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BACKGROUND Infantile-onset inflammatory bowel disease (IO-IBD) occurs in very young children and causes severe clinical manifestations, which has poor responses to traditional inflammatory bowel disease (IBD) treatments. At present, there are no simple and reliable laboratory indicators for early screening IO-IBD patients, especially those in whom the disease is caused by monogenic diseases. AIM To search for valuable indicators for early identifying IO-IBD patients, especially those in whom the disease is caused by monogenic diseases. METHODS A retrospective analysis was performed in 73 patients with IO-IBD admitted to our hospital in the past 5 years. Based on the next-generation sequencing results, they were divided into a monogenic IBD group (M-IBD) and a non-monogenic IBD group (NM-IBD). Forty age-matched patients with allergic proctocolitis (AP) were included in a control group. The clinical manifestations and the inflammatory factors in peripheral blood were evaluated. Logistic regression analysis and receiver operating characteristic (ROC) curve analysis were used to identify the screening factors and cut-off values of IO-IBD as well as monogenic IO-IBD, respectively. RESULTS Among the 44 M-IBD patients, 35 carried IL-10RA mutations, and the most common mutations were c.301C>T (p.R101W, 30/70) and the c.537G>A (p.T179T, 17/70). Patients with higher serum tumor necrosis factor (TNF)-α value were more likely to have IBD [odds ratio (OR) = 1.25, 95% confidence interval (CI): 1.05-1.50, P = 0.013], while higher serum albumin level was associated with lower risk of IBD (OR = 0.86, 95%CI: 0.74-1.00, P = 0.048). The cut-off values of TNF-α and albumin were 17.40 pg/mL (sensitivity: 0.78; specificity: 0.88) and 36.50 g/L (sensitivity: 0.80; specificity: 0.90), respectively. The increased ferritin level was indicative of a genetic mutation in IO-IBD patients. Its cut-off value was 28.20 ng/mL (sensitivity: 0.93; specificity: 0.92). When interleukin (IL)-10 level was higher than 33.05 pg/mL (sensitivity: 1.00; specificity: 0.84), or the onset age was earlier than 0.21 mo (sensitivity: 0.82; specificity: 0.94), the presence of disease-causing mutations in IL-10RA in IO-IBD patients was strongly suggested. CONCLUSION Serum TNF-α and albumin level could differentiate IO-IBD patients from allergic proctocolitis patients, and serum ferritin and IL-10 levels are useful indicators for early diagnosing monogenic IO-IBD.

Allergic diseases are increasing worldwide, associating with increased health costs and decreased quality of life. Allergy is immune-related diseases caused by an allergic immune response to innocuous substance in the environment. At present, research has focussed on the study of the relevance to the microbiome and the phenotypes of allergy, including the relationships among the gastrointestinal microbiome, immune function, and allergic sensitisation. Probiotics as functional food ingredient are thought to secrete functional metabolites that have antibacterial effects on ameliorating intestinal health and CD4+ T helper cells-mediated immunity. This review will summarise the role of probiotics in the immune regulation and flora balance, highlighting recent advances in our understanding of the imbalance of Th subsets and cytokine leading to the immunopathology of allergic reactions. Finally, we discussed the unresolved problems and future research directions in order to promote the clinical application of probiotics immunotherapy.

Background: Anti-TNF-α antibody has been an efficient therapy for managing ulcerative colitis (UC). However, IgA vasculitis may be a rare complication that occurs during inflammatory bowel disease (IBD) or after TNF blocker treatment.Case presentation: We report a 14-year-old female patient with a history of purpuric skin lesions and UC. Two months prior to the current admission, she developed canker sores with fever, which was alleviated after the application of clindamycin hydrochloride. One month prior to the current admission, she was diagnosed with UC because of her abdominal pain and severe bloody diarrhoea. Ten days before admission, she developed a bilateral lower extremity purpuric rash. After admission, her abdominal symptoms mildly improved with glucocorticoids and infliximab. However, soon after, she developed two episodes of severe haematochezia and markedly aggravated purpura on the extensor side of both lower extremities. Following colonoscopy examination and intestinal IgA staining, she was diagnosed with IgA vasculitis, which induced severe haematochezia. We decided to continue the original treatment. After the fifth dose of infliximab, the gastrointestinal symptoms disappeared, and the purpuric rash resolved after 1 month.Discussion and conclusion: IgA vasculitis is a rare adverse effect of extraintestinal manifestations of UC, appearing at any age. IgA vasculitis is triggered by infections, specific drugs (infliximab, adalimumab, etanercept) and malignancy. The abdominal and intestinal manifestations of UC and IgA vasculitis may overlap, making it difficult to diagnose IgA vasculitis. Therefore, colonoscopy and intestinal biopsy with IgA staining are useful to detect intestinal involvement of IgA vasculitis.

It is widely accepted that neuronal fate is initially determined by spatial and temporal cues acting in progenitors, followed by transcription factors (TFs) that act in post-mitotic neurons to specify their functional identity (e.g. ion channels, cell surface molecules, and neurotransmitters). It remains unclear, however, whether a single TF can coordinately regulate both steps. The five lamina neurons (L1-L5) in the Drosophila visual system, are an ideal model for addressing this question. Here we show that the homeodomain TF Brain-specific homeobox (Bsh) is expressed in a subset of lamina precursor cells (LPCs) where it specifies L4 and L5 fate, and suppresses homeodomain TF Zfh1 to prevent L1 and L3 fate. Subsequently, in L4 neurons, Bsh initiates a feed forward loop with another homeodomain TF Apterous (Ap) to drive recognition molecule DIP-β expression, which is required for precise L4 synaptic connectivity. We conclude that a single homeodomain TF expressed in both precursors and neurons can coordinately generate neuronal fate and synaptic connectivity, thereby linking these two developmental events. Furthermore, our results suggest that acquiring LPC expression of a single TF, Bsh, may be sufficient to drive the evolution of increased brain complexity.

There is a growing attention regarding the toxic effect of microplastics pollutants. However, comprehensive phenotyping- and omics-based strategies for the toxicity evaluation of microplastics on the host remain to be established. To this end, we designed an encompassing phenotyping and multi-omics analysis method to detect the molecular interference of nanopolystyrene (PS)-exposed mice. The exposure time was 28 days with 1000 μg/L PS. We found that PS induced microbial alteration and metabolic disorders, which was closely related to immune disturbances. In addition, the altered expression of some genes related to immune dysregulation was observed. Interestingly, Bifidobacterium breve M-16V (B. breve M-16V) significantly inhibited Th2 and Th17 lymphocyte subset. Simultaneously, B.breve M-16V may activate MyD88 expression and promote Th1-related cytokine IL-12 production. In addition, B. breve M-16V may partially restore the gut microbiota dysbiosis. In summary, we demonstrated that the combined phenotyping and omics-based profiling established a practical framework that allowed us to gain a deeper understanding of the maladaptive consequences of PS exposure. It can be utilized to evaluate the toxicity of other environmental microplastics pollutants. Meanwhile, we found that B. breve M-16V has certain anti-inflammatory and immunomodulatory functions through host-microbiome interactions.

BACKGROUND: Endoscopic retrograde cholangiopancreatography (ERCP) has been widely used in pediatric patients with cholangiopancreatic diseases. AIM: To evaluate the efficacy, safety, and long-term follow-up results of ERCP in symptomatic pancreaticobiliary maljunction (PBM). METHODS: A multicenter, retrospective study was conducted on 75 pediatric patients who were diagnosed with PBM and underwent therapeutic ERCP at three endoscopy centers between January 2008 and March 2019. They were divided into four PBM groups based on the fluoroscopy in ERCP. Their clinical characteristics, specific ERCP procedures, adverse events, and long-term follow-up results were retrospectively reviewed. RESULTS: Totally, 112 ERCPs were performed on the 75 children with symptomatic PBM. Clinical manifestations included abdominal pain (62/75, 82.7%), vomiting (35/75, 46.7%), acholic stool (4/75, 5.3%), fever (3/75, 4.0%), acute pancreatitis (47/75, 62.7%), hyperbilirubinemia (13/75, 17.3%), and elevated liver enzymes (22/75, 29.3%). ERCP interventions included endoscopic sphincterotomy, endoscopic retrograde biliary or pancreatic drainage, stone extraction, etc. Procedure-related complications were observed in 12 patients and included post-ERCP pancreatitis (9/75, 12.0%), gastrointestinal bleeding (1/75, 1.3%), and infection (2/75, 2.7%). During a mean follow-up period of 46 mo (range: 2 to 134 mo), ERCP therapy alleviated the biliary obstruction and reduced the incidence of pancreatitis. The overall effective rate of ERCP therapy was 82.4%; seven patients (9.3%) were lost to follow-up, eight (11.8%) re-experienced pancreatitis, and eleven (16.2%) underwent radical surgery, known as prophylactic excision of the extrahepatic bile duct and hepaticojejunostomy. CONCLUSION: ERCP is a safe and effective treatment option to relieve biliary or pancreatic obstruction in symptomatic PBM, with the characteristics of minor trauma, fewer complications, and repeatability.

Crohn's disease (CD) is a chronic granulomatous disease that affects the gastrointestinal system. Additionally, CD has multiple extraintestinal manifestations, and bronchopulmonary manifestations are extremely rare. Pulmonary lesions can occur before the diagnosis of CD; thus, pulmonary manifestations are often overlooked, which leads to misdiagnoses. Herein, we present a case with pulmonary nodules being exhibited before the patient was diagnosed with CD. To the best of our knowledge, only a few cases concerning this phenomenon have been reported. We describe an 11-year-old boy with a two-year history of anemia and without any gastrointestinal symptoms. He did not receive any thorough inspection until arthralgia occurred. Multiple nodules were found in his bilateral lungs via computed tomography scan. Combined with the child's medical history, physical examinations, and all of the investigations, the final diagnosis was CD with pulmonary nodules and arthritis. After 2 months of treatment, the patient's symptoms had significantly improved. To summarize the clinical manifestations, auxiliary examination features, and treatments of CD in children with pulmonary involvement, we also review the relevant characteristics of pulmonary involvement in CD patients. This case indicates the importance of recognizing the pulmonary manifestations of CD. Clinicians should be aware of the possibility of CD when their patients have lung nodules, even in children with no typical manifestations of CD.

BACKGROUND Interleukin 10 receptor alpha subunit (IL10RA) dysfunction is the main cause of very early-onset inflammatory bowel disease (VEO-IBD) in East Asians. AIM To identify disease-causing gene mutations in four patients with VEO-IBD and verify functional changes related to the disease-causing mutations. METHODS From May 2016 to September 2020, four young patients with clinically diagnosed VEO-IBD were recruited. Before hospitalization, using targeted gene panel sequencing and trio-whole-exome sequencing (WES), three patients were found to harbor a IL10RA mutation (c.301C>T, p.R101W in one patient; c.537G>A, p.T179T in two patients), but WES results of the fourth patient were not conclusive. We performed whole-genome sequencing (WGS) on patients A and B and reanalyzed the data from patients C and D. Peripheral blood mononuclear cells (PBMCs) from patient D were isolated and stimulated with lipopolysaccharide (LPS), interleukin 10 (IL-10), and LPS + IL-10. Serum IL-10 levels in four patients and tumor necrosis factor-α (TNF-α) in the cell supernatant were determined by enzyme-linked immunosorbent assay. Phosphorylation of signal transducer and activator of transcription 3 (STAT3) at Tyr705 and Ser727 in PBMCs was determined by western blot analysis. RESULTS The four children in our study consisted of two males and two females. The age at disease onset ranged from 18 d to 9 mo. After hospitalization, a novel 333-bp deletion encompassing exon 1 of IL10RA was found in patients A and B using WGS and was found in patients C and D after reanalysis of their WES data. Patient D was homozygous for the 333 bp deletion. All four patients had elevated serum IL-10 levels. In vitro, IL-10-stimulated PBMCs from patient D failed to induce STAT3 phosphorylation at Tyr705 and only minimally suppressed TNF-α production induced by LPS. Phosphorylation at Ser727 in PBMCs was not affected by LPS or LPS + IL-10 in both healthy subjects and in patient D. CONCLUSION WGS revealed a novel 333-bp deletion of IL10RA in four patients with VEO-IBD, whereas the WES results were inconclusive.

Significance Functionally relevant neuronal connections are often organized within discrete layers of neuropil to ensure proper connectivity and information processing. While layer-specific assembly of neuronal connectivity is a dynamic process involving stepwise interactions between different neuron types, the mechanisms underlying this critical developmental process are not well understood. Here, we investigate the role of the transcription factor dFezf in layer selection within the Drosophila visual system, which is important for synaptic specificity. Our findings show that dFezf functions as a transcriptional repressor governing the precise temporal expression pattern of downstream genes, including other transcription factors required for proper connectivity. Layer-specific assembly of neuronal connectivity in the fly visual system is thus orchestrated by precise, temporally controlled transcriptional cascades., The layered compartmentalization of synaptic connections, a common feature of nervous systems, underlies proper connectivity between neurons and enables parallel processing of neural information. However, the stepwise development of layered neuronal connections is not well understood. The medulla neuropil of the Drosophila visual system, which comprises 10 discrete layers (M1 to M10), where neural computations underlying distinct visual features are processed, serves as a model system for understanding layered synaptic connectivity. The first step in establishing layer-specific connectivity in the outer medulla (M1 to M6) is the innervation by lamina (L) neurons of one of two broad, primordial domains that will subsequently expand and transform into discrete layers. We previously found that the transcription factor dFezf cell-autonomously directs L3 lamina neurons to their proper primordial broad domain before they form synapses within the developing M3 layer. Here, we show that dFezf controls L3 broad domain selection through temporally precise transcriptional repression of the transcription factor slp1 (sloppy paired 1). In wild-type L3 neurons, slp1 is transiently expressed at a low level during broad domain selection. When dFezf is deleted, slp1 expression is up-regulated, and ablation of slp1 fully rescues the defect of broad domain selection in dFezf-null L3 neurons. Although the early, transient expression of slp1 is expendable for broad domain selection, it is surprisingly necessary for the subsequent L3 innervation of the M3 layer. DFezf thus functions as a transcriptional repressor to coordinate the temporal dynamics of a transcriptional cascade that orchestrates sequential steps of layer-specific synapse formation.

Background: Previous studies have suggested that Helicobacter pylori (H. pylori, Hp) infection has a protective function in inflammatory bowel disease (IBD); Exosomes (Exo) are novel cell-cell communication mediators and their association with inflammatory immune responses has received great attention. however the mechanisms regarding the role of exosomes between Hp infection and IBD are limited.Methods: Human intestinal epithelial cells were treated with serum exosomes derived from Hp-positive chronic gastritis patients (Exo(Hp)), the expression of cytokines, inflammasome and signal pathway genes were detected by antibody microarray or PCR array. Furthermore, DSS-induced colitis mice were treated with exosomes by intraperitoneally injection to study the effect of Exo(Hp) in IBD.Results: Serum exosomes derived from Hp-positive chronic gastritis patients promoted NLRP12 expression in intestinal epithelial cells, and NLRP12 decreased chemokine MCP-1 and MIP-1α expression by inhibiting the Notch signaling pathway. In vivo, Exo(Hp) could attenuated inflammatory responses in DSS-induced colitis and improved colitis symptoms, which was associated with the increase in NLRP12 expression. Furthermore, the immunohistochemistry results showed that NLRP12 was negatively correlated with the disease activity of pediatric IBD patients. Conclusions: Exo(Hp) inhibited the Notch signaling pathway through the promotion of NLRP12 expression to further down-regulate MCP-1 and MIP-1α expression in intestinal epithelial cells and thereby attenuate DSS-induced colitis in mice. These results provide new theoretical bases for further elucidation of the intestinal protection mechanisms of Hp infection in IBD, and provide new targets for explorations of effective interventional strategies for IBD.

Summary Emerging evidence has linked the exosomes to many immunological disorders, including infectious diseases. However, knowledge regarding the role of exosomes in Helicobacter pylori infection is limited. Here, we show that serum exosomes from chronic gastritis patients with H. pylori infection (Hp exosomes) stimulate the expression of the soluble interleukin (IL)-6 receptor (sIL-6R), which is involved in IL-6 trans-signalling in gastric epithelial cells. Interestingly, sIL-6R up-regulates expression of the proinflammatory cytokine IL-1α, and the neutralization of sIL-6R suppresses IL-1α secretion. Thus, Hp exosomes regulate IL-1α expression via sIL-6R-mediated IL-6 trans-signaling. Altogether, this study reveals a novel perspective in which exosomes play a vital role in immunological mechanisms during H. pylori infection.

// Jing Wu 1, 2, * , Yuanyan Yang 1, * , Shenshen Gao 1, 3, * , Hong Jiang 2 , Xin-Qiong Wang 1 , Yuan Xiao 1 , Xue-Hua Chen 1 , Pu Li 1 and Chun-Di Xu 1 1 Department of Pediatrics, Ruijin Hospital and Ruijin Hospital North, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China 2 Department of Oncology, East Hospital, Tongji University School of Medicine, Shanghai, People’s Republic of China 3 Department of Human Resource, Ruijin Hospital North, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China * These authors have contributed equally to this work Correspondence to: Pu Li, email: leerockygood@yahoo.com Chun-Di Xu, email: chundixu55@163.com Keywords: ERp29, EMT, ERK1/2, AKT, gastric cancer Received: May 04, 2017 Accepted: July 25, 2017 Published: August 12, 2017 ABSTRACT ERp29 is a novel endoplasmic reticulum (ER) protein that plays an important role in protein unfolding and secretion. Recently, it has been reported to be widely implicated in control of tumorigenesis in some tumors. However, the potential function of ERp29 in gastric cancer remains poorly understood. In this study, we found that the positive rate of ERp29 in gastric cancer tissues was significantly lower than that in adjacent non-tumor tissues. And tumor with high ERp29 expression had inclinations towards smaller tumor size and earlier TNM stage. The in vitro experiments indicated that over-expression of ERp29 in gastric cancer cells significantly suppressed the proliferation and migration of tumor cells, which is consistent with the result of the in vivo animal experiments. Furthermore, our mechanistic investigations revealed that ERp29 reversed EMT process in gastric carcinoma, and its effect was related to the inactivation of ERK1/2 and AKT phosphorylation. Thus, we conclude that ERp29 acts as a tumor suppressor gene in gastric cancer, and is expected to become a novel target of the treatment of GC.

Endocrine disrupting chemicals (EDCs) have gradually become a global health hazard in recent decades. Gut microbiota (GM) provides a crucial interface between the environment and the human body. A triad relationship may exist between EDCs exposure, host phenotypic background, and GM effects. In this review, we attempted to parse out the contribution of GM on the alteration of host phenotypic responses induced by EDCs, suggesting that GM intervention may be used as a therapeutic strategy to limit the expansion of pathogen. These studies can increase the understanding of pathogenic mechanisms, and help to identify the modifiable environmental factors and microbiota characteristics in people with underlying disease susceptibility for prevention and remediation.

Abnormal pattern recognition receptor (PRR) signaling plays an important role in gastric mucosal damage caused by stomach microbiota; however, the underlying molecular mechanisms remain obscure. Here, we show that DC-SIGN, a surface phenotype marker of dendritic cells, is overexpressed in gastric epithelial cells facing LPS stimulation. NLRP3 expression in gastric epithelial cells are significantly increased and related to the degree of LPS stimulation. Furthermore, DC-SIGN could interact with TLR4, promote NLRP3 and related genes expression via MyD88-independent signaling pathway and regulate the secretion of IL-1β and IL-18 in gastric epithelial cells. The results of flow cytometry analysis show that DC-SIGN primarily mediates Th1 differentiation when co-cultured with gastric epithelial cells. These results reveal that LPS-induced DC-SIGN expression modulates NLRP3 inflammasomes formation via MyD88-independent TLR4 signaling in gastric epithelial cell, and induces a Th1-predominant host immune response,these findings may indicate a new function of DC-SIGN in non-immune cells, and elucidate the diversity role of gastric epithelial cells in mechanism of immune damage caused by microbial flora.

Epidemiological and basic research has suggested that Helicobacter pylori (H. pylori, Hp) infection has a protective function in inflammatory bowel disease (IBD); however, the mechanisms are not very clear. Here, we investigated the role of exosomes derived from Hp-infected patients in IBD. Human intestinal epithelial cells were treated with serum exosomes derived from Hp-positive chronic gastritis patients (Exo(Hp)), the expression of cytokines, inflammasome and signal pathway genes were detected by antibody microarray or PCR array. Furthermore, DSS-induced colitis mice were treated with exosomes by intraperitoneally injection. The results demonstrated that Exo(Hp) promoted NLRP12 expression in intestinal epithelial cells, and NLRP12 decreased chemokine MCP-1 and MIP-1α expression by inhibiting the Notch signaling pathway. Next, in vivo, results showed that Exo(Hp) attenuated the inflammatory responses in DSS-induced colitis mice and improved colitis symptoms, outcomes associated with an increase in NLRP12 expression. Furthermore, the immunohistochemistry results showed that NLRP12 was negatively correlated with the disease activity of pediatric IBD patients. These results provide new theoretical bases for further elucidation of the protective mechanisms of Hp infection in IBD, and suggest new targets for explorations of effective interventional strategies for IBD.

SUMMARYThe ability of neurons to distinguish appropriate from inappropriate synaptic partners in their local environment is fundamental to the proper assembly and function of neural circuits. How synaptic partner selection is regulated is a longstanding question in Neurobiology. A prevailing hypothesis is that appropriate partners express complementary molecules that match them together and promote synaptogenesis. Dpr and DIP IgSF proteins bind heterophilically and are expressed in a complementary manner between synaptic partners in the Drosophila visual system. Here, we show that in the lamina, DIP mis-expression is sufficient to promote synapse formation with Dpr-expressing neurons, and that DIP proteins are not necessary for synaptogenesis but rather function to prevent ectopic synapse formation. These findings indicate that Dpr-DIP interactions regulate synaptic specificity by biasing synapse formation towards specific cell-types. We propose that synaptogenesis occurs independent of synaptic partner choice, and that precise synaptic connectivity is established by limiting promiscuous synapse formation.

Background To investigate the unique features of inflammatory bowel disease (IBD) in children, we wanted to identify whether there might be a strong correlation between the disease phenotype and its prognosis at various ages in paediatric patients. Methods We collected data from patients diagnosed with IBD (ulcerative colitis (UC) or Crohn’s disease (CD)) from 2002 to 2016. The diagnosis was made according to the Porto criteria and Paris Classification. Patient characteristics, clinical manifestations and treatments were collected. Risk factors for surgery, mortality and relapse were analysed by Cox proportional hazard models. Results Of the 143 patients, 113 had CD, and 30 had UC; there were 89 males and 54 females with a median age of 9 years (y). Thirteen patients in the 0–2 y group were identified as having mutations in IL-10 receptor A, and this mutation was significantly more common in this age group than in 3–9 and 10–16 y patients. The risk factor for surgery was the B3 phenotype; risk factors for death were age 0–2 y and B3 phenotype; 0–2 y, B3 phenotype and steroid dependency were risk factors for early relapse. Conclusions Clinical manifestations of the onset of IBD in infants and toddlers were extensive and aggressive and were closely associated with early relapse and death. It is of particular interest that some of these patients developed IBD due to monogenic disorders; thus, introduction of genetic testing is essential for these patients.

Renal fibrosis is widely considered a common mechanism leading to end-stage renal failure. Epithelial-to-mesenchymal transition (EMT) plays important roles in the pathogenesis of renal fibrosis. Runt-related transcription factor 1(RUNX1) plays a vital role in hematopoiesis via Endothelial-to-Hematopoietic Transition (EHT), a process that is conceptually similar to EMT, but its role in EMT and renal fibrosis is unclear. Here, we demonstrate that RUNX1 is overexpressed in the processes of TGF-β-induced partial EMT and renal fibrosis and that the expression level of RUNX1 is SMAD3-dependent. Knockdown of RUNX1 attenuated both TGF-β-induced phenotypic changes and the expression levels of EMT marker genes in renal tubular epithelial cells (RTECs). In addition, overexpression of RUNX1 promoted the expression of EMT marker genes in renal tubular epithelial cells. Moreover, RUNX1 promoted TGF-β-induced partial EMT by increasing transcription of the PI3K subunit p110δ, which mediated Akt activation. Specific deletion of Runx1 in mouse RTECs attenuated renal fibrosis, which was induced by both unilateral ureteral obstruction (UUO) and folic acid (FA) treatment. These findings suggest that RUNX1 is a potential target for preventing renal fibrosis., Highlights • RUNX1 is required for TGF-β induced renal tubular EMT, which increases p110δ transcription for Akt activation. • Ablation of RUNX1 in mouse RTECs inhibits renal fibrosis induced by unilateral ureteral obstruction or folic acid. • These findings suggest that RUNX1 might be used as a potential target to prevent renal fibrosis. Kidney fibrosis is a critical pathologic step during the development of renal failure, while epithelial-to-mesenchymal transition (EMT) contributes to the pathogenesis of renal fibrosis. Exploring the new effectors as potential targets to inhibit renal fibrosis is currently under extensive investigation. This manuscript has identified that RUNX1 is required for TGF-β induced renal tubular EMT via increasing expression levels of the PI3K subunit p110δ and Akt activation. Importantly, ablation of Runx1 in mouse renal tubular epithelial cells or the RUNX1 inhibitor could reduce renal fibrosis in response to unilateral ureteral obstruction or under the treatment of folic acid. These findings suggest that the RUNX1 inhibitor might be used to prevent renal fibrosis.

Summary Podocytes, the main target of immune complex, participate actively in the development of glomerular injury as immune cells. Dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin (DC-SIGN) is an innate immune molecular that has an immune recognition function, and is involved in mediation of cell adhesion and immunoregulation. Here we explored the expression of DC-SIGN on podocytes and its role in immune and inflammatory responses in lupus nephritis (LN). Expression of DC-SIGN and immunoglobulin (Ig)G1 was observed in glomeruli of LN patients. DC-SIGN was co-expressed with nephrin on podocytes. Accompanied by increased proteinuria of LN mice, DC-SIGN and IgG1 expressions were observed in the glomeruli from 20 weeks, and the renal function deteriorated up to 24 weeks. Mice with anti-DC-SIGN antibody showed reduced proteinuria and remission of renal function. After the podocytes were stimulated by serum of LN mice in vitro, the expression of DC-SIGN, major histocompatibility complex (MHC) class II and CD80 was up-regulated, stimulation of T cell proliferation was enhanced and the interferon (IFN)-γ/interleukin (IL)-4 ratio increased. However, anti-DC-SIGN antibody treatment reversed these events. These results suggested that podocytes in LN can exert DC-like function through their expression of DC-SIGN, which may be involved in immune and inflammatory responses of renal tissues. However, blockage of DC-SIGN can inhibit immune functions of podocytes, which may have preventive and therapeutic effects.

How extracellular cues direct axon–dendrite polarization in mouse developing neurons is not fully understood. Here, we report that the radial glial cell (RGC)–cortical neuron interaction directs axon formation at the opposite side of the neuron from the contact site. N-cadherin accumulates at the contact site between the RGC and cortical neuron. Inhibition of the N-cadherin-mediated adhesion decreases this oriented axon formationin vitro, and disrupts the axon–dendrite polarizationin vivo. Furthermore, the RGC–neuron interaction induces the polarized distribution of active RhoA at the contacting neurite and active Rac1 at the opposite neurite. Inhibition of Rho–Rho-kinase signaling in a neuron impairs the oriented axon formationin vitro, and prevents axon–dendrite polarizationin vivo. Collectively, these results suggest that the N-cadherin-mediated radial glia–neuron interaction determines the contacting neurite as the leading process for radial glia-guided neuronal migration and directs axon formation to the opposite side acting through the Rho family GTPases.SIGNIFICANCE STATEMENTNeurons are highly polarized cell lines typically with a single axon and multiple dendrites, which underlies the ability of integrating and transmitting the information in the brain. How is the axon–dendrite polarity of neurons established in the developing neocortex? Here we show that the N-cadherin-mediated radial glial cell–neuron interaction directs axon–dendrite polarization, the radial glial cell–neuron interaction induces polarized distribution of active RhoA and active Rac1 in neurons, and Rho–Rho-kinase signaling is required for axon–dendrite polarization. Our work advances the overall understanding of how extracellular cues direct axon–dendrite polarization in mouse developing neurons.

Neurons are one of the highly polarized cells in the body. One of the fundamental issues in neuroscience is how neurons establish their polarity; therefore, this issue fascinates many scientists. Cultured neurons are useful tools for analyzing the mechanisms of neuronal polarization, and indeed, most of the molecules important in their polarization were identified using culture systems. However, we now know that the process of neuronal polarization in vivo differs in some respects from that in cultured neurons. One of the major differences is their surrounding microenvironment; neurons in vivo can be influenced by extrinsic factors from the microenvironment. Therefore, a major question remains: How are neurons polarized in vivo? Here, we begin by reviewing the process of neuronal polarization in culture conditions and in vivo. We also survey the molecular mechanisms underlying neuronal polarization. Finally, we introduce the theoretical basis of neuronal polarization and the possible involvement of neuronal polarity in disease and traumatic brain injury.

Neurons are highly polarized cells with structurally and functionally distinct processes called axons and dendrites. This polarization underlies the directional flow of information in the central nervous system, so the establishment and maintenance of neuronal polarization is crucial for correct development and function. Great progress in our understanding of how neurons establish their polarity has been made through the use of cultured hippocampal neurons, while recent technological advances have enabled in vivo analysis of axon specification and elongation. This short review and accompanying poster highlight recent advances in this fascinating field, with an emphasis on the signaling mechanisms underlying axon and dendrite specification in vitro and in vivo.

microRNAs (miRNAs or miRS) have been demonstrated to be essential for neural development. miR-125b-2, presented on human chromosome 21, is overexpressed in neurons of individuals with Down syndrome (DS) with cognitive impairments. It has been reported that miR-125b-2 promotes specific types of neuronal differentiation; however, the function of miR-125b-2 in the early development of the embryo has remained to be fully elucidated. In the present study, a mouse embryonic stem cell (mESC) line was stably transfected with a miR-125b-2 lentiviral expression vector and found that miR-125b-2 overexpression did not affect the self-renewal or proliferation of mESCs. However, miR-125b-2 overexpression inhibited the differentiation of mESCs into endoderm and ectoderm. Finally, miR-125b-2 overexpression was found to impair all-trans-retinoic acid-induced neuron development in embryoid bodies. The findings of the present study implied that miR-125b-2 overexpression suppressed the differentiation of mESCs into neurons, which highlights that miR-125b-2 is important in the regulation of ESC differentiation. The present study provided a basis for the further identification of novel targets of miR-125b-2, which may contribute to an enhanced understanding of the molecular mechanisms of ESC differentiation.

// Jing Wu 1,* , Xue-hua Chen 2,* , Xin-qiong Wang 1 , Yi Yu 1 , Jian-min Ren 1 , Yuan Xiao 1 , Tong Zhou 1 , Pu Li 2 , Chun-di Xu 1 1 Department of Pediatrics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China 2 Shanghai Key Laboratory of Gastric Neoplasms, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China * These authors have contributed equally to this work Correspondence to: Chun-di Xu, email: // Pu Li, email: // Keywords : ERp19, gastric cancer, tumorigenicity, FAK, paxillin Received : January 07, 2015 Accepted : March 02, 2015 Published : March 26, 2015 Abstract ERp19, a mammalian thioredoxin-like protein, plays a key role in defense against endoplasmic reticulum stress. It belongs to the protein disulfide isomerize (PDI) family, whose members have been implicated in development of breast, ovarian and gastrointestinal cancers. However, the role of ERp19 in gastric cancer (GC) remains undefined. Therefore, we sought to investigate the expression and prognostic value of ERp19 in GC patients, and to explore the role of ERp19 in tumorigenicity. Expression of ERp19 in gastric tissues was assessed by immunohistochemical staining and real-time PCR in clinical samples of GC patients. Statistical analysis of clinical cases revealed that the expression levels of ERp19 were higher in tumor tissues than non-tumor tissues. And the level of ERp19 expression was correlated with tumor size, lymph node involvement and poor clinical prognosis. Furthermore, ERp19 knockdown dramatically suppressed gastric cancer cell growth, inhibited cellular migration/invasion and down-regulated the phosphorylation of FAK and paxillin, whereas ERp19 over-expression reversed these changes. We conclude that ERp19 contributes to tumorigenicity and metastasis of GC by activating the FAK signaling pathway, and may function as an oncogene in GC. ERp19 may represent a new diagnostic and prognostic marker and a novel target for the treatment of GC.

Laminar arrangement of neural connections is a fundamental feature of neural circuit organization. Identifying mechanisms that coordinate neural connections within correct layers is thus vital for understanding how neural circuits are assembled. In the medulla of the Drosophila visual system neurons form connections within ten parallel layers. The M3 layer receives input from two neuron types that sequentially innervate M3 during development. Here we show that M3-specific innervation by both neurons is coordinated by Drosophila Fezf (dFezf), a conserved transcription factor that is selectively expressed by the earlier targeting input neuron. In this cell, dFezf instructs layer specificity and activates the expression of a secreted molecule (Netrin) that regulates the layer specificity of the other input neuron. We propose that employment of transcriptional modules that cell-intrinsically target neurons to specific layers, and cell-extrinsically recruit other neurons is a general mechanism for building layered networks of neural connections.

Hypoxia commonly occurs in solid cancers, especially in gastric cancer due to its rapid growth. The ability of gastric cancer cells to survive and progress under hypoxic conditions has been known for decades, but the mechanisms underlying this characteristic remain poorly understood. As cancer cells undergo changes in their genetic profile under certain conditions, we investigated the expression profile of non-coding RNAs (circRNAs, lncRNAs, and miRNAs) and mRNAs in gastric cancer MKN-28 cells under hypoxic conditions via sequencing and subsequent bioinformatic analyses. In addition, quantitative reverse transcription polymerase chain reaction (qRT-PCR) was used to validate the results. We identified a number of significantly differentially expressed circRNAs, lncRNAs, miRNAs, and mRNAs in hypoxia-exposed MKN-28 cells relative to the normoxia control, and results of qRT-PCR were consistent with sequencing data. Pathway enrichment analyses revealed the principal functions of the significantly deregulated genes. Furthermore, examination of co-expression and competing endogenous RNA (ceRNAs) networks illustrated the complex regulatory pathways among non-coding RNAs and mRNAs, implicating these pathways in gastric cancer. In conclusion, our findings provide a novel perspective on non-coding RNAs and mRNAs and lay the foundation for future research on the potential roles of non-coding RNAs in gastric cancer under hypoxic conditions.