Search

Pulmonary fibrosis (PF) is one of the sequelae of Corona Virus Disease 2019 (COVID-19), and currently, lung transplantation is the only viable treatment option. Hence, other effective treatments are urgently required. We investigated the therapeutic effects of an approved botanical drug, cepharanthine (CEP), in a cell culture model of transforming growth factor-β1 (TGF-β1) and bleomycin (BLM)-induced pulmonary fibrosis rat models both in vitro and in vivo. In this study, CEP and pirfenidone (PFD) suppressed BLM-induced lung tissue inflammation, proliferation of blue collagen fibers, and damage to lung structures in vivo. Furthermore, we also found increased collagen deposition marked by α-smooth muscle actin (α-SMA) and Collagen Type I Alpha 1 (COL1A1), which was significantly alleviated by the addition of PFD and CEP. Moreover, we elucidated the underlying mechanism of CEP against PF in vitro. Various assays confirmed that CEP reduced the viability and migration and promoted apoptosis of myofibroblasts. The expression levels of myofibroblast markers, including COL1A1, vimentin, α-SMA, and Matrix Metallopeptidase 2 (MMP2), were also suppressed by CEP. Simultaneously, CEP significantly suppressed the elevated Phospho-NF-κB p65 (p-p65)/NF-κB p65 (p65) ratio, NOD-like receptor thermal protein domain associated protein 3 (NLRP3) levels, and elevated inhibitor of NF-κB Alpha (IκBα) degradation and reversed the progression of PF. Hence, our study demonstrated that CEP prevented myofibroblast activation and treated BLM-induced pulmonary fibrosis in a dose-dependent manner by regulating nuclear factor kappa-B (NF-κB)/ NLRP3 signaling, thereby suggesting that CEP has potential clinical application in pulmonary fibrosis in the future.

Background and Purpose: Patients with basilar artery (BA) dolichosis are at high risk of acute pontine infarction (API), but the association between BA dolichosis and long–term stroke recurrence has received little attention. We aimed to identify the effect of BA dolichosis on the risk of long–term brainstem infarction recurrence in patients with API.Methods: In this prospective cohort study, we enrolled 113 patients with API admitted to our department. BA dolichosis was diagnosed by a BA curve length >29.5 mm or bending length (BL) >10 mm on magnetic resonance angiography. The primary outcome was the occurrence of diffusion–weighted imaging (DWI)–confirmed brainstem infarction. The Cox proportional hazard model was used to detect possible predictors of brainstem infarction recurrence.Results: Among 113 patients with API, 39 (34.5%) patients had BA dolichosis, and DWI–confirmed brainstem infarction recurred in 15 (13.3%) patients with a mean follow–up time of 31.2 months; the estimated 5–year incidence of brainstem infarction recurrence was 23.1% in patients with BA dolichosis, which was significantly higher than the incidence of 8.1% in patients without BA dolichosis. Cox proportional hazard analysis showed that age ≥65 years (hazard ratio (HR) = 3.341, 95% confidence interval (CI): 1.079–10.348, P = 0.036) and BA dolichosis (HR = 3.048, 95% CI: 1.069–8.693, P = 0.037) were significantly associated with a higher risk of brainstem infarction recurrence. In a subgroup analysis stratified by age, the patients aged ≥65 years with BA dolichosis had a higher risk of brainstem infarction recurrence (HR = 7.319, 95% CI: 1.525–35.123, P = 0.013).Conclusions: This study indicates that BA dolichosis may increase the risk of long–term brainstem infarction recurrence in patients with API, especially in elderly patients, and therefore warrants more attention in clinical practice.

Previous studies have suggested that Lycium barbarum (L. barbarum) has a radioprotective function, although more in-depth investigation is still required. We investigated the radioprotective efficacy of extract of the fruits of L. barbarum (LBE) and its radioprotective mechanisms. Mice were exposed to 8.5 Gy, 5.5 Gy, or 6.0 Gy total body irradiation (TBI), and the survival rate, lymphocyte percentage, amount of cytokines, and viability of the irradiated cells, as well as the gut microbiome and fecal metabolomics were studied. LBE enhanced the survival of the mice exposed to 8.5 Gy γ-ray TBI or 5.5 Gy X-ray TBI. After 6.0 Gy γ-ray TBI, LBE exhibited good immunomodulatory properties, mainly characterized by the accelerated recovery of lymphocyte percentages, and the enhanced expression of immune-related cytokines. LBE reconstituted the gut microbiota of irradiated mice, increased the relative abundance of potentially beneficial genera (e.g., Turicibacter, Akkermansia), and decreased the relative abundance of potentially harmful bacterial genera (e.g., Rikenellaceae_RC9_gut_group). Beneficial regulatory effects of LBE on the host metabolites were also noted, and the major upregulated metabolites induced by LBE, such as Tetrahydrofolic acid and N-ornithyl-L-taurine, were positively correlated with the immune factor interleukin (IL)-6. In vitro, LBE also increased the vitality of rat small intestinal epithelial cells (IEC-6) after 4.0 Gy γ-ray irradiation and promoted the growth of Akkermansia muciniphila. These results confirmed a radioprotective function of LBE and indicated that the radioprotective mechanism may be due to immunomodulation and the synergistically modulating effect on the gut microbiota and related metabolites.

BackgroundNon-small cell lung cancer (NSCLC) accounts for about 85% of lung cancers. This study aimed to discover the potential miRNA biomarkers for early detection of NSCLC.MethodsTotal circulating miRNAs were extracted from six patients and six volunteers and run on the miRNA chip. The differentially expressed miRNAs acquired by data mining were intersected with chip results, and qRT-PCR were carried out. Then the differentially miRNAs were validated by using a validation cohort (120 participants). ROC curves were established to evaluate the diagnostic efficacy of the differentially circulating miRNAs. The target genes of the differential miRNAs were identified using the miRTarBase database, and follow-up GO and KEGG enrichment analysis were conducted.ResultsWe identified 577 miRNA which screened according to the criteria (fold change > 2 and p value < 0.05). Among them, seven circulating miRNAs passed additional filtering based on data mining. These miRNAs were further validated in the training and validation cohort. miR-492, miR-590-3p, and miR-631 were differentially expressed in the patients’ serum, and the area under the ROC curve (AUC) values of these miRNAs were 0.789, 0.792, and 0.711, respectively. When using them as a combination to discriminate healthy volunteers from patients, the AUC reached 0.828 (95% CI, 0.750–0.905, p = 0.000) with a sensitivity of 86.7% and specificity of 71.7%. The follow-up enrichment analysis showed that target genes of three miRNA were associated with tumorigenesis and progression, such as cell cycle and P53 signaling pathway.ConclusionsThe combination of miR-492, miR-590-3p, and miR-631 can be utilized to distinguish healthy individuals and early-stage NSCLC patients.ImpactThe combination of miR-492, miR-590-3p, and miR-631 might be a promising serum biomarker in patients for the early diagnosis of NSCLC.

Primary Sjögren’s syndrome (pSS) is a chronic autoimmune disease characterized by lymphocytic infiltration and tissue destruction of exocrine glands such as salivary glands. Although the formation of ectopic lymphoid tissue in exocrine glands and overproduction of autoantibodies by autoreactive B cells highlight the critical involvement of B cells in disease development, the precise roles of various B cell subsets in pSS pathogenesis remain partially understood. Current studies have identified several novel B cell subsets with multiple functions in pSS, among which autoreactive age-associated B cells, and plasma cells with augmented autoantibody production contribute to the disease progression. In addition, tissue-resident Fc Receptor-Like 4 (FcRL4)+ B cell subset with enhanced pro-inflammatory cytokine production serves as a key driver in pSS patients with mucosa-associated lymphoid tissue (MALT)-lymphomas. Recently, regulatory B (Breg) cells with impaired immunosuppressive functions are found negatively correlated with T follicular helper (Tfh) cells in pSS patients. Further studies have revealed a pivotal role of Breg cells in constraining Tfh response in autoimmune pathogenesis. This review provides an overview of recent advances in the identification of pathogenic B cell subsets and Breg cells, as well as new development of B-cell targeted therapies in pSS patients.

PurposeRadiation therapy (RT) induces an immune response, but the relationship of this response with tumor type is not fully understood. This meta-analysis further elucidated this relationship by analyzing the changes in T lymphocyte subsets in different tumors before and after radiotherapy.MethodsWe searched English-language electronic databases including PubMed, EMBASE, and the Cochrane Library to collect studies on the changes in peripheral blood CD3+ T lymphocytes, CD4+ T lymphocytes, and CD8+ T lymphocytes before and after radiotherapy in tumor patients from January 2015 to April 2021. The quality of the included literature was evaluated using the NOS scale provided by the Cochrane Collaboration, and statistical software RevMan 5.4 was used to analyze the included literature. P

Abstract To develop a deep learning system based on 3D convolutional neural networks (CNNs), and to automatically predict EGFR‐mutant pulmonary adenocarcinoma in CT images. A dataset of 579 nodules with EGFR mutation status labels of mutant (Mut) or wild‐type (WT) was retrospectively analyzed. A deep learning system, namely 3D DenseNets, was developed to process 3D patches of nodules from CT data, and learn strong representations with supervised end‐to‐end training. The 3D DenseNets were trained with a training subset of 348 nodules and tuned with a development subset of 116 nodules. A strong data augmentation technique, mixup, was used for better generalization. We evaluated our model on a holdout subset of 115 nodules. An independent public dataset of 37 nodules from the cancer imaging archive (TCIA) was also used to test the generalization of our method. Conventional radiomics analysis was also performed for comparison. Our method achieved promising performance on predicting EGFR mutation status, with AUCs of 75.8% and 75.0% for our holdout test set and public test set, respectively. Moreover, strong relations were found between deep learning feature and conventional radiomics, while deep learning worked through an enhanced radiomics manner, that is, deep learned radiomics (DLR), in terms of robustness, compactness and expressiveness. The proposed deep learning system predicts EGFR‐mutant of lung adenocarcinomas in CT images noninvasively and automatically, indicating its potential to help clinical decision‐making by identifying eligible patients of pulmonary adenocarcinoma for EGFR‐targeted therapy.

Background The satisfactory prognostic indicator of gastric cancer (GC) patients after surgery is still lacking. Perioperative plasma extracellular vesicular programmed cell death ligand-1 (ePD-L1) has been demonstrated as a potential prognosis biomarker in many types of cancers. The prognostic value of postoperative plasma ePD-L1 has not been characterized.Methods We evaluated the prognostic value of preoperative, postoperative and change in plasma ePD-L1, as well as plasma soluble PD-L1, in short-term survival of GC patients after surgery. The Kaplan-Meier survival model and Cox proportional hazards models for both univariate and multivariate analyzes were used. And the comparison between postoperative ePD-L1 and conventional serum biomarkers (carcinoembryonic antigen (CEA), cancer antigen 19–9 (CA19-9) and CA72-4) in prognostic of GC patients was made.Results The prognostic value of postoperative ePD-L1 is superior to that of preoperative ePD-L1 on GC patients after resection, and also superior to that of conventional serum biomarkers (CEA, CA19-9 and CA72-4). The levels of postoperative ePD-L1 and ePD-L1 change are independent prognostic factors for overall survival and recurrence free survival of GC patients. High plasma level of postoperative ePD-L1 correlates significantly with poor survival, while high change in ePD-L1 level brings the significant survival benefit.Conclusions The level of plasma postoperative ePD-L1 could be considered as a candidate prognostic biomarker of GC patients after resection.

Abstract Objectives This study aims to determine a role of interleukin‐17A (IL‐17) in salivary gland (SG) dysfunction and therapeutic effects of targeting IL‐17 in SG for treating autoimmune sialadenitis in primary Sjögren’s syndrome (pSS). Methods Salivary IL‐17 levels and IL‐17‐secreting cells in labial glands of pSS patients were examined. Kinetic changes of IL‐17‐producing cells in SG from mice with experimental Sjögren’s syndrome (ESS) were analysed. To determine a role of IL‐17 in salivary secretion, IL‐17‐deficient mice and constructed chimeric mice with IL‐17 receptor C (IL‐17RC) deficiency in non‐hematopoietic and hematopoietic cells were examined for saliva flow rates during ESS development. Both human and murine primary SG epithelial cells were treated with IL‐17 for measuring cholinergic activation‐induced calcium movement. Moreover, SG functions were assessed in ESS mice with salivary retrograde cannulation of IL‐17 neutralisation antibodies. Results Increased salivary IL‐17 levels were negatively correlated with saliva flow rates in pSS patients. Both IL‐17‐deficient mice and chimeric mice with non‐hematopoietic cell‐restricted IL‐17RC deficiency exhibited no obvious salivary reduction while chimeric mice with hematopoietic cell‐restricted IL‐17RC deficiency showed significantly decreased saliva secretion during ESS development. In SG epithelial cells, IL‐17 inhibited acetylcholine‐induced calcium movement and downregulated the expression of transient receptor potential canonical 1 via promoting Nfkbiz mRNA stabilisation. Moreover, local IL‐17 neutralisation in SG markedly attenuated hyposalivation and ameliorated tissue inflammation in ESS mice. Conclusion These findings identify a novel function of IL‐17 in driving salivary dysfunction during pSS development and may provide a new therapeutic strategy for targeting SG dysfunction in pSS patients.

Objective. To evaluate monosodium urate (MSU) crystal deposition and related lesions in the joints of patients with gout and hyperuricemia (HUA) using ultrasound. To explore the association between ultrasound findings and clinical features in gout and HUA. Methods. A total of 202 patients with gout and 43 asymptomatic patients with HUA were included. The clinical data and ultrasonic assessment results were collected and statistically analyzed. Results. Deposition of MSU crystals was found in 25.58% (11/43) of patients with asymptomatic HUA and 76.24% (154/202) of patients with gout. Of the 1,082 joints from patients with gout examined, 33.09% (358/1082) displayed MSU crystal deposition. In the joints with MSU crystal deposition, 77.37% (277/358) had a history of attacks. Among the joints of gouty arthritis, double contour sign (DCS), hyperechoic aggregate (HAG), and tophi were found in 32.65% (159/487), 7.80% (38/487), and 24.64% (120/487) of the joints, respectively. DCS and tophi, but not HAG, increasingly appeared with the extension of gout duration. In patients with more than 15 years of gout history, DCS, Tophi, and HAG were found in 48.18%, 40.00%, and 6.36% of US assessed joints, respectively. In patients with gout, synovial lesion and bone erosion were found in 17.74% (192/1082) and 7.58% (82/1082) of joints, respectively. The synovial lesion was related to HAG, while bone erosion was related to tophi and DCS. Nephrolithiasis was detected in 20.30% (41/202) of patients with gout and 4.65% (2/43) of HUA patients, indicating that nephrolithiasis occurred in more patients with gout than in patients with HUA. Conclusion. HAG is an early performance of MSU crystal deposition in joints of gout and HUA. Both DCS and tophi are risk factors for bone erosion. Early urate-lowering therapy (ULT) should be considered in patients with gout, DCS, or tophi.

Radiotherapy plays an increasingly crucial role in the treatment of non-small cell lung cancer (NSCLC). Local tumor recurrence and tumor progression caused by intratumoral heterogeneity induced radiotherapy resistance remain the primary causes of radiotherapy failure. However, the lack of a suitable cell line model has hampered the exploration of the dynamic mechanisms of radiation resistance. We established 3 groups of equidifferent gradient dose irradiation surviving/resistant human lung cancer cell lines based on A549, H520, and H460 cells with clinical conventional fractionated radiotherapy (CFRT) (2 Gy × 20 F, 2 Gy × 30 F, and 2 Gy × 40 F). The radiosensitivity of the cells was detected by clone formation assay, EDU cell proliferation assay, neutral comet assay, and γ-H2AX immunofluorescence staining. The radiosensitivity and proliferation viability were increased in a received dose-dependent manner. Compared with parental cells, DNA double-strand breaks (DSBs) in cell lines that received higher-dose irradiation were significantly reduced. We successfully constructed equidifferent gradient dose irradiation surviving/resistant NSCLC cell lines whose radiation surviving and resistant abilities were increased in a received dose-dependent manner. This preclinical cell model could be used to dynamically observe and detect the radiation surviving/resistant biomarkers during radiotherapy stress, elucidate the mechanism of radiation resistance.

Uncontrolled hemorrhage from trauma or surgery can lead to death. In this study, chitosan/kaolin (CSK) and chitosan/montmorillonite (CSMMT) composites were prepared from chitosan (CS), kaolin (K), and montmorillonite (MMT) as raw materials to control bleeding. The physiochemical properties and surface morphology of CSK and CSMMT composites were analyzed by Fourier transform infrared spectrometry (FT-IR), X-ray diffraction (XRD), scanning electron microscopy (SEM), zeta potentials, and X-ray fluorescence (XRF). The hemostatic mechanism was measured in vitro by activated partial thromboplastin time (APTT), prothrombin time (PT), in vitro clotting time, erythrocyte aggregation, and thromboelastogram (TEG). The hemostasis ability was further verified by using tail amputation and arteriovenous injury models in rats. The biocompatibility of CSK and CSMMT was evaluated by in vitro hemolysis, cytotoxicity assays, as well as acute toxicity test and skin irritation tests. The results show that CSK and CSMMT are promising composite materials with excellent biocompatibility and hemostatic properties that can effectively control bleeding.

Cepharanthine (CEP) has excellent anti-SARS-CoV-2 properties, indicating its favorable potential for COVID-19 treatment. However, its application is challenged by its poor dissolubility and oral bioavailability. The present study aimed to improve the bioavailability of CEP by optimizing its solubility and through a pulmonary delivery method, which improved its bioavailability by five times when compared to that through the oral delivery method (68.07% vs. 13.15%). An ultra-performance liquid chromatography tandem-mass spectrometry (UPLC-MS/MS) method for quantification of CEP in rat plasma was developed and validated to support the bioavailability and pharmacokinetic studies. In addition, pulmonary fibrosis was recognized as a sequela of COVID-19 infection, warranting further evaluation of the therapeutic potential of CEP on a rat lung fibrosis model. The antifibrotic effect was assessed by analysis of lung index and histopathological examination, detection of transforming growth factor (TGF)-β1, interleukin-6 (IL-6), α-smooth muscle actin (α-SMA), and hydroxyproline level in serum or lung tissues. Our data demonstrated that CEP could significantly alleviate bleomycin (BLM)-induced collagen accumulation and inflammation, thereby exerting protective effects against pulmonary fibrosis. Our results provide evidence supporting the hypothesis that pulmonary delivery CEP may be a promising therapy for pulmonary fibrosis associated with COVID-19 infection.

Anton’s syndrome is a rare neuropsychiatric syndrome that is characterized by cortical blindness and anosognosia with visual confabulation, but without global cognitive impairment. We herein report a rare case of Anton’s syndrome as a presentation of Trousseau syndrome involving the bilateral optic radiation. The patient had been diagnosed with gallbladder cancer 2 months previously, and he was admitted to the hospital with confusion and quadriplegia. He was found to be blind, but denied any visual impairment and demonstrated visual confabulation despite evidence of his blindness. These signs were consistent with a diagnosis of Anton’s syndrome. Brain computed tomography (CT) and magnetic resonance imaging revealed infarcts in the bilateral temporo-parieto-occipital junction with hemorrhagic transformation, mainly involving the bilateral optic radiation. The presence of gallbladder cancer with peripheral metastasis on abdominal CT, as well as markedly increased tumor markers and D-dimer levels, supported the presence of cancer-related hypercoagulability and the diagnosis of Trousseau syndrome.

Objective(s): This study aims to investigate the pathogenicity and possible mechanisms of S100A9 function in mice models of scleroderma. Materials and Methods: The content of S100A9 in the skin tissues of mice with scleroderma was determined. Different concentrations of bleomycin (BLM) and S100A9 were subcutaneously injected into the backs of mice simultaneously, and then pathological changes in the skin of these mice were monitored. Specifically, the levels of inflammatory cytokines and alpha smooth muscle actin (α-SMA), the activation of extracellular regulated kinase 1/2 (ERK1/2), mitogen-activated protein kinase (MAPK) and nuclear factor-kappa B (NF-κB) pathways, and the expression of the receptor for advanced glycation end-product (RAGE) in the skin were determined. Results: The content of S100A9 in the skin tissues of mice with scleroderma was determined. Different concentrations of BLM and S100A9 were subcutaneously injected into the backs of mice simultaneously, and then pathological changes in the skin of these mice were monitored. Specifically, the levels of inflammatory cytokines and alpha smooth muscle actin (α-SMA), the activation of extracellular regulated kinase 1/2 (ERK1/2) mitogen-activated protein kinase (MAPK) and nuclear factor-kappa B (NF-κB) pathways, and the expression of the receptor for advanced glycation end-product (RAGE) in the skin were determined. Conclusion: S100A9 aggravates dermal fibrosis in BLM-induced scleroderma (BIS ) mice, and its mechanisms might be mediated by RAGE, ERK1/2, and NF-κB pathway.

The slow accumulation of inflammatory biomarker levels in the body—also known as inflammaging—has been linked to a myriad of age-related diseases. Some of these include neurodegenerative conditions such as Parkinson’s disease, obesity, type II diabetes, cardiovascular disease, and many others. Though a direct correlation has not been established, research connecting age-related hearing loss (ARHL)—the number one communication disorder and one of the most prevalent neurodegenerative diseases of our aged population—and inflammaging has gained interest. Research, thus far, has found that inflammatory markers, such as IL-6 and white blood cells, are associated with ARHL in humans and animals. Moreover, studies investigating ion channels and mitochondrial involvement have shown promising relationships between their functions and inflammaging in the cochlea. In this review, we summarize key findings in inflammaging within the auditory system, the involvement of ion channels and mitochondrial functions, and lastly discuss potential treatment options focusing on controlling inflammation as we age.

Here we present a 3D-printed, wirelessly controlled microsystem for drug delivery, comprising a refillable microreservoir and a phase-change peristaltic micropump. The micropump structure was inkjet-printed on the back of a printed circuit board around a catheter microtubing. The enclosure of the microsystem was fabricated using stereolithography 3D printing, with an embedded microreservoir structure and integrated micropump. In one configuration, the microsystem was optimized for murine inner ear drug delivery with an overall size of 19 × 13 × 3 mm3. Benchtop results confirmed the performance of the device for reliable drug delivery. The suitability of the device for long-term subcutaneous implantation was confirmed with favorable results of implantation of a microsystem in a mouse for six months. The drug delivery was evaluated in vivo by implanting four different microsystems in four mice, while the outlet microtubing was implanted into the round window membrane niche for infusion of a known ototoxic compound (sodium salicylate) at 50 nL/min for 20 min. Real-time shifts in distortion product otoacoustic emission thresholds and amplitudes were measured during the infusion, demonstrating similar results with syringe pump infusion. Although demonstrated for one application, this low-cost design and fabrication methodology is scalable for use in larger animals and humans for different clinical applications/delivery sites.

The auditory system is a fascinating sensory organ that overall, converts sound signals to electrical signals of the nervous system. Initially, sound energy is converted to mechanical energy via amplification processes in the middle ear, followed by transduction of mechanical movements of the oval window into electrochemical signals in the cochlear hair cells, and finally, neural signals travel to the central auditory system, via the auditory division of the 8th cranial nerve. The majority of people above 60 years have some form of age-related hearing loss, also known as presbycusis. However, the biological mechanisms of presbycusis are complex and not yet fully delineated. In the present article, we highlight ion channels and transport proteins, which are integral for the proper functioning of the auditory system, facilitating the diffusion of various ions across auditory structures for signal transduction and processing. Like most other physiological systems, hearing abilities decline with age, hence, it is imperative to fully understand inner ear aging changes, so ion channel functions should be further investigated in the aging cochlea. In this review article, we discuss key various ion channels in the auditory system and how their functions change with age. Understanding the roles of ion channels in auditory processing could enhance the development of potential biotherapies for age-related hearing loss.

Abstract Background Genome-wide association studies (GWASs) have identified dozens of loci associated with gout, but for most cases, the risk genes and the underlying molecular mechanisms contributing to these associations are unknown. This study sought to understand the molecular mechanism of a common genetic variant, rs780093, in the development of gout, both in vitro and in vivo. Results Nuclear receptor binding protein 1 (NRBP1), as a gout risk gene, and its regulatory region, 72 bp upstream of the transcription start site, designated as B1, were identified through integrative analyses of genome-wide genotype and DNA methylation data. We observed elevated NRBP1 expression in human peripheral blood mononuclear cells (PBMCs) from gout patients. In vitro luciferase reporter and protein pulldown assay results showed that DNA methylation could increase the binding of the transcription factor TFAP2A to B1, leading to suppressed gene expression. There results were further confirmed by in vivo bisulfite pyrosequencing showing that hypomethylation on B1 is associated with increased NRBP1 expression in gout patients. Conclusions Hypomethylation at the promoter region of NRBP1 reduces the binding of TFAP2A and thus leads to elevated NRBP1 expression, which might contribute to the development of gout.

How asymmetries in motor behavior become established normally or atypically in mammals remains unclear. An established model for motor asymmetry that is conserved across mammals can be obtained by experimentally inducing asymmetric striatal dopamine activity. However, the factors that can cause motor asymmetries in the absence of experimental manipulations to the brain remain unknown. Here, we show that mice with inner ear dysfunction display a robust left or right rotational preference, and this motor preference reflects an atypical asymmetry in cortico-striatal neurotransmission. By unilaterally targeting striatal activity with an antagonist of extracellular signal-regulated kinase (ERK), a downstream integrator of striatal neurotransmitter signaling, we can reverse or exaggerate rotational preference in these mice. By surgically biasing vestibular failure to one ear, we can dictate the direction of motor preference, illustrating the influence of uneven vestibular failure in establishing the outward asymmetries in motor preference. The inner ear-induced striatal asymmetries identified here intersect with non-ear-induced asymmetries previously linked to lateralized motor behavior across species and suggest that aspects of left-right brain function in mammals can be ontogenetically influenced by inner ear input. Consistent with inner ear input contributing to motor asymmetry, we also show that, in humans with normal ear function, the motor-dominant hemisphere, measured as handedness, is ipsilateral to the ear with weaker vestibular input.

In recent years, internet development provides new channels and opportunities for small- and middle-sized enterprises’ (SMEs) financing. Supply chain finance is a hot topic in theoretical and practical circles. Financial institutions transform materialized capital flows into online data under big data scenario, which provides networked, precise, and computerized financial services for SMEs in the supply chain. By drawing on the risk management theory in economics and the distributed hydrological model in hydrology, this paper presents a supply chain financial risk prediction method under big data. First, we build a “hydrological database” used for the risk analysis of supply chain financing under big data. Second, we construct the risk identification models of “water circle model,” “surface runoff model,” and “underground runoff model” and carry on the risk prediction from the overall level (water circle). Finally, we launch the supply chain financial risk analysis from breadth level (surface runoff) and depth level (underground runoff); moreover, we integrate the analysis results and make financial decisions. The results can enrich the research on risk management of supply chain finance and provide feasible and effective risk prediction methods and suggestions for financial institutions.

The physicochemical properties and potential hemostatic application of Wenchang kaolin and Maoming kaolin were inspected and evaluated. Chemical composition analysis, Fourier transform infrared (FTIR) spectroscopy, surface area determination, X-ray diffraction, particle size, scanning electron microscopy (SEM) observations, and zeta potential analysis were performed to quantify the physical and chemical properties of the two kaolins. The results showed that both kaolins have typical FTIR bands of kaolinite with a weight fraction for kaolinite over 90 wt%. Larger conglobate aggregates of Maoming kaolin demonstrated wider particle size distributions with two peaks at 3.17 and 35.57 μm, while the book-like Wenchang kaolin had narrow particle size distribution, with a frequent size of 5.64 μm. Furthermore, thrombelastography, the whole blood clotting tests (WBCT), plasma recalcification time (PRT) measurement, and MTT assay were performed to measure the clotting activities and biocompatibility of the two kaolins. The results showed that both kaolins could promote blood coagulation with good cytocompatibility, while Wenchang kaolin had a better procoagulant activity than Maoming kaolin. These findings demonstrated Wenchang kaolin to be a more suitable local source material for application as a hemostatic agent.

A rapid and sensitive method was established for arsenic (As) speciation based on high performance liquid chromatography coupled to inductively coupled plasma mass spectrometry (HPLC-ICP-MS). This method was validated for the quantification of four arsenic species, including arsenite (AsIII), arsenate (AsV), monomethylarsonic acid (MMAV) and dimethylarsinic acid (DMAV) in cynomolgus macaque plasma. Separation was achieved in just 3.7 min with an alkyl reverse phase column and highly aqueous mobile phase containing 20 mM citric acid and 5 mM sodium hexanesulfonate (pH = 4.3). The calibration curves were linear over the range of 5–500 ng·mL−1 (measured as As), with r > 0.99. The above method was validated for selectivity, precision, accuracy, matrix effect, recovery, carryover effect and stability, and applied in a comparative pharmacokinetic study of arsenic species in cynomolgus macaque samples following intravenous and intragastrical administration of arsenic trioxide solution (0.80 mg·kg−1; 0.61 mg·kg−1 of arsenic); in addition, the absolute oral bioavailability of the active ingredient AsIII of arsenic trioxide in cynomolgus macaque samples was derived as 60.9 ± 16.1%.

Purpose: Low-carbon economy requires the pursuit of eco-efficiency, which is a win-win situation between economic and environmental efficiency. In this paper the question of trading off the economic and environmental effects embodied in eco-efficiency in the hybrid manufacturing/remanufacturing logistics network design in the context of low-carbon economy is examined.Design/methodology/approach: A multi-objective mixed integer linear programming model to find the optimal facility locations and materials flow allocation is established. In the objective function, three minimum targets are set: economic cost, CO2 emission and waste generation. Through an iterative algorithm, the Pareto Boundary of the problem is obtained.Findings: The results of numeric study show that in order to achieve a Pareto improvement over an original system, three of the critical rates (i.e. return rate, recovery rate, and cost substitute rate) should be increased.Practical implications: To meet the need of low-carbon dioxide, an iso- CO2 emission curve in which decision makers have a series of optimal choices with the same CO2 emission but different cost and waste generation is plotted. Each choice may have different network design but all of these are Pareto optimal solutions, which provide a comprehensive evaluation of both economics and ecology for the decision making.Originality/value: This research chooses carbon emission as one of the three objective functions and uses Pareto sets to analyze how to balance profitability and environmental impacts in designing remanufacturing closed-loop supply chain in the context of low-carbon economy.

Red blood cells (RBCs) are routinely stored for 35 to 42 days in most countries. During storage, RBCs undergo biochemical and biophysical changes known as RBC storage lesion, which is influenced by alternative storage additive solutions (ASs). Metabolomic studies have been completed on RBCs stored in a number of ASs, including SAGM, AS-1, AS-3, AS-5, AS-7, PAGGGM, and MAP. However, the reported metabolome analysis of laboratory-made MAP-stored RBCs was mainly focused on the time-dependent alterations in glycolytic intermediates during storage. In this study, we investigated the time-course of alterations in various small molecule metabolites in RBCs stored in commercially used MAP for 49 days using ultra-high performance liquid chromatography quadruple time-of-flight mass spectrometry (UPLC-QTOF-MS). These alterations indicated that RBC storage lesion is related to multiple pathways including glycolysis, pentose phosphate pathway, glutathione homeostasis, and purine metabolism. Thus, our findings might be useful for understanding the complexity of metabolic mechanisms of RBCs in vitro aging and encourage the deployment of systems biology methods to blood products in transfusion medicine.

Background and objective Epidemiology of lung cancer will be changed along with time and region. The aim of this study is to acknowledge the tendency of primary lung cancer in hunan province in recent years by comparing and analyzing the distribution of gender, age, area, smoking and pathology of patients who were initial diagnosed lung cancer and ancestral or permanent residence of hunan province in 1997 and 2007. Methods Clinical data of 908 patients with primary lung cancer hospitalized in Xiangya hospital were collected and evaluated. Results Compared patients in 2007 with those in 1997, ratio between male and female dropped from 3.8:1 to 2.98:1, while the proportion of young patients who were under 40 years old raised from 4.4% to 8.6% (χ2=4.465, P=0.035), patients living in the county raised from 19.9% to 40.1% (χ2=30.670, P < 0.001), smoking rate of patients from county raised from 16.9% to 39.9% (χ2= 24.939, P < 0.01). In addition, the proportion of rare histological types of lung cancer were also increased from 1.3% to 4.5% (χ2= 5.142, P=0.023). Conclusion Female patients, young patients, rural patients and rare histological types of lung cancer may have a tendency of increase in hunan province in recent years, whereas smoking cessation education should be strengthened.

Sustained estrogenic exposure increases the risk and/or the progression of various cancers, including those of the breast, endometrium and ovary. Unexpectedly, physiological level of estrogen together with a novel IKKα inhibitor BAY11-7082 could effectively induce cell apoptosis in ER-positive breast cancer cells, suggesting combining estrogen with IKKα inhibition may be beneficial for breast cancer patients. This opinion article touches upon the dual role estrogen played in inducing cancer cell death and asks whether use of estrogen in combination with IKKα-targeted therapy would be possible reconsider the newly identified crosstalk between ER and NFκB pathway which can be utilized to switch the effects of estrogen on cell death.

Age-related hearing loss - presbycusis - is the number one neurodegenerative disorder and top communication deficit of our aged population. Like many aging disorders of the nervous system, damage from free radicals linked to production of reactive oxygen and/or nitrogen species (ROS and RNS, respectively) may play key roles in disease progression. The efficacy of the antioxidant systems, e.g., glutathione and thioredoxin, is an important factor in pathophysiology of the aging nervous system. In this investigation, relations between the expression of antioxidant-related genes in the auditory portion of the inner ear - cochlea, and age-related hearing loss was explored for CBA/CaJ mice. Forty mice were classified into four groups according to age and degree of hearing loss. Cochlear mRNA samples were collected and cDNA generated. Using Affymetrix® GeneChip, the expressions of 56 antioxidant-related gene probes were analyzed to estimate the differences in gene expression between the four subject groups. The expression of Glutathione peroxidase 6, Gpx6; Thioredoxin reductase 1, Txnrd1; Isocitrate dehydrogenase 1, Idh1; and Heat shock protein 1, Hspb1; were significantly different, or showed large fold-change differences between subject groups. The Gpx6, Txnrd1 and Hspb1 gene expression changes were validated using qPCR. The Gpx6 gene was upregulated while the Txnrd1 gene was downregulated with age/hearing loss. The Hspb1 gene was found to be downregulated in middle-aged animals as well as those with mild presbycusis, whereas it was upregulated in those with severe presbycusis. These results facilitate development of future interventions to predict, prevent or slow down the progression of presbycusis.

Pulmonary fibrosis is a progressive and fatal fibrotic disease of the lungs with unclear etiology. Recent insight has suggested that early injury/inflammation of alveolar epithelial cells could lead to dysregulation of tissue repair driven by multiple cytokines. Although dysregulation of interleukin- (IL-) 22 is involved in various pulmonary pathophysiological processes, the role of IL-22 in fibrotic lung diseases is still unclear and needs to be further addressed. Here we investigated the effect of IL-22 on alveolar epithelial cells in the bleomycin- (BLM-) induced pulmonary fibrosis. BLM-treated mice showed significantly decreased level of IL-22 in the lung. IL-22 produced γδT cells were also decreased significantly both in the tissues of lungs and spleens. Administration of recombinant human IL-22 to alveolar epithelial cell line A549 cells ameliorated epithelial to mesenchymal transition (EMT) and partially reversed the impaired cell viability induced by BLM. Furthermore, blockage of IL-22 deteriorated pulmonary fibrosis, with elevated EMT marker (α-smooth muscle actin (α-SMA)) and overactivated Smad2. Our results indicate that IL-22 may play a protective role in the development of BLM-induced pulmonary fibrosis and may suggest IL-22 as a novel immunotherapy tool in treating pulmonary fibrosis.

T follicular helper (Tfh) cells can mediate humoral immune responses and augment autoimmunity, whereas the role of Tfh cells on regulatory B (B10) cells in autoimmunity diseases is not clear. Here, we investigated the percentages of Tfh cells and B10 cells in lupus-prone MRL/Mp-lpr/lpr (MRL/lpr) mice and examined the effects and mechanism of Tfh cell-derived interleukin-21 (IL-21) on IL-10 production during the differentiation of B10 cells. Both Tfh cells and B10 cells were expanded in spleens of MRL/lpr mice. In addition, a positive correlation between the proportions of Tfh cells and B10 cells was observed. Tfh cell-derived IL-21 from MRL/lpr mice could promote IL-10 production during the differentiation of B10 cells. Importantly, neutralization of IL-21 inhibited IL-10 production and expansion of B10 cells both in vitro and in vivo. IL-21 induced IL-10 production via activation of phosphorylated signal transduction and activator of transcription 3 (p-STAT3). Inhibition of p-STAT3 effectively blocked IL-10 production during the differentiation of B10 cells. Moreover, IL-21-induced IL-10 exerted a regulatory function by inhibiting the proliferation of T cells. These data suggest that Tfh cells not only mediate humoral immune responses and augment autoimmunity but also play a broader role in immune regulatory actions via the induction of IL-10 production.

Significant bone remodeling with disordered osteoclastogenesis has been implicated in the pathogenesis of psoriatic arthritis (PsA). And there is a high prevalence of the metabolic syndrome (MS) in PsA patients. Adipokines, especially leptin and adiponectin, have recently been reported to be involved in the development and regulation of some autoimmune diseases. In this study, we examined the alternation of circulating osteoclastogenesis related cytokines [tumor necrosis factor-α (TNF-α), osteoprotegerin (OPG) and receptor activator of nuclear factor-κB ligand (RANKL)] and adipokines (leptin, adiponectin, resistin, chemerin, omentin) in PsA patients, and analysed the correlations between these factors and osteoclast precursors numbers, radiographic damage scores, and disease activity index. 41 PsA patients, 20 psoriasis patients, and 24 healthy controls were recruited. Blood samples were obtained for detecting the levels of TNF-α, OPG, RANKL and the adipokines. The numbers of osteoclast precursors (OCs) in peripheral blood were assessed. Radiographs of affected joints in PsA patients were scored for erosion, joint-space narrowing, osteolysis, and new bone formation. Compared with healthy controls, patients with PsA had higher TNF-α, RANKL, OCs, leptin and omentin but lower adiponectin and chemerin. Increased serum levels of TNF-α, RANKL, leptin, and omentin were positively correlated with OCs numbers. In contrast, serum adiponectin levels were decreased in PsA patients and negatively correlated with OCs numbers. TNF-α, RANKL and leptin were positively correlated with Psoriatic Arthritis Joint Activity Index (PsAJAI). Only TNF-α was positively correlated with radiographic damage scores. Our data demonstrated that systemic expression of soluble mediators of osteoclastogenesis and adipokines were disordered in PsA. Certain adipokines were elevated in the circulation of patients with PsA and might contribute to pathogenesis of arthritis. Prospective studies will be of interest to determine the pluripotent effects of adipokines on osteoclastogenesis in chronic inflammatory rheumatic diseases. Future studies may lead to novel therapeutic strategies.

Inflammation is one of main mechanisms of autoimmune disorders and a common feature of most diseases. Appropriate suppression of inflammation is a key resolution to treat the diseases. Sirtuin1 (Sirt1) has been shown to play a role in regulation of inflammation. Resveratrol, a potent Sirt1 activator, has anti-inflammation property. However, the detailed mechanism is not fully understood. In this study, we investigated the anti-inflammation role of Sirt1 in NIH/3T3 fibroblast cell line. Upregulation of matrix metalloproteinases 9 (MMP-9), interleukin-1beta (IL-1β), IL-6 and inducible nitric oxide synthase (iNOS) were induced by tumor necrosis factor alpha (TNF-α) in 3T3 cells and resveratrol suppressed overexpression of these pro-inflammatory molecules in a dose-dependent manner. Knockdown of Sirt1 by RNA interference caused 3T3 cells susceptible to TNF-α stimulation and diminished anti-inflammatory effect of resveratrol. We also explored potential anti-inflammatory mechanisms of resveratrol. Resveratrol reduced NF-κB subunit RelA/p65 acetylation, which is notably Sirt1 dependent. Resveratrol also attenuated phosphorylation of mammalian target of rapamycin (mTOR) and S6 ribosomal protein (S6RP) while ameliorating inflammation. Our data demonstrate that resveratrol inhibits TNF-α-induced inflammation via Sirt1. It suggests that Sirt1 is an efficient target for regulation of inflammation. This study provides insight on treatment of inflammation-related diseases.