechanisms, such as protein binding, methylation, or intercellular exosome pathways. In this sense, circRNAs might serve as potential novel biomarkers and therapeutic targets for OA.

Abstract Background Pregnancy loss is one of the most common complications during pregnancy. Clinical consultation based on etiology analysis are critical for reducing anxiety and distress. This study aimed to perform a comprehensive analysis for products of conception (POC) in miscarriage based on genetic etiology and clinical information. Methods A retrospective study was conducted according to cytogenetic findings of 1252 POC from spontaneous pregnancy loss over 11 years. The frequencies and profiles of chromosomal abnormalities were discussed according to the classification of women with different maternal ages, previous miscarriage history, normal live birth history, and different modes of conception. Results A total of 667 (53.2%) chromosomal abnormalities were observed, including 592 (47.3%) cases of numerical abnormalities, 38 (3.0%) cases of structural abnormalities, and 37 (3.0%) cases of mosaic aberrations. In women above 40 years of age, the rates of chromosomal abnormalities and viable autosomal trisomy were significantly higher than those in women with ≤ 29, 30–34, and 35–39 years of age (p 0.05); viable autosomal trisomy was less common in women with ≥ 3 previous miscarriages than women with 0.05), respectively; monosomy X was more frequently detected in women with natural conception than assisted conception. Conclusion The frequencies and profiles of chromosomal abnormalities in early miscarriages are strongly associated with clinical information including maternal age, previous miscarriage, live birth history, and mode of conception. Cytogenetic analysis of POC should be recommended to women with a first miscarriage and women with normal live birth history.

Antarctic krill oil (KO) prepared using supercritical carbon dioxide extraction and characterized using gas chromatography-mass spectrometry was used to investigate its preventive effect on ethanol-induced gastric tissue damage in a rat model in vivo. KO characterization showed that 74.96% of the unsaturated fatty acids consist of oleic acid, eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA). Rats pre-treated with KO (100, 200, and 500 mg/kg) showed mitigated oxidative stress through enhanced antioxidant enzyme superoxide dismutase (SOD) and reducing enzymes malondialdehyde (MDA) and myeloperoxidase (MPO) in gastric mucosal injury induced by ethanol. Additionally, the secretion of pro-inflammatory cytokines (TNF-α, IL-6, and IL-1β), the expression of the IκBα/NF-κB signaling pathway, and nitric oxide (NO) production was suppressed. The results also demonstrated a significant decrease in histological injury and hemorrhage scores in a dose-dependent manner in the KO range. Therefore, KO has potential as a food supplement to alleviate ethanol-induced acute gastric mucosal injury.

Dietary compounds significantly affected starch enzymatic digestion. However, effects of dietary compounds on starch digestion and their underlying mechanisms have been not systematically discussed yet. This review summarized the effects of dietary compounds including cell walls, proteins, lipids, non-starchy polysaccharides, and polyphenols on starch enzymatic digestion. Cell walls, proteins, and non-starchy polysaccharides restricted starch disruption during hydrothermal treatment and the retained ordered structures limited enzymatic binding. Moreover, they encapsulated starch granules and formed physical barriers for enzyme accessibility. Proteins, non-starchy polysaccharides along with lipids and polyphenols interacted with starch and formed ordered assemblies. Furthermore, non-starchy polysaccharides and polyphenols showed robust abilities to reduce activities of α-amylase and α-glucosidase. Accordingly, it can be concluded that dietary compounds lowered starch digestion mainly by three modes: (i) prevented ordered structures from disruption and formed ordered assemblies chaperoned with these dietary compounds; (ii) formed physical barriers and prevented enzymes from accessing/binding to starch; (iii) reduced enzymes activities. Dietary compounds showed great potentials in lowering starch enzymatic digestion, thereby modulating postprandial glucose response to food and preventing or treating type II diabetes disease.

NETosis is a form of neutrophil cell death during which extracellular fibrillary structures composed of cytosolic and granule proteins assembled on scaffolds of decondensed chromatin, called neutrophil extracellular traps (NETs), are released. NETs normally contribute to host immune defense. Accumulating evidence implicates aberrant NET production and/or reduced NET clearance, along with alterations of molecules involved in NETosis pathway, in humans and animals with lupus. The extruded nuclear antigens released by NET are a source of autoantigens, which can contribute to the breakdown of self-tolerance in lupus. Excessive NET can also promote the production of pro-inflammatory cytokine interferon-α, elicit direct cytotoxic effect on various renal cells, and cause capillary necrosis and podocyte loss. Additionally, NET can induce endothelial-to-mesenchymal transdifferentiation, which can promote activated myofibroblasts leading to extracellular matrix production. Thus, aberrant NETosis can play diverse roles, including autoantibody production, inflammation, and tissue damage, at different stages of lupus pathogenesis. Evidence suggests that treatments currently used in lupus may reduce NETosis, suggesting a potential utility of targeting NETosis to treat lupus. In fact, several approaches are being experimented to therapeutically target pathways of NETosis. Future studies should precisely delineate distinct roles of NETosis at different stages of lupus pathogenesis in humans, which would offer a rational basis for NETosis-targeting treatments in the clinic.

Objective: To evaluate the effects of ganciclovir combined with recombinant human interferon on clinical efficacy and immune function of children with infectious mononucleosis(IM). Methods: This was a retrospective study. Children (n=120) with IM hospitalized in Beijing Children’s Hospital Affiliated to Capital Medical University Baoding Hospital from January 2020 to January 2022 were selected and randomly divided into study group and control group((n=60). Patients in the control group were treated with ganciclovir by intravenous infusion, and patients in the study group were given ganciclovir+recombinant human interferon-α1b. The time for eliminating clinical symptoms, the levels of inflammatory cytokines, immune function condition and T-lymphocyte subsets between the two groups were compared and analyzed. Results: After treatment, the time for body temperature returned to normal, time for recovery from cervical lymphadenopathy, time for recovery from hepatosplenomegaly and time for disappearance of angina and oral mucosal congestion in the study group were significantly shorter than those in the control group(p= 0.00); after treatment, the levels of TNF-a and IL-6 in the study group were significantly lower than those in the control group; the indexes of CD3+ and CD8+ in the study group were significantly lower than those in the control group; after treatment, the levels of CD4+ and CD4+ /CD8+ in the study group were significantly higher than those in the control group. Conclusion: Ranciclovir combined with recombinant human interferon-α1b, rapid improvements of clinical symptoms, significantly decreased inflammatory cytokines, improved T-lymphocyte function and no significant increase in adverse drug reactions were found in children with IM. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the biological effect and mechanisms of C-reactive protein (CRP) on the activation of fibroblast-like synoviocytes (FLSs) from patients with rheumatoid arthritis (RA).Study design: To understand if CRP is involved in RA, expression of CRP and its receptors CD32/64 was examined in synovial tissues from RA patients and normal controls. In vitro, the potential role and mechanisms of CRP in FLS proliferation and invasion, expression of pro-inflammatory cytokines, and activation of signaling pathways were investigated in both RA - FLS and a normal human fibroblast-like synoviocyte line (HFLS).Results: Compared to normal controls, synovial tissues from 21 RA patients exhibited highly activated CRP signaling, particularly by FLSs as identified by 65% of CRP-expressing cells being CRP+vimentin+ and CD32/64+vimentin+ cells. In vitro, FLSs from RA patients, but not HFLS, showed highly reactive to CRP by largely increasing proliferative and invasive activities and expressing pro-inflammatory cytokines and chemokines, including CCL2, CXCL8, IL-6, and MMP2/9. All these changes were blocked largely by a neutralizing antibody to CD32 and, to a less extent by the anti-CD64 antibody, revealing CD32 as a primary mechanism of CRP signaling during synovial inflammation. Further studies revealed that CRP also induced synovial inflammation differentially via CD32/CD64- NF-κB or p38 pathways as blockade of CRP-CD32-NF-κB signaling inhibited CXCL8, CCL2, IL-6, whereas CRP induced RA-FLS invasiveness through CD32-p38 and MMP9 expression via the CD64-p38-dependent mechanism.Conclusions: CRP signaling is highly activated in synovial FLSs from patients with RA. CRP can induce synovial inflammation via mechanisms associated with activation of CD32/64-p38 and NF-κB signaling.

Abstract Background Submicroscopic chromosomal imbalance is associated with an increased nuchal translucency (NT). Most previous research has recommended the use of chromosomal microarray analysis (CMA) for prenatal diagnosis if the NT ≥ 3.5 mm. However, there is no current global consensus on the cutoff value for CMA. In this study, we aimed to discuss the fetuses with smaller increased NT which was between cutoff value of NT for karyotype analysis (NT of 2.5 mm in China) and the recommended cutoff value for CMA (NT of 3.5 mm) whether should be excluded from CMA test. Methods Singleton pregnant women (N = 192) who had undergone invasive procedures owing to an increased NT (NT ≥ 2.5 mm) were enrolled. Fetal cells were collected and subjected to single nucleotide polymorphism array and karyotype analyses simultaneously. Cases were excluded if the karyotype analysis indicated aneuploidy and apparent structural aberrations. Results Fourteen cases of aneuploidy and four cases of structural abnormalities were excluded. Of the remaining 174 cases, 119 fetuses had NTs of 2.5–3.4 mm, and 55 fetuses with NT ≥ 3.5 mm. Eleven copy number variants (CNVs) were identified. In fetuses with smaller NTs, six (6/119, 5.9%) variations were detected, including two (2/119, 1.6%) clinically significant CNVs (pathogenic or likely pathogenic CNV), one likely benign CNV, two variants unknown significance, and one incidental CNV. Five (5/55, 9.1%) variations were found in fetuses with NT ≥ 3.5 mm. Among these CNVs, three (3/55, 5.5%) cases had clinically significant CNVs, and two had likely benign CNV. There were no statistically significant differences in the incidence of all CNVs and clinically significant CNVs in the two groups (p > 0.05). Conclusion CMA improved the diagnostic yield of chromosomal aberrations for fetuses with NTs of 2.5–3.4 mm and apparently normal karyotype, regardless of whether other ultrasonic abnormalities were observed.

Abstract Background Chemokines and chemokine receptors play important roles in autoimmune diseases; however, their role in immune thrombocytopenia (ITP) is unclear. High-dose dexamethasone (HD-DXM) may become a first-line therapy for adult patients with ITP, but the effect of HD-DXM on chemokines in ITP patients is unknown. Our aim was to investigate the mechanism of pulsed HD-DXM for management of ITP, specifically regarding the chemokine pathways. Methods Th1-/Th2-associated chemokine and chemokine receptor profiles in ITP patients before and after pulsed HD-DXM was studied. Plasma levels of CCL5 and CXCL11 (Th1-associated) and of CCL11 (Th2-associated) were determined by ELISA. Gene expression of these three chemokines and their corresponding receptors CCR5, CXCR3, and CCR3, in peripheral blood mononuclear cells (PBMCs) was determined by quantitative RT-PCR. Results Thirty-three of the thirty-eight ITP patients responded effectively to HD-DXM (oral, 40 mg/day, 4 days). In ITP patients, plasma CXCL11 levels increased, while CCL11 and CCL5 decreased compared to controls (P

Objective: Smad7 is an inhibitory Smad and plays a protective role in many inflammatory diseases. However, the roles of Smad7 in rheumatoid arthritis (RA) remain unexplored, which were investigated in this study.Methods: The activation of TGF-β/Smad signaling was examined in synovial tissues of patients with RA. The functional roles and mechanisms of Smad7 in RA were determined in a mouse model of collagen-induced arthritis (CIA) in Smad7 wild-type (WT) and knockout (KO) CD-1 mice, a strain resistant to autoimmune arthritis induction.Results: TGF-β/Smad3 signaling was markedly activated in synovial tissues of patients with RA, which was associated with the loss of Smad7, and enhanced Th17 and Th1 immune response. The potential roles of Smad7 in RA were further investigated in a mouse model of CIA in Smad7 WT/KO CD-1 mice. As expected, Smad7-WT CD-1 mice did not develop CIA. Surprisingly, CD-1 mice with Smad7 deficiency developed severe arthritis including severe joint swelling, synovial hyperplasia, cartilage damage, massive infiltration of CD3+ T cells and F4/80+ macrophages, and upregulation of proinflammatory cytokines IL-1β, TNFα, and MCP-1. Further studies revealed that enhanced arthritis in Smad7 KO CD-1 mice was associated with increased Th1, Th2 and, importantly, Th17 over the Treg immune response with overactive TGF-β/Smad3 and proinflammatory IL-6 signaling in the joint tissues.Conclusions: Smad7 deficiency increases the susceptibility to autoimmune arthritis in CD-1 mice. Enhanced TGF-β/Smad3-IL-6 signaling and Th17 immune response may be a mechanism through which disrupted Smad7 causes autoimmune arthritis in CD-1 mice.

Considering the harmful effect of dynamic SSDF attack against cooperative spectrum sensing technologies，a dynamic trust evaluation scheme based on the real-time observation and analysis of cognitive users’ sensing behaviors was proposed.Time attenuation，additive reward and additive penalty factors based on the historical sensing variation of cognitive users were introduced to calculate the dynamic trust value which changes with time and the number of collaborations.Meanwhile，trusted cognitive users were selected to participate in cooperative sensing，and thus improving the accuracy of the final sensing decision.Simulation results show that the scheme can effectively suppress the growth of trust of malicious users，and reduce the attack success rate for“OR”，“AND”and“Majority”which are three kinds of cooperative spectrum sensing data fusion schemes.

In response to inflammatory stimuli in conditions such as autoimmune disorders, infections and cancers, immune cells organize in nonlymphoid tissues, which resemble secondary lymphoid organs. Such immune cell clusters are called tertiary lymphoid structures (TLS). Here, we describe the potential role of TLS in the pathogenesis of autoimmune disease, focusing on lupus nephritis, a condition that incurs major morbidity and mortality. In the kidneys of patients and animals with lupus nephritis, the presence of immune cell aggregates with similar cell composition, structure, and gene signature as lymph nodes and of lymphoid tissue-inducer and -organizer cells, along with evidence of communication between stromal and immune cells are indicative of the formation of TLS. TLS formation in kidneys affected by lupus may be instigated by local increases in lymphorganogenic chemokines such as CXCL13, and in molecules associated with leukocyte migration and vascularization. Importantly, the presence of TLS in kidneys is associated with severe tubulointerstitial inflammation, higher disease activity and chronicity indices, and poor response to treatment in patients with lupus nephritis. TLS may contribute to the pathogenesis of lupus nephritis by increasing local IFN-I production, facilitating the recruitment and supporting survival of autoreactive B cells, maintaining local production of systemic autoantibodies such as anti-dsDNA and anti-Sm/RNP autoantibodies, and initiating epitope spreading to local autoantigens. Resolution of TLS, along with improvement in lupus, by treating animals with soluble BAFF receptor, docosahexaenoic acid, complement inhibitor C4BP(β-), S1P1 receptor modulator Cenerimod, dexamethasone, and anti-CXCL13 further emphasizes a role of TLS in the pathogenesis of lupus. However, the mechanisms underlying TLS formation and their roles in the pathogenesis of lupus nephritis are not fully comprehended. Furthermore, the lack of non-invasive methods to visualize/ quantify TLS in kidneys is also a major hurdle; however, recent success in visualizing TLS in lupus-prone mice by photon emission computed tomography provides hope for early detection and manipulation of TLS. [ABSTRACT FROM AUTHOR]