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

Interferon dysregulation and virus-induced cell death in avian influenza H5N1 virus infections.

1. Hyper-induction of cytokines and chemokines was found in human blood macrophages infected with the avian influenza H5N1 and H9N2/G1 viruses, as compared to those infected with human influenza H1N1 virus. 2. IRF3 played a significant role in the hyperinduction of cytokines including IFN-β, IFN-λ1,IFN-α subtypes, MCP-1, and TNF-α, and also played a part in subsequent cytokine-induced cell signalling cascades. 3. Compared with H1N1 viruses, avian influenza viruses including H5N1/97 and its precursors triggered a caspase-mediated but delayed apoptotic response in human macrophages. 4. Therapies that can minimise immunopathology-associated dysregulation of innate immunity without impairing effective host defence may be valuable adjuncts to antiviral therapy.published_or_final_versio

Time-dependent trapping of pollinators driven by the alignment of floral phenology with insect circadian rhythms

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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

Microwave enhanced ion-cut silicon layer transfer

Microwave heating has been used to decrease the time required for exfoliation of thin single-crystalline silicon layers onto insulator substrates using ion-cut processing. Samples exfoliated in a 2.45 GHz, 1300 W cavity applicator microwave system saw a decrease in incubation times as compared to conventional anneal processes. Rutherford backscattering spectrometry, cross sectional scanning electron microscopy, cross sectional transmission electron microscopy, and selective aperture electron diffraction were used to determine the transferred layer thickness and crystalline quality. The surface quality was determined by atomic force microscopy. Hall measurements were used to determine electrical properties as a function of radiation repair anneal times. Results of physical and electrical characterizations demonstrate that the end products of microwave enhanced ion-cut processing do not appreciably differ from those using more traditional means of exfoliation. © 2007 American Institute of Physics

Wavelet packets based denoising method for measurement domain repeat-time multipath filtering in GPS static high-precision positioning

Repeatable satellite orbits can be used for multipath mitigation in GPS-based deformation monitoring and other high-precision GPS applications that involve continuous observation with static antennas. Multipath signals at a static station repeat when the GPS constellation repeats given the same site environment. Repeat-time multipath filtering techniques need noise reduction methods to remove the white noise in carrier phase measurement residuals in order to retrieve the carrier phase multipath corrections for the next day. We propose a generic and robust three-level wavelet packets based denoising method for repeat-time-based carrier phase multipath filtering in relative positioning; the method does not need tuning to work with different data sets. The proposed denoising method is tested rigorously and compared with two other denoising methods. Three rooftop data sets collected at the University of Nottingham Ningbo China and two data sets collected at three Southern California Integrated GPS Network high-rate stations are used in the performance assessment. Test results of the wavelet packets denoising method are compared with the results of the resistor–capacitor (RC) low-pass filter and the single-level discrete wavelet transform (DWT) denoising method. Multipath mitigation efficiency in carrier phase measurement domain is shown by spectrum analysis of two selected satellites in two data sets. The positioning performance of the repeat-time-based multipath filtering techniques is assessed. The results show that the performance of the three noise reduction techniques is about 1–46 % improvement on positioning accuracy when compared with no multipath filtering. The statistical results show that the wavelet packets based denoising method is always better than the RC filter by 2–4 %, and better than the DWT method by 6–15 %. These results suggest that the proposed wavelet packets based denoising method is better than both the DWT method and the relatively simple RC low-pass filter for noise reduction in multipath filtering. However, the wavelet packets based denoising method is not significantly better than the RC filter

First Report of a Fatal Case Associated with EV-D68 Infection in Hong Kong and Emergence of an Interclade Recombinant in China Revealed by Genome Analysis

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Surface-modified biochar in a bioretention system for Escherichia coli removal from stormwater

Bioretention systems have been recommended as one of the best management practices for low impact development for water recycling/reuse systems. Although improvement of the stormwater quality has been reported regarding pollutants eliminations such as suspended solids and heavy metals, a substantial removal of indicator bacteria is required for possible non-potable reuse. This study investigated the efficiency of wood biochar with H2SO4-, H3PO4-, KOH-, and amino-modifications for E. coli removal from synthetic stormwater under intermittent flow. The H2SO4-modified biochar showed a specific surface area of 234.7 m(2) g(-1) (approximately double the area of original biochar), whereas a substantial reduction in surface area was found with amino-modified biochar. The E. coli removal (initial concentration of 0.3-3.2 × 10(6) CFU mL(-1)) by modified biochars as filter media was very promising with, for example, over 98% removal efficiency in the first 20 pore volumes of stormwater infiltration and over 92% removal by the end of the second infiltration cycle. Only a small portion of E. coli attached on the modified biochars (<0.3%, except KOH- and amino-modified biochars) was remobilized during the drainage phase of intermittent flow. The high removal capacity and stability against drainage were attributed to the high surface area, porous structure, and surface characteristics (e.g. hydrophobicity and O-containing functional groups) of the biochars. Thus, the H2SO4-modified biochar appeared to give the best treatment performance