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We aimed to characterize the alterations in the immune phenotypes and explore the potential relevance to pathogenesis in IgG4-RD.Forty-two IgG4-RD patients and thirty-eight healthy controls were recruited in this study. Peripheral immunocompetent cells including T cells, CD4 + T cells, CD8 + T cells, B cells, NK cells CD4 + CD45RA + T cells (naïve T cells), CD4 + CD25 - / + Foxp3 - T cells (Teff), CD4 + CD25hiCD127lowCD161 + T cells (CD161 + Treg), CD4 + CD25hiFoxp3 + T cells (Foxp3 + Treg), CD4 + CD4RA-CXCR5 + PD1 + CCR7low T cells (pTfh), T helper (Th) 1, Th2, and Th17 before and after treatment were immunophenotyped by flow cytometry.Compared with healthy controls, IgG4-RD patients showed higher proportions of NK (20.1% vs 13.6%, p 0.01), Th1 (CD4 + IFN-γ + : 17.9% vs 14.2%, p = 0.061; TNF-α: 43.7% vs 36.7%, p 0.05), Th2 (CD4 + IL-4 + : 2.4% vs 1.3%, p 0.0001), CD161 + Treg (14.9% vs 11.6%, p 0.01), pTfh (3.2% vs 2.4%, p 0.05), and Foxp3 + Treg (8.3% vs 7.0%, p 0.01) and lower proportions of B lymphocytes (8.4% vs 13.1%, p 0.001), Teff (91.6% vs 92.6%, p 0.01), and naïve Th cells (19.9% vs 32.1%, p 0.01) before treatment. Foxp3 + Treg percentage decreased significantly after treatment (8.6% vs 6.9%, p 0.05). Both serum C3 (r = - 0.6374, p 0.01) and C4 (r = - 0.6174, p 0.01) levels were in negative correlation with CD161 + Treg. The eosinophil percentage was positively correlated with Foxp3 + Treg (r = 0.5435, p 0.05). Serum IgE level was positively correlated with Th2 (r = 0.5545, p 0.05). There was a positive correlation between CD161 + Treg and pTfh (r = 0.4974, p 0.05) while a negative correlation between Th2 and B cells (r = - 0.4925, p 0.05).Immune phenotypes were altered in IgG4-RD. Treg/Teff balance was shifted toward Treg in IgG4-RD. CD161 + Treg was likely to be involved in the pathogenesis of IgG4-RD. Key Points •Immune phenotypes were altered in B cells, T cells, and NK cells in IgG4-RD. •Treg/Teff balance was shifted toward Treg in IgG4-RD. •CD161+ Treg maybe play a proinflammatory role in IgG4-RD.

This phase III trial (NCT04178850) evaluated the efficacy, safety, and immunogenicity of GB242, an infliximab biosimilar, vs. infliximab (Remicade®) reference product in patients with moderate-to-severe active rheumatoid arthritis (RA) combination with methotrexate (MTX) therapy. Patients were randomized in a 1:1 ratio to receive either GB242 or INF (3 mg/kg). Therapeutic equivalence of clinical response according to the American College of Rheumatology 20% (ACR20) response rate at week 30 was declared if the two-sided 95% CI for the treatment difference was within ± 14%. The comparison of GB242 with INF also included the proportion of patients achieving a week 30 ACR 50 response, ACR70 response, change in Disease Activity Score 28 (DAS28), as well as safety and immunogenicity. A total of 570 subjects were randomized into GB242 (N = 285) or INF (N = 285) and 283 subjects in each group were analyzed. At week 30, the ACR20 was 62.54% for the GB242 group (95% CI 56.62–68.20%) and 56.89% for the INF group (95% CI 50.90–62.74%). The difference between the two groups was 5.65% with a 95% CI of – 2.48 to 13.74. ACR50 response was 37.12% for GB242 and 32.86% for INF at week 30. ACR70 response was 19.79% for GB242 and 16.96% for INF at week 30, respectively. The incidence of treatment-emergent adverse events was comparable (77.4% in GB242 vs. 80.2% in INF) and detection of antidrug antibodies (ADA) to infliximab up to week 30 (60.8% in GB242 vs. 59.4% in INF) was comparable. GB242 demonstrated equivalent efficacy to INF at week 30. Moreover, GB242 was well tolerated, with a similar immunogenicity and safety profile comparable to INF.

In this paper, we report in situ preparation of nickel hydroxide nanoflake array on carbon cloth (Ni(OH)2 NA/CC) by a rapid and simple microplasma method. Using this technique, Ni(OH)2 nanoflake can be prepared on carbon cloth in only 1.5 h at atmospheric pressure and ambient temperature. As an electrode with highly efficient catalytic and non-enzymatic sensor for detecting glucose, such a Ni(OH)2 NA/CC electrode showed excellent electrocatalytic activity with a short response time within 5 s, low detection limit (LOD) of 62 nM (S/N=3), and response sensitivity of 2216.2 mA mM−1 cm−2, meanwhile a satisfactory reproducibility and selectivity.

In clinical practice, we found that IgG4-related disease (IgG4-RD) patients complicated with allergic rhinitis (AR)/chronic rhinosinusitis (CRS) seemed to have unique characteristics different from patients with IgG4-RD alone. In this study, demographic, clinical and laboratory characteristics of IgG4-RD patients complicated with AR/CRS were investigated. We retrospectively analyzed 756 IgG4-RD patients who were recruited in four medical centers from 2009 to 2021. We divided 756 IgG4-RD patients into 2 groups: the case group included IgG4-RD patients complicated with AR/CRS, and the control group included IgG4-RD patients without AR/CRS. 411 patients were complicated with AR/CRS among 756 IgG4-RD patients. Multiple organs involvement (≥ 3, p p p p p p p

Rheumatoid arthritis (RA) is an aggressive autoimmune arthritis, and current therapies remain unsatisfactory due to low remission rate and substantially adverse effects. Low-dose interleukin-2 (Ld-IL2) is potentially a therapeutic approach to further improve the disease. This randomized, double-blind, placebo-controlled trial was undertaken to evaluate the efficacy and safety of Ld-IL2 in patients with active RA. Patients were randomly assigned (1:1) to receive Ld-IL2, defined as a dose of 1 million IU, or placebo in a 12-week trial with a 12-week follow-up. Three cycles of Ld-IL2 or placebo were administered subcutaneously every other day for 2 weeks (a total of 7 doses), followed by a 2-week break. All patients received a stable dose of methotrexate (MTX). The primary outcomes were the proportion of patients achieving the ACR20, DAS28-ESR n = 17) than for the placebo+MTX group (n = 23) (P = 0.018 and P = 0.015, respectively). More patients achieved ACR20 response in the Ld-IL2 + MTX group than those in the placebo+MTX group at week 12 (70.6% vs 43.5%) and at week 24 (76.5% vs 56.5%) (P = 0.014). In addition, low Treg and high IL-21 were associated with good responses to Ld-IL2. Ld-IL-2 treatment was well-tolerated in this study. These results suggested that Ld-IL2 was effective and safe in RA. ClinicalTrials.gov number: NCT 02467504.

BackgroundLung cancer is the leading cause of cancer-related mortality. The alteration of DNA methylation plays a major role in the development of lung cancer. Methylation biomarkers become a possible method for lung cancer diagnosis.ResultsWe identified eleven lung cancer-specific methylation markers (CDO1, GSHR, HOXA11, HOXB4-1, HOXB4-2, HOXB4-3, HOXB4-4, LHX9, MIR196A1,PTGER4-1,andPTGER4-2), which could differentiate benign and malignant pulmonary nodules. The methylation levels of these markers are significantly higher in malignant tissues. In bronchoalveolar lavage fluid (BALF) samples, the methylation signals maintain the same differential trend as in tissues. An optimal 5-marker model for pulmonary nodule diagnosis (malignant vs. benign) was developed from all possible combinations of the eleven markers. In the test set (57 tissue and 71 BALF samples), the area under curve (AUC) value achieves 0.93, and the overall sensitivity is 82% at the specificity of 91%. In an independent validation set (111 BALF samples), the AUC is 0.82 with a specificity of 82% and a sensitivity of 70%.ConclusionsThis model can differentiate pulmonary adenocarcinoma and squamous carcinoma from benign diseases, especially for infection, inflammation, and tuberculosis. The model’s performance is not affected by gender, age, smoking history, or the solid components of nodules.

Mitochondrial dysfunction and oxidative stress play a key role in ischemia/reperfusion (I/R) induced brain injury. We previously showed that ubiquilin-1 (Ubqln1), a ubiquitin-like protein, improves proteostasis and protects brains against oxidative stress and I/R induced brain injury. We demonstrate here that nialamide (NM), a non-selective monoamine oxidase (MAO) inhibitor, upregulated Ublqn1 and protected neurons from oxygen-glucose deprivation- and I/R-caused cell death in in vitro and in vivo, respectively. Post-ischemic administration of the NM in a stroke mouse model even at 3 h following I/R still reduced neuronal injury and improved functional recovery and survival. Treating stroke animals with NM also increased the association of Ubqln1 with mitochondria and decreased the total oxidized and polyubiquitinated protein levels. Intriguingly, NM-enhanced proteostasis was also associated with reduced I/R-caused neuroinflammation, as reflected by attenuated activation of microglia and astrocytes as well as reduced TNF-α level. Thus, our results suggest that MAO inhibition-induced neuroprotection following I/R involves improved proteostasis and reduced neuroinflammation.

Room temperature sodium-sulfur battery has special research value due to the low cost of sulfur resource and its high specific capacity. However, the cathode material of the room temperature sodium-sulfur battery mainly combines carbon materials and elemental sulfur now, and the utilization of the sulfur is low. Herein, a two-dimensional layered material Ti3C2Tx was prepared. The cathode material of Ti3C2Tx@S was prepared by a simple melting method at 155 °C, and the mass percentage of the sublimed sulfur was 55%. Then, the valence states of Ti and C were characterized by XPS after loading the sublimed sulfur. The results indicated that a part of Ti3+ turned into the Ti4+, and some C–S bonds were formed. Additionally, the electrochemical properties of Ti3C2Tx@S were studied in sodium-ion battery under ambient conditions. The battery exhibited excellent rates performance, the first discharge specific capacity was 447.0 mAh g−1, and a specific capacity of 120.0 mAh g−1 was maintained at the current density of 1000 mA g−1. In addition, Ti3C2Tx@S demonstrated excellent cycle stability in room temperature sodium-sulfur battery. In the case of a current density of 100 mA g−1, the discharge specific capacity was maintained at 150.0 mAh g−1 after 300 cycles, and the capacity retention rate was 80% from the second cycle. For the electrode, the specific capacity still remained 107.7 mAh g−1 after 150 cycles.

BackgroundColorectal cancer (CRC) is a leading cause of cancer-related deaths worldwide. Early detection of CRC can significantly reduce its mortality rate. Current method of CRC diagnosis relies on the invasive endoscopy. Non-invasive assays including fecal occult blood testing (FOBT) and fecal immunological test (FIT) are compromised by low sensitivity and specificity, especially at early stages. Thus, a non-invasive and accurate approach for CRC screening would be highly desirable.ResultsA new qPCR-based assay combining the simultaneous detection of the DNA methylation status of ten candidate genes was used to examine plasma samples from 56 normal controls, 6 hyperplastic polys, 9 non-advanced adenomas (NAAs), 22 advanced adenomas (AAs) and 175 CRC patients, using 10 ng of cfDNA. We further built a logistic regression model for CRC diagnosis. We tested ten candidate methylation markers including twist1, vav3-as1, fbn1, c9orf50, sfmbt2, kcnq5, fam72c, itga4, kcnj12 and znf132. All markers showed moderate diagnostic performance with AUCs ranging from 0.726 to 0.815. Moreover, a 4-marker model, comprised of two previously reported markers (c9orf50 and twist1) and two novel ones (kcnj12 and znf132), demonstrated high performance for detecting colorectal cancer in an independent validation set (N = 69) with an overall AUC of 0.911 [95% confidence interval (CI) 0.834–0.988], sensitivity of 0.800 [95% CI 0.667–0.933] and specificity of 0.971 [95% CI 0.914–1.000]. The stage-stratified sensitivity of the model was 0.455 [95% CI 0.227–0.682], 0.667 [95% CI 0.289–1.000], 0.800 [95% CI 0.449–1.000], 0.800 [95% CI 0.449–1.000] and 0.842 [95% CI 0.678–1.000] for advanced adenoma and CRC stage I-IV, respectively.Conclusionkcnj12 and znf132 are two novel methylation biomarkers for CRC diagnosis. The 4-marker methylation model provides a new non-invasive choice for CRC screening and interception.

Background IgG4-related ophthalmic disease (IgG4-ROD) is one of the phenotypes of IgG4-related disease (IgG4-RD), and its lesions are mainly located in the ocular. Currently, there are few studies on IgG4-ROD and no study has compared the phenotypic differences between IgG4-ROD and non IgG4-ROD (nIgG4-ROD). Thus, it is difficult to establish the optimal treatment strategy for IgG4-ROD. The aim of this study was to identify the disparities between the two groups and to clarify the risk factors for IgG4-ROD relapse. Methods 434 IgG4-RD patients met comprehensive diagnostic criteria and diagnosed at Peking University People’s Hospital between January 2009 and January 2020 were recruited in this study. Patients were divided into IgG4-ROD and nIgG4-ROD group according to the ophthalmic involvement. Demographic, clinical, and laboratory data of two groups were collected and compared. Cox regression analysis was used to identify the independent risk factors for IgG4-ROD relapse. Results 255 IgG4-ROD patients were identified in this study. IgG4-ROD group had almost equal sex ratio, younger age of disease onset and diagnosis comparing with nIgG4-ROD patients. As compared to nIgG4-ROD group, higher percentage of IgG4-ROD patients met the 2019 American College of Rheumatology/European League Against Rheumatism classification criteria (AECC) for IgG4-RD; moreover, IgG4-ROD patients had higher AECC scores and IgG4-RD responder index (RI). Allergic diseases and multiorgan involvement were more common in IgG4-ROD group. IgG4-ROD was frequently associated with salivary gland, paranasal sinus, lung, and lymph node involvement, while retroperitoneal fibrosis and biliary system lesions were more common in nIgG4-ROD. IgG4-ROD patients had higher serum IgG4 levels, IgG4/IgG ratio, IgE levels, and lower CRP levels. The initial glucocorticoid plus immunosuppressant was a protective factor for IgG4-ROD relapse. IgG4-ROD patients treated with initial glucocorticoid plus immunosuppressant had longer relapse-free survival time than patients treated with initial glucocorticoid monotherapy. Conclusions IgG4-ROD patients had distinctive clinical features compared with nIgG4-ROD patients. The initial glucocorticoid plus immunosuppressant was a protective factor for IgG4-ROD relapse, which could prolong the relapse-free survival time of IgG4-ROD patients. These findings may have important implications for understanding and management of IgG4-ROD.

Background Whether routine lymph node dissection for early endometrial cancer is beneficial to survival is still controversial. However, surgeons usually perform lymph node dissection on all patients with early endometrial cancer. This study aimed to prove that the risk of lymph node metastasis, as defined by our standard, is very low in such patients and may change the current surgical practice. Methods 36 consecutive patients who had staged surgery for endometrial cancer were collected. All eligible patients meet the following very low risk criteria for lymph node metastasis, including: (1) preoperative diagnosis of endometrial cancer (preoperative pathological diagnosis), (2) tumors confined to the uterine cavity and not beyond the uterine body, (3) PET-MRI lymph node metastasis test is negative. PET-MRI and pathological examination were used to assess the extent and size of the tumor, the degree of muscular invasion, and lymph node metastasis. Results The median age at diagnosis was 52 years (range 35–72 years). The median tumor size on PET-MRI was 2.82 cm (range 0.66–6.37 cm). Six patients underwent robotic surgery, 20 underwent laparoscopic surgery, 8 underwent Laparoscopic-assisted vaginal hysterectomy, and 2 underwent vaginal hysterectomy. 23% (63.9%) patients had high-grade (i.e. 2 and 3) tumors. Among the 36 patients who underwent lymph node sampling, the median number of lymph nodes retrieved was 32 (range 9–57 nodules). No patient (0%) was diagnosed with lymph node metastasis. According to the policy of each institution, 8 patients (22.2%) received adjuvant therapy, and half of them also received chemotherapy (4 patients; 50%). Conclusions None of the patients who met the criteria had a pathological assessment of lymph node metastasis. Omitting lymph node dissection may be reasonable for patients who meet our criteria.

This work reports the surface coating of Li1.2Mn0.54Ni0.13Co0.13O2 cathode material with nano-CeO2 by a versatile hydrothermal method. Thus, obtained nano-CeO2-coated Li1.2Mn0.54Ni0.13Co0.13O2 material was characterized by XRD, SEM, and TEM. It is revealed that the synthesized nano-CeO2 material has rich oxygen vacancies, and a spinel-phase layer is formed on the surface of host material. The electrochemical testing results show that Li1.2Mn0.54Ni0.13Co0.13O2 with 4 wt% CeO2 coating (denoted as C3) has good rate capability and enhanced cyclic stability, enhanced initial discharge capacity of 298.5 mA h g−1 (0.05 C) compared to 281.9 mAh g−1, and excellent initial coulombic efficiency of 86.94% compared to 77.28% for the pristine one in the potential range 2.0–4.8 V (vs. Li/Li+). It is worth noting that this modified strategy greatly reduces the irreversible capacity loss (ICR) of the first cycle of active materials, the ICR of the C3 (44.8 mAh g−1) is markedly lower than pristine material (82.9 mAh g−1) at the current density of 12.5 mA g−1 (0.05 C). Such improvements are mainly ascribed to the oxygen vacancies in nano-CeO2 coating layer, which are responsible for the promoted activation of Li2MnO3. Moreover, the formation of the spinel structure is beneficial to stabilize the crystal lattice of the bulk material and facilitate Li+ diffusion by unique 3D transport channels.

The effect of the Nb5+ substitution with a charge-compensated strategy in lithium-rich layered oxides (LLOs) Li1.2Ni0.13+xCo0.13-xMn0.54-xNbxO2 (x = 0, 0.01, 0.02, and 0.03) has been investigated systematically. A hydroxide co-precipitation method followed by a high-temperature solid-state reaction is adopted in the synthesis process. Structural characterization confirms that the low dose substituting of Nb5+ in the layered structures forms a solid solution, and the samples show low cation mixing and enlarged Li+-diffusing channels, which imply favorable high-rate capability. The initial charge/discharge measurements suggest that the oxygen loss from the network during the delithiation process has been suppressed by the substitution of Nb5+ due to the formation of robust Nb–O bonds and a decrease in TM-O (TMs are transition metals) covalence. Moreover, these Nb–O bonds contribute to the stabilization of the crystalline framework, resulting in an excellent cycle stability with a mitigated voltage decay.

Patients with IgG4-related disease (IgG4-RD) often have elevated serum IgG4 levels. Here, we aimed to evaluate the diagnostic performances of elevated serum IgG4 concentration and IgG4/IgG ratio for IgG4-RD. We retrospectively analyzed 1381 patients subjected to serum IgG subclass testing to differentiate IgG4-RD from other diseases at Peking University People’s Hospital from 2012 to 2016. This sample included 133 IgG4-RD patients and 1248 non-IgG4-RD patients. Serum IgG subclass concentrations were measured using Siemens reagents. The median values (25th–75th percentile) for serum IgG4 concentration and IgG4/IgG ratio, respectively, were 8640 (3970–17750) mg/L and 0.339 (0.229–0.517) in IgG4-RD patients and 450 (220–920) mg/L and 0.032 (0.014–0.061) in non-IgG4-RD patients (p

Lithium-excess oxide shows great potential for its high specific capacity of exceeding 280 mAh g−1. However, the poor rate capability caused by the poor electrochemical kinetics condition as well as the structure instability block the way of its application. Here, we aimed to improve the kinetics circumstance for lithium ion transference through the material bulk by synthesizing lithium-excess oxide with high specific surface area. Petal-like nanoplates and nanoparticles with excellent electrochemical performance were obtained at different sintering temperatures and times by the electrospinning-sintering method, which facilitates the sufficient contact of electrode and electrolyte and helps to reduce the polarization during the electrochemical reaction process. Cyclic voltammetry tests verify that a portion of oxidized oxygen is reduced reversibly at 3.0 V and the reduction of oxygen contributes to the discharge capacity. Electrochemical impedance spectroscopy plots illustrate the ameliorative electrochemical kinetics is conductive to the oxidation of oxygen at 4.5 V.

Stroke is pathologically associated with oxidative stress, protein damage, and neuronal loss. We previously reported that overexpression of a ubiquitin-like protein, ubiquilin-1 (Ubqln), protects neurons against ischemia-caused brain injury, while knockout of the gene exacerbates cerebral ischemia-caused neuronal damage and delays functional recovery. Although these observations indicate that Ubqln is a potential therapeutic target, transgenic manipulation-caused overexpression of Ubqln occurs before the event of ischemic stroke, and it remains unknown whether delayed Ubqln overexpression in post-ischemic brains within a clinically relevant time frame is still beneficial. To address this question, we generated lentiviruses either overexpressing or knocking down mouse Ubqln, and treated post-ischemic stroke mice 6 h following the middle cerebral artery occlusion with the lentiviruses before animal behaviors were evaluated at day 1, 3, 5, and 7. Our data indicate that post-ischemic overexpression of Ubqln significantly promoted functional recovery, whereas post-ischemic downregulation of Ubqln expression delays functional recovery. To further understand the mechanisms underlying how Ubqln functions, we also isolated protein aggregates from the brains of wild-type mice or the mice overexpressing Ubqln following ischemia/reperfusion. Western blot analysis indicates that overexpression of Ubqln significantly reduced the accumulation of protein aggregates. These observations not only suggest that Ubqln is a useful candidate for therapeutic intervention for ischemic stroke but also highlight the significance of proteostasis in functional recovery following stroke.

Background Immunoglobulin G4-related sialadenitis (IgG4-RS) is a newly recognized immune-mediated systemic disease. Despite its good response to steroid therapy, its treatment protocol is not standardized and the long-term outcome is controversial. The study was conducted to determine the short-term and long-term outcomes of IgG4-RS patients treated with glucocorticoids and steroid-sparing immunosuppressive agents, to analyze secretory function, serological and radiological changes in salivary glands and to assess the usefulness of serum IgG4 level as an indicator of disease activity. Methods IgG4-RS patients who were treated for more than 3 months were enrolled. Serological tests, salivary gland function assessment and computed tomography (CT) were performed before treatment and during follow up. The treatment outcomes in the short and the long term were evaluated, and the relationship between serum IgG4 level and salivary gland volume was analyzed. Results Glucocorticoids were used in all 43 patients and steroid-sparing immunosuppressive agents in 38 patients (88.4%). The follow-up period was 24.6 ± 14.9 months. Clinical remission was achieved in all patients after induction therapy. During short-term observation, salivary gland secretion significantly increased, and the serum IgG4 levels, the volumes and CT values of submandibular and parotid gland decreased significantly (P

We aimed to characterize the molecular differences and effects from prednisone treatment among IgG4-related disease with salivary gland lesions (RD-SG), without SG lesions (RD-nonSG), and IgG4-related retroperitoneal fibrosis (RF). RNA sequencing was conducted on blood from 25 RD-SG, 11 RD-nonSG, 3 RF and 10 control subjects. Among these, 8 RD-nonSG and 12 RD-SG patients were subjected to treatment with prednisone and/or glucocorticoid-sparing agents. Six RD patients had a longitudinal time point. The mRNA levels of IgG4 and IgE, genes specific for Th2 cells, eosinophils, and neutrophils were over-expressed in RD-SG and RD-nonSG. A B-cell signature was suppressed in patients group versus controls, while Th1, Th2, Treg, and eosinophil gene signatures were increased in patients without treatment. Interestingly, Tfh genes and B cell signature were decreased at flare disease state. Prednisone treatment led to increased neutrophil, but decreased Treg signatures. Serum IgG4 levels correlated with the eosinophil and neutrophil gene signatures in RD-SG patients, and with a B cell signature in only RD-nonSG patients. IgG4, IgE, and cell-specific signatures are regulated in patients, suggesting the imbalance of immune and inflammatory cells in IgG4-related disease. Prednisone treatment selectively modulates Treg, eosinophil, and neutrophil signatures.

Alzheimer's disease (AD), the most common cause of dementia, is neuropathologically characterized by accumulation of insoluble fibrous inclusions in the brain in the form of intracellular neurofibrillary tangles and extracellular senile plaques. Perturbation of the ubiquitin-proteasome system (UPS) has long been considered an attractive hypothesis to explain the pathogenesis of AD. However, studies on UPS functionality with various methods and AD models have achieved non-conclusive results. To get further insight into UPS functionality in AD, we have crossed a well-documented APPswe/PS1dE9 AD mouse model with a UPS functionality reporter, GFPu, mouse expressing green fluorescence protein (GFP) fused to a constitutive degradation signal (CL-1) that facilitates its rapid turnover in conditions of a normal UPS. Our western blot results indicate that GFPu reporter protein was accumulated in the cortex and hippocampus, but not striatum in the APPswe/PS1dE9 AD mouse model at 4 weeks of age, which is confirmed by fluorescence microscopy and elevated levels of p53, an endogenous UPS substrate. In accordance with this, the levels of ubiquitinated proteins were elevated in the AD mouse model. These results suggest that UPS is either impaired or functionally insufficient in specific brain regions in the APPswe/PS1dE9 AD mouse model at a very young age, long before senile plaque formation and the onset of memory loss. These observations may shed new light on the pathogenesis of AD.

A rapid, sensitive and accurate high performance liquid chromatography method using tandem mass spectrometry detection for hydralazine in BALB/C mouse plasma and brain was developed and validated. The method involved a derivatization with 2,4-pentanedione at 50 °C for 1 h, and a step of solid phase extraction to purify and concentrate hydralazine derivative. Chromatographic separation was carried out on an Agilent ZORBAX SB-C18 column by elution with methanol–0.01 mol L−1 ammonium acetate (60:40, v/v). The multiple reaction monitoring transition used for quantification was m/z 225.2 → 129.5 in the electrospray positive ionization mode. Good linearity was obtained over the concentration range of 10–200 ng mL−1. The limits of detection were 0.49 and 1.05 ng mL−1 for hydralazine in mouse plasma and brain, respectively. The limits of quantitation were 1.5 and 3.18 ng mL−1 for hydralazine in mouse plasma and brain, respectively. Sample analysis time was 6 min including sample separation. The method was successfully applied to a pharmacokinetic study following intraperitoneal injection of hydralazine in BALB/C mice at the dose of 20 mg kg−1.

Introduction Immunoglobulin G4-related disease (IgG4-RD) is a newly recognized fibro-inflammatory condition. Forty-two cases with immunoglobulin G4-related sialadenitis (IgG4-RS) confirmed by histopathological and immunohistochemical assessment were studied to clarify the clinicopathologic characteristics of the salivary glands involved in IgG4-RS, especially the relationship between the histopathologic features and function of salivary glands or serum levels of IgG4. Methods Clinical, serologic, imaging and histopathological data of these cases were analyzed. CT volumes of submandibular, parotid, and lacrimal glands were calculated. The saliva flow rate was measured. Scintigraphy with 99mTc-pertechnetate was undertaken in 31 cases, and the concentration index (CI) and secretion index (SI) was calculated. Relationships between fibrosis severity and salivary gland function or serum IgG4 levels were analyzed. Results The first symptom was swelling of bilateral submandibular or lacrimal glands. Physical examination showed multiple bilateral major salivary glands (including sublingual and accessory parotid glands) and lacrimal glands were enlarged in IgG4 RS. Multiple enlarged cervical lymph nodes were noted in 30 patients. Saliva flow at rest was lower than normal in 34 cases; stimulated saliva flow was lower than normal in 15 cases. Secretory function was reduced more severely in the submandibular glands than in the parotid glands. Serum levels of IgG4 were elevated in 95.2% of cases and 78.6% patients had increased IgE levels. Serum IgG4 level was higher and saliva secretion lower as glandular fibrosis increased. Conclusions Prominent changes in the morphology, histology, immunohistochemistry and secretion of the major salivary glands of IgG4-RS patients were accompanied by involvement of the lacrimal glands and cervical lymph nodes. Elevated IgE, allergic history, eosinophil infiltration suggest allergic reactions as a potential pathogenesis of IgG4-RS. Severity of glandular fibrosis correlated with salivary function and serum levels of IgG4.

Rheumatoid arthritis (RA) is a T-cell-mediated systemic autoimmune disease, characterized by synovium inflammation and articular destruction. Bone marrow mesenchymal stem cells (MSCs) could be effective in the treatment of several autoimmune diseases. However, there has been thus far no report on umbilical cord (UC)-MSCs in the treatment of RA. Here, potential immunosuppressive effects of human UC-MSCs in RA were evaluated.The effects of UC-MSCs on the responses of fibroblast-like synoviocytes (FLSs) and T cells in RA patients were explored. The possible molecular mechanism mediating this immunosuppressive effect of UC-MSCs was explored by addition of inhibitors to indoleamine 2,3-dioxygenase (IDO), Nitric oxide (NO), prostaglandin E2 (PGE2), transforming growth factor β1 (TGF-β1) and interleukin 10 (IL-10). The therapeutic effects of systemic infusion of human UC-MSCs on collagen-induced arthritis (CIA) in a mouse model were explored.In vitro, UC-MSCs were capable of inhibiting proliferation of FLSs from RA patients, via IL-10, IDO and TGF-β1. Furthermore, the invasive behavior and IL-6 secretion of FLSs were also significantly suppressed. On the other hand, UC-MSCs induced hyporesponsiveness of T cells mediated by PGE2, TGF-β1 and NO and UC-MSCs could promote the expansion of CD4(+) Foxp3(+) regulatory T cells from RA patients. More importantly, systemic infusion of human UC-MSCs reduced the severity of CIA in a mouse model. Consistently, there were reduced levels of proinflammatory cytokines and chemokines (TNF-α, IL-6 and monocyte chemoattractant protein-1) and increased levels of the anti-inflammatory/regulatory cytokine (IL-10) in sera of UC-MSCs treated mice. Moreover, such treatment shifted Th1/Th2 type responses and induced Tregs in CIA.In conclusion, human UC-MSCs suppressed the various inflammatory effects of FLSs and T cells of RA in vitro, and attenuated the development of CIA in vivo, strongly suggesting that UC-MSCs might be a therapeutic strategy in RA. In addition, the immunosuppressive activitiy of UC-MSCs could be prolonged by the participation of Tregs.