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To evaluate the dynamic contrast-enhanced MRI parameters for monitoring the neoadjuvant chemotherapy (NAC) response in osteosarcoma prospectively. A total of 19 patients with osteosarcoma were recruited and underwent two dynamic contrast-enhanced MRI (DCE-MRI) examinations before and after chemotherapy. Patients with ≥ 90% tumor necrosis were defined as responders (10 patients), and those

Background Costello syndrome (CS, OMIM 218040) is a rare congenital disorder caused by mutations in HRAS. Previous studies reported that approximately 80% of patients with CS share the same pathogenic variant in HRAS gene in c.34G> A (p.G12S). Here, we report a CS patient with c.34G> A (p.G12D) variant in HRAS gene and she presented with special manifestation. Methods and Results We describe a 31‐year‐old female patient who presented with distinctive facial appearance, intellectual disability, dental abnormalities, hyperkeratosis of palmer and planter, loose skin at birth, papillomata on the face and nipples. The whole‐exome sequencing (WES) technology provided by Haotian Biotechnology (China) confirmed p.G12D variant in HRAS gene. To elucidate the typical features of CS with p.G12D variant, we further reviewed these previously reported cases and found that patients with G12D variant died within three months after birth due to multiple organ failure. They had the typical facial characteristics, failure to thrive, skin and cardiac abnormalities, and gene testing confirmed the diagnosis of CS. Conclusion To the best of our knowledge, this is the first article to report a patient with a p.G12D variant that had special but mild manifestation. Moreover, this report and literature review casts new light on the clinical features of p.G12D variant., BLURB FOR ETOC: Costello syndrome with p.G12D mutation in HRAS gene. Costello syndrome with irregular hypo‐and hyperpigmentation.

Macrophages constitute a major component in human hepatocellular carcinoma (HCC) and perform various functions to facilitate disease progression. Reprogramming or reconstituting the tumor surveillance phenotypes of macrophages represents an attractive immunotherapeutic strategy in cancer treatments. The current study identified CD169 as a potential target for macrophage repolarization since it signified a population of macrophages positively correlated with an activated immune signature and better prognosis of patients with HCC. In vitro experiments revealed that a low dose of type I interferon (IFN) could effectively reprogram human monocyte-derived macrophages to upregulate CD169 expression, and such induced CD169(+) macrophages exhibited significantly enhanced phagocytotic and CD8(+) T cell-activating capacities compared to controls. A low dose of IFNα also inhibited hepatoma growth in mice in vivo, presumably through polarizing the CD169(+) macrophage population and enhancing CD8(+) T cell activities. Notably, IFNα also induced substantial PD-L1 expression on macrophages in vivo, and thus blockade of PD-L1 could further increase the anti-tumor efficacy of IFNα in the treatment of HCC. We propose a low dose of IFNα in combination with a PD-L1 blocking agent as a potential anti-tumor therapeutic strategy via its effects on macrophage polarization.

Decline in immune function during aging increases susceptibility to different aging related diseases. However, the underlying molecular mechanisms, especially the genetic factors contributing to imbalance of naïve/memory T-cell subpopulations, still remain largely elusive. Here we show that loss of DJ-1 encoded by PARK7/DJ-1, causing early-onset familial Parkinson’s disease (PD), unexpectedly delayed immunoaging in both human and mice. Compared with two gender-matched unaffected sibling carriers of similar ages, the index PD patient with DJ-1 deficiency showed a decline in many critical immunoaging features, including almost doubled frequencies of non-senescent T cells. The observation of a ‘younger’ immune system in the index patient was further consolidated by the results in aged DJ-1 knockout mice. Our data from bone marrow chimera models and adoptive transfer experiments demonstrated that DJ-1 regulates several immunoaging features via hematopoietic-intrinsic and naïve-CD8-intrinsic mechanisms. Our finding suggests an unrecognized critical role of DJ-1 in regulating immunoaging, discovering a potent target to interfere with immunoaging- and aging-associated diseases.

Objective To perform a meta-analysis comparing the structural progression and clinical symptom outcomes as well as adverse events experienced from intra-articular injections of sprifermin compared to a placebo treatment for patients with knee osteoarthritis (KOA). Method We systematically searched the literature for studies that compared long-term outcomes between sprifermin and placebo injections for KOA treatment. Meta-analysis was performed with RevMan5.3 using an inverse variance approach with fixed or random effects models. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated. Results Eight studies were included. Overall, there was significantly less improvement of WOMAC total scores in patients receiving sprifermin, compared with the placebo (mean difference (MD) = 3.23, 95% CI 0.76–5.69; I2 = 0%; P = 0.01). Further, sprifermin injection patients gained more, and lost less, cartilage thickness and volume in total femorotibial joint (cartilage thickness: standardized mean differences (SMD) = 0.55, 95% CI 0.26–0.84; I2 = 78%; P = 0.0002; cartilage volume: SMD = 0.39, 95% CI 0.20–0.58; I2 = 49%; P I2 = 0%; P I2 = 0%; P = 0.004) showed a significant difference between the sprifermin and placebo injections. Moreover, there were no significant differences between sprifermin and the placebo in the risk of treatment-emergent adverse events (OR = 1.05; 95% CI 0.52–2.14; I2 = 48%; P = 0.89). Conclusion The data from the included studies provide strong evidence to determine the effect of intra-articular sprifermin on joint structure in individuals with KOA and show no specific adverse effects. Nevertheless, intra-articular sprifermin did not likely have any positive effect on symptom alleviation.

Objective: The formyl peptide receptor-1 (FPR-1) has been reported to be implicated in the regulation of inflammatory disorders, while its role in cigarette smoke (CS)–induced airway inflammation has not been fully explained. In this study, we investigated the role of FPR-1 in CS-induced airway inflammation and the possible mechanism through gene knockout (KO) technology and transcriptional study.Methods: FPR-1 KO or wild-type C57BL/6 mice were exposed to mainstream CS to establish an airway inflammation model. Cell counts and pro-inflammatory cytokines were measured in bronchoalveolar lavage fluid (BALF). Lung tissues were collected for histological examination, polymerase chain reaction, Western blot, transcriptomic gene study, and related bioinformatics analysis.Results: CS exposure induced significant histological inflammatory changes, increased neutrophils, and pro-inflammatory cytokines in the BALF of wild-type mice, which were all attenuated by KO of FPR-1. The transcriptomic gene study showed a total of 198 up-regulated genes and 282 down-regulated genes in mouse lungs. Bioinformatics analysis including Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) suggested these differentiated expressed genes were significantly related to the immune, chemotaxis responses, and cross-talked with a complicated network of signaling pathways including NF-κB. Western blot validated that KO of FPR-1 inhibited CS-induced NF-κB activation.Conclusion: Knockout of FPR-1 significantly ameliorates CS-induced airway inflammation in mice, possibly via its related immune-chemotaxis responses and inhibition of NF-κB activation.

Objective: To investigate the risk factors of pregnancy failure in elderly infertile patients undergoing human assisted reproductive technology (ART). Methods: A total of 565 infertile patients undergoing ART were selected and divided into failed pregnancy group (127 cases) and continued pregnancy group (438 cases). Their clinical data were collected, and the influencing factors of pregnancy failure were assessed and compared by univariate and multivariate analysis. Results: The success and failure rates of in vitro fertilization-embryo transfer (IVF-ET) in pregnant women were 79.44% and 20.56%, while those of intracytoplasmic sperm injection (ICSI) were 75.96% and 24.04%, respectively. There was no remarkable difference between them (all P>0.05). Women’s age, numbers of embryos transferred and previous abortion history in the failed pregnancy group were higher than those in the continued pregnancy group, while the number of high-quality embryos, BMI and endometrial thickness (EMT) on human chorionic gonadotropin (hCG) day in the former were lower (all P

Adrenocortical carcinoma (ACC) is a rare malignant tumor with poor prognosis. Ferroptosis, a new form of cell death, differs from other forms of cell death and plays a vital role in tumor progress. Our study aimed to establish a ferroptosis-related signature with prognostic value in ACC. RNA-seq data and corresponding clinical characteristics for ACC were downloaded from TCGA and GEO databases. Genes included in ferroptosis risk signature were assessed by univariable and multivariable Cox regression analysis as well as lasso regression analysis. The prognostic value of the ferroptosis risk signature was assessed using K-M and ROC curves. Furthermore, we performed GSEA to discover the enriched gene sets in high-risk group. Additionally, TIMER website was applied to detect a possible connection between the signature and immune cells infiltration. ssGSEA was performed to evaluate scores of immune cells and immune-related pathways in two groups. A ferroptosis signature comprised of six genes (SLC7A11, TP53, HELLS, ACSL4, PCBP2, and HMGB1) was constructed to predict prognosis and reflect the immune infiltration in ACC. Patients in high-risk group were inclined to have worse prognosis. The ferroptosis model performed well in predicting prognosis and could be served as an independent indicator in ACC. GSEA revealed that gene sets correlated with biological processes including cell cycle, DNA replication, base excision repair, and P53 signaling pathway were highly enriched in high-risk group. In addition, we discovered that the expressional levels of hub genes were linked to six immune cells’ infiltration in ACC tumor. ssGSEA revealed that contents of most immune cells significantly decreased in the high-risk group. In conclusion, the novel ferroptosis risk signature could be useful in predicting prognosis and reflecting immune infiltration in ACC. It also brings us new insights into the possible value of targeting ferroptosis during the therapy of ACC.

Increasing evidence has shown that microRNAs (miRNAs) participate in cardiac fibrosis. We aimed to elucidate the effect of miRNA miR-25-3p on cardiac fibrosis. MiRNA microarray was used to profile miRNAs in the myocardium of angiotensin-II (Ang-II)-infused mice. Effect of miR-25-3p on expression of fibrosis-related genes, including Col1a1, Col3a1, and Acta2, was investigated both in vitro and in vivo. MiR-25-3p was shown increased in the myocardium of Ang-II-infused mice and patients with heart failure. MiR-25-3p enhanced fibrosis-related gene expression in mouse cardiac fibroblasts (mCFs) and in the myocardium of Ang-II-infused mice. Dickkopf 3 (Dkk3) was identified as a target gene of miR-25-3p, and Dkk3 could ameliorate Smad3 activation and fibrosis-related gene expression via enhancing Smad7 expression in mCFs. Additionally, NF-κB signal was proven to mediate upregulation of miR-25-3p in cardiac fibrosis. Our findings suggest that miR-25-3p enhances cardiac fibrosis by suppressing Dkk3 to activate Smad3 and fibrosis-related gene expression.

SOX9 (Sex-determining region Y Box 9) is a well-characterized transcription factor that is a marker for progenitor cells in various tissues. In the liver, cells delineated by SOX9 are responsible for regenerating liver parenchyma when cell proliferation is impaired following chronic injury. However, whether these SOX9+ cells play a role in liver carcinogenesis has not been fully understood, although high SOX9 expression has been linked to poor survival outcome in liver cancer patients. To address this question, we developed a liver cancer mouse model (PtenloxP/loxP; Sox9-CreERT+; R26RYFP) where tumor suppressor Pten (phosphatase and tensin homolog deleted on chromosome ten) is deleted in SOX9+ cells following tamoxifen injection. In this paper, we employ lineage-tracing to demonstrate the tumorigenicity potential of the Pten-, SOX9+ cells. We show that these cells are capable of giving rise to mixed-lineage tumors that manifest features of both hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (CCA). Our results suggest that PTEN loss induces the transformation of SOX9+ cells. We further show that to activate these transformed SOX9+ cells, the presence of liver injury is crucial. Liver injury, induced by hepatotoxin 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) or high-fat diet (HFD), substantially increases tumor incidence and accelerates liver carcinogenesis from SOX9+ cells in Pten null mice but not in control mice. We further examine the mechanisms underlying tumor formation in this model to show that concurrent with the induction of niche signal (i.e., Wnt signaling), liver injury significantly stimulates the expansion of tumor-initiating cells (TICs). Together, these data show that (1) SOX9+ cells have the potential to become TICs following the primary transformation (i.e. Pten deletion) and that (2) liver injury is necessary for promoting the activation and proliferation of transformed SOX9+ cells, resulting in the genesis of mixed-lineage liver tumors.

Objectives To investigate the effect of mitochondrial damage-associated molecular patterns on the lung fluid homeostasis in experimental acute lung injury. Design Experimental study. Setting Research laboratory. Subjects Patients with acute respiratory distress syndrome and control subjects, wild-type C57BL/6 and formyl peptide receptor-1 gene knockout mice, and primary rat alveolar epithelial type II cells. Interventions Samples of bronchoalveolar lavage fluid and serum were obtained from patients and control subjects. Mice were intratracheally instilled with lipopolysaccharide and mitochondrial damage-associated molecular patterns. The primary rat alveolar epithelial type II cells were isolated and incubated with mitochondrial damage-associated molecular patterns. Measurements and main results Patients were divided into direct (pulmonary) and indirect (extrapulmonary) injury groups based on etiology. The release of mitochondrial peptide nicotinamide adenine dinucleotide dehydrogenase 1 in both bronchoalveolar lavage fluid and serum was induced in patients and was associated with etiology. In the lipopolysaccharide-induced lung injury, administration of mitochondrial damage-associated molecular patterns exacerbated the lung fluid imbalance, which was mitigated in formyl peptide receptor-1 knockout mice. Proteomic analysis of mouse lung tissues revealed the involvement of ion channels and tight junction proteins in this process. Treatment with mitochondrial damage-associated molecular patterns decreased the expression of epithelial sodium channel α, zonula occludens-1, and occludin via the formyl peptide receptor-1/p38 pathway in the primary rat alveolar epithelial type II cells. Conclusions Mitochondrial damage-associated molecular patterns exacerbate lung fluid imbalance in the experimental acute lung injury model through formyl peptide receptor-1 signaling, the inhibition of which may prevent exacerbation of lung fluid imbalance induced by mitochondrial damage-associated molecular patterns. Thus, formyl peptide receptor-1 is a potential therapeutic target for acute respiratory distress syndrome.

Osteoarthritis (OA) represents the most prevalent and disabling arthritis worldwide due to its heterogeneous and progressive articular degradation. However, effective and timely diagnosis and fundamental treatment for this disorder are lacking. Metabolomics, a growing field in life science research in recent years, has the potential to detect many metabolites and thus explains the underlying pathophysiological processes. Hence, new specific metabolic markers and related metabolic pathways can be identified for OA. In this review, we aimed to provide an overview of studies related to the metabolomics of OA in animal models and humans to describe the metabolic changes and related pathways for OA. The present metabolomics studies reveal that the pathogenesis of OA may be significantly related to perturbations of amino acid metabolism. These altered amino acids (e.g., branched-chain amino acids, arginine, and alanine), as well as phospholipids, were identified as potential biomarkers to distinguish patients with OA from healthy individuals.

Sign Language Synthesis (SLS) is a domain-specific problem where multiple sign language words are stitched to generate a whole sentence in video, which serves to facilitate communications between the hearing-impaired people and healthy population. This paper presents a Variable Motion Frame Interpolation (VMFI) method for highly fluent SLS in scattered videos. Existing approaches for SLS mainly focus on mechanical virtual human technology, lacking high flexibility and natural effect. Also, the representative solutions to interpolate frames usually assume that the motion object moves at a constant speed which is not suitable for predicting the complex hand motion in frames of scattered sign language videos. To address the above issues, the proposed VMFI adopts acceleration to predict more accurate interpolated frames based on an end-to-end convolutional neural network. The framework of VMFI consists of variable optical flow estimation network and high-quality frame synthesis network that can approximate and fuse the intermediate optical flow to generate interpolated frames for synthesis. Experimental results on our realistic collected Chinese sign language dataset demonstrate that the proposed VMFI model achieves efficiency by performing better in PSNR (Peak Signal to Noise Ratio), SSIM (Structural Similarity) and MA (Motion Activity) and gets higher score in MOS (Mean Opinion Score) than other two representative methods.

Background Myocardial infarction (MI) is a common cause of death worldwide. It is characterized by coronary artery occlusion that causes ischemia and hypoxia of myocardial cells, leading to irreversible myocardial damage. Materials and Methods To explore potential targets for treatment of MI, we reorganized and analyzed two microarray datasets (GSE4648 and GSE775). The GEO2R tool was used to screen for differentially expressed genes (DEGs) between infarcted and normal myocardium. We used the Database for Annotation, Visualization and Integrated Discovery (DAVID) to perform Gene Ontology functional annotation analysis (GO analysis) and the Kyoto Encyclopedia of Genes and Genomes for pathway enrichment analysis (KEGG analysis). We examined protein–protein interactions to characterize the relationship between differentially expressed genes, and we screened potential hub genes according to the degree of connection. PCR and Western blotting were used to identify the core genes. Results At different times of infarction, a total of 35 genes showed upregulation at all times; however, none of the genes showed downregulation at all 3 times. Similarly, 10 hub genes with high degrees of connectivity were identified. In vivo and in vitro experiments suggested that expression levels of MMP-9 increased at various times after myocardial infarction and that expression increased in a variety of cells simultaneously. Conclusion Expression levels of MMP-9 increase throughout the course of acute myocardial infarction, and this expression has both positive and negative sides. Further studies are needed to explore the role of MMP-9 in MI treatment. The potential values of Il6, Spp1, Ptgs2, Serpine1, Plaur, Cxcl5, Lgals3, Serpinb2, and Cd14 are also worth exploring.

The polymorphism of the gene FAM13A (family with sequence similarity 13, member A) is strongly linked to the risk of lung cancer and chronic obstructive pulmonary disease, which are among the leading causes of mortality and morbidity in lung-related diseases worldwide. However, the underlying molecular and cellular mechanisms through which FAM13A contributes to the pathogenesis of these diseases largely remain unclear. Here, using a Fam13a knock out (KO) mouse model, we showed that Fam13a depletion upregulated the expression of the terminal differentiation and inhibitory marker, KLRG1 (killer cell lectin-like receptor G1) in natural killer (NK) cells. NK cells from Fam13a-deficient mice showed impaired IFN-γ production either against target tumor cells or following various cytokine cocktail stimulations. Furthermore, the number of lung metastases induced by B16F10 melanoma cells was increased in Fam13a-KO mice. Collectively, our data suggest a key role of FAM13A in regulating NK cell functions, indicating that the key lung-disease risk gene FAM13A might contribute to the pathogenesis of several lung diseases via regulating NK cells.

High circulating lipids occurring in obese individuals and insulin resistant patients are considered a contributing factor to Type 2 Diabetes (T2D). Exposure to high lipids initially causes the beta-cells to expand in population. Long-term exposure to high lipids however is associated with failure of beta-cells and the development of T2D. To prevent the failure of beta-cells and development of Type 2 Diabetes, this study focuses on understanding the molecular mechanisms that underlie this biphasic response of beta-cells to lipid exposure. Using palmitic acid (PA) in cultured beta-cells and islets, we demonstrated that chronic exposure to lipids leads to reduced viability and inhibition of cell cycle progression concurrent with downregulation of a pro-growth/survival kinase AKT, independent of glucose. This AKT downregulation by PA treatment is correlated with a consistent induction of mTOR/S6K activity concurrent with AKT downregulation. Inhibiting mTOR activity restores AKT activity and allows beta-cells to gain proliferation capacity that are lost after high fat diet exposure. In summary, we elucidated a novel mechanism for which lipid exposure may cause the dipole effects on beta-cell growth, where mTOR acts as a lipid sensor. These mechanisms can be novel targets for future therapeutic developments.

To date, no vaccine or monoclonal antibody (mAb) against Staphylococcus aureus has been approved for use in humans. Our laboratory has developed a 5-antigen S. aureus vaccine (rFSAV), which is now under efficacy evaluation in a phase 2 clinical trial. In the current study, using overlapping peptides and antiserum from rFSAV-immunized volunteers, we identified 7 B-cell immunodominant epitopes on 4 antigens in rFSAV, including 5 novel epitopes (Hla48-65, IsdB402-419, IsdB432-449, SEB78-95, and MntC7-24). Ten immunodominant epitope mAbs were generated against these epitopes, and all of them exhibited partial protection in a mouse sepsis model. Four robust mAbs were used together as an mAb cocktail to prevent methicillin-resistant S. aureus strain 252 infection. The results showed that the mAb cocktail was efficient in combating S. aureus infection and that its protective efficacy correlated with a reduced bacterial burden and decreased infection pathology, which demonstrates that the mAb cocktail is a promising S. aureus vaccine candidate.

Background Superior vena cava occlusion (SVCO) induced by tunneled central venous catheter (tCVC) is an uncommon but challenging complication of hemodialysis patients. The aim of this study was to access the efficacy, safety, and patency of stents in tCVC-related SVCO via through-and-through technique. Method We retrospectively identified seven patients with benign SVCO secondary to tCVC treated with endovascular approaches successfully between 1 March 2013 and 31 October 2019. Patients' demographic data, clinical signs and symptoms, and imaging data were followed up and recorded. Results Technical success was achieved in all cases. All the patients were performed with percutaneous transcatheter angioplasty (PTA) and subsequently stent placement via the through-and-through technique. During follow-up, four patients underwent secondary interventions, including PTA and/or stent placement. The primary patency after 3, 6, 9 and 12 months was 100%, 100%, 86% and 86%, and secondary patency after 12 months was 100%. No procedure-related deaths occurred. Conclusions Endovascular management of SVCO is a safe and effective approach. CT examination can provide a direction for endovascular treatment and periodic surveillance.

Isoforms of protein kinase B (also known as AKT) play important roles in mediating insulin and growth factor signals. Previous studies have suggested that the AKT2 isoform is critical for insulin-regulated glucose metabolism, while the role of the AKT1 isoform remains less clear. This study focuses on the effects of AKT1 on the adaptive response of pancreatic β cells. Using a mouse model with inducible β-cell-specific deletion of the Akt1 gene (βA1KO mice), we showed that AKT1 is involved in high-fat-diet (HFD)-induced growth and survival of β cells but is unnecessary for them to maintain a population in the absence of metabolic stress. When unchallenged, βA1KO mice presented the same metabolic profile and β-cell phenotype as the control mice with an intact Akt1 gene. When metabolic stress was induced by HFD, β cells in control mice with intact Akt1 proliferated as a compensatory mechanism for metabolic overload. Similar effects were not observed in βA1KO mice. We further demonstrated that AKT1 protein deficiency caused endoplasmic reticulum (ER) stress and potentiated β cells to undergo apoptosis. Our results revealed that AKT1 protein loss led to the induction of eukaryotic initiation factor 2 α subunit (eIF2α) signaling and ER stress markers under normal-chow-fed conditions, indicating chronic low-level ER stress. Together, these data established a role for AKT1 as a growth and survival factor for adaptive β-cell response and suggest that ER stress induction is responsible for this effect of AKT1.

Post-traumatic osteoarthritis (PTOA) develops after joint injury. Specifically, patients with anterior cruciate ligament (ACL) injury have a high risk of developing PTOA. In this review, we outline the incidence of ACL injury that progresses to PTOA, analyze the role of ACL reconstruction in preventing PTOA, suggest possible mechanisms thought to be responsible for PTOA, evaluate current diagnostic methods for detecting early OA, and discuss potential interventions to combat PTOA. We also identify important directions for future research. Although much work has been done, the incidence of PTOA among patients with a history of ACL injury remains high due to the complexity of ACL injury progression to PTOA, the lack of sensitive and easily accessible diagnostic methods to detect OA development, and the limitations of current treatments. A number of factors are thought to be involved in the underlying mechanism, including structural factors, biological factors, mechanical factors, and neuromuscular factor. Since there is a clear “start point” for PTOA, early detection and intervention is of great importance. Currently, imaging modalities and specific biomarkers allow early detection of PTOA. However, none of them is both sensitive and easily accessible. After ACL injury, many patients undergo surgical reconstruction of ACL to restore joint stability and prevent excessive loading. However, convincing evidence is still lacking for the superiority of ACL-R to conservative management in term of the incidence of PTOA. As for non-surgical treatment such as anti-cytokine and chemokine interventions, most of them are investigated in animal studies and have not been applied to humans. A complete understanding of mechanisms to stratify the patients into different subgroups on the basis of risk factors is critical. And the improvement of standardized and quantitative assessment techniques is necessary to guide intervention. Moreover, treatments targeted toward different pathogenic pathways may be crucial to the management of PTOA in the future.

Many players regulating the CD4+ T cell-mediated inflammatory response have already been identified. However, the critical nodes that constitute the regulatory and signalling networks underlying CD4 T cell responses are still missing. Using a correlation network-guided strategy based on time-series transcriptome data of human CD4+CD25- effector T cells (Teffs), here we identified VIMP (VCP-interacting membrane protein), one of the 25 genes encoding selenocysteine in humans, as a gene regulating the effector functions of human CD4 T cells. Knocking-down VIMP in Teffs enhanced their proliferation and expression of several cytokines, including IL-2 and CSF2. We identified VIMP as an endogenous inhibitor of cytokine production in Teffs via both, the E2F5 transcription regulatory pathway and the Ca2+/NFATC2 signalling pathway. Our work not only indicates that VIMP might be a promising therapeutic target for various diseases involving CD4 T cells, but also shows that our network-guided approach might be generally applicable to different types of cells and can significantly aid in predicting new functions of the genes of interest.One-sentence summaryUsing a network-guided approach, we identified that Selenoprotein S (SELS or VIMP) negatively regulates cytokine expression of human CD4+ effector T cells via the E2F5 and calcium Ca2+/NFATC2 pathways.

Surface defect detection is an indispensable step in the production process. Recent researches based on deep learning have paid primarily attention to improving accuracy. However, it is difficult to apply in real situation, because of huge number of parameters and the strict hardware requirements. In this paper, a lightweight fully convolutional neural network, named LFCSDD, is proposed. The parameters of our model are 11x fewer than baselines at least, and obtain the accuracy of 99.72% and 98.74% on benchmark defect datasets, DAGM 2007 and KolektorSDD, respectively, outperforming all the baselines. In addition, our model can process the images with different sizes, which is verified on the RSDDs with the accuracy of 97.00%.

Several studies have suggested that patients with pancreatic neuroendocrine neoplasm (pNEN) with the Ki-67 index of 5% are more likely to show better prognosis after clinical intervention. Moreover, the Ki-67 index at 5% has also been suggested as a potential threshold by the 2016 European Neuroendocrine Tumor Society guidelines.Based on preoperative enhanced computed tomography (CT), this study aimed to investigate imaging characteristics eligible to discriminate the ≤ 5% Ki-67 group from the 5% Ki-67 group of patients with nonmetastatic pNEN.Patients with pathologically diagnosed pNEN and preoperative multiphase CT were enrolled. Their Ki-67 index was calculated and grouped according to the 5% cutoff value. The following CT imaging characteristics and some serum biomarkers were assessed between the two groups: the diameter, location, tumor margin, calcification, pancreatic atrophy, distal pancreatic duct dilation, vessel involvement, and enhancement pattern characteristics of both arterial phase (AP) and portal vein phase (PVP).A total of 142 patients with pNEN were enrolled in this study, comprising 104 in the low (Ki-67, 1%-5%) and 38 in the high index group (Ki-67,5%). Alpha fetoprotein and cancer antigen 125 were significantly different between the two groups (P-values, 0.030 and 0.049, respectively). The diameter (P0.0001), margin (P = 0.003), distal main ductal dilation (P = 0.021), vessel involvement (P = 0.002), AP hypoenhancement (P0.0001), PVP hypoenhancement (P = 0.003), AP ratio (P = 0.0001), and PVP ratio (P = 0.0003) were significantly different between the low and high index groups. The area under the curve of the multivariate logistic regression model was 0.853.Nonmetastatic pNENs with larger diameter, ill-defined margin, distal main ductal dilation, and tumor hypoenhancement in AP in preoperative enhanced CT tend to have a Ki-67 index of 5%.The results of this study provide an alternative method to clinicians to decide whether surgery is appropriate.

Correction for ‘Ultrasmall Prussian blue nanoparticles attenuate UVA-induced cellular senescence in human dermal fibroblasts via inhibiting the ERK/AP-1 pathway’ by Yueyue Li et al., Nanoscale, 2021, 13, 16104–16112, https://doi.org/10.1039/D1NR04268H.

As we all know, the normally-off HEMT is very important to the safety of power electronic systems. To increase the threshold voltage of the device, this article proposes to cover Al2O3 on the recessed P-GaN to form the recessed p-GaN HEMT covered with Al2O3. Through simulation calculation, covering Al2O3 on P-GaN can effectively increase the threshold voltage, but the saturation current and transconductance will be severely reduced. Therefore, this article optimizes the structure and proposes a composite recessed-gate HEMT for the first time. It can obtain high saturation current and high transconductance while maintaining a high threshold voltage. Compared with the recessed p-GaN HEMT covered with Al2O3, the transconductance and saturation current of the composite recessed-gate HEMT are increased by 13.14% and 121.33%, respectively, while the threshold voltage is only reduced by 4.44% (4.3 V). In addition, the gate dielectric has a greater impact on device performance. Therefore, this paper analyzes the influence of the thickness of the Al2O3 layer on the device through theoretical calculations and obtains the optimal value of the thickness. (T1 = 18.3 nm, Vth = 4.5 V, Isat = 456 mA/mm). The results show that the composite recessed gate has broad application prospects in the next generation of normally-off power device applications.

The photocatalytic [3+2] cycloadditions of phenols and olefins are normally limited by the relatively tedious process. Herein, based on accelerated microdroplet reactions, a nano-electrospray ionization (nESI) was constructed for online acceleration of photocatalytic [3+2] cycloaddition between phenols and olefins. As demonstrated, the high reaction rates were obtained by nESI tips with smaller orifice inner diameter and the electrode closed to the nESI tip. These were further confirmed by the calculations on the conversion ratios and apparent acceleration factors. Meanwhile, the important intermediates (especially short-lived radicals) were recorded by virtue of the online monitoring of nESI mass spectrometry (MS). Subsequently, the dynamic information of substrates, intermediates and products were examined. Therefore, the mechanism of photocatalytic [3+2] cycloaddition reactions between phenols and olefins was proposed. This work not only enlarges the application of microdroplet synthesis, but also would provide a possible perspective for accelerating photocatalytic reactions and mechanism examinations.

Prostate cancer is a prevalent public health problem, especially because noncutaneous advanced malignant forms significantly affect the lifespan and quality of life of men worldwide. New therapeutic targets and approaches are urgently needed. The current study reports elevated expression of R1 (CDCA7L/RAM2/JPO2), a c-Myc–interacting protein and transcription factor, in human prostate cancer tissue specimens. In a clinical cohort, high R1 expression is associated with disease recurrence and decreased patient survival. Overexpression and knockdown of R1 in human prostate cancer cells indicate that R1 induces cell proliferation and colony formation. Moreover, silencing R1 dramatically reduces the growth of prostate tumor xenografts in mice. Mechanistically, R1 increases c-Myc protein stability by inhibiting ubiquitination and proteolysis through transcriptional suppression of HUWE1, a c-Myc–targeting E3 ligase, via direct interaction with a binding element in the promoter. Moreover, transcriptional repression is supported by a negative coexpression correlation between R1 and HUWE1 in a prostate cancer clinical dataset. Collectively, these findings, for the first time, characterize the contribution of R1 to prostate cancer pathogenesis. Implications: These findings provide evidence that R1 is a novel regulator of prostate tumor growth by stabilizing c-Myc protein, meriting further investigation of its therapeutic and prognostic potential.

Reliable markers for accurately diagnosing tuberculous pleural effusions (TPE) are needed. This study sought to investigate the diagnostic potential of pleural interleukin-22 (IL-22) and compare it with the performance of adenosine deaminase (ADA).This prospective study involved 49 patients with TPE and 60 patients with pleural effusion of other causes. Pleural levels of IL-22 and ADA were determined, respectively, using ELISA or an enzymatic method. A receiver operating characteristic curve was constructed and the area under the curve (AUC) was calculated to summarize the diagnostic accuracy of single markers or marker combinations.Levels of IL-22 in pleural effusion were significantly higher in TPE patients than in other patients (322.36 ± 406.65 vs. 83.13 ± 22.15 pg/ml, P 0.05). With a cut-off value of 97.82 pg/ml, the diagnostic sensitivity of IL-22 for TPE was 71.42%, specificity was 81.67%, and the area under the curve (AUC) was 0.83. ADA levels were also increased in TPE, and its AUC for diagnosing TPE was 0.90. The combination of IL-22 and ADA enhanced diagnostic accuracy, offering sensitivity of 83.67%, specificity of 91.67%, and an AUC of 0.93.IL-22 may be useful for diagnosing TPE, and combining it with ADA may further enhance diagnostic accuracy. Our results justify more rigorous studies with larger samples to confirm the diagnostic potential of IL-22 for TPE.

Suppression of xanthine oxidase (XO) may contribute to control hyperuricemia and gout. In this study, baicalein and baicalin, two dietary flavones, were found to inhibit the formation of uric acid and generation of superoxide anion (O2−) catalysed by XO through interaction with primary amino acid residues located in flavin adenine dinucleotides center of XO. Baicalein or baicalin binding to XO mainly facilitated by hydrophobic interactions and hydrogen bonds resulted in more compact of XO structure. The concentration profiles and pure spectra of the components extracted from highly overlapping spectral signal by multivariate curve resolution–alternating least squares chemometrics algorithm confirmed the formation of complexes and monitored the reaction kinetics process between XO and these flavones. Furthermore, the isobolographic analysis found that baicalein or baicalin exhibited a moderate synergy on the inhibition of XO when it combined with allopurinol as well as the joint use of baicalein and baicalin.

Acute lung injury (ALI) is characterized by alveolar epithelial damage and uncontrolled pulmonary inflammation. Mitochondrial damage-associated molecular patterns (DAMPs), including mitochondrial peptides [ N-formyl peptides (NFPs)], are released during cell injury and death and induce inflammation by unclear mechanisms. In this study, we have investigated the role of mitochondrial DAMPs (MTDs), especially NFPs, in alveolar epithelial injury and lung inflammation. In murine models of ALI, high levels of mitochondrial NADH dehydrogenase 1 in bronchoalveolar lavage fluid (BALF) were associated with lung injury scores and increased formyl peptide receptor (FPR)-1 expression in the alveolar epithelium. Cyclosporin H (CsH), a specific inhibitor of FPR1, inhibited lung inflammation in the ALI models. Both MTDs and NFPs upon intratracheal challenge caused accumulation of neutrophils into the alveolar space with elevated BALF levels of mouse chemokine KC, interleukin-1β, and nitric oxide and increased pulmonary FPR-1 levels. CsH significantly attenuated MTDs or NFP-induced inflammatory lung injury and activation of MAPK and AKT pathways. FPR1 expression was present in rat primary alveolar epithelial type II cells (AECIIs) and was increased by MTDs. CsH inhibited MTDs or NFP-induced CINC-1/IL-8 release and phosphorylation of p38, JNK, and AKT in rat AECII and human cell line A549. Inhibitors of MAPKs and AKT also suppressed MTD-induced IL-8 release and NF-κB activation. Collectively, our data indicate an important role of the alveolar epithelium in initiating immune responses to MTDs released during ALI. The potential mechanism may involve increase of IL-8 production in MTD-activated AECII through FPR-1 and its downstream MAPKs, AKT, and NF-κB pathways.

This study focused on the covalent immobilization of TiO2 on the surface of a porous polymer monolith by a two-step method. Firstly, porous polymeric monolith with trimethoxysilane anchor groups was fabricated by w/o emulsion templated copolymerization of vinyl acetate (VAc) and methacryloxypropyl-trimethoxysilane (MPS). Then, anatase TiO2 were covalently immobilized within the voids of poly(VAc-MPS) monolith via an acid-catalyzed co-condensation of the trimethoxysilane group with a TiO2 sol precursor at low temperate. Scanning electron microscopy images demonstrated that both poly(VAc-MPS) and Ti-P(VAc-MPS) possess dense honeycomb-like macroporous structures. The chemical structure analysis by Fourier transform infrared spectroscopy, powder X-ray diffraction, and X-ray photoelectron spectroscopy revealed that (i) acid-catalyzed sol-gel method in this case could fully convert the amorphous TiO2 sol to anatase TiO2 even at low temperature (70°); (ii) TiO2 particles were covalently immobilized within the voids of the polymer monolith via Si–O–Ti linkage; (iii) acid-catalyzed hydrolysis of the trimethoxysilane groups and VAc led to significant increase in the hydrophilicity of the obtained hybrid porous monolith, Ti-P(VAc-MPS), with a water contact angle of 19.6°. Exemplified by the photo-degradation of methyl orange (MO) in aqueous solution, Ti-P(VAc-MPs) exhibited good photocatalytic activity and excellent recyclability for water decontamination. The as-prepared Ti-P(VAc-MPS) monolith could be efficiently regenerated for cyclic runs without further energy-consuming separation process such as centrifugation and filtration. The present approach opens a green way for obtaining other porous inorganic-organic photocatalyst for water contaminant removal.

Although branched polymers find widespread applications, the rational design and synthesis of branched vinyl polymers via the conventional radical (co)polymerization of commercially available monomers is still a challenge for researchers in this field. Using branched polyvinyl acetate (PVAc) as a proof-of-concept, we report a facile approach to synthesize branched polymers via redox-initiated radical copolymerization. In this case, the commercially available monomer 2-(dimethylamino)ethyl methacrylate (DMAEMA), containing both a vinyl group and an initiator fragment (tertiary amine group), serves as an inimer in the presence of an oxidant to copolymerize with vinyl acetate (VAc), leading to the formation of branching architectures. The copolymerization kinetics investigation as well as electron paramagnetic resonance (EPR) measurements were conducted to reveal the reactivity of DMAEMA and the development of branching architectures, while TD-SEC and 1H-NMR were employed to study the structures of the resulted polymers. The results confirm that DMAEMA can serve as an inimer for the preparation of branched PVAc. Moreover, balancing the feed ratio of DMAEMA to VAc enables the fine control of branching degree. Within our experimental design, a high feed ratio of DMAEMA to VAc leads to high branching, as demonstrated by the Zimm branching factor, g′. This novel methodology involves only commercially available monomers and conventional radical polymerization and hence offers a promising future for preparing branched vinyl polymers on a large scale and at low cost.

Generally, the point cloud data obtained by 3D scanner cannot express the overall information of objects at a single time due to the limited field of view, so registration algorithm is needed to obtain the complete information. For the registration of point cloud data sets with large scale stretches and outliers, this paper proposed a new iterative nearest point algorithm named Improved-ICP. In the case of isotropic point extension, the iterative reweighted least squares method is constructed by incorporating a weight function to the minimum error function. In calculation, the weight function is equivalent to increasing the weight the point pairs, and the weights are obtained by an M-estimation criterion. In the paper, the initial registration was optimized to get global convergence for the algorithm, and compared the Improved-ICP algorithm with the ICP algorithm and the Scale-ICP algorithm to verify the effectiveness of the algorithm. To demonstrate the robustness of the Improved-ICP algorithm, we performed several comparative experiments with different scales and different noise between the Scale-ICP and the proposed algorithm in the presence of abnormal points. Experiment results illustrate the Improved-ICP algorithm has high accuracy and strong robustness to scale and abnormal points.

Dextran hydrogels (Dex-SS) containing both disulfide and Schiff base bonds were developed via facile method based on the dextran oxidation and subsequent formation of Schiff base linkages between polyaldehyde dextran and cystamine, denoted as the disulfide-containing Schiff base reactions. Results of rheology, swelling and 13C CP/MAS NMR study indicated that cross-linking degree of Dex-SS hydrogels depended strongly on the molar ratio of -CHO/-NH2. Acidic and reductive (GSH) environment sensitive degradation behaviors of Dex-SS hydrogels were then evidenced by SEM, rheology study and Ellman's assay. Moreover, doxorubicin (DOX) was loaded into the hydrogel matrix and pH/GSH-responsive release behaviors were demonstrated. Cytocompatibility of Dex-SS hydrogel and effective cell uptake of released DOX was finally proved by transwell assay with HepG2 cells. Take advantages of the abundance of vicinal hydroxyl on a variety of polysaccharides, the disulfide-containing Schiff base reactions is considered as versatile method to develop stimuli-sensitive hydrogels for local drug delivery.

Several studies have demonstrated the function of long nonâ€'coding RNAs (lncRNAs) in various biological processes, yet their role underlying the susceptibility to cigarette smoke (CS)-induced airway inflammation remains limited. In the present study, we aimed to profile the expression of lncRNAs and mRNAs in CS-exposed mice. C57BL/6 mice were assigned into a single cigarette-smoking machine with or without CS exposure for 4 weeks, followed by lung tissue harvest and RNA isolation. Microarray analysis identified 108 lncRNAs and 119 mRNAs with differential expression levels in CS-exposed mouse lung tissue compared with those in control mice. The expression patterns of several lncRNAs were further confirmed by qRT-PCR. GO and pathway analyses showed that the altered mRNAs were mainly related to the processes of immune response, defense response and cell chemotaxis, cytokine-cytokine receptor interaction and chemokine signaling pathway. Moreover, a single lncRNA may co-expressed with several mRNAs, and so was the mRNA. Our findings uncovered the expression profile of lncRNAs and mRNAs in the lungs of CS-exposed mice, which may offer new insights into pathogenesis of CS-associated airway inflammatory disorders.

Early embryo development and endometrial differentiation are initially independent processes, and synchronization, imposed by a limited window of implantation, is critical for reproductive success. A putative negative regulator of endometrial receptivity is LEFTY2, a member of the transforming growth factor (TGF)-β family. LEFTY2 is highly expressed in decidualizing human endometrial stromal cells (HESCs) during the late luteal phase of the menstrual cycle, coinciding with the closure of the window of implantation. Here, we show that flushing of the uterine lumen in mice with recombinant LEFTY2 inhibits the expression of key receptivity genes, including Cox2, Bmp2, and Wnt4, and blocks embryo implantation. In Ishikawa cells, a human endometrial epithelial cell line, LEFTY2 downregulated the expression of calcium release-activated calcium channel protein 1, encoded by ORAI1, and inhibited store-operated Ca2+ entry (SOCE). Furthermore, LEFTY2 and the Orai1 blockers 2-APB, MRS-1845, as well as YM-58483, inhibited, whereas the Ca2+ ionophore, ionomycin, strongly upregulated COX2, BMP2 and WNT4 expression in decidualizing HESCs. These findings suggest that LEFTY2 closes the implantation window, at least in part, by downregulating Orai1, which in turn limits SOCE and antagonizes expression of Ca2+-sensitive receptivity genes. •Endometrial receptivity is negatively regulated by LEFTY2. •LEFTY2 inhibits the expression of key murine receptivity genes, including Cox2, Bmp2 and Wnt4, and blocks embryo implantation. •LEFTY2 downregulates the expression of Orai1 and inhibits SOCE. •LEFTY2 and the Orai1 blockers 2-APB, MRS-1845, and YM-58483 inhibit COX2, BMP2, and WNT4 expression in endometrial cells. •Targeting LEFTY2 and Orai1 may represent a novel approach for treating unexplained infertility.

Background The gene polymorphism of interleukin-6 (IL-6) has been shown to be implicated in tuberculosis susceptibility in many studies, but with conflicting results. This study aimed to provide more accurate estimation of the relationship between IL-6 gene polymorphism and tuberculosis risk through a meta-analysis. Method A literature search was performed in PubMed, EMBASE, and other databases. Data were retrieved, and pooled odds ratio (OR) with 95% CI were calculated. Statistical analyses were performed by using STATA 12.0. Results Twelve publications with 2635 cases and 3049 controls were included. The pooled analysis demonstrated significant evidence of association between IL-6 (-174G/C) and low risk of tuberculosis in dominant model (CC+GC vs GG: OR =0.693, 95% CI 0.581-0.826, p

The identification of aberrant microRNA (miRNA) expression during chemical-induced hepatic dysfunction will lead to a better understanding of the substantial role of miRNAs in liver diseases. 1,2-Dichloroethane (1,2-DCE), a chlorinated organic toxicant, can lead to hepatic abnormalities in occupationally exposed populations. To explore whether aberrant miRNA expression is involved in liver abnormalities mediated by 1,2-DCE exposure, we examined alterations in miRNA expression patterns in the livers of NIH Swiss mice after dynamic inhalation exposure to 350 or 700 mg m-3 1,2-DCE for 28 days. Using a microarray chip, we discovered that only mmumiR-451a was significantly upregulated in the liver tissue of mice exposed to 700 mg m-3 1,2-DCE; this finding was validated by quantitative real-time polymerase chain reaction. In vitro study revealed that it was metabolite 2-chloroacetic acid, not 1,2-DCE that resulted in the upregulation of mmu-miR-451a in the mouse AML12 cell line. Furthermore, our data showed that the upregulation of mmu-miR-451a induced by 2-chloroacetic acid could suppress the expression of glycerol kinase and lead to the inhibition of glycerol gluconeogenesis in mouse liver tissue and AML12 cells. These observations provide evidence that hepatic mmu-miR-451a responds to 1,2-DCE exposure and might induce glucose metabolism disorders by suppressing the glycerol gluconeogenesis process.

// Hao Wang 1, * , Shujin Guo 2, * , Chun Wan 1, * , Ting Yang 1 , Ni Zeng 1 , Yanqiu Wu 1 , Lei Chen 1 , Yongchun Shen 1 and Fuqiang Wen 1 1 Department of Respiratory and Critical Care Medicine, West China Hospital of Sichuan University and Division of Pulmonary Diseases, State Key Laboratory of Biotherapy of China, Chengdu 610041, China 2 Internal Medicine of Sichuan Provincial People's Hospital and Sichuan Academy of Medical Science, Chengdu 610072, China * These authors contributed equally to this work Correspondence to: Yongchun Shen, email: shen_yongchun@126.com Fuqiang Wen, email: wenfuqiang.scu@gmail.com Keywords: sepsis, mortality, polymorphism, meta-analysis Received: June 28, 2017 Accepted: August 27, 2017 Published: September 13, 2017 ABSTRACT Background: The -308G/A polymorphism in the gene encoding tumor necrosis factor-α (TNF-α) has been implicated in sepsis risk in many studies but with variable results. This study aimed to comprehensively assess the evidence of association between this polymorphism and risk of sepsis and sepsis-related mortality. Materials and Methods: PubMed, EMBASE and other databases were searched to identify relevant studies, and data were analyzed using Review Manager 5.0 and STATA 12.0. Results: Data from 34 publications involving 12,284 subjects were meta-analyzed. Combined analysis revealed an association between TNF-α -308G/A gene polymorphism and risk of sepsis (AA+GA vs. GG, OR 1.35, 95% CI 1.10–1.67, P = 0.005). This association was observed in the Caucasian subgroup (OR 1.50, 95% CI 1.13–2.00, P = 0.006), but not in the Asian subgroup. Across the entire study population, the polymorphism was also significantly related to septic shock risk (OR 1.52, 95% CI 1.18–1.95, P = 0.001) but not to sepsis-related mortality (OR 0.99, 95% CI 0.71–1.40, P = 0.97). Conclusions: This meta-analysis suggests that the -308G/A gene polymorphism in the TNF-α gene may contribute to risk of sepsis and septic shock, but not risk of mortality.

// Shaqiu Zhang 1,2,6,* , Tamer al-Maghout 2,6,* , Rosi Bissinger 2,6 , Ni Zeng 2,3,6 , Lisann Pelzl 2,6 , Madhuri S. Salker 2,4,6 , Anchun Cheng 1,** , Yogesh Singh 2,5,6,** and Florian Lang 2,6** 1 Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu, Sichuan, P.R. China 2 Department of Internal Medicine III, Tubingen University, Gmelinstraβe, Tubingen, Germany 3 Department of Cleft Lip and Palate Surgery, State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, P.R. China 4 Institute of Women’s Health, Tubingen University, Calwerstraβe, Tubingen, Germany 5 Institute of Medical Genetics and Applied Genomics, Tubingen University, Calwerstraβe, Tubingen, Germany 6 Institute of Physiology I, Tubingen University, Gmelinstraβe, Tubingen, Germany * Equal contributions thus sharing first authorship ** Equal contributions thus sharing last authorship Correspondence to: Anchun Cheng, email: // Yogesh Singh, email: // Florian Lang, email: // Keywords : Murine CD4 + T cells, human leukaemic T cell lymphoblasts, EGCG, SOCE, miR-15b, Immunology and Microbiology Section, Immune response, Immunity Received : January 10, 2017 Accepted : July 26, 2017 Published : August 08,2017 Abstract CD4 + T cells are key elements in immune responses and inflammation. Activation of T cell receptors in CD4 + T cells triggers cytosolic Ca 2+ release with subsequent store operated Ca 2+ entry (SOCE), which is accomplished by the pore forming Ca 2+ release activated Ca 2+ (CRAC) channel Orai1 and its regulator stromal cell-interaction molecule 2 (STIM2). Green tea polyphenol epigallocatechin-3-gallate (EGCG) acts as a potent anti-inflammatory and anti-oxidant agent for various types of cells including immune cells. However, how post-transcriptional gene regulators such as miRNAs are involved in the regulation of Ca 2+ influx into murine CD4 + T cells and human Jurkat T cells through EGCG is not defined. EGCG treatment of murine CD4 + T cells significantly down-regulated the expression of STIM2 and Orai1 both at mRNA and protein levels. Furthermore, EGCG significantly decreased SOCE in both murine and human T cells. EGCG treatment increased miRNA-15b (miR-15b) abundance in both murine and human T cells. Bioinformatics analysis reveals that miR-15b, which has a STIM2 binding site, is involved in the down-regulation of SOCE. Overexpression of miR-15b significantly decreased the mRNA and protein expression of STIM2 and Orai1 in murine T cells. Treatment of Jurkat T cells with 10 µM EGCG further decreased mTOR and PTEN protein levels. EGCG decreased mitochondrial membrane potential (MMP) in both human and murine T cells. In conclusion, the observations suggest that EGCG inhibits the Ca 2+ entry into murine and human T cells, an effect accomplished at least in part by up-regulation of miR-15b.

Obesity confers an independent risk for carcinogenesis. In the liver, steatosis often proceeds cancer formation; however, the mechanisms by which steatosis promotes carcinogenesis is unknown. We hypothesize that steatosis alters the microenvironment to promote proliferation of tumor initiating cells (TICs) and carcinogenesis. We used several liver cancer models to address the mechanisms underlying the role of obesity in cancer and verified these findings in patient populations. Using bioinformatics analysis and verified by biochemical assays, we identified that hepatosteatosis resulting from either Pten deletion or transgenic expression of HCV core/NS5A proteins, promotes the activation of Wnt/β-catenin. We verified that high fat diet lipid accumulation is also capable of inducing Wnt/β-catenin. Caloric restriction inhibits hepatosteatosis, reduces Wnt/β-catenin activation and blocks the expansion of TICs leading to complete inhibition of tumorigenesis without affecting the phosphatase and tensin homologue deleted on chromosome 10 (PTEN) loss regulated protein kinase B (AKT) activation. Pharmacological inhibition or loss of the Wnt/β-catenin signal represses TIC growth in vitro, and decreases the accumulation of TICs in vivo. In human liver cancers, ontology analysis of gene set enrichment analysis (GSEA)-defined Wnt signature genes indicates that Wnt signaling is significantly induced in tumor samples compared with healthy livers. Indeed, Wnt signature genes predict 90% of tumors in a cohort of 558 patient samples. Selective depletion of macrophages leads to reduction of Wnt and suppresses tumor development, suggesting infiltrating macrophages as a key source for steatosis-induced Wnt expression. These data established Wnt/β-catenin as a novel signal produced by infiltrating macrophages induced by steatosis that promotes growth of tumor progenitor cells, underlying the increased risk of liver tumor development in obese individuals.

Herein, we report a new approach to fabricate polyvinyl alcohol (PVA) based hydrophilic monoliths by alcoholysis of porous emulsion-templated polyvinyl acetate (PVAc). The precursory PVAc-based monolith is obtained by polymerization of a W/O high internal phase emulsion (HIPE) containing vinyl acetate as the external phase while water as the internal phase. As an alcoholysis-stable tri-functional commonomer, triallyl isocyanurate is chosen as the crosslinking agent to prevent possible collapse of the polymeric skeleton and the consequent losses in mechanical properties during the alcoholysis step. By alcoholysis of the resulting PVAc-based monolith, the PVA-based monoliths are successful prepared as confirmed by FTIR analysis. BET analysis and SEM observation confirm the formation of open-cell and highly interconnected porous structures of PVA-based monoliths with surface areas of around 16 m2/g. Stemming from the intrinsic hydrophilicity of hydroxyl and morphology, PVA-based monoliths exhibit great enhancement in hydrophilicity with a much lower water contact angles than that of PVAc-based monoliths.

In situ gelling delivery systems for the ocular administration of drugs has been a major focus of research over the past two decades, improving the treatment of diseases of the anterior segment of the eye by simple, safe, and reproducible drug administration. This drug delivery strategy results in high ocular bioavailability by avoiding rapid precorneal clearance resulting from nasolacrimal drainage and eye blinking. However, the development of such unconventional forms requires many parameters to be mastered, such as gelation time, viscoelastic behavior, mucoadhesion, and sustained release. In this review, we describe and assess the in vitro and in vivo methods available for in situ gelling ophthalmic delivery systems, highlighting the advantages of existing methods and, in some cases, the need for more relevant assays.

Excessive exposure to 1,2-Dichloroethane (1,2-DCE), a chlorinated organic toxicant, can lead to liver dysfunction. To fully explore the mechanism of 1,2-DCE-induced hepatic abnormalities, 30 male National Institutes of Health (NIH) Swiss mice were exposed to 0, 350, or 700mg/m3 of 1,2-DCE, via inhalation, 6h/day for 28days. Increased liver/body weight ratios, as well as serum AST and serum ALT activity were observed in the 350 and 700mg/m3 1,2-DCE exposure group mice, compared with the control group mice. In addition, decreased body weights were observed in mice exposed to 700mg/m3 1,2-DCE, compared with control mice. Exposure to 350 and 700mg/m3 1,2-DCE also led to significant accumulation of hepatic glycogen, free fatty acids (FFA) and triglycerides, elevation of blood triglyceride and FFA levels, and decreases in blood glucose levels. Results from microarray analysis indicated that the decreases in glucose-6-phosphatase catalytic subunit (G6PC) and liver glycogen phosphorylase (PYGL) expression, mediated by the activation of AKT serine/threonine kinase 1 (Akt1), might be responsible for the hepatic glycogen accumulation and steatosis. Further in vitro study demonstrated that 2-chloroacetic acid (1,2-DCE metabolite), rather than 1,2-DCE, up-regulated Akt1 phosphorylation and suppressed G6PC and PYGL expression, resulting in hepatocellular glycogen accumulation. These results suggest that hepatic glucose and lipid homeostasis are impaired by 1,2-DCE exposure via down-regulation of PYGL and G6PC expression, which may be primarily mediated by the 2-chloroacetic acid-activated Akt1 pathway.