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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.

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.

Metformin is widely used for the treatment of type 2 diabetes, and increasing numbers of studies have shown that metformin also ameliorates tumor progression, inflammatory disease, and fibrosis. However, the ability of metformin to improve non-diabetic glomerular disease and chronic kidney disease (CKD) has not been explored. To investigate the effect of metformin on non-diabetic glomerular disease, we used a mouse model of Alport syndrome (Col4a5 G5X) which were treated with metformin or losartan, used as a control treatment. We also investigated the effect of metformin on adriamycin-induced glomerulosclerosis model. Pathological and biochemical analysis showed that metformin or losartan suppressed proteinuria, renal inflammation, fibrosis, and glomerular injury and extended the lifespan in Alport syndrome mice. Transcriptome analysis showed that metformin and losartan influenced molecular pathways-related to metabolism and inflammation. Metformin altered multiple genes including metabolic genes not affected by losartan. Metformin also suppressed proteinuria and glomerular injury in the adriamycin-induced glomerulosclerosis mouse model. Our results showed that metformin ameliorates the glomerular sclerosis and CKD phenotype in non-diabetic chronic glomerular diseases. Metformin may have therapeutic potential for not only diabetic nephropathy but also non-diabetic glomerular disease including Alport syndrome.

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.

Background Idiopathic pulmonary fibrosis (IPF) is a fatal chronic pulmonary fibrosis disease and pathological mechanisms of fibrogenesis in IPF are still to be elucidated. Here, we investigated the potential role of Nogo-B in pulmonary fibrogenesis. Methods A mouse model of pulmonary fibrosis was established by intratracheal injection of bleomycin (BLM). Lung epithelial cells MLE-12 and TC-1 JHU-1 were cultured for TGF-β treatment. The extent of lung fibrosis was evaluated using hematoxylin and eosin (HE) staining and Masson staining in model mice and Nogo-B knockout mice. The protein levels of Nogo-B, endoplasmic reticulum stress (ERS) sensors including PERK, IRE1α, ATF6 and epithelial-mesenchymal transition (EMT) markers including E-cadherin and N-cadherin, vimentin were assayed by Western blotting respectively after Nogo-B knockdown or overexpression with lentivirus. Enzyme-linked immunosorbent assay (ELISA) was used to evaluate cytokine levels of TGF-β, TNF-α, IL-1β, IL-6 and IL-10 in bronchoalveolar lavage fluid (BALF). Results Nogo-B expression was up-regulated in lung tissues of fibrosis model mice and alveolar epithelial cells. Nogo-B knockdown significantly attenuated lung fibrogenesis, downregulated the levels of inflammatory cytokines, inhibited EMT as well as decreased the level of phosphor-PERK/PERK but not the levels of phosphor-IRE1α/IRE1α and c-ATF6. Additionally, a potential efficacy of PERK blockade was demonstrated in improving the extent of lung fibrosis in model mice. Conclusions This study discovered that involvement of Nogo-B in pulmonary fibrogenesis was associated with the PERK branch of ERS pathway and EMT. Nogo-B could be considered as a potential therapeutic target for the treatment of IPF.

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.

Regulatory and effector T helper (Th) cells are abundant at mucosal surfaces, especially in the intestine, where they control the critical balance between tolerance and inflammation. However, the key factors that reciprocally dictate differentiation along these specific lineages remain incompletely understood. Here we report that the interleukin-1 (IL-1) family member IL-36γ signals through IL-36 receptor, myeloid differentiation primary response gene 88, and nuclear factor-κBp50 in CD4+ T cells to potently inhibit Foxp3-expressing induced regulatory T cell (Treg) development, while concomitantly promoting the differentiation of Th9 cells via a IL-2-STAT5- (signal transducer and activator of transcription factor 5) and IL-4-STAT6-dependent pathway. Consistent with these findings, mice deficient in IL-36γ were protected from Th cell-driven intestinal inflammation and exhibited increased colonic Treg cells and diminished Th9 cells. Our findings thus reveal a fundamental contribution for the IL-36/IL-36R axis in regulating the Treg-Th9 cell balance with broad implications for Th cell-mediated disorders, such as inflammatory bowel diseases and particularly ulcerative colitis.

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.

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.