Sonic Hedgehog signalling in the regulation of barrier tissue homeostasis and inflammation

Epithelial barrier tissues such as the skin and airway form an essential interface between the mammalian host and its external environment. These physical barriers are crucial to prevent damage and disease from environmental insults and allergens. Failure to maintain barrier function against such risks can lead to severe inflammatory disorders, including atopic dermatitis and asthma. Here, we discuss the role of the morphogen Sonic Hedgehog in postnatal skin and lung and the impact of Shh signalling on repair, inflammation and atopic disease in these tissues

The effectiveness of nonsteroidal anti-inflammatory agents in the treatment of pelvic inflammatory disease: a systematic review

BACKGROUND: Pelvic inflammatory disease (PID) is the result of infection ascending through the endocervix to the uterus and fallopian tubes. Inflammation driven by infected host cells appears to be central to the development of tissue damage and associated reproductive complications. Nonsteroidal anti-inflammatory agents (NSAIDs) therefore have the potential to reduce the sequelae associated with pelvic infection. METHODS: A search of four electronic reference databases, an internet search for relevant grey literature and a review of the bibliographies of identified publications was used to identify studies evaluating NSAIDs in the management of PID. A predefined search strategy was used to identify studies that included women with PID aged over 16 and diagnosed after 1980. Randomized controlled trials, nonrandomized controlled trials, and cohort studies with comparison group data were included without language restriction. Two reviewers independently assessed the studies against agreed criteria and extracted relevant data using a standardized pro forma. A meta-analysis to calculate the relative risk associated with NSAID use was planned if appropriate. RESULTS: Forty-three studies were identified. After reviewing abstracts or full texts, two randomized controlled trials were found to meet the selection criteria for inclusion. The use of NSAIDs was reported to improve tubal patency, reduce pelvic adhesions and reduce suprapubic pain but the studies were of poor quality with a high risk of bias. Meta-analysis of the data was not performed. CONCLUSIONS: Insufficient data is available to support or refute the efficacy of NSAIDs in the prevention of short or long-term complications of PID

Gland segmentation in gastric histology images: detection of intestinal metaplasia

Gastric cancer is one of the most frequent causes of cancer-related deaths worldwide. Gastric intestinal metaplasia (IM) of the mucosa of the stomach has been found to increase the risk of gastric cancer and is considered as one of the precancerous lesions. Therefore, early detection of IM may have a valuable role in histopathological risk assessment regarding the possibility of progression to cancer. Accurate segmentation and analysis of gastric glands from the histological images plays an important role in the diagnostic confirmation of IM. Thus, in this paper, we propose a framework for segmentation of gastric glands and detection of IM. More specifically, we propose the GAGL-Net for the segmentation of glands. Then, based on two features of the extracted glands we classify the tissues into normal and IM cases. The results showed that the proposed gland segmentation approach achieves an F1 score equal to 0.914. Furthermore, the proposed methodology shows great potential for the IM detection achieving an accuracy score equal to 96.6%. To evaluate the efficiency of the proposed methodology we used a publicly available dataset and we created the GAGL dataset consisting of 59 Whole Slide Images (WSI) including both IM and normal cases

The pioneer transcription factors Foxa1 and Foxa2 regulate alternative RNA splicing during thymocyte positive selection.

During positive selection at the transition from CD4+CD8+ double-positive (DP) to single positive (SP) thymocyte, TCR signalling results in appropriate MHC-restriction and signals for survival and progression. We show that the pioneer transcription factors Foxa1 and Foxa2 are required to regulate RNA splicing during positive selection. Foxa1 and Foxa2 had overlapping/compensatory roles. Conditional deletion of both Foxa1 and Foxa2 from DP thymocytes reduced positive selection and development of CD4SP, CD8SP and peripheral naïve CD4+T-cells. Foxa1 and Foxa2 regulated expression of many genes encoding splicing-factors and regulators, including Mbnl1, H1f0, Sf3b1, Hnrnpa1, Rnpc3, Prpf4b, Prf40b and Snrpd3. Within the positively selecting CD69+DP cells, alternative RNA splicing was dysregulated in the double Foxa1/Foxa2 conditional knockout, leading to >850 differentially used exons (DEU). Many genes important for this stage of T-cell development (Ikzf1-3, Ptprc, Stat5a, Stat5b, Cd28, Tcf7) and splicing-factors (Hnrnpab, Hnrnpa2b1, Hnrnpu, Hnrnpul1, Prpf8) showed multiple DEU. Thus Foxa1 and Foxa2 are required during positive selection to regulate alternative splicing of genes essential for T-cell development, and that by also regulating splicing of splicing-factors, they exert widespread control of alternative splicing

In the fetal thymus, Gli3 in thymic epithelial cells promotes thymocyte positive selection and differentiation by repression of Shh

Gli3 is a Hedgehog (Hh) responsive transcription factor that can function as a transcriptional repressor or activator. We show that Gli3 activity in thymic epithelial cells (TEC) promotes positive selection and differentiation from CD4+CD8+ to CD4+CD8- single positive (SP4) cell in the fetal thymus and that Gli3 represses Shh Constitutive deletion of Gli3, and conditional deletion of Gli3 from TEC, reduced differentiation to SP4, whereas conditional deletion of Gli3 from thymocytes did not. Conditional deletion of Shh from TEC increased differentiation to SP4, and expression of Shh was upregulated in the Gli3-deficient thymus. Use of a transgenic Hh-reporter showed that the Hh pathway was active in thymocytes, and increased in the Gli3-deficient fetal thymus. Neutralisation of endogenous Hh proteins in the Gli3-/- thymus restored SP4 differentiation, indicating that Gli3 in TEC promotes SP4 differentiation by repression of Shh Transcriptome analysis showed that Hh-mediated transcription was increased but TCR-mediated transcription decreased in Gli3-/- thymocytes compared to WT

The transcriptional repressor Bcl6 promotes pre-TCR induced differentiation to CD4+CD8+ thymocyte and attenuates Notch1 activation

Pre-TCR signal transduction is required for developing thymocytes to differentiate from CD4-CD8- double negative (DN) to CD4+CD8+ double positive (DP) cell. Notch signalling is required for T-cell fate specification and must be maintained throughout β-selection, but inappropriate Notch activation in DN4 and DP cells is oncogenic. Here, we show that pre-TCR signalling leads to increased expression of the transcriptional repressor Bcl6 and that Bcl6 is required for differentiation to DP. Conditional deletion of Bcl6 from thymocytes reduced pre-TCR-induced differentiation to DP cell, disrupted expansion and enrichment of icTCRβ+ cells within the DN population and increased DN4 cell death. It also increased Notch1 activation and Notch-mediated transcription in the DP population. Thus, Bcl6 is required in thymocyte development for efficient differentiation from DN3 to DP cell and to attenuate Notch1 activation in DP cells. Given the importance of inappropriate NOTCH1 signalling in T-ALL, and the involvement of Bcl6 in other types of leukaemia, this study is important to our understanding of T-ALL

The time-dependent localization of Ki 67 antigen-positive cells in human skin wounds

A total of 77 human skin wounds with a post-infliction interval between 3 h and 7 months were investigated and the proliferation marker antigen Ki 67 was visualized in paraffin sections using a specific monoclonal antibody (MIB). The re-built epidermal layer covering the former lesional area showed only a few basal cells positively staining for Ki 67 antigen. No enhanced reactivity was found when compared to uninjured skin. In basal cells of the epidermis adjacent to the wound area, however, varying numbers of positive cells occurred, but no information useful for a reliable time estimation of skin wounds could be obtained due to the considerable variability in the number of Ki 67 positive epidermal basal cells found in non-damaged skin. Fibroblastic cells in the wound area revealed an increased number of Ki 67-positive sites which could first be detected in a 1.5-day-old skin lesion. Positive results could be obtained in every specimen investigated after a post-infliction interval of 6 days up to 1.5 months. Only the scar tissue of the oldest wound examined (wound age 7 months) revealed no increase in the number of positively staining fibroblasts. Therefore, positive results indicate a wound age of at least approximately 1.5 days and the lack of an increased number of positive fibroblastic cells in a sufficient number of specimens indicates at a wound age of less than 6 days, but cannot totally exclude longer post-infliction intervals

Case study in six sigma methadology : manufacturing quality improvement and guidence for managers

This article discusses the successful implementation of Six Sigma methodology in a high precision and critical process in the manufacture of automotive products. The Six Sigma define–measure–analyse–improve–control approach resulted in a reduction of tolerance-related problems and improved the first pass yield from 85% to 99.4%. Data were collected on all possible causes and regression analysis, hypothesis testing, Taguchi methods, classification and regression tree, etc. were used to analyse the data and draw conclusions. Implementation of Six Sigma methodology had a significant financial impact on the profitability of the company. An approximate saving of US$70,000 per annum was reported, which is in addition to the customer-facing benefits of improved quality on returns and sales. The project also had the benefit of allowing the company to learn useful messages that will guide future Six Sigma activities

Comparison and Mapping Facilitate Relation Discovery and Predication

Relational concepts play a central role in human perception and cognition, but little is known about how they are acquired. For example, how do we come to understand that physical force is a higher-order multiplicative relation between mass and acceleration, or that two circles are the same-shape in the same way that two squares are? A recent model of relational learning, DORA (Discovery of Relations by Analogy; Doumas, Hummel & Sandhofer, 2008), predicts that comparison and analogical mapping play a central role in the discovery and predication of novel higher-order relations. We report two experiments testing and confirming this prediction