bluuebunny/crossref_metadata_2025_split huggingface dataset:
Deletion of microRNA-183-96-182 Cluster in Lymphocytes Suppresses Anti-DsDNA Autoantibody Production and IgG Deposition in the Kidneys in C57BL/6-Faslpr/lpr Mice
Authors: Wang Zhuang , Heid Bettina , Lu Ran , Sachdeva Mohit , Edwards Michael R. , Ren JingJing , Cecere Thomas E. , Khan Deena , Jeboda Taschua , Kirsch David G. , Reilly Christopher M. , Dai Rujuan , Ahmed S. Ansar 
Published: July 2022

Dysregulated miRNAs have been implicated in the pathogenesis of systemic lupus erythematosus (SLE). Our previous study reported a substantial increase in three miRNAs located at the miR-183-96-182 cluster (miR-183C) in several autoimmune lupus-prone mice, including MRL/lpr and C57BL/6-lpr (B6/lpr). This study reports thatin vitroinhibition of miR-182 alone or miR-183C by specific antagomirs in activated splenocytes from autoimmune-prone MRL/lpr and control MRL mice significantly reduced lupus-related inflammatory cytokines, interferon-gamma (IFNγ), and IL-6 production. To further characterize the role of miR-182 and miR-183C clusterin vivoin lupus-like disease and lymphocyte phenotypes, we used hCD2-iCre to generate B6/lpr mice with conditional deletion of miR-182 or miR-183C in CD2+lymphocytes (miR-182−/−B6/lpr and miR-183C−/-B6/lpr). The miR-182−/−B6/lpr and miR-183C−/−B6/lpr mice had significantly reduced deposition of IgG immunocomplexes in the kidney when compared to their respective littermate controls, although there appeared to be no remarkable changes in renal pathology. Importantly, we observed a significant reduction of serum anti-dsDNA autoantibodies in miR-183C−/−B6/lpr mice after reaching 24 weeks-of age compared to age-matched miR-183Cfl/flB6/lpr controls.In vitroactivated splenocytes from miR-182−/−B6/lpr mice and miR-183C−/−B6/lpr mice showed reduced ability to produce lupus-associated IFNγ. Forkhead box O1(Foxo1), a previously validated miR-183C miRNAs target, was increased in the splenic CD4+cells of miR-182−/−B6/lpr and miR-183C−/−B6/lpr mice. Furthermore,in vitroinhibition of Foxo1 with siRNA in splenocytes from miR-182−/−B6/lpr and miR-183C−/-B6/lpr mice significantly increased IFNγ expression following anti-CD3/CD28 stimulation, suggesting that miR-182 and miR-183C miRNAs regulate the inflammatory IFNγ in splenocytes via targeting Foxo1. The deletion of either miR-182 alone or the whole miR-183C cluster, however, had no marked effect on the composition of T and B cell subsets in the spleens of B6/lpr mice. There were similar percentages of CD4+, CD8+, CD19+, as well as Tregs, follicular helper T (TFH), germinal center B (GCB), and plasma cells in the miR-183C−/−B6/lpr and miR-182−/−B6/lpr mice and their respective littermate controls, miR-183Cfl/flB6/lpr and miR-182fl/flB6/lpr mice. Together, our data demonstrate a role of miR-183C in the regulation of anti-dsDNA autoantibody productionin vivoin B6/lpr mice and the induction of IFNγ inin vitroactivated splenocytes from B6/lpr mice.
Increased Expression of Multiple Co-Inhibitory Molecules on Malaria-Induced CD8+ T Cells Are Associated With Increased Function Instead of Exhaustion
Authors: Brandi Johannes , Riehn Mathias , Hadjilaou Alexandros , Jacobs Thomas 
Published: July 2022

Activated cytotoxic CD8+ T cells can selectively kill target cells in an antigen-specific manner. However, their prolonged activation often has detrimental effects on tissue homeostasis and function. Indeed, overwhelming cytotoxic activity of CD8+ T cells can drive immunopathology, and therefore, the extent and duration of CD8+ T cell effector function needs to be tightly regulated. One way to regulate CD8+ T cell function is their suppression through engagement of co-inhibitory molecules to their cognate ligands (e.g., LAG-3, PD-1, TIM-3, TIGIT and CTLA-4). During chronic antigen exposure, the expression of co-inhibitory molecules is associated with a loss of T cell function, termed T cell exhaustion and blockade of co-inhibitory pathways often restores T cell function. We addressed the effect of co-inhibitory molecule expression on CD8+ T cell function during acute antigen exposure using experimental malaria. To this end, we infected OT-I mice with a transgenic P. berghei ANKA strain that expresses ovalbumin (PbTG), which enables the characterization of antigen-specific CD8+ T cell responses. We then compared antigen-specific CD8+ T cell populations expressing different levels of the co-inhibitory molecules. High expression of LAG-3 correlated with high expression of PD-1, TIGIT, TIM-3 and CTLA-4. Contrary to what has been described during chronic antigen exposure, antigen-specific CD8+ T cells with the highest expression of LAG-3 appeared to be fully functional during acute malaria. We evaluated this by measuring IFN-γ, Granzyme B and Perforin production and confirmed the results by employing a newly developed T cell cytotoxicity assay. We found that LAG-3high CD8+ T cells are more cytotoxic than LAG-3low or activated but LAG-3neg CD8+ T cells. In conclusion, our data imply that expression of co-inhibitory molecules in acute malaria is not necessarily associated with functional exhaustion but may be associated with an overwhelming T cell activation. Taken together, our findings shed new light on the induction of co-inhibitory molecules during acute T cell activation with ramifications for immunomodulatory therapies targeting these molecules in acute infectious diseases.
IL-7 Promotes the Expansion of Circulating CD28- Cytotoxic T Lymphocytes in Patients With IgG4-Related Disease via the JAK Signaling
Authors: Xia Chang-sheng , Long Yan , Liu Yanying , Alifu Aikede , Zeng Xingyue , Liu Chen 
Published: July 2022

ObjectivesThis study aimed to elucidate the changes and associated mechanisms of circulating CD28- cytotoxic T lymphocytes (CTLs) in patients with IgG4-related disease (IgG4-RD).MethodsFifty IgG4-RD patients and 15 healthy controls (HCs) were recruited. Peripheral blood mononuclear cells (PBMCs) were isolated, the levels of circulating CD28- CTLs were detected by flow cytometry, and the proportions of CD127lo or GZMB+CD28- CTL subsets were analyzed in the meantime. Mechanistically, PBMCs isolated from IgG4-RD patients were stimulated with IL-7 in the presence or absence of the JAK inhibitor tofacitinib. Flow cytometry was used to analyze the proliferation of CD28- CTLs and the changes in related subpopulations.ResultsCirculating CD4+CD28- CTLs and CD8+CD28- CTLs were significantly increased in IgG4-RD patients compared with HCs, accompanied by an elevation of CD127lo or GZMB+ CTL subsets. Theex vivoculture of PBMCs showed that IL-7 could induce the amplification of CD4+CD28- CTLs and CD8+CD28- CTLs in IgG4-RD. Furthermore, IL-7 promotes the proliferation and functional subset changes of these CD28- CTLs in this disease. The selective JAK inhibitor tofacitinib significantly inhibited the effects of IL-7 on CD4+CD28- CTLs and CD8+CD28- CTLs.ConclusionIL-7 can affect the immune balance of IgG4-RD patients by promoting the expansion and function of CD4+CD28- and CD8+CD28- CTLs in IgG4-RD through the JAK pathway. Blockade of the IL-7 signaling pathway may be a new therapeutic strategy for IgG4-RD.
A T3SS Regulator Mutant HY9901 ΔaraC of Vibrio alginolyticus Decreased the Expression of HopPmaJ and Provided Protection to Danio rerio as a Live-Attenuated Vaccine
Authors: Wang Junlin , Zeng Fuyuan , Feng Haiyun , Chen Liangchuan , Zhang Weijie , Xiao Xing , Monaghan Sean J. , Jian Jichang , Pang Huanying , Wang Na 
Published: July 2022

Vibrio alginolyticus, a zoonotic bacterial pathogen, expresses a type III secretion system (T3SS) that is critical for pathogen virulence and disease development. In this study, the mutant HY9901 ΔaraC was obtained from the laboratory and its biological characteristics were analyzed. The swimming ability of ΔaraC decreased and exhibited a 2,600 times reduction in virulence to zebrafish. However, ΔaraC showed no difference in growth and extracellular protease activity compared to wild type. Biofilm-forming ability was improved at 24 h, but no difference was observed at other time points. The results of drug sensitivity testing showed that compared with the wild-type HY9901 strain, ΔaraC was sensitive to amikacin, tetracycline, neomycin, minocycline, and gentamicin. The transcription levels of T3SS effector proteins HopPmaJ, VopS, VcrV, and VopN were analyzed by qRT-PCR. The results showed that ΔaraC had significantly upregulated the mRNA expression of VopS, VcrV, and VopN, but significantly downregulated the mRNA expression of HopPmaJ at each stage compared with HY9901. Western blotting and the β-galactosidase reporter gene experiment also showed that the deletion of araC gene significantly downregulated the expression of HopPmaJ. Finally, the relative percent survival (RPS) rate of grouper inoculated by intramuscular (IM) injection of HY9901 ΔaraC was 61.3% after being challenged with HY9901. Real-time qPCR analysis showed that vaccination of HY9901 ΔaraC could enhance the expression of immune-related genes, including gata-1, il6, IgM, il-1β, and lyz in liver and spleen, indicating that ΔaraC applied as a live-attenuated vaccine effectively induced an immune response in the zebrafish. This study provides evidence for the subsequent development of an effective live-attenuated V. alginolyticus vaccine.
The Risk of Major Adverse Cardiovascular Events in Ankylosing Spondylitis Patients With a History of Acute Anterior Uveitis: A Nationwide, Population Based Cohort Study
Authors: Bai Yi-Chiao , Liu Chin-Hsiu , Leong Pui-Ying , Lai Kuo-Lung , Chen Hsin-Hua , Wei James Cheng-Chung 
Published: July 2022

BackgroundTo investigate the association between a history of acute anterior uveitis (AAU) and the risk of major adverse cardiovascular events (MACE) among patients with ankylosing spondylitis (AS).MethodsWe identified 38,691 newly diagnosed AS patients between 2003 and 2013 from the Taiwan National Health Insurance Research Database. The exposure group was defined as people with uveitis diagnosis by ophthalmologist before AS diagnosis date. The incidence of MACE in patients with AS according to the International Classification of Diseases, Ninth Revision. We randomly selected a comparison group without a history of AAU at a 1:4 ratio matched by age, sex, and index year in relation to the risk of developing MACE. We used cox proportional hazard regression model to compare the risk of MACE between groups, shown as adjusted hazard ratios (aHRs) with 95% confidence intervals (CI). Further subgroup analysis and sensitivity tests were also performed.ResultsThere were 3,544 patients in the AAU group and 14,176 patients in the non-AAU group. The aHR of MACE for the AAU group was 0.79 (95% CI = 0.57–1.10) at a 1:4 ratio for age, sex and index year. Sensitivity analyses using various adjustment variables showed consistent results. Cox proportional hazard regression model demonstrated that use of non-steroidal anti-inflammatory drugs (NSAIDs) was associated with an increased risk of MACE in this cohort (HR = 3.44; 95% CI = 2.25–5.25).ConclusionThis cohort study showed that subjects with AAU was not associated with the risk of MACE among AS patients, compared to non-AAU controls.
In silico Identification of Immune Cell-Types and Pathways Involved in Chronic Spontaneous Urticaria
Authors: Prosty Connor , Gabrielli Sofianne , Ben-Shoshan Moshe , Le Michelle , Giménez-Arnau Ana M. , Litvinov Ivan V. , Lefrançois Philippe , Netchiporouk Elena 
Published: July 2022

BackgroundThe immunopathogenesis of chronic spontaneous urticaria (CSU) is poorly understood, but recent research suggests that patients can be divided into autoallergic and autoimmune subtypes. Given that not all patients can be controlled with current treatment regimens, including anti-IgE monoclonal antibodies, a better understanding of the immune pathways involved in CSU may enable the repurposing of monoclonal antibodies used for other dermatologic diseases (e.g., Th2 and Th17 inhibitors). Therefore, we investigated the implicated immune cells and pathways by reanalyzing publicly available transcriptomic data.MethodsMicroarray data of CSU and healthy control (HC) skin and blood were obtained from the Gene Expression Omnibus (GSE72542, GSE57178). Differentially expressed genes were defined as a false discovery rate &lt;0.05 and a |log2 fold change| ≥1. Pathway analyses were conducted using ToppGene and KEGG. Cell-type enrichment was determined by CIBERSORT and xCell and was correlated with clinical characteristics.ResultsTh2 (IL-4/13 signaling) and Th17-related (IL-17/23 signaling) pathways were upregulated in lesional compared to non-lesional and HC samples. In non-lesional versus lesional samples, CIBERSORT analysis revealed increased regulatory T-cells (Treg) and resting mast cells. xCell analysis established that Th1 and Th2 scores were not significantly different between lesional and HC samples. However, Th2 scores in both lesional and non-lesional samples correlated positively with disease severity. Few differentially expressed genes and pathways were identified between CSU and HC blood samples.ConclusionOur results support the involvement of Th2 and Th17-related genes and pathways in CSU. Th2 scores associate with disease severity, which indicates the clinical relevance of these findings. Increased resting mast cell and Treg scores in non-lesional samples may suggest local suppression of wheal formation. Moreover, disease activity seemed to be restricted to the skin as there were limited findings from blood. Larger studies using next-generation sequencing will be helpful to confirm these results.
Benchmarking of ATAC Sequencing Data From BGI’s Low-Cost DNBSEQ-G400 Instrument for Identification of Open and Occupied Chromatin Regions
Authors: Naval-Sanchez Marina , Deshpande Nikita , Tran Minh , Zhang Jingyu , Alhomrani Majid , Alsanie Walaa , Nguyen Quan , Nefzger Christian M. 
Published: July 2022

Background: Chromatin falls into one of two major subtypes: closed heterochromatin and euchromatin which is accessible, transcriptionally active, and occupied by transcription factors (TFs). The most widely used approach to interrogate differences in the chromatin state landscape is the Assay for Transposase-Accessible Chromatin using sequencing (ATAC-seq). While library generation is relatively inexpensive, sequencing depth requirements can make this assay cost-prohibitive for some laboratories.Findings: Here, we benchmark data from Beijing Genomics Institute’s (BGI) DNBSEQ-G400 low-cost sequencer against data from a standard Illumina instrument (HiSeqX10). For comparisons, the same bulk ATAC-seq libraries generated from pluripotent stem cells (PSCs) and fibroblasts were sequenced on both platforms. Both instruments generate sequencing reads with comparable mapping rates and genomic context. However, DNBSEQ-G400 data contained a significantly higher number of small, sub-nucleosomal reads (&gt;30% increase) and a reduced number of bi-nucleosomal reads (&gt;75% decrease), which resulted in narrower peak bases and improved peak calling, enabling the identification of 4% more differentially accessible regions between PSCs and fibroblasts. The ability to identify master TFs that underpin the PSC state relative to fibroblasts (via HOMER, HINT-ATAC, TOBIAS), namely, foot-printing capacity, were highly similar between data generated on both platforms. Integrative analysis with transcriptional data equally enabled direct recovery of three published 3-factor combinations that have been shown to induce pluripotency.Conclusion: Other than a small increase in peak calling sensitivity for DNBSEQ-G400 data (BGI), both platforms enable comparable levels of open chromatin identification for ATAC-seq library sequencing, yielding similar analytical outcomes, albeit at low-data generation costs in the case of the BGI instrument.
Implementing a Scoring Function Based on Interaction Fingerprint for Autogrow4: Protein Kinase CK1δ as a Case Study
Authors: Pavan Matteo , Menin Silvia , Bassani Davide , Sturlese Mattia , Moro Stefano 
Published: July 2022

In the last 20 years, fragment-based drug discovery (FBDD) has become a popular and consolidated approach within the drug discovery pipeline, due to its ability to bring several drug candidates to clinical trials, some of them even being approved and introduced to the market. A class of targets that have proven to be particularly suitable for this method is represented by kinases, as demonstrated by the approval of BRAF inhibitor vemurafenib. Within this wide and diverse set of proteins, protein kinase CK1δ is a particularly interesting target for the treatment of several widespread neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis. Computational methodologies, such as molecular docking, are already routinely and successfully applied in FBDD campaigns alongside experimental techniques, both in the hit-discovery and in the hit-optimization stage. Concerning this, the open-source software Autogrow, developed by the Durrant lab, is a semi-automated computational protocol that exploits a combination between a genetic algorithm and a molecular docking software for de novo drug design and lead optimization. In the current work, we present and discuss a modified version of the Autogrow code that implements a custom scoring function based on the similarity between the interaction fingerprint of investigated compounds and a crystal reference. To validate its performance, we performed both a de novo and a lead-optimization run (as described in the original publication), evaluating the ability of our fingerprint-based protocol to generate compounds similar to known CK1δ inhibitors based on both the predicted binding mode and the electrostatic and shape similarity in comparison with the standard Autogrow protocol.
Evaluation of the Reddesa Chart, a New Red Desaturation Testing Method, for Optic Neuritis Screening and Grading in Clinical Routine
Authors: Bruegger Dominik , Koth Anna-Lucia , Dysli Muriel , Goldblum David , Abegg Mathias , Tschopp Markus , Tappeiner Christoph 
Published: July 2022

Background:Optic neuritis usually leads to reduced color sensitivity. Most often, the change of red color, the so-called red desaturation, is tested in clinical routine. The aim of this study was to test the feasibility of the Reddesa chart, a new red desaturation test based on polarization, as a screening method for optic neuropathy.MethodsA total of 20 patients with unilateral optic neuritis and 20 healthy controls were included in this prospective pilot study. Ophthalmological examination included assessment of best corrected visual acuity (BCVA), slit lamp examination, fundoscopy, testing of relative afferent pupillary defect (RAPD) and red desaturation with the red cup test and the Reddesa chart.ResultsThe mean BCVA in the optic neuritis group was 0.76 ± 0.36 in the affected eye (95% of eyes with RAPD, 75% of eyes with difference in the Reddesa test) and 1.28 ± 0.24 in the healthy eye, whereas in the control group, BCVA was 1.14 ± 0.11 in the right eye and 1.15 ± 0.14 in the left eye (none of the eyes with RAPD or abnormal Reddesa test). In our study, the Reddesa test showed a positive predictive value of 100% and a negative predictive value of 80% for detecting optic neuritis.ConclusionThe Reddesa chart allows to quantify red desaturation and has the potential to be implemented as a screening test in clinical routine.
Starch and Fiber Contents of Purified Control Diets Differentially Affect Hepatic Lipid Homeostasis and Gut Microbiota Composition
Authors: Schipke Julia , Brandenberger Christina , Vital Marius , Mühlfeld Christian 
Published: July 2022

BackgroundInterpretation of results from diet-induced-obesity (DIO) studies critically depends on control conditions. Grain-based chows are optimized for rodent nutrition but do not match the defined composition of purified diets used for DIO, severely limiting the comparability. Purified control diets are recommended but often contain high starch and only minor fiber amounts. It is unknown whether this composition leads to metabolic alterations compared with chow and whether the addition of refined fibers at the expense of starch affects these changes.MethodsIn this experiment, 6-week-old C57BL/6N mice were fed (i) a conventional purified control diet (high-starch, low-fiber; Puri-starch), (ii) an alternative, custom-made purified control diet containing pectin and inulin (medium-starch, higher-fiber; Puri-fiber), or (iii) grain-based chow for 30 weeks (N = 8–10).ResultsPuri-starch feeding resulted in significantly elevated levels of plasma insulin (p = 0.004), cholesterol (p &lt; 0.001), and transaminases (AST p = 0.002, ALT p = 0.001), hepatic de novo lipogenesis and liver steatosis, and an altered gut microbiota composition compared with chow-fed mice. In contrast, Puri-fiber exerted only minor effects on systemic parameters and liver lipid homeostasis, and promoted a distinct gut microbiota composition.ConclusionCarbohydrate-rich purified diets trigger a metabolic status possibly masking pathological effects of nutrients under study, restricting its use as control condition. The addition of refined fibers is suited to create purified, yet physiological control diets for DIO research.
Fruquintinib in Combination With PD-1 Inhibitors in Patients With Refractory Non-MSI-H/pMMR Metastatic Colorectal Cancer: A Real-World Study in China
Authors: Gou Miaomiao , Qian Niansong , Zhang Yong , Yan Huan , Si Haiyan , Wang Zhikuan , Dai Guanghai 
Published: July 2022

BackgroundFruquintinib, a vascular endothelial growth factor receptor inhibitor, is a new anticancer drug independently developed in China to treat refractory metastatic colorectal cancer (mCRC). In Japan, regorafenib combined with nivolumab has been demonstrated to be promising in patients with refractory mCRC. Here, in a real-world study, we were aimed to evaluate the efficacy of fruquintinib with various programmed death-1 (PD-1) inhibitors after standard treatment in Chinese non-microsatellite instability-high (MSI-H)/mismatch repair proficient mCRC patients.MethodsA total of 45 patients with refractory mCRC were involved in the study. They received fruquintinib (3 or 5 mg, orally administered once a day for 3 weeks followed by 1 week off in 4-week cycles) and a PD-1 inhibitor(200 mg pembrolizumab, 3 mg/kg nivolumab, 200 mg sintilimab or camrelizumab, intravenously administered on D1 once every 3 weeks). Progression-free survival (PFS), overall survival (OS), disease control rate (DCR), and objective response rate (ORR) were reviewed and evaluated.ResultsAmong the 45 patients, the median age was 54 years (29-85). The ORR was 11.1% (5/45), DCR 62.2% (28/45), median PFS equal 3.8 months, and median OS was 14.9 months. The response duration was 3.4 months. PFS between left and right primary tumors and PFS with or without lung metastases were both not significantly different (p &gt; 0.05), which was inconsistent with the result of REGONIVO study. The multivariate analysis indicated no association of OS benefit in the specified subgroups. No adverse-effect-related deaths were reported.ConclusionsFruquintinib, in combination with anti-PD-1, was observed to have clinical activity in a small population of patients with heavily pretreated mCRC in our center. Further studies are needed to verify this outcome in a large population.