Myeloid-derived suppressor cells (MDSCs) emerge as a promising candidate for the immunotherapy of autoimmune hepatitis (AIH). However, targets for modulating MDSC in AIH are still being searched. ...Liver X receptors (LXRs) are important nuclear receptors linking lipid metabolism and immune responses. Despite the extensive studies of LXR in myeloid compartment, its role in MDSCs is currently less understood. Herein, expression of LXRα was found to be upregulated in AIH patients and colocalized with hepatic MDSCs. In ConA-induced hepatitis, deletion of LXRα led to increased expansion of MDSCs in the liver and alleviated the hepatic injury. MDSCs in LXRα
mice exhibited enhanced proliferation and survival comparing with WT mice. T-cell proliferation assay and adoptive cell transfer experiment validated the potent immunoregulatory role of MDSCs
and
. Mechanistically, MDSCs from LXRα
mice possessed significantly lower expression of interferon regulatory factor 8 (IRF-8), a key negative regulator of MDSC differentiation. Transcriptional activation of IRF-8 by LXRα was further demonstrated.
We reported that abrogation of LXRα facilitated the expansion of MDSCs
downregulating IRF-8, and thereby ameliorated hepatic immune injury profoundly. Our work highlights the therapeutic potential of targeting LXRα in AIH.
Boron is an essential, widely used, micronutrient element and is abundant in salt lakes on the Qinghai-Tibet Plateau. The origin and distribution of boron brine deposits on the Qinghai-Tibet Plateau ...is an important foundation for B resource formation, evolution, and enrichment, which have long been the subject of debate. The boron isotope system is a sensitive geochemical tracer, making it useful for effectively and precisely tracking a wide range of geological processes and sources. This study investigates the major cations, B, and δ
11
B values of samples (lake brine, river waters, and cold spring water) from the Bangor Co Lake which is a typical salt lake rich in boron in Tibet, China. There are magnitude-scale differences in B among different sample types: river samples < cold spring water < < brine lakes. B values vary from 0.73 to ~ 1113 mg/L. Similar to B, the δ
11
B values of the samples exhibit magnitude-scale variations as B, ranging from − 7.35‰ to + 7.66‰. There are also magnitude-scale differences in δ
11
B among different sample types. The δ
11
B values of cold spring water are relatively low, and the values range from − 1.26‰ to -7.75‰. However, the river water samples and saline lakes have higher values, from 0.38‰ to 4.62‰, and the δ
11
B values of river water samples are basically in the distribution range of those of Bangor Co Lake. This indicates that the sources of boron in Bangor Co Lake are mainly the recharge water with higher δ
11
B values and spring water with lower δ
11
B values, and the boron sources and the uneven mixing of lake water are two reasons that account for the large change in the δ
11
B value of Bangor Co Lake.
Interleukin-35 (IL-35) is a novel anti-inflammatory cytokine of IL12 cytokine family, however, the role of IL-35 in patients with AIH and its effect on myeloid-derived suppressor cells (MDSCs) has ...not yet been analyzed. The expression of IL-35 subunits (p35 and EBI3) in liver tissues was quantified by immunochemistry and its correlation with clinical parameters was explored in patients with AIH. The expression of MDSCs and IL-35 receptor (gp130 and IL-12Rβ2) were analyzed using flow cytometry and confocal staining. Besides, we utilized
culture to explore the role of IL-35 on MDSCs expansion and activation. We found that the elevated expression of both IL-35 subunits (EBI3 and p35) in liver tissue was positively associated with degrees of hepatic inflammatory and fibrosis in patients with AIH. Furthermore, the expression of EBI3 in liver was positively correlated with patient age, serum IgG levels and serum AST, and was negatively correlated with hemoglobin and albumin. Moreover, our results showed that ratio of MDSC in peripheral blood increased significantly in AIH patients as compared with healthy controls. Further study showed that CD33, a representative marker of MDSCs, co-localized well with gp130 and IL12Rβ2, suggesting MDSCs as target cell for IL-35. Consistently, MDSCs from AIH displayed a substantial higher abundance of gp130 and IL12Rβ2 and were expanded by IL-35
. IL-35-induced MDSCs showed a significant increase in Nitric oxide (NO) production but not reactive oxygen species (ROS).
IL-35 might play an important role in AIH by regulating MDSCs and it could provide new insights into the therapy of AIH.
Intrahepatic cholangiocarcinoma (ICC) is an aggressive type of cancer, and its incidence and mortality rates are increasing worldwide. Mortalin is a highly conserved chaperone protein involved in ...multiple pathological and physiological processes, including anti-apoptosis, carcinogenesis and metastasis. The Bcl-2 family of proteins can be divided into pro-survival and pro-apoptotic members, including B-cell lymphoma 2 (Bcl-2) and Bcl-2-like protein 4 (Bax). The aim of the present study was to investigate the association between mortalin, Bcl-2 and Bax, as well as the prognostic significance of the combined expression of mortalin, Bcl-2 and Bax in ICC. Immunohistochemistry was used to determine the expression of mortalin, Bcl-2 and Bax in 116 ICC samples and to assess the association between expression of 3 markers and clinicopathological features of ICC patients. This revealed that ICC tumor tissues overexpressed mortalin and Bcl-2 and exhibited low expression of Bax in ICC tumor tissues compared with that in corresponding peritumoral samples. According to Pearson's correlation coefficient analysis, high expression of mortalin in ICC was positively correlated with Bcl-2 expression and negatively correlated with Bax expression. Furthermore, multiple linear regression analysis demonstrated that mortalin was positively associated with Bcl-2, but not with Bax, in patients with ICC. Patients with ICC exhibiting high expression of mortalin/Bcl-2 or low expression of Bax were closely associated with a malignant ICC phenotype, a relatively low overall survival rate and a high recurrence rate. Multivariate analysis indicated that mortalin and Bcl-2 were independent prognostic indicators for ICC patients. Meanwhile, the concomitant overexpression of mortalin and Bcl-2 and the low expression of Bax were independent markers for predicting a relatively poor prognosis of ICC. The overexpression of mortalin and Bcl-2 and/or the low expression of Bax are implicated in the anti-apoptotic effect and tumor progression of ICC. Mortalin or Bcl-2, or a combination of mortalin, Bcl-2 and Bax may be used to predict the prognosis of ICC, as well as potential therapeutic targets.
Very-high-frequency (VHF) gun photoinjectors, capable of producing high-brightness and high-repetition-rate electron bunches, are some of the best electron sources for driving MHz-class ...repetition-rate free-electron lasers. In this study, the beam dynamics optimization of a VHF gun photoinjector for Shanghai HIgh Repetition Rate X-ray Free Electron Laser and Extreme Light Facility (SHINE) is systematically demonstrated using a genetic algorithm. Through the inclusion of the solenoid geometry as an optimization variable into the genetic algorithm, the optimum projected normalized emittance for 100 pC bunches with bunch length of 1 mm rms is reduced to 0.1 mm mrad for 100% of the particles and 0.075 mm mrad for 95% of the particles, proving that sub-100 nm emittance can be achieved in the SHINE injector using a single-cell Tsinghua University (THU) VHF gun. This emittance fulfills the requirements not only of SHINE and Linac Coherent Light Source (LCLS)-II but also of LCLS-II-High Energy (LCLS-II-HE). We demonstrate that the optimal emittance in the VHF gun injector is reduced via the optimization of the solenoid geometry, thereby reducing solenoid spherical aberration. Through the inclusion of high-order (H.O.) energy spread among the optimization objectives, the H.O. energy spread can be reduced by a factor of nearly six using a high-harmonic cavity despite a 38% emittance growth. Finally, the beam dynamics in the SHINE main accelerator show that reducing the H.O. energy spread in the injector is of great significance to improving compression efficiency and reducing bunch current spike.
Brucellosis, a neglected and global zoonotic disease, infect a variety of mammals, among which sheep are one of the main hosts. This disease results in huge economic losses and is a widespread ...concern around the world.
Based on the selection criteria, 40 articles from 2010 to 2021 of five databases (CNKI, Wanfang, VIP, PubMed and Science Direct) reported in America, Africa and Asia were included. The data showed that during this period, the overall seroprevalence of sheep brucellosis on these three continents was 6.2%. At the regional level, sheep brucellosis had the highest seroprevalence (8.5%) in Africa and the lowest seroprevalence (1.9%) in the Americas. With regard to the age of the sheep, the seroprevalence was significantly higher in adult sheep (15.5%) than in lambs (8.6%). Further, the seroprevalence was significantly higher in sheep that had abortion (44.3%) than in pregnant (13.0%) and non-pregnant sheep (9.5%). With regard to herd size, herds with >20 sheep (35.4%) had a significantly higher seroprevalence than herds with <20 sheep (16.8%). In terms of farming and grazing mode, free-range rearing (8.4%) was associated with a significantly higher seroprevalence than intensive farming (2.8%), and mixed grazing (37.0%) was associated with a significantly higher seroprevalence than single grazing (5.7%).
Sheep brucellosis is widely distributed in sheep-rearing regions of America, Africa and Asia, and sheep are susceptible to brucellosis by themselves or from other infectious sources. Therefore, timely monitoring of ovine brucellosis and improving farming and grazing patterns are critical to reducing the prevalence of brucellosis.
•Brucellosis is more common in Asia and Africa than in the Americas.•Brucellosis distribution is related to the income level of countries.•Lambs showed lower seroprevalence to brucellosis than adult sheep.•Ewe that have had an abortion have high seropositivity for Brucella spp.•Mixed grazing and free-range rearing are linked to high brucellosis prevalence.
Insulin resistance has been observed in individuals born small for gestational age (SGA) with catch-up growth (CUG), yet the mechanisms involved remain unclear. This study examined the role of GH and ...insulin signaling crosstalk in insulin resistance of SGA rats with CUG.
SGA rats were developed by dietary restriction in pregnant rats. GH receptor inhibition was performed on four-week old CUG-SGA and AGA rats. Phosphorylation of IRS-1, AKT, and ERK, and expression of SOCS3 in the skeletal muscle were determined via immunoblot analysis at baseline and after insulin stimulation in CUG-SGA, NCUG-SGA and AGA groups.
Compared to AGA controls, phosphorylation of IRS-1 and AKT in response to insulin stimulation in CUG-SGA rats was significantly blunted (P<0.05), and phosphorylation of ERK at baseline was dramatically activated (P<0.05). SOCS3 expression was significantly increased in CUG-SGA compared to AGA (P = 0.001) and NCUG-SGA (P = 0.006) rats, and was significantly suppressed following GHR inhibition (P<0.05). Furthermore, phosphorylation of IRS-1 and AKT in response to insulin stimulation increased after GHR inhibition (P<0.05).
Insulin resistance in CUG-SGA rats is associated with impairment of IRS-1-PI3K-AKT signaling, which may result from GH signaling-induced up-regulation of SOCS3.
Background: Increasing data suggests an interaction between bile acids and intestinal microbiota in the pathogenesis of primary biliary cholangitis (PBC). Bile acid sequestrants are widely used to ...bind bile acids in the intestinal lumen and are therefore posited to impact gut bacteria. Herein we aimed to investigate the effects of cholestyramine on the bile acid profile and gut microbiome in a cohort of icteric PBC patients.
Results: Thirty-three PBC patients were treated with cholestyramine, serum and stool samples were collected at baseline, 4 and 16 weeks. Shotgun metagenomic sequencing and targeted metabolomic profiling were performed. Following cholestyramine administration, patients exhibited a high interpersonal variability in remission of cholestasis, and were therefore dichotomized according to the decrease of total bilirubin. Gut microbial co-abundance networks showed distinct taxa interactions between subjects with superior remission (SR) and those with inferior remission (IR) at baseline. After treatment, compositional shifts of the microbiome in the SR group were characterized with enrichment of two Lachnospiraceae species, typically producing short-chain fatty acids (SCFAs). In contrast, Klebsiella pneumonia, a commensal pathobiont, was only increased in the IR group. Correspondingly, metabolome analysis demonstrated that patients with SR, but not IR, were marked by elevations of SCFAs including valeric acid and caproic acid. Finally, integrative analysis identified robust associations between the variations of microbiota, metabolites, and inflammatory cytokines in SR group, indicating potential mechanistic links.
Conclusions: Beneficial responses caused by cholestyramine were closely related with compositional and functional alterations in gut commensal, highlighting the possibility of exploring bile acid-microbiota interactions for treating PBC.
To determine the current prevalence and mean ages of onset of pubertal characteristics in healthy urban Chinese girls.
A cross-sectional study of sexual maturation of healthy Chinese girls was ...conducted in 9 representative cities of the eastern, western, southern, and northern parts and central region of China between 2003 and 2005. At examination, stages of breast and pubic hair development were rated on girls 3 through 19.83 years of age, and height and weight were also recorded. Data on menses were collected by the status quo method. Probit analysis was used to calculate the median age and 95% confidence interval (CI) for onset of breast and pubic hair development and menarche.
Data were analyzed for 20654 apparently healthy girls. At age 8 years, 19.57% of these girls had evidence of breast development. The median ages of onset of Tanner stages 2 and 3 for breast development were 9.20 (95% CI: 9.06-9.32) years and 10.37 (95% CI: 10.28-10.45) years, respectively. The median ages of onset of Tanner stages 2 and 3 for pubic hair development were 11.16 (95% CI: 11.03-11.29) years and 12.40 (95% CI: 12.25-12.55) years, respectively. Menses occurred at 12.27 years (95% CI: 12.16-12.39).
These data suggest that urban Chinese girls are actually experiencing earlier breast development than currently used norms. The up-to-date reference for normal pubertal development in urban Chinese girls needs to be established for the purpose of determining precocious puberty or pubertal delay.
Background
The aim of this study was to investigate the relation between the metastatic lymph node ratio (LNR) and the prognosis of non-small-cell lung cancer (NSCLC).
Methods
A total of 301 patients ...with N1 or N2 NSCLC who underwent complete pulmonary resection were analyzed retrospectively. The correlations between the LNR and clinical and pathologic data were analyzed using χ
2
test analysis. The prognostic value of the LNR was calculated by univariate Kaplan–Meier survival analysis and multivariate Cox proportional hazard model analysis. The risk groups were classified by a combination of the LNR and pN stage.
Results
The LNR was correlated with age, smoking status, pathologic type, subcarinal lymph node, clinical staging, N stage (
P
< 0.05), and the number of positive lymph nodes and positive lymph node stations (
P
< 0.0001). In the univariate analysis, the LNR played an important role in predicting overall survival (OS) (
P
< 0.0001) and disease-free survival (
P
< 0.0001) by Kaplan–Meier survival analysis. In the multivariate analysis, high LNR (>18%) was an independent poor prognostic factor for OS hazard ratio (HR) 2.5034, 95% confidence interval (CI) 1.6096–3.8933,
P
< 0.0001 and DFS (HR 1.9023, 95% CI 1.2465–2.9031,
P
= 0.0031). Stratification into high-, medium-, and low-risk groups—based on high-risk factors (LNR > 18%, N2) intermediate-risk factors (LNR > 18%, N1 or LNR < 18%, N2), and low-risk factors (LNR < 18%, N1)—could efficiently predicted outcomes (
P
< 0.0001) of patients with lymph node-positive NSCLC.
Conclusions
The combination of the LNR and pN status provides a valuable help with prognosis. However, these results must be evaluated further in a large prospective randomized clinical trial.
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