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Introduction: Neonatal hyperbilirubinemia is common and remains a clinical concern in China. Since neonatal hyperbilirubinemia is linked to genetic factors, we aimed to identify the gene variants of the red blood cell membrane (RBCM) and evaluate the clinical risk factors in Chinese neonates with hyperbilirubinemia. Methods: 117 hyperbilirubinemia neonates (33 cases of moderate hyperbilirubinemia and 84 cases of severe hyperbilirubinemia) and 49 controls with normal bilirubin levels were selected as our study subjects. A customized 22-gene panel with next-generation sequencing (NGS) was designed to characterize genetic variations among the neonates. Sanger sequencing was used to verify the accuracy of the NGS. The clinical risk factors and potential effects of genetic variations in neonates with hyperbilirubinemia were subsequently assessed. Results: After data filtering, suspected pathogenic variants of UGT1A1, SLCCO1B1, and RBCM-associated gene were identified in neonates, the combined numbers of RBCM-associated gene variants were found to have differences between the hyperbilirubinemia group and the controls (p = 0.008), they were also different between severe hyperbilirubinemia and moderate hyperbilirubinemia (p = 0.008), and were correlated with an increased risk of hyperbilirubinemia (odds ratio = 9.644, p = 0.006). The UGT1A1-rs4148323 variant in neonates with hyperbilirubinemia was significantly increased as compared with the controls (p < 0.001). However, there was no statistical difference for the SLCO1B1-rs2306283 variant between the hyperbilirubinemia group and the controls. In addition, breastfeeding contributed to an increased risk of hyperbilirubinemia. Conclusion: Our study highlights that the RBCM-related gene variants are an underestimated risk factor, which may play an important role in developing hyperbilirubinemia in Chinese newborns.

Streptococcus pneumoniae is major cause of otitis media (OM) and life-threatening pneumonia. Overproduction of mucin, the major component of mucus, plays a critical role in the pathogenesis of both OM and pneumonia. However, the molecular mechanisms underlying the tight regulation of mucin upregulation in the mucosal epithelium by S. pneumoniae infection remain largely unknown. In this study, we show that S. pneumoniae pneumolysin (PLY) activates AMP-activated protein kinase α1 (AMPKα1), the master regulator of energy homeostasis, which is required for S. pneumoniae–induced mucin MUC5AC upregulation in vitro and in vivo. Moreover, we found that PLY activates AMPKα1 via cholesterol-dependent membrane binding of PLY and subsequent activation of the Ca2+– Ca2+/calmodulin-dependent kinase kinase β (CaMKKβ) and Cdc42–mixed-lineage protein kinase 3 (MLK3) signaling axis in a TLR2/4-independent manner. AMPKα1 positively regulates PLY-induced MUC5AC expression via negative cross-talk with TLR2/4-dependent activation of MAPK JNK, the negative regulator of MUC5AC expression. Moreover, pharmacological inhibition of AMPKα1 suppressed MUC5AC induction in the S. pneumoniae–induced OM mouse model, thereby demonstrating its therapeutic potential in suppressing mucus overproduction in OM. Taken together, our data unveil a novel mechanism by which negative cross-talk between TLR2/4-independent activation of AMPKα1 and TLR2/4-dependent activation of JNK tightly regulates the S. pneumoniae PLY-induced host mucosal innate immune response.

Gut microbiota and their metabolites are instrumental in regulating homeostasis at intestinal and extraintestinal sites. However, the complex effects of prenatal and early postnatal microbial exposure on adult health and disease outcomes remain incompletely understood. Here, we showed that mice raised under germ-free conditions until weaning and then transferred to specific pathogen-free (SPF) conditions harbored altered microbiota composition, augmented inflammatory cytokine and chemokine expression, and were hyper-susceptible to colitis-associated tumorigenesis later in adulthood. Increased number and size of colon tumors and intestinal epithelial cell proliferation in recolonized germ-free mice were associated with augmented intratumoral CXCL1, CXCL2, and CXCL5 expression and granulocytic myeloid-derived suppressor cell (G-MDSC) accumulation. Consistent with these findings, CXCR2 neutralization in recolonized germ-free mice completely reversed the exacerbated susceptibility to colitis-associated tumorigenesis. Collectively, our findings highlight a crucial role for early-life microbial exposure in establishing intestinal homeostasis that restrains colon cancer in adulthood.

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Low-profile angle-stable spacer Zero-P is claimed to reduce the morbidity associated with traditional plate and cage construct (PCC). Both Zero-P and PCC could achieve comparable mid- and long-term clinical and radiological outcomes in anterior cervical discectomy and fusion (ACDF). It is not clear whether Zero-P can reduce the incidence of adjacent segment degeneration (ASD), especially in multi-segmental fusion. This study aimed to test the effect of fusion level with Zero-P versus with PCC on adjacent-segment biomechanics in ACDF. A three-dimensional finite element (FE) model of an intact C2-T1 segment was built and validated. Six single- or double-level instrumented conditions were modeled from this intact FE model using Zero-P or the standard PCC. The biomechanical responses of adjacent segments at the cephalad and caudal levels of the operation level were assessed in terms of range of motion (ROM), stresses in the endplate and disc, loads in the facets. When comparing the increase of adjacent-segment motion in single-level PCC fusion versus Zero-P fusion, a significantly larger increase was found in double-level fusion condition. The fold changes of PCC versus Zero-P of intradiscal and endplate stress, and facet load at adjacent levels in the double-level fusion spine were significantly larger than that in the single-level fusion spine during the sagittal, the transverse, and the frontal plane motion. The increased value of biomechanical features was greater at above segment than that at below. The fold changes of PCC versus Zero-P at adjacent segment were most notable in flexion and extension movement. Low-profile device could decrease adjacent segment biomechanical burden compared to traditional PCC in ACDF, especially in double-level surgery. Zero-P could be a good alternative for traditional PCC in ACDF. Further clinical/in vivo studies will be necessary to explore the approaches selected for this study is warranted.

BackgroundThe incidence of diabetes mellitus (DM) in China is increasing yearly and has become a major problem plaguing national public health. The diagnosis of diabetic kidney disease (DKD) is based primarily on clinical criteria, and most patients do not receive a formal evaluation by renal biopsy; thus, misdiagnosis and underdiagnosis are common. The incidence of non-diabetic kidney disease (NDKD) is also higher in those with DM. To date, many cases of IgA nephropathy (IgAN) among those with DKD have been reported, while cases of IgAN in patients with long-duration DM who did not develop DKD are less commonly reported.Case descriptionA 70-year-old male patient with a diabetes duration of 26 years had proteinuria for one year. The clinical manifestations of nephrotic syndrome and IgAN were confirmed by renal biopsy. The patient received targeted treatment for three years with partial alleviation of proteinuria.ConclusionRenal biopsy might aid in the definitive diagnosis of DKD, NDKD, and NDKD combined with DKD. Precise therapy based on renal pathology might help to improve outcomes in the kidney.

BackgroundThis study aimed to investigate the influence of a variant of the UGT1A1 gene on the occurrence and severity of prolonged jaundice in Chinese infants at term.Methods175 infants with prolonged jaundice and 149 controls were used in this retrospective case-control study. The infants with prolonged jaundice were subdivided into the mild-medium and severe jaundice groups (TSB ≥ 342 µmol/L). The frequency and genotype distribution of the UGT1A1 and G6PD genes, and clinical parameters including sex, birth weight, delivery mode, gestational age, and feeding mode, were analyzed, and the differences in the parameters between the two groups were compared.ResultsThe allele frequency of UGT1A1*6 in the prolonged jaundice group was higher than that in the control group. Similarly, it was also higher in the severe jaundice group than in the mild-medium jaundice group. Homozygous and heterozygous UGT1A1*6 were also found more frequently in the prolonged jaundice group than in the control group. Exclusive breastfeeding, homozygous and heterozygous forms of UGT1A1*6 were significant risk indicators for prolonged jaundice. Moreover, UGT1A1*6 was the best predictor of prolonged severe jaundice.ConclusionUGT1A1*6 appears to be a risk factor for prolonged jaundice with hyperbilirubinemia in term infants of Chinese ancestry who are exclusively breastfed.

Background Tumor suppressor CYLD dysfunction by loss of its expression, triggers malignant transformation, especially drug resistance and tumor invasion/metastasis. Although loss of CYLD expression is significantly associated with poor prognosis in a large variety of tumors, no clinically-effective treatment for CYLD-negative cancer patients is available. Methods We focused on oral squamous cell carcinoma (OSCC), and sought to develop novel therapeutic agents for CYLD-negative cancer patients with poor prognosis. CYLD-knockdown OSCC cells by using CYLD-specific siRNA, were used to elucidate and determine the efficacy of novel drug candidates by evaluating cell viability and epithelial-mesenchymal transition (EMT)-like change. Therapeutic effects of candidate drug on cell line-derived xenograft (CDX) model and usefulness of CYLD as a novel biomarker using patient-derived xenograft (PDX) model were further investigated. Results CYLD-knockdown OSCC cells were resistant for all currently-available cytotoxic chemotherapeutic agents for OSCC, such as, cisplatin, 5-FU, carboplatin, docetaxel, and paclitaxel. By using comprehensive proteome analysis approach, we identified epidermal growth factor receptor (EGFR), a receptor tyrosine kinase, played key roles in CYLD-knockdown OSCC cells. Indeed, cell survival rate in the cisplatin-resistant CYLD-knockdown OSCC cells was markedly inhibited by treatment with clinically available EGFR tyrosine kinase inhibitors (EGFR-TKIs), such as gefitinib. In addition, gefitinib was significantly effective for not only cell survival, but also EMT-like changes through inhibiting transforming growth factor-β (TGF-β) signaling in CYLD-knockdown OSCC cells. Thereby, overall survival of CYLD-knockdown CDX models was significantly prolonged by gefitinib treatment. Moreover, we found that CYLD expression was significantly associated with gefitinib response by using PDX models. Conclusions Our results first revealed that EGFR-targeted molecular therapies, such as EGFR-TKIs, could have potential to be novel therapeutic agents for the CYLD-negative OSCC patients with poor prognosis.

ObjectiveThe aim of this study was to analyze the epidemiological characteristics of the causes of chronic kidney disease (CKD) stage 5 patients in North China and to investigate the economic burden of those on hemodialysis (HD) or peritoneal dialysis (PD), as well as the associated influencing factors.MethodsGeneral clinical information, etiological categories, and hospitalization costs for HD or PD were collected from 1,515 patients hospitalized with stage 5 CKD at the Affiliated Hospital of Hebei University from 2016 to 2018. Logistic regression analysis was used to analyze the independent influencing factors affecting patients' financial burden.ResultsThe highest rate of DN was found in patients aged 70 years or older (27.0%) and the highest incidence of primary glomerulopathy was found in patients aged ConclusionChronic kidney disease, with its complex etiology and the heavy financial burden required for treatment, remains a more serious public health problem globally, and it is therefore necessary to further improve medical coverage for dialysis patients, increase management efforts, broaden pro-poor policies and increase the accessibility of medical services in low- and middle-income areas.

Nogo-B receptor (NgBR) is a specific receptor of Nogo-B, a member of reticulon 4 protein family. It is widely expressed in many tissues and mainly located in cell membrane and endoplasmic reticulum. Previous studies have revealed that NgBR is involved in a variety of physiological and pathophysiological processes, such as dolichol synthesis, lipid metabolism, cholesterol trafficking, insulin resistance, vascular remodeling and angiogenesis, tumorigenesis and nervous system diseases. Further studies on the molecular characteristics and biological function of NgBR might be of great significance to understand its role in diverse diseases and provide possible clinical strategies for the treatment of diseases.

Otitis media (OM) is the most common bacterial infection in children. It remains a major health problem and a substantial socioeconomic burden. Streptococcus pneumoniae (S. pneumoniae) is one of the most common bacterial pathogens causing OM. Innate inflammatory response plays a critical role in host defense against bacterial pathogens. However, if excessive, it has a detrimental impact on the middle ear, leading to middle ear inflammation, a hallmark of OM. Currently, there has been limited success in developing effective therapeutic agents to suppress inflammation without serious side effects. In this study, we show that vinpocetine, an antistroke drug, suppressed S. pneumoniae–induced inflammatory response in cultured middle ear epithelial cells as well as in the middle ear of mice. Interestingly, vinpocetine inhibited S. pneumoniae–induced inflammation via upregulating a key negative regulator cylindromatosis (CYLD). Moreover, CYLD suppressed S. pneumoniae–induced inflammation via inhibiting the activation of ERK. Importantly, the postinfection administration of vinpocetine markedly inhibited middle ear inflammation induced by S. pneumoniae in a well-established mouse OM model. These studies provide insights into the molecular mechanisms underlying the tight regulation of inflammation via inhibition of ERK by CYLD and identified vinpocetine as a potential therapeutic agent for suppressing the inflammatory response in the pathogenesis of OM via upregulating negative regulator CYLD expression.

Maternal high-fat diet (HFD) is associated with metabolic syndrome and cardiovascular diseases in adult offspring. Our previous study demonstrated that maternal HFD enhances pressor responses to ANG II or a proinflammatory cytokine (PIC), which is associated with increased expression of brain renin-angiotensin system (RAS) components and PICs in adult offspring. The present study further investigated whether inhibition of angiotensin-converting enzyme (ACE) or tumor necrosis factor-α (TNF-α) blocks sensitization of ANG II hypertension in offspring of HFD dams. All offspring were bred from dams with normal fat diet (NFD) or HFD starting two weeks before mating and maintained until weaning of the offspring. Then the weaned offspring were treated with an ACE inhibitor (captopril) or a TNF-α inhibitor (pentoxifylline) in the drinking water through the end of testing with a slow-pressor dose of ANG II. RT-PCR analyses of the lamina terminalis and paraventricular nucleus revealed upregulation of mRNA expression of several RAS components and PICs in male offspring of HFD dams when compared with age-matched offspring of NFD dams. The enhanced gene expression was attenuated by blockade of either RAS or PICs. Likewise, ANG II administration produced an augmented pressor response in offspring of HFD dams. This was abolished by either ACE or TNF-α inhibitor. Taken together, this study provides mechanistic evidence and a therapeutic strategy that systemic inhibition of the RAS and PICs can block maternal HFD-induced sensitization of ANG II hypertension, which is associated with attenuation of brain RAS and PIC expression in offspring.

Background: Glucose-6-phosphate dehydrogenase (G6PD) deficiency, which may manifest as neonatal hyperbilirubinemia, is the most prevalent erythrocytic enzyme-related disease in the world.Objective: To investigate the association between neonatal hyperbilirubinemia and co-inheritance of G6PD deficiency and 211 G to A variation of UGT1A1 in Chaozhou city of eastern Guangdong province, the effects of G6PD deficiency and UGT1A1 gene variant on the bilirubin level were determined in neonates with hyperbilirubinemia.Method: The activity of G6PD was assayed by an auto-bioanalyzer. PCR and flow-through hybridization were used to detect 14 common G6PD mutations in G6PD deficient neonates. 211 G to A variation of UGT1A1 was determined by PCR and sequencing. The data of neonatal peak bilirubin was collected and analyzed retrospectively.Results: 74 cases of the 882 hyperbilirubinemia neonates were G6PD deficiency (8.39%) while 12 cases of the 585 non-hyperbilirubinemia neonates (control group) were G6PD deficiency (2.05%). The rate of G6PD deficiency in the hyperbilirubinemia group was higher than that of the control group. Moreover, the peak bilirubin in the G6PD-deficient group of hyperbilirubinemia neonates was 334.43±79.27μmol/L, higher than that of the normal G6PD group of hyperbilirubinemia neonates (300.30±68.62 μmol/L). The most common genotypes of G6PD deficiency were c.1376G>T and c.1388G>A, and the peak bilirubin of neonates with these two variants were 312.60±71.81μmol/L and 367.88±75.79 μmol/L, respectively. The bilirubin level of c.1388G>A was significantly higher than that of c.1376G>T. Among the 74 hyperbilirubinemia neonates with G6PD deficiency, 6 cases were 211 G to A homozygous mutation (bilirubin levels 369.55±84.51 μmol/L), 27 cases were 211 G to A heterozygous mutation (bilirubin levels 341.50±63.21 μmol/L), and 41 cases were wild genotypes (bilirubin levels 324.63±57.52 μmol/L). Conclusion: The rate of G6PD deficiency in hyperbilirubinemia neonates was significantly higher than that of the non-hyperbilirubinemia neonates in Chaozhou. For the hyperbilirubinemia group, neonates with G6PD deficiency had a higher bilirubin level compared to those with normal G6PD. For hyperbilirubinemia neonates with G6PD deficiency, there was a declining trend of bilirubin levels among 211 G to A homozygous mutation, heterozygous mutation, and wild genotype, but there was no significance statistically among the three groups.

Ionic soil stabilization additives can improve soil compactness and strength rapidly and efficiently by chemical reaction. In order to study the stabilization mechanism of the F1 ionic soil stabilization additive and the basic engineering properties of the stabilized soil, the basic physical parameters, CBR value, unconfined compressive strength, expansion characteristics, and microscopic pore structure characteristics of the loess before and after F1 stabilization were studied by using micro and macro testing methods. The results show that the high-energy H3O+ of F1 dissociated with water can exchange with the metal cation and polar water molecule on the surface of clay particles, and neutralize the vacancy anion, so that the charged property, ion type, and concentration on the surface of stabilized soil particles can change. In F1, the sulfonated oil-coated soil particles form a hydrophobic oily layer, which reduces the plastic limit and optimal water content of the soil, increases the plastic index, and reduces the water sensitivity. The F1, through a series of physical and chemical effects, reduces the clay minerals’ surface electric potential and the electric double layer thickness of the water film; changes the pore structure and the form of contact between the soil particles; causes the soil particles through fine flocculation to join together into large particles; reduces the soil micro-pore area, the total number of pores, and the pore distribution fractal dimension, inhibiting the expansion deformation of the soil; increases the connection strength between the soil particles, the maximum dry density, and the CBR value; and makes the arrangement closer; a layer-stacked structure with more compact arrangement, larger aggregates, and surface-to-surface contact was formed under the action of compaction. F1 has many advantages that traditional soil stabilization additives do not have and has a broad application potential in soil reinforcement engineering in loess areas.

This paper discusses the history, fundamental theory and current concepts, and latest trends of information communication networks. The important challenges faced by such networks are analyzed and the performance gains of collaborative multi-dimensional resource management and control are explored. The coupling relationships among data, network, and intelligence, as well as the key technologies that pave the way to future information communication networks with full spectrum, space, and intelligence are also discussed.

Gut microbiota and their metabolites are instrumental in regulating homeostasis at intestinal and extraintestinal sites. However, the complex effects of prenatal and early postnatal microbial exposure on adult health and disease outcomes remain incompletely understood. Here, we showed that mice raised under germ-free conditions until weaning and then transferred to specific pathogen-free (SPF) conditions harbored altered microbiota composition, augmented inflammatory cytokine and chemokine expression, and were hyper-susceptible to colitis-associated tumorigenesis later in adulthood. Increased number and size of colon tumors and intestinal epithelial cell proliferation in recolonized germ-free mice were associated with augmented intratumoral CXCL1, CXCL2, and CXCL5 expression and granulocytic myeloid-derived suppressor cell (G-MDSC) accumulation. Consistent with these findings, CXCR2 neutralization in recolonized germ-free mice completely reversed the exacerbated susceptibility to colitis-associated tumorigenesis. Collectively, our findings highlight a crucial role for early-life microbial exposure in establishing intestinal homeostasis that restrains colon cancer in adulthood.

BackgroundNeonatal hyperbilirubinemia causing jaundice is common in East Asian population. Uridine diphosphate glucuronosyltransferase isoenzyme (UGT1A1) glucuronidates bilirubin and converts the toxic form of bilirubin to its nontoxic form.MethodA retrospective study was conducted to review clinical information of ABO hemolysis neonates (ABO HDN) admitted to the Department of Neonatology, referred for neonatal hyperbilirubinemia, in a large general hospital of southern China from 2011 to 2017. Variation status of UGT1A1 was determined by direct sequencing or genotype assays.ResultSixty-nine ABO HDNs were included into the final analysis. UGT1A1 c.211 G > A mutation (UGT1A1*6, p.Arg71Gly, rs4148323) was significantly associated with the increased bilirubin level in ABO HDNs, after adjusted by age, sex and feeding method (P = 0.019 for TBIL,P = 0.02 for IBIL). Moreover, heterozygous and/or homozygous UGT1A1 mutations in the coding sequence region were significantly associated with the increased risk of developing hazardous hyperbilirubinemia (as defined by TSB > 427 umol/L) as compared those with a normal UGT1A1 genotype (ORadj = 9.16, 95%CI 1.99–42.08,P = 0.002) in the study cohort.ConclusionUGT1A1 variant in coding region is actively involved in the pathogenesis of ABO hemolysis related neonatal hyperbilirubinemia. Genetic assessment of UGT1A1 may be useful for clinical diagnosis of neonatal unconjugated hyperbilirubinemia.

Objective To review and highlight significant advances made towards vaccine development and understanding of the immunology of otitis media (OM) since the 19th International Symposium on Recent Advances in Otitis Media (ISOM) in 2015, as well as identify future research directions and knowledge gaps. Data sources PubMed database, National Library of Medicine. Review methods Key topics were assigned to each panel member for detailed review. Draft reviews were collated, circulated, and thoroughly discussed when the panel met at the 20th ISOM in June 2019. The final manuscript was prepared with input from all panel members. Conclusions Since 2015 there have been a number of studies assessing the impact of licensed pneumococcal vaccines on OM. While these studies have confirmed that these vaccines are effective in preventing carriage and/or disease caused by vaccine serotypes, OM caused by non-vaccine serotype pneumococci and other otopathogens remains a significant health care burden globally. Development of multi-species vaccines is challenging but essential to reducing the global burden of OM. Influenza vaccination has been shown to prevent acute OM, and with novel vaccines against nontypeable Haemophilus influenzae (NTHi), Moraxella catarrhalis and Respiratory Syncytial Virus (RSV) in clinical trials, the potential to significantly prevent OM is within reach. Research into alternative vaccine delivery strategies has demonstrated the power of maternal and mucosal vaccination for OM prevention. Future OM vaccine trials must include molecular diagnostics of middle ear effusion, for detection of viruses and bacteria that are persisting in biofilms and to enable accurate assessment of vaccine impact on OM etiology. Understanding population differences in natural and vaccine-induced immune responses to otopathogens is also important for development of the most effective OM vaccines. Improved understanding of the interaction between otopathogens will also advance development of effective therapies and encourage the assessment of the indirect benefits of vaccination. Implications for practice While NTHi and M. catarrhalis are the predominant otopathogens, funding opportunities to drive vaccine development for these species are limited due to a focus on prevention of childhood mortality rather than morbidity. Delivery of a comprehensive report on the high financial and social costs of OM, including the potential for OM vaccines to reduce antibiotic use and subsequent development of antimicrobial resistance (AMR), would likely assist in engaging stakeholders to recognize the value of prevention of OM and increase support for efforts on OM vaccine development. Vaccine trials with OM prevention as a clinical end-point are challenging, however a focus on developing assays that measure functional correlates of protection would facilitate OM vaccine development.

Glucagon-like peptide-1 (GLP-1) is a gastrointestinal hormone that stimulates glucose-mediated insulin production by pancreatic beta cells. It is also associated with protective effects in multiple tissues. GLP-1 receptor is highly expressed in pulmonary tissue, hinting possible pulmonary delivery of GLP-1 drugs. However, little is known about the role of GLP-1 signaling in the lung, especially in mucus hypersecretory obstructive lung diseases. Here, we showed that treatment with exendin-4, a clinically available GLP-1 receptor agonist, up-regulates mucin expression in normal airway epithelial cells and in the lung of normal mice, indicating mucus stimulatory effect of GLP-1 under physiological condition. Exendin-4 also increased mucin expression in in vitro cellular and in vivo murine models of obstructive lung diseases via the activation of p38 MAP kinase. Notably, mucin induction in vivo exacerbated key pulmonary abnormalities including emphysematous phenotypes, implying that GLP-1 signaling in the lung is detrimental under pulmonary obstructive condition. Another GLP-1 receptor agonist liraglutide had similar induction of mucin. Together, our studies not only demonstrate novel physiological and pathological roles of GLP-1 in the lung but may also caution against the clinical use of inhaled GLP-1 receptor agonists in the patients with obstructive lung diseases.

Oral squamous cell carcinoma (OSCC) has a very poor prognosis because of its highly invasive nature, and the 5-year survival rate has not changed appreciably for the past 30 years. Although cylindromatosis (CYLD), a deubiquitinating enzyme, is thought to be a potent tumour suppressor, its biological and clinical significance in OSCC is largely unknown. This study aimed to clarify the roles of CYLD in OSCC progression. Our immunohistochemical analyses revealed significantly reduced CYLD expression in invasive areas in OSCC tissues, whereas CYLD expression was conserved in normal epithelium and carcinoma in situ. Furthermore, downregulation of CYLD by siRNA led to the acquisition of mesenchymal features and increased migratory and invasive properties in OSCC cells and HaCaT keratinocytes. It is interesting that CYLD knockdown promoted transforming growth factor-β (TGF-β) signalling by inducing stabilization of TGF-β receptor I (ALK5) in a cell autonomous fashion. In addition, the response to exogenous TGF-β stimulation was enhanced by CYLD downregulation. The invasive phenotypes induced by CYLD knockdown were completely blocked by an ALK5 inhibitor. In addition, lower expression of CYLD was significantly associated with the clinical features of deep invasion and poor overall survival, and also with increased phosphorylation of Smad3, which is an indicator of activation of TGF-β signalling in invasive OSCC. These findings suggest that downregulation of CYLD promotes invasion with mesenchymal transition via ALK5 stabilization in OSCC cells. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Vinpocetine, a derivative of the alkaloid vincamine, has been clinically used in many countries for treatment of cerebrovascular disorders such as stroke and dementia for more than 30 years. Currently, vinpocetine is also available in the market as a dietary supplement to enhance cognition and memory. Due to its excellent safety profile, increasing efforts have been put into exploring the novel therapeutic effects and mechanism of actions of vinpocetine in various cell types and disease models. Recent studies have revealed a number of novel functions of vinpocetine, including anti-inflammation, antagonizing injury-induced vascular remodeling and high-fat-diet-induced atherosclerosis, as well as attenuating pathological cardiac remodeling. These novel findings may facilitate the repositioning of vinpocetine for preventing or treating relevant disorders in humans.

We herein disclose a series of compounds with potent inhibitory activities towards histone deacetylases (HDAC) and cyclooxygenases (COX). These compounds potently inhibited the growth of cancer cell lines consistent with their anti-COX and anti-HDAC activities. While compound 2b showed comparable level of COX-2 selectivity as celecoxib, compound 11b outperformed indomethacin in terms of selectivity towards COX-2 relative to COX-1. An important observation with our lead compounds (2b, 8, 11b, and 17b) is their enhanced cytotoxicity towards androgen dependent prostate cancer cell line (LNCaP) relative to androgen independent prostate cancer cell line (DU-145). Interestingly, compounds 2b and 17b arrested the cell cycle progression of LNCaP in the S-phase, while compound 8 showed a G0/G1 arrest, similar to SAHA. Relative to SAHA, these compounds displayed tumor-selective cytotoxicity as they have low anti-proliferative activity towards healthy cells (VERO); an attribute that makes them attractive candidates for drug development.

Objective: Chronic rhinosinusitis (CRS) involves inflammation of the nasal and para-nasal mucosa. Due to its heterogeneous nature, unknown pathogenesis, and high recurrence rate, effective treatment is difficult. Nasal cytology is presently not a part of the routine diagnosis or treatment decision for CRS. Data sources: A literature search was performed for published papers in English between January 1990 and June 2019 using MEDLINE. Study selection: Terms used were chronic rhinosinusitis, eosinophils, etiology, immunopathology, inflammation, mast cells, nasal cytology, polyps, and treatment. Both reviews and original articles were collected and studied. Results: There is no standard nasal fluid, mucus sampling, or staining techniques for identifying inflammatory cell types. Results were divergent from different countries. Moreover, the main focus of these papers on the cells in nasal washings was eosinophils, with infrequent mentioning of other cell types that may imply different etiology and pathology. The heterogeneous cell profile of CRS and the role of mast cells have been unappreciated due to the lack of specific immunohistochemical technique or study of its unique mediators. Conclusions: Nasal cytology could help distinguish the type and the activation state of inflammatory cells. Thus it can help in providing a clearer picture of CRS pathogenesis, identifying different patient groups, and developing effective treatments. Key words: Rhinitis; Sinusitis; Nasal polyps; Nasal mucosa; Cytology; Inflammation; Eosinophils; Mast cells

Since the inner ear is an important but sensitive organ of hearing, bacteria-driven immune responses must be tightly controlled. In this issue of Cell Host & Microbe, Jung et al. (2019) demonstrate that cleaved cochlin plays a dual role to trap bacteria and recruit immune cells to improve ear function.

Cystic fibrosis transmembrane regulator (CFTR) is a cyclic AMP-dependent Cl- channel, and its dysfunction, due to CFTR gene mutations, causes the lethal inherited disorder cystic fibrosis (CF). To date, widespread dysregulation of certain coding genes in CF airway epithelial cells is well studied and considered as the driver of pulmonary abnormality. However, the involvement of non-coding genes, novel classes of functional RNAs with little or no protein-coding capacity, in the regulation of CF-associated gene dysregulation is poorly understood. Here, we utilized integrative analyses of human transcriptome array (HTA) and characterized 99 coding and 91 non-coding RNAs that are dysregulated in CFTR-defective CF bronchial epithelial cell line CFBE41o-. Among these genes, the expression level of linc-SUMF1-2, an intergenic non-coding RNA (lincRNA) whose function is unknown, was inversely correlated with that of WT-CFTR and consistently higher in primary human CF airway epithelial cells (DHBE-CF). Further integrative analyses under linc-SUMF1-knockdown condition determined MXRA5, SEMA5A, CXCL10, AK022877, CTGF, MYC, AREG and LAMB3 as both CFTR- and linc-SUMF1-2-dependent dysregulated gene sets in CF airway epithelial cells. Overall, our analyses reveal linc-SUMF1-2 as a dysregulated non-coding gene in CF as well as CFTR-linc-SUMF1-2 axis as a novel regulatory pathway involved in CF-associated gene dysregulation.

Objectives To update the medical literature on recent large-scale studies employing bioinformatics data analysis tools in otitis media (OM) disease models with a principal focus on developments in the past 5 years. Data sources Pubmed indexed peer-reviewed articles. Review methods Comprehensive review of the literature using the following search terms: ‘genomics, inflammasome, microRNA, proteomics, transcriptome, bioinformatics’ with the term ‘otitis media’, and ‘middle ear’. Included articles published in the English language from January 1, 2015–April 1, 2019. Implications for practice Large scale bioinformatics tools over the past five years lend credence to the paradigm of innate immune response playing a critical role in host defense against bacteria contributing to Otitis Media (OM) progression from acute to chronic. In total, genomic, miRNAomic, and proteomic analyses all point to the need for a tightly regulated innate immune and inflammatory response in the middle ear. Currently, there is an urgent need for developing novel therapeutic strategies to control immunopathology and tissue damage, improve hearing and enhance host defense for both acute and chronic OM based on full understanding of the basic molecular pathogenesis of OM.

Influenza is a persistent threat to public health. Here we report that double-layered peptide nanoparticles induced robust specific immunity and protected mice against heterosubtypic influenza A virus challenges. We fabricated the nanoparticles by desolvating a composite peptide of tandem copies of nucleoprotein epitopes into nanoparticles as cores and cross-linking another composite peptide of four tandem copies of influenza matrix protein 2 ectodomain epitopes to the core surfaces as a coating. Delivering the nanoparticles via dissolvable microneedle patch-based skin vaccination further enhanced the induced immunity. These peptide-only, layered nanoparticles demonstrated a strong antigen depot effect and migrated into spleens and draining (inguinal) lymph nodes for an extended period compared with soluble antigens. This increased antigen-presentation time correlated with the stronger immune responses in the nanoparticle-immunized group. The protection conferred by nanoparticle immunization was transferable by passive immune serum transfusion and depended partially on a functional IgG receptor FcγRIV. Using a conditional cell depletion, we found that CD8+ T cells were involved in the protection. The immunological potency and stability of the layered peptide nanoparticles indicate applications for other peptide-based vaccines and peptide drug delivery.

Accumulating evidence indicates that maternal high-fat diet (HFD) is associated with metabolic syndrome and cardiovascular disease in adult offspring. The present study tested the hypothesis that maternal HFD modulates the brain renin-angiotensin system (RAS), oxidative stress, and proinflammatory cytokines that alter angiotensin II (ANG II) and TNF-α actions and sensitize the ANG II-elicited hypertensive response in adult offspring. All offspring were cross fostered by dams on the same or opposite diet to yield the following four groups: offspring from normal-fat control diet-fed dams suckled by control diet-fed dams (OCC group) or by HFD-fed dams (OCH group) and offspring from HFD-fed dams fed a HFD suckled by control diet-fed dams (OHC group) or by HFD-fed dams (OHH group). RT-PCR analyses of the lamina terminalis and paraventricular nucleus indicated upregulation of mRNA expression of several RAS components, NADPH oxidase, and proinflammatory cytokines in 10-wk-old male offspring of dams fed a HFD during either pregnancy, lactation, or both (OHC, OCH, and OHH groups). These offspring also showed decreased cardiac baroreflex sensitivity and increased pressor responses to intracerebroventricular microinjection of either ANG II or TNF-α. Furthermore, chronic systemic infusion of ANG II resulted in enhanced upregulation of mRNA expression of RAS components, NADPH oxidase, and proinflammatory cytokines in the lamina terminalis and paraventricular nucleus and an augmented hypertensive response in the OHC, OCH, and OHH groups compared with the OCC group. The results suggest that maternal HFD blunts cardiac baroreflex function and enhances pressor responses to ANG II or proinflammatory cytokines through upregulation of the brain RAS, oxidative stress, and inflammation. NEW & NOTEWORTHY The results of our study indicate that a maternal high-fat diet during either pregnancy or lactation is sufficient for perinatal programming of sensitization for hypertension, which is associated with hyperreactivity of central cardiovascular nuclei that, in all likelihood, involves elevated expression of the renin-angiotensin system, NADPH oxidase, and proinflammatory cytokines. The present study demonstrates, for the first time, the central mechanism underlying maternal high-fat diet sensitization of the hypertensive response in adult offspring.

This study demonstrates that immunization with non-replicating virus-like particle (FFG VLP) containing RSV F and G glycoproteins together with RSV F DNA induced T helper type 1 antibody responses to RSV F similar to live RSV infection. Upon RSV challenge 21 weeks after immunization, FFG VLP vaccination induced protection against RSV infection as shown by clearance of lung viral loads, and the absence of eosinophil infiltrates, and did not cause lung pathology. In contrast, formalin-inactivated RSV (FI-RSV) vaccination showed significant pulmonary eosinophilia, severe mucus production, and extensive histopathology resulting in a hallmark of pulmonary pathology. Substantial lung pathology was also observed in mice with RSV re-infections. High levels of systemic and local inflammatory cytokine-secreting cells were induced in mice with FI-RSV but not with FFG VLP immunization after RSV challenge. Therefore, the results provide evidence that recombinant RSV FFG VLP vaccine can confer long-term protection against RSV without causing lung pathology.

Accumulating evidence indicates that maternal high fat diet (HFD) is associated with metabolic syndrome and cardiovascular disease in adult offspring. The present study tested the hypothesis that maternal HFD modulates the brain renin-angiotensin system (RAS), oxidative stress and proinflammatory cytokines that alters angiotensin II and tumor necrosis factor-α (TNF-α) actions to sensitize the angiotensin II-elicited hypertensive response in adult offspring. All offspring were cross-fostered by dams on the same or opposite diet to yield 4 groups: offspring from normal fat control diet (CD)-fed dams suckled by CD-fed dams (OCC) or by HFD-fed dams (OCH) and offspring from HFD-fed dams fed HFD suckled by CD-fed dams (OHC) or by HFD-fed dams (OHH). RT-PCR analyses of the lamina terminalis (LT) and paraventricular nucleus (PVN) indicated upregulation of mRNA expression of several RAS components, NADPH oxidase and proinflammatory cytokines in 10-week old male offspring of dams fed HFD during either pregnancy, lactation or both (OHC, OCH and OHH). These offspring also showed decreased baroreflex sensitivity and increased pressor responses to intracerebroventricular microinjection of either angiotensin II or TNF-α. Furthermore, chronic systemic infusion of angiotensin II resulted in enhanced upregulation of mRNA expression of RAS components, NADPH oxidase and proinflammatory cytokines in the LT and PVN and an augmented hypertensive response in the OHC, OCH and OHH groups when compared to the OCC. The results suggest that maternal HFD blunts baroreflex function and enhances pressor responses to angiotensin II or proinflammaroty cytokines through upregulation of the brain RAS, oxidative stress and inflammation.

Oral squamous cell carcinoma (OSCC) has a very poor prognosis because of its highly invasive nature, and the 5-year survival rate has not changed appreciably for the past 30 years. Although cylindromatosis (CYLD), a deubiquitinating enzyme, is thought to be a potent tumour suppressor, its biological and clinical significance in OSCC is largely unknown. This study aimed to clarify the roles of CYLD in OSCC progression. Our immunohistochemical analyses revealed significantly reduced CYLD expression in invasive areas in OSCC tissues, whereas CYLD expression was conserved in normal epithelium and carcinoma in situ. Furthermore, downregulation of CYLD by siRNA led to the acquisition of mesenchymal features and increased migratory and invasive properties in OSCC cells and HaCaT keratinocytes. It is interesting that CYLD knockdown promoted transforming growth factor-β (TGF-β) signalling by inducing stabilization of TGF-β receptor I (ALK5) in a cell autonomous fashion. In addition, the response to exogenous TGF-β stimulation was enhanced by CYLD downregulation. The invasive phenotypes induced by CYLD knockdown were completely blocked by an ALK5 inhibitor. In addition, lower expression of CYLD was significantly associated with the clinical features of deep invasion and poor overall survival, and also with increased phosphorylation of Smad3, which is an indicator of activation of TGF-β signalling in invasive OSCC. These findings suggest that downregulation of CYLD promotes invasion with mesenchymal transition via ALK5 stabilization in OSCC cells. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John WileySons, Ltd.

Background Jumonji C domain 2A (JMJD2A), as a histone demethylases, plays a vital role in tumorigenesis and progression. But, its functions and underlying mechanisms of JMJD2A in nasopharyngeal carcinoma (NPC) metabolism are remained to be clarified. In this study, we investigated glycolysis regulation by JMJD2A in NPC and the possible mechanism. Methods JMJD2A expression was detected by Western blotting and Reverse transcription quantitative real-time PCR analysis. Then, we knocked down and ectopically expressed JMJD2A to detect changes in glycolytic enzymes. We also evaluated the impacts of JMJD2A-lactate dehydrogenase A (LDHA) signaling on NPC cell proliferation, migration and invasion. ChIP assays were used to test whether JMJD2A bound to the LDHA promoter. Finally, IHC was used to verify JMJD2A and LDHA expression in NPC tissue samples and analyze their correlation between expression and clinical features. Results JMJD2A was expressed at high levels in NPC tumor tissues and cell lines. Both JMJD2A and LDHA expression were positively correlated with the tumor stage, metastasis and clinical stage. Additionally, the level of JMJD2A was positively correlated with LDHA expression in NPC patients, and higher JMJD2A and LDHA expression predicted a worse prognosis. JMJD2A alteration did not influence most of glycolytic enzymes expression, with the exception of PFK-L, PGAM-1, LDHB and LDHA, and LDHA exhibited the greatest decrease in expression. JMJD2A silencing decreased LDHA expression and the intracellular ATP level and increased LDH activity, lactate production and glucose utilization, while JMJD2A overexpression produced the opposite results. Furthermore, JMJD2A could combine to LDHA promoter region and regulate LDHA expression at the level of transcription. Activated JMJD2A-LDHA signaling pathway promoted NPC cell proliferation, migration and invasion. Conclusions JMJD2A regulated aerobic glycolysis by regulating LDHA expression. Therefore, the novel JMJD2A-LDHA signaling pathway could contribute to the Warburg effects in NPC progression. Electronic supplementary material The online version of this article (doi:10.1186/s12885-017-3473-4) contains supplementary material, which is available to authorized users.

Objective: This study aims to investigate the effects of hybrid blood purification treatment on secondary hyperparathyroidism for maintenance hemodialysis (HD) patients. Methods: A total of 40 patients were randomly divided into 2 groups: HD combined with hemoperfusion (HD + HP) group (n = 20) and HD group (n = 20). Changes in intact parathyroid hormone (iPTH) in these 2 groups were compared before and after treatment, and iPTH levels in the HD + HP group were monitored before and after treatment. Results: iPTH, β2 microglobulin (β2-MG), and cystatin C (CysC) levels were significantly lower in the HD + HP group than in the HD group (p < 0.05), iPTH levels were significantly higher than at the first day after treatment (p < 0.05), and iPTH level was significantly higher (p < 0.05). Conclusion: The clearance effects of HD + HP on iPTH, β2-MG, and CysC are better than HD alone. Treatment with HD + HP every 2 weeks is recommended for maintenance HD patients.

Objective The objective is to perform a comprehensive review of the literature up to 2015 on the genetics and precision medicine relevant to otitis media. Data Sources PubMed database of the National Library of Medicine. Review Methods Two subpanels were formed comprising experts in the genetics and precision medicine of otitis media. Each of the panels reviewed the literature in their respective fields and wrote draft reviews. The reviews were shared with all panel members, and a merged draft was created. The entire panel met at the 18th International Symposium on Recent Advances in Otitis Media in June 2015 and discussed the review and refined the content. A final draft was made, circulated, and approved by the panel members. Conclusion Many genes relevant to otitis media have been identified in the last 4 years in advancing our knowledge regarding the predisposition of the middle ear mucosa to commensals and pathogens. Advances include mutant animal models and clinical studies. Many signaling pathways are involved in the predisposition of otitis media. Implications for Practice New knowledge on the genetic background relevant to otitis media forms a basis of novel potential interventions, including potential new ways to treat otitis media.

Otitis media (OM), characterized by the presence of mucus overproduction and excess inflammation in the middle ear, is the most common childhood infection. NontypeableHaemophilus influenzae(NTHi) pathogen is responsible for approximately one-third of episodes of bacteria-caused OM. Current treatments for bacterial OM rely on the systemic use of antibiotics, which often leads to the emergence of multidrug resistant bacterial strains. Therefore there is an urgent need for developing alternative therapies strategies for controlling mucus overproduction in OM. MUC5AC mucin has been shown to play a critical role in the pathogenesis of OM. Here we show that curcumin derived fromCurcuma longaplant is a potent inhibitor of NTHi-induced MUC5AC mucin expression in middle ear epithelial cells. Curcumin inhibited MUC5AC expression by suppressing activation of p38 MAPK by upregulating MAPK phosphatase MKP-1. Thus, our study identified curcumin as a potential therapeutic for inhibiting mucin overproduction in OM by upregulating MKP-1, a known negative regulator of inflammation.

Research slope stability under rainfall condition in geotechnical centrifuge is an ideal test method, however, the influence of high centrifugal force field produced by running geotechnical centrifuge cannot be neglected. Droplet deformation and breakup under different gravity and of different diameters were studied with VOF method, the results shows that the process of droplet deformation and breakup is similar under condition of different g-value and diameters, droplet breakup in a very short time in high gravity field, and with the increase of g-value, the breakup time of droplet became shorter, with the increase of droplet diameter, the breakup time of droplet became longer under same gravity acceleration. Studies in this paper have important significance in developing geotechnical centrifuge artificial rainfall equipment.

Aiming at the phenomenon that the production line of the strip steel’s detection is fast speed and detection quantity of data is large, which are difficult for worker to detect on line, we put forward a detecting system on defect area of the strip steel’s surface. Using CCD camera regularly to collect the images of the strip steel’s surface and to reflect it back to the detecting device on defect of the strip steel’s surface, and adopting specific arithmetic to analyze and handle images, what can accurately sound a warning while it detects the defected image. It is convenient for worker to take corresponding measures right away. This system has simple structure, low cost, and high defect detection rate, which has the great promotional value.

// Jianying Guo 1,4 , Satoru Shinriki 1 , Yu Su 4 , Takuya Nakamura 5 , Mitsuhiro Hayashi 6 , Yukimoto Tsuda 7 , Yoshitaka Murakami 7 , Masayoshi Tasaki 1,4 , Takuichiro Hide 8 , Tatsuya Takezaki 8 , Jun-ichi Kuratsu 8 , Satoshi Yamashita 4 , Mitsuharu Ueda 4 , Jian-Dong Li 9 , Yukio Ando 4 and Hirofumi Jono 2,3 1 Department of Diagnostic Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan 2 Department of Clinical Pharmaceutical Sciences, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan 3 Department of Pharmacy, Kumamoto University Hospital, Kumamoto, Japan 4 Department of Neurology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan 5 Department of Oral and Maxillofacial Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan 6 Department of Breast and Endocrine Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan 7 School of Medicine, Kumamoto University, Kumamoto, Japan 8 Department of Neurosurgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan 9 Center for Inflammation, Immunity and Infection and Department of Biology, Georgia State University, Atlanta, Georgia Correspondence: Hirofumi Jono, email: // Yukio Ando, email: // Keywords : bevacizumab, CYLD, glioblastoma, hypoxia, inflammation Received : May 11, 2014 Accepted : July 13, 2014 Published : July 14, 2014 Abstract Cylindromatosis (CYLD) is a tumor suppressor that regulates signaling pathways by acting as a deubiquitinating enzyme. CYLDdown-regulation occurred in several malignancies, with tumor-promoting effects. Although we found loss of CYLD expression in hypoxic regions of human glioblastoma multiforme (GBM), the most aggressive brain tumor, biological roles of CYLD in GBM remain unknown. This study aimed to determine the biological significance of CYLD down-regulation to GBM progression and therapy. CYLD mRNA transcription was dramatically down-regulated in hypoxic GBM cells, consistent with our clinical observations of human GBM tissues. Hypoxia enhanced both basal and tumor necrosis factor-α-induced expression of various proinflammatory cytokines, whereas CYLD overexpression strongly counteracted these responses. In addition, chronic anti-angiogenic therapy with bevacizumab, an anti-vascular endothelial growth factor (VEGF) antibody, with enhanced hypoxia produced responses similar to these CYLD-regulated proinflammatory responses in a xenograft mouse model. Histologically, CYLD clearly prevented massive immune cell infiltration surrounding necrotic regions, and pseudopalisades appeared in bevacizumab-treated control tumors. Furthermore, CYLD overexpression, which had no impact on survival by itself, significantly improved the prosurvival effect of bevacizumab. These data suggest that CYLD down-regulation is crucial for hypoxia-mediated inflammation in GBM, which may affect the long-term efficacy of anti-VEGF therapy.

The design reasonability of cooling pipe greatly affects the quenching performance of hot stamping die. In this paper, rectangular box is the carrier, the parameters of cooling pipe section, such as the diameter of cooling pipe, the distance between cooling pipes, the distance between cooling pipes and die surface, were studied by numerical simulation and orthogonal experiments. The quenching uniformity was taken as the evaluation criterion during research. Finally, the optimal parameters about cooling pipes distributed in hot stamping die were obtained and the quenching uniformity was improved.

Cylindromatosis (CYLD) is a tumor suppressor gene that is mutated in familial cylindromatosis, a rare autosomal dominant disorder associated with numerous benign skin adnexal tumors. CYLD is now known to regulate various signaling pathways, including transforming growth factor-β signaling, Wnt/β-catenin signaling, and NF-κB signaling by deubiquitinating upstream regulatory factors. Downregulation of CYLD has been reported in several malignancies; however, the clinical significance of CYLD expression in many malignancies, including breast cancer, remains to be elucidated. This study investigated the clinical significance of CYLD in breast cancer and its roles in tumor progression. We evaluated CYLD expression in matched normal breast tissue samples and tumor breast tissue samples from 26 patients with breast cancer and in a series of breast cancer cell lines. In addition, by means of immunohistochemistry, we investigated CYLD protein expression and its clinical significance in 244 breast cancer cases. We also analyzed the effects of CYLD repression or overexpression on breast cancer cell viability, cell migration, and NF-κB activity with or without receptor activator of NF-κB ligand (RANKL) stimulation. Breast cancer tissues demonstrated significantly reduced CYLD mRNA expression compared with normal breast tissues. Downregulation of CYLD promoted cell survival and migratory activities through NF-κB activation, whereas CYLD overexpression inhibited those activities in MDA-MB-231 cells. As an important finding, CYLD overexpression also inhibited RANKL-induced NF-κB activation. Our immunohistochemical analysis revealed that reduced CYLD protein expression was significantly correlated with estrogen receptor negativity, high Ki-67 index, high nuclear grade, decreased disease-free survival, and reduced breast cancer-specific survival in primary breast cancer. Moreover, reduced CYLD expression was an independent factor for poor prognosis in breast cancer. CYLD downregulation may promote breast cancer metastasis via NF-κB activation, including RANKL signaling.

In order to filter the impulse noise existing in the weld surface defect images, the traditional median filtering will dim image, even destroy some details in the image, We put forward a new filtering algorithm based on dual threshold Criterion. This way distinguishes the noise point and signal location in the first, and it only doing median filter to the noise point. Lastly, it solves the image’s boundary. We can find it when compared to the traditional median filtering and modified extremum median filtering, the way in this article can be good for filtration, and can keep the image’s details, which have obvious advantage.

Phosphodiesterase 4B (PDE4B) plays an important role in inflammation. Recently we have reported that roflumilast as a PDE4-selective inhibitor, synergizes with nontypeable Haemophilus influenzae (NTHi) to up-regulate PDE4B expression in vitro and in vivo. Clinical evidence and our previous results suggest that synergistic induction of PDE4B could be counterproductive for suppressing inflammation or may contribute to tolerance to roflumilast. We thus investigated if dexamethasone inhibits the synergistic induction of PDE4B by roflumilast and NTHi as well as inflammation. Here, dexamethasone markedly suppressed the synergistic induction of PDE4B in human lung epithelial cells and in vivo. We also found that dexamethasone further suppressed NTHi-induced inflammatory response in vitro and in vivo. Moreover, Compound A, as a dissociating non-steroidal glucocorticoid receptor (GR) ligand, inhibited the synergistic induction of PDE4B, thereby suggesting the requirement of dexamethasone-mediated GR activation in the suppression of PDE4B expression. Taken together, our data suggest that dexamethasone may help attenuate inflammation and tolerance through suppressing the PDE4B expression in chronic obstructive pulmonary disease (COPD) patients using roflumilast.

We investigated the effects of tonsillectomy by low-temperature plasma on the growth development and psychological behavior in children with obstructive sleep apnea hypopnea syndrome (OSAHS). This study included 72 moderate and severe OSAHS children with tonsils or adenoids hypertrophy, which were randomly assigned into either the study group (n = 36) or the control group (n = 36). Patients in study group underwent tonsillectomy by low-temperature plasma, while in the control group underwent tonsil-pecking, then the efficacy were compared. The time of surgery, VAS scores on postoperative day 1, 3, and 7 were significantly lower in the study group than in the control group, and the efficiency was significantly higher in the study group than the control group (P = .018). In the study group, the BMI was lower, the score of C-WISC (VIQ, PIQ, and FIQ) was higher, the score of CBCL social competence was higher and the score of behavioral questions was lower than that in the control group; differences were statistically significant (P = .022). The serum levels of IgA, IgG, and IgM, as well as the percentage of T lymphocytes, between the study group and the control group were not significantly different (P = .132). Tonsillectomy by low-temperature plasma was effective on the treatment of children with severe OSAHS, and could improve growth development and psychological behavior.

Based on the introduction of the control principle of path machining of NC machine tools, this paper studies and simulates the dynamic path error of machine tools. Simulation result shows that the dynamic path error is related to the path curvature and the feed speed of machine tools. In the case that the path curvature has been set, this paper proposes a variable feed speed strategy to optimize the dynamic path error of NC machine tools. The comparison simulation result shows that this strategy can decrease dynamic path error and improve the machining precision effectively.

A new species of Leymus Hochst. (Poaceae, Triticeae) from Inner Mongolia, China, L. pubens H. X. Xiao, is described, illustrated, and compared with its closest relatives. This species was initially identified as L. chinensis (Trin.) Tzvelev, but the upper surfaces of its leaf blades are spinulose, and the internode below the spike, upper half of the rachis, rachilla, and lemmas are sparsely puberulent. A key is provided for L. pubens and closely related species of Leymus. The identification of the new species is also supported by nuclear ribosomal ITS and chloroplast trnL-F sequence analyses.