A review of TSHR- and IGF-1R-related pathogenesis and treatment of Graves' orbitopathy.

Graves' orbitopathy (GO) is an organ-specific autoimmune disease, but its pathogenesis remains unclear. There are few review articles on GO research from the perspective of target cells and target antigens. A systematic search of PubMed was performed, focusing mainly on studies published after 2015 that involve the role of target cells, orbital fibroblasts (OFs) and orbital adipocytes (OAs), target antigens, thyrotropin receptor (TSHR) and insulin-like growth factor-1 receptor (IGF-1R), and their corresponding antibodies, TSHR antibodies (TRAbs) and IGF-1R antibodies (IGF-1R Abs), in GO pathogenesis and the potentially effective therapies that target TSHR and IGF-1R. Based on the results, OFs may be derived from bone marrow-derived CD34+ fibrocytes. In addition to CD34+ OFs, CD34- OFs are important in the pathogenesis of GO and may be involved in hyaluronan formation. CD34- OFs expressing Slit2 suppress the phenotype of CD34+ OFs. ß-arrestin 1 can be involved in TSHR/IGF-1R crosstalk as a scaffold. Research on TRAbs has gradually shifted to TSAbs, TBAbs and the titre of TRAbs. However, the existence and role of IGF-1R Abs are still unknown and deserve further study. Basic and clinical trials of TSHR-inhibiting therapies are increasing, and TSHR is an expected therapeutic target. Teprotumumab has become the latest second-line treatment for GO. This review aims to effectively describe the pathogenesis of GO from the perspective of target cells and target antigens and provide ideas for its fundamental treatment.

In Vivo Inhibition of MicroRNA-326 in a NOD.H-2h4 Mouse Model of Autoimmune Thyroiditis.

Background: Previous studies reported that various miRNAs participate in autoimmune diseases, but the potential regulatory mechanism of miRNAs in autoimmune thyroiditis (AIT) needs further exploration. Objective: This study aimed to further verify that miR-326 contributes to AIT by regulating Th17/Treg balance through Ets-1 using lentiviral gene delivery through tail vein and thyroid injection in NOD.H-2h4 mice. Materials and Methods: Five-week-old NOD.H-2h4 mice were divided randomly into tail vein and thyroid injection groups, and each received either mmu-miR-326 sponge (LV-sponge) or lentiviral vector control. Mice were divided for tail vein injection: the therapeutic LV-ctrl, therapeutic LV-sponge, prophylactic LV-ctrl, and prophylactic LV-sponge groups. The control group was fed high-iodine water without vein injection. The thyroid infiltration of lymphocytes and serum TgAb value were investigated by thyroid hematoxylin and eosin (HE) staining and ELISA, respectively. Ets-1 and lymphocyte counts were measured by RT-PCR, western blotting, and flow cytometry. The thyroid CD4+IL-17a+ cells and CD4+Ets-1+ cells were detected by immunofluorescence, and the serum cytokines were tested by ELISA. Results: In the tail vein injection groups, the thyroid inflammatory score and serum TgAb titer were significantly lower in the LV-sponge groups than in the control and LV-ctrl groups while Ets-1 protein expression in mouse spleens was increased in the LV-sponge groups. Moreover, Th17/Treg ratio declined in the LV-sponge group and decreased significantly in the prophylactic LV-sponge group (P = 0.036) tested by flow cytometry. Immunofluorescence showed that, in LV-sponge groups, CD4+IL-17a+ cells were decreased significantly (P = 0.001), while CD4+Ets-1+ cells were increased significantly in the LV-sponge group (P = 0.029). The serum IL-17/IL-10 was decreased significantly in the LV-sponge group (P < 0.05). In the thyroid injection groups, the thyroid inflammatory score and serum TgAb titer in the LV-sponge group decreased significantly compared with those in the LV-ctrl group (P < 0.05). In addition, in LV-sponge groups, CD4+IL-17a+ cells were decreased, while CD4+Ets-1+ cells were increased significantly in the inhibition group evaluated by immunofluorescence. Moreover, tail vein injection of LV-sponge resulted in much lower TgAb levels in thyroiditis compared with thyroid injection. Conclusion: MiR-326 targeted therapy may be a promising approach for AIT. In addition, tail vein injection may achieve a better intervention effect than thyroid injection.

Evaluation on two types of paramyosin vaccines for the control of Haemaphysalis longicornis infestations in rabbits.

BACKGROUND: Haemaphysalis longicornis is an obligate hematophagous ectoparasite that transmits a variety of pathogens causing life-threatening diseases in humans and animals. Paramyosin (Pmy) is not only an invertebrate-specific myofibrillar protein but also an important immunomodulatory protein. Therefore, it is one of the ideal candidate antigens for vaccines. METHODS: We conducted two vaccine trials to evaluate the protective efficacy of Pmy recombinant protein (rPmy) and peptide vaccine (KLH-LEE). Each rabbit was immunized with three doses of rPmy or KLH-LEE adjuvanted with Freund's complete/incomplete at 500 µg/dose at 2-week intervals before challenge with 40 female H. longicornis/rabbit. PBS plus adjuvant, Trx or KLH was used as control group. The antibodies of rabbits were detected by ELISA. Then, female ticks were fed on the rabbits until detachment. RESULTS: ELISA results showed that both vaccines induced rabbits to produce antibodies. Compared with the Trx group, the engorgement weight, oviposition and hatchability of the rPmy group decreased by 8.87%, 26.83% and 38.86%, respectively. On the other hand, engorgement weight, oviposition and hatchability of female ticks in the KLH-LEE group correspondingly resulted in 27.03%, 53.15% and 38.40% reduction compared with that of the KLH group. Considering the cumulative effect of vaccination on the evaluated parameters, results showed 60.37% efficacy of the rPmy vaccine formulation and 70.86% efficacy in the KLH-LEE group. CONCLUSIONS: Pmy and particularly epitope LEE have potential for further development of an effective candidate vaccine to protect the host against tick infection. GRAPHIC ABSTARCT.

Circulating Exosomes From Patients With Graves' Disease Induce an Inflammatory Immune Response.

Exosomes are extracellular vesicles that can participate in autoimmune diseases. The purpose of this study was to explore whether circulating exosomes are involved in Graves' disease (GD) pathogenesis. In this study, serum exosomes were extracted from 26 healthy controls (HC-EXO), 26 GD patients (GD-EXO), and 7 Graves' ophthalmopathy patients (GO-EXO). For each group, the total protein content was detected, and thyrotropin receptor, insulin-like growth factor 1 receptor (IGF-1R), heat shock protein 60 (HSP60), and cluster of differentiation (CD) 63 expression were analyzed by Western blotting (WB). Healthy volunteer-derived peripheral blood mononuclear cells (PBMCs) and HC-EXO or GD-EXO were cocultured for 24 h, and immunofluorescence was used to observe the locations of the exosomes and toll-like receptor (TLR) 2/3. CD11c+TLR2+ and CD11c+TLR3+ cell percentages were determined by flow cytometry. Myeloid differentiation factor 88 (MyD88), toll/interleukin (IL)-1 receptor domain-containing adaptor inducing interferon-ß (TRIF) and p-P65 expression were analyzed by WB. IL-6 and IL-1ß supernatant levels were detected using enzyme-linked immunosorbent assay. The results showed that the total protein concentration was similar among GD-EXO, GO-EXO, and HC-EXO. IGF-1R and HSP60 expression was significantly higher in GD-EXO and GO-EXO than in HC-EXO. After coculturing PBMCs with GD-EXO or HC-EXO for 24 h, GD-EXO could bind to TLR2/3. GD-EXO significantly increased CD11c+TLR2+ and CD11c+TLR3+ cell percentages; MyD88, TRIF, and p-P65 protein expression; and IL-6 and IL-1ß levels. In conclusion, we first demonstrated that GD-EXO and GO-EXO highly expressed IGF-1R and HSP60. GD-EXO may induce an inflammatory response through the TLR/NF-κB signaling pathway and be involved in the pathogenesis of GD.

Roles of Endogenous IL-10 and IL-10-Competent and CD5+ B Cells in Autoimmune Thyroiditis in NOD.H-2h4 Mice.

Interleukin (IL)-10 is a highly important anti-inflammatory cytokine in the immune system. CD1dhi and CD5+ B cells are both traditionally defined IL-10-secreting B cells. In recent years, a B cell group with combined markers of CD1dhi and CD5+ has been widely studied as it has been reported to suppress autoimmunity in mouse models of autoimmune diseases through IL-10 mechanisms. From the perspective of origination, CD1dhi and CD5+ B cells are developed from different B cell lineages. Whether the regulatory capacity of these 2 B cell groups is consistent with their ability to secrete IL-10 has not been determined. In this study, we generated IL-10 knockout NOD.H-2h4 mice to investigate the function of endogenous IL-10 in autoimmune thyroiditis and conducted adoptive transfer experiments to explore the respective roles of CD5+ and CD1dhi B cells. In our results, the IL-10-/- NOD.H-2h4 mice developed thyroiditis, similar to wild-type NOD.H-2h4 mice. The CD5+ B cells were more capable of secreting IL-10 than CD1dhi B cells in flow cytometric analysis, but the CD1dhi B cells showed more suppressive effects on thyroiditis development and autoantibody production, as well as Th17 cell response. In conclusion, endogenous IL-10 does not play an important role in autoimmune thyroiditis. CD1dhi B cells may play regulatory roles through mechanisms other than secreting IL-10.

Elevated MicroRNA-326 Levels Regulate the IL-23/IL-23R/Th17 Cell Axis in Hashimoto's Thyroiditis by Targeting a Disintegrin and Metalloprotease 17.

Background: MicroRNAs (miRNAs) are a class of critical epigenetic regulators involved in several autoimmune diseases. Our previous study reported an miR-326-induced increase in T helper (Th) 17 cells in a mouse model of Hashimoto's thyroiditis (HT), but the pathogenic effect of miR-326 in HT patients has not been verified. The goal of the present study was to explore the pathogenic role of miR-326 and its underlying molecular mechanism in HT patients. Methods: A total of 58 HT patients and 55 normal controls were enrolled in this study. We examined whether Th17 cells and miR-326 were aberrantly altered in the peripheral blood mononuclear cells (PBMCs) of HT patients with flow cytometry and real-time polymerase chain reaction. Levels of membrane interleukin (IL)-23R (mIL-23R) were determined by flow cytometry and Western blot to explore the critical role of mIL-23R in the development of Th17 cells. Isolated CD3+ T cells were used to further investigate the ectodomain shedding of mIL-23R by a disintegrin and metalloprotease (ADAM17). Furthermore, miR-326 inhibitor and mimics were transfected into PBMCs derived from HT patients and healthy controls to verify the regulation of ADAM17 by miR-326. Results: We observed elevated miR-326 levels in the PBMCs of HT patients compared with those in the PBMCs of healthy controls. Consistent with IL-23-induced STAT3 overactivation, substantially more HT patient-derived PBMCs differentiated into Th17 cells under polarization culture conditions, which may, at least in part, have resulted from enhanced mIL-23R levels. Furthermore, ADAM17, an ectodomain sheddase of mIL-23R, was targeted and negatively regulated by miR-326. Inhibiting ADAM17 might attenuate the ectodomain shedding of mIL-23R. Conclusions: Our findings suggest that the effect of miR-326 on the IL-23/IL-23R/Th17 cell axis in HT patients might be partially due to the targeting of ADAM17.

Two-Years Prospective Follow-Up Study of Subacute Thyroiditis.

Purpose: The aim of the present prospective follow-up study was to explore the early indicators of hypothyroidism and the final changes in thyroid volume in subacute thyroiditis (SAT) patients. Methods: We enrolled 61 SAT patients and followed them up for 2 years to assess the incidence of hypothyroidism and changes in thyroid volume. Binary logistic regression and receiver operating characteristic (ROC) curves were used for data analysis. Results: During the 2 years follow-up period, we found that the volumes of the thyroid gland in SAT patients at 1 and 2 years were significantly smaller than those in the healthy control group, which were significantly smaller compared to the initial thyroid volumes after SAT onset (p < 0.001). Also, the thyroid volumes of SAT patients with hypothyroidism were significantly smaller than those of SAT patients without hypothyroidism. The early maximum thyroid-stimulating hormone (TSH) values (within 3 months after SAT onset) were closely related to the incidence of hypothyroidism at 2 years. The OR value was 1.18 (95% CI = 1.01-1.38, p = 0.032). The early maximum TSH value had a maximum area under the ROC curve (AUC) of 0.866 for the development of hypothyroidism 2 years after SAT onset vs. euthyroidism (p < 0.001). Conclusions: The thyroid volumes of patients increased significantly after the onset of SAT, while during the follow-up these volumes decreased; the thyroid volumes at 1 and 2 years were significantly smaller than those of normal healthy subjects, especially in SAT patients with hypothyroidism. Furthermore, the early maximum TSH value could be used as an effective indicator of the development of hypothyroidism 2 years after the onset of SAT.

Thyrocyte-derived exosome-targeted dendritic cells stimulate strong CD4+ T lymphocyte responses.

Exosomes have been intensively studied in autoimmune diseases, and circulating exosomes and microvesicles have also been explored in autoimmune thyroiditis (AITD). However, the role of thyroid cell-derived exosomes in immune responses is unclear. We showed that IFN-γ-treated Nthy-ori 3-1 cell-derived exosomes (IFN-γ-Exo) harbored TPO, HSP60 and MHC-II and activated dendritic cells (DCs) in vitro. Compared with Exo-targeted DCs (DCExo), IFN-γ-Exo-targeted DCs (DCIFN-γ-Exo) promoted the expression and release of proinflammatory cytokines, such as IFN-γ, IL-17A and IL-22, from CD4+ T lymphocytes and inhibited the expression and release of anti-inflammatory cytokines, such as IL-4, IL-10 and TGF-ß1; however, IFN-γ-Exo did not have this effect compared with Nthy-ori 3-1 cell-derived exosomes (Exo). DCIFN-γ-Exo stimulates the expression and release of cytokines from CD4+ T lymphocytes more efficiently than IFN-γ-Exo. Thus, DCIFN-γ-Exo may effectively induce CD4+ T lymphocyte-mediated immune responses and play a role in the occurrence and development of AITD.

A recombinant infectious bronchitis virus from a chicken with a spike gene closely related to that of a turkey coronavirus.

Using viral metagenomics, the complete genome sequence of an infectious bronchitis virus (IBV) strain (named ahysx-1) from a fecal sample from a healthy chicken in Anhui province, China, was determined. The genome sequence of ahysx-1 was found to be very similar to that of IBV strain ck/CH/LLN/131040 (KX252787), except for the spike gene region, which is similar to that of a turkey coronavirus strain (EU022526), suggesting that ahysx-1 is a recombinant. Recombination analysis and phylogenetic analysis based on the genomic sequences of ahysx-1 and other related strains confirmed that ahysx-1 appears to be a recombinant resulting from a recombination event that occurred between a chicken coronavirus and a turkey coronavirus. Further studies need to be performed to determine whether this recombinant IBV strain is pathogenic and whether it is transmitted between chickens and turkeys.

Consistent gene signature of schizophrenia identified by a novel feature selection strategy from comprehensive sets of transcriptomic data.

The etiology of schizophrenia (SCZ) is regarded as one of the most fundamental puzzles in current medical research, and its diagnosis is limited by the lack of objective molecular criteria. Although plenty of studies were conducted, SCZ gene signatures identified by these independent studies are found highly inconsistent. As one of the most important factors contributing to this inconsistency, the feature selection methods used currently do not fully consider the reproducibility among the signatures discovered from different datasets. Therefore, it is crucial to develop new bioinformatics tools of novel strategy for ensuring a stable discovery of gene signature for SCZ. In this study, a novel feature selection strategy (1) integrating repeated random sampling with consensus scoring and (2) evaluating the consistency of gene rank among different datasets was constructed. By systematically assessing the identified SCZ signature comprising 135 differentially expressed genes, this newly constructed strategy demonstrated significantly enhanced stability and better differentiating ability compared with the feature selection methods popular in current SCZ research. Based on a first-ever assessment on methods' reproducibility cross-validated by independent datasets from three representative studies, the new strategy stood out among the popular methods by showing superior stability and differentiating ability. Finally, 2 novel and 17 previously reported transcription factors were identified and showed great potential in revealing the etiology of SCZ. In sum, the SCZ signature identified in this study would provide valuable clues for discovering diagnostic molecules and potential targets for SCZ.

ANPELA: analysis and performance assessment of the label-free quantification workflow for metaproteomic studies.

Label-free quantification (LFQ) with a specific and sequentially integrated workflow of acquisition technique, quantification tool and processing method has emerged as the popular technique employed in metaproteomic research to provide a comprehensive landscape of the adaptive response of microbes to external stimuli and their interactions with other organisms or host cells. The performance of a specific LFQ workflow is highly dependent on the studied data. Hence, it is essential to discover the most appropriate one for a specific data set. However, it is challenging to perform such discovery due to the large number of possible workflows and the multifaceted nature of the evaluation criteria. Herein, a web server ANPELA (https://idrblab.org/anpela/) was developed and validated as the first tool enabling performance assessment of whole LFQ workflow (collective assessment by five well-established criteria with distinct underlying theories), and it enabled the identification of the optimal LFQ workflow(s) by a comprehensive performance ranking. ANPELA not only automatically detects the diverse formats of data generated by all quantification tools but also provides the most complete set of processing methods among the available web servers and stand-alone tools. Systematic validation using metaproteomic benchmarks revealed ANPELA's capabilities in 1 discovering well-performing workflow(s), (2) enabling assessment from multiple perspectives and (3) validating LFQ accuracy using spiked proteins. ANPELA has a unique ability to evaluate the performance of whole LFQ workflow and enables the discovery of the optimal LFQs by the comprehensive performance ranking of all 560 workflows. Therefore, it has great potential for applications in metaproteomic and other studies requiring LFQ techniques, as many features are shared among proteomic studies.

Preoperative insomnia and its association with psychological factors, pain and anxiety in Chinese colorectal cancer patients.

PURPOSE: Sleep disturbances are common in cancer patients, but little is known about preoperative insomnia and its associated factors in colorectal cancer (CRC) patients. The aim of this study was to clarify the relationship between preoperative insomnia and its associated factors (i.e., pain, anxiety, self-esteem, and coping styles) in CRC patients. METHODS: A cross-sectional study was conducted in consecutive CRC inpatients (N = 434), who were required to complete the questionnaires about insomnia, pain, anxiety, self-esteem, and coping styles (acceptance/resignation, confrontation, avoidance) before the day of surgery. Hierarchical regression analyses were conducted to explore the relationships between preoperative anxiety and its associated factors. RESULTS: Based on the cutoff value of Athens Insomnia Scale (scores ≥ 6) in Chinese cancer patients, the prevalence of insomnia was 38.2% before surgery. Pain (ß = 0.087, p = 0.015) and anxiety (ß = 0.372, p < 0.001) were positively associated with preoperative insomnia, while self-esteem (ß = - 0.479, p < 0.001) and confrontation coping (ß = - 0.124, p = 0.003) showed protective effects on preoperative insomnia when putting them together into hierarchical regression. The associated factors together accounted for an additional variance of preoperative insomnia (47.6%). CONCLUSIONS: In line with previous findings, the detrimental effects of pain and anxiety on preoperative insomnia were also observed in our study. More importantly, our main new findings were that self-esteem and confrontation coping played important roles in alleviating preoperative insomnia among CRC patients. Clinicians should take these results into account when developing cancer care management to relieve preoperative insomnia.

Circulating Exosomes Activate Dendritic Cells and Induce Unbalanced CD4+ T Cell Differentiation in Hashimoto Thyroiditis.

OBJECTIVE: This study explored whether circulating exosomes effectively participate in the inflammatory response in Hashimoto thyroiditis (HT). DESIGN: Exosomes were extracted from the serum of 30 patients with HT and 30 healthy control (HC) subjects. The expression of thyroperoxidase (TPO), thyroglobulin, high mobility group box 1 (HMGB1), heat shock protein 60 (HSP60), major histocompatibility complex class II (MHC-II), and intercellular adhesion molecule 1 (ICAM1) in exosomes was determined by Western blotting. Flow cytometry and immunofluorescence were performed to confirm that exosomes were taken up by healthy peripheral blood mononuclear cells (PBMCs) and dendritic cells (DCs). Then, either DCs or PBMCs were stimulated with HT exosomes (serum exosomes from patients with HT) or HC exosomes (serum exosomes from HC subjects) in the presence or absence of Toll-like receptor (TLR)2/3 inhibitors. RESULTS: TPO, HSP60, and MHC-II expression was higher in HT exosomes than in HC exosomes. Exosomes were mainly taken up by CD14+ monocytes and CD11c+ DCs. After DCs were stimulated by HT exosomes, significant elevations were observed in MyD88, TRIF, and p-P65 expression; median fluorescence intensity of CD40 and CD83; and IL-6 production. After stimulating PBMCs with HT exosomes, CD11c+TLR2+/TLR3+ and CD4+IFN-γ+Th1/IL-17A+Th17A cell percentages were significantly elevated, and CD4+CD25+Foxp3+ Treg cell percentage was significantly decreased. HT exosomes induced increased IL-17A and IFN-γ production, whereas IL-10 production was suppressed. However, addition of TLR2 or TLR3 inhibitor reversed most of the abovementioned results. CONCLUSIONS: Our study demonstrates that HT exosomes can present antigens to DCs and bind TLR2/3, causing DC activation via the nuclear factor κB signaling pathway, leading to an imbalance in CD4+ T lymphocyte differentiation, and potentially contributing to HT onset.

Simultaneous Improvement in the Precision, Accuracy, and Robustness of Label-free Proteome Quantification by Optimizing Data Manipulation Chains.

The label-free proteome quantification (LFQ) is multistep workflow collectively defined by quantification tools and subsequent data manipulation methods that has been extensively applied in current biomedical, agricultural, and environmental studies. Despite recent advances, in-depth and high-quality quantification remains extremely challenging and requires the optimization of LFQs by comparatively evaluating their performance. However, the evaluation results using different criteria (precision, accuracy, and robustness) vary greatly, and the huge number of potential LFQs becomes one of the bottlenecks in comprehensively optimizing proteome quantification. In this study, a novel strategy, enabling the discovery of the LFQs of simultaneously enhanced performance from thousands of workflows (integrating 18 quantification tools with 3,128 manipulation chains), was therefore proposed. First, the feasibility of achieving simultaneous improvement in the precision, accuracy, and robustness of LFQ was systematically assessed by collectively optimizing its multistep manipulation chains. Second, based on a variety of benchmark datasets acquired by various quantification measurements of different modes of acquisition, this novel strategy successfully identified a number of manipulation chains that simultaneously improved the performance across multiple criteria. Finally, to further enhance proteome quantification and discover the LFQs of optimal performance, an online tool (https://idrblab.org/anpela/) enabling collective performance assessment (from multiple perspectives) of the entire LFQ workflow was developed. This study confirmed the feasibility of achieving simultaneous improvement in precision, accuracy, and robustness. The novel strategy proposed and validated in this study together with the online tool might provide useful guidance for the research field requiring the mass-spectrometry-based LFQ technique.

Assessing the Effectiveness of Direct Data Merging Strategy in Long-Term and Large-Scale Pharmacometabonomics.

Because of the extended period of clinic data collection and huge size of analyzed samples, the long-term and large-scale pharmacometabonomics profiling is frequently encountered in the discovery of drug/target and the guidance of personalized medicine. So far, integration of the results (ReIn) from multiple experiments in a large-scale metabolomic profiling has become a widely used strategy for enhancing the reliability and robustness of analytical results, and the strategy of direct data merging (DiMe) among experiments is also proposed to increase statistical power, reduce experimental bias, enhance reproducibility and improve overall biological understanding. However, compared with the ReIn, the DiMe has not yet been widely adopted in current metabolomics studies, due to the difficulty in removing unwanted variations and the inexistence of prior knowledges on the performance of the available merging methods. It is therefore urgently needed to clarify whether DiMe can enhance the performance of metabolic profiling or not. Herein, the performance of DiMe on 4 pairs of benchmark datasets was comprehensively assessed by multiple criteria (classification capacity, robustness and false discovery rate). As a result, integration/merging-based strategies (ReIn and DiMe) were found to perform better under all criteria than those strategies based on single experiment. Moreover, DiMe was discovered to outperform ReIn in classification capacity and robustness, while the ReIn showed superior capacity in controlling false discovery rate. In conclusion, these findings provided valuable guidance to the selection of suitable analytical strategy for current metabolomics.

Ordered Domains and Microwave Properties of Sub-micron Structured Ba(Zn1/3Ta2/3)O3 Ceramics Obtained by Spark Plasma Sintering.

The degree of Zn2+ and Ta5+ ions ordering could play an important role in the dielectric loss in Ba(Zn1/3Ta2/3)O3 (BZT) ceramics. However, the influence of the grain size of Ba(B'1/3B″2/3)O3 ceramics with nano or sub-micron grains on the ordering domains structure is still not clear. In the present paper, highly dense (~98%) BZT microwave dielectric ceramics with homogeneous sub-micron structure (~330 nm) were prepared through spark plasma sintering (SPS). High resolution transmission electron microscopy combined with X-ray diffraction (XRD)clearly showed that the B-site ordering structure of sintered BZT samples by SPS becomes the B-site long-range 1:2 ordering as annealing proceeds. In contrast, the short-range 1:2 ordering in non-annealed counterparts was also present, which was not detectable by XRD. The size of B-site ordering domains enlarged with annealing temperature. The sub-micron structure of sintered BZT ceramics by SPS remained stable at up to 1400 C; however, the size of B-site 1:2 ordering domain was more than five times larger, which led to a significant increase of the quality factor (Q·f) to 37,700 GHz from 15,000 GHz.

IL-34 Expression Is Reduced in Hashimoto's Thyroiditis and Associated With Thyrocyte Apoptosis.

Hashimoto's thyroiditis (HT) is a common autoimmune disease accompanied by lymphocyte infiltration and thyroid tissue destruction. IL-34 was first described in 2008, and its involvement in the development of many autoimmune diseases has been recently identified. However, whether IL-34 is a regulatory factor in HT is unclear. Here, we demonstrate that IL-34 is expressed on thyroid follicular epithelial cells and that IL-34 expression is significantly reduced in thyroid tissue in patients with HT and spontaneous autoimmune thyroiditis (SAT) models. Serum IL-34 levels in patients with HT are also significantly reduced. In addition, IL-34 is associated with thyroid autoantibodies in both thyroid tissue and serum. Furthermore, our data show that IL-34 participates in the apoptosis resistance of thyrocytes in HT induced by CSF-1R and may be a potential indicator for evaluating thyrocyte damage.

Discovery of the Consistently Well-Performed Analysis Chain for SWATH-MS Based Pharmacoproteomic Quantification.

Sequential windowed acquisition of all theoretical fragment ion mass spectra (SWATH-MS) has emerged as one of the most popular techniques for label-free proteome quantification in current pharmacoproteomic research. It provides more comprehensive detection and more accurate quantitation of proteins comparing with the traditional techniques. The performance of SWATH-MS is highly susceptible to the selection of processing method. Till now, ≥27 methods (transformation, normalization, and missing-value imputation) are sequentially applied to construct numerous analysis chains for SWATH-MS, but it is still not clear which analysis chain gives the optimal quantification performance. Herein, the performances of 560 analysis chains for quantifying pharmacoproteomic data were comprehensively assessed. Firstly, the most complete set of the publicly available SWATH-MS based pharmacoproteomic data were collected by comprehensive literature review. Secondly, substantial variations among the performances of various analysis chains were observed, and the consistently well-performed analysis chains (CWPACs) across various datasets were for the first time generalized. Finally, the log and power transformations sequentially followed by the total ion current normalization were discovered as one of the best performed analysis chains for the quantification of SWATH-MS based pharmacoproteomic data. In sum, the CWPACs identified here provided important guidance to the quantification of proteomic data and could therefore facilitate the cutting-edge research in any pharmacoproteomic studies requiring SWATH-MS technique.

Therapeutic target database update 2018: enriched resource for facilitating bench-to-clinic research of targeted therapeutics.

Extensive efforts have been directed at the discovery, investigation and clinical monitoring of targeted therapeutics. These efforts may be facilitated by the convenient access of the genetic, proteomic, interactive and other aspects of the therapeutic targets. Here, we describe an update of the Therapeutic target database (TTD) previously featured in NAR. This update includes: (i) 2000 drug resistance mutations in 83 targets and 104 target/drug regulatory genes, which are resistant to 228 drugs targeting 63 diseases (49 targets of 61 drugs with patient prevalence data); (ii) differential expression profiles of 758 targets in the disease-relevant drug-targeted tissue of 12 615 patients of 70 diseases; (iii) expression profiles of 629 targets in the non-targeted tissues of 2565 healthy individuals; (iv) 1008 target combinations of 1764 drugs and the 1604 target combination of 664 multi-target drugs; (v) additional 48 successful, 398 clinical trial and 21 research targets, 473 approved, 812 clinical trial and 1120 experimental drugs, and (vi) ICD-10-CM and ICD-9-CM codes for additional 482 targets and 262 drugs against 98 disease conditions. This update makes TTD more useful for facilitating the patient focused research, discovery and clinical investigations of the targeted therapeutics. TTD is accessible at http://bidd.nus.edu.sg/group/ttd/ttd.asp.

Increased Circulating Th17 but Decreased CD4+Foxp3+ Treg and CD19+CD1dhiCD5+ Breg Subsets in New-Onset Graves' Disease.

Th17 and regulatory lymphocyte subsets such as Tregs and Bregs have been reported to play important roles in autoimmune diseases. The aim of this work was to perform quantitative studies of circulating Th17, Tregs, and Bregs in patients with new-onset Graves' disease (GD). Twenty GD patients and 20 healthy controls were involved in this study. Blood samples were taken for flow cytometry detection of CD4+IL-17+ Th17, CD4+Foxp3+ Tregs, and CD19+CD1dhiCD5+ Bregs and meanwhile, for real-time PCR measurement of gene expressions of RORγt, IL-17 and IL-10. The proportions of Tregs and Bregs as well as the Foxp3 gene expression but not IL-10 were significantly decreased in GD group compared with the healthy controls. The frequency of Th17 together with the gene expressions of RORγt and IL-17 were significantly increased in the GD group. Furthermore, the Th17/Treg ratio was also significantly higher in GD group. A significant positive correlation between Th17 and TSAb (r = 0.656, p < 0.001) but significant negative correlations between Treg/Breg and TSAb (r = -0.339, p = 0.032; r = -0.759, p < 0.001) were identified among the participants. This study indicated that increased Th17 and impaired Treg responses, along with a decreased number of CD19+CD1dhiCD5+ Breg cells, were involved in GD pathogenesis.